Effect of hydroxypropyl methylcellulose (HPMC) hard capsules on in vitro rumen fermentation kinetics of commonly used feeds in ruminant feeding.

BACKGROUND: Accurate dosing of feed additives is often required to evaluate their effects on rumen fermentation. This can be done using soluble but nonfermentable hydroxypropyl methylcellulose (HPMC) hard capsules. OBJECTIVES: The aim of the study was to evaluate the effect of HPMC hard capsules on the extent and rate of in vitro gas production in eleven feeds. METHODS: Six high-fibre feeds and five concentrates, were weighed into syringes either directly or into HPMC capsules and incubated anaerobically in 30 mL buffered rumen fluid at 39°C. Data obtained from gas production measurements were fitted using the Gompertz model to obtain kinetic parameters for gas production. RESULTS: HPMC hard capsules had no effect on the gas production of the blank sample and concentrate feeds. In contrast, high-fibre feeds weighed in HPMC showed a significant decrease (p < 0.05) in total gas production and gas produced within 24 h of incubation. CONCLUSIONS: The use of HPMC hard capsules was found to be inappropriate for determining gas production kinetics because fermentation subsides at a certain point when peak fermentation is reached (at TMFR), resulting in a decrease in both total potential gas production and gas production within 24 h of incubation. This is particularly evident when high-fibre feeds are incubated.

Effect and Mechanism of Pharmaceutical Excipients on Berberine to Alleviate Ulcerative Colitis via Regulating Gut Microbiota.

BACKGROUND: Various potential effect of drugs on alleviating diseases by regulating intestinal microbiome as well as the pharmaceutical excipients on gut microbiota has been revealed. However, the interaction between them is rarely investigated. METHODS: Histological analysis, immunohistochemistry analysis, enzyme-linked immunosorbent assay (ELISA) analysis, RT-qPCR, and 16S rRNA analysis were utilized to explore the effect mechanism of the five excipients including hydroxypropyl methylcellulose (HPMC) F4M, Eudragit (EU) S100, chitosan (CT), pectin (PT), and rheum officinale polysaccharide (DHP) on berberine (BBR) to cure UC. RESULTS: The combined BBR with PT and DHP group exhibited better therapeutic efficacy of UC with significantly increased colon length, and decreased hematoxylin-eosin (H&E) scores than other groups. Furthermore, the expression of tight junction ZO-1 and occludin in colon tissue were upregulated, and claudin-2 was downregulated. Ultimately, the serum content of tumor necrosis (TNF)-α, interleukin (IL)-1ß, and IL-6 was decreased. Moreover, the combined BBR with PT significantly promoted the restoration of gut microbiota. The relative abundance of Firmicutes and Lactobacillus was significantly increased by the supplement of PT and DHP, and the relative abundance of Proteobacteria was downregulated. CONCLUSIONS: Our study may provide a new perspective that the selection of pharmaceutical excipients could be a crucial factor affecting the drugs' therapeutic efficiency outcome.

Therapeutic Efficacy of Sesquiterpene Farnesol in Treatment of Cutibacterium acnes-Induced Dermal Disorders.

Acne vulgaris is a highly prevalent skin disorder requiring treatment and management by dermatologists. Antibiotics such as clindamycin are commonly used to treat acne vulgaris. However, from both medical and public health perspectives, the development of alternative remedies has become essential due to the increase in antibiotic resistance. Topical therapy is useful as a single or combined treatment for mild and moderate acne and is often employed as maintenance therapy. Thus, the current study investigated the anti-inflammatory, antibacterial, and restorative effects of sesquiterpene farnesol on acne vulgaris induced by Cutibacterium acnes (C. acnes) in vitro and in a rat model. The minimum inhibitory concentration (MIC) of farnesol against C. acnes was 0.14 mM, and the IC50 of 24 h exposure to farnesol in HaCaT keratinocytes was approximately 1.4 mM. Moreover, 0.8 mM farnesol exhibited the strongest effects in terms of the alleviation of inflammatory responses and abscesses and necrotic tissue repair in C.acnes-induced acne lesions; 0.4 mM farnesol and clindamycin gel also exerted similar actions after a two-time treatment. By contrast, nearly doubling the tissue repair scores, 0.4 mM farnesol displayed great anti-inflammatory and the strongest reparative actions after a four-time treatment, followed by 0.8 mM farnesol and a commercial gel. Approximately 2-10-fold decreases in interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, found by Western blot analysis, were predominantly consistent with the histopathological findings and tissue repair scores. The basal hydroxypropyl methylcellulose (HPMC) gel did not exert anti-inflammatory or reparative effects on rat acne lesions. Our results suggest that the topical application of a gel containing farnesol is a promising alternative remedy for acne vulgaris.

Desenvolvimento e caracterização de dispersões sólidas de efavirenz / Development and characterization of efavirenz solid dispersions

A baixa solubilidade aquosa dos insumos farmacêuticos ativos (IFA) é um grande desafio no desenvolvimento de formulações farmacêuticas, pois pode resultar em biodisponibilidade insuficiente e variável. Diversas estratégias de modificação do estado sólido dos compostos ativos, têm sido propostas para incrementar a solubilidade de fármacos pouco solúveis em água. Dentre as estratégias abordadas a ispersão sólida (DS) é uma das formas mais promissoras de aumentar a solubilidade, dissolução e a biodisponibilidade de IFAs com baixa solubilidade aquosa. O efavirenz (EFV) é um inibidor não nucleosídeo da transcriptase reversa (NNRTI) e um dos componentes da terapia antirretroviral de alta atividade (HAART), sendo parte da primeira linha de tratamento de infecções do vírus HIV tipo 1. O antirretroviral está classificado como pertencente à classe II do SCB, e exibe baixa solubilidade aquosa (solubilidade menor que 10 µg/mL) e alta permeabilidade com absorção dependente da taxa de dissolução, resultando em biodisponibilidade oral baixa e variável. A administração de fármacos pouco solúveis na forma de DS é um método atraente para aumentar a biodisponibilidade in vivo. Neste estudo, um método de triagem rápida por evaporação de solvente foi empregado para preparar DS de EFV, variando-se proporções em misturas compostas pelos carreadores, polivinilpirrolidona K-28/32 (PVP K-28/32), copovidona (CoPVP), hidroxipropilmetilcelulose ftalato (HPMCP-50, HPMCP-55 e HPMCP-55s), poloxâmero 188 (P188) e poloxâmero 407 (P407). A solubilidade das DS foi avaliada por meio do método do equilíbrio (shake-flask), onde selecionou-se os polímeros P188 e P407 que conduziram a uma elevada capacidade de saturação em meio aquoso, superior a 1.000 vezes ao fármaco puro. As propriedades físico-químicas e do estado sólido das amostras foram avaliadas por meio de calorimetria exploratória diferencial (DSC); termogravimetria (TG); espectroscopia do infravermelho com transformada de Fourier (FTIR), difratometria de raios X pelo método do pó (DRXP) e ensaios de dissolução com emprego do aparato IV USP. Os resultados de DRXP demonstraram que os carreadores P188 e P407 foram capazes de estabilizar o EFV na forma amorfa nas DS, fato esse evidenciado pela ausência de picos característicos do antirretroviral

he low aqueous solubility of the active pharmaceutical ingredient (API) is a major challenge in the development of pharmaceutical formulations as it may result in insufficient and variable bioavailability. Several strategies for modifying the solid-state of the active compounds have been proposed to increase solubility of drugs that are poorly soluble in water. Among the strategies approaches, solid dispersion (SD) is one of the most promising ways to increase solubility, dissolution and bioavailability of APIs with low aqueous solubility. Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and one of the components of highly active antiretroviral therapy (HAART), being part of the first line of treatment of type 1 HIV virus infections. The antiretroviral is classified as belonging to BCS class II, and exhibits low aqueous solubility (solubility less than 10 µg / mL) and high permeability with dissolution ratedependent absorption, resulting in low and variable oral bioavailability. Drug delivery of poorly aqueous soluble drugs in form SD is an appealing method to increase in vivo bioavailability. In this study, a fast screening method of solvent evaporation method was used to prepare EFV SD, varying the proportions in mixtures composed by the carriers polyvinylpyrrolidone K-28/32 (PVP K-28/32), copovidone (CoPVP), hydroxypropylmethylcellulose phthalate (HPMCP-50, HPMCP-55 e HPMCP-55s), poloxamer 188 (P188) e poloxamer 407 (P407). The solubility of the samples was evaluated by the method of equilibrium (shake-flask), wherein the polymers P188 and P407 were selected due to the capacity to promote high saturation in aqueous medium, 1,000 times superior to the pure drug. The physicochemical and solid-state properties of the samples were evaluated by differential scanning calorimetry (DSC); thermogravimetry (TG); Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRPD) and dissolution assays using the IV USP apparatus. The results of XRPD demonstrated that the carriers P188 and P407 were able to stabilize the EFV in amorphous form in the SD, a fact evidenced by the absence of characteristic peaks of the antiretroviral

Evaluation of the Physico-mechanical Properties and Electrostatic Charging Behavior of Different Capsule Types for Inhalation Under Distinct Environmental Conditions.

Capsule-based dry powder inhaler (DPI) products can be influenced by a multitude of interacting factors, including electrostatic charging. Tribo-charging is a process of charge transfer impacted by various factors, i.e., material surface characteristics, mechanical properties, processing parameters and environmental conditions. Consequently, this work aimed to assess how the charging behavior of capsules intended for inhalation might be influenced by environmental conditions. Capsules having different chemical compositions (gelatin and hydroxypropyl methylcellulose (HPMC)) and distinct inherent characteristics from manufacturing (thermally and cold-gelled) were exposed to various environmental conditions (11%, 22% and 51% RH). Their resulting properties were characterized and tribo-charging behavior was measured against stainless steel and PVC. It was observed that all capsule materials tended to charge to a higher extent when in contact with PVC. The tribo-charging of the thermally gelled HPMC capsules (Vcaps® Plus) was more similar to the gelatin capsules (Quali-G™-I) than to their HPMC cold-gelled counterparts (Quali-V®-I). The sorption of water by the capsules at different relative humidities notably impacted their properties and tribo-charging behavior. Different interactions between the tested materials and water molecules were identified and are proposed to be the driver of distinct charging behaviors. Finally, we showed that depending on the capsule types, distinct environmental conditions are necessary to mitigate charging and assure optimal behavior of the capsules.

Structure-Based Gastro-Retentive and Controlled-Release Drug Delivery with Novel 3D Printing.

In the present contribution, the aim is to explore and establish a way in which 3D printing and gastro-retentive drug delivery systems (GRDDSs) are combined (focusing on inner structure innovation) to achieve extended and stable gastro-retention and controlled-release of drug. Three digital models diverse in construction were designed and substantialized by a pressure-assisted microsyringe (PAM) 3D printer. Preparations were characterized by means of DSC, XRD, FTIR, and SEM. In vitro buoyancy study and in vivo gamma scintigraphy method were conducted to validate gastro-retention property of these innovative preparations in vitro/in vivo respectively. Release kinetic model was established and release mechanism was discussed. Tablets manufactured under certain range of parameters (intersecting angle, full filling gap) were tight and accurate in shape. Tablets printed with specific parameters (full filling gap, 50%; nozzle extrusion speed, 0.006 mm/s; layer height, 0.4 mm; compensation value, 0.25; quantity of layers, 15; outline printing value, 2) exhibited satisfactory in vitro (10-12 h)/in vivo (8-10 h) retention ability and possessed stable 10-12 h controlled-release quality. In general, 3D printing has tremendous advantage over conventional fabrication technique in intricate drug delivery systems and will be widely employed in pharmacy.

Optimal Selection of Incoming Materials from the Inventory for Achieving the Target Drug Release Profile of High Drug Load Sustained-Release Matrix Tablet.

In the pharmaceutical process, raw material (including APIs and excipients) variability can be delivered to the final product, and lead to batch-to-batch and lot-to-lot variances in its quality, finally impacting the efficacy of the drug. In this paper, the Panax notoginseng saponins (PNS) sustained-release matrix tablet was taken as the model formulation. Hydroxypropyl methylcellulose with the viscosity of 4000 mPa·s (HPMCK4M) from different vendors and batches were collected and their physical properties were characterized by the SeDeM methodology. The in-vitro dissolution profiles of active pharmaceutical ingredients (APIs) from matrix tablets made up of different batches HPMC K4M displayed significant variations. Multi-block partial least squares (MB-PLS) modeling results further demonstrated that physical properties of excipients played dominant roles in the drug release. In order to achieve the target drug release profile with respect to those far from the criteria, the optimal selection method of incoming materials from the available was established and validated. This study provided novel insights into the control of the input variability of the process and amplified the application of the SeDeM expert system, emphasizing the importance of the physical information of the raw materials in the drug manufacturing process.

Sustained Release of Poorly Water-Soluble Drug from Hydrophilic Polymeric Film Sandwiched Between Hydrophobic Layers.

This proof-of-concept study explores the feasibility of using a drug-loaded hydrophilic polymeric layer sandwiched between two hydrophobic layers for improving film drug load while achieving sustained release of poorly water-soluble drug. Such films having total thickness in range ~ 146-250 µm were prepared by slurry-based casting using hydrophilic hydroxypropyl methylcellulose (HPMC) as matrix layer containing fenofibrate (FNB) as the model drug, encased between two very thin rate-limiting layers of 10 µm each of hydrophobic poly-ɛ-caprolactone (PCL). Film precursor slurry consisted of HPMC with plasticizer and water along with micronized FNB powders, which were dry-coated with hydrophilic silica. Characterization techniques demonstrated the presence of homogeneously dispersed crystalline FNB in films. The films are very thin and hence two-dimensional; hence, average drug load per unit area in range ~ 5 to ~ 9 mg/cm2 could be achieved by altering the thickness of the drug matrix layer. Drug amount and drug content uniformity were measured through assay of ten circular samples ~ 0.712 cm2 in area punched out using a circular-shaped punch tool. Drug release rate was investigated using USP IV flow-through cell and surface dissolution imaging system. Thinner films followed Fickian diffusion, and thicker films followed non-Fickian anomalous diffusion. Overall, the application of middle layer thickness could be used as a tool to manipulate drug load without the need for altering its formulation or precursor preparation by changing its thickness, hence achieving relatively high drug loading yet having sustained release of drug.

Formulation, Characterization, and Optimization of Captopril Fast-Dissolving Oral Films.

This work aimed to using optimization study to formulate a patient-friendly captopril fast-dissolving oral film with satisfactory disintegration time. Films were made with pullulan and hydroxypropyl methyl cellulose (HPMC) by using the solvent-casting method. Cellulose nanofiber (CNF) was used as a compatibilizer and glycerine was used as a plasticizer. In order to find an optimum formulation, a response surface methodology and a central composite design were employed. The concentration percentages of pullulan and glycerine were considered to be the design factors. Disintegration time, tensile strength, percent elongation at break, and folding endurance were considered to be the responses. The results showed that CNF improved the compatibility and tensile strength of the pullulan and HPMC blend. Also, the rigid nature of CNF reduced the film elongation but the addition of glycerine improved its flexibility. All formulations showed an acceptable uniformity content and dissolution rate. Complete dissolution for all formulations occurred within 2 min. Films with 26% pullulan, 74% HPMC, 1% CNF, and 5% glycerine were reported to be optimum formulations for captopril fast-dissolving oral films, with 95% confidence levels. The in vivo comparison of optimized formulation with a conventional captopril sublingual tablet exhibited significant increase in AUC (~ 62%) and Cmax (~ 52%) and a major decrease in Tmax (~ 33%). The overall results showed that the captopril FDF is a promising candidate for enhanced in vivo orotransmucosal absorption.

Impact of Physicochemical Properties of Cellulosic Polymers on Supersaturation Maintenance in Aqueous Drug Solutions.

The precipitation inhibitory effect of cellulosic polymers in relation to their physicochemical properties was studied. Using a poorly water-soluble model drug, griseofulvin, the precipitation inhibitory effect of a series of hydroxypropyl methylcellulose (HPMC) and methylcellulose polymers was studied using solvent-shift method. The extent of supersaturation maintenance of each polymer was then quantified by the parameter, supersaturation factor (SF). Partial least square (PLS) regression analysis was employed to understand the relative contribution from viscosity, hydroxypropyl content (HC), methoxyl content, methoxyl/hydroxypropyl ratio, and drug-polymer interaction parameter (χ) on SF. All grades of cellulosic polymers effectively prolonged supersaturation of griseofulvin. PLS regression analysis revealed that HC and χ appeared to have the strongest influence on SF response. A regression model of SF = 1.65-0.16 χ + 0.05 HC with a high correlation coefficient, r of 0.921, was obtained. Since the value of χ is inversely related to the strength of drug-polymer interaction, the result shows that SF increases with increasing drug-polymer interaction and increasing HC. As such, it can be implied that strong drug-polymer interaction and presence of hydroxypropyl groups in cellulosic polymers for hydrogen bonding are two key parameters for effective supersaturation maintenance. This knowledge on the relative contribution of polymer physicochemical properties on precipitation inhibition will allow the selection of suitable cellulosic polymers for systematic development of supersaturating drug delivery systems.

Formulation and Characterization of Fast-Dissolving Sublingual Film of Iloperidone Using Box-Behnken Design for Enhancement of Oral Bioavailability.

Iloperidone is a second-generation antipsychotic drug which is used for the treatment of schizophrenia and has very low aqueous solubility and bioavailability. This drug also undergoes first-pass metabolism. The aim of this work is to formulate fast-dissolving sublingual films of iloperidone to improve its bioavailability. Sublingual films were prepared by solvent casting method. Hydroxypropyl methyl cellulose E5, propylene glycol 400, and transcutol HP were optimized using Box-Behnken three-level statistical design on the basis of disintegration time and folding endurance of films. Iloperidone:hydroxypropyl-ß-cyclodextrin kneaded complex was used in films instead of plain drug due to its low solubility. Optimized film was further evaluated for drug content, pH, dissolution studies, ex vivo permeation studies, and pharmacokinetic studies in rats. The optimized film disintegrated within 30 s. The in vitro dissolution of the film showed 80.3 ± 3.4% drug dissolved within first 5 min. In ex vivo permeation studies using sublingual tissue, flux achieved within first 15 min by film was around 117.1 ± 0.35 (mcg/cm2/h) which was ten times more than that of plain drug. This formulation showed excellent uniformity. AUC and Cmax of film were significantly higher (p < 0.001) as compared to plain drug and relative bioavailability of the films was 148% when compared to the plain drug. Thus, this study showed optimized fast-dissolving sublingual film to improve permeation and bioavailability of iloperidone. Fast-dissolving films will be customer-friendly approach for geadiatric schizophrenic patients.

Improving Solubility and Oral Bioavailability of Febuxostat by Polymer-Coated Nanomatrix.

Here, the mesoporous silica (Sylysia 350) was selected as mesoporous material, hydroxypropyl methylcellulose (HPMC) was selected as crystallization inhibitor, and febuxostat (FBT) was selected as model drug, respectively. The FBT-Sylysia-HPMC nanomatrix (FBT@SHN) was prepared. The characteristics of FBT@SHN were investigated in vitro and in vivo. Our results indicated that the FBT in FBT@SHN was in amorphous form. The solubility and dissolution of FBT in FBT@SHN were significantly increased. The oral bioavailability of FBT in FBT@SHN was greatly improved 5.8-fold compared with that in FBT suspension. This nanomatrix could be used as a drug delivery platform for improving the oral bioavailability.

Comparative interfacial in vitro digestion of protein and polysaccharide oil/water films.

The behaviour of proteins (ß-lactoglobulin (ßlg) and soy protein isolate (SPI)) and a surface active polysaccharide (hydroxypropylmethylcellulose, HPMC) o/w interfacial films under simulated gastrointestinal conditions using the interfacial tensiometer Octopus were compared and related to the performance of the emulsions (using the same emulsifiers) under in vitro digestion. The evolution of interfacial tension (γ) was used to investigate the effect of gastrointestinal fluids on o/w interfacial films. Clear differences were observed among these emulsifiers. During the gastric phase, HPMC showed the lowest change in γ values as compared to protein films. The most important changes occurred during the intestinal stage where it was observed an important decrease of γ associated with the rapid penetration of BS, followed by a lower rate of decrease attributable to the accumulation of FFA at the interface. In the last stage, the subphase was exchanged by buffer alone, to remove the reversibly adsorbed digestion products. SPI formed the most resistant interface to the remotion of digestion products, followed by HPMC and finally by ßlg. The results agree with the degree of lipolysis reported for the emulsions stabilized by these emulsifiers, which suggest that lipid digestion could be modulated by the ability of emulsifiers to prevent the BS activity (to adsorb at the O/W interface or remove the inhibitory digestion products from the interface). Thus, emulsifiers-BS interactions appears as a key factor in controlling the lipolysis.

Pyrene conjugation and spectroscopic analysis of hydroxypropyl methylcellulose compounds successfully demonstrated a local dielectric difference associated with in vivo anti-prion activity.

Our previous study on prion-infected rodents revealed that hydroxypropyl methylcellulose compounds (HPMCs) with different molecular weights but similar composition and degree of substitution have different levels of long-lasting anti-prion activity. In this study, we searched these HPMCs for a parameter specifically associated with in vivo anti-prion activity by analyzing in vitro chemical properties and in vivo tissue distributions. Infrared spectroscopic and thermal analyses revealed no differences among HPMCs, whereas pyrene conjugation and spectroscopic analysis revealed that the fluorescence intensity ratio of peak III/peak I correlated with anti-prion activity. This correlation was more clearly demonstrated in the anti-prion activity of the 1-year pre-infection treatment than that of the immediate post-infection treatment. In addition, the intensity ratio of peak III/peak I negatively correlated with the macrophage uptake level of HPMCs in our previous study. However, the in vivo distribution pattern was apparently not associated with anti-prion activity and was different in the representative tissues. These findings suggest that pyrene conjugation and spectroscopic analysis are powerful methods to successfully demonstrate local dielectric differences in HPMCs and provide a feasible parameter denoting the long-lasting anti-prion activity of HPMCs in vivo.

In Vitro and In Vivo Modeling of Hydroxypropyl Methylcellulose (HPMC) Matrix Tablet Erosion Under Fasting and Postprandial Status.

PURPOSE: To develop a model linking in vitro and in vivo erosion of extended release tablets under fasting and postprandial status. METHODS: A nonlinear mixed-effects model was developed from the in vitro erosion profiles of four hydroxypropyl methylcellulose (HPMC) matrix tablets studied under a range of experimental conditions. The model was used to predict in vivo erosion of the HPMC matrix tablets in different locations of the gastrointestinal tract, determined by magnetic marker monitoring. In each gastrointestinal segment the pH was set to physiological values and mechanical stress was estimated in USP2 apparatus rotation speed equivalent. RESULTS: Erosion was best described by a Michaelis-Menten type model. The maximal HPMC release rate (VMAX) was affected by pH, mechanical stress, HPMC and calcium hydrogen phosphate content. The amount of HPMC left at which the release rate is half of VMAX depended on pH and calcium hydrogen phosphate. Mechanical stress was estimated for stomach (39.5 rpm), proximal (93.3 rpm) and distal (31.1 rpm) small intestine and colon (9.99 rpm). CONCLUSIONS: The in silico model accurately predicted the erosion profiles of HPMC matrix tablets under fasting and postprandial status and can be used to facilitate future development of extended release tablets.

Prolonged-release minitablets with carbamazepine - preliminary observations in vitro.

OBJECTIVE: The aim was to develop prolonged-release minitablets (MT) with carbamazepine (CBZ). METHODS: Matrix-type 3-mm MT (5 mg CBZ) were prepared by direct compression using hydrophilic (hypromellose) or hydrophobic polymers (ethylcellulose, Kollidon SR, glyceryl behenate). Coated prolonged-release MT (2.5 mm/3 mg of CBZ) were produced using ethylcellulose or Eudragit RL/RS. The release tests were performed in a basket apparatus with water or 1% sodium lauryl sulphate solution as dissolution media. KEY FINDINGS: High-viscosity hypromellose used as a matrix polymer resulted in slow release of CBZ (80% released during 12 h). Dissolution was slower from hydrophobic matrices. Non-swelling MT cores were successfully coated with Eudragit RL/RS, which resulted in the prolonged release of CBZ (80%/14 h), depending on the film thickness and Eudragit composition. Careful choice of pore formers in the coating film allowed to reduce lag time. Ethylcellulose was unsuitable as coating polymer due to low permeability to CBZ and unsatisfying mechanical resistance of the films modified with hypromellose. CONCLUSION: Prolonged release of CBZ was obtained from both matrix-type and coated MT. Further development of MT as a single unit or multicompartment prolonged-release new dosage form especially suitable for children has been justified.

Synergetic Role of Hypromellose and Methacrylic Acid Copolymer in the Dissolution Improvement of Amorphous Solid Dispersions.

Synergetic role of polymer blending on dissolution of amorphous solid dispersion was investigated. Dissolution rates of hypromellose (HPMC) and methacrylic acid copolymer (EUD) from the HPMC/EUD spray-dried sample (SPD) were improved compared to those of each single polymer SPD. Differential scanning calorimetry measurements revealed that the structural change in HPMC following heating was inhibited by co-spray-drying with EUD, suggesting an intermolecular interaction between the polymers. 13C solid-state nuclear magnetic resonance (NMR) spectroscopy detected the change induced in the hydroxyl group of HPMC by co-spray-drying with EUD. Moreover, the carbonyl peak shape of EUD in the 13C NMR spectra differed between EUD SPD and HPMC/EUD SPD, indicating that the dimer structure of the carboxylic acid of EUD was partially disrupted by the interaction with HPMC. An intermolecular interaction occurred between HPMC and EUD. The hydrogen bond reformation likely improved the dissolution rates of the polymers. The ternary griseofulvin (GRF)/HPMC/EUD SPD showed a significantly higher supersaturation level of GRF than the mixtures containing equal amounts of binary GRF/HPMC and GRF/EUD SPDs. The change of interaction mode between polymers improved the dissolution of solid dispersion. Therefore, polymer blending based on interpolymer interactions could be a practical strategy for designing excellent solid dispersion formulations.

Formulation, functional evaluation and ex vivo performance of thermoresponsive soluble gels - A platform for therapeutic delivery to mucosal sinus tissue.

Mucoadhesive in situ gelling systems (soluble gels) have received considerable attention recently as effective stimuli-transforming vectors for a range of drug delivery applications. Considering this fact, the present work involves systematic formulation development, optimization, functional evaluation and ex vivo performance of thermosensitive soluble gels containing dexamethasone 21-phosphate disodium salt (DXN) as the model therapeutic. A series of in situ gel-forming systems comprising the thermoreversible polymer poloxamer-407 (P407), along with hydroxypropyl methyl cellulose (HPMC) and chitosan were first formulated. The optimized soluble gels were evaluated for their potential to promote greater retention at the mucosal surface, for improved therapeutic efficacy, compared to existing solution/suspension-based steroid formulations used clinically. Optimized soluble gels demonstrated a desirable gelation temperature with Newtonian fluid behaviour observed under storage conditions (4-8°C), and pseudoplastic fluid behaviour recorded at nasal cavity/sinus temperature (≈34°C). The in vitro characterization of formulations including rheological evaluation, textural analysis and mucoadhesion studies of the gel form were investigated. Considerable improvement in mechanical properties and mucoadhesion was observed with incorporation of HPMC and chitosan into the gelling systems. The lead poloxamer-based soluble gels, PGHC4 and PGHC7, which were carried through to ex vivo permeation studies displayed extended drug release profiles in conditions mimicking the human nasal cavity, which indicates their suitability for treating a range of conditions affecting the nasal cavity/sinuses.

Molecular Dynamics Simulation of Amorphous Hydroxypropylmethylcellulose and Its Mixtures With Felodipine and Water.

Understanding drug-polymer molecular interactions, their miscibility, supersaturation potential, and the effects of water uptake may be invaluable for selecting amorphous polymer dispersions that can maximize the oral bioavailability of poorly water-soluble drugs. Molecular dynamics simulations were performed using a model for hydroxypropylmethylcellulose (HPMC) resembling the substitution patterns found experimentally. HPMC at low and high water contents (0.9%-23.0% wt/wt) and mixtures with a hydrophobic drug, felodipine (FEL), were constructed. Tg values and densities after ∼30 ns aging at 298 K were close to published results. Except for hydrogen bonds (HBs) between the 5-O- and a 3-OH group in a neighboring repeat unit, HPMC oxygen atoms have a low HB probability (p < 0.1) perhaps due to shielding by surrounding substituents. Water molecules tend to be isolated at low water content while clusters were prevalent at ≥10.7% water. The Flory-Huggins FEL-HPMC interaction parameter (-0.20 ± 0.07) predicts complete miscibility at all HPMC compositions, in agreement with experiments. However, HBs between the FEL-N-H and HPMC favoring miscibility are disrupted with increasing water. Apparent diffusion coefficients versus water content were generated for water and FEL and a theory for the non-Einsteinian nature of water diffusion is proposed.