78 research outputs found
Applications of Alginates in the Design and Preparation of Orodispersible Dosage Forms
No full textOrodispersible dosage forms are attractive and innovative drug delivery systems that can fulfill individual patient needs, especially in children, elderly and among dysphagic patients. Indeed, they rapidly disperse in the mouth upon contact with the saliva without the need for water or munching. Examples of such dosage forms include orodispersible tablets (ODT), and orodispersible films (ODF). The ability to obtain ODF with different dimensions (sizes and thicknesses) makes them a suitable for personalized dosing of single or a fixed-dose combination of drugs in special patient populations. Several biopolymers are currently being exploited in the development of orodispersible dosage forms including alginates due to their versatility, availability, naturally occurring, and biosafety profile. This chapter provides an appraisal on the various applications of alginates in the preparations and their role on the properties of orodispersible dosage forms and highlights future perspectives of this very versatile biopolymer for these innovative drug delivery systems
Olanzapine orodispersible films: a feasibility study
No full textOlanzapine (OLZ) is an effective atypical antipsychotic drug with an acceptable safety profile widely used in the treatment of psychiatric disorders. The administration as orodispersible tablets meets the patients’ preferences improving the medication adherence [1]. However, this drug presents some formulative issues due to the conversion into different polymorphic and pseudopolymorphic forms as a function of the preparation process and in presence of water [2]. This feature is particularly relevant in the design OLZ loaded orodispersible films (ODF) which represent a valuable alternative to orodispersible tables [3]. ODF are generally manufactured by hot-melt extrusion or solvent-casting.
In this preliminary study, the feasibility to prepare OLZ loaded ODF by a water-based process was investigated. In particular, ODF were obtained by laminating and casting an aqueous dispersion of OLZ and maltodextrins (MDX) plasticized with glycerol and dried by a solvent casting technique in order to obtain the theorical drug content of 10 mg per 6 cm2 ODF. ODF were characterized in terms of disintegration time and dissolution profile in deionized water and phosphate buffer pH 6. The solid-state of OLZ loaded ODF was studied using X-ray diffraction (XRP) and ATR-FTIR spectroscopy. ODF visually appeared homogeneous with smooth surface and yellow colored due to the presence of olanzapine. They were easy-to-handle and easy-to-cut into desired dimensions without cracks. The film thickness was about 140±4.5 μm. The disintegration time was about 40 s, complying the requirements of Ph. Eur. monograph. An erratic drug release pattern was observed during the in vitro dissolution of ODF with a concomitant formation of a yellow precipitate after 3 min. XRD patterns of OLZ loaded into ODF evidenced the phase conversion from anhydrous form into dihydrate one. This feature was in line with a variation in ATR-FTIR spectra since a shift in the stretching bands of CN group of OLZ loaded in films was evident with respect the pure drug.
Overall data suggested that OLZ undergoes to phase transition after solvent casting compromising the biopharmaceutical performances due to its variation in solubility. Hence, a solvent-free preparation process or different excipients must be evaluated to avoid the variation in OLZ solid-state
Biosimilars: Regulatory Aspects in the USA and the EU
No full textBackground: The high cost of biotechnological medicinal products and the increasing number of patent and data protection expirations is motivating manufacturers to develop biosimilar products and physicians to prescribe them, either spontaneously or due to payers’ policies (non-medical switch or constrained prescription). Unlike generics, biosimilars approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) are similar, but not equivalent, to the originator in terms of quality, efficacy and safety. Therefore, biosimilarity does not necessarily implicate interchangeability and the possibility of automatic substitution. Purpose: The purpose of this work is to assess the differences between the concepts of biosimilarity, interchangeability and substitution of biological medicinal products and their implications on the practice of health care professionals. Methods: US Law and EU Law on biological medicinal products and biosimilars were analyzed, along with guidelines by the FDA and the EMA. Results: The FDA and the EMA have already successfully addressed the issues related to the data required to obtain the Marketing Authorisation for biosimilar medicinal products. The FDA also explicitly addresses the issue of interchangeability between biological products. However, it considers difficult, from a scientific viewpoint, to establish interchangeability in a Marketing Application. The EMA, instead, leaves the decision about interchangeability to the individual member states. Conclusion: The similarity of biosimilar medicinal products approved by the FDA or by the EMA is guaranteed. However, the issues of interchangeability and substitution remain open and will require further consideration
A comparison of preparation methods on the in vitro performances of olanzapine orodispersible films
No full textIntroduction: Olanzapine (OLZ) is a poorly water-soluble drug with an intricate polymorphism (1), available on the market as orodispersible tablets to improve the patient’s adherence in the treatment of schizophrenia. Orodispersible films (ODF) represents a valid alternative which allow to eliminate the fear of choking. Unfortunately, production methods of ODF require the preparation of an aqueous dispersion of the drug or the melting of the components (2). Both processes can cause unintended drug phase transformations which directly affect its dissolution rate and, therefore, biopharmaceutical performances. This work focused on the influence of two different preparation methods, namely solvent casting and hot melt printing, on the in vitro performances of OLZ ODF aiming to evaluate the possible loading of drug substances with a significant physical instability.
Methods: An amount of 10 mg OLZ was loaded into 23 cm ODF prepared by solvent-casting and hot-melt ram-extrusion printing using maltodextrin DE 6 and glycerol as film forming material and plasticizer, respectively. X-ray diffraction and DSC were carried out to study the OLZ solid state. ODF were characterized in terms of thickness, stickiness, loss on drying. Moreover, disintegration time and the in vitro dissolution profiles were also evaluated.
Results: The adopted experimental conditions permitted to obtain ODF without visual defects, easy to handle with a thickness around 140 μm and 278 μm for cast and printing, respectively. Residual water content in ODF was in the 6-8% w/w range. All ODF disintegrated within 80 s, complying the Pharmacopeia specifications. Regarding the in vitro dissolution, about 90% OLZ was released within 3 min from the printed films; in contrast, an erratic drug release was observed for cast ODF with the concomitant formation of a yellow precipitate after 3 min. The X-ray diffraction patterns of OLZ loaded into ODF suggested that the casting process caused a variation in the drug form, which could be responsible of this anomalous behavior.
Conclusion: This study highlighted the potential of hot-melt printing as a method to load drugs which can undergo to solid-state modification after exposure to water.
References: (1) GI Polla, DR Vega, H Lanza, DG Tombari, R Baggio, AP Pedro, AJM Filho, DFG Leyva, G Dartayet, Int J Pharm 301 (1–2)2005: 33-40. (2) UM Musazzi, GM Khalid, F Selmin, P Minghetti, Int J Pharm 576(2020) 118963
Trends in the production methods of orodispersible films
No full textInterest in orodispersible films (ODF) is growing day-by-day, since this dosage form overcomes some therapeutic obstacles, such as impaired swallowing, and offers several benefits, such as the possibility to adapt the dosing requirements for a subset of patients. As a consequence, technologies to produce ODF have risen attention for possible applications in the development of patient-centric formulations. This review critically discusses current trends in the technology platforms proposed to manufacture ODF, including the innovation and opportunities to produce very small batches in a pharmacy setting. Although the main Pharmacopoeias recommend testing customized dosage forms for quality assurance, pharmaceutical assays are a matter of debate due to the complexity and high cost of conventional methods. Alternatively, non-disruptive online analytic methods can be proposed to assay ODF properties, above all to assure the uniformity of drug content
Relevance of production method on the physical stability and in vitro biopharmaceutical performances of olanzapine orodispersible film
No full textThis study assessed the relevance of the preparation process, namely solvent casting and hot-melt ram printing, on the biopharmaceutical performances of olanzapine orodispersible films (ODF) made of maltodextrin. Beside the clinical rationale, olanzapine was selected since it is subjected to polymorphism which impacts on its bioavailability. All ODF disintegrated in less than 3 min and showed content uniformity within the acceptable values. Dissolution testing in 3 mL of artificial saliva at pH=6.8 evidenced that cast and printed ODF released after 5 min about 2% and 100%, respectively; at higher volume, a yellow precipitate was formed after disintegration of the cast ODF. At pH=1.2, the t85% for cast ODF was reached after about 20 min and only the 90% olanzapine was dissolved increasing the pH to 6.8. These differences were explained by DSC, TGA and X-ray diffraction data which demonstrated that the casting method, which included the preparation of an aqueous slurry, favours the conversion from Form I to a hydrated one. Since extruded ODF resulted physically stable after 30 months, this suggests the potentiality of this technique to load in ODF drugs undergoing solid-state modification after exposure to aqueous media
Personalized orodispersible films by hot melt ram extrusion 3d printing
No full textThis work demonstrated 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 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
Trends in the characterization methods of orodispersible films
No full textThe recent increased interest in orodispersible films (ODF) stems from their ideal potential to circumvents several pharmacotherapy related problems, such as improved medication compliance and adherence especially in children, elderly and uncooperative patients. Their administration is well accepted by the majority of patients because ODF dissolve upon in contact with the saliva in the oral cavity without need of water intake. ODF application in personalized pharmacotherapy is currently being exploited. Moreover, innovative preparation methods and characterization technologies have been evolving in recent years, highlighting promising future both from the technological and clinical standpoints. However, the key obstacles to the attainment of full potentials of ODF in the pharmaceutical field is the lack of harmonized and well-defined quality characterization procedures, standard evaluation parameters, guidance on appropriate final product properties and specifications. This review provides an appraisal on the ODF characterization methods from slurries to the finished medicinal products with a specific focus on the technologies suitable for identification, quantification, and quality evaluation of extemporaneously prepared ODF on small batches in individualized pharmacotherapy. Generally, there is a paradigm shift from the use of the conventional quality evaluation tools and/or protocols for oral solid dosage forms to characterize ODF to more specific equipment and procedures that suit the peculiarities of the ODF
Printing a diclofenac orodispersiblefilm by ram extrusion
No full textHot melt ram extrusion 3D printing was recently proposed to prepare small batches of orodispersible films (ODF) (1), but the feasibility of loading thermosensitive drugs with low palatability has not been investigated. Among the possible candidates, diclofenac sodium (DNa) at a dose of 25 mg could be loaded in ODF, despite the limited formulative space, when an immediate release is required. However, the addition of taste masking agents (TMA) should be carefully evaluated as they can compromise the ODF processability and handling (2).
This study aims to design ODF loaded by DNa and TMA by hot melt ram extrusion 3D printing and to study their influence on the mechanical and physico-chemical properties of ODF (2).
ODF made of maltodextrins with a dextrose equivalent of 6 containing DNA and TMA (i.e. mint, licorice-mint and sucralose) or a combination thereof were characterized in terms of drug content, disintegration time and tensile properties. The in vitro dissolution test was carried out both in water and in pH=5.7 artificial saliva.
All ODF disintegrated within 2 min complying the compendial specification. Impurity A of DNa was detected below the Ph. Eur. limits (< 0.2%). The in vitro dissolution profiles of DNa from ODF with and without TMA were superimposable (t80%3 min) in deionized water; t80% decreased about 1-fold for ODF containing TMA in artificial saliva at pH=5.7 (t80%2 min). Independently of the presence of TMA, drug loaded ODF were flexible and easy to handle without fracture, even if the presence of DNa significantly increased the tensile strength (placebo ODF=0.17±0.03 MPa vs DNa loaded ODF=2.21±0.54 MPa).
In conclusion, hot melt ram extrusion 3D printing can be also proposed to prepare palatable ODF loaded by a thermosensitive drug
Diclofenac orodispersible films by hot melt ram extrusion 3D printing
No full textBackground: Hot melt ram extrusion 3D printing was recently proposed to prepare small batches of orodispersible films (ODF), but the feasibility of loading thermosensitive drugs with low palatability has not been investigated. Among the possible candidates, diclofenac sodium (DNa) at a dose of 25 mg could be loaded in ODF, despite the limited formulative space, when an immediate release is required. However, the addition of taste masking agents (TMA) should be carefully evaluated as they can compromise the ODF processability and handling. Purpose: This study aims to design ODF loaded by DNa and TMA by hot melt ram extrusion 3D printing and to study their influence on the mechanical and physico-chemical properties of ODF. Methods: ODF made of maltodextrins with a dextrose equivalent of 6 containing DNA and TMA (i.e. mint, licorice-mint and sucralose) or a combination thereof were characterized in terms of drug content, disintegration time, in vitro dissolution test and tensile properties. Results: All ODF disintegrated within 2 min complying the compendial specification. Impurity A of DNa was detected below the Ph. Eur. limits (< 0.2%). The in vitro dissolution profiles of DNa from ODF with and without TMA were superimposable (t80%3 min) in deionized water; t80% decreased about 1-fold for ODF containing TMA in artificial saliva at pH=5.7 (t80%2 min). Independently of the presence of TMA, drug loaded ODF were flexible and easy to handle without fracture, even if the presence of DNa significantly increased the tensile strength (placebo ODF=0.17±0.03 MPa vs DNa loaded ODF=2.21±0.54 MPa). Conclusion: Hot melt ram extrusion 3D printing can be also proposed to prepare palatable ODF loaded by a thermosensitive drug
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