Development and characterization of a mucoadhesive sublingual formulation for pain control: extemporaneous oxycodone films in personalized therapy

Objective: The aim of this work was the development of mucoadhesive sublingual films, prepared using a casting method, for the administration of oxycodone.

Materials and methods: A solvent casting method was employed to prepare the mucoadhesive films. A calibrated pipette was used to deposit single aliquots of different polymeric solutions on a polystyrene plate lid. Among the various tested polymers, hydroxypropylcellulose at low and medium molecular weight (HPC) and pectin at two different degrees of esterification (PC) were chosen for preparing solutions with good casting properties, capable of producing films suitable for mucosal application.

Results and discussion: The obtained films showed excellent drug content uniformity and stability and rapid drug release, which, at 8?min, ranged from 60% to 80%. All films presented satisfactory mucoadhesive and mechanical properties, also confirmed by a test on healthy volunteers, who did not experience irritation or mucosa damages. Pectin films based on pectin at lower degrees of esterification have been further evaluated to study the influence of two different amounts of drug on the physicochemical properties of the formulation. A slight reduction in elasticity has been observed in films containing a higher drug dose; nevertheless, the formulation maintained satisfactory flexibility and resistance to elongation.

Conclusions: HPC and PC sublingual films, obtained by a simple casting method, could be proposed to realize personalized hospital pharmacy preparations on a small scale.     

Development of a Soluplus budesonide freeze-dried powder for nasal drug delivery

Objective: The aim of this work was to develop an amorphous solid dispersions/solutions (ASD) of a poorly soluble drug, budesonide (BUD) with a novel polymer Soluplus^® (BASF, Germany) using a freeze-drying technique, in order to improve dissolution and absorption through the nasal route.

Significance: The small volume of fluid present in the nasal cavity limits the absorption of a poorly soluble drug. Budesonide is a corticosteroid, practically insoluble and normally administered as a suspension-based nasal spray.

Methods: The formulation was prepared through freeze-drying of polymer-drug solution. The formulation was assessed for its physicochemical (specific surface area, calorimetric analysis and X-ray powder diffraction), release properties and aerodynamic properties as well as transport in vitro using RPMI 2650 nasal cells, in order to elucidate the efficacy of the Soluplus–BUD formulation.

Results: The freeze-dried Soluplus–BUD formulation (LYO) showed a porous structure with a specific surface area of 1.4334?±?0.0178 m²/g. The calorimetric analysis confirmed an interaction between BUD and Soluplus and X-ray powder diffraction the amorphous status of the drug. The freeze-dried formulation (LYO) showed faster release compared to both water-based suspension and dry powder commercial products. Furthermore, a LYO formulation, bulked with calcium carbonate (LYO-Ca), showed suitable aerodynamic characteristics for nasal drug delivery. The permeation across RPMI 2650 nasal cell model was higher compared to a commercial water-based BUD suspension.

Conclusions: Soluplus has been shown to be a promising polymer for the formulation of BUD amorphous solid suspension/solution. This opens up opportunities to develop new formulations of poorly soluble drug for nasal delivery.     

Preparation of an optimized ciprofloxacin-loaded chitosan nanomicelle with enhanced antibacterial activity

Objective: The objective of this study was to evaluate the effect of lipid structure on physicochemical properties of chitosan-fatty acid nanomicelles and prepare an optimum ciprofloxacin-loaded formulation from these conjugates which could enhance the antibacterial effects of drug against some important pathogens like P. aeruginosa.

Significance: Nowadays, resistance in infectious diseases is a growing worldwide concern. Nanocarriers can increase the therapeutic index and consequently reduce the antibiotic resistance. By site-specific delivery of drug, the adverse effects of broad-spectrum antibiotics such as ciprofloxacin would be reduced.

Methods: Fatty acid grafted chitosan conjugates were synthetized in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. The effects of fatty acid type (stearic acid, palmitic acid, and linoleic acid) on physicochemical properties of conjugates were investigated. Ciprofloxacin was encapsulated in nanomicelles by thin film hydration method. Also, the preparation process was optimized with a central composite design. The antibacterial effect of optimum formulation against P. aeruginosa, K. pneumoniae, and S. pneumoniae species was determined.

Results: All conjugates were synthetized with high yield values and the substitution degrees ranged between 2.13 and 35.46%. Ciprofloxacin was successfully encapsulated in nanomicelles. The optimum formulation showed high drug loading (≈?19%), with particle size of about 260?nm and a sustained release profile of ciprofloxacin. The minimum inhibitory concentrations of ciprofloxacin in optimum formulation against P. aeruginosa and K. pneumoniae species were 4 and 2 times lower in comparison with the free drug, respectively.

Conclusions: The antibacterial effect of ciprofloxacin was improved by encapsulation of drug in chitosan nanomicelles.     

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.     

A Diffusion Model for Studying the Drug Release from Semisolid Dosage Forms I. Methodology Using Agar Gel as Diffusion Medium

Abstract

Several ointment bases containing three sulfonamides widely different in their physicochemical properties were evaluated for their drug release properties using agar gel as the drug acceptor phase. The drug release/diffusion model was created by making an empty cylindrical core in the center of agar gel plate which was filled with ointment containing the drugs. The results showed that a linear correlation existed when the amount of drug released from each ointment was plotted against the logarithmic time. The solubility of drugs in the base and partition properties into the agar medium played the major role for the release of drugs. The effect of temperature on the diffusion into the acceptor phase was also recorded.     

Nanocrystal-based drug delivery system of risperidone: lyophilization and characterization

Objective: In the present work nanocrystal-based formulation of risperidone (RIS) was proposed to overcome solubility issue of RIS, while lyophilization technique was used effectively, for conversion of RIS nanosuspension to solid state.

Significance: RIS nanosuspension was developed and stabilized with a combination of polycaprolactone and Pluronic^® F-68 as stabilizers. With focus on critical parameters like nature of cryoprotectants and effect of eutectic temperature on properties of nanosuspension, the suitability of lyophilization technique in improving the physical stability of prepared nanosuspension was also evaluated. Additionally, the developed nanocrystals were also assessed for their solid states properties.

Methods: Various process parameters affecting average particle size and polydispersity index (PDI), viz. drug to surfactant ratio, solvent to anti-solvent ratio, stirring speed, type of stabilizer were optimized. Assessment of lyophilization as a suitable solidification technique (for conversion to powder form) was done with selective cryoprotectants (trehalose dihydrate and sorbitol).

Results: The formulation was found to be stable at 4?°C for 3 months with size, PDI and zeta potential of 214?±?3.4?nm, 0.120, and –10.2?±?0.90?mV, respectively. Release profile of developed nanosuspension showed cumulative % release of ～90% in initial 10?h whereas the value for the unprocessed drug was ～11% in same time frame.

Conclusions: These findings suggest that developed formulation was able to enhance water solubility of the drug effectively and can be potentially used in the management of psychotic disorders.     

Enhanced solubility of piperine using hydrophilic carrier-based potent solid dispersion systems

Context: Piperine alkaloid, an important constituent of black pepper, exhibits numerous therapeutic properties, whereas its usage as a drug is limited due to its poor solubility in aqueous medium, which leads to poor bioavailability.

Objective: Herein, a new method has been developed to improve the solubility of this drug based on the development of solid dispersions with improved dissolution rate using hydrophilic carriers such as sorbitol (Sor), polyethylene glycol (PEG) and polyvinyl pyrrolidone K30 (PVP) by solvent method. Physical mixtures of piperine and carriers were also prepared for comparison.

Methods: The physicochemical properties of the prepared solid dispersions were examined using SEM, TEM, DSC, XRD and FT-IR. In vitro dissolution profile of the solid dispersions was recorded and compared with that of the pure piperine and physical mixtures. The effect of these carriers on the aqueous solubility of piperine has been investigated.

Results: The solid dispersions of piperine with Sor, PEG and PVP exhibited superior performance for the dissolution of piperine with a drug release of 70%, 76% and 89%, respectively after 2?h compared to physical mixtures and pure piperine, which could be due to its transformation from crystalline to amorphous form as well as the attachment of hydrophilic carriers to the surface of poorly water-soluble piperine.

Conclusion: Results suggest that the piperine solid dispersions prepared with improved in vitro release exhibit potential advantage in delivering poorly water-soluble piperine as an oral supplement.     

Optimization of piribedil mucoadhesive tablets for efficient therapy of Parkinson’s disease: physical characterization and ex vivo drug permeation through buccal mucosa

Objective: The aim of this study was optimization of buccal piribedil (PR) mucoadhesive tablets to improve its low bioavailability and provide controlled release for the treatment of Parkinson’s disease.

Methods: Buccal tablets were prepared by direct compression method using carbomer (CP), carboxymethyl cellulose (CMC), and hydroxypropyl methylcellulose (HPMC) as mucoadhesive polymers. Physical properties of powder mixtures and buccal tablets were evaluated. Physicochemical compatibility between ingredients was investigated with infrared spectroscopy and differential scanning calorimetry analysis. In vitro dissolution profiles and drug release kinetics of buccal tablets were investigated. Mucoadhesion and ex vivo permeation studies were performed using sheep buccal mucosa.

Results: Powder mixtures demonstrated sufficient flow properties and physical characteristics of all tablet formulations were within compendia limits. Tablet ingredients were absent of any chemical interactions. CP tablets displayed slower drug release compared to HPMC tablets with zero order release, while CMC tablets lost their integrity and released entire drug after 6?h following Higuchi model. All formulations displayed adequate mucoadhesion and steady state flux of PR through buccal mucosa were higher with HPMC compared to CP-containing tablets.

Conclusion: Overall, HPMC was found to combine desired controlled release and mucoadhesion characteristics with sufficient pharmaceutical quality for optimization of buccal tablets. Piribedil mucoadhesive buccal tablets designed for the first time may introduce a new alternative for the treatment of Parkinson’s disease.     

Mechanical properties and drug release of venlafaxine HCl solid mini matrices prepared by hot-melt extrusion and hot or ambient compression

Objective/significance: To elucidate the role of plasticizers in different mini matrices and correlate mechanical properties with drug release.

Methods: Cylindrical pellets were prepared by hot-melt extrusion (HME) and mini tablets by hot (HC) and ambient compression (AC). Venlafaxine HCl was the model drug, Eudragit^® RSPO the matrix former and citric acid or Lutrol^® F127 the plasticizers. The matrices were characterized for morphology, crystallinity, and mechanical properties. The influence of plasticizer’s type and content on the extrusion pressure (P_e) during HME and ejection during tableting was examined and the mechanical properties were correlated with drug release parameters.

Results: Resistance to extrusion and tablet ejection force were reduced by Lutrol^® F127 which also produced softer and weaker pellets with faster release, but harder and stronger HC tablets with slower release. HME pellets showed greater tensile strength (T) and 100 times slower release than tablets. P_e correlated with T and resistance to deformation of the corresponding pellets (r²?=?0.963 and 0.945). For both HME and HC matrices the decrease of drug release with T followed a single straight line (r²?=?0.990) and for HME the diffusion coefficient (D_e) and retreat rate constant (k_b) decreased linearly with T (r²?=?0.934 and 0.972).

Conclusions: Lutrol^® F127 and citric acid are efficient plasticizers and Lutrol^® F127 is a thermal binder/lubricant in HC compression. The different bonding mechanisms of the matrices were reflected in the mechanical strength and drug release. Relationships established between T and drug release parameters for HME and HC matrices may be useful during formulation work.     

Appropriate selection of an aggregation inhibitor of fine particles used for inhalation prepared by emulsion solvent diffusion

Abstract

Context: Dry powder inhaler (DPI) formulations have been developed to deliver large amounts of drugs to the lungs.

Objective: Fine particles of a poorly water-soluble drug, the model drug ONO-2921, were prepared by the emulsion solvent diffusion (ESD) method for use in a DPI.

Methods: The effects of additives on the fine particle formation of ONO-2921 were estimated when droplets of an ethanolic drug solution were dispersed into aqueous media containing various additives. Subsequently, the suspensions were freeze-dried to create powdered samples to estimate the inhalation properties using a twin impinger and an Andersen cascade impactor.

Results: This simple ESD method produced submicron-sized ONO-2921 particles (approximately 600?nm) in combination with suitable additives. In addition, the freeze-dried powder produced using additives exhibited superior in vitro inhalation properties. Among these methods, the freeze-dried powder produced with 0.50% weight/volume one type of polyvinyl alcohol (PVA-205) displayed the most efficient features in the fine particle fraction (FPF). These results could be explained by the stabilization of the ONO-2921 suspension by PVA-205, indicating that PVA-205 acts as an aggregation inhibitor of fine particles.

Conclusions: The ESD method, in combination with appropriate types and amounts of additives, may be useful for preparing a DPI suitable for delivering drugs directly to the lungs without the assistance of carrier particles.     

Feasibility of electrospray deposition for rapid screening of the cocrystal formation and single step,continuous production of pharmaceutical nanococrystals

Objectives: This study employed electrospray deposition (ESD) for simultaneous synthesis and particle engineering of cocrystals.

Significance: Exploring new methods for the efficient production of cocrystals with desired particle properties is an essential demand.

Methods: The possibility of cocrystal formation by ESD was examined for indomethacin-saccharin, indomethacin-nicotinamide, naproxen-nicotinamide, and naproxen-iso-nicotinamide cocrystals. Solutions of the drug and coformer at stoichiometric ratios were sprayed to a high electric field which caused rapid evaporation of the solvent and the formation of fine particles. The phase purity, size, and morphology of products were compared with reference cocrystals. Experiments were performed to evaluate the effects of stoichiometric ratio, concentration and solvent type on the cocrystal formation. Physical stability and dissolution properties of the electrosprayed cocrystals were also compared with reference cocrystals.

Results: ESD was found to be an efficient and rapid method to produce cocrystals for all studied systems other than indomethacin-nicotinamide. Pure cocrystals only formed at a specific drug:coformer ratio. The solvent type has a weak effect on the cocrystal formation and morphology. Electrosprayed cocrystals exhibited nano to micrometer sizes with distinct morphologies with comparable physical stability with reference cocrystals. Nanococrystals of indomethacin-saccharin with a mean size of 219?nm displayed a threefold higher dissolution rate than solvent evaporated cocrystal.

Conclusion: ESD successfully was utilized to produce pure cocrystals of poorly soluble drugs with different morphologies and sizes ranging from nano to micrometer sizes in one step. This study highlighted the usefulness of ESD for simultaneous preparation and particle engineering of pharmaceutical cocrystals.     

Design and evaluation of dental films of PEGylated rosin derivatives containing sparfloxacin for periodontitis

Objective: In this study, PEGylated rosin derivatives (PRDs) namely D1 and D2 were synthesized and evaluated for their application to produce sustained-release antibacterial films containing sparfloxacin for periodontitis.

Significance: PRDs are biodegradable and biocompatible, and therefore sustained-release dental implant of PRD-sparfloxacin can provide an effectual treatment for periodontitis.

Methods: Films were produced by solvent casting technique and characterized for morphology, swelling-index, in vitro degradation and drug release kinetics. The impact of type of PRD, concentration of PRDs, and addition of plasticizer (dibutyl phthalate) on various film properties was evaluated. The films were also subjected to stability study at 30?°C and 40?°C for 90?days.

Results: Both D1 and D2 produced smooth and non-porous films with sparfloxacin. The D1 films, due to lower amount of polyethylene glycol 400 in D1, exhibited lower swelling-index, slower degradation, and slower drug release compared to D2 films. An increase in PRDs concentration decreased swelling-index, prolonged degradation time, and decreased drug release rate of films; addition of plasticizer showed the similar effect. At pH 7.6, D1 and D2 films showed complete degradation at the end of 58 and 51?days, respectively. At the end of 21?days, D1 and D2 films released 41.85% and 61.53% sparfloxacin, respectively. The drug release from D1 films followed Higuchi square-root kinetics, while D2 films released drug by the zero order kinetics. The stability conditions did not significantly alter PRDs-film properties.

Conclusion: Results revealed that PRDs can be used successfully to produce sustained-release antibacterial films containing sparfloxacin for the treatment of periodontitis.     

Application of a Compaction Simulator to the Design of a High-Dose Tablet Formulation. Part I

Abstract

The compaction properties of an investigational drug are studied by the use of a compaction simulator. The effects of punch velocity over the range of 30-640 mm^?1 on the compaction properties of the pure drug and a variety of formulas incorporating a high dose of the active compound have been investigated. The data were analyzed by applying the Heckel equation. The pure drug was found to have a high yield pressure at a relatively low punch velocity of 31 mm^?1. As the punch velocity was increased there was a decrease in crushing strength, primarily as a result of increasing yield pressure. These findings indicate that the pure drug predominantly consolidated by fragmentation and elastic deformation, with a slow plastically deforming component. The information obtained on the consolidation mechanism of the pure drug and, subsequently, on model formulas were instrumental in the design and selection of a robust formula and granulation process. The advantages of conducting dosage form design and characterization studies during the early phase of tablet formulation using means such as a compaction simulator are emphasized in this investigation.     

Thermosensitive bioadhesive gels for the vaginal delivery of sildenafil citrate: in vitro characterization and clinical evaluation in women using clomiphene citrate for induction of ovulation

Objective: The objective of this study is to develop and characterize in situ thermosensitive gels for the vaginal administration of sildenafil as a potential treatment of endometrial thinning occurring as a result of using clomiphene citrate for ovulation induction in women with type II eugonadotrophic anovulation. While sildenafil has shown promising results in the treatment of infertility in women, the lack of vaginal pharmaceutical preparation and the side effects associated with oral sildenafil limit its clinical effectiveness.

Methods: Sildenafil citrate in situ forming gels were prepared using different grades of Pluronic^® (PF-68 and PF-127). Mucoadhesive polymers as sodium alginate and hydroxyethyl cellulose were added to the gels in different concentrations and the effect on gel properties was studied. The formulations were evaluated in terms of viscosity, gelation temperature (T_sol-gel), mucoadhesion properties, and in vitro drug release characteristics. Selected formulations were evaluated in women with clomiphene citrate failure due to thin endometrium (Clinicaltrial.gov identifier NCT02766725).

Results: The T_sol-gel decreased with increasing PF-127 concentration and it was modulated by addition of PF-68 to be within the acceptable range of 28–37?°C. Increasing Pluronic® concentration increased gel viscosity and mucoadhesive force but decreased drug release rate. Clinical results showed that the in situ sildenafil vaginal gel significantly increased endometrial thickness and uterine blood flow with no reported side effects. Further, these results were achieved at lower frequency and duration of drug administration.

Conclusion: Sildenafil thermosensitive vaginal gels might result in improved potential of pregnancy in anovulatory patients with clomiphene citrate failure due to thin endometrium.     

Development,optimization and evaluation of curcumin loaded biodegradable crosslinked gelatin film for the effective treatment of periodontitis

Objective: Aim of the present study was to prepare curcumin (CUR) loaded biodegradable crosslinked gelatin (GE) film to alleviate the existing shortcomings in the treatment of periodontitis.

Significance: Gelatin film was optimized to provide anticipated mucoadhesive strength, mechanical properties, folding endurance, and prolonged drug release over treatment duration, for successful application in the periodontitis.

Methods: The film was developed by using solvent casting technique and “Design of Experiments” approach was employed for evaluating the influence of independent variables on dependent response variables. Solid-state characterization of the film was performed by FTIR, XRD, and SEM. Further, prepared formulations were evaluated for drug content uniformity, surface pH, folding endurance, swelling index, mechanical strength, mucoadhesive strength, in vitro biodegradation, and in vitro drug release behavior.

Results: Solid state characterization of the formulation showed that CUR is physico-chemically compatible with other excipients and CUR was entrapped in an amorphous form inside the smooth and uniform film. The optimized film showed degree of crosslinking 51.04?±?2.4, swelling index 138.10?±?1.25, and folding endurance 270?±?3 with surface pH around 7.0. Crosslinker concentrations positively affected swelling index and biodegradation of film due to altered matrix density of the polymer. Results of in vitro drug release demonstrated the capability of the developed film for efficiently delivering CUR in a sustained manner up to 7?days.

Conclusions: The developed optimized film could be considered as a promising delivery strategy to administer medicament locally into the periodontal pockets for the safe and efficient management of periodontitis.     

Relationship Between film Properties and Drug Release from Acrylic Films

Abstract

An in vitro technique was used to determine the release rates of drugs from different acrylic copolymers as carrier systems. The drugs used in this investigation were pilocarpine, streptomycine, isosorbide salts and nitroglycerol. By applying the Higuchi equations the diffusion coefficients of the drugs were calculated. A tensile stress test was used to examine certain mechanical properties of the films.

It was found that the incorporation of drugs into acrylic films by different techniques allowed the facile preparation of various compositions with diffusion coefficients in a relativly large range (10^-8…10^-15cm² s^-1). The choice of the physicochemical state of the drug and the film composition can significantly affect drug release. The strain of the films depended on the tensile stress, the water and additives content.

It was examined that the drug release depended on the mechanical properties of the films. In general the drug release was faster from the lower viscosity grades and higher humidity contents of the films. This can be done by modifying the chemical structure of the used polymer system or by making use additives with alcoholic groups.     

Physical Aspects of Wet Granulation IV – Effect of Kneadign time on Dissolution Rates and Tablet Properties

Abstract

The phsical properties of sucrose-lactoes-strach granulations containing a water soluble drug are characterized, and the relationship between granulaion kneading time and each of the these properties is examined. In addition, the effect of granulation kneading time on the properties of tablets prepared from the granules is examined.     

Effect of Micronization of Norfloxacin on Tablet Properties

Abstract

The particle size of norfloxacin was reduced through the use of an air attrition mill. Not unexpectedly, this treatment also increased the surface area of the drug. Granulations were then prepared from nonmicronized as well as micronized drug. Tablets were compressed from each of these granulations and their physicochemical properties determined. Tablets containing micronized drug showed faster in-vitro dissolution rates and an improvement in bioavailability when tested in Rhesus monkeys.     

Natural polysaccharides platforms for oral controlled release of ketoprofen lysine salt

Context: Ketoprofen lysinate (KL) is one of the most widely used non-steroidal anti-inflammatory drugs in the symptomatic treatment of some chronic inflammatory diseases. Compared to ketoprofen, KL shows better pharmacokinetics and tolerability. However, due to its short half-life of 1–2?h, a multiple dose regimen is required for oral administration. Thus, the present work deals with its encapsulation in a hydrogel-based system by prilling in order to prolong its activity.

Objective: In this paper, we propose alginate and pectin as carriers and release tailoring agent for the development of hydrogel-based beads for KL retarded and sustained release.

Materials and methods: Beads were produced by a Nisco Encapsulator® using alginate or pectin. Operative variables were optimized to produce beads with desired morphology and size. Solid state properties were analyzed by SEM and DSC. Drug release performance was studied by Pharmacopeia pH-change assay to simulate gastrointestinal environment.

Results and discussion: Prilling technique was successfully used to encapsulate high soluble drugs as KL in polysaccharides-based hydrogels. Pectin proved to be a proper polymer able to encapsulate ketoprofen lysine salt. Formulation (F8) showed good morphological properties and size, high drug content (15.6%) and encapsulation efficiency (93.5%) and promising drug release profiles. Hosting F8 in an acid-resistant capsule (DR^®caps) a delivery platform has been developed to control KL release in a delayed (90?min lag time) and prolonged way (270?min complete release).

Conclusion: The platform may be proposed as potentially useful in the oral administration of NSAIDs in chronic inflammatory diseases affected by circadian rhythm.     

Mucoadhesive tablets for the vaginal delivery of progesterone: in vitro evaluation and pharmacokinetics/pharmacodynamics in female rabbits

Objective: To develop mucoadhesive tablets for the vaginal delivery of progesterone (P4) to overcome its low oral bioavailability resulting from drug hydrophobicity and extensive hepatic metabolism.

Methods: The tablets were prepared using mixtures of P4/Pluronic^® F-127 solid dispersion and different mucoadhesive polymers. The tablets physical properties, swelling index, mucoadhesion and drug release kinetics were evaluated. P4 pharmacokinetic and pharmacodynamic properties were evaluated in female rabbits and compared with vaginal micronized P4 tablets and intramuscular (IM) P4 injection, respectively.

Results: The tablets had satisfactory physical properties and their swelling, in vitro mucoadhesion force and ex vivo mucoadhesion time were dependent on tablet composition. Highest swelling index and mucoadhesion time were detected for tablets containing 20% chitosan-10% alginate mixture. Most tablets exhibited burst release (～25%) during the first 2?h but sustained the drug release for ～48?h. In vivo study showed that chitosan-alginate mucoadhesive tablets had ～2-fold higher P4 mean residence time (MRT) in the blood and 5-fold higher bioavailability compared with oral P4. Further, same tablets showed 2-fold higher myometrium thickness in rabbit uterus compared with IM P4 injection.

Conclusion: These results confirm the potential of these mucoadhesive vaginal tablets to enhance P4 efficacy and avoid the side effects associated with IM injection.