Low-substituted Hydroxypropylcellulose Research Articles

Development, Characterization, and Cellular Toxicity Evaluation of Solid Dispersion-Loaded Hydrogel Based on Indomethacin.

Indomethacin (IND) as a non-selective cyclooxygenase 1 and 2 inhibitor administered orally causes numerous adverse effects, mostly related to the gastrointestinal tract. Moreover, when applied exogenously in topical preparations, there are obstacles to its permeation through the stratum corneum due to its low water solubility and susceptibility to photodegradation. In this work, solid dispersions (SDs) of IND with low-substituted hydroxypropyl cellulose (LHPC) were developed. The IND-SDs were incorporated into a hydroxypropyl guar (HPG) hydrogel to enhance drug solubility on the skin. The hydrogels were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR), viscosity, drug release, and unspecific cytotoxicity in mammalian cells. SEM showed a highly porous structure for SD hydrogels. DSC and XRPD studies showed that amorphous IND species were formed; therefore, these hydrogels exhibited superior drug release in comparison with IND raw material hydrogels. FTIR evidenced the presence of the hydrogen bond in the SD hydrogel. The rheology parameter viscosity increased across gels formulated with SDs in comparison with hydrogels with pure IND. In addition, IND-SD hydrogels combine the advantages of a suitable viscosity for dermal use and no potentially hazardous skin irritation. This study suggests that the formulated IND-SD hydrogels represent a suitable candidate for topical administration.

A Novel Lactose/MCC/L-HPC Triple-Based Co-Processed Excipients with Improved Tableting Performance Designed for Metoclopramide Orally Disintegrating Tablets.

New co-processed excipients comprising lactose (filler and sweetener), microcrystalline cellulose (MCC, filler), and low-substituted hydroxypropyl cellulose (L-HPC, disintegrant and binder) were developed via solvent evaporation for the preparation of metoclopramide orally disintegrating tablets (MCP ODTs). Single-factor and Box-Behnken experimental designs were employed to optimize the formulation. The optimized formulation ratios were water: MCC: lactose (g/g) = 17.26:2.79:4.54:1. The results demonstrated that particles formed by solvent evaporation had superior flowability and compressibility compared to the physical mixture. Tablets compressed with these co-processed excipients exhibited a significantly reduced disintegration time of less than 25 s and achieved complete dissolution within 5 min. Pharmacokinetic studies revealed that MCP ODTs significantly improved Cmax, which was 1.60-fold higher compared to conventional tablets. In summary, the lactose/L-HPC/MCC triple-based co-processed excipients developed in this study are promising and could be successfully utilized in orally disintegrating and fast-release tablets.

Hydroxypropyl Cellulose-Based Orally Dissolving Film Loaded with Insoluble Dexamethasone for Treatment of Oral Ulcers.

Oral ulcers present as recurrent and spontaneous lesions, often causing intolerable burning pain that significantly disrupts patients' daily lives and compromises their quality of life. In addressing this clinical challenge, oral dissolving films (ODFs) have emerged as promising pharmaceutical formulations for oral ulcer management due to their rapid onset of action, ease of administration, and portability. In this study, ODFs containing the insoluble drug dexamethasone (Dex) were formulated for the treatment of oral ulcers in rabbits using a solvent casting method with ethanol as the solvent. To optimize the composition of the ODFs, a Box-Behnken Design (BBD) experiment was employed to investigate the effects of varying concentrations of hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), and plasticizer (glycerol) on key parameters, such as disintegration time, tensile strength, and peel-off efficiency of the films. Subsequently, the film properties of the Dex-loaded ODFs (ODF@Dex) were thoroughly assessed, revealing favorable attributes, including homogeneity, mechanical strength, and solubility. Notably, the use of ethanol as the solvent in the ODF preparation facilitated the homogeneous distribution of insoluble drugs within the film matrix, thereby enhancing their solubility and dissolution rate. Leveraging the potent pharmacological activity of Dex, ODF@Dex was further evaluated for its efficacy in promoting ulcer healing and mitigating the expression of inflammatory factors both in vitro and in vivo. The findings demonstrated that the ODF@Dex exerted significant antiulcer effects by modulating the PI3K/Akt signaling pathway, thus contributing to ulcer resolution. In conclusion, our study underscores the potential of HPC-based ODFs formulated with ethanol as a solvent as a promising platform for delivering insoluble drugs, offering a viable strategy for the clinical management of oral ulcers.

Topical Meloxicam Hydroxypropyl Guar Hydrogels Based on Low-Substituted Hydroxypropyl Cellulose Solid Dispersions.

Meloxicam (MX) is a poorly water-soluble drug with severe gastrointestinal side effects. Topical hydrogel of hydroxypropyl guar (HPG) was formulated using a solid dispersion (SD) of MX with hydroxypropyl cellulose (LHPC) as an alternative to oral administration. The development of a solid dispersion with an adequate MX:LHPC ratio could increase the topical delivery of meloxicam. Solid dispersions showed high MX solubility values and were related to an increase in hydrophilicity. The drug/polymer and polymer/polymer interactions of solid dispersions within the HPG hydrogels were evaluated by SEM, DSC, FTIR, and viscosity studies. A porous structure was observed in the solid dispersion hydrogel MX:LHPC (1:2.5) and its higher viscosity was related to a high increase in hydrogen bonds among the -OH groups from LHPC and HPG with water molecules. In vitro drug release studies showed increases of 3.20 and 3.97-fold for hydrogels with MX:LHPC ratios of (1:1) and (1:2.5), respectively, at 2 h compared to hydrogel with pure MX. Finally, a fitting transition from zero to first-order model was observed for these hydrogels containing solid dispersions, while the n value of Korsmeyer-Peppas model indicated that release mechanism is governed by diffusion through an important relaxation of the polymer.

Optimizing Nonsink Dissolution Testing for Amorphous Solid Dispersions: Exploring Sample Handling Variables.

This study aims to investigate key variables affecting the dissolution of amorphous pharmaceuticals. We examined sample treatment methods (centrifugation vs syringe filtration), time delays between sample collection and processing (immediate, 2, or 24 h), and different sample preparations (bare powder, capsules, or tablets). These factors were evaluated through both sink and nonsink dissolution experiments, using controlled supersaturation conditions (sink index ≈ 0.1) with amorphous solid dispersions (ASDs) containing low-substituted hydroxypropyl cellulose (L-HPC) and either indomethacin or posaconazole as model drugs. Our results highlighted the significant impact of syringe filtration on nonsink dissolutions, particularly the notable reduction in dissolved drug concentration, possibly due to filtration-induced precipitation. Moreover, introducing a delay of 2 or 24 h between sample collection and quantitation under nonsink conditions led to substantial concentration changes. This effect was not as pronounced when samples underwent centrifugation, and only the analysis was delayed for 2 h. The findings also emphasize the importance of accounting for delays introduced by pharmaceutical formulations, particularly in assessing the kinetic-solubility profiles of ASDs. This research offers valuable insights into the field of ASDs, enhancing our understanding of how these variables can influence dissolution results.

Composite excipients for preparing concentrated water pills of personalized traditional Chinese medicine prescriptions by extruding-rounding method

This study aims to optimize the composite excipients suitable for the preparation of concentrated water pills of personalized traditional Chinese medicine prescriptions by the extruding-rounding method and investigate the roles of each excipient in the preparation process. The fiber materials and powder materials were taken as the standard materials suitable as excipients in the preparation of personalized concentrated water pills without excipient. Water absorption properties and torque rheology were used as indicators for selecting the materials of composite excipients. The ratio of composite excipients was optimized by D-optimal mixture design. Moreover, to demonstrate the universal applicability of the optimal composite excipients, this study selected three traditional Chinese medicine prescriptions with low, medium, and high extraction rates to verify the optimal ratio. Finally, the effects of each selected excipient on the molding of personalized concentrated water pills were investigated with the four parameters of the pill molding quality as indicators. The optimized composite excipients were dextrin∶microcrystalline cellulose(MCC)∶low-substituted hydroxypropyl cellulose(L-HPC) at a ratio of 1∶2∶4. The composite excipients were used for the preparation of personalized concentrated water pills with stable process, good quality, and a wide range of application. Dextrin acted as a diluent and accelerated the speed of extruding. MCC mainly served as an adhesive, increasing the cohesion and viscosity of the pills. L-HPC as a water absorbent and disintegrating agent can absorb and hold the water of the concentrate and has a strong disintegration effect.

Development and Assessment of a New Oral Selenium Fast-disintegrating Tablets

Selenium is an essential trace element and its deficiency causes myositis, myocardial damage, and other symptoms. Patients receiving long-term intravenous nutrition or tube-feeding in particular are deficient in essential trace elements, including selenium, and require regular supplementation. In Japan, injectable selenium-containing products are listed on the National Health Insurance drug price list, and oral solutions are prepared and used in hospitals. However, these formulations have problems related to preservation and require complicated administration procedures. In this study, we developed a new fast-disintegrating tablet formulation of selenium, using SmartEx® (D-mannitol·low substituted hydroxypropylcellulose (L-HPC)·fully hydrolyzed polyvinyl alcohol (PVA) mixture) as a coprocessing additive, that can be administered orally or by feeding tube. The tablet formulation had excellent disintegrable capability, sufficient hardness, and did not cause tube blockage when administered in the simple suspension method. In addition, the tablet formulation showed no changes in properties in an accelerated test without packaging for 42 d, indicating that it could be stored for a long period. Fast-disintegrating tablets prepared with SmartEx® are expected to improve the adherence and quality of life of patients who require selenium supplementation.

Effects of Granulated Lactose Characteristics and Lubricant Blending Conditions on Tablet Physical Properties in Direct Powder Compression.

Lactose is an excipient used extensively for bulking, diluting, and molding active pharmaceutical ingredients in tablet manufacturing. Particularly, granulated lactose (GL) intended for direct powder compression has distinct properties due to differences in manufacturing methods. It contributes to handling blended powders for tableting and tablet quality. In this study, we aimed to compare the functions of different forms of GL added as excipients during direct powder compression on the tablet properties and the effect of magnesium stearate (Mg-S) used as a lubricant on each type of GL. Different GL types obtained using different manufacturing methods (agitated granulation, GL-AG; spray-dried granulation, GL-SD; fluidized bed granulation, GL-FB) were blended with maize starch, low-substituted hydroxypropyl cellulose, and paracetamol in a V-type blender for 10 min. Mg-S was added at varying amounts (0.1, 1.0, and 2.0%) and blending times (5, 10, and 30 min) for the nine types of blended powders for tableting formulation. The powders were tableted, and the tablets were evaluated for weight and drug loading variations, tensile strength, friability, and disintegration time. When tablets with the same blending conditions were compared, the tensile strength and disintegration time were in the order of GL-FB > GL-SD > GL-AG. For each GL, we analyzed the effects of changes in the added amount of Mg-S and blending time using contour plots, evaluated the effects of blending conditions on tablet properties, and determined the target tablet properties. We investigated the optimization of the lubricant blending conditions to obtain suitable tablets.

Amorphous solid dispersions in high-swelling, low-substituted hydroxypropyl cellulose for enhancing the delivery of poorly soluble drugs

Amorphous solid dispersions (ASDs) based on water-insoluble hydrophilic polymers can sustain supersaturation in their kinetic solubility profiles (KSPs) compared to soluble carriers. However, in the limit of very high swelling capacity, the achievable extent of drug supersaturation has not been fully examined. This study explores the limiting supersaturation behavior of ASDs of poorly soluble indomethacin (IND) and posaconazole (PCZ) based on a high-swelling excipient, low-substituted hydroxypropyl cellulose (L-HPC). Using IND as a reference, we showed that the rapid initial supersaturation buildup in the KSP of IND ASD can be simulated through sequential IND infusion steps, however at large times the KSP of IND release from ASD appears more sustained than direct IND infusion. This has been attributed to potential trapping of seed crystals generated in the L-HPC gel matrix thus limiting their growth and rate of desupersaturation. Similar result is also expected in PCZ ASD. Furthermore, the current drug loading process for ASD preparation resulted in the agglomeration of L-HPC based ASD particles, producing granules of up to 300–500 µm (cf. 20 µm individual particle), with distinct kinetic solubility profiles. This feature makes L-HPC particularly suitable as ASD carriers for fine tuning of supersaturation to achieve enhanced bioavailability for poorly soluble drugs.

The potential therapeutic effects of hydroxypropyl cellulose on acute murine colitis induced by DSS

In this study, high-substituted hydroxypropyl cellulose (HHPC) and low-substituted hydroxypropyl cellulose (LHPC) were orally administered (150 or 300 mg/kg) to investigate the inflammation inhibitory effects on DSS-induced colitis mice. In addition, the anti-inflammatory potential of HHPC in-vitro (RAW 264.7 cells) was evaluated. The result showed that HHPC could inhibit the excessive secretion of TNF-α, IL-6, and NO in RAW 264.7 cells induced by lipopolysaccharide. Oral administration of HHPC and LHPC could dose-dependently mitigate the pathological damage of colon tissue, suppressed spleen edema, preserved thymus index, reduced the serum level of inflammatory mediators (TNF-α, IL-6, IL-1β, and MPO), increased the secretion of sIgA in the colon, and restored the balance of the intestinal flora such as Rikenellaceae_RC9_gut_group, Lachnospiraceae_UCG-006, and Blautia. Overall, this study elucidated the therapeutic potential of LHPC and HHPC as a prebiotic to treat acute ulcerative colitis.

Development and optimization of Curcuma longa Linn. oleoresin non-aqueous gel for transdermal delivery

A long-term oral administration of NSAID and DMARD on rheumatoid arthritis (RA) treatment may cause gastritis, kidney, and cardiovascular disorder. One of the alternative therapies that have been investigated is by using herbal medicine such as Curcuma longa Linn. which contains curcumin and essential oils. Even though both compounds are quite effective in treating RA, poor aqueous solubility and low intestinal absorption limit their oral bioavailability. To overcome these drawbacks, transdermal delivery was chosen as an alternative route of administration. This study was aimed to formulate the Curcuma longa Linn. oleoresin into a transdermal non-aqueous gel system using Carbopol 934 and low substituted hydroxypropyl cellulose (4.25:0.75 %) as the gelling agent. In this study, multiple solvents (PEG 400, PG, glycerin, ethanol, and tween 20) were used in the system. The solvents were chosen based on their ability to dissolve the gelling agents. Optimization was done using a simplex lattice design based on the physical characteristics (viscosity, pH, spreadability, and adhesivity) of the prepared gel. The system with the optimum concentration of PEG 400 and PG was then observed for its stability and in vitro transport through snakeskin membrane using Franz diffusion cell with PBS pH 7.4 as acceptor medium. The optimal formula was comprised of 75% PEG and 25% PG which has a viscosity of 6.34 + 0.19 dPa.s, adhesivity of 6.05 + 0.11 seconds, pH of 5.16 + 0.09, spreadability of 6.94 + 0.06 cm, and quite stable after freeze-thaw cycling test, whilst around 26.85% curcumin was diffused through the membrane (flux = 0.084 mg.cm -2 ) after 2 hours. It can be concluded that the Curcuma longa Linn. oleoresin can be formulated into a non-aqueous gel system, which showed a fair gel physical characteristic with good stability and ability to permeate across the skin membrane, and is promising to be further developed as an alternative for RA treatment.

Effect of Physical Properties and Chemical Substitution of Excipient on Compaction and Disintegration Behavior of Tablet: A Case Study of Low-Substituted Hydroxypropyl Cellulose (L-HPC)

As final attributes of dosage form largely depend on the properties of excipients used, understanding the effect of physicochemical properties of excipients is important. In the present study, six grades of L-HPC with varying degrees of particle size and hydroxypropyl content and the influence of the grade on compaction as well as disintegration behavior were studied. All grades of L-HPC were compressed at different compression loads to achieve different tablet porosity. Compressibility and compactibility of L-HPC grades were evaluated using a modified Heckel equation and percolation model. Further effects of particle size and hydroxypropyl content of L-HPC on tablet porosity and disintegration time were evaluated using a 32 full-factorial design. From compaction studies, it was found that compressibility of L-HPC largely depends upon the particle size with lower particle size grade showing lower compressibility. Whereas consolidation/bonding behavior of L-HPC is independent of particle size and % hydroxypropyl content. By factorial design, it was found that particle size and % hydroxypropyl content have a significant effect on the disintegration behavior of L-HPC. It was found that smaller particle sizes and higher hydroxypropyl content of L-HPC show longer disintegration time. Thus, careful consideration of excipients selection should be made to achieve desired quality attribute of the product.

Orally Disintegrating Tablet Manufacture via Direct Powder Compression Using Cellulose Nanofiber as a Functional Additive.

In recent years, orally disintegrating (OD) tablets have been continuously improved to increase efficacy. Herein, we focused on the benefits of cellulose nanofiber (CNF), a highly functional material, in OD tablet manufacturing. We studied its effects on the physical properties of tablets during manufacture. The analyzed tablet formulations included different content CNF (0-50%; 6 preparations), lactose hydrate, acetaminophen, and magnesium stearate (Mg-St). We measured the angles of repose and evaluated the flowability of the powder. Tablets were prepared on a tabletop and rotary tableting presses, whereafter their weight, drug content, hardness, friability, and disintegration time were evaluated. Although CNF addition slightly reduced powder flowability, continuous tableting was feasible via direct powder compression. Tablet hardness (~40 N) was comparable between CNF-containing (20%) tablets and those prepared with crystalline cellulose under 10 kN compression force. Disintegration time (~30 s) was similar between CNF-supplemented tablets and those supplemented with low-substituted hydroxypropyl cellulose, crospovidone, or croscarmellose sodium. At higher CNF fractions, tablet hardness increased, while friability decreased. Adding ≥30% CNF prolonged the tablet disintegration time. To set the optimized manufacturing condition for ensuring the desired tablet physical properties, we created contour plots for evaluating the effects of CNF concentration and compression force on hardness and disintegration time. A CNF concentration of 10-20% and a compression force of 12-13 kN would allow for the preparation of tablets with a hardness ≥30 N and a disintegration time ≤60 s. Altogether, addition of CNF to the OD tablet formulation for direct powder compression enhanced hardness and disintegration.

Downstream processing of spray-dried ASD with hypromellose acetate succinate – Roller compaction and subsequent compression into high ASD load tablets

Despite wide commercial application of hypromellose acetate succinate (HPMCAS) in spray-dried amorphous solid dispersion (ASD) drug products, little information is available in the references on downstream processing of spray-dried dispersions with HPMCAS. Poor flow and high dilution factor are a challenge in formulating spray-dried ASDs into tablets, leaving little space for other excipients facilitating binding and disintegration. Direct compression is not possible due to the poor powder flow of spray-dried ASDs. Moisture has to be avoided due to the plasticizing properties of water on the ASD, resulting in reduced stability of the amorphous state. Thus, dry granulation by roller compaction and subsequent tablet compression is the preferred downstream process. We report the investigation of downstream processing by roller compaction and tablet compression of a high load formulation with 75% of spray-dried amorphous solid dispersion (Nifedipine:HPMCAS 1:2). A head to head comparison of microcrystalline cellulose/croscarmellose (MCC/cl-NaCMC) as binder/disintegrant vs. MCC and low-substituted hydroxypropyl cellulose (L-HPC) as excipient for binding and disintegration showed improved re-workability of the formulation with MCC/L-HPC after roller compaction. Upon transfer to the rotary press, a 45% higher tensile strength of tablets is observed after dry granulation with MCC/L-HPC.

Preparation, evaluation, and pharmacokinetics in beagle dogs of a taste-masked flunixin meglumine orally disintegrating tablet prepared using hot-melt extrusion technology and D-optimal mixture design

Flunixin meglumine (FM) is a nonsteroidal anti-inflammatory drug limited by irritation of the respiratory tract and mucosa in veterinary tissue. This study aimed to develop a taste-masked FM solid dispersion (SD) by hot-melt extrusion (HME) and formulate an orally disintegrating tablet (ODT) with selected excipients by direct compression. Eudragit® E PO was chosen as the matrix, and HME parameters were optimized: extrusion temperature, 135℃; screw speed, 100 rpm; and drug loading, 20%. Characterization techniques proved that FM was rendered amorphous in the HME extrudate. In vitro dissolution studies showed that FM SD released significantly slower than the corresponding physical mixture in artificial saliva. Excipients were selected based on compression formability, disintegration, and solubility. A D-optimal mixture design was used to optimize the composition: 25% FM SD, 18.75% microcrystalline cellulose, 52.5% mannitol, 3.75% low-substituted hydroxypropyl cellulose, and 1% magnesium stearate. Taste-masked FM ODT had a tensile strength of 0.7 ± 0.01 MPa and a disintegration time of 17.6 ± 0.1 s. E-tongue and E-nose analysis showed that FM ODT had a better taste-masked effect than commercial granules. Finally, a pharmacokinetic study proved that the main pharmacokinetic parameters of FM ODT were not significantly different from those of commercial granules, which indicated that these formulations had similar pharmacokinetic behaviours in beagles.

Quality-by-Design Approach and Optimization of Risk Factors by Box-Behnken Design in Formulation Development of Aspirin and Glycine Orally Disintegrating Tablet

Quality-by-design approach (QbD) was applied to develop an orally disintegrating tablet (ODT) formulation of aspirin and glycine. At first, the target quality profile and critical quality attributes (CQAs) of the product were identified. Risk assessment was accomplished by failure mode and effects analysis (FMEA) method to assess the factors having a significant effect on CQAs like disintegration time (DT), friability and assay of aspirin and glycine. Low substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium (CCS) and punch-diameter were found critical for DT and friability. The box-Behnken design was applied to optimize those 3 factors to reach a target DT of ≤ 30 sec. It was found that a punch-diameter between 8.7 ~ 9.3 mm, CCS in a range of 4 % ~ 5 %, and L-HPC in a range of 2 % ~ 8 % produced the best oral disintegrating property and reduced the risk. In summary, this work represented an excellent example of the application of QbD approach in ODT formulation development.

Time-domain NMR analysis for the determination of water content in pharmaceutical ingredients and wet granules

The application of time-domain NMR (TD-NMR) analysis to quantify water content in pharmaceutical ingredients is demonstrated. The initial phase of the study employed a range of disintegrants with defined amounts of added water (0–30% of the total weight) as samples; the disintegrants included croscarmellose sodium, corn starch, low-substituted hydroxypropyl cellulose, and crospovidone. After acquisition of the T2 relaxation curves of the samples by TD-NMR measurements, these curves were analyzed by partial least squares (PLS) regression. According to the analysis, accurate and reliable PLS models were created that enabled accurate assessment of water content in the samples. A powder blend consisting of acetaminophen (paracetamol) and tablet excipients was also examined. Both a physical mixture of the powder blend and a wet granule prepared with a high-speed granulator were tested as samples in this study. Precise determination of water content in the powder blend was achieved by using the TD-NMR method. The accuracy of water content determination was equivalent to or better than that of the conventional loss on drying method. TD-NMR analysis samples were measured nondestructively and rapidly with low cost; thus, it could be a powerful quantitative method for determining water content in pharmaceuticals.

Formulation and Evaluation of Taste Masking Lercanidipine Hydrochloride Oral Disintegrating Tablets

Lercanidipine is an antihypertensive drug. It is a dihydropyridine class of calcium channel blockers. It is extremely bitter. The reason for this exploration was to build up a non-bitter orally breaking down the tablet of inadequately solvent medication viz Lercanidipine. The bitterness of drug, masked through complexing Tulsion 339 in various ratios. Sodium starch glycolate, crospovidone, low substituted hydroxypropyl cellulose selected as super disintegrants in the formulation. The formulated tablets were assessed for various properties like Drug content, crushing strength, friability, wetting time, water retention proportion, breaking downtime and in-vitro disintegration time and dissolution studies. The disintegration time obtained in the range between 38.46-51.40 seconds. Release studies observed between 5 to 30 minutes. From the prepared formulations, formulation using Low substituted hydroxypropyl cellulose with 5% concentration showed 98.89% drug release within 30minutes. Thus F9 was considered as best among the other formulations With effective dissolution and improves patient intake. Drug release Kinetic analysis (r2) based on best curve fitting method for optimized lercandipine formulation showed first order kinetics proves that the drug release depends upon its concentration.

Development, In Vitro and In Vivo Evaluation of Racecadotril Orodispersible Films for Pediatric Use.

The present study endeavored to develop orodispersible films (ODFs) containing 30 mg racecadotril for pediatric use, which focuses on improving the compliance of pediatric patients and reducing risk of choking. The challenge of this study is to prepare high drug loading ODFs with successful mechanical and physicochemical properties. Compatibilities between drug and different polymers (hydroxypropyl methylcellulose, HPMC; polyvinyl alcohol, PVA; low-substituted hydroxypropyl cellulose, L-HPC; pullulan, PU) were investigated to select stable and safe film-forming polymers. Afterwards, the study explored the maximum amount of racecadotril incorporated into PVA films and PU films. Subsequently, disintegrant (Lycoat RS720, 4-10%, w/w) and plasticizers (glycerol, 2-6%, w/w) were investigated to reduce disintegration time of PVA films and enhance the flexibility of PU films, respectively. Formulation characteristics (appearance, tensile strength, percent elongation, disintegration time, drug content, weight, thickness, pH value, moisture content, moisture uptake, and Q5min) of prepared ODFs were examined to obtain the optimal compositions of racecadotril ODFs. Differential scanning calorimetry (DSC) study, powder X-ray diffraction (XRD) study, Fourier transform infrared (FTIR) study, comparative in vitro dissolution study, and pharmacokinetic study in Beagle dogs of optimized racecadotril ODFs were then conducted. Eventually, ODFs containing 50% racecadotril, 38% PVA, 7% Lycoat RS720, 2% sucralose, 2% apricot, and 1% titanium dioxide could achieve desirable mechanical properties, disintegrating within a few seconds and releasing more than 85% drug within 5min in four dissolution media. An in vivo study showed optimized racecadotril ODF and Hidrasec were bioequivalent in Beagle dogs. In summary, ODFs containing 30 mg racecadotril were successfully prepared by solvent casting method, and it was suitable for the administration to the pediatric patients.

Optimization of solid self-dispersing micelle for enhancing dissolution and oral bioavailability of valsartan using Box-Behnken design.

A novel solid self-dispersing micelle (S-SDM) was developed to enhance the oral bioavailability of valsartan (VST) and to reduce the total mass of solidified supersaturable self-microemulsifying drug delivery system (S-SuSMEDDS), composed of Capmul MCM, Tween 80 (T80), Gelucire 44/14 (G44), Poloxamer 407, Florite PS-10 (FLO), and low-substituted hydroxypropyl cellulose B1 (HPC). Excluding oil component from S-SuSMEDDS, S-SDM was optimized using a Box-Behnken design with three independent variables: X1 (T80/G44, 0.63), X2 (FLO/HPC, 0.41), and X3 (solid carrier, 177.6mg); and three response factors: Y1 (droplet size, 191.9nm), Y2 (dissolution efficiency at 15min, 55.0%), and Y3 (angle of repose, 32.4°). The desirability function was 0.636, showing an excellent agreement between the predicted and experimental values. With approximately 75% weight of S-SuSMEDDS, no distinct crystallinity of VST was observed in S-SDM, resulting in critical micelle concentration value of 32μg/mL. Optimized S-SDM showed an approximate 4-fold improved dissolution (pH 1.2, 500mL) compared with raw VST. Following oral administration in rats, optimized S-SDM improved relative bioavailability by approximately 235%, 216%, and 127% versus raw VST, Diovan® (commercial reference), and S-SuSMEDDS, respectively. Thus, optimized S-SDM could be a selectable candidate for developing water-insoluble drugs in reduced quantity.