Solid Dispersions Obtained by Ball Milling as Delivery Platform of Etodolac, a Model Poorly Soluble Drug.

Poor water solubility of drugs is a limiting factor for their bioavailability and pharmacological activity. Many approaches are known to improve drug solubility, and among them, the physical method, solid dispersions (SDs), is applied. SDs are physical mixtures of a drug and a carrier, sometimes with the addition of a surfactant, which can be obtained by milling, cryomilling, spray-drying, or lyophilization processes. In this study, solid dispersions with etodolac (ETD-SDs) were prepared by the milling method using different carriers, such as hypromellose, polyvinylpyrrolidone, copovidone, urea, and mannitol. Solubility studies, dissolution tests, morphological assessment, thermal analysis, and FTIR imaging were applied to evaluate the SD properties. It was shown that the ball-milling process can be applied to obtain SDs with ETD. All designed ETD-SDs were characterized by higher water solubility and a faster dissolution rate compared to unprocessed ETD. SDs with amorphous carriers (HPMC, PVP, and PVP/VA) provided greater ETD solubility than dispersions with crystalline features (urea and mannitol). FTIR spectra confirmed the compatibility of ETD with tested carriers.

Utilization of the Drug-Polymer Solid Dispersion Obtained by Ball Milling as a Taste Masking Method in the Development of Orodispersible Minitablets with Hydrocortisone in Pediatric Doses.

The objective of the conducted research was to design 2 mm orodispersible minitablets of pediatric doses of hydrocortisone (0.5 mg; 1.0 mg) with desirable pharmaceutical properties and eliminate the sensation of a bitter taste using preparation of solid dispersion by ball mill. Hydrocortisone was selected as the model substance, as it is widely utilized in the pediatric population. ODMTs were prepared by compression (preceded by granulation) in a traditional single-punch tablet machine and evaluated using pharmacopoeial tests, DSC, and FTIR analysis. The methods used to evaluate the effectiveness of the taste-masking effect included in vivo participation of healthy volunteers, in vitro drug dissolution and utilization of an analytical device-"electronic tongue". The research employed a preclinical animal model to preliminary investigate the bioequivalence of the designed drug dosage form in comparison to reference products. The study confirmed the possibility of manufacturing good-quality hydrocortisone ODMTs with a taste-masking effect owing to the incorporation of a solid dispersion in the tablet mass.

Mucoadhesive Alginate/Pectin Films Crosslinked by Calcium Carbonate as Carriers of a Model Antifungal Drug-Posaconazole.

The mucosal membrane of the oral cavity, due to its unique structure and availability, constitutes an appropriate site for the delivery of drugs, both with local and systemic effects. Mucoadhesive buccal films are drug dosage forms that due to their convenience of application, flexibility and size, are characterized by patients' compliance. Sodium alginate and pectin are natural polymers from the polysaccharides group, with mucoadhesive properties, that are widely applied to obtain buccal films. However, their hydrophilic nature and poor water resistance limit their application in sustained drug release formulations. Hence, the aim of this investigation was to design alginate/pectin buccal films by a one-step crosslinking technique-with the application of calcium carbonate. This technique was applied to prepare crosslinked alginate and alginate/pectin mucoadhesive films with a model antifungal drug-posaconazole. The obtained formulations were evaluated for the impact of crosslinking and pectin's presence on their pharmaceutical, mucoadhesive, mechanical and physicochemical properties. Additionally, the antifungal activity of the prepared films against Candida spp. was evaluated. It was shown that pectin's presence in the formulations improved flexibility, mucoadhesion and antifungal activity. The crosslinking process reduced mucoadhesiveness and antifungal activity but significantly enhanced the mechanical properties and stability and enabled prolonged drug release.

The Spray-Dried Alginate/Gelatin Microparticles with Luliconazole as Mucoadhesive Drug Delivery System.

Candida species are opportunistic fungi, which are primary causative agents of vulvovaginal candidiasis. The cure of candidiasis is difficult, lengthy, and associated with the fungi resistivity. Therefore, the research for novel active substances and unconventional drug delivery systems providing effective and safe treatment is still an active subject. Microparticles, as multicompartment dosage forms due to larger areas, provide short passage of drug diffusion, which might improve drug therapeutic efficiency. Sodium alginate is a natural polymer from a polysaccharide group, possessing swelling, mucoadhesive, and gelling properties. Gelatin A is a natural high-molecular-weight polypeptide obtained from porcine collagen. The purpose of this study was to prepare microparticles by the spray-drying of alginate/gelatin polyelectrolyte complex mixture, with a novel antifungal drug-luliconazole. In the next stage of research, the effect of gelatin presence on pharmaceutical properties of designed formulations was assessed. Interrelations among polymers were evaluated with thermal analysis and Fourier transform infrared spectroscopy. A valid aspect of this research was the in vitro antifungal activity estimation of designed microparticles using Candida species: C. albicans, C. krusei, and C. parapsilosis. It was shown that the gelatin addition affected the particles size, improved encapsulation efficiency and mucoadhesiveness, and prolonged the drug release. Moreover, gelatin addition to the formulations improved the antifungal effect against Candida species.

Nanostructured Lipid Carriers (NLC)-Based Gel Formulations as Etodolac Delivery: From Gel Preparation to Permeation Study.

Topical administration of drug is an attractive alternative to the oral administration as it provides a reduction in adverse reactions and an enhancement of therapeutic effects. The use of lipid carriers in hydrogel structures makes it possible to introduce lipophilic substances in a dissolved form. In this study, an NSAID from the BCS class II, etodolac (ETD), was used. The nanostructured lipid carriers (NLC) obtained with ETD were incorporated into semi-solid forms (gels). Hydrogels with the suspended drug and oleogel were also prepared for comparison purposes. The obtained gels were tested in terms of pH, viscosity, rheological, mechanical, and bioadhesive properties. The release and permeation through membranes were also studied. All tested formulations were characterized by a pH below 7, which ensured the physiological state of the skin. The viscosities of all gels decreased with increasing shear rate, indicating non-Newtonian behavior. The fastest ETD release was observed for NLC with a Carbopol base (formulation F1); a similar result was noticed in the permeation test. The developed gel formulations containing ETD-NLC dispersion and Carbopol or Poloxamer as gelling agents were stable and possessed beneficial pharmaceutical properties.

Nanostructured Lipid Carriers Engineered as Topical Delivery of Etodolac: Optimization and Cytotoxicity Studies.

Etodolac (ETD), a nonsteroidal anti-inflammatory drug, exhibits antinflammatory, analgesic, and antipyretic activity. The main type of ETD administration is oral route, which is associated with significant systemic side effects. Nanostructured lipid carriers (NLC), a modern lipid formulation, are non-toxic, biocompatible, can improve the solubility and stability of drugs. Nanostructured lipid carriers (NLC) containing etodolac were prepared by a melt-emulsification and ultrasonication technique. Full factorial design (FFD) was applied to optimize the composition of NLC and their properties such as zeta potential, polidyspersity index, and entrapment efficiency. Formulations consisting of Capryol 90, glicerol monostearate, and Tween 20 displayed particle size below 300 nm, encapsulated drug with efficiency of approximately 87% and prolonged drug release up to 24 h. Stable formulations displayed moderately negative surface charge suggesting their limited ability to interact with skin surface but simultaneously presenting their lower risk to cause cell-membrane disruption. In fact, cytotoxicity assessment using human dermal fibroblasts and human epidermal keratinocytes revealed that etodolac-loaded NLC had no important impact on skin cells viability evaluated in vitro, which might evidence that NLC formulations are safe for dermal delivery. The studies developed were relatively fast and simple, requiring no specialized equipment method to prepare NLC as ETD carriers ensuring better solubility and prolonged drug release.

Nanostructured lipid carriers: A potential use for skin drug delivery systems.

Skin application of pharmaceutical products is one of the methods used for drug administration. The problem of limited drug penetration via topical application makes searching for safe drug carriers that will provide an expected therapeutic effect of utmost importance. Research into safe drug carriers began with liposome structures, paving the way for work with nanocarriers, which currently play a large role as drug vehicles. Nanostructured lipid carriers (NLC) consist of blended solid and liquid lipids (oils) dispersed in an aqueous solution containing a surfactant. These carriers have many advantages: good biocompatibility, low cytotoxicity, high drug content; they enhance a drug's stability and have many possibilities of application (oral, intravenous, pulmonary, ocular, dermal). The following article presents properties, methods of preparation and tests to assess the quality and toxicity of NLC. This analysis indicates the possibility of using NLC for dermal and transdermal drug application.

Calcium Chloride Modified Alginate Microparticles Formulated by the Spray Drying Process: A Strategy to Prolong the Release of Freely Soluble Drugs.

Alginate (ALG) cross-linking by CaCl2 is a promising strategy to obtain modified-release drug delivery systems with mucoadhesive properties. However, current technologies to produce CaCl2 cross-linked alginate microparticles possess major disadvantages, such as a poor encapsulation efficiency of water-soluble drugs and a difficulty in controlling the process. Hence, this study presents a novel method that streamlines microparticle production by spray drying; a rapid, continuous, reproducible, and scalable technique enabling obtainment of a product with low moisture content, high drug loading, and a high production yield. To model a freely water-soluble drug, metformin hydrochloride (MF) was selected. It was observed that MF was successfully encapsulated in alginate microparticles cross-linked by CaCl2 using a one-step drying process. Modification of ALG provided drug release prolongation-particles obtained from 2% ALG cross-linked by 0.1% CaCl2 with a prolonged MF rate of dissolution of up to 12 h. Cross-linking of the ALG microparticles structure by CaCl2 decreased the swelling ratio and improved the mucoadhesive properties which were evaluated using porcine stomach mucosa.

EVALUATION OF ALGINATE MICROSPHERES WITH METRONIDAZOLE OBTAINED BY THE SPRAY DRYING TECHNIQUE.

In the present study, nine formulations (F1-F9) of alginate microspheres with metronidazole were prepared by the spray drying technique with using different drug:polymer ratio (1:2, 1:1, 2:1) and different sodium alginate concentration (1, 2, 3%). The obtained microspheres were characterized for size, morphology, drug loading, (potential and swelling degree. Mucoadhesive properties were examined using texture analyzer and three different models of adhesive layers--gelatin discs, mucin gel and porcine vaginal mucosa. In vitro drug release, mathematical release profile and physical state of microspheres were also evaluated. The obtained results indicate that sodium alginate is a suitable polymer for developing mucoadhesive dosage forms of metronidazole. The optimal formulation F3 (drug:polymer ratio 1:2 and 1% alginate solution) was characterized by the highest metronidazole loading and sustained drug release. The results of this study indicate promising potential of ALG microspheres as alternative dosage forms for metronidazole delivery.

Development and Evaluation of Liquid and Solid Self-Emulsifying Drug Delivery Systems for Atorvastatin.

The objective of this work was to design and characterize liquid and solid self-emulsifying drug delivery systems (SEDDS) for poorly soluble atorvastatin. To optimize the composition of liquid atorvastatin-SEDDS, solubility tests, pseudoternary phase diagrams, emulsification studies and other in vitro examinations (thermodynamic stability, droplet size and zeta potential analysis) were performed. Due to the disadvantages of liquid SEDDS (few choices for dosage forms, low stability and portability during the manufacturing process), attempts were also made to obtain solid SEDDS. Solid SEDDS were successfully obtained using the spray drying technique from two optimized liquid formulations, CF3 and OF2. Despite liquid SEDDS formulation, CF3 was characterized by lower turbidity, higher percentage transmittance and better self-emulsifying properties, and based on the in vitro dissolution study it can be concluded that better solubilization properties were exhibited by solid formulation OF2. Overall, the studies demonstrated the possibility of formulating liquid and solid SEEDS as promising carriers of atorvastatin. SEDDS, with their unique solubilization properties, provide the opportunity to deliver lipophilic drugs to the gastrointestinal tract in a solubilized state, avoiding dissolution-a restricting factor in absorption rate of BCS Class 2 drugs, including atorvastatin.

Comparison of cytotoxicity in vitro and irritation in vivo for aqueous and oily solutions of surfactants.

The in vivo model on rabbit eyes and the in vitro cytotoxicity on fibroblasts were used to compare irritation effect of aqueous and oily (Miglyol 812) solutions of surfactants. Tween 20, Tween 80 and Cremophor EL were tested in different concentrations (0.1, 1 or 5%) and the in vitro test demonstrated that surfactants in oil are less cytotoxic than in aqueous solutions. In the in vivo study, the aqueous solutions of surfactants were characterized as non-irritant while small changes in conjunctiva were observed after application the oily solutions of surfactants and the preparations were classified as slightly irritant, however this effect was similar when Miglyol was applied alone. In conclusion, it is reported that the MTT assay does not correlate well with the Draize scores.

Application of differential scanning calorimetry in evaluation of solid state interactions in tablets containing acetaminophen.

Differential scanning calorimetry (DSC) is an analytical procedure used to determine the differences in the heat flow generated or absorbed by the sample. This method allows to assess purity and polymorphic form of drug compounds, to detect interactions between ingredients of solid dosage forms and to analyze stability of solid formulations. The aim of this study was the assessment of compatibility between acetaminophen (API) and different types of excipients often used in tablets compression: polyvinylpyrrolidone, crospovidone, pregelatinized starch, microcrystalline cellulose and magnesium stearate by differential scanning calorimetry. The study contains results of thermal analysis of excipients and individually performed mixtures of these substances with acetaminophen before and after compression and after 6 months storage of tablets at different temperature and relative humidity conditions (25 +/- 2 degrees C /40 +/- 5% RH, 25 +/- 2 degrees C /60 +/- 5% RH, 40 +/- 2 degrees C /75 +/- 5% RH) for a period of 6 months. To detect possible changes of API chemical structure, gas chromatography-mass spectrometry (GC-MS) was also applied. GC-MS with electron impact ionization (EI) was employed to determine the fragmentation pattern of API. It was shown that the developed formulations showed excellent compatibility among all excipients used except Kollidon CL. The interaction with Kollidon CL is probably a result of a physical reaction as confirmed by GC-MS analyses. Obtained results revealed that DSC can be successfully applied to evaluate possible incompatibilities between acetaminophen and Kollidon.

Self-emulsifying oils for ocular drug delivery. II. In vitro release of indomethacin and hydrocortisone.

The objective of this study was to compare the in vitro release of indomethacin and hydrocortisone from self-emulsifying drug delivery systems (SEDDS) and aqueous or oily suspensions. SEDDS carriers were obtained by dissolving Cremophor EL, Tween 20 or Span 80 in Miglyol oil. The release experiment was performed over 6 h using a dialysis cellulose membrane and acceptor fluid imitating composition of a lacrimal fluid. The release data fitted to the Higuchi's equation. Apparent diffusion constant of indomethacin (k(H)) was in the range 2.55-3.78 mgh(-0.5) and was hardly affected by the formulation type. In the case of hydrocortisone k(H) value was the highest for aqueous and oily suspensions (2.16-2.33 mgh(-0.5)) and for SEDDS systems was not increased even if solubility of the drug was almost 3 times higher than in water or oil. This observation leads to the conclusion that SEDDS does not enhance diffusion rate and other factors can be responsible for the expected better drug absorption through cornea from SEDDS in vivo. Analysis of the release kinetics from sus pension type formulations supports the hypothesis that it may be reasonable to propose SEDDS with the small access of the suspended drug as the most promising formulation.

Stability of extemporaneous enalapril maleate suspensions for pediatric use prepared from commercially available tablets.

In this paper, the stability of enalapril maleate in oral formulations prepared from commercially available tablets was investigated. Extemporaneously compounded, 0.1 mg/mL and 1.0 mg/mL, oral suspensions of enalapril maleate in sugar-containing and sugar-free vehicles were stored in the absence of light at 4 degrees and 25 degrees C for 30 days. Enalapril maleate stability was quantified after 7, 14, 21, and 30 days using HPLC method. Viscosities and pH of prepared suspensions were measured on each study day and no appreciable changes from the initial pH and initial viscosities occurred in any of the samples both at 25 degrees and 4 degrees C. It was shown that all the formulations retain minimum 98% of the initial enalapril maleate concentration after 30 days of storage at 25 degrees and 4 degrees C and they may provide an option in situations where the marketed suspension is unavailable.

Solubility of ocular therapeutic agents in self-emulsifying oils. I. Self-emulsifying oils for ocular drug delivery: solubility of indomethacin, aciclovir and hydrocortisone.

Self-emulsifying drug delivery systems (SEDDS) were prepared by dissolving Cremophor EL, Tween 20, Tween 80 and Span 80 (1% or 5%) in oils (Miglyol 812 or castor oil). Solubilities of three ophthalmic drugs, namely aciclovir, hydrocortisone and indomethacin were determined in these systems. In addition, the effect of a small amount of water (0.5% and 2%) on solubilization properties of the systems was estimated. Of the three substances, indomethacin showed the best solubility in Miglyol while aciclovir was practically insoluble in this oil. The surfactants usually increased drug solubility in the oily phase. Only Tween 20 was found to decrease the solubility of aciclovir and hydrocortisone in Miglyol. Addition of a small amount of water to the oil/surfactant system increased solubility of hydrocortisone, but not of indomethacin. The results of the current study may be utilized to design a suitable composition of SEDDS and allow continuation of research on this type of drug carriers.