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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&ndash, 35 &mu, m. 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.

Recently, potential applications for β-chitosan (β-CS) have been examined. In the present study, calcium-induced alginate gel beads (Alg-Ca) containing weak acid salts of β-CS were prepared and examined with regard to their ability to adsorb bile acids in vitro. More than 70% of taurocholate dissolved in solution was taken up by Alg-Ca containing 100 mg β-CS, sim. ilar to the degree of uptake observed with Alg-Ca containing α-CS salt. The adsorption of bile acid was affected by the absolute amount of β-CS and/or the acid concentration of the preparation. A secondary bile acid, taurodeoxycholate, was also adsorbed by Alg-Ca containing weak acid salts of β-CS. Therefore, β-CS might be used to adsorb bile acids within the gastrointestinal tract in the same manner as an anion-exchange resin, and thus serve as a complementary means by which to prevent hyperlipidemia.

Alginic acid (Alg) is a natural anionic polysaccharide, which consists of α-L-guluronic acid (G) and β-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.

Film dosage forms (FDs) containing miconazole (MCZ) for the treatment of oral candidiasis were prepared using water-soluble polysaccharides, and the dissolution profiles of MCZ from the FDs were investigated. In addition, the forms were modified by the addition of a surface active agent to accelerate the drug dissolution rate. Circular films incorporating MCZ were obtained using each polysaccharide. Most FDs were easy to handle and resistant to tearing. No diffraction peaks were observed in the X-ray diffractograms of FDs. FDs prepared with sodium alginate or pullulan immediately swelled and disintegrated in aqueous medium, whereas MCZ incorporated in the FD gradually dissolved. A marked acceleration in the MCZ dissolution rate was observed when FD was prepared with polysaccharide containing a surfactant. These results confirmed that modified FDs are useful for treating localized conditions in the oral cavity, such as oral candidiasis, and that FDs can simplify the administration of drugs to patients.

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.

β-Glucans extracted from barley, which mainly contains β-(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 β-glucan was examined to assess potential new benefits associated with β-glucan, because oxidative stress is considered one of the primary causal factors for various diseases and aging. β-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 β-glucan, which varied depending on the source and extraction method used. The antioxidant activity of β-glucan was significantly higher than that of various polymers that are used as food additives. These results indicate that β-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.

Oral dissolving gelatin beads (GBs) containing allopurinol (AP) were prepared by the seamless capsule method and their rheological properties were examined. The release profiles of both gelatin and AP from GBs were also investigated in limited dissolution medium. GBs containing AP provided an easy-to-handle dosage form, but the physical strength of the beads immediately decreased upon contact with physiological saline at 37℃. Gelatin was released from the outer layer of GBs in physiological saline, with almost all the gelatin dissolved after 5 min, together with approximately 30% of the AP contained in the inner layer of the GB. The oral administration of GBs likely results in immediate softening of the GB upon contact with saliva. The released AP acts directly at inflammation sites, in a manner similar following oral rinsing with an AP suspension. Therefore, GBs are a useful dosage form for preventing or treating localized problems in the oral cavity, such as mucositis.

We investigated preparation of film dosage form (FD) from natural polysaccharides using the casting method without organic solvents, heating or pH control. Ferulic acid (FA) and catechin were employed as model compounds incorporated in the FD, and the release profile of each compound from the form was investigated in the limited medium. Film formation was affected by the addition of the model compound to the polysaccharide solution. Rigid FD was obtained with 2% low-molecular-weight alginate (L-ALG; thickness, 65 µm), and it hardened after the addition of 0.5% polygalacturonic acid, although the thickness of the film did not change. The FDs immediately released the model compound, and the forms dissolved in phosphate-buffered saline. FD modification did not affect the FA release rate except in the early stage. FD would be a useful dosage form, especially for preventing or treating localized problems in the oral cavity.

A transparent wound dressing sheet was obtained by forming a complex between β-glucan and chitosan (CS). These materials were chosen for their biocompatible, bioabsorbable, and biodegradable properties, and they were expected to promote the therapeutic efficacy of the dressing by increasing the wound healing response. The therapeutic efficacy of the β-glucan–CS complex sheet as a wound dressing was evaluated in wounds created on the dorsal surfaces of mice. β-glucan–CS complex sheets demonstrated therapeutic efficacies comparable or superior to that of Beschitin®W, a commercial wound dressing made from CS. Additionally, the β-glucan–CS complex sheet did not dissolve during the application period, did not adhere to wounds, and was easy to remove. Cumulatively, these results indicate that β-glucan–CS complex sheets are a promising new wound dressing product.

A chitosan (CS)-ferulic acid (FA) salt was prepared. FA release from CS-FA and bile acid (BA) adsorption by CS-FA were investigated in vitro. CS-FA released FA into artificial gastric juice or a medium containing BA. Two functions were recognized on alginate or pectin gel beads containing CS-FA: FA release and BA adsorption. Anti-hypertensive effects of CS, FA or CS-FA on hypertensive rats were tested. In rats given a diet containing CS-FA or FA, elevation of systolic blood pressure was suppressed compared to the control diet group, but no difference in food intake or body weight was observed between groups.

Alpha-lipoic acid (ALA) is an essential cofactor for mitochondrial multi-enzyme complexes related to energy production. However, it is unstable under light and heat and its biological half-life ( t 1/2 ) is short. In this study, ALA was incorporated into alginic acid (Alg) gel beads to achieve stabilisation and sustained release. The cationic polymer chitosan (CS) was also added to the Alg gel beads to better control ALA release. In artificial gastric juice (pH 1.2), ALA release from the Alg gel beads was controlled through simple diffusion from the gel matrix. However, in artificial intestinal juice (pH 6.8), the Alg gel beads were immediately disintegrated. On the other hand, Alg gel beads with CS were not disintegrated in artificial intestinal juice (pH 6.8), and achieved pH-independent sustained release of ALA through an electrostatic interaction between the carboxyl groups of Alg and the amino groups of CS. ALA contained within the Alg gel beads was protected from light (UV) and heat (65 °C) compared with ALA alone. Addition of CS to the Alg gel beads further increased the stability of ALA. Thus, stabilisation and controlled release of ALA was achieved through incorporation of ALA in Alg gel beads containing CS.

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.

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.

Crystallinity of poly(ɛ- l -lysine) (ɛ-PL) was discussed by analyzing the differences in the 1H spin–spin relaxation times (T2H), the 13C spin-lattice relaxation times (T1C), and the 13C NMR signal shapes between the crystalline and the non-crystalline phases. The observed 1H relaxation curve (free induction decay followed by solid-echo method) showed the sum of Gaussian and exponential decays. Similarly, the observed 13C relaxation curves obtained from the Torchia method were double-exponential. The 13C NMR spectrum of ɛ-PL was divided into the narrow and the broad lines by utilizing the intrinsic differences in the 1H spin-lattice relaxation times in the rotating-frame between them, which are attributed to the crystalline and the non-crystalline phases, respectively. Even though the crystallinity is obtained from the identical NMR measurements, the estimated values are different with each other. The crystallinity estimated from the T2H differences was 75.8 ± 0.1% at 333 K and 60.7 ± 0.4% at 353 K. From the T1C differences, the value was estimated to be 62 ± 11%. Furthermore, the value estimated from the NMR signal separation was 54 ± 5%. In this study we have explained these discrepancies by the difference in susceptibility among the experiments for the inter-phase, which exists in-between the crystalline and the amorphous phases. Furthermore, the estimated crystallinity was ascertained by the X-ray diffraction experiment.

The relation between crystallinity and miscibility of semicrystalline polymer blends of poly(vinyl isobutyl ether) (PVIBE) and poly(e-L-lysine) (e-PL) is investigated by 13C cross-polarization with magic-angle-spinning (CPMAS) NMR (nuclear magnetic resonance) and DSC measurements. Analysis of the 1H spin-lattice relaxation curves observed from both PVIBE and e-PL signals, which are indirectly obtained from well-resolved 13C CPMAS NMR spectra, suggested that the domains of e-PL in the blends are in the range of 50–100 nm scale. Two-spin or three-spin models were used to simulate the 1H relaxation curves taking into account the contribution of a 1H spin-diffusion rate between PVIBE and e-PL. Furthermore, it was found that blending e-PL largely influences the crystallinity of PVIBE but that of e-PL is little affected by blending PVIBE except for 10/1 composition. The observed melting point of e-PL shifted towards lower temperature accompanied by PVIBE content. This shift was explained by the Gibbs-Thomson effect that the decrease of thickness of crystalline phase causes the depression of the melting point.

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.

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.

In order to select an ideal chitosan (CS) species as a material for implantation vehicle to control drug release in the body, the relationship between physicochemical characteristics (including molecular weight, degree of deacetylation, and viscosity) and functional properties (including ability to form spherical gel, control of drug release from CS gel, and biodegradation of CS) was investigated for various CS. The ease of spherical gel formation in aqueous amino acid solution or aqueous solution containing metal ions was affected mainly by viscosity of the CS solution. Drug diffusion rate from the CS gel was controlled by density of the gel matrix structure, which was governed by viscosity of the CS solution prior to gelation. Biodegradation of CS tended to vary with degree of deacetylation. However, linear relationships for these trends were not observed, and the possibility that characteristics other than CS molecular weight, degree of deacetylation, and viscosity of the CS solution, such as distribution of acetamide groups in the CS molecule affect functional properties of CS, was also indicated. These observations demonstrate that CS functions are affected by various CS characteristics and that investigation of individual CS characteristics is important for the selection of the appropriate CS as a material for drug delivery vehicles.

A calcium-induced pectin gel bead (PB) containing pectin hydrolysate and/or chitosan (CS) was prepared, after which the relationship between erosion of the PB and drug release from the PB in artificial gastrointestinal juice was investigated. The PB gradually disintegrated in gastric fluid, and the rate of erosion of the PB was changed by modification of the gel matrix. The amount of calcium ion used to make the PB had little effect on drug release; however, adding CS to the PB markedly suppressed drug release in intestinal fluid. © 2005 Wiley Periodicals, Inc. Adv Polym Techn 24:46–50, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/adv.20029

In order to develop an implantable vehicle for enhanced control of drug release into the body, chitosan (CS) microparticles were prepared where CS was chelated by a metal ion using the emulsion coalescence technique. Aqueous solutions of CS and metal ion were separately emulsified in vegetable oil containing lecithin. After both the water-in-oil (w/o) emulsions were mixed and stirred, CS microparticles were formed as a result of gelation due to contact between the aqueous droplets of CS and metal ion. The CS microparticle formation was influenced by the stability of both the w/o emulsions, which was dependent on the w/o ratio, the lecithin concentration in vegetable oil, and the CS types (i.e., viscosity of the CS solution prior to emulsification). These CS microparticles are expected to be useful vehicles for clinical applications, because they are prepared using only biocompatible materials and reagents.

The model anti-inflammatory drug prednisolone (PS) was retained in chitosan (CS) gel beads, which were prepared in a 10% aqueous amino acid solution (pH 9.0). Sustained release of PS from the CS gel beads was observed. Carrageenan solution was injected into air pouches (AP), which were prepared subcutaneously on the dorsal surface of mice, in order to induce local inflammation. CS gel beads retaining PS were then implanted into the AP to investigate the therapeutic efficacy of sustained PS release against local inflammation. In vivo PS release from CS gel beads was governed by both diffusion of the drug and degradation of the gel matrix. Sustained drug release by CS gel beads allowed the supply of the minimum effective dose and facilitated prolonged periods of local drug presence. Inflammation indexes were significantly reduced after implantation of CS gel beads when compared with injection of PS suspension. Thus, extension of the duration of drug activity by CS gel beads resulted in improved therapeutic efficacy. These observations indicate that CS gel beads are a promising biocompatible and biodegradable vehicle for treatment of local inflammation.

A chitosan (CS)-orotic acid salt (CS-OT) was prepared, and the release of orotic acid (OT) from CS-OT as well as the adsorption of bile acids by CS-OT was investigated in vitro. The amount of OT released from CS-OT was about 2-2.7 micromol/mg CS-OT and this changed depending on the species of CS. CS-OT also adsorbed bile acids and the amount increased incrementally according to the number of amino group contained in CS. Furthermore, CS-OT was given to rats as feed in order to investigate the influence on serum cholesterol levels. A decrease in serum cholesterol levels was observed in the group, which was fed a diet containing CS-OT or CS for 1-2 weeks, but no differences in body weight changes were recognized. Therefore, CS-OT may be applied to treating hyperlipidemia.

Chitosan (CS) gel beads were prepared in 10% amino acid solution (pH 9) and modified by forming an electrostatic complex between the amino group of CS and the carboxyl group of chondroitin sulfate (Cho). Modification of the CS gel matrix by Cho inhibited the in vitro release of prednisolone (PS) from the gel beads. CS gel beads modified by Cho (CS-Cho) were implanted into air pouches (AP) prepared subcutaneously on the dorsal surfaces of mice. No inflammatory response was observed. The in vivo release of PS from CS-Cho gel beads and their biodegradation in the AP was slower than beads without Cho treatment. After 28 days of implantation, CS-Cho gel beads (deacetylation of CS: 90%) were still detectable, although they had become softer and smaller. Modification of the CS gel matrix by Cho controls the biodegradation of the beads and the release of the drug. This effect makes these beads a promising biocompatible and biodegradable vehicle for sustained drug delivery.

Chitosan (CS) gel beads were prepared in 10% amino acid solution (pH 9) and implanted into air pouches (AP) prepared subcutaneously on the dorsal surface of mice. No inflammatory response was observed, and degradation of the beads in the AP increased as their degree of deacetylation decreased. Degradation could be altered by changing the nature of the CS or by increasing the CS concentration. The release of prednisolone (PS) in vivo from CS gel beads was similar to the release in vitro. When a suspension of PS was injected into the AP, the PS had almost completely disappeared 24 h after injection. Retention of PS in the AP was not increased by using a viscous CS solution. Alginate (Alg) gel beads, which were not degraded, released PS slowly into the AP over 3d. The in vitro release profile of PS using 1% CS (deacetylation: 70% (7B) and 80% (8B)) and 1.5% CS (deacetylation: 90% (9B)) gel beads was similar to that with Alg gel beads. However, the in vivo release of PS was affected by the degradability of the gel beads. CS7B and 8B (1%) gel beads had released PS into the AP earlier than 3 d according to their rate of degradation. CS9B (1.5%) gel beads were not degraded after 3 d and went on to release PS into the AP for 3 d similar to the release profile of Alg gel beads. CS9B (2%) gel beads were also not degraded after 3 d and the release of PS from these beads into the AP was sustained; 76% and 27% of administered PS remained in the gel beads after 1 and 3 d, respectively. Therefore, degradation and drug release of CS gel beads can be controlled by changing the structure of the gel matrix, which appears to make these beads a promising biodegradable vehicle for sustained drug delivery.

Two types of alginate gel beads capable of floating in the gastric cavity were prepared. The first, alginate gel bead containing vegetable oil (ALGO), is a hydrogel bead and its buoyancy is attributable to vegetable oil held in the alginate gel matrix. The model drug, metronidazole (MZ), contained in ALGO was released gradually into artificial gastric juice, the release rate being inversely related to the percentage of oil. The second, alginate gel bead containing chitosan (ALCS), is a dried gel bead with dispersed chitosan in the matrix. The drug-release profile was not affected by the kind of chitosan contained in ALCS. When ALCS containing MZ was administered orally to guinea pigs, it floated on the gastric juice and released the drug into the stomach. Furthermore, the concentration of MZ at the gastric mucosa after administration of ALCS was higher than that in the solution, though the MZ serum concentration was the same regardless of which type of gel was administered. These release properties of alginate gels are applicable not only for sustained release of drugs but also for targeting the gastric mucosa.

Calcium-induced alginate gel beads containing chitosan salt (Alg-CS) was prepared using nicotinic acid (NA), a drug for hyperlipidemia, and investigated its two functions in gastrointestinal tract, (a) NA release from Alg-CS, (b) uptake of bile acids into Alg-CS. The amount of NA incorporated in Alg-CS increased according to increment of CS content. NA was rapidly released from Alg-CS in diluted HCl solution (pH 1.2) or physiological saline without disintegration of the beads. When Alg-CS was placed in bile acid solution it took bile acid into itself. About 80% of taurocholic acid dissolved in the medium was taken into Alg-CS. According to increment of bile acid concentration, the uptake amount increased and an approximately linear relationship existed among them.

Alginate gel bead containing chitosan salt was prepared and the function was investigated. When the bead was placed in bile acid solution it rapidly took bile acid into itself. The uptake amount of taurocholate was about 25 μmol per 0.2 g dried gel beads. This phenomenon was observed on the case of the beads incorporating colestyramine instead of chitosan. Therefore, it seems that the ion-exchange reaction accompanying the insoluble complex-formation between chitosan salt and bile acid occurs in calcium alginate gel matrix.

Control of drug release from alginate gel beads by application of a complex formed between chondroitin sulfate and chitosan was investigated. The complex suppressed the disintegration of the gel beads, and the release pattern of diclofenac incorporated within them was obviously changed. Although prolongation of the preparation time gradually decreased the apparent release rate, the pattern of release was not markedly affected. Release of the drug from the gel beads was also influenced by the types of chitosan employed or the properties of the drug itself.

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.

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.

キトサンにより崩壊を抑制されたアルギン酸ゲルビーズに関し, さらにヒアルロン酸の添加による含有薬物放出に対する影響を検討した. 高分子量アルギン酸ゲルの燐酸緩衝液(pH6.8)中における崩壊は穏やかに進行し, ヒアルロン酸添加効果は, モデル薬物ジクロフェナクの放出では観察されなかった. 一方, 低分子量(特にグルロン酸含有量の多い)のものより調製されたゲルは急速に崩壊しながら薬物を放出するが, その崩壊はヒアルロン酸添加により明らかに抑制され, また, 含有薬物の徐放化が認められた. なお, この効果はプルランなどの添加ではまったく観察されなかった.

Chitosan-reinforced alginate gel beads were prepared and the release patterns of coloring matter (Brilliant Blue G, BB) held within them were investigated. The release rates of BB from the gel beads were much slower after an initial lag time when they were incubated with chitosan compared with the original intact gels prepared without chitosan. These differences were observed irrespective of the β- d -mannuronic acid/α- l -guluronic acid (M/G) ratio of the alginate used and an additive effect on the release rate was observed when two species of alginates were combined. The initial release rates were reduced gradually in proportion to the increases in the chitosan concentration and/or incubation times used when preparing the gel beads. Furthermore, erosion of the gel beads was suppressed by chitosan treatment. The release of phenytoin from alginate gel beads showed the same characteristics as that of BB.

The relationship between the release of a dye (Brilliant Blue; BB) incorporated in calcium-induced alginate gels and the erosion of the gel itself was investigated. The release rate of BB from gel formed from low-molecular-weight alginate was faster than that from high-molecular-weight alginate, and the erosion of the gel was also faster in the former case. As the alginate concentration in the gel was increased, the release of both BB and alginate from the gel was controlled. No remarkable differences in the release of BB were found among two kinds of gel formed from alginates with different monomeric composition. Furthermore, some gels formed from high-molecular-weight alginate also decayed in aqueous media containing sufficient levels of univalent cations. It was confirmed that the erosion of gels accelerates the rate of BB release from them.

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.

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.

In the hospital pharmacy, the analysis of the ingredients in a mixed powder and the codeless tablets or capsules is important pharmaceutical service, but the complete analysis is currently almost impossible because a drug in the mixture is mainly deduced from its characteristic odor or taste and/or color. In this article, the application of X-ray powder diffractometry to the analysis of the ingredients was studied.Each ingredient was identified by comparing the intensity and number of the diffraction peaks with those of the standard substances. The ingredients in the mixture were determined successively by subtracting the peaks of the identified ingredient from the whole peaks of the mixture. For the purpose of this diffractometric analysis, four data bases such as the powder of organic medicines, the granule of organic medicines and the pulverized tablet and capsule were newly constructed.Since these data bases identify the whole peaks pattern of the preparation containing many constituents as a pattern of a certain drug, each drug, even in the complicated mixed powder containing granules (and/or fine granules) and tablets (and/or capsules) pulverized, could be easily analyzed. However, in the complicated mixture containing fine granules or granules, the concentration of the ingredients was necessary to raise analytic precision for this diffractometry. Each ingredient in the mixture could be qualitatively determined by the combined use of these data bases and the rough sieving through No 30 and 80 screens.It proved that the ingredients of codeless tablets or capsules were identified by using these data bases.In conclusion, the results presented suggests that this X-ray powder diffractometry can be applied to the routine DI and dispensing services in hospital pharmacy.

Chitosan (CS) forms a gel in solutions with a pH above 12, and the gelation occurs at pH of about 9 in 10% amino acid solutions. In this paper, we investigated the enzymatic degradation and the drug release profile of this novel CS gel beads. The degradability of the CS gel beads was affected by the CS properties, e.g. the degree of deacetylation. The release of prednisolone (PS), as a model drug, from the CS gel beads was sustained significantly compared with the gel prepared with NaOH only. However, the release was not able to be sustained by the increment of NaOH concentration in the solution employed for the preparation of CS gel beads. We also investigated the control of drug release from CS gel beads by application of a complex formed between chondroitin sulfate (Cho) and CS. The release of PS from the CS gel beads treated with Cho was prolonged, and the release pattern was not affected by the treatment time. The time to 50% drug release was about 5 min with PS powder, about 200 min in CS gel beads with 10% glycine (Gly) (pH 9.0), and about 330 min in the CS gel beads with 10% Gly (pH 9.0) treated with Cho. Thus CS gel beads appear promising as a vehicle for sustained drug delivery, and the degradation of CS gel beads may be controlled by the degree of deacetylation of CS.

Calcium-induced alginate-phosphate composite gel beads were prepared, and model drug release profiles were investigated in vitro. The formation of calcium phosphate in the alginate gel matrix was observed and did not affect the rheological properties of the hydrogel beads. X-ray diffraction patterns showed that the calcium phosphate does not exist in crystalline form in the matrix. The initial release amount and release rate of a water-soluble drug, diclofenac, from the alginate gel beads could be controlled by modifying the composition of the matrix with calcium phosphate. In contrast, the release profile was not affected by the modification for hydrocortisone, a drug only slightly soluble in water.