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Colon-specific drug delivery using ethylcellulose and chitosan in the coat of compression-coated tablets
Drug Development and Industrial Pharmacy
Abstract
This study investigates a new means to achieve colon-specific drug delivery.
This study assesses the use of chitosan and ethylcellulose in the coat of a compression-coated tablet to achieve colon-specific drug delivery. The effects of chitosan type and its level as well as the coat thickness were evaluated.
Caffeine-containing core tablets were prepared by direct compression. Three chitosan samples with different molecular weight and degree of deacetylation were used. Direct compression produced the finished coated tablet. The product was tested for its potential in colon-specific drug delivery by conducting release studies in simulated gastric and intestinal fluids. Enzymes harvested from rat cecal and colonic contents contributed to a medium to study drug release under colonic conditions.
Essentially no drug was released until action on the tablet by either the acidic pH or the presence of enzymes in the release medium. Chitosan type had no effect on drug release as long as the coating level was the same. Lowering the chitosan level in the coat or increasing the coat thickness increased the lag time.
The type of chitosan can be changed and yet the product is still susceptible to enzyme or pH effects. This indicates that chitosan present in the coat is still available for such action by the release medium. One can control the chitosan level or the thickness of the coat to achieve a desired delivery profile.
As colonic media can dramatically promote drug release, the potential for colon-specific drug delivery is confirmed.
... Coatings of chitosan can facilitate organ-or tissue-specific drug delivery. Omwancha et al. achieved a colon-specific drug delivery by coating caffeine-containing core tablets with chitosan and ethylcellulose using a direct compression method [38]. Core tablets of 200 mg were prepared by 2000 psi compression of the powder blend consisting of 50% caffeine as the model drug, 48% Avicel as the diluent and 2% magnesium stearate as the lubricant, using a 5/16" flat-faced circular punch and die set and a Korsch PH103 tablet press. ...
... The rapid release is undesired in colon specific delivery, which explains why the tablets were coated with ethylcellulose and chitosan to delay release. To assess the effect of particle size on drug release, chitosan (CH2) with a particle size of 105-125 μm was isolated [38]. The results of this study also revealed that including large particle sized chitosan further delayed drug release. ...
... The results of this study also revealed that including large particle sized chitosan further delayed drug release. Omwancha et al. hypothesize that this may be due to a more even distribution of the smaller chitosan particles in the coat, leading to relatively well-hydrated tablets that ruptured at an earlier time [38]. While the in vitro results are promising, in vivo, an enteric coating may also be necessary to achieve colon-specific delivery in order to prevent premature release in the stomach due to the acidic conditions or presence of endogenous gastric chitinase. ...
The natural biopolymer chitosan has versatile applications in therapeutic delivery. Coating drug delivery matrices or biomaterials with chitosan offers several advantages in drug delivery, including control of drug release, slowing degradation rate and improving biocompatibility. Advanced uses of chitosan in coating form include targeting drug delivery vehicles to specific tissue as well as providing a stimulus-controlled release response. The present review summarizes the current applications of chitosan coatings in the context of different biomaterial delivery technologies, as well as future directions of chitosan coatings for drug delivery technologies under development.
... [11]. Although the composition of human gut ecosystem may be altered by various factors [12], microbially triggered systems which are based on compression coating of an immediate release tablet with a biodegradable polysaccharide have been investigated extensively [13][14][15][16][17]. However, available literatures indicate that after a satisfactory lag period, the drugs from compression coated tablets are released in the colon in a sustained release manner rather than in a rapid pulse release fashion [13][14][15][16]. ...
... Although the composition of human gut ecosystem may be altered by various factors [12], microbially triggered systems which are based on compression coating of an immediate release tablet with a biodegradable polysaccharide have been investigated extensively [13][14][15][16][17]. However, available literatures indicate that after a satisfactory lag period, the drugs from compression coated tablets are released in the colon in a sustained release manner rather than in a rapid pulse release fashion [13][14][15][16]. ...
Objective: This work was undertaken to develop colon targeted tablets that can minimize premature release of ibuprofen (IBP) and metronidazole (MNZ) in a lag period of 7h during which the tablets are likely to remain in the upper gastro-intestinal tract, and produce rapid pulse release within 1-5 h after the lag period when the tablets could be located in the colon with or without intervention of colonic microflora. Methods: Core tablets of ibuprofen and metronidazole containing different amounts of tri-sodium citrate (TSC) as osmogen were compression coated with locust bean gum (LBG) and carboxymethyl LBG (CMLBG). In vitro drug release studies were performed in a dynamic pH shift condition with or without rat cecal matters. The release of the drugs were also monitored at different hydrodynamic conditions. Results: In vitro release studies revealed that increase in the amount of TSC, decrease in coat-weight and change in hydrodynamic conditions influenced the drug release considerably. While LBG coated tablets under the stated conditions failed to provide complete release of the drugs in 12 h, CMLBG coated tablets produced complete release rapidly in the post lag period minimizing the release in the initial 7 h. Presence of rat cecal matter in dissolution medium further accentuated the release of the drugs from CMLBG compression coated tablets in the post lag period. Conclusion: The study revealed that tablets containing appropriate amount of osmogen in the core and compression coated with suitable amount of CMLBG may be suitable for colon targeting of drugs even in the absence of colonic microflora.
... Although several polysaccharides such as guar gum, pectin, sodium alginate, locust bean gum, chitosan, boswellia gum, and xanthan gum have been used as compressioncoating material (16)(17)(18)(19)(20), carboxymethyl xanthan gum (CMXG), neither alone nor in combination with other polysaccharides, has been explored to assess its suitability for the development of compression-coated colon-targeted tablets. In a previous study, we evaluated Ca +2 ion cross-linked CMXG (Ca-CMXG) matrix tablets for colon delivery of prednisolone (PDL) (21). ...
... When CMXG is brought in contact with water, the interaction between many hydrophilic groups of CMXG and water leads to the formation of a viscous polymer solution around the tablet surface (21,39). Cross-linking of CMXG with Ca +2 ion further restricts the mobility of the polymer chain resulting in the formation of a true gel layer around the tablet surface (34) and reduces the macromolecular mess size (19). This in turn decreases the water penetration velocity through the coat (22). ...
This work was envisaged to develop compression-coated tablets using a blend of Ca(+2) ion cross-linked carboxymethyl xanthan gum (CMXG) and sodium alginate (SAL) for delayed release of immediate pulse release tablets of prednisolone (PDL) in the colon without the need of colonic bacterial intervention for degradation of the polysaccharide coat. The core tablets containing PDL and other compatible excipients were prepared by direct compression method and subsequently compression coated with different ratios of CMXG and SAL. Long T lag, the time required to restrict the drug release below 10%, and short T rap, the time required for immediate release following the T lag, were considered as suitable release parameters for evaluation of colon targeting of PDL tablets. Among the various compression coats, a blend of CMXG and SAL in a ratio of 1.5:3.5 provided T lag of 5.12 ± 0.09 h and T rap of 6.50 ± 0.05 h. The increase in microcrystalline cellulose (MCC) and crospovidone (CP) in the core tablets did not change T lag significantly although decreased the T rap marginally. Inclusion of an osmogen in the core tablets decreased the T lag to 4.05 ± 0.08 h and T rap to 3.56 ± 0.06 h. The increase in coat weight to 225 mg provided a reasonably long T lag (6.06 ± 0.09 h) and short T rap (4.36 ± 0.20 h). Drug release from most of the formulations followed the Hixson-Crowell equation and sigmoidal pattern as confirmed by the Weibull equation. In conclusion, tablets, compression coated with CMXG and SAL in a ratio of 1.5:3.5 and having 225-mg coat weight, were apparently found suitable for colon targeting.
... The use of xanthan gum and guar gum in combination as coat has also been demonstrated where the tablet does not release the drug until it reaches colon [25]. Polysaccharides like Chitosan [26,27] aliginates [28], amylose [29][30][31], locust bean gum [32,33] have also been used as compression coat polymers to achieve colon-specific drug delivery. However, there are limited reports on press-coated tablets using natural polysaccharides for potential applications in prophylaxis of colorectal cancer. ...
Background
We report the effectiveness of a targeted delivery system containing Meloxicam using polysaccharides for the treatment of colorectal cancer. We also propose a novel biorelevant dissolution method to overcome drawbacks of existing dissolution methodologies of polysaccharide-based systems. The proposed method includes a mixture of probiotics cultured under anaerobic conditions in presence of prebiotic in the in vitro dissolution study to surrogate colonic conditions. Polysaccharide-based system can be simple, safe and effective drug delivery system to target drugs to colon.
Methods
Press-coated tablets of Meloxicam were prepared by direct compression using various polysaccharides such as xanthan gum, guar gum and pectin as coating polysaccharides. Developed tablets were evaluated for physical parameters, lag phase and in vitro drug release. Developed probiotics-based dissolution method was validated and explored for versatility using other polysaccharides.
Results
Press-coated tablets of Meloxicam were successfully developed exhibiting targeted delivery to the colon using guar gum as coat and releasing more than 80% of drug in simulated colonic fluid. The developed probiotics based dissolution method may prove to be useful as a bio-relevant and discriminatory method.
Conclusion
Developed Meloxicam tablets press-coated with guar gum can be taken orally for treatment or as an adjuvant therapy in colon cancer. Polymers used in this formulation are abundant, nontoxic, biodegradable and inexpensive which make this as a very promising approach for treatment of different colonic diseases. The proposed biorelevant, animal sparing, probiotics based dissolution medium was found versatile to study drug release from other polysaccharide based formulations for colonic delivery.
... Several polysaccharides such as guar gum, locust bean gum, chitosan, boswellia gum, sodium alginate, either alone or in combination with other polymers have been used to develop compression coated tablets for colon targeted drug release [1][2][3][4][5]. A compression coated tablet is formulated by compression coating of an immediate release tablet with polysaccharides that are resistant to the pancreatic enzymes of the upper gastro-intestinal tract (g.i.t.) but are degraded by the enzymes secreted by the colonic microflora. ...
Tablets, compression coated with certain polysaccharides and intended for colon delivery, retain the integrity of the coat for an initial period of about 6 h (lag period) beyond which (post-lag period) the coat is degraded by colonic enzymes to induce drug release. This work was undertaken to investigate the factors which influence the integrity of the coat during the lag period. Core tablets containing two model drugs were compression coated with various amounts of carboxymethyl locust bean gum (CMLBG). In-vitro release of drugs, erosion of coat, and steady shear viscosity of CMLBG solutions having different concentrations and solution pH were determined. The viscosity of CMLBG that depended primarily on CMLBG concentration and partly on solution pH was responsible for erosion and integrity of the coat in the lag period. Evaluation of polymer viscosity could describe the integrity of coat of a polysaccharide coated tablet in the lag period.
... Treatment of IBD is minimal, but some drugs can reduce the severity of inflammation, increase the duration of remission, and reduce the risk of more serious health problems, such as colorectal cancer. Years of research have demonstrated the suitability of the colon as an absorption site, especially in GI diseases [79]. Conventional drug-delivery systems rely primarily on several nonstable parameters in the gastrointestinal tract, such as changes in pH and local enzyme-induced drug release. ...
Inflammatory bowel disease (IBD) is a common disease characterized by chronic inflammation in gastrointestinal tracts, which is primarily treated by administering anti-inflammatory and immunosuppressive drugs that inhibit the burden of intestinal inflammation and improve disease-related symptoms. However, the established therapeutic strategy has limited therapeutic efficacy and adverse drug reactions. Therefore, new disease-targeting drug-delivery strategies to develop more effective treatments are urgent. This review provides an overview of the drug-targeting strategies that can be used to treat IBD, and our recent attempts on the colon-specific delivery system (Pae-SME-CSC) with a paeonol-loaded self-microemulsion (Pae-SMEDDS) are introduced.
... This kind of drug release mechanism has been reported in numerous studies. 13,28 CTNase hydrolyzes partially acetylated CTN, in which the reducing-and nonreducing-end residues are N-acetyl-glucosamine (GlcNAc) and glucosamine (GlcN), respectively, resulting in the endohydrolysis of β-1,4-glycosidic linkage GlcNAc-GlcN in addition to GlcN-GlcN. 29 When CTN-polymer conjugates were incubated with CTNase for 1 hour, complete hydrolysis of CTN into monomers, dimers, and oligomers was accomplished. ...
A double layer-coated colon-specific drug delivery system (DL-CDDS) was developed, which consisted of chitosan (CTN) based polymeric subcoating of the core tablet containing citric acid for microclimate acidification, followed by an enteric coating. The polymeric composition ratio of Eudragit E100 and ethyl cellulose and amount of subcoating were optimized using a two-level factorial design method. Drug-release characteristics in terms of dissolution efficiency and controlled-release duration were evaluated in various dissolution media, such as simulated colonic fluid in the presence or absence of CTNase. Microflora activation and a stepwise mechanism for drug release were postulated. Consequently, the optimized DL-CDDS showed drug release in a controlled manner by inhibiting drug release in the stomach and intestine, but releasing the drug gradually in the colon (approximately 40% at 10 hours and 92% at 24 hours in CTNase-supplemented simulated colonic fluid), indicating its feasibility as a novel platform for CDD.
... Chitosan is a biocompatible polymer which is generally regarded as a nontoxic and non-irritant material [17]. It is used in cosmetics preparations and has also been investigated for use in a number of pharmaceutical formulations including colonic drug delivery device [30][31][32][33][34][35]. Chitosan dissolves in the acidic pH of the stomach but swells at pH 6.8. ...
Natural polysaccharides are found in abundance, are inexpensive, safe and available in a variety of structures which can easily be modified chemically and biochemically. A number of natural gums and mucilages along with their chemically modified forms have been evaluated as controlled drug delivery devices. They are reported to be capable of providing the desired drug release profiles and in some cases, have shown comparable drug release properties with currently available sustained release products in the market. Colon specific drug delivery based on natural polysaccharides has highly been acclaimed in recent years. A colon specific drug delivery system should prevent drug release in the stomach as well as the small intestine. Several polysaccharides have been reported to be capable of preventing drug release in the upper GI tract while being susceptible to enzymatic degradation by colonic bacterial enzymes. A wide range of natural or modified polysaccharides has been investigated for peroral delivery of drugs to the colon. As the release of drug from these polysaccharides based systems is independent of pH and gastric emptying time these polysaccharides based systems are considered the most effective and preferable means for colonic drug delivery in terms of target specificity.
... It was also shown that resistance of the system to the simulated gastrointestinal media was reduced as the chitosan coating weight decreased [50]. Similarly, chitosan coating of the ethylcellulose compression coated tablet could provide a release profile appropriate for colon-specific drug delivery [51]. Additionally, chitosan-pectin complex and chitosan-chondroitin sulfate complex were investigated as carriers for colon targeted drug delivery [52,53]. ...
Solid oral modified-release dosage forms provide numerous advantages for drug delivery compared to dosage forms where the drugs are released and absorbed rapidly following ingestion. Natural polymers are of particular interest as drug carriers due to their good safety profile, biocompatibility, biodegradability, and rich sources. This review described the current applications of important natural polymers, such as chitosan, alginate, pectin, guar gum, and xanthan gum, in solid oral modified-release dosage forms. It was shown that natural polymers have been widely used to fabricate solid oral modified-release dosage forms such as matrix tablets, pellets and beads, and especially oral drug delivery systems such as gastroretentive and colon drug delivery systems. Moreover, chemical modifications could overcome the shortcomings associated with the use of natural polymers, and the combination of two or more polymers presented further advantages compared with that of single polymer. In conclusion, natural polymers and modified natural polymers have promising applications in solid oral modified-release dosage forms. However, commercial products based on them are still limited. To accelerate the application of natural polymers in commercial products, in vivo behavior of natural polymers-based solid oral modified-release dosage forms should be deeply investigated, and meanwhile quality of the natural polymers should be controlled strictly, and the influence of formulation and process parameters need to be understood intensively.
... It has recently been reported that the physicochemical properties of this gum exudate (13). Ethylcellulose, being hydrophobic in nature, does not readily allow water penetration across the coating and avoids premature film dissolution in the upper GI tract (14)(15). The main reason for selecting Albizia procera gum, an arabinogalactan, in this study was because of the known biodegradation of arabinogalactans in the colon by the colonic microflora since these microorganisms produce a wide range of enzymes including α-arabinosidase, β-galactosidase and so on. ...
The objective of the present research was to a develop colonic delivery system for budesonide based on polymer blends of natural polysaccharides from Albizia procera and the GI-insoluble polymer ethylcellulose. An emulsion solvent evaporation method was used for the preparation of the microspheres. In vitro drug
release was studied in a medium simulating gastrointestinal fluid and the mechanism of drug release was determined using the Korsemeyer-Peppas equation. In vivo performance of the microsphere was evaluated in acetic acid induced colitis in rats. Drug release studies showed that the microspheres with a procera gumethylcellulose coating were able to resist premature drug release in the upper GI tract and yet were susceptible
to enzyme effects in the colon. Treatment of rats with a budesonide test formulation for five days significantly attenuated the extent and severity of the cell damage and could thus be a promising system for the treatment of ulcerative colitis.
... It has been reported that the rat colon contains much the same microbial contents as the human colon (Hawksworth et al., 1971;Rowland et al., 1983) and that chitosan is indeed degraded by the enzyme systems found there (Zhang and Neau, 2002). In our previous study (Omwancha et al., 2011), these enzymes were used to evaluate the potential for colon-specific delivery by chitosan and ethylcellulose in the coat of a compression-coated tablet. The tablets swelled and ruptured to release the drug when exposed to a release medium with or without enzymes after a lag time that depended on the coat level. ...
A multiparticulate product for colon-specific delivery of a small molecule drug has been developed and characterized. Microcrystalline cellulose core beads containing 5-aminosalicylic acid produced by extrusion-spheronization were coated with chitosan and Aquacoat(®) ECD mixtures according to a factorial design. Coated beads were characterized in terms of drug release, shape, and friability. The optimum formulation was enteric coated and exposed to media simulating conditions in the stomach, small intestine, and colon. Release studies in simulated intestinal fluid revealed that the drug release rate from the coated beads, which were spherical and rugged, depended on the level of chitosan in the coat and the coat thickness. Enlarged pores observed on the surface of the coated beads exposed to the medium containing rat cecal and colonic enzymes are believed to have caused a significant enhancement of the drug release rate compared to the control exposed only to simulated gastric and intestinal fluids. The release mechanisms involved polymer relaxation and dissolved drug diffusion for simulated intestinal fluid and simulated colonic fluid, respectively. From the facilitated drug release in a colonic environment and the inhibition of drug release under gastric and intestinal conditions, it can be concluded that this multiparticulate system demonstrates the potential for colon-specific drug delivery.
... Caffeine Direct compression-CH and ethylcellulose used in the coat CH level or the thickness of the coat can be varied to achieve a desired delivery profile [120] CH--CS interpolymer complex 5-FU Compression coating technique using granulated CH The X-ray imaging gave rise to the in vivo selectivity of this system for colon targeting [121] CH--CS-based matrix tablets Budesonide Tablets prepared by using Avicel pH 102 as diluent and Eudragit Ò L-100-55 as binder were coated to a weight gain of 10% w/w employing aqueous mixtures containing CH and CS ...
Introduction:
There is an enormous growth and awareness of the potential applications of natural polymers for colon delivery of therapeutic bioactives. Chitosan (CH), a cationic polysaccharide, has a number of vital applications in the field of colon delivery and has attracted a great deal of attention from formulation scientists, academicians and environmentalists due to its unique properties.
Areas covered:
CH has been widely explored for the delivery of drugs, peptides, proteins and genes to the colon for different therapeutic applications. Sustained and controlled delivery can be achieved with CH-based formulations like CH-coated tablets, capsules, beads, gels, microparticles and nanoparticles. This review mainly focuses on various aspects of CH-based formulations, particularly development of colon-specific delivery of drug.
Expert opinion:
The vital properties of CH make it a versatile excipient, not only for sustained/controlled release applications but also as biodegradable, biocompatible, bioadhesive polymer. The colon is recognized as the preferred absorption site for orally administered protein and peptide drugs. The main problem associated with CH is limited solubility at higher pH due to reduced cationic nature, which also reduces mucoadhesiveness. The application of newer targeting moiety with CH-based formulations for highly site-specific delivery of bioactive has to be evaluated for further improvement of therapeutic index (bioavailability).
PurposeThe present study is concerned with the formulation of compression coated tablets of deflazacort. Research aimed to formulate a novel delivery system, based on chronomodulated approach for the management of rheumatoid arthritis, which is a chronic inflammatory disorder following a circadian pattern.Method
The formulation consisted of a fast disintegrating core tablet and compressed-coated layer of polymers that delayed the release of drug. The core tablets were prepared by directly compressing powder blend of drug substance, superdisintegrants, talc, magnesium stearate, and Avicel PH 101. In case of compressed-coated layer, three types of polymers (HPMC K4M, ethyl cellulose, and sodium alginate) were used to modify the release of drug from delivery system.ResultPreliminary batches were prepared to determine the effect of HPMC K4M, ethyl cellulose, and sodium alginate on lag time of the compression coated tablets. The effect of concentrations of polymers on lag time was studied for the optimization of formulation. Optimization of formulation was carried out by employing Box-Behnken Design using Design Expert 7.0. The lag time obtained from optimized batch was found to be 363.33±5.77 min. Thus, by means of an appropriate combination of excipients and suitable technique, it was possible to formulate a delivery system in which lag time followed by immediate release of drug was obtained.Conclusion
It was found that it is possible to formulate a chronotherapeutic delivery system in which the lag time and time-controlled release behavior of drug from compression-coated tablet could be modulated by varying the concentration of hydrophilic and hydrophobic polymers so that the release of drug could coordinate with the circadian pattern of disease.
Certain issues with the use of particles of chitosan (Ch) crosslinked with tripolyphosphate (TPP) in sustained release formulations include inefficient drug loading, burst drug release, and incomplete drug release. Acetaminophen was added to Ch:TPP particles to test for advantages to drug addition extragranularly over during crosslinking. The influences of chitosan concentration, Ch:TPP ratio, temperature, ionic strength, and pH were assessed. Design of experiments allowed identification of factors and two factor interactions that have significant effects on average particle size and size distribution, yield, zeta potential, and true density of the particles, as well as drug release from the directly compressed tablets. Statistical model equations directed production of a control batch that minimized Span, maximized Yield, and targeted a t50 of 90 min (Sample A); Sample B that differed by targeting a t50 of 240-300 min to provide sustained release; and Sample C that differed from Sample B by maximizing Span. Sample B provided its targeted t50 and maximized Yield, the smallest average particle size, with the higher zeta potential and the lower Span of samples B and C. Extragranular addition of drug to Ch:TPP particles achieved 100% drug loading, eliminated a burst drug release and can accomplish complete drug release.
Tritrichomonas foetus is a flagellated protozoan parasite that colonizes the feline colon causing colitis and chronic foul smelling diarrhea. Despite the efficacy of Ronidazole in the treatment of Tritrichomonas foetus, Ronidazole has been reported to cause neurotoxicity in some cats due to rapid absorption in the small intestine. A novel amphoteric derivative of chitosan was synthesised and characterized. A combination of time, pH, and an enzyme controlled system was used in a study of a new compression coated tablet for delivery of Ronidazole to the colon. Axial, radial swelling and erosion of selected tablets were carried out in various media. The effect of weight ratio, enzyme and pH on in vitro drug release profile was investigated. The results show that less than 2% of the drug was released in the physiological environment of the stomach and small intestine.
Investigate the potential of coated minispheres (SmPill®) to enhance localized Ciclosporin A (CsA) delivery to the colon.
CsA self-emulsifying drug delivery systems (SEDDS) were encapsulated into SmPill® minispheres. Varying degrees of coating thickness (low, medium and high) were applied using ethylcellulose and pectin (E:P) polymers. In vitro CsA release was evaluated in simulated gastric and intestinal media. Bioavailability of CsA in vivo following oral administration to pigs of SmPill® minispheres was compared to Neoral® po and Sandimmun® iv in a pig model. CsA concentrations in blood and intestinal tissue were determined by HPLC-UV.
In vitro CsA release from coated minispheres decreased with increasing coating thickness. A linear relationship was observed between in vitro CsA release and in vivo bioavailability (r(2) = 0.98). CsA concentrations in the proximal, transverse and distal colon were significantly higher following administration of SmPill®, compared to Neoral® po and Sandimmun® iv (p < 0.05). Analysis of transverse colon tissue subsections also revealed significantly higher CsA concentrations in the mucosa and submucosa using SmPill® minispheres (p < 0.05).
Modulating E:P coating thickness controls release of CsA from SmPill® minispheres. Coated minispheres limited CsA release in the small intestine and enhanced delivery and uptake in the colon. These findings demonstrate clinical advantages of an oral coated minisphere-enabled CsA formulation in the treatment of inflammatory conditions of the large intestine.
The present study was aimed at designing a microflora triggered colon-targeted drug delivery system (MCDDS) based on swellable polysaccharide, sterculia gum in combination with biodegradable polymers with a view to target azathioprine (AZA) in the colon for the treatment of IBD with reduced systemic toxicity. The microflora degradation study of gum was investigated in rat cecal medium. The polysaccharide tablet was coated to different film thicknesses with blends of chitosan/Eudragit RLPO and over coated with Eudragit L00 to provide acid and intestinal resistance. Swelling and drug release studies were carried out in simulated gastric fluid (SGF) (pH 1.2), simulated intestinal fluid (SIF) (pH 6.8) and simulated colonic fluid (SCF) (pH 7.4 under anaerobic environment), respectively. Drug release study in SCF revealed that swelling force of the gum could concurrently drive the drug out of the polysaccharide core due to the rupture of the chitosan/Eudragit coating in microflora-activated environment. Chitosan in the mixed film coat was found to be degraded by enzymatic action of the microflora in the colon. Release kinetic data revealed that, the optimized MCDDS was fitted well into first order model and apparent lag time was found to be 6 h, followed by Higuchi spherical matrix release. The degradation of chitosan was the rate-limiting factor for drug release in the colon. In-vivo study in rabbit shows delayed T(max), prolonged absorption time, decreased C(max) and absorption rate constant (K(a)) indicating reduced systemic toxicity of the drug as compared to other dosage forms.
Context:
Alginate-chitosan pellets prepared by extrusion-spheronization technique exhibited fast drug dissolution.
Objective:
This study aimed to design sustained-release alginate pellets through rapid in situ matrix coacervation by chitosan during dissolution.
Methods:
Pellets made of alginate with chitosan and/or calcium acetate were prepared using solvent-free melt pelletization technique which prevented reaction between processing materials during agglomeration and allowed such reaction to occur only in dissolution phase.
Results:
Drug release was retarded in pH 2.2 medium when pellets were formulated with calcium acetate or chitosan till a change in medium pH to 6.8. The sustained-release characteristics of calcium alginate pellets were attributed to pellet dispersion and rapid cross-linking by soluble Ca(2+) during dissolution. The slow drug release characteristics of alginate-chitosan pellets were attributed to polyelectrolyte complexation and pellet aggregation into swollen structures with reduced erosion. The drug release was, however, not retarded when both calcium acetate and chitosan coexisted in the same matrix as a result of chitosan shielding of Ca(2+) to initiate alginate cross-linkages and rapid in situ solvation of calcium acetate induced fast pellet dispersion and chitosan losses from matrix.
Conclusion:
Similar to calcium alginate pellets, alginate-chitosan pellets demonstrated sustained drug release property though via different mechanisms. Combination of alginate, chitosan and calcium acetate in the same matrix nevertheless failed to retard drug release via complementary drug release pattern.
Gastrointestinal (GI) pH has been measured in 66 normal subjects using a pH sensitive radiotelemetry capsule passing freely through the gastrointestinal tract. Signals were recorded with a portable solid state receiver and recording system, enabling unconstrained measurements with normal ambulatory activities for up to 48 h during normal GI transit. Capsule position in the gut was monitored by surface location using a directional detector. Gastric pH was highly acidic (range 1.0-2.5) in all subjects. The mean pH in the proximal small intestine was 6.6 (0.5) for the first hour of intestinal recording. By comparison the mean pH in the terminal ileum was 7.5 (0.4) (p less than 0.001). In all subjects there was a sharp fall in pH to a mean of 6.4 (0.4) (p less than 0.001) as the capsule passed into the caecum. Values are means (SD). pH then rose progressively from the right to the left colon with a final mean value of 7.0 (0.7) (p less than 0.001).
As part of a study of the metabolic activities of intestinal bacteria, the activity of the principal glycosidases produced by the major groups of intestinal bacteria has been estimated. The results are discussed in terms of the toxicological and pharmacological effects of various ingested glycosides and of the enterohepatic circulation of compounds by four laboratory animal species commonly used in toxicological studies.
Cecal contents of conventional and germfree rats were examined for glycosidases which may have a role in degrading glycoprotein oligosaccharides. Utilizing p-nitrophenylglycosides as substrates, we identified glycosidases in bacteria-free supernatants from cecal contents which act on β-linkages. These cecal glycosidases appear to be of bacterial origin since: (1) direct comparisons of the enzymes in similar contents from germfree rats showed negligible activities; (2) most of the glycosidase levels in bacterial extracts were at least as high as those of soluble supernatants; and (3) disk gel electrophoresis of contents and bacterial extracts revealed in both preparations a β-N-acetylglucosaminidase band with similarR
fs. Also, the blood group B antigenicity of germfree cecal glycoproteins was greatly decreased by conventional cecal contents. These findings indicate that β-galactosidase and β-N-acetylgalactosaminidase in cecal contents are bacterial in origin, and they may have a role in the bacterial catabolism of intestinal glycoproteins.
In this study, we report pectin-HPMC compression coated core tablets of 5-aminosalicylic acid (5-ASA) for colonic delivery. Each 100 mg core tablet contained 5-ASA and was compression coated at 20 kN or 30 kN using 100% pectin, 80% pectin-20% HPMC, or 60% pectin-40% HPMC, at two different coat weights as 400 or 500 mg. Drug dissolution/system erosion/degradation studies were carried out in pH 1.2 and 6.8 buffers using a pectinolytic enzyme. The system was designed based on the gastrointestinal transit time concept, under the assumption of colon arrival times of 6 h. It was found that pectin alone was not sufficient to protect the core tablets and HPMC addition was required to control the solubility of pectin. The optimum HPMC concentration was 20% and such system would protect the cores up to 6 h that corresponded to 25-35% erosion and after that under the influence of pectinase the system would degrade faster and delivering 5-ASA to the colon. The pectin-HPMC envelope was found to be a promising drug delivery system for those drugs to be delivered to the colon.
Two distinct chitinases have been identified in mammals: a phagocyte-specific enzyme named chitotriosidase and an acidic mammalian chitinase (AMCase) expressed in the lungs and gastrointestinal tract. Increased expression of both chitinases has been observed in different pathological conditions: chitotriosidase in lysosomal lipid storage disorders like Gaucher disease and AMCase in asthmatic lung disease. Recently, it was reported that AMCase activity is involved in the pathogenesis of asthma in an induced mouse model. Inhibition of chitinase activity was found to alleviate the inflammation-driven pathology. We studied the tissue-specific expression of both chitinases in mice and compared it to the situation in man. In both species AMCase is expressed in alveolar macrophages and in the gastrointestinal tract. In mice, chitotriosidase is expressed only in the gastrointestinal tract, the tongue, fore-stomach, and Paneth cells in the small intestine, whereas in man the enzyme is expressed exclusively by professional phagocytes. This species difference seems to be mediated by distinct promoter usage. In conclusion, the pattern of expression of chitinases in the lung differs between mouse and man. The implications for the development of anti-asthma drugs with chitinases as targets are discussed.
Chitin digestion by humans has generally been questioned or denied. Only recently chitinases have been found in several human tissues and their role has been associated with defense against parasite infections and to some allergic conditions. In this pilot study we tested the gastric juices of 25 Italian subjects on the artificial substrates 4-methylumbelliferyl-beta-D-N,N',diacetylchitobiose or/and fluorescein isothiocyanate (FITC) chitin to demonstrate the presence of a chitinase activity. Since this chitinase activity was demonstrated at acidic pH, it is currently referred to acidic mammalian chitinase (AMCase). AMCase activity was present in gastric juices of twenty of 25 Italian patients in a range of activity from 0.21 to 36.27 nmol/ml/h and from 8,881 to 1,254,782 fluorescence emission (CPS), according to the used methods. In the remaining five of 25 gastric juices, AMCase activity was almost absent in both assay methods. An allosamidine inhibition test and the measurement at different pH values confirmed that this activity was characteristic of AMCase. The absence of activity in 20% of the gastric juices may be a consequence of virtual absence of chitinous food in the Western diet.
Recently, there is increasing interest in the targeting of these drugs to the colon because of the low activity of proteolytic enzymes in the colon. Therefore, many dosage forms such as a time controlled-release dosage form and a pH-sensitive coating dosage form were examined for the specific drug delivery to the colon. However, these approaches have recently been shown to lack site specificity, since the variability of pH and small intestinal transit time of these dosage forms were observed. On the other hand, chitosan, which is one of the polysaccharides widely distributed in nature, is known to be specifically degraded by microorganisms distributed in the colon. In this study, therefore, we prepared chitosan capsules containing insulin and examined the effectiveness of these capsules to colon-specific delivery of insulin.The chitosan capsules containing CF or insulin were obtained from Aicello Chemical Co. Ltd (Toyohashi, Japan). The mean diameter and weight of these capsules were 3.5 x 1.6 mm and 1.2-1.5 mg, respectively. The surface of these capsules were coated with hydroxypropyl methylcellulose phthalate-4 and rosephthalate as enteric coating materials. The release studies of drug from the chitosan capsules were carried out using Japan Pharmacopoeia (J.P.) rotating basket method 6-Carboxyfluorescein (CF), which was encapsulated in the chitosan capsules was used as a water soluble model compound No release of CF from the capsules was observed in liquid 1 as an artificial gastric juice (pH 1) and liquid 2 as an artificial intestinal juice (pH 7). However, the release of CF was markedly increased in the presence of rat decal contents. These findings suggested that the chitosan capsules were degraded by the microorganisms in rat cecal contents. The effectiveness of the chitosan capsules to the colon specific delivery of insulin was investigated by an in vivo absorption experiment. A marked decrease in plasma glucose levels was observed following oral administration of these capsules containing 20 IU insulin and Na-glycodtolate, as compared with the capsules containing lactose or insulin only. In addition, the chitosan capsules containing insulin and Na-glycocholate were more effective for reducing the plasma glucose levels than the gelatin capsules containing the same components. Thus, this capsule may be a useful carrier for colon-specific delivery of peptides including insulin.
The viability of the compression coating technique for colon specific delivery of two model drugs: the low water soluble indomethacin and the highly water soluble insulin, using calcium pectinate as a drug carrier was examined in vitro and in vivo. The release of indomethacin from plain matrix and compression coated calcium pectinate tablets was measured in simulated gastric and intestinal fluids, followed by a buffer solution containing a mixture of pectinolytic enzymes. It was found that highly compressed matrices, either in the form of plain tablets or in the form of compression coated tablets were able to retain their indomethacin load in simulated gastric and intestinal fluids prior to their degradation by a mixture of pectinolytic enzymes. Therefore these formulations could be used for colonspecific delivery of low water soluble drug molecules. Calcium pectinate compression coated tablets containing insulin as a drug marker were administered orally to dogs. The delayed insulin absorption was related to a break down of the drug carrier in the dogs' large intestine. Non-coated calcium pectinate tablets were not able to prevent insulin diffusion and started to release their drug content right after the administration. It is concluded that the use of calcium pectinate matrices for colon specific drug delivery may be restricted to low water soluble drugs. In the case of water soluble drugs such as insulin, an additional protective coat may be required.
A glucosamine residue, in the ammonium form, does not give a c.d. signal in the 200–250 nm range whereas an N-acetyl glucosamine residue gives an n-π∗ transition with a c.d. band located near 211 nm. Thus circular dichroism allows one to deduce the N-acetyl content of chitosans with relatively great accuracy. The c.d. results are compared with three i.r. determinations in the literature.
Different molecular weight, 90% deacetylated chitosans were obtained by ultrasonic degradation on 90% deacetylated chitosan at 80 °C for various times.Ninety percent deacetylated chitosan was prepared from alkali treatment of chitin that was obtained from red shrimp waste. Number average-, viscosity average- molecular weights were measured by gel permeation chromatography and the viscometric method, respectively. Degree of deacetylation was measured by the titration method. Enthalpy, maximum melting temperature, tensile strength and elongation of the membranes, flow rate of permeates and water are properties measured to elucidate the effect of molecular weight of chitosan on the above thermal, mechanical, and permeation properties, respectively of the prepared membranes. Results show tensile strength, tensile elongation, and enthalpy of the membrane prepared from high molecular weight chitosans were higher than those from low molecular weight. However, the permeability show membranes prepared from high molecular weight chitosans are lower than that from those of low molecular weight.
The influence of compression force to inner core tablet or to outer coating layer of the compression-coated tablet on the function of time-controlled disintegration was investigated. The inner core tablet was directly compacted by sodium diclofenac (model drug) and ethylcellulose (EC) with 4.6-μm particle size was used as an outer coating layer. The immersion time of the compression-coated tablet previously soaked in pH 1.2 solution to simulate the residence time of the tablet in the GI tract affecting the dissolution behavior of the compression-coated tablet was also investigated. The effect of the amount of the outer coating layer used on the drug release was examined. The results indicate that sodium diclofenac released from these compression-coated tablets exhibited a longer lag of a period about 16.3 h in both distilled water and pH 6.8 buffer solution, followed by a different drug release behavior. The lag time was independent of the pH of dissolution medium, and the immersion time in pH 1.2 solution. After that lag time, the outer shell of the compression-coated tablets broke into two halves to make a rapid drug release. However, the drug release behavior of the soaked tablet in pH 6.8 buffer solution was dependent on the immersion time. The compression force < 200 kg/cm2 to the inner core tablet influenced the release behavior of drug less, but > 200 kg/cm2 might delay the lag time. The lag time of the compression-coated tablets was linearly correlated with the compression force to the outer coating layer (r = 0.9896). We also found that the more the amount of outer coating layer added, the longer the lag time obtained. The study demonstrates that the time-controlled disintegration of the compression-coated tablet was effectively controlled by the compression force applied and the amount of outer coating layer added. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:2005–2009, 2001
Colon-specific drug delivery systems based on a polysaccharide, guar gum, were evaluated using in vitro and in vivo methods. In vitro drug release studies have shown that guar gum in the form of compression coat applied over indomethacin core tablets protects the drug from being released under conditions mimicking mouth to colon transit. Studies in pH 6.8 phosphate buffered saline (PBS) containing 4% w/v rat caecal contents have demonstrated the susceptibility of guar gum to the colonic bacterial enzyme action with consequent drug release. gamma-scintigraphic studies in human volunteers with technetium-99m-DTPA as a tracer in sodium chloride core tablets compression coated with guar gum have shown that the gum coat protect the drug (tracer in the present study) from being released in the stomach and small intestine. On entering the ascending colon, the tablets commenced to release the tracer indicating the breakdown of the gum coat by the enzymatic action of colonic bacteria. The tablets disintegrated in the ascending colon of all the volunteers, except one, resulting in the distribution of released tracer across the entire colon. The study clearly established that guar gum, in the form of compression coat, is a potential carrier for drug targeting to colon.
Endopolygalacturonases (EPGs) hydrolyze glycosidic linkages between galacturonic acid (GalA) residues in polygalacturonans, a major fraction of plant pectins. However, most polygalacturonans occur naturally with some of the GalA residues methylesterified. Methylesterification is known to inhibit the activity of EPG. A commercial apple pectin sample was partially saponified to give three pectin samples of degree of methylesterification (DM) 52, 32, and 16. Each was digested to completion by a cloned EPG of Erwinia carotovora subsp. carotovora and the sizes of the resulting fragments were determined by HPLC. A mathematical model was devised to predict the distribution of fragment lengths expected from the three different DM pectins depending on how many adjacent GalA residues are necessary for the enzyme to be able to bind and act on its substrate. For all three DM pectins, the enzyme digestion pattern fit fairly well to that predicted if the enzyme needs four adjacent non-esterified residues to act. As an independent test for the substrate requirements for the enzyme, we determined the maximum cluster size of adjacent non-esterified GalA residues, which remained after complete EPG digestion of the three pectin samples. In each case it was three residues. Thus both methods show that the EPG of E. carotovora needs four adjacent non-esterified GalA residues within a partially-esterified region to be able to act.
With the determination of the exact mode of action of sulfasalazine 20 years ago, attention and interest was drawn to the colonic delivery of drugs. A few years before that it became clear that some orally administered laxative drugs are active only after arrival at the large intestine. This resulted in research activity that led to the development of colonic dosage forms. Two major approaches were reported: (1) protective coats that bring the dosage form as close as possible to the colon after oral administration, (2) prodrugs, polymeric prodrugs, and biodegradable polymers that are degraded mostly by the unique enzymes of the colon. Usually, these enzymes are related to the normal colonic microflora. The new drug carriers were examined in vitro and in vivo (laboratory animals). Recently, an increasing number of studies suggest the use of polysaccharide hydrogels for oral delivery of colon-specific drug carriers. Colonic delivery of drugs is associated with the local delivery of salicylate derivatives to the large intestine for the topical treatment of ulcerative colitis and sometimes the local treatment of irritable bowel syndrome. A common belief is that colonic delivery for orally administered protein drugs is possible because of the postulated low proteolysis activity in the large intestine, an assumption that requires further verification. Yet, other opportunities for colonic delivery of drugs also exist. Some recent examples include bypassing small intestine metabolism, achieving constant absorption rates for some molecules, and delivering cationized antioxidant enzymes to the colonic epithelium. This article reviews the surge of research activity in the new area of colon-specific drug delivery systems and suggests some possible therapeutic opportunities in this field.
Commercially available lattices are often used to coat nonpareils or beads. Drug release occurs via diffusion through the polymer coating. Adequate release rates may be achieved with small particles because the surface area is large. However, tablets coated with unmodified lattices have exceedingly slow release rates. Therefore, a pore-forming agent, urea, was added to a commercially available ethyl cellulose latex, Aquacoat, to increase the release rate of drugs from coated osmotic tablets. Modified lattices were used to coat KCl and diltiazem.HCl tablets. Release of KCl and diltiazem into water or buffer solutions was determined in a standard U.S.P. dissolution apparatus. Rates varying from 1 to 100% release in 12 hr were obtained by varying the coating thickness, pore-former level, and plasticizer type and concentration. Scanning electron microscopy (SEM) showed that the urea was eluted from the coat in aqueous solution leaving a porous coating. Coat burst strengths were dependent on the coat thickness and the concentrations of pore former and plasticizer. Hence, modified lattices hold potential for use as coatings for controlled release osmotic formulations.
1. Crystalline beef insulin was administered orally in capsules composed of a methacrylic acid copolymer which prevented breakdown of the insulin by enteric and pancreatic peptidases. 2. In studies performed in 3 individuals blood was sampled before oral ingestion of the insulin (40 144 units), and at 15 or 30 min intervals thereafter for 5.5 hr for measurement of immunoreactive insulin and C-peptide concentrations. 3. Following the administration of oral insulin, plasma immunoreactive insulin concentrations became elevated 4-5 hr after ingestion. 4. The rise in plasma insulin concentrations was associated with a corresponding fall in the concentration of C-peptide. 5. The data suggest that this preparation of oral insulin can produce significant enteric absorption of the peptide, and that further investigation of agents that facilitate insulin absorption from the gut might render the use of methacrylic acid copolymer coated capsules a physiologically sound and a commercially feasible method of oral insulin administration.
Gastrointestinal transit of an enteric coated delayed release 5-aminosalicylic acid tablet radiolabelled with 111indium has been monitored in a total of 13 patients with Crohn's disease and ulcerative colitis. More than 70% of the tablets disintegrated in the small intestine, on average 3.2 hours after emptying from the stomach. Dispersed preparation was detected in the proximal colon of all the patients, except one with an ileostomy. Mean peak plasma concentrations of 5-aminosalicylic acid and its metabolite acetyl-5-aminosalicylic acid occurred 3-4 hours after gastric emptying. The tablets provide a reliable means of drug delivery to the ileum and proximal colon.
1. The relation between bacterial degradation of three viscous polysaccharides (guar gum, ispaghula and xanthan gum) by colonic bacteria in vitro and their effects on colonic function were investigated by comparing the results of anaerobic in vitro incubations with fresh faeces from seven healthy volunteers (measuring viscosity, pH and gas production) with the effects of feeding all three polysaccharides to the same volunteers for 1 week each (14–15 g/d) on faecal mass and whole-gut transit time.
2. Guar gum was rapidly fermented in vitro by faecal bacteria from all volunteers with concomitant loss of viscosity, reduction in pH and generation of gases. Ispaghula maintained its viscosity during incubation, but the pH fell significantly. The results of xanthan gum incubations showed considerable individual variation.
3. Only ispaghula significantly increased faecal mass, whilst none of the gums significantly affected stool frequency or transit time. Statistical analysis of the pooled results showed that although transit time and faecal output were inversely related, feeding viscous polysaccharides could influence these indices independently. Stool frequency was significantly correlated with the transit time, but not the faecal output.
4. Transit time was reduced by gum feeding to a significantly greater extent in those subjects whose faecal bacteria reduced or removed the viscosity of that gum, than in those subjects where the viscosity was maintained. In contrast, there was a smaller increase in faecal mass when the viscosity of the appropriate cultures was removed than when it was maintained or reduced. Increases in stool frequency were significantly associated with hydrogen production from in vitro cultures.
We assessed oral 5-aminosalicylic acid (5-ASA) prepared with a pH-sensitive polymer coating in 87 patients with mildly to moderately active ulcerative colitis in a double-blind, placebo-controlled trial. Patients were randomly assigned to receive 5-ASA at a dosage of either 4.8 or 1.6 g per day or placebo for six weeks. The outcome was monitored by flexible proctosigmoidoscopic examinations and physicians' assessments at three-week intervals and by patients' recordings of daily symptoms. Results showed 24 percent complete and 50 percent partial responses in those receiving 4.8 g of 5-ASA per day as compared with 5 percent complete and 13 percent partial responses in those receiving placebo (P less than 0.0001, rank-sum test). At a dosage of 1.6 g per day, the response was twice as good as with placebo, but the difference did not reach statistical significance (P = 0.51). Age, sex, duration of disease, duration of active symptoms, or extent of disease did not affect the clinical outcome. We conclude that oral 5-ASA administered in a dosage of 4.8 g per day is effective therapy, at least in the short term, for mildly to moderately active ulcerative colitis.
The major host defense mechanisms against bacterial overgrowth in the small bowel are the normal propulsive activity of the bowel itself and gastric acid secretion. Microbial interactions are a major factor in regulating the indigenous bacterial flora. Studies of the bacterial enzymes of the gut suggest that changes in diet may lead to marked changes in the colonic flora. Antibiotics affect the composition of the colonic microflora. The microflora also influence the degradation of mucin, the conversion of urobilin to urobilinogen, of cholesterol to coprostanol, and the production of short chain fatty acids. Current interests are focused on the bacterial flora of tropical sprue, the role of bacteria in colorectal cancer, and the involvement of intestinal microflora in the enterohepatic circulation of sex steroid hormones.
We reviewed the courses of 63 patients with inflammatory bowel disease (IBD) treated in a private gastroenterology practice. All were allergic, unresponsive, or in some way intolerant of sulfasalazine and therefore were treated with Eudragit-S-coated mesalamine (Asacol). Thirty-eight patients had ulcerative colitis (UC) and 25 had Crohn's disease. In 22 and 14, respectively, mesalamine was used to treat active disease; in 16 and 11, respectively, it was introduced to maintain remission. In some patients, mesalamine was used along with other medications. Symptomatic and endoscopic response was seen in seven of nine (77%) with active UC treated with measalamine alone; remission was maintained in seven of eight (94%) when mesalamine was used alone. Therapeutic success was noted in eight of 10 (80%) with active Crohn's disease, and remission was maintained in seven of nine (78%) when mesalamine was used alone. Adverse reactions of varying severity occurred in 21 of 63 (33%), but the drug had to be terminated in only 9 of 63 (14%). Eudragit-S-coated mesalamine appears to be effective in the treatment and maintenance of remission of UC in 82% of those patients allergic or intolerant to the parent drug, sulfasalazine. Furthermore, contrary to what was expected, we found it effective in a much larger percentage of patients with Crohn's disease (79%) than the parent drug.
The purpose of the study was to investigate the potential of pectin, ethylcellulose combinations as a practical film coating for colonic delivery.
Combinations of pectin and ethylcellulose, in the form of an aqueous dispersion, were used as coating formulations. Paracetamol cores were used as the substrate. The coatings were assessed by a flow through dissolution system simulating in vivo conditions by changes in pH and residence time. Pectinolytic enzymes were used to simulate the bacterial flora of the colon.
Drug release was controlled by the ratio of ethylcellulose to pectin in the film coat. Increasing the proportion of ethylcellulose and increasing the coat weight reduced drug release in pH1 and pH7.4 media. The addition of pectinolytic enzymes to pH6 media increased the release of drug.
Combinations of ethylcellulose and pectin can provide protection to a drug in the upper g.i. tract while allowing enzymatic breakdown and drug release in the colon.
Polysaccharides have over the years been used widely in pharmaceutical, chemical, and biochemical drug delivery. This family of natural polymers has an appeal to the area of drug delivery as it is comprised of polymers with a large number of derivatizable groups, a wide range of molecular weights, varying chemical compositions, and for the most part, a low toxicity and biodegradability, yet a high stability. The main scope of this review is to relate the polysaccharides available now to the rapidly growing field of colonic drug delivery. Polysaccharides have been applied to the area as controlled release coatings, matrices, macromolecular carriers, and biodegradable carriers. Bacterial sources of polysaccharidases as well as a detailed treatise of the enzymatic flora of the colonic region are discussed, followed by a presentation of the polysaccharides available for the purpose of colon-specific drug delivery. A final overview of the various approaches to obtain colon-specific delivery by using polysaccharides and a summary of available in vitro and in vivo testing methods will lead to the conclusion that polysaccharides at this point appear to be very promising compounds for use in obtaining colon-specific drug delivery systems.
The objective of this study was to estimate colon-specific insulin delivery with chitosan capsules. In vitro drug release experiments from chitosan capsules containing 5(6)-carboxyfluorescein (CF) were carried out by the Japan Pharmacopoeia (J. P.) rotating basket method with some slight modifications. The intestinal absorption of insulin was evaluated by measuring the plasma insulin levels and its hypoglycemic effects after oral administration of the chitosan capsules containing insulin and additives. Little release of CF from the capsules was observed in liquid 1, an artificial gastric juice (pH 1), or in liquid 2, an artificial intestinal juice (pH 7). However, the release of CF was markedly increased in the presence of rat cecal contents. A marked absorption of insulin and a corresponding decrease in plasma glucose levels was observed following the oral administration of these capsules that contain 20 IU of insulin and sodium glycocholate (PA% = 3.49%), as compared with the capsules containing only lactose or only 20 IU of insulin (PA% = 1.62%). The hypoglycemic effect started from 8 h after the administration of chitosan capsules when the capsules entered the colon, as evaluated by the transit time experiments with chitosan capsules. These findings suggest that chitosan capsules may be useful carriers for the colon-specific delivery of peptides including insulin.
5-Amino salicylic acid preparations are used in therapy for patients with inflammatory bowel diseases. The bioavailability of these drugs depends on their coating.
To determine whether intraluminal pH is decreased by the presence of inflammation, thereby altering the release of 5-amino salicylic acid in the intestinal lumen.
Intraluminal gastrointestinal pH was measured by means of a radiotelemetry capsule in 12 healthy controls, in 12 patients with Crohn's disease (five with active disease), and in 11 patients with ulcerative colitis (seven with active disease).
The median gastric pH values in the patient groups (Crohn's disease 2.4, range 1.5-4.1; ulcerative colitis 1.95, range 1.55-4.4) were significantly higher than those observed in the controls (1.55, range 0.95-2.6). In the small bowel and colonic segments, all the pH values of Crohn's disease patients were comparable to those of the controls, as were the pH values in the proximal small intestine and in the left colon in patients with ulcerative colitis. However, the latter group had higher pH values in the terminal ileum, the caecum and the right colon. Patients with active disease had comparable median gastrointestinal pH values to patients in remission.
The luminal release of 5-amino salicylic acid might not be inhibited by low pH in patients with active inflammatory bowel diseases. This supports a safe disintegration of the slow release mesalazine preparations even in the presence of severe disease.
The aim of this study was to develop colon-specific delivery systems for 5-aminosalicylic acid (5-ASA) using guar gum as a carrier. Core tablets containing 5-ASA were prepared by wet granulation with starch paste and were compression coated with coating formulations containing different quantities of guar gum (300, 200, 150, and 125 mg). In vitro drug release studies were carried out in simulated gastric and intestinal fluids and in pH 6.8 buffer containing rat cecal contents. The application of 175 mg of coating formulation containing 150 mg of guar gum over 5-ASA core tablets resulted in the release of less than 2% drug in simulated gastric and intestinal fluids and about 93% of 5-ASA in pH 6.8 buffer containing rat cecal contents. Differential scanning calorimetric (DSC) studies showed the absence of any interaction between 5-ASA and the excipients on storage at 45 degrees C for 12 weeks. The study confirmed that selective delivery of 5-ASA to the colon can be achieved using guar gum as a carrier in the form of a compression coating over the drug core.
Chitinases are ubiquitous chitin-fragmenting hydrolases. Recently we discovered the first human chitinase, named chitotriosidase,
that is specifically expressed by phagocytes. We here report the identification, purification, and subsequent cloning of a
second mammalian chitinase. This enzyme is characterized by an acidic isoelectric point and therefore named acidic mammalian
chitinase (AMCase). In rodents and man the enzyme is relatively abundant in the gastrointestinal tract and is found to a lesser
extent in the lung. Like chitotriosidase, AMCase is synthesized as a 50-kDa protein containing a 39-kDa N-terminal catalytic
domain, a hinge region, and a C-terminal chitin-binding domain. In contrast to chitotriosidase, the enzyme is extremely acid
stable and shows a distinct second pH optimum around pH 2. AMCase is capable of cleaving artificial chitin-like substrates
as well as crab shell chitin and chitin as present in the fungal cell wall. Our study has revealed the existence of a chitinolytic
enzyme in the gastrointestinal tract and lung that may play a role in digestion and/or defense.
A multiparticulate system of chitosan hydrogel beads has been investigated for colon-specific delivery of macromolecules using fluorescein isothiocyanate-labeled bovine serum albumin as a model protein. The hydrogel bead was formed by polyelectrolyte complexation of chitosan with its counterion, tripolyphosphate (TPP). The protein release experiments were carried out in vitro under different conditions to simulate the pH and times likely to be encountered during intestinal transit to the colon. The results show that the hydrogel beads were degraded by rat cecal and colonic enzymes, resulting in a marked acceleration in the release of protein. The ability of rat cecal and colonic enzymes to degrade chitosan hydrogel beads was independent of pretreatment conditions. A commercial beta-glucosidase preparation containing a chitinase did not have a similar effect on the chitosan bead, even though it has been found to mimic the degradation function of rat cecal and colonic enzymes in vitro for chitosan in solution. Degradation of the chitosan-TPP hydrogel beads in the presence of rat cecal and colonic enzymes indicates the potential of this multiparticulate system to serve as a carrier to deliver macromolecules specifically to the colon.
The degradative activities of extracellular and cell-associated portions of rat cecal and colonic enzymes, whose activities are comparable to that in the human colon, against five chitosan samples were characterized. The effects of the molecular weight (MW) and degree of deacetylation (DD) of chitosan on its susceptibility to degradation were investigated. In addition, the degradation function of rat bacterial enzymes was compared to that of a commercially available almond emulsin beta-glucosidase that contains a chitinase. The results show that rat bacterial enzymes had the ability to degrade chitosan with extracellular enzymes exhibiting a more profound effect than did cell-associated enzymes. The reaction to bacterial enzymes degradation was dependent on both the MW and DD of the chitosan sample. Those samples with a lower MW and lower DD were more susceptible substrates. A similar degradation function of rat bacterial enzymes and of almond emulsin beta-glucosidase on chitosan was revealed, which indicates that almond emulsin beta-glucosidase might be able to be used as an in vitro enzyme system to predict the large intestinal degradation of chitosan.
The effect of excipient, drug, and osmotic agent loaded in the inner core tablet on the time-controlled disintegration of compression-coated tablet prepared by direct compression with micronized ethylcellulose was investigated. The excipients [spray-dried lactose, hydroxypropyl methyl cellulose, sodium starch glycolate, microcrystalline cellulose, different drugs (sodium diclofenac: model drug, salbutamol sulfate, and theophylline anhydrate) and osmotic agent (sodium chloride)] were used to formulate the composition of the inner core tablet. The result indicates that drug release from all the compression-coated tablets was characterized by a distinctive lag of time followed by a faster drug release, dependent on the types of excipient and drug, and osmotic agent used in the inner core tablet. Respectively, the lag of time was 8.5, 12.4, 14.6, or 15.8 h for spray-dried lactose, hydroxypropyl methyl cellulose, sodium starch glycolate, or microcrystalline cellulose-loaded inner core tablet, as compared with 16.4 h for an inner core made of sodium diclofenac alone. The direct-compressible excipients such as spray-dried lactose, sodium starch glycolate, and microcrystalline cellulose seemed not to illustrate a marked disintegration function to rapidly rapture the outer coating layer. The lag of time was only slightly shortened from 16.4 to 14.6 h, >24 to 17.8 h, or >24 to 21.3 h for sodium diclofenac, theophylline anhydrate, or salbutamol sulfate incorporated with sodium starch glycolate into the inner core tablet, respectively, suggesting that sodium starch glycolate did not perform its superdisintegration. Once an osmotic agent of sodium chloride was incorporated into the inner core tablet, the lag of time for the compression-coated tablet was markedly shortened to <1 h, as compared with 16.4 h for drug alone. The more the amount of sodium chloride added, the less the time of lag obtained. Osmotic pressure did have a key role in controlling the drug dissolution. The present result implies that osmotic function is more suitable than superdisintegration function in designing a compression-coated tablet with time-controlled disintegration.
Colon targeted drug delivery has the potential to deliver bioactive agents for the treatment of a variety of colonic diseases and to deliver proteins and peptides to the colon for their systemic absorption. Various strategies, currently available to target the release of drugs to colon, include formation of prodrug, coating of pH-sensitive polymers, use of colon-specific biodegradable polymers, timed released systems, osmotic systems, and pressure controlled drug delivery systems. Among the different approaches to achieve targeted drug release to the colon, the use of polymers especially biodegradable by colonic bacteria holds great promise. Polysaccharidases are bacterial enzymes that are available in sufficient quantity to be exploited in colon targeting of drugs. Based on this approach, various polysaccharides have been investigated for colon-specific drug release. These polysaccharides include pectin, guar gum, amylose, inulin, dextran, chitosan, and chondroitin sulphate. This family of natural polymers has an appeal to drug delivery as it is comprised of polymers with a large number of derivatizable groups, a wide range of molecular weights, varying chemical compositions, and, for the most part, low toxicity and biodegradability yet high stability. The most favorable property of these materials is their approval as pharmaceutical excipients.
Compression coating has been found to be useful for colonic drug delivery. The aim of the present investigation was to evaluate a formulation with a considerably reduced coat weight and gum concentration for colonic drug delivery in vivo using gamma scintigraphy. In vitro studies have found this formulation to be useful for delivery of 5-fluorouracil to the colon. Rapidly disintegrating core tablets containing (99m)Tc-DTPA were prepared and compression coating with 150 mg of granules containing a mixture of xanthan (XG), guar gum (GG) and starch. The ratios of the two gums XG:GG in the coat was kept 10:20. In vitro dissolution studies on XG:GG::10:20 tablets containing (99m)Tc-DTPA were carried out in simulated upper GIT conditions and also in presence of colonic contents. Cumulative percent release of technetium in the upper GIT conditions and transit time amounted to 4%. The total amount of technetium released in the 24 h of the dissolution study was 53+/-3.23%. Upon introduction of cecal content into the dissolution medium (4%), the release of technetium from the compression-coated tablet increased to 78.34+/-5.34%. Gamma scintigraphy studies carried out in six healthy human volunteers showed that the tablet remained intact during its transit through the upper GIT. The anatomical site of disintegration was found to be the ascending colon/hepatic flexure and the disintegration of the tablet started between 4 and 6 h post-dose in all the volunteers with a further spread of tracer into the ascending, transverse, descending and sigmoidal colon.
An oral press-coated tablet was developed by means of direct compression to achieve the time-controlled disintegrating or rupturing function with a distinct predetermined lag time. This press-coated tablet containing sodium diclofenac in the inner core was formulated with an outer shell by different weight ratios of hydrophobic polymer of micronized ethylcellulose (EC) powder and hydrophilic excipients such as spray-dried lactose (SDL) or hydroxypropyl methylcellulose (HPMC). The effect of the formulation of an outer shell comprising both hydrophobic polymer and hydrophilic excipients on the time lag of drug release was investigated. The release profile of the press-coated tablet exhibited a time period without drug release (time lag) followed by a rapid and complete release phase, in which the outer shell ruptured or broke into 2 halves. The lag phase was markedly dependent on the weight ratios of EC/SDL or EC/HPMC in the outer shell. Different time lags of the press-coated tablets from 1.0 to 16.3 hours could be modulated by changing the type and amount of the excipients. A semilogarithmic plot of the time lag of the tablet against the weight ratios of EC/SDL or EC/HPMC in the outer shell demonstrated a good linear relationship, with r = 0.976 and r = 0.982, respectively. The predetermined time lag prior to the drug release from a press-coated tablet prepared by using a micronized EC as a retarding coating shell can be adequately scheduled with the addition of hydrophilic excipients according to the time or site requirements.
A microbially triggered colon-targeted osmotic pump (MTCT-OP) has been studied. The gelable property at acid condition and colon-specific biodegradation of chitosan were used to: (1) produce the osmotic pressure, (2) form the drug suspension and (3) form the in situ delivery pores for colon-specific drug release, respectively. The scanning electron microscopy (SEM) study and the calculation of membrane permeability were applied to elucidate the mechanism of MTCT-OP. The effects of different formulation variables, including the level of pH-regulating excipient (citric acid) and the amount of chitosan in the core, the weight gain of semipermeable membrane and enteric-coating membrane, and the level of pore former (chitosan) in the semipermeable membrane, have been studied. Results of SEM showed that the in situ delivery pores could be formed in predetermined time after coming into contact with dissolution medium, and the number of pore was dependent on the initial level of pore former in the membrane. The amount of budesonide release was directly proportional to the initial level of pore former, but inversely related to the weight of semipermeable membrane. The effects of variations in the level of citric acid and chitosan in the core formulation on drug release were studied. The different levels of enteric-coating membrane could prevent cellulose acetate membrane (containing chitosan as pore former) from forming pore or rupture before contact with simulated colonic fluid, but had no effect on the drug release. Budesonide release from the developed formulation was inversely proportional to the osmotic pressure of the release medium, confirming that osmotic pumping was the major mechanism of drug release. These results showed that MTCT-OP based on osmotic technology and microbially triggered mechanism had a high potential for colon-specific drug delivery.
Nisin containing pectin/HPMC compression coated tablets were prepared and their in vitro behavior tested for colonic delivery. Nisin is a 34-amino-acid residue long, heat stable peptide belonging to the group A lantibiotics with wide antimicrobial activity against Gram-positive bacteria. The invention can be useful for treating colonic infectious diseases such as by Clostridium difficile, and also by colonization of vancomycin-resistant enterococci. In this study, each 100mg core tablet of nisin was compression coated with 100% pectin, 90% pectin-10% HPMC, 85% pectin-15% HPMC, 80% pectin-20% HPMC, 75% pectin-25% HPMC, 100% HPMC at a coat weight of 400mg. The concentration and the activity of nisin were quantified using Well Diffusion Agar Assay. Drug release studies were carried out in pH 3.3 buffer solution. System degradation/erosion experiments were carried out in pH 1.2, 3.3, and 6.8 buffers using a pectinolytic enzyme. The biological activity and NMR studies were performed to assess the stability of nisin during the processing and after the in vitro tests. It was found that pectin alone was not sufficient to protect the nisin containing core tablets. At the end of the 6h 40% degradation was observed for 100% pectin tablets. HPMC addition required to control the solubility of pectin, a 5% increase in HPMC ratio in pectin/HPMC mixture provided a 2-h lag time for nisin release. Eighty percent pectin-20% HPMC appeared to be an optimum combination for further evaluation. Tablets maintained their integrity during the 6-h dissolution test, approximating the colon arrival times. Nisin was found to be active/stable during processing and after in vitro tests. Effect of polymer hydration on pectin degradation was found to be crucial for the enzyme activity. Sufficiently hydrated pectin degraded faster. The pectin/HPMC envelope was found to be a good delivery system for nisin to be delivered to the colon.
Influence of excipients, drugs, and osmotic agent in the inner core on the time-controlled disintegration of compression-coated ethylcellulose tablets Chitosan capsules for colonspecific drug delivery: improvement of insulin absorption from the rat colon
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Lin SY, Lin KH, Li MJ. (2002). Influence of excipients, drugs, and osmotic agent in the inner core on the time-controlled disintegration of compression-coated ethylcellulose tablets. J Pharm Sci, 91:2040–2046. 18. Tozaki H, Komoike J, Tada C, Maruyama T, Terabe A, Suzuki T, Yamamoto A, Muranishi S. (1997). Chitosan capsules for colonspecific drug delivery: improvement of insulin absorption from the rat colon. J Pharm Sci, 86:1016–1021.
The United States Pharmacopeial Convention
- Usp23 Nf
USP23/NF18. 1995. The United States Pharmacopeial Convention, Inc., Rockville, MD.