Performance of Tablet Splitters, Crushers, and Grinders in Relation to Personalised Medication with Tablets.

Swallowing problems and the required dose adaptations needed to obtain optimal pharmacotherapy may be a hurdle in the use of tablets in daily clinical practice. Tablet splitting, crushing, or grinding is often applied to personalise medication, especially for the elderly and children. In this study, the performance of different types of (commercially available) devices was studied. Included were splitters, screwcap crushers, manual grinders, and electric grinders. Unscored tablets without active ingredient were prepared, with a diameter of 9 and 13 mm and a hardness of 100-220 N. Tablets were split into two parts and the difference in weight was measured. The time needed to pulverise the tablets (crush time) was recorded. The residue remaining in the device (loss) was measured. The powder was sieved to obtain a particle fraction >600 µm and <600 µm. The median particle size and particle size distribution of the later fraction were determined using laser diffraction analysis. Splitting tablets into two equal parts appeared to be difficult with the devices tested. Most screwcap grinders yielded a coarse powder containing larger chunks. Manual and especially electric grinders produced a finer powder, making it suitable for administration via an enteral feeding tube as well as for use in individualised preparations such as capsules. In conclusion, for domestic and incidental use, a screwcap crusher may provide sufficient size reduction, while for the more demanding regular use in hospitals and nursing residences, a manual or electric grinder is preferred.

Development of an Orodispersible Film Containing Stabilized Influenza Vaccine.

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, ß-galactosidase was used as a model antigen. Solutions containing ß-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 ß-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 ß-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.

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

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.

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

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.

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

Introduction: 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. Areas covered: 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. Expert opinion: 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.

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

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 ß-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 ß-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.

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

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.

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

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 ß-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.

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

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.

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

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.

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

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.

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

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.