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1.  Identification of Phthalates in Medications and Dietary Supplement Formulations in the United States and Canada 
Environmental Health Perspectives  2011;120(3):379-384.
Background: In animal studies, some ortho-phthalates, including di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP), have been shown to be reproductive and developmental toxicants. Human studies show widespread population exposure to background levels of phthalates. Limited evidence suggests that particularly high exposure levels may result from orally ingested medicinal products containing phthalates as excipients (inactive ingredients).
Objective: In this study we aimed to identify and describe the scope of prescription (RX) and nonprescription (over-the-counter; OTC) medicinal products and dietary supplements marketed in the United States and Canada since 1995 that include phthalates as excipients.
Methods: We used lists of modified-release drug products to identify potential drug products. Inclusion of phthalates was verified using available electronic databases, print references, published package inserts, product packages, and direct communication from manufacturers. Additional products were identified using Internet searches utilizing keywords for phthalates.
Results: Based on labeling information, 6 RX drug products included DBP as an excipient, and 45 specified the use of diethyl phthalate (DEP). Phthalate polymers with no known toxicity—hypromellose phthalate (HMP), cellulose acetate phthalate (CAP), and polyvinyl acetate phthalate (PVAP)—were included in 75 RX products. Three OTC drug and dietary supplement products listed DBP, 64 listed DEP, and > 90 indicated inclusion of polymers.
Conclusions: Numerous RX and OTC drug products and supplements from a wide range of therapeutic categories may use DBP or DEP as excipients in oral dosage forms. The potential effects of human exposure to these phthalates through medications are unknown and warrant further investigation.
PMCID: PMC3295354  PMID: 22169271
coating; dietary supplements; excipients; medications; phthalates
2.  Microbicide excipients can greatly increase susceptibility to genital herpes transmission in the mouse 
BMC Infectious Diseases  2010;10:331.
Several active ingredients proposed as vaginal microbicides have been shown paradoxically to increase susceptibility to infection in mouse genital herpes (HSV-2) vaginal susceptibility models and in clinical trials. In addition, "inactive ingredients" (or excipients) used in topical products to formulate and deliver the active ingredient might also cause epithelial toxicities that increase viral susceptibility. However, excipients have not previously been tested in susceptibility models.
Excipients commonly used in topical products were formulated in a non-toxic vehicle (the "HEC universal placebo"), or other formulations as specified. Twelve hours after exposure to the excipient or a control treatment, mice were challenged with a vaginal dose of HSV-2, and three days later were assessed for infection by vaginal lavage culture to assess susceptibility.
The following excipients markedly increased susceptibility to HSV-2 after a single exposure: 5% glycerol monolaurate (GML) formulated in K-Y® Warming Jelly, 5% GML as a colloidal suspension in phosphate buffered saline, K-Y Warming Jelly alone, and both of its humectant/solvent ingredients (neat propylene glycol and neat PEG-8). For excipients formulated in the HEC vehicle, 30% glycerin significantly increased susceptibility, and a trend toward increased HSV-2 susceptibility was observed after 10% glycerin, and 0.1% disodium EDTA, but not after 0.0186% disodium EDTA. The following excipients did not increase susceptibility: 10% propylene glycol, 0.18%, methylparaben plus 0.02% propylparaben, and 1% benzyl alcohol.
As reported with other surfactants, the surfactant/emulsifier GML markedly increased susceptibility to HSV-2. Glycerin at 30% significantly increased susceptibility, and, undiluted propylene glycol and PEG-8 greatly increased susceptibility.
PMCID: PMC2996397  PMID: 21087496
3.  Effects of Commonly Used Excipients on the Expression of CYP3A4 in Colon and Liver Cells 
Pharmaceutical research  2010;27(8):1703-1712.
The objective of this investigation was to assess whether common pharmaceutical excipients regulate the expression of drug-metabolizing enzymes in human colon and liver cells.
Nineteen commonly used excipients were evaluated using a panel of experiments including cell-based human PXR activation assays, real-time RT-PCR assays for CYP3A4 mRNA expression, and immunoblot analysis of CYP3A4 protein expression in immortalized human liver cells (HepG2 and Fa2N4), human primary hepatocytes, and the intestinal LS174T cell models.
No excipient activated human PXR or practically induced CYP3A4. However, three excipients (polysorbate 80, pregelatinized starch, and hydroxypropyl methylcellulose) tended to decrease mRNA and protein expression across experimental models.
This study represents the first investigation of the potential role of excipients in the expression of drug-metabolizing enzymes. Findings imply that some excipients may hold potential for excipient-drug interactions by repression of CYP3A4 expression.
PMCID: PMC3718039  PMID: 20503067
Excipients; CYP3A4; PXR; Induction; Repression
4.  In Vitro Evaluation of Viability, Integrity, and Inflammation in Genital Epithelia upon Exposure to Pharmaceutical Excipients and Candidate Microbicides▿  
Antimicrobial Agents and Chemotherapy  2010;54(12):5105-5114.
The use of microbicides is a promising approach for the prevention of HIV-1 transmission. Unfortunately, various candidates failed in clinical trials. In some cases, the candidate microbicide even resulted in enhanced virus transmission. Therefore, there is an urgent need to develop more predictive preclinical strategies to anticipate the in vivo efficiency/toxicity rate, including in vitro assays that evaluate effects on epithelial integrity and inflammation. The present study aims to identify potential safety issues concerning the use of microbicides and excipients commonly used in vaginal microbicide preparations. The toxicities of various active pharmaceutical ingredients (APIs; TMC-120, UC-781, tenofovir [PMPA], PRO-2000, and glycerol monolaurate [GML]) and excipients (preservatives, cosolvents, surfactants, and cyclodextrins) were evaluated using an in vitro dual-chamber model and uterine cervical explants. Epithelial viability and permeation of fluorescent virus-sized beads, as well as induction of interleukin-8 (IL-8; as a sensitive marker of an inflammatory response), were assessed. Surprisingly, cell viability and epithelial layer integrity were compromised by most excipients at concentrations near the typical concentration used in vaginal gels, and a significant increase in the production of IL-8 was observed at subtoxic concentrations. Within the APIs, TMC-120, UC-781, and PMPA showed higher selectivity indices than PRO-2000 and GML. In conclusion, identification of safety issues concerning the use of pharmaceutical excipients could help to formulate less toxic vaginal microbicide preparations.
PMCID: PMC2981258  PMID: 20921308
5.  Thermal behaviour of procaine and benzocaine Part II: compatibility study with some pharmaceutical excipients used in solid dosage forms 
The compatibility study of active substances with excipients finds an important role in the domain of pharmaceutical research, being known the fact that final formulation is the one administered to the patient. In order to evaluate the compatibility between active substance and excipients, different analytical techniques can be used, based on their accuracy, reproducibility and fastness.
Compatibility study of two well-known active substances, procaine and benzocaine, with four commonly used excipients, was carried out employing thermal analysis (TG/DTG/HF) and Fourier Transform Infrared Spectroscopy (UATR-FT-IR). The selected excipients were microcrystalline cellulose, lactose monohydrate, magnesium stearate and talc. Equal proportion of active substance and excipients (w/w) was utilized in the interaction study. The absolute value of the difference between the melting point peak of active substances and the one corresponding for the active substances in the analysed mixture, as well the absolute value of the difference between the enthalpy of the pure active ingredient melting peak and that of its melting peak in the different analysed mixtures were chosen as indexes of the drug-excipient interaction degree. All the results obtained through thermal analysis were also sustained by FT-IR spectroscopy.
The corroboration of data obtained by thermal analysis with the ones from FT-IR spectroscopy indicated that no interaction occurs between procaine and benzocaine, with microcrystalline cellulose and talc, as well for the benzocaine-lactose mixture. Interactions were confirmed between procaine and benzocaine respectively and magnesium stearate, and for procaine and lactose.
PMCID: PMC4015284  PMID: 23962059
Procaine; Benzocaine; Excipients; Compatibility studies; TG/DTG/HF
6.  Comparison of two alternative study designs in assessment of medicines utilisation in neonates 
Estimates of prevalence are known to be affected by the design of cross-sectional studies. A pan-European study provided an opportunity to compare the effect of two cross-sectional study designs on estimates of medicines use.
A Service evaluation survey (SES) and a web-based point-prevalence study (PPS) were conducted as part of a European study of neonatal exposure to excipients. Neonatal units from all European Union countries plus Iceland, Norway, Switzerland and Serbia were invited to participate. All medicines prescribed to neonates were recorded during three-day and one-day study periods in the SES and PPS, respectively. In the PPS individual demographic and prescription data were also collected.
To compare the probabilities that a particular medicine would be reported by each study multilevel mixed effects logistic regression models with crossed random effects were applied. The relationship between medicines exposure at the unit and individual levels in the PPS data was assessed using polynomial regression with square root transformation.
Of 31 invited countries 20 and 21 with 115 and 89 units joined the SES and PPS, respectively. Out of 5,572,859 live births in invited countries in 2010 a higher proportion was covered by units participating in the SES compared to the PPS (11% vs 6%, respectively; OR 1.89; 95% CI 1.87-1.89). A greater number of active pharmaceutical ingredients (API), manufacturers and trade names were registered in the SES compared to the PPS. High correlation between the two studies in frequency of use for each specified API was seen (R2 = 0.86). The average probability of a department to use a given API was greater in the SES compared to the PPS (OR 2.36; 95% CI 2.05-2.73) with higher frequency of use and longer average duration of prescription further increasing the difference. The polynomial regression model described the correlation between APIs exposure on unit and individual level well (R2 = 0.93).
The simple data structure and longer study period of the SES resulted in improved recruitment and higher likelihood of capture for a given API. The frequency of use at the unit level appears a good surrogate of individual exposure rates.
PMCID: PMC4110064  PMID: 25027048
Pharmacoepidemiologic methods; Cross-sectional studies; Data collection; Drug/excipient exposure
7.  Preliminary Studies on Validation of Calu-3 Cell Line as a Model for Screening Respiratory Mucosa Irritation and Toxicity 
Pharmaceutics  2014;6(2):268-280.
There is need to develop reproducible methods and experimental models for screening mucosal irritation and toxicity for drugs and pharmaceutical excipients. The aim of this study was to validate Calu-3 cell line as a model for screening respiratory irritation and toxicity of drugs and excipients. Eighteen test compounds were selected according to their irritation potential and European Centre for the Validation of Alternative Methods (ECVAM) guidelines. Cell toxicity and irritation was determined using MTT assay. Data analysis and interpretation were done using modified ECVAM approach; where replicate values met acceptance criteria if percent relative standard deviation (RSD) of the raw data is <18%. Compounds with mean relative viability values of 50% and below were classified as irritant (I); those above 50% were non-irritant (NI). At low concentration (0.2% w/v) and 1 h incubation, the Calu-3 cell culture model accurately predicted the toxicity of most test compounds. The specificity of our proposed model (percentage of in vivo non-irritants correctly predicted), concordance (percentage of compounds correctly predicted) and sensitivity (percentage of in vivo irritants correctly predicted) at 0.2% w/v and 60 min exposure were 100%, 72%, and 44%, respectively. In conclusion, the Calu-3 cell line in conjunction with MTT assay appears to be a potentially useful tool for screening drugs and excipients for respiratory mucosa irritation and toxicity. However, as the data reported in this study were solely based on MTT assay, additional studies are needed using other toxicity-/irritation-indicating methods to confirm the observed trend.
PMCID: PMC4085599  PMID: 24962675
Calu-3 cells; MTT; toxicity prediction; mucosal toxicity
8.  Analysis of Structural Variability in Pharmaceutical Excipients Using Solid-State NMR Spectroscopy 
AAPS PharmSciTech  2011;12(3):821-833.
Polysaccharide-based excipients comprise the majority of most solid dosage forms and can vary dramatically in terms of structural and functionally related properties. Analytical methods for characterizing these important formulation components are crucial. Solid-state NMR spectroscopy (SSNMR) can provide a wealth of information on these materials while offering the advantages of non-destructive sample preparation and selectivity. The overall objective of this work is to identify SSNMR parameters that can be used to detect differences among these excipients. Excipients were obtained from a wide range of suppliers and analyzed as received; 13C SSNMR spectra were acquired using a Chemagnetics CMX-300 spectrometer operating at approximately 75 MHz. The resolution of SSNMR signals of many excipients allows for positive identification of the major form present. Alginic acid and sodium alginate can be differentiated based on carbonyl peak position. Analysis of relative peak intensities provides insight into the purity of a carrageenan sample compared to known standards. The SSNMR spectrum of starch can be used to identify the source and to quantitate the amorphous and crystalline content. Relaxation values and peak areas of starch derivatives can be related to the degree of hydrolysis, providing an alternative method for determining dextrose equivalent. Differences in peak intensities and relaxation time values of HPMC samples can be correlated to the amount of methoxy subsituent groups. Important characteristics of excipients such as form identification, structural differences, crystalline and amorphous content, and water content variations can be detected using SSNMR spectroscopy.
PMCID: PMC3167250  PMID: 21710337
excipients; polysaccharide; relaxation time; solid-state NMR spectroscopy
9.  Excipient selection can significantly affect solid-state phase transformation in formulation during wet granulation 
AAPS PharmSciTech  2005;6(2):E311-E322.
Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The influences of formulation design on the optimal dosage forms should be specified. The aim here was to investigate whether excipients with different water sorption behavior affect hydrate formation of nitrofurantoin in wet masses. Nitrofurantoin anhydrate was used as a hydrate-forming model drug, and 4 excipients with different water-absorbing potential (amorphous low-substituted hydroxypropylcellulose, modified maize starch, partially amorphous silicified microcrystalline cellulose, and crystalline α-lactose monohydrate) were granulated with varying amounts of purified water. Off-line evaluation of wet masses containing nitrofurantoin anhydrate and excipient (1∶1) was performed using an X-ray powder diffractometer (XRPD) and near-infrared spectroscopy, and drying phase was evaluated by variable temperature XRPD. Only amorphous excipient in the formulation retarded hydrate formation of an active pharmaceutical ingredient (API) at high water contents. Hygroscopic partially crystalline excipient hindered hydrate formation of API at low water contents. Crystalline excipient was unable to control hydrate formation of API. The character of excipient affects the stability of formulation. Thus, correct selection of excipients for the formulation can control processing-induced phase transitions and improve the storage stability of the final dosage form.
PMCID: PMC2750544  PMID: 16353990
nitrofurantoin; near-infrared spectroscopy; sorption; X-ray powder diffraction
10.  Influence of Formulation and Processing Factors on Stability of Levothyroxine Sodium Pentahydrate 
AAPS PharmSciTech  2010;11(2):818-825.
Stability of formulations over shelf-life is critical for having a quality product. Choice of excipients, manufacturing process, storage conditions, and packaging can either mitigate or enhance the degradation of the active pharmaceutical ingredient (API), affecting potency and/or stability. The purpose was to investigate the influence of processing and formulation factors on stability of levothyroxine (API). The API was stored at long-term (25°C/60%RH), accelerated (40°C/75%RH), and low-humidity (25°C/0%RH and 40°C/0%RH) conditions for 28 days. Effect of moisture loss was evaluated by drying it (room temperature, N2) and placed at 25°C/0%RH and 40°C/0%RH. The API was incubated with various excipients (based on package insert of marketed tablets) in either 1:1, 1:10, or 1:100 ratios with 5% moisture at 60°C. Commonly used ratios for excipients were used. The equilibrium sorption data was collected on the API and excipients. The API was stable in solid state for the study duration under all conditions for both forms (potency between 90% and 110%). Excipients effect on stability varied and crospovidone, povidone, and sodium laurel sulfate (SLS) caused significant API degradation where deiodination and deamination occurred. Moisture sorption values were different across excipients. Crospovidone and povidone were hygroscopic whereas SLS showed deliquescence at high RH. The transient formulation procedures where temperature might go up or humidity might go down would not have major impact on the API stability. Excipients influence stability and if possible, those three should either be avoided or used in minimum quantity which could provide more stable tablet formulations with minimum potency loss throughout its shelf-life.
PMCID: PMC2902299  PMID: 20454876
excipients; formulation; levothyroxine sodium pentahydrate; moisture sorption; stability
11.  Evaluation of Gum of Moringa oleifera as a Binder and Release Retardant in Tablet Formulation 
The present study was undertaken to find out the potential of gum from Moringa oleifera to act as a binder and release retardant in tablet formulations. The effect of calcium sulphate dihydrate (water insoluble) and lactose (water soluble) diluent on the release of propranolol hydrochloride was studied. The DSC thermograms of drug, gum and mixture of gum/drug indicated no chemical interaction. Tablets (F1, F2, F3, and F4) were prepared containing calcium sulphate dihydrate as diluent, propranolol hydrochloride as model drug using 10%, 8%, 6% and 4% w/v of gum solution as binder. Magnesium stearate was used as lubricant. Physical and technological properties of granules and tablets like flow rate, Carr index, Hausner ratio, angle of repose, hardness, friability and disintegration time were determined and found to be satisfactory. Tablets were prepared by wet granulation method containing calcium sulphate dihydrate as excipient, propranolol hydrochloride as model drug using 10%, 20% and 30% of gum as release retardant, magnesium stearate was used as lubricant. Similarly tablets were prepared replacing lactose with calcium sulphate dihydrate. Despite of the widely varying physico-chemical characteristics of the excipients, the drug release profiles were found to be similar. The drug release increased with increasing proportions of the excipient and decreased proportion of the gum irrespective of the solubility characteristics of the excipient. The values of release exponent ‘n’ are between 0.37 and 0.54. This implies that the release mechanism is Fickian. There is no evidence that the dissolution or erosion of the excipient has got any effect on the release of the drug. The t50% values for tablets containing calcium sulphate dihydrate were on an average 10%-15% longer than the tablets containing lactose as excipient. These relatively small differences in t50% values suggest that the nature of excipient used appeared to play a minor role in regulating the release, while the gum content was a major factor.
PMCID: PMC3038286  PMID: 21394258
Binder; gum; Moringa oleifera; release retardant; tablet
12.  Herbal Excipients in Novel Drug Delivery Systems 
The use of natural excipients to deliver the bioactive agents has been hampered by the synthetic materials. However advantages offered by these natural excipients are their being non-toxic, less expensive and freely available. The performance of the excipients partly determines the quality of the medicines. The traditional concept of the excipients as any component other than the active substance has undergone a substantial evolution from an inert and cheap vehicle to an essential constituent of the formulation. Excipients are any component other than the active substance(s) intentionally added to formulation of a dosage form. This article gives an overview of herbal excipients which are used in conventional dosage forms as well as novel drug delivery systems.
PMCID: PMC2792536  PMID: 20046764
Polysaccharides; volatile oils; controlled delivery
13.  Design and development of a stable polyherbal formulation based on the results of compatibility studies 
Pharmacognosy Research  2011;3(2):122-129.
Ayurvedic and herbal medicinal products contain a combination of botanicals; each of these contains a number of chemical compounds that may give the anticipated activity in combination. Therefore, it is very important to analyze and evaluate the compatibility of various active constituents and markers from different medicinal plants for their possible chemical interactions with various excipients at different storage conditions during the development of a stable polyherbal formulation.
To study chemical stability of kalmegh (Andrographis paniculata) and kutki (Picrorhiza kurroa) extract for their active markers andrographolide, kutkoside and picroside-I and to develop stable polyherbal formulation based on the incompatibility studies.
Materials and Methods:
The compatibility study was carried out on individual ethanolic extracts of these two plants along with the commonly used excipients in the ratio of 1:1 at 40 ± 2°C and 75 ± 5% relative humidity and at a refrigeration temperature of 5 ± 1°C for initial, 7-, 15- and 30-day intervals. The analysis was carried out using the validated reverse phase–high-performance liquid chromatography methods. A stable tablet dosage form was developed based on the results of these studies.
The study suggested that the active markers of kutki (kutkoside and picroside-I) were found to be degraded in the presence of the kalmegh extract. However, the active marker of the kalmegh extract (andrographolide) was found to be stable. Both the extracts showed excellent compatibility with all the excipients used in making this formulation. No significant decrease in the kutkoside and picroside-I content from the formulation was observed.
By separate granulation process the exposure of both the extracts can be minimized thus avoiding the degradation of active markers.
PMCID: PMC3129021  PMID: 21772756
Compatibility; andrographolide; kutkoside; picroside-I
14.  The Molecular Chaperone α-Crystallin as an Excipient in an Insulin Formulation 
Pharmaceutical Research  2010;27(7):1337-1347.
To investigate insulin fibrillation under accelerated stress conditions in the presence of a novel excipient, the molecular chaperone α-crystallin, in comparison with common excipients.
To induce fibrillation, recombinant human insulin (0.58 mg ml−1) formulations without excipient or with bovine α-crystallin (0.01–0.2 mg ml−1), human serum albumin (1–5 mg ml−1), sucrose (10–100 mg ml−1) or polysorbate 80 (0.075–0.3 mg ml−1) were subjected to stirring stress in a fluorescence well plate reader and formulation vials. Protein fibrillation was monitored by thioflavin T. The formulations were further characterized by size-exclusion chromatography, light obscuration, UV/Vis and circular dichroism spectroscopy.
In both methods, insulin formed thioflavin T-binding species, most likely fibrils. Addition of α-crystallin in the well plate assay greatly improved insulin’s resistance to fibrillation, measured as a 6-fold increase in fibrillation lag time for the lowest and 26-fold for the highest concentration used, whereas all other excipients showed only a marginal increase in lag time. The stabilizing effect of α-crystallin was shown by all characterization techniques used.
The effect of α-crystallin on insulin’s physical stability outperforms that of commonly used excipients. α-Crystallin is proposed to bind specifically to pre-fibrillation species, thereby inhibiting fibrillation. This makes α-crystallin an interesting excipient for proteins with propensity to fibrillate.
PMCID: PMC2883933  PMID: 20333453
fibrillation; formulation design; insulin; protein excipients; α-crystallin
15.  Reactive Impurities in Excipients: Profiling, Identification and Mitigation of Drug–Excipient Incompatibility 
AAPS PharmSciTech  2011;12(4):1248-1263.
Reactive impurities in pharmaceutical excipients could cause drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants. The levels of reactive impurities in excipients may vary between lots and vendors. Screening of excipients for these impurities and a thorough understanding of their potential interaction with drug candidates during early formulation development ensure robust drug product development. In this review paper, excipient impurities are categorized into six major classes, including reducing sugars, aldehydes, peroxides, metals, nitrate/nitrite, and organic acids. The sources of generation, the analytical method for detection, the stability of impurities upon storage and processing, and the potential reactions with drug candidates of these impurities are reviewed. Specific examples of drug–excipient impurity interaction from internal research and literature are provided. Mitigation strategies and corrective measures are also discussed.
PMCID: PMC3225520  PMID: 21948318
excipients; impurities; interaction; mitigation; variability
16.  Development of co-processed excipients in the design and evaluation of atorvastatin calcium tablets by direct compression method 
Co-processed excipients were prepared to improve the process ability and efficacy of commonly used excipients and to impart multi-functional qualities to the excipients and hence that the tablets with the desired attributes can be produced. In this study, acacia and calcium carbonate (CaCO3) were used to prepare a co-processing excipient suitable for the preparation of atorvastatin calcium tablets. Acacia is used as binder and CaCO3 as filler. CaCO3 also acts as alkalizer and thus suitable to improve the dissolution rate of pH dependent soluble drugs like atorvastatin.
Materials and Methods:
The tablets were prepared by direct compression method and the physical properties of tablets such as hardness, friability and dissolution profiles of tablets were evaluated. Acacia was used in the form of mucilage. Various ratios of the co-processing excipients were formulated by granulation technique and the blend properties were evaluated by their Hausner's ratio and Carr's index values. Based on the Kawakita plots, it was found that the formulation with 3% acacia mucilage (0.9 mg acacia and 26.6 mg of CaCO3) showed good fluidity and the formulations with 4% (1.27 mg of acacia and 26.23 mg of CaCO3) and 5% acacia mucilage (1.62 mg of acacia and 25.88 mg of CaCO3) showed more cohesiveness. The formulations include 1-5% of the acacia mucilage as the binding agent.
The granules of formulations with low percentage of acacia mucilage (1% and 2%) failed the test for friability. The granules of the formulations with pure acacia (F1) and pure CaCO3 (F2) showed passable flow properties.
The formulation with 3% acacia mucilage (F3, 0.9 mg acacia and 26.6 mg of CaCO3) showed least dissolution time (<1 min) and is found as the best formulation among the other formulations containing 4% (F4, 1.27 mg of acacia and 26.23 mg of CaCO3) and 5% (F5, 1.62 mg of acacia and 25.88 mg of CaCO3) acacia mucilage.
PMCID: PMC4083533  PMID: 25006555
Acacia; alkalizer; calcium carbonate; granulation technique
17.  Intrinsic Fibrillation of Fast-Acting Insulin Analogs 
Aggregation of insulin into insoluble fibrils (fibrillation) may lead to complications for diabetes patients such as reduced insulin potency, occlusion of insulin delivery devices, or potentially increased immunological potential.
Even after extensive investigation of fibril formation in regular human insulin, there are little published data about the intrinsic fibrillation of fast-acting analogs. This article investigates and compares the intrinsic fibrillation of three fast-acting insulin analogs—lispro, aspart, and glulisine—as a function of their primary protein structure and exclusive of the stabilizing excipients that are added to their respective commercial formulations.
The insulin analogs underwent a buffer exchange into phosphate-buffered saline to remove formulation excipients and then were heated and agitated to characterize intrinsic fibrillation potentials devoid of excipient stabilizing effects. Different analytical methods were used to determine the amount of intrinsic fibrillation for the analogs. After initial lag times, intrinsic fibrillation was detected by an amyloid-specific stain. Precipitation of insulin was confirmed by ultraviolet analysis of soluble insulin and gravimetric measurement of insoluble insulin. Electron microscopy showed dense fibrous material, with individual fibrils that are shorter than typical insulin fibrils. Higher resolution kinetic analyses were carried out in 96-well plates to provide more accurate measures of lag times and fibril growth rates.
All three analogs exhibited longer lag times and slower intrinsic fibrillation rates than human insulin, with glulisine and lispro rates slower than aspart. This is the first study comparing the intrinsic fibrillation of fast-acting insulin analogs without the stabilizing excipients found in their commercial formulations.
Data show different intrinsic fibrillation potentials based on primary molecular structures when the formulation excipients that are critical for stability are absent. Understanding intrinsic fibrillation potential is critical for evaluating insulin analog stability and device compatibility.
PMCID: PMC3380767  PMID: 22538135
amyloid; circular dichroism; excipients; fibrils; insulin; insulin stability; intrinsic fibrillation; protein aggregation; protein precipitation; thioflavine T
18.  Numerical Model to Characterize the Size Increase of Combination Drug and Hygroscopic Excipient Nanoparticle Aerosols 
Enhanced excipient growth is a newly proposed respiratory delivery strategy in which submicrometer or nanometer particles composed of a drug and hygroscopic excipient are delivered to the airways in order to minimize extrathoracic depositional losses and maximize lung retention. The objective of this study was to develop a validated mathematical model of aerosol size increase for hygroscopic excipients and combination excipient-drug particles and to apply this model to characterize growth under typical respiratory conditions. Compared with in vitro experiments, the droplet growth model accurately predicted the size increase of single component and combination drug and excipient particles. For typical respiratory drug delivery conditions, the model showed that droplet size increase could be effectively correlated with the product of a newly defined hygroscopic parameter and initial volume fractions of the drug and excipient in the particle. A series of growth correlations was then developed that successively included the effects of initial drug and excipient mass loadings, initial aerosol size, and aerosol number concentration. Considering EEG delivery, large diameter growth ratios (2.1–4.6) were observed for a range of hygroscopic excipients combined with both hygroscopic and non-hygroscopic drugs. These diameter growth ratios were achieved at excipient mass loadings of 50% and below and at realistic aerosol number concentrations. The developed correlations were then used for specifying the appropriate initial mass loadings of engineered insulin nanoparticles in order to achieve a predetermined size increase while maximizing drug payload and minimizing the amount of hygroscopic excipient.
PMCID: PMC3143486  PMID: 21804683
Respiratory drug delivery; enhanced excipient growth (EEG); nanoaerosols; hygroscopic droplet growth; hygroscopic excipients; combination particles; engineered particles; in vitro experiments of aerosol growth; capillary aerosol generation; numerical simulations; targeted drug delivery
19.  The solution and solid state stability and excipient compatibility of parthenolide in feverfew 
AAPS PharmSciTech  2007;8(4):200-205.
The objectives of this research were to evaluate the stability of parthenolide in feverfew solution state and powdered feverfew (solid state), and explore the compatibility between commonly used excipients and parthenolide in feverfew. Feverfew extract solution was diluted with different pH buffers to study the solution stability of parthenolide in feverfew. Powdered feverfew extract was stored under 40°C/0%∼75% relative humidities (RH) or 31% RH/5∼50°C to study the influence of temperature and relative humidity on the stability of parthenolide in feverfew solid state. Binary mixtures of feverfew powered extract and different excipients were stored at 50°C/ 75% RH for excipient compatibility evaluation. The degradation of parthenolide in feverfew solution appears to fit a typical first-order reaction. Parthenolide is comparatively stable when the environmental pH is in the range of 5 to 7, becoming unstable when pH is less than 3 or more than 7. Parthenolide degradation in feverfew in the solid state does not fit any obvious reaction model. Moisture content and temperature both play important roles affecting the degradation rate. A fter 6 months of storage, parthenolide in feverfew remains constant at 5°C/31% RH. However, ∼40% parthenolide in feverfew can be degraded if stored at 50°C/31% RH. When the moisture changed from 0% to 75% RH, the degradation of parthenolide in feverfew increased from 18% to 32% after 6-month storage under 40°C. Parthenolide in feverfew exhibits good compatibility with commonly used excipients under stressed conditions in a 3-week screening study.
PMCID: PMC2750691  PMID: 18181526
Feverfew; Botanical; Parthenolide; Stability; Excipient compatibility
20.  Neonates need tailored drug formulations 
Drugs are very strong tools used to improve outcome in neonates. Despite this fact and in contrast to tailored perfusion equipment, incubators or ventilators for neonates, we still commonly use drug formulations initially developed for adults. We would like to make the point that drug formulations given to neonates need to be tailored for this age group. Besides the obvious need to search for active compounds that take the pathophysiology of the newborn into account, this includes the dosage and formulation. The dosage or concentration should facilitate the administration of low amounts and be flexible since clearance is lower in neonates with additional extensive between-individual variability. Formulations need to be tailored for dosage variability in the low ranges and also to the clinical characteristics of neonates. A specific focus of interest during neonatal drug development therefore is a need to quantify and limit excipient exposure based on the available knowledge of their safety or toxicity. Until such tailored vials and formulations become available, compounding practices for drug formulations in neonates should be evaluated to guarantee the correct dosing, product stability and safety.
PMCID: PMC4145637  PMID: 25254168
Drug formulation; Newborn; Excipient; Safety; Quality control
21.  Influence of intestinal efflux pumps on the absorption and transport of furosemide 
Furosemide is a commonly used diuretic which is used in the treatment of edema, congestive heart failure, hypertension and renal failure. Its absorption exhibits inter- and intra-subject variability that can be attributed to many factors including the intestinal efflux pumps such as the P-glycoprotein (P-gp). This study was done due to the great disagreement between what is published in the literature regarding the influence of P-gp on furosemide and at the same time due to the importance of this drug in the treatment of different conditions as described above. In addition, an investigation of the effect of two of the commonly used pharmaceutical excipients (hydroxypropyl β-cyclodextrin [HPβCD] and Tween 80) and also a P-gp inhibitor (verapamil hydrochloride) on the intestinal absorption of this drug were also done.
The study utilized the everted intestinal sacs technique to investigate both the effect of the efflux transporter (P-gp) on furosemide absorption and also the effect of the chosen excipients.
The absorption of furosemide was significantly influenced by the P-gp as confirmed by the everted vis the non-everted sacs together with the verapamil study in which the transport of furosemide was inhibited by verapamil. In addition, Tween 80 was also shown to inhibit the P-gp pump whereas the HPβCD did not significantly influence the efflux of furosemide in this study.
P-glycoprotein and some of the used excipients in the formulation play a very important role in the transport of furosemide and other drugs. Thus excipients that affect the activity of P-gp should be avoided when formulating drugs that are substrate for the P-gp or other efflux pumps.
PMCID: PMC3730994  PMID: 23960725
Intestinal efflux; Furosemide intestinal absorption; Furosemide efflux
22.  A Systematic Approach to Design and Prepare Solid Dispersions of Poorly Water-Soluble Drug 
AAPS PharmSciTech  2014;15(3):641-657.
The objective of the present study was to define a systematic approach to design and prepare solid dispersions of poorly water-soluble drug. The systematic approach can be defined in four phases. In the first phase, glass forming ability is assessed, and in the second phase, probable excipients are screened. The screened excipients are evaluated (third phase) for glass transition temperatures (Tg) and miscibility studies according to Florey–Huggins interaction parameter. The predicted excipients are used to prepare the solid dispersion and evaluated for Tg and any interactions using Fourier transfer infrared studies (fourth phase), and the findings are correlated with phase three predictions. For this investigation, cilostazol (CIL) was selected as model drug, which was classified as a poor glass former. As per the physical chemical properties of CIL, ten excipients, both polymeric and non-polymeric, were selected and screened. Out of these, povidone, copovidone, hypromellose and Eudragit EPO were found theoretically miscible with CIL. After going through phase 2 to phase 4, only povidone, copovidone and hypromellose were confirmed as polymer of choice for preparing the solid dispersion of CIL with a prediction of better physical solid-state stability on the basis of good miscibility between drug and carrier.
PMCID: PMC4037479  PMID: 24563175
amorphous; cilostazol; glass transition temperature; miscibility; solid dispersions; solubility parameters
23.  Protein aggregation and lyophilization: Protein structural descriptors as predictors of aggregation propensity 
Computers & chemical engineering  2013;58(2013):369-377.
Lyophilization can induce aggregation in therapeutic proteins, but the relative importance of protein structure, formulation and processing conditions are poorly understood. To evaluate the contribution of protein structure to lyophilization-induced aggregation, fifteen proteins were co-lyophilized with each of five excipients. Extent of aggregation following lyophilization, measured using size-exclusion chromatography, was correlated with computational and biophysical protein structural descriptors via multiple linear regression. Descriptor selection was performed using exhaustive search and forward selection. The results demonstrate that, for a given excipient, extent of aggregation is highly correlated by eight to twelve structural descriptors. Leave-one-out cross validation showed that the correlations were able to successfully predict the aggregation for a protein “left out” of the data set. Selected descriptors varied with excipient, indicating both protein structure and excipient type contribute to lyophilization-induced aggregation. The results show some descriptors used to predict protein aggregation in solution are useful in predicting lyophilized protein aggregation.
PMCID: PMC3917556  PMID: 24516290
Protein formulation; Biologics; Aggregation prediction; Lyophilization; Multiple linear regression; Structural descriptors
24.  Targeting Aerosol Deposition to and Within the Lung Airways Using Excipient Enhanced Growth 
Previous studies have characterized the size increase of combination submicrometer particles composed of a drug and hygroscopic excipient when exposed to typical airway thermodynamic conditions. The objective of this study was to determine the deposition and size increase characteristics of excipient enhanced growth (EEG) aerosols throughout the tracheobronchial (TB) airways and to evaluate the potential for targeted delivery.
Submicrometer particles composed of a poorly water-soluble drug (insulin) and hygroscopic excipient (sodium chloride) were considered at drug:excipient mass ratios of 50:50 and 25:75. A previously validated computational fluid dynamics model was used to predict aerosol size increase and deposition in characteristic geometries of the mouth–throat (MT), upper TB airways through the third bifurcation (B3), and remaining TB airways through B15. Additional validation experiments were also performed for albuterol sulfate:mannitol particles. Both growth of combination particles and deposition are reported throughout the conducting airways for characteristic slow and deep (SD) and quick and deep (QD) inhalations.
For all EEG cases considered, MT deposition was less than 1% of the drug dose, which is at least one order of magnitude lower than with state-of-the-art and conventional inhalers. Final aerosol sizes exiting the TB region and entering the alveolar airways were all greater than 3 μm. For SD inhalation, deposition fractions of 20% were achieved in the lower TB region of B8–B15, which is a factor of 20–30×higher than conventional delivery devices. With QD inhalation, maximum alveolar delivery of 90% was observed.
Increasing the dose delivered to the lower TB region by a factor of 20–30×or achieving 90% delivery to the alveolar airways was considered effective aerosol targeting compared with conventional devices. The trend of higher flow rates resulting in better alveolar delivery of aerosols is unique to EEG and may be used to design highly efficient dry powder inhalers.
PMCID: PMC3826577  PMID: 23286828
respiratory drug delivery; excipient enhanced growth (EEG); nanoaerosols; hygroscopic droplet growth; engineered combination particles; stochastic individual path (SIP) airway modeling; computational fluid dynamics (CFD) simulations; in vitro aerosol experiments
25.  A comparative study on the physicochemical and biological stability of IgG1 and monoclonal antibodies during spray drying process 
The main concern in formulation of antibodies is the intrinsic instability of these labile compounds. To evaluate the physicochemical stability of antibody in dry powder formulations, physical stability of IgG1 and a monoclonal antibody (trastuzumab) during the spray drying process was studied in a parallel study and the efficacy of some sugar based excipients in protection of antibodies was studied.
The SDS-PAGE analysis showed no fragmentation of antibodies after spray drying in all formulations. The secondary structure of antibodies contained 40.13 to 70.19% of β structure in dry state. Also, CD spectroscopy showed the similar secondary structure for trastuzumab after reconstitution in water. ELISA analysis and cell culture studies were conducted in order to evaluate bioactivity of monoclonal antibody. Formulations containing combination of excipients provided maximum tendency of trastuzumab to attach to the ELISA antigen (86.46% ± 2.3) and maximum bioactivity when incubated with SKBr3 cell line (the cell viability was decreased to 65.99% ± 4.6). Incubation of formulations with L929 cell line proved the biocompatibility of the excipients and non-toxic composition of formulations.
The IgG1 and trastuzumab demonstrated similar behavior in spray drying process. The combination of excipients containing trahalose, hydroxypropyl beta cyclodextrin and beta cyclodextrin with proper ratio improved the physical and chemical stability of both IgG1 and monoclonal antibody.
PMCID: PMC3972992  PMID: 24641877
Antibody; Trastuzumab; Spray drying; Trehalose; Hydroxypropyl beta cyclodextrin; Beta cyclodextrin

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