Valentine J. Stella

CYCLODEXTRINS: THEIR FUTURE IN DRUG FORMULATION AND DELIVERY

Since their discovery, cyclodextrins and their ability to form inclusion complexes have fascinated chemists, formulators and recently, entrepreneurs. This mini-review has as its objective, a critical assessment of the current status of cyclodextrins in the formulation and delivery of pharmaceuticals and commentary on their potential future uses. The emphasis will be on answers to common questions often asked of pharmaceutical scientists working in this area. Why use cyclodextrins for drug solubilization and stabilization when alternative techniques are available? Why the greater interest in modified cyclodextrins and not the parent cyclodextrins? If a drug forms a strong cyclodextrin inclusion complex, how is the drug releasedin vivo? Does the injection of a cyclodextrin/drug complex alter the pharmacokinetics of the drug? Are there drug products on the market which contain cyclodextrins? What is the regulatory status of cyclodextrins? Although definitive answers to all these questions are not possible at this time, many of these questions are answerable, and educated and informed responses are possible for the rest.

Effect of Cyclodextrin Charge on Complexation of Neutral and Charged Substrates: Comparison of (SBE)7M-β-CD to HP-β-CD

AbstractPurpose. To understand the role of charge in substrate/cyclodextrin complexation by comparing the binding of neutral and charged substrates to a neutral cyclodextrin, such as hydroxypropyl β–CD (HP–β–CD) with 3.5 degrees of substitution, and an anionically charged cyclodextrin, such as sulfobutyl ether β–CD ((SBE)7M–β–CD) with 6.8 degrees of substitution. Method. HP–β–CD and (SBE)7M–β–CD were evaluated in their ability to form inclusion complexes with neutral compounds, as well as to cationic and anionic substrates in their charged and uncharged forms. The complexation constants (Kc) were determined via a UV spectrophotometric technique, by monitoring the change in substrate absorbance upon incremental addition of a concentrated cyclodextrin solution. The role of electrostatic interaction was probed by observing Kc as a function of solution ionic strength. Results. Neutral molecules displayed a stronger interaction with (SBE)7M–β–CD compared to HP–β–CD. In those cases where the guest possessed a charge (positive or negative), HP–β–CD/substrate complexes exhibited a decrease in complexation strength (2 to 31 times lower) compared to the neutral forms of the same substrate. The same was true (but to a larger extent, 41 times lower) for negatively charged molecules binding to (SBE)7M–β–CD due to charge–charge repulsion. However, positively charged molecules interacting with the negatively charged (SBE)7M–β–CD displayed a similar binding capability as their neutral counterpart, due to charge–charge attraction. Further evaluation through manipulation of solution ionic strength revealed strong electrostatic interactions between substrate and cyclodextrin charges. In addition, the studies suggested that on average two sulfonates out of seven may be involved in forming ionic attraction or repulsion effects with the positive charges on prazosin and papaverine, or negative charges of ionized naproxen and warfarin. Conclusions. Presence of charge on the cyclodextrin structure provides an additional site of interaction compared to neutral cyclodextrins, which may be modified using solution ionic strength.

The Role of Calcium Ions and Bile Salts on the Pancreatic Lipase-Catalyzed Hydrolysis of Triglyceride Emulsions Stabilized with Lecithin

Lecithin-stabilized triglyceride emulsions are subject to hydrolysis by pancreatic lipase. The time profiles of these reactions are characterized by a lag-phase and a zero-order phase. Lag phases are more pronounced with long-chain triglycerides. Ca2+ is effective in reducing the lag-phase and activating lipase. Kinetic analysis of the reactions suggests that, like previous findings by others, taurodeoxycholate (TDC) micellar solutions combine with the lipase–colipase complex to form another catalytically active enzyme form. This enzyme form exhibits reduced activity in the absence of Ca2+. In the presence of Ca2+ the mixed micelle–lipase complex becomes more active and opens a new pathway for lipolysis. It is suggested that this enzyme form can bind more easily to interfaces with different physicochemical properties. Under these conditions, Ca2+ activates the lipolysis of short-, medium-, and long-chain triglycerides by a similar mechanism. Maximum activities were measured in the presence of approximately 6 mM TDC and 30 mM Ca2+. The experimental conditions approximate the physiological conditions in the gastrointestinal tract since all of the factors studied here have been reported to be necessary for in vivo lipolysis and/or absorption of triglycerides. A mechanistic model for lipolysis in the presence of Ca2+ and the bile salt TDC is proposed which accounts for most of the experimental observations in a quantitative manner.

Design and evaluation of an osmotic pump tablet (OPT) for prednisolone, a poorly water soluble drug, using (SBE)7m-β-CD

AbstractPurpose. The purpose of this study was to develop a controlled-porosity osmotic pump tablet (OPT) for poorly water soluble drugs using a sulfobutyl ether-β-cyclodextrin, (SBE)7m-β-CD or Captisol™, which acted as both a solubilizer and as an osmotic agent. Methods. Prednisolone (PDL) was chosen as a model drug for this study. The release of PDL from osmotic pump devices and tablets was studied. In vivo absorption of PDL from OPT was evaluated in male beagle dogs. Results. PDL release from the osmotic pump tablet with (SBE)7m-β-CD was complete. Another cyclodextrin, hydroxypropyl-β-cyclodextrin (HP-β-CD), and a sugar mixture of lactose and fructose resulted in incomplete release. Although PDL release from the OPT with (SBE)7m-β-CD and the sugar formulation displayed mainly zero-order release characteristics, the tablet utilizing HP-β-CD showed apparent first-order release characteristics. An in vivo absorption study in dogs correlated very well with the in vitro release profiles using the Japanese Pharmacopoeia dissolution method. Conclusions. The present results confirm that (SBE)7m-β-CD can serve as both the solubilizer and the osmotic agent for OPT of PDL, and modify the input rate of PDL without compromising oral bioavailability.

Plasma Pharmacokinetics of the Lactone and Carboxylate Forms of 20(S)-Camptothecin in Anesthetized Rats

Abstract20(S)-Camptothecin exists in equilibrium between its lactone (CPT) and its carboxylate forms (Na-CPT) under simulated physiological conditions, with the equilibrium favoring the carboxylate form. The rates of lactone hydrolysis were studied in plasma, serum albumin, and blood and were found to be faster than in aqueous buffers at equivalent pH values. From mechanistic information and in vivo activity data, the lactone appears to be the active form of the drug. It has been argued, therefore, that if an equilibrium existed between the lactone and the carboxylate, Na-CPT could be used to deliver the lactone effectively. In the present study, plasma pharmacokinetics were performed in sodium pentobarbital-anesthetized rats treated with both CPT (lactone) and the sodium salt of camptothecin (carboxylate, Na-CPT) and the lactone and carboxylate, as well as the total drug, concentration versus time profiles were assessed. It was found that plasma concentrations and AUC values for the lactone were significantly higher after dosing with CPT than after dosing with Na-CPT. After i.v. administration, the ratio of plasma lactone to carboxylate was skewed by the apparent rapid and extensive uptake of the lactone into tissues and the rapid clearance of both species. From our results, it appears that the lower in vivo activity of Na-CPT compared to that from CPT administration might be attributed to the altered conversion of carboxylate into lactone in vivo compared to that predicted from in vitro data.

The Effect of Conformation on Membrane Permeability of an Acyloxyalkoxy-linked Cyclic Prodrug of a Model Hexapeptide

AbstractPurpose. To determine the different conformations of the acyloxyalkoxy-linked cyclic prodrug 1 of the model hexapeptide 2 in solution and to investigate the relationship between these solution conformations and the cellular permeability characteristics of this prodrug. Methods. Two-dimensional Homonuclear Hartmann-Hahn spectroscopy, Rotating-Frame Overhouser effect spectroscopy, circular dichroism and molecular dynamics simulations were used to find the solution conformers of cyclic prodrug 1. Results. Our spectroscopic findings suggest that cyclic prodrug 1 exhibits a major and a minor conformer in solution. The major conformer appears to have a well-defined secondary structure, which involves a β-turn and 4 → 1 intramolecular hydrogen bond, creating a compact structure with a reduced average hydrodynamic radius compared to the model hexapeptide 2. Conclusions. The increased ability of cyclic prodrug 1 to permeate membranes compared to the model hexapeptide 2 could be due to reduction in the average hydrodynamic radius of the molecule facilitating paracellular flux and/or the reduction in the hydrogen bonding potential facilitating transcellular flux.

Thermodynamics of Binding of Neutral Molecules to Sulfobutyl Ether β-Cyclodextrins (SBE-β-CDs): The Effect of Total Degree of Substitution

AbstractPurpose. To understand the role of degree of substitutionon binding of molecules to β-Cyclodextrins (β-CDs) with varyingdegrees of sulfobutyl ether (SBE) substitution. Methods. Using UV spectroscopy, complexation constants ofmolecules to SBE-β-CDs were estimated as a function of temperature,allowing for calculation of thermodynamic parameters, including the enthalpyand entropy of binding. Results. Binding constants of various molecules toSBE-β-CDs did not show a uniform trend to total degree of SBEsubstitution. However, a distinct pattern was observed with the enthalpy andentropy of complexation. The results showed the complexation of substratesto SBE-β-CDs to be more entropy-favored as the number of SBE groupsincreased. This favorable entropy of interaction was compensated by a lessfavorable enthalpy of interaction. Conclusions. Enthalpy and entropy of complexation providedadditional insight into the role that the alkylsulfonate groups may play inthe complexation of molecules with SBE-β-CDs.

The in Vitro Enzymic Labilities of Chemically Distinct Phosphomonoester Prodrugs

The kinetics of decomposition of phosphomonoesters of hydroxy-methyl-5,5-diphenylhydantoin (1), estrone (2), 17β-testosterone (3), 1-phenylvinyl alcohol (4), and 17α-testosterone (5) were studied in rat whole blood at 25 and/or 37°C. As the acidity of the leaving hydroxyl group of the phosphomonoester increased, there was a tendency for the rate of hydrolysis to increase, except for the anomalous behavior of 4, which was consistent with its relative rate of hydrolysis in aqueous solutions (1). In addition, the kinetics of hydrolysis of 1–5 and p-nitrophenyl phosphate (p-NPP) were studied in the presence of isolated alkaline phosphatases from a variety of sources. The initial rate of production of 17α- and 17β-testosterone from their respective phosphate esters (5 and 3), in the presence of human placental alkaline phosphatase, revealed that 3 was hydrolyzed 5.3-fold more rapidly than 5. This difference in reactivity might have been the result of differences in the stereochemical and/or steric nature of the two isomers. For p-NPP, 1, 2, and 4, the kcat and kcat / Km values determined in the presence of the various alkaline phosphatases showed little variation, whereas for 3, the catalytic constants, kcat and kcat / Km, were found to be dramatically less than those found for p-NPP, 1, 2, and 4. This suggested that the reaction steps, involving the noncovalent binding of the phosphomonoester to the enzyme and/or the nucleophilic displacement of the leaving alcohol of the phosphomonoester by the reactive amino acid residue of the enzyme, might have been less favorable in the case of 3, where the carbon atom of the ester linkage was secondary and was associated with a rigid ring system.

Pancreatic Lipase-Catalyzed Hydrolysis of Esters of Hydroxymethyl Phenytoin Dissolved in Various Metabolizable Vehicles, Dispersed in Micellar Systems, and in Aqueous Suspensions

Lipase-catalyzed hydrolysis of fatty acid esters of 3-hydroxymethyl phenytoin was studied in various triglyceride and ethyl oleate emulsions, dispersed in micellar solutions, and suspended in an aqueous buffered solution. Phenytoin release from ethyl oleate emulsions of the prodrugs show apparent first-order kinetics with the pentanoate to nonanoate derivatives and sigmoidal kinetics with the long-chain fatty acid derivatives (stearate and oleate). A transition in the kinetic behavior, between the short- and the long-chain acyl prodrugs, was observed with the decanoate derivative. These observations are accounted for by a proposed kinetic model. Phenytoin release from the solid prodrugs follows zero-order kinetics and is independent of the total amounts of suspended material but directly proportional to the lipase concentration. Lipolysis of the solid suspended prodrugs was dependent on the length of the acyl side chain of the prodrug, with maxima for the pentanoate and the octanoate derivatives. The short-chain derivatives, acetate and propionate, as well as the long-chain prodrug, stearate, showed the slowest lipolysis rate when present as solid dispersions. The zero-order rate is qualitatively correlated with the melting point of the prodrugs. This result might be expected if the melting point is taken as a measure of the cohesivity or packing of the molecules at the surface of a crystal.

The importance of structural factors on the rate and the extent of N,O-acyl migration in cyclic and linear peptides.

The chemistry associated with the process of N,O-acyl migration was explored in both cyclic and linear peptides under aqueous acid conditions. The importance of backbone cyclization and N-methylation of the peptide bond on the kinetics of N,O-acyl migration in a series of linear and cyclic peptides related in structure to cyclosporin A (CsA) were examined. The similarity in the chemical reactivity of the cyclic peptide [MeLeu (3-OH)]1-CsA and the corresponding linear peptide [Val-MeLeu (3-OH)-Abu], suggested that for this series, cyclization of the peptide backbone may not play an important role in controlling the kinetics of N,O-acyl migration. In contrast, the disparity in the chemical reactivity of tripeptides [Val-MeLeu (3-OH)-Abu] and [Val-Leu (3-OH)-Abu], indicated that N-methylation of amide bond significantly impacted the kinetics. Various hypothesis are proposed to account for this observation.