Lipid Emulsions as Drug Delivery Systems

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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“…7 ]nonyl)-3,7-dihydro-1H-purine-2,6-dione, see Fig. 1) is a newly synthesized adenosine A 1 -receptor antagonist.…”

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confidence: 99%

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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“…Their use includes the preparation of liposome vesicles, immunostimulating complexes (ISCOMs) and water-in-oil emulsions like Freund's complete and incomplete adjuvants (18)(19)(20). We suggest that ovalbumin coupled with lipid residues might induce immune responses instead of tolerance when administered by the oral route.…”

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confidence: 99%

Coupling of palmitate to ovalbumin inhibits the induction of oral tolerance

Oliveira

Silva-Neto

Silva

et al. 1998

Braz J Med Biol Res

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Oral tolerance is a phenomenon that may occur in animals exposed to protein antigens for the first time by the oral route. They become unable to produce immune responses at the levels normally observed when they are immunized parenterally with antigen in the presence of adjuvants. Lipids have been used as adjuvants for both parenteral and oral immunization. In the present study we coupled ovalbumin with palmitate residues by incubating the protein with the N-hydroxysuccinimide palmitate ester and tested the preparation for its ability to induce oral tolerance. This was performed by giving 20 mg of antigen to mice by the oral route 7 days prior to parenteral immunization in the presence of Al(OH) 3 . Mice were bled one week after receiving a booster that was given 2 weeks after primary immunization. Specific antibodies were detected by ELISA. Despite the fact that the conjugates are as immunogenic as the unmodified protein when parenterally injected in mice, they failed to induce oral tolerance. This discrepancy could be explained by differences in the intestinal absorption of the two forms of the antigen. In fact, when compared to the non-conjugated ovalbumin, a fast and high absorption of the lipid-conjugated form of ovalbumin was observed by "sandwich" ELISA.

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“…Emulsions are well-accepted carriers for both hydrophilic and lipophilic drugs and have been widely used in the pharmaceutical and cosmetic fields (Chidambaram and Burgess, 1999;Collins-Gold et al, 1990;Davis et al, 1985Davis et al, , 1987Klang and Benita, 1998;MartiMestres and Nielloud, 2002;Prestige and Simovic, 2006;Otto et al, 2009). Submicron and nanoemulsions have been used as drug and other bioactive carriers not only for parenteral and ocular use, but also for topical and pharmaceutical-cosmetic applications (e.g., vitamins and anti-aging agents) (Benita and Levy, 1993;Constantinides et al, 2000;Davis et al, 1987;Fernandez et al, 2000;Nicolaos et al, 2003;Piemi et al, 1999;Sonneville-Aubrun et al, 2004;Sznitowska et al, 2001;Tamilvanan, 2004;Teeranachaideekul et al, 2007;Wiechers, 2005;Yilmaz and Borchert, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Submicron and nanoemulsions have been used as drug and other bioactive carriers not only for parenteral and ocular use, but also for topical and pharmaceutical-cosmetic applications (e.g., vitamins and anti-aging agents) (Benita and Levy, 1993;Constantinides et al, 2000;Davis et al, 1987;Fernandez et al, 2000;Nicolaos et al, 2003;Piemi et al, 1999;Sonneville-Aubrun et al, 2004;Sznitowska et al, 2001;Tamilvanan, 2004;Teeranachaideekul et al, 2007;Wiechers, 2005;Yilmaz and Borchert, 2005).…”

Section: Introductionmentioning

confidence: 99%