Rainer H Müller

Freie Universität Berlin, Berlín, Berlin, Germany

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Publications (157)

  • [Show abstract] [Hide abstract] ABSTRACT: A cationic nanocrystal formulation containing dexamethasone acetate nanocrystals (0.05%) and polymyxin B (0.10%) for ophthalmic application was produced using a self-developed small scale method for wet bead milling. The formulation developed offers the advantage of increased saturation solubility of the drug (due to the nano-size of the crystals), increased residence time in the eye (due to small size and increased mucoadhesion by the cationic charge) resulting ultimately in potential increased bioavailability. Characterization of the nanosuspensions by photon correlation spectroscopy (PCS) and transmission electron microscopy showed that the production method was successful in achieving dexamethasone crystals in the range of about 200-250 nm. The physical stabilization of the nanocrystals and generation of the positive charge was realized by using cetylpyridinium chloride (CPC) and benzalkonium chloride (BAC) at the concentration of 0.01%. In contrast to other cationic excipients, they are regulatorily accepted due to their use as preservatives. The drug polymyxin B also contributed to the positive charge. Positive zeta potentials in the range +20 to +30 mV were achieved. Isotonicity was adjusted using NaCl and non-ionic excipients (glycerol, sorbitol, dextrose). Physical and chemical stabilities were monitored for a period of 6 months at room temperature, 5 °C and 40 °C. Particle size of the bulk population assessed by PCS remained practically unchanged over 6 months of storage for the various formulations without isotonicity agents, and for the CPC-containing formulations with non-ionic isotonicty excipients. The chemical content also proved stable after 6 months for all 3 temperatures evaluated. In-vitro investigation of mucoadhesion was tested using mucin solutions at different concentrations, and the generated negative zeta potential was used as a measure of the interaction. The zeta potential reversed to about -15 mV, indicating distinct interaction. The results show the potential of increased mucoadhesion of such cationic nanocrystals compared to standard eye drop formulations. The positively charged nanocrystals formulation also showed no in vitro cytotoxity as assessed on fibroblasts cell culture. In summary, 3 formulation candidates were identified being a promising alternative for ocular delivery with increased performance compared to what is presently available.
    Article · Jul 2016 · European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
  • [Show abstract] [Hide abstract] ABSTRACT: Propylene glycol is one of the known substances added in cosmetic formulations as a penetration enhancer. Recently, nanocrystals have been employed also to increase the skin penetration of active components. Caffeine is a component with many applications and its penetration into the epidermis is controversially discussed in the literature. In the present study, the penetration ability of two components - caffeine nanocrystals and propylene glycol, applied topically on porcine ear skin in the form of a gel, was investigated ex vivo using two confocal Raman microscopes operated at different excitation wavelengths (785 nm and 633 nm). Several depth profiles were acquired in the fingerprint region and different spectral ranges, i.e., 526-600 cm-1 and 810-880 cm-1 were chosen for independent analysis of caffeine and propylene glycol penetration into the skin, respectively. Multivariate statistical methods such as principal component analysis (PCA) and linear discriminant analysis (LDA) combined with Student's t-test were employed to calculate the maximum penetration depths of each substance (caffeine and propylene glycol). The results show that propylene glycol penetrates significantly deeper than caffeine (20.7-22.0 μm versus 12.3-13.0 μm) without any penetration enhancement effect on caffeine. The results confirm that different substances, even if applied onto the skin as a mixture, can penetrate differently. The penetration depths of caffeine and propylene glycol obtained using two different confocal Raman microscopes are comparable showing that both types of microscopes are well suited for such investigations and that multivariate statistical PCA-LDA methods combined with Student's t-test are very useful for analyzing the penetration of different substances into the skin.
    Article · Jul 2016 · European Journal of Pharmaceutics and Biopharmaceutics
  • Sung Min Pyo · Martina Meinke · Anja F. Klein · [...] · Rainer H. Müller
    [Show abstract] [Hide abstract] ABSTRACT: For the post laser treatment of couperosis a new dermal formulation was developed combining three actives: vitamin K1, A1 and rutin, where both vitamins were incorporated into solid lipid nanoparticles (SLN) and the poorly soluble antioxidant rutin formulated as nanocrystal. All three formulations were stable over 6 months either on their own or after their incorporation into a hydrogel. Vitamin A1 at 0.3% in emulsions shows local skin irritation due to very rapid release. By forming SLN, prolonged release with less irritation potential but deeper penetration was achieved in porcine ear skin. Due to the nanosized rutin, the new hydrogel showed clearly increased antioxidant activity, representing a stronger protection potential against reactive oxygen species (ROS), compared to marketed anti-redness products with rutin as raw drug powder or water-soluble derivative. In addition, rutin nanocrystals showed up to 5 times pronounced penetration compared to μm-sized raw drug powder. The orientating in-vivo case study revealed a three to six times faster recovery after laser treatment of couperosis by twice daily application of the new hydrogel, regarding scabbed-over areas and erythema. Continued use of the new gel also showed preventive properties against recurrences of veins for at least 8 month.
    Article · Jun 2016
  • Lucie Vidlářová · Gregori B. Romero · Jaroslav Hanuš · [...] · Rainer H. Müller
    [Show abstract] [Hide abstract] ABSTRACT: Nanocrystals have received considerable attention in dermal application due to their ability to enhance delivery to the skin and overcome bioavailability issues caused by poor water and oil drug solubility. The objective of this study was to investigate the effect of nanocrystals on the mechanism of penetration behavior of curcumin as a model drug. Curcumin nanocrystals were produced by the smartCrystals® process, i.e. bead milling followed by high pressure homogenization. The mean particle size of the curcumin crystals was about 200 nm. Stabilization was performed with alkyl polyglycoside surfactants. The distribution of curcumin within the skin was determined in vitro on cross-sections of porcine skin and visualized by fluorescent microscopy. The skin penetration profile was analyzed for the curcumin nanosuspension with decreasing concentrations (2%, 0.2%, 0.02% and 0.002% by weight) and compared to nanocrystals in a viscous hydroxypropylcellulose (HPC) gel. This study demonstrated there was minor difference between low viscous nanosuspension and the gel, but low viscosity seemed to favor skin penetration. Localization of curcumin was observed in the hair follicles, also contributing to skin uptake. Looking at the penetration of curcumin from formulations with decreasing nanocrystal concentration, formulations with 2%, 0.2% and 0.02% showed a similar penetration profile, whereas a significantly weaker fluorescence was observed in the case of a formulation containing 0.002% of curcumin nanocrystals. In this study we have shown that curcumin nanocrystals prepared by the smartCrystal® process are promissing carriers in dermal application and furthermore, we identified the ideal concentration of 0.02% nanocrystals in dermal formulations. The comprehensive study of decreasing curcumin concentration in formulations revealed that the saturation solubility (Cs) is not the only determining factor for the penetration. A new mechanism based also on the concentration of the nanocrystals on skin surface was proposed.
    Article · May 2016 · European Journal of Pharmaceutics and Biopharmaceutics
  • Sung Min Pyo · Martina Meinke · Cornelia M. Keck · Rainer H. Müller
    [Show abstract] [Hide abstract] ABSTRACT: Rutin is a well-known antioxidant from the group of flavonoids. Its use in cosmetic dermal products is, however, limited due to its poor water solubility. In order to increase rutin saturation solubility and improve the diffusion to the skin, rutin nanocrystals were produced by the smartCrystal process, e.g., bead milling followed by high pressure homogenization. Rutin nanocrystals were further incorporated into hydroxypropyl cellulose (HPC) gel and its long-term stability was assessed. Determination of the antioxidant activity was made by the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay for these formulations: rutin nanocrystals (mean size 300 nm), rutin raw drug powder (mean size 33 μm) and commercial product. Furthermore, the skin penetration profile of rutin was investigated by the tape-stripping method on porcine skin. This study demonstrated that rutin nanocrystal gel had the highest neutralizing activity (90%), followed by a commercial product and rutin raw drug powder. According to the skin study, rutin nanocrystals penetrated to the deeper layers of the stratum corneum, the horny layer of the skin.
    Article · Feb 2016
  • Rainer H. Müller · Xuezhen Zhai · Gregori B. Romero · Cornelia M. Keck
    [Show abstract] [Hide abstract] ABSTRACT: Pharmaceutical nanocrystals were developed at the beginning of the 1990s and entered the pharmaceutical market in the year 2000. With less than one decade, they belong to the most successful nanosystems. In 2005 the first dermal cosmetic products were put on the market. Nanocrystals consist of 100 % active, surrounded by a stabilizer layer. They enhance penetration into the skin via physical effects of increased kinetic solubility (supersaturation), thus increasing concentration gradient, fast dissolution from the nanocrystal depot on the skin, adhesive properties, and size-dependent localization in hair follicles. Nanocrystals do not need to penetrate themselves into the skin. Production is possible on a large industrial scale by bead milling or high-pressure homogenization. Nanocrystal concentrates are on the market available which can easily be incorporated into dermal products by admixing in the production process. By formulation as nanocrystals, poorly soluble molecules are made biologically active in the skin, which were not active before as microcrystals (e.g., flavonoids, up to factor 1000 bioactivity enhancement). First cosmetic products with nanocrystals are meanwhile marketed worldwide, and identical to liposomes the dermal pharmaceutical applications are expected to come. The nanocrystals belong to class I or II of the nanotoxicological classification system (NCS); therefore, they are well tolerated.
    Chapter · Jan 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Solid lipid nanoparticles (SLN) were invented in 1991 as a delivery system combining advantages of other nanoparticulate systems and at the same time avoiding/minimizing some of their limitations. In 1999/2000 the second generation of nano(structured) lipid carriers (NLC) was developed, showing improved properties such as increased drug loading and physical stability. Differences to the first generation are discussed. Large-scale production, incorporation of NLC concentrates in final dermal products, and accepted regulatory status of excipients – as prerequisites for market introduction – are presented. Special emphasis is also given to the problem of nanotoxicity/nanotolerability, considering the increasing concern in the public perception. The mechanisms of action are presented. As the most important criterion for the performance of a delivery system, in vivo data in the literature are reviewed. An overview of marketed dermal products (cosmetics) is given and the future for dermal pharma products and cosmetics forecasted.
    Chapter · Jan 2016
  • Gregori B. Romero · Anja Arntjen · Cornelia M. Keck · Rainer H. Müller
    [Show abstract] [Hide abstract] ABSTRACT: Cylosporin A (CyA) was formulated as amorphous nanoparticle suspension to increase dermal penetration, e.g. applicable in psoriasis. The suspension consisted of 5% CyA in water, stabilized with vitamin E polyethylene glycol succinate (TPGS, Kolliphor(®) TPGS) and was produced by bead milling. The diameter of the bulk population was about 350nm, laser diffraction diameter 99% was 690nm. The suspension was physically stable over one year of storage at room temperature, and most important the amorphous state also remained stable. Despite the high dispersitivity and related large surface area in contact with water, the drug content reduced only by 5% over 1 year of storage. i.e. the formulation is feasible as commercial product with expiry date. The CyA nanoparticles and μm-sized CyA particles were incorporated into hydroxypropylcellulose (HPC) gels and the penetration studied into fresh pig ear skin applying the tape stripping method. At tape number 30, the penetrated cumulative amount of CyA from nanoparticles was 6.3 fold higher compared to the μm-sized raw drug powder (450.1μg/cm(2) vs. 71.3μg/cm(2)). A theoretical mechanism is presented to explain the observed superiority in penetration. Based on amorphous CyA nanoparticles, dermal formulations for improved dermal CyA delivery seem to be feasible.
    Article · Dec 2015 · International Journal of Pharmaceutics
  • Gregori B. Romero · Cornelia M. Keck · Rainer H. Müller
    [Show abstract] [Hide abstract] ABSTRACT: Systematic screening for optimal formulation composition and production parameters for nanosuspensions consumes a lot of time and also drug material when performed at lab scale. Therefore, a cost-effective miniaturized scale top down approach for nanocrystals production by wet bead milling was developed. The final set-up consisted of 3 magnetic stirring bars placed vertically one over the other in a 2mL glass vial and agitated by a common magnetic stirring plate. All of the tested actives (cyclosporin A, resveratrol, hesperitin, ascorbyl palmitate, apigenin and hesperidin) could be converted to nanosuspensions. For 4 of them, the particles sizes achieved were smaller than previously reported on the literature (around 90nm for cyclosporin A; 50nm for hesperitin; 160nm for ascorbyl palmitate and 80nm for apigenin). The "transferability" of the data collect by the miniaturized method was evaluated comparing the production at larger scale using both wet bead milling and high pressure homogenization. Transferable information obtained from the miniaturized scale is minimum achievable size, improvements in size reduction by reduction of beads size, diminution kinetics and potentially occurring instabilities during processing. The small scale batches also allow identification of optimal stabilizer types and concentrations. The batch size is 0.5mL, requiring approximately 50mg or 5mg of drug (5% and 1% suspension, respectively). Thus, a simple, accessible, low-cost miniaturized scale method for the production of pharmaceutical nanocrystals was established.
    Article · Nov 2015 · International Journal of Pharmaceutics
  • Tao Liu · Rainer H Müller · Jan P Möschwitzer
    [Show abstract] [Hide abstract] ABSTRACT: Introduction: The top-down approach is frequently used for drug nanocrystal production. A large number of review papers have referred to the top-down approach in terms of process parameters such as stabilizer selection. However, a very important factor, that is, the influence of drug properties, has been not addressed so far. Areas covered: This review will first discuss different nanocrystal technologies in brief. The focus will be on reviewing the different drug properties such as solid state and particle morphology on the efficiency of particle size reduction during top-down processes. Furthermore, the drug properties in the final nanosuspensions are critical for drug dissolution velocity. Therefore, another focus is the characterization of drugs in obtained nanosuspension. Expert opinion: Drug physical properties play an important role in the production efficiency. The combinative technologies using modified drugs could significantly improve the performances of top-down processes. However, further understanding of the drug millability and homogenization will still be needed. In addition, a carefully established characterization system for nansuspension is essential.
    Article · Jun 2015 · Expert Opinion on Drug Delivery
  • [Show abstract] [Hide abstract] ABSTRACT: The surface properties of intravenously injected nanoparticles determine the acquired blood protein adsorption pattern and subsequently the organ distribution and cellular recognition. A series of poly[acrylonitrile-co-(N-vinyl pyrrolidone)] (PANcoNVP) model nanoparticles (133-181nm) was synthesized, in which the surface properties were altered by changing the molar content of NVP (0-33.8mol%) as the more hydrophilic repeating unit. The extent of achieved surface property variation was comprehensively characterized. The residual sodium dodecyl sulfate (SDS) content from the synthesis was in the range 0.3-1.6μgml(-1), potentially contributing to the surface properties. Surface hydrophobicity was determined by Rose Bengal dye adsorption, hydrophobic interaction chromatography (HIC) and aqueous two-phase partitioning (TPP). Particle charge was quantified by zeta potential (ZP) measurements including ZP-pH profiles. The interaction with proteins was analyzed by ZP measurements in serum and by adsorption studies with single proteins. Compared to hydrophobic polystyrene model nanoparticles, all PANcoNVP particles were very hydrophilic. Differences in surface hydrophobicity could be detected, which did not linearly correlate with the systematically altered bulk composition of the PANcoNVP nanoparticles. This proves the high importance of a thorough surface characterization applying a full spectrum of methods, complementing predictions solely based on bulk polymer composition. Copyright © 2015. Published by Elsevier B.V.
    Article · Mar 2015 · International Journal of Pharmaceutics
  • [Show abstract] [Hide abstract] ABSTRACT: The role of a surface modifier is important in the formation of stable nanosuspensions. In this study, a simple and systematic screening method for selecting optimum surface modifiers was performed by utilizing a low-energy wet ball milling method. Nine surface modifiers from different classes with different stabilization mechanisms were applied on six different models of active pharmaceutical ingredients (API). Particle size analysis showed that at concentration five times higher than the critical micelle concentration, SDS and sodium cholate (anionic surfactant) showed the highest percent success to produce stable nanosuspensions with particle size smaller than 250 nm. Similar findings were also shown by poloxamer 188 (nonionic surfactant) and hydroxypropylmethylcellulose E5 (polymeric stabilizer) at concentration 1% (w/v) and 0.8% (w/v), respectively. In addition, combinations of anionic surfactant and nonionic surfactant as well as combinations of anionic surfactant and polymeric stabilizer showed high percent success in the formation of stable nanosuspensions. In general, no correlation can be found between the physicochemical characteristics of the model API (molecular weight, melting point, log P, pKa, and crystallinity) with its feasibility to be nanosized. The concentration and the principle of stabilization of surface modifier determine the formation of stable nanosuspensions. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci
    Article · Jan 2015 · Journal of Pharmaceutical Sciences
  • Cornelia M. Keck · Nuttakorn Baisaeng · Philippe Durand · [...] · Rainer H. Müller
    [Show abstract] [Hide abstract] ABSTRACT: For the development of ultra-small NLC (usNLC) the determination of the required HLB (hydrophilic lipophilic balance) was found to be a suitable method, i.e., usNLC with a size below 50 nm were obtained by this method. Loading with 5% (w/w) coenzyme Q10 (Q10) led to usNLC with a size of about 85 nm. In comparison to classical NLC with a size of 230 nm and a nanoemulsion with similar size, the Q10 loaded usNLC show a higher release, a higher antioxidant capacity, and a better skin penetration for Q10. The reason for this is a flip–flop core–shell structure of the lipid matrix, i.e., the oil with dissolved active is surrounding the solid lipid based core. As the flip–flop structure was probably achieved by admixing high contents of liquid lipid, oil enriched usNLC might represent a novel and promising carrier system for the improved delivery of lipophilic actives.
    Article · Dec 2014 · International Journal of Pharmaceutics
  • Source
    Silke B Lohan · Sonja Bauersachs · Sebastian Ahlberg · [...] · Martina C Meinke
    [Show abstract] [Hide abstract] ABSTRACT: UV irradiation leads to formation of reactive oxygen species (ROS). An imbalance between the antioxidant system and ROS can lead to cell damage, premature skin aging or skin cancer. To counteract these processes, antioxidants such as coenzyme Q10 (CoQ10) are contained in many cosmetics. To improve and optimize cell/ tissue penetration properties of the lipophilic CoQ10, ultra-small lipid nanoparticles (usNLC) were developed. The antioxidant effectiveness of CoQ10-loaded usNLC compared to conventional nanocarriers was investigated in the human keratinocyte cell line HaCaT. Using confocal laser scanning microscopy investigations of the carriers additionally loaded with nile red showed a clear uptake into cells and their distribution within the cytoplasm. By use of the XTT cell viability test, CoQ10 concentrations of 10 to 50μg/ ml were shown to be non-toxic, and the antioxidant potential of 10 μg/ml CoQ10 loaded usNLC in the HaCaT cells was analyzed via electron paramagnetic resonance spectroscopy after cellular exposure to UVA (1J/ cm(2)) and UVB (18mJ/ cm(2)) irradiation. In comparison to the CoQ10-loaded conventional carriers, usNLC-CoQ10 demonstrated the strongest reduction of the radical formation; reaching up to 23% compared to control cells without nanocarrier treatment. Therefore, usNLC-CoQ10 are very suitable to increase the antioxidant potential of skin. Copyright © 2014. Published by Elsevier B.V.
    Full-text Article · Dec 2014 · European Journal of Pharmaceutics and Biopharmaceutics
  • Qionghua Wei · Cornelia M Keck · Rainer H Müller
    [Show abstract] [Hide abstract] ABSTRACT: The CapsMorph(®) technology prepares amorphous drugs for oral delivery by encapsulating them into porous materials. Hesperidin as model compound was loaded onto AEROPERL(®) 300 Pharma using the wetness impregnation method. Hesperidin was dissolved in dimethyl sulfoxide (DMSO) and alternatively in DMSO with addition of Tween 80. The drug solutions were added dropwise to the porous material and subsequently DMSO was evaporated. The AEROPERL(®) 300 Pharma could be loaded with about 30% hesperidin in the amorphous form. Amorphous state was verified by X-ray diffraction and differential scanning calorimetry. The CapsMorph(®) formulation was compared regarding properties determining oral bioavailability, i.e., kinetic saturation solubility and dissolution rate to raw drug powder and hesperidin nanocrystals. The saturation solubility of CapsMorph(®) without Tween 80 was 654μg/ml, which is 36-fold higher than the raw drug powder (18μg/ml) and about 20 times higher than nanocrystals (30μg/ml). In vitro release was faster (100% in 10min at pH 6.8) compared to dissolution of nanocrystals with about 15%. Addition of Tween 80 to CapsMorph(®) lowered the solubility (168μg/ml) and slowed down the release, but provided longer times of supersaturation without precipitation of drug. Based on these data, it appears that drug loaded porous materials provide better formulation compared to nanocrystals for poorly soluble drugs. Copyright © 2014. Published by Elsevier B.V.
    Article · Nov 2014 · International Journal of Pharmaceutics
  • Gregori B Romero · Run Chen · Cornelia M Keck · Rainer H Müller
    [Show abstract] [Hide abstract] ABSTRACT: Industrial concentrates of hesperidin nanocrystals (5.0% nominal concentration) were produced applying the smartCrystal(®) combination technology of wet bead milling and subsequent high pressure homogenization. Stabilization was performed by Kolliphor(®) P 188, preservation by Euxyl PE 9010 and glycerol. Physical and chemical stability were monitored over 1.5 years of storage at 4-6°C. The size of the bulk population stayed unchanged with about 250nm (photon correlation spectroscopy). Absence of crystal growth by Ostwald ripening and absence of agglomerates were shown by laser diffraction (LD) and light microscopy. The LD diameter 90% was still 0.7μm after 1.5 years. Despite the large surface of the nanosuspension in contact with the water phase, the chemical content proved also stable, only a reduction by 0.15% from 5.70% to 5.55% content was observed. The nanocrystals kept their crystalline state unchanged as shown by X-ray diffraction. The saturation solubility of the nanosuspension was more than triple compared to the raw drug powder in water. The data show the availability of a stable hesperidin concentrate as intermediate for industry to produce dermal formulations. Copyright © 2014. Published by Elsevier B.V.
    Article · Nov 2014 · International Journal of Pharmaceutics
  • Sven Staufenbiel · Cornelia M. Keck · Rainer H. Müller
    [Show abstract] [Hide abstract] ABSTRACT: The surface hydrophobicity of nanoparticles is one factor determining blood protein adsorption after intravenous administration, thus the organ distribution. Hydrophobic surfaces lead to opsonization and uptake by the liver macrophages, when hydrophilic nanoparticles avoid this and can circulate in the blood. To predict, at least to a certain degree, the in vivo distribution, the surface hydrophobicity needs to be measured and quantified. Methods need to be used which quantify hydrophobicity of nanoparticles in liquid environment similar to the body situation (= real environment), not using e.g. dry methods from tabletting. Different of those methods are mentioned in this work. In the present study the hydrophobicity of differently coated azithromycin nanocrystals was analyzed with hydrophobic interaction chromatography (HIC) and aqueous two-phase partitioning (TPP). Investigated stabilizers were Poloxamer 188, Poloxamer 407, caprylyl/capryl polyglucoside (Plantacare® 810), decyl polyglucoside (Plantacare® 2000), polyethylene glycol (PEG)-20 sorbitan monooleate (Tween 80) and tocopheryl polyethylene glycol succinate. HIC results revealed that coating with PEG free Plantacares leads to more hydrophobic surfaces (e.g. Plantacare 2000 retention time (tr) = 17.0 ± 1.9 min and tr = 6.5 ± 0.1 min for Tween 80), when also an increase of the amount of polypropylene glycol (PPG) in the Poloxamers lead to a stronger retention. Furthermore, PEG containing samples were analyzed by TPP whereby HIC results could be confirmed. Additionally, TPP showed differences between stabilizers having only 1 PEG chain and stabilizers with more than 1 PEG chain. In perspective, these stabilizers leading to a low hydrophobicity are promising candidates for further in vivo studies due to a decreased opsonization.
    Article · Nov 2014 · Macromolecular Symposia
  • Sven Staufenbiel · Christoph Weise · Rainer H. Müller
    [Show abstract] [Hide abstract] ABSTRACT: The organ distribution of intravenously injected nanoparticles is determined by the composition of the blood protein adsorption pattern occurring after injection. This is exploited in the concept of “differential protein adsorption” for drug targeting, which is briefly discussed. The surface properties of the nanoparticles determine the adsorption patterns, by controlling the surface properties one can generate adsorption patterns required for achieving the desired organ distribution. The efficiency of this principle is shown by reviewing different organ distributions achieved using various polymeric nanoparticles with different surface properties. Surface modification can be obtained by polymer adsorption and can create nanoparticles circulating in the blood, or accumulating in targets such as bone marrow and brain. The protein adsorption patterns were analyzed using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). Here, adsorption patterns of dendritic polymer nanoparticles were investigated, where the used polymer was dendritic polyglycerol sulfate. They showed reduced opsonization and preferential adsorption of apolipoprotein A-I with brain targeting potential. In perspective, the principle of surface property modification by polymer/stabilizer adsorption can be transferred to intravenous drug nanocrystals. A hybrid system of nanocrystal and polymeric nanoparticles is suggested, the polymeric nanoparticle with nanocrystal core.
    Article · Nov 2014 · Macromolecular Symposia
  • Xuezhen Zhai · Jürgen Lademann · Cornelia M. Keck · Rainer H. Müller
    [Show abstract] [Hide abstract] ABSTRACT: Nanocrystals are meanwhile applied to increase the dermal penetration of drugs, but were applied by now only to poorly soluble drugs (e.g. 1-10 μg/ml). As a new concept nanocrystals from medium soluble actives were produced, using caffeine as model compound (solubility 16 mg/ml at 20°C). Penetration should be increased by a) further increase in solubility and b) mainly by increased hair follicle targeting of nanocrystals compared to pure solution. Caffeine nanocrystal production in water lead to pronounced crystal growth. Therefore the stability of nanocrystals in water-ethanol (1:9) and ethanol-propylene glycol (3:7) mixtures with lower dielectric constant D was investigated, using various stabilizers. Both mixtures in combination with Carbopol(®) 981 (non-neutralized) yielded stable nanosuspensions over 2 months at 4°C and room temperature. Storage at 40°C lead to crystal growth, attributed to too strong solubility increase, supersaturation and Ostwald ripening effects. Stability of caffeine nanocrystals at lower temperatures could not only be attributed to lower solubility, because the solubilities of caffeine in mixtures and in water are not that much different. Other effects such as quantified by reduced dielectric constant D, and specific interactions between dispersion medium and crystal surface seem to play a role. With the 2 mixtures and Carbopol(®) 981, a basic formulation composition for this type of nanocrystals has been established, to be used in the in vivo proof of principle of the new concept.
    Article · Sep 2014 · European Journal of Pharmaceutics and Biopharmaceutics
  • Source
    Cornelia M Keck · Andjelka Kovačević · Rainer H Müller · [...] · Jela Milić
    [Show abstract] [Hide abstract] ABSTRACT: Alkyl polyglycosides (APGs) represent a group of nonionic tensides with excellent skin compatibility. Thus they seem to be excellent stabilizers for lipid nanoparticles for dermal application. To investigate this, different APGs were selected to evaluate their influence on the formation and characteristics of solid lipid nanoparticles (SLN). Contact angle analysis of the aqueous solutions/dispersions of the APGs on cetyl palmitate films revealed good wettability for all APG surfactants. Cetyl palmitate based SLN were prepared by hot high pressure homogenization and subjected to particle size, charge and inner structure analysis. 1% of each APG was sufficient to obtain SLN with a mean size between 150nm and 175nm and a narrow size distribution. The zeta potential in water was ∼ -50mV; the values in the original medium were distinctly lower, but still sufficient high to provide good physical stability. Physical stability at different temperatures (5°C, 25° and 40°C) was confirmed by a constant particle size over an observation period of 90 days in all dispersions. In comparison to SLN stabilised with classical surfactants, e.g. Polysorbate, APG stabilised SLN possess a smaller size, improved physical stability and contain less surfactant. Therefore, the use of APGs for the stabilization of lipid nanoparticles is superior in comparison to classical stabilizers. Further, the results indicate that the length of the alkyl chain of the APG influences the diminution efficacy, the final particle size and the crystallinity of the particles. APGs with short alkyl chain led to a faster reduction in size during high pressure homogenization, to a smaller particle size of the SLN and to a lower recrystallization index, i.e. to a lower crystallinity of the SLN. The crystallinity of the SLN increased with an increase in the alkyl chain length of APGs. Therefore, by using the tested APGs differing in the alkyl chain length, not only small sized and physically stable but also SLN with different sizes and crystallinity can be obtained. An optimised selection of these stabilizers might therefore enable the production of lipid nanoparticles with "tailor-made" properties.
    Full-text Article · Aug 2014 · International Journal of Pharmaceutics

Publication Stats

10k Citations

Institutions

  • 1992-2015
    • Freie Universität Berlin
      • • Institute of Pharmacy
      • • Division of Pharmaceutical Technology
      Berlín, Berlin, Germany
    • Christian-Albrechts-Universität zu Kiel
      • Department of Pharmaceutics and Biopharmaceutics
      Kiel, Schleswig-Holstein, Germany
  • 2010
    • Universidade Fernando Pessoa
      • Faculty of Health Sciences
      Porto, Distrito do Porto, Portugal
  • 2005
    • Technische Universität Dresden
      Dresden, Saxony, Germany
  • 2003
    • Ludwig-Maximilian-University of Munich
      • Department of Paediatrics
      München, Bavaria, Germany