Artificial neural networks: comparison of two programs for modeling a process of nanoparticle preparation

Artificial Neural Networks (ANNs) were used to predict nanoparticle size and micropore surface area of polylactic acid nanoparticles, prepared by a double emulsion method. Different batches were prepared while varying polymer and surfactant concentration, as well as homogenization pressure. Two commercial ANNs programs were evaluated: Neuroshell Predictor, a black-box software adopting both neural and genetic strategies, and Neurosolutions, allowing a step-by-step building of the network. Results were compared to those obtained by statistical method. Predictions from ANNs were more accurate than those calculated using non-linear regression. Neuroshell Predictor allowed quantification of the relative importance of the inputs. Furthermore, by varying the network topology and parameters using Neurosolutions, it was possible to obtain output values which were closer to experimental values. Therefore, ANNs represent a promising tool for the analysis of processes involving preparation of polymeric carriers and for prediction of their physical properties.     

Facile development,characterization, and optimization of new metformin-loaded nanocarrier system for efficient colon cancer adjunct therapy

Purpose: Metformin hydrochloride (MF) repurposing as adjuvant anticancer therapy for colorectal cancer (CRC) proved effective. Several studies attempted to develop MF-loaded nanoparticles (NPs), however the entrapment efficiency (EE%) was poor. Thus, the present study aimed at the facile development of a new series of chitosan (CS)-based semi-interpenetrating network (semi-IPN) NPs incorporating Pluronic^® nanomicelles as nanocarriers for enhanced entrapment and sustained release of MF for efficient treatment of CRC.

Methods: The NPs were prepared by ionic gelation and subsequently characterized using FTIR, DSC, TEM, and DLS. A full factorial design was also adopted to study the effect of various formulation variables on EE%, particle size, and zeta-potential of NPs.

Results: NPs had a spherical shape and a mean particle size ranging between 135 and 220?nm. FTIR and DSC studies results were indicative of successful ionic gelation with the drug being dispersed in its amorphous form within CS-Pluronic^® matrix. Maximum EE% reaching 57.00?±?12.90% was achieved using Pluronic^®-123 based NPs. NPs exhibited a sustained release profile over 48?h. The MF-loaded NPs sensitized RKO CRC cells relative to drug alone.

Conclusion: The reported results highlighted the novel utility of the developed NPs in the arena of colon cancer treatment.     

Comparative study of different approaches for preparation of chlorzoxazone orodispersible tablets

Abstract

Context: Muscle spasm is a painful involuntary contraction of muscles, which causes involuntary movement and distortion. Chlorzoxazone is a centrally acting muscle-relaxant with sedative properties, but given orally, it is hepatically metabolized leading to decreased bioavailability.

Objective: Orodispersible tablets (ODTs) of chlorzoxazone were formulated using two different approaches; by coprocessed excipients (CE) or by liquisolid (LS) technique.

Materials and methods: Pharmaburst^® 500, Starlac^®, Pearlitol flash^®, Prosolv^® odt and F-melt^® were used as coprocessed superdisintegrants, whereas in LS, Avicel^® PH101, Microcelac^® 100 and Cellactose^® 80 were used as carriers, while Aerosil^® 200 was the coating material. ODTs were evaluated in terms of weight and thickness variations, drug content, hardness, friability, wetting time, dissolution, disintegration time (DT) and palatability.

Results: In vitro DT of CE-ODTs ranged from 26.43?±?1.693?s to >180?s, whereas it was between 25.42±?0.203?s to >180?s in LS-ODTs. Complete drug release within 15?min was attained by CE1 prepared with 92.5?mg Pharmaburst^® 500. In vivo DT of CE1 and LS3 were 19.779?±?0.810 and 18.105?±?0.423?s, respectively, using six volunteers. Volunteers found that CE1 had more acceptable taste and was more palatable than LS3.

Conclusion: It was concluded that chlorzoxazone ODTs could be successfully formulated using either CE or LS techniques and be used as novel dosage forms for pediatrics and geriatrics showing improved drug release. Moreover, CE technique was superior to LS technique in terms of palatability.     

Simple Prediction of Stability Constants for Inclusion Complexes of β-Cyclodextrin with various Drug Molecules Using β-Cyclodextrin Bonded Phases(Cyclobond® I Column)

Abstract

The stability constants(K_c) for inclusion complexes of cyclodextrin with sulfonamides, sulfonylureas and p-aminobenzoic acid esters were investigated by high performance liquid chromatography (HPLC) using the cyclodextrin bonded phase. The retention time(R_t) of these drugs on a Cyclobond® I column showed a good relationship to K, values obtained by the solubility method and/or conventional HPLC method. The advantages of this method were that the K, values could be rapidly predicted by a simple procedure using a minimum quantity of the drugs.     

Nanoparticulation improves bioavailability of Erlotinib

Objectives: Nanoparticulation using fat and supercritical fluid (NUFS^TM) is a drug delivery platform technology enabling efficient and effective formulation of poorly soluble drugs. We performed experiments to examine whether NUFS? could improve poor bioavailability and reduce fed-fasted bioavailability variances of erlotinib (Ert).

Methods: NUFS-Ert was prepared using NUFS? technology; its physical properties were characterized, and drug release was measured. Furthermore, in vitro and in vivo efficacy tests and pharmacokinetic analysis were performed.

Results: NUFS-Ert nanoparticles had an average size of 250?nm and were stable for 2 months at 40?°C, 4?°C, and room temperature. The dissolution rate of NUFS-Ert increased in bio-relevant dissolution media. NUFS-Ert was more potent in inhibiting EGF signaling and in suppressing the proliferation of A549, a human non-small cell lung cancer cell line. Furthermore, A549 xenografts in BALB/c nude mice treated with NUFS-Ert regressed more efficiently than those in the mice treated with vehicle or Tarceva^®. In addition, experimental lung metastasis was more efficiently inhibited by NUFS-Ert than by Tarceva^®. The relative bioavailability of NUFS-Ert compared with that of Tarceva^® was 550% and the ratio of the area under the concentration–time curve (AUC) of fed state to the AUC of fasted state was 1.8 for NUFS-Ert and 5.8 for Tarceva^®.

Conclusions: NUFS-Ert could improve poor bioavailability and reduce fed-fasted bioavailability variances of Ert. NUFS-Ert was more efficacious than Tarceva^®.     

The Quantitative Evaluation of a Granulation Milling Process III. Prediction of Output Particle Size

Abstract

Regression analysis was performed using comminution data from the previously presented Comil®G/aspirin granulation characterization study. Polynomial models were constructed using mill speed, output screen size and impeller shape as independent variables. The models were used to predict the mean particle size (µ_d) and geometric standard deviation (σ_d) of particle size distributions resulting from the comminution of aspirin using the Comil®G. The predictions were found to compare well with observed values.     

Preparation and evaluation of curcumin-loaded self-assembled micelles

Objective: Curcumin being used to treat various chronic diseases while its poor bioavailability issue limited its wide clinical application as a therapeutic agent. The aim of this work was to prepare curcumin-loaded self-assembled micelles using soluplus and solutol^®HS15 (SSCMs) to enhance curcumin’s solubility and thus oral bioavailability.

Methods: Optimum formulation was investigated and the optimized ratio of drugs and excipients was obtained and the SSCMs were prepared via ethanol solvent evaporation method. The optimal SSCMs were characterized by transmission electron microscopy, drug content analysis including loading efficiency (LE%) and entrapment efficiency (EE%), and the cumulative amount of curcumin released from the micelles were all calculated using HPLC method. The in vitro cytotoxicity and the permeability of SSCMs were measured by Caco-2 cell monolayers and the oral bioavailability was evaluated by SD rats.

Key findings: The solubility of curcumin in self-assembled micelles was dramatically increased by 4200 times as compared to free curcumin. Caco-2 cells transport experiment exhibited that while soluplus and solutol^®HS15 were self-assembled into micelles, it could not only promote the permeability of curcumin across membrane for better absorption, but also could restrain the curcumin pumped outside due to the role of P-gp efflux mechanism of soluplus and solutol^®HS15. Furthermore, the prepared SSCMs formulation was almost nontoxic and had safety performance on Caco-2 cells model. Moreover, curcumin’s oral bioavailability of SSCMs formulation in SD rats had doubled than that of free curcumin.

Conclusions: The prepared SSCMs were characterized by PS, PDI, LE%, EE% data analysis. After the soluplus and solutol^®HS15 were self assembled into micelles, both the solubility and membrane permeability of curcumin were evaluated to have been enhanced, as well as the effect of efflux pump of curcumin was inhibited, hence to promote oral absorption and generate an increased bioavailability.     

Low temperature processing of NiZn ferrite by citrate precursor method and study of properties

Abstract

Nickel zinc ferrite of composition Ni_0·5 Zn_0·5 Fe₂O₄ was prepared by the citrate precursor method at temperatures as low as 100°C. This is much lower than those used in the conventional ceramic method for the preparation of ferrites (~1000°C). The dc resistivity of the sintered specimens was observed to be ~10⁸ Ω cm which is greater, by at least two orders of magnitude, than that for specimens prepared by the conventional method. Although the initial permeability values are similar to those for conventionally prepared specimens, the losses are lower and the operational frequency range is larger. The significance of the citrate method lies, therefore, in producing ferrites with better properties at reduced processing temperatures.     

Film Coated Pellets Containing Verapamil Hydrochloride: Enhanced Dissolution into Neutral Medium

Abstract

Weakly basic drugs, such as verapamil hydrochloride, that are poorly soluble in neutral/alkaline medium may have poor oral bioavailability due to reduced solubility in the small intestine and colon. Film coated pellets were prepared using two strategies to enhance drug release at high pH values. Firstly, pellets were coated with Eudragit® RS/hydroxypropyl methylcellulose acetate succinate (HMAS) mixtures in proportions of 10:1 and 10:3, respectively. The enteric polymer, HMAS, would dissolve in medium at pH>6 creating pores through the insoluble Eudragit RS membrane to increase drug release. Secondly, an acidic environment was created within the core by the inclusion of fumaric acid at concentrations of 5 and 10% in order to increase drug solubility. Both strategies enhanced drug release into neutral medium in dissolution studies using the pH change method to simulate GIT transit. Dissolution profiles of samples tested in pH 1.2 for 12 hr were compared with those using the pH change method (pH 1.2 for first 1.5 hr, pH raised to 6.8 for remaining 10.5 hr) using the area under the dissolution curve (AUC), the dissolution half-life (t_50%), and the amount of drug released in 3 hr (A_{3 hr}) values. Both strategies enhanced drug release into neutral medium although the strategy using HMAS in the film was more effective. The formulation least affected by pH change was a combination of the two strategies, i.e., pellets containing 5% fumaric acid coated with Eudragit RS 12% w/w and HMAS 1.2% w/w.     

The Effect of Compaction Force and Type of Pregelatinized Starch on the Dissolution of Acetaminophen

Abstract

The influence of four pregelatinized starches—National® 1551, Lycatabps, Pregeflo®M, and Starch 1500®—as binders, on the dissolution of acetaminophen was evaluated in a model wet-granulated system. Systems containing 82% acetaminophen were prepared under the same processing conditions and compacted to three target tablet thicknesses. The dissolution performance was assessed using a point estimate of percent dissolved at 30 min (%T₃₀) as well as dissolution eflciency through 30 min (DE₃₀). All four binders evaluated meet USP requirements for purity. National 1551, Lycatab PGS, and Starch 1500 were not affected by compaction force in terms of dissolution performance. Differences were observed between the fully pregelatinized systems of National 1551 and Lycatab PGS, in comparison to the partially pregelatinized system, Starch 1500. The Pregeflo M starch produced a system with delayed drug dissolution and was influenced by compaction force.     

Effects of Lubricant Level,Method of Mixing,and Duration of Mixing on a Controlled-Release Matrix Tablet Containing Hydroxypropyl Methylcellulose

Abstract

The effects of the lubricant magnesium stearate at different concentrations, mixing shear rates, and mixing times on the tablet properties and drug dissolution from controlled-release matrix tablets containing hydroxypropyl methylcellulose 2208, USP (METHOCEL® K4M Premium) have been studied. Diphenhydramine HCl and hydrochlorothiazide were chosen as the model drugs. Spray-dried hydrous lactose (Fast Flo Lactose-316®) and anhydrous dibasic calcium phosphate (A-TAB®) were chosen as the model excipient/fillers. The impact of magnesium stearate on the mechanical strength of tablets appeared to be dependent on the bonding mechanism of the components of the powder mix. Tablets containing A-TAB, which compacts via a brittle fracture mechanism, were harder and had significantly better friability patterns than those prepared using Fast Flo Lactose-316. The compaction of Fast Flo Lactose-316 appears to be a combination of brittle fracture and plastic deformation. Mixes containing lower levels of lubricant (0.2%) generated tablets that had higher crushing strengths than those with higher lubricant levels (2.0%). Drug release was impacted to the greatest extent by the solubility of the drug and excipient/filler but was only slightly affected by the level of magnesium stearate and duration of mixing.     

Preparation and Evaluation of Eudragit® Acrylic Resin for Controlled Drug Release of Pseudoephedrine Hydrochloride

Abstract

The preparation of a sustained release dosage form for pseudoephedrine hydrochloride was evaluated. Beadlets (PS) containing pseudoephedrine hydrochloride were prepared by spraying a slurry of pseudoephedrine hydrochloride, Eudragit® S-100, dibutyl sebacate and alcohol onto non-pariel seeds via the Wurster column process. The oven-dried PS beadlets were coated with different levels of Eudragit® RS (poorly water permeable) and Eudragit® S-100 (enteric resin). In-vitro dissolution     

Hot melt extrusion versus spray drying: hot melt extrusion degrades albendazole

Abstract

The purpose of this study was to enhance the dissolution properties of albendazole (ABZ) by the use of amorphous solid dispersions. Phase diagrams of ABZ–polymer binary mixtures generated from Flory–Huggins theory were used to assess miscibility and processability. Forced degradation studies showed that ABZ degraded upon exposure to hydrogen peroxide and 1 N NaOH at 80?°C for 5?min, and the degradants were albendazole sulfoxide (ABZSX), and ABZ impurity A, respectively. ABZ was chemically stable following exposure to 1 N HCl at 80?°C for one hour. Thermal degradation profiles show that ABZ, with and without Kollidon^® VA 64, degraded at 180?°C and 140?°C, respectively, which indicated that ABZ could likely be processed by thermal processing. Following hot melt extrusion, ABZ degraded up to 97.4%, while the amorphous ABZ solid dispersion was successfully prepared by spray drying. Spray-dried ABZ formulations using various types of acids (methanesulfonic acid, sulfuric acid and hydrochloric acid) and polymers (Kollidon^® VA 64, Soluplus^® and Eudragit^® E PO) were studied. The spray-dried ABZ with methanesulfonic acid and Kollidon^® VA 64 substantially improved non-sink dissolution in acidic media as compared to bulk ABZ (8-fold), physical mixture of ABZ:Kollidon^® VA 64 (5.6-fold) and ABZ mesylate salt (1.6-fold). No degradation was observed in the spray-dried product for up to six months and less than 5% after one-year storage. In conclusion, amorphous ABZ solid dispersions in combination with an acid and polymer can be prepared by spray drying to enhance dissolution and shelf-stability, whereas those made by melt extrusion are degraded.     

Evaluation of Propylene Glycol Rosin Ester as Microencapsulating Material and Study of Dissolution Kinetics

Abstract

Propylene glycol rosin ester (PgR Ester) was prepared by heating rosin with propylene glycol at 220°C. The physicochemical properties were studied. Aspirin granules were encapsulated using a standardized coating technique. The microcapsules were evaluated for moisture absorption, flow properties and friability studies. The dissolution studies were carried out in five different pH media to know the effect of pH on release characteristics. The dissolution studies revealed that PgR Ester films impart varying degrees of resistance to different pH media. The t50% values were found to be 57,47,63,93 and 88 min in pH 1.2,3.0,5.0,7.2 and 8.0 media, exhibiting potential usefulness of PgR Ester as film coating material. The release patterns obey Hixson Crowell cube root dissolution law, the values of cube root constant are given.     

Development of an Implantable,Biodegradable, Controlled Drug Delivery System for Local Antibiotic Therapy

Abstract

A novel drug delivery system was developed using a monoglyceride (Glycerol Monostearate) and a water-soluble release rate modifier as the matrix. Cefuroxime sodium (Zinacef®) was chosen as a model drug in this study. Formulations (cylindrical implants 6 × 6 mm) were prepared by a melt-dispersion method. Dissolution studies were performed using USP paddle method. The effect of glycerol, PEG 400 and their combination on drug release profiles was studied. Two assay methods (UV and HPLC) for cefuroxime analysis were compared. Percent recovery from four formulations (A-D) was higher with UV than HPLC assay. While both UV and HPLC assay methods were developed for cefuroxime, only HPLC assay is stability indicating. Glycerol showed higher accelerating effect than PEG 400 on the drug release. All formulations exhibited extended release of cefuroxime. Degradation of cefuroxime occurred mainly during dissolution suggesting drug stability in the formulations.     

Development of Controlled-Release Buccoadhesive Hydrophilic Matrices of Diltiazem Hydrochloride: Optimization of Bioadhesion,Dissolution, and Diffusion Parameters

ABSTRACT

Buccoadhesives have long been employed to improve the bioavailability of drugs undergoing significant hepatic first-pass metabolism. Diltiazem hydrochloride (DLZ) is also reported to have low oral bioavailability due to an extensive hepatic first-pass effect. Controlled-release buccoadhesive hydrophilic matrices containing DLZ were prepared using a 3² factorial design. Amounts of Carbopol® 934P (CP) and Methocel® K100LV (HPMC) were taken as the formulation variables (factors) for optimizing bioadhesion, and kinetics of dissolution and diffusion. A mathematical model was generated for each response parameter. Bioadhesive strength tended to vary quite linearly in increasing order with increasing amount of each polymer. The drug release pattern for all the formulation combinations was found to be non-fickian, approaching zero-order kinetics. The values of permeation coefficient tended to vary non-linearly with polymer amount, depicting the plausibility of interaction between the two polymers. Suitable combinations of the two polymers provided adequate bioadhesive strength and a fairly regulated release profile up to 10 hr. The response surfaces and contour plots for each response parameter are presented for further interpretation of the results. The optimum formulations were chosen and their predicted results found to be in close agreement with experimental findings.     

Preparation and Characterization of Solid Dispersions of Piroxicam with Hydrophilic Carriers

ABSTRACT

The objective of this study was to improve the dissolution rate of a poor water soluble drug, piroxicam, by solid dispersion technique. Solid dispersions were prepared by three different methods depending on the type of carrier. The dissolution rate of piroxicam was markedly increased in solid dispersion of myrj 52, Eudragit® E100 and mannitol. Solubility studies revealed a marked increase in the solubility of piroxicam with an increase in myrj 52 and Eudragit® E100 concentrations. Data from the X-ray diffraction and FT-IR spectroscopy showed that piroxicam was amorphous in the solid dispersions prepared with dextrin and Eudragit® E100.     

Controlled release tablet formulation containing natural Δ9-tetrahydrocannabinol

Cannabinoids are increasingly being used in the treatment of chemotherapy-induced nausea and vomiting (CINV) because of their action on the cannabinoid receptors, CB1 and CB2. The currently marketed capsule formulations (sesame oil based and crystalline powder) are required to be administered frequently to maintain therapeutic levels, which leads to non-compliance. In the present study, oral controlled release tablet formulations of Δ⁹-tetrahydrocannabinol (THC) were prepared using the lipids Precirol® and Compritol®. Release profiles using THC-lipid matrices and/or with the lipids in the external phase (blend) were evaluated. The effect of directly compressible diluents lactose mixture (Ludipress®), dicalcium phosphate anhydrous (Emcompress®) and microcrystalline cellulose (Avicel® 102) on tablet characteristics and in vitro drug release was also investigated. Further, in vitro THC release in the presence of a lipase inhibitor, Pluronic® F68, was also studied. A 24 h zero-order THC release profile was obtained with a combination of Precirol® and Compritol® in the compression blend. Addition of Pluronic® F68 did not alter THC release in vitro. These optimized tablets were chemically and physically stable for 3 months, the last time point tested, at 25?°C/60% RH. The overall results demonstrate the feasibility of preparing oral THC tablets for once a day administration which can improve CINV management.     

Release of Theophylline from Ethyl Cellulose Mecrocapsues Alone and in Conjuction with Fat Embedded (Precirol®) Granules and Hydroxypropyl Methycellulose

Abstract

Microcapsules of theophylline with ethyl cellulose were prepared by coacervation technique using cabosil® (silicon dioxide) as separant. Tablets were prepared from microcapsules, microcapsules + theophylline fat embedded granules, and microcapsules and hydroxypropyl methylcellulose 4000 (HPMC). Release was studied in vitro by the rotating basket method. Prolonged release of theophylline was observed from microcapsules with no drug dumping. The release from microcapsules was of first-order whereas that from all the tablet formulation was diffusion controlled according to the Higuchi model. Good correlation was found between release rate and core:wall ratio for all the systems. Decrease in hardness of tablets made from microcapsules alone decreased the release rate, indicating damage of microcapsules during compression. The tablets compressed from fat embedded granules, microcapsules with fat embedded granules, and microcapsules with HPMC gave a desired release for a 74 hour sustained release preparation.     

A computational method to differentiate normal individuals,osteoarthritis and rheumatoid arthritis patients using serum biomarkers

The objective of this study was to develop a method for categorizing normal individuals (normal, n = 100) as well as patients with osteoarthritis (OA, n = 100), and rheumatoid arthritis (RA, n = 100) based on a panel of inflammatory cytokines expressed in serum samples. Two panels of inflammatory proteins were used as training sets in the construction of two separate artificial neural networks (ANNs). The first training set consisted of all proteins (38 in total) and the second consisted of only the significantly different proteins expressed (12 in total) between at least two patient groups. Both ANNs obtained high levels of sensitivity and specificity, with the first and second ANN each diagnosing 100% of test set patients correctly. These results were then verified by re-investigating the entire dataset using a decision tree algorithm. We show that ANNs can be used for the accurate differentiation between serum samples of patients with OA, a diagnosed RA patient comparator cohort and normal/control cohort. Using neural network and systems biology approaches to manage large datasets derived from high-throughput proteomics should be further explored and considered for diagnosing diseases with complex pathologies.