Capsules For Delivery Research Articles

Mucosal immunization using recombinant plant-based oral vaccines

The induction of mucosal immunity is very important in conferring protection against pathogens that typically invade via mucosal surfaces. Delivery of a vaccine to a mucosal surface optimizes the induction of mucosal immunity. The apparent linked nature of the mucosal immune system allows delivery to any mucosal surface to potentially induce immunity at others. Oral administration is a very straightforward and inexpensive approach to deliver a vaccine to the mucosal lining of the gut. However, vaccines administered by this route are subject to proteolysis in the gastrointestinal tract. Thus, dose levels for protein subunit vaccines are likely to be very high and the antigen may need to be protected from proteolysis for oral delivery to be efficacious. Expression of candidate vaccine antigens in edible recombinant plant material offers an inexpensive means to deliver large doses of vaccines in encapsulated forms. Certain plant tissues can also stably store antigens for extensive periods of time at ambient temperatures, obviating the need for a cold-chain during vaccine storage and distribution, and so further limiting costs. Antigens can be expressed from transgenes stably incorporated into a host plant’s nuclear or plastid genome, or from engineered plant viruses infected into plant tissues. Molecular approaches can serve to boost expression levels and target the expressed protein for appropriate post-translational modification. There is a wide range of options for processing plant tissues to allow for oral delivery of a palatable product. Alternatively, the expressed antigen can be enriched or purified prior to formulation in a tablet or capsule for oral delivery. Fusions to carrier molecules can stabilize the expressed antigen, aid in antigen enrichment or purification strategies, and facilitate delivery to effector sites in the gastrointestinal tract. Many antigens have been expressed in plants. In a few cases, vaccine candidates have entered into early phase clinical trials, and in the case of farmed animal vaccines into relevant animal trials.

Use of cell therapy as a means of targeting chemotherapy to inoperable pancreatic cancer.

Although approved for the treatment of pancreatic cancer, the chemotherapeutic agent ifosfamide is not an effective therapy for this type of tumour. Ifosfamide must be activated by cytochrome P450 (P450) enzymes in the liver, initially to a short lived intermediate and then to toxic metabolites that are subsequently distributed by the circulatory system. Particularly for pancreatic cancer, this liver-mediated conversion results in relatively high systemic toxicities and poor therapeutic concentrations at the liver-distant site of the tumour. Activation of ifosfamide at the site of the tumour may allow lower doses to be used, while increasing the therapeutic index due to the resultant active concentrations generated locally. A cell-based therapy has been conceived where encapsulated, 293-derived cells genetically modified to overexpress a cytochrome P450 enzyme, are implanted near solid tumours. The cells are encapsulated in polymers of cellulose sulphate in order to provide a means of immunoprotection in vivo as well as to physically constrain them to the vicinity of the tumour. A major advantage of this strategy is that it allows one standard cell line to be applied to all patients and this approach can be extended to the treatment of other tumour types. After proof of principle studies in animal models, a phase I/II clinical trial was initiated in patients with stage III/IV nonresectable pancreatic cancer. Encapsulated cells were angiographically placed into the tumour vasculature of 14 patients and followed by systemic low dose ifosfamide treatment. Angiographic delivery of encapsulated cells proved feasible in all but one patient, and was well tolerated with no capsule or ifosfamide treatment-related adverse events. Four of the treated patients showed tumour regressions after capsule delivery and ifosfamide treatment in computer-tomography scans. The other 10 patients showed no further tumour growth (i.e. stable disease) during 20 weeks observation period. The median life expectancy of the patient collective was extended two fold as compared to age and status matched historical controls, with a 3-fold improvement in one year survival being attained. Evidence for a clinical benefit of the treatment was also obtained on the basis of standard parameters for quality of life. This approach has been evaluated by the European Medicines Evaluation Agency (EMEA) and orphan drug status has been granted. A pivotal clinical trial is now being planned with the help of the EMEA. Taken together, the data from this clinical trial suggest that encapsulated cytochrome P450-expressing cells combined with chemotherapy may be useful for the local treatment of a number of solid tumours and support the performance of further clinical studies of this new treatment.

Cover Picture: Biomineralized Polysaccharide Capsules for Encapsulation, Organization, and Delivery of Human Cell Types and Growth Factors (Adv. Funct. Mater. 6/2005)

The cover shows biomineralized polysaccharide capsules with specifiable make-up, which can provide microenvironments for stabilization, growth, and differentiation of human cell types, as reported by Oreffo and co-workers on p. 917. The capsules are amenable to complexation with a range of bioactive molecules and cells, offering tremendous potential as multifunctional scaffolds and delivery vehicles in tissue regeneration of hard and soft tissues. The construction of biomimetic microenvironments with specific chemical and physical cues for the organization and modulation of a variety of cell populations is of key importance in tissue engineering. We show that a range of human cell types, including promyoblasts, chondrocytes, adipocytes, adenovirally transduced osteoprogenitors, immunoselected mesenchymal stem cells, and the osteogenic factor, rhBMP-2 (BMP: bone morphogenic protein), can be successfully encapsulated within mineralized polysaccharide capsules without loss of function in vivo. By controlling the extent of mineralization within the alginate/chitosan shell membrane, degradation of the shell wall and release of cells or rhBMP-2 into the surrounding medium can be regulated. In addition, we describe for the first time the ability to generate bead-in-bead capsules consisting of spatially separated cell populations and temporally separated biomolecule release, entrapped within alginate/chitosan shells of variable thickness, mineralization, and stability. Such materials offer significant potential as multifunctional scaffolds and delivery vehicles in tissue regeneration of hard and soft tissues.

Asymmetric membrane capsules for delivery of poorly water-soluble drugs by osmotic effects

A non-disintegrating polymeric capsule system, in which asymmetric membrane offers an improved osmotic effect, was used to deliver poorly water-soluble drugs in a control manner. The capsule wall membrane was made by a phase inversion process, in which asymmetric membrane was formed on stainless-steel mold pins by dipping the mold pins into a coating solution containing a polymeric material followed by dipping into a quench solution. This study evaluates the influence of coating formulation that was cellulose acetate (CA), ethylcellulose (EC), and plasticizer (glycerin and triethyl citrate). Results show capsule that made by CA with glycerin (formulation A), which appear in asymmetric structure and are able to release chlorpheniramine maleate (CM) in significant percentage. Two poorly water-soluble drugs of felodipine (FL) and nifedipine (NF) were selected as the model drug to demonstrate how the controlled release characteristics can be manipulated by the design of polymeric capsules with an asymmetric membrane and core formulations. Results show that sodium lauryl sulfate (SLS) is able to promote the release of FL from polymeric capsules prepared with CA with asymmetrical membrane. The addition of solubilizer, including RH40, PVP K-17, and PEG 4000 could enhance the release of FL but with an extent not being related to its solubility. Based on these results, influence of core formulation variables, including the viscosity and added amount of hydroxypropyl methylcellulose (HPMC), the added amount of SLS, and drug loading were examined on the release of NF. It was found that HPMC of 50 cps was suitable to be a thickening agent and both added amount of HPMC and SLS showed a comparable and profoundly positive effect, whereas NF loading had no influence on the drug release percent and rate. There existed a synergistic interaction between HPMC and SLS on the release percent and rate.

Biomineralized Polysaccharide Capsules for Encapsulation, Organization, and Delivery of Human Cell Types and Growth Factors

The construction of biomimetic microenvironments with specific chemical and physical cues for the organization and modulation of a variety of cell populations is of key importance in tissue engineering. We show that a range of human cell types, including promyoblasts, chondrocytes, adipocytes, adenovirally transduced osteoprogenitors, immunoselected mesenchymal stem cells, and the osteogenic factor, rhBMP-2 (BMP: bone morphogenic protein), can be successfully encapsulated within mineralized polysaccharide capsules without loss of function in vivo. By controlling the extent of mineralization within the alginate/chitosan shell membrane, degradation of the shell wall and release of cells or rhBMP-2 into the surrounding medium can be regulated. In addition, we describe for the first time the ability to generate bead-in-bead capsules consisting of spatially separated cell populations and temporally separated biomolecule release, entrapped within alginate/chitosan shells of variable thickness, mineralization, and stability. Such materials offer significant potential as multifunctional scaffolds and delivery vehicles in tissue regeneration of hard and soft tissues.

Pharmacokinetics of an immediate release, a controlled release and a two pulse dosage form in dogs

Clinical studies have shown that circadian patterns influence the pharmacokinetics of certain drugs used in the treatment of different diseases. For such drugs, the bioavailability is influenced by the time of administration. The objective of this study was to investigate differences in the pharmacokinetic patterns between a pulsatile drug delivery system using a pulsatile capsule, an immediate release tablet and a controlled release tablet. Metoprolol was chosen as a model drug because of its high solubility and high permeability pattern throughout the GI tract. The dosage forms were administered to four dogs and the plasma levels were measured using LC-MS/MS. Pharmacokinetic parameters were determined for each dosage form. Fluctuations in the plasma time curves over the observation period indicated that physiological factors like motility have an influence on the drug absorption. The comparison of the plasma time curves of the dosage forms showed that each dosage form caused significant differences in the drug plasma levels. The pulsatile drug delivery capsule caused two defined C max values for each dose between 1–1.75 and 2.5–3.5 h. Implications for the use of a pulsatile drug delivery device for chronopharmacotherapy are discussed. Pulsatile drug delivery offers a promising way for chronopharmacotherapy if the time of administration and pulse time are adjusted to the circadian pattern.

A novel solvent-free method for the manufacture of biodegradable antibiotic-capsules for a long-term drug release using compression sintering and ultrasonic welding techniques

This report was to develop a novel solvent-free method for the manufacture of biodegradable capsules for a long-term drug delivery. To manufacture an antibiotic capsule, polylactide–polyglycolide copolymers were pre-mixed with vancomycin. The mixture was then injection compression molded to form a cylinder with a cover of 8 mm in diameter. After the addition of gentamicin sulfate into the core, an ultrasonic welder was used to seal the capsule. An elution method and an high-performance liquid chromatography assay were employed to characterize the in vitro release rates of the antibiotics over a 30-day period. It was found that biodegradable capsules released high concentration of vancomycin and gentamicin (well above the minimum inhibition concentration) in vitro for the period of time needed to treat bone infection; i.e., 2–4 weeks. A bacterial inhibition test was carried out to determine the relative activity of the released antibiotics. The diameter of the sample inhibition zone ranged from 3 to 18 mm, which is equivalent to 16.7–100% of relative activity. By adopting this novel technique, we will be able to manufacture biodegradable capsules of various medicines for long-term drug delivery.

811 機械ストレスによるバイオ組織への影響に関する研究(GS-2 生体の力学,研究発表講演)

Recently electric appliances such as portable phones and personal computers are being increasingly used. The influences of microwaves upon living organs are very important problems which are under investigations by many researchers. However the extent of these influences has not been made clear. Similar to microwave, the effects of magnetic fields and vibrations are matters of serious concern. For example, the appliances which produce magnetic fields or vibration are MRI (magnetic resonance imaging), sensors in body, minute capsules for drug delivery, and so on. In this study, the cells were cultured under external stress such as the microwave, magnetic and vibration. The trace metallic elements (such as Ca, Fe, Cu and Zn) in the cells were non-destructively examined by synchrotron radiation x-ray fluorescence spectroscopy (SRXRF) at single cell level. The influences of microwave, magnetic field and vibration stresses upon the balance of metallic elements in single cells will be discussed in this paper..

The effect of wet granulation on the erosion behaviour of an HPMC–lactose tablet, used as a rate-controlling component in a pulsatile drug delivery capsule formulation

The purpose of this study was to investigate the variability in the performance of a pulsatile capsule delivery system induced by wet granulation of an erodible HPMC tablet, used to seal the contents within an insoluble capsule body. Erodible tablets containing HPMC and lactose were prepared by direct compression (DC) and wet granulation (WG) techniques and used to seal the model drug propranolol inside an insoluble capsule body. Dissolution testing of capsules was performed. Physical characterisation of the tablets and powder blends used to form the tablets was undertaken using a range of experimental techniques. The wet granulations were also examined using the novel technique of microwave dielectric analysis (MDA). WG tablets eroded slower and produced longer lag-times than those prepared by DC, the greatest difference was observed with low concentrations of HPMC. No anomalous physical characteristics were detected with either the tablets or powder blends. MDA indicated water-dipole relaxation times of 2.9, 5.4 and 7.7×10 −8 ms for 15, 24 and 30% HPMC concentrations, respectively, confirming that less free water was available for chain disentanglement at high concentrations. In conclusion, at low HPMC concentrations water mobility is at its greatest during the granulation process, such formulations are therefore more sensitive to processing techniques. Microwave dielectric analysis can be used to predict the degree of polymer spreading in an aqueous system, by determination of the water-dipole relaxation time.

A new technique of endoscopic video capsule delivery for patients with dysphagia, pyloric stenosis, or prior gastric surgery

A new technique of endoscopic video capsule delivery for patients with dysphagia, pyloric stenosis, or prior gastric surgery

Pharmacoscintigraphic Assessment of the Regional Drug Absorption of the Dual Angiotensin‐Converting Enzyme/Neutral Endopeptidase Inhibitor, M100240, in Healthy Volunteers

M100240 is the thioester of MDL 100,173, a dual angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor currently in phase II development. The purpose of this study was to evaluate the relative bioavaibility of M100240 in various regions of the gastrointestinal tract using the Enterion capsule, a noninvasive radiocontrolled device providing targeted drug delivery, to explore the absorption characteristics of M100240 in healthy volunteers. In addition, the absolute bioavailability of an immediate-release formulation of M100240 was assessed. Pharmacokinetic data were obtained from 13 healthy subjects in an open-label, single-dose, randomized, five-period crossover study. Treatments included 25 mg M100240 administered via short intravenous infusion, oral immediate-release tablet administration, and oral Enterion capsule delivery of drug substance to the proximal small bowel, distal small bowel, and ascending colon. Each treatment was separated by a 14-day drug-free washout period. The localization of the Enterion capsule in the gastrointestinal tract was monitored using scintigraphic imaging. M100240 and MDL 100,173 plasma concentrations were quantified using a validated LC/MS/MS method, and pharmacokinetic parameters were calculated using noncompartmental methods. The estimates of relative bioavailability in the proximal small bowel, distal small bowel, and ascending colon relative to the oral immediate-release tablet are approximately 94%, 97%, and 41%, respectively. M100240 is primarily absorbed throughout the proximal and distal small bowel with modest absorption in the ascending colon. The absolute bioavailability estimate of the M100240 immediate-release formulation is 49%. These data characterize the fundamental in vivo performance attributes of M100240, thereby providing an approach for optimizing prototype modified-release formulations for this compound.

Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence in syngeneic islet cell transplantation of NOD mice.

Islet transplantation represents a potential cure for type 1 diabetes, yet persistent autoimmune and allogeneic immunities currently limit its clinical efficacy. For alleviating the autoimmune destruction of transplanted islets, newly diagnosed NOD mice were provided a single intramuscular injection of recombinant adeno-associated viral vector encoding murine IL-10 (rAAV-IL-10) 4 weeks before renal capsule delivery of 650 syngeneic islets. A dose-dependent protection of islet grafts was observed. Sixty percent (3 of 5) of NOD mice that received a transduction of a high-dose (4 x 10(9) infectious units) rAAV-IL-10 remained normoglycemic for at least 117 days, whereas diabetes recurred within 17 days in mice that received a low-dose rAAV-IL-10 (4 x 10(8) infectious units; 5 of 5) as well as in all of the control mice (5 of 5 untreated and 4 of 4 rAAV-green fluorescent protein-transduced). Serum IL-10 levels positively correlated with prolonged graft survival and were negatively associated with the intensity of autoimmunity. The mechanism of rAAV-IL-10 protection involved a reduction of lymphocytic infiltration as well as induction of antioxidant enzymes manganese superoxide dismutase and heme oxygenase 1 in islet grafts. These studies support the utility of immunoregulatory cytokine gene therapy delivered by rAAV for preventing autoimmune disease recurrence in transplant-based therapies for type 1 diabetes.

In situ chemical experiments in carbon nanotubes

Understanding the interaction of water-based liquids with carbon at the nanoscale is very important for exploring the potential of carbon nanotubes in nanofluidic chips, probes, and capsules for drug delivery. By using hydrothermal synthesis, we produced closed hydrophilic multiwall carbon nanotubes filled with aqueous fluid. They allow for the first time high-resolution in situ studies of an interface between fluid and carbon in TEM. Strong interaction between the liquid and walls, intercalation of nanotubes with O–H species and dissolution of walls upon heating have been demonstrated. Thermodynamics simulation was used to explain the interaction of nanotubes with fluid.

Cationic triple-chain amphiphiles facilitate vesicle fusion compared to double-chain or single-chain analogues

Cationic, triple-chain amphiphiles promote vesicle fusion more than structurally related double-chain or single-chain analogues. Two types of vesicle fusion experiments were conducted, mixing of oppositely charged vesicles and acid-triggered self-fusion of vesicles composed of cationic amphiphile and anionic cholesteryl hemisuccinate (CHEMS). Vesicle fusion was monitored by standard fluorescence assays for intermembrane lipid mixing, aqueous contents mixing and leakage. Differential scanning calorimetry was used to show that triple-chain amphiphiles lower the lamellar–inverse hexagonal (L α–H II) phase transition temperature for dipalmitoleoylphosphatidylethanolamine. The triple-chain amphiphiles may enhance vesicle fusion because they can stabilize the inversely curved membrane surfaces of the fusion intermediates, however, other factors such as extended conformation, packing defects, chain motion, or surface dehydration may also contribute. From the perspective of drug delivery, the results suggest that vesicles containing cationic, triple-chain amphiphiles (and cationic, cone-shaped amphiphiles in general) may be effective as fusogenic delivery capsules.

Chitosan capsules for colon-specific drug delivery: enhanced localization of 5-aminosalicylic acid in the large intestine accelerates healing of TNBS-induced colitis in rats

The objective of this study was to achieve the colon-specific delivery of an anti-ulcerative colitis drug using chitosan capsules and to accelerate healing of 2,4,6-trinitrobenzene sulfonic acid sodium salt (TNBS)-induced colitis in rats. 5-Aminosalicylic acid (5-ASA) was used as a model of an anti-inflammatory drug. The gastrointestinal transit of chitosan capsules was determined by counting the number of capsules in the gastrointestinal lumen by celiotomy at certain times after their oral administration to rats. The chitosan capsules reached the large intestine 3.5 h after oral administration in rats. We studied the release of 5-ASA from chitosan capsule by the Japan Pharmacopoeia (JP) rotating basket method. The release of 5-ASA from the chitosan capsule markedly increased in the presence of rat cecal contents. After oral administration of chitosan capsules containing 5-ASA, the concentrations of 5-ASA in the large intestinal mucosa were higher than those in the CMC suspension. For the treatment of colitis in rats, 5-ASA was orally administered using chitosan capsules or a carboxy methyl cellulose (CMC) suspension to TNBS-induced rats. The colonic injury and inflammation were assessed by measuring the myeloperoxidase (MPO) activities, colon wet weight/body weight (C/B) ratio and the damage score, respectively. When 5-ASA was orally administered using chitosan capsules in TNBS-induced colitis rats, we found better therapeutic effects with 5-ASA than with a 5-ASA CMC suspension, as evaluated by the MPO activities, C/B ratio and the damage score. In conclusion, chitosan capsules may be useful carriers for the colon-specific delivery of anti-inflammatory drugs including 5-ASA and the healing of TNBS-induced colitis in rats.

Evaluation of an intestinal pressure-controlled colon delivery capsules prepared by a dipping method

A new method for preparation of large amounts of empty pressure-controlled colon delivery capsules (PCDCs) by a dipping method has been developed. Empty PCDCs are composed of two polymer membranes. The inner one was a water-insoluble polymer membrane, ethylcellulose (EC). The outer one was an enteric polymer membrane, hydroxypropylmethylcellulose phthalate (HPMCP) or hydroxypropylmethylcellulose acetate succinate (HPMCAS). By consequently dipping into an ethanolic EC solution and an alkalized enteric polymer solution, empty PCDCs were obtained after both the capsule body and cap were adjusted to the size of #2 capsules. With each enteric polymer, two types of empty PCDCs of different thickness were prepared. Fluorescein (FL) was formulated with suppository base, PEG1000, and used as a model drug. FL/PEG1000 suspension was introduced into empty PCDCs which were then sealed with enteric polymer solution. The PCDCs were evaluated by an in vivo experiment using beagle dogs. After oral administration of the test PCDC preparations containing 30 mg of FL, blood samples were obtained from the jugular vein and serum FL levels were measured. The thickness of the EC membrane layer varied in both the capsule body and cap. HPMCAS PCDCs had 62.1±5.0 (S.E.) μm (body) and 49.7±3.3 μm (cap) with thicker ones and 55.7±6.6 μm (body) and 46.8±6.2 μm (cap) with thinner ones. HPMCP PCDCs had 28.1±3.3 μm (body), 30.9±1.0 μm (cap) with thinner ones and 43.1±9.8 μm (body), 42.4±8.2 μm (cap) with thicker ones. The mean T i values, the first appearance time, of FL in the serum of HPMCAS PCDCs were 2.0±0.7 h for thicker ones and 3.8±0.5 h for thinner ones, while the mean T i values of HPMCP PCDCs were 2.0±0.0 h for thinner ones and 3.5±0.7 h for thicker ones. Since the colon arrival time in beagle dogs was 3.5±0.3 h as determined by a sulfasalazine test, thinner HPMCAS PCDCs and thicker HPMCP PCDCs were thought to deliver FL to the colon.

Micronutrient Interventions: Options for Africa

In recent years, increasing attention has been drawn to the relatively slow pace of progress in intervention efforts against micronutrient deficiencies in sub-Saharan Africa. Recent data indicate that the problem of micronutrient deficiencies remains severe, a situation compounded by inadequacy of institutional capacities and resources required for implementing well-defined control strategies. Supplementation programmes started in earnest after the 1992 International Conference on Nutrition. More recently, there has been an increase in the rate of coverage of vitamin A supplementation of children under five years of age, attributed to the integration of vitamin A capsule distribution into national immunization days. However, a major constraint to vitamin A capsule delivery is a poorly functioning health infrastructure. Transportation facilities are poor, and there are shortages of equipment and trained personnel. Food fortification, which was initially not considered a front-line approach because of the lack of infrastructural facilities in most countries, is currently being pursued with new ideas for adapting existing technologies to local resources and needs. Early attempts at developing food-based strategies involved promoting the production and consumption of vitamin A– rich foods as well as encouraging small-scale animal production. A major shortcoming of these earlier food-based interventions is a lack of quantifiable and convincing data demonstrating impact. There is a growing movement to involve women in intervention programmes. Africa is primarily agrarian. Micronutrient intervention efforts have not fully exploited the untapped potential of the existing food systems and the immense human resources of the agricultural sector.

Characteristics of intestinal absorption and disposition of glycyrrhizin in mice.

As basic studies to apply an intestinal pressure-controlled colon delivery capsule (PCDC) for glycyrrhizin (GZ), the characteristics of intestinal absorption and disposition of GZ were investigated in mice. In the in vivo study, after intravenous (iv) administration of GZ, 10 mg/kg dose, plasma GZ disappeared from the systemic circulation with t(1/2(alpha)) of 0.0063 h, thereafter, it slowly declined with t(1/2(beta)) of 15.23 h. The area under the plasma drug concentration versus time curve (AUC) values of iv (10 mg/kg), intracolonic (50 mg/kg) and intraduodenum (50 mg/kg) administrations were 115.1, 16.7 and 2.7 microgh/mL, respectively. The AUC values of plasma glycyrrhetic acid (GA), a degradation product after intracolonic and intraduodenum administrations were 2.8 and 8.4 microgh/mL, respectively. In the in situ closed loop study, the concentrations of GZ in plasma and liver after intracolonic administration were significantly increased (p<0.05) in comparison with those after intrajejunum or intraileum administration, while the concentration of GA in plasma and liver after intracolonic administration had trends to increase. These observations clearly suggest that the intracolonic administration is a useful way to improve the oral bioavailability of GZ and to enhance its pharmacological efficacy. These pharmacokinetic results of GZ suggest that GZ is a subject drug to be applied for the PCDC system we previously developed. The PCDCs formulation of GZ will enable us to carry GZ to the colon and enhance the oral bioavailability of GZ.

A self-assembled cylindrical capsule: new supramolecular phenomena through encapsulation.

The synthesis and spectroscopic characterization of self-assembled cylindrical capsule 1a x 1a of nanometer dimensions is described. Encapsulation studies of large organic guest molecules were performed by using 1H NMR sprectroscopy in [D12]mesitylene solution. In addition to the computational (MacroModel 5.5, Amber* force field) analysis of the capsule's shape and geometry, an experimental approach towards estimation of the internal cavity dimensions is described. This involves using series of homologous molecular "rulers" (e.g. aromatic amides 5a-i). The available space inside the capsule 1a x 1a can be estimated as 5.7 x 14.7 A (error +/- 0.2 A) with this technique. Dibenzoyl peroxide is readily encapsulated in [D12]mesitylene and was shown to be stable to decomposition for at least three days at 70 degrees C inside the capsule. Moreover, 1a x 1a prevents the encapsulated peroxide from oxidizing Ph3P or diphenyl carbazide present in solution. The normal chemical reactivity of the peroxide is restored by release from the capsule by DMF, a solvent that competes for the hydrogen bonds that hold the capsule together. The protection and release of encapsulated species augurs well for the application of capsules in catalysis and delivery.

Evaluation of colonic absorbability of drugs in dogs using a novel colon-targeted delivery capsule (CTDC)

A series of dog studies were performed to examine the in vitro/in vivo relationship of drug release behavior of the newly developed colon-targeted delivery capsule (CTDC). The four kinds of CTDCs containing theophylline, each of which has a different in vitro dissolution lag time, were orally administered to four beagle dogs under fasted condition, and the onset times of drug absorption were compared. The CTDC with longer in vitro lag time had a later onset of drug absorption. It was also found that the time difference between the gastric emptying and the onset of drug absorption was almost equal to the in vitro dissolution lag time of the capsule, suggesting a similar performance of CTDC in the gastrointestinal tract. From the comparison to the absorption behavior of the colon arrival marker, i.e. sulfasalazine, it was proved that the CTDC with the lag time of 3 h can deliver the drug directly to the colon. This result implied that the CTDC can be used as a non-invasive means for assessing the regional absorbability of drugs in the gastrointestinal tract. To evaluate the absorbability of drugs in the colon, three model drugs, theophylline (THEO), acetaminophen (ACET), and phenylpropanolamine hydrochloride (PPA) were directly delivered to the colons of beagle dogs using the CTDC with the lag time of about 3 h. The obtained relative bioavailabilities to the solution form were as high as 94.2%, 71.0%, and 91.5% for THEO, ACET and PPA, respectively, suggesting that the colonic absorbability of those drugs is essentially good.