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PubMed2003

Detection and genetic analysis of group II capsules in Aeromonas hydrophila.

The genetic organization and sequences of the group II capsule gene cluster of Aeromonas hydrophila PPD134/91 have been determined previously. The purified capsular polysaccharides can increase the ability of avirulent strain PPD35/85 to survive in naive tilapia serum but have no inhibitory effect on the adhesion of PPD134/91 to carp epithelial cells. In this study, the presence of group II capsules among 33 randomly chosen A. hydrophila strains was examined by electron microscopy and genetic analysis. Ten strains were found to produce group II capsules. A PCR detection system was developed to identify two types of group II capsules (IIA and IIB) based on their genetic organization in the region II gene clusters. Group IIA capsules in the authors' collection of A. hydrophila strains are mainly found in the O : 18 and O : 34 serogroups, while group IIB capsules are found in the O : 21 and O : 27 serogroups. The presence of group II capsules in A. hydrophila strongly correlates with the serum and phagocyte survival abilities (seven out of ten strains). The results indicate that the authors' PCR detection system can constitute a reliable assay for the classification of group II capsules in A. hydrophila.

Aeromonas hydrophila↗

PubMed2006

Co-ordinate action of bacterial adhesins and human carcinoembryonic antigen receptors in enhanced cellular invasion by capsulate serum resistant Neisseria meningitidis.

Neisseria meningitidis (Nm) is a human specific opportunistic pathogen that occasionally penetrates mucosal barriers via the action of adhesins and invasins and evades host immune mechanisms during further dissemination via capsule expression. From in vitro studies, the primary adhesion of capsulate bacteria is believed to be mediated by polymeric pili, followed by invasion via outer membrane adhesins such as Opa proteins. As the latter requires the surface capsule to be down-modulated, invading bacteria would be serum sensitive and thus avirulent. However, there is recent evidence that capsulate bacteria may interact via Opa proteins when host cells express high levels of carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), their target receptors. Such a situation may arise following increased circulation of inflammatory cytokines that upregulate certain adhesion molecules on host cells. In this study, using a tetracycline controlled expression system, we have developed cell lines with inducible CEACAM expression to mimic post-inflammation state of target tissues and analysed the interplay between the three surface components capsule, pili and Opa proteins in cellular interactions. With two distinct cell lines, not only the level but also the rate of adhesion of capsulate Opa-expressing Nm increased concurrently with CEACAM density. Moreover, when threshold levels of receptor were reached, cellular invasion ensued in an Opa-dependent manner. In studies with cell lines intrinsically expressing pilus receptors, notable synergism in cellular interactions between pili and Opa of several meningococcal strains was observed and was independent of capsule type. A number of internalized bacteria were shown to express capsule and when directly isolated from host cells, these bacteria were as serum resistant as the inoculated phenotype. Furthermore, we observed that agents that block Opa-CEACAM binding substantially reduced cellular invasion, while maintaining a low level of cellular adhesion. These studies highlight some of the factors that may determine increased host susceptibility to infection by serum resistant phenotypes; and demonstrate the potential of selective inhibition of key interactions in preventing target tissue penetration while maintaining a level of colonization.

Adhesins, Bacterial↗

PubMed1993

Virulence of capsulated and noncapsulated isolates of Pasteurella multocida and their adherence to porcine respiratory tract cells and mucus.

The virulence and the adherence to porcine respiratory tract cells and mucus of three toxigenic, capsular type D Pasteurella multocida isolates and their noncapsulated variants were evaluated in the present study. Loss of capsule by P. multocida, verified by transmission electron microscopy after polycationic ferritin labeling, was associated with a massive reduction in virulence of the organisms in mice. Specific-pathogen-free piglets inoculated intranasally with one of the capsulated isolates or its noncapsulated variant developed turbinate lesions characterized by bone resorption and by an inflammation of the mucosa associated with hyperplasia and squamous metaplasia of the epithelium. Infection with the capsulated isolate led to more severe lesions and atrophy of turbinates. The interactions of these P. multocida isolates with porcine respiratory tract cells and mucus were studied in vitro. The presence of capsule resulted in a decrease in binding of respiratory tract mucus were studied in vitro. The presence of capsule resulted in a decrease in binding of respiratory tract mucus to P. multocida isolates as determined by a dot blot assay. The presence of capsule also resulted in a significant decrease in adherence to porcine tracheal rings maintained in culture. The capsule seemed to mask outer membrane components which are involved in adherence. One of these components might be lipopolysaccharide since purified lipopolysaccharide bound respiratory tract mucus and blocked adherence of this microorganism to porcine tracheal rings. Our data indicate that capsular material does not seem to be involved in adherence of P. multocida to respiratory tract cells and mucus, but capsulated isolates are more virulent in mice and also in piglets.

Animals↗

PubMed1997

Relative contributions of hyaluronic acid capsule and M protein to virulence in a mucoid strain of the group A Streptococcus.

The antiphagocytic effect of M protein has been considered a critical element in virulence of the group A streptococcus. The hyaluronic acid capsule also appears to play an important role: studies of an acapsular mutant derived from the mucoid or highly encapsulated M protein type 18 group A streptococcal strain 282 indicated that loss of capsule expression was associated with decreased resistance to phagocytic killing and with reduced virulence in mice. To study directly the relative contributions to virulence of M protein and the hyaluronic acid capsule in strain 282, we inactivated the gene encoding the M protein (emm18) both in wild-type strain 282 and in its acapsular mutant, strain TX72. Inactivation of emm18 was accomplished by integrational plasmid mutagenesis, using the temperature-sensitive shuttle vector pJRS233 harboring a 5' DNA segment of emm18. As reported previously, wild-type strain 282 was resistant to phagocytic killing in vitro, both in whole human blood and in 10% serum. The capsule mutant TX72 was highly susceptible to phagocytic killing in 10% serum and moderately sensitive in whole blood. The M protein mutant 282KZ was highly susceptible to phagocytic killing in blood but only moderately sensitive in 10% serum. The double mutant TX74 was sensitive to killing in both conditions. In a mouse infection model, the 50% lethal dose was increased by 60- and 80-fold for the capsule and double mutants, respectively, compared with that of strain 282, but only by 6-fold for the M protein mutant. Integration of the strain 282 capsule genes into the chromosome of a nonmucoid M1 strain resulted in high-level capsule production and rendered the transformed strain resistant to phagocytic killing in 10% serum. These results provide further evidence that the hyaluronic acid capsule confers resistance to phagocytosis and enhances group A streptococcal virulence. The results suggest also that assessment of in vitro resistance to phagocytosis in 10% serum rather than in whole blood may be a more accurate reflection of virulence in vivo of group A streptococci.

Animals↗

PubMed2001

Requirement for capsule in colonization by Streptococcus pneumoniae.

Nasopharyngeal colonization is a necessary first step in the pathogenesis of Streptococcus pneumoniae. Using isolates containing defined mutations in the S. pneumoniae capsule locus, we found that expression of the capsular polysaccharide is essential for colonization by the type 2 strain D39 and the type 3 strains A66 and WU2. Nonencapsulated derivatives of each of these strains were unable to colonize BALB/cByJ mice. Similarly, type 3 mutants that produced < 6% of the parental amounts of capsule could not colonize. Capsule production equivalent to that of the parent strain was not required for efficient colonization, however, as type 3 mutants producing approximately 20% of the parental amounts of capsule colonized as effectively as the parent. This 80% reduction in capsule level had only a minimal effect on intraperitoneal virulence but caused a significant reduction in virulence via the intravenous route. In the X-linked immunodeficient CBA/N mouse, the type 3 mutant producing ~20% of the parental amount of capsule (AM188) was diminished in its ability to cause invasive disease and death following intranasal inoculation. Following intravenous or intraperitoneal challenge, however, only extended survival times were observed. Our results demonstrate an additional role for capsule in the pathogenesis of S. pneumoniae and show that isolates producing reduced levels of capsule can remain highly virulent.

Animals↗

PubMed1988

Capsulation and gene copy number at the cap locus of Haemophilus influenzae type b.

Although more than 98% of natural isolates of Haemophilus influenzae type b carry a duplication of 17 kilobases (kb) of DNA at the chromosomal capsulation locus, only one copy is required for capsulation. In one laboratory-derived and two clinical type b strains, the capsulation locus had a single copy of this 17-kb segment, together with 1.3 kb of DNA identified as lying between the repeats of the duplicated locus. This 1.3 kb appears to be crucial for capsule production, since strains lacking it, although retaining a 17-kb segment, were capsule deficient. On comparing capsule polysaccharide production by these three type b strains with that by a prototypic type b strain with a duplicated locus, a gene dosage effect was demonstrated, with a halving of detectable polysaccharide in the single-copy strains. Despite this reduction in polysaccharide, these strains retained virulence potential as evidenced by bacteremia and meningitis in infant rats. As well as subserving augmented capsule polysaccharide production, a duplicated configuration of the type b cap locus endows strains with genetic instability not found in capsulate single-copy variants. We speculate that a survival advantage might be conferred on strains carrying a duplication at this locus as a result of gene dosage, the genetic instability of the locus, or both.

Animals↗

PubMed1992

Involvement of rcsB in Klebsiella K2 capsule synthesis in Escherichia coli K-12.

Escherichia coli K-12 harboring a part of the structural genes for the Klebsiella K2 capsular polysaccharide (cpsK*) expresses a large amount of K2 capsular polysaccharide as a thick capsule in the presence of plasmids carrying rmpA and rcsB. We have previously shown that expression of the Klebsiella K2 capsule in E. coli HB101 harboring cpsK* depends on the presence of rmpA, a regulatory gene from a large plasmid of Klebsiella pneumoniae Chedid (O1:K2). E. coli K-12 JM109, however, produces only a small amount of K2 capsular polysaccharide, even in the presence of plasmids carrying rmpA as well as the cpsK* structural genes. Introduction of the rcsB gene, a positive regulator of colanic acid capsule synthesis in E. coli K-12 which was cloned from HB101 on a plasmid, into JM109 cells carrying cpsK* and rmpA, results in the expression of a thick K2 capsule. By Northern (RNA) hybridization analysis, rcsB has been found to enhance transcription of a long strand of mRNA (longer than 14 kb) from cpsK*. These E. coli transformants which produce a thick K2 capsule also express colanic acid production at high levels. Therefore, rcsB can act as a positive regulator of Klebsiella K2 capsule production and two capsular polysaccharides can be expressed in E. coli simultaneously. With a somewhat different strain background, we have found that both of the colanic acid regulators, rcsA and rcsB, contribute to the basal level of Klebsiella K2 capsule expression but that the presence of multicopy rcsB in either an rcsB or an rcsA mutant of E. coli is sufficient to increase the expression of K2 capsular polysaccharide. These results suggest further parallels between the regulation of colanic acid synthesis in E. coli and the regulation of Klebsiella K2 capsule synthesis.

Bacterial Capsules↗

PubMed1993

An extraintestinal, pathogenic isolate of Escherichia coli (O4/K54/H5) can produce a group 1 capsule which is divergently regulated from its constitutively produced group 2, K54 capsular polysaccharide.

We are studying an O4/K54/H5 Escherichia coli bacteremic isolate (CP9) as a model pathogen for extraintestinal infection. Its group 2, K54 capsular polysaccharide is an important virulence determinant and confers serum resistance. In this study the effect of the group 1 capsule regulators, RcsA, RcsB, and Lon protease, on the regulation of CP9's capsular polysaccharides was assessed. It was established that in the presence of multicopy rcsA or with disruption of lon, CP9 can be induced to produce a group 1 capsule. RcsA, RcsB, and Lon are present in this K54 background and regulate group 1 capsule expression in a fashion similar to that described for K-12 strains. Two independent group 2 capsule gene protein fusions (cl1.29::TnphoA and cl1.137::TnphoA) were used to evaluate the effects of these regulators on group 2 K54 capsule production. Disruption of lon resulted in 1.9-fold (TR293 [cl1.29::TnphoA lon-146]) and 3.4-fold (TR1373 [cl1.137::TnphoA lon-146]) decreases in fusion activity at 28 degrees C, relative to the baseline level. However, decreases in fusion activity at 42 degrees C were only 1.2- and 1.4-fold, respectively. Inactivation of both lon and rcsA or lon and rcsB restored fusion activity to baseline levels at 28 degrees C, but only a partial restoration of activity was seen at higher temperatures. To assess whether these differences in fusion activity reflected a functional change in capsule production, the effects of 80% normal human serum (NHS) were tested against CP9 and TR93 (lon-146). Since the group 2 K54 capsule protects against the bactericidal activity of 80% NHS, a decrease in its production results in an increase in serum sensitivity. Viable counts of CP9 increased 10-fold in 80% NHS over 3 h at 28 degrees C, as expected. In contrast to CP9, TR93 (lon-146) incurred a 10-fold loss in viability under the same conditions. The levels of RcsA are increased in TR93 (lon 146) as consequence of lon disruption; therefore, these results in conjunction with the cl1::TnphoA protein fusion data establish RcsA as a negative regulator of the group 2 K54 capsular polysaccharide. Furthermore, these results also suggest existence of another Lon-sensitive negative regulator of group 2 K54 capsule production, which is active higher temperatures.

ATP-Dependent Proteases↗

PubMed2004

Deposition of silicone oil droplets in the residual anterior lens capsule after vitrectomy and lensectomy in rabbits.

AIM: To examine the histology of preserved anterior lens capsule in vitrectomised and lensectomised rabbit eyes with and without silicone oil tamponade. METHODS: Forty adult Japanese albino rabbits received two port vitrectomy and lensectomy with or without silicone oil tamponade in one eye under both general and topical anaesthesia. Anterior lens capsule was preserved during operation. After healing intervals residual anterior capsule was histologically observed under light or electron microscopy. RESULTS: Immediately after operation, cuboidal lens epithelial cells were observed on the posterior surface of the preserved anterior capsule. During healing intervals in eyes with or without silicone oil tamponade, regenerated lens structure of Sommerring's ring and fibrous tissue formed in the peripheral and central areas of the residual capsule, respectively. Ultrastructural observation revealed the presence of many vacuoles amid matrix accumulation on the posterior capsular surface, suggesting the deposition of emulsified silicone oil droplets. CONCLUSION: Lens epithelial cells produce regenerated lenticular structure and fibrous tissue on the residual capsule following vitrectomy and lensectomy in rabbits. Silicone oil droplets formed by its emulsification deposit in extracellular matrix accumulated on the posterior surface of the anterior capsule. Emulsified silicone may potentially enhance opacification of residual anterior capsule following pars plana vitrectomy by silicone oil deposition and subsequent activation of lens epithelial cells.

Animals↗

PubMed1998

Adhesion of lens capsule to intraocular lenses of polymethylmethacrylate, silicone, and acrylic foldable materials: an experimental study.

AIMS: To investigate the adhesion characteristics of several intraocular lenses (IOLs) to the simulated and rabbit lens capsule. METHODS: Adhesive force to bovine collagen sheets was measured in water with polymethylmethacrylate (PMMA), three piece silicone, and acrylic foldable IOLs. In rabbit eyes, phacoemulsification and IOL implantation were performed. Three weeks later, adhesion between the anterior/posterior capsules and IOL optic was tested, and the capsule was examined histologically. RESULTS: The mean adhesive force to the collagen sheet was 1697 (SD 286) mg for acrylic foldable, 583 (49) mg for PMMA, and 0 mg for silicone IOLs (p = 0.0003, Kruskal-Wallis test). Scores (0-5) of adhesion between rabbit anterior capsule and IOL optic were 4.50 (0.55) for acrylic foldable, 3.20 (0.84) for PMMA, and 0.40 (0.55) for silicone IOLs (p = 0.004). Scores between rabbit posterior capsule and IOL optic displayed a similar tendency; 4.50 (0.84) for acrylic foldable, 3.00 (1.00) for PMMA, and 0.40 (0.55) for silicone IOLs (p = 0.021). Histological observation indicated that the edge of IOL optic suppressed the migration of lens epithelial cells towards the centre of the posterior capsule. This inhibitory effect was most pronounced with acrylic foldable IOL and least with silicone IOL. CONCLUSIONS: The acrylic foldable IOL adhered to the lens capsule more than the PMMA IOL, and the silicone IOL showed no adhesiveness. These differences seem to play a role in preventing lens epithelial cells from migrating and forming posterior capsule opacification.

Acrylic Resins↗

PubMed1975

Measurement of renal interstitial fluid pressure with polyethylene matrix capsules.

The renal interstitial fluid pressure was measured in dogs from small chronically implanted solid capsules made of porous polyethylene matrix material (pore size approximately 60 mum). Tissue does not grow into the polyethylene and the matrix creates a permanent fluid-filled space in communication with the interstitium. The fluid pressure in the capsule matrix was measured from a tube leading from the capsule with an active servo-null pressure-measuring device. Renal interstitial fluid pressure measured from 28 hydropenic dogs averaged 6.1 plus or minus 0.51 mmHg (SE). Increasing oncotic pressure inside the capsule to 90 mmHg resulted in a small but significant increase in hydrostatic pressure inside the capsule of 3.3 plus or minus 0.46 mmHg. However, the hydrostatic pressure returned to control levels within 30 min. In vitro studies indicated that the pressure measured from the capsule was highly sensitive to change in surrounding hydrostatic pressure, but insensitive to change in surrounding oncotic pressure. Histological studies showed a small layer of connective tissue surrounding the capsule less than 100 mum thick in many areas. There was no evidence of inflammation or tissue rejection. It is concluded that the small chronically implanted polyethylene capsule is a reliable method for the measurement of renal interstitial fluid pressure.

Animals↗

PubMed1997

Possible mechanism of exacerbating cataract formation in cataractous human lens capsules induced by systemic hypertension or glaucoma.

To clarify the role of the lens capsule in cataract formation, changes in the protein conformational structure of immature cataractous lens capsules from patients with systemic hypertension or glaucoma have been investigated, as compared to normal lens capsules. The protein secondary structure and composition of these capsular samples were determined using Fourier transform infrared microspectroscopy with second-derivative, deconvolution and curve-fitting methods. We found that the composition of both random coil and beta-type (beta-sheet and beta-turn) structures in the immature cataractous human lens capsules was increasingly induced by systemic hypertension or glaucoma, but alpha-helix content clearly decreased, leading to the alteration of protein conformational structures in lens capsules. A possible pathway of cataract formation exacerbated by systemic hypertension or glaucoma is discussed. According to the results, we propose that systemic hypertension or glaucoma induce changes in the protein conformational structures of the lens capsule, then cause alteration of membrane transport and permeability for ions, and finally increase intraocular pressure, resulting in the exacerbation of cataract formation. The effect on the conformational structure of cataractous human lens capsules is more pronounced for systemic hypertension than for glaucoma. The present study implies that systemic hypertension or glaucoma can exacerbate cataract formation in senile patients by modifying the protein secondary structures in the lens capsule.

Adult↗

PubMed2001

Effect of preparation conditions on properties and permeability of chitosan-sodium hexametaphosphate capsules.

Capsules were obtained by interpolymer complexation between chitosan (polycation) and sodium hexametaphosphate (SMP, oligoanion). The effect of the preparation conditions on the capsule characteristics was evaluated. Specifically, the influence of variables such as pH, ionic strength, reagent concentration, and additives on the capsule permeability properties was investigated using dextran as a model permeant. The capsule membrane permeability was found to increase by decreasing the chitosan/SMP ratio as well as adding mannitol to the oligoanion recipient bath. Increasing the ionic strength or the pH of the initial chitosan solution was also found to enhance the membrane permeability, moving the membrane exclusion limit to higher values. Generally, the capsules prepared tinder all tested conditions had a relatively low permeability which rarely exceeded a molecular cut-off of 40 kD based on dextran standards. Furthermore, the diffusion rate showed a strong temporal dependence, indicating that the capsules prepared under various conditions exhibit different apparent pore size densities on the surface. The results indicated that, in order to obtain the desired capsule mass-transfer properties, the preparation conditions should be carefully considered and adjusted. Adding a polyol as well as low salt amount (less than 0.15%) is preferable as a means of modulating the diffusion characteristics, without disturbing the capsule mechanical stability.

Capsules↗

PubMed2005

Safety, tolerability, and pharmacokinetics of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory cancer patients in a bridging phase I study.

The purpose of this bridging phase I study was to characterize the toxicity, pharmacokinetics, and antitumor effects of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given daily for 5 consecutive days for 2 weeks, repeated every 3 weeks at 81 mg/m(2). Adverse events were monitored following NCI-CTC. Blood samples were processed for bioanalysis using a validated high-performance liquid chromatography method. The pharmacokinetics of lactone and total (lactone + carboxylate) forms was determined on days 1 and 12 using a noncompartmental pharmacokinetic method. Pharmacokinetic data with the capsule formulation were compared with previously reported pharmacokinetic parameters with a suspension formulation. Efficacy was evaluated by applying World Health Organization criteria. Six patients received 10 courses of therapy. Thrombocytopenia and diarrhea were dose-limiting toxicities. The upper limit of the area under the curve of DRF-1042 (lactone and total) with the capsule formulation was higher than a suspension formulation at a similar dose on day 1 (lactone: capsule = 8.53 microMxh, suspension = 5.33 microMxh; total: capsule = 393 microMxh, suspension = 176 microMxh) and day 12 (lactone: capsule = 22.1 microMxh, suspension = 6.1 microMxh; total: capsule = 1302 microMxh, suspension = 309 microMxh). The upper limit of the area under the curve of DRF-1042 (lactone and total) was higher under fed conditions (lactone = 15.9 microMxh, total = 605 microMxh) relative to fasted conditions (lactone = 8.53 microMxh, total = 393 microMxh) on day 1. One patient experienced stable disease. The toxicity and pharmacokinetics of the capsule correlated well with the suspension. The recommended phase II dose is 81 mg/m(2).

Adult↗

PubMed2000

Morphologic alterations in the anterior lens capsule of canine eyes with cataracts.

OBJECTIVE: To examine the morphologic changes in the anterior lens capsule and lens epithelium of canine eyes with cataracts. SAMPLE POPULATION: Anterior lens capsules from the eyes of 25 dogs with cataracts and from an additional 10 canine globes with lenses subjectively assessed to be normal. PROCEDURE: Thickness of each anterior lens capsule was measured by use of a digital microscopic camera and imaging software. All 25 capsules from eyes with cataracts were submitted for light microscopy; 4 were also submitted for electron microscopy. RESULTS: Thickness of the anterior lens capsule increased with age for the normal lenses and the lenses with cataracts; the change with age was similar for both groups. Light microscopy revealed fibrous metaplasia of lens epithelial cells in 7 of 25 anterior lens capsules with focal thickenings of the posterior aspect of the capsule. Electron microscopy revealed deposition of collagen and basement membrane-like material by fibroblast-like cells. CONCLUSIONS: Results indicate that thickness of the anterior lens capsule in dogs increases with age and that this increase in thickness is not significantly different between normal lenses and lenses with cataracts. In addition, epithelial cells from lenses with cataracts may undergo metaplasia to form plaques composed of fibrous tissue and ectopic basement membrane produced by epithelial cells.

Aging↗

PubMedDate not supplied

Influence of dextran molecular weight on capture in and release from decylamine carboxymethylcellulose capsules.

A series of dextran molecular weight markers were encapsulated in decylamine carboxymethylcellulose microcapsules to serve as probes of capsule retentivity. The capsules were prepared by allowing microdrops of aqueous sodium carboxymethylcellulose to fall into aqueous decylamine acetate solution. Salt exchange reaction at the droplet pseudointerface resulted in self-assembling films which essentially instantaneously enclosed the droplets. Concentrations of anionic polymer were varied in the range from 1-3%. Chromophore-bearing dextrans were incorporated into these capsules by blending the dextrans with the carboxymethylcellulose prior to the encapsulation step. Four dextrans of differing (light scattering) molecular weights were used: 2 x 10(6), 6 x 10(5), 7 x 10(4), and 1.9 x 10(4) amu. The mass balance of dextran retained in the capsules, released on washing the capsules or which escaped encapsulation was determined spectrophotometrically. To measure total dextran in a population of washed capsules, the capsules were lysed in a 0.3 M solution of sodium chloride. To monitor dextran release, washed capsules were suspended in water and dextran concentration in the supernatant was measured. Encapsulation efficiency exceeded 80% for high molecular weight dextran but was lower with the smaller dextrans.

Adsorption↗

PubMed1998

Effect of glycine/citric acid on the dissolution stability of hard gelatin capsules.

Gelatin capsule crosslinking is a well-known phenomenon that results in reduced dissolution of capsule products with the passage of time and/or under accelerated stability conditions. These studies describe one means of preventing capsule crosslinking by incorporating glycine and citric acid into a triamterene/hydrochlorothiazide 37.5/25 mg capsule formulation (triam/HCTZ). Triam/HCTZ without glycine and citric acid showed extensive capsule crosslinking and then failed the USP dissolution specification after a 4-week accelerated (40 degrees C/85% relative humidity [RH]) stability study. Triam/HCTZ containing glycine alone showed some improvement in the dissolution stability but did not prevent gelatin crosslinking. This formulation also failed dissolution specifications after a 4-week accelerated stability study. The same results were obtained when only citric acid was incorporated into the triam/HCTZ. However when glycine and citric acid were incorporated together into the triam/HCTZ, crosslinking was completely prevented. Dissolution profiles remained the same throughout 12-week accelerated stability studies, with little or no drop in the dissolution values throughout the test period. The above results were confirmed with follow-up studies using gemfibrozil and piroxicam as model drugs. Disintegration times for gemfibrozil and piroxicam capsule formulations without glycine and citric acid increased dramatically with observed pellicle formation, but there was little or no change in the disintegration time of the model drugs formulated with glycine and citric acid. The results of these studies demonstrated that when glycine and citric acid are present in some gelatin capsule formulations, pellicle formation or crosslinking of the capsule gelatin is prevented.

Capsules↗

PubMed1995

Preparation and evaluation of a time-controlled release capsule made of ethylcellulose for colon delivery of drugs.

A novel ethylcellulose (EC) capsule which releases drug with a time-controlled fashion has been prepared. This capsule is composed of four parts, drug container, swellable substance, capsule body and cap. At the bottom of the body, micropores are made. As water penetrates through these micropores, the swellable substance such as low substituted hydroxypropyl cellulose (L-HPC) swells. When the cap made of water-insoluble macromolecular substance such as EC cannot persist the swelling pressure, the EC cap disintegrates and the drug in the container is released from the capsule. The lag-time is utilized for the delivery of drug to the colon. The release time of the drug from the capsule was measured both in vitro and in vivo experiments. In the case of an in vitro experiment, after 12mg of fluorescein as a model drug and 238mg of starch were filled into the container, caps having different thickness were attached to the capsule body and release study was performed. The release time of the drug was mainly dependent on the thickness of the cap. Using test capsules of which mean cap thickness were 39.1 +/- 2.3 (SE)microns, 63.1 +/- 5.0 microns and 75.6 +/- 4.1 microns, the in vivo release time was estimated after administration to beagle dogs. As a parameter, the peak time (tmax) when plasma fluorescein concentration reached to its maximum level was determined for the estimation of the release time of the drug from the capsule in the gastrointestinal tract. The in vivo tmax was well correlated with the cap thickness.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗