Casein Hydrolysate as a Rapid and/or Enteric Dissolving Additive for Oral Drugs

ABSTRACT

Two types of casein hydrolysates, casein A (mean peptide length 3.3) and casein B (mean peptide length 17.4) were prepared by the enzymatic hydrolysis of casein, and their effects on in vitro dissolution rates and oral bioavailability of drugs were evaluated. The in vitro dissolution behavior of the kneaded mixture of three drugs (diclofenac acid, diazepam, and prednisolone) with caseins A and B were significantly improved compared to the drugs alone, even at 1:1 weight ratio of drug and casein hydrolysate, even though casein A and casein B did not interact with drug molecules in the kneaded mixture. Only diclofenac, an acidic drug, showed an increased dissolution rate with added casein hydrolysates, and a more rapid dissolution with casein A than with casein B was observed. When the dissolution of prednisolone from kneaded mixture was compared at pH 1.2 and 6.8, the dissolution rate of prednisolone from the casein A kneaded mixture was considerably higher than that of prednisolone powder at both pHs, and the rate from the casein B kneaded mixture was higher only at pH 6.8. The plasma concentration-time profile showed that prednisolone was completely and rapidly absorbed from the casein A kneaded mixture as well as the prednisolone solution. In addition, prednisolone in the kneaded mixture with casein B was more difficult to absorb up to 1 hr after administration in comparison to prednisolone powder. The slow and lowered absorption of prednisolone by casein B might be explained by conversion of casein B to a shorter soluble peptide in the gastrointestinal tract and by the slow dissolution of prednisolone at acidic conditions. The toxicological tests revealed that casein hydrolysate is a safe drug carrier. Consequently, casein hydrolysates might be safely used to control the dissolution rate and bioavailability of a variety of drugs, depending on the peptide length of the casein fragments.     

Triblock polymeric micelles as carriers for anti-inflammatory drug delivery

Abstract

This study evaluated the properties of poly(ethylene oxide)-b-poly(n-butyl acrylate)-b-poly(acrylic acid) (PEO-PnBA-PAA) polymeric micelles as carriers for anti-inflammatory drugs (prednisolone and budesonide). The micelles comprising a hydrophobic PnBA core and a PEO/PAA corona showed average diameter less than 40?nm. The size of the drug-loaded micelles did not change during eight hours into media that mimic physiological fluids indicating high colloidal stability. The calculation of Flory–Huggins parameter showed greater compatibility between budesonide and micellar core suggesting its location in the micellar core, whereas prednisolone was located also into the interface layer. This observation correlated further with slower release of budesonide, especially in acid medium (pH?=?1.2). The inclusion of budesonide into micelles showed significant protective effect against the cytotoxic damage induced by the co-cultivation of differentiated human EOL-1 and HT-29 cells. This study revealed the capacity of PEO-PnBA-PAA terpolymer as carrier of nanosized micelles suitable for oral delivery of anti-inflammatory drugs.     

Buccal films of prednisolone with enhanced bioavailability

Abstract

The conventional formulation of prednisolone is considered to be low in efficacy, primarily on account of their failure in providing and maintaining effective therapeutic drug levels. This study aims to focus on development of a mucoadhesive buccal delivery system with a twofold objective of offering a rapid as well as a prolonged delivery of prednisolone coupled with enhanced therapeutic efficacy. Buccoadhesive films of prednisolone were prepared by solvent-casting method using hydroxyl propyl methyl cellulose (K100), Carbopol 940 and/or Eudragit® NE 40?D. Placebo films possessing the most desirable physicomechanical properties were selected for drug loading. The effect of polymer and its content on film properties, i.e. mucoadhesive strength, swelling and hydration, in vitro drug release was studied. Based on these studies, film F7D was selected for ex vivo permeation across porcine cheek mucosa. The steady state flux of prednisolone across the buccal mucosa was found to be 105.33?±?32.07?µg/cm²/h. A comparative pharmacokinetic study of prepared film (F7D) and oral suspension of prednisolone was conducted. In vivo data of buccal film show greater bioavailability (AUC_0–α: 24.26?±?4.06?µg.h/ml versus 10.65?±?2.15?µg.h/ml) and higher C_max (2.70?±?0.38?µg/ml versus 2.29?±?0.32?µg/ml) value when compared to oral suspension. The data observed from this study highlight the feasibility of the buccal route as a viable option for delivery of prednisolone.     

Fabrication of poly(γ-glutamic acid)-based biopolymer as the targeted drug delivery system with enhanced cytotoxicity to APN/CD13 over-expressed cells

Poly(γ-glutamic acid)-based targeted drug delivery system (PAMCN) targeting transmembrane metalloprotease aminopeptidase-N (APN/CD13) was fabricated and evaluated for the enhancement of targeting efficiency and cytotoxicity. The cisplatin (CDDP) loading content of PAMCN was about 36?±?5% and PAMCN showed a sustainable release profile with a half-maximal release time (t_1/2) of 23?h. The average size of PAMCN was 132?±?18?nm determined by light scattering (LS) and 158?±?67?nm by atomic force microscopy (AFM). Flow cytometry and fluorescence microscope analysis showed that the drug carrier (PAMN) could specifically bind to human umbilical vein endothelial cells (HUVEC). PAMCN enhanced the efficacy of CDDP to HUVEC cells with the half maximal inhibitory concentration (IC₅₀) value decreased to 90.83?±?33.00?μg/ml comparing with free CDDP treatment and showed less tube formation amounts (p?<?0.01) than free CDDP in matrigel angiogenesis inhibition assay in vitro. In vivo toxicity experiment indicated that the survival rate of KM mice in PAMCN group was 100% and PAMCN reduced the hepatic and renal toxicity significantly compared to free CDDP group. Therefore, this novel drug delivery system presents a promising potential for antiangiogenic chemotherapy.     

Evaluation of dose-related pharmacokinetics and pharmacodynamics of prednisolone in man

The pharmacokinetics and pharmacodynamics of prednisolone were evaluated in normal male volunteers. Seven subjects completed 3 phases: 16.4–and 49.2–mg iv prednisolone, and a phase with no drug to assess baseline responses. Plasma concentrations of prednisolone and urine concentrations of prednisolone and 5 metabolites were assayed by HPLC. Protein binding of prednisolone was measured by ultrafiltration. The polyexponential disposition of free and total plasma prednisolone were evaluated and apparent parameters were compared between doses. Suppression of plasma cortisol and alterations in blood basophil and helper-T cell trafficking were used as pharmacodynamic indices. Pharmacodynamic models were used to relate total or free plasma prednisolone concentrations to each of these effects generating response parameters and IC₅₀ (50% inhibitory) concentrations common to both doses. The pharmacokinetics of total drug were comparable to previous findings with CLand V_ss increasing with dose. Free prednisolone exhibited slight capacitylimited elimination and distribution as CLand V_ss decreased with the larger dose. Pharmacodynamic models jointly fitting all three phases characterized the suppression/trafficking phenomena equally well with use of total or free drug concentrations. In each case the models provided realistic values of parameters relating to steroid sensitivity-in particular IC₅₀-and to the underlying physiology of the affected systems. This study comprehensively elucidates the complexities of prednisolone pharmacokinetics and demonstrates how plasma concentration-time profiles of total or free prednisolone can be utilized for evaluation of prednisolone pharmacodynamics.Supported in part by Grants 24211 and 150-1885-0 from the National Institute of General Medical Sciences, National Institutes of Health. Presented in part at The American Society for Clinical Pharmacology and Therapeutics meeting, San Antonio, Texas. (Abstract:Clin. Pharmacol. Ther,49:179, 1991).     

Preparation of liposomal brucine and its pharmaceutical/pharmacodynamic characterization

Aim： To prepare a novel transdermal preparation of liposomal brucine （LB） and investigate its pharmaceutical/pharmacodynamic characterization. Methods： LB was prepared by a modified ethanol-dripping method. Its drug encapsulation efficiency （EE）, particle size, in vitro release, and skin permeation were studied. Furthermore, a safety evaluation and pharmacodynamic analysis of LB, including acute dermal toxicity, skin irritation, and analgesic and anti-inflammatory effects were investigated. Results： the EE of LB was 72% and the mean particle size of the liposomes was 55.4 nm. The in vitro release profile indicated that less than 68% of the encapsulated brucine was released in 10 h. A skin permeation study showed that compared with the free brucine, LB exhibited higher cumulative drug permeation through the skin and lower drug accumulation in skin tissue, indicative of an obvious promotion of skin permeation with liposomal encapsulation. The acute dermal LD50 of LB was greater than 100 mg/kg （brucine content） and skin irritation tests revealed that LB had no irritation to both integrity and broken skin. A pharmacodynamic evaluation of LB was performed by xylene-induced mouse ear edema test and acetic acid-induced writhing test at the dosage of 1.5, 3, and 6 mg/kg, respectively. The results showed that anti-inflammatory activities and analgesic effects of brucine encapsulated were significantly higher than that of the free brucine （P〈0.01）. Moreover, LB maintained a remarkably longer antiinflammatory and analgesic duration. Conclusion： It can be proposed that LB prepared here could represent a safe, effective and promising transdermal formulation for analgesic and anti-inflammatory effects.     

Optimizing the therapeutic index of liposomal glucocorticoids in experimental arthritis

Small-sized (less than 150 nm) long-circulating liposomes (LCL) may be useful as drug-targeting vehicles for anti-inflammatory agents in arthritis, since they selectively home at inflamed joints after i.v. administration. Previously it was shown in experimental arthritis that encapsulation of glucocorticoids (GC) as water-soluble phosphate esters in PEG-liposomes resulted in a strong improvement of the anti-inflammatory effect as compared to the free drug. In the present study, we compared the therapeutic activity and adverse effects induced by 3 different GC encapsulated in LCL in an attempt to further optimize the therapeutic index of liposomal GC in arthritis. Our data showed that with GC (dexamethasone, budesonide) of higher potency than prednisolone, the therapeutic activity of liposomal GC can be increased. However, side effects at the level of body weight and hyperglycemia were noted, related to the sustained free GC level observed after injection of the liposomal GC. An inverse relationship with the clearance rate of the free GC in question was shown. This study stresses the importance of a high clearance rate of the GC to be encapsulated for achieving a maximal therapeutic index with liposomal GC. Therefore high-clearance GC, which until now are only applied in local treatment approaches, may be very useful for the development of novel, highly effective anti-inflammatory preparations for systemic treatment of inflammatory disorders.     

Randomly 50% N-acetylated low molecular weight chitosan as a novel renal targeting carrier

Selective targeting of drugs to kidneys may improve renal effectiveness and reduce extrarenal toxicity. Using fluorescence imaging, we found for the first time that randomly 50% N-acetylated low molecular weight chitosan (LMWC) selectively accumulated in the kidneys, especially in the renal tubules after i.v. injection in mice. To develop and evaluate the novel renal drug carrier, prednisolone, used as a model drug, was covalently coupled with various molecular weight LMWCs via a succinic acid spacer. The mean residence time (MRT) in plasma of prednisolone conjugates increased as the molecular weight increased. The conjugate with molecular weight 19 kD (conjugate-19k) displayed the highest accumulation rate in the kidneys, which was 14.06 ± 2.81% of the administered dose 15 min after i.v. injection. The total amount of the conjugate-19k in the kidneys was 13-fold higher than that of controlled prednisolone group. Both conjugate-19k and conjugate-31k had higher retention and about 10% of injected dose was still retained in the kidneys after 120 min. Additionally, MTT assay showed LMWCs were noncytotoxic towards L929 and NRK-52E cells. Conclusion can be drawn that the coupling of prednisolone to the proper molecular weight LMWC results in increased prednisolone concentration in the kidneys. Therefore, LMWC with a proper molecular weight can be applied as a promising carrier for renal targeting.     

Alterations in prednisolone disposition as a result of time of administration, gender and dose.

The disposition of total and free prednisolone has been studied in four male and four female volunteers, each of whom received an intravenous dose of 0.075 mg/kg (low) and 1.5 mg/kg (high) of prednisolone at both 06.00 h and 18.00 h. For the low dose, free prednisolone clearance was 14% lower (P = 0.012) and time-averaged prednisolone free fraction was 22% higher (P less than 0.001) in the morning, there being no circadian difference in total prednisolone clearance. There was no circadian differences in prednisolone disposition at the high dose. These findings are consistent with a mechanism in which cortisol causes a simultaneous competitive inhibition of prednisolone clearance and plasma protein binding at low, but not at high prednisolone doses. Prednisolone clearance was higher in female than in male subjects, the mean increase being 18% (P = 0.022) for total prednisolone and 21% (P = 0.036) for free prednisolone. Mean total prednisolone clearance and steady-state distribution volume were two-fold higher at the high vs the low dose (P less than 0.001), but free prednisolone clearance showed a dose dependent decrease of 11% (P = 0.019). There was no change in free prednisolone steady-state distribution volume.     

Develop a novel superparamagnetic nano-carrier for drug delivery to brain glioma

Abstract

Magnetic drug carrier has been employed in drug delivery for over 30 years. Modern nanotechnology has improved its efficiency dramatically by decreasing its diameter into nano-scale. It may help chemotherapeutic agents penetrate BBB and raise local drug concentration in brain, which is the ideal model for glioma treatment. In our study, magnetic carrier was fabricated with octadecyl quaternized caroxymethyl chitosan (OQCMC), hydrophobic Fe₃O₄ ferrofluid and cholesterol, which showed a uniform diameter of 20?nm under transmission electronic microscopy and superparamagnetic character in vibration sample magnetical measurement system. To investigate the efficacy of drug delivery, paclitaxel was used as loaded drug and analyzed by the HPLC. Results showed that magnetic carrier released drugs for more than 20?d in vitro and maintain the drug concentration above 0.4?μg/g for 16?h in rat brain after magnetic targeting. Drug concentration increased by 1–3 folds when delivered by carrier without magnetic targeting, and by 3–15 folds after magnetic targeting. Cellular study revealed that the magnetic carrier was clearly localized in the targeted cortex neural cells and U251-MG cell lines. These results showed that this magnetic carrier is capable of maintaining high drug concentration in magnetically targeted area and carrying drugs or genes into cells, which is potentially promising for local chemotherapy to brain tumors.     

Anti-inflammatory activity of injectable dexamethasone acetate-loaded nanostructured lipid carriers

This work studied the intravenous injection formulation of nanostructured lipid carriers (NLCs) loaded with dexamethasone acetate (DA), a poorly water-soluble drug. The goal of this study was to design nanoparticles which could improve therapeutic efficacy of DA on inflammations. Based on the optimized results of single-factor screening experiment, DA-loaded NLCs (DA-NLCs) prepared by an emulsification-ultrasound method were found to be relatively uniform in size (178?±?4?nm) with a negative zeta potential (-38?±?4 mV). The average drug entrapment efficiency was 91?±?3 %. In vitro release tests indicated DA-NLCs possessed a sustained release characteristic and the accumulative release percentage was near 80 % at 23?h. DA-NLCs exhibited an average peak concentration of DA (7.6 μg/ml) in the pleural exudate after intravenous administration to an experimental model of γ-carrageenan-induced pleuritis rats, which was 8.3 times higher than that of free DA (0.9 μg/ml). The γ-carrageenan-induced edema test showed that the anti-acute inflammatory activity of DA-NLCs was stronger than that of free drug at the same drug concentration (P<0.05). In addition, biodistribution results clearly indicated that DA-NLCs preferentially accumulated in mice livers and lungs after intravenous injection. These results revealed that injectable NLCs may serve as a promising carrier for DA, greatly enhancing the selective effect on inflammatory sites, reducing systematic side effects and may be a potential carrier to increase therapeutic efficacy on inflammatory diseases.     

Anti-inflammatory activity of injectable dexamethasone acetate-loaded nanostructured lipid carriers

This work studied the intravenous injection formulation of nanostructured lipid carriers (NLCs) loaded with dexamethasone acetate (DA), a poorly water-soluble drug. The goal of this study was to design nanoparticles which could improve therapeutic efficacy of DA on inflammations. Based on the optimized results of single-factor screening experiment, DA-loaded NLCs (DA-NLCs) prepared by an emulsification-ultrasound method were found to be relatively uniform in size (178?±?4?nm) with a negative zeta potential (-38?±?4 mV). The average drug entrapment efficiency was 91?±?3 %. In vitro release tests indicated DA-NLCs possessed a sustained release characteristic and the accumulative release percentage was near 80 % at 23?h. DA-NLCs exhibited an average peak concentration of DA (7.6 μg/ml) in the pleural exudate after intravenous administration to an experimental model of γ-carrageenan-induced pleuritis rats, which was 8.3 times higher than that of free DA (0.9 μg/ml). The γ-carrageenan-induced edema test showed that the anti-acute inflammatory activity of DA-NLCs was stronger than that of free drug at the same drug concentration (P<0.05). In addition, biodistribution results clearly indicated that DA-NLCs preferentially accumulated in mice livers and lungs after intravenous injection. These results revealed that injectable NLCs may serve as a promising carrier for DA, greatly enhancing the selective effect on inflammatory sites, reducing systematic side effects and may be a potential carrier to increase therapeutic efficacy on inflammatory diseases.     

Randomly 50% N-acetylated low molecular weight chitosan as a novel renal targeting carrier

Selective targeting of drugs to kidneys may improve renal effectiveness and reduce extrarenal toxicity. Using fluorescence imaging, we found for the first time that randomly 50% N-acetylated low molecular weight chitosan (LMWC) selectively accumulated in the kidneys, especially in the renal tubules after i.v. injection in mice. To develop and evaluate the novel renal drug carrier, prednisolone, used as a model drug, was covalently coupled with various molecular weight LMWCs via a succinic acid spacer. The mean residence time (MRT) in plasma of prednisolone conjugates increased as the molecular weight increased. The conjugate with molecular weight 19 kD (conjugate-19k) displayed the highest accumulation rate in the kidneys, which was 14.06+/-2.81% of the administered dose 15 min after i.v. injection. The total amount of the conjugate-19k in the kidneys was 13-fold higher than that of controlled prednisolone group. Both conjugate-19k and conjugate-31k had higher retention and about 10% of injected dose was still retained in the kidneys after 120 min. Additionally, MTT assay showed LMWCs were noncytotoxic towards L929 and NRK-52E cells. Conclusion can be drawn that the coupling of prednisolone to the proper molecular weight LMWC results in increased prednisolone concentration in the kidneys. Therefore, LMWC with a proper molecular weight can be applied as a promising carrier for renal targeting.     

Receptor-mediated prednisolone pharmacodynamics in rats: Model verification using a dose-sparing regimen

Our receptor/gene-mediated model of corticosteroid action was tested and extended by examining the pharmacokinetics/dynamics of multiple low doses vs. a single higher dose of intravenously administered prednisolone in adrenalectomized male Wistar rats. Low-dose rats received 3 bolus doses (5 mg/kg) of prednisolone at 0, 0.5 and 1.0hr. High-dose animals were given a single 25 mg/kg dose of prednisolone. Both regimens were expected to produce equivalent net responses based on model predictions. Control rats were not dosed. The profiles of free hepatic cytosolic glucocorticoid receptors and the hepatic tyrosine aminotransferase (TAT) enzyme were examined. Plasma prednisolone concentrations showed bi-exponential decline for both doses using pooled animal data. Clearance of total plasma prednisolone was 4.16 and 3.21 L/hr per kg in low- and high-dose groups. Volume of distribution at steady state (1.50 L/kg) and central volume (0.6 L/kg) were similar for both groups. Receptor levels from 5–16 hr stabilized at 64% of the 0-hr control value. Receptor and TAT profiles were essentially superimposable for both dosing groups. Our previous model was used to simultaneously describe prednisolone plasma concentrations, hepatic receptors, and TAT activity. The ability of total plasma prednisolone (C_p), corticosteroid binding globulin (CBG)-free plasma prednisolone (C_CBG), and free plasma prednisolone (C_F) to describe the kinetics/dynamics were examined. The C_F values produced optimum fitting of all receptor data. The similarity of the two dosing groups supports the view that appropriately timed doses of a steroid can be used in an optimally efficacious manner by first filling all receptor sites and then replacing steroid as receptors are expected to recycle from nuclear/DNA binding sites as the steroid is eliminated.Supported in part by Grant No. 24211 from the National Institutes of General Medical Sciences, National Institutes of Health.     

抗肿瘤药物靶向载体系统的研究与开发

综述肿瘤靶向给药的基础和抗肿瘤药物靶向载体系统的发展。分类介绍普通被动靶向载药系统（如微乳、传统脂质体、聚合物纳米粒、固体脂质纳米粒、纳米脂质载体、药-脂结合物纳米粒等）、表面修饰的被动靶向载药系统及主动靶向载药系统（如免疫脂质体、免疫聚合物纳米粒及受体-配体介导靶向纳米载体）的研究与开发。在传统药物制剂的基础上，发展抗肿瘤药物的新型靶向载体系统，改善药物在体内的代谢动力学特性，增加药物定向富集到肿瘤部位甚至肿瘤细胞内，提高疗效，降低毒副作用，是近年来备受关注的课题。     

Drug stabilization and controlled release from AB3 type tetra block copolymer based polymersome

In order to increase the bioavailability of hydrophilic unstable drugs, polymersomes from AB₃ type tetra block copolymers composing of poly(ethylene glycol)-b-(3) poly(lactic acid) (EO-3LA) as a water-soluble drug delivery carrier have been investigated due to its unique properties such as high stability and high water soluble drug loading efficiency. The sizes of EO-3LA polymersomes determined by dynamic light scattering were ranged in 190?C220?nm with monodispersion. Its polymeric layer with 10?C20?nm at the outershell was observed by field emission scanning electron microscopy. The polymersomes showed low critical aggregation concentrations (9.2?C14.9?ug/ml). Anthocyanin was employed as a model drug for unstable drug in this study. The anthocyanin loading contents of EO-3LA polymersomes are depending on PLLA content in the polymers. The high loading contents (6.6?C7.0?wt%) of the polymersomes are due to their tight and rigid polymeric membranes. The polymeric membrane in EO-3LA polymersomes contributed to improve drug stability on various pHs. Moreover, this property induced sustained anthocyanin release pattern from the polymersome. Therefore, the polymersome has potential as a drug carrier for water-soluble and unstable drugs.     

The protective effect of tinoridine against carbon tetrachloride hepatotoxicity

The effect of tinoridine, an anti-inflammatory drug with a potent anti-peroxidative ability, on CCl₄ hepatotoxicity was investigated in rats. CCl₄ administration to rats produced not only marked increases in serum glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase but also decreases in liver microsomal cytochrome P-450 and glucose-6-phosphatase. These CCl₄-induced alterations in the enzyme activities were markedly decreased by pretreatment with tinoridine. The protective effect of tinoridine was also ascertained by histologic evaluation. α-Tocopherol also showed a similar protection, but anti-inflammatory drugs such as phenylbutazone, indomethacin, ibuprofen, and prednisolone failed to protect against the CCl₄-induced hepatotoxicity. These findings suggest that the anti-peroxidative action of tinoridine contributes to the protective effect against CCl₄ hepatotoxicity.     

Assessment of in vivo efficacy of eravacycline against Enterobacteriaceae exhibiting various resistance mechanisms: a dose-ranging study and pharmacokinetic/pharmacodynamic analysis

After the pharmacokinetic (PK) profile of eravacycline, a novel fluorocycline, was defined, understanding its pharmacodynamic (PD) profile became essential. This study aimed to assess the correlation of the PK/PD index fAUC/MIC (ratio of area under the free drug concentration–time curve to MIC) and its magnitude with eravacycline's efficacy against Enterobacteriaceae using an immunocompetent murine thigh infection model to resemble the immunocompetent environment in eravacycline's clinical trials. Eight Enterobacteriaceae isolates with various resistance mechanisms were tested. Eravacycline doses ranged from 1–10?mg/kg/day and were given either once daily (q24h) or divided into doses every 12?h (q12h) over the 24-h treatment period. Antibacterial efficacy was measured as the change in log₁₀CFU at 24?h compared with 0?h controls. Composite data were modelled using a sigmoid E_max model. Eravacycline MICs ranged from 0.125–0.5?µg/mL. The mean fAUC/MIC magnitudes required for stasis and 1-log reduction for the eight isolates were 2.9?±?3.1 and 5.6?±?5.0, respectively. Whilst the humanised eravacycline regimen (2.5?mg/kg q12h) pharmacokinetically achieves an fAUC_0–24 that is higher than the fAUC_0–24 achieved with the 5?mg/kg q24h dose, the latter was associated with greater efficacy, raising a suggestive correlation of the peak free drug concentration to MIC (fC_max/MIC) ratio with eravacycline's efficacy. This study showed that the magnitudes associated with eravacycline's efficacy in an immunocompetent murine thigh model appear to be close to achievable targets in human. These data support further development of eravacycline for treatment of infections caused by drug-resistant Enterobacteriaceae.     

Anti-inflammatory action of a novel peptide, SEK-1005, isolated from a Streptomyces

The pharmacological activity of a novel cyclic peptide (SEK-1005: C(45)H(70)N(8)0(13)) isolated from Streptomyces nobilis was studied in rats during the development of inflammation. SEK-1005 (0.1-0.5 mg/kg, i.p.) suppressed the passive Arthus reaction and the carrageenin-induced oedema. A steroidal anti-inflammatory drug, prednisolone (10 mg/kg, i.p.), also was effective on both inflammations. However, indomethacin (5 mg/kg, i.p.), a cyclooxygenase inhibitor, was less effective on the passive Arthus reaction. Also interesting was that the SEK-1005 effect showed its maximum level after a 24-h lag period and that its effect, as well as the prednisolone effect, was reduced by the treatment with a protein synthesis inhibitor, cycloheximide. SEK-1005 and prednisolone also showed marked protection against the adjuvant-induced arthritis, but failed to prevent the tuberculin response. These findings indicate that SEK-1005 is a new type of non-steroidal anti-inflammatory agent with an action similar to that of prednisolone.     

Lipid microspheres as novel drug carriers

Summary: Lipid microsphere preparations of corticosteroid, non-steroid anti-inflammatory drugs and prostaglandin E1 (PGE1) all showed more potent activity than the free drugs. Lipo-PGE1 in particular was significantly more active than free PGE1 at about one-tenth the dose of free PGE1. A large mass of data obtained in studies of liposomes suggest many applications for the lipid microsphere, which is considered to be a very promising carrier in drug delivery systems.