James A. Rogers

Thermodynamics of partitioning of β-blockers in the n-octanol- buffer and liposome systems

Abstract The thermodynamics of partitioning ( K m ) of 10 β-adrenergic receptor blocking agents have been determined in the n -octanolbuffer and liposome-buffer systems at pH 7.4. Plots of log K m vs 1/ T were linear in the n -octanol-buffer system from 30°C to 50 ° C, but some drugs exhibited a lower than expected or a zero K m at lower temperatures. Partitioning was generally greater in dimyristoylphosphatidylcholine liposomes than in the n -octanol-buffer system, but it was less below than above the T c of the phospholipid. A K m of nadolol in n -octanol-buffer was detected only at 50°C, however, significant values were obtained in liposomes, but only above the T c . A correlation between log K m ( n -octanol) and log K m (liposome) ( r = 0.986) was obtained at 30° C for all β-blockers except acebutolol. Enthalpies and entropies of partitioning were positive in the n -octanol-buffer system and in liposomes above the T c , but negative below the T c . Hydrophobie substituent constants were 55% greater in liposomes overall and varied depending on the polarity of the substituent and its position on the aromatic ring structure. Enthalpy-entropy compensation was not observed in the n -octanol-buffer system or in liposomes below the T c , but it was found in liposomes above the T c . Thus, it is concluded that the liposome system is a more selective partitioning model than the n -octanol-buffer system.

The liposome as a distribution model in QSAR studies

Quantitative structure-activity relationships (QSAR) were determined for β-adrenoceptor blocking agents based on their published pharmacokinetic properties and corneal penetrations, and experimental partition coefficients in the n-octanol-buffer and liposome systems. Apparent partition coefficient (K′m) correlations were better than the intrinsic (or ion-corrected) values (Km) in liposomes (P < 0.01) and in the n-octanol-buffer system (P < 0.05). The hydrophobic properties of these drugs appear to be the primary determinants of their pharmacokinetic and corneal penetration behaviour. Liposomes of various compositions yielded better correlations in all cases than the n-octanol-buffer system, but a DMPC/CHOL/DCP (7:2:1 mole ratio) liposome composition yielded the best results with pharmacokinetic parameters whereas a DMPC/CHOL (1:1 mole ratio) composition was superior in correlations of corneal penetration. When the values of the pharmacokinetic parameters and corneal penetration behaviour of the β-blockers were predicted from regression analysis of K′m, the error was considerably less in the liposome system (9–29%) compared to the n-octanol-buffer system (24–192%). It is concluded that the model liposome partitioning system is more versatile and selective than the n-octanol-buffer system in predicting biological activities of the β-blocker drugs.

The Liposome as a Model Membrane in Correlations of Partitioning with α-Adrenoceptor Agonist Activities

The apparent partition coefficients of a group of imidazoline α-adrenoceptor agonists in liposome/buffer systems (K′m) and in the n-octanol/buffer system (P′) have been compared in quantitative structure–activity relationships (QSAR) employing biological activities and receptor binding affinities. A parabolic relationship between log K′m and log P′ was found, and log K′m was greater than log P′ for all liposome compositions. In liposomes, log K′m decreased in the order, negatively charged > neutral > positively charged. Overall, hyper- and hypotensive activities of these drugs correlated better with log K′m than with log P′; however, poor correlations were obtained between partition coefficients and in vitro binding affinities. Linear correlations of log K′m with hypotensive activities were obtained with negatively charged liposomes, whereas correlations with hypertensive activities were obtained using positively charged liposomes. Multiple regressions of biological activities with binding affinities showed positive correlations with hypotensive but not hypertensive activities with or without the inclusion of log K′m or log P′. Thus, the liposome represents a more selective model membrane system than a bulk oil phase for predicting the biological activities of imidazoline α-adrenoceptor agonists.

Formulation and Evaluation of a Folic Acid Receptor-Targeted Oral Vancomycin Liposomal Dosage Form

AbstractPurpose. To demonstrate utility of folic acid-coated liposomes for enhancing the delivery of a poorly absorbed glycopeptide, vancomycin, via the oral route. Methods. Liposomes prepared as dehydration-rehydration vesicles (DRVs) containing vancomycin were optimized for encapsulation efficiency and stability. A folic acid-poly(ethylene oxide)-cholesterol construct was synthesized for adsorption at DRV surfaces. Liposomes were characterized by differential scanning calorimetry (DSC) and assessed in vitroin the Caco-2 cell model and in vivoin male Sprague-Dawley rats. Non-compartmental pharmacokinetic analysis of vancomycin was conducted after intravenous and oral administration of solution or liposome-encapsulated vancomycin with or without 0.05 mole ratio FA-PEO-Chol adsorbed at liposome surfaces. Results. Optimal loading of vancomycin (32%) was achieved in DRVs of DSPC:Chol:DCP, 3:1:0.25 mole ratio (m.r.) after liposome extrusion. Liposomes released less than 40% of the entrapped drug after 2 hours incubation in simulated gastrointestinal (GI) fluid and simulated intestinal fluid containing a 10 mM bile salt cocktail. Incorporation of FA-PEO-Chol in liposomes increased drug leakage by 20% but resulted in a 5.7-fold increase in Caco-2 cell uptake of vancomycin. Liposomal delivery significantly increased the area under the curve of oral vancomycin resulting in a mean 3.9-fold and 12.5-fold increase in relative bioavailability for uncoated and FA-PEO-Chol-coated liposomes, respectively, compared with an oral solution. Conclusions. The design of FA-PEO-Chol-coated liposomes resulted in a dramatic increase in the oral delivery of a moderate-size glycopeptide in the rat compared with uncoated liposomes or oral solution. It is speculated that the cause of the observed effect was due to binding of liposome-surface folic acid to receptors in the GI tract with subsequent receptor-mediated endocytosis of entrapped vancomycin by enterocytes.

The Liposome Partitioning System for Correlating Biological Activities of Imidazolidine Derivatives

The partitioning of 10 imidazolidines in various liposome/buffer systems (log K′m) has been determined and compared to partitioning in the n-octanol/buffer system (log P′). The log K′m, which was generally greater than the log P′, increased or decreased upon the addition of dicetylphosphate (DCP) or stearylamine (STA), respectively, to dimyristoylphosphatidylcholine (DMPC) liposomes. Quantitative correlations of α2-adrenergic potencies of imidazolidines have been made by regression analyses with log P′, log K′m, binding affinity, and intrinsic activity. Both central and peripheral potencies correlated with log K′m but not with log P′ Multiple regressions yielded improved predictable quantification of these potencies. Thus, the liposomal membrane system shows certain advantages over the n-octanol/buffer system for the prediction of biological activities of the imidazolidines.

Polymer-coated liposomes; stability and release of ASA from carboxymethyl chitin-coated liposomes

Abstract Liposomes of dipalmitoylphosphatidylcholine (DPPC) were coated with carboxymethyl chitin (CM-chitin), a water-soluble polysaccharide, either during the formation of reverse phase evaporation vesicles (REVs) or using preformed REVs. Acetylsalicylic acid (ASA) encapsulation efficiency was not affected by the polymer coating. Liposomes coated with CM-chitin during processing were more stable in sodium cholate solutions and yielded significantly lower release rates of ASA than preformed liposomes coated with CM-chitin-coated liposomes. The release rate reached a minimum when liposomes were coated from a 1% CM-chitin solution and was approximately one-third of that obtained from uncoated liposomes. Thus, these improvements in liposome behaviour may be beneficial for the oral administration of drugs.

The temperature dependence and thermodynamics of partitioning of phenols in the n-octanol-water system

Abstract The temperature dependency of the n -octanol—water partition coefficient and the hydrophobic substituent constant, π, for a series of substituted phenols has been determined. The thermodynamics of transfer of p -alkylphenols revealed both a favorable enthalpic and entropic contribution whereas xylenols having an ortho substituted methyl group reduced the enthalpic and increased the entropic contributions. Polar substituents in the para position of the ring, such as halogen, nitro or methyl ester, increased the free energy of transfer of phenol through increased enthalpy and in spite of an unfavorable entropy. Para-methoxy or ethoxy groups caused a reversal of the enthalpy of transfer from negative to positive and at the same time increased the entropie contribution. A comparison of the n -octanol—water system results with those obtained using artificial membranes suggests that the bulk organic phase—water system can serve as a good model for distribution only when specific polar group interaction between the compound and the phospholipid bilayer is minimal or absent.

Studies on dissolution testing of the nifedipine gastrointestinal therapeutic system. II. Improved in vitro-in vivo correlation using a two-phase dissolution test

Abstract The nifedipine gastrointestinal therapeutic system (GITS) produces relatively linear fractional absorption-time plots between 6 and 24 h and about 70% of the available dose is absorbed within 24 h in human beings. However, conventional single-phase in vitro dissolution tests with the GITS demonstrate pseudo zero-order release of nifedipine suspension between about 2 to 20 h and ≥90% of the labeled dose is released within 24 h. Using the two-phase dissolution test developed in part I, mean in vitro data obtained from 2 strengths of the nifedipine GITS were compared with mean in vivo data from a human bioequivalency study in anticipation of improved in vitro-in vivo correlations. For the in vivo data, deconvolution was performed using the Wagner-Nelson method (model-dependent, WN) and DeMonS which is a new method of numerical deconvolution (model-independent, DS). Calculated zero-order rates of drug absorption (0.95(WN)/1.03(DS) mg h −1 and 1.88(WN)/1.94(DS) mg h −1 ; 30 mg and 60 mg strengths, respectively) compared reasonably well with the calculated zero-order rates of drug transfer (0.96 and 2.02 mg h −1 ; 30 mg and 60 mg, respectively). These values, however, are considerably less than zero-order drug release rates obtained using single-phase dissolution methods or reported as the manufacturers design specifications (1.7 and 3.4 mg h −1 ; 30 mg and 60 mg strengths, respectively). Hence, improved in vitro-in vivo correlations were demonstrated with the two-phase dissolution test, yielding 1:1 (Level A) correlations ( r 2 >0.99 in all cases).

Folic acid-PEO-labeled liposomes to improve gastrointestinal absorption of encapsulated agents.

The design of targeted oral liposomes is anticipated to improve the systemic delivery of poorly absorbed agents, such as proteins and peptides. A poly(ethylene oxide) (PEO)-folic acid (FA) derivative was prepared and evaluated for improving liposome transport across a model gastrointestinal cell line (Caco-2). FA-PEO-cholesterol (Chol) derivatives were synthesized and adsorbed at liposome surfaces encapsulating Texas Red((R))-Dextran 3000 (TR-dex), a poorly-absorbed, neutral, hydrophilic, large molecular weight (M(w)) marker. Apparent permeabilities (P(app)) of Caco-2 cells to FA-PEO conjugates, TR-dex, uncoated TR-dex liposomes, and FA-coated TR-dex liposomes were compared at 2 h post-administration. Intracellular delivery of TR-dex was detected by fluorescence microscopy. An increase in intracellular accumulation of TR-dex associated with FA-PEO-coated liposomes, but not other formulations, was evidence of the potential of FA-targeted liposomes in the oral delivery of poorly absorbed, large M(w) agents.

Acacia-Gelatin Microencapsulated Liposomes: Preparation, Stability, and Release of Acetylsalicylic Acid

Liposomes of dipalmitoylphosphatidylcholine (DPPC) containing acetylsalicylic acid (ASA) have been microencapsulated by acacia-gelatin using the complex coacervation technique as a potential oral drug delivery system. The encapsulation efficiency of ASA was unaltered by the microencapsulation process. The stability of the microencapsulated liposomes in sodium cholate solutions at pH 5.6 was much greater than the corresponding liposomes. The optimum composition and conditions for stability and ASA release were 3.0% acacia-gelatin and a 1- to 2-hr formaldehyde hardening time. Approximately 25% ASA was released in the first 6 hr from microencapsulated liposomes at 23°C and the kinetics followed matrix-controlled release (Q ∝ tl/2). At 37°C, this increased to 75% released in 30 min followed by a slow constant release, likely due to lowering of the phase transition temperature of DPPC by the acacia-gelatin to near 37°C. At both temperatures, the release from control liposomes was even more rapid. Hardening times of 4 hr and an acacia-gelatin concentration of 5% resulted in a lower stability of liposomes and a faster release of ASA. It is concluded that under appropriate conditions the microencapsulation of liposomes by acacia-gelatin may increase their potential as an oral drug delivery system.