Intraoral medical devices for sustained drug delivery.

OBJECTIVES: The oral cavity constitutes an attractive organ for the local and systemic application of drug substances. Oromucosal tablets, gels, or sprays are examples of the formulations applied. Due to the elution through the saliva, the residence time of the formulation at the application site is relatively short. Medical devices placed in the oral cavity, with a reservoir for an active substance, play an important role in solving this problem. MATERIALS AND METHODS: In this review, we discuss the devices described in the literature that are designed to be used in the oral cavity, highlighting the advantages, disadvantages, and clinical applications of each of them. RESULTS: Among the intraoral medical devices, special types are personalized 3D-printed devices, iontophoretic devices, and microneedle patches. CONCLUSION: We anticipate that with the development of 3D printing and new polymers, the technology of flexible and comfortable devices for prolonged drug delivery in the oral cavity will develop intensively. CLINICAL RELEVANCE: The presented review is therefore a useful summary of the current technological state, when in fact none of the existing devices has been widely accepted clinically.

Optimization of the coating process of minitablets in two different lab-scale fluid bed systems.

The optimization of the coating process for minitablets is extremely important in fluidized bed systems, and allows knowledge acquisition about the process for modern multiparticulate forms. The coating of minitablets allows the development of modified-release pediatric drugs. In our study, 3-mm minitablets with pantoprazole were coated to obtain an enteric product. The experiments were designed to evaluate the quality of the enteric product by efficiency and quality of film coating. Four process parameters at two levels were examined, and 16 experiments for two different fluid bed systems in laboratory-scale batches were performed. During analysis, the critical parameters of inlet airflow rate (X1) and coating mixture flow rate (X3) in different fluid bed coaters were examined. The findings indicate that apparatus construction has a significant effect on the different process parameters. Despite the fact that statistical analysis is directly related to the tested conditions, it creates opportunity to anticipate certain problems while scaling up, and a possibility to minimize them.

The use of novel tools for the assessment of powders and granules flow properties and for the analysis of minitablets compression process.

Objective: The purpose of this study was to apply the rheological measurements to assess the flow properties of powders and granules and to compare the results with the standard pharmacopeial tests. Quality by design approach was utilized to better understand the compression of the solids into minitablets.Significance: Insights are provided regarding the methodology of rheological properties of powders and granules using powder flow analyzer (PFA). The 'six sigma' approach was presented as a tool for assessment of the minitablets manufacturing process.Methods: Pharmacopeial methods and rheological tests using PFA were performed to assess the flow properties of designed powder and fractionated granule mixtures - placebo and with benzodiazepines. Compression of 2.5 and 3 mm minitablets was carried out and the compression force registered during the process and weight uniformity were statistically analyzed by calculating the capability indices.Results: The flow rate measurement and cohesion test (PFA test) resulted in the best differentiation between mixtures. Higher values of capability indices were obtained for processes in which granule mixtures with better flow properties were compressed and 3 mm minitablets were produced and the usefulness of QbD tools in assessment of minitablets compression process was confirmed.Conclusion: Performed study showed that the flow properties are the critical quality attributes determining the performance of minitablets compression. The cohesion test is the most discriminative to distinguish the analyzed mixtures. Capability indices can be used to assess the manufacturing process as a useful tool in pharmaceutical development of minitablets.

Comparison of Different Liquid and Semisolid Vehicles Selected for Oral Administration of Pellets and Minitablets with Diazepam: In Vitro Investigation.

The acceptability and palatability of a dosage form are extremely important to improve patient compliance. Mixing oral solid dosage forms with food carriers is often necessary to ease swallowing and provide the taste-masking effect. The present research investigated how a liquid or semisolid carrier influences the disintegration time and drug dissolution rate of pellets and minitablets with diazepam. The disintegration of pellets and minitablets in liquid carriers (water, milk and apple juice) was determined using a texture analyser. Dissolution tests were performed for the dosage forms dispersed in gel vehicles (2% carmellose and 0.5% carbomer gels) or applesauce. The disintegration of minitablets in water and apple juice was fast (1 min), but it slowed to 3 and 5 min in milk and gel vehicles, respectively. The pellets disintegrated in liquid carriers within 3 min. The drug dissolution rate in 0.1 M HCl depended on the gel viscosity in this medium. The preserved high viscosity of a carmellose gel inhibited the dissolution of diazepam. On the other hand, the viscosity of the carbomer gel decreased rapidly, and in effect, the dissolution rate of diazepam from the incorporated pellets or minitablets was comparable to the dissolution from loose pellets or minitablets. Graphical abstract.

Influence of Experimental Conditions on Electronic Tongue Results-Case of Valsartan Minitablets Dissolution.

A potentiometric electronic tongue was applied to study the release of valsartan from pharmaceutical formulations, i.e., minitablets uncoated and coated with Eudragit E. Special attention was paid to evaluate the influence of medium temperature and composition, as well as to compare the performances of the sensor arrays working in various hydrodynamic conditions. The drug dissolution profiles registered with the ion-sensitive electrodes were compared with standard dissolution tests performed with USP Apparatus 2 (paddle). Moreover, the signal changes of all sensors were processed by principal component analysis to visualize the release modifications, related to the presence of the coating agent. Finally, the importance and influence of the experimental conditions on the results obtained using potentiometric sensor arrays were discussed.

Choice of excipients for gelly-like pulp prepared ex tempore "on a spoon"- "placebo" and with sartans.

CONTEXT: To ensure safe oral administration, pediatric patients require an appropriate dosage form to be swallowed without relevant difficulties. Ex tempore hydrated powders, forming viscous pulp "on a spoon", have recently gained much interest as pediatric formulations. The aim of this study was to evaluate the viscosity-increasing substances and disintegrants, alone or in mixtures, as excipients suitable for preparing such formulations, with candesartan and valsartan chosen as model active substances. METHODS: The mixtures of excipients were prepared in the form of powders, granules or lyophilizates, which were evaluated in terms of their ability to form a homogenous mass after hydration with a small amount of water. The best compositions were tested with candesartan cilexetil and valsartan (2% and 10% w/w, respectively). Performed studies include macroscopic, organoleptic and microscopic observations, as well as a textural analysis, determination of gelation time and rheological measurements. RESULTS: Mixtures of guar gum, lactose and one of the disintegrants (F-Melt M, Prosolv 50, Prosolv Easy, Lycatab, Pharmaburst, Pearlitol) demonstrated the best properties. With regard to drug-incorporating formulations, granules were evaluated as the most satisfying form, while the functional properties of lyophilized formulations were poor. CONCLUSION: Granules with candesartan cilexetil (2%) were found to be the most promising for further development.

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.

Development and validation of UHPLC method for the determination of cyclosporine A in biological samples.

The aim of the study was to develop and validate a simple and rapid method for the determination of cyclosporine A (CsA) in ocular rabbit tissues using reversed-phase ultra-high-performance liquid chromatography (UHPLC) with UV detection. Previous publications on chromatographic methods of CsA determination in ocular tissues involved only reversed-phase HPLC separation, usually in combination with such detection techniques as radio-immunoassay and mass spectrometry. The application of the UHPLC technique allowed us to significantly decrease the analysis time. Cyclosporine D (CsD) was applied as the internal standard. Satisfactory separation was achieved on an XB-C18 Kinetex column at 60°C with the use of gradient elution mode. The retention times of CsA and CsD were found to be 4.5 and 5.1 min, respectively. The developed assay is specific, sensitive (limit of detection = 6 ng/mL and limit of quantitation = 18 ng/mL) and linear within the analyte concentration range of 0.018-5 µg/mL, with a correlation coefficient of 0.999. High sensitivity, low injection volume (10 µL), short time of analysis (6.5 min) and simplicity make this method useful for the fast analysis of CsA in rabbit ocular tissues and fluids: lacrimal fluid, aqueous humor, cornea, conjunctiva and eye globe.

The effect of polysorbate 20 on solubility and stability of candesartan cilexetil in dissolution media.

The addition of polysorbate 20 (T20) is required to achieve "sink" conditions during a dissolution test for tablets with candesartan cilexetil (CC). Polysorbate 20 (0.35%-0.7% w/w) added to 0.05 mol/L of phosphate buffer pH 6.5 dramatically increased the apparent solubility of the drug from 0.8 µg/ml even to 353 µg/ml, while its effect in lower pH or in water was much smaller (20 µg/ml in pH 4.5). The increased concentration of phosphate salts (0.2 mol/l) at pH 6.5 in the presence of 0.7% of polysorbate 20, resulted in further increase of candesartan cilexetil solubility to 620 µg/ml. The change of pH from 1.2 to 7.4 resulted in a 1.5-fold increase of the activation energy and, depending on temperature, 8-14-fold decrease of the degradation rate. When polysorbate 20 increased the activation energy 2-fold, independent of pH, it protected candesartan cilexetil from degradation; however, this effect was temperature dependent and was very small at 310 K-the degradation rate in pH 6.5 decreased by 13% only. It was calculated that in the phosphate buffer pH 6.5 with polysorbate, one can expect during 24 h the degradation at the level of 9.3%, thus a flow-through dissolution apparatus was recommended for testing prolonged release dosage forms.

Effect of enoxaparin and onion extract on human skin fibroblast cell line - therapeutic implications for the treatment of keloids.

CONTEXT: Keloids and hypertrophic scars are hyperproliferative skin disorders resulting in abnormal wound healing. In the prevention and treatment of keloids and hypertrophic scars, ointments containing heparin and onion extract are very popular. Their therapeutic effects, however, are still controversial and the mechanism of action is not fully understood. OBJECTIVE: The aim of this study was to assess the effect of enoxaparin and dry onion extract on proliferation, apoptosis and ß1 integrin expression in human fibroblasts. MATERIALS AND METHODS: Fibroblast human cell lines (46 BR.1 N) were treated for 48 h with various concentrations of enoxaparin sodium (20, 100, 500 µg/mL) and/or onion [Allium cepa L. (Alliaceae)] extract (50, 250, 1000 µg/mL). The cell proliferation was evaluated by [(3)H]-thymidine incorporation assay. Furthermore, the expression of ß1 integrin and apoptosis was determined by flow cytometry. RESULTS AND DISCUSSION: The results demonstrate that enoxaparin and onion extract inhibited the proliferation of human fibroblasts. Almost complete inhibition of cell proliferation was achieved by enoxaparin in 500 µg/mL concentration (91.5% reduction). The onion extract at a concentration of 250 µg/mL also strongly inhibited the proliferation of cells (50.8% reduction). Depending on concentration, enoxaparin and onion extract induced apoptosis (500 and 1000 µg/mL, respectively) and, depending on concentration, downregulated the expression of ß1 integrin on human fibroblasts. CONCLUSION: This work points at possible mechanism of action of enoxaparin and onion extract, when administered in the treatment of patients with keloids and hypertrophic scars.

[Prolonged-release drug formulations for parenteral administration. Part II. Microspheres and implants for injection]. / Pozajelitowe formy leków o przedluzonym dzialaniu Czesc II. Mikrosfery i implanty do wstrzykiwan.

Microspheres and implants are injectable drug forms, which by special design and selection of appropriate excipients, provide for a long time constant release rate of an active substance in the body. Development of both would not be possible without advances in polymer technology and invention of safe and biocompatible polymers such as: polyesters, vinyl acetate derivatives or silicones. Polymeric matrices provide retardation of drug release--for some implants up to a few years. In addition, this paper presents examples of all commercially available medicinal products containing microspheres and implants, currently registered in Poland, together with their characteristics: composition, time course and frequency of administration. Comments are also enclosed on frequently occurring inconsistent terminology in pharmaceutical forms.

Suspensions of antibiotics in self-emulsifying oils as a novel approach to formulate eye drops with substances which undergo hydrolysis in aqueous environment.

The aim of this study was to develop eye-drops with cefuroxime (CEF) sodium or vancomycin (VAN) hydrochloride, antibiotics that are instable in water. Anhydrous self-emulsifying oils (SEO) are proposed as a carrier and antibiotics are suspended. In the contact with tear fluid, the formulation should transform into emulsion, with fast dissolution of an antibiotic. CEF or VAN (5% w/w) was suspended in SEO carriers prepared by dissolving surfactants (Tween 20 or Span 80 5% w/w) in Miglyol, castor oil, or olive oil. Formulations with or without sodium citrate (2% w/w) were compared. Six-months or 1-year stability tests were carried out at 40 °C. The content of CEF and VAN was evaluated using HPLC and the potency of the antibiotic was assessed with agar diffusion method. In contact with water, drug particles suspended in SEO dissolved rapidly and o/w emulsion was formed. After 1-year at 40 °C, the content of degradation products was at most 0.5% in CEF and 4.0% in VAN formulations. The agar diffusion assay has shown that CEF and VAN loaded into SEO retained its potency against the sensitive microorganisms comparable to an aqueous solution. Therefore, SEO can be used as a novel carrier for the active substances which may not require improved solubility or absorption but need to be protected from moisture. This is a formulation that can be produced on industrial scale, with no limitation of stability or drug concentration.

Stability of extemporaneous pediatric oral liquids compounded from tablets and drug substance: case of propranolol and theophylline.

The stability of theophylline (T) and propranolol hydrochloride (P) in extemporaneously compounded oral suspensions (25 mg/mL or 50 mg/mL for T and 2 mg/mL or 5 mg/mL for P) were studied. Suspension with P and T were prepared with bulk substance or tablets using three different suspending vehicles: Ora-Sweet (M1), modified Ora-Sweet (M2) and simple syrup with glycerol and sorbitol (M3). Each suspension was stored for 35 days in a dark place at 25 degrees C and 4 degrees C. The results demonstrated that the prepared suspensions with P either from tablets or from a substance were stable in all three studied vehicles (more than 95% of initial concentration remaining). However, it is recommended that storage at 4 degrees C of suspensions prepared with M2 should be avoided because of crystallization of the buffer substances. Extemporaneous suspensions with T in an appropriate pediatric concentrations of the drug were not obtained because the problem of fast crystallization of T was not eliminated.

[Prolonged-release drug formulations for parenteral administration. Part l. Suspensions and oily solutions for injection]. / Pozajelitowe formy leków o przedluzonym dzialaniu. Czesc I. Zawiesiny i roztwory olejowe do wstrzykiwan.

The article presents description of the most important parenteral forms, which release an active substance in sustained manner. Technological and biopharmaceutical information is supplemented with examples of commercial products, currently registered in Poland. Mechanism of drug release from the dosage form and duration of the process, role of other excipients and characteristics of certain medicinal products is presented. The information about suspensions and oily solutions for injection is summarized. Owing to specific chemical modifications and selection of suitable excipients, it was possible to develop these types of medicinal products for some antibiotics, hormones, antipsychotics and cytostatics. These formulations, after subcutaneous or intramuscular injection, release the active substances even for several weeks allowing to reduce the frequency of drug administration and finally help to improve patient's compliance. Here also the modified time course of insulin products achieved by selection of appropriate suspension form or insulin analogue is discussed.

The Impact of Liquid Components on Alteration of the Adhesion of Polyacrylate and Silicone Patches.

Polyacrylates and polysiloxanes are polymers used in pressure-sensitive adhesive (PSA) patches. Liquid additives are co-solvents of the active substances or permeation enhancers, and their compatibility with the polymeric matrix and the effect on adhesive properties should be considered. The patches were prepared from commercial polyacrylates (three types of Duro-Tak®) and siloxanes (Bio-PSA® and Soft Skin Adhesive®). Propylene glycol, polyoxyethylene glycol, isopropyl myristate, triacetin, triethyl citrate and silicone oil were added (10% w/w). Formulations were evaluated microscopically and with a texture analyzer in terms of in vitro adhesiveness and hardness. Only silicone oil was compatible with the silicone matrices. The best compatibility of acrylic PSA was observed with triethyl citrate; one out of three Duro-Tak matrices was incompatible with every additive. In all compositions, the adhesiveness was impaired by the liquid additives. A significant drop in adhesiveness was noted after immersion of the patches in buffer and drying. The probe tack test was considered as the most useful for evaluation of the effect of the liquid additive on adhesiveness, but the results obtained with a spherical and cylindrical probe were contradictory. The structural changes caused by the additives were also demonstrated by a 90° peel test, considered as complementary to the tack test.

Microscopic and Biopharmaceutical Evaluation of Emulsion and Self-Emulsifying Oil with Cyclosporine.

Among the currently available commercial eye drops with cyclosporine A (Cs) there is a lack of long-acting dosage forms and products with a concentration of the drug substance higher than 0.1%, although Cs is widely used in ophthalmology. The aim of the research was to conduct the microscopic and biopharmaceutical evaluation of two formulations, an emulsion (EM) and a self-emulsifying oil (SEO), both with 0.5% of Cs, proposed for use in eye drops, and the comparison of both. SEO eye drops with Cs or any other drug substance are currently not available as marketed products, and the highest concentration of Cs in the ocular emulsion is only 0.1%. The microscopic evaluation of the emulsion and the SEO after emulsification with water was carried out using a high-resolution digital microscopy. The properties of both preparations were compared using the high dynamic range function or optical shadow effect mode. Images in the 3D composition mode were also recorded. The in vivo study of the Cs formulations was performed on male albino rabbits. The eye tolerance of the preparations was assessed using the ocular irritation test, which is a modified Draize test. Placebo carriers (without the drug substance) were also subjected to irritation testing. The concentration of Cs in the tissues (cornea and conjunctiva) and fluids (tear fluid and aqueous humor) of the rabbit eye was determined after multiple instillations of Cs-EM or Cs-SEO. The tested preparations were compared using the digital microscopy technique, which highlights the features of the formulations and eliminates the risk of unnoticeable properties that are difficult to observe in classical optical microscopy. Both tested Cs-loaded formulations are classified as practically non-irritating. There were also no significant differences when testing the placebo carriers. After a topical administration, Cs was widely distributed in all tissues (e.g., in cornea 1.3 ng/mg and 1.0 ng/mg) and fluids of the eye (e.g., in tear fluid 11.6 µg/mL and 4.3 µg/mL), after the administration of Cs-SEO and Cs-EM, respectively. The obtained results allow us to recognize both tested formulations, the emulsion and the self-emulsifying oil with 0.5% Cs content, as carriers safe for ophthalmic use and effective in delivering the drug substance to the structures of the eye.

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.

Design of Experiments as a Tool to Optimize the Process of Coating Minitablets with Commercial Gastro-Resistant Coating Mixtures.

According to the Quality by Design (QbD) concept, Design of Experiment (DoE) was used to indicate critical process parameters and optimize the fluid bed coating of minitablets in a laboratory size batch. Full factorial design was employed to increase knowledge of the process for three kinds of minitablet (MT) cores using two commercial gastro-resistant coating mixtures. The statistical analysis showed that different critical process parameters were indicated for the tested minitablets: X3: the coating mixture flow rate for MTs with pantoprazole sodium and Eudragit L; X2: the product temperature; X3 and X4: the spraying pressure for MTs with pantoprazole sodium and Acryl Eze II; and X1 and X2: MTs with diclofenac sodium. Such differences were the result of features, such as the sub-coat, size, and mass of the cores and the core and coating mixture composition. No optimal parameters were found for any of the tested MT types. Therefore, DoE should be considered as a statistical tool to individually optimize the process for the product, equipment, and tested parameters. However, optimization of the fluid bed coating allowed us to predict the values of the process parameters necessary to obtain good-quality products. Therefore, fluid bed coating may be successfully used to obtain modified-release MTs of high quality after applying the statistical tool DoE.

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.

Polypharmacy among elderly patients in Poland: prevalence, predisposing factors, and management strategies.

INTRODUCTION: The world's elderly population is growing dramatically. Pharmacotherapy in seniors is particularly challenging due to changes in metabolism, multimorbidity, and a great interest in nonprescription drugs. OBJECTIVES: We aimed to provide up­to­datedata on pharmacotherapy in the geriatric population of Poland, to determine factors predisposing to polypharmacy and excessive polypharmacy, and to identify seniors who are most likely to require multidisciplinary interventions in the field of pharmacotherapy. PATIENTS AND METHODS: We analyzed the use of all prescription and nonprescription drugs taken within 2 weeks preceding the study in a representative national sample of 3014 home­dwelling seniors aged over 65 years. The variables of age, sex, place of residence, level of education, and multimorbidity were considered. Poststratification was used to balance the sample structure to match the Polish population of 2017. RESULTS: Consumption of at least 1 drug was reported by 90.7% of the participants, and the mean number of drugs used was 5.01 (95% CI, 4.87-5.15). At least 1 nonprescription drug was used by 44.2% of the respondents, with a mean number of 0.52 (95% CI, 0.49-0.55). More than 5 drugs were taken by 53.5% of the entire population, while the use of more than 10 drugs was reported by 8.7% of the respondents, with multimorbidity as the most predisposing factor. Single­pill combinations accounted for 27.2% of medications. CONCLUSIONS: The high prevalence of polypharmacy resulting from multimorbidity confirms the need for the implementation of combined medical and pharmaceutical care of the geriatric patients.