Oral Lyophilisates Research Articles

Formulation and characterization of piroxicam/cyclodextrin taste masked oral lyophilisates

Formulation and characterization of piroxicam/cyclodextrin taste masked oral lyophilisates

Comparative Evaluation of Metformin and Metronidazole Release from Oral Lyophilisates with Different Methods

The aim of this study is to compare three different dissolution methods to assess the drug release from oral lyophilisates, based on interpolyelectrolyte complexes (IPECs). IPECs were prepared by mixing solutions of a linear polymer, Eudragit® EPO, with a polymer with a cross-linked structure, Noveon® AA-1 or Carbopol® 10 Ultrez (in ratios of 1:2 and 1:1, respectively). Metformin or metronidazole were used as model drugs to achieve a systemic or local effect. A comparative assessment of the drug release kinetics was carried out using artificial saliva and three different set-ups: a paddle stirrer (USP apparatus 2), a flow cell (USP apparatus 4) and a Franz diffusion cell. The results demonstrated that oral lyophilisates disintegrated within 1 min. In the case of metformin, the drug release was completed in about 90 min independently of the set-up. The static conditions in the Franz diffusion cell and USP apparatus 2 permitted the aggregation of the IPEC; therefore, the release profiles show a significant difference compared to the USP apparatus 4.

POSC202 Estimated Migraine Patient Population in England Progressing Beyond First-Line Acute Management

In England, NICE clinical guidelines on acute management of migraine recommend first-line use of an oral triptan, followed by a non-oral triptan if first-line treatment is ineffective or not tolerated.[1] NHS formularies further suggest trial of tablet formulations before orodispersible tablets and oral lyophilisates.[2-3] New acute therapies with novel mechanisms of action may offer relief for patients who progress beyond first-line triptan tablets.[4] This study aimed to assess the size of this patient population, using recent triptan prescription data for England.

Desmopressin 25 and 50 μg oral lyophilisates (Noqdirna®; Nocdurna®) in nocturia due to nocturnal polyuria in adults: a profile of its use

Desmopressin 25 and 50 μg oral lyophilisates (hereafter Noqdirna®/Nocdurna®) are a new rapid-dispersing formulation of desmopressin that is indicated for the symptomatic treatment of nocturia due to nocturnal polyuria in adults of all ages. Noqdirna®/Nocdurna® is administered by placing the lyophilisate under the tongue until it dissolves, and provides greater absorption and bioavailability, as well as a more predictable pharmacokinetic profile, than standard oral desmopressin tablets, allowing lower desmopressin dosages to be used to achieve the same clinical outcomes. As responses to desmopressin differ by gender, dosages of Noqdirna®/Nocdurna® are also gender specific (25 μg in women and 50 μg in men). These dosages effectively reduced the number of nocturnal voids and increased the time to first nocturnal void in patients with nocturia, leading to improvements in sleep and nocturia-related quality of life. The use of desmopressin is associated with a risk of hyponatraemia; however, the risk is lower when lower dosages, such as 25 and 50 μg, are used. To further reduce the risk of hyponatraemia, gender-specific dosages of Noqdirna®/Nocdurna® should be used and serum sodium levels monitored appropriately before and during treatment.

Mucoadhesive Interpolyelectrolyte Complexes for the Buccal Delivery of Clobetasol.

This work aimed to investigate the feasibility to design: (a) a mucoadhesive interpolyelectrolyte complex (IPEC) loaded with clobetasol propionate (CP) intended to treat oral lichen planus and (b) individuate an orodispersible dosage form suitable for its administration. IPECs were synthesized by mixing Eudragit® E PO (EPO) and different grades of cross-linked polyacrylate derivatives, in different molar ratios, namely 1:1, 1:2, and 2:1. All IPECs resulted at nanoscale independently of their composition (120–200 nm). Both zeta-potentials (ζ) and mucoadhesive performances were influenced by the ratio between polymers. On the bases of the preliminary data, IPECs made of Polycarbophil and EPO in the 1:2 ratio were loaded with CP. The encapsulation efficiency was up 88% independently of the CP-IPEC ratio. The drug encapsulation caused IPEC destabilization in water, as it was noticed by the increase of ζ values and the formation of aggregates. Oral lyophilisates were prepared by freeze-drying slurries made of placebo or CP loaded IPECs, maltodextrin with a dextrose equivalent 38 and Span®80. The optimized formulation permitted to obtain a fast disintegration upon contact with water reducing the tendency of IPECs to aggregate. Moreover, oral lyophilisates allowed improving the apparent solubility of CP throughout the in vitro release experiment.

The pharmaceutical applications of a biopolymer isolated from Trigonella foenum-graecum seeds: Focus on the freeze-dried matrix forming capacity

The aim of the present study was to evaluate the funtion of fenugreek seed mucilage (FSM) as potential matrix forming agent for orodispersible pharmaceutical lyophilisates. The FSM was isolated and characterized. FSM colloidal dispersions were prepared and the rheological evaluation was performed. Oral lyophilisates (OLs) with different FSM concentrations, containing meloxicam as model drug were prepared by freeze drying method. The OLs were characterized and compared to gelatin containing tablets, prepared under the same conditions.The FSM dispersions revealed shear thinning flow type. Based on colloidal dispersions' rheological properties, five FSM concentrations were taken forward to the lyophilization step. Completely dry and elegant tablets were obtained. Texture analysis indicated highly porous structures, confirmed by SEM analysis, which explain the fast disintegration properties. All the prepared tablets disintegrated in less than 47 s. The disintegration process was prolonged by the increase in FSM content, due to the high viscosity the polymer creates in aqueous media. FSM tablets presented longer disintegration times, as compared to gelatin tablets, but also higher crushing strength. Considering the fast disintegration and the high crushing strength, FSM is a good candidate as matrix forming agent for fast disintegrating dosage forms or other freeze-dried preparations.

QbD for pediatric oral lyophilisates development: risk assessment followed by screening and optimization

Objective: This study proposed the development of oral lyophilisates with respect to pediatric medicine development guidelines, by applying risk management strategies and DoE as an integrated QbD approach.Methods: Product critical quality attributes were overviewed by generating Ishikawa diagrams for risk assessment purposes, considering process, formulation and methodology related parameters. Failure Mode Effect Analysis was applied to highlight critical formulation and process parameters with an increased probability of occurrence and with a high impact on the product performance. To investigate the effect of qualitative and quantitative formulation variables D-optimal designs were used for screening and optimization purposes.Results: Process parameters related to suspension preparation and lyophilization were classified as significant factors, and were controlled by implementing risk mitigation strategies. Both quantitative and qualitative formulation variables introduced in the experimental design influenced the product’s disintegration time, mechanical resistance and dissolution properties selected as CQAs. The optimum formulation selected through Design Space presented ultra-fast disintegration time (5 seconds), a good dissolution rate (above 90%) combined with a high mechanical resistance (above 600 g load).Conclusions: Combining FMEA and DoE allowed the science based development of a product with respect to the defined quality target profile by providing better insights on the relevant parameters throughout development process. The utility of risk management tools in pharmaceutical development was demonstrated.

Taste-masking assessment of orally disintegrating tablets and lyophilisates with cetirizine dihydrochloride microparticles

Orally disintegrating tablets and oral lyophilisates are novel attractive dosage forms that disintegrate or dissolve in the buccal cavity within seconds without necessity of drinking. The major limitation in designing of these dosage forms is unpleasant taste of the drug substance. Cetirizine dihydrochloride is a H1-antihistamine substance indicated for the treatment of allergy. It is characterized by extremely bitter taste, therefore in order to deliver cetirizine dihydrochloride using orodispersible formulations, effective taste-masking is required. The aim of this study was to investigate whether microparticles containing cetirizine dihydrochloride could be successfully used to formulate orally disintegrating tablets by direct compression method and oral lyophilisates by freeze-drying process. Taste masking of cetirizine dihydrochloride was achieved by the spray-drying technique using Eudragit® E PO as the drug agent carrier. Based on the preliminary studies, optimal compositions of microparticles, tablets and lyophilisates were chosen. Obtained dosage forms were characterized for drug content, disintegration time and mechanical properties. In order to determine whether the microparticles subjected to direct compression and freeze-drying process effectively mask the bitter taste of cetirizine dihydrochloride, the in vivo and in vitro evaluation was performed. The results showed that designed formulates with microparticles containing cetirizine dihydrochloride were characterized by appropriate mechanical properties, uniformity of weight and thickness, short disintegration time, and the uniform content of the drug substance. Taste-masking assessment performed by three independent methods (e-tongue evaluation, human test panel and the in vitro drug release) revealed that microparticles with Eudragit® E PO are effective taste – masking carriers of cetirizine dihydrochloride and might be used to formulate orally disintegrating tablets and oral lyophilisates.

Development of oral lyophilisates containing meloxicam nanocrystals using QbD approach

The aim of this study was to develop oral lyophilisates with improved meloxicam (MEL) dissolution, optimizing each step of the preparation by design of experiments. First, meloxicam nanosuspensions were prepared by high-pressure homogenization (HPH), using PVP, Poloxamer or PEG as stabilizers and were subjected to freeze-drying using mannitol as cryoprotectant. The effects of the stabilizers and cryoprotectant were assessed and an optimal formulation was generated within the Design Space where the particle sizes and the PDIs are at their lowest values. The optimal formulation was used at the preparation of oral lyophilisates. Sodium alginate (SA) and croscarmellose sodium (CCS) were tested as matrix forming agents and three different freezing regimes were applied. The formulation was optimized, choosing the polymer that yielded both high mechanical strength and fast MEL dissolution. Poloxamer led to particle size reduction down to 10.27% of the initial size, meaning 477.6±7.5nm, with a slight increase during freeze-drying process. PEG showed lower nanonizing capacity during HPH, but freeze-drying produced further diminution of the particle size. Since Poloxamer provided advanced size reduction while preserving MEL crystallinity, it was used for the optimized formulation containing 1% Poloxamer and 5% mannitol added before freeze-drying. SA showed good structural properties when compared to CCS and allowed fast MEL dissolution at low ratios. The optimal formulation contained 1.157% of SA was subjected to thermal treatment during freeze-drying. It disintegrated in 3.33s and released 77.14% of the MEL after 2min. The quality by design (QbD) approach for the development of pharmaceutical products ensured high quality of the dosage form and good understanding of the preparation process.

The influence of excipients on physical and pharmaceutical properties of oral lyophilisates containing a pregabalin-acetaminophen combination

ABSTRACTObjectives: The purpose of the study was to investigate and characterize the oral lyophilisates containing the pregabalin-acetaminophen drug combination and as xcipients mannitol with microcrystalline cellulose or hydroxypropyl methylcellulose, in order to conclude upon drug-excipient interactions and their stability implications, impact of excipients on drug release and on the physicochemical and mechanical properties of the pharmaceutical formulations.Methods: The oral tablets were made by using a Christ freeze-dryer alpha 2–4-LSC lyophilizer, and evaluated for stability, drug-excipient compatibility and homogeneity of the prepared pharmaceutical formulations. The formulations were evaluated for in vivo absorption in rabbits by histopathological exams.Results: FTIR and thermogravimetric analyses, DLS technique, SEM and NIR-CI studies confirmed the compatibility between compounds. From the determined physical and biochemical parameters of the formulations it was established that they are stable, homogeneous, and meet the conditions for orally disintegrating tablets.Conclusion: In the case of the investigated pharmaceutical formulations the study evidenced the assembling through physical bonds between the excipients and the ‘codrug’ complex, which do not affect the release of the bioactive compounds.

In-vitro and in-vivo evaluation of taste-masked cetirizine hydrochloride formulated in oral lyophilisates

The use of solid oral dosage forms is typically favored with regard to stability and ease of administration. The aim of this study was to investigate whether cyclodextrins (CD) or ion exchange resins (IER) could be used to taste-mask cetirizine HCl when formulated in a freeze-dried oral formulation. The oral lyophilisates were produced using the Zydis(®) technology that offer the opportunity to produce the dosage form directly in the aluminum laminate blister packs. This study confirmed that a pre-formed resinate of cetirizine HCl and various cyclodextrins can be successfully incorporated into the Zydis(®) oral lyophilisate. A chemically stable product with acceptable release profile was obtained in the case of cyclodextrin. This study has also demonstrated that the Insent(®) taste sensing system is a useful technique for predicting the taste-masking potential of Zydis(®) formulations. The electronic taste sensing system (e-tongue) data can be used to provide guidance on the selection of taste-masked formulations. Principal component analysis (PCA) of sensor data by plotting the PCA scores revealed the effects of used taste-masking techniques on the e-tongue sensors, indicating the successful taste improvement. The PCA plot of the taste sensor data revealed larger distances between the non-taste-masked sample and the CD- and IER-loaded samples, and the shift toward the drug-free formulations and excipient signals indicates a modification of the product taste. The human taste trial confirms the acceptability of the selected promising formulations. The taste evaluation results showed that an effectively taste-masked formulation has been achieved using β-cyclodextrin and cherry/sucralose flavor system with over 80% of volunteers finding the tablet to be acceptable.

Influence of Prosolv and Prosolv:Mannitol 200 direct compression fillers on the physicomechanical properties of atorvastatin oral dispersible tablets

The objective of the present study was to evaluate the influence of Prosolv® and Prosolv®: Mannitol 200 direct compression (DC) fillers on the physicomechanical characteristics of oral dispersible tablets (ODTs) of crystalline atorvastatin calcium. ODTs were formulated by DC and were analyzed for weight uniformity, hardness, friability, drug content, disintegration and dissolution. Three disintegration time (DT) test methods; European Pharmacopoeia (EP) method for conventional tablets (Method 1), a modification of this method (Method 2) and the EP method for oral lyophilisates (Method 3) were compared as part of this study. All ODTs showed low weight variation of <2.5%. Prosolv® only ODTs showed the highest tablet hardness of ∼73 N, hardness decreased with increasing mannitol content. Friability of all formulations was <1% although friability of Prosolv®:Mannitol ODTs was higher than for pure Prosolv®. DT of all ODTs was <30 s. Method 2 showed the fastest DT. Method 3 was non-discriminatory giving a DT of 13–15 s for all formulations. Atorvastatin dissolution from all ODTs was >60% within 5 min despite the drug being crystalline. Prosolv® and Prosolv®:Mannitol-based ODTs are suitable for ODT formulations by DC to give ODTs with high mechanical strength, rapid disintegration and dissolution.

Pharmacokinetics of tepoxalin and its active metabolite in broiler chickens

Tepoxalin, [5(4-chlorophenyl)-N-hydroxy-(4-methoxyphenyl)N-methyl-1H-pyrazole-3-propanamide], is an orally active dual cyclooxygenase ⁄ lipoxygenase inhibitor, with a favourable gastrointestinal profile with respect to gastric mucosal injury (Wallace et al., 1991, 1993; Argentieri et al., 1994; Knight et al., 1996; Kirchner et al., 1997). Tepoxalin is indicated for the control of pain and inflammation associated with osteoarthritis in dogs. Besides its anti-inflammatory and analgesic properties, tepoxalin has been reported to inhibit T cell proliferation and to have cytokine modifying activity (Rainsford et al., 1993, 1996; Zhou et al., 1994; Kazmi et al., 1995; Ritchie et al., 1995; Willburger et al., 1998; Fiebich et al., 1999). After oral administration in humans and dogs, tepoxalin is rapidly converted to its active, carboxylic acid metabolite RWJ-20142, which inhibits cyclooxygenase but not lipoxygenase (Waldman et al., 1996; Homer et al., 2005). The objective of the present experiment was to study the pharmacokinetics of tepoxalin and its active metabolite in broiler chickens, in order to use it in future experiments as an anti-inflammatory and a potential cytokine inhibiting drug in an inflammation model in chickens developed in our laboratory (Baert et al., 2005a,b; De Boever et al., 2008). Experiments were carried out on six healthy broiler chickens (Ross, mean body weight 1.16 ± 0.108 kg), obtained from a local commercial poultry farm. The study was approved by the Ethics Committee of the Faculty of Veterinary Medicine (2004 ⁄077). The animals were housed according to the requirements of the EU (Anonymous, 2004). The study was designed as a two-way cross-over study using two groups (n = 6) of broilers. A drug free period of 1 week was allowed between the two treatments. Before oral administration, chickens were fasted for 14 h. Intravenous tepoxalin was prepared by dissolving the tepoxalin standard (Schering-Plough Co., Wicklow, Ireland) in sterile polyethylene glycol at a concentration of 60 mg ⁄mL. The drug was slowly injected at a dose of 30 mg ⁄kg via a 25 G needle in the wing vein. For the oral administration, tepoxalin lyophilisates tablets [Zubrin Oral Lyophilisates, 50 mg; Schering-Plough, Brussels, Belgium; Schering-Plough Animal Health (2003)] were weighed and the amount corresponding to 30 mg ⁄kg was given directly into the beak of the animal. Blood samples were collected from the leg vein (vena metatarsea plantaris) before (0) and at 15, 30, 45 min, 1, 1.5, 2, 2.5, 3, 4, 6, 7, 8 and 10 h after administration. Plasma was collected after centrifugation of the blood sample for 10 min at 2400 g and stored at )20 C until assayed. Plasma concentrations of tepoxalin and its active, acid metabolite were determined by a HPLC method with fluorescence detection. Briefly; 225 lL of plasma were pipetted into a 1.5 mL Eppendorf tube, followed by the addition of 25 lL of internal standard (RWJ-20294, Schering-Plough Co.) (25 or 250 lg ⁄mL) and 500 lL of acetonitrile. After vortexing briefly and centrifugation (10 000 g for 10 min at room temperature), 50 lL of the supernatant were injected in the HPLC system (TSP, Fremont, CA, USA) (kex = 290 nm and kem = 440 nm). A PLRP-S column (Polymer Laboratories, Shropshire, UK) attached to an appropriate guard column was used. The mobile phase (MF) A consisted of 0.01 M 1-octane-sulfonic acid in 0.01 M acetic acid in water, mobile phase B consisted of tetrahydrofuran. The retention time was 6.5, 8.8 and 12.6 min. for tepoxalin, its acid metabolite and the IS, respectively, using an isocratic elution at 58% MF A and 42% MF B at 0.7 mL ⁄min. The calibration curves for tepoxalin and acid metabolite were linear between 0.025 and 1 lg ⁄mL and 2.5 and 100 lg ⁄mL (r > 0.99). The precision fell between the ranges specified by EU at for different concentration levels and the accuracy fell within ranges of )20% to +10% at the same concentration levels (Anonymous, 2005). The LOQ was set at 25 ng ⁄mL for both compounds and the LOD was 5.9 ng ⁄mL and 6.8 ng ⁄mL for tepoxalin and its acid metabolite, respectively (Anonymous, 2005). The extraction recovery was 98% and 95% for tepoxalin and the acid metabolite, respectively. Stock solutions were stable for at least 3 months. The pharmacokinetic parameters of tepoxalin were calculated using a computer modelling program (WinNonlin Standard Edition Version 5.01; Pharsight Corporation, Mountain View, CA, USA). Akaike’s information criterion was used to determine J. vet. Pharmacol. Therap. 32, 97–100, doi: 10.1111/j.1365-2885.2008.01000.x. SHORT COMMUNICATION