Pressure-controlled Colon Delivery Capsule Research Articles

A new pressure-controlled colon delivery capsule for chronotherapeutic treatment of nocturnal asthma

The purpose of this study was to prepare a pressure-controlled colon delivery capsule (PCDC) containing theophylline (TPH) dispersion in a lipid matrix as a chronotherapeutic drug delivery system for the treatment of nocturnal asthma. The system was made by film coating using Eudragit S100- based formula over the sealed-hard gelatin capsules containing the drug-lipid dispersion. The lipid formula was composed mainly of Gelucire 33/01 (G33) with different ratios of surfactants (1–10%). The efficiency of the prepared system was evaluated in vitro for its ability to withstand both the gastric and intestinal medium. In addition, the drug plasma concentrations were monitored after single administration to Beagle dogs and compared to that obtained after administration of a reference marketed, generic, sustained-release TPH tablets, Avolen® SR. It was found that the optimum lipid formula was GL2 containing 90% G33 and 10% Labrasol. The film-coated capsules showed complete resistance to both the acidic environment (pH 1.2) for 2 hours and phosphate buffer pH 6.8 for 3 hours at 37°C. In vivo evaluation of the TPH-based PCDCs showed longer lag time compared TO the marketed formula followed by sudden increase in TPH blood levels, which recommends the high potential of this system as a chronotherapeutic drug delivery for nocturnal asthma. The prepared PCDCs exhibited a significantly higher Cmax and Tmax and a nonsignificantly different AUC compared with Avolen® SR. Higher TPH blood levels from 1 to 8 hours postadministration was detected in the case of the prepared PCDCs.

Colon delivery efficiencies of intestinal pressure-controlled colon delivery capsules prepared by a coating machine in human subjects.

Large quantities of pressure-controlled colon delivery capsules (PCDCs) were prepared by a Hicoater-mini pharmaceutical coating machine and colon delivery efficiencies were evaluated in man. Caffeine powder as a model drug was suspended with a polyethylene glycol (PEG) 1000 suppository base at 50 degrees C, and was hardened in no. 0- and no. 2-sized capsular shapes. The capsule-shaped suppositories were coated with 5% w/v ethanolic ethylcellulose (7G grade) solution using the coating machine. By increasing the coating weight of ethylcellulose from 28.6 +/- 1.1 mg to 45.3 +/- 0.2 mg, the mean coating thickness of no. 0 PCDCs increased from 56 +/- 1 microm to 64 +/- 1 microm. With no. 2 PCDCs, the mean coating thickness increased from 50 micro +/- 1 microm to 57 +/- 1 microm by increasing the coating weight of ethylcellulose from 8.1 +/- 0.5 mg to 11.2 +/- 0.3 mg. The no. 0 PCDCs, having a mean ethylcellulose coating membrane thicknesses of 56 +/- 1 microm (type 1) and 64 +/- 1 microm (type 2), as well as no. 2 PCDCs, having thicknesses of 50 +/- 1 microm (type 3) and 57 +/- 1 microm (type 4), were used for in-vivo evaluation in man. After oral administration of test preparations containing 75 mg of caffeine, saliva samples were obtained and salivary caffeine levels were measured by an HPLC method. The first appearance time, Ti, of caffeine in the saliva was used as a parameter for the estimation of the release time of caffeine from PCDCs in the gastrointestinal tract. The mean Ti values of no. 0 PCDCs were 3.3 +/- 0.3 h for type- 1 and 5.3 +/- 0.3 h for type-2 preparations while the mean Ti values of no. 2 PCDCs were 4.3 +/- 0.5 h for type 3 and 5.3 +/- 0.3 h for type 4. There were good correlations between ethylcellulose coating membrane thicknesses and in-vivo Ti values. A colon arrival time of 5 h was reported in our subjects by gastrointestinal magnetomarkergraphy. PCDCs having a mean coating thickness of 64 +/- 1 microm for no. 0 capsules and of 57 +/- 1 microm for no. 2 capsules were thought to deliver caffeine to the human colon efficiently.

A dissolution test for a pressure-controlled colon delivery capsule: rotating beads method.

The rotating beads method is a new in-vitro dissolution test proposed for drugs formulated as pressure-controlled colon delivery capsules (PCDCs). The apparatus consisted of a glass vessel (500 mL) containing 4-mm (i.d.) glass beads (5000, 10000 or 15000) and dissolution medium (0-067 M phosphate buffer, pH 7; 25, 50 or 100 mL) containing polyvinyl alcohol (PVA; 5, 10 or 20 w/v%) to simulate the viscosity of the colon. The vessel was rotated at 5, 10 or 25 rev min(-1) and the temperature was maintained at 37 degrees C. Fluorescein was used as a model drug to explore the optimized conditions under which differences in the drug dissolution rate are detected between colon delivery systems. Fluorescein was formulated in four types of colon delivery systems. One was a tablet coated with an enteric polymer, Eudragit S-100, and the other three were PCDCs prepared with different thicknesses of ethylcellulose coating membrane (type I, II, III). The dissolution behaviour of fluorescein from the PCDC formulation was significantly different from that of the Eudragit S-100-coated tablets, when the dissolution conditions were as follows: rotation speed, 10 rev min(-1); bead number, 10000; dissolution medium, 50mL with 10% PVA. This dissolution method was applied to acetaminophen sustained-release tablets and two other drugs having low solubility in the colon, tegafur and 5-aminosalicylic acid. Similarly, significant differences in the dissolution rates of drugs from the PCDC formulation and the enteric tablet were detected. There was good correlation between the in-vitro dissolution rates and in-vivo absorption rates using T50 (the time for half of the amount of drug to be released from the preparation) and Cmax/Tmax (enteric tablet) or Cmax/(Tmax-Ti) (PCDC), where Ti is the first appearance time in the systemic circulation. The rotating beads method is a valuable technique for evaluating the dissolution rate of drugs formulated in PCDC.

Application of pressure-controlled colon delivery capsule to oral administration of glycyrrhizin in dogs.

A colon delivery system has been used to improve the bioavailability of glycyrrhizin, a glycoside of glycyrrhetic acid. The bioavailability of glycyrrhizin is low when administered in conventional oral galenic dosage forms because glycyrrhizin is enzymatically hydrolysed both in the stomach and in the intestine. It was reasoned that if large amounts of glycyrrhizin were directly delivered to the colon, enzymatic activity should be reduced due to saturation so that intact glycyrrhizin could be absorbed into the systemic circulation. Based on this assumption, pressure-controlled colon delivery capsules (PCDCs) were used as a colon delivery system. Eight types of glycyrrhizin solution were prepared and were introduced into PCDCs. After oral administration of the test PCDCs to beagle dogs, blood samples were obtained over 24 h and plasma glycyrrhizin concentrations were measured by an HPLC method. With PCDCs containing aqueous glycyrrhizin and propylene glycol solutions, plasma glycyrrhizin levels were extremely low and the bioavailabilities of glycyrrhizin were 0.6% and 0.4%, respectively. When Labrasol was added to both types of glycyrrhizin solution, the bioavailability was improved to 4.6% for aqueous solution and 3.8% for propylene glycol solution. When a surfactant, Polysorbate 80, was added in combination with Labrasol, synergistic effects were not obtained. Furthermore, dose-dependent effects of Polysorbate 80 were not obtained. Labrasol, which is a component of self-emulsifying drug delivery systems (SEDDS), has been shown to strongly improve the bioavailability of glycyrrhizin from the colon.

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.

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.

大腸内圧崩壊型大腸デリバリーカプセルｉｎｔｅｓｔｉｎａｌ　ｌｕｍｉｎａｌ　ｐｒｅｓｓｕｒｅ‐ｃｏｎｔｒｏｌｌｅｄ　ｃｏｌｏｎ　ｄｅｌｉｖｅｒｙ　ｃａｐｓｕｌｅ（ＰＣＤＣ）のコーティング機による量産法の確立とその大腸送達性評価

A new method for preparing large amounts of intestinal luminal pressure-controlled colon delivery capsule (PCDC) which employs a pharmaceutical coating machine, Hicoater-mini®, has been developed. As a model drug, fluorescein (FL) powder was suspended with suppository base, polyethylene glycol (PEG) 1000, at 50°C, and was hardened in the capsular shape. The capsular shaped suppositories were coated with 5w/v % ethanolic EC (7G grade) solution by a coating machine. By increasing the coating time from 55min to 75min, the mean coating thickness of PCDCs increased. Several kinds of #0 PCDCs having the mean EC coating membrane thickness of 141±7 μm (type 1), 166±4 μm (type 2), 188±4 μm (type 3), 211±4 μm (type 4) as well as #2 PCDCs having thickness of 102±3 μm (type 5) and 110±5 μm (type 6) were administrated to beagle dogs. The mean first appearance times (Tis) of FL into the systemic circulation from #0 PCDCs were 2.3±0.5 for type 1, 3.3±0.5 for type 2, 4.8±1.0 for type 3 and 7.8±1.7hr for type 4 preparations while the mean Tis of #2 PCDCs were 3.2±0.4 for type 5 and 3.8±0.4 hr for type 6, respectively. Therefore, it was suggested that types 2, 3 and 5 PCDCs were delivered to the colon.

Technology to Obtain Sustained Release Characteristics of Drugs after Delivered to the Colon

To determine the necessary technology by which sustained drug release is obtained after drug is delivered to the colon, two kinds of microcapsules were prepared and were filled in a pressure-controlled colon delivery capsule (PCDC). As a model drug 5-aminosalicylic acid (5-ASA) was used, because the target site of 5-ASA is the entire large intestine. 5-ASA was microencapsulated using a water-insoluble polymer, ethylcellulose (EC) or with pH-sensitive polymers, Eudragit™ L-100 or S-100 and encased in PCDC. The particle size of these microcapsules was around 800 μm and the loading efficiencies of 5-ASA were approximately 90%. In vitro dissolution tests were performed with the prepared microcapsules. The release rate of 5-ASA from the microcapsules was significantly prolonged as compared to 5-ASA powder, although there were no significant differences in the release rates between these microcapsules. By incorporating the 5-ASA microcapsules into PCDC, sustained release PCDCs for colon delivery were prepared and in vivo evaluation was performed using beagle dogs. As a fast release colon delivery system, PCDCs were prepared with 5-ASA powder suspended in suppository base. After oral administration of the test preparations to beagle dogs, plasma 5-ASA concentrations were measured and sustained release characteristics of 5-ASA from the test preparations were evaluated from the plasma 5-ASA concentration-time profiles. The first appearance time of 5-ASA into the systemic circulation after oral administration were 3 h for all the colon delivery preparations and it was thought that these test preparations were delivered to the colon. Both EC microcapsules and Eudragit S-100/RS-100 microcapsules in PCDC showed longer the mean residence time MRT, 8.2 ± 0.6 h and 8.7 ± 0.9 h, than Eudragit L-100/RS-100 microcapsules in PCDC where the MRT was 6.6 ± 0.2 h. Since PCDCs containing 5-ASA powder exhibited a MRT of 7.0 ± 1.0 h, these two types of preparations have suggested sustained release characteristics.

大腸ターゲティング徐放性製剤技術

To determine the necessary technology by which sustained drug release is obtained after drug is delivered to the colon, two kinds of microcapsules were prepared and were filled in a pressure-controlled colon delivery capsule (PCDC). 5-aminosalicylic acid (5-ASA) was microencapsulated with a water-insoluble polymer, ethylcellulose (EC) or with pH-sensitive polymers, Eudragit™ L-100 or S-100 and encased in PCDC, After oral administration of the test preparations to beagle dogs, the first appearance time of 5-ASA into the systemic circulation were 3 hr for all the colon delivery preparations. These test preparations were thought to be delivered to the colon. Both EC microcapsules and Eudragit S/RS microcapsules in PCDC showed longer mean residence time MRT, 8.2±0.6 hr and 8.7±0.9 hr, than Eudragit L/RS microcapsules in PCDC of which MRT was 6.6±0.2 hr, Since PCDC containing 5-ASA powder exhibited a MRT of 7.0±1.0 hr, these two types of preparations have sustained release characteristics.

Characterization of Norfloxacine Release from Tablet Coated with a New pH-Sensitive Polymer, P-4135F

A new pH-sensitive polymer, P-4135F, was evaluated as a colon delivery device for norfloxacine (NFLX) which is used for the therapy of patients with Vero toxin-producing Escherichia coli gastroenteritis. P-4135F has a dissolution threshold pH of 7.2 which is higher than the conventional pH-sensitive polymers, Eudragit S100 and L100. To compare the dissolution site of P-4135F coated tablets with other enteric polymer coatings, mini-tablets containing sodium fluorescein (FL) as a model drug were prepared by coating them with the three polymers. After oral administration of FL mini-tablets to rats, the first-appearance time, Ti, of FL into the systemic circulation was measured. The Tis were 0.7 ± 0.2h for Eudragit L100, 1.8 ± 0.4 h for S100 and 2.0 ± 0.3 h for P-4135F. Direct inspection of the dissolution process of the FL mini-tablets after oral administration to rats was performed by abdominal incision studies. All of the coated FL mini-tablets started to dissolve in the rat ileum. The dissolution sites were identified to be proximal to the ileocecal junction for P-4135F, at the middle part of the ileum for Eudragit SI00 and at the proximal part of the ileum for Eudragit L100. NFLX tablets with different membrane thicknesses of P-4135F were prepared and were orally administered to beagle dogs. The colon delivery efficiency was evaluated by measuring the Ti of NFLX into the systemic circulation. The mean Tis were 1.33 ± 0.33 h for 56.8 ± 0.5 μm membranes, 3.75 ± 0.25 h for 64.6 ± 0.7 μm membranes, 4.00 ± 1.00 h for 70.5 ± 0.5 μm membranes and 3.00 ± 1.00 h for 74.9 ± 0.4 μm membranes. By comparing the Ti, 4.33 ± 0.33 h, obtained after oral administration of NFLX in a pressure-controlled colon delivery capsule, and the colon arrival time, 3.5 ± 0.3 h, determined by a sulfasalazine test in beagle dogs, P-4135F coated NFLX tablets appeared to dissolve and disintegrate before reaching the colon. Studies using rats and beagle dogs have suggested that P-4135F dissolves in the lower part of the small intestine, i.e., the ileum. These studies also suggest that this new polymer will be useful for the delivery of NFLX to the lower part of the small intestine.

New preparation method of intestinal pressure-controlled colon delivery capsules by coating machine and evaluation in beagle dogs

A new method for preparing large amounts of pressure-controlled colon delivery capsules (PCDCs) which employs a pharmaceutical coating machine, Hicoater-mini, has been developed. In contrast to our original method for preparing PCDCs where the inner surfaces of gelatin capsule were coated with the water-insoluble polymer ethylcellulose (EC), PCDC were directly prepared by coating the capsular shaped suppositories with EC. As a model drug, fluorescein (FL) was used in this study. FL powder was suspended with the suppository base, polyethylene glycol (PEG) 1000, at 50°C, and was hardened in the capsular shape the sizes of which were #0 and #2. The capsular shaped suppositories were coated with 5% w/v ethanolic EC (7G grade) solution by a coating machine. By increasing the coating time from 55 to 75 min, the mean coating thickness of #0 PCDCs increased from 141±7 to 211±4 μm. In the case of #2 PDDCs, the mean coating thickness increased from 102±3 to 110±5 μm by increasing the coating time from 35 min to 40 min. Several kinds of #0 PCDCs having the mean EC coating membrane thickness of 141±7 μm (type 1), 166±4 μm (type 2), 188±4 μm (type 3), 211±4 μm (type 4) as well as #2 PCDCs having thickness of 102±3 μm (type 5) and 110±5 μm (type 6) were used for in vivo evaluation using beagle dogs. After oral administration of the test preparations containing 30 mg of FL, blood samples were obtained from the jugular vein and plasma FL levels were measured. The first appearance time, T i, of FL in the plasma was used as a parameter for the estimation of the release time of FL from PCDCs in the gastrointestinal tract. The mean T i of #0 PCDCs were 2.3±0.5 for type 1, 3.3±0.5 for type 2, 4.8±1.0 for type 3 and 7.8±1.7 h for type 4 preparations while the mean T i of #2 PCDCs were 3.2±0.4 for type 5 and 3.8±0.4 h for type 6, respectively. There were good correlations between EC coatings.

Evaluation of intestinal pressure-controlled colon delivery capsule containing caffeine as a model drug in human volunteers

The delivery ability of a pressure-controlled colon delivery capsule (PCDC) containing caffeine as a test drug was evaluated after oral administration to healthy male human volunteers. The driving force causing PCDC disintegration in the intestinal tract is the physiological luminal pressure which results from peristalsis. Three kinds of PCDCs having different thickness of a water-insoluble polymer membrane were prepared by coating the inner surface of the gelatin capsules with ethylcellulose (EC). The mean thicknesses were 40±1 (S.E.) for type 1, 44±1 for type 2 and 50±1 μm for type 3 PCDC, respectively. Caffeine was dissolved with a suppository base (PEGs 400 and 1000) and the capsules were filled. Doses were 15, 45 or 75 mg. After blank saliva samples were obtained, test preparations were orally administered to the volunteers and saliva samples were collected for 1 min intervals hourly from 1 to 10 h in the fasted state study, and from 1 to 20 h and at 25 h in the fed state study. Caffeine concentrations in the saliva samples were analyzed by HPLC. The maximum salivary caffeine excretion rate increased as the oral caffeine dose increased. The maximum salivary caffeine excretion rate increased predominantly compared to the pre-dose level in 75 mg dose study. Therefore, all following studies were performed with this dose. The first appearance time of caffeine into the saliva, T i, was used as a parameter to estimate the disintegration time of test preparations in the gastrointestinal tract. The mean T i of types 1, 2, and 3 PCDCs were 3.0±0.4, 4.0±0.4 and 4.5±0.3 h, respectively. After oral administration of 75 mg caffeine in plain gelatin capsule as a reference preparation, caffeine appeared in the saliva within 0.5 h. The mean hardness of the PCDCs were 1.05±0.10 (type 1), 1.55±0.06 (type 2) and 2.08±0.15 newton (type 3), respectively. There were good correlations between three parameters: EC coating membrane thickness, hardness and T i (determination coefficient r 2=0.935 between T i and thickness, r 2=0.998 between thickness and hardness, r 2=0.958 between hardness and T i). The effect of food intake on the delivery ability was examined with type 3 PCDCs. Food intake prolonged the mean T i from 4.5±0.3 to 7.8±1.3 h. This increase is thought to be ascribed to prolonged gastric emptying time. Comparison with reported colon arrival times indicates that the type 3 PCDC functions in colon delivery of caffeine and is thought to be applicable to other drugs.

Importance of dissolution process on systemic availability of drugs delivered by colon delivery system

The relationship between in vitro drug release characteristics from colon delivery systems and in vivo drug absorption was investigated using three kinds of delayed-release systems. 5-aminosalicylic acid (5-ASA), tegafur (FT) and carbamazepine (CBZ) were selected as model drugs. Pressure-controlled colon delivery capsules (PCC) for liquid preparations, time-controlled colon delivery capsules (TCC) for liquid and solid preparations and Eudragit S coated tablets for solid preparations were used in this study. At first, in vitro dissolution tests for all preparations were performed. Drug release from solid preparations was delayed compared to that from liquid preparations with all three drugs. Next, these preparations were administered to fasted beagle dogs. For 5-ASA, the mean C maxs (peak level) of Eudragit S coated tablets and PCC were 5.52 and 16.89 μg ml −1, respectively. The mean T maxs (time when drug reached peak level) were 3.0 and 5.3 h. AUCs were 22.57 and 48.09 μg·h ml −1, respectively. For FT, C maxs of Eudragit S coated tablet and PCC were 0.87 and 1.46 μg ml −1, and T maxs were 7.0 and 6.7 h, respectively. AUCs were 9.73 and 15.55 μg·h ml −1 and bioavailabilities were 43.79 and 70.84%. For CBZ, the mean C maxs of liquid preparations and solid preparations were 0.37 and 0.22 μg ml −1, respectively. The mean T maxs were 4.7 and 4.3 h. AUCs were 0.673 and 0.392 μg·h ml −1. With liquid preparations, drug was thought to contact to the colonic membrane easily because of lack of interference by stools, and to be absorbed well as compared with solid preparations. From these findings, drug release from colon delivery systems and drug dissolution in the colonic lumen are very important factors for the systemic availability of drugs from the colon delivery systems.

ペプチド・蛋白質性薬物の大腸デリバリーシステム

The advances in biotechnology and medicinal chemistry in 1980s made it possible to produce large amount of useful peptide/protein drugs. However, their clinical use is limited to parenteral route. Among them, we selected recombinant human granulocyte-colony stimulating factor (rhG-CSF) as a representative peptide/protein drug. For the sake of the QOL of patients, non-parenteral, especially oral, preparation is needed now. For the development of oral peptide/protein preparations, colon delivery system has attracted the interests of many scientists. The most important reason is the lower hydrolytic enzyme activities in the colon than in the small intestine. We have developed two colon delivery capsules (CDC). One is intestinal inner pressure-controlled CDC (PCDC) and the other is release time-controlled CDC. As PCDC does not receive the effect of food on the delivery efficiency of drugs to the colon, PCDC was used for the preparation of oral rhG-CSF. At first, the colon delivery ability of PCDC was ascertained by administering 5-aminosalicylic acid (5-ASA), a drug for inflammatory bowel disease, in PCDC. After oral administration of 5-ASA in PCDC to beagle dogs, plasma 5-ASA levels vs. time curves were analyzed. The first appearance time of 5-ASA into the systemic circulation was approximately 4hr which corresponds to the colon arrival time in the beagle dogs. Based on these results, rhG-CSF was formulated into the PCDC and was orally administered to beagle dogs, 25 μg/kg. Blood samples were collected consecutively for 96 hr and blood total leukocyte counts (BTLC) were measured. At 8 hr after administration, BTLC increased to 1.3 times higher than the pre-dose level and thereafter declined gradually to the normal level at 96 hr. These results support the usefulness of PCDC for designing the oral delivery system of peptide/protein drugs.

Application of a Colon Delivery Capsule to 5-Aminosalicylic Acid and Evaluation of the Pharmacokinetic Profile after Oral Administration to Beagle Dogs

Pressure-controlled colon delivery capsule (PCC) containing 5-aminosalicylic acid (5-ASA) for the treatment of inflammatory bowel disease (IBD) was prepared and evaluated by an in vivo experiment using beagle dogs. As a reference drug, sulfasalazine (SASP), prodrug of 5-ASA, was used as a plain gelatin capsule preparation. After the oral administration of SASP at the dose of 25.0 mg/kg, the mean time when the plasma 5-ASA concentration reaches to its maximum (Tmax) was 9.0 hr. In the case of 5-ASA administered in PCC, at the doses of 12.5 and 25.0 mg/kg, Tmaxs were 5.3 and 5.3 hr, respectively. Although the time for the first appearance of 5-ASA into the systemic circulation was almost the same value between SASP capsule and PCC containing 5-ASA, longer Tmax was observed from SASP capsule than from PCC. These results suggest that this 5-ASA preparation would be an useful dosage form for the therapy of IBD from the point of avoiding the side effect of sulfapyridine, one of the metabolites of SASP.

エチルセルロース製大腸デリバリーカプセルの大腸疾患治療薬への適用

We have developed a pressure-controlled colon delivery capsule (PCC) made of ethylcellulose and reported its application to a protein drug, recombinant human granulocyte colony-stimulating factor (rhG-CSF) in last year. In this report, PCC was applied to the drugs for colon diseases, and the relationship between the drug release characteristics from colon delivery systems and bioavailability (BA) was investigated using Eudragit S coated tablet as a reference solid preparation. As model drugs, 5-aminosalicylic acid (5-ASA) and tegafur (FT) were selected. With each drug, PCC and Eudragit S coated tablet were prepared, and these test preparations were administered to fasted male beagle dogs and drug concentration in the systemic circulation was measured by HPLC methods. In addition, the in vitro dissolution tests were performed according to JP XIII method. Mean AUC values of 5-ASA, 25 mg/kg, were 22. 57 for Eudragit S coated tablet and 48.09 μg·h/ml for PCC, respectively. On the other hand, mean AUG values of FT, 1 mg/kg, were 9.73 for Eudragit S coated tablet and 15.55 μg·h/ml for PCC. Mean AUC values of PCC were significantly higher than those of Eudragit S coated tablets, with two drugs. On the other hand, the in vitro dissolution test showed that the release rate of drug from tablet delayed as compared to that from PCC. As less water is present in the colon than in the small intestine, it was speculated that in the case of Eudragit S coated tablet, the solid materials inside the colon such as stools decreased both the amount and the time of drug molecules being contact to the gut wall, and drug molecules were not well dissolved by the gastrointestinal fluid, because solid preparation was used. Both the release rate from PCC and the dissolution rate of drugs were improved, because PCC can contain drug molecules as liquid state. In conclusion, PCC is thought to be safe and useful colon delivery system for the oral delivery of protein drugs and drugs for colon diseases.