Towards the Continuous Manufacturing of Liquisolid Tablets Containing Simethicone and Loperamide Hydrochloride with the Use of a Twin-Screw Granulator.

Continuous manufacturing is becoming the new technological standard in the pharmaceutical industry. In this work, a twin-screw processor was employed for the continuous production of liquisolid tablets containing either simethicone or a combination of simethicone with loperamide hydrochloride. Both active ingredients present major technological challenges, as simethicone is a liquid, oily substance, and loperamide hydrochloride was used in a very small amount (0.27% w/w). Despite these difficulties, the use of porous tribasic calcium phosphate as a carrier and the adjustment of the settings of the twin-screw processor enabled the optimization of the characteristics of the liquid-loaded powders and made it possible to efficiently produce liquisolid tablets with advantages in physical and functional properties. The application of chemical imaging by means of Raman spectroscopy allowed for the visualization of differences in the distribution of individual components of the formulations. This proved to be a very effective tool for identifying the optimum technology to produce a drug product.

Development of Safirinium dyes for new applications: fluorescent staining of bacteria, human kidney cells, and the horny layer of the epidermis.

Low-molecular synthetic fluorophores are convenient tools in bioimaging applications. Several derivatives of Safirinium dyes as well as their reactive N-hydroxysuccinimide (NHS) esters bearing diverse substituents were synthesized and evaluated experimentally in terms of their lipophilicity by means of reverse-phase and immobilized artificial membrane high-performance liquid chromatography. Subsequently, the selected compounds were employed as novel cellular imaging agents for staining Gram-positive and Gram-negative bacteria, human kidney cell line, as well as human skin tissue. The analyzed dyes allowed for visualization of cellular structures such as mitochondria, endoplasmic reticulum, and cellular nuclei. They proved to be useful in fluorescent staining of stratum corneum, especially in the aspect of xenobiotic exposure and its penetration into the skin. The best results were obtained with the use of moderately lipophilic NHS esters of Safirinium Q. The development of Safirinium dyes is a promising alternative for commercially available dyes since the reported molecules have low molecular masses and exhibit efficient staining and remarkable water solubility. Moreover, they are relatively simple and low-cost in synthesis.

Microscopic and Spectroscopic Imaging and Thermal Analysis of Acrylates, Silicones and Active Pharmaceutical Ingredients in Adhesive Transdermal Patches.

Dermal or transdermal patches are increasingly becoming a noteworthy alternative as carriers for active pharmaceutical ingredients (APIs), which makes their detailed physicochemical evaluation essential for pharmaceutical development. This paper demonstrates mid-infrared (FTIR) and Raman spectroscopy with complementary microscopic methods (SEM, optical and confocal Raman microscopy) and differential scanning calorimetry (DSC) as tools for the identification of the state of model API (testosterone TST, cytisine CYT or indomethacin IND) in selected adhesive matrices. Among the employed spectroscopic techniques, FTIR and Raman may be used not only as standard methods for API identification in the matrix, but also as a means of distinguishing commercially available polymeric materials of a similar chemical structures. A novel approach for the preparation of adhesive polymers for the FTIR analysis was introduced. In silicone matrices, all three APIs were suspended, whereas in the case of the acrylic PSA, Raman microscopy confirmed that only IND was dissolved in all three acrylic matrices, and the dissolved fraction of the CYT differed depending on the matrix type. Moreover, the recrystallization of TST was observed in one of the acrylates. Interestingly, a DSC analysis of the acrylic patches did not confirm the presence of the API even if the microscopic images showed suspended particles.

Comparative study of the percutaneous permeation and bioaccumulation of a cyclic siloxane using frozen-thawed and nonfrozen ex vivo human skin.

Literature shows contradictory information regarding the effect of freezing the excise skin ex vivo on the diffusion of substances into the skin. Few studies indicate that storing the human or animal skin in a frozen state decreases the barrier properties after thawing. Therefore, to understand the properties of frozen skin, we evaluated the effect of storage of ex vivo human skin (2 weeks at -20 °C) on the penetration of stratum corneum and permeation into deeper skin layers (epidermis, and dermis) as well as to the receptor fluid by octamethylcyclotetrasiloxane (D4) a representative test compound of cyclic siloxanes. The main research were preceded by checking the integrity of nonfrozen ex vivo human skin in comparison to the frozen-thawed one by using the Electrical Resistance technique (ER) and the fluorescence microscopy. Samples collected in the skin absorption experiment were analyzed by gas chromatography equipped with a flame ionization detector (GC-FID). The results of this study demonstrated that freezing of excised ex vivo human skin at -20 °C for up to 14 days does not alter the permeability of D4 in a statistically significant manner. Thus, our results confirmed the validity of using skin storage conditions for testing the penetration and permeation of xenobiotics recommended by the OECD, EMA, and WHO guidelines.

Evidence of Skin Barrier Damage by Cyclic Siloxanes (Silicones)-Using Digital Holographic Microscopy.

Cyclic siloxanes (D4, D5, D6) are widely used in skin products. They improve skin sensory properties and alleviate dry skin, but there is still one report (published 2019), which regards their effects on the destruction of the skin barrier, by using fluorescence microscopy and attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR). A new skin-imaging technique, digital holographic microscopy (DHM), was used for the first time to investigate the impact of D4, D5, and D6 on the skin barrier. We observed irreversible damage of the stratum corneum due to the interaction with cyclic siloxanes. These substances changed: (a) the first level of the skin barrier through destabilization of the intercellular lipid lamellae and destruction of the corneocyte structure (measured with axial nanometer resolution), (b) the second level by collapse of not only corneocytes but also of a significant part of the clusters, leading to the loss of the stratum corneum integrity and formation of the lacunae, (c) the third level as an effect of the change in the surface geometrical topography of the stratum corneum and disruption of the integrity of this skin layer, measured with lateral micrometer resolution. DHM allowed also to identify an important pathway for substances to penetrate into the skin through canyons surrounding the clusters. Our investigations provide advanced information for understanding the mechanisms by which various substances pass the skin barrier, including uncontrolled diffusion into the skin.

Ex Vivo Human Skin is not a Barrier for Cyclic Siloxanes (Cyclic Silicones): Evidence of Diffusion, Bioaccumulation, and Risk of Dermal Absorption Using a New Validated GC-FID Procedure.

Cyclic methylsiloxanes D4, D5, D6 (also called cyclic silicones) are widely used in various dermatological products and cosmetics, both for children and adults. As a result of their unique physicochemical properties, the production of cyclic methylsiloxanes has greatly increased over the last few years, which has resulted in increased exposure to mankind. The validated quantitative for gas chromatography-flame ionization detector (GC-FID) analysis with using the transdermal diffusion system with vertical Franz cells demonstrated that ex vivo human skin is not a barrier to cyclic siloxanes. D4, D5, and D6 have a specific affinity to stratum corneum (SC) (especially D6), and can even diffuse into the deeper layers of the skin (epidermis (E) and dermis (D)), or into the receptor fluid as well. An important achievement of this work was the observation of the characteristic ratio partitioning D4, D5, and D6 in skin layers and receptor fluid (RF). The studies have shown that, in order to thoroughly understand the mechanism, it is important to determine not only the differences in the amounts of cumulated doses in total in all skin layers and receptor fluid, but also the mutual ratios of analyte concentrations existing between matrices. For example, in the case of the stratum corneum, the cumulative doses of D4, D5, and D6 were 27.5, 63.9, and 67.2 µg/cm2/24 h, respectively, and in the epidermis, they were 6.9, 29.9, and 10.7 µg/cm2/24 h, respectively, which confirmed the highest affinity of D6 to stratum corneum as the amount diffused into the epidermis was 2.8 times smaller compared to D5. The calculated epidermis-to-stratum corneum ratios of analyte concentrations also confirm this. The largest ratio was identified for D5 (E/SC = 47), followed by D4 (E/SC = 25), and finally by D6 (E/SC = 16). The analysis of the next stage of diffusion from epidermis to dermis revealed that in dermis the highest cumulative dose was observed for D5 (13.9 µg/cm2/24 h), while the doses of D4 and D6 were similar (5.1 and 5.3 µg/cm2/24 h). Considering the concentration gradient, it can be concluded that the diffusion of D5 and D6 occurs at a similar level, while D4 diffuses at a much higher level. These observations were also confirmed by the dermis-to-epidermis concentration ratios. The final stage of diffusion from dermis to the receptor fluid indicated that D4 was able to permeate easily, while D5 exhibited a difficult diffusion and the diffusion of D6 was limited. The receptor fluid-to-dermis concentration ratios (RF/D) were calculated for D4, D5, and D6: 80, 53, and 17, respectively. Our results also revealed the increased risk of D4 and D5 absorption into the blood and lymphatic systems, whereas D6 demonstrated the lowest risk. Therefore, we can argue that, among the three tested compounds, D6 is the safest one that can be used in dermatological, cosmetic, and personal care products. This study demonstrates that the stratum corneum, epidermis, and dermis can be also considered reservoirs of cyclic methylsiloxanes. Therefore, these compounds can demonstrate potential long-term bioaccumulation, and can be absorbed to the bloodstream in a long-term and uncontrolled process.

The consequences of overcoming the human skin barrier by siloxanes (silicones) Part 1. Penetration and permeation depth study of cyclic methyl siloxanes.

Dynamic production of cyclic siloxanes: octamethylcyclotetrasiloxane D4, decamethylcyclopentasiloxane D5 and dodecamethylcyclohexasiloxane D6 increases their concentrations in environment. It is considered that both environmental pollution and the usage of personal care products and cosmetics containing cyclic siloxanes can be the main source of the human exposure by transdermal route. The aim of the study was to verify the possibility to overcome the skin barrier by cyclic siloxanes (ATR-FTIR and GC-FID), evaluation of diffusion pathway to stratum corneum SC (Fluorescence microscopy), and determination of depth of permeation to deeper skin layers: epidermis and dermis (ATR-FTIR) and also of potential interaction with SC lipids and proteins (Fluorescence microscopy, ATR-FTIR) and the cytotoxicity studies against HaCaT cells (MTT test). The results show that D4, D5 and D5 can penetrate to SC and permeate into the deeper layers of the skin: epidermis and dermis. The quantitative analysis (GC-FID) showed that total cumulative doses for D4, D5 and D6 were: 42.50; 95.37 and 77.19 µg/cm2/24 h, respectively. The microscopic analysis proved, transepidermal route through the lipid matrix as well as through the canyons (intercluster spaces) were a diffusion pathway to the SC as well as disruption of human SC lipid structure by: D4 (the most), D5 and D6 (the least). The cytotoxicity studies demonstrated that the tested range of concentrations of D5 and D6 (up to 300 mM, 111 300 mg and 133 500 mg respectively) did not impaired the HaCaT growth, while D4 had IC50 value of 40 098 mM ±â€¯7.94 (10 906 ±â€¯872,5 mg).

Evolution of consciousness of exposure to siloxanes-review of publications.

The purpose of this description is to review scientific literature from 1944 to 2017 as a source of information on the reasons for the increased interest in siloxanes (silicones). Not only the research area, but first, the changes in the tendency of research aims are important issues in the evaluation. On the one hand, the authors emphasize the unique properties of linear and cyclic siloxanes, providing many examples of beneficial applications, and on the other hand, there are some warnings of overcoming of the safety barrier of their presence in human environment. Analyzing the results from the SCOPUS database, it can be argued that the increased interest of scientists and government agencies particularly relates to the analysis of siloxanes in biological and environmental samples. This is caused not only by the widespread use of various siloxanes in the pharmaceutical, medical, cosmetic and food industries, but also by the direct contact of these compounds with tissues, as well as an increased access to knowledge and modern research tools that have developed the awareness of hazards. The development of research methods enables not only constant monitoring of progressively lower siloxanes concentrations in various samples, but because of the specificity of these methods, it also enables an identification of specific siloxane compounds and evaluation of their effects on humans and environment. This paper discusses the issues of the evolution of consciousness of exposure to siloxanes due to their increased synthesis and widespread use in many areas of human life, which contributes to environmental pollution.

Direct Human Contact with Siloxanes (Silicones) - Safety or Risk Part 1. Characteristics of Siloxanes (Silicones).

Siloxanes are commonly known as silicones. They belong to the organosilicon compounds and are exclusively obtained by synthesis. Their chemical structure determines a range of physicochemical properties which were recognized as unique. Due to the susceptibility to chemical modifications, ability to create short, long or complex polymer particles, siloxanes found an application in many areas of human life. Siloxanes differ in particle size, molecular weight, shape and chemical groups. As a result, this determines the different physico-chemical properties, that directly affect the safety or the risk of their use. The areas that can be a source of danger to human health will be commented in this paper.

Physical and Mechanical Evaluation of Silicone-Based Double-Layer Adhesive Patch Intended for Keloids and Scar Treatment Therapy.

Growing interest in silicone elastomers for pharmaceutical purposes is due to both their beneficial material effect for scar treatment and their potential as drug carriers. Regarding their morphological structure, silicone polymers possess unique properties, which enable a wide range of applicability possibilities. The present study focused on developing a double-layer adhesive silicone film (DLASil) by evaluating its physical and mechanical properties, morphology, and stability. DLASil suitability for treatment of scars and keloids was evaluated by measurement of tensile strength, elasticity modulus, and elongation. The results indicated that mechanical and physical properties of the developed product were satisfying.

Double layer adhesive silicone dressing as a potential dermal drug delivery film in scar treatment.

The present studies focused on the evaluation of design of an adhesive silicone film intended for scar treatment. Developed silicone double layer film was examined in terms of its future relevance to therapy and applicability on the human skin considering properties which included in vitro permeability of water vapor and oxygen. In order to adapt the patches for medical use in the future there were tested such properties as in vitro adhesion and occlusion related to in vivo hydration. From the silicone rubbers double layer silicone film was prepared: a non-adhesive elastomer as a drug carrier (the matrix for active substances - enoxaparin sodium - low molecular weight heparin) and an adhesive elastomer, applied on the surface of the matrix. The novel adhesive silicone film was found to possess optimal properties in comparison to commercially available silicone dressing: adhesion in vivo, adhesion in vitro - 11.79N, occlusion F=85% and water vapor permeability in vitro - WVP=105g/m(2)/24h, hydration of stratum corneum in vivoH=61-89 (RSD=1.6-0.9%), oxygen permeation in vitro - 119-391 cm(3)/m(2)/24 (RSD=0.17%). In vitro release studies indicated sufficient LMWH release rate from silicone matrix. Developed novel adhesive silicone films were considered an effective treatment of scars and keloids and a potential drug carrier able to improve the effectiveness of therapy.

Size exclusion chromatography with evaporative light scattering detection as a method for speciation analysis of polydimethylsiloxanes. III. Identification and determination of dimeticone and simeticone in pharmaceutical formulations.

The pharmaceutical industry is one of the more important sectors for the use of polydimethylsiloxanes (PDMS), which belong to the organosilicon polymers. In drugs for internal use, they are used as an active pharmaceutical ingredient (API) called dimeticone or simeticone. Due to their specific chemical nature, PDMS can have different degrees of polymerization, which determine the molecular weight and viscosity. The Pharmacopoeial monographs for dimeticone and simeticone, only give the permitted polymerization and viscosity range. It is, however, essential to know also the degree of polymerization or the specific molecular weight of PDMS that are present in pharmaceutical formulations. In the literature there is information about the impact of particle size, and thus molecular weight, on the toxicity, absorption and migration in living organisms. This study focused on the use of a developed method - the exclusion chromatography with evaporative light scattering detector (SEC-ELSD) - for identification and determination of dimeticone and simeticone in various pharmaceutical formulations. The method had a high degree of specificity and was suitable for speciation analysis of these polymers. So far the developed method has not been used in the control of medicinal products containing dimeticone or simeticone.

Technology of an adhesive silicone film as drug carrier in transdermal therapy. I: Analytical methods used for characterization and design of the universal elastomer layers.

Silicone polymers possess unique properties, which make them suitable for many different applications, for example in the pharmaceutical and medical industry. To create an adhesive silicone film, the appropriate silicone components have to be chosen first. From these components two layers were made: an adhesive elastomer applied on the skin, and a non-adhesive elastomer on the other side of the film. The aim of this study was to identify a set of analytical methods that can be used for detailed characterization of the elastomer layers, as needed when designing new silicone films. More specifically, the following methods were combined to detailed identification of the silicone components: Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (¹H NMR) and size exclusion chromatography with evaporative light scattering detector (SEC-ELSD). It was demonstrated that these methods together with a rheological analysis are suitable for controlling the cross-linking reaction, thus obtaining the desired properties of the silicone film. Adhesive silicone films can be used as universal materials for medical use, particularly for effective treatment of scars and keloids or as drug carriers in transdermal therapy.

Size exclusion chromatography with evaporative light scattering detection as a method for speciation analysis of polydimethylsiloxanes. II. Validation of the method for analysis of pharmaceutical formulations.

The aim of this study was to demonstrate the usefulness of the size exclusion chromatography with evaporative light scattering detection (SEC-ELSD) method in the identification and quantitative analysis of polydimethylsiloxanes (PDMS). The process of validation for the method was conducted, and the values obtained were compared with the acceptance criteria. Particularly important was the conclusion that SEC-ELSD method showed a high specificity for PDMS. PDMS is an organosilicon polymer and for this reason, it does not exist as a concrete chemical species. Depending on the length of the chain, PDMS can be toxic for organism. So far, the SEC-ELSD method has not been applied for the control of pharmaceutical products containing such PDMS as dimeticone or simeticone. The safety of use and effectiveness of such pharmaceutical products relies on the control of their quality. Therefore, the analytical methods and procedures that meet acceptance criteria for qualitative and quantitative analysis of the PDMS should be used. In the case of the analysis of pharmaceutical products, the acceptance criteria are established and recommended by, for example, the Pharmacopoeias, the U.S. Food and Drug Administration (FDA), the International Conference on Harmonisation (ICH) and the World Health Organization (WHO). The progress of knowledge, however, requires the development of new analytical tools which are able to solve incoming problems. In the case of pharmaceutical formulations containing PDMS, which are used not only by adults but also by children, it is necessary to use analytical methods which are characterized by a high specificity.

Size exclusion chromatography with evaporative light scattering detection as a method for speciation analysis of polydimethylsiloxanes. I: Influence of selected factors on the signal intensity of the detector.

Evaporative light scattering detector (ELSD) is widely recognized as a universal tool in chromatography. In this paper, the characteristics of the ELSD detector response and the influence of different factors on the signal intensity are described. Further, results are presented on the influence of some selected factors on the signal intensity and repeatability of results for linear structure polydimethylosiloxanes (PDMS), differing in molecular weight and viscosity. The following factors were studied: (i) the flow velocity of the nebulising gas, (ii) the temperature of the drift tube and the detection cell, and (iii) the flow velocity of the mobile phase, as they all constitute important parameters of the detector. Based on such studies, the optimal parameters of detector indications can be selected for a specific analysis. The results confirmed the possibility to select one set of values for those parameters that allow for analysis of linear PDMS molecules with viscosities ranging from 10 to 60,000 cSt. The following optimal and common parameter values were specified: temperature drift tube 50 degrees C, carrier gas pressure (for nebulisation) 140 kPa, and mobile phase flow rate 0.7 ml/min. A high repeatability of the results was demonstrated as the relative standard deviation was less than 2.5%. This type of tests for polydimethylosiloxanes has not been presented in any previous publication.

Size-exclusion chromatography with evaporative light scattering detection: Method for determination of polydimethylsiloxanes. I. Testing dependence of molecular weight of polydimethylsiloxanes and injected mass upon the detector signal.

In recent years the evaporative light scattering detector has become a promising device in the analysis of variable chemical compounds using liquid chromatography. Due to the detection specificity, based on the scattering of the laser light on non-volatile analyte particles, this detector is considered a most universal one. Many authors consider detector signal as a mass signal and subsequently, evaporative light scattering detector has been regarded as a mass detector. Although the scientists pinpoint to many advantages of this device, many of its drawbacks were also noticed. Due to variable examinations carried out some scientist characterised the detector response as a non-linear, seeing in fact a significant limitation of this detector for the purposes of quantitative tests. The author of the present study researched, in many ways, for the solution to this problem, by carrying out tests on polydimethylsiloxanes (PDMS) of a linear structure. The aim of this study was to test the dependence of the evaporative light scattering detector signal upon the molecular weight of PDMS of a linear structure and viscosity ranging from 10 to 60,000 cSt and the injected mass. The evaluation of function monotonicity of the detector response and determination of the function for particular analytes referred to the mass ranges of 8.9-149.0 microg. In order to find the dependence of the integrated signal value of the detector signal intensity, expressed as a surface area in mug, upon analyte mass for particular PDMS, several analytical functions and formulas were used. Parameters of regression equations were calculated for linear and non-linear functions as well as their logarithmic transformations. The aim of the research for the optimal regression equation could mean increased reliability of results obtained from analyses of PDMS.

Size exclusion chromatography with evaporative light scattering detection: Method for the determination of polydimethylsiloxanes. II. Application of TSK-GEL H HR GMH HR -M column to determine and separate molecular weight of linear polydimethylsiloxanes.

Issues concerned with molecular weight distribution analysis of linear polydimethylsiloxanes have not been extensively investigated and mastered, yet. Current publications do not provide detailed research data on the evaluation of the polymerization degree of polydimethylsiloxanes (PDMS) present in variable matrices: e.g. pharmaceuticals, cosmetics, foodstuffs nor indicate molecular weights of the polymer used. However, the information on molecular weight, i.e. viscosity, is of primary importance as it directly affects PDMS toxicity, absorption and migration in the living organism. The vast majority of currently applied methods prove to be insufficiently specific for PDMS of a particular molecular weight and therefore alternative analytical methods have to be further researched. In this paper the results of determination of molecular weights in linear polydimethylsiloxanes, using size exclusion chromatography with the evaporative light scattering detector are described. The column calibration curve obtained from low-dispersion standard polystyrene of molecular weights ranging 376-2,570,000 Da was used to determine PDMS molecular weights. Precision and accuracy of determination was obtained. For the mobile phase flow-rate of 0.3 ml/min relative standard deviation RSD ranged to 0.45% and the accuracy of measurement amounted to -0.42%, whereas for flow-rate of 1.0 ml/min RSD ranged to 0.38% and accuracy to +2.15%.