Formulation Development of a Filter-Sterilizable Lipid Emulsion for Lipophilic KW-3902, a Newly Synthesized Adenosine A1-Receptor Antagonist.

Hosokawa, Toshihito; Yamauchi, Masahiro; Yamamoto, Yoshihiko; Iwata, Koichi; Kato, Yasuki; Hayakawa, Eiji

doi:10.1248/cpb.50.87

Cited by 13 publications

(11 citation statements)

References 34 publications

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“…In a previous paper, 22) we reported the development of a lipid emulsion of KW-3902, a compound that is lipophilic (partition coefficient: log Pϭ4.7) and water-insoluble (solubility is less than 1 mg/ml). Lipid emulsions have been employed as carriers for lipophilic drugs with some clinical success.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, em-KW-3902 has a large amount of egg lecithin, the mixing ratio of PL to oil being 1 : 1, to give a mean particle size of 130 nm. 22) It is highly likely that liposome-like vesicles would exist in this lipid emulsion. Therefore, we performed a structural analysis of the lipid emulsion.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19] Additionally, KW-3902 induces a diuretic effect in various models of acute renal failure in rats 20,21) and would be expected to have therapeutic value. In a previous study, 22) we developed a lipid emulsion of KW-3902 as an injectable formulation, because KW-3902 has a solubility of less than 1 mg/ml in water.However, intravenously injected emulsions and liposomes are rapidly captured by the reticuloendothelial system (RES) in organs such as the liver and spleen. [23][24][25][26][27] This is a major barrier to the delivery of drugs to non-RES tissues, and raises the specter that lipid emulsion formulations may affect the intrinsic therapeutic profiles of agents such as KW-3902 that targets the kidney.…”

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Role of the Lipid Emulsion on an Injectable Formulation of Lipophilic KW-3902, a Newly Synthesized Adenosine A1-Receptor Antagonist.

Hosokawa

Yamauchi

Yamamoto

et al. 2002

Biological & Pharmaceutical Bulletin

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Several approaches to obtaining parenteral formulations for water-insoluble or poorly soluble drugs have been reported and dispersed systems for drug delivery such as emulsions, liposomes and nanospheres are improving all the time.1-12) For instance, diazepam recently became commercially available in a lipid emulsion form, 13,14) which was developed to reduce the incidence of local side effects after intravenous injection of conventional preparations of diazepam containing organic solvents. 7 ]nonyl)-3,7-dihydro-1H-purine-2,6-dione, see Fig. 1) is a newly synthesized adenosine A 1 -receptor antagonist. 15,16) Recently, it was reported that KW-3902 has potent diuretic and renal protective activities in rats and dogs. [17][18][19] Additionally, KW-3902 induces a diuretic effect in various models of acute renal failure in rats 20,21) and would be expected to have therapeutic value. In a previous study, 22) we developed a lipid emulsion of KW-3902 as an injectable formulation, because KW-3902 has a solubility of less than 1 mg/ml in water.However, intravenously injected emulsions and liposomes are rapidly captured by the reticuloendothelial system (RES) in organs such as the liver and spleen. [23][24][25][26][27] This is a major barrier to the delivery of drugs to non-RES tissues, and raises the specter that lipid emulsion formulations may affect the intrinsic therapeutic profiles of agents such as KW-3902 that targets the kidney.28) However, KW-3902 shows potent diuretic and renal protective activities even as a lipid emulsion. 21,29) In the present study, we have examined the influence of dispersed systems such as lipid emulsion or liposome on the pharmacokinetic profiles of KW-3902 and its main metabolite, M1 (Fig. 1). Moreover, to define the role of the lipid emulsion on the formulation of KW-3902, we investigated in vitro the binding to blood components of KW-3902 in each formulation. MATERIALS AND METHODSMaterials KW-3902 was synthesized at Kyowa Hakko Kogyo Co., Ltd. Egg yolk lecithin (containing 99% of phosphatidylcholine), oleic acid and concentrated glycerin were purchased from NOF Corporation (Tokyo, Japan). Soybean oil was purchased from the Nisshin Oil Mills, Ltd. (Tokyo, Japan). All other chemicals were of reagent grade and obtained from Kanto Chemical Co. (Tokyo, Japan).Lipid Emulsion Table 1 shows the formulation of the lipid emulsion of KW-3902 (Em-KW-3902). The preparation was described before.22) Briefly, KW-3902 was dissolved in soybean oil and mixed with egg yolk lecithin, oleic acid, concentrated glycerin and water for injection using a high-shear homogenizer (Model PVQS-1(3), Mizuho Industrial Co., Ltd., Osaka, Japan) at 8000 rpm for 15 min at 50°C. After adjustment of the pH to 7 with 1 N NaOH, the primary emulsion was passed through a microfluidizer (Model M-110EH, Microfluidics Corp., Newton, MA, U.S.A.) 5 times at 120 MPa. The emulsion was filtrated through a 0.22 mm Ultipor filter (Pall Corp., East Hills, NY, U.S.A.), then packaged in 10 ml ampules (Type 1 glass) and sealed after nitrogen...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Role of the Lipid Emulsion on an Injectable Formulation of Lipophilic KW-3902, a Newly Synthesized Adenosine A1-Receptor Antagonist.

Hosokawa

Yamauchi

Yamamoto

et al. 2002

Biological & Pharmaceutical Bulletin

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“…OA is a biocompatible fatty acid which can not be dissolved in water and also an agent that induces the stability of many NP systems. 12 13 The aim of our study was to develop an optimal preparation without the use of an organic solvent for a wide application in manufacturing and for good health and the environment. Because gelatin has amine groups that cannot bind directly with OA in water, OA must be activated for a reaction.…”

Section: Introductionmentioning

confidence: 99%

Novel Multifunctional Biocompatible Gelatin-Oleic Acid Conjugate: Self-Assembled Nanoparticles for Drug Delivery

Tran¹,

Tran²,

Vo³

et al. 2013

j biomed nanotechnol

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In this work, a novel, biocompatible conjugates of gelatin and oleic acid (GOC) were synthesized by a novel aqueous solvent-based method that overcame challenges of completely contrary solubility between gelatin and oleic acid (OA). The GO nanoparticles (GONs) and Paclitaxel encapsulated nanoparticles (PTX-GON) were prepared by self-assembly in water. These nanoparticles (NPs) were then conjugated with folic acid (FA) for targeting cervical cancer cells (Hela cells) and were characterized for their various physicochemical and pharmaceutical properties. Fourier transform infrared spectroscopy (FT-IR) and 1H NMR studies indicated the successful synthesis of GOC which showed low critical aggregation concentration in water (0.015 mg/ml). All NPs were stable in human blood serum and their mean diameters were below 300 nm suitable for passive targeting. Powder X-ray diffraction (PXRD) diffractograms showed the reduction in drug crystallinity and hence, leading to the solubility enhancement of PTX. The release of PTX from both PTX-GON and FA conjugated PTX-GON (PTX-FA-GON) was controlled for a long time. The cytotoxicity results demonstrated great advantages of PTX-FA-GON and PTX-GON over the conventional dosage form of pacliaxel (Taxol). These results, therefore, indicate that GOC is a promising material to prepare drug encapsulated NP as a controlled delivery system and PTX-FA-GON is a potential targeted delivery system for cancer therapy.

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Filtration Sterilization

Walsh

Denyer

2012

Russell, Hugo &Amp; Ayliffe's

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Formulation Development of a Filter-Sterilizable Lipid Emulsion for Lipophilic KW-3902, a Newly Synthesized Adenosine A1-Receptor Antagonist.

Cited by 13 publications

References 34 publications

Role of the Lipid Emulsion on an Injectable Formulation of Lipophilic KW-3902, a Newly Synthesized Adenosine A1-Receptor Antagonist.

Role of the Lipid Emulsion on an Injectable Formulation of Lipophilic KW-3902, a Newly Synthesized Adenosine A1-Receptor Antagonist.

Novel Multifunctional Biocompatible Gelatin-Oleic Acid Conjugate: Self-Assembled Nanoparticles for Drug Delivery

Filtration Sterilization

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