betadex and tristearin

Lipid microparticles loaded with the complex between hydroxypropyl-β-cyclodextrin (HP-β-CD) and the sunscreen agent, butyl methoxydibenzoylmethane (BMDBM) were evaluated for their effect on the UV filter percutaneous penetration. The microparticles were prepared by the melt emulsification technique using tristearin as lipidic material and hydrogenate phosphatidylcholine as the surfactant. Human skin penetration was investigated in vivo by the tape stripping technique, a minimal invasive procedure based on the progressive removal of the upper cutaneous layers (stratum corneum) with adhesive tape strips. The amount of sunscreen fixed to each strip was determined by HPLC after solvent extraction. The recovery of the UV filter from spiked adhesive tapes was >94.4% and the precision of the method was better than 7.6% relative standard deviation. Non-encapsulated BMDBM, its complex with HP-β-CD, the lipid microparticles loaded with the sunscreen alone or the BMDBM/HP-β-CD complex were introduced into oil-in-water emulsions and applied to human volunteers. Compared to the cream with the non-encapsulated sunscreen agent (percentage of the applied dose penetrated, 9.7%±2.5), the amount of BMDBM diffusing into the stratum corneum was increased by the formulations containing the BMDBM/HP-β-CD complex (17.1%±3.2 of the applied dose) or the microparticles loaded with BMDBM only (15.1%±2.7 of the applied dose). On the contrary, a significant decrease in the level of UV filter penetrated into the stratum corneum was achieved by the cream containing the microencapsulated BMDBM/HP-β-CD complex (percentage of the applied dose penetrated, 6.0%±1.5). The reduced BMDBM percutaneous penetration attained by the latter system should enhance the UV filter efficacy and limit potential toxicological risks.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adult; Alkanes; beta-Cyclodextrins; Chalcones; Cyclodextrins; Drug Compounding; Emulsions; Filtration; Humans; Hydrogenation; Lipids; Microscopy, Electron, Scanning; Microspheres; Middle Aged; Molecular Structure; Particle Size; Phosphatidylcholines; Propiophenones; Skin; Skin Absorption; Sunscreening Agents; Surface-Active Agents; Triglycerides; Ultraviolet Rays

A novel mathematical theory is presented allowing for a quantitative description of the various mass transport processes involved in the control of drug (in particular protein) release from lipid implants. Importantly, the model takes into account the simultaneous diffusion of multiple compounds, including the drug and water-soluble excipients, such as release modifiers (e.g., PEG) and drug stabilizers (e.g., HP-beta-CD). Also dynamic changes of the implant structure resulting from drug and excipient leaching into the release medium are considered, resulting in a significant time- and position-dependent mobility of the diffusing species within the systems. Furthermore, the limited solubility of the drug and/or excipients under the given conditions in water-filled channels within the implants can be considered. This includes for instance the limited solubility of IFN-alpha in the presence of dissolved PEG. Importantly, good agreement between the novel theory and experimentally determined protein, PEG and HP-beta-CD release kinetics from tristearin-based implants was obtained. In this particular case it could be shown that the precipitation effect of PEG on IFN-alpha in water-filled pores plays a crucial role for the overall control of protein release. Neglecting this phenomenon and assuming constant apparent diffusion coefficients, significant deviations between theory and experiment are observed. Importantly, the novel mathematical theory also allows for a quantitative prediction of the effects of different formulation and processing parameters on the resulting drug release kinetics. For instance the importance of the initial PEG content of the systems for the resulting IFN-alpha release kinetics could be successfully predicted. Interestingly, independent experiments confirmed the theoretical predictions and, thus, proved the validity and suitability of the mathematical theory.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Diffusion; Drug Implants; Excipients; Interferon-alpha; Kinetics; Models, Chemical; Polyethylene Glycols; Reproducibility of Results; Solubility; Technology, Pharmaceutical; Triglycerides; Water

Different types of tristearin-based implants for controlled rh-interferon alpha-2a (IFN-alpha) release were prepared by compression and thoroughly characterised in vitro. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was added as a co-lyophilisation agent for protein stabilisation and different amounts of polyethylene glycol (PEG) as efficient protein release modifier. To get deeper insight into the underlying mass transport mechanisms, the release of IFN-alpha, HP-beta-CD and PEG into phosphate buffer pH 7.4 was monitored simultaneously and appropriate analytical solutions of Fick's second law of diffusion were fitted to the experimental results. Importantly, the addition of only 5-20% PEG to the lipidic implants significantly altered the resulting protein release rates and the relative importance of the underlying mass transport mechanisms. The release of IFN-alpha from PEG-free implants was purely diffusion controlled. In contrast, in PEG-containing devices other phenomena were also involved in the control of protein release: the IFN-alpha release rate remained about constant over prolonged periods of time and the total amounts of mobile IFN-alpha increased. Interestingly, the release of PEG itself as well as of HP-beta-CD from the implants remained purely diffusion controlled, irrespective of the amount of added PEG. Thus, different mass transport mechanisms govern the release of the drug, co-lyophilisation agent and release modifier out of the lipidic implants.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Buffers; Chemistry, Pharmaceutical; Diffusion; Drug Carriers; Drug Compounding; Drug Implants; Drug Stability; Excipients; Freeze Drying; Humans; Hydrogen-Ion Concentration; Interferon alpha-2; Interferon-alpha; Kinetics; Lipids; Models, Chemical; Polyethylene Glycols; Recombinant Proteins; Solubility; Technology, Pharmaceutical; Triglycerides

It has recently been shown that the addition of polyethylene glycol 6000 (PEG) to lipidic implants fundamentally affects the resulting protein release kinetics and moreover, the underlying mass transport mechanisms (Herrmann, Winter, Mohl, F. Siepmann, & J. Siepmann, J. Control. Release, 2007). However, it is yet unclear in which way PEG acts. It was the aim of this study to elucidate the effect of PEG in a mechanistic manner.. rh-interferon alpha-2a (IFN-alpha)-loaded, tristearin-based implants containing various amounts of PEG were prepared by compression. Protein and PEG release was monitored in phosphate buffer pH 4.0 and pH 7.4. IFN-alpha solubility and stability were assessed by reverse phase and size exclusion HPLC, SDS PAGE, fluorescence and FTIR.. Importantly, in presence of PEG IFN-alpha was drastically precipitated at pH 7.4. In contrast, at pH 4.0 up to a PEG concentration of 20% no precipitation occurred. These fundamental effects of PEG on protein solubility were reflected in the release kinetics of IFN-alpha from the tristearin implants: At pH 7.4 the protein release rates remained nearly constant over prolonged periods of time, whereas at pH 4.0 high initial bursts and continuously decreasing release rates were observed. Interestingly, it could be shown that IFN-alpha release was governed by pure diffusion at pH 4.0, irrespective of the PEG content of the matrices. In contrast, at pH 7.4 both--the limited solubility of the protein as well as diffusion through tortuous liquid-filled pores--are dominating.. For the first time it is shown that the release of pharmaceutical proteins can be controlled by an in-situ precipitation within inert matrices.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Chemical Precipitation; Crystallization; Delayed-Action Preparations; Diffusion; Drug Implants; Drug Stability; Humans; Hydrogen-Ion Concentration; Interferon alpha-2; Interferon-alpha; Lipids; Microscopy, Fluorescence; Models, Theoretical; Polyethylene Glycols; Protein Structure, Secondary; Recombinant Proteins; Solubility; Spectroscopy, Fourier Transform Infrared; Triglycerides

The aim of this study was to investigate the incorporation into lipospheres of the complex between hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and the sunscreen agent, butyl methoxydibenzoylmethane (BMDBM) and to examine the influence of this system on the sunscreen photostability. The formation of the inclusion complex was confirmed by thermal analysis and powder X-ray diffraction. Lipid microparticles loaded with free BMDBM or its complex with HP-beta-CD were prepared using tristearin as the lipid material and hydrogenated phosphatidylcholine as the emulsifier. The obtained lipospheres were characterized by scanning electron microscopy and differential scanning calorimetry. The microparticle size (15-40 microm) was not affected by the presence of the complex. Release of BMDBM from the lipospheres was lower when it was incorporated as inclusion complex rather than as free molecule. Unencapsulated BMDBM, its complex with HP-beta-CD, the sunscreen-loaded lipospheres or the lipoparticles containing the BMDBM/HP-beta-CD complex, were introduced into a model cream (oil-in-water emulsion) and irradiated with a solar simulator. The photodegradation studies showed that all the examined systems achieved a significant reduction of the light-induced decomposition of the free sunscreen agent (the BMDBM loss decreased from 28.9 to 17.3-15.2%). However, photolysis experiments performed during 3 months storage of the formulations, demonstrated that the photoprotective properties of the HP-beta-CD complex and of BMDBM alone-loaded lipospheres decreased over time, whereas the microencapsulated HP-beta-CD/BMDBM complex retained its photostabilization efficacy. Therefore, incorporation in lipid microparticles of BMDBM in the cyclodextrin complex form is more effective in enhancing the sunscreen photostability than the complex alone or the liposphere-entrapped free BMDBM.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Alkanes; beta-Cyclodextrins; Chalcones; Drug Compounding; Drug Stability; Emulsions; Excipients; Liposomes; Particle Size; Phosphatidylcholines; Photolysis; Propiophenones; Solubility; Sunscreening Agents; Time Factors; Triglycerides; Ultraviolet Rays