Publications by authors named "Herman J Woerdenbag"

52 Publications

Educational Video Improves Knowledge about Outpatients' Usage of Antibiotics in Two Public Hospitals in Indonesia.

Antibiotics (Basel) 2021 May 20;10(5). Epub 2021 May 20.

Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Indonesia, Depok 16424, Indonesia.

The inappropriate use or misuse of antibiotics, particularly by outpatients, increases antibiotic resistance. A lack of public knowledge about "Responsible use of antibiotics" and "How to obtain antibiotics" is a major cause of this. This study aimed to assess the effectiveness of an educational video about antibiotics and antibiotic use to increase outpatients' knowledge shown in two public hospitals in East Java, Indonesia. A quasi-experimental research setting was used with a one-group pre-test-post-test design, carried out from November 2018 to January 2019. The study population consisted of outpatients to whom antibiotics were prescribed. Participants were selected using a purposive sampling technique; 98 outpatients at MZ General Hospital in the S regency and 96 at SG General Hospital in the L regency were included. A questionnaire was used to measure the respondents' knowledge, and consisted of five domains, i.e., the definition of infections and antibiotics, obtaining the antibiotics, directions for use, storage instructions, and antibiotic resistance. The knowledge test score was the total score of the Guttman scale (a dichotomous "yes" or "no" answer). To determine the significance of the difference in knowledge before and after providing the educational video and in the knowledge score between hospitals, the (paired) Student's -test was applied. The educational videos significantly improved outpatients' knowledge, which increased by 41% in MZ General Hospital, and by 42% in SG General Hospital. It was concluded that an educational video provides a useful method to improve the knowledge of the outpatients regarding antibiotics.
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http://dx.doi.org/10.3390/antibiotics10050606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161411PMC
May 2021

Biofilm Formation Assay on Essential Oil Coated Silicone Rubber.

Bio Protoc 2021 Mar 5;11(5):e3941. Epub 2021 Mar 5.

Hacettepe University, Faculty of Sciences, Department of Biology (Biotechnology Division), Beytepe, Ankara, Turkey.

Development of biofilm associated candidemia for patients with implanted biomaterials causes an urgency to develop antimicrobial and biofilm inhibitive coatings in the management of recalcitrant infections. Recently, there is an increase in the number of patients with biofilm formation and resistance to antifungal therapy. Therefore, there is a growing interest to use essential oils as coating agents in order to prevent biomaterial-associated infections. Often high costs, complicated and laborious technologies are used for both applying the coating and determination of the antibiofilm effects hampering a rapid screening of essential oils. In order to determine biofilm formation of on essential oil coated surfaces easier, cheaper and faster, we developed an essential oil (lemongrass oil) coated surface (silicone-rubber) by using a hypromellose ointment/essential oil mixture. Furthermore, we modified the "crystal violet binding assay" to quantify the biofilm mass of biofilm formed on the lemongrass oil coated silicone rubber surface. The essential oil coating and the biomass determination of biofilms on silicone rubber can be easily applied with simple and accessible equipment, and will therefore provide rapid information about whether or not a particular essential oil is antiseptic, also when it is used as a coating agent.
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http://dx.doi.org/10.21769/BioProtoc.3941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005879PMC
March 2021

Legislation and current developments in adverse drug reaction reporting in Mongolia: how far are we?

J Pharm Policy Pract 2021 Mar 8;14(1):15. Epub 2021 Mar 8.

Pharmacovigilance Centre Lareb, Goudsbloemvallei 7, 5237 MH, 's-Hertogenbosch, The Netherlands.

Monitoring adverse drug reactions is a vital issue to ensure drug safety and to protect the general public from medication-related harmful effects. In order to properly monitor drug safety, a regulatory system needs to be in place as well as an infrastructure that allows for analyzing national and international safety data. In Mongolia, adverse drug reaction (ADR) reporting activities have been implemented in the past decade. During this period, the basic structure and legal basis of an adverse drug reaction monitoring system was established. Because of the fragmented but growing healthcare system and the complexity of pharmaceutical issues in Mongolia, a sustainable process for the development of the adverse drug reaction reporting system is a key issue. The aim of this article is to disclose the Mongolian situation for the rest of the world and to share experiences on how an ADR reporting system can be developed towards a higher and more advanced level to contribute to both national and international drug safety issues. In this article, we review the features of the Mongolian health care and pharmaceutical systems, as well as the current development of the adverse drug reaction reporting system.
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http://dx.doi.org/10.1186/s40545-021-00298-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938544PMC
March 2021

Alignment of CanMEDS-based Undergraduate and Postgraduate Pharmacy Curricula in The Netherlands.

Pharmacy (Basel) 2020 Jul 10;8(3). Epub 2020 Jul 10.

Department of Pharmaceutical Science, Utrecht University, David de Wiedgebouw, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.

In this article the design of three master programs (MSc in Pharmacy) and two postgraduate specialization programs for community or hospital pharmacist is described. After a preceding BSc in Pharmacy, these programs cover the full pharmacy education capacity for pharmacists in primary and secondary health care in the Netherlands. All programs use the CanMEDS framework, adapted to pharmacy education and specialization, which facilitates the horizontal integration of pharmacists' professional development with other health care professions in the country. Moreover, it is illustrated that crossing the boundary from formal (university) education to experiential (workplace) education is eased by a gradual change in time spent in these two educational environments and by the use of comparable monitoring, feedback, and authentic assessment instruments. A reflection on the curricula, based on the principles of the and the , suggests that the alignment of these educational programs facilitates the development of professional expertise and professional identity of Dutch pharmacists.
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http://dx.doi.org/10.3390/pharmacy8030117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558760PMC
July 2020

pH-dependent ileocolonic drug delivery, part II: preclinical evaluation of novel drugs and novel excipients.

Drug Discov Today 2020 08 17;25(8):1374-1388. Epub 2020 Jun 17.

University of Groningen, Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Electronic address:

Novel drugs and novel excipients in pH-dependent ileocolonic drug delivery systems have to be tested in animals. Which animal species are suitable and what in vivo methods are used to verify ileocolonic drug delivery?
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http://dx.doi.org/10.1016/j.drudis.2020.06.012DOI Listing
August 2020

pH-dependent ileocolonic drug delivery, part I: in vitro and clinical evaluation of novel systems.

Drug Discov Today 2020 08 15;25(8):1362-1373. Epub 2020 Jun 15.

University of Groningen, Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Electronic address:

After the pH dependency of novel pH-dependent ileocolonic drug delivery systems is confirmed in vitro, their performance should be evaluated in human volunteers.
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http://dx.doi.org/10.1016/j.drudis.2020.06.011DOI Listing
August 2020

Effect of Roux-en-Y gastric bypass on the bioavailability of metoprolol from immediate and controlled release tablets: a single oral dose study before and after surgery.

Eur J Hosp Pharm 2020 03 15;27(e1):e19-e24. Epub 2019 Feb 15.

Department of Clinical Pharmacy and Clinical Pharmacology, Medisch Centrum Leeuwarden, Leeuwarden, The Netherlands.

Objective: Roux-en-Y gastric bypass (RYGB) surgery induces major changes in the gastrointestinal tract that may alter the pharmacokinetics of orally administered drugs. Results from pharmacokinetic studies are sparse. This study aimed to investigate the effect of RYGB on the bioavailability of metoprolol from immediate release (IR) and controlled release (CR) tablets in female patient volunteers before and after surgery.

Methods: An explorative, two-phase, single oral dose pharmacokinetic study of metoprolol in female patients undergoing RYGB was carried out. The dose was administered twice in each patient, 1 month before and 6 months after surgery. After intake of either 100 mg of metoprolol IR or CR tablet serum concentration-time profiles of metoprolol were determined. The endpoint was the ratio of AUC/AUC of metoprolol.

Results: Twelve patients were included in the study (metoprolol IR: 7; metoprolol CR: 5). After intake of a metoprolol IR tablet major intraindividual and interindividual differences for area under the serum concentration versus time curve (AUC) of metoprolol before and after surgery were observed (range ratio AUC/AUC: 0.74-1.98). For metoprolol CR tablets a significant reduction in bioavailability of metoprolol was observed after surgery (range ratio AUC/AUC: 0.43-0.77).

Conclusion: RYGB may influence the bioavailability of metoprolol from an IR tablet. The magnitude of changes in bioavailability after RYGB requires close monitoring of patients using metoprolol IR tablets and dose adjustment if deemed necessary. RYGB clearly reduces the bioavailability of metoprolol from a CR tablet. After RYGB clinicians may consider to increase the dose according to clinical response.
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http://dx.doi.org/10.1136/ejhpharm-2018-001804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147559PMC
March 2020

Development of an Orodispersible Film Containing Stabilized Influenza Vaccine.

Pharmaceutics 2020 Mar 8;12(3). Epub 2020 Mar 8.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Most influenza vaccines are administered via injection, which is considered as user-unfriendly. Vaccination via oral cavity using an orodispersible film (ODF) might be a promising alternative. To maintain the antigenicity of the vaccine during preparation and subsequent storage of these ODFs, sugars such as trehalose and pullulan can be employed as stabilizing excipients for the antigens. In this study, first, β-galactosidase was used as a model antigen. Solutions containing β-galactosidase and sugar (trehalose or trehalose/pullulan blends) were pipetted onto plain ODFs and then either air- or vacuum-dried. Subsequently, sugar ratios yielding the highest β-galactosidase stability were used to prepare ODFs containing H5N1 whole inactivated influenza virus vaccine (WIV). The stability of the H5N1 hemagglutinin was assessed by measuring its hemagglutination activity. Overall, various compositions of trehalose and pullulan successfully stabilized β-galactosidase and WIV in ODFs. WIV incorporated in ODFs showed excellent stability even at challenging storage conditions (60 °C/0% relative humidity or 30 °C/56% relative humidity) for 4 weeks. Except for sugars, the polymeric component of ODFs, i.e., hypromellose, possibly improved stability of WIV as well. In conclusion, ODFs may be suitable for delivering of WIV to the oral cavity and can possibly serve as an alternative for injections.
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http://dx.doi.org/10.3390/pharmaceutics12030245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150837PMC
March 2020

A Pediatrics Utilization Study in The Netherlands to Identify Active Pharmaceutical Ingredients Suitable for Inkjet Printing on Orodispersible Films.

Pharmaceutics 2020 Feb 17;12(2). Epub 2020 Feb 17.

Department of PharmacoTherapy, Epidemiology and Economics, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Background: The use of medication in pediatrics, children aged 0-5 years, was explored so as to identify active pharmaceutical ingredients (APIs) suitable for inkjet printing on a plain orodispersible film (ODF) formulation in a pharmacy.

Methods: The database IADB.nl, containing pharmacy dispensing data from community pharmacies in the Netherlands, was used to explore medication use in the age group of 0-5 years old, based on the Anatomical Therapeutic Chemical classification code (ATC code). Subsequently, a stepwise approach with four exclusion steps was used to identify the drug candidates for ODF formulation development.

Results: there were 612 Active Pharmaceutical Ingredients (APIs) that were dispensed to the target group, mostly antibiotics. Of the APIs, 221 were not registered for pediatrics, but were used off-label. After the exclusion steps, 34 APIs were examined regarding their suitability for inkjet printing. Almost all of the APIs were sparingly water soluble to practically insoluble.

Conclusion: Pharmaceutical inkjet printing is a suitable new technique for ODF manufacturing for pediatric application, however the maximal printed dose as found in the literature remained low. From the selected candidates, only montelukast shows a sufficiently high water-solubility to prepare a water-based solution. To achieve higher drug loads per ODF is ambitious, but is theoretically possible by printing multiple layers, using highly water-soluble APIs or highly loaded suspensions.
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http://dx.doi.org/10.3390/pharmaceutics12020164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076503PMC
February 2020

Orodispersible films as a personalized dosage form for nursing home residents, an exploratory study.

Int J Clin Pharm 2020 Apr 13;42(2):436-444. Epub 2020 Feb 13.

Department of PharmacoTherapy, Epidemiology and Economics, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.

Background A frequent problem in ageing patients, and thus in nursing home residents, is dysphagia, affecting the ability to swallow solid dosage forms. A promising and personalized drug delivery system for this patient group is the orodispersible film. Orodispersible films could be prepared extemporaneously in a (hospital) pharmacy setting or in specialty compounding community pharmacies using the solvent casting method. Little has been done to systematically investigate which medications should be chosen for orodispersible film formulation development. Objective In this study, the medication use of nursing home residents was examined to identify medications that are suitable for orodispersible film formulation development. Setting Nursing homes of three Northern provinces of Netherlands. Method Medication intake data from 427 nursing home residents from nine nursing homes from the three northern provinces of the Netherlands were used to identify candidates for orodispersible film formulation development. A stepwise approach, with exclusion steps, was used. Selection criteria included systemic use with a maximum amount of 100 mg per dose unit, no commercially available suitable dosage forms for administration in dysphagia, indication for diseases associated with dysphagia. Furthermore, the characteristics of the active pharmaceutical ingredient needed for the orodispersible film formulation development, such as water solubility and taste, were reviewed. Main outcome measure Active pharmaceutical ingredients suitable for orodispersible film formulation development. Results The nursing home residents used three hundred forty one different medications. Of those, 34 active pharmaceutical ingredients from six therapeutic groups were considered as candidates for orodispersible film formulation development. Most of these active pharmaceutical ingredients have a bitter taste and poor water solubility, which is a challenge for orodispersible film production. Conclusions The most suitable active pharmaceutical ingredient candidates for manufacturing of orodispersible films for the ageing patient population may be the combination of levodopa and carbidopa used to treat the symptoms of Parkinson's disease, and baclofen used to treat spasticity.
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http://dx.doi.org/10.1007/s11096-020-00990-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192866PMC
April 2020

A Retrospective Surveillance of the Antibiotics Prophylactic Use of Surgical Procedures in Private Hospitals in Indonesia.

Hosp Pharm 2019 Oct 21;54(5):323-329. Epub 2018 Aug 21.

University of Surabaya (UBAYA), Indonesia.

According to international guidelines, prophylactic antibiotics in elective surgery should be given as a single dose 30 to 60 minutes before the operation is conducted. Postoperative administration of antibiotics should be discontinued 24 hours after surgery to minimize bacterial resistance and to keep control over hospitalization costs. There is a lack of data on the actual antibiotic use around surgical procedures in Indonesia. This retrospective surveillance study aimed to obtain defined daily doses (DDD) and DDDs per 100 bed days (DDD-100BD) for prophylactically used antibiotics in two private hospitals in Surabaya, East Java. These hospitals are considered to be representative for the current situation in Indonesia. Data from a total of 693 patients over a nearly 1-year period (2016) were collected and evaluated. The overall DDD per patient was 1.5 for hospital A and 1.7 for hospital B. The overall DDD-100BD was 30 for hospital B. Of the 24 antibiotics given prophylactically, ceftriaxone was the most commonly used in both hospitals. There was a clear discrepancy between daily practice in both hospitals and the recommendations in the guidelines. This study shows that better adherence to antibiotic stewardship is needed in Indonesia. Substantial improvements need to be made toward guided precision therapy regarding quantity (dose and frequency), route of administration (prolonged intravenous), and choice of the type of antibiotic.
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http://dx.doi.org/10.1177/0018578718792804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751973PMC
October 2019

Antifungal and biofilm inhibitory effect of Cymbopogon citratus (lemongrass) essential oil on biofilm forming by Candida tropicalis isolates; an in vitro study.

J Ethnopharmacol 2020 Jan 27;246:112188. Epub 2019 Aug 27.

Hacettepe University, Faculty of Sciences, Department of Biology (Biotechnology Division) Beytepe, 06800, Ankara, Turkey. Electronic address:

Ethnopharmacological Relevance: Cymbopogon citratus (lemongrass) essential oil has been widely used as a traditional medicine and is well known for antimicrobial properties. Therefore, it might be a potent anti-infective and biofilm inhibitive against Candida tropicalis infections. Until now, no ideal coating or cleaning method based on an essential oil has been described to prevent biofilm formation of Candida strains on silicone rubber maxillofacial prostheses, voice prostheses and medical devices susceptible to C. tropicalis infections.

Aim Of The Study: To investigate the antifungal and biofilm inhibitory effects of Cymbopogon citratus oil. Clinical isolates of C. tropicalis biofilms on different biomaterials were used to study the inhibitory effect.

Materials And Methods: The efficacy of Cymbopogon citratus, Cuminum cyminum, Citrus limon and Cinnamomum verum essential oils were compared on biofilm formation of three C. tropicalis isolates on 24 well polystyrene plates. C. citratus oil coated silicone rubber surfaces were prepared using hypromellose ointment as a vehicle. The antifungal tests to determine minimum inhibitory and minimum fungicidal concentrations were assessed by a microbroth dilution method and biofilm formation was determined by a crystal violet binding assay.

Results: C. tropicalis strains formed more biofilm on hydrophobic materials than on hydrophilic glass. C. citratus oil showed a high antifungal effect against all C. tropicalis strains. For comparison, C. limon oil and C. cyminum oil showed minor to no killing effect against the C. tropicalis strains. C. citratus oil had the lowest minimal inhibitory concentration of all essential oils tested and inhibited biofilm formation of all C. tropicalis strains. C. citratus oil coating on silicone rubber resulted in a 45-76% reduction in biofilm formation of all C. tropicalis strains.

Conclusion: Cymbopogon citratus oil has good potential to be used as an antifungal and antibiofilm agent on silicone rubber prostheses and medical devices on which C. tropicalis biofilms pose a serious risk for skin infections and may cause a shorter lifespan of the prosthesis.
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http://dx.doi.org/10.1016/j.jep.2019.112188DOI Listing
January 2020

Respiratory syncytial virus subunit vaccines based on the viral envelope glycoproteins intended for pregnant women and the elderly.

Expert Rev Vaccines 2019 09 25;18(9):935-950. Epub 2019 Aug 25.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen , Groningen , The Netherlands.

: Respiratory syncytial virus (RSV) causes high morbidity and mortality rates among infants, young children, and the elderly worldwide. Unfortunately, a safe and effective vaccine is still unavailable. In 1966, a formalin-inactivated RSV vaccine failed and resulted in the death of two young children. This failure shifted research toward the development of subunit-based vaccines for pregnant women (to passively vaccinate infants) and the elderly. Among these subunit-based vaccines, the viral envelope glycoproteins show great potential as antigens. : In this review, progress in the development of safe and effective subunit RSV vaccines based on the viral envelope glycoproteins and intended for pregnant women and the elderly, are reviewed and discussed. Studies published in the period 2012-2018 were included. : Researchers are close to bringing safe and effective subunit-based RSV vaccines to the market using the viral envelope glycoproteins as antigens. However, it remains a major challenge to elicit protective immunity, with a formulation that has sufficient (storage) stability. These issues may be overcome by using the RSV fusion protein in its pre-fusion conformation, and by formulating this protein as a dry powder. It may further be convenient to administer this powder via the pulmonary route.
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http://dx.doi.org/10.1080/14760584.2019.1657013DOI Listing
September 2019

A gastrointestinal simulation system for dissolution of oral solid dosage forms before and after Roux-en-Y gastric bypass.

Eur J Hosp Pharm 2019 May 8;26(3):152-156. Epub 2018 Feb 8.

Department of Clinical Pharmacy and Clinical Pharmacology, Medical Centre Leeuwarden, Leeuwarden, The Netherlands.

Background: The Roux-en-Y gastric bypass (RYGB) is a bariatric procedure, greatly reducing the stomach size and bypassing the duodenum and proximal jejunum. Hence, RYGB may reduce the absorption and bioavailability of oral medication. For clinical decisions on the use of medication, knowledge of altered modifications in drug disposition is a prerequisite. An in vitro dissolution method for solid oral medications, simulating conditions before and after RYGB, might be a valuable tool to predict the pharmaceutical availability of medicines frequently used by patients after RYGB.

Objectives: To develop a gastrointestinal simulation system (GISS), mimicking conditions before and after RYGB for investigating dissolution characteristics of solid oral medications, and to assess the pharmaceutical availability of metoprolol from immediate-release (IR) and controlled-release (CR) tablets under these conditions.

Methods: With an adjusted, pharmacopoeial paddle dissolution apparatus, the GISS enables variation in parameters which are relevant to drug release in vivo: pH, volume, residence time, osmolality and agitation. Metoprolol tartrate 100 mg IR tablets and metoprolol CR tablets were tested. Release profiles were determined by measuring the concentrations of metoprolol spectrophotometrically.

Results: From IR tablets, under all conditions applied, >85% of metoprolol was released within 25 min. From all tested CR tablets >90% of metoprolol was released after 22 hours.

Conclusions: This GISS is a suitable dissolution system to assess pharmaceutical availability before and after RYGB. In patients who have undergone RYGB, no problems in pharmaceutical availability of metoprolol IR and CR tablets are to be expected. Any changes in response to metoprolol in patients after RYGB should therefore be ascribed to changes in bioavailability.
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http://dx.doi.org/10.1136/ejhpharm-2017-001360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684018PMC
May 2019

Oromucosal films: from patient centricity to production by printing techniques.

Expert Opin Drug Deliv 2019 09 8;16(9):981-993. Epub 2019 Aug 8.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen , Groningen , AV , The Netherlands.

: Oromucosal films, comprising mucoadhesive buccal films (MBFs) and orodispersible films (ODFs), are considered patient-centric dosage forms. Target groups are patients with special needs. Various active pharmaceutical ingredients have been shown to be suitable for oromucosal film production. A shift is seen in the production techniques, from conventional solvent casting to printing techniques. : In this review, the patient acceptability of oromucosal films is discussed. An overview is given of the small molecule drugs, biopharmaceuticals and herbal extracts that have been incorporated so far. Finally, the current state of 2D and 3D printing techniques for production purposes is discussed. : The patient-centric features are important for the further development and acceptance of this oral solid dosage form. Oromucosal films perfectly fit in the current attention for personalized medicine. Both MBFs and ODFs are intended for either a local or a systemic effect. For buccal absorption, sufficient mucoadhesion is one of the most important criteria an oromucosal film must comply with. For the preparation, the solvent casting technique is still predominately used. Some limitations of this production method can be tackled by printing techniques. However, these novel techniques introduce new requirements, yet to be set, for oromucosal film preparation.
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http://dx.doi.org/10.1080/17425247.2019.1652595DOI Listing
September 2019

Identifying critical process steps to protein stability during spray drying using a vibrating mesh or a two-fluid nozzle.

Eur J Pharm Sci 2019 Feb 3;128:152-157. Epub 2018 Dec 3.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands. Electronic address:

The aim of this study was to identify critical steps to protein stability during spray drying using two different nozzle types: a vibrating mesh nozzle and a standard two-fluid nozzle in a Büchi B-90 spray dryer. l-Lactic dehydrogenase was used as a model protein as it is a heat and shear stress sensitive protein. Trehalose was used as excipient because of its excellent stabilizing capacities. The entire spray drying process was split up into smaller steps and after each step the enzymatic activity of the protein was measured. With the vibrating mesh nozzle in total 78% of activity was lost. About 68% was due to atomizing and heating and 10% was caused by dehydration and circulation of the liquid. With the two-fluid nozzle the total activity loss was only 23%, to which atomization, dehydration, and circulation contributed almost equally. Heating was not an issue, as the two-fluid nozzle could be cooled with water. In conclusion, the type and the configuration of the nozzle used for spray drying are important determinants for maintaining protein stability, as atomizing, heating, ultra-sonication, and recirculation of the feed solution negatively influence it. The possibility to cool the two-fluid nozzle offers an important advantage to the vibrating mesh nozzle in the spray drying process of proteins. In this study, we show that, next to the optimization of the formulation, optimization of the spray drying process should be taken into account to maintain protein stability.
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http://dx.doi.org/10.1016/j.ejps.2018.11.027DOI Listing
February 2019

Orodispersible films based on blends of trehalose and pullulan for protein delivery.

Eur J Pharm Biopharm 2018 Dec 29;133:104-111. Epub 2018 Sep 29.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.

During the last decades the number of therapeutic proteins increased tremendously on the pharmaceutical market. However, due to their often poor stability and limitations of the administration route, the application of therapeutic proteins is a major challenge. The oral mucosa has been suggested as a possible route for protein delivery. In this study, we prepared protein loaded orodispersible films (ODFs), based on blends of trehalose/pullulan by air- and freeze-drying. These two carbohydrates were selected based on the excellent protein stabilizing capacity of trehalose and film-forming ability of pullulan. ODFs were loaded with three model proteins. Ovalbumin was used to study the effect of protein incorporation on the mechanical properties, disintegration time, uniformity of weight and thickness of the ODFs. Lysozyme and β-galactosidase were used to evaluate protein stability. Ovalbumin loading did not significantly influence the mechanical properties of freeze-dried ODFs, while incorporation of ovalbumin in air-dried ODFs led to a substantial reduction in tensile strength. The trehalose/pullulan ratio had no impact on the stability of lysozyme, while the stability of β-galactosidase increased with increasing trehalose/pullulan ratios. Furthermore, freeze-drying appeared to be favorable over air-drying for process stability while the reverse was found for storage stability. In conclusion, trehalose/pullulan-based ODFs are from a technical point promising for possible protein delivery via the oral cavity.
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http://dx.doi.org/10.1016/j.ejpb.2018.09.016DOI Listing
December 2018

Comparison of Rheological and Sedimentation Behavior of Commercially Available Suspending Vehicles for Oral Pharmaceutical Preparations.

Int J Pharm Compd 2018 May-Jun;22(3):247-251

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.

A pharmaceutical suspension is a semi-liquid dosage form suitable for patients being unable to swallow solid medicines such as tablets and capsules. A vehicle used for the preparation of pharmaceutical oral suspensions preferably shows pseudo-plastic behavior. In a product that gets thinner with agitation and thicker upon standing, slow settlement of the suspended active pharmaceutical ingredient is combined with good pourability and rehomogenization. This gives the best guarantee of uniformity of dose for oral suspensions. In this study, the rheological behavior of commercially available ready-to-use vehicles for oral pharmaceutical preparations was compared, and the sedimentation of paracetamol dispersed in these vehicles was investigated. With SuspendIt and SyrSpend SF PH4 (Liquid), both pseudoplastic vehicles, very stable paracetamol suspensions were obtained. Of these two vehicles, SyrSpend SF PH4 (Liquid) displayed somewhat higher viscosity, which is a favorable quality characteristic for suspensions.
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September 2018

Addition of Pullulan to Trehalose Glasses Improves the Stability of β-Galactosidase at High Moisture Conditions.

Carbohydr Polym 2017 Nov 24;176:374-380. Epub 2017 Aug 24.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands,. Electronic address:

Incorporation of therapeutic proteins in a matrix of sugar glass is known to enhance protein stability, yet protection is often lost when exposed to high relative humidity (RH). We hypothesized that especially in these conditions the use of binary glasses of a polysaccharide and disaccharide might yield advantages for protein stability. Therefore, different amounts of the polysaccharide pullulan were introduced in freeze-dried trehalose glasses. In these homogeneous blends, the presence of pullulan above 50 weight % prevented crystallization of trehalose when exposed to high RH. Storage stability testing up to 4 weeks of the model protein β-galactosidase incorporated in pullulan/trehalose blends showed superior behavior of pure trehalose at 30°C/0% RH, while pullulan/trehalose blends yielded the best stability at 30°C/56% RH. In conclusion, binary glasses of pullulan and trehalose may provide excellent stability of proteins under storage conditions that may occur in practice, namely high temperature and high RH.
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http://dx.doi.org/10.1016/j.carbpol.2017.08.084DOI Listing
November 2017

Increased drug load and polymer compatibility of bilayered orodispersible films.

Eur J Pharm Sci 2017 Sep 12;107:183-190. Epub 2017 Jul 12.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.

The addition of enalapril maleate to a casting solution for orodispersible films (ODFs) containing hypromellose and carbomer 974P as film forming agents (standard casting solution, SCS) caused a dose dependent reduction of the viscosity. This phenomenon was a serious problem in the preparation of ODFs with an increased enalapril load (>1mg per ODF) when using the solvent casting method. The aim of the present work was twofold. Firstly, the influence of enalapril on the viscosity of SCS was studied in more detail. Secondly, two methods for increasing the enalapril load of an ODF were investigated that did not negatively influence the properties of SCS. The casting height was increased and the preparation of bilayered ODF, using the double-casting method, was explored. In the framework of the bilayered ODFs the compatibility between the film forming agents hydroxypropyl cellulose (HPC), sodium alginate (SA), hydroxyethyl cellulose (HEC) and the combination hypromellose-carbomer 974P (SCS) was investigated.

Results And Conclusions: We found that enalapril concentration dependently reduced the pH, thereby negatively influencing the gel formation and the viscosity of SCS. An increased casting height did not result in a proportionally increased enalapril load. The enalapril load could be doubled when a bilayered ODF containing two layers of SCS was produced. Finally, not all combinations of film forming agents could be used for the preparation of bilayered ODFs. Besides, the sequence in which the different polymer layers were casted affected the appearance of the ODFs. In conclusion, the best formulations were produced with the polymer combinations SCS/SCS and SCS/HPC.
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http://dx.doi.org/10.1016/j.ejps.2017.07.010DOI Listing
September 2017

Ready-to-use parenteral amiodarone: a feasibility study towards a long-term stable product formulation.

Eur J Hosp Pharm 2017 Mar 13;24(2):110-114. Epub 2016 Apr 13.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.

Objectives: To determine the feasibility of preparing a long-term stable ready-to-use parenteral amiodarone formulation using cyclodextrins as dissolution enhancer.

Methods: A preformulation study was performed with different molar ratios of hydroxypropyl-beta-cyclodextrin (HP-BCD) or sulfobutylether-beta-cyclodextrin (SBE-BCD) to amiodarone in order to investigate enhancement of amiodarone's water solubility. Further, effects of pH and temperature on the dissolution rate during production were investigated. Shelf-life was determined for a ready-to-use iso-osmotic preparation of 1.8 mg/mL amiodarone with SBE-BCD in a molar ratio of 1:3. Amiodarone content was assessed using a validated high-pressure liquid chromatography ultraviolet method.

Results: Amiodarone-SBE-BCD in a molar ratio of 1:3 at pH 4.0-5.0 yielded the best results in terms of increased solubility and dissolution time (90 min). With SBE-BCD, a smaller molar ratio to amiodarone was needed than with HP-BCD. The amiodarone content of the final formulation stored 12 months at 21°C in daylight remained unchanged.

Conclusions: A ready-to-use or ready-to-administer amiodarone product, prepared in a hospital pharmacy, for intravenous application in an acute clinical setting is a feasible option from a chemical, physical and microbiological point of view. The availability of such a product will have a significant impact on medication safety, and production should therefore be considered.
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http://dx.doi.org/10.1136/ejhpharm-2015-000860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451646PMC
March 2017

Personalized Medicine in Pediatrics: The Clinical Potential of Orodispersible Films.

AAPS PharmSciTech 2017 Feb 4;18(2):267-272. Epub 2016 Apr 4.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.

Children frequently receive medicines that are designed for adults. The dose of commercially available products is adapted, mostly based on the child's bodyweight, thereby neglecting differences in pharmacokinetic and pharmacodynamics parameters. If commercial products are unsuitable for administration to children or are unavailable, extemporaneous pharmacy preparations are a good alternative. For this particular population, orodispersible films (ODFs) can be a highly attractive dosage form for the oral administration of drugs. ODFs are relatively easy to prepare in a hospital setting, create dose flexibility, and may suit an individual approach, especially for patients having difficulties in swallowing tablets or being fluid restricted. In this article, various aspects related to pharmacy preparations, clinical application, and preparation of ODFs for pediatric patients are highlighted and discussed.
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http://dx.doi.org/10.1208/s12249-016-0515-1DOI Listing
February 2017

Development and potential application of an oral ColoPulse infliximab tablet with colon specific release: A feasibility study.

Int J Pharm 2016 May 17;505(1-2):175-86. Epub 2016 Mar 17.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Electronic address:

The monoclonal antibody infliximab is one of the cornerstones in the treatment of Crohn's disease. Local delivery of infliximab would be an alternative to overcome the inherent disadvantages of intravenous therapy. For this purpose 5mg infliximab tablets were developed. To stabilize the antibody during production and storage it was incorporated in a sugar glass containing the oligosaccharide inulin. To obtain colon-specific release a ColoPulse coating was applied. The tablets were stored for 16 months under different conditions based on ICH climatic zone I.
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http://dx.doi.org/10.1016/j.ijpharm.2016.03.027DOI Listing
May 2016

Oromucosal film preparations: points to consider for patient centricity and manufacturing processes.

Expert Opin Drug Deliv 2016 8;13(4):493-506. Epub 2015 Dec 8.

a Institute of Pharmaceutics and Biopharmaceutics , Heinrich-Heine-University Düsseldorf , Düsseldorf , Germany.

Introduction: According to the European Pharmacopoeia, oromucosal films comprise mucoadhesive buccal films and orodispersible films. Both oral dosage forms receive considerable interest in the recent years as commercially available pharmaceutical products and as small scale personalized extemporaneous preparations.

Areas Covered: In this review, technological issues such as viscosity of the casting liquid, mechanical properties of the film, upscaling and the stability of the casting solution and produced films will be discussed. Furthermore, patient-related problems like appearance, mucosal irritation, taste, drug load, safety and biopharmaceutics are described. Current knowledge and directions for solutions are summarized.

Expert Opinion: The viscosity of the casting solution is a key factor for producing suitable films. This parameter is amongst others dependent on the polymer and active pharmaceutical ingredient, and the further excipients that are used. For optimal patient compliance, an acceptable taste and palatability are desirable. Safe and inert excipients should be used and appropriate packaging should be provided to produced films. Absorption through the oral mucosa will vary for each active compound, formulation and patient, which gives rise to pharmacokinetic questions. Finally, the European Pharmacopoeia needs to specify methods, requirement and definitions for oromucosal film preparations based on bio-relevant data.
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http://dx.doi.org/10.1517/17425247.2016.1118048DOI Listing
October 2016

Gastrointestinal pH and Transit Time Profiling in Healthy Volunteers Using the IntelliCap System Confirms Ileo-Colonic Release of ColoPulse Tablets.

PLoS One 2015 15;10(7):e0129076. Epub 2015 Jul 15.

University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands; University of Groningen, Department Pharmacy, Section of Pharmacotherapy and Pharmaceutical Care, Groningen, The Netherlands.

Introduction: ColoPulse tablets are an innovative development in the field of oral dosage forms characterized by a distal ileum and colon-specific release. Previous studies in humans showed release in the ileo-colonic region, but the relationship between gastrointestinal pH and release was not experimentally proven in vivo. This information will complete the in vivo release-profile of ColoPulse tablets.

Materials And Methods: Release from ColoPulse tablets was studied in 16 healthy volunteers using the dual label isotope strategy. To determine gastrointestinal pH profiles and transit times the IntelliCap system was used. A ColoPulse tablet containing 13C-urea and an uncoated, immediate release tablet containing 15N2-urea were taken simultaneously followed by a standardized breakfast after three hours. Five minutes after intake of the tablets the IntelliCap capsule was swallowed and pH was measured until excretion in the feces. Breath and urine samples were collected for isotope analysis.

Results: Full analysis could be performed in 12 subjects. Median bioavailability of 13C -urea was 82% (95% CI 74-94%, range 61-114%). The median lag time (5% release of 13C) was 5:42 h (95% CI 5:18-6:18 h, range 2:36-6:36 h,) There was no statistically significant difference between lag time based on isotope signal and colon arrival time (CAT) based on pH (median 5:42 vs 5:31 h p = 0.903). In all subjects an intestinal pH value of 7.0 was reached before release of 13C from the ColoPulse tablet occurred.

Discussion And Conclusions: From the combined data from the IntelliCap system and the 13C -isotope signal it can be concluded that release from a ColoPulse tablet in vivo is not related to transit times but occurs in the ileo-colonic region after pH 7.0 is reached. This supports our earlier findings and confirms that the ColoPulse system is a promising delivery system for targeting the distal ileum and colon.

Trial Registration: ISRCTN Registry 18301880.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129076PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503763PMC
April 2016

Quality by design approach for optimizing the formulation and physical properties of extemporaneously prepared orodispersible films.

Int J Pharm 2015 May 5;485(1-2):70-6. Epub 2015 Mar 5.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.

The quality by design (QbD) approach was applied for optimizing the formulation of extemporaneously prepared orodispersible films (ODFs) using Design-Expert® Software. The starting formulation was based on earlier experiments and contained the film forming agents hypromellose and carbomer 974P and the plasticizer glycerol (Visser et al., 2015). Trometamol and disodium EDTA were added to stabilize the solution. To optimize this formulation a quality target product profile was established in which critical quality attributes (CQAs) such as mechanical properties and disintegration time were defined and quantified. As critical process parameters (CPP) that were evaluated for their effect on the CQAs the percentage of hypromellose and the percentage of glycerol as well as the drying time were chosen. Response surface methodology (RMS) was used to evaluate the effects of the CPPs on the CQAs of the final product. The main factor affecting tensile strength and Young's modulus was the percentage of glycerol. Elongation at break was mainly influenced by the drying temperature. Disintegration time was found to be sensitive to the percentage of hypromellose. From the results a design space could be created. As long as the formulation and process variables remain within this design space, a product is obtained with desired characteristics and that meets all set quality requirements.
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http://dx.doi.org/10.1016/j.ijpharm.2015.03.005DOI Listing
May 2015

Orodispersible films in individualized pharmacotherapy: The development of a formulation for pharmacy preparations.

Int J Pharm 2015 Jan 7;478(1):155-163. Epub 2014 Nov 7.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Orodispersible films (ODFs) are promising drug delivery systems for customized small scale pharmacy preparations. The aim of the present study was to develop a versatile casting solution suitable for the extemporaneous production of ODFs to which active pharmaceutical ingredients (APIs) can be added. Different combinations of film forming agents and other excipients and different casting heights were tested for their suitability for production of ODFs. The best suitable casting solution contained hypromellose, carbomer, glycerol, disodium EDTA and trometamol. This casting solution was used to prepare ODFs containing water-soluble APIs (enalapril maleate and prednisolone disodium phosphate) and a poorly water-soluble API (diazepam) for which ethanol 96% was used as co-solvent.The water-soluble APIs as well as ethanol influenced the viscosity of the casting solution, mechanical properties and disintegration time of the ODFs. All ODFs containing API met the requirements on uniformity of mass and uniformity of content set by the European Pharmacopoeia (2014) (Ph. Eur.) 8th edition. In conclusion, ODFs of good pharmaceutical quality can be prepared on small scale. Hereby opening the perspective of using ODFs for individualized pharmacotherapy.
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http://dx.doi.org/10.1016/j.ijpharm.2014.11.013DOI Listing
January 2015

Natural products from resurrection plants: potential for medical applications.

Biotechnol Adv 2014 Nov 26;32(6):1091-101. Epub 2014 Mar 26.

University of Potsdam, Institute of Biochemistry and Biology, Department of Molecular Biology, Karl-Liebknecht str. 24-25, Haus 20, 14476 Potsdam-Golm, Germany; Max-Planck Institute of Molecular Plant Physiology, Plant Signalling Group, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany.

Resurrection species are a group of land plants that can tolerate extreme desiccation of their vegetative tissues during harsh drought stress, and still quickly - often within hours - regain normal physiological and metabolic functions following rehydration. At the molecular level, this desiccation tolerance is attributed to basal cellular mechanisms including the constitutive expression of stress-associated genes and high levels of protective metabolites present already in the absence of stress, as well as to transcriptome and metabolome reconfigurations rapidly occurring during the initial phases of drought stress. Parts of this response are conferred by unique metabolites, including a diverse array of sugars, phenolic compounds, and polyols, some of which accumulate to high concentrations within the plant cell. In addition to drought stress, these metabolites are proposed to contribute to the protection against other abiotic stresses and to an increased oxidative stress tolerance. Recently, extracts of resurrection species and particular secondary metabolites therein were reported to display biological activities of importance to medicine, with e.g. antibacterial, anticancer, antifungal, and antiviral activities, rendering them possible candidates for the development of novel drug substances as well as for cosmetics. Herein, we provide an overview of the metabolite composition of resurrection species, summarize the latest reports related to the use of natural products from resurrection plants, and outline their potential for medical applications.
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http://dx.doi.org/10.1016/j.biotechadv.2014.03.005DOI Listing
November 2014

Vietnamese traditional medicine from a pharmacist's perspective.

Expert Rev Clin Pharmacol 2012 Jul;5(4):459-77

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.

Traditional medicine plays an important role in the healthcare system of Vietnam. Vietnamese traditional medicine (VTM) is underpinned by the oriental philosophy and theory of healing. VTM is largely influenced by traditional Chinese medicine, but differs to a certain extent. VTM is largely not evidence-based from a clinical perspective but subclinical research data from the past decades support the traditional use of many herbal VTM drugs. For safe use, knowledge of the occurrence of adverse reactions and herb-drug interactions is necessary. The Vietnamese government supports further development of VTM in a scientific way and integration of VTM with Western medicine. This article first gives an overview of the general aspects of VTM (historical perspective, regulatory aspects, comparison with traditional Chinese medicine, philosophical background, the Vietnamese market situation, quality assurance and formulations), and subsequently focuses on its safe and effective use in Vietnamese clinical pharmacy and medical practice.
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http://dx.doi.org/10.1586/ecp.12.34DOI Listing
July 2012

In vitro regeneration of wild chervil (Anthriscus sylvestris L.).

In Vitro Cell Dev Biol Plant 2012 Jun 25;48(3):355-361. Epub 2011 Oct 25.

Anthriscus sylvestris (L.) Hoffm. (Apiaceae) is a common wild plant that accumulates the lignan deoxypodophyllotoxin. Deoxypodophyllotoxin can be hydroxylated at the C-7 position in recombinant organisms yielding podophyllotoxin, which is used as a semi-synthetic precursor for the anticancer drugs, etoposide phosphate and teniposide. As in vitro regeneration of A. sylvestris has not yet been reported, development of a regeneration protocol for A. sylvestris would be useful as a micropropagation tool and for metabolic engineering of the plant. Calli were induced from hypocotyl explants and transferred to shoot induction medium containing zeatin riboside. Regenerated shoots were obtained within 6 mo and were transferred onto growth regulator-free root induction medium containing 1% sucrose. Regenerated plants transferred to soil and acclimatized in a greenhouse. Plants were transferred to the field with a 100% survival rate. Regenerated plants flowered and were fully fertile. This is the first report of complete regeneration of A. sylvestris via shoot organogenesis from callus.
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http://dx.doi.org/10.1007/s11627-011-9410-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375414PMC
June 2012
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