Development of orally disintegrating tablets of Perphenazine/hydroxypropyl-β-cyclodextrin inclusion complex

The aim of the present work was to prepare perphenazine (PPZ) orally disintegrating tablets (ODTs) based on the use of hydroxypropyl-β-cyclodextrin (HP-β-CD) forming inclusion complex with PPZ to improve the solubility and dissolution of this practically insoluble drug. Phase solubility studies were performed to evaluate the complexation of PPZ with HP-β-CD in three aqueous systems. The inclusion complex prepared by evaporation method was characterized by different physicochemical techniques, including the dissolution studies. The prepared complex was incorporated into ODTs containing different fillers and disintegrants. The ODTs prepared by direct compression were evaluated for drug content, hardness, porosity, friability, in vitro disintegration time (DT), wetting time (WT) and dissolution profiles. The solubility and dissolution rate were substantially improved compared with that of PPZ. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR) analyses suggested that PPZ could form true inclusion complex with HP-β-CD. The optimized formulation F6 exhibited short DT (15.5 ± 1.9 s) and WT (34.2 ± 2.3 s), sufficient hardness (30.4 ± 1.6 N/mm) and rapid drug dissolution. The developed tablet formulation could be a promising drug delivery system with improvements in PPZ bioavailability and patient compliance.     

Efficacy, safety, and palatability of RACTAB(®) formulation amlodipine orally disintegrating tablets

Objective: The aim of this study was to confirm the efficacy, safety, and expected palatability of amlodipine orally disintegrating tablets (ODT) [RACTAB® formulation (Towa, Osaka, Japan)]. We report the re-analyzed results of 1687 cases in clinical settings obtained through postmarketing surveillance in Japan.Method: Study subjects were patients receiving treatment for the first time with amlodipine ODT for hypertension under routine care. A multicenter central registration system was used for this prospective survey. The survey was conducted from October 2008 to October 2010. The observational period was 12 weeks, during which time surveys on outpatient blood pressure, adverse events, palatability, etc. were conducted.Results: Blood pressure stabilized following treatment, and both systolic and diastolic blood pressures were favorably controlled. Adverse events observed were not significantly different from those observed during drug use trials of amlodipine formulations reported in 2003. Moreover, palatability of amlodipine ODT showed a 99.6% (227 of 228 cases) favorable patient acceptance, which is consistent with the initial design concept of RACTAB® formulation.Conclusions: The results of this postmarketing surveillance study indicated that the efficacy, safety, and palatability of amlodipine ODT met our expectations (dissolves quickly in the mouth, tastes good, and is not rough on the tongue). Accordingly, amlodipine ODT are believed to be an easy-to-use formulation for prescribing doctors, dispensing pharmacists, and patients receiving treatment.     

Do formulation switches exacerbate existing medical illness? Results of an open‐label transition to orally disintegrating risperidone tablets

BACKGROUND: Orally disintegrating risperidone tablets (Risperdal* M-TABs*) present an alternative method of drug delivery that may benefit physicians struggling to treat non-compliant patients, since it begins to dissolve within 5 s, preventing tablet cheeking or spitting. OBJECTIVES: To evaluate safety and maintenance of effect in symptomatically stable patients transitioned from compressed risperidone tablets to orally disintegrating risperidone tablets. METHODS: This open-label, multi-centre study enrolled 82 adults from four diagnostic groups (major depressive disorder (MDD), n = 25; bipolar disorder (BP), n = 21; dementia (DE), n = 20; schizophrenia (SZ), n = 16). Patients were switched from their previous dosage of compressed tablets (0.5, 1.0, 2.0, 3.0, or 4.0 mg/day) to an equivalent dosage of orally disintegrating risperidone and followed for 4 weeks. The primary effectiveness parameter evaluated was the Clinical Global Impression-Severity (CGI-S) scale. RESULTS: Most patients (24/25 MDD; 20/21 BP; 17/18 DE; 14/15 SZ) improved by 1 point on CGI-S from baseline or experienced no change at endpoint. Adverse events (AEs) occurring in any group at a > or =10% incidence included headache (19%) and pharyngolaryngeal pain (10%), reported in the BP group only. CONCLUSIONS: Patients stabilized on compressed risperidone tablets transitioned to the equivalent dose of orally disintegrating risperidone tablets with continued maintenance of effect, no decompensation and with minimal side effects.     

Safety and efficacy of newly formulated selegiline orally disintegrating tablets as an adjunct to levodopa in the management of ‘off’ episodes in patients with Parkinson's disease

ABSTRACT

Objective: Patients receiving levodopa for Parkinson's disease experience motor fluctuations and immobility (‘off’ episodes) between doses. This study assessed adjunctive Zelapar^? (selegiline orally disintegrating tablet (ODT)) for managing off episodes and for long-term safety.

Methods: This open-label extension evaluated long-term safety, efficacy, and tolerability of adjunctive selegiline ODT 2.5?mg in patients who completed either of two large phase 3 double-blind studies. The study was to end after 12 months but was amended to be open-ended. Investigators could increase levodopa doses and introduce controlled-release formulations of levodopa or dopamine agonists if warranted. Additionally, results of a small randomized trial of open-label selegiline ODT 1.25?mg in comparison to conventional selegiline was added only to the safety analysis. Efficacy variables included changes in daily off time and Patient's Global Impression of Improvement (PGI-I) and Clinical Global Impressions Severity of Disease (CGI-S) ratings. Safety assessments included adverse events and oropharyngeal findings.

Results: This study enrolled 254 patients: 248 from the large phase 3 studies (efficacy analysis) and an additional six from the prior open-label comparison (safety analysis) in order to evaluate a larger population for safety purposes. Mean reduction from baseline in daily off time was 9.4% (1.6?h) for patients previously given selegiline ODT, 6.0% (1.2?h) for those switched from placebo, and 8.1% (1.4?h) overall. PGI-I and CGI-S ratings indicated little or no change from baseline. Treatment-related adverse events occurred in 132 (52%) patients. No severe oral irritations were attributed to selegiline ODT or prompted discontinuation.

Conclusions: Long-term selegiline ODT 2.5?mg/day was effective, safe, and well tolerated in patients with Parkinson's disease experiencing off episodes during levodopa therapy.     

800 mg Darunavir tablets prepared by hot melt extrusion

Darunavir (TMC 114) is a protease inhibitor used in the therapy of HIV-1. The aim of this study was to formulate 800?mg of Darunavir in a single unit dosage form, with suitable mechanical properties and dissolution behavior, using a corotating twin screw extruder. In preliminary investigations, extrudates of 1?mm diameter were prepared to evaluate the extrusion and dissolution behavior of Darunavir. Two different poloxamers (188 and 407) were used to modify the dissolution properties of Darunavir, and a higher solubilization for poloxamer 188 was observed. Furthermore, a zero order drug release from pure Darunavir extrudates was found which was modulated by the extrudate diameter. Extrudates of 13?mm diameter were cut into tablets containing 800?mg of Darunavir. Due to the lower specific surface area in comparison to the 1?mm extrudates, an addition of solubilizing agent was required to obtain the desired dissolution profiles. Therefore, the influence of Mannitol and poloxamer 188 was investigated in different formulations. The formulations exhibited acceptable extrusion behavior and dissolution properties.     

Clinical acceptability study of micronized purified flavonoid fraction 1000 mg tablets versus 500 mg tablets in patients suffering acute hemorrhoidal disease

Objective: To compare the clinical acceptability of micronized purified flavonoid fraction (MPFF) 1000?mg with MPFF 500?mg tablets, administered at the same daily dose in patients suffering non-complicated acute hemorrhoids.

Background: MPFF is an established treatment for hemorrhoidal disease.

Methods: This was a double-blind, multi-center, randomized study. Patients took either MPFF 1000?mg or 500?mg tablets for 7 days (daily dose; 3?g over 4 days followed by 2?g over 3 days). Adverse events were recorded in a patient diary. On day 7, anal pain and bleeding were assessed (visual analog scale [VAS] and Dimitroulopoulos scale, respectively).

Results: Patients (162) were randomized to MPFF 1000?mg (79) and MPFF 500?mg (83). No serious adverse events (AEs) occurred; 10 emergent AEs were considered treatment-related (6 for MPFF 1000?mg and 4 for 500?mg). Both regimens were associated with significant reduction in anal pain (VAS); ?2.37?cm MPFF 1000?mg (P?<?0.001) and ?2.17?cm 500?mg (P?<?0.001), with a slight trend in favor of MPFF 1000?mg (mean global reduction ?2.27?cm, P?<?0.001). Bleeding improved significantly in both groups of patients, 56% of patients on MPFF 1000?mg versus 61% on MPFF 500?mg. Bleeding ceased after treatment in 47% patients on MPFF 1000?mg versus 54% on 500?mg.

Conclusion: After 7 days of treatment with MPFF at the same daily dose, both regimens reduced anal pain and bleeding. MPFF 1000?mg had a comparable safety profile to MPFF 500?mg, with the advantage of fewer tablets.

Key limitations: Safety study.     

Cladribine tablets for the treatment of relapsing–remitting multiple sclerosis

Introduction: Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system leading to progressive neurodegeneration and disability. Until 2010, all approved disease-modifying drugs for MS required parenteral administration, which is associated with suboptimal adherence. It was anticipated that new approaches to treatment, including oral agents such as cladribine tablets, may improve adherence. In 2011, the development of cladribine tablets was stopped following negative feedback from the EMA and FDA.

Areas covered: This article provides an overview of the chemistry, mechanism of action and pharmacological properties of cladribine tablets therapy, and highlights the rationale for its development as an oral treatment for MS. Key efficacy and safety data from the pivotal Phase III CLARITY study are presented, providing context for the opinion received from the regulatory agencies.

Expert opinion: Despite the promising efficacy data observed in the cladribine tablets clinical trial program, regulatory agencies identified a potential risk of increased malignancies, and raised concerns about the implications of sustained lymphocyte depletion. Following the feedback received from the regulatory agencies, Merck Serono made the decision to withdraw the agent from the regulatory approval process. The experience gained will benefit other research efforts to address the outstanding unmet treatment needs of patients with relapsing MS.     

Paracetamol orodispersible tablets: a risk for severe poisoning in children?

Purpose  

Childhood paracetamol (acetaminophen) ingestion with subsequent risk of hepatotoxicity is a major medical problem. The aim of this study was to investigate the risk of high-dose ingestion of orodispersible, fast-disintegrating paracetamol tablets in children.     

Formation and identification of a degradant in chlorproguanil-dapsone-artesunate (Dacart™) tablets

Chlorproguanil hydrochloride, dapsone and artesunate are three compounds with anti-malarial properties developed as a triple combination drug product (Dacart™) for the treatment of malarial infections. During long-term stability studies, a degradant was observed which increased with time and had the potential to limit the shelf-life of the product. Through a combination of HPLC and spectroscopic analyses, the structure of the degradant was identified to be an adduct of a fragment of artesunate with dapsone. The response factor was determined to allow an accurate assessment of its levels in drug product. The likely mechanism for its formation is postulated to be via the water-mediated degradation of artesunate to give succinic acid followed by reaction of the liberated succinic acid with dapsone. The formation of this degradant demonstrates a potential stability risk for future combination therapies incorporating artesunate. These risks are particularly pertinent to products of this type given the climatic conditions which prevail in countries where such therapies are likely to be employed.     

Does the preferred orientation of crystallites in tablets affect the intrinsic dissolution?

The aim of this study was to examine the effect of preferred orientation of crystallites, i.e. texture, on the intrinsic dissolution rate of some active pharmaceutical ingredients. Although it has often been speculated that the intrinsic dissolution of pharmaceutical tablets is affected by texture, no experimental evidence of this effect has been reported. The texture of acetylsalicylic acid, tolbutamide, carbamazepine and entacapone tablets was measured using three different methods both before and after the dissolution measurements. To clarify the effect of texture, texturizing and less-texturizing batches of each material were used. The texturizing batches had big needle or plate-like particles and the less-texturizing batches were prepared by grinding the texturizing powders. The USP rotation disc method was used to measure the intrinsic dissolution rate of the samples. The results indicated that the acetylsalicylic acid, tolbutamide and entacapone tablets texturized strongly in compression and the grinding of the texturizing powders decreased the degree of texture. Also the carbamazepine tablets were slightly texturized. All of the texture measurement methods used were found to give acceptable and consistent results and therefore a special texture goniometer is not required to perform these measurements. The intrinsic dissolution rate of all the tablets compacted from the ground powder was slightly higher than the intrinsic dissolution rate of the more texturized samples. However, these differences were not significant on a large scale. After the dissolution tests the degree of texture of the samples was decreased. The intrinsic dissolution rates of the samples were presumably affected by several different parameters such as texture, solubility, pH, surface energetics and crystal strains. Although only small differences were found between the intrinsic dissolution rates of texturized and less texturized samples the effect of texture on the dissolution behavior of the pharmaceuticals should be considered when performing accurate intrinsic dissolution studies.     

Influence of ethanol on swelling and release behaviors of Carbopol®-based tablets

The aim of this work was to investigate the effect of ethanol on the in vitro swelling and release behaviors of Carbopol^®-based tablets. The swelling behavior of drug-free compacts and the release of model drugs (metformin HCl, caffeine and theophylline) from matrix tablets were evaluated in acidic and buffered media with 0, 20 and 40% (v/v) ethanol. Release data were analyzed by fitting to Higuchi and Peppas models and calculation of similarity factor (f₂). ANOVA tests were performed to determine significant factors on swelling and release. It was found that ethanol affects swelling and erosion of drug-free Carbopol^® compacts, and the effect was highly dependent on medium pH. For matrix tablets, no dose dumping due to ethanol was manifested. The release rate and mechanism, however, were significantly affected by ethanol concentration as indicated by ANOVA applied to the constant, K_H, from Higuchi model and the exponent, n, from Peppas model, respectively. The effect of ethanol on release was further confirmed by similarity factor results, which indicated that ethanol led to different release profiles (f₂ < 50) in seven of eight cases for matrices containing metformin HCl and in three of eight cases for matrices containing caffeine and theophylline.     

Assessment of absolute oral bioavailability of linezolid tablets in Chinese healthy male volunteers

AIM： Linezolid is a member of oxazolidinones, which is a novel class of antibiotics. The study is to determine the absolute bioavailability of linezolid tablets in Chinese healthy male volunteers. METHODS： A randomized, open cross-over study was conducted in 22 healthy male volunteers, a single oral dose of 600 mg linezolid tablets or Ⅳ infusion of 600 mg linezolid were given to subjects, respectively. Blood sampies were obtained at different time points and sent to American AvTech laboratories. Plasma concentrations of linezolid were determined by high-performance liquid chromatography （HPLC）, pharmacokinetic parameters and absolute bioavailability were calculated. RESULTS： After oral and IV infusion administration of 600 mg linezolid, the elimination half-life （ t1/2 ） was （4.3 ± 1.0） h and （4.4±0.9） h, respectively. The area under plasma concentration-time curve （AUC0-∞ ） of linezolid were （87 ± 20） μg·mL^-1·h and （96 ± 21） μg·mL^-1·h, respectively. The absolute oral bioavailability was 93 % ± 23 % following single oral dose of 600 mg linezolid tablets. Analyses of two one-sided t tests and 90% confidence interval showed that linezolid tablet and Ⅳ formulation are equivalent with respect to AUC.[第一段]     

Determination of talinolol tablets plasma concentration in healthy volunteers by LC-MS/MS

AIM： To establish an LC-MS/MS method for determination of talinolol in human plasma. METHODS： Propranolol was added as internal standard before extraction. The analysis involved a Cosmosil C18 （2.0 mm × 150 mm, 5 μm） column and the column temperature was set at 40℃. The mobile phase included in acetonitrile： 10 mmol ammonium formate water solution （with 0.05% formic acid） （60： 40, v/v）,the flow rate was 0.2 mL/min. ESI ＋ was performed in the MRM mode using target ions at m/z 364- 308 （talinolol） and m/z 260 - 184 （propranolol）.[第一段]     

Particle agglomeration of chitosan–magnesium aluminum silicate nanocomposites for direct compression tablets

Exfoliated nanocomposites of chitosan-magnesium aluminum silicate (CS-MAS) particles are characterized by good compressibility but poor flowability. Thus, the aims of this study were to investigate agglomerates of CS-MAS nanocomposites prepared using the agglomerating agents water, ethanol, or polyvinylpyrrolidone (PVP) for flowability enhancement and to evaluate the agglomerates obtained as direct compression fillers for tablets. The results showed that the addition of agglomerating agents did not affect crystallinity, but slightly influenced thermal behavior of the CS-MAS nanocomposites. The agglomerates prepared using water were larger than those prepared using 95% ethanol because high swelling of the layer of chitosonium acetate occurred, allowing formation of solid bridges and capillary force between particles, leading to higher flowability and particle strength. Incorporation of PVP resulted in larger agglomerates with good flowability and high strength due to the binder hardening mechanism. The tablets prepared from agglomerates using water showed lower hardness, shorter disintegration times and faster drug release than those using 95% ethanol. In contrast, greater hardness and more prolonged drug release were obtained from the tablets prepared from agglomerates using PVP. Additionally, the agglomerates of CS-MAS nanocomposites showed good carrying capacity and provided desirable characteristics of direct compression tablets.     

Bioavailability of β-acetyldigoxin after single and repeated doses of tablets and solution

Summary In eight healthy volunteers the bioavailability of -acetyldigoxin solution and tablets was measured after single and multiple doses. Plasma and urine data were used to calculate bioavailability by four different methods. The differences obtained and the interindividual variations suggested that different and independent methods should be employed to assess absolute and true bioavailability. There was no significant difference between the regimens and both preparations had similar bioavailability; mean values (± SD) for the solution were 68.3 ± 8.7 % (single dose) and 68.6±5.9 % (multiple doses), and for the tablets 72.8±7.5 % and 66.1±6.0 %, respectively. For routine measurements, single dose studies with plasma and urine sampling for 24 hours and 48 hours, respectively, were an accurate and practicable procedure.     

Novel time and site specific “tablets in capsule” system for nocturnal asthma treatment

The objective of present work was to develop a “tablets in capsule” system for facilitating both immediate and pulsatile drug deliveries of theophylline to mimic the circadian rhythm of nocturnal asthma. The system comprised of capsule filled with two tablets, first pulse and second pulse tablet prepared by wet granulation method. First pulse tablet was not coated and was responsible for providing loading dose whereas; second pulse tablet was coated with Eudragit L100 and Eudragit S100 to release drug in colon after specific lag time. Two independent variables, amount of polymers and coating thickness, were optimized by 3² full factorial design. The optimum formulation consisted of Eudragit L100: Eudragit S100 in 1:1.5 ratio and coating thickness of 20 % (w/w). In vitro drug release of “tablets in capsule” system in three different media (pH 1.2, pH 6.8, and pH 7.4) revealed immediate and pulsatile release patterns.     

Simultaneous determination of melatonin–pyridoxine combination in tablets by zero-crossing derivative spectrophotometry and spectrofluorimetry

Two methods have been developed for the analysis of melatonin (M) and pyridoxine hydrochloride (PH) in combination. The first method depends on first- and second-derivative ultraviolet spectrophotometry, with the zero crossing technique of measurement. First-derivative amplitudes at 296 nm and second-derivative amplitudes at 294 and 322 nm are selected for the determination of M and PH, respectively. The second method is based on the native fluorescence of both M and PH, in methanol and 0.1 M hydrochloric acid, respectively, after a preliminary solvent extraction procedure. The relative standard deviation of both methods was less than 2.0%. The two methods have been successfully applied to the determination of both drugs in laboratory-prepared mixtures and in tablets