Publications by authors named "Karim Amighi"

65 Publications

The combination of an innovative dry powder for inhalation and a standard cisplatin-based chemotherapy in view of therapeutic intensification against lung tumours.

Eur J Pharm Biopharm 2021 Jul 3;164:93-104. Epub 2021 May 3.

Unit of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium.

Cisplatin is one of the most commonly used chemotherapy in lung cancer despite its high nephrotoxicity leading to an administration only every 3-4 weeks. This study is the first report of a preclinical investigation of therapeutic intensification combining a cisplatin dry powder for inhalation (CIS-DPI) with an intravenous (iv) cisplatin-based treatment. CIS-DPI with 50% cisplatin content (CIS-DPI-50) was developed using lipid excipients through scalable processes (high-speed and high-pressure homogenization and spray-drying). CIS-DPI-50 showed good aerodynamic performance (fine particle fraction of ~ 55% and a mass median aerodynamic particle size of ~ 2 µm) and a seven-fold increase and decrease in C in the lungs and in plasma, respectively, in comparison with an iv cisplatin solution (CIS-iv) in healthy mice. Finally, the addition of CIS-DPI-50 to the standard cisplatin/paclitaxel iv doublet increased the response rate (67% vs 50%), decreased the tumour growth and prolonged the median survival (31 vs 21 days), compared to the iv doublet in the M109 lung carcinoma model tending to demonstrate a therapeutic intensification of cisplatin.
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http://dx.doi.org/10.1016/j.ejpb.2021.04.018DOI Listing
July 2021

Drug-related problems and risk factors related to unplanned hospital readmission among cancer patients in Belgium.

Support Care Cancer 2021 Jul 3;29(7):3911-3919. Epub 2021 Jan 3.

Department of Pharmacotherapy and Pharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Boulevard du Triomphe, CP 205/07, Access 2, Campus de la Plaine, Building BC, 1050, Brussels, Belgium.

Introduction: There are about 60,000 diagnoses of cancer per year in Belgium. After hospital care, about 12-13% of cancer patients are readmitted within 30 days after discharge. These readmissions are partly related to drug-related problems (DRP), such as interactions or adverse drug effects (ADE).

Objectives: The aim of this study is to quantify and to classify DRP readmissions within 30 days for cancer patients and to highlight risk factors potentially correlated to readmissions.

Methods: This study is a 6-month observational retrospective study in two care facilities in Brussels: an academic general hospital and an academic oncology center. Patients readmitted within 30 days after their last hospital care for a potential DRP were included. Patient files were evaluated with an intermediate medication review that included interactions analysis (Lexicomp®). The probability of DRP readmission was assessed using the World Health Organization's Uppsala Monitoring Centre (WHO-UMC) system.

Results: The final population included 299 patients; among them, 123 (41.1%) were readmitted due to DRP (certain DRP (4.9%), probable DRP (49.6%), and possible DRP (45.5%)). Risks factors linked to these DRP were a low Charlson Comorbidity Index, polypharmacy, the kind of hospital, and some chemotherapies (platinum preparations). Among all readmitted patients, the D-type interactions were the most common (44.8%), which suggest a possible therapy modification. However, around 10% of interactions were X-type (drug combination to avoid).

Conclusion: Almost 10% of patient readmitted within 30 days were potentially related to a DRP, most of them from adverse drug effects. Four risk factors (low Charlson Comorbidity Index, polypharmacy, the hospital, and some chemotherapies) were highlighted to prevent these readmissions.
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http://dx.doi.org/10.1007/s00520-020-05916-wDOI Listing
July 2021

Inhaled cytotoxic chemotherapy: clinical challenges, recent developments, and future prospects.

Expert Opin Drug Deliv 2021 03 14;18(3):333-354. Epub 2020 Oct 14.

Unit of Pharmaceutics and Biopharmaceutics, Université Libre De Bruxelles, Brussels, Belgium.

Introduction: Since 1968, inhaled chemotherapy has been evaluated and has shown promising results up to phase II but has not yet reached the market. This is due to technological and clinical challenges that require to be overcome with the aim of optimizing the efficacy and the tolerance of drug to re-open new developments in this field. Moreover, recent changes in the therapeutic standard of care for treating the patient with lung cancer also open new opportunities to combine inhaled chemotherapy with standard treatments.

Areas Covered: Clinical and technological concerns are highlighted from the reported clinical trials made with inhaled cytotoxic chemotherapies. This work then focuses on new pharmaceutical developments using dry powder inhalers as inhalation devices and on formulation strategies based on controlled drug release and with sustained lung retention or based on nanomedicine. Finally, new clinical strategies are described in regard to the impact of the immunotherapy on the patient's standard of care.

Expert Opinion: The choice of the drug, inhalation device, and formulation strategy as well as the position of inhaled chemotherapy in the patient's clinical care are crucial factors in optimizing local tolerance and efficacy as well as in its scalability and applicability in clinical practice.
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http://dx.doi.org/10.1080/17425247.2021.1829590DOI Listing
March 2021

Deciphering the chemical instability of sphaeropsidin A under physiological conditions - degradation studies and structural elucidation of the major metabolite.

Org Biomol Chem 2020 Oct;18(40):8147-8160

Department of Chemistry and Polymer Science, University of Stellenbosch, Matieland, 7600, Stellenbosch, Western Cape, South Africa.

The fungal metabolite sphaeropsidin A (SphA) has been recognised for its promising cytotoxicity, particularly towards apoptosis- and multidrug-resistant cancers. Owing to its intriguing activity, the development of SphA as a potential anticancer agent has been pursued. However, this endeavour is compromised since SphA exhibits poor physicochemical stability under physiological conditions. Herein, SphA's instability in biological media was explored utilizing LC-MS. Notably, the degradation tendency was found to be markedly enhanced in the presence of amino acids in the cell medium utilized. Furthermore, the study investigated the presence of degradation adducts, including the identification, isolation and structural elucidation of a major degradation metabolite, (4R)-4,4',4'-trimethyl-3'-oxo-4-vinyl-4',5',6',7'-tetrahydro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-2-ene-2-carboxylic acid. Considering the reduced cytotoxic potency of aged SphA solutions, as well as that of the isolated degradation metabolite, the reported antiproliferative activity has been attributed primarily to the parent compound (SphA) and not its degradation species. The fact that SphA continues to exhibit remarkable bioactivity, despite being susceptible to degradation, motivates future research efforts to address the challenges associated with this instability impediment.
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http://dx.doi.org/10.1039/d0ob01586eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881364PMC
October 2020

Feasibility study into the potential use of fused-deposition modeling to manufacture 3D-printed enteric capsules in compounding pharmacies.

Int J Pharm 2019 Oct 29;569:118581. Epub 2019 Jul 29.

Laboratory of Pharmaceutics and Biopharmaceutics, Université libre de Bruxelles, Campus de la Plaine, CP 207, Boulevard du Triomphe, Brussels 1050, Belgium; FabLab ULB, Rue Fritz Toussaint 8, 1050 Ixelles, Belgium. Electronic address:

The purpose of this work was to investigate the feasibility to manufacture enteric capsules, which could be used in compounding pharmacies, by fused-deposition modeling. It is well-known that conventional enteric dip coating of capsules in community pharmacies or hospitals is a time-consuming process which is characterized by an erratic efficacy. Fused-deposition modeling was selected as a potential 3D printing method due its ease and low-cost implementation. Before starting to print the capsules, an effective sealing system was designed via a computer-aided design program. Hot melt extrusion was used to make printable enteric filaments. They were made of the enteric polymer, a plasticizer and a thermoplastic polymer, namely Eudragit® L100-55, polyethylene glycol 400 and polylactic acid, respectively. Riboflavine-5'-phosphate was selected as a coloured drug model to compare the efficacy of the 3D printed capsules to that of enteric dip coated capsules as they are currently produced in community pharmacies and hospitals. Different parameters of fabrication which could influence the dissolution profile of the model drug, such as the layer thickness or post-processing step, were studied. It was demonstrated that our 3D printed enteric capsules did not release the drug for 2 h in acid medium (pH 1.2). However, they completely dissolved within 45 min at pH 6.8 which allowed the release of a minimal amount of 85% w/w of drug as it was recommended by the European Pharmacopoeia 9th Edition for enteric products.
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http://dx.doi.org/10.1016/j.ijpharm.2019.118581DOI Listing
October 2019

Development and evaluation of an omeprazole-based delayed-release liquid oral dosage form.

Int J Pharm 2019 Aug 5;567:118416. Epub 2019 Jun 5.

Laboratory of Pharmaceutics and Biopharmaceutics, Université Libre de Bruxelles, Campus de la Plaine, CP 207, Boulevard du Triomphe, Brussels 1050, Belgium. Electronic address:

Modified-release oral dosage forms are commonly used in pharmaceutics to delay or sustain the release of drugs. Nowadays, they are only marketed as solid dosage forms such as capsules or tablets. Therefore, the development of a liquid oral dosage form with modified-release properties has been keenly awaited to increase the compliance of patients with a swallowing impairment, such as paediatric, older or critically ill patients. In this study, a new technology has been developed that consists of multi-layered particles suspended extemporaneously in a syrup, using omeprazole as a model drug. The coating procedure was optimized to obtain a yield of minimum 90% w/w and a mean diameter below 500 µm. Eudragit® E100 and Eudragit® L100-55 were used to prevent the early release of omeprazole in the syrup and in the acidic environment of the stomach, respectively. These polymers allowed the stability of the coated particles to be ensured when dispersed in a liquid and the enteric release of the drug to be targeted. It was demonstrated that our new system presented similar release performances to existing marketed enteric dosage forms. It is able to protect omeprazole for 2 h in acidic medium at pH 1.2, while omeprazole was entirely released at pH 6.8 within 45 min. Once the final suspension is prepared extemporaneously, it presents sufficient stability to guarantee the administration of multiple doses filled into a syrup bottle and kept for a limited storage time at room temperature (e.g. up to 10 doses to be administered within 10 days).
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http://dx.doi.org/10.1016/j.ijpharm.2019.06.007DOI Listing
August 2019

Development of PLGA microparticles with high immunoglobulin G-loaded levels and sustained-release properties obtained by spray-drying a water-in-oil emulsion.

Int J Pharm 2019 Jul 28;566:291-298. Epub 2019 May 28.

Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Bd. du Triomphe CP 207, Campus de la Plaine, 1050 Brussels, Belgium.

In this study, the possibility of producing highly antibody-loaded microparticles with sustained-release properties was evaluated. Polyclonal immunoglobulin G (IgG) was used as a model of antibody and its encapsulation into poly(lactide-co-glycolide) acid (PLGA) microparticles was performed by spray-drying a water-in-oil (w/o) emulsion. It was demonstrated that the use of the Resomer RG505 PLGA allowed an IgG loading of 20% w/w with an encapsulation efficiency higher than 85%. The produced microparticles were characterized by a mean diameter lower than 10 µm. The burst effect was shown to reach a maximal value of 40%. IgG stability after encapsulation was also assessed. The use of this single PLGA provided a lag time of 3 months which dramatically slowed down the release rate after the initial release of the encapsulated IgG. Using blends of PLGA characterized by different inherent viscosities allowed decreasing the lag time and modulating the dissolution profile of the IgG from the spray-dried microparticles. Therefore, spray-drying a water-in-oil emulsion appeared to be a promising strategy to produce highly antibody-loaded microparticles characterized by sustained-release properties.
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http://dx.doi.org/10.1016/j.ijpharm.2019.05.070DOI Listing
July 2019

The Position of Inhaled Chemotherapy in the Care of Patients with Lung Tumors: Clinical Feasibility and Indications According to Recent Pharmaceutical Progresses.

Cancers (Basel) 2019 Mar 7;11(3). Epub 2019 Mar 7.

Unité de Pharmacie Galénique et de Biopharmacie, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Brussels 1050, Belgium.

Despite new treatment modalities, including targeted therapies and checkpoint inhibitors, cytotoxic chemotherapy remains central in the care of patients with lung tumors. Use of the pulmonary route to deliver chemotherapy has been proved to be feasible and safe in phase I, Ib/IIa and II trials for lung tumors, with the administration of drug doses to the lungs without prior distribution in the organism. The severe systemic toxicities commonly observed with conventional systemic chemotherapy are consequently reduced. However, development has failed in phase II at best. This review first focuses on the causes of failure of inhaled chemotherapy. It then presents new promising technologies able to take up the current challenges. These technologies include the use of a dry powder inhaler or a smart nebulizer with advanced drug formulations such as controlled-release formulations and nanomedicine. Finally, the potential position of inhaled chemotherapy in patient care is discussed and some indications are proposed based on the literature.
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http://dx.doi.org/10.3390/cancers11030329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468657PMC
March 2019

How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods.

Int J Pharm 2019 Apr 26;561:47-65. Epub 2019 Feb 26.

Laboratoire de Pharmacie Galénique et de Biopharmacie, Université libre de Bruxelles (ULB), Brussels, Belgium.

Nasal delivery offers many benefits over other conventional routes of delivery (e.g. oral or intravenous administration). Benefits include, among others, a fast onset of action, non-invasiveness and direct access to the central nervous system. The nasal cavity is not only limited to local application (e.g. rhinosinusitis) but can also provide direct access to other sites in the body (e.g. the central nervous system or systemic circulation). However, both the anatomy and the physiology of the nose impose their own limitations, such as a small volume for delivery or rapid mucociliary clearance. To meet nasal-specific criteria, the formulator has to complete a plethora of tests, in vitro and ex vivo, to assess the efficacy and tolerance of a new drug-delivery system. Moreover, depending on the desired therapeutic effect, the delivery of the drug should target a specific pathway that could potentially be achieved through a modified release of this drug. Therefore, this review focuses on specific techniques that should be performed when a nasal formulation is developed. The review covers both the tests recommended by regulatory agencies (e.g. the Food and Drug Administration) and other complementary experiments frequently performed in the field.
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http://dx.doi.org/10.1016/j.ijpharm.2019.02.026DOI Listing
April 2019

Implementation study of an interprofessional medication adherence program for HIV patients in Switzerland: quantitative and qualitative implementation results.

BMC Health Serv Res 2018 Nov 20;18(1):874. Epub 2018 Nov 20.

Community pharmacy, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.

Background: An interprofessional medication adherence program (IMAP) for chronic patients was developed and successfully implemented in the community pharmacy of the Department of ambulatory care and community medicine (Lausanne, Switzerland). This study assesses the capacity of a physician and a nurse at the infectious diseases service of a public hospital and of community pharmacists in the Neuchâtel area (Switzerland) to implement the IMAP in their practice.

Methods: Mixed method, prospective, observational study. Quantitative and qualitative analyses of the implementation process were conducted following the RE-AIM model (reach, effectiveness, adoption, implementation and maintenance).

Results: Implementation started in November 2014. One physician, one nurse, and five pharmacists agreed to participate. Healthcare professionals perceived the benefits of the program and were motivated to implement it in their practice (adoption). Seventeen patients were included in the program; 13 refused to participate. The inclusion of naïve HIV patients was easier than the inclusion of experienced patients with difficult psychosocial issues (reach). Pharmacists were engaged in reinforcing patient medication adherence in 25% of interviews (effectiveness). Key facilitators expressed by healthcare professionals were patient inclusion by the physician and the nurse instead of the pharmacist and the organisation of regular meetings between all stakeholders. In contrast, the encountered barriers were the lack of time and resources, the lack of team uptake, and the lack of adoption by senior managers (implementation). Interviewed patients were all satisfied with this new program, encouraging healthcare professionals to scale it up. Structural changes allowed the hospital and one pharmacy to enter the maintenance stage (maintenance).

Conclusion: The research team and collaboration between all professionals involved played an important role in this implementation. However, the dissemination of such a program to a larger scale and for the long term requires financial and structural resources as well as transitional external support.
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http://dx.doi.org/10.1186/s12913-018-3641-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247756PMC
November 2018

Impact of capsule type on aerodynamic performance of inhalation products: A case study using a formoterol-lactose binary or ternary blend.

Int J Pharm 2018 Dec 12;553(1-2):47-56. Epub 2018 Oct 12.

Laboratoire de Pharmacie Galénique et de Biopharmacie, Université libre de Bruxelles (ULB), Brussels, Belgium. Electronic address:

The aerodynamic performance of a dry powder for inhalation depends on the formulation and the dry powder inhaler (DPI). In the case of capsule-based DPIs, the capsule also plays a role in the powder aerosolisation and the dispersion of the micronized drug during the inhalation. This study evaluated the impact of gelatine capsules (Quali-G™ and Hard Gelatine Capsules for DPIs), cold-gelled hypromellose (HPMC) capsules (Quali-V-I and Vcaps) and thermal-gelled HPMC capsules (VcapsPlus) from Qualicaps and Capsugel respectively, on the delivered dose (DD), fine particle dose (FPD), and capsule retention for formoterol-lactose binary and ternary blends. This study used a low resistance Axahaler DPI based on the RS01 design (Plastiape, Italy). Similar trends were observed with the different capsule types that packaged both dry powder formulations. The highest DD and FPD and the lowest formoterol capsule retention were observed with cold-gelled HPMC capsules such as Quali-V-I and Vcaps, without significant differences between these capsules (p > 0.05, one-way ANOVA with Newman-Keuls post-hoc test) for both dry powders. Therefore, the capsule composition and manufacturing process have an influence on aerodynamic performance. In addition, the ternary blend showed higher DDs and FPDs but also higher capsule retention in comparison to the binary blend.
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http://dx.doi.org/10.1016/j.ijpharm.2018.10.034DOI Listing
December 2018

Corrigendum to "Chitosan-coated liposome dry-powder formulations loaded with ghrelin for nose-to-brain delivery" [Eur. J. Pharm. Biopharm. 129 (2018) 257-266].

Eur J Pharm Biopharm 2018 10 20;131:151. Epub 2018 Aug 20.

Laboratoire de Pharmacie Galénique et de Biopharmacie, Université libre de Bruxelles (ULB), Brussels, Belgium.

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http://dx.doi.org/10.1016/j.ejpb.2018.08.005DOI Listing
October 2018

Implementation of an interprofessional medication adherence program for HIV patients: description of the process using the framework for the implementation of services in pharmacy.

BMC Health Serv Res 2018 Sep 10;18(1):698. Epub 2018 Sep 10.

Community Pharmacy, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.

Background: The community pharmacy center of the Department of Ambulatory Care and Community Medicine of the Policlinique Médicale Universitaire (PMU), Lausanne, Switzerland developed and implemented an interprofessional medication adherence program for chronic patients (IMAP). In 2014, a project was launched to implement the IMAP for HIV patients in a public non-academic hospital with the collaboration of community pharmacists in the Neuchâtel area (Switzerland). This article aims to describe the different implementation stages and strategies of the project.

Methods: A posteriori description of the implementation process, including the conceptualization strategies and stages (exploration, preparation, operation, sustainability) using the Framework for the Implementation of Services in Pharmacy (FISpH).

Results: In 2014, an attending infectious disease physician and a nurse at a public hospital (Neuchâtel, Switzerland) contacted the PMU to implement the IMAP in their setting in collaboration with community pharmacies. Five volunteer community pharmacies in Neuchâtel were trained to deliver the program. Three factors were found to be essential to the successful launch and progress of the implementation project: the experience of the community pharmacy center of the PMU with the IMAP, the involvement of the PMU research team, and collaboration with an external start up (SISPha) to train and support pharmacists. During the operation stage, the most important strategy developed was that of regular meetings between all stakeholders. These allowed healthcare professionals to discuss the implementation progress, to address each stakeholder's expectations, and to exchange experiences to facilitate interprofessional collaboration and program delivery. Structural changes allowed the formalization of the activities at the hospital and in a community pharmacy. This formalization was identified as the transition step between the operation and the sustainability stages.

Conclusions: The transfer of the IMAP for HIV patients to a non-academic setting and its implementation are feasible. However, implementation of a new model of pharmacy service such as IMAP implies a deep change in practice. A transitional external support and the allocation of sufficient resources to carry out the IMAP are essential for its long-term sustainability.
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http://dx.doi.org/10.1186/s12913-018-3509-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131735PMC
September 2018

Chitosan-coated liposome dry-powder formulations loaded with ghrelin for nose-to-brain delivery.

Eur J Pharm Biopharm 2018 Aug 15;129:257-266. Epub 2018 Jun 15.

Laboratoire de Pharmacie Galénique et de Biopharmacie, Université libre de Bruxelles (ULB), Brussels, Belgium.

The nose-to-brain delivery of ghrelin loaded in liposomes is a promising approach for the management of cachexia. It could limit the plasmatic degradation of ghrelin and provide direct access to the brain, where ghrelin's specific receptors are located. Anionic liposomes coated with chitosan in either a liquid or a dry-powder formulation were compared. The powder formulation showed stronger adhesion to mucins (89 ± 4% vs 61 ± 4%), higher ghrelin entrapment efficiency (64 ± 2% vs 55 ± 4%), higher enzymatic protection against trypsin (26 ± 2% vs 20 ± 3%) and lower ghrelin storage degradation at 25 °C (2.67 ± 1.1% vs 95.64 ± 0.85% after 4 weeks). The powder formulation was also placed in unit-dose system devices that were able to generate an appropriate aerosol characterized by a Dv50 of 38 ± 6 µm, a limited percentage of particles smaller than 10 µm of 4 ± 1% and a reproducible mass delivery (CV: 1.49%). In addition, the device was able to deposit a large amount of powder (52.04% w/w) in the olfactory zone of a 3D-printed nasal cast. The evaluated combination of the powder formulation and the device could provide a promising treatment for cachexia.
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http://dx.doi.org/10.1016/j.ejpb.2018.06.011DOI Listing
August 2018

Evaluation of compliance with isotretinoin PPP recommendations and exploration of reasons for non-compliance: Survey among French-speaking health care professionals and patients in Belgium.

Pharmacoepidemiol Drug Saf 2018 06 3;27(6):668-673. Epub 2018 May 3.

Université libre de Bruxelles (ULB), Faculté de Pharmacie, Brussels, Belgium.

Purpose: To evaluate awareness of and compliance in Belgium by French-speaking health care professionals and patients with the isotretinoin safety recommendations regarding its teratogenic risk.

Method: Survey using online questionnaires, delivered from December 2014 to March 2015 for patients, pharmacists, dermatologists, and GPs and delivered again from September 2015 to October 2015 for GPs.

Results: Questionnaires were completed by 24 dermatologists, 24 GPs, 58 pharmacists, and 33 female patients. The pregnancy prevention programme was poorly known by health care professionals (23.6%) and patients (15.2%). Health care professionals informed women of childbearing age in depth about the teratogenic risk (98.3% of pharmacists and 100.0% of GPs and dermatologists) and the importance of an effective contraceptive method (87.9% and 100.0%, respectively). Patients were less informed about the pregnancy test (25.9% and 14.6%) and the need to use a second contraceptive method (29.3% and 27.1%). The low compliance with the last 2 recommendations was due to a lack of adoption by health care professionals regarding the need for these recommendations if female patients have an effective contraceptive method and the pregnancy risk is discussed in detail with them.

Conclusion: The effectiveness of the pregnancy prevention programme recommendations should be reconsidered by an expert committee. Justifications should be added to effective recommendations to increase their adoption by health care professionals and patients.
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http://dx.doi.org/10.1002/pds.4441DOI Listing
June 2018

Assessment of medication adherence and responsible use of isotretinoin and contraception through Belgian community pharmacies by using pharmacy refill data.

Patient Prefer Adherence 2018 19;12:153-161. Epub 2018 Jan 19.

Department of Pharmacotherapy and Pharmaceutics, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Brussels, Belgium.

Purpose: The aims of the study were to evaluate medication adherence and the influencing factors for isotretinoin and contraception (oral, patches, and rings) and to evaluate the concomitant use of contraception and isotretinoin.

Methods: Reimbursed prescription data from January 2012 to August 2015 of all patients in Belgium were received from Pharmanet-National Institute for Health and Disability Insurance. Medication adherence was measured according to the medication possession ratio. The influence of gender and age was analyzed using the Mann-Whitney test and the Spearman coefficient correlation. The independence between adherence to contraception and adherence to isotretinoin was analyzed using the Pearson chi-square test of independence. Persistence was defined as the number of days between initiation and presumed end of treatment. The Kaplan-Meier method was used to plot the medication persistence curves, and the log-rank test was used to compare the curves. The concomitant use of contraception and isotretinoin was analyzed using descriptive statistics.

Results: The medication possession ratio was ≥0.8 for 46.1% of patients receiving isotretinoin and for 74.0% of women using contraception. For isotretinoin, this percentage decreased as the number of attempts increased (29.8% for the second attempt and 19.8% for more than two attempts). Men seemed more adherent than women, and a weak negative correlation between adherence and age was observed. The adherence data of isotretinoin and contraception were independent. The median persistence for isotretinoin treatment was 139 days (interquartile range 71-209) and was higher for men. Among women between 12 and 21 years old taking isotretinoin, 63.8% received at least one contraceptive prescription. However, 15.7% of women taking isotretinoin adhered to the use of contraception 1 month before, during, and 1 month after treatment.

Conclusion: Medication adherence to isotretinoin and contraception and compliance with the isotretinoin safety recommendation could be improved. Health service interventions, using pharmacy refill data, should be delivered to ensure patient safety and strict adherence to contraception when under isotretinoin treatment.
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http://dx.doi.org/10.2147/PPA.S149355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783016PMC
January 2018

New Folate-Grafted Chitosan Derivative To Improve Delivery of Paclitaxel-Loaded Solid Lipid Nanoparticles for Lung Tumor Therapy by Inhalation.

Mol Pharm 2018 03 30;15(3):899-910. Epub 2018 Jan 30.

Center for Microscopy and Molecular Imaging (CMMI), B-6041 Gosselies , Belgium.

Inhaled chemotherapy for the treatment of lung tumors requires that drug delivery systems improve selectivity for cancer cells and tumor penetration and allow sufficient lung residence. To this end, we developed solid lipid nanoparticles (SLN) with modified surface properties. We successfully synthesized a new folate-grafted copolymer of polyethylene glycol (PEG) and chitosan, F-PEG-HTCC, with a PEG-graft ratio of 7% and a molecular weight range of 211-250 kDa. F-PEG-HTCC-coated, paclitaxel-loaded SLN were prepared with an encapsulation efficiency, mean diameter, and zeta potential of about 100%, 250 nm, and +32 mV, respectively. The coated SLN entered folate receptor (FR)-expressing HeLa and M109-HiFR cells in vitro and M109 tumors in vivo after pulmonary delivery. The coated SLN significantly decreased the in vitro half-maximum inhibitory concentrations of paclitaxel in M109-HiFR cells (60 vs 340 nM, respectively). We demonstrated that FR was involved in these improvements, especially in M109-HiFR cells. After pulmonary delivery in vivo, the coated SLN had a favorable pharmacokinetic profile, with pulmonary exposure to paclitaxel prolonged to up to 6 h and limited systemic distribution. Our preclinical findings therefore demonstrated the positive impact of the coated SLN on the delivery of paclitaxel by inhalation.
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http://dx.doi.org/10.1021/acs.molpharmaceut.7b00846DOI Listing
March 2018

Development of coated liposomes loaded with ghrelin for nose-to-brain delivery for the treatment of cachexia.

Int J Nanomedicine 2017 28;12:8531-8543. Epub 2017 Nov 28.

Laboratoire de Pharmacie Galénique et de Biopharmacie, Université libre de Bruxelles (ULB), Brussels.

The aim of the present study was to develop a ghrelin-containing formulation based on liposomes coated with chitosan intended for nose-brain delivery for the treatment of cachexia. Among the three types of liposomes developed, anionic liposomes provided the best results in terms of encapsulation efficiency (56%) and enzymatic protection against trypsin (20.6% vs 0% for ghrelin alone) and carboxylesterase (81.6% vs 17.2% for ghrelin alone). Ghrelin presented both electrostatic and hydrophobic interactions with the anionic lipid bilayer, as demonstrated by isothermal titration calorimetry. Then, anionic liposomes were coated with -(2-hydroxy) propyl-3-trimethyl ammonium chitosan chloride. The coating involved a size increment from 146.9±2.7 to 194±6.1 nm, for uncoated and coated liposomes, respectively. The ζ-potential was similarly increased from -0.3±1.2 mV to 6±0.4 mV before and after coating, respectively. Chitosan provided mucoadhesion, with an increase in mucin adsorption of 22.9%. Enhancement of permeation through the Calu3 epithelial monolayer was also observed with 10.8% of ghrelin recovered in the basal compartment in comparison to 0% for ghrelin alone. Finally, aerosols generated from two nasal devices (VP3 and SP270) intended for aqueous dispersion were characterized with either coated or uncoated liposomes. Contrarily to the SP270 device, VP3 device showed minor changes between coated and uncoated liposome aerosols, as shown by their median volume diameters of 38.4±5.76 and 37.6±5.74 µm, respectively. Overall, the results obtained in this study show that the developed formulation delivered by the VP3 device can be considered as a potential candidate for nose-brain delivery of ghrelin.
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http://dx.doi.org/10.2147/IJN.S147650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713684PMC
March 2018

Proposed algorithm for healthcare professionals based on product characteristics and in vitro performances in different use conditions using formoterol-based marketed products for inhalation.

Int J Pharm 2017 Sep 27;530(1-2):415-429. Epub 2017 Jul 27.

Laboratoire de Pharmacie Galénique et de Biopharmacie, Université libre de Bruxelles (ULB), Brussels, Belgium. Electronic address:

Healthcare professionals require an easy algorithm for selecting the most appropriate inhalation product for each patient at the beginning of a treatment. As a case study, we selected five marketed formoterol products: Foradil and Formagal, capsule-based dry powder inhalers (DPIs), Novolizer Formoterol and Oxis, reservoir-based DPIs and Formoair, a pressurized metered dose inhaler. We generated an algorithm based on device properties (i.e. device handling, feedback and remaining dose/end of product indication) and in vitro aerodynamic performances (i) along the product use life in optimal conditions, (ii) at different airflows and (iii) after exposing pre-loaded doses to 40°C and 75% relative humidity for 4h. Based on these results, an algorithm was built where Formoair and Formagal can be proposed when there is high risk of humidity and for patients presenting suboptimal or optimal airflows. When no risk of humidity is present, Formoair, Foradil, Formagal and Novolizer Formoterol equipped with a trigger valve could be proposed for patients presenting suboptimal airflows. When no risk of humidity is present and for patients presenting optimal airflow, all products, including Oxis, could be proposed. Ultimately, the optimal inhalation product will be selected after checking the patient's preference and capacity for correct device handling and inhalation technique.
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http://dx.doi.org/10.1016/j.ijpharm.2017.07.021DOI Listing
September 2017

Sensitization of glioblastoma tumor micro-environment to chemo- and immunotherapy by Galectin-1 intranasal knock-down strategy.

Sci Rep 2017 04 27;7(1):1217. Epub 2017 Apr 27.

Research Group Experimental Neurosurgery and Neuroanatomy, KU Leuven, Herestraat 49, Leuven, 3000, Belgium.

In this study, we evaluated the consequences of reducing Galectin-1 (Gal-1) in the tumor micro-environment (TME) of glioblastoma multiforme (GBM), via nose-to-brain transport. Gal-1 is overexpressed in GBM and drives chemo- and immunotherapy resistance. To promote nose-to-brain transport, we designed siRNA targeting Gal-1 (siGal-1) loaded chitosan nanoparticles that silence Gal-1 in the TME. Intranasal siGal-1 delivery induces a remarkable switch in the TME composition, with reduced myeloid suppressor cells and regulatory T cells, and increased CD4+ and CD8+ T cells. Gal-1 knock-down reduces macrophages' polarization switch from M1 (pro-inflammatory) to M2 (anti-inflammatory) during GBM progression. These changes are accompanied by normalization of the tumor vasculature and increased survival for tumor bearing mice. The combination of siGal-1 treatment with temozolomide or immunotherapy (dendritic cell vaccination and PD-1 blocking) displays synergistic effects, increasing the survival of tumor bearing mice. Moreover, we could confirm the role of Gal-1 on lymphocytes in GBM patients by matching the Gal-1 expression and their T cell signatures. These findings indicate that intranasal siGal-1 nanoparticle delivery could be a valuable adjuvant treatment to increase the efficiency of immune-checkpoint blockade and chemotherapy.
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http://dx.doi.org/10.1038/s41598-017-01279-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430862PMC
April 2017

Platinum pharmacokinetics in mice following inhalation of cisplatin dry powders with different release and lung retention properties.

Int J Pharm 2017 Jan 19;517(1-2):359-372. Epub 2016 Dec 19.

Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Bd. du Triomphe CP 207, Campus de la Plaine, 1050 Brussels, Belgium. Electronic address:

Pharmacokinetics of cisplatin administered by the pulmonary route were established in mice using dry powders inhaler (DPI) formulations showing immediate (F1) and controlled release (CR, solid lipid microparticles) in vitro, without (F2) or with PEGylated excipients (F3, F4). Formulation administration was realized using dry powder blends (correspondingly named thereafter F1 to F4) able to reproducibly deliver particles in vivo using a DP-4M Dry Powder Insufflator™. Their platinum pharmacokinetics were established over 48h in lungs, total blood and non-target organs vs. IV and endotracheal nebulization (EN). EN and F1 were rapidly distributed from the lungs (t 2.6 and 5.0min). F2 was eliminated in ∼1h (t 9.0min). F3 lung retention was sustained for ∼7h (t 59.9min), increasing lung AUC 11-, 4- and 3-fold vs. IV, F1 and F2. Total blood t were higher and AUC and C lower using the pulmonary route vs. IV. Kidney C was reduced 6-, 2- and 3-fold for F1, F2 and F3. AUC in kidneys were 2- to 3-fold lower for F1 and F2vs. IV but comparable for IV vs. F3, probably because of kidney saturation. PEGylated solid lipid microparticles provided cisplatin particles with interesting lung retention and CR properties.
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http://dx.doi.org/10.1016/j.ijpharm.2016.12.037DOI Listing
January 2017

Development of controlled-release cisplatin dry powders for inhalation against lung cancers.

Int J Pharm 2016 Dec 11;515(1-2):209-220. Epub 2016 Oct 11.

Laboratory of Pharmaceutics and Biopharmaceutics, CP207, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Boulevard du Triomphe, Campus Plaine, B-1050 Brussels, Belgium.

The present study focuses on the development of dry powders for inhalation as adjuvant chemotherapy in lung cancer treatment. Cisplatin was chosen as a potential candidate for a local treatment as it remains the main platinum component used in conventional chemotherapies, despite its high and cumulative systemic toxicities. Bulk cisplatin was reduced to submicron sizes using high-pressure homogenization, mixed with a solubilized lipid and/or PEGylated component and then spray-dried to produce controlled-release dry powder formulations. The obtained formulations were characterized for their physicochemical properties (particle size and morphology), aerodynamic performance and release profiles. Cisplatin content and integrity were assessed by electrothermal atomic absorption spectrometry and Pt nuclear magnetic resonance spectroscopy. DPI formulations with cisplatin contents ranging from 48.5 to 101.0% w/w exhibited high fine particle fractions ranging from 37.3% to 51.5% of the nominal dose. Formulations containing cisplatin microcrystals dispersed in solid lipid microparticles based on acceptable triglycerides for inhalation and PEGylated excipients showed a controlled-release for more than 24h and a limited burst effect. These new formulations could provide an interesting approach to increasing and prolonging drug exposure in the lung while minimizing systemic toxicities.
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http://dx.doi.org/10.1016/j.ijpharm.2016.10.019DOI Listing
December 2016

Inflammation induced by inhaled lipopolysaccharide depends on particle size in healthy volunteers.

Br J Clin Pharmacol 2016 11 28;82(5):1371-1381. Epub 2016 Jul 28.

Clinic of Immuno-allergology, CHU Brugmann, Université Libre de Bruxelles (ULB), Brussels, Belgium.

Aims: In drug development, the anti-inflammatory properties of new molecules in the lung are currently tested using the inhaled lipopolysaccharide (LPS) model. The total and regional lung bioavailability of inhaled particles depends significantly on their size. The objective of the present study was to compare inflammatory responses in healthy volunteers after the inhalation of LPS of varying droplet size.

Methods: Three nebulizers were characterized by different droplet size distributions [mean mass median aerodynamic diameters: Microcirrus (2.0 μm), MB2 (3.2 μm) and Pari (7.9 μm)]. Participants inhaled three boluses of a 20 μg (technetium 99 m-labelled) solution of LPS, randomly delivered by each nebulizer. We measured the lung deposition of the nebulized LPS by gamma-scintigraphy, while blood and sputum biomarkers were evaluated before and after challenges.

Results: MB2 and Pari achieved greater lung deposition than Microcirrus [171.5 (±72.9) and 217.6 (±97.8) counts pixel , respectively, vs. 67.9 (±20.6) counts pixel ; P < 0.01]. MB2 and Pari caused higher levels of blood C-reactive protein and more total cells and neutrophils in sputum compared with Microcirrus (P < 0.05). C-reactive protein levels correlated positively with lung deposition (P < 0.01).

Conclusions: Inhalation of large droplets of LPS gave rise to greater lung deposition and induced a more pronounced systemic and bronchial inflammatory response than small droplets. The systemic inflammatory response correlated with lung deposition. NCT01081392.
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http://dx.doi.org/10.1111/bcp.13052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061781PMC
November 2016

Development of siRNA-loaded chitosan nanoparticles targeting Galectin-1 for the treatment of glioblastoma multiforme via intranasal administration.

J Control Release 2016 Apr 21;227:71-81. Epub 2016 Feb 21.

Research Group Experimental Neurosurgery and Neuroanatomy, KU Leuven, Herestraat 49, Leuven 3000, Belgium; Department of Neurosurgery, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium.

Galectin-1 (Gal-1) is a naturally occurring galactose-binding lectin, which is overexpressed in glioblastoma multiforme (GBM). Gal-1 is associated with tumor progression, and is a potent immune suppressor in the tumor micro-environment. To inhibit Gal-1 in GBM, an effective therapy is required that reaches the central nervous system tumor, with limited systemic effects. In this study, we report for the first time that concentrated chitosan nanoparticle suspensions can deliver small interfering RNA (siRNA) into the central nervous system tumor within hours after intranasal administration. These nanoparticles are able to complex siRNA targeting Gal-1 to a high percentage, and protect them from RNAse degradation. Moreover, a successful intracellular delivery of anti-Gal-1 siRNA resulted in a decreased expression of Gal-1 in both murine and human GBM cells. Sequence specific RNAinterference, resulted in more than 50% Gal-1 reduction in tumor bearing mice. This study indicates that the intranasal pathway is an underexplored transport route for delivering siRNA-based therapies targeting Gal-1 in the treatment of GBM.
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http://dx.doi.org/10.1016/j.jconrel.2016.02.032DOI Listing
April 2016

Development and evaluation of well-tolerated and tumor-penetrating polymeric micelle-based dry powders for inhaled anti-cancer chemotherapy.

Int J Pharm 2016 Mar 2;501(1-2):148-59. Epub 2016 Feb 2.

Laboratoire de Pharmacie Galénique et de Biopharmacie, Faculté de Pharmacie Université libre de Bruxelles (ULB), Brussels, Belgium.

Despite the direct access to the lung offered by the inhalation route, drug penetration into lung tumors could remain an important issue. In this study, folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD) micelles were developed as an effective pulmonary drug delivery system to reach and penetrate lung tumors and cancer cells. The F-PEG-HMD micelles were able to enter HeLa and M109-HiFR, two folate receptor-expressing cancer cell lines, in vitro, and in vivo after administration by inhalation to orthotopic M109-HiFR lung tumor grafted mice. Paclitaxel-loaded F-PEG-HMD micelles characterized in PBS by a Z-average diameter of ∼50 nm and a zeta potential of ∼-4 mV were prepared with an encapsulation efficiency of ∼100%. The loaded micelles reduced HeLa and M109-HiFR cell growth, with half maximal inhibitory concentrations of 37 and 150 nM, respectively. Dry powders embedding the paclitaxel-loaded F-PEG-HMD micelles were developed by spray-drying. In vitro, good deposition profiles were obtained, with a fine particle fraction of up to 50% and good ability to re-disperse the micelles in physiological buffer. A polymeric micelle-based dry powder without paclitaxel was well-tolerated in vivo, as assessed in healthy mice by determination of total protein content, cell count, and cytokine IL-1β, IL-6, and TNF-α concentrations in bronchoalveolar lavage fluids.
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http://dx.doi.org/10.1016/j.ijpharm.2016.01.073DOI Listing
March 2016

3D printing in pharmaceutics: A new tool for designing customized drug delivery systems.

Int J Pharm 2016 Feb 3;499(1-2):376-394. Epub 2016 Jan 3.

Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium.

Three-dimensional printing includes a wide variety of manufacturing techniques, which are all based on digitally-controlled depositing of materials (layer-by-layer) to create freeform geometries. Therefore, three-dimensional printing processes are commonly associated with freeform fabrication techniques. For years, these methods were extensively used in the field of biomanufacturing (especially for bone and tissue engineering) to produce sophisticated and tailor-made scaffolds from patient scans. This paper aims to review the processes that can be used in pharmaceutics, including the parameters to be controlled. In practice, it not straightforward for a formulator to be aware of the various technical advances made in this field, which is gaining more and more interest. Thus, a particular aim of this review is to give an overview on the pragmatic tools, which can be used for designing customized drug delivery systems using 3D printing.
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http://dx.doi.org/10.1016/j.ijpharm.2015.12.071DOI Listing
February 2016

New dry powders for inhalation containing temozolomide-based nanomicelles for improved lung cancer therapy.

Int J Oncol 2015 Sep 20;47(3):1131-42. Epub 2015 Jul 20.

Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), B-1050 Brussels, Belgium.

Besides the numerous advantages of a chemotherapy administered by the inhalation route for lung cancer therapy, dry powder for inhalation (DPI) offers many advantages compared to other techniques and seems to be a technique that is well-adapted to an anticancer treatment. DPI formulations were developed using the cytotoxic drug temozolomide and a new folate-grafted self-assembling copolymer, a conjugate of three components, folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD). F-PEG-HMD was synthesized using carbodiimide-mediated coupling chemistry in three main steps. F-PEG-HMD was characterized by 1H-NMR, mass spectrometry and thermal analysis. F-PEG-HMD presented a critical micellar concentration in water of 4x10-7 M. F-PEG-HMD nanomicelles were characterized by a trimodal particle size distribution with Z-average diameter of 83±1 nm in water. Temozolomide-loaded nanomicelles were prepared by solubilization of F-PEG-HMD in the presence of temozolomide. Temozolomide solubility in water was increased in the presence of F-PEG-HMD (2-fold increase in molar solubility) which could potentially lead to increased local concentrations in the tumor site. The temozolomide-loaded F-PEG-HMD nanomicelles were characterized by a Z-average diameter of ~50 to ~60 nm, depending on the F-PEG-HMD concentration used. The nanomicelles were then spray-dried to produce dry powders. Temozolomide remained stable during all the formulation steps, confirmed by similar in vitro anticancer properties for the DPI formulations and a raw temozolomide solution. Two of the developed DPI formulations were characterized by good aerodynamic properties (with a fine particle fraction of up to 50%) and were able to release the F-PEG-HMD nanomicelles quickly in aqueous media. Moreover, in vitro, the two DPI formulations showed wide pulmonary deposition in the lower respiratory tract where adenocarcinomas are more often found. The present study, therefore, shows that F-PEG-HMD-based dry powders for inhalation could constitute an interesting drug delivery system able to release nanomicelles that are useful in adenocarcinomas that overexpress folate receptors.
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http://dx.doi.org/10.3892/ijo.2015.3092DOI Listing
September 2015

Development and evaluation in vitro and in vivo of injectable hydrolipidic gels with sustained-release properties for the management of articular pathologies such as osteoarthritis.

Int J Pharm 2015 Jul 28;490(1-2):74-84. Epub 2015 Apr 28.

Laboratory of Pharmaceutics and Biopharmaceutics, Université Libre de Bruxelles (ULB), Campus de la Plaine, BC B-1050 Brussels, Belgium. Electronic address:

This study aimed to evaluate glycerol monooleate (GMO) as a carrier to develop viscoelastic and injectable sustained-release drug delivery systems. The potential pro- and antioxidant activity of the developed hydrolipidic gels were evaluated by measuring the production of ROS by polymorphonuclear leukocytes (PMNs). In addition, the biocompatibility and effectiveness of two selected gel candidates were evaluated in vivo by evaluating the benefit of a single intraarticular injection of these new treatments in a model of osteoarthritis in rabbits. The in vitro study demonstrated that the carrier F1 did not have a pro-oxidative effect and even protected PMNs against natural auto-activation, regardless of the incorporation of either clonidine chlorhydrate or betamethasone dipropionate. The in vivo study demonstrated that F1 and F1-BDP induced a loss of cartilage quality in comparison to the control and reference groups but that the lesions of cartilage observed were generally mild, with not much full-depth erosion. Moreover, no exacerbating inflammation was observed when considering the synovial membranes and the PGE2 and CRP levels. These results seemed to demonstrate that the sustained-release formulation based on GMO could be well-tolerated after intraarticular injection. Moreover, it could have the potential to prevent inflammatory conditions while sustaining drug activity locally over weeks.
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http://dx.doi.org/10.1016/j.ijpharm.2015.04.064DOI Listing
July 2015

Ciprofloxacin monoolein water gels as implants for the treatment of chronic osteomyelitis: In vitro characterization.

J Adv Pharm Technol Res 2014 Oct;5(4):158-63

Laboratory of Pharmaceutics and Biopharmaceutics, Pharmacy Institute, Université Libre de Bruxelles (ULB), Campus Plaine, Brussels, Belgium.

This work investigated the possibility of using the biodegradable gentamicin-monoolein-water gels as models, in order to obtain a similar sustained release of ciprofloxacin hydrochloride. Four gels containing antibiotics were prepared and were examined with regard to their physicochemical properties and in vitro drug release characteristics. Ciprofloxacin, unlike gentamicin, which was dissolved in the matrix, was in dispersed form. However, despite its insolubility, microscopic observation, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and X-ray diffraction showed that the developed gel was in the cubic liquid crystalline structure and have maintained their ability to progressively release ciprofloxacin. ciprofloxacin-monoolein-water (5:80:15% w/w), which released in vitro approximately 85% of ciprofloxacin after 16 days could possibly be considered as an alternative to a gentamicin-monoolein-water gel for the treatment of chronic osteomyelitis.
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http://dx.doi.org/10.4103/2231-4040.143029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215478PMC
October 2014

Formulations for Intranasal Delivery of Pharmacological Agents to Combat Brain Disease: A New Opportunity to Tackle GBM?

Cancers (Basel) 2013 Aug 14;5(3):1020-48. Epub 2013 Aug 14.

Laboratory of Experimental Neurosurgery and Neuroanatomy, KU Leuven, Leuven 3000, Belgium.

Despite recent advances in tumor imaging and chemoradiotherapy, the median overall survival of patients diagnosed with glioblastoma multiforme does not exceed 15 months. Infiltration of glioma cells into the brain parenchyma, and the blood-brain barrier are important hurdles to further increase the efficacy of classic therapeutic tools. Local administration methods of therapeutic agents, such as convection enhanced delivery and intracerebral injections, are often associated with adverse events. The intranasal pathway has been proposed as a non-invasive alternative route to deliver therapeutics to the brain. This route will bypass the blood-brain barrier and limit systemic side effects. Upon presentation at the nasal cavity, pharmacological agents reach the brain via the olfactory and trigeminal nerves. Recently, formulations have been developed to further enhance this nose-to-brain transport, mainly with the use of nanoparticles. In this review, the focus will be on formulations of pharmacological agents, which increase the nasal permeation of hydrophilic agents to the brain, improve delivery at a constant and slow release rate, protect therapeutics from degradation along the pathway, increase mucoadhesion, and facilitate overall nasal transport. A mounting body of evidence is accumulating that the underexplored intranasal delivery route might represent a major breakthrough to combat glioblastoma.
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http://dx.doi.org/10.3390/cancers5031020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795377PMC
August 2013