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# In vitro dissolution considerations associated with nano drug delivery systems

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Abstract Nano drug delivery systems (NDDS) offer promising solution for the translation of future nanomedicines. As bioavailability and therapeutic outcomes can be improved by altering the drug release from these NDDS, it becomes essential to thoroughly understand their drug release kinetics. Moreover, U.S. Food and Drug Administration requires critical evaluation of potential safety, efficacy, and public health impacts of nanomaterials. Spiraling up market share of NDDS has also stimulated the pharmaceutical industry to develop their cost‐effective generic versions after the expiry of patent and associated exclusivity. However, unlike the conventional dosage forms, the in vivo disposition of NDDS is highly intricate and different from their in vitro behavior. Significant challenges exist in the establishment of in vitro–in vivo correlation (IVIVC) due to incomplete understanding of nanoparticles' in vivo biofate and its impact on in vitro experimental protocols. A rational design of dissolution may serve as quality and quantity control tool and help develop a meaningful IVIVC for favorable economic implications. Clinically relevant drug product specifications (critical quality attributes) can be identified by establishing a link between in vitro performance and in vivo exposure. In vitro dissolution may also play a pivotal role to understand the dissolution‐mediated clearance and safety of NDDS. Prevalent in vitro dissolution methods for NDDS and their limitations are discussed in this review, among which USP 4 is gaining more interest recently. Researchers are working diligently to develop biorelevant in vitro release assays to ensure optimal therapeutic performance of generic versions of these NDDS. This article focuses on these studies and presents important considerations for the future development of clinically relevant in vitro release methods. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine
(a) Methods for dissolution rate assessment of NPs. In vivo dissolution studies are not always feasible. Acellular in vitro tests could reflect the dissolution behavior in blood (en route to target tissues) while cellular in vitro tests could reflect dissolution inside target cells. (b) Dissolution methods to test liposomes (based on 56 publications accessed for 2010–2020). During last decade more than one thousand articles were published illustrating different in vitro dissolution studies for various NDDS. As liposomes are most widely approved NDDS an account was made for them specifically
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Nano drug delivery systems (NDDS) for various Biopharmaceutics Classification System (BCS) class. Class I drugs are straightforward to develop. NDDS offer promising drug delivery solutions for potential drug candidates belonging to BCS class II, III, and IV by overcoming poor solubility/permeability issues. (b) DCS classification system. SLAD marks the boundary between DCS class IIa and IIb drugs. Below SLAD all the doses could be dissolved, and above SLAD only a fraction of dose is dissolved (fraction dissolved decreases with increasing dose). DCS class IIa drugs show “dissolution‐rate limited” absorption. Simple particle size reduction can suitably formulate such drugs. Therefore, particle size (in contrast to dose/solubility ratio of BCS classification) can better predict the extent of absorption. DCS class IIb drugs have “solubility‐limited” absorption, and they present major formulation challenges (bioavailability depends on gastric pH and intestinal precipitation can occur). These drugs remain incompletely absorbed unless suitably solubilized (e.g., lipid‐based formulation or amorphous solid dispersion)
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(a) Dialysis method. NPs are filled inside the dialysis bag placed into the outer medium reservoir. Samples are collected at specified intervals from outer compartment. (b) Reverse dialysis method. Opposite setup‐NPs are placed in the outer compartment and the inner medium reservoir is sampled for drug release. (c) Side‐by‐side dialysis method. Equal volume donor and receiver compartments are separated by a dialysis membrane. Samples are taken from the receiver cell. (d) USP 4 (flow through cell). Four different platforms comprising of dissolution platform, pump assembly, dissolution media (reservoir) and fraction collector. (e) Open loop system. Fresh solvent from the reservoir (media selector) continuously replenishes through the flow cells to maintain infinite sink conditions. (f) Close loop system. Small media volume is recirculated again and again from flow cell to reservoir. Sampling is done from the recirculating dissolution medium
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