Drug Release Profiles and Disintegration Properties of Pectin Films.

We assessed the disintegration profiles of the film dosage forms (FDs) prepared using pectin by measuring the amount of pectin dissolved from the films in a limited amount of aqueous medium. Furthermore, we used miconazole and dexamethasone as standard drugs and investigated the relationship between the disintegration rate of the FDs and the rate of drug release. We used two types of pectin in this study to develop thin films with a thickness of approximately 25⁻35 µm. The FDs gradually disintegrated in the aqueous medium, and the disintegration profile of the FDs differed depending on the types of pectin. In addition, the rate of disintegration of the film matrix affected the dissolution rate of the drug incorporated into the FD. Thus, our results show that FDs prepared using pectin are beneficial because of their high solubility in a limited amount of medium, and the rate of drug release from the FDs can be regulated by selecting a specific type of pectin or by altering the concentration of the film base.

Control of Drug Dissolution Rate from Film Dosage Forms Containing Valsartan.

Film dosage forms (FDs) containing valsartan (VST), a popular antihypertensive drug, were prepared using a casting method with sodium alginate and other polysaccharides as the film base. Drug dissolution profiles of the FDs were investigated in limited medium. The FDs were 170-200 µm thick and were easy to handle. All FDs immediately swelled and disintegrated in the medium. About 23% of the VST incorporated into the FD prepared with 1.5% sodium alginate dissolved at 5 min. The initial dissolution rate of VST increased upon the addition of chitosan to the film base; this effect was not observed in the case of chitin. On the other hand, the rate apparently decreased upon modification with alginic acid. In addition, the solubility of VST in the dissolution medium was changed by the addition of chitosan or alginic acid. FDs prepared with polysaccharides are useful for simplifying the administration of drugs to patients, and the drug dissolution rate from FDs can be controlled by modification.

Adsorption of histones on natural polysaccharides: The potential as agent for multiple organ failure in sepsis.

Histones are intracellular proteins that are structural elements of nuclear chromatin and regulate gene transcription. However, the extracellular histones released in response to bacterial challenges have been identified as mediators contributing to endothelial dysfunction, organ failure, and death during sepsis. In the present study, the adsorption of histones as well as plasma proteins (α1-acid glycoprotein (AGP), albumin, and γ-globulin) on alginic acid, pectin, dextran, and chitosan was examined in order to evaluate the potential of natural polysaccharides as therapeutic agents for multiple organ failure in sepsis. Alginic acid and pectin strongly adsorbed histones, whereas the adsorption abilities of dextran and chitosan toward histones were very low or negligible. Among the natural polysaccharides examined, only alginic acid did not adsorb any of the plasma proteins. These results demonstrated that alginic acid strongly adsorbed histones, but not plasma proteins; therefore, it has potential as a candidate drug for the treatment of multiple organ failure in sepsis.

Characteristics of drug release from gel beads formed by hydrolysis of alginic acid into guluronic acid blocks.

Alginic acid (Alg) is a natural anionic polysaccharide, which consists of α-L-guluronic acid (G) and ß-D-mannuronic acid (M). G-G sequence-rich chain regions, known as G-blocks (GB), are important regions for gelation of Alg using divalent cations. In this study, calcium-induced GB gel beads were prepared, and drug release profiles and degradation properties of the GB gel beads were investigated in aqueous media. The GB gel beads swelled slightly in JP XVI 1st fluid (pH 1.2), and only slight release of sodium diclofenac (DF) from the GB gel beads was observed. Disintegration of the GB gel beads was not observed in the 1st fluid. On the other hand, the GB gel beads disintegrated in JP XVI 2nd fluid (pH 6.8), and the rate of disintegration depended on the concentration of calcium chloride used to prepare the GB gel beads. The DF release profiles of the GB gel beads in the 2nd fluid could be controlled by the concentration of CaCl2 used to prepare the GB gel beads. The initial release profile of DF from GB gel beads was not consistent with the profile of disintegration. According to the Higuchi-plot of the percentage of drug content released against the square root of time, gel disintegration did not affect the release of DF from GB gel beads. It appears that a diffusion-type mechanism was responsible for DF release. We propose that the GB gel bead gel matrix is an effective medium by which to control the release of drug within the gastrointestinal tract.

Development of film dosage form containing allopurinol for prevention and treatment of oral mucositis.

Film dosage forms (FDs) containing allopurinol (AP) were prepared using a casting method with water-soluble polysaccharides, such as sodium alginate (ALG), and the release profile of AP from FDs was investigated in limited dissolution medium. Some ALGs were able to form FDs incorporating AP, and the thickness was about 50 µm. All FDs were easy to handle, though the rheological properties varied with ALG species. AP was homogenously present throughout the FDs and was released with disintegration in 10 mL of physiological saline. These results confirmed that FDs are useful for preventing or treating localized problems in the oral cavity, such as mucositis. FDs are also useful for administering drugs to cancer patients receiving chemotherapy and/or radiotherapy.

Antioxidant Activity of ß-Glucan.

ß-Glucans extracted from barley, which mainly contains ß-(1,3-1,4)-D-glucan, are used extensively as supplements and food additives due to their wide biologic activities, including a reduction in blood lipid level. In this study, the antioxidant activity of ß-glucan was examined to assess potential new benefits associated with ß-glucan, because oxidative stress is considered one of the primary causal factors for various diseases and aging. ß-Glucan extracted from barley was found to possess significant antioxidant activity. The amount of antioxidant activity was influenced by different physiologic properties (e.g., structure and molecular size) of ß-glucan, which varied depending on the source and extraction method used. The antioxidant activity of ß-glucan was significantly higher than that of various polymers that are used as food additives. These results indicate that ß-glucan has promise as a polymeric excipient for supplement and food additive with antioxidant and other benefits, which may contribute to enhancing health and beauty.

[Property of metronidazole film prepared with natural polysaccharides].

Film dosage forms containing metronidazole (MZ) were prepared from natural polysaccharides, such as pullulan (PUL) or sodium alginate (ALG), without heating or controlling the pH. The release profiles of MZ from the films were investigated. In the absence of a drug, the casting method resulted in the polysaccharide forming a circular film, and the presence of MZ affected film formation. The thickness of the film was controllable by adjusting the concentration of ALG, and regular unevenness was observed on the surface of film. The film prepared with PUL or ALG readily swelled in dissolution medium, and released MZ with disintegration. The films prepared from the polysaccharides could be promising candidates as dosage forms containing MZ, and would be expected to show drug dissolution in the surface of skin.

Preparation of Fast Dissolving Films for Oral Dosage from Natural Polysaccharides.

Fast-dissolving films (FDFs) were prepared from natural polysaccharides, such as pullulan, without heating, controlling the pH, or adding other materials. The release profiles of model drugs from the films were investigated. In the absence of a drug, the casting method and subsequent evaporation of the solvent resulted in the polysaccharide forming a circular film. The presence of drugs (both their type and concentration) affected film formation. The thickness of the film was controllable by adjusting the concentration of the polysaccharide, and regular unevenness was observed on the surface of 2% pullulan film. All films prepared with polysaccharides readily swelled in dissolution medium, released the incorporated compound, and subsequently disintegrated. The release of dexamethasone from the films was complete after 15 min, although this release rate was slightly slower than that of pilocarpine or lidocaine. Therefore, FDFs prepared from polysaccharides could be promising candidates as oral dosage forms containing drugs, and would be expected to show drug dissolution in the oral cavity.

Properties of an oral preparation containing a chitosan salt.

The 2-(4-chlorophenoxy)-2-methylpropionic acid (CMP) salt of chitosan (CS), CS-CMP, and that of a CS derivative (CP), were prepared and their ability to adsorb bile acids investigated. CS-CMP and CP-CMP rapidly adsorbed taurocholate (TCA) and glycocholate (GCA) when these bile acids were present together in the medium, with simultaneous release of CMP. A secondary bile acid, taurodeoxycholate, was preferentially adsorbed over TCA and GCA. Alginate gel beads containing CS-CMP did not differ from CS-CMP alone in their manner of bile acids take up. Furthermore, oral administration of CS-CMP to rats resulted in decreased serum cholesterol and triacylglycerol levels for two weeks. Therefore, CS-CMP, as well as a vehicle containing CS-CMP, might be a useful agent with which to treat hyperlipidemia.

Stabilization of α-lipoic acid by complex formation with chitosan.

α-Lipoic acid (ALA) is an essential cofactor in mitochondrial multi-enzyme complexes related to energy production. However, it is unstable under light or heat, and its decomposition is accompanied by an unpleasant odor. Therefore, its stabilization by complex formation with the cationic polymer chitosan (CS) was investigated. The ALA dissolved in demineralized water was efficiently adsorbed on the precipitated insoluble CS particles, and an ALA-CS complex was obtained. The amount of ALA adsorbed on CS was affected by the CS species and the quantity ratio of ALA to CS. The ALA from the ALA-CS complex was released immediately by changing the pH. When ALA was incubated at 65°C, it melted and polymerized. In addition, some decomposition of ALA was also observed in the physical mixture of ALA with CS. However, the ALA-CS complex did not decompose at all under the same conditions. Thus, the stabilization of ALA was achieved by complex formation with CS. CS is useful as a material for the stabilization of ALA, leading to its clinical use.

The drug release profile from calcium-induced alginate gel beads coated with an alginate hydrolysate.

Calcium-induced alginate gel bead (Alg-Ca) coated with an alginate hydrolysate (Alg), e.g. the guluronic acid block (GB) was prepared and the model drug, hydrocortisone release profiles were investigated under simulated gastrointestinal conditions. Their molecular weights were one sixth or one tenth that of Alg and the diffraction patterns of the hydrolysates resembled that of Alg. The drug release rate from Alg-Ca coated with GB apparently lowered than that of Alg-Ca (coating-free) in the gastric juice (pH1.2). And the coating did not resist the disintegration of Alg-Ca in the intestinal juice (pH 6.8) and the gel erosion accelerated the drug release. On the other hand, for the coated Alg-Ca containing chitosan, the drug release showed zero-order kinetics without rapid erosion of Alg-Ca. The drug release rate from Alg-Ca was able to be controlled by the coating and modifying the composition of the gel matrix.

Adsorption of bile acid by chitosan salts prepared with cinnamic acid and analogue compounds.

A chitosan (CS) powder treated with cinnamic acid and an analogue compound (CN) was prepared as CS-CN. Using it, bile acid adsorption by CS-CN and the release of CN were investigated in vitro. When CS-CN was soaked in a taurocholate solution, it released CN and simultaneously adsorbed the bile acid. For CS-CN prepared with cinnamic acid, the amount of CN released was 0.286 +/- 0.001 mmol/g CS-CN; the amount of taurocholate adsorbed was 0.284 +/- 0.003 mmol/g CS-CN. These two functions were recognized on alginate or pectin gel beads containing CS-CN. The amount of released CN was altered extensively by the species of CN used for gel-bead preparation. Results suggest that CS-CN is a candidate for complementary medicine to prevent lifestyle-related diseases.

Profile analysis and immunoglobulin E reactivity of wheat protein hydrolysates.

BACKGROUND: Wheat protein hydrolysates have been traditionally used as food additives and are now being used in cooking worldwide. There have been a few studies on the relationship between the molecular mass distribution and the immunoglobulin E (IgE) reactivity of the wheat protein hydrolysates. METHOD: We analyzed the peptide profile of commercial wheat protein hydrolysate samples from enzymatic or acid hydrolysis of wheat protein using size exclusion chromatography. We further investigated the IgE reactivity of the wheat protein hydrolysates using the inhibition ELISA method and sera of 5 patients sensitive to wheat. RESULTS: The wheat protein enzymatic hydrolysate samples showed high concentrations of peptides with molecular masses greater than 1,050 Da, whereas in contrast, the wheat protein acid hydrolysates showed extremely low concentrations of peptides with molecular masses greater than 1,050 Da. Tested wheat protein acid hydrolysates hardly inhibited the patient IgE binding ability to wheat proteins in the five patient sera. On the contrary, some tested wheat protein enzymatic hydrolysate samples inhibited the IgE binding ability to wheat proteins. CONCLUSION: These results suggested that the uptake of wheat protein enzymatic hydrolysates might still have the possibility of causing food allergic reactions in patients allergic to wheat and the processed foods containing them.

Sustained insulin release with biodegradation of chitosan gel beads prepared by copper ions.

Chitosan (CS) gel beads were prepared with chelated copper (II) ions as a vehicle for the delivery of peptide and protein drugs. Insulin, which is a model of peptide and protein drugs, was scarcely released from the CS gel beads in vitro, presumably due to the nature of interactions occurring between insulin, CS and the copper (II) ions. The efficacy of insulin released from the CS gel beads was confirmed by implantation into diabetic mice. A consistent reduction in blood glucose level was observed in vivo due to insulin release as the CS gel beads were degraded. Control over insulin release was achieved by altering the properties of the CS. Thus, CS gel beads are promising as a biocompatible and biodegradable vehicle by which peptide and protein drugs can be delivered.

The controlled release of insulin-mimetic metal ions by the multifunction of chitosan.

Vanadium, which is an insulin-mimetic metal ion, was efficiently adsorbed on chitosan (CS). The adsorption of vanadium on CS was affected by the vanadium/CS ratio and the initial concentration of vanadium in preparative medium under constant pH condition. The vanadium-CS complex was able to control vanadium release. Moreover, a consistent control of vanadium release was achieved by incorporation of the vanadium-CS complex into a CS gel. After implantation of the CS gel retaining the vanadium-CS complex into diabetic mice, insulin-mimetic efficacy was confirmed by observation of a steady reduction in blood glucose levels. The sustained vanadium release also contributed to minimization of the side-effects. Thus, CS gel retaining the vanadium-CS complex appears promising as a vehicle for vanadium with long-term action and a low toxicity leading to its clinical use.

Adsorption of bile acid by chitosan-orotic acid salt and its application as an oral preparation.

The orotic acid (OT) salt of chitosan (CS), CS-OT, and that of a CS derivative, CP, were prepared, and the adsorption of primary or secondary bile acid was investigated. Calcium-induced alginate gel beads (Alg-Ca) containing CS-OT were also prepared and autoclaved, and the possibility of these beads to act as a vehicle for oral administration to prevent hyperlipidemia was investigated. When taurocholate (TCA) and glycocholate (GCA) were present together in the medium, CS-OT adsorbed identical amounts of both bile acids. This trend was seen in all CPs, although the capacity to adsorb bile acid was affected by the number and/or structure of the amino groups in the CP. On the other hand, taurodeoxycholate, a secondary bile acid was preferentially adsorbed over TCA and GCA. Alg-Ca containing CS-OT took up bile acids in a similar manner as CS-OT irrespective of the water content of the gel matrix. As all elements can be taken as a food, Alg-Ca containing CS-OT could serve as a useful dietary agent for the prevention of hyperlipidemia, which is a lifestyle-related disease.

Properties of calcium-induced gel beads prepared with alginate and hydrolysates.

Calcium-induced alginate gel beads (Alg-Ca) containing alginate hydrolysate, such as the guluronic acid block (GB), was prepared and the drug release profiles were investigated under simulated gastrointestinal conditions. The addition of GB to Alg-Ca altered its rheological properties. A model drug (hydrocortisone) was incorporated at 78% of its theoretical yield within the dried Alg-Ca containing 5% GB and it was gradually released from the beads in JP XIV 1st medium for disintegration test (pH 1.2), while it was rapidly released with disintegration of the gel matrix in JP XIV 2nd medium (pH 6.8). In contrast, for Alg-Ca containing GB and chitosan, disintegration was not observed in these media and the drug release rate was markedly different. These results demonstrate that the release profiles of drugs incorporated into Alg-Ca can be controlled by adding these polysaccharides.

Properties of an alginate gel bead containing a chitosan-drug salt.

A calcium-induced alginate gel bead (Alg-CS) containing chitosan (CS) and 2-(4-chlorophenoxy)-2-methylpropionic acid (CMP) was prepared. We then investigated (a) CMP release from Alg-CS, and (b) uptake of bile acid into the Alg-CS, within the gastrointestinal tract. Dried Alg-CS gradually swelled in taurocholate solution, while releasing CMP and taking up bile acid. The amount of bile acid taken up into the Alg-CS increased incrementally according to the degree of deacetylation of CS. Furthermore, the molecular weight of CS also affected the properties of the Alg-CS. An approximately linear relationship was observed between CMP release and bile acid uptake of Alg-CS.

Drug release properties of a gel bead prepared with pectin and hydrolysate.

A calcium-induced pectin gel bead (PB) containing pectin hydrolysate was prepared, and the drug release profiles and degradation properties of the PB were investigated in aqueous media. The stiff PB swelled in physiological saline and its drug release rate decreased with exposure to increasing concentrations of CaCl2 during preparation. And erosion of the PB was not observed in physiological saline. However, the PB did disintegrate in phosphate buffer (pH 6.8) and the rate of disintegration depended on the calcium chloride concentration used to prepare the PB. In addition, the drug release rate of the PB in buffer solution decreased as the rate of gel erosion declined. Consequently, it appears that the PB gel matrix is an effective medium by which to control the release of drug within the gastrointestinal tract.

Preparation of floating alginate gel beads for drug delivery to the gastric mucosa.

Alginate gel beads containing ethylcellulose (ALECs) were prepared and investigated with regard to buoyancy, in vitro and in vivo drug release profiles, and drug targeting specificity in the gastric mucosa. When the ethylcellulose (EC) content of ALECs containing metronidazole (MZ) was higher than 3%, the beads floated in all test solutions with a specific gravity of approx. 1.01. ALECs containing 5% EC released MZ gradually and floated throughout the experimental period in simulated gastric juice (pH 1.2), and all of the drug had been released after 90 min. When we orally administered ALECs to guinea pigs, about 85% of the incorporated MZ was released at 1 h. The MZ concentration of the gastric mucosa after administration of ALECs was greater than that observed with administration of MZ solution, despite lower serum concentrations. Furthermore, the similar data were obtained for ALECs with 7% EC. These results suggest that ALECs may become a practical vehicle for delivering drugs to the gastric mucosa.