Millennial drinks: acidity, fluoride content, and enamel softening.

This in vitro study aimed to evaluate the acidity and fluoride content of beverages commonly consumed by millennials and the enamel-softening effect of these drinks on tooth enamel. The study included 13 beverages in 4 categories: energy (sports) drink, flavored sparkling water, kombucha, and other (an unsweetened iced tea, a vegetable-fruit juice blend, and a soft drink). The acidity was measured with a pH/ion meter, and the fluoride concentration was measured with a combined fluoride electrode coupled to the meter (n = 10 measurements per beverage). The Vickers hardness number of extracted molars was measured before and after a 30-minute immersion in 4 representative beverages via 2 immersion protocols (n = 10 per beverage per protocol): (1) immersion in the beverage only and (2) immersion alternating between the beverage and artificial saliva every other minute. The pH and fluoride concentrations of the beverages ranged from 2.652 to 4.242 and from 0.0033 to 0.6045 ppm, respectively. One-way analysis of variance (ANOVA) revealed that all differences between beverages in pH values were statistically significant, as were the majority of differences in fluoride concentrations (P < 0.001). The beverages and the 2 immersion methods significantly affected enamel softening (2-way ANOVA, P = 0.0001 to 0.033). The representative energy drink (pH 2.990; 0.0102 ppm fluoride) caused the greatest enamel softening followed by the representative kombucha (pH 2.820; 0.2036 ppm fluoride). The representative flavored sparkling water (pH 4.066; 0.0098 ppm fluoride) caused significantly less enamel softening than the energy drink and kombucha. A root beer (pH 4.185; 0.6045 ppm fluoride) had the least enamel softening effect. All tested beverages were acidic and had a pH below 4.5; only some contained fluoride. Flavored sparkling water, likely due to its higher pH, caused less enamel softening than the tested energy drink and kombucha. The fluoride content of kombucha and root beer lower their enamel-softening effects. It is imperative that consumers be aware of the erosive potential of beverages they consume.

Evaluation of fluoride levels in commercially available tea in the United States.

The objective of this study was to compare fluoride levels in commercially available black tea, green tea, and matcha tea. Tea samples were purchased from a local supermarket in the United States and prepared according to the manufacturer's directions to mimic consumer activity. The selected products included 3 black teas (Bigelow Earl Grey, Twinings of London Lady Grey, and Lipton), 2 green teas (Bigelow and Lipton), and 3 matcha teas (Mighty Leaf, Celestial Seasonings, and Matcha Love). For all products except Mighty Leaf and Matcha Love, 250 mL of deionized water (DIW) was heated to boiling. One tea bag was added and stirred for 2 minutes. For Mighty Leaf matcha, 300 mL of DIW was used, but the sample was otherwise prepared as previously described. Matcha Love was prepared by stirring 0.5 tsp of green tea powder for 2 minutes in 30 mL of DIW heated to boiling. A 10-mL aliquot was taken from each tea group and from DIW alone (control) and combined with 10 mL of total ionic strength adjustment buffer (TISAB II) before it was measured with a combination fluoride electrode and pH/ion meter. The sample size was 5 separately prepared and independently measured tea servings per group. Fluoride concentrations were calculated from a calibration curve constructed from appropriate fluoride standards and then statistically analyzed using analysis of variance followed by the Student-Newman-Keuls post hoc test (α = 0.05). The DIW control group had negligible fluoride content. All tested tea samples contained fluoride in amounts ranging from 0.521 to 6.082 mg/L. The mean concentration differed significantly among brands and types of tea. Matcha green tea powder had the highest concentration of fluoride. Most teas contain a higher fluoride concentration than optimally fluoridated water (0.7 mg/L). Dental healthcare professionals should consider this information when advising caries prevention regimens for patients and determining the potential for dental or skeletal fluorosis in at-risk patients.

An Update on Pharmaceutical Strategies for Oral Delivery of Therapeutic Peptides and Proteins in Adults and Pediatrics.

While each route of therapeutic drug delivery has its own advantages and limitations, oral delivery is often favored because it offers convenient painless administration, sustained delivery, prolonged shelf life, and often lower manufacturing cost. Its limitations include mucus and epithelial cell barriers in the gastrointestinal (GI) tract that can block access of larger molecules including Therapeutic protein or peptide-based drugs (TPPs), resulting in reduced bioavailability. This review describes these barriers and discusses different strategies used to modify TPPs to enhance their oral bioavailability and/or to increase their absorption. Some seek to stabilize the TTPs to prevent their degradation by proteolytic enzymes in the GI tract by administering them together with protease inhibitors, while others modify TPPs with mucoadhesive polymers like polyethylene glycol (PEG) to allow them to interact with the mucus layer, thereby delaying their clearance. The further barrier provided by the epithelial cell membrane can be overcome by the addition of a cell-penetrating peptide (CPP) and the use of a carrier molecule such as a liposome, microsphere, or nanosphere to transport the TPP-CPP chimera. Enteric coatings have also been used to help TPPs reach the small intestine. Key efficacious TPP formulations that have been approved for clinical use will be discussed.

Long-Term Exposure and Safety of a Novel Topical Rapamycin Cream for the Treatment of Facial Angiofibromas in Tuberous Sclerosis Complex: Results From a Single-Center, Open-Label Trial.

Facial angiofibromas, composed of fibrous tissue and blood vessels appearing on the face, are closely associated with tuberous sclerosis complex. Historically, oral rapamycin, a mammalian target of the rapamycin inhibitor of cell proliferation, has been used to treat visceral tuberous sclerosis-related tumors; however, the side effect profile of this medicine generally precludes its use in patients lacking significant internal involvement. The authors developed a novel topical formulation of rapamycin cream to treat the facial angiofibroma without exposing patients to possible systemic side effects. We followed 11 patients in a long-term, open-label, prospective study to evaluate the safety and effectiveness of rapamycin cream when used chronically. All of the patients showed an improvement in the appearance of their facial angiofibroma which was maintained in long-term follow-up without safety concerns or systemic absorption. The novel rapamycin cream was tolerated well by all patients and represents a way to address the cutaneous manifestation of tuberous sclerosis complex.

Bioavailability testing of a newly developed clindamycin oral suspension in a pediatric porcine model.

Background: Clindamycin's bitter taste and odor is known to affect treatment adherence in children. Recently, a formulation of clindamycin HCl complexed with ion exchange resin IRP 69 was shown to mask the bitter taste. Because of the potential benefit of this formulation for children, a pilot study using a porcine model was conducted to evaluate its relative bioavailability. Methods: A randomized two-way crossover study design using six (n = 6) healthy male piglets 10-12 kg was used to evaluate the absorption profiles and pharmacokinetic parameters of clindamycin from the resinate complex formulation (Test) compared to a commercialized reference suspension. A dose of 15 mg/kg was administered orally by gastric gavage to each piglet followed by repeated blood sampling over 12 h. A wash-out period of 48 h occurred between treatments. Plasma concentration vs. time data was analyzed by non-compartmental analysis. Results: The mean relative bioavailability of clindamycin from the resinate formulation was 78.8%. A two-tailed, paired Student t test yielded a p < 0.05 for AUC∞ and Tmax parameters. A two one-sided test (TOST) suggested a difference in AUC∞ and Cmax for the Test formulation compared to the reference formulation according to the FDA's criteria for bioequivalence. Conclusion: The bioavailability of clindamycin from this novel oral formulation supports continued evaluation of the drug in humans for potential pediatric applications.

Development of a fast dissolving film of epinephrine hydrochloride as a potential anaphylactic treatment for pediatrics.

OBJECTIVE: To develop a fast dissolving film strip containing epinephrine HCl for the potential treatment of pediatric anaphylaxis. METHODS: Four different films have been prepared by solvent casting technique where the percentages of the polymer (Lycoat RS720) were optimized. The polymer percentages were (20%, 25%, 27% and 30%) of the total formulation weighs. The thickness and elastic modulus of the optimized film was evaluated using dynamic mechanical analyzer. Epinephrine content uniformity was assessed using UV at wavelength 280 nm. For the dissolution test, fast dissolving films (FDFs) were evaluated in 500 Simulated Saliva, with 50 rpm. In vivo taste and disintegration evaluation was performed on six healthy volunteers. RESULTS: Films formed by formulations 1, 2 and 3 were too sticky after drying, while formulation 4 that has 30% polymer content formed smooth, transparent, flexible and uniform film, and therefore, it was selected for further testing. The value of elastic modulus was determined at 1.325 MPa. The thickness of the film at different locations was measured at 0.29 mm. Drug content in film was measured at 93% ±10. More than 90% of epinephrine was released from the film within 7.2 min. Bitterness of epinephrine was masked efficiently according to volunteer's comments with average disintegration time of 20 s. CONCLUSION: This study presents potential proof for using FDFs as a replacement therapy of epinephrine injections for pediatrics.

Development of a taste-masked oral suspension of clindamycin HCl using ion exchange resin Amberlite IRP 69 for use in pediatrics.

PURPOSE: The purpose of this study is to develop an oral suspension of clindamycin resin complex for the potential use in pediatrics. METHODS: Several types of Ion exchange resins were screened for their binding efficiency with clindamycin. In order to develop a suspension formulation, several thickening agents, surfactants, sweeting, and flavoring agents were evaluated for their influence on the release of clindamycin from resinate. Rheological studies were also conducted to select the optimum amounts of the suspending agents. The release profiles of clindamycin in SGF and SIF were also evaluated from freshly prepared suspension and from suspension formulation after storage for 1 month at 25 °C and 40 °C. Clindamycin bitterness threshold was determined based on volunteers' evaluation, and taste evaluation was conducted in 12 adult volunteers who evaluated the taste of the optimized suspension against clindamycin solution. RESULTS: Among all resins tested, Amberlite IRP 69 showed the highest binding efficiency to clindamycin. Several excipients were selected into the suspension formulation based on no or minimum influence on the release of clindamycin from the resinate complex. Moreover, xanthan gum was selected as the optimal suspending agent for the suspension. Clindamycin release profiles in SGF or SIF showed 90% release within 30 min from freshly prepared sample. Clindamycin exhibited good stability profiles at 25 °C and 40 °C over 1 month storage. The mean bitterness threshold of clindamycin was 12.5 µg/ml, and taste evaluation study in adults showed sustainable taste improvement for suspension over clindamycin solution. CONCLUSION: Clindamycin/resin complexation has shown to be an efficient method to mask the taste of clindamycin and was developed into a suspension formulation that can be used in pediatrics.

Development and physicochemical characterization of clindamycin resinate for taste masking in pediatrics.

PURPOSE: To evaluate the physicochemical characteristics of clindamycin HCl in a complex form (resinate) with ion exchange resin (IER) (Amberlite IRP69). METHODS: Drug-resin complex was prepared by simple aqueous binding method. Drug binding study was carried out at different drug and resin concentrations. Several physicochemical characterization studies were conducted to evaluate the resinate complex. These studies included flow properties, in vitro drug release in SGF and SIF, DSC, TGA, mass spectroscopy and XPRD evaluations. In addition, stability study of resinate complex was conducted at 25 and 40 °C for up to 1 month. RESULTS: Clindamycin and Amberlite IRP69 have formed a complex (resinate) and have shown good flow properties, good thermal properties and chemical stability (short term over 4 weeks) at 25 and 40 °C. Clindamycin release profiles from resinate in SGF and SIF have shown immediate release characteristics and release in simulated saliva has shown dependence on water volume. CONCLUSION: The clindamycin stable complex with IER (Amberlite IRP69) has the potential for further development as a compatible pediatric liquid formulation (suspension) or a fast disintegrating tablet.

In Vivo Evaluation of Transdermal Iodide Microemulsion for Treating Iodine Deficiency Using Sprague Dawley Rats.

The objective of this study was to evaluate the transdermal efficiency of iodide microemulsion in treating iodine deficiency using rats as an animal model. Animals were fed either iodine-deficient diet (20 µg/kg iodide) or control diet (200 µg/kg iodide) over a 17-month period. At month 14, iodide microemulsion was applied topically in iodine-deficient group and physiological evaluations of thyroid gland functions were characterized by monitoring the thyroid hormones (T3, T4), thyroid-stimulating hormone (TSH), iodide ion excretion in urine, and the overall rat body weights in both groups. Moreover, morphological evaluations of thyroid gland before and after treatment were performed by ultrasound imaging and through histological assessment. Prior to microemulsion treatment, the levels of T3, T4, and TSH in iodine-deficient group were statistically significant as compared to that in the control group. The levels of T3 and T4 increased while TSH level decreased significantly in iodine-deficient group within the first 4 weeks of treatment. After treatment, iodide concentration in urine increased significantly. There was no statistical difference in weight between the two groups. Ultrasound imaging and histological evaluations showed evidence of hyperplasia in iodine-deficient group. Topical iodide microemulsion has shown a promising potential as a novel delivery system to treat iodine deficiency.

The influence of sodium salts (iodide, chloride and sulfate) on the formation efficiency of sulfamerazine nanocrystals.

OBJECTIVE: The purpose of this study is to evaluate the influence of sodium iodide, sodium chloride and sodium sulfate on the formation efficiency of sulfamerazine nanocrystals by wet ball milling. METHODS: Sulfamerazine was milled using zirconium oxide beads in a solution containing polyvinylpyrrolidone (PVP) and a sodium salt (iodide, chloride or sulfate). Particle size distributions were evaluated by light diffraction before and after milling. High-performance liquid chromatography was utilized to determine the amount of PVP adsorbed onto sulfamerazine surface. Lyophilized nanocrystals were further characterized by differential scanning calorimetry and dissolution testing. RESULTS: Sulfate ion had more profound effect on reducing particle size via milling than iodide or chloride. We linked our findings to Hofmeister ion series, which indicates that sulfate ions tends to break the water structure, increases the surface tension and lowers the solubility of hydrocarbons in water. We hypothesized that the addition of sulfate ions dehydrated the PVP molecules and enhanced its adsorption onto the sulfamerazine particle surfaces. Consequently, the adsorbed PVP helped to stabilize of the nanosuspension. The nanocrystals that were obtained from the lyophilized milled suspensions exhibited a notable increase in dissolution rate. CONCLUSION: The addition of sodium sulfate enhanced the formation efficiency of sulfamerazine nanocrystals.

Evaluation of Chlorpheniramine Maleate microparticles in orally disintegrating film and orally disintegrating tablet for pediatrics.

OBJECTIVE: To mask the bitterness of Chlorpheniramine Maleate via encapsulating drug into Eudragit EPO microparticles, and then incorporate these microparticles into orally disintegrating films (ODF) and orally disintegrating tablets (ODT) for pediatric uses. METHODS: Spray drying of water-in-oil emulsion was utilized to encapsulate Chlorpheniramine Maleate into Eudragit EPO microparticles. Based on an orthogonal experimental design L9 (3(3)), polynomial regression models were developed to evaluate correlation between microparticle properties (encapsulation efficiency and drug release) and variables (X1: weight ratio of polymer to drug, X2: volume ratio of oil to water and X3: Q-flow of spray dryer). ODF and ODT formulations were evaluated including weight variation, content uniformity, tensile strength, disintegration time, friability and dissolution profiles. The bitterness taste test was evaluated in 10 adult volunteers. RESULTS AND DISCUSSION: From polynomial regression analysis, the best values of variables leading to the optimized microparticles were X1 = 10, X2 = 3 and X3 = 45. The optimized microparticles were incorporated into ODF and ODT with satisfactory weight and drug content uniformity, and acceptable physical strength. Both dosage forms disintegrated immediately (less than 40 s) in simulated saliva solutions. The outcome of taste-masking test indicated that microparticles alleviated drug bitterness significantly; bitterness was not discernible with microparticles incorporated in ODT, whereas only slight bitterness was detected from microparticles incorporated into ODF. CONCLUSION: Both ODF and ODT are shown to be suitable vehicles for taste masked Chlorpheniramine Maleate microparticles with potential for pediatric uses.

A novel topical rapamycin cream for the treatment of facial angiofibromas in tuberous sclerosis complex.

Facial angiofibromas are dermatological manifestations of tuberous sclerosis complex, a neurocutaneous disorder characterized by excess cell growth and proliferation. Oral rapamycin has been used to treat visceral tuberous sclerosis-related tumors; however, the side effect profile of this medicine precludes its routine use in patients lacking significant internal involvement. The authors formulated a novel rapamycin cream that is easy to compound and apply, does not cause local or systemic side effects, and results in a dramatic improvement of facial angiofibromas.

Development of w/o microemulsion for transdermal delivery of iodide ions.

The objective of this study was to develop a water-in-oil (w/o) microemulsion which can be utilized as a transdermal delivery for iodide ions. Several w/o microemulsion formulations were prepared utilizing Span 20, ethanol, Capryol 90®, and water. The selected formulations had 5%, 10%, 15%, 20%, and a maximum of 23% w/w water content. Potassium iodide (KI) was incorporated in all formulations at 5% w/v. Physicochemical characterizations were conducted to evaluate the structure and stability. These studies included: mean droplet size, pH, viscosity, conductivity, and chemical stability tests. In vitro human skin permeation studies were conducted to evaluate the diffusion of the iodide ion through human skin. The w/o microemulsion formulations were stable and compatible with iodide ions with water content ranging from 5% to 23% w/w. The addition of KI influenced the physicochemical properties of microemulsion as compared to blank microemulsion formulations. In vitro human skin permeation studies indicated that selected formulations improved iodide ion diffusion significantly as compared to control (KI solution; P value<0.05). Iodide ions were entrapped within the aqueous core of w/o microemulsion. Span 20, ethanol and Capryol 90 protected the iodide ions against oxidation and formed a stable microemulsion. It is worth to note that according to Hofmeister series, iodide ions tend to lower the interfacial tension between water and oil and consequently enhance overall stability. This work illustrates that microemulsion system can be utilized as a vehicle for the transdermal administration of iodide.

Controlled release of modified insulin glargine from novel biodegradable injectable gels.

The objective of this study was to investigate the duration of biological effects of modified insulin glargine released from a novel biodegradable injectable gel in type II diabetic Zucker diabetic fatty (ZDF) rats. Modified insulin glargine was purified from the marketed formulation by process of dialysis followed by freeze-drying, and the purity was confirmed by the single peak, corresponding to insulin glargine in the HPLC chromatogram. To determine and to compare the biological activity of purified insulin glargine with marketed formulation, it was suspended in isotonic saline solutions and administered subcutaneously to ZDF rats at a dose of 10 IU/kg of insulin and the blood glucose levels were measured. The blood glucose levels of ZDF rats after a subcutaneous injection of a suspension of purified insulin glargine decreased below 200 mg/dL within 2 h and remained at this level up to 6 h, then steadily raised above 400 mg/dL in 12 h. Insulin glargine particles were loaded into a novel biodegradable injectable gel formulation prepared from a blend of polylactic-co-glycolic acid (PLGA) and biocompatible plasticizers. Approximately 0.1 mL of insulin glargine-loaded gel prepared with PLGA was administered subcutaneously to the ZDF rats, and blood glucose levels were measured. The PLGA gel formulations prepared with insulin glargine particles had duration of action of 10 days following a single subcutaneous injection. The addition of zinc sulfate to the formulations prepared with purified insulin glargine particles further slowed down the drop in blood glucose concentrations.

Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH.

PURPOSE: To evaluate the effect of pH on solubility and dissolution rates of a model weak base, haloperidol, and two different salt forms, hydrochloride and mesylate. METHODS: pH-solubility profiles were determined by using haloperidol base, haloperidol hydrochloride, and haloperidol mesylate as starting materials; concentrated or diluted HCl or NaOH solutions were added to aqueous suspensions of solids to adjust pH to desired values. Intrinsic dissolution rates were determined using intrinsic dissolution apparatus under various pH-stat conditions. Further, approximation of diffusion layer pH was estimated from that of 10% w/w slurries of drug substances in dissolution media, which were used to correlate with intrinsic dissolution rates of haloperidol and its salt forms under different pHs. RESULTS: pH-solubility profiles of haloperidol base and its HCl salt were similar, while when the mesylate salt was used as starting material, it exhibited a higher solubility between pH 2 and 5. The higher solubility of the mesylate salt at pH 2-5 is attributed to its higher solubility product (K(sp)) than that of the hydrochloride salt. The pH-solubility profiles indicated a pH(max) (pH of maximum solubility) of approximately 5, indicating that the free base would exist as the solid phase above this pH and a salt would be formed below this pH. Below pH 1.5, all solubilities were comparable due to a conversion of haloperidol base or the mesylate salt to the HCl salt form when HCl was used as the acidifying agent. These were confirmed by monitoring the solid phase by differential scanning calorimeter. When their dissolution rates are tested, dissolution rates of the mesylate salt were much higher than those of the free base or the HCl salt, except at very low pH (<2). Dissolution rates of free base and HCl salt also differed from each other, where that of HCl salt exhibits higher dissolution rates at higher pHs. A direct correlation of dissolution rate with solubility at diffusion layer pH at the surface of dissolving solid was established for haloperidol, its hydrochloride, and mesylate salts. CONCLUSIONS: Using pH-solubility and pH-dissolution rate interrelationships, it has been established that diffusion layer pH could be used to explain the observed rank order in dissolution rates for different salt forms. A non-hydrochloride salt, such as a mesylate salt, may provide advantages over a hydrochloride salt due to its high solubility and lack of common ion effect unless at very low pH.

Stability of sotalol hydrochloride in extemporaneously prepared oral suspension formulations.

The physical, chemical, and microbial stabilities of extemporaneously compounded oral liquid formulations of sotalol hydrochloride were studied. Sotalol hydrochloride oral liquid suspensions (5mg/mL) were prepared from commercially available tablets (Betapace) in a 1:1 mixture of Ora-Plus: Ora-Sweet, a 1:1 mixture of Ora-Plus:Ora-Sweet SF, and a 1:2.4 mixture of simple syrup:methylcellulose vehicle. Six batches of each formulation were prepared; three were stored at refrigerated temperature (2 deg to 8 deg C) and three at room temperature (20 deg to 25 deg C). Samples were collected from each batch weekly for 6 weeks, and again at 12 weeks. Samples were analyzed by means of a high-performance liquid chromatographic method, and the concentrations obtained were compared to the theoretical time zero value. Samples were examined for pH, odor, color, and consistency changes. The suspensions also were evaluated for their microbial stability. Sotalol hydrochloride oral liquid suspensions (5mg/mL) were chemically stable for 12 weeks regardless of storage conditions (room temperature or refrigerated). Bacterial growth was not supported by any of the formulations. Suspensions stored at refrigerated temperature retained better physical quality (e.g., odor, color, and consistency) than suspensions stored at room temperature. Overall, this study demonstrates that oral formulations of sotalol hydrochloride can be readily prepared with commercially available vehicles. The method of preparation is relatively simple, the materials are relatively inexpensive, and the products have a shelf-life of at least 12 weeks.