American Peptide Co.

Sunnyvale, CA, United States

American Peptide Co.

Sunnyvale, CA, United States
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Onoue S.,University of Shizuoka | Sato H.,University of Shizuoka | Ogawa K.,University of Shizuoka | Kojo Y.,University of Shizuoka | And 7 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2012

The main purpose of the present study was to develop a novel respirable powder (RP) formulation of cyclosporine A (CsA) using a spray-dried O/W-emulsion (DE) system. DE formulation of CsA (DE/CsA) was prepared by spray-drying a mixture of erythritol and liquid O/W emulsion containing CsA, polyvinylpyrrolidone, and glyceryl monooleate as emulsifying agent. The DE/CsA powders were mixed with lactose carriers to obtain an RP formulation of DE/CsA (DE/CsA-RP), and its physicochemical, pharmacological, and pharmacokinetic properties were evaluated. Spray-dried DE/CsA exhibited significant improvement in dissolution behavior with ca. 4500-fold increase of dissolution rate, and then, nanoemulsified particles were reconstituted with a mean diameter of 317 nm. Laser diffraction analysis on the DE/CsA-RP suggested high dispersion of DE/CsA on the surface of the lactose carrier. Anti-inflammatory properties of the inhaled DE/CsA-RP were characterized in antigen-sensitized asthma/COPD-model rats, in which the DE/CsA-RP was more potent than the RP formulation of physical mixture containing CsA and erythritol in inhibiting inflammatory responses, possibly due to the improved dissolution behavior. Pharmacokinetic studies demonstrated that systemic exposure of CsA after intratracheal administration of the DE/CsA-RP at a pharmacologically effective dose (100 μg-CsA/rat) was 50-fold less than that of the oral CsA dosage form at a toxic dose (10 mg/kg). From these findings, use of inhalable DE formulation of CsA might be a promising approach for the treatment of airway inflammatory diseases with improved pharmacodynamics and lower systemic exposure. © 2011 Elsevier B.V. All rights reserved.


Onoue S.,University of Shizuoka | Matsui T.,University of Shizuoka | Kuriyama K.,University of Shizuoka | Ogawa K.,University of Shizuoka | And 6 more authors.
Peptides | Year: 2012

The present study was undertaken to develop a respirable sustained-release powder (RP) formulation of long-acting VIP derivative, [Arg 15, 20, 21, Leu17]-VIP-GRR (IK312532), using PLGA nanospheres (NS) with the aim of improving the duration of action. NS formulation of IK312532 (IK312532/NS) was prepared by an emulsion solvent diffusion method in oil, and a mixture of the IK312532/NS and erythritol was jet-milled and mixed with lactose carrier to obtain the IK312532/NS-RP. Physicochemical properties were characterized focusing on appearance, particle size, and drug release, and in vivo pharmacological effects were assessed in antigen-sensitized rats. The IK312532/NS with a diameter of 140 nm showed a biphasic release pattern in distilled water with ca. 20% initial burst for 30 min and a sustained slow release up to ca. 55% for 24 h. Laser diffraction analysis demonstrated that IK312532/NS-RP had fine dispersibility and suitable particle size for inhalation. In antigen-sensitized rats, insufflated IK312532/NS-RP (10 μg of IK312532/rat) could suppress increases of granulocyte recruitment and myeloperoxidase in pulmonary tissue for up to 24 h after antigen challenge, although IK312532-RP at the same dose was less effective with limited duration of action. From these findings, newly prepared IK312532/NS-RP might be of clinical importance in improving duration of action and medication compliance for treatment of airway inflammatory diseases. © 2012 Elsevier Inc. All rights reserved.


Sato H.,University of Shizuoka | Sato H.,Osaka University of Pharmaceutical Sciences | Ogawa K.,University of Shizuoka | Kojo Y.,University of Shizuoka | And 4 more authors.
Chemical and Pharmaceutical Bulletin | Year: 2015

The main purpose of the present study was to evaluate the physicochemical stability of cyclosporine A (CsA)-loaded glycerol monooleate-based dry emulsion (DE). DE formulations containing 5-25% CsA (DE5-25) were stored at 25°C/60% relative humidity for 4 weeks, and freeze-dried solid dispersion formulations containing 5-30% CsA (FD5-30) were also prepared as reference formulations. Even after the storage, no significant changes were observed in the appearance of any formulations. In the dissolution study, both DE and FD exhibited marked enhancement of solubility and there was at least 2.0-fold improvement in the initial dissolution rate of DE formulations compared with that of FD formulations. After storage, DE5, DE15 and FD5 maintained relatively high solubility, with 10% reduction compared with the initial state. However, the solubility of DE25 gradually decreased during storage, as evidenced by 76% reduction of the dissolution amount. No significant changes were seen in DE5-25 using powder X-ray diffraction, although thermal analysis revealed moderate changes in crystallinity in DE25 after storage, possibly leading to the decreased dissolution. Furthermore, particle size distributions of micelles in DE5 and DE15 were almost unchanged after storage for 4 weeks. From these findings, it appears that the physicochemical stability of CsA-loaded DE might vary depending on the manufacturing method and that further optimization could improve physical properties and stability. © 2015 The Pharmaceutical Society of Japan.


Misaka S.,University of Shizuoka | Sato H.,University of Shizuoka | Aoki Y.,University of Shizuoka | Mizumoto T.,ILS Inc. | And 3 more authors.
Peptides | Year: 2011

Vasoactive intestinal peptide (VIP) has been thought to be a promising candidate for asthma/chronic obstructive pulmonary disease (COPD), and our group previously developed several long-lasting VIP derivatives. The objective of the present study was to clarify the therapeutic potential of new VIP derivatives with improved chemical and metabolic stability. Exposure of rat alveolar L2 cells to cigarette smoke extract (CSE) for 1 h led to release of lactate dehydrogenase (LDH) and decreased viability in a CSE concentration-dependent manner. There appeared to be marked induction of apoptosis after CSE exposure, as demonstrated by 59% elevation of caspase-3 activity and TUNEL staining. In contrast, a stabilized VIP derivative, [R15,20,21, L 17]-VIP-GRR (IK312532), at a concentration of 10-7 M, exhibited 71% attenuation of LDH release and 85% decrease of the number of apoptotic cells. In addition to IK312532, new VIP derivatives also showed anti-apoptotic effects against CSE toxicity and marked reduction of nitric oxide production. In terms of cytoprotective effects, [R15,20,21, L 17, A24,25, des-N28]-VIP-GRR was more effective than VIP and IK312532, possibly due to the improved stability. Thus, the present study is the first to demonstrate that novel stabilized VIP derivatives exert anti-apoptotic and cytoprotective effects on CSE-induced cytotoxicity. © 2010 Elsevier Inc.


Onoue S.,University of Shizuoka | Suzuki H.,University of Shizuoka | Kojo Y.,University of Shizuoka | Matsunaga S.,University of Shizuoka | And 6 more authors.
European Journal of Pharmaceutical Sciences | Year: 2014

The present study aimed to develop a self-micellizing solid dispersion (SMSD) of cyclosporine A (CsA) using an amphiphilic block copolymer, poly[MPC-co-BMA], to improve the biopharmaceutical properties of CsA. The cytotoxicity of poly[MPC-co-BMA] was assessed in rat intestinal IEC-6 cells, and the pMB was less cytotoxic than polysorbate 80, a non-ionic surfactant with a wide safety margin. SMSD/CsA was prepared using a wet-milling system, and its physicochemical properties were characterized in terms of morphology, crystallinity, dissolution, particle size distribution, and stability. The SMSD/CsA exhibited immediate formation of fine micelles with a mean diameter of ca. 180 nm when introduced into aqueous media. There was marked improvement in the dissolution behavior of the SMSD/CsA compared with amorphous CsA. Even after storage at 40 °C/75% relative humidity, the dissolution behavior of aged SMSD/CsA seemed to be almost identical to that of its freshly prepared equivalent, and CsA in aged SMSD/CsA was still in amorphous form. After oral administration of SMSD/CsA (10 mg CsA/kg) in rats, enhanced CsA exposure was observed with increases of Cmax and BA by ca. 11- and 42-fold, respectively, compared with those of amorphous CsA. The poly[MPC-co-BMA]-based SMSD formulation system might be an efficacious dosage option for CsA to achieve improvements in oral bioavailability.


Onoue S.,University of Shizuoka | Kuriyama K.,University of Shizuoka | Uchida A.,University of Shizuoka | Mizumoto T.,Ito Life science Inc. | And 2 more authors.
Pharmaceutical Research | Year: 2011

Purpose: The present study aimed to develop novel glucagon-loaded PLGA nanospheres without cytotoxic fibril formation for chronic glucagon replacement therapy. Methods: Glucagon-loaded nanospheres (GLG/NS) were prepared by an emulsion solvent diffusion method in oil, and a respirable powder formulation (GLG/NS-RP) was prepared with a jet mill. Physicochemical and inhalation properties of GLG/NS-RP were characterized, and pharmacokinetic behavior and hyperglycemic effect of intratracheally instilled GLG/NS-RP were evaluated in rats. Results: Although preparation of GLG/NS using glucagon solution at concentrations over 10 mg/mL led to significant formation of cytotoxic glucagon aggregates, glucagon solution at less than 5 mg/mL did not cause structural changes. Drug release behavior of GLG/NS showed a biphasic pattern with an initial burst and slow diffusion. Laser diffraction and cascade impactor analyses of GLG/NS-RP suggested high dispersion and deposition in the respiratory organs with a fine particle fraction of 20.5%. After the intratracheal administration of the GLG/NS-RP (200 μg glucagon/kg) in rats, glucagon was released in a sustained manner, leading to sustained hyperglycemic effects compared with those of normal glucagon powder. Conclusion: These data would suggest a therapeutic benefit of the newly developed GLG/NS-RP as an alternative to the injection form of glucagon currently used. © 2011 Springer Science+Business Media, LLC.


Thundimadathil J.,American Peptide Co.
Reading for the R and D Community | Year: 2012

Application of click chemistry in several areas is rapidly increasing with possibilities of exciting discoveries in the horizon. Apart from the general areas of materials science, nanoscience, medicinal chemistry, drug discovery, and bioconjugation, the concept has already made huge impact in synthetic chemistry. A constant drive towards simpler chemical reactions such as CuAAC with a wide scope is in progress. Synthesis of large molecules such as peptides, proteins, and supramolecular structures, as well as their modifications, will be positively influenced by the progress in click chemistry. Due to the simplicity of click reactions, biochemists and molecular biologists are able to make complex molecular systems without much bothering about the synthetic chemistry. Click chemistry is approaching the level of ready-made chemistry as many kits are already available in the market for an easy mix and shake approach.


Liu B.,American Peptide Co.
Pharmaceutical Technology | Year: 2011

Linking peptides to polyethylene glycol, or PEGylation, has helped improve pharmaceutical therapeutics in several ways. A wave of new techniques is now ushering in further advances.

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