https://onlinelibrary.wiley.com/doi/pdf/10.1021/js980403l

Solid dispersion of poorly water‐soluble drugs: Early promises, subsequent problems, and recent breakthroughs

Highly potent, but poorly water-soluble, drug candidates are common outcomes of contemporary drug discovery programmes and present a number of challenges to drug development - most notably, the issue of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance drug solubilization in the intestinal milieu, recruit intestinal lymphatic drug transport (and thereby reduce first-pass drug metabolism) and alter enterocyte-based drug transport and disposition.

Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs

In vitro human digestion models for food applications

Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies.

Enhancing intestinal drug solubilisation using lipid-based delivery systems.

The influence of lipid vehicles on the intestinal absorption of Ciclosporin was studied in vitro. The effect of the intestinal lipid digestion was considered on the partition of the drug from olive oil or middle-chain triglyceride (MCT) into phases of simulated intestinal content. The phases obtained after ultracentrifugation were analyzed for their Ciclosporin content and characterized for their lipid classes. For both lipid vehicles the presence of lipolysis products did not promote the partition of the drug into the aqueous phase. The absorption in vivo was not related to the drug amount in the aqueous phase and in the oil phase. Therefore, phase quantification in vitro cannot simulate the dynamics of in vivo absorption events following application of a poorly water-soluble drug in a lipid vehicle.

In vitro model for ciclosporin intestinal absorption in lipid vehicles.

This paper describes the preparation of solid solutions of ciclosporin as model solubilizate in water-soluble sugar esters, which are solid, biodegradable, and nontoxic surfactants. Sugar esters were found to be excellent solubilizers for poorly water-soluble drugs such as ciclosporin. Such systems are suitable for the preparation of solid dosage forms for the purpose of oral administration. Addition of water to the solid solutions yields clear solutions of the solubilizate.

Solid surfactant solutions of active ingredients in sugar esters.

The local tissue damage after intramuscular injection caused by various commercially available injection solutions was determined in the albino rat, by measuring plasma activities of creatine phosphokinase, aspartate aminotransferase, and lactic dehydrogenase, the tissue activity of creatine phosphokinase, and macroscopic changes in the muscle at the injection site (gastrocnemius muscle) The plasma enzyme activities were determined 2, 6, 18, and 28 hr after the injection After 28 hr the animals were sacrificed for macroscopic inspection of the injection site and for the determination of tissue enzyme activity The tissue injury caused by the test substances correlated well with the elevated creatine phosphokinase activity (2 hr) The elevations of aspartate aminotransferase (18 hr) and lactate dehydrogenase (2 hr) activity as well as the loss of tissue creatine phosphokinase activity were less indicative of differences between test preparations The ip administration of some of the test preparations caused increased enzyme activity without muscle damage, which could interfere with the test results The creatine phosphokinase determination indicates the damage occurring immediately after the administration of the test solution, and the macroscopic inspection offers the possibility to obtain some information on the evolution of the muscular lesion

Tissue tolerance of intramuscular injectables and plasma enzyme activities in rats.

Our interest in calculating the thermodynamic data by means of the Arrhenius equation was based on two observations: (a) the thermal death time increases considerably when the bioindicators Bacillus subtilis var. niger and Bacillus stearothermophilus are sterilized in nonaqueous hydrophilic solutions as found in propylene glycol (PG) with low water concentrations; and (b) the inactivation kinetics of Bac. stearothermophilus does not follow a first-order reaction. The frequency factor A and the entropy of activation ΔS* have the highest values in water and the lowest value in PG; ΔS* for Bac. stearothermophilus in water is 812 J/mol K; however, in PG it is −9.6 J/mol K. A good correlation between ΔS* and the enthalpy ΔH* is found, indicating possible protein denaturation during thermal inactivtion. The moderate positive and negative ΔS* values in PG and PG with low water concentrations might be explained by (a) rigid conformation of proteins due to stabilization and (b) slow reaction, making the complex a less probable structure, when the activated complex is built only under considerable rearrangement of the structure of the reactant molecules. The opposite was observed with the Z and Z* values, the latter being defined as Z values of nonlogarithmic survival curves. The Z values increase with increasing concentrations of PG, i.e., for Bac. subtilis of Z = 8°C in water up to Z = 23°C in PG and for Bac. stearothermophilus of Z = 6°C up to Z* = 27°C. The calculated free enthalpy of activation ΔG* is about 100 kJ/mol for both spore formers tested in the mentioned suspending medium. The ΔG* values found are similar to literature data of the denaturation of most proteins. These thermodynamic data do not explain the enormous increase of resistance in PG–water mixtures.

Heat sterilization of bioindicators in propylene glycol and propylene glycol-water mixtures: arrhenius equation, thermodynamic data, and Z values.

B. PHILIPP AND H. SUCKER. 1992. The heat sterilization of spores of Bacillus stearothermophilus ATCC 7953 in propylene glycol (PG) and PG—water mixtures was investigated. Unusual non-logarithmic survival curves with a marked long shoulder, designated as the lag-time, were observed at the maximum of resistance. When the number of colony-forming units were determined after intervals of incubation, the growth curves of spores previously treated at 121°C in PG or PG-4% water varied considerably. Spores receiving a heat treatment that was longer than the lag-time showed no growth. When the heat treatment was shorter than the lag-time, spores showed a delayed growth phase. When spores received heat treatment that was long but which fell within the lag-time, there was a greater decrease in spore counts before the exponential growth phase began. In PG and PG with low water concentrations, a suppressed release of the specific spore substance calcium dipicolinate was observed during sterilization at 121°C of B. stearothermophilus ATCC 7953 and B. subtilis var. niger ATCC 9372. Calcium dipicolinate release, however, was observed in water.

Heinz Sucker

Papers

In vitro model for ciclosporin intestinal absorption in lipid vehicles.

Solid surfactant solutions of active ingredients in sugar esters.

Tissue tolerance of intramuscular injectables and plasma enzyme activities in rats.

Heat sterilization of bioindicators in propylene glycol and propylene glycol-water mixtures: arrhenius equation, thermodynamic data, and Z values.

Repair and calcium dipicolinate release of bioindicators in propylene glycol and propylene glycol-water mixtures