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

Abstract

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...

Evaluation of the Carrier Potential for the Lipid Dispersion System with Lipophilic Compound

“…36) A denser fraction detected in the density range of 1.006-1.063 g/ml corresponds to liposomes or liposome-like vesicles, according to the result of lipo-KW-3902 mentioned below. As we reported in the previous paper, 29) em-KW-3902 showed the KW-3902 distribution in which 78.8% was in the fraction of dϽ1.006 g/ml and 21.2% in 1.006-1.063 g/ml, corresponding to liposomes or liposome-like vesicles. In the case of lipo-KW-3902, 100% of KW-3902 was detected in the density range of 1.006-1.063 g/ml.…”

“…We previously 29) investigated the influence of the emulsion formulation on the pharmacokinetics of KW-3902 using three different formulations: a lipid emulsion, a liposome and a saline solution, and found no significant difference in the pharmacokinetic parameters of the compound after injection of any of the formulations in rats. This confirmed that the lipid emulsions or the liposome formulations does not influence the intrinsic pharmacokinetics of KW-3902 and these formulations were defined as a solvent.…”

“…[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 target the kidney. 28) In the previous study 29) we examined the influence of an emulsion formulation on the pharmacokinetic profiles of KW-3902 and showed that this antagonist in lipid emulsions had pharmacokinetic parameters, which are similar to that it has in solution. This means that lipid emulsion formulation does not influence the intrinsic pharmacokinetics of KW-3902 after injection.…”

A1 Adenosine Receptor Antagonists, Agonists, and Allosteric Enhancers

“…During the development of intravenously (IV) injectable formulations for KW3902, which has a solubility in water of <1 μg mL −1 , Hosokawa et al (2002) investigated the effects of a lipid emulsion and liposome formulation on the pharmacokinetics of KW3902 and its metabolite (M1-KW3902) in comparison to a 1 N NaOH-DMSO-containing formulation (Fig. 3).…”

Injectable Lipid Emulsions—Advancements, Opportunities and Challenges

“…These studies demonstrate that emulsions may or may not have a significant impact on the distribution and elimination of drugs. Several molecules formulated as emulsions have exhibited pharmacokinetic parameters similar to that of a solution dosage form (107)(108)(109)(110)(111)(112). One of the main reasons for not observing any difference has been attributed to a rapid release of the drug from the emulsion.…”