Matrix Tablets: The Effect of Hydroxypropyl Methylcellulose/Anhydrous Dibasic Calcium Phosphate Ratio on the Release Rate of a Water-Soluble Drug Through the Gastrointestinal Tract I. In Vitro Tests

Different hydroxypropyl methylcellulose (HPMC)/anhydrous dibasic calcium phosphate (ADCP) matrix tablets have been developed aiming to evaluate the influence of both components ratio in the control release of a water-soluble drug (theophylline). In order to characterise the matrix tablets, swelling, buoyancy and dissolution studies have been carried out in different aqueous media (demineralised water, progressive pH medium, simulated gastric fluid, simulated intestinal fluid and simulated colonic fluid). The HPMC/ADCP ratio has turned out to be the determinant in the matrix behaviour: the HPMC characteristic swelling behaviour was modulated, in some cases, by the ADCP characteristic acidic dissolution. When the HPMC/ADCP ratio was ≥0.69, buoyancy, continuous swelling and low theophylline dissolution rate from the matrices (H1, H2 and H3) were observed in all dissolution media. Consequently, these formulations could be adequate as gastro-retentive drug delivery systems. Additionally, HPMC/ADCP ratio ≤0.11 (H5 and H6) induces a pH-dependent drug release which could be applied to design control drug release enteric formulations (with a suitable enteric coating). Finally, a HPMC/ADCP ratio between 0.11 and 0.69 (H4) yield a gastrointestinal controlled drug release, due to its time-dependent buoyancy (7 h) and a total drug delivery in 17 h in simulated colonic fluid.Key words: anhydrous dibasic calcium phosphate, hydroxypropyl methylcellulose, matrix tablets, oral controlled release, theophylline     

Use of Polyvinyl Alcohol as a Solubility Enhancing Polymer for Poorly Water-Soluble Drug Delivery (Part 2)

The KinetiSol® Dispersing (KSD) technology has enabled the investigation into the use of polyvinyl alcohol (PVAL) as a concentration enhancing polymer for amorphous solid dispersions. Our previous study revealed that the 88% hydrolyzed grade of PVAL was optimal for itraconazole (ITZ) amorphous compositions with regard to solid-state properties, non-sink dissolution performance, and bioavailability enhancement. The current study investigates the influence of molecular weight for the 88% hydrolyzed grades of PVAL on the properties of KSD processed ITZ:PVAL amorphous dispersions. Specifically, molecular weights in the processable range of 4 to 18 mPa · s were evaluated and the 4-88 grade provided the highest AUC dissolution profile. Amorphous dispersions at 10, 20, 30, 40, and 50% ITZ drug loads in PVAL 4-88 were also compared by dissolution performance. Analytical tools of diffusion-ordered spectroscopy and Fourier transform infrared spectroscopy were employed to understand the interaction between drug and polymer. Finally, results from a 30-month stability test of a 30% drug loaded ITZ:PVAL 4-88 composition shows that stable amorphous dispersions can be achieved. Thus, this newly enabled polymer carrier can be considered a viable option for pharmaceutical formulation development for solubility enhancement.KEY WORDS: amorphous solid dispersion, itraconazole, polyvinyl alcohol, PVAL, solubility enhancement     

Development of Sustained Release Capsules Containing “Coated Matrix Granules of Metoprolol Tartrate”

The objective of this investigation was to prepare sustained release capsule containing coated matrix granules of metoprolol tartrate and to study its in vitro release and in vivo absorption. The design of dosage form was performed by choosing hydrophilic hydroxypropyl methyl cellulose (HPMC K100M) and hydrophobic ethyl cellulose (EC) polymers as matrix builders and Eudragit® RL/RS as coating polymers. Granules were prepared by composing drug with HPMC K100M, EC, dicalcium phosphate by wet granulation method with subsequent coating. Optimized formulation of metoprolol tartrate was formed by using 30% HPMC K100M, 20% EC, and ratio of Eudragit® RS/RL as 97.5:2.5 at 25% coating level. Capsules were filled with free flowing optimized granules of uniform drug content. This extended the release period upto 12 h in vitro study. Similarity factor and mean dissolution time were also reported to compare various dissolution profiles. The network formed by HPMC and EC had been coupled satisfactorily with the controlled resistance offered by Eudragit® RS. The release mechanism of capsules followed Korsemeyer–Peppas model that indicated significant contribution of erosion effect of hydrophilic polymer. Biopharmaceutical study of this optimized dosage form in rabbit model showed 10 h prolonged drug release in vivo. A close correlation (R² = 0.9434) was established between the in vitro release and the in vivo absorption of drug. The results suggested that wet granulation with subsequent coating by fluidized bed technique, is a suitable method to formulate sustained release capsules of metoprolol tartrate and it can perform therapeutically better than conventional immediate release dosage form.Key words: biopharmaceutical evaluation, coated granules, metoprolol tartrate, sustained release     

Investigation of Thermal and Viscoelastic Properties of Polymers Relevant to Hot Melt Extrusion,IV: Affinisol™ HPMC HME Polymers

Most cellulosic polymers cannot be used as carriers for preparing solid dispersion of drugs by hot melt extrusion (HME) due to their high melt viscosity and thermal degradation at high processing temperatures. Three HME-grade hydroxypropyl methylcelluloses, namely Affinisol™ HPMC HME 15 cP, Affinisol™ HPMC HME 100 cP, and Affinisol™ HPMC HME 4 M, have recently been introduced by The Dow Chemical Co. to enable the preparation of solid dispersion at lower and more acceptable processing temperatures. In the present investigation, physicochemical properties of the new polymers relevant to HME were determined and compared with that of Kollidon^® VA 64. Powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), thermogravimetric analysis (TGA), moisture sorption, rheology, and torque analysis by melt extrusion were applied. PXRD and mDSC showed that the Affinisol™ polymers were amorphous in nature. According to TGA, the onset of degradation for all polymers was >220°C. The Affinisol™ polymers exhibited less hygroscopicity than Kollidon^® VA 64 and another HPMC polymer, Methocel™ K100LV. The complex viscosity profiles of the Affinisol™ polymers as a function of temperature were similar. The viscosity of the Affinisol™ polymers was highly sensitive to the shear rate applied, and unlike Kollidon^® VA 64, the viscosity decreased drastically when the angular frequency was increased. Because of the very high shear rate encountered during melt extrusion, Affinisol™ polymers showed capability of being extruded at larger windows of processing temperatures as compared to that of Kollidon^® VA 64.KEY WORDS: Affinisol™ HPMC HME, hot melt extrusion, hydroxypropyl methylcellulose, solid dispersion, thermal analysis, viscosity     

Formulation and In Vitro Evaluation of Salbutamol Sulphate In Situ Gelling Nasal Inserts

The aim of this study was to formulate salbutamol sulfate (SS), a model drug, as mucoadhesive in situ gelling inserts having a high potential as nasal drug delivery system bypassing the first-pass metabolism. In situ gelling inserts, each containing 1.4% SS and 2% gel-forming polymer, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose sodium (CMC Na), sodium alginate (AL), and chitosan (CH) were prepared. The inserts were investigated for their different physicochemical properties. The weight of inserts was 16–27 mg, drug content was 3.9–4.2 mg, thickness ranged between 15 and 28 μm and surface pH was 5–7. Cumulative drug released from the inserts exhibited extended release for more than 10 h following the decreasing order: CH > AL > CMC Na > HPMC. The drug release from CMC Na and AL inserts followed zero-order kinetics while HPMC and CH inserts exhibited non-Fickian diffusion mechanism. The inserts exhibited different water uptake (7–23%) with the smallest values for CH. Differential scanning calorimetry study pointed out possible interaction of SS and oppositely charged anionic polymers (CMC Na and AL). The mucoadhesive in situ gelling inserts exhibited satisfactory mucoadhesive and extended drug release characteristics. The inserts could be used for nasal delivery of SS over about 12 h; bypassing the hepatic first-pass metabolism without potential irritation.KEY WORDS: in situ gelling inserts, mucoadhesion, nasal delivery, salbutamol sulfate     

Controlled Release Matrix Tablets of Olanzapine: Influence of Polymers on the <Emphasis Type="Italic">In Vitro</Emphasis> Release and Bioavailability

Controlled-release (CR) tablet formulation of olanzapine was developed using a binary mixture of Methocel® K100 LV-CR and Ethocel® standard 7FP premium by the dry granulation slugging method. Drug release kinetics of CR tablet formulations F1, F2, and F3, each one suitably compressed for 9-, 12-, and 15-kg hardness, were determined in a dissolution media of 0.1 N HCl (pH 1.5) and phosphate buffer (pH 6.8) using type II dissolution apparatus with paddles run at 50 rpm. Ethocel® was found to be distinctly controlling drug release, whereas the hardness of tablets and pH of the dissolution media did not significantly affect release kinetics. The CR test tablets containing 30% Methocel® and 60% Ethocel® (F3) with 12-kg hardness exhibited pH-independent zero-order release kinetics for 24 h. In vivo performance of the CR test tablet and conventional reference tablet were determined in rabbit serum using high-performance liquid chromatography coupled with electrochemical detector. Bioavailability parameters including C_max, T_max, and AUC_0–48 h of both tablets were compared. The CR test tablets produced optimized C_max and extended T_max (P < 0.05). A good correlation of drug absorption in vivo and drug release in vitro (R² = 0.9082) was observed. Relative bioavailability of the test tablet was calculated as 94%. The manufacturing process employed was reproducible and the CR test tablets were stable for 6 months at 40 ± 2°C/75 ± 5% relative humidity. It was concluded that the CR test tablet formulation successfully developed may improve tolerability and patient adherence by reducing adverse effects.Key words: bioavailability, controlled release, Ethocel®, olanzapine     

Development and Characterisation of Ursolic Acid Nanocrystals Without Stabiliser Having Improved Dissolution Rate and In Vitro Anticancer Activity

Ursolic acid (UA), which is a natural pentacyclic triterpenoid, has the potential to be developed as an anticancer drug, whereas its poor aqueous solubility and dissolution rate limit its clinical application. The aim of the present study was to develop UA nanocrystals to enhance its aqueous dispersibility, dissolution rate and anticancer activity. Following the investigation on the effects of stabiliser, the ratio of organic phase to aqueous solution and drug concentration, the UA nanocrystals without stabiliser were successfully prepared by anti-solvent precipitation approach. The nanocrystals maintained similar crystallinity with particle size, polydispersion index and zeta potential values of 188.0 ± 4.4 nm, 0.154 ± 0.022, and −25.0 ± 5.9 mV, respectively. Compared with the raw material, the UA nanocrystals showed good aqueous dispensability and a higher dissolution rate, and they could be completely dissolved in 0.5% SDS solution within 120 min. Moreover, the suspension of UA nanocrystals was physically stable after storage at 4°C for 7 weeks. By inducing G₂/M phase cell cycle arrest, the UA nanocrystals significantly induced stronger cell growth inhibition activity against MCF-7 cells compared with free drug in vitro, although the uptake of free UA was approximately twice higher than that of the UA nanocrystals. The UA nanocrystals may be used as a potential delivery formulation for intravenous injection with enhanced dissolution velocity and anticancer activity.Key words: anticancer, dissolution, MCF-7, nanocrystals, ursolic acid     

Development of Controlled-Release Matrix Tablet of Risperidone: Influence of Methocel®- and Ethocel®-Based Novel Polymeric Blend on <Emphasis Type="Italic">In Vitro</Emphasis> Drug Release and Bioavailability

Controlled-release (CR) matrix tablet of 4 mg risperidone was developed using flow bound dry granulation–slugging method to improve its safety profile and compliance. Model formulations F1, F2, and F3, consisting of distinct blends of Methocel® K100 LV-CR and Ethocel® standard 7FP premium, were slugged. Each batch of granules (250–1,000 μm), obtained by crushing the slugs, was divided into three portions after lubrication and then compressed to 9-, 12-, and 15-kg hard tablets. In vitro drug release studies were carried out in 0.1 N HCl (pH 1.2) and phosphate buffer (pH 6.8) using a paddle dissolution apparatus run at 50 rpm. The CR test tablet, containing 30% Methocel® and 60% Ethocel® (F3) with 12-kg hardness, exhibited pH-independent zero-order release kinetics for 24 h. The drug release rate was inversely proportional to the content of Ethocel®, while the gel layer formed of Methocel® helped in maintaining the integrity of the matrix. Changes in the hardness of tablet did not affect the release kinetics. The tablets were reproducible and stable for 6 months at 40 ± 2°C/75 ± 5% relative humidity. Risperidone and its active metabolite, 9-hydroxyrisperidone, present in the pooled rabbit’s serum, were analyzed with HPLC-UV at λ_max 280 nm. The CR test tablet exhibited bioequivalence to reference conventional tablet in addition to the significantly (p < 0.05) optimized peak concentration, C_max, and extended peak time, T_max, of the active moiety. There was a good association between drug absorption in vivo and drug release in vitro (R² = 0.7293). The successfully developed CR test tablet may be used for better therapeutic outcomes of risperidone.KEY WORDS: controlled release, dry granulation slugging method, risperidone     

Thermoreversible Nasal In situ Gel of Venlafaxine Hydrochloride: Formulation, Characterization, and Pharmacodynamic Evaluation

In order to improve the bioavailability of the antidepressant drug, venlafaxine hydrochloride, in situ mucoadhesive thermoreversible gel, was formulated using Lutrol F127 (18%) as a thermo gelling polymer. Mucoadhesion was modulated by trying carbopol 934, PVP K30, HPMC K4M, sodium alginate, tamarind seed gum, and carrageenan as mucoadhesive polymers. Results revealed that as the concentration of mucoadhesive polymer increased the mucoadhesive strength increased but gelation temperature decreased. Formulation was optimized on the basis of clarity, pH, gelation temperature, mucoadhesive strength, gel strength, viscosity, drug content, diffusion through sheep nasal mucosa, histopathological evaluation of mucosa, and pharmacodynamic study in rats. Final formulation T5 containing 18% Lutrol F127 and 0.3% PVP K30 was considered as an optimized formulation. T5 released 97.86 ± 0.073% drug in 150 min with a flux of 0.1545 mg cm⁻² min⁻¹ and gelation temperature 31.17 ± 0.30°C. Histopathological evaluation of nasal mucosa revealed that T5 formulation was safe for nasal administration as it caused no damage to nasal epithelium. From the results of pharmacodynamic study, mainly forced swim test (FST), it was concluded that venlafaxine hydrochloride was more effective as an antidepressant by nasal route as in situ gel nasal drops in comparison to oral administration of equivalent dose.Key words: lutrol F127, mucoadhesive, nasal in situ gel, thermoreversible, venlafaxine HCl     

A Novel Approach to Flurbiprofen Pulsatile Colonic Release: Formulation and Pharmacokinetics of Double-Compression-Coated Mini-Tablets

A significant plan is executed in the present study to study the effect of double-compression coating on flurbiprofen core mini-tablets to achieve the pulsatile colonic delivery to deliver the drug at a specific time as per the patho-physiological need of the disease that results in improved therapeutic efficacy. In this study, pulsatile double-compression-coated tablets were prepared based on time-controlled hydroxypropyl methylcellulose K100M inner compression coat and pH-sensitive Eudragit S100 outer compression coat. Then, the tablets were evaluated for both physical evaluation and drug-release studies, and to prove these results, in vivo pharmacokinetic studies in human volunteers were conducted. From the in vitro drug-release studies, F6 tablets were considered as the best formulation, which retarded the drug release in the stomach and small intestine (3.42 ± 0.12% in 5 h) and progressively released to the colon (99.78 ± 0.74% in 24 h). The release process followed zero-order release kinetics, and from the stability studies, similarity factor between dissolution data before and after storage was found to be 88.86. From the pharmacokinetic evaluation, core mini-tablets producing peak plasma concentration (C_max) was 14,677.51 ± 12.16 ng/ml at 3 h T_max and pulsatile colonic tablets showed C_max = 12,374.67 ± 16.72 ng/ml at 12 h T_max. The area under the curve for the mini and pulsatile tablets was 41,238.52 and 72,369.24 ng-h/ml, and the mean resident time was 3.43 and 10.61 h, respectively. In conclusion, development of double-compression-coated tablets is a promising way to achieve the pulsatile colonic release of flurbiprofen.KEY WORDS: core mini-tablets, double-compression coating, inner compression coat, outer compression coat, similarity factor     

Development,Characterization and Permeability Assessment Based on Caco-2 Monolayers of Self-Microemulsifying Floating Tablets of Tetrahydrocurcumin

Novel self-microemulsifying floating tablets were developed to enhance the dissolution and oral absorption of the poorly water-soluble tetrahydrocurcumin (THC). Their physicochemical properties and THC permeability across Caco-2 cell monolayers were assessed. The self-microemulsifying liquid containing THC was adsorbed onto colloidal silicon dioxide, mixed with HPMC, gas-generating agents (sodium bicarbonate and tartaric acid), lactose and silicified-microcrystalline cellulose and transformed into tablets by direct compression. The use of different types/concentrations of HPMC and sodium bicarbonate in tablet formulations had different effects on the floating characteristics and in vitro THC release. The optimum tablet formulation (F2) provided a short floating lag time (∼23 s) together with a prolonged buoyancy (>12 h). About 72% of THC was released in 12 h with an emulsion droplet size in aqueous media of 33.9 ± 1.0 nm while that of a self-microemulsifying liquid was 29.9 ± 0.3 nm. The tablet formulation was stable under intermediate and accelerated storage conditions for up to 6 months. The THC released from the self-microemulsifying liquid and tablet formulations provided an approximately three- to fivefold greater permeability across the Caco-2 cell monolayers than the unformulated THC and indicated an enhanced absorption of THC by the formulations. The self-microemulsifying floating tablet could provide a dosage form with the potential to improve the oral bioavailability of THC and other hydrophobic compounds.KEY WORDS: Caco-2 cells, controlled release, permeability, self-microemulsifying floating tablets, tetrahydrocurcumin     

Comparison of Release-Controlling Efficiency of Polymeric Coating Materials Using Matrix-type Casted Films and Diffusion-Controlled Coated Tablet

Polymeric coating materials have been widely used to modify release rate of drug. We compared physical properties and release-controlling efficiency of polymeric coating materials using matrix-type casted film and diffusion-controlled coated tablet. Hydroxypropylmethyl cellulose (HPMC) with low or high viscosity grade, ethylcellulose (EC) and Eudragit® RS100 as pH-independent polymers and Eudragit S100 for enteric coatings were chosen to prepare the casted film and coated tablet. Tensile strength and contact angle of matrix-type casted film were invariably in the decreasing order: EC> Eudragit S100> HPMC 100000> Eudragit RS100>HPMC 4000. There was a strong linear correlation between tensile strength and contact angle of the casted films. In contrast, weight loss (film solubility) of the matrix-type casted films in three release media (gastric, intestinal fluid and water) was invariably in the increasing order: EC < HPMC 100000 < Eudragit RS100 < HPMC 4000 with an exception of Eudragit S100. The order of release rate of matrix-type casted films was EC > HPMC 100000 > Eudragit RS100 > HPMC 4000 > Eudragit S100. Interestingly, diffusion-controlled coated tablet also followed this rank order except Eudragit S100 although release profiles and lag time were highly dependent on the coating levels and type of polymeric coating materials. EC and Eudragit RS100 produced sustained release while HPMC and Eudragit S100 produced pulsed release. No molecular interactions occurred between drug and coating materials using ¹H-NMR analysis. The current information on release-controlling power of five different coating materials as matrix carrier or diffusion-controlled film could be applicable in designing oral sustained drug delivery.Key words: diffusion-controlled coated tablet, drug release rate, matrix-type casted film, polymeric coating materials, release-controlling power     

Formulation of a Novel Tianeptine Sodium Orodispersible Film

The present investigation was undertaken with the objective of formulating orodispersible film(s) of the antidepressant drug tianeptine sodium to enhance the convenience and compliance by the elderly and pediatric patients. The novel film former, lycoat NG73 (granular hydroxypropyl starch), along with different film-forming agents (hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and polyvinyl alcohol), in addition to three film modifiers; namely, maltodextrin, polyvinyl pyrrolidone K90 and lycoat RS780 (pregelatinized hydroxypropyl starch) were evaluated. Eight formulae were prepared by the solvent-casting method; and were evaluated for their in vitro dissolution characteristics, in vitro disintegration time, and their physico-mechanical properties. The promising orodispersible film based on lycoat NG73 (F1); showing the greatest drug dissolution, satisfactory in vitro disintegration time and physico-mechanical properties that are suitable for orodispersible films, was evaluated for its bioavailability compared with a reference marketed product (Stablon® tablets) in rabbits. Statistical analysis revealed no significant difference between the bioavailability parameters (C_max (ng/ml), t_max (h), AUC_0–t (ng h ml⁻¹), and AUC_0–∞ (ng h ml⁻¹)] of the test film (F1) and the reference product. The mean ratio values (test/reference) of C_max (89.74%), AUC_0–t (110.9%), and AUC_0–∞ (109.21%) indicated that the two formulae exhibited comparable plasma level-time profiles. These findings suggest that the fast orodispersible film containing tianeptine is likely to become one of choices for acute treatment of depression.Key words: bioavailability from orodispersible films and tablets, fast-dissolving films, orodispersible films, solvent-casting method, tianeptine sodium     

Ditosylate Salt of Itraconazole and Dissolution Enhancement Using Cyclodextrins

Salt formation has been a promising approach for improving the solubility of poorly soluble acidic and basic drugs. The aim of the present study was to prepare the salt form of itraconazole (ITZ), a hydrophobic drug to improve the solubility and hence dissolution performance. Itraconazolium ditolenesulfonate salt (ITZDITOS) was synthesized from ITZ using acid addition reaction with p-toluenesulfonic acid. Salt characterization was performed using ¹H NMR, mass spectrometry, Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The particle size and morphology was studied using dynamic light scattering technique and scanning electron microscopy, respectively. The solubility of the salt in water and various pharmaceutical solvents was found multifold than ITZ. The dissolution study exhibited 5.5-fold greater percentage release value in 3 h of ITZDITOS (44.53%) as compared with ITZ (8.54%). Results of in vitro antifungal studies using broth microdilution technique indicate that ITZDITOS possessed similar antifungal profile as that of ITZ when tested against four fungal pathogens. Furthermore, the physical mixtures of ITZDITOS with two cyclodextrins, β-cyclodextrin (β-CD), and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) were prepared in different molar ratios and were evaluated for in vitro release. It was observed that in only 30 min of dissolution study, about 74 and 81% of drug was released from 1:3 molar ratios of ITZDITOS with β-CD and ITZDITOS with HP-β-CD, respectively, which was distinctly higher than the drug released from ITZ commercial capsules (70%). The findings warrant further preclinical and clinical studies on ITZDITOS so that it can be established as an alternative to ITZ for developing oral formulations.KEY WORDS: antifungal, BCS class II, dissolution rate, insoluble, itraconazole     

Use of First Derivative of Displacement vs. Force Profiles to Determine Deformation Behavior of Compressed Powders

Displacement (D) vs. force (F) profiles obtained during compaction of powders have been reported by several researchers. These profiles are usually used to obtain mechanical energies associated with the compaction of powders. In this work, we obtained displacement–force data associated with the compression of six powders; Avicel PH101, Avicel PH301, pregelatinized corn starch, anhydrous lactose, dicalcium phosphate, and mannitol. The first three powders are known to deform predominantly by plastic behavior while the later ones are known to deform predominantly by brittle fracture. Displacement–force data was utilized to perform in-die Heckel analysis and to calculate the first derivative (dD/dF) of displacement–force plots. First derivative results were then plotted against mean force (F′) at each point and against 1/F′ at compression forces between 1 and 20 kN. Results of the in-die Heckle analysis are in very good agreement with the known deformation behavior of the compressed materials. First derivative plots show that materials that deform predominantly by plastic behavior have first derivative values (0.0006–0.0016 mm/ N) larger than those of brittle materials (0.0004 mm/N). Moreover, when dD/dF is plotted against 1/F′ for each powder, a linear correlation can be obtained (R² = > 0.98). The slopes of the dD/dF vs. 1/F′ plots for plastically deforming materials are relatively larger than those for materials that deform by brittle behavior. It is concluded that first derivative plots of displacement–force profiles can be used to determine deformation behavior of powders.KEY WORDS: compression, deformation, first derivative     

Effect of Grewia Gum as a Suspending Agent on Ibuprofen Pediatric Formulation

The purpose of this work was to evaluate the potential of grewia gum (GG) as a suspending agent in pharmaceutical oral formulation using ibuprofen as model drug. Ibuprofen pediatric suspension (25 mg/5 mL) was formulated with grewia gum (0.5% w/v) as the suspending agent. Similar suspensions of Ibuprofen containing either sodium carboxymethylcellulose (Na-CMC) or hydroxymethylpropylcellulose (HPMC) were also produced. The suspensions were evaluated for ease of redispersion, sedimentation, rheological properties, and the effect of aging on the rheological properties at 25°C. The particle size and particle size distributions of the dispersed solute were determined. The redispersion time was 19, 11, and 0.5 min, respectively, for formulation containing Na-CMC, HPMC, and GG .The sedimentation volumes were 0.05, 0.05, and 0.125 mL, respectively, for Na-CMC, HPMC, and GG . Viscosities of suspensions at spindle speed of 25 rpm were of the order: GG > HPMC > Na-CMC when freshly prepared and of the order: HPMC > GG > Na-CMC within 6 months of storage. The particles size was 72.72, 73.82, 81.93, and 83.41 μm, respectively, for suspensions containing Na-CMC, ibuprofen alone, HPMC, and GG. Greatest hysteresis was observed in formulation containing HPMC. All the formulations were stable. It was our conclusion that the difference in the physicochemical properties of ibuprofen pediatric formulations was influenced more by the suspending agent used in the formulations than the drug. GG combined better redispersion with minimal changes in viscosity on storage compared to Na-CMC and HPMC as suspending agent. Thus GG may serve as a good suspending agent requiring no further aid in suspension redispersibility.KEY WORDS: grewia gum, oral pharmaceutical formulations, physicochemical properties, potential suspending agent     

Product Development Studies on Surface-Adsorbed Nanoemulsion of Olmesartan Medoxomil as a Capsular Dosage Form

The present study aimed at development of capsular dosage form of surface-adsorbed nanoemulsion (NE) of olmesartan medoxomil (OLM) so as to overcome the limitations associated with handling of liquid NEs without affecting their pharmaceutical efficacy. Selection of oil, surfactant, and cosurfactant for construction of pseudoternary phase diagrams was made on the basis of solubility of drug in these excipients. Rationally selected NE formulations were evaluated for percentage transmittance, viscosity, refractive index, globule size, zeta potential, and polydispersity index (PDI). Formulation (F3) comprising of Capmul MCM® (10% v/v), Tween 80® (11.25% v/v), polyethylene glycol 400 (3.75% v/v), and double-distilled water (75% v/v) displayed highest percentage cumulative drug release (%CDR; 96.69 ± 1.841), least globule size (17.51 ± 5.87 nm), low PDI (0.203 ± 0.032), high zeta potential (−58.93 ± 0.98 mV), and hence was selected as the optimized formulation. F3 was adsorbed over colloidal silicon dioxide (2 ml/400 mg) to produce free-flowing solid surface-adsorbed NE that presented a ready-to-fill capsule composition. Conversion of NE to surface-adsorbed NE and its reconstitution to NE did not affect the in vitro release profile of OLM as the similarity factor with respect to NE was found to be 66% and 73% respectively. The %CDR after 12 h for optimized NE, surface-adsorbed NE, and reconstituted NE was found to be 96.69 ± 0.54, 96.07 ± 1.76, and 94.78 ± 1.57, respectively (p > 0.05). The present study established capsulated surface-adsorbed NE as a viable delivery system with the potential to overcome the handling limitations of NE.KEY WORDS: bioavailability, nanoemulsion, olmesartan medoxomil, oral     

Enhancing and Sustaining AMG 009 Dissolution from a Bilayer Oral Solid Dosage Form via Microenvironmental pH Modulation and Supersaturation

Enhancing and sustaining AMG 009 dissolution from a matrix tablet via microenvironmental pH modulation and supersaturation, where poorly soluble acidic AMG 009 molecule was intimately mixed and compressed together with a basic pH modifier (e.g., sodium carbonate) and nucleation inhibitor hydroxypropyl methylcellulose K100 LV (HPMC K100 LV), was demonstrated previously. However, not all acidic or basic drugs are compatible with basic or acidic pH modifiers either chemically or physically. The objective of this study is to investigate whether similar dissolution enhancement of AMG 009 can be achieved from a bilayer dosage form, where AMG 009 and sodium carbonate are placed in a separate layer with or without the addition of HPMC K100 LV in each layer. Study results indicate that HPMC K100 LV-containing bilayer dosage forms gained similar dissolution enhancement as matrix dosage forms did. Bilayer dosage forms without HPMC K100 LV benefitted the least from dissolution enhancement.     

Formulation of Microemulsion Systems for Dermal Delivery of Silymarin

Silymarin is a standardized extract from Silybum marianum seeds, known for its many skin benefits such as antioxidant, anti-inflammatory, and immunomodulatory properties. In this study, the potential of several microemulsion formulations for dermal delivery of silymarin was evaluated. The pseudo-ternary phase diagrams were constructed for the various microemulsion formulations which were prepared using glyceryl monooleate, oleic acid, ethyl oleate, or isopropyl myristate as the oily phase; a mixture of Tween 20®, Labrasol®, or Span 20® with HCO-40® (1:1 ratio) as surfactants; and Transcutol® as a cosurfactant. Oil-in-water microemulsions were selected to incorporate 2% w/w silymarin. After six heating–cooling cycles, physical appearances of all microemulsions were unchanged and no drug precipitation occurred. Chemical stability studies showed that microemulsion containing Labrasol® and isopropyl myristate stored at 40°C for 6 months showed the highest silybin remaining among others. The silybin remainings depended on the type of surfactant and were sequenced in the order of: Labrasol® > Tween 20® > Span 20®. In vitro release studies showed prolonged release for microemulsions when compared to silymarin solution. All release profiles showed the best fits with Higuchi kinetics. Non-occlusive in vitro skin permeation studies showed absence of transdermal delivery of silybin. The percentages of silybin in skin extracts were not significantly different among the different formulations (p > 0.05). Nevertheless, some silybin was detected in the receiver fluid when performing occlusive experiments. Microemulsions containing Labrasol® also were found to enhance silymarin solubility. Other drug delivery systems with occlusive effect could be further developed for dermal delivery of silymarin.Key words: dermal delivery, microemulsion, silybin, silymarin     

Controlled Release of Ropinirole Hydrochloride from a Multiple Barrier Layer Tablet Dosage Form: Effect of Polymer Type on Pharmacokinetics and IVIVC

The purpose of the present study was to control in vitro burst effect of the highly water-soluble drug, ropinirole hydrochloride to reduce in vivo dose dumping and to establish in vitro–in vivo correlation. The pharmacokinetics of two entirely different tablet formulation technologies is also explored in this study. For pharmacokinetics study, FDA recommends at least 10% difference in drug release for formulations to be studied but here a different approach was adopted. The formulations F8A and F9A having similar dissolution profiles among themselves and with Requip® XL™ (f₂ value 72, 77, 71 respectively) were evaluated. The C_max of formulation F8A comprising hypromellose 100,000 cP was 1005.16 pg/ml as compared to 973.70 pg/ml of formulation F9A comprising hypromellose 4000 cP irrespective of T_max of 5 and 5.75 h, respectively. The difference in release and extent of absorption in vivo was due to synergistic effect of complex RH release mechanism; however, AUC_0–t and AUC_0–∞ values were comparable. The level A correlation using the Wagner–Nelson method supported the findings where R² was 0.7597 and 0.9675 respectively for formulation F8A and F9A. Thus, in vivo studies are required for proving the therapeutic equivalency of different formulation technologies even though f₂ ≥ 50. The technology was demonstrated effectively at industrial manufacturing scale of 200,000 tablets.KEY WORDS: controlled release polymer, in vitro–in vivo correlation (IVIVC), multiple barrier layer tablets, pharmacokinetics, ropinirole hydrochloride (RH)