Topical Pharmaceutical Products Research Articles

Homogeneity of Two Semisolid Formulations Using Simple In-tube Mixing Method

To accelerate therapeutic effects, the mixtures of two or more topical pharmaceutical products having different medicinal purposes are often applied in the medical field. In this study, we aimed to develop a simple mixing method/procedure to achieve excellent homogeneity in the mixture of two topical products, a steroidal ointment and a skin moisturizer. To assess an in-tube mixing method as a simple mixing procedure, we injected both topical products into an empty resin tube, a flexible hollow tube with an open end that can be closed on one side, and a closed end on the other, removed as less air as possible inside the tube, and then thermocompressed (sealed) the open end to close it. The two topical products were then mixed uniformly by repeated finger pressure along the longitudinal axis of the tube. The homogeneity of the two topical products in the tube was evaluated by measuring the content of methyl paraoxybenzoate (MP), an additive loaded in the skin moisturizer. In addition, the mixability was qualitatively evaluated from the distribution of white petrolatum, another additive loaded in the steroid ointment, using Raman spectroscopy. As a result, the measured value of MP relative to the label claim was in the range of 100±12%, and the coefficients of variation value was also less than 12%. These results indicate that the in-tube mixing method using two topical products is approximately hologenetic preparations that do not cause therapeutic problems.

A Novel Microparticle Based Formulation for Topical Delivery of FOL-005, a Small Peptide

Although many therapeutically active peptides and proteins have been developed there is a lack of topical pharmaceutical products on the market containing these sensitive molecules. The main reasons may be lack of stability and a limitation of larger molecules to penetrate into the skin. In this study we investigated the possibility to develop a peptide formulation which enables follicular permeation of peptides and passes the following criteria: 1) The formulation should be chemically and physically stable, 2) The formulation should have appealing cosmetical properties and 3) The formulation should be compatible with skin as well as sebum. The hypothesis was that increased stability of the peptide could be obtained by keeping the peptide in solid form and in a water-free environment, and that permeation into skin could be facilitated by reducing the particle size to < 10 µm and by formulating the peptide in sebum compatible excipients. By this method a safe and a cosmetically attractive formulation, facilitating the local distribution of the model peptide FOL-005 into the skin and at the same time securing chemical and physical stability, was successfully developed.

Safety Profile of Caesalpinia spinosa Aqueous Extract Tested in Oreochromis niloticus Toward Its Application in Dermocosmetics

Herbal extracts have been widely used in dermocosmetics as a source of biomolecules and also as a natural claim. Fruits from Caesalpinia spinosa show great potential for their polyphenolic content, preservative, and film-forming features, as previously reported in specialized literature; however, the toxicity requires investigation. We explored Oreochromis niloticus (tilapia) in larval, alevins, and juvenile stages to evaluate the ex vivo and in vivo genotoxicity and in vivo acute and chronic toxicity of C. spinosa aqueous extract in different concentrations. Cytotoxicity, animal behavior, morphological deformities, and DNA damage were evaluated. Our results showed genotoxic effect in ex vivo tests, but no DNA damage in in vivo erythrocytes. We suggest a mechanism of cell permeability involved in the toxicity of C. spinosa aqueous extract. Internal validation showed the feasibility of O. niloticus applied for toxicity evaluation. Further studies could contribute for better understanding the uses and safety of C. spinosa in cosmetics and topical pharmaceutical products.

Kynurenic Acid Accelerates Healing of Corneal Epithelium In Vitro and In Vivo

Kynurenic acid (KYNA) is an endogenous compound with a multidirectional effect. It possesses antiapoptotic, anti-inflammatory, and antioxidative properties that may be beneficial in the treatment of corneal injuries. Moreover, KYNA has been used successfully to improve the healing outcome of skin wounds. The aim of the present study is to evaluate the effects of KYNA on corneal and conjunctival cells in vitro and the re-epithelization of corneal erosion in rabbits in vivo. Normal human corneal epithelial cell (10.014 pRSV-T) and conjunctival epithelial cell (HC0597) lines were used. Cellular metabolism, cell viability, transwell migration, and the secretion of IL-1β, IL-6, and IL-10 were determined. In rabbits, after corneal de-epithelization, eye drops containing 0.002% and 1% KYNA were applied five times a day until full recovery. KYNA decreased metabolism but did not affect the proliferation of the corneal epithelium. It decreased both the metabolism and proliferation of conjunctival epithelium. KYNA enhanced the migration of corneal but not conjunctival epithelial cells. KYNA reduced the secretion of IL-1β and IL-6 from the corneal epithelium, leaving IL-10 secretion unaffected. The release of all studied cytokines from the conjunctival epithelium exposed to KYNA was unchanged. KYNA at higher concentration accelerated the healing of the corneal epithelium. These favorable properties of KYNA suggest that KYNA containing topical pharmaceutical products can be used in the treatment of ocular surface diseases.

Iatrogenic allergic contact dermatitis in the (peri)anal and genital area.

Allergic contact dermatitis (ACD) from topical medication often occurs in occluded areas, for example, with wound treatment, but also in certain body locations, such as the anogenital area. To investigate the demographics and specific lesion location of patients with ACD from topical drugs applied onto the (peri)anal/genital area, and to identify the respective causal topical pharmaceutical products and ingredients involved. From January 2000 to December 10, 2018, 532 patients were tested with the baseline series, sometimes with additional series, and the topical medication used along with the ingredients. The relevant data were extracted from our electronic databases developed in-house. Forty-four patients (9%) out of 473 patients suffering from lesions in the (peri)anal/genital area had positive patch test results to topical drug preparations and/or their ingredients, sometimes in association with cosmetics for intimate hygiene. The most frequent sensitizing active principles were local anaesthetics and corticosteroids, while wool alcohols and to a minor extent benzoic acid were the most frequent culprits among the vehicle components and preservative agents, respectively. The local conditions (eg, occlusion, sweating, moist) in the anogenital area may favour skin sensitization to topical medication used to treat various skin diseases.

Impact of Pluronic F-68 vs Tween 80 on Fabrication and Evaluation of Acyclovir SLNs for Skin Delivery

The solid lipid nanoparticles (SLNs) of Acyclovir (ACV) were fabricated with Soya lecithin and Fractionated Coconut oil (medium chain glyceride) as a first time combination. The research was focused on developing ACV-SLN by using high pressure hot-homogenization technique. The ingredients were used in different concentrations and ratios to identify the best formulation design. The tween 80 and Pluronic F-68 were used in various concentrations in formulation design to assess the impact on the fabrication and evaluation of SLNs. The impact of nanotechnology gain to play a vital role in the topical pharmaceutical products and the related patents will play a significant role in related industries. The SLNs were subjected to various characterization techniques such as XRD, FTIR, Master sizer analysis and zeta potential. The mean particle size was determined by master sizer and zeta sizer. Transmission electron microscopy (TEM) was used as a tool to analyze the morphology and other features. The zeta potential and drug entrapment efficiency (EE%) were also determined for the prepared ACV-SLNs. The efficiency of drug release from prepared formulations was studied by using in vitro study with the utilization of dialysis membrane technique. SLN dispersions exhibited the average size in nano range. SLNs with small particle size found to have predetermined encapsulation efficiency, and relatively high loading capacity and predetermined in vitro drug release profile.

Contact Allergy in Atopic Patients: What We Suspected and What We Know

Contact allergy in children was previously considered to be uncommon. However, data from the last decades have shown an increase in its prevalence, which is thought to result from more frequent exposure to allergens at a younger age, new trends in body piercing, use of cosmetic and pharmaceutical products, and participation in sports and hobbies. Factors that may influence the onset of sensitization in children are atopic dermatitis, skin barrier defects, and intense or repetitive contact with allergens. Although there are many similarities between adult and children with contact allergy, the patch test results obtained in adults cannot always be applied to children. Moreover, the notion of an association between atopy and contact allergy in children has been challenged. Experimental studies have shown that individuals with atopic dermatitis (AD) have suppressed contact sensitivity due to their disease. Patch testing should be considered at early stages in patients with AD; it is indicated not only when contact allergy is suspected but also in cases of persistent eczema on specific localizations, such as on the hands and the feet, around the mouth, and also in the umbilical region. Patients with AD should be tested when multiple exacerbations occur, even when they are treated, or when the dermatitis is asymmetrical. The most frequent contact allergens in children are metals, fragrances, hair dyes, adhesive and rubber chemicals, preservatives, and topical pharmaceutical products. Toys and portable electronic devices are another potential source of hapten exposure in children. Positive reactions in atopic children must be interpreted carefully, as atopic skin is readily irritated; this is specially the case for metals. Patch testing in children is safe, but false-positive reactions can occur. In addition, an abbreviated baseline series, supplemented with allergens suggested by the child’s history, should be tested. The fundamental relationship between atopic disease and environmental chemical exposure in children is complex and occurs more tightly than previously supposed.

Zinc Oxide and Zinc Oxide Nanoparticles as Enhancers in Topical Pharmaceutical and Cosmetic Products

Objectives : Scientists have widely investigated the use of chemical enhancers to improve drug transport through the skin. In this study, ZnO and ZnO nanoparticles (ZnO-NPs) has been used as dermal absorption enhancers for Ibuprofen (IP). Methods : Seven different formulations containing IP, ZnO, or ZnO-NPs were prepared. Dermal absorption experiments were performed at 32°C using a diffusion cell containing phosphate buffer saline (pH 7.4) and a slice of chicken skin. Cumulative amounts of skin permeated IP, ZnO or ZnO-NPs were plotted over time. Results : After 60 minutes, 90, 8 and 81 mg ZnO, ZnO-NPs and IP were passed through the skin, respectively. This amount for IP was 105, 114, 131 and 183 mg in presence of 100 mg ZnO, 100 mg ZnONPs, 200 mg ZnO-NPs, and 500 mg ZnO-NPs, respectively. Maximum amount of not-permeated IP was seen for formulation 1 (IP without enhancer) and minimum notpermeated IP was seen for formulation 5 (IP with 500 mg ZnO-NPs as enhancer). Conclusion : ZnO and more strongly ZnO-NPs could act as enhancers for transdermal delivery of IP. Such effect was improved by increase in concentration of ZnO-NPs. Therefore, ZnO-NPs can be used as enhancer in dermal drug delivery formulations.

Frequency and antimicrobial resistance of bacteria isolated from oral and topical medicaments from Hilla, Iraq

The presence of microorganisms in pharmaceuticals is undesirable because they may cause spoilage of the product and may present an infection hazard to the consumers or patients. A total of 102 samples of oral and topical non-sterile pharmaceutical products were collected at random from different drug houses and pharmacies in Iraq, to investigate the microbial contamination of these products. Bacterial isolates recovered from these medicaments were subjected to susceptibility testing against various antibiotics by disk diffusion method according to Clinical and Laboratory Standards (CLSI) guidelines. The results revealed that the occurrence of gram-positive bacteria was in oral and topical medicaments while gram-negative bacteria were only detected in topical medicaments. More than 58% of Bacillus isolates were resistant to lincomycin and Bacillus mycoides isolates were resistant to beta-lactam antibiotics and trimethoprim-sulfamethoxazole. Staphylococcus spp. showed a relatively high resistance to ampicillin, amoxicillin, penicillin, tetracycline, and trimethoprim-sulfamethoxazole. S. epidermidis had the highest number of multi-resistant isolates. Furthermore, 87.5% of isolated gram-negative rods showed high resistance to beta-lactam antibiotics and 75% of them were highly resistant to erythromycin. One isolate of Pseudomonas aeruginosa was the most resistant among all gram-negative rod isolates. The high rate of resistance to antimicrobial agents of bacterial isolates recovered from oral and topical medicaments in this study may indicate a widespread antibiotic resistance among bacteria isolated from different sources, including those of anthropological and environmental origin.

ALERGIA CUTÂNEA EM CRIANÇAS

No diagnóstico de dermatite de contacto alérgica é fundamental, tal como nos adultos, a história e loca- lização das lesões, mas alguns produtos e/ou hábitos característicos das crianças e adolescentes podem ser respon- sáveis por quadros clínicos pouco usuais. Os alergenos mais importantes na criança são os metais, como o crómio (calçado) e o níquel (por vezes associado ao cobalto ou paládio; este último também responsável por reacções gra- nulomatosas de contacto), sobretudo nas jovens, dada a popularidade dos adornos baratos. Recentemente, surgiram entre os jovens outras fontes de sensibilização, como os telemóveis. Outros potenciais alergenos são os ingredientes de produtos tópicos, sobretudo antissépticos; o mercúrio e derivados ainda são utilizados nalguns países, mas as re- acções alérgicas, mesmo em crianças pequenas, não são em geral clinicamente relevantes. Cosméticos, em particular de limpeza cutânea, podem originar sensibilização a componentes das fragrâncias ou conservantes. Derivados da borracha, muitas vezes responsáveis por dermatite ao calçado ou às fraldas, resinas e plantas também podem ser fonte de sensibilização. Adicionalmente, alguns alergenos ocupacionais (p. ex, cabeleireiras, construção civil e me- talúrgicos) também ocorrem em adolescentes. A alteração da legislação, referente à presença de alergenos em pro- dutos comuns, pode levar à redução da incidência de alergia de contacto em crianças (p. ex, ao níquel nos adornos e telemóveis e às tintas capilares em menores de 16 anos). O uso de p-fenilenodiamina nas tatuagens temporárias de henna continua a ser um problema. As provas epicutâneas em crianças são seguras; a maioria dos autores con- sideram as reacções irritativas pouco frequentes (excepto em atópicos, em particular a metais) e podem utilizar-se as mesmas concentrações que no adulto. No entanto, não se pode excluir a possibilidade de reacções falso+ ou falso- e, na suspeita de potencial irritativo, devem também testar-se concentrações inferiores. Dada a reduzida área cutânea para testes, a menor exposição ambiental a alguns alergenos e a hipermobilidade das crianças pequenas, alguns autores recomendam utilizar séries standard reduzidas, embora outros alertem para o risco de se ignorarem muitas reacções. De qualquer modo, é importante ter em conta a história e o quadro clínico e testar, sempre que necessário, outros possíveis alergenos e produtos pessoais.PALAVRAS-CHAVE – Dermatite; Alergia de Contacto; Criança; Alergenos; Hipersensibilidade.

Œil, paupières et allergènes de contact

Contact allergy is a common cause of conjunctivitis and eyelids dermatitis. Allergens may reach the skin in many different ways: intentional application in the eyes and the eyerlids, transfer from other site of the body, airborn dermatitis, connubial dermatitis, photoallergy. The main sensitization sources are topical pharmaceutical products, cosmetics and professional allergens. Treatments of eyelid contact dermatitis are eviction of allergens and application of topical corticosteroids. Tacrolimus may be a promising alternative therapy.

Composants parfumés. Nouvelles sources d’exposition aux allergènes de la batterie standard

The increasing frequency of contact allergy to fragrances led to change European standard baseline series with integration of new screening patch tests for fragrances. However, not all cases are detected by the standard series and tests with the patient's personal products remain relevant especially as some sources of exposure to perfumes are difficult to identify as in cosmetics containing vegetal extracts and some topical pharmaceutical products.

Solid lipid nanoparticle and nanoparticle lipid carrier for controlled drug delivery &amp;ndash; a review of state of art and recent advances

It is estimated that nearly 40% of new drug molecules are suffering from poor water solubility, insufficient bioavailability, fluctuating plasma levels or high food dependency. Major efforts have been spent for the development of customised drug carriers to overcome the disappointing in vivo fates of the drug. Both the SLN and NLC are attractive carriers for topical cosmetic and pharmaceutical products. Solid lipid nanoparticles (SLNs) introduced as an alternative carrier system to traditional colloidal carriers, such as emulsions, liposomes and polymeric micro- and nanoparticles. SLN combine advantages of the traditional systems but avoid some of their major disadvantages. This paper reviews the present state of the art regarding production techniques for SLN, drug incorporation, loading capacity and drug release, especially focusing on drug release mechanisms. The potential of SLN to be exploited for the different administration routes is highlighted and also reviews about SLN and NLC's stability, toxicity, pharmacokinetic profile, application and its future perspectives.

Allergic contact dermatitis from fragrance components in specific topical pharmaceutical products in Belgium

To determine which topical pharmaceutical products marketed in Belgium contain fragrances and to examine the nature of the fragrance allergens in specific pharmaceutical products having caused iatrogenic contact dermatitis. All topical pharmaceutical products marketed in Belgium, that is 3820 products, were examined as to their fragrance content as labelled. Data of 18, 960 patients investigated for contact allergy between 1978 and 2008 were retrieved from our database, including information on the nature of the topical pharmaceutical products used, the results of patch tests, and the sensitization sources. Three hundred and seventy (10%) of 3280 of the topical pharmaceutical products were found to contain a total of 66 fragrance substances. Among 3378 patients suffering from iatrogenic allergic contact dermatitis, 127 were found to react to 48 specific products, for which 38 different fragrance substances gave relevant positive reactions. Women were more affected than men, and legs, hands, and face were the most commonly affected body sites. Fragrances, the presence of which is in most cases unnecessary, do contribute to iatrogenic allergic contact dermatitis. Moreover, sensitized patients have difficulties in avoiding their specific allergens because standardized labelling of the ingredients in pharmaceutical products is lacking.

A comparison of pentane-1,5-diol to other diols for use in dermatology

Background: The use of pentane-1,5-diol in topical pharmaceutical products is relatively new compared with, e.g., propane-1,2-diol (propylene glycol), also an aliphatic diol, which has been used for many years. Yet, what are the differences between diols in clinical efficacy, safety and other characteristics? Objective: The objective of this overview was to compare the efficacy, safety, chemical and pharmaceutical characteristics of pentane-1,5-diol with other aliphatic diols used in pharmaceutical formulations in dermatology. Methods: A survey of the literature was carried out based on searches limited to aliphatic diols. Results/conclusion: Pentane-1,5-diol was found to be safe and more effective than several other diols with respect to drug delivery-enhancing potency, pharmaceutical and cosmetic properties, antimicrobial spectrum and toxicity. Results from formal clinical trials with pentane-1,5-diol verify its efficacy and safety. These characteristics together with its low cost make pentane-1,5-diol an attractive substance for use in pharmaceutical formulations for topical administration.

A Review of Thimerosal (Merthiolate) and its Ethylmercury Breakdown Product: Specific Historical Considerations Regarding Safety and Effectiveness

Thimerosal (Merthiolate) is an ethylmercury-containing pharmaceutical compound that is 49.55% mercury and that was developed in 1927. Thimerosal has been marketed as an antimicrobial agent in a range of products, including topical antiseptic solutions and antiseptic ointments for treating cuts, nasal sprays, eye solutions, vaginal spermicides, diaper rash treatments, and perhaps most importantly as a preservative in vaccines and other injectable biological products, including Rho(D)-immune globulin preparations, despite evidence, dating to the early 1930s, indicating Thimerosal to be potentially hazardous to humans and ineffective as an antimicrobial agent. Despite this, Thimerosal was not scrutinized as part of U.S. pharmaceutical products until the 1980s, when the U.S. Food and Drug Administration finally recognized its demonstrated ineffectiveness and toxicity in topical pharmaceutical products, and began to eliminate it from these. Ironically, while Thimerosal was being eliminated from topicals, it was becoming more and more ubiquitous in the recommended immunization schedule for infants and pregnant women. Furthermore, Thimerosal continues to be administered, as part of mandated immunizations and other pharmaceutical products, in the United States and globally. The ubiquitous and largely unchecked place of Thimerosal in pharmaceuticals, therefore, represents a medical crisis.

Contact Allergic Reactions of the Vulva: A 14-Year Review

In women with vulval complaints, irritant contact dermatitis is more common than allergic contact dermatitis, but secondary sensitization has to be taken into consideration since these patients often use several topical medications. The aims of this retrospective study were to establish the prevalence of allergic contact dermatitis in patients with vulval complaints and to verify how many patients with allergic contact dermatitis suffered from a previous pathology. We reviewed patch- and prick-test results from 92 women. The women had all been administered the European Standard series, and most had also been tested for other allergens such as the ingredients of topical pharmaceutical products and cosmetics. Thirty-five patients (38%) presented with one or more positive allergic reactions. For 15 of the patients, these reactions were considered to be relevant to their clinical condition and were most often due to contact dermatitis from topical pharmaceutical products. Three patients presented with positive and relevant contact urticaria syndrome from latex, and two patients presented with protein contact dermatitis from human seminal plasma. Patients with vulval dermatitis are at risk of developing contact sensitivities, particularly to topical pharmaceutical products; therefore, attention should be paid to this problem when such products are prescribed.

SCREENING FOR CORTICOSTEROIDS IN TOPICAL PHARMACEUTICALS BY HPLC WITH A SCANNING ULTRAVIOLET DETECTOR1*

A screening procedure was developed for the detection of 49 corticosteroids in topical pharmaceutical products. These products were analyzed by reversed-phase HPLC using two gradient systems: a linear gradient of 18–82% acetonitrile over 12 min and a linear gradient of 38–88% methanol over 12 min. Although all corticosteroids were not resolved during a single 12-min gradient analysis, a peak retention time from a sample analysis was usually sufficient to limit an unknown to 1–3 probable corticosteroids. Steroids unresolved with the first gradient system were resolved with the second one, with the exception of three steroid pairs. Assignments based on retention times were supported by spectra provided by a rapid scanning ultraviolet detector. Two extraction procedures were developed to isolate corticosteroids from both water-soluble and lipid-soluble sample components. When applied to a variety of topical formulations, the two extraction methods eliminated most of the sample excipients, recovered corticosteroids in high yield, and allowed for detection to a level of 0.001% of the sample. Presented in part at HPLC'98, St. Louis, MO, USA on May 6, 1998.

Artificial Intelligence and Contact Dermatitis: The CODEX/E System

The Contact Dermatitis Index or CODEX consists primarily of data on patients, products, and their ingredients that we began compiling in 1978 to form a computerized information system. These data bases are used to provide patients with lists of all the topical pharmaceutical products containing their allergens, to help dermatologists identify potential allergens and avoid prescription errors, and to assist scientists, authorities, and the industry by means of reports and epidemiological studies. Based on this system, we developed the CODEX/E, an expert system that has been operational in our contact dermatitis unit since September 1989. The dermatologist preparing the contact-allergy anamnesis and testing program is given on-line support in the determination of possible allergens. The primary rules are based on sex, lesion location, exposure, profession/hobbies, and topical pharmaceuticals used. The secondary rules are based on the nature of the lesions, cosmetic usage, literature data, and, are used to detect new trends data from the last 1,000 patients examined. The contact-allergy expert can also introduce “user rules.” The rules are derived from the Codex Patient File, which contains information on some 12,000 patients; the Codex Product File, which contains the complete composition of over 7,000 pharmaceutical products intended for application on the skin and mucous membranes and information on compiled on some 500 cosmetic products; and the Codex Raw Material File, which contains all the names of all the ingredients used in the manufacture of these pharmaceutical products to which an automatically updated allergenicity score has been assigned.

Toxicology of topical therapy

Clinical toxicity can result from accidental exposure to therapeutic agents designed for topical use. Each year, poison centers in the United States and Canada report more than 45,000 cases of exposure to topical pharmaceutical products. Although the vast majority of these patients are exposed accidentally to products available in the home, a few patients experience serious poisoning from therapeutic products found in the physician's office. It is imperative that the physician be aware of the potential chemical hazards in the office, how to store them safely, how to recognize clinical toxicity, and where to obtain expert advice on treating a potential poisoning. This chapter discusses the toxicity of selected products commonly found in the offices of physicians who practice dermatology.