Orodispersible Films Research Articles

Towards Printed Pediatric Medicines in Hospital Pharmacies: Comparison of 2D and 3D-Printed Orodispersible Warfarin Films with Conventional Oral Powders in Unit Dose Sachets.

To date, the lack of age-appropriate medicines for many indications results in dose manipulation of commercially available dosage forms, commonly resulting in inaccurate doses. Various printing technologies have recently been explored in the pharmaceutical field due to the flexible and precise nature of the techniques. The aim of this study was, therefore, to compare the currently used method to produce patient-tailored warfarin doses at HUS Pharmacy in Finland with two innovative printing techniques. Dosage forms of various strengths (0.1, 0.5, 1, and 2 mg) were prepared utilizing semisolid extrusion 3D printing, inkjet printing and the established compounding procedure for oral powders in unit dose sachets (OPSs). Orodispersible films (ODFs) drug-loaded with warfarin were prepared by means of printing using hydroxypropylcellulose as a film-forming agent. The OPSs consisted of commercially available warfarin tablets and lactose monohydrate as a filler. The ODFs resulted in thin and flexible films showing acceptable ODF properties. Moreover, the printed ODFs displayed improved drug content compared to the established OPSs. All dosage forms were found to be stable over the one-month stability study and suitable for administration through a naso-gastric tube, thus, enabling administration to all possible patient groups in a hospital ward. This work demonstrates the potential of utilizing printing technologies for the production of on-demand patient-specific doses and further discusses the advantages and limitations of each method.

Diagnostic and Therapeutic Workup of Erectile Dysfunction: Results From a Delphi Consensus of Andrology Experts.

IntroductionErectile dysfunction is a highly prevalent condition. Existing guidelines provide recommendations for diagnosis and treatment, but they are often disregarded in clinical practice in favor of a “patient-tailored” approach.ObjectivesWe planned a Delphi consensus method to bridge the gap between evidence-based medicine and the real-life approach in daily practice.Materials and MethodsThe Advisory Board prepared 15 statements on debated topics in andrology, each including 4–6 items designed as a 5-point Likert scale. After a validation phase, the questionnaire was sent by e-mail to a panel of experts for a first round of voting; members of the panel were later invited to a second round of voting, preceded by discussion of the “hot topics” identified in the first round.ResultsThe first round of the Delphi consensus involved 101 experts; 71 (70%) also took part in the second round of voting. The Advisory Board deemed 22 items to be worthy of debate, and these underwent the second round of voting. “Real-life” results from the survey proved quite different from evidence-based recommendations.ConclusionAlthough guidelines suggest the best approach for a “standard” patient, real-life settings require flexibility. Diagnostic and therapeutic approaches should be tailored to the patients’ needs. Phosphodiesterase type 5 inhibitors are recognized as the first-line therapy in both settings, including the newly introduced sildenafil orodispersible film. Indications from the panel might help close the gap between recommendations from guidelines and real-life practice in relation to the diagnosis and treatment of erectile dysfunction.Isidori AM, Giammusso B, Corona G, et al. Diagnostic and Therapeutic Workup of Erectile Dysfunction: Results From a Delphi Consensus of Andrology Experts. Sex Med 2019;7:292–302.

Additive manufacturing of personalized orodispersible warfarin films

Warfarin is a narrow therapeutic index drug that requires personalized dosing which is currently not achieved by the marketed products. Further, pediatric and geriatric patients may face swallowing problems with solid oral dosage forms. To face these issues, the aim of the present study was to investigate semisolid extrusion 3D printing for production of warfarin containing orodispersible films. Extrusion 3D printing was successfully utilized to produce transparent, smooth and thin, yet flexible and strong orodispersible films containing therapeutic doses of warfarin (3.9–7.4 mg). Excellent linearity (R2 = 0.9996) between the designed sizes of the films and the drug contents was achieved indicating semisolid extrusion 3D printing as a promising way to produce orodispersible warfarin films with personalized doses. This one-step-process utilizes disposable syringes hindering the printing material to be in contact with the printing equipment making it a potential method for on-demand in-hospital compounding.

How to assess orodispersible film quality? A review of applied methods and their modifications.

In recent years, there has been a tendency toward creating innovative, easy to use and patient-friendly drug delivery systems suitable for every consumer profile, which would ensure safety, stability and acceptability of a drug. One of the relatively novel and promising approaches is the manufacture of orodispersible films (ODFs), which is an upcoming area of interest in drug delivery. They are defined as polymer thin films that disintegrate in the oral cavity within seconds, without drinking water or chewing, and eliminate the risk of choking. Gaining special usefulness in therapies of children and the elderly, ODFs seem to fill the gap in the range of preparations available for these groups of patients. As no detailed monography of ODFs including testing methods and uniform requirements has been presented in any of the pharmacopoeias to date, the aim of this article is to give an overview of the applied testing methods, their modifications and innovative approaches related to ODF quality assessment.

SOFTs – Structured orodispersible film templates

Orodispersible films (ODFs) have a high potential to accelerate the individualized medication. The films can be produced as drug-free templates and subsequently printed with an API (active pharmaceutical ingredient) solution or suspension according to the needs of the patient. While the printing technology already enables a precise dosing of fluids, there is still a high need of suitable, edible templates with elevated loading capacity. The structured orodispersible film templates (SOFTs) developed in this study should overcome this void. The SOFTs are pervaded with pores to realize a high API load into the film structure and possess a closed bottom side to prevent the printed fluids to pass through the film. They consist of a water-soluble cellulose derivative and are produced with the solvent casting method.This study focused on the influence of the formulation of the film casting mass on the film properties, like porosity and disintegration time due to changed pore sizes and numbers. Due to the porous film structure a mass load of up to 6.1 mg cm−2 could be realized already in SOFTs, but, higher loads are feasible. The mechanical film properties could further be improved by additional matrix material in the suspension formulation, also inhibiting particle agglomeration and aggregation during the drying process, and positively influencing the dissolution behavior of the applied nanoparticles. An application of a protection layer on top of the loaded SOFTs improves the handling safety by inhibiting contact to the API and it prevents a removal of the particles from the film surface.

Model-based description of disintegration time and dissolution rate of nanoparticle-loaded orodispersible films

The embedding of nanoparticles in orodispersible films (ODFs) is an innovative strategy to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (API). As the films are supposed to disintegrate within seconds when placed in the mouth, the disintegration time of the ODFs as well as the dissolution behavior of the API are of great interest. This study introduces a new possibility for a model-based description of these film properties to enable a prediction for the process layout for the manufacturing of the nanoparticle-loaded ODFs. Furthermore, this fundamental understanding can provide information on process robustness as a tool applied in future Quality by Design (QbD) approaches.The disintegration times of the nanoparticle-containing ODFs were measured with the SFaB method (slide frame and ball) and could be mathematically described considering the impact of the particle load and the dry film thickness on the disintegration behavior. Furthermore, it is considered if the films are disintegrated at the calculated time with a probability of 50% or any other probability. Besides the disintegration time, a clear influence of film parameters like the particle load, size of the embedded particles, film thickness and sample sizes was shown which affect the dissolution rate of the API from the ODF. The second model developed in the study identified a clear correlation between the total surface area of API particles in the film and the dissolution rate of the API, to predict the time period needed to release the API embedded in the ODFs.

Evaluation of self-nanoemulsifying drug delivery systems using multivariate methods to optimize permeability of captopril oral films

The present report demonstrates a quality by design approach to understand and optimize self-nanoemulsifying orodispersible films (SNEODF) of captopril for hypertension. A central composite experimental design was used to study the formulation parameters effects (primary emulsion, aqueous phase, and surfactant) on the film properties (globule size, film burst, adhesion, Young's moduli, disintegration time, tensile strength and dissolution). Principle component analysis (PCA) and principle component regression (PCR) were employed to identify and quantify the effects of formulation variables and physico-mechanical properties of the film on the drug permeability. PCA classified three distinct groups of film formulations based on their composition and properties. PCR quantified the impact of main variables, their interactions, and square effects on the drug permeability. The main effect of the aqueous phase exhibited a negative impact, while that of flux and tensile strength showed a positive impact on the permeability. Interactions of primary emulsions with disintegration time and tensile strength displayed a synergistic impact. Interactions of aqueous phase with flux, Young's moduli, and tensile strength, as well as between Young's moduli and tensile strength showed a significant positive effect on the permeability. A negative correlation of square effects of primary emulsion and flux, and a positive square effect of Young's moduli confirmed their non-linear influence on the drug permeability across porcine buccal mucosa. This research work demonstrates application of design of experiment and multivariate methods to achieve targeted product quality of captopril (SNEODF) having improved permeability and pH independent release profile.

A new melatonin oral delivery platform based on orodispersible films containing solid lipid microparticles

An innovative delivery system for melatonin, based on the incorporation of solid lipid microparticles in orodispersible films (ODFs) made of maltodextrin, was designed and developed. Lipid microparticles at two different melatonin concentrations (10 and 20% w/w) were produced by the spray congealing technology using two different lipid carrier (tristearin and hydrogenated castor oil) and characterized in terms of size, solid state, drug loading and drug release pattern. Tristearin microparticles were discarded due to a polymorphic modification of the carrier. The incorporation of hydrogenated castor oil microparticles in ODFs by using the casting method did not alter significantly the shape and dimension of the microparticles and the mechanical properties (elasticity and strength) of the films, which remained acceptable for manufacturing and handling. The in vitro release studies performed in saliva, gastric and intestinal simulated media on ODFs containing melatonin loaded in hydrogenated castor oil microparticles revealed the possibility to combine with an immediate release of the drug and a sustained release over at least 5 h period.In conclusion, the proposed drug delivery system maintains the advantages of ODFs, i.e. the suitability to be swallowed without water, and permits the tuning of drug release according to the clinical needs by modulating the ratio of free and microencapsulated drug in the ODF.

Behaviour of Tetrabenazine in Acid Medium: Reassessment and Impact on Formulation.

Thorough studies of previous analytical stress data of tetrabenazine, a dopamine depleting agent, showed a potential susceptibility to acidic conditions. Hence, the behavior of tetrabenazine acidic solutions was studied by LC-MS and NMR spectroscopy. Reverse-phase LC-MS analysis of tetrabenazine acidic aqueous solutions consistently showed a main lipophilic impurity in a proportion of 15 to 20%. NMR spectroscopy studies did not allow to completely ascertain its structure. However, we hypothesize an interconversion of trans-tetrabenazine with its unstable cis isomer via an open isoquinolinium intermediate. Evaluation of tetrabenazine integrity in orodispersible films was reassessed in light of these observations after formulation and during stability study. Even if interconversion of trans-tetrabenazine with its cis isomer was observed in orodispersible films containing tetrabenazine, this phenomenon seems not to have any consequences for the overall tetrabenazine bioavailability.

Natural and semisynthetic polymers blended orodispersible films of citalopram

This study was aimed at developing orodispersible films of citalopram using combination of natural and semisynthetic polymers for patients with swallowing problem. Okra biopolymer and moringa gum were utilized in combination with hydroxypropyl methylcellulose (HPMC) and pullulan. The disintegration time was less than 30 seconds and the drug content uniformity was 97.89–102.05% for all film formulations. Films formulated with HPMC (K15 and K4M) combination (F1) and combination of okra and HPMC K15 (F2) had superior mechanical properties as compared with F3 (okra and pullulan) and F4 (moringa gum and HPMC). Thermal analysis revealed stable formulations over the studied temperature range and the crystalline citalopram was completely or partially transformed into amorphous form as revealed by the differential thermal analysis, X-ray diffraction and scanning electron microscopy images. In conclusion, okra biopolymer could be used in combination with HPMC for the development of orodispersible films.

Formulation development of a continuously manufactured orodispersible film containing warfarin sodium for individualized dosing

Continuously manufactured orodispersible films (ODFs) offer a promising approach for individualized therapy with an easy to administer solid dosage form. The aim of this study was to develop a long ODF containing warfarin sodium to enable safe and more flexible dosing. Formulation development was conducted systematically for the continuous film coating process. A continuously working pilot-scale coating bench was used for film manufacturing and the viscosities of the polymer solutions were investigated to obtain processible formulations. The investigation of the mechanical properties of the long film was an integral part of the study, because the handling of the long film during flexible dosing differs distinctly from the handling of a single dosed ODF. The secant modulus and the yield stress were evaluated as parameters with high information value about the deformation behavior of the ODF. A long warfarin ODF was successfully produced using the pilot-scale coating bench equipped with an optical probe for in-line film thickness measurement. It was feasible to use the principle of a tape dispenser for flexible and, therefore, individualized dosing as proof of concept. Combining the long ODF with a dosing device allows individualized therapy with warfarin for all age groups manageable by the patient himself.

In Vitro Oral Cavity Model for Screening the Disintegration Behavior of Orodispersible Films: A Bespoke Design

The availability of biorelevant methods for the disintegration study of pharmaceutical orodispersible dosage forms is required. The disintegration of orodispersibles should be assessed using in vitro methods that can combine biorelevant volumes of disintegration medium and mechanical stresses mimicking in vivo conditions. This study proposes an adaptation of a mechanical oral cavity model for the disintegration study of orodispersible films. A periodic compression is applied to the sample in the presence of a biorelevant volume of artificial salivary fluid. Four orodispersible film samples (P1, C1, P2, and C2), differing in polymer type and molecular weight, and Listerine® were tested and filmed during disintegration. An image analysis program was developed for the determination of the volume reduction of the film matrix over time, as a descriptor of film disintegration behavior. Samples P1 and Listerine® showed a volume reduction at 180 s of >90%, C1, P2, and C2 were 85%, 48%, and 37%, respectively. The model was able to detect differences in the disintegration behavior of the 4 samples, and results were comparable with the benchmark product. The concept of disintegration behavior of orodispersible films was introduced for the first time as an informative method for the study of orodispersible dosage form.

Orodispersible Films of an Antipsychotic Drug: Development and Physicochemical Characterization

To deliver maximum amount of paroxetine in shortest duration of time, the orodispersible films (ODF) were formulated and tested for their suitability as a carrier system. ODF were prepared by using hydroxypropyl methylcellulose and polyvinyl alcohol and different superdisintegrants at a specific proportion. The newly developed ODF were subjected to characterization for folding endurance, weight variations, thickness, disintegration time, drug release pattern and drug content. The surface morphology of orodispersible film was examined by means of scanning electron microscope. Moreover physical compatibility between the drug and excipients was guaranteed in the orodispersible film by Fourier transform infrared spectroscopy. It was found that all films prepared were transparent, smooth and elegant in appearance. ODF showed good folding endurance, uniform thickness, weight and drug content. The surface pH of all orodispersible film was found to be neutral and they disintegrate within few seconds. FTIR spectroscopy supported compatible among all excipients and they can be used together in formulation. It was concluded that stable paroxetine orodispersible films can be made by solvent casting technique with ultrafast dissolution rate.

Orally Dispersible films a new platform for Drug Delivery System

Orodispersible films are thin films, when in contact with saliva gets rapidly disintegrate and dissolve to release the medication for oral mucosal absorption. The film plays a major alternative approach to conventional oral dosage form like tablets, capsule, syrups. The thin films are considered to be convenient to swallow,self-administrable, rapid disintegration, dissolution and quick onset of effect which make it as a versatile platform for effective drug delivery. Oral disintegrating films have superiority over the tablet formulations because there is no risk of chocking and friability. Compared with the traditional dosage forms this dosage forms give greater advantage as it provides a new way for the pediatrics, geriatrics, bedridden patients etc. Several types of approaches are there for preparation of the films. Mostly solvent casting method is used for the development of orodispersible films. For the development of dosage forms polymers and plasticizers along with other excipients are used. Usually hydrophilic polymers are used for the preparation. The design of the film requires comprehensive knowledge of pharmaceutical and pharmacological properties of drug and polymers along with the manufacturing therefore the aim of the review provide an overview of preparation the film The present review focus on benefit, composition, approaches for formulation and evaluation of the Orally dispersible film.

DEVELOPMENT OF FORMULATION AND EVALUATION OF GARLIC ORODISPERSIBLE FILMS

DEVELOPMENT OF FORMULATION AND EVALUATION OF GARLIC ORODISPERSIBLE FILMS

Needs and Expectations of Patients with Erectile Dysfunction: An Update on Pharmacological Innovations in Phosphodiesterase Type 5 Inhibition with Focus on Sildenafil.

IntroductionPhosphodiesterase type 5 inhibitors (PDE5-Is) have an excellent efficacy and tolerability profile and remain the first-line choice for the treatment of erectile dysfunction (ED). However, ED is still an underdiagnosed and undertreated condition, and many men prematurely discontinue therapy with conventional dosage formulations despite successful intercourse.AimTo review the unmet needs and expectations of patients with ED and describe the latest pharmaceutical innovations in the field of PDE5-I formulations designed to address these needs, with particular reference to a new orodispersible film (ODF) formulation of the PDE5-I, sildenafil.MethodsOnline literature search in PubMed and the Cochrane Library.Main Outcome MeasureTo identify English-language publications relevant to the aims of the present review.ResultsImproved recognition and management of ED would enable the early diagnosis of underlying and comorbid conditions that contribute to ED, leading to improved patient health and health-related quality of life. To ensure successful outcomes and patient and partner satisfaction, the complex and personal issues that influence the patient’s needs and expectations regarding treatment for ED must be considered along with their personal experiences and preferences. Innovative drug delivery systems, including orally disintegrating formulations, have been developed as alternatives to conventional dosage forms with the aim of improving patient convenience and acceptability and enhancing compliance. These alternative formulations include the sildenafil ODF, which is designed to improve acceptance and compliance over conventional solid dosage forms and extend the treatment options for men with ED by offering a convenient and discrete dosage form of a drug with proven efficacy.ConclusionThe sildenafil ODF is an example of an innovative dosage formulation for ED that can be used interchangeably with the conventional film-coated formulation to better address the needs and expectations of men with ED.Jannini EA, Droupy S. Needs and Expectations of Patients with Erectile Dysfunction: An Update on Pharmacological Innovations in Phosphodiesterase Type 5 Inhibition with Focus on Sildenafil. Sex Med 2019;7:1–10.

Prolonged release from orodispersible films by incorporation of diclofenac-loaded micropellets

Prolonged drug release provided by multiple-unit dosage forms is highly beneficial to enhance the compliance and safety of the pharmacotherapy even for patients with swallowing deficiencies. To facilitate the intake for these patients, multiple-unit tablets and capsules have to be crushed or opened. An attempt to overcome these issues has been made by the introduction of orodispersible films (ODFs), which rapidly disintegrate within the oral cavity and facilitate the intake of oral solid dosage forms. The aim of this study was to develop a rapidly disintegrating ODF with prolonged release properties by incorporation of small-sized micropellets (MPs). MPs with a drug load of 70% were produced by wet extrusion and spheronization using Vivapur® MCG as pelletizing aid and diclofenac sodium (DS) as model drug. MPs were film-coated with an Eudragit® RS/RL coating and incorporated into the ODF-forming hypromellose solution. ODFs were produced by solvent casting technique. Disintegration times were determined using the PharmaTest® disintegration tester equipped with sample holders for ODFs. Dissolution studies were performed for MPs and ODFs. X-ray micro-computed tomography was used to visualize internal and external surface structures of MPs before and after release studies. MP-loaded ODFs show fast disintegration within 30 s, whereby film-coated MPs remain intact. Uncoated MPs are disintegrating thus revealing immediate DS release. In comparison, DS release was prolonged for film-coated MPs and corresponding ODFs. Incorporation of different amounts of MPs had no effect on the dissolution, but on mechanical properties of ODFs, which decrease with increasing amounts of MPs.The production of rapidly disintegrating ODFs with prolonged release properties for DS, representing a freely water-soluble drug, was feasible.

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 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.

Personalized orodispersible films by hot melt ram extrusion 3D printing

This work demonstrates the feasibility of the extemporaneous preparation of maltodextrins orodispersible films (ODF) by hot-melt ram-extrusion 3D printing. This method consists of three simple technological operations which can be also implemented in a pharmacy setting. First, maltodextrins, drug, and other excipients are mixed in a mortar and wetted with the plasticizer (i.e. glycerine). Then, the mixture is fed in the chamber of the ram-extruder and heated. ODF are individually printed on the packaging material foil and sealed without further manipulations. The critical formulation attributes and process variables were investigated to define the processability space. In particular, the optimal conditions to print a mixture of maltodextrins/glycerine in a 80/20 w/w ratio resulted: heating temperature: 85 °C; needle gauge: 18 G; needle-packaging material foil distance: 0.6 mm; maximum print rate: 50 mm/s; filling angle: 120°. The maximum drug loading was about 40%, when paracetamol was used as model drug. The compounded ODF complied with USP and Ph. Eur. specifications for disintegration time (<1 min). The dissolution pattern of paracetamol overlapped with that obtained from ODF with a similar composition prepared by the consolidated solvent casting technique, demonstrating the suitability of the proposed technology.

Comparative study on disintegration methods for oral film preparations

Orodispersible films (ODFs) provide high application comfort due to rapid disintegration in the oral cavity. They increasingly found the approval of pharmaceutical research and development and were added to the European Pharmacopeia in 2012. The European Pharmacopeia explicitly demands disintegration testing for ODFs, but does not refer to a suitable method. The aim of this study was to collect and evaluate existing disintegration methods regarding their suitability to investigate different ODF formulations. Therefore, 21 ODF formulations produced at different gap heights and/or different amounts of suspended microcrystalline cellulose (MCC) particles were manufactured by solvent casting technique, using hypromellose (HPMC) as film-forming polymer. Four disintegration methods described in literature were applied to characterize the disintegration behavior of these formulations. They were the petri dish, the slide frame, slide frame and ball (SFaB) method as well as the PharmaTest® disintegration tester equipped with a film sample holder. All methods show similar tendencies, at which the disintegration time proportionally increases with increasing dry film thicknesses. Reduced disintegration times were observed for ODFs containing insoluble MCC particles compared to their corresponding particle-free formulations. However, the suitability to investigate varying types of ODFs applying the four different test methods highly depends on the intended purpose. Therefore, the slide frame and SFaB method seems to be particularly applicable for research and development purposes, whereas the PharmaTest® disintegration tester and the SFaB method fulfil the demands required for testing methods within the quality control.