روش آزمایش آزادسازی دارو برای فرم های تجویز دوز با اندازه نانو به صورت آزمایشگاهی

ABSTRACT A Review of In Vitro Drug Release Test Methods for Nano-Sized Dosage Forms

Ever since reports documenting the utility of polycyanoacrylate and poly-ε-caprolactone nanocapsules for ocular administration were published over two decades ago, several publications have highlighted the benefits of using nano-sized dosage forms for medical and imaging purposes [1–3]. Indeed, advantages such as improved drug solubility and stability, enhanced performance as well as increased efficacy have been well established with nanoparticulate preparations [4]. The increasing interest in nanotechnology based drug delivery systems has been a key factor in the design and development of numerous novel dosage forms and complex delivery therapies such as liposomes, nanoemulsions, nanocrystals, polymeric nanoparticles, solid lipid nanoparticles, nanofibers, and dendrimers, to treat a variety of disease states [5–7]. As an example, researchers have investigated nanoparticles of Fenofibrate for the treatment of hypercholesterolemia and Cyclosporine nanoparticles against cancer [8, 9]. Unsurprisingly, several nanoparticulate preparations are currently undergoing clinical investigation for the delivery of a wide range of therapeutics like antibiotics, antigens, cytostatics, and so forth, via the intramuscular, subcutaneous, oral, and intravenous route [10, 11]. A few examples of currently marketed nanotechnology based dosage forms are listed in Table 1.

tab1 Table 1: List of a few currently marketed nanoparticulate products.

By the ISO definition, the size for these formulations can range between 1 and 100 nm. Since sizes below 10 nm have a greater propensity for renal clearance and tissue extravasations, and larger sizes are quickly opsonized via the macrophages of the reticuloendothelial system, the 10–100 nm size range is considered optimal for nanoparticulate preparations [12]. Hence, for medical and therapeutic purposes, a range of less than 10–100 nm (in at least one dimension) for nanoparticulates appears to be generally accepted, with a few exceptions where sizes greater than 100 nm may be applicable [4, 13]. Due to their small size, nano-sized dosage forms possess an unusually large surface-to-volume ratio that alters the chemical, physical, and biological properties of the dosage form allowing them to cross cell and tissue barriers, thereby altering the pharmacokinetics and pharmacodynamics of the therapeutic agent. This unique aspect of nanoparticulate preparations has been exploited to deliver therapeutics to specific cells, organs, and other challenging in vivo targets. Another consequence of enhanced delivery to the target site is an increase in potency of the drug, including the potential for elevated toxicity due to the carrier material, possibly leading to reduced safety. Therefore, determination of product quality and performance becomes a crucial aspect during nanoparticulate dosage form development.

As with most dosage forms, product quality and performance may be verified through several in vivo and/or in vitro experiments [14]. Of these, drug release kinetics provides critical information about dosage form behavior and is a key parameter used to assess product safety and efficacy. Due to the expense, time, labor, and need for human subjects/animals when performing in vitro measurements of drug release kinetics, in vitro release is gaining greater attention as a surrogate test for product performance. Indeed, in vitro release testing is commonly used as a predictor of in vivo behavior, historically with traditional dosage forms like capsules and tablets (i.e., dissolution), and more recently with novel dosage forms like injectable biodegradable microspheres and implants [15–17]. Generally, in vitro release studies are performed at 37°C (physiological temperature), though in some instances testing at elevated temperatures has been explored to characterize drug release from a variety of dosage forms [18, 19]. Some of the key objectives of in vitro release testing are one or more of the following: (a) assessing the effect of formulation factors and manufacturing methods on the drug product, (b) routine assessment of quality control to support batch release, (c) substantiating product label claims, (d) establishing an in vitro in vivo correlation/relationship (IVIVC/R), (e) assuring product sameness under the SUPAC guidelines, (f) as a compendial requirement [20, 21].

Without exception, in vitro release testing is an important analytical tool that is used to investigate and establish product behavior during the various stages of drug product development, as well as life cycle management. When designed appropriately, an in vitro release profile can reveal fundamental information on the dosage form and its behavior, as well as provide details on the release mechanism and kinetics, enabling a rational and scientific approach to drug product development. Understandably, for complex dosage forms like nanoparticulates, in vitro release testing assumes greater significance.

Despite the great strides in design and development of nano-sized dosage forms, no compendial or regulatory standards exist for in vitro release testing. Although there have been attempts to use the existing USP apparatus for in vitro drug assessment of nanoparticles, the set-ups were designed primarily for oral and transdermal products and as such pose many challenges during a release study. Hence, several in vitro release methods, both compendial and noncompendial, have been utilized and reported. Certainly, the area of in vitro testing for nanoparticulates lags behind the advances realized in drug product development.

Given the urgent need for improved product safety while maintaining quality of novel dosage forms like nanoparticles, the past decade witnessed a series of international in vitro release workshops co-sponsored by the AAPS (American Association of Pharmaceutical Scientists), US FDA (Food and Drug Administration), FIP (Federation International Pharmaceutique), and several other scientific groups and agencies [22–25]. The outcomes of these workshops were published as position papers with the general consensus that dissolution or in vitro release testing was an important tool in pharmaceutical development and quality control for a plethora of dosage forms, both traditional and novel. Further, the attendees highlighted the fact when compared to traditional formulations, the characteristics of novel/special dosage forms including site and mode of administration was vastly different, and, hence, appropriate consideration should be taken during selection of the apparatus, release medium, agitation (flow rate), and temperature. In summary, the workshops concluded that, along with a few other novel dosage forms, nanoparticulate preparations were categorized as those “dosage forms requiring more work before a (dissolution) method can be recommended” [22, 23].

In a separate endeavor, the Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the US FDA, published a regulatory note outlining the risk assessment and management process on a hypothetical nanomaterial drug, to be administered orally [4]. In this example, the Working Group identified “dissolution/release rate” as a risk factor that may impact the evaluation of quality, safety, and efficacy of the drug product containing nano-sized drug, that is, during ingestion and in vitro release/dissolution. Hence, the utility of in vitro release testing, from a drug product development as well as regulatory standpoint, cannot be ignored.

Thus, the purpose of this review is to provide the reader with a summary of existing in vitro release methods for nano-sized dosage forms along with their strengths and shortcomings. It is hoped that this review will serve as a guideline for developing suitable techniques for assessment of exploratory formulations, clinical and commercial dosage forms, and establishment of an in vitro in vivo correlation (IVIVC).