Limitations and Challenges in the Stability of Cysteamine Eye Drop Compounded Formulations.

Accumulation of cystine crystals in the cornea of patients suffering from cystinosis is considered pathognomonic and can lead to severe ocular complications. Cysteamine eye drop compounded formulations, commonly prepared by hospital pharmacy services, are meant to diminish the build-up of corneal cystine crystals. The objective of this work was to analyze whether the shelf life proposed for six formulations prepared following different protocols used in hospital pharmacies is adequate to guarantee the quality and efficacy of cysteamine eye drops. The long-term and in-use stabilities of these preparations were studied using different parameters: content of cysteamine and its main degradation product cystamine; appearance, color and odor; pH and viscosity; and microbiological analysis. The results obtained show that degradation of cysteamine was between 20% and 50% after one month of storage in the long-term stability study and between 35% and 60% in the in-use study. These data confirm that cysteamine is a very unstable molecule in aqueous solution, the presence of oxygen being the main degradation factor. Saturation with nitrogen gas of the solutions offers a means of reducing cysteamine degradation. Overall, all the formulae studied presented high instability at the end of their shelf life, suggesting that their clinical efficacy might be dramatically compromised.

Current situation of carboplatin desensitisation protocols in the hospitals of Spain.

Desensitisation protocols allow the continuation of treatment in patients who have presented hypersensitivity reactions. Carboplatin desensitisation solutions are usually prepared in the chemotherapy centralised units of hospital pharmacies and they are diluted under the established concentration limit to guarantee the stability of the preparation. An online survey was sent to hospital pharmacies, inquiring about local desensitisation protocols: reasons for use of desensitisation protocols, the protocols used and the stability given to carboplatin solutions. An important variability among the hospitals in carboplatin desensitisation practice was detected. Six different carboplatin desensitisation protocols were described and discordance with the storage period of the carboplatin solutions was observed. The lack of consensus on which protocol must be followed and data supporting the stability of the diluted product, contribute to distrust of carboplatin desensitisation protocols. Although the efficacy and safety of carboplatin desensitisation protocols has been widely demonstrated, many professionals still have concerns.

Development of a Solid Formulation Containing a Microemulsion of a Novel Artemisia Extract with Nematocidal Activity for Oral Administration.

BACKGROUND: Intestinal nematode infections are usually treated with benzimidazole drugs, but the emergence of resistance to these drugs has led to an increasing demand of new anthelmintic strategies. A new microemulsion formulation (ME) consisting of an Artemisia absinthium extract with proven nematocidal efficacy was previously developed. The aim of our study is to implement a D-optimal mixture design methodology to increase the amount of a silica material (loaded with this ME) in a tablet formulation, considering its tensile strength and disintegration time. METHODS: 16 experiments or combinations of the 6 tablet components (loaded silica, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose, Syloid® 244 FP and magnesium stearate) were assessed. Tensile strength and disintegration time models were developed, and an optimization process was carried out. RESULTS: Tensile strength was improved by increasing the polyvinylpyrrolidone content, while croscarmellose decreased the disintegration time. The optimized powder mixture contains 49.7% w/w of the loaded silica material. A compression force of 12 kN was applied to the powder mixture to form tablets with a tensile strength of 2.0 MPa and a disintegration time of 3.8 min. CONCLUSIONS: Our results show that D-optimal mixture designs provide a promising approach to formulate liquid-loaded silica materials.

Unexpected Toxicity of Green Tea Polyphenols in Combination with the Sambucus RIL Ebulin.

The safety of concentrated food complements intake is a major health concern. It has been well established that green tea polyphenols (GTPs) consumption promotes healthy effects. However, the ingestion of large amounts of GTPs is a matter of controversy due to reported adverse effects. We underwent a preliminary exploration of the effects of the oral administration of a standardized concentrated GTPs preparation on mice which suffered from reversible intestinal derangement promoted by sublethal amounts of the antiribosomal lectin ebulin f from dwarf elder (Sambucus ebulus L.). Neither independent oral administration of 30 mg/kg body weight Polyphenon 60 nor intraperitoneal administration of 2.5 mg/kg body weight ebulin f triggered lethal toxicity. In contrast, the simultaneous administration of these same doses of both Polyphenon 60 and ebulin f triggered an important and unexpected synergistic toxic action featured by the biphasic reduction of weight, which continued after eight days, reaching a reduction of 40%. Lethality appeared 2 days after the onset of the combined treatment and reached more than 50% after 10 days.

Human Health Effects of Lactose Consumption as a Food and Drug Ingredient.

Lactose is a reducing sugar consisting of galactose and glucose, linked by a ß (1→4) glycosidic bond, considered as an antioxidant due to its α-hydroxycarbonyl group. Lactose is widely ingested through the milk and other unfermented dairy products and is considered to be one of the primary foods. On the other hand, lactose is also considered as one of the most widely used excipients for the development of pharmaceutical formulations. In this sense, lactose has been related to numerous drug-excipient or drug-food pharmacokinetic interactions. Intolerance, maldigestion and malabsorption of carbohydrates are common disorders in clinical practice, with lactose-intolerance being the most frequently diagnosed, afflicting 10% of the world's population. Four clinical subtypes of lactose intolerance may be distinguished, namely lactase deficiency in premature infants, congenital lactase deficiency, adult-type hypolactasia and secondary lactase intolerance. An overview of the main uses of lactose in human nutrition and in the pharmaceutical industry and the problems derived from this circumstance are described in this review.

Transungual Delivery of Ciclopirox Is Increased 3⁻4-Fold by Mechanical Fenestration of Human Nail Plate in an In Vitro Model.

Onychomycosis is a fungal infection of nails that is widespread and difficult to treat because of the impermeable nature of human nails. Topically applied anti-fungal agents cannot penetrate this structure, and treatment regimens often resort to systemic antifungals with concomitant side effects. One recent clinical study suggested that mechanical fenestration of the nail using an intelligent nail drill might be a possible solution to this problem. In this work, an in vitro model of the transungual delivery of antifungal agents is presented, which utilizes real nail tissue and an inline flow system. This system was deployed to measure transungual delivery of ciclopirox and determined that nail fenestration improved drug delivery by 3⁻4-fold after 42 days. This study bolsters the argument that nail fenestration should be accepted as a pretreatment for onychomycosis and offers a way of evaluating new drugs or formulations designed to combat this condition.

Endotoxins from a Pharmacopoeial Point of View.

A pyrogen is a substance that causes fever after intravenous administration or inhalation. Gram negative endotoxins are the most important pyrogens to pharmaceutical laboratories. In the International, United States, Japanese and European Pharmacopoeias, there are two official methods to evaluate pyrogenicitythat is, the bacterial endotoxin test, and the pyrogen test. The main objective of this review is to compare the monographs of each test among the different Pharmacopeias, to detect similarities and differences. The former can be considered fully harmonized, and only non-significant differences were detected. The latter, which is the only available assay for some products and formulations to demonstrate apyrogenicity, shows large differences, which should be considered.

Stability of daptomycin reconstituted vials and infusion solutions.

OBJECTIVES: Daptomycin is a cyclic lipopeptide with selective action against drug-resistant Gram-positive bacteria. The stability of daptomycin solutions in different containers while stored at different temperatures was assessed. METHODS: Daptomycin vials were reconstituted with NaCl (50 mg/mL). Daptomycin infusion solutions (5.6 and 14.0 mg/mL) were prepared in polypropylene infusion bags. All test solutions were stored either under refrigeration or at room temperature over 7 days. Samples were withdrawn on days 0, 2, 4 and 7 and assayed in triplicate using a stability-indicating high-performance liquid chromatography (HPLC) method. RESULTS: The HPLC analysis revealed no significant loss in daptomycin concentration in vials or bags when stored at 2-8°C. All samples remained clear and colourless and there were no significant changes in pH throughout the study period. CONCLUSIONS: Reconstituted daptomycin vials (50 mg/mL) and infusion bags (5.6 and 14 mg/mL) were found to be physicochemically stable over a period of 1 week when stored at 2-8°C.

Lectin Digestibility and Stability of Elderberry Antioxidants to Heat Treatment In Vitro.

Elderberry contains healthy low molecular weight nutraceuticals and lectins which are sequence-related to the elderberry allergen Sam n1. Some of these lectins are type II ribosome-inactivating proteins. The sensitivity of native lectins present in elderberry fruits and bark to the proteolysis triggered by in vitro simulated gastric and duodenal fluids has been investigated. It was found that these lectins are refractory to proteolysis. Nonetheless, incubation for 5-10 min in a boiling water bath completely sensitized them to the hydrolytic enzymes in vitro. Under these conditions neither total Folin-Ciocalteau's reagent reactive compounds, total anthocyanins and the mixture of cyanidin-3-glucoside plus cyanidin-3-sambubioside, nor antioxidant and free-radical scavenging activities were affected by more than 10% for incubations of up to 20 min. Therefore, short-time heat treatment reduces potential allergy-related risks deriving from elderberry consumption without seriously affecting its properties as an antioxidant and free-radical scavenging food.

Effects of temperature, pH and sugar binding on the structures of lectins ebulin f and SELfd.

Ebulin f and SELfd are two lectins of Sambucus ebulus L. that show different stability and digestibility properties in gastric fluid due to their structural differences which may explain their different toxicological profiles. The main aim was to determine the effects of pH, temperature and sugar binding on the intrinsic structures of both proteins by fluorescence analyses. Quenching experiments were conducted, under different pH and temperature conditions, with acrylamide (uncharged) and iodide (charged), to study the possible changes of their intrinsic fluorescence. Results revealed that the native structure of SELfd is more folded than that of ebulin f. At pH 2.0, ebulin f displayed a more open structure than at neutral pH. It can be concluded that this is the main reason why ebulin f is accessible to pepsin action and more sensitive to degradation, in contrast to SELfd as we reported previously.

Anti-Human Endoglin (hCD105) Immunotoxin-Containing Recombinant Single Chain Ribosome-Inactivating Protein Musarmin 1.

Endoglin (CD105) is an accessory component of the TGF-ß receptor complex, which is expressed in a number of tissues and over-expressed in the endothelial cells of tumor neovasculature. Targeting endoglin with immunotoxins containing type 2 ribosome-inactivating proteins has proved an effective tool to reduce blood supply to B16 mice tumor xenografts. We prepared anti-endoglin immunotoxin (IT)-containing recombinant musarmin 1 (single chain ribosome-inactivating proteins) linked to the mouse anti-human CD105 44G4 mouse monoclonal antibody via N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP). The immunotoxin specifically killed L929 fibroblast mouse cells transfected with the short form of human endoglin with IC50 values in the range of 5 × 10(-10) to 10(-9) M.

Physical Stability Studies of Semi-Solid Formulations from Natural Compounds Loaded with Chitosan Microspheres.

A chitosan-based hydrophilic system containing an olive leaf extract was designed and its antioxidant capacity was evaluated. Encapsulation of olive leaf extract in chitosan microspheres was carried out by a spray-drying process. The particles obtained with this technique were found to be spherical and had a positive surface charge, which is an indicator of mucoadhesiveness. FTIR and X-ray diffraction results showed that there are not specific interactions of polyphenolic compounds in olive leaf extract with the chitosan matrix. Stability and release studies of chitosan microspheres loaded with olive leaf extract before and after the incorporation into a moisturizer base were performed. The resulting data showed that the developed formulations were stable up to three months. The encapsulation efficiency was around 44% and the release properties of polyphenols from the microspheres were found to be pH dependent. At pH 7.4, polyphenols release was complete after 6 h; whereas the amount of polyphenols released was 40% after the same time at pH 5.5.

Elderberries: a source of ribosome-inactivating proteins with lectin activity.

Sambucus (Adoxaceae) species have been used for both food and medicine purposes. Among these, Sambucus nigra L. (black elder), Sambucus ebulus L. (dwarf elder), and Sambucus sieboldiana L. are the most relevant species studied. Their use has been somewhat restricted due to the presence of bioactive proteins or/and low molecular weight compounds whose ingestion could trigger deleterious effects. Over the last few years, the chemical and pharmacological characteristics of Sambucus species have been investigated. Among the proteins present in Sambucus species both type 1, and type 2 ribosome-inactivating proteins (RIPs), and hololectins have been reported. The biological role played by these proteins remains unknown, although they are conjectured to be involved in defending plants against insect predators and viruses. These proteins might have an important impact on the nutritional characteristics and food safety of elderberries. Type 2 RIPs are able to interact with gut cells of insects and mammals triggering a number of specific and mostly unknown cell signals in the gut mucosa that could significantly affect animal physiology. In this paper, we describe all known RIPs that have been isolated to date from Sambucus species, and comment on their antiviral and entomotoxic effects, as well as their potential uses.

Polihexanide solution is more efficient than alcohol to remove phenol in chemical matricectomy: an in vitro study.

For treatment of ingrown toenails, a phenolization approach is often chosen. Many reports describe a lavage of the wound with alcohol to neutralize any residual phenol; however, it remains uncertain if there is a more effective solution for use in the lavage step. The aim of our study was to analyze the suitability and effectiveness of 0.1% polihexanide solution compared with isopropyl alcohol in the removal of excess phenol after treatment for ingrown toenails. We performed an in vitro study using human matrix and a diffusion cell apparatus to measure the amount of phenol remaining after two lavage washes. The effect of phenol evaporation was also examined.When phenol was irrigated with alcohol alone, 27.43 ± 4.10 mg (57.74%) of the initial amount of phenol was recovered. If irrigated with 0.1% polihexanide, 35.98 ± 2.93 mg (75.74%) of phenol was recovered. These results indicate that a polihexanide lavage step has significantly higher efficiency for removing excess phenol relative to alcohol.

Effects of short-term heating on total polyphenols, anthocyanins, antioxidant activity and lectins of different parts of dwarf elder (Sambucus ebulus L.).

Dwarf elder (Sambucus ebulus L.) berries are rich in health-promoting phytochemicals such as polyphenols and anthocyanins, and display a significant antioxidant activity. They are also rich in two lectins (ebulin f and SELfd) that share amino acid sequence homology with the elderberry allergen Sam n1 present in Sambucus nigra pollen and fruits. Ebulin f displays toxicity by oral ingestion. This study was aimed at eliminating the toxicity of these lectins whilst having little or no effect on the antioxidant properties of dwarf elder berries. We thus investigated the potential effects of incubation in a boiling water bath of extracts from several parts of the plant on total polyphenol content, antioxidant activity, total anthocyanins, cyanidin-3-glycoside content, and the sensitivity of purified dwarf elder fruit lectins to a simulated gastric fluid. The study shows that five minutes of said heat treatment fully sensitized both lectins to pepsin digestion, whilst minimally reducing phenol and antioxidant as well as free radical scavenging activities to below 13%. It proved possible to eliminate the potential risks derived from the presence of lectins in dwarf elder juices without any significant reduction in the content of the antioxidant compounds. Dwarf elder berries may thus be a valuable nutritional source.

Effectiveness of standard lavage with supplemental chlorhexidine in patients undergoing chemical matricectomy for ingrown toenails: a clinical trial.

BACKGROUND: Phenolization is often used to treat ingrown toenails. Alcohol lavage with or without supplemental chlorhexidine may be used to remove residual phenol, which can contribute to side effects such as persistent oozing or drainage. OBJECTIVE: We sought to compare the effectiveness in removing residual phenol of lavage with alcohol plus chlorhexidine versus alcohol alone. METHODS: We studied 80 patients who underwent unilateral phenol matricectomy: 40 who received irrigation with alcohol alone and 40 who received irrigation with alcohol plus chlorhexidine. Phenol levels were measured after each of 5 rounds of 3-mL irrigations. RESULTS: After the first irrigation, an average of 44.92% and 38.35% of the phenol remained in the nailfold in the alcohol and the alcohol/chlorhexidine groups, respectively (P < .05). After all 5 irrigations, no difference in efficacy between the 2 solutions was found (P > .005). LIMITATIONS: It was not possible to calculate the quantity of phenol initially introduced into the nail bed. The percentage remaining was calculated from the total amount of phenol recovered. CONCLUSION: When a single irrigation step is performed after phenolization, alcohol plus chlorhexidine is more effective than alcohol alone for removing residual phenol. When multiple irrigations are performed, the 2 solutions are equally effective.

Alcohol irrigation after phenol chemical matricectomy: an in vivo study.

BACKGROUND: For treatment of ingrown toenails, a phenolization is often chosen. Many reports describe an intra-operative irrigation, or lavage, of the wound with alcohol to neutralize any residual phenol. There are conflicting reports in the literature as to whether a true neutralization is required or merely effective removal of excess phenol. We hypothesized that intra-operative irrigation with 70% alcohol after the application of phenol does not remove enough phenol and a quantity of phenol still remains in the wound nail fold performing its action. OBJECTIVE: The aim of our study was to analyze the suitability and effectiveness of the alcohol lavage step during the treatment of ingrown toenails with a phenolization procedure. METHODS: We performed an in vivo study in 29 patients who underwent unilateral phenol chemical matricectomy to measure the amount of phenol remaining after five irrigations with a total of 15 ml of alcohol. RESULTS: There were measurable amounts of phenol collected after five alcohol irrigation steps, suggesting that phenol was not neutralized by the alcohol. After the first irrigation, only 45.74% of phenol was eliminated. An additional 12 ml of alcohol were necessary to eliminate the remaining 54.25% in the nail bed. CONCLUSIONS: A single alcohol lavage step after the phenolization procedure did not eliminate enough phenol. However, 15 ml of alcohol can serve as a suitable and effective means of diluting and removing any excess or residual phenol from the exposed area by its drag effect.

Alcohol plus chlorhexidine is more efficient than alcohol alone for phenol-based chemical matricectomy: an in vitro study.

BACKGROUND: A phenolization approach is often chosen for treatment of ingrown toenails. Many reports describe lavage of the wound with alcohol to neutralize any residual phenol. The aim of our study was to compare the suitability and effectiveness of a solution consisting of alcohol plus chlorhexidine with that of alcohol alone in a lavage step during the treatment of ingrown toenails using a phenolization procedure. METHODS: We performed an in vitro study using human matrix and a diffusion cell apparatus to measure the amount of phenol remaining after various lavage washes. The effect of phenol evaporation was also examined. RESULTS: When phenol was irrigated with alcohol alone, total phenol recovered was 29.9 ± 4.8 mg (62.9% of the initial amount). When the phenol was irrigated with isopropyl alcohol plus 0.5% chlorhexidine, 39.8 ± 1.7 mg (83.8%) of phenol was recovered. CONCLUSION: A lavage step including alcohol and chlorhexidine is more effective than alcohol alone for removal of excess phenol. The addition of chlorhexidine also contributed to inhibition of the action of phenol. This approach provides a suitable and effective means of diluting and removing any excess or residual phenol from the exposed area.

Enhanced removal of phenol with saline solution over alcohol: an in vitro study.

BACKGROUND: Phenol cauterization is a chemical equivalent often chosen for treatment of ingrown toenails. Many reports describe intraoperative irrigation, or lavage, of the wound with various types of alcohol to neutralize any remaining phenol. There are conflicting reports in the literature as to whether true neutralization or merely effective removal of excess phenol is needed. OBJECTIVE: The aim of our study was to analyze the suitability and effectiveness of ethyl alcohol versus sterile saline when used in a lavage step after phenol application in the treatment of ingrown toenails. METHODS: We performed an in vitro study using human skin and a diffusion cell apparatus to measure the amount of phenol recovered after lavage with ethyl alcohol or sterile saline. RESULTS: When the wound was irrigated with ethyl alcohol, the total phenol recovered after two irrigation washes was 55.7% of the original amount initially used in treatment, compared with 80.4% when sterile saline solution was used for irrigation. CONCLUSION: Alcohol and sterile saline solution do not neutralize phenol but dilute it and aid in its removal. We found that saline solution recovered more phenol than when washing with alcohol and recommend its use instead of alcohol for irrigation purposes after chemical matrixectomy.

Elastic vesicles of sumatriptan succinate for transdermal administration: characterization and in vitro permeation studies.

Elastic liposomes, including sumatriptan succinate, were prepared for their transdermal administration. Lipid vesicles containing 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or l-α-phosphatidylcholine dilauroyl (DLPC) phospholipids were characterized for various parameters, including size, particle-size distribution (i.e., polydispersity index), and elasticity. In vitro transdermal experiments for the study of the skin penetration of sumatriptan succinate contained in liposomes were performed by using flow-through diffusion cells. The diameter of sumatriptan liposomes with different lipid compositions varied between 279 and 282 nm, and the polydispersity index value for the size distribution of liposomal formulations was <0.5. DLPC vesicles proved to be more elastic and provided a higher sumatriptan transdermal flux than vesicles formulated with DOPC phospolipid.