No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Polysaccharide hydrogels for protein drug delivery
Abstract
Delivery of protein drugs is highly challenging due to the low permeability, short circulatory half-life, rapid proteolysis, low stability, and immunogenicity of the protein drugs. Studies using polysaccharide hydrogels to overcome these problems are reviewed. The different approaches are divided into four classes: (1) polysaccharide microspheres; (2) polysaccharide-conjugated protein drugs; (3) polysaccharide matrix in protein drug delivery; and (4) microencapsulation of protein drugs. Polysaccharide hydrogels will be useful in the development of controlled release formulations for protein drugs.
... In theory, this could naturally remove the drug delivery system once the active agent has been released [21]. It is well known the research with EPS has yielded results that revealed next to no toxicity of any kind [5,[22][23][24][25]27]. Many studied polysaccharides have shown natural bioactivity that can direct mucoadhesion, improved specific tissue targeting, and overall inflammatory response reduction [22,23]. ...
... Polysaccharides are easily altered and can be found in positive, negative, or neutral states [23,27]. Several polysaccharides have been found to be bioactive and subsequently can assist in enhancing the therapeutic efficacy of a drug of choice, or may improve the overall targeting ability of a drug carrier system [24]. They are diverse in their nature in that they can exist either as linear or branched, depending on the monosaccharide unit. ...
... They are diverse in their nature in that they can exist either as linear or branched, depending on the monosaccharide unit. When discussing their chemical structure, polysaccharides show several reactive functional groups, including amino, carboxylic acid, and hydroxyl groups [23,24,27]. The reactive groups ultimately show means for chemical modification. ...
Microbial exopolysaccharides (EPSs) exhibit diverse functionalities and offer a variety of structural options that can be altered to fit a specific purpose. EPSs can degrade within the body via biological processes, and polysaccharides are regarded as generally safe. More so, microbial EPS is replicable from several known, inexpensive, and plentiful sources. Drug delivery-related research involving polysaccharides have continuously cited minimal to zero cytotoxicity and, where tested, sufficient drug release and a competent release profile. Transdermal drug delivery systems as films not only avoids first-pass metabolism, but also provides pain-free administration, assists patients with dysphagia, has increased patient compliance, can be self-administered, and can be removed at any time. Commonly used synthetic polymers in the field of drug delivery have been related to problems regarding toxicity and immunogenicity, escalating the need for an alternative. Ultimately, the risks while using synthetic polymers could result in serious negative influences involving physiological, physiochemical, and molecular events. Research involving exopolysaccharides from extremophiles is only recently gaining attention. However, commercial use of microbial polysaccharides in other areas as well as the positive results from preliminary research suggests microbial EPSs have a promising future in biomedical engineering and medicine, especially as an alternative to current synthetic polymers.
... This is corroborated with the literature suggesting that cassava fibres are generally non-toxic and biodegradable [36,37]. Some important properties for a wound dressing material are biocompatibility, biodegradability, moisture absorption and non-toxicity [39]. The ability to act as a hemostatic agent, promoting blood clotting may also be beneficial. ...
... Three different genotypes of cassava (IITA-TMS-GAEC-160006 (IT6), IITA-TMS-GAEC-160004 (IT4) and Afisiafi (Afi)) were obtained from the Biotechnology and Nuclear Agriculture Research Institute (BNARI) of the Ghana Atomic Energy Commission (GAEC). Most natural fibres are cemented to adjacent cells with pectin thus following a water retting method of extracting cassava fibres, non-cellulosic material closely associated with the fibres were removed to release individual fibres [39][40][41]. In this method, the tubers of cassava were washed with water, peeled and washed again. ...
Wound dressing is the application of a sterile pad to protect a wound from further harm and promote healing. Over the past decades, various materials including calcium alginate, hydrogel, hydrocolloid and gauze based wound dressing materials have been developed. Unfortunately, shortcomings such as potential allergic reaction, high cost, short shelf life and scarcity have been associated with their use. In developing countries such as Ghana, sterilized gauze is commonly used in wound dressing but it causes scar formation and traumatic pain during removal. In addressing the issues of cost and availability, there may be local materials like cassava (Manihot esculenta) with the ability to aid in wound healing. Cassava is a cheap staple crop grown in Africa which is rich in carbohydrate, fibre and minerals. This research characterized three genotypes of cassava (IITA-TMS-GAEC-160006 (IT6), IITA-TMS-GAEC-160004 (IT4) and Afisiafi (Afi)). These genotypes have been studied in terms of their fibre content, fluid absorption capacity, hemolytic ability and their ability to promote rapid blood coagulation (coagulation time). Fibre samples were soaked in deionized (DI) water and PBS (Phosphate buffered saline) and at different time intervals the swollen samples were weighed. Fibre samples were also brought into contact with human blood and toxicity of samples determined. The results reveal that the rate of absorption of fluid by fibres in both DI water and PBS ranges between 0.66-0.93 g/min and fibres are generally non-toxic to blood cells. The fibre properties were compared with gauze and from these, some genotypes of cassava fibre were recommended for further research towards the design of a wound dressing material.
... This is corroborated with the literature suggesting that cassava fibres are generally non-toxic and biodegradable [36,37]. Some important properties for a wound dressing material are biocompatibility, biodegradability, moisture absorption and non-toxicity [39]. The ability to act as a hemostatic agent, promoting blood clotting may also be beneficial. ...
... Three different genotypes of cassava (IITA-TMS-GAEC-160006 (IT6), IITA-TMS-GAEC-160004 (IT4) and Afisiafi (Afi)) were obtained from the Biotechnology and Nuclear Agriculture Research Institute (BNARI) of the Ghana Atomic Energy Commission (GAEC). Most natural fibres are cemented to adjacent cells with pectin thus following a water retting method of extracting cassava fibres, non-cellulosic material closely associated with the fibres were removed to release individual fibres [39][40][41]. In this method, the tubers of cassava were washed with water, peeled and washed again. ...
Wound dressing is the application of a sterile pad to protect a wound from further harm
and promote healing. Over the past decades, various materials including calcium alginate, hydrogel,
hydrocolloid and gauze based wound dressing materials have been developed. Unfortunately,
shortcomings such as potential allergic reaction, high cost, short shelf life and scarcity have been
associated with their use. In developing countries such as Ghana, sterilized gauze is commonly used
in wound dressing but it causes scar formation and traumatic pain during removal. In addressing the
issues of cost and availability, there may be local materials like cassava (Manihot esculenta) with
the ability to aid in wound healing. Cassava is a cheap staple crop grown in Africa which is rich in
carbohydrate, fibre and minerals. This research characterized three genotypes of cassava (IITA�TMS-GAEC-160006 (IT6), IITA-TMS-GAEC-160004 (IT4) and Afisiafi (Afi)). These genotypes
have been studied in terms of their fibre content, fluid absorption capacity, hemolytic ability and
their ability to promote rapid blood coagulation (coagulation time). Fibre samples were soaked in
deionized (DI) water and PBS (Phosphate buffered saline) and at different time intervals the
swollen samples were weighed. Fibre samples were also brought into contact with human blood and
toxicity of samples determined. The results reveal that the rate of absorption of fluid by fibres in
both DI water and PBS ranges between 0.66-0.93 g/min and fibres are generally non-toxic to blood
cells. The fibre properties were compared with gauze and from these, some genotypes of cassava
fibre were recommended for further research towards the design of a wound dressing material.
... In past decades, researchers were interested in natural biopolymer polysaccharides due to their availability, biodegradability, low cost and non-toxicity. Biopolymers are used in different fields like food and cosmetic industries [1][2][3]. Food production usually contains natural polysaccharides such as xanthan gum (XG) [4,5]. ...
... After extraction, purified copolymer products were dried in an air oven at 50°C to constant weight (W 1 ). The percentage of grafting yield (%G), grafting efficiency (% GE), total conversion (%TC) and homopolymer percentage (%H) were calculated according to the following equations (1)(2)(3)(4) [3,14,15]. ...
Xanthan gum (XG) is natural polysaccharides used in food industries as stabilizers and thickener agents. The problem is that some food products are found to be contaminated by pathogenic bacteria such as Escherichia coli (E. coli) and Staphyloccus aureus (S. aureus) that reduce their shelf life. This research aims to synthesize biodegradable antibacterial XG-grafted-poly(N-vinyl imidazole) PVI and the effect of reaction parameters were studied on grafting yield (G), grafting efficiency (GE), total conversion (TC) and homopolymer (H) %. XG-g-PVI was characterized via various analysis tools. Thermal analysis showed that grafted XG was more thermally stable than unmodified XG and their stability increased with increasing PVI %. XG-g-PVI was acting as antibacterial agent against (E. coli and S. aureus) bacteria that cause food borne diseases. Their activity increases with increasing grafting yield %. Surface morphology showed change from irregular lobules shape in XG to smooth surface in its graft with PVI.
... The mechanical properties of poly (vinyl alcohol) (PVA) hydrogel was improved by incorporation of chemical and physical crosslinking by formaldehyde [4] and crystallization [5]. Hydrogels of natural polymers, especially polysaccharide also have been used recently because of their unique properties such as non-toxic, biocompatible, biodegradable and abundant [6] to improve some properties like gel strength, swelling ratio, etc. Sago starch, a polysaccharides improve the gel strength and reduce the swelling ratio [7] of PVA hydrogel, but addition of carboxymethyl cellulose (CMC) enhances the swelling properties. It was also found that addition of agar improves the gel strength of poly (vinyl pyrrolidone) (PVP) hydrogels but the swelling ratio reduces [8]. ...
... Water desorption (%)=(W 0 -W t /W 0 ) × 100 (6) Where W 0 is the weight of the wet Hydrogel and W t is the weight of the Hydrogel after time, t. Room temperature and average humidity were maintained at 23-25°C and 50-55% respectively. ...
γ-Irradiated polyvinyl alcohol (PVA)/Citric acid blend hydrogels were prepared. Effect of radiation dose on gel fraction and swelling properties were observed. Effect of pH and NaCl concentration on swelling ratio, water absorption and water desorption of γ-irradiated hydrogels were studied. It was found that gel fraction attains maximum up to a certain dose but swelling ratio as well as water absorption decreases with increase in radiation doses. Swelling properties decreases with the increase in concentration of NaCl solution too and increases with the increase of pH.
... For instance, polyethylene glycol (PEG)-based nanocarriers have been reported to prolong circulation of drugs, but the usage of PEG for drug delivery has been limited by several inherent drawbacks, most notably, its high toxicity and frequent stimulation of immune responses (4,5). Consequently, natural biopolymers, in particular, polysaccharides, have received great attention as more favorable precursors in the formulation of drug delivery nanocarriers as they are nontoxic, biodegradable, biocompatible, renewable and abundant in nature (6,7). Polysaccharide-based nanoparticles have been studied extensively for the development of drug delivery systems with desirable therapeutic features (8). ...
... Typically, 0.1 g of SM powder was first dissolved in 10mL of 40% ethanol, and 10mL of 1% curcumin solution in absolute ethanol was then added. The resulting clear yellow solution was stirred continuously at a constant stirring rate for various predetermined time intervals (3,4,5,6,8,12, and 16 hrs) at 50-60°C. The resulting SM/curcumin solution mixture was then added drop wise into excess absolute ethanol. ...
Polysaccharide-based nanoparticles have been developed as drug delivery nanocarriers for encapsulating and releasing optimum doses of drug at targeted sites over a predictable period of time. We have reported herein the successful loading of curcumin onto both native starch and starch-maleate nanoparticles prepared via in-situ nanoprecipitation in aqueous medium and water-in-oil emulsion, respectively. The physico-chemical characteristics of curcumin-loaded polysaccharide-based nanoparticles such as sizes, porosity, and hydrophilicity or hydrophobicity were subsequently optimized by tailoring synthesis parameters which include solvents, surfactants, cross-linkers, and polysaccharide precursors. Under optimum conditions, native starch nanoparticles with a mean diameter of 87 nm exhibited a maximum curcumin loading efficiency of 78%. Curcumin was observed to release from native starch nanoparticles at physiological pH in sustained and predictable manners over a period of 10 days. On the other hand, the diameter of curcumin-loaded starch-maleate nanoparticles varied between 30 nm and 110 nm and a mean diameter of 50 nm. The loading of curcumin onto starch-maleate nanoparticles occurred rapidly initially but declined gradually until the curcumin loading capacity of 15 mg/g was achieved within 12 hours. Curcumin-loaded starch-maleate nanoparticles exhibited a water solubility of 6.0 x 10-2 mg/mL, which was about 300 times higher than that of free curcumin. Increased water solubility coupled with desirable loading capacity and release kinetic profile of curcumin in polysaccharide-based nanoparticles should, in turn, lead to enhanced bioavailability of curcumin. The potential utility of native starch and starch-maleate nanoparticles as cost-effective polysaccharide-based drug delivery nanocarriers is therefore envisaged.
... Functional foods are promising delivery systems for living cells, nutrients, vitamins, etc., but also, and perhaps more importantly, for the targeted delivery of a range of therapeutic agents to the human body. Biopolymers have attracted considerable attention for the formulation of functional foods due to their properties, i.e. non-toxic, biodegradable, biocompatible, are generally regarded as safe and are currently used in food industry (as thickeners, emulsifi ers, stabilisers) extensively ( Chen et al ., 1995 ). Proteins and polysaccharides are also excellent material for formulating, either individually or as mixtures, delivery structures within food matrices ( Brownlee, 2011 ). ...
... One type of such therapeutic agents that has recently been investigated more extensively is protein drugs, mainly due to their high activity and great selectivity. A number of studies have been carried out in order to increase circulatory half-life of these therapeutic proteins, restrain proteolysis, improve storage stability and immunogenicity as well as protein drugs ' permeability and denaturation ( Chen et al ., 1995 ). Administration of drugs to the systemic circulation, and hence to the targeted tissues, reaches 100% only when these are directly injected into the human veins, with any other drug delivery method resulting in reduced drug fractions reaching the systemic circulation. ...
This chapter highlights that hydrocolloids and/or hydrocolloid-based formulations have a significant role to play in the design of functional foods that are “engineered” to convey properties in the gastrointestinal (GI) tract mainly relating to the promotion of good health. It focuses on hydrocolloid-based delivery systems for the encapsulation and targeted delivery of nutrients (e.g. vitamins), microbial supplements (biopolymers as prebiotic material), dietary fibre (prebiotics), lipids or therapeutic species (e.g. drugs). The chapter discusses the effects on gastrointestinal transit time, as a result of increased viscosity or gel formation, and absorption rates (as a result of enzymatic activity). It describes appetite control and satiety. The chapter examines hydrocolloids' additional benefits, such as the ability to aid in mucosa healing, reduce post-prandial blood glucose levels, reduce cholesterol absorption and the ability to bind mutagens and heavy metals present within the intestinal lumen, thus reducing carcinogenic effects.
... Tree wound exudates gum of natural acid polysaccharide which has attracted huge attention among researcher because of their immense potential application in food industry, biomedical as well as material science [1][2][3][4][5][6][7][8]. Natural anionic acid polysaccharides are inexpensive, easily available, non-toxic, biodegradable materials which exhibit peculiar physicochemical properties and applications [6,9,10]. ...
... Acknowledgements The research reported in this paper was supported in part by the Project OP VaVpI Centre for Nanomaterials, Advanced Technologies and Innovation CZ. 1 ...
A quantitative measurement of degree of deacetylation of Sterculia urens gum and its effect on the thermal properties changes is presented in this study. Sterculia urens gum was deacetylated at varying deacetylation reaction temperature and time. The acetyl group is replaced by hydroxyl which leads to better solubility of the sterculia gum in water. Thermal properties were characterized using differential scanning calorimetry and thermogravimetric analysis. DSC analysis reveals that after the deacetylation, the glass transition temperature appears at around 60 °C of the S. urens gum. After deacetylation, the TG degradation clearly shows three different peaks. Deacetylation reaction temperature plays the major role in the thermal stability and structure of the S. urens gum.
... Polyelectrolyte complexes have gained much attention in the past few years because of their potential applications. These can be used as membranes, [1][2][3] for coating on films and fibers, [4] for isolation and fractionation of proteins, [5,6] for isolation of nucleic acid, [7][8][9] for binding pharmaceutical products, [10] as supports for catalyst [11] and for preparation of microcapsules for drug delivery. [12,13] Many of the applications are based on the functional properties of the polyelectrolyte (PE). ...
... In vivo studies were carried out for oral DS solution and selected optimized formulation (F4) both containing 100 mg of DS on albino rabbits. Blood samples were withdrawn at different time intervals and plasma concentrations of DS were estimated, and the plasma drug concentration time profile is presented in Figure 8. From the data obtained, it may be observed that after oral administration, peak plasma concentration C max were 10 Mean ± SD, n = 3 ...
Polyelectrolyte complexes (PECs) are the association complexes formed between oppositely charged particles (e.g., polymer-polymer, polymer-drug and polymer-drug-polymer). These are formed due to electrostatic interaction between oppositely charged polyions. Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) advocated in use of painful and inflammatory rheumatic and certain non-rheumatic conditions. The drug has a relatively short elimination half-life, which limits the potential for drug accumulation. As an analgesic, it has a fast onset and long duration of action.
invitro-invivo evaluation of Xanthan gum and Eudragit E100 inter polyelectrolyte complex based sustained release tablet.
Xanthan gum and Eudragit E100 were used as PEC and were prepared using different proportions i.e. in 1:1 to 1:6 ratio. The optimum ratio of E100 and XG was 1:6 used to characterize the IPC and the formulation of tablet. The tablets were prepared by wet granulation using PVP K30 as binder.
FT-IR and DSC studies confirmed the formation of IPC. Scanning Electron Microscopy (SEM) studies showed highly porous tablet surface. The tablets were evaluated for hardness, weight variation, and drug content, found to be within limits. In vitro and in vivo studies concluded that tablets showed sustained release profile. The short term stability study of the optimized formulation indicated that the formulation was stable.
Since the Poly Electrolyte Complex delay the release of the drug, it can be employed in formulating sustained release matrix tablets.
... Polysaccharides such as alginates and carrageenans as carbohydrate biopolymers are generally nontoxic, biocompatible, biodegradable, and abundant. They play an important role in development of controlled drug release formulations, since they possess unique advantages [1,2]. It is needed to say that chitosan and cyclodextrin have also been used to design devices of controlled drug delivery systems [3,4]. ...
... Loading efficiency (LE%) = 100× (D actual /D theory ) (1) Theoretical percentage of drug in the extraction ...
H ighly practical conditions were accomplished to prepare new ionically cross-linked polymer network hydrogel beads (Caralgi) composed of polysaccharides carrageenan and sodium alginate. Disodium phosphate and the acetate deriv-atives of betamethasone were simultaneously loaded while the hydrogel network was being formed. A maximum loading efficiency of 91% was achieved at pH 4.8 and tem-perature 75ºC. The morphology of the Caralgi hydrogels with and without drug was investigated using SEM analysis. A more regulated morphology was observed when the drug was incorporated into the hydrogel. The in vitro release behaviour of the drug-loaded Caralgi samples prepared under various conditions was also studied. The full natural system has exhibited release behaviour with no burst effect. No major differ-ence was found in the loading and release when a highly water-soluble derivative of the drug, i.e., betamethasone disodium phosphate was used.
... With that, one could deduce that the body would naturally remove the drug delivery system once the active compound has been released [20]. It has been widely reported that the research with EPSs has yielded results that revealed next to no toxicity of any kind [5,[21][22][23][24][25]. Furthermore, the majority of polysaccharides are naturally antimicrobial and are easily replicable from several known, cheap, and plentiful sources [21,26,27]. ...
Natural polysaccharides being investigated for use in the field of drug delivery commonly require the addition of sugars or pretreated biomass for fabrication. Geobacillus sp. strain WSUCF1 is a thermophile capable of secreting natural polymers, termed exopolysaccharides (EPSs), cultivated from cost-effective, non-treated lignocellulosic biomass carbon substrates. This preliminary investigation explores the capabilities of a 5% wt/wt amikacin-loaded film constructed from the crude EPS extracted from the strain WSUCF1. Film samples were seen to be non-cytotoxic to human keratinocytes and human skin-tissue fibroblasts, maintaining cell viability, on average, above 85% for keratinocytes over 72-h during a cell viability assay. The drug release profile of a whole film sample revealed a steady release of the antibiotic up to 12 h. The amikacin eluted by the EPS film was seen to be active against Staphylococcus aureus, maintaining above a 91% growth inhibition over a period of 48 h. Overall, this study demonstrates that a 5% amikacin-EPS film, grown from lignocellulosic biomass, can be a viable option for preventing or combating infections in clinical treatment.
... PECs have gained much attention in the past few years because of their potential applications in scientifi c and industrial interest. [69,70] These can be used as membranes, [71][72][73] for coating on fi lms and fi bers, [74] for isolation and fractionation of proteins, [75,76] for isolation of nucleic acid, [77][78][79] for binding pharmaceutical products, [80] as supports for catalyst [24] and for preparation of microcapsules for drug delivery. [81,82] Many of the applications are based on the functional properties of the polyelectrolytes [83] and the interaction between protein-polyelectrolyte, [84] nucleic acid-polyelectrolyte, [85] surfactant-polyelectrolyte, [86] polyelectrolyte-polyelectrolyte [87] and drug-polyelectrolyte. [88] The functional applications of PECs are summarized in Table 1. ...
Multiple charged macromolecular compounds with opposite charges precipitate from aqueous solutions depending on the charge distribution and molecular weight. These complexes are composed of a macromolecular multiple-charged component of one polarity and many low molecular weight ions of the other polarity, or two macromolecular partners with different polarity. The interaction between two oppositely charged polyions results in the formation of a complex is termed as a polyelectrolyte complex. These complexes meet the profi les of biocompatible polymer systems and can be adapted to meet the various requirements like carrier substances and components for active substances. These types of complexes not only convert the active substances into a nondeleterious form that can be administered, but also have specifi c effect on the biodistribution, bioavailability, or absorption of the active substances and hence increasingly are gaining importance in modern pharmaceutical technology.
... Owing to these properties, dextran is widely used for hydrogel formulations and drug delivery systems. In particular, dextran is widely used as an antithrombotic agent that can be applied as a dressing and bandage, and it is effective as a coating agent that protects and stabilizes metal ions from oxidation [8,9]. Hydrophilic cellulose (CMC), a natural biomass resource widely used as a superabsorbent material, is a biodegradable natural polymer produced by microorganisms, and is used in various cosmetics, disposable diapers, and women's hygiene products (sanitary pads) because it is stable for skin moisturization and has ultra-absorbent properties. ...
This study focused on the manufacturing of functional superabsorbent sponges using natural polymers. An alginate/CMC-embedded dextran hybrid dual-layer formulation was prepared using the freeze-drying method. The physical properties of the formulation were characterized using a field emission scanning electron microscope and a universal testing machine, and the swelling ratio was calculated. Cell viability assays were performed using keratinocytes (HaCaT cells). The results showed that this formulation can absorb a large amount of moisture and provide morphological stability through its tensile strength and uniform porosity, and this was verified by its biocompatibility. We believe that in the future, by combining this novel hybrid dual-layer superabsorbent sponge with antibacterial agents with excellent porosity, it would serve as a medical material for producing bandages that can absorb blood and body fluids, feminine hygiene products, and functional antibacterial masks.
... To date, various kinds of water-soluble polysaccharides have been modified to achieve amphiphilic copolymers for building micelles due to their meritorious biocompatibility and biodegradability [16][17][18]. Dextran (DEX) is a biocompatible polysaccharide specifically suitable for the micelle construction due to its several advantages: (1) high in vivo safety, being evidenced by its common use as a plasma volume expander and antithrombotic agent for years [19]; (2) a broad range of derivatization produced via chemical modifiability through its hydroxyl groups, imparting DEX with many possibilities to construct diverse micelles with designed structures and intended functions; and (3) excellent water solubility, allowing DEX chains to carry a large number of hydrophobic branches [20]. Among available DEX-based amphiphilic derivatives, the copolymers synthesized by grafting polylactide (PLA) onto DEX backbone are particularly useful for building micelles because the length of PLA side chains and the degree of PLA substitution for DEX-PLA copolymers can be effectively controlled, and the fabricated DEX-PLA micelles could have finely tunable sizes and well-constructed structure [21][22][23]. ...
Image-guided chemo-photothermal therapy based on near-infrared (NIR) theranostic agents has found promising applications in treating tumors. In this multimodal treatment, it is of critical importance to image real-time distribution of photothermal agents in vivo and to monitor therapeutic outcomes for implementing personalized treatment. In this study, an optimally synthesized dextran-polylactide (DEX-PLA) copolymer was assembled with doxorubicin (DOX) and DiR, a kind of NIR dye, to construct desirable micelles ((DiR + DOX)/DEX-PLA) for performing image-guided chemo-photothermal therapy. These (DiR + DOX)/DEX-PLA micelles had good physical and photothermal stability in aqueous media and showed high photothermal efficiency in vivo. Based on the H22-tumor-bearing mouse model, (DiR + DOX)/DEX-PLA micelles were found to accumulate inside tumors sustainably and to emit strong fluorescence signals for more than three days. The (DiR + DOX)@DEX-PLA micelles together with NIR laser irradiation were able to highly inhibit tumor growth or even eradicate tumors with one injection and two dose-designated 5-minute laser irradiations at the tumor site during 14 days of treatment. Furthermore, they showed almost no impairment to the body of the treated mice. These (DiR + DOX)@DEX-PLA micelles have confirmative translational potential in clinical tumor therapy on account of their persistent image-guided capacity, high antitumor efficacy and good in vivo safety.
... 11 Delivery of biotherapeutics remains an enormous challenge due to their rapid degradation and metabolism once administrated by classical routes, which result in poor bioavailability. 12 Currently, therapeutic biomolecules are receiving increased attention for their potential applications in clinical settings, 13,14 including in the most recent diseases such as Covid-19, 15 because of the high specificity for their target and, in some cases, their functional importance in physiological mechanisms. 3 Preservation of the conformation of biomolecules is essential for the maintenance of their activity, particularly in the case of proteins or peptides. ...
... Furthermore, materials with an extracellular matrix are essential for tissue regeneration. Dextran (Dex) [14] and hyaluronic acid (HA) [15,16] are widely used as drug delivery materials. HA is generally water soluble; however, HA must be insoluble in aqueous solutions for cells to attach to it. ...
Although there is no cure for atopic dermatitis (AD), treatments to relieve AD symptoms are available. A previously developed topical patch for AD treatment minimizes skin irritation but does not sufficiently adhere and absorb to specific areas. Centella asiatica extract (CAE) is a natural polymer for atopic treatment. This study fabricated a CAE-loaded hyaluronic acid-dextran (HA-Dex) hybrid hydrogel patch for use as an AD treatment and evaluated the effect of varying CAE concentrations in the patch. The CAE-loaded HA-Dex hybrid hydrogel patch was fabricated into a sheet-type scaffold using a freeze-drying process and 1,4-butanediol diglycidyl ether (BDDE). Fibroblasts (L929 cells) were used to evaluate cell survival, and physical properties were evaluated using Fourier transform infrared spectroscopy, field emission scanning electron microscopy, a universal testing machine, and high-performance liquid chromatography. A 0.4 wt% CAE-loaded HA-Dex hybrid hydrogel patch produced the most stable release profile and the highest level of cellular activity. These hydrogel patches provided moisture and released CAE over an extended period of time, making them ideal for relieving atopic itching. This delivery system enables the extended release of CAE to localized areas and could potentially be used to apply a variety of products to treat AD.
... 1-4 Among these biopolymers, polysaccharides, which are naturally occurring polymers, have contributed to considerable advances in the field of biomedicine owing to their outstanding attributes such as bioadhesion, non-toxicity, biocompatibility, and biodegradability. [5][6][7][8][9][10] Importantly, another advantage of these polysaccharides is that they can be utilized in the production of various biomedical compounds by the use of their reactive groups (e.g. hydroxyl, amino, and carboxyl groups). ...
In this study, we designed and synthesized polysaccharidic nanogels comprising starch cross-linked with hyaluronic acid. These hyaluronated starch nanogels were prepared by cross-linking primary hydroxyl groups in polysaccharides (starch and hyaluronic acid) and epoxide groups in 1,4-butanediol diglycidyl ether (used as a cross-linking agent). The nanogels take advantage of hyaluronic acid as a specific ligand for CD44 receptors overexpressed on tumors and the hyaluronic acid/starch core as a compartment for the encapsulation of docetaxel (as model antitumor drug). Here, hyaluronic acid can be enzymatically degraded by tumor cell–specific enzyme (e.g. hyaluronidase-1), which could significantly accelerate docetaxel release from the nanogels. Our experimental results demonstrate that the nanogels promote the release of docetaxel content in the presence of hyaluronidase-1 enzyme. As a result, the nanogels selectively inhibited MCF-7 (with CD44 receptor and hyaluronidase-1 enzyme) tumor cell growth in vitro, suggesting their therapeutic potential for efficient tumor ablation.
... hydrogel formulations including alginate, dextran, chitosan, starch, and purified hemicellulose (Chang, Duan, & Zhang, 2009;Chen, Jo, & Park, 1995;Hennink, Franssen, van Dijk-Wolthuis, & Talsma, 1997). In the agricultural field, release systems for fertilizers are a long-known opportunity to reduce costs and environmental impact as well as increase the profit. ...
... The mechanical properties of poly (vinyl alcohol) (PVA) hydrogel was improved by incorporation of chemical and physical crosslinking by formaldehyde [4] and crystallization [5]. Hydrogels of natural polymers, especially polysaccharide also have been used recently because of their unique properties such as non-toxic, biocompatible, biodegradable and abundant [6] to improve some properties like gel strength, swelling ratio, etc. Sago starch, a polysaccharides improve the gel strength and reduce the swelling ratio [7] of PVA hydrogel, but addition of carboxymethyl cellulose (CMC) enhances the swelling properties. It was also found that addition of agar improves the gel strength of poly (vinyl pyrrolidone) (PVP) hydrogels but the swelling ratio reduces [8]. ...
... Despite remarkable development of protein drugs, many obstacles are still faced because of their high cost regarding multi-step processing and their inherent disadvantages, such as short circulatory half-life and low stability (Chen et al., 1995;Sinha et al., 2003). To overcome the problems, various stabilizers have been employed and the size-regulated protein delivery system was suggested, e.g. ...
Delivery of therapeutic protein drugs is a hot issue in the clinical application, because protein drugs have low side effects and highly therapeutic effects compared with chemical drugs. Despite their prominent advantages, protein drugs have high risk for human therapy such as their easy degradation by proteolytic enzymes, renal filtration and immune response. Over the past few decades, a large number of polysaccharides as vehicles for the protein delivery system have been developed to overcome the problems. This review presents the studies on protein delivery based on polysaccharides used as stabilizer and vehicles comprising nano- or microspheres to overcome inherent limitations of therapeutic proteins.
... The chemical amalgamation of natural and synthetic polymer results in a yield of new materials which could have enviable properties. In the past decade, polysaccharides, have been shown to play a significant role in the biomedical, controlled release and biochemical field along with its numerous industrial application [3]. ...
In the present work, an unreported graft copolymer of carboxymethyl xanthan gum and acrylamide has
been synthesised by free radical polymerisation in a nitrogen atmosphere using ammonium persulphate
as an initiator. The optimum reaction conditions adopted for affording maximum percentage of grafting
including its grafting efficiency were obtained by varying the concentration of carboxymethyl xanthan
gum from 4 to 24 g dm−3; ammonium persulphate from 5 × 10−4 to 30 × 10−4 mol dm−3; acrylamide from
0.4 to 1.2 mol dm−3; reaction temperature from 55 to 75 ◦C and reaction time from 30 to 90 min. The
synthesised graft copolymer has been characterised by 1H NMR, FTIR spectroscopy, X-ray diffraction
measurement, thermal analysis, viscosity measurement and scanning electron microscopy. However,
grafting of acrylamide onto carboxymethyl xanthan gum backbone enhanced its thermal stability. This
graft copolymer might be well exploited globally as a potential carrier for drug delivery system
... Effective delivery of protein is a challenge for researchers due to several drawbacks, such as instability, speedy proteolysis, and short plasma half-life (Chen et al. 1995). Protein drugs undergo rapid degradation through enzyme proteolytic activity in blood. ...
N-succinyl chitosan (NSC) remains a promising chitosan derivative to develop targeted drug delivery, wound dressings, and tissue engineering systems. All these systems are important in life sciences. NSC is an amphiprotic derivative obtained from the N-acylation of chitosan. NSC exhibits extraordinary biocompatibility, significantly increased aqueous solubility in acidic and basic media without affecting the biological properties, appreciable transfection efficiency, and the ability to stimulate osteogenesis. NSC shows enhanced bioavailability, which highlights its potential applications in the biomedical field. This review briefly introduces chitosan, including its limitations as a biomaterial, and modifications of chitosan with a particular focus on acylation, along with a comprehensive overview of the synthesis, characterization, properties, biodistribution, and toxicological/biopharmaceutical profile of NSC. Furthermore, it extensively surveys current state-of-the-art NSC-based formulations for drug delivery with special emphasis on protein delivery, anti-cancer activity in the colon, as well as nasal and ophthalmic targeted gene/drug delivery. Moreover, it discusses NSC-based biomaterial applications in articular, adipose, and bone tissue engineering. In addition, it describes recent contributions of NSC-based hydrogels in wound dressings along with a brief account of drug delivery in combination with tissue engineering. Finally, it presents potential current challenges and future perspectives of NSC-based formulations in the biomedical field.
... Bulk determination of mechanical properties has largely focused on resistance to shear forces generated by shaking (Chen, Jo, & Park, 1995;Uludag, De Vos, & Tresco, 2000;Wang, 2000), bubble columns (Lu, Gray, & Thompson, 1992;Martins dos Santos et al., 1997), and turbine reactors (Poncelet & Neufeld, 1989). These methods have the disadvantage that breakage depends on the hydrodynamics of the processing equipment as well as the mechanical properties of the microcapsules. ...
Research into the fundamental properties of microcapsules and use of the results to develop a wide variety of products in industries such as printing, fast-moving consumer goods, construction, pharmaceuticals, and agrochemicals is a dynamic and ever-progressing field of study. For microcapsules to be effective in providing protection from harsh environments or delivering large payloads, it is essential to have a good understanding of their properties to enable quality control during formulation, storage, and applications. This review aims to outline the commonly used techniques for determining the physicochemical, structural, and mechanical properties of microcapsules, and highlights the interlinked nature of these three areas with respect to the end-use industrial application. This review provides information on techniques that are well supported in the literature, and also examines microcapsule analytical techniques that will become more prevalent as a result of new technological developments or extensions from other areas of study.
... This reaction occurs when a cross-linking agent introduces intermolecular bridges and/or cross-links between polysaccharide macromolecules. Epichlorohydrin (EPI), 1-chloro-2,3-epoxypropane, is the most common cross-linker used in polysaccharide chemistry (Holmberg et al., 1994(Holmberg et al., , 1995Kuniak and Marchessault, 1972) and abundant information on this reaction can be found in the literature (Delval et al., 2005;Seidel et al., 2001;Shiftan et al., 2000;Kim and Lim, 1999;Dumoulin et al., 1998;Chen et al., 1995;Gough, 1967). Indeed, while several methods have been reported for producing cross-linked polymers and gels, the most common procedure involves the use of bifunctional EPI. ...
... Hydrogel of natural polymers, especially polysaccharides have been used because of their unique abilities to improve properties. Polysaccharides are generally nontoxic, biocompatible, biodegradable and abundant [7] . Sago starch, a polysaccharide, improves gel strength and reduces swelling ratio of poly(vinyl alcohol) hydrogel [8] , but the addition of kappa-carrageenan enhances gel strength and swelling ratio of PVP hydrogel [9] . ...
Poly (vinyl pyrrolidone) (PVP) hydrogels with chitosan were prepared from their aqueous solution by the application of gamma radiation from Co-60 source at room temperature. The parameters like variation of total radiation dose and concentration of chitosan in PVP/chitosan mixture were studied. The properties of prepared hydrogel such as gel fraction, water absorption, swelling ratio and equilibrium water content were investigated. Gel fraction of hydrogel increases with increased radiation dose and reaches a maximum value at the radiation dose of 25 kGy, beyond which the gel fraction remains almost unchanged with further increased radiation dose. Water absorption of hydrogel reaches a maximum value at 27 hours standing time in water. It is also found that water absorption, swelling ratio and equilibrium water content decreases with increased radiation dose and concentration of chitosan in the feed solution.
... In hydrogels, the networks are generally cross-linked and are rich in hydrophilic groups/domains [34]. Every hydrogel has a great affinity toward water and can absorb several times the water than their parent weight without being dissolved as a result of chemical/physical bonding between the numerous polymer chains [35,36]. The facile penetration of water in the hydrogels causes the swelling and gives the hydrogel its forms [34]. ...
... Many properties of polysaccharides such as biocompatibility, solubility, potential for modification, and innate bioactivity provide great potential for their use in drug delivery systems ( Figure 3). Despite many synthetic polymers, polysaccharides have very low or no toxicity levels [97][98][99][100]. For example, dextrans are biopolymers composed of glucose with α-1,6 linkages, with possible branching from α-1,2, α-1,3, and α-1,4 linkages, that exhibit low toxicity and high biocompatibility, that makes them biocompatible hydrogels for controlled prolonged therapeutic release [101] and microspheres with no inflammatory response following subcutaneous injection into rats [102]. ...
An agar/polyethylene glycol hydrogel was synthesized and modified with iminodiacetic acid (IDA-agar/PEG),
and its ability as a biocompatible sorbent for extraction of manganese (II) ions from different environmental and
food samples was investigated. The prepared IDA-agar/PEG hydrogel was characterized by scanning electron
microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, energy dispersive X-ray (EDX) spectroscopy,
thermogravimetric analysis (TGA), and X-ray diffraction (XRD). The crucial parameters of manganese (II)
extraction before its determination by flow injection flame atomic absorption spectrometry were optimized. At
optimized conditions, a detection limit of 0.12 μg/L, a limit of quantification of 0.41 μg/L, and the relative
standard deviations of 3.5 % (intra-day) and 5.5 % (inter-day) for six replicate quantifications of Mn (5.0 μg/L)
were obtained. The linearity range (LR) and preconcentration factor (PF) were determined as 0.4–50.0 μg/L and
187.5, respectively. The IDA-agar/PEG hydrogel sorbent was successfully employed for the dispersive microsolid
phase extraction (DMSPE) of Mn(II) in waters, soil, vegetables, and nuts with good recoveries
(97.2–101.0 %).
The usage of short peptide-based polysaccharide hydrogels for tissue engineering was discussed in this review. It explained the drawbacks of employing short peptide-based polysaccharide hydrogels as tissue regeneration scaffolds, while highlighting their benefits. In this review, we first gave a brief overview of short peptide-based polysaccharide hydrogel design process. Then, we provided additionally detailed information of the hydrogels with categorized polysaccharides (hyaluronic acid, dextran, chitosan, alginate, and agarose). We also explained the bioactive short peptides Arg-Gly-Asp (RGD), Ile-Lys-Val-Ala-Val (IKVAV), and Tyr-Ile-Gly-Ser-Arg (YIGSR) that were used to modify these polysaccharide hydrogels in order to enhance cell behaviors, including survival, adhesion, proliferation, and migration. Their applications in tissue engineering were also demonstrated and summarized in this review.
Hydrogels based on cellulose comprising many organic biopolymers including cellulose, chitin, and chitosan are the hydrophilic material, which can absorb and retain a huge proportion of water in the interstitial sites of their structures. These polymers feature many amazing properties such as responsiveness to pH, time, temperature, chemical species and biological conditions besides a very high-water absorption capacity. Biopolymer hydrogels can be manipulated and crafted for numerous applications leading to a tremendous boom in research during recent times in scientific communities. With the growing environmental concerns and an emergent demand, researchers throughout the globe are concentrating particularly on naturally derived hydrogels due to their biocompatibility, biodegradability and abundance. Cellulose-based hydrogels are considered as useful biocompatible materials to be used in medical devices to treat, augment or replace any tissue, organ, or help function of the body. These hydrogels also hold a great promise for applications in agricultural activity, as smart materials and some other useful industrial purposes. This review offers an overview of the recent and contemporary research regarding physiochemical properties of cellulose-based hydrogels along with their applications in multidisciplinary areas including biomedical fields such as drug delivery, tissue engineering and wound healing, healthcare and hygienic products as well as in agriculture, textiles and industrial applications as smart materials.
Graphical abstract
Open image in new window
The non-catalyst polymerization of 2-ethynylpyridine using tri(ethylene glycol)methyl ether tosylate yielded an ionic polyacetylene with the N-[(triethylene glycol)methyl ether]pyridinium tosylate substituents. The polymerization proceeded well in homogeneous manner to give the resulting poly{2-ethynyl-N[(triethylene glycol)methyl ether]pyridinium tosylate} in moderate yield. The polymer was completely soluble in such organic solvents as methanol, DMF, DMSO, NMP including water. The chemical structure of the resulting polymer was characterized by such instrumental methods as IR, NMR, and UV-visible spectroscopies to have the conjugated backbone system with the N-[(triethylene glycol)methyl ether]pyridinium tosylate. The absorption spectrum starts around 600 nm, which is due to the π→ π* interband transition of conjugated polymer system. HOMO and LUMO level were 5.46 and 3.39 eV. The electrochemical properties of polymer was also measured. This polymer exhibited initial onset voltage of 0.73 V for oxidation and stable redox property up to 50 cycles.
Poly(N-bromo-2-ethynylpyridinium bromide) was synthesized via the catalyst-free polymerization of 2-ethynylpyridine using bromine in high yield. The activated triple bonds of N-bromo-2-ethynylpyridinium bromide formed at the initial quaternization reaction are susceptible to linear polymerization, followed by an identical propagation step that contains the produced macroanion and quaternized N-bromo-2-ethynylpyridinium bromide species. The chemical structure of polymer was characterized by various instrumental methods to have the conjugated polymer backbone system bearing the designed N-bromo-2-pyridinium bromide substituents. The optical and electrochemical properties of polymer were studied. The UV-visible spectrum of polymer showed a characteristic absorption peak in the visible region (up to 800 nm). The photoluminescence emission spectrum of polymer shows two distinct peaks at 407 and 516 nm. The cyclic voltammetry of polymer exhibited irreversible electrochemical behavior between the oxidation and reduction peaks.
The present research work is targeted to develop an orally bioavailable form of Ceftriaxone using natural polysaccharide for sustaining and site specific release. The polysaccharide is linked with Ceftriaxone, a third generation cephalosporin (even effective against various flouroquinolone resistant strains) via an enzyme specific spacer dipeptide. The research work explains method for synthesis of polymeric prodrugs using natural polysaccharides and peptide spacer. The in vitro release of ceftriaxone from the polymeric prodrugs were evaluated in pH 1.2 (acidic buffer), simulated gastric fluid (pH 1.2 with pepsin), pH 7.4 (phosphate buffer) and simulated intestinal fluid (pH 7.4 with trypsin-chymotrypsin). The data showed that the release of Ceftriaxone is sustained over a period of 24 h (with a total of 69.38% drug release) at pH 1.2 while at pH 7.4 there was a sudden increase in the drug concentration (> 45% drug release within 15 min) with a total of 70.56% drug release in 24 h. The hydrolytic stability of AG (Gly-Phe-Ceftriaxone]n to pepsin was assessed in simulated gastric fluid (SGF) (pepsin) and simulated intestinal fluid (SIF) (trypsin, chymotrypsin). The amount of ceftriaxone released over a period of 24 h in the SGF was found to be 88.91%, which is less than that release in SIF, i.e., 91.44% indicating that the drug release takes place predominantly at higher pH of intestine. Also it was observed that in SGF, the drug release is sustained (T50 = 5.9) while in SIF there was a sudden increase in the drug concentration (> 66% drug release within 15 min) with a total of 91.44% drug release in 24 h. On the basis of above work Prunus amygdalus polysaccharide can be considered as a promising tool for the preparation of polymeric prodrugs. Method was found suitable for preparing prodrugs of required release profile. The prepared batches were found to release the drug within 24 hour period. Present data are supporting the utility of extracted natural polysaccharide as a polymer for developing polymeric prodrugs for oral sustained delivery of drugs.
Cell culture or fermentation is the well&;#x02010;known workhorse for the production of various bioproducts, including primary and secondary metabolites. The application of immobilized cell technology in industrial processes has attracted considerable attention during the past four to five decades due to its many advantages over traditional suspension cell culture processes. Various types of cells, including microbial cells, plant cells, and mammalian and insect cells, have been immobilized for improving biosynthesis, bio&;#x02010;analytic approaches, environmental applications, and even cell therapy. Meanwhile, many immobilization techniques with different mechanisms have been developed for effectively immobilizing different types of cells. This chapter provides a critical review on the fundamentals and technologies of cell immobilization as well as various bioproducts and applications from the immobilized cell systems. Cell immobilization technology has also triggered interest in bioreactor design and development. Different types of bioreactors currently employed for cell immobilization are also introduced in this chapter.
Several kinds of polymeric particles designed for drug delivery purposes can be successfully synthesized via heterogeneous polymerization processes. Due to the high ability to produce tailor-made polymers, suspension, mass-suspension, suspension-emulsion, miniemulsion and emulsion polymerization processes deserve special attention in the drug delivery field, as the process operating conditions play a significant role on both the morphology and the macromolecular architecture of the polymeric materials. The present paper also focuses on the main features of important polymer system used in drug delivery, as well as, the cancer therapy, exploring the receptor-based targeting of therapeutics and the cancer recognition mechanisms given special attention to the combined action of immunotherapy and chemotherapy. Dissolution models are also discussed due to their importance to the prediction of the dissolution process and drug release in the blood, providing fundamental insight into the dissolution profiles of the drug along the treatment time.
The gellan gum (GG) micro-carriers were prepared by ionic and covalent crosslinking reactions for pH-sensitive delivery of glipizide. Fourier transformed infrared (FTIR) analysis confirmed the synthesis of particle carriers and chemical drugpolymer interaction. The particles ranged between 910 and 1050 mu m and showed similar to 82-95% drug entrapment efficiency. Scanning electron microscopy (SEM) revealed spherical particle morphology. Ca+2-GG particles swelled in simulated gastric fluid without enzymes (pH 1.2) less than in simulated intestinal fluids (pH 6.8) and therefore resulted in the release of small amounts of drugs in acidic fluid (8-12%). The swelling and surface erosion behaviours were accounted for drug release from the Ca+2-GG particles. Glutaraldehyde (GA) treated Ca+2-GG particles eventually swelled in highly acidic and weakly alkaline media with limited surface erosion. However, the amount of drug released did not corroborate with the degree of swelling of the particles. They released only 66% entrapped drug in simulated bio-fluids after 8 h. The relative contribution of simple diffusion and polymer relaxation phenomena in the anomalous transport of drug was evaluated by Peppas-Sahlin mathematical modelling. The pH-responsive GA-treated GG-micro-carriers had the potential to control the release of drug over a long period of time in simulated fluids.
The electrostatic interactions between oppositely charged polyelectrolytes lead to formation of insoluble polyelectrolyte complexes in aqueous medium. The polyelectrolyte complexes formed between a poly acid and poly base are little affected by the pH variation of the dissolution medium. In the present study attempts were made to prepare polyelectrolyte complexes of polyvinyl pyrrolidone (poly base) and carbopol (poly acid) into which diclofenac sodium is incorporated and studied for its controlled release. The polyelectrolyte complexation was evaluated by pH, conductivity, Fourier transform infrared spectroscopy, X-ray diffractometry and scanning electron microscopy studies. The dried polyelectrolyte complexes were also evaluated for micromeritic properties and drug release kinetics. Promising results were obtained suggesting the application of these polyelectrolyte microparticles of diclofenac sodium in the design of controlled release systems.
Different kinds of hemicellulose-based hydrogels have been made by radical polymerization using hydrosoluble hemicellulose from spruce chips with a number-average molecular weight and polydispersity of 2400 and 1.5 respectively. 80% of the hemicellulose was galactoglucomannan. and the remainder mainly 4-O-methylglucuronoxylan. Hemicellulose/poly(2-hydroxyethyl methacrylate) based hydrogels were prepared by polymerization in water of 2-hydroxyethyl methacrylate with hemicellulose modified with well-defined amounts of methacrylic functions. The chemical modification of hemicellulose was performed in dimethyl sulfoxide using 2[(l-imidazolyl) formyloxy]ethyl methacrylate as modifying agent. The kinetics of the modification reaction were monitored by H-1 NMR. The degree of modification of the hemicellulose used for the hydrogel synthesis varied from 10% to 40%. The ratio of modified hemicellulose to 2-hydroxyethyl methacrylate in the hydrogels was 1: 1 by weight. The resulting hydrogels were elastic, homogeneous, soft, transparent and easily swollen in water.
The body can't control massive bleeding without treatment. Different hemostatic agents have been prepared recently, but most of them are ineffective in severe bleeding and expensive or cause safety concerns. In this study, in order to achieve fast control of bleeding, we synthesized and characterized fast-swelling porous superabsorbent hydrogel (FSPSH) and investigated its use as a hemostatic agent. The FSPSH was prepared by grafting acrylic acid and acrylamide onto starch through free-radical polymerization in aqueous solution. The FSPSH was characterized by Fourier transform infrared, X-ray diffraction, field emission scanning electron microscope, and thermogravimetric analysis. Then, temporal swelling behavior and coagulation time experiments were used to predict the in vivo behavior of the FSPSH. The hemocompatibility of synthesized FSPSH was evaluated by hemolysis test and blood cells function. In vivo study using femoral artery injury in rat demonstrated the FSPSH's ability to aid in rapid hemostasis. Furthermore, monitoring the rat on first and seventh day after femoral artery injury also showed no harmful effect. This study indicates that FSPSH adsorbs fluid and swells, thus forms a physical barrier to blood loss. FSPSH, moreover, as hemostat is simple to use, lightweight, stable, and harmless.
This chapter demonstrates how encapsulating drugs into a polymeric microparticle can increase the circulation time of the drug, decrease systemic clearance, protect the drug from enzymatic or acidic degradation, control the rate of drug release, and provide targeting to a specific area. It reviews the basic principles of polymeric microparticle design, polymer selection such as synthetic biodegradable polymers, and microparticle synthesis and characterization methods. The chapter defines polymer microparticles and explains why the micrometer size range is desirable for particulate drug delivery. Researchers are looking to microparticles as a new method for treating many diseases ranging from simple treatments such as vaccines to more complex treatments for diseases such as cancer.
Hydrogel wound dressing can protect injured skin and keep the woundsurface appropriately moist to speed the healing process by absorbingexudates while maintaining the products of tissue repair, including growthfactor and lysosomes, in contact with the wound. The design anddevelopment of novel membrane of hydrogel prepared by crosslinking ofpolyvinyl alcohol with starch suspension using glutaraldehyde as acrosslinking agent was attempted. The membrane was characterized byFTIR spectroscopy. The mechanical property of the hydrogel membranewas characterized by tensile tests. The diffusion coefficient of salicylic acidthrough the membrane was also evaluated using diaphragm celltechnique. FTIR spectra of the membrane indicated the absence of freealdehydic groups of glutaraldehyde. The membrane had sufficient strengthto be used as artificial skin. At 30 °C, the measured value of the diffusioncoefficient of salicylic acid was approximately 4.11×10- 6 cm2/s.(Afr. J. Biomed. Res. 9:23 – 29, 2006)
With a view to developing UV curable systems from renewable biocompatible raw materials, the present work deals with the encapsulation of pigments with polysaccharide derivatives that can undergo crosslinking upon exposure to UV radiation. Maleate ester derivatives were prepared in anhydrous conditions using maleic anhydride in the presence of pyridine. Encapsulation of the pigment core in the prepared UV curable systems occurred by applying the prepared guar derivative as a shell material in a UV curable formulation that can be induced by a photoinitiator. Encapsulation is done by the o/w/o miniemulsion polymerization technique. In another approach, and for the sake of comparison, microencapsulation was performed via chemical crosslinking of the prepared guar maleate derivative in a W/O emulsion .The resultant nanocapsules were characterized using FTIR, DSC, and SEM. The nanocapsules were spherical with average particle size of 100 nm.
Chondroitin sulfate (CS) is one of the major glycosaminoglycans (GAGs) present in the connective tissue extracellular matrix (ECM) and is responsible for the regulation of cellular activities as well as providing mechanical support for the surrounding tissue. Due to presence of CS in the natural tissues including cartilage, hydrogels of CS and other GAGs have been widely used in cartilage regeneration. Due to their polyelectrolyte nature, GAG-based hydrogels are brittle and require modifications to overcome the weak mechanical properties. In this work, we showed copolymerization of methacrylated chondroitin sulfate with oligo(ethylene glycol)s improved the crosslink density of the gels from 2 to 20 times depending on the methacrylation degree of CS and length of the crosslinking monomer. Copolymerization of CS with oligo(ethylene glycol) acrylates is a method to design hydrogels with tunable swelling and mechanical properties.
Sucrose esters (SE) are surfactants with potential pharmaceutical applications because of their low toxicity, biocompatibility, and excellent biodegradability. Biodegradable and biocompatible copolymeric hydrogels based on glucose-6-acrylate-1, 2, 3, 4-tetraacetate (GATA) and methacrylic acid (MAA) were designed and synthesized. Because of the growing importance of sugar-based hydrogels as drug delivery systems, these new pH-responsive glucose-containing copolymeric hydrogels were investigated for oral drug delivery. The GATA monomer was synthesized and characterized. The copolymeric hydrogel was synthesized by free-radical polymerization. Azobisisobutyronitrile (AIBN) was the free-radical initiator employed and Cubane-1, 4-dicarboxylic acid (CDA) linked to two 2-hydroxyethyl methacrylate (HEMA) group was the crosslinking agent (CA) used for hydrogel preparations. The hydrogels were characterized by differential scanning calorimetry and FT-IR. Equilibrium swelling studies were carried out in enzyme-free simulated gastric and intestinal fluids (SGF and SIF, respectively). A model drug, olsalazine [3, 3-َazobis (6-hydroxy benzoic acid)] (OSZ) an azo derivative of 5-aminosalicylic acid (5-ASA), was entrapped in these gels and the in vitro release profiles were established separately in both enzyme-free SGF and SIF. The drug release was found to be faster in SIF. The drug-release profiles indicated that amount of drug release depends on their degree of swelling and crosslinking.
Novel polymeric micelles were synthesized based on Hyaluronic acid (HA) and phospholipids (PEs) including 1,2 dimiristoyl phosphatidylethanolamine (DMPE) and 1,2 distearoyl phosphatidylethanolamine (DSPE). The newly developed micelles evaluated for the physicochemical properties including structural analysis by means of FTIR. Micelles were optimized for delivery of paclitaxel (PTX). The D-optimal design was applied in order to reach micelles with high entrapment efficiency (EE %) and minimum size, simultaneously. In this design the independent variables were the co-polymer type, the drug to polymer ratio and the formulation temperature, whereas the dependent variables were EE% and micelle size. The EE% of the optimized micelles was 46.8% and 59.9% for HA-DMPE and HA-DSPE micelles, respectively. The size of the optimized micelles was in the range of around 250 nm. In vitro release study of the optimized micelles showed that PTX was released from HA-DMPE and HA-DSPE micelles as long as 23 h and 34 h, respectively. Differential scanning calorimetry (DSC) studies showed a conversion of the crystalline PTX molecules into the amorphous form in the micelles. In vivo real time image analysis showed that micellar system was mostly accumulated in the liver, spleen and heart. Accelerated stability studies represented that PTX loaded micelle formulations were stable both physically and chemically at least in 6 months' time.
Over the past decades, injectable hydrogels have emerged as promising biomaterials because of their biocompatibility, excellent permeability, minimal invasion, and easy integration into surgical procedures. These systems provide an effective and convenient way to administer a wide variety of bioactive agents such as proteins, genes, and even living cells. Additionally, they can be designed to be degradable and eventually cleared from the body after completing their missions. Given their unique characteristics, injectable biodegradable hydrogels have been actively explored as drug reservoir systems for sustained release of bioactive agents and temporary extracellular matrices for tissue engineering. This review provides an overview of state-of-the-art strategies towards constructing a rational design of injectable biodegradable hydrogels for protein drug delivery and tissue engineering. We also discuss the use of injectable hydrogels for gene delivery systems and biomedical adhesives.
A polysaccharide was obtained by fermentation of glycerol in the presence of Pseudomonas spp. bacteria. It was characterized by FTIR spectroscopy, SEC chromatography, conductimetric titrations, and viscometric measurements; its emulsifying activity was tested using various mixtures of a hydrocarbon compound and polymer solution. Based on this polysaccharide, new crosslinked ionic derivatives were synthesized and characterized; their interaction with lysozyme was studied. From the data presented, one can suggest some applications for this new, less expensive polysaccharide—it could be used as a thickener and specific bioemulsifier, while its derivatives—as a support for controlled release of biomolecules. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
The aim of this research was to obtain biodegradable amphiphilic graft copolymers suitable for developing matrices capable of controlling the release of proteins in oral drug administration. To this end, high-AM starch was grafted with methacrylic acid (MA) using potassium persulphate (K2S2O8) as the initiator in an aqueous solution. Tablets were obtained by compressing the graft copolymer in powder form with a model drug to make a loaded matrix. When these tablets came in contact with water, the particles split into nano- or microparticles. Thus, microholes or micropores were formed allowing drugs and peptides to be released. In order to obtain matrices with better resistance to hydrolysis, other graft copolymers were synthesized using a cross-linking agent.
In this paper, we report on the synthesis and physicochemical characterization of different graft copolymers and on the study of these copolymers as nano- and microparticles. It was observed that these copolymers offered good controlled release of a model drug, as well as of a model protein.
Recent advances in hydrogel technology have focused on finding more biocompatible, nontoxic materials intended for pharmaceutical and biomedical applications. In this study, a series of pH‐sensitive hydrogels were prepared from poly(ethylene oxide) (PEO) and chitosan in aqueous solutions by electron beam irradiation. This method is a suitable tool for the formation of biocompatible hydrogels because in radiation processing no initiators or crosslinkers, potentially toxic and difficult to remove, are needed. In this frame, also the PEO and chitosan choice was based on their characteristic of low toxicity. The properties of the prepared hydrogels were investigated in terms of the gel fraction and of the swelling behavior in solutions at different pHs. Some swelling kinetic and diffusional parameters were also determined. The observed properties show that increasing the chitosan content, or lowering the pH, the crosslinking density of these networks increases inducing the formation of more stable, but less swellable, hydrogels. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2012
Some polysaccharides activated by bromocyanide react with proteins to give cyclic iminocarbonates. Macromolecular derivatives of dextran and amino compounds presenting pharmacological activity (cobamide, insulin, noradrenalin) were prepared. They have the same activity as the initial products, but this activity is prolonged and more stabile.
We have shown previously that attachment of polysaccharides such as dextran to enzymes markedly increases their stability in vitro (1-7), and we have recently demonstrated that enzyme-dextran conjugates have greater circulatory lifetimes than do the corresponding native enzymes (8,9). In this report we present evidence that the allergic response resulting from administration of enzyme-dextran conjugates also differs from that towards the unmodified enzymes. Although the primary immune response to the enzyme proteins is apparently not abolished by conjugation with dextran, occurrence of allergic reactions is suppressed when preimmunized animals are challenged with the modified antigens.
The mechanisms of the promoting effect of surfactants on the nasal absorption of insulin was investigated in rats. The promoting effect of several non-ionic surfactants, sodium lauryl sulfate and saponin, were paralleled by their abilities to lyze the rabbit erythrocyte and to release protein from the nasal mucosa, whereas the promoting effect of bile acid salts was attributed not only to their direct effect on the nasal mucosa, but also to their inhibitory effect on proteolytic enzymes. Mucosal alterations, observed by scanning electron microscopy, were reversible and the membrane was relatively rapidly restored. Bile acid salts were found to be less irritative to the nasal mucosa than non-ionic ether type surfactants.
Covalent attachment of low molecular weight sugars and polysaccharides to enzymes alters greatly the properties of the enzymes in vitro and their behavior in vivo. Some carbohydrate—enzyme conjugates may have potential as therapeutic agents.
The use of the bioadhesive microsphere system for the intranasal delivery of insulin was investigated in sheep. The effect of combining the above system with lysophosphatidylcholine, as a biological absorption enhancer, was also assessed. For comparison, insulin was also administered by the intravenous and subcutaneous routes. The plasma glucose and insulin levels were determined by a glucose oxidase method and a radioimmunoassay, respectively. The bioadhesive system produced large and significant changes in the plasma insulin and glucose levels. The relative bioavailability (± standard error of measurement) of insulin administered with the microsphere system alone was found to be 10.7% (±2.6) and that of insulin administered with the microsphere /enhancer system to be 31.5% (±6.5).
Glucose sensitive membranes which increase their permeability in the presence of glucose have been developed. The potential of these membranes to deliver insulin at rates controlled by the external glucose concentration is assessed in this study. In order to perform meaningful membrane transport measurements of 125I-labelled insulin, it has been found necessary to thoroughly remove unbound 125 I. Substantial errors in the apparent permeation rate will be obtained if this unbound material is not completely removed. Membranes that have insulin permeation rates that are great enough to achieve estimated physiologic insulin requirements must have a macroporous as opposed to homogenous structure. Macroporous membranes containing amine groups and entrapped glucose oxidase have been found to alter insulin permeability in response to external glucose concentration.
To create microencapsulated liposomes, liposomes containing a biologically active agent are coated with phospholipase A2 and then embedded in alginate. Release of agents from the system are influenced by a number of factors. In this paper, concentration of alginate and the volume ratio of alginate solution to liposomes were shown to affect the enzymatically triggered release profile of macromolecules both in terms of release rate and the extent of cumulative release. The nature of the phospholipase also affects the release profile. Whereas phospholipase A2 is known to cause a pulsatile release, phospholipase C caused a zero order release of macromolecules from microencapsulated liposomes to occur and phospholipase D had little effect on the release process. Storage of the microencapsulated liposomes with phospholipase A2 at 10° C for 30 days kept the system latent with no release occurring indicating that the system has a reasonable shelf life. The system could be activated simply by exposure to 37° C.
Nafarelin, or d-Nal(2)6 LHRH, is an agonistic analogue of luteinising hormone releasing hormone (LHRH). It was designed as a pro-fertility agent, to initiate the cascade of events culminating in the production of the reproductive steroid hormones from the gonads in both females and males. However, it has since become apparent that native LHRH is secreted in a short pulsatile fashion, and administration of nafarelin by other regimens, including continuous administration, results in a suppression of the sequence of events. This provides utility for hormone dependent syndromes, particularly prostatic cancer and endometriosis. Nafarelin has been micro-encapsulated into poly (d,l-lactic-co-glycolic) acid by a phase separation process. The microspheres are readily administered as an injectable suspension. The release of compound from such microspheres is triphasic, being predominantly erosion-controlled, with an early diffusional component. Adjustment of the system design provides overlap of these two phases. The initial rapid diffusional release of compound providing an immediate pharmacological response, and the abrupt termination of release, are two significant properties of the system.In vitro release of the compound is similarly triphasic, correlating closely with suppression of estrus in the female rat, and correlating quantitatively with plasma levels of compound in primates. The pharmacological effects seen are unique to the controlled release system, being more profound that those provided by intermittent administration.
The absorption of recombinant methionyl human growth hormone (Met-hGH) from the nasal mucosa into the systemic circulation was studied in anesthetized rats. Met-hGH was administered intranasally (i.n.), intramuscularly (i.m.) and intravenously (i.v.) to determine the relative and absolute bioavailability of an intranasal Met-hGH formulation. In the absence of detergent enhancers, the absolute bioavailability of meth hGH was <1%. Hypotonicity enhanced absorption slightly. The absolute bioavailability of Met-hGH increased markedly in the presence of the non-ionic surfactant, polyoxyethylene 9-lauryl ether (laureth-9). The histological changes in the nasal mucosa of rats treated with 1% laureth-9 were severe, however, and included complete removal of the nasal epithelium in places. The bile salt sodium glycocholate was also evaluated for its permeation enhancing abilities. At 0.5% glycocholate there were few noticeable histological changes relative to controls and the absolute biovailability of Met-hGH was approximately 7–8%. While absorption of Met-hGH from the nasal epithelium is demonstrated, the effects of permeation enhancing detergents on the delicate nasal mucosa must be better understood before the intranasal route of administration may be considered suitable for delivering Met-hGH to the systemic circulation.
Dextran microspheres and polymer solutions have been evaluated as potential vehicles for nasal administration of insulin in rats. The polymer solutions were either viscous (polyacrylic acid and sodium hyaluronate) or showed thermal gelation (poly-N-iso-propylacrylamide and ethyl(hydroxyethyl)cellulose). The spheres were epichlorohydrin cross-linked dextran, Sephadex and DEAE-Sephadex. Administration of insulin at 1 IU/kg caused a significant decrease in plasma glucose level with two of the investigated polymer systems, polyacrylic acid and ethyl(hydroxyethyl)cellulose, and with the Sephadex spheres. Sodium hyaluronate and poly-N-isopropylacrylamide exerted a significant influence on the plasma glucose level when used as vehicle for an insulin dose of 5 IU/kg. Insulin in DEAE-Sephadex had no effect at all on the plasma glucose level. A larger reduction in plasma glucose level was observed with insulin carried in the particle system than in the polymer systems. Powder formulations which take up water and swell appear to be more efficient in promoting absorption of insulin than the polymer systems.
We examined ten d,l-lactide/glycolide copolymers representing a range of monomer ratios and molecular weights. We characterized the molecular weight distributions by intrinsic viscosity measurements (in two solvents) and by size-exclusion chromatography (SEC) using the "universal calibration" procedure. In tetrahydrofuran, the copolymers obey the following Mark-Houwink relationship: [η]THF = (1.07 × 10-4)M0.761. In hexafluoro-2-propanol they obey [η]HFIP = (1.67 × 10-4)M0.794. Using a 50:50 lactide:glycolide copolymer, we prepared cylindrical samples and incubated them for timed intervals in pH 4.5-7.4 aqueous buffers at 37°C. We also implanted parallel samples subcutaneously in rats. We then monitored the time-dependent changes in sample total weight (TW) and molecular weight (MW). TW and MW profiles were superimposable for all samples, demonstrating pH-independent hydrolysis in vitro and equivalent in vivo versus in vitro copolymer degradation rates. TW loss lagged behind MW loss, indicating copolymer erosion via internal (versus surface) hydrolysis and dissolution. The copolymer MW loss rates adhered well to a pseudo-first-order kinetic model where the number of chain cleavages (X) per initial number average molecule is given by the following expression: In [X] = -2.04 - 1.08t(week-1).
The Kunitz-type soybean trypsin inhibitor (STI), a model protein, was conjugated with dextran (Mw, ∼9900; STI-D), and its physicochemical and biochemical properties were studied to develop a novel delivery system for a protein drug. Conjugation was carried out using periodate oxidation, and cyanogen bromide, carbodiimide, cyanuric chloride, epichlorhydrin, and N-succiniimidyl-3-(2-pyridyldithio)propionate (SPDP) reagent methods. Dextran was conjugated to STI at a molar ratio of 1.5 to 4.6, but the degree of modification, as well as yield and contamination extent of unreacted STI and dextran, varied with the method of synthesis. Gel filtration and electrophoresis confirmed the covalent attachment of dextran to STI but also demonstrated the broad molecular weight distribution of the conjugates. The STI-D conjugate retained satisfactory activity, although the attachment partially reduced its inhibitory activity against trypsin. The periodate oxidation method seemed to be the best for the preparation of STI-D since it gave the conjugate with a high modification ratio (4.6 molecules per STI), high yield (95%), and satisfactory activity recovery (63%). Chemical modification of STI was also carried out with activated polyethylene glycol (PEG) for comparison. The STI-PEG conjugate was obtained in a satisfactory yield (96%) and modification degree (5.8 molecules per STI), but the remaining activity was considerably lower (34%). Thus, conjugation of protein with dextran by the periodate oxidation method is suggested to be preferable for preparing a protein-carrier system without significant diminution of its biological activity.
The use of hyaluronic acid ester microspheres for the intranasal delivery of insulin was investigated in sheep. The formulations were based on two types of microspheres produced from the same polymer but using different stabilising agents. Furthermore, the effect of varying the dose of microspheres was also assessed. For comparison, insulin was also administered nasally as a simple solution and subcutaneously as an injectable preparation. Overall, the microsphere system produced large and significant increases in the nasal absorption of insulin similar to what has been obtained for bioadhesive starch microspheres. Generally, the increase in nasal absorption of insulin (AUC and Cmax) achieved by the microsphere system was found to be independent of the dose of microspheres in the range 0.5–2.0 mg/kg. The mean relative bioavailability of the developed system was found to be 11% when compared with insulin administered by the subcutaneous route.
Microspheres prepared from various polymers were evaluated for their usefulness as carriers for the targeted delivery of vaccine antigens to the gut-associated lymphoid tissues. Following oral administration to mice, microspheres consisting of polystyrene, poly(methyl methacrylate), poly(hydroxybutyrate), poly(dl-lactide), poly(l-lactide), and of poly(dl-lactide-co-glycolide) with various ratios of lactide to glycolide were absorbed into the Peyer's patches of the small intestine. In contrast, no or very little uptake was observed with microspheres consisting of ethyl cellulose, cellulose acetate hydrogen phthalate or cellulose triacetate. Tissue penetration was specific to the Peyer's patches and was restricted to microspheres ⩽ 10 μm in diameter. Time-course studies on the fate of the poly(dl-lactide-co-glycolide) microspheres within the gut-associated lymphoid tissue showed that the majority of the microspheres < 5 μm in diameter were transported through the efferent lymphatics within macrophages, while the majority of those 5 μm in diameter remained fixed in the Peyer's patches. Poly (dl-lactide-co-glycolide) microspheres containing a toxoid vaccine of staphylococcal enterotoxin B were prepared and characterized for their size distribution, surface morphology and toxoid release kinetics in an aqueous environment. Oral immunization with these microspheres effectively delivered and released the vaccine in the gutassociated lymphoid tissue as determined by their ability to induce a disseminated mucosal IgA anti-toxin antibody response.
A number of natural or partially modified polymers was screened for mucoadhesive properties by routinely measuring the force of detachment for swollen polymer films from pig intestinal mucosa in a saline medium. Suprisingly, hydroxypropyl- and carboxymethylcellulose showed almost no mucoadhesion, whereas the cationic polymer chitosan was fairly mucoadhesive in comparison to Polycarbophil as a reference substance. It is suggested that a strict difference be made between mucoadhesion of dry polymers on a wet tissue in air, and mucoadhesion of a swollen hydrogel in the presence of a third liquid phase. Cationic polymers should be further investigated with respect to possibly improved mucoadhesive properties in a neutral or slightly alkaline environment.
In this work, the phase separation of different poly(d,l-lactic acid-co-glycolic acid) batches induced by the addition of silicone oil was studied, for peptide microencapsulation purposes. The phase separation phenomena can be divided in 4 steps according to the amount of incompatible polymer added. But the stabilization of the coacervate droplets and, consequently, the formation of the microspheres, can only be obtained in the third step defined as the stability window. Two experimental parameters influencing the presence, the width and the displacement of the stability window inside ternary diagrams, have been studied: the physicochemical nature of the copolymers and the viscosity of the silicone oil. The results are discussed with respect to the presence of low molecular weight compounds in the studied polymer batches. It is concluded that this characteristic dramatically affects the phase separation of the copolymers by modifying their overall hydrophobicity.
This paper describes an assessment of the potential of using bioadhesive microspheres as a nasal delivery system for biosynthetic human growth hormone (hGH) in sheep. The microsphere system was used alone and in combination with a biological surfactant, lysophosphatidylcholine (LPC). For comparison, hGH was also administered nasally as a solution and subcutaneously as an injection. The levels of hGH in the blood samples obtained were determined by an ELISA technique. The hGH was absorbed to only a very low extent when administered as a nasal solution. However, the microsphere delivery system without added enhancer was capable of considerably enhancing the nasal absorption of hGH. A delay in absorption was observed with the microspheres alone, which may be partially due to low aqueous solubility of hGH. Rapid and much higher absorption was observed when hGH was administered in combination with the microspheres and LPC as an enhancer.
Nerve growth factor (NGF), a protein which plays an important role in the growth and maintenance of sympathetic and certain sensory neurons, was physically incorporated into four different types of hyaluronane derivative microspheres. In addition, four analogous formulations were prepared, introducing also GM1, a monosialoganglioside which seems to potentiate the neuritic outgrowth induced by NGF (Matta et al., Devel. Brain Res., 27 (1986) 243–252). All the products obtained were analyzed to quantify the amount of incorporated protein and to characterise the in vitro release profiles. It has been demonstrated that the preparation techniques employed were useful for the development of microspheres able to protect, carry and release bioactive polypeptidic molecules in their pharmacologically active form. The protein release profiles were significantly influenced by the physico-chemical properties of the polymeric derivatives used and by the copresence of GM1 which increased the amount of NGF released.
Degradable starch microspheres (DSM) with a diameter of 45 μm were investigated as a nasal delivery system for insulin in rats. Insulin (0.75 IU/kg and 1.70 IU/kg)-DSM preparations administered nasally as a dry powder resulted in a dose-dependent decrease in blood glucose and a concomitant increase in serum insulin. The blood glucose was reduced within 30–40 min by 40% and 64% respectively, using the aforementioned doses. The glucose level was normalized after 4 h. The insulin peak was reached 8 min after dosing. The bioavailability was approx. 30%. DSM alone or soluble insulin had no effect on these parameters. The results obtained indicate that DSM offer a system for improving the nasal absorption of drugs.
This chapter summarises the problems associated with and the potential of nasal drug administration. The physiology and the anatomy of the nasal cavity are briefly discussed. Limitations of currently available nasal formulations are presented and solutions to the major problem, low bioavailability, are proposed. The biopharmaceutical properties and toxicity of both old and new enhancer systems are discussed. A dry particulate system, starch microspheres which are water insoluble but adsorb water, and sodium tauro-24,25-dihydrofusidate (STDHF), which is surface active, are two promising enhancer systems promoting the nasal absorption of drugs by different mechanisms. These systems are discussed in this review.
Permeability and partition coefficients were measured for a series of solutes in membranes formed from ethyl or benzyl esters of the polysaccharide hyaluronic acid. The solutes were primarily peptides and proteins, with molecular weights ranging from 108 to 66 000 Da. Logarithms of the apparent diffusion coefficients (log Dapp), as calculated from the measured permeability and partition coefficients, were linearly related to the logarithm of solute molecular weight. In addition, log Dapp was linearly related to the square of the solute radius, in keeping with Yasuda's free volume theory. As expected, measured partition coefficients were not correlated to solute size. The results suggest that these biocompatible and biodegradable hyaluronate esters may be useful in peptide controlled release.
Strategies for the controlled parenteral delivery of polypeptides and proteins are reviewed. The different approaches are divided into five classes: (a) hydrogels, (b) self-diffusion systems, (c) microparticles, (d) biodegradable polymers, and (e) porous membranes; self-regulated delivery represents an additional subset. These methods are discussed in the light of difficulties associated with delivery of proteins, including their low permeability, rapid proteolysis, and denaturation within the delivery system.
Microspheres of starch and dextran, cross-linked with epichlorohydrine, function as an enhancer system for the absorption of insulin in rats. The effect on the glucose level is rapid and maximal reduction of plasma glucose is seen within 30–40 min. Starch microspheres are more effective than dextran spheres in inducing a decrease in blood sugar. The starch microspheres have been evaluated from a toxicological point of view in rabbits. The spheres were administered 2 times per day for 8 weeks and in two dosages, 10 and 20 mg. Scanning electron microscopy of the nasal mucosa showed no alterations. The only finding observed in light microscopy was a small hyperplasia in the septum wall. A preliminary test on healthy volunteers with starch microspheres given nasally for 1 week shows good acceptability. A temporary widening of the tight junctions in a monolayer of human epithelial (Caco2) cells was seen in the presence of dry starch microspheres. The widening of the tight junctions coincided with the increased absorption rate of insulin. A conceivable hypothesis with regard to the mechanism of action of DSM can be that the epithelial mucosa is dehydrated, with a reversible “shrinkage” of the cells, thus giving a physical separation of the intercellular junctions.
Intranasal administration of starch microspheres and insulin as a dry powder results in a rapid decrease in plasma glucose. The optimal dose of spheres for a given dose of insulin is approx. 3–7 mg per kg body weight in the rat. The degree of cross-Unking governs the water uptake and swelling and thereby the release of insulin from the spheres in vitro. No significant differences could be seen in vivo between spheres with different swelling factors. Starch microspheres do not induce erythrocyte hemolysis. A comparison between microspheres and starch powders (molecular weights: 25 000 and 11 000, respectively) shows that the insoluble starch of mol. wt. 25 000 and the microspheres reduce the plasma glucose level to the same extent. Water-soluble starch powder (mol. wt. 11 000) does not affect the plasma glucose level. The crucial properties for the absorption-promoting effect of microspheres are water absorption and water insolubility.
The rapid mucociliary clearance mechanism in the nasal cavity can be considered as an important factor when low bioavailabilities are obtained for drugs given intranasally. A nasal delivery system in the form of bioadhesive microspheres has been developed. Studies in human volunteers using gamma scintigraphy showed great differences in clearance times between 3 microsphere systems and two controls. The half life of clearance for starch microspheres was found to be in the order of 240 min as compared to 15 min for the liquid and powder control formulations. The microspheres form a gel-like layer in contact with the nasal mucosa that is cleared slowly from the nasal cavity. In vitro studies using model compounds (cromoglycate and Rose bengal) showed high degrees of loading capacities for the various microsphere systems. Using various physical and chemical approaches, it was possible to a certain degree to control the release of the compounds from the microsphere systems.
Asparaginases isolated from Escherichia coli and Erwinia carotovora are used in the treatment of acute lymphoblastic leukemia. Unfortunately, their use has been limited by their relatively short circulatory half-lives and by immune reactions that develop in response to repeated injections of the enzymes. This review describes studies that have used dextran to improve the therapeutic potential of l-asparaginase. Dextran, a biocompatible polymer of d-glucose, is bound covalently to the surface of asparaginase. The resulting soluble dextran-asparaginase conjugates show increased circulatory persistence and markedly reduced antigen reactivity. These studies have shown that it is possible to use dextran to create a steric barrier around asparaginase that not only protects the enzyme from degradation in vivo but also slows its inactivation by the immune system. Soluble-dextran conjugates provide a means of avoiding the biological limitations to the use of microbial enzymes in therapy.
The persistence in circulating blood of rabbits and mice of Erwinia carovotora asparaginase and some of its chemically modified derivatives was compared. Derivatives of various molecular size were obtained by reacting the enzyme with some bifunctional reagents and activated dextrans. The persistence of the larger molecular weight derivatives of the enzyme was many-fold higher than that of the native enzyme. Radioactive labelling of the enzyme showed that it may be removed intact from the circulation.
The preparation and some properties of microspheres composed of oxidized polysaccharides and some vinyl polymers are described. The microspheres contain immobilized enzyme and can be slowly solubilized in water solutions, thereby releasing active a enzyme into the surrounding medium. The kinetic characteristics of the immobilized enzyme bound with a fragment of matrix after complete solubilization are unchanged, but the enzyme exhibits high thermostability. These preparations could have a wide range of medical applications, e.g., to form a drug "depot" directly in an affected organ.
Semipermeable microcapsules were prepared using biodegradable material as the enclosing membranes. For instance, polylactic acid was used as membrane material to microencapsulate biologically active materials. Asparaginase microencapsulated within polylactic acids functions effectively in converting external asparagine into aspartic acid and ammonium. By variations in permeability characteristics, insulin microencapsulated within polylactic acid can be released at pre-adjusted rates. Thus, release rates of 50% in 5 hours, 50% in 20 hours, and 2.5% in 24 hours have been demonstrated. Drugs and vaccines have also been similarily microencapsulated. The advantage of the biodegradable microcapsules is the ability of the body to convert the injected polymer material to normal body metabolites (e.g., CO2 and H2O in the case of polylactic acid) after completion of its function.
The effects of viscous solutions of hyaluronate-sodium of various average molecular weights (MW) on the nasal absorption of vasopressin (AVP) and its analogue, 1-deamino-8-D-arginine vasopressin (1-d-8-DAVP), were examined in rats. Solutions of hyaluronate with MW greater than 3 x 10(5) daltons enhanced the nasal absorption of AVP; solutions of MW 5.5 x 10(4) daltons were not effective. The enhancing effects on the nasal absorption of AVP and 1-d-8-DAVP were dependent on the concentration in the range of 0-1.5% (w/v) hyaluronate (MW 1.4 x 10(6) daltons). The nasal absorption of AVP was increased with this solution at lower pH. Bioavailabilities after nasal administration of AVP and 1-d-8-DAVP in hyaluronate solutions (MW 1.4 x 10(6) and 2 x 10(6) daltons) increased more than 2-and 1.6-fold as compared to nasal administration of AVP and 1-d-8-DAVP in buffer solutions (pH 7.0), respectively. Hyaluronate solution (MW 1.4 x 10(6) daltons) did not affect the ciliary beat frequency of rabbit nasal mucosal membranes in vitro. Therefore, hyaluronate solution may be useful as a vehicle for nasal delivery of AVP and 1-d-8-DAVP.
The covalent attachment of the therapeutic enzyme carboxypeptidase G2 to soluble dextrans of varying molecular weight resulted in a 5-15-fold increase in plasma persistence in normal and tumour-bearing mice. The molecular weight of the dextran used markedly affected the number of dextran molecules present in the conjugate, resulting in a molecular weight distribution between 6 and 12 X 10(5) daltons. The isoelectric point of the conjugates varied between 4.1 and 4.8 compared to native enzyme 7.8. Conjugates were resistant to proteolysis by trypsin and chymotrypsin, but showed little difference in their affinity for substrate.
The enhancement of nasal insulin absorption by sodium taurodihydrofusidate (STDHF) was studied in rabbits and rats. Using identical nasal formulations remarkable interspecies differences were observed. The fusidate derivative at 1% (w/v) enhanced nasal insulin bioavailability from 0.9 to 5.2% and from 0.3 to 18.0% in rabbits and rats, respectively. In both species the insulin formulations with STDHF resulted in strong hypoglycemic responses. Coadministration with the trypsin inhibitor aprotinin tended further to increase insulin bioavailability in rats and decrease insulin bioavailability in rabbits; however, these aprotinin effects were not statistically significant. Addition of the aminopeptidase inhibitor bacitracin to the STDHF containing formulation did not have any effect on insulin bioavailability in rats. Hence, STDHF is a potent enhancer of nasal insulin absorption, probably both by facilitating insulin transport through the nasal mucosa and possibly also by inhibiting enzymatic degradation. Further, interspecies differences and, experimental animal conditions can greatly affect nasal drug absorption.
The release of the peptide hormone nafarelin, 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-3-(2-naphthyl)- D-alanyl-L-leucyl-L-arginyl-L-prolylglycinamide, a potent luteinizing hormone-releasing hormone (LHRH) agonist, from implants of the biodegradable copolymer poly(d,l-lactide-co-glycolide) (PLGA) has been studied both in vivo and in vitro. The release has a triphasic profile typical for bulk-eroding monolithic controlled-release systems, characterized by a secondary phase of lower release preceded and followed by phases of higher release. The primary factor controlling the peptide release profile is polymer erosion, which in turn may be controlled by modifying physical properties of the polymer such as the molecular weight or the ratio of the more hydrophobic lactic acid monomer to the less hydrophobic glycolic acid monomer. The duration of the secondary phase has been found to be directly proportional to the molecular weight of the copolymer, and the total duration as well as the duration of the secondary phase are both directly proportional to the monomer ratio. A system has been identified in which the secondary phase is sufficiently reduced to provide essentially continuous efficacy in the rat for greater then eight months, with partially effective levels of release of nafarelin continuing beyond 15 months.
Polylactic acid (PLA) or copoly(lactic/glycolic) acid (PLGA) microcapsules containing leuprolide acetate were prepared by an in-water drying process and the release patterns were examined in vitro. The release rates were extremely small from microcapsules prepared with PLA of average molecular weight 22500, and from microcapsules prepared with PLGA having average molecular weight 21200 and a copolymer ratio of 75/25 (molar ratio of lactic acid to glycolic acid). The release rate of leuprolide acetate from the microcapsules prepared with PLA of average molecular weight 6000 was relatively fast, but was still too slow to give the desired drug level over one month. Several water-soluble compounds were incorporated into microcapsules prepared with PLA of average molecular weight 22500, in an attempt to increase the release rate by the creation of aqueous channels. These compounds only induced a high initial release and failed to increase drug release. The release profile of the drug from microcapsules prepared with PLGA of average molecular weight 14000 and a copolymer ratio of 75/25 was ideal for one month's release. A small initial release was observed followed by a steady release which lasted for 35d, and approximately followed zero-order kinetics.
To investigate the utility of a novel adjuvant, sodium taurodihydrofusidate (STDHF), as an enhancer of mucosal permeation of drugs, experiments involving intranasal insulin:STDHF administration in sheep were performed. Rabbit erythrocyte lysis assays were employed to assess the relative membrane lytic activity of STDHF, as well as that of its glycine-conjugated analogue, compared with a nonionic detergent and a common bile salt. Equivalent weight concentrations of the fusidates were found to be 5- to 10-fold less lytic than the bile salt and at least 100-fold less lytic than the nonionic detergent laureth-9. Provided the concentration of STDHF was greater than its critical micellar concentration, formulations of insulin with STDHF greatly enhanced intranasal insulin absorption. Optimal nasal insulin absorption was attained at a molar ratio of STDHF to insulin of 5:1. In addition, intranasal absorption was linearly related to insulin dose. Compared with intravenous administration, the mean bioavailability of intranasal insulin was 16.4%. Interovine variability was low, with a coefficient of variation of 14% for 12 animals. It was found that intranasal absorption of sodium insulin was not significantly different from that of zinc insulin. However, formulations of both crystalline insulin preparations were absorbed more efficiently than a formulation prepared using commercially available solutions of U-500 insulin. The results taken together indicate that STDHF is an excellent enhancer of insulin absorption from the nasal mucosa.
Polymeric prodrugs can be defined as latent pharmaceutical agents which must undergo chemical or enzymatic transformation to the active or parent drug in the organism after administration. Polymeric prodrugs may also be considered special types of drug delivery systems where the drug release is realized by cleavage of a chemical bond. The concept of polymeric prodrugs finds application in the design of novel agents when pharmacokinetical modification of a parent drug is necessary, or when the aim is to achieve selective action at a target site, utilizing enzymatic activation specific for that site. The types of polymeric prodrugs synthetized in the last decade are reviewed regarding the chemical structure of the carrier backbone and the drug linkages applied. Relationship between the chemical structure, physicochemical characteristics of polymeric prodrugs, and their physiological behavior is discussed, with special regard to the bioavailability, body distribution, and rate of elimination of the carrier from the living organism. In vitro and in vivo experimental data concerning drug activation processes, as well as potential clinical applications of polymeric prodrugs, are surveyed.
The preparation of polymeric derivatives of drugs, in which drug moieties are covalently linked to polymeric or oligomeric matrices, in such a way that they can be released at the site of action, is one of the most promising ways to achieve results which often can be hardly obtained by other means, such as, for instance, better adsorption by some ways of administration (e.g., oral administration), preferential localization in the body, and longer duration of activity. The aim of this review is to provide an up-to-date picture of the state of art in this field. The synthetic aspects of the preparation of polymeric derivatives of drugs will be discussed, with special emphasis on general methods. The main criteria for selecting a particular type of matrix, and a particular bond between drug and matrix, in order to achieve a given purpose, will be also discussed. The main pharmacological results so far obtained by this technique will be emphasized.
The carbohydrate moieties of the glycoenzyme, glucoamylase I from are linked by -glycosidic bonds to approximately 45 serine and threonine residues, presumably on the surface of the enzyme molecule. The glucoamylase is remarkably stable on storage at low temperatures. Extensive oxidation of the carbohydrate residues in the enzyme by periodate markedly affects the stability of the enzyme. It is suggested that the carbohydrate moieties function as stabilizers of the tridimensional structure of the glycoenzyme, and, in turn, of the catalytic property of the molecule.
C3H/HEJ mice were given i.p. injections of one of the following: L asparaginase solution, microencapsulated L asparaginase, saline or control microcapsules. After injection of L asparaginase solution, enzyme activity appeared in the blood very rapidly with the highest concentration occurring after 4 hr and was then cleared from the circulation with a half life of 4.4 hr. In marked contrast, when microencapsulated L asparaginase was injected, no significant L asparaginase activity appeared in the blood for the entire duration of this study. 'Body' L asparaginase levels declined very rapidly with a half life of 2 hr after injection of L asparaginase solution, whereas it took 60 to 72 hr for the 'body' L asparaginase to decrease to 50% of the original activity after injection of microencapsulated L asparaginase. The microencapsulated L asparaginase still retained about 20% of its original activity up to 16 days after injection. Plasma L asparagine was maintained at zero concentration for 3 days after injection of L asparaginase solution, compared to 8 days after injection for microencapsulated L asparaginase. Liver L aparaginase activity was found to increase after injection of L asparaginase solution but not after injection of microencapsulated L asparaginase. The response of the host to i.p. injection of nylon microcapsules is described. Preliminary experiments indicate that the half life for clearance of the free enzyme from the circulation of 6C3HED lymphosarcoma bearing mice was 13.2 hr as compared to 4.4 hr for normal mice, and that microencapsulated L asparaginase was capable of causing regression of the tumor in the advanced, well established stage.
Insulin has been covalently linked to dextran, 2,000,000. The soluble derivative has intrinsic biological activity in lowering blood glucose levels and in glucose uptake in isolated fat cells .
The degree of substitution of macroporous cellulose withtrans-2,3-cyclic carbonate groups has been controlled by moderating the reaction with water. Exercise of this control enabled the preparation of a matrix with physical and chemical properties which facilitated the covalent binding of chymotrypsin A in such a way that the activity of the insoluble enzyme was appreciable towards a high molecular weight substrate (casein) as well as towards a low molecular weight substrate (tyrosine ethyl ester). Under the optimum conditions of preparation the bound protein had a relative activity towards casein of 26% and towards the ester of 65% of the activity of the free enzyme.