Film Tablet Research Articles

Bioequivalence study of eltrombopag 75 mg film-coated tablets under fasting conditions during the Covid-19 pandemic in healthy Caucasian male subjects

This study aims to determine the bioequivalence of the reference preparation and the test preparation containing eltrombopag when both were given during the COVID-19 pandemic while fasting. Participants in the research were healthy male Caucasian subjects. One film-coated tablet of the test preparation or one film tablet of the reference preparation, equivalent to 75 mg of eltrombopag, was given to the participants in a randomized order throughout each treatment session. At pre determined blood sampling points, blood samples were taken to determine the pharmacokinetics of eltrombopag. Eltrombopag concentrations in the samples were determined using an LC-MS/MS technique verified using ESI(−). The study results were used to calculate the rate (the maximum plasma concentration, or Cmax) and extent (area under the concentration-time curve of plasma, or AUC(0−72) and AUC(0−t) of eltrombopag absorption from the test preparation and reference preparation. The 90% confidence intervals (CI) of the ln-transformed AUC(0−72), AUC(0−t), and Cmax of eltrombopag met the bioequivalence requirements of 80.00–125.00%. Both trial preparations had a similar and very satisfactory safety profile.

Evaluation of Pharmacokinetics of a BCS Class III Drug with Two Different Study Designs: Tenofovir Alafenamide Monofumarate Film-coated Tablet.

Tenofovir alafenamide (TAF) is a BCS Class III compound and an oral pro-drug of Tenofovir (TFV) with limited oral bioavailability. The bioavailability of the oral intake increases with food as a result of the low stability of the active substance in the stomach. The reference drug is "Vemlidy® 25mg Film Tablet", which contains 25mg of TAF in "hemifumarate" form, is under patent protection until 15.08.2032 by Gilead, and so the "monofumarate" form was used in the present study. At first, a pilot study was conducted involving 12 subjects under fed conditions. The results of the pilot study revealed the test and reference products were not bioequivalent, as a result of insufficient statistical power and high inter-subject variability. Secondly, a physiologically based pharmacokinetic (PBPK) simulation was performed based on the pilot study results and literature data. Finally, the power of the design was increased and the pivotal study design was optimized into a four-period, full-replicated, cross-over study with 34 subjects under fed conditions and it was concluded that the test and reference products were bioequivalent. In conclusion, the present study proved the importance of a correct study design with higher statistical power for a BCS Class III compound with high variability, to present the pharmacokinetics.

Cell culture and pharmacokinetic evaluation of a solid dosage formulation containing a water-insoluble orphan drug manufactured by FDM-3DP technology

The in-vitro cytotoxicity, in-vitro permeability and in-vivo pharmacokinetics of a BCS Class-II drug – rufinamide – in a 3DP tablet formulation were evaluated. The cytotoxicity of the 3DP tablet formulation was evaluated with an MTT test; in-vitro permeability was evaluated with a Caco-2 cell culture study; and in-vivo pharmacokinetics were evaluated in Wistar albino male rats. The pharmacokinetic studies were performed following a two-sequence and single-period design approach. The highest Caco-2 permeability was obtained with the 3DP tablet formulation; and the highest cell viability was achieved with the 3DP tablet in both the Hep G2 and Caco-2 cell lines. In the in-vivo pharmacokinetic study, AUC and Cmax values were higher in the 3DP tablet formulation than in the Inovelon® film tablet at a 40 mg/kg dose. Thanks to the increased solubility of the active substance, higher in-vitro permeability and in-vivo absorption were achieved with the 3DP tablet formulation, and with lower cytotoxicity. Based on these promising findings, the 3DP tablet formulation can be considered an effective lower-dose treatment than commercial preparations.

A Study to Compare Bioequivalence Approach Between FDA and EMA in a Highly Variable Drug: Pinaverium Bromide Film Tablets

The aim of this study is to investigate pharmacokinetic parameters of test and reference film tablet formulations of a highly variable drug, pinaverium bromide, under fasting conditions and to assess their bioequivalence in accordance with the FDA and EMA criteria. A randomised open-label, single oral dose, three-sequence, three-period, semi-replicated, cross-over trial was conducted with 36 healthy subjects. The intrasubject variability of reference products for Cmax and AUC0-tlast was found to be more than 50%. While bioequivalence was proven according to the FDA reference scaled average bioequivalence approach with only 36 subjects, more than 200 subjects are required to demonstrate bioequivalence in accordance with the EMA bioequivalence guideline. It is believed that the EMA bioequivalence criteria are too stringent for highly variable drugs whose intrasubject variability are more than 30% for both Cmax and AUC0-tlast and that in consequence the EMA ought to revise their bioequivalence guidelines for such drugs in the future.

Alpha lipoic acid bioequivalence study redesigned: a candidate for highly variable drugs

Background and Aims: Alpha lipoic acid 600 mg HR film tablet showed high intra-subject variabilities in bioequivalence studies. In this regard, this study aims to determine whether Alpha lipoic acid 600 mg HR film coated tablet is a highly variable drug. Methods: First, a randomized, open-label, balanced, two-treatment, two-period, two-sequence, single-dose, two-way crossover oral bioequivalence study comparing the test product (Alpha lipoic acid HR film tablet - ILKO Pharmaceuticals, Turkey) with the reference product (Thioctacid®- Meda Pharma, Germany) was conducted in normal, healthy, adult human subjects under fasting conditions (Study 1). Secondly, a randomized, open-label, balanced, two-treatment, four-period, two-sequence, single-dose, fully replicate crossover oral bioequivalence study was conducted in normal, healthy, adult human subjects under fasting conditions (Study 2). Results: Study 1 failed. It had a 90% confidence interval for LnCmax (ng/mL) value between 79.69% – 138.98% with a high intra-subject coefficient of variability (ISCV=57.5%). In study 2 a 90% confidence interval for LnCmax (ng/mL) was found between 88.40% – 129.81% while the ISCV value for LnCmax was 64.5%. Conclusion: The findings suggest that bioequivalence study for Alpha lipoic acid HR film tablet should be redesigned since this is a highly variable drug. Therefore, conventional bioequivalence acceptable limits (80.0%-125.0%) should be adjusted to 69.84% – 143.19% for alpha lipoic acid.

Exposures to traditional automatic dishwashing tablets and a comparison with exposures to soluble film tablets reported to the United Kingdom National Poisons Information Service 2008–2015

Introduction: Traditional automatic dishwashing tablets are contained within an external wrapper that requires removal prior to use.Objective: To determine the toxicity of traditional tablets and to compare this with our previously reported experience of soluble film dishwashing tablets.Methods: Telephone enquiries regarding traditional tablets were analysed retrospectively for the period January 2008 to December 2015.Results: Traditional tablets: There were 503 enquiries relating to 492 patients who had been exposed to a traditional tablet. Most involved children aged 5 years or less (87.4%). The majority (78.6%) of patients did not develop symptoms after exposure; 21.1% developed minor (PSS 1) symptoms while one patient developed moderate features. Exposure occurred predominantly as a result of ingestion (n = 476, 96.7%); the most common feature in symptomatic patients (n = 99, 20.8%) was vomiting (70 [14.7%] cases). Significantly (p < 0.0001) more adults (44.9% of 49 adults; 95% CI = 31.9–58.7) were reported with features than children (18.2% of 434; 95% CI = 14.9–22.1). There were five cases of eye contact which resulted in eye pain in two patients and eye irritation in another. Only one of 11 patients exposed dermally developed features (a rash around the mouth).Comparison with soluble film exposures: The percentage of patients that were reported with clinical symptoms following ingestion of a soluble film dishwashing tablet (31.7% of 473 patients; 95% CI = 27.7–36.0) was significantly greater (p < 0.0001) than that for a traditional tablet (20.9% of 483 patients; 95% CI = 17.5–24.8). Vomiting was the most commonly reported feature and occurred significantly (p < 0.0001) more frequently amongst patients who had ingested a soluble film tablet (25.5%; 95% CI = 21.8–29.6) than a traditional tablet (14.7%; 95% CI = 11.8–18.1).Conclusions: Exposure to both traditional and soluble film tablets only rarely produced clinically significant symptoms (PSS ≥2). However, ingestion of a soluble film tablet was significantly more likely to result in clinical features than ingestion of a traditional tablet.

New developments in the management of opioid dependence: focus on sublingual buprenorphine-naloxone.

Opioid maintenance therapy is a well-established first-line treatment approach in opioid dependence. Buprenorphine, a partial opioid agonist, has been found by numerous studies to be an effective and safe medication in the treatment of opioid dependence. At present, buprenorphine is available as a monodrug or in a fixed 4:1 ratio combination with naloxone. A diminished risk of diversion and abuse for the buprenorphine–naloxone combination is likely but not firmly established. Conventional formulations are given sublingually to avoid the hepatic first-pass effect. A novel film tablet is available only in the US and Australia. Other novel, sustained-release formulations (implant, depot) are currently being developed and tested. Recent studies, including a Cochrane meta-analysis, suggest that the retention with buprenorphine is lower than for methadone, but that buprenorphine may be associated with less drug use. Higher doses of buprenorphine are associated with better retention rates. Buprenorphine has a ceiling effect at the opioid receptor with regard to respiratory depression, and may cause fewer fatal intoxications than methadone. Possible antidepressant effects of buprenorphine and its use in comorbid psychiatric patients has not been studied in much detail. Clinical implications are discussed.

Ventricular tachycardia induced by pseudoephedrine tablets for common cold

A 62-year-old male patient admitted to the emergency department with the complaints of palpitation and presyncope for 10min. He also had an one-week history of common cold. His family physician prescribed Benical Cold b.i.d (Bayer Turk, Istanbul, Turkey), a film tablet that contains 500mg paracetamol, 30mg dextromethorphan hydrobromide and 20mg pseudoephedrine. Over the next 36h the patient developed anxiety and reported short episodes of palpitations. On the day of admission he had taken 2 tablets of Benical Cold.

Determination of Rosuvastatin at Picogram Level in Serum by Fluorimetric Derivatization with 9-Anthryldiazomethane using HPLC

For the first time, a carboxyl group derivatization assay has been developed and validated for the determination of the cholesterol-lowering drug rosuvastatin in human serum at picogram level by high-performance liquid chromatography with fluorescence detection. The assay procedure involved a simple one-step liquid-liquid extraction of rosuvastatin with lovastatin as internal standard from serum with an ethyl acetate-methyl tertiary buthyl ether (1:1) mixture. After pre-column derivatization with 9-anthryldiazomethane at room temperature for one hour, the reaction mixture was injected onto a Phenomenex, Synergi C18 column (250 × 4.6 mm, 4 µ i.d.). The analytes were separated with a mobile phase composed of acetonitrile-water in gradient elution mode and detected at λ(em) = 410 nm, exciting at 366 nm. Calibration curves were constructed in concentration range of 0.01-20.0 ng/mL and limit of detection and limit of quantification values were found to be 0.68 and 2.30 pg/mL, respectively. To test suitability of the developed methods for clinic use, the pharmacokinetics of rosuvastatin were investigated after oral administration of a 20 mg rosuvastatin film tablet to a healthy volunteer and maximum plasma concentration, time to reach that concentration and elimination half life were found to be 17.5 ng/mL, 3.5 h and 18.09 h, respectively.

Comparison of the radioactivity and biomechanical properties of strontium and magnesium composites and chitosan, chitin

Lead material is usually used to protect from X-ray for medical or other purposes. The aim of this project is the development of a new material to protect from X-rays. For this purpose, composite samples from four different groups were prepared as a film tablet. In the first group chitosan, the second one Sr (strontium), the third one chitin, the fourth one Mg (magnesium) were used in the same percentages. 66 kV–81 kV–102 kV–150 kV X-ray was performed on composite samples for 15.5 ms–15.2 ms–15.0 ms–17.6 ms and for 4 mA s–3.2 mA s−2.5 mA s−2 mA s, respectively. The distance of the materials and anode was 1.10 m in this test. Each sample was placed on bone and muscle tissue for the simulation of the real situation in the body. After performing X-ray on the samples, the biomechanical tests were performed by using the axial compression testing machine (AG-I 10 kN, Shimadzu, Japan). The axial compression was applied to all specimens with the loading speed of 5 mm/min (max. 100 N). The compression tests were performed at room temperature. It was found that Sr (strontium) has the best X-ray protection and mechanical resistance among these groups. In conclusion, Sr and Sr composites materials can be used for medical protection and other purposes in the future instead of lead.

The adhesion characteristics of some pigmented and unpigmented aqueous-based film coatings applied to aspirin tablets.

The adhesion of pigmented (with talc and titanium dioxide) and unpigmented aqueous-based films, derived from hydroxypropyl methylcellulose, to aspirin tablets and the effect of ageing on the measured adhesion have been assessed. The adhesion of hydroxypropyl methylcellulose film attained maximum values at polyethylene glycol 400 and polyvinyl alcohol levels of 10 and 20 wt%, respectively. Above these concentrations, adhesion decreased. For solid loaded films it is proposed that the effect of pigments on film adhesion is dependent on the balance between their influence on the internal stress of the film coating and the strength of the film-tablet interface. Adhesion was enhanced when a pigment increased the strength of the interface faster than it increased internal stress, and vice versa. A simple relation between the measured adhesion and the incidence of edge splitting of film-coated tablets was not observed. Generally, film adhesion fell when the tablets were aged at 37 degrees C and 75% r.h. as a result of swelling-induced stresses in the film and at the film tablet interface. The effect of ageing on the adhesion of the system plasticized with polyethylene glycol 400 was eased when the film was pigmented. Adhesion was largely unaffected with film-coated tablets stored in tightly closed bottles at 20 degrees C for five months.

Multivitamin and mineral supplementation modulates oxidative stress and antioxidant vitamin levels in serum and follicular fluid of women undergoing in vitro fertilization

We investigated effects of multivitamin and mineral supplementation on lipid peroxidation, reduced glutathione, glutathione peroxidase, vitamin A, vitamin C and vitamin E values in serum and follicular fluid of 56 women undergoing IVF and 13 age matched control. We concluded that multivitamin and mineral supplementation in serum and follicular fluid of women undergoing IVF may strengthen the antioxidant defense system by decreasing oxidative stress.

Quantitative Determination of Underivatized α-Tocopherol in Cow Milk, Vitamin and Multivitamin Drugs by GC-FID

A simple and rapid method for direct determination of α-tocopherol (α-T, vitamin E) in pharmaceutical preparations (vitamin and multivitamin tablets) and cow milk obtained from different villages of Erzurum in Turkey was developed and validated by GC-FID. Separation of underivatized α-T in pure substance, milk samples, vitamin and multivitamin tablets was performed in about 8.4 min, using an HP-5 capillary column. The range of quantification for the GC-FID was 1–30 μg mL−1. Within-day and between-day precision (RSD %) were less than 8.5%, and accuracy (relative error) was less than 11.0% (n = 6). LOQ and LOD values were found to be 0.35 and 0.30 μg mL−1, respectively. The developed method was applied directly and easily to the analysis of α-T in vitamin and multivitamin preparations and cow milk. RSD values were found to be 6.59% (Grandpherol soft gelatine capsule: 200 I.U.), 0.59% (Megadyn film tablet: 10 mg) and 1.54% (Supradyn drage: 10 I.U.). The developed method was also applied to cow milk samples and mean values of α-T content was found 2.99 μg mL−1 in cow milk samples. This developed and validated GC–FID method, in conjunction with other methods, could be successfully applied for routine laboratory because of its simplicity, rapidity, sensitivity, precision and accuracy.

A Novel Imaging Technique to Investigate the Influence of Atomization Air Pressure on Film–Tablet Interfacial Thickness

A novel X-ray photoelectron spectroscopic (XPS) technique combined with principal component analysis of spectra-to-image datasets was employed to study the effects of atomization air pressure used during the coating process on film–tablet interfacial thickness. Placebo tablet cores were prepared and coated with Eudragit® RL 30 D. Atomization air pressure was varied from 10 to 20 psi, whereas all other processing parameters were held constant. Higher air pressures generally produced thinner interfaces, although the interfacial region was not uniform across the tablet surface and was dependent on the sampling location. These results demonstrate the suitability of this XPS technique to study the coating–tablet interface. Moreover, the variability in the interfacial thickness illustrates the need to further study such systems.

BIOEQUIVALENCE OF TWO FEXOFENADINE FORMULATIONS IN HEALTHY HUMAN VOLUNTEERS AFTER SINGLE ORAL ADMINISTRATION

A randomized, two-way, crossover, bioequivalence study was conducted in 25 fasting, healthy, male volunteers to compare two brands of fexofenadine 180 mg tablets, FEXOFENADINE 180 mg Film Tablet (Drogsan A.S., Ankara, Turkey) as test and Telfast 180 mg Tablet (Aventis Pharma, Frankfurt am Main, Germany) as a reference product. One tablet of either formulation was administered after 10 h of overnight fasting. After dosing, serial blood samples were collected during a period of 48 hours. Plasma samples were analysed for fexofenadine by a validated HPLC method. The pharmacokinetic parameters AUC(0-48), AUC(0-alpha), C(max), T(max), K(el), T(1/2), and CL were determined from plasma concentration-time profiles for both formulations and were compared statistically. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range, satisfying the bioequivalence criteria of the FDA. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetics profiles and that Drogsan's Fexofenadine is equivalent to Telfast of Aventis Pharma, Frankfurt am Main, Germany.

Treatment for diabetic mononeuropathy with α-lipoic acid

Twenty-three diabetic patients -- 16 men and seven women (mean age: 50.7 +/- 17.4 years; mean duration of diabetes: 13.6 +/- 6.9 years) -- with diabetic mononeuropathy of the cranial nerves participated in the study. Four of them were with mononeuropathia multiplex and total ophthalmoplegia, affecting the oculomotor, trochlear and abducent nerves; 12 with paresis of the oculomotor nerve, one -- of the trochlear nerve and six -- of the abducent nerve. They were treated with alpha-lipoic acid (600 mg) for 10 days daily intravenously, thereafter one film tablet of 600 mg daily for 60 days. On the 10th day, we found significant improvement in the clinical signs of diabetic mononeuropathy - double vision, motility and position of the eyeball, ptosis of the upper eyelid and mydriasis. The mean period of oral treatment was 69.1 +/- 23.8 days, following the 10-day intravenous application of alpha-lipoic acid, and full recovery of the diabetic mononeuropathy was achieved with this therapeutic approach. Peripheral neuropathy was present in 17 patients (74%). On the 10th day, we established a decrease in total symptom score by an average of 2.7 +/- 1.4 points and by the end of the treatment period it was improved by 5.9 +/- 1.9 points (p = 0.04). On the 10th day, we found a decrease of 33% in foot pain and by the end of the second month, it fell by 65.5% (p < 0.0001). Vibration perception threshold was reduced in these patients at entry -- mean: 2.42 +/- 1.8 at the great toe, 2.89 +/- 1.8 at the first metatarsal and 3.65 +/- 1.7 at the medial malleolus. By the end of the second month, it reached mean 4.7 +/- 1.8 (p < 0.002) at the great toe, 4.92 +/- 2.1 (p = 0.004) at the first metatarsal and 5.3 +/- 1.4 (p < 0.01) at the medial malleolus. Cardiovascular autonomic neuropathy was present in two of the patients and there was improvement after treatment in the Ewing's tests -- Valsalva manoeuvre, deep-breathing test and lying-to-standing test. The results of our study demonstrate that alpha-lipoic acid appears to be an effective drug in the treatment for not only peripheral and autonomic diabetic neuropathy, but also diabetic mononeuropathy of the cranial nerves leading to full recovery of the patients.

Quantitation of film coating on Zantac® 75 mg tablets and Epivir HBV® 100 mg tablets by ICP-AES

Purpose: To present a selective analytical Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES) method developed and validated for the quantitation of tablet film coatings containing titanium. Methods: Tablet samples were decomposed by either digestion or dry ashing. The amount of film tablet coating was calculated based on titanium content of the sample. Results: The reported ICP-AES method was accurate, precise, sensitive and linear for determination of titanium concentrations from 2.9 to 8.6 ppm. Conclusion: This method provides an accurate determination of the amount of coating on a tablet and has general applicability for a variety of coating formulations containing different elements.

Effect of Anionic Water-Soluble Dyes on Film Coating Properties of Chitosan Acetate

Solution of chitosan in dilute acetic acid was prepared to have an apparent viscosity of 125 mPa s and mixed with solution of anionic water-soluble dye. The effects of concentration and type of dye and molecular weight and percentage deacetylation of chitosan on their miscibility and physical stability were investigated. High concentration of dye and high molecular weight and percentage deacetylation of chitosan resulted in precipitation or colloidal dispersion due to ionic interaction between dye and the polymer. The effect was more prominent upon storage. The miscibility of dye and the polymer depended on the molecular configuration and ionic group in the dye molecule. It was ranked brilliant blue ≅ green FS>fast green>ponceau SX ≅ sunset yellow>erythrosine ≅ tartrazin>indigo carmine. Solutions of low molecular weight chitosan with and without green FS were then used as coating formulations onto propranolol hydrochloride core tablets. There was no color migration on coated tablets even after storage for 1 year. Disintegration and drug dissolution from tablets coated with colored film were slightly slower than those from tablets coated with plain film and core tablet, respectively. This was corresponding to the results of swelling and dissolution of cast films. However, all tablets conformed to the specification in monograph of USP XXIV.

A Novel Technique to Quantify Film–Tablet Interfacial Thickness

The purpose of the project was to develop an x-ray photoelectron spectroscopic technique to quantify film–tablet interfacial thickness. Tablets containing 99% dibasic calcium phosphate were coated with an acrylic polymer containing chlorine (Eudragit® RL 30 D). The film–tablet interface was defined as the region where phosphorous from the tablet and chlorine from the film coating were detected simultaneously. Five-minute intermittent ion-sputtering was used in conjunction with the conventional x-ray photoelectron spectroscopy to achieve depth profiling of the sample. The slow ion-sputtering rate of approximately 56 nm/min was overcome through sample preparation and analysis from the tablet side of the sample. This process eliminated the need to sputter through the entire film coating to reach the area of interest. Initially, only phosphorous from the tablet was detected. As the depth profiling proceeded, the chlorine signal increased and the relative intensity of the phosphorous decreased. By plotting the relative intensities of each element against the ion-sputtering time and using linear regression, the point at which the two lines intersected (tmid) was determined. By doubling tmid and multiplying by the estimated ion-sputtering rate, the thickness of the film–tablet interface was estimated to be approximately 34 μm. Further studies are needed to correlate the film–tablet interfacial thickness with the adhesive properties of coated solids.

Influence of Curing on the Adhesive and Thermomechanical Properties of an Applied Acrylic Polymer

The objective of the current study was to investigate the relationship between polymer adhesion and post-coating thermal treatment. A novel adhesion technique was used to quantify the adhesive properties of applied acrylic films. Differential scanning calorimetry was used to determine the glass transition temperature of the applied polymer. Post-coating thermal treatment, or curing, was found to significantly influence the adhesive and thermomechanical properties of the applied film coating. Adhesion of triethyl citrate-plasticized films to tablets increased during storage at elevated temperatures, equilibrating within four hours. The glass transition temperature of the applied triethyl citrate-plasticized coatings also increased during curing. Equilibration of polymer properties was found to be dependent on the hydrophobicity of the plasticizer incorporated into the coating formulation, with longercuring times required for films containing the hydrophobic plasticizer tributyl citrate. The curing temperature was shown to influence polymer properties, with stronger film–tablet adhesion and higher glass transition temperatures resulting when the coated tablets were stored at higher temperatures. Substrate hydrophobicity was also found to influence the curing process, suggesting that the mechanisms involved in film formation and polymer–substrate adhesion may contribute to the internal stresses within the film.