Publications by authors named "Gaia Colombo"

55 Publications

Orphan Designation and Cisplatin/Hyaluronan Complex in an Intracavitary Film for Malignant Mesothelioma.

Pharmaceutics 2021 Mar 9;13(3). Epub 2021 Mar 9.

Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.

Pleural mesothelioma is a lung diffuse tumor, whose complete resection is unlikely. Consequently, metastases reappear where the primary tumor was removed. This paper illustrates the orphan medicine designation procedure of an intracavitary cisplatin film and related pharmaceutical development aspects requested by the European Medicines Agency (EMA) in its Scientific Advice. Since cisplatin pharmacokinetics from the implanted film in sheep resulted substantially modified compared to intravenous administration, the formation of a cisplatin/hyaluronan complex had been hypothesized. Here, the interaction between sodium hyaluronate (NaHA) and cisplatin (CisPt) was demonstrated. Size exclusion chromatography qualitatively evidenced the complex in the film-forming mixture, only showing the NaHA peak. Atomic absorption spectroscopy of the corresponding fraction revealed platinum, confirming the interaction. Reverse phase HPLC quantified about 5% free cisplatin in the film-forming mixture, indirectly meaning that 95% was complexed. Finally, a study of CisPt release from the film assessed how CisPt/NaHA complex affected drug availability. In water, a medium without chloride ions, there was no release and the film remained intact for 48 h and longer, whereas the placebo film dissolved in 15 min. In 0.9% NaCl medium, the film became more soluble, dissolving within 3-4 h. However, cisplatin release was still controlled by the existing complex in solution until chloride ions displaced it. While the film modified its dissolution with aging, CisPt release remained unaffected (90% released in 48 h).
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http://dx.doi.org/10.3390/pharmaceutics13030362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000699PMC
March 2021

Preparation and Biophysical Characterization of Quercetin Inclusion Complexes with β-Cyclodextrin Derivatives to be Formulated as Possible Nose-to-Brain Quercetin Delivery Systems.

Mol Pharm 2020 11 19;17(11):4241-4255. Epub 2020 Oct 19.

Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Zografou 15771, Greece.

Quercetin (Que) is a flavonoid associated with high oxygen radical scavenging activity and potential neuroprotective activity against Alzheimer's disease. Que's oral bioavailability is limited by its low water solubility and extended peripheral metabolism; thus, nasal administration may be a promising alternative to achieve effective Que concentrations in the brain. The formation of Que-2-hydroxypropylated-β-cyclodextrin (Que/HP-β-CD) complexes was previously found to increase the molecule's solubility and stability in aqueous media. Que-methyl-β-cyclodextrin (Que/Me-β-CD) inclusion complexes were prepared, characterized, and compared with the Que/HP-β-CD complex using biophysical and computational methods (phase solubility, fluorescence and NMR spectroscopy, differential scanning calorimetry (DSC), and molecular dynamics simulations (MDS)) as candidates for the preparation of nose-to-brain Que's delivery systems. DSC thermograms, NMR, fluorescence spectroscopy, and MDS confirmed the inclusion complex formation of Que with both CDs. Differences between the two preparations were observed regarding their thermodynamic stability and inclusion mode governing the details of molecular interactions. Que's solubility in aqueous media at pH 1.2 and 4.5 was similar and linearly increased with both CD concentrations. At pH 6.8, Que's solubility was higher and positively deviated from linearity in the presence of HP-β-CD more than with Me-β-CD, possibly revealing the presence of more than one HP-β-CD molecule involved in the complex. Overall, water solubility of lyophilized Que/Me-β-CD and Que/HP-β-CD products was approximately 7-40 times and 14-50 times as high as for pure Que at pH 1.2-6.8. In addition, the proof of concept experiment on permeation across rabbit nasal mucosa revealed measurable and similar Que permeability profiles with both CDs and negligible permeation of pure Que. These results are quite encouraging for further and evaluation toward nasal administration and nose-to-brain delivery of Que.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00672DOI Listing
November 2020

Excipient-free pulmonary insulin dry powder: Pharmacokinetic and pharmacodynamics profiles in rats.

J Control Release 2020 07 21;323:412-420. Epub 2020 Apr 21.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy. Electronic address:

A novel pure insulin spray-dried powder for DPI product (Ins_SD) was studied with respect to physico-chemical stability, in vitro respirability, bioavailability, activity and tolerability. Ins_SD powder exhibited a very high in vitro respirability, independently of the DPI product preparation (manual or semi-automatic). Physico-chemical characteristics of Ins_SD powder remained within the pharmacopoeia limits during 6 months of storage at room temperature. PK/PD profiles were measured in rats that received the pulmonary powders by intratracheal insufflation and compared with Afrezza inhalation insulin. Due to the low drug powder mass to deliver, both insulin powders were diluted with mannitol. Insulin from Ins_SD was promptly absorbed (t 15 min and C4.9 ± 1.5 mU/ml). Afrezza had a slower absorption (t 30 min and C of 1.8 ± 0.37 mU/ml). After glucose injection, Ins_SD determined a rapid reduction of glucose level, similar to Afrezza. As reference, insulin subcutaneous injection showed a long-lasting hypoglycemic effect due to the slow absorption that prolonged insulin plasma level. In summary, Ins_SD product is suitable for post-prandial glucose control, providing a convenient and compliant product, in particular in the event of using a disposable device. Albeit the product has to be stored in fridge, its stability at room temperature allows the diabetic individual to carry the daily dose in normal conditions.
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http://dx.doi.org/10.1016/j.jconrel.2020.04.015DOI Listing
July 2020

Aerosolization Performance of Jet Nebulizers and Biopharmaceutical Aspects.

Pharmaceutics 2019 Aug 11;11(8). Epub 2019 Aug 11.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.

In this work, 13 jet nebulizers, some of which in different configurations, were investigated in order to identify the biopharmaceutical constraints related to the quality attributes of the medicinal products, which affect their safety, efficiency, compliance, and effectiveness. The aerosolization parameters, including the aerosol output, aerosol output rate, mass median aerodynamic diameter, and fine particle fraction, were determined according to the European Standard EN 13544-1, using sodium fluoride as a reference formulation. A comparison between the aerosol output nebulization time and the fine particle fraction displayed a correlation between the aerosol quality and the nebulization rate. Indeed, the quality of the nebulization significantly increased when the rate of aerosol emission was reduced. Moreover, the performance of the nebulizers was analyzed in terms of respirable delivered dose and respirable dose delivery rate, which characterize nebulization as the rate and amount of respirable product that could be deposited into the lungs. Depending on which of these two latter parameters was used, the nebulizers showed different performances. The differences, in terms of the rate and amount of delivered aerosol, could provide relevant information for the appropriate choice of nebulizer as a function of drug product, therapy, and patient characteristics.
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http://dx.doi.org/10.3390/pharmaceutics11080406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723557PMC
August 2019

Dry powder inhaler of colistimethate sodium for lung infections in cystic fibrosis: optimization of powder construction.

Drug Dev Ind Pharm 2019 Oct 30;45(10):1664-1673. Epub 2019 Aug 30.

Department of Life Sciences and Biotechnology , Ferrara , Italy.

Colistimethate sodium (CMS) for treatment of lung infections in cystic fibrosis patient was transformed into a dry powder for inhalation by spray drying. Design of Experiment was applied for understanding the role of the spray-drying process parameters on the critical quality attributes of the CMS spray-dried (SD) powders and agglomerates thereof. Eleven experimental SD microparticle powders were constructed under different process conditions according to a central composite design. The SD microparticles were then agglomerated in soft pellets. Eleven physico-chemical characteristics of SD CMS microparticle powders or agglomerates thereof were selected as critical quality attributes. The yield of SD process was higher than 75%. The emitted fraction of agglomerates from RS01 inhaler was 75-84%, and the fine particle fraction (particles <5 µm) was between 58% and 62%. The quality attributes of CMS SD powders and respective agglomerates that were significantly influenced by spray-drying process parameters were residual solvent and drug content of the SD microparticles as well as bulk density and respirable dose of the agglomerates. These attributes were also affected by the combination of the process variables. The air aspiration rate was found as the most positively influential on drug and solvent content and respirable dose. The residual solvent content significantly influenced the powder bulk properties and aerodynamic behavior of the agglomerates, i.e. quality attributes that govern drug metering in the device and the particles lungs deposition. Agglomerates of CMS SD microparticles, in combination with RS01 DPI, showed satisfactory results in terms of dose emitted and fine particle fraction.
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http://dx.doi.org/10.1080/03639045.2019.1652636DOI Listing
October 2019

Thermal Forces from a Microscopic Perspective.

Phys Rev Lett 2019 Jul;123(2):028002

Dipartimento di Scienza e Alta Tecnologia, Università degli Studi dell'Insubria, Via Valleggio 11, 22100 Como, Italy.

Thermal gradients lead to macroscopic fluid motion if a confining surface is present along the gradient. This fundamental nonequilibrium effect, known as thermo-osmosis, is held responsible for particle thermophoresis in colloidal suspensions. A unified approach for thermo-osmosis in liquids and in gases is still lacking. Linear response theory is generalized to inhomogeneous systems, leading to an exact microscopic theory for the thermo-osmotic flow, showing that the effect originates from two independent physical mechanisms, playing different roles in the gas and liquid phases, reducing to known expressions in the appropriate limits.
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http://dx.doi.org/10.1103/PhysRevLett.123.028002DOI Listing
July 2019

Chitosan-Coated Nanoparticles: Effect of Chitosan Molecular Weight on Nasal Transmucosal Delivery.

Pharmaceutics 2019 02 18;11(2). Epub 2019 Feb 18.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.

Drug delivery to the brain represents a challenge, especially in the therapy of central nervous system malignancies. Simvastatin (SVT), as with other statins, has shown potential anticancer properties that are difficult to exploit in the central nervous system (CNS). In the present work the physico⁻chemical, mucoadhesive, and permeability-enhancing properties of simvastatin-loaded poly-ε-caprolactone nanocapsules coated with chitosan for nose-to-brain administration were investigated. Lipid-core nanocapsules coated with chitosan (LNC) of different molecular weight (MW) were prepared by a novel one-pot technique, and characterized for particle size, surface charge, particle number density, morphology, drug encapsulation efficiency, interaction between surface nanocapsules with mucin, drug release, and permeability across two nasal mucosa models. Results show that all formulations presented adequate particle sizes (below 220 nm), positive surface charge, narrow droplet size distribution (PDI < 0.2), and high encapsulation efficiency. Nanocapsules presented controlled drug release and mucoadhesive properties that are dependent on the MW of the coating chitosan. The results of permeation across the RPMI 2650 human nasal cell line evidenced that LNC increased the permeation of SVT. In particular, the amount of SVT that permeated after 4 hr for nanocapsules coated with low-MW chitosan, high-MW chitosan, and control SVT was 13.9 ± 0.8 μg, 9.2 ± 1.2 µg, and 1.4 ± 0.2 µg, respectively. These results were confirmed by SVT ex vivo permeation across rabbit nasal mucosa. This study highlighted the suitability of LNC as a promising strategy for the administration of simvastatin for a nose-to-brain approach for the therapy of brain tumors.
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http://dx.doi.org/10.3390/pharmaceutics11020086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409859PMC
February 2019

Chitosan coated human serum albumin nanoparticles: A promising strategy for nose-to-brain drug delivery.

Int J Biol Macromol 2019 May 3;129:267-280. Epub 2019 Feb 3.

Department of Chemistry, via U. Schiff 6, 50519, Sesto Fiorentino, Florence, Italy. Electronic address:

The aim of the present study was the development of human serum albumin nanoparticles (HSA NPs) as nose-to-brain carrier. To strengthen, the efficacy of nanoparticles as drug delivery system, the influence of chitosan (CS) coating on the performance of HSA NPs was investigated for nasal application. HSA NPs were prepared by desolvation technique. CS coating was obtained adding the CS solution to HSA NPs. The mean particle sizes was 241 ± 18 nm and 261 ± 8 nm and the ζ-potential was -47 ± 3 mV and + 45 ± 1 mV for HSA NPs and CS-HSA NPs, respectively. The optimized formulations showed excellent stability upon storage both as suspension and as freeze-dried product after 3 months. The mucoadhesion properties were assessed by turbidimetric and indirect method. NPs were loaded with sulforhodamine B sodium salt as model drug and the effect of CS coating was investigated performing release studies, permeation and uptake experiments using Caco-2 and hCMEC/D3 cells as model of the nasal epithelium and blood-brain barrier, respectively. Furthermore, ex vivo diffusion experiments have been carried out using rabbit nasal mucosa. Finally, the ability of the formulations to reversibly open tight and gap junctions was explored by western blotting and RT-PCR analyzing in both Caco-2 and hCMEC/D3 cells.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.02.005DOI Listing
May 2019

Anti-inflammatory flurbiprofen nasal powders for nose-to-brain delivery in Alzheimer's disease.

J Drug Target 2019 11 11;27(9):984-994. Epub 2019 Feb 11.

c Department of Pharmacy, University of Salerno , Fisciano (SA) , Italy.

Neuroinflammation occurs in the early stages of Alzheimer's disease (AD). Thus, anti-inflammatory drugs in this asymptomatic initial phase could slow down AD progression, provided they enter the brain. Direct nose-to-brain drug transport occurs along olfactory or trigeminal nerves, bypassing the blood-brain barrier. Nasal administration may enable the drug to access the brain. Here, flurbiprofen powders for nose-to-brain drug transport in early AD-related neuroinflammation were studied. Their target product profile contemplates drug powder deposition in the nasal cavity, prompt dissolution in the mucosal fluid and attainment of saturation concentration to maximise diffusion in the tissue. Aiming to increase drug disposition into brain, poorly soluble flurbiprofen requires the construction of nasal powder microparticles actively deposited in nose for prompt drug release. Two groups of powders were formulated, composed of flurbiprofen acid or flurbiprofen sodium salt. Two spray dryer apparatuses, differing for spray and drying mechanisms, and particle collection, were applied to impact on the characteristics of the microparticulate powders. Flurbiprofen sodium nasal powders disclosed prompt dissolution and fast transport across rabbit nasal mucosa, superior to the acid form, in particular when the powder was prepared using the Nano B-90 spray dryer at the lowest drying air temperature.
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http://dx.doi.org/10.1080/1061186X.2019.1574300DOI Listing
November 2019

Dose administration maneuvers and patient care in tobramycin dry powder inhalation therapy.

Int J Pharm 2018 Sep 5;548(1):182-191. Epub 2018 Jun 5.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.

The purpose of this work was to study a new dry powder inhaler (DPI) of tobramycin capable to simplify the dose administration maneuvers to maximize the cystic fibrosis (CF) patient care in antibiotic inhalation therapy. For the purpose, tobramycin/sodium stearate powder (TobraPS) having a high drug content, was produced by spray drying, characterized and the aerodynamic behavior was investigated in vitro using different RS01 DPI inhalers. The aerosols produced with 28, 56 or 112 mg of tobramycin in TobraPS powder using capsules size #3, #2 or #0 showed that there was quasi linear relationship between the amount loaded in the device and the FPD. An in vivo study in healthy human volunteers showed that 3-6 inhalation acts were requested by the volunteers to inhale 120 mg of TobraPS powder loaded in a size #0 capsule aerosolized with a prototype RS01 device, according to their capability to inhale. The amount of powder emitted at 4 kPa pressure drop at constant air flow well correlated with the in vivo emission at dynamic flow, when the same volume of air passed through the device. The novel approach for the administration of 112 mg of tobramycin in one capsule could improve the convenience and adherence of the CF patient to the antibiotic therapy.
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http://dx.doi.org/10.1016/j.ijpharm.2018.06.006DOI Listing
September 2018

Surface-Modified Nanocarriers for Nose-to-Brain Delivery: From Bioadhesion to Targeting.

Pharmaceutics 2018 Mar 15;10(1). Epub 2018 Mar 15.

Interdipartmental Center for Innovation in Health Products, BIOPHARMANET TEC, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.

In the field of nasal drug delivery, nose-to-brain delivery is among the most fascinating applications, directly targeting the central nervous system, bypassing the blood brain barrier. Its benefits include dose lowering and direct brain distribution of potent drugs, ultimately reducing systemic side effects. Recently, nasal administration of insulin showed promising results in clinical trials for the treatment of Alzheimer's disease. Nanomedicines could further contribute to making nose-to-brain delivery a reality. While not disregarding the need for devices enabling a formulation deposition in the nose's upper part, surface modification of nanomedicines appears the key strategy to optimize drug delivery from the nasal cavity to the brain. In this review, nanomedicine delivery based on particle engineering exploiting surface electrostatic charges, mucoadhesive polymers, or chemical moieties targeting the nasal epithelium will be discussed and critically evaluated in relation to nose-to-brain delivery.
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http://dx.doi.org/10.3390/pharmaceutics10010034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874847PMC
March 2018

The use of fatty acids as absorption enhancer for pulmonary drug delivery.

Int J Pharm 2018 Apr 16;541(1-2):93-100. Epub 2018 Feb 16.

Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, Sydney, Australia. Electronic address:

A limitation in the systemic uptake of many inhalable drugs is the restricted permeation through the pulmonary epithelial layer barrier. One strategy to bypass the epithelial layer when delivering non-permeable drugs is to alter the paracellular transport, allowing the uptake of drugs into the systemic circulation. In this study, the potential of sodium decanoate (Na dec), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) as absorption enhancers has been investigated to increase pulmonary paracellular permeability by modulating epithelial cells' tight junctions. By incorporating Na dec, DHA and EPA, separately, into a nebulising formulation, the aim was to enhance the absorption of a fluorescent marker (flu-Na, used as model drug) across pulmonary epithelial cells (Calu-3). Results indicate that the aerosol performance of all the nebulizing formulations containing absorption enhancers was significantly better than control. Furthermore, the in vitro cell assays demonstrated a significant increase in paracellular transport of the fluorescent marker with Na dec and DHA formulations. This finding supports the potential use ofDHA and Na dec to enhance epithelial transport of poorly permeable drugs delivered via inhalation.
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http://dx.doi.org/10.1016/j.ijpharm.2018.02.027DOI Listing
April 2018

In vivo nose-to-brain delivery of the hydrophilic antiviral ribavirin by microparticle agglomerates.

Drug Deliv 2018 Nov;25(1):376-387

b Department of Food and Drug , University of Parma , Parma , Italy.

Nasal administration has been proposed as a potential approach for the delivery of drugs to the central nervous system. Ribavirin (RBV), an antiviral drug potentially useful to treat viral infections both in humans and animals, has been previously demonstrated to attain several brain compartments after nasal administration. Here, a powder formulation in the form of agglomerates comprising micronized RBV and spray-dried microparticles containing excipients with potential absorption enhancing properties, i.e. mannitol, chitosan, and α-cyclodextrin, was developed for nasal insufflation. The agglomerates were characterized for particle size, agglomeration yield, and ex vivo RBV permeation across rabbit nasal mucosa as well as delivery from an animal dry powder insufflator device. Interestingly, permeation enhancers such as chitosan and mannitol showed a lower amount of RBV permeating across the excised nasal tissue, whereas α-cyclodextrin proved to outperform the other formulations and to match the highly soluble micronized RBV powder taken as a reference. In vivo nasal administration to rats of the agglomerates containing α-cyclodextrin showed an overall higher accumulation of RBV in all the brain compartments analyzed as compared with the micronized RBV administered as such without excipient microparticles. Hence, powder agglomerates are a valuable approach to obtain a nasal formulation potentially attaining nose-to-brain delivery of drugs with minimal processing of the APIs and improvement of the technological and biopharmaceutical properties of micronized API and excipients, as they combine optimal flow properties for handling and dosing, suitable particle size for nasal deposition, high surface area for drug dissolution, and penetration enhancing properties from excipients such as cyclodextrins.
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http://dx.doi.org/10.1080/10717544.2018.1428242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058489PMC
November 2018

Opportunity and challenges of nasal powders: Drug formulation and delivery.

Eur J Pharm Sci 2018 Feb 20;113:2-17. Epub 2017 Sep 20.

Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy. Electronic address:

In the field of nasal drug delivery, among the preparations defined by the European Pharmacopoeia, nasal powders facilitate the formulation of poorly water-soluble active compounds. They often display a simple composition in excipients (if any), allow for the administration of larger drug doses and enhance drug diffusion and absorption across the mucosa, improving bioavailability compared to nasal liquids. Despite the positive features, however, nasal products in this form still struggle to enter the market: the few available on the market are Onzetra Xsail® (sumatriptan) for migraine relief and, for the treatment of rhinitis, Rhinocort® Turbuhaler® (budesonide), Teijin Rhinocort® (beclomethasone dipropionate) and Erizas® (dexamethasone cipecilate). Hence, this review tries to understand why nasal powder formulations are still less common than liquid ones by analyzing whether this depends on the lack of (i) real evidence of superior therapeutic benefit of powders, (ii) therapeutic and/or commercial interest, (iii) efficient manufacturing methods or (iv) availability of suitable and affordable delivery devices. To this purpose, the reader's attention will be guided through nasal powder formulation strategies and manufacturing techniques, eventually giving up-to-date evidences of therapeutic efficacy in vivo. Advancements in the technology of insufflation devices will also be provided as nasal drug products are typical drug-device combinations.
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http://dx.doi.org/10.1016/j.ejps.2017.09.027DOI Listing
February 2018

Dry powder inhalers: An overview of the in vitro dissolution methodologies and their correlation with the biopharmaceutical aspects of the drug products.

Eur J Pharm Sci 2018 Feb 5;113:18-28. Epub 2017 Sep 5.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27A, 43124 Parma, Italy. Electronic address:

In vitro dissolution testing is routinely used in the development of pharmaceutical products. Whilst the dissolution testing methods are well established and standardized for oral dosage forms, i.e. tablets and capsules, there are no pharmacopoeia methods or regulatory requirements for testing the dissolution of orally inhaled powders. Despite this, a wide variety of dissolution testing methods for orally inhaled powders has been developed and their bio-relevance has been evaluated. This review provides an overview of the in vitro dissolution methodologies for dry inhalation products, with particular emphasis on dry powder inhalers, where the dissolution behavior of the respirable particles can have a role on duration and absorption of the drug. Dissolution mechanisms of respirable particles as well as kinetic models have been presented. A more recent biorelevant dissolution set-ups and media for studying inhalation biopharmaceutics were also reviewed. In addition, factors affecting interplay between dissolution and absorption of deposited particles in the context of biopharmaceutical considerations of inhalation products were examined.
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http://dx.doi.org/10.1016/j.ejps.2017.09.002DOI Listing
February 2018

Multi-kinetics and site-specific release of gabapentin and flurbiprofen from oral fixed-dose combination: in vitro release and in vivo food effect.

J Control Release 2017 Sep 31;262:296-304. Epub 2017 Jul 31.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27/A, Parma, Italy. Electronic address:

In this work, a fixed-dose combination of gabapentin and flurbiprofen formulated as multilayer tablets has been designed, developed and studied in vitro and in vivo. The aim was to construct a single dosage form of the two drugs, able to perform a therapeutic program involving three release kinetics and two delivery sites, i.e., immediate release of gabapentin, intra-gastric prolonged release of gabapentin and intestinal (delayed) release of flurbiprofen. An oblong three-layer tablet was manufactured having as top layer a floating hydrophilic polymeric matrix for gastric release of gabapentin, as middle layer a disintegrating formulation for immediate release of a gabapentin loading dose and as bottom layer, an uncoated hydrophilic polymeric matrix, swellable but insoluble in gastric fluids, for delayed and prolonged release of flurbiprofen in intestinal environment. The formulations were studied in vitro and in vivo in healthy volunteers. The in vitro release rate assessment confirmed the programmed delivery design. A significant higher bioavailability of gabapentin administered 30min after meal, compared to fasting conditions or to dose administration 10min before meal, argued in favor of the gastro-retention of gabapentin prolonged release layer. The two drugs were delivered at different anatomical sites, since the food presence prolonged the gastric absorption of gabapentin from the floating layer and delayed the flurbiprofen absorption. The attainment of a successful delayed release of flurbiprofen was realized by a matrix based on a polymers' combination. The combined use of three hydrophilic polymers with different pH sensitivity provided the dosage form layer containing flurbiprofen with gastro-resistant characteristics without the use of film coating.
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http://dx.doi.org/10.1016/j.jconrel.2017.07.042DOI Listing
September 2017

Design of experiments (DoE) in pharmaceutical development.

Drug Dev Ind Pharm 2017 Jun 23;43(6):889-901. Epub 2017 Feb 23.

a Department of Pharmaceutical Technology, Faculty of Pharmacy , National and Kapodistrian University of Athens , Athens , Greece.

At the beginning of the twentieth century, Sir Ronald Fisher introduced the concept of applying statistical analysis during the planning stages of research rather than at the end of experimentation. When statistical thinking is applied from the design phase, it enables to build quality into the product, by adopting Deming's profound knowledge approach, comprising system thinking, variation understanding, theory of knowledge, and psychology. The pharmaceutical industry was late in adopting these paradigms, compared to other sectors. It heavily focused on blockbuster drugs, while formulation development was mainly performed by One Factor At a Time (OFAT) studies, rather than implementing Quality by Design (QbD) and modern engineering-based manufacturing methodologies. Among various mathematical modeling approaches, Design of Experiments (DoE) is extensively used for the implementation of QbD in both research and industrial settings. In QbD, product and process understanding is the key enabler of assuring quality in the final product. Knowledge is achieved by establishing models correlating the inputs with the outputs of the process. The mathematical relationships of the Critical Process Parameters (CPPs) and Material Attributes (CMAs) with the Critical Quality Attributes (CQAs) define the design space. Consequently, process understanding is well assured and rationally leads to a final product meeting the Quality Target Product Profile (QTPP). This review illustrates the principles of quality theory through the work of major contributors, the evolution of the QbD approach and the statistical toolset for its implementation. As such, DoE is presented in detail since it represents the first choice for rational pharmaceutical development.
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http://dx.doi.org/10.1080/03639045.2017.1291672DOI Listing
June 2017

Esomeprazole immediate release tablets: Gastric mucosa ex vivo permeation, absorption and antisecretory activity in conscious rats.

J Control Release 2016 10 26;239:203-10. Epub 2016 Aug 26.

Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy. Electronic address:

The aim of this work was to study the esomeprazole activity on the control of gastric secretion after administration of a novel immediate release tablet. The ex vivo permeation of esomeprazole across porcine gastric mucosa from immediate release tablets, containing sodium carbonate or magnesium oxide as alkalinizing agents, was firstly assessed. Pharmacokinetics and pharmacodynamics studies in conscious rats following the administration of immediate release tablets with sodium carbonate, in comparison with delayed-release tablets having the same formula, were also conducted. The results showed an important effect of sodium carbonate and magnesium oxide on the drug release, on the ex vivo trans-mucosal transport and the stability in acid environment. In particular, the presence of sodium carbonate in esomeprazole tablet formulation provided the maximum increase of the drug in vitro transport across the mucosa. Then, the absorption and the antisecretory activity of this proton pump inhibitor orally administered in rats as immediate release tablets containing Na2CO3, was superior but not significantly different compared to delayed-release tablets having the same formula. In the adopted animal model, an activity of esomeprazole from immediate release alkaline formulation was seen also in presence of partial gastric absorption allowing inhibition of proton pumps reached via systemic circulation. This esomeprazole immediate release formulation could be used for the on-demand treatment of acid-related disorders such as gastro-esophageal reflux disease.
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http://dx.doi.org/10.1016/j.jconrel.2016.08.032DOI Listing
October 2016

The development of a single-use, capsule-free multi-breath tobramycin dry powder inhaler for the treatment of cystic fibrosis.

Int J Pharm 2016 Dec 5;514(2):392-398. Epub 2016 Apr 5.

Respiratory Technology, Woolcock Institute of Medical Research, Australia; Discipline of Pharmacology, Sydney Medical School, The University of Sydney, NSW 2037, Australia.

The aerosol performance and delivery characteristics of tobramycin for the treatment of respiratory infection were evaluated using the Orbital™, a multi-breath, high dose, dry powder inhaler (DPI). Micronised tobramycin was prepared and tested in the Orbital and in the commercially available TOBI Podhaler (Novartis AG). Furthermore, the TOBI Podhaler formulation containing tobramycin as Pulmospheres was tested in both the commercial Podhaler device (T-326) and Orbital for comparison. By varying the puck geometry of the Orbital, it was possible to deliver equivalent doses of micronised tobramycin (114.09±5.86mg) to that of the Podhaler Pulmosphere product (116.01±2.59mg) over 4 sequential simulated breaths (60Lmin for 4s) without the need for multiple capsules. In general, the aerosol performance of the micronised tobramycin from the Orbital was higher than the T-326 Podhaler device, with fine particle fraction (FPF) of 44.99%±1.09% and 37.03%±0.86%, respectively. When testing the Pulmosphere powder in the two devices, the T-326 had marginally better performance with a FPF of 68.77%±2.10% compared to 61.30%±3.45%. This is to be expected since the TOBI Podhaler and Pulmosphere are an optimised powder and device combination. The Orbital was shown to be capable of delivering high efficiency, high dose antibiotic therapy for inhalation without the need for the use of multiple capsules as used in current devices. This approach may pave the way for a number of antibiotic therapies and medicaments where high dose respiratory deposition is required.
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http://dx.doi.org/10.1016/j.ijpharm.2016.04.009DOI Listing
December 2016

Combinations of colistin solutions and nebulisers for lung infection management in cystic fibrosis patients.

Int J Pharm 2016 Apr;502(1-2):242-8

Interdepartmental Centre, Biopharmanet-TEC, University of Parma, Viale delle Scienze 27/A, 43124 Parma, Italy.

In this work different nebulisers were investigated in order to assess their efficiency in combination with colistimethate sodium (CMS) inhalation products. Four nebulisers, namely I-neb(®), Aeroneb(®) Go, eFlow(®)rapid and PARI LC(®) Sprint were studied in terms of delivered dose (DD), drug delivery rate (DDR) and respirable dose (RD) of CMS. The goal was to provide scientific data to physicians for prescribing the most appropriate nebuliser for the CMS specific user. All the apparatuses nebulised ColiFin 1MIU/3 ml solution (80 mg of CMS) with delivered doses between 31% and 41% of the loaded amount. Aeroneb Go showed the longest nebulisation time (more than 20 min). When ColiFin 2 MIU/4 ml was nebulised with eFlow rapid or PARI LC Sprint, the CMS respirable dose was 45.3mg and 39.2mg, in times of 5.6 and 10.8 min, respectively. I-neb, having a medication cup capacity limited to 0.4 ml, loaded with Promixin 0.4 MIU/0.4 ml (32 mg of CMS), provided in a time of 9 min a RD of 21.5mg, a value slightly higher than those obtained by nebulising ColiFin 1 MIU/3 ml with the other nebulisers (range 15.9-17.6 mg). The results illustrate that the clinical outcome depends on the comparative analysis of nebulisation efficiency (respirable dose) and convenience (time), not disregarding the ratios between the amount loaded, delivered and deposited at lung level.
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http://dx.doi.org/10.1016/j.ijpharm.2016.02.005DOI Listing
April 2016

Floating modular drug delivery systems with buoyancy independent of release mechanisms to sustain amoxicillin and clarithromycin intra-gastric concentrations.

Drug Dev Ind Pharm 2016 11;42(2):332-9. Epub 2015 Jun 11.

a Department of Pharmacy , University of Parma , Parma , Italy .

Release modules of amoxicillin and clarithromycin combined in a single dosage form designed to float in the gastric content and to sustain the intra-gastric concentrations of these two antibiotics used for the eradication of Helicobacter pylori have been studied. The modules having a disc shape with curved bases were formulated as hydrophilic matrices. Two modules of clarithromycin were assembled by sticking the concave base of one module to the concave base of the other, creating an internal void chamber. The final dosage form was a floating assembly of three modules of clarithromycin and two of amoxicillin in which the drug release mechanism did not interfere with the floatation mechanism. The assembled system showed immediate in vitro floatation at pH 1.2, lasting 5 h. The in vitro antibiotics release profiles from individual modules and assembled systems exhibited linear release rate during buoyancy for at least 8 h. The predicted antibiotic concentrations in the stomach maintained for long time levels significantly higher than the respective minimum inhibitory concentrations (MIC). In addition, an in vivo absorption study performed on beagle dogs confirmed the slow release of clarithromycin and amoxicillin from the assembled system during the assembly's permanence in the stomach for at least 4 h.
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http://dx.doi.org/10.3109/03639045.2015.1054397DOI Listing
October 2016

Spray-dried amikacin sulphate powder for inhalation in cystic fibrosis patients: The role of ethanol in particle formation.

Eur J Pharm Biopharm 2015 Jun 4;93:165-72. Epub 2015 Apr 4.

Department of Pharmacy, University of Parma, Viale delle Scienze 27/A, Parma 43124, Italy; Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, SE19NH London, United Kingdom. Electronic address:

A Central Composite Design (CCD) was applied in order to identify positive combinations of the production parameters of amikacin sulphate spray-dried powders for inhalation, with the intent to expand the experimental space defined in a previous half-fractional factorial design. Three factors, namely drying temperature, feed rate and ethanol proportion, have been selected out of the initial five. In addition, the levels of these factors were increased from two to three and their effect on amikacin respirability was evaluated. In particular, focus was given on the role of ethanol presence on the formation of the microparticles for inhalation. The overall outcome of the CCD was that amikacin respirability was not substantially improved, as the optimum region coincided with areas already explored with the fractional factorial design. However, expanding the design space towards smaller ethanol levels, including its complete absence, revealed the crucial role of this solvent on the morphology of the produced particles. Peclet number and drug solubility in the spraying solution helped to understand the formation mechanism of these amikacin sulphate spray-dried particles.
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http://dx.doi.org/10.1016/j.ejpb.2015.03.023DOI Listing
June 2015

Immunomodulatory effects of a low-dose clarithromycin-based macrolide solution pressurised metered dose inhaler.

Pharm Res 2015 Jun 24;32(6):2144-53. Epub 2014 Dec 24.

Respiratory Technology Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.

Purpose: The aim of this study was to assess the effects of low-dose clarithromycin, formulated as solution pressurized metered dose inhaler, following deposition on the Calu-3 respiratory epithelial cells.

Methods: Clarithromycin was deposited on the air-interface culture of Calu-3 cells using a modified Andersen cascade impactor. Transport of fluorescein-Na, production of mucus and interleukin-8 release from Calu-3 cells following stimulation with transforming growth factor-β and treatment with clarithromycin was investigated.

Results: The deposition of clarithromycin had significant effect on the permeability of fluorescein-Na, suggesting that the barrier integrity was improved following a short-term treatment with clarithromycin (apparent permeability values were reduced to 3.57 × 10(-9) ± 2.32 × 10(-9) cm.s(-1), compared to 1.14 × 10(-8) ± 4.30 × 10(-8) cm.s(-1) for control). Furthermore, the amount of mucus produced was significantly reduced during the course of clarithromycin treatment. The concentration of interleukin-8 secreted from Calu-3 cells following stimulation with transforming growth factor-β resulted in significantly lower level of interleukin-8 released from the cells pre-treated with clarithromycin (5.2 ± 0.5 ng.ml(-1) clarithromycin treated vs. 7.7 ± 0.8 ng.ml(-1) control, respectively).

Conclusions: Our data demonstrate that treatment with clarithromycin decreases the paracellular permeability of epithelial cells, mucus secretion and interleukin-8 release and therefore, inhaled clarithromycin holds potential as an anti-inflammatory therapy.
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http://dx.doi.org/10.1007/s11095-014-1605-yDOI Listing
June 2015

Spray dried amikacin powder for inhalation in cystic fibrosis patients: a quality by design approach for product construction.

Int J Pharm 2014 Aug 2;471(1-2):507-15. Epub 2014 Jun 2.

Department of Pharmacy, University of Parma, Viale delle Scienze 27/A, Parma 43124, Italy. Electronic address:

An amikacin product for convenient and compliant inhalation in cystic fibrosis patients was constructed by spray-drying in order to produce powders of pure drug having high respirability and flowability. An experimental design was applied as a statistical tool for the characterization of amikacin spray drying process, through the establishment of mathematical relationships between six Critical Quality Attributes (CQAs) of the finished product and five Critical Process Parameters (CPPs). The surface-active excipient, PEG-32 stearate, studied for particle engineering, in general did not benefit the CQAs of the spray dried powders for inhalation. The spray drying feed solution required the inclusion of 10% (v/v) ethanol in order to reach the desired aerodynamic performance of powders. All desirable function solutions indicated that the favourable concentration of amikacin in the feed solution had to be kept at 1% w/v level. It was found that when the feed rate of the sprayed solution was raised, an increase in the drying temperature to the maximum value (160 °C) was required to maintain good powder respirability. Finally, the increase in drying temperature always led to an evident increase in emitted dose (ED) without affecting the desirable fine particle dose (FPD) values. The application of the experimental design enabled us to obtain amikacin powders with both ED and FPD, well above the regulatory and scientific references. The finished product contained only the active ingredient, which keeps low the mass to inhale for dose requirement.
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http://dx.doi.org/10.1016/j.ijpharm.2014.05.055DOI Listing
August 2014

Expanding the therapeutic potential of statins by means of nanotechnology enabled drug delivery systems.

Curr Top Med Chem 2014 ;14(9):1182-93

Graduate School of Health - Pharmacy, 15, Broadway, NSW 2007 Ultimo, Australia.

Statins are effective lipid lowering agents traditionally used for the primary and secondary prevention of cardiovascular disease. Statins also exert a range of pleiotropic effects that make them attractive candidates for use in a wide range of disorders, in particular inflammatory and immune mediated conditions. However, the exploitation of such pleiotropic effects has been greatly hindered by poor bioavailability and adverse effects on muscles and the liver at higher doses. Nanotechnology is often suggested as the solution to this problem, as it enables an increased bioavailability of statins. Moreover, colloidal carriers can offer targeted drug delivery approaches that enable localised biological effects of statins, further reducing their potential for unwanted toxicity and adverse effects. This article reviews the available evidences for the increased potential of statin therapy when administered in nano-formulations such as nanocrystals, nanoparticles, liposomes, micelles and various nano-enabled devices.
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http://dx.doi.org/10.2174/1568026614666140329232252DOI Listing
December 2014

The formulation, chemical and physical characterisation of clarithromycin-based macrolide solution pressurised metered dose inhaler.

J Pharm Pharmacol 2014 May 11;66(5):639-45. Epub 2013 Dec 11.

Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.

Objectives: The formulation of a clarithromycin (CLA) pressurised metered dose inhalers (pMDIs) solution formulation opens up exciting therapeutic opportunities for the treatment of inflammation in chronic obstructive lung diseases. In this study, we have formulated and tested a low dose macrolide formulation of CLA for treatment of inflammation and studied its physicochemical and aerosol properties.

Methods: The system was characterised for in-vitro aerosol performance using an Andersen cascade impactor. Short-term chemical and physical stability was assessed by dose content uniformity over a range of temperatures. Standard physicochemical characteristics were also investigated using scanning electron microscopy, thermo analysis and laser diffraction techniques.

Key Findings: The formulation had a relatively high fine particle fraction (47%) and produced a particle size distribution suitable for inhalation drug delivery. Particles had an irregular morphology and were predominately amorphous. Furthermore, the short-term stability showed the formulation to be stable from 4 to 37°C.

Conclusions: This study demonstrated the feasibility of formulating a solution-based pMDI containing CLA for the treatment of lung inflammatory diseases.
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http://dx.doi.org/10.1111/jphp.12190DOI Listing
May 2014

Pure insulin highly respirable powders for inhalation.

Eur J Pharm Sci 2014 Jan 24;51:110-7. Epub 2013 Aug 24.

Interdepartmental Center, Biopharmanet-TEC, University of Parma, Viale delle Scienze 27/A, 43124 Parma, Italy.

The aim of the present research was to investigate the possibility to obtain by spray drying an insulin pulmonary powder respirable and stable at room temperature without the use of excipients. Several insulin spray-dried powders were prepared with or without the addition of excipients (mannitol, bovine serum albumin, aspartic acid) from water dispersions or from acidic aqueous solutions. Each formulation was characterized using laser diffraction, scanning electron microscopy and in vitro aerosol performance with a Turbospin DPI device. Stability was assessed by the quantification of impurities with a molecular mass greater than that of insulin (HMWP) and related proteins (A21+ORP). Insulin powders prepared without excipients from an acid solution showed a shrivelled, raisin-like shape of non-aggregated microparticles and a high respirability (FPF>65%). The optimal result with respect to respirability and stability was reached when the pH of the insulin acetic acid solution to spray dry was adjusted at pH 3.6 with ammonium hydroxide. The median volume diameter of the obtained powder was 4.04 μm, insulin content 95%, emitted dose of 89.5%, MMAD 1.79 μm and fine particle fraction of 83.6%. This powder was stable at room temperature over a period of eighteen months with respect to the content of A21+ORP. As far as the HMWP content was concerned, the powder complied with the specification limits for a period of five months. The insulin acetic powder opens up the possibility of a more effective pulmonary therapy less dependent on refrigerated storage.
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http://dx.doi.org/10.1016/j.ejps.2013.08.009DOI Listing
January 2014

Multicomponent antibiotic substances produced by fermentation: implications for regulatory authorities, critically ill patients and generics.

Int J Antimicrob Agents 2014 Jan 3;43(1):1-6. Epub 2013 Aug 3.

Bacteriology Laboratory, Faculty of Medicine, University Hospital Strasbourg, Strasbourg, France.

Teicoplanin and polymyxin E (colistin) are antibiotics consisting of multiple, closely related subcomponents, produced by fermentation. The principal components comprise a complex mixture of chemically related, active substances (teicoplanin A(2-1)-A(2-5) and polymyxin E(1-2), respectively), which might be required to be present in specific ratios to ensure optimal antibacterial and clinical efficacy. These subcomponents differ in their fatty acid and amino acid composition and, as such, the lipophilic and protein binding characteristics differ between components. This has therapeutic implications for critically ill patients, as the volume of distribution of the teicoplanin A2 and polymyxin E analogues at the onset of an intravenous infusion may impact on expected pharmacokinetics and influence outcome.
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http://dx.doi.org/10.1016/j.ijantimicag.2013.06.013DOI Listing
January 2014

Agglomerated oral dosage forms of artemisinin/β-cyclodextrin spray-dried primary microparticles showing increased dissolution rate and bioavailability.

AAPS PharmSciTech 2013 Sep 24;14(3):911-8. Epub 2013 May 24.

Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.

Artemisinin, a poorly water-soluble antimalarial drug, presents a low and erratic bioavailability upon oral administration. The aim of this work was to study an agglomerated powder dosage form for oral administration of artemisinin based on the artemisinin/β-cyclodextrin primary microparticles. These primary microparticles were prepared by spray-drying a water-methanol solution of artemisinin/β-cyclodextrin. β-Cyclodextrin in spray-dried microparticles increased artemisinin water apparent solubility approximately sixfold. The thermal analysis evidenced a reduction in the enthalpy value associated with drug melting, due to the decrease in drug crystallinity. The latter was also evidenced by powder X-ray diffraction analysis, while (13)C-NMR analysis indicated the partial complexation with β-cyclodextrin. Agglomerates obtained by sieve vibration of spray-dried artemisinin/β-cyclodextrin primary microparticles exhibited free flowing and close packing properties compared with the non-flowing microparticulate powder. The in vitro dissolution rate determination of artemisinin from the agglomerates showed that in 10 min about 70% of drug was released from the agglomerates, whereas less than 10% of artemisinin was dissolved from raw material powder. Oral administration of agglomerates in rats yielded higher artemisinin plasma levels compared to those of pure drug. In the case of the agglomerated powder, a 3.2-fold increase in drug fraction absorbed was obtained.
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http://dx.doi.org/10.1208/s12249-013-9982-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755174PMC
September 2013

Complex product composition generates risks for generic substitution also with dosage forms for intravenous administration.

Int J Pharm 2013 Jul 27;451(1-2):50-6. Epub 2013 Apr 27.

Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.

Teicoplanin is an antibiotic made by fermentation in which a glycopeptide core is substituted by different fatty acids. The chemical structure and proportion of the various components are strictly dependent on the production process (Actinoplanes sp. strain, cell culture conditions and downstream process). Thus, a relevant variability can be introduced from different manufacturers. Interchangeability or substitution among the originator and the generic products of teicoplanin for injection is under debate with respect to pharmaceutical similarity. In fact, depending on the manufacturer, the six major components of teicoplanin show different quantitative distributions compared to that of the originator. The European Pharmacopoeia fixed an undifferentiated upper limit for the component content. A statistical approach is required for comparing complex products. In this paper the use of principal component analysis (PCA) as a tool for identifying the pharmaceutical equivalence among teicoplanin products from different sources was explored. The results obtained show that PCA can distinguish the differing origin of this biological drug.
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http://dx.doi.org/10.1016/j.ijpharm.2013.04.064DOI Listing
July 2013