Ralph Lipp

Transdermal delivery of highly lipophilic drugs: In vitro fluxes of antiestrogens, permeation enhancers, and solvents from liquid formulations

AbstractPurpose. Highly lipophilic basic drugs, the antiestrogens AE 1 (log P = 5.82) and AE 2 (log P = 7.8) shall be delivered transdermally. Methods. Transdermal permeation of drugs, enhancers, and solvents from various fluid formulations were characterized by in-vitro permeation studies through excised skin of hairless mice. Furthermore, differential scanning calorimetry (DSC) measurements of skin lipid phase transition temperatures were conducted. Results. Transdermal flux of highly lipophilic drugs was extraordinarily enhanced by the unique permeation enhancer combination propylene glycol-lauric acid (9 + 1): steady-state fluxes of AE 1 and AE 2 were as high as 5.8 μg·cm−2·h−1 and 3.2 μg·cm−2·h−1, respectively. This dual enhancer formulation also resulted in a marked increase in the transdermal fluxes of the enhancers. Furthermore, skin lipid phase transition temperatures were significantly reduced by treatment with this formulation. Conclusion. Transdermal delivery of highly lipophilic drugs can be realized by using the permeation enhancer combination propylene glycol-lauric acid. The extraordinary permeation enhancement for highly lipophilic drugs by this formulation is due to mutual permeation enhancement of these two enhancers and their synergistic lipid-fluidising activity in the stratum corneum.

Pharmaceutics: Selection and Use of Crystallization Inhibitors for Matrix‐type Transdermal Drug‐delivery Systems Containing Sex Steroids*

The purpose of this study was to stabilize transdermal drug‐delivery systems (TDDS) highly loaded with sex steroids against recrystallization of drugs during storage. To facilitate the selection of potential crystallization inhibitors a drug‐excipient interaction test was also established.

Use of X-ray crystallography for the characterization of single crystals grown in steroid containing transdermal drug delivery systems.

Target of the study was to characterize crystals which had grown in steroid-containing matrix patches during short-term storage and to thereby establish a rationale for the inhibition of crystal formation in those patches in general. Matrix type transdermal drug delivery systems (TDDS) containing either 2.2% gestodene or 3.3% estradiol were free of crystals directly after their production. However, crystals of up to 800 microns in length grew during 3 months of storage at ambient temperature. The application of several analytical methods did not help to identify the crystals. This was mainly due to the fact that the adhesive matrix surrounding the crystals could not be fully removed in the course of sample preparation with routine laboratory methods and thus impaired DSC, FTIR microscopy and hot stage polarized microscopy. However, within X-ray diffractometry, the residual amorphous patch matrix did not hamper the measurement of the crystals. Thus, they were identified as estradiol hemihydrate and gestodene form I, respectively. These results suggest that steroid-containing matrix TDDS should be stabilized against drug recrystallization e.g. by the addition of suitable crystallization inhibitors. Furthermore, systems containing estradiol may be stabilized by efficient removal water.

In-vitro release and transdermal fluxes of a highly lipophilic drug and of enhancers from matrix TDS.

Transdermal systems (TDS) are a well-known application form for small, moderately lipophilic molecules. The aim of this study was to investigate the possibility of applying a highly lipophilic drug, the antiestrogen AE (log P=5.82) transdermally by polyacrylate-based matrix TDS. For this purpose, two effects of both drug and enhancer concentration in TDS were investigated: in-vitro release and transdermal permeation of drug and enhancers. In the TDS investigated, in-vitro release as well as in-vitro permeation of AE through excised skin of hairless mice was found to be independent of concentrations of both drug and enhancers. The steady-state fluxes observed were low (about 50-100 ng cm(-2) h(-1)). But skin pretreatment with permeation enhancers resulted in a markedly enhanced permeability (1400 ng cm(-2) h(-1)). Therefore, the permeation of this highly lipophilic drug seems to be limited by the stratum corneum barrier function. In contrast, the transdermal permeation of the enhancers was dependent on the TDS composition. Increase in enhancer content resulted in a higher permeation of enhancers, whereas skin pretreatment did not. In conclusion, it was shown that the highly lipophilic antiestrogen can be administered transdermally by pretreating the skin with the fluid permeation enhancer combination propylene glycol-lauric acid (9+1) and then applying a matrix TDS.

Prodrugs of Gestodene for Matrix-Type Transdermal Drug Delivery Systems

AbstractPurpose. The aim of this study was to enhance the transdermal absorption of the highly active progestin gestodene from matrix type transdermal delivery systems (TDDS) by formation of prodrugs with improved matrix solubility. Methods. Gestodene esters were synthesized via acylation of the drug with the respective carboxylic anhydrides. Subsequently TDDS were produced using the solvent cast method. Selected formulations were examined with in vitro diffusion experiments using skin of nude mice. Results. One prodrug, gestodene caproate proved to be an oil at ambient temperature and showed a very high solubilty of over 10.5% in the TDDS matrix. Within in vitro penetration studies using those systems the prodrug exhibited a significantly higher transdermal penetration rate than gestodene from reference systems. Furthermore, the prodrug was hydrolyzed to the parent drug to a high extent during the passage of the skin. Conclusions. Designing prodrugs to the requirements of matrix TDDS is an efficient way of enhancing the transdermal drug flux rate.

Novel drug delivery systems for steroidal hormones

There are two main goals in the development of steroid containing drug delivery systems (DDS); firstly, to enhance the therapeutic value of the resulting systems versus standard dosage forms such as peroral tablets or injections. And secondly to manage the life cycle of drug substances which are going off patents. An example of an important development is patient friendly transdermal delivery systems (TDS) for oestrogen replacement therapy, which requires application intervals of once-a-week only, despite the fact that the biological half-life of the delivered oestradiol is ~ 20 min. Even more impressive are the achievements in the classes of intrauterine systems (IUS) and implants where the application intervals can be up to 5 years, throughout which low dosages of levonorgestrel are constantly released with high precision and reproducibility. Novel system developments also include steroid loaded vaginal rings for fertility control. On the basis of the technologies already available in the aforementioned areas of TDS, IUS, implants and vaginal rings, many efforts currently concentrate on expanding the therapeutic value of these system types via integrated technological and clinical development activities. Main targets are fertility control, hormone replacement therapy, treatment of gynaecological conditions (e.g. menorrhagia) and andropause (male hormone replacement therapy).

Development of Matrix Patches for Transdermal Delivery of a Highly Lipophilic Antiestrogen

Abstract The aim of this study was to develop matrix-type transdermal systems (TDSs) containing the highly lipophilic (log P = 5.82) antiestrogen (AE) and the permeation enhancers propylene glycol and lauric acid. For that purpose, permeation of AE from various adhesive matrices through excised skin of hairless mice was evaluated. It was found that pretreatment of the skin with permeation enhancers raised the transdermal flux of subsequently applied antiestrogen. Highest steady-state transdermal fluxes (1.1 µg cm−2 h−1) were obtained from Gelva®, polyacrylate adhesive, followed by 0.55 µg cm−2 h−1 from Oppanol® polyisobutylene, 0.31 µg cm−2 h−1 from BIO-PSA® silicone, and 0.12 µg cm−2 h−1 from Sekisui polyacrylate matrices. In order to develop TDS with high content of fluid permeation enhancer propylene glycol, two different strategies were investigated. One strategy was the addition of hydroxypropyl cellulose (HPC) as thickening agent to Gelva matrices. This allowed for propylene glycol loading levels of up to 30%, resulting in transdermal AE fluxes of 0.09 µg cm−2 h−1. On the other hand, a fleece-laminated backing foil was loaded with the described permeation enhancer formulation and laminated with polyacrylate adhesive layer, resulting in transdermal AE fluxes of 0.06 µg cm−2 h−1. However, application of these TDSs on skin pretreated with permeation enhancers raised the fluxes to 2.6 µg cm−2 h−1 from Gelva/HPC and 0.46 µg cm−2 h−1 from fleece/Sekisui.