HHS Public Access
`Author manuscript
`J Control Release. Author manuscript; available in PMC 2016 December 10.
`Published in final edited form as:
`J Control Release. 2015 December 10; 219: 644–651. doi:10.1016/j.jconrel.2015.09.052.
`
`In Vitro-In Vivo Correlation for Complex Non-Oral Drug
`Products: Where Do We Stand?
`
`Jie Shen and Diane J. Burgess*
`University of Connecticut, School of Pharmacy, Storrs, CT 06269
`
`Abstract
`In vitro -in vivo correlation (IVIVC) is a predictive mathematical model describing the
`relationship between an in vitro property and a relevant in vivo response of drug products. Since
`the U.S. Food and Drug Administration (FDA) published a regulatory guidance on the
`development, evaluation, and applications of IVIVC for extended release (ER) oral dosage forms
`in 1997, IVIVC has been one of the most important issues in the field of pharmaceutics. However,
`even with the aid of the FDA IVIVC Guidance, only very limited Abbreviated New Drug
`Application (ANDA) submission for ER oral drug products included adequate IVIVC data to
`enable the completion of bioequivalence (BE) review within first review cycle. Establishing an
`IVIVC for non-oral dosage forms has remained extremely challenging due to their complex nature
`and the lack of in vitro release methods that are capable of mimicking in vivo drug release
`conditions. This review presents a general overview of recent advances in the development of
`IVIVC for complex non-oral dosage forms (such as parenteral polymeric microspheres/implants,
`and transdermal formulations), and briefly summarizes the knowledge gained over the past two
`decades. Lastly this review discusses possible directions for future development of IVIVC for
`complex non-oral dosage forms.
`
`Graphical abstract
`
`*Address for Correspondence: Diane J. Burgess, Department of Pharmaceutical Sciences, School of Pharmacy, University of
`Connecticut, 69 North Eagleville Road U3092, Storrs, CT 06269-3092, USA. d.burgess@uconn.edu.
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`SHIRE EX. 2077
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`Keywords
`In vitro-in vivo correlation (IVIVC); non-oral; parenteral; prediction; in vitro release testing;
`modeling
`
`1. Introduction
`In vitro-in vivo correlation (IVIVC) is defined by the U.S. Food and Drug Administration
`(FDA) as “a predictive mathematical model describing the relationship between an in vitro
`property of a dosage form and a relevant in vivo response” [1]. Generally the in vitro
`property is the rate or extent of drug dissolution or release, while the in vivo response is the
`plasma drug concentration or amount absorbed. In the case of non-oral drug products (e.g.
`transdermal and ophthalmic dosage forms), an in vitro property could be in vitro drug
`permeation across the membrane of interest, while an in vivo property could be in vivo drug
`permeation. The history of IVIVC can be traced back to as early as 1950s, when
`pharmaceutical scientists attempted to correlate in vitro drug dissolution profiles of oral
`formulations with their respective in vivo pharmacokinetic profiles by means of
`mathematical modeling [2, 3]. In 1997, the U.S. FDA published a regulatory guidance
`related to the development, evaluation, and applications of IVIVC for extended release oral
`dosage forms. Since then, the establishment and application of IVIVC has increasingly
`gained more significance in the field of pharmaceutics. Generally, IVIVC can be categorized
`into five different levels: Levels A, B, C, D, and multiple Level C (Figure 1).
`•
`Level A represents a point-to-point relationship between in vitro and in vivo
`profiles. Generally the correlations are linear. However, non-linear correlations are
`also acceptable [4]. A Level A correlation is considered the most informative and is
`recommended by the U.S. FDA. It is also the only level of IVIVC that can be used
`to obtain biowaiver.
`Level B correlation utilizes the principles of statistical moment analysis. A mean in
`vitro dissolution time (MDTin vitro) is compared to either a mean in vivo residence
`(MRTin vivo) or dissolution time (MDTin vivo). Similar to a Level A IVIVC, a Level
`B correlation compares all in vitro and in vivo data available. However, since
`various in vivo release profiles may result in the same MRTin vivo or MDTin vivo, a
`Level B correlation is not considered to be a point-to-point correlation, and does
`not necessarily reflect the actual in vivo plasma profile and hence may lack
`sufficient predictability.
`Level C correlation establishes a single point relationship between a dissolution
`parameter (e.g. the time required for 50% dissolution, T50%) and a pharmacokinetic
`parameter such as Cmax, Tmax or AUC. Since it is based on a single point analysis,
`it is does not reflect the complete shape of the plasma concentration time curve,
`which is critical to define in vivo performance of a drug product. Accordingly, a
`Level C IVIVC is limited in predicting in vivo drug performance. Nevertheless,
`Level C correlations may be useful in the early stages of formulation development
`when pilot formulations are being selected.
`
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`•
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`• Multiple Level C correlation relates multiple dissolution time points to one or more
`pharmacokinetic parameter(s) (e.g. Cmax, Tmax or AUC). A multiple Level C
`correlation should be based on at least three dissolution time points covering the
`early, middle, and late stages of the dissolution profile. A multiple Level C
`correlation can be as useful as a Level A correlation. However, if a multiple Level
`C correlation is obtainable, then the development of a Level A correlation should
`also be feasible and is more preferable.
`Level D correlation is a rank order correlation comparing in vitro and in vivo
`release profiles. A level D correlation is only qualitative and is not adopted in the
`U.S. FDA IVIVC Guidance.
`A meaningful IVIVC can be used to guide formulation and/or process development changes
`in the various stages of drug product development. In addition, an IVIVC can be used to
`support and/or validate the use of an in vitro dissolution method and can help set clinically
`relevant dissolution specifications to ensure product quality [5]. Most importantly, when a
`Level A IVIVC is established and validated, the in vitro release method can be used as a
`surrogate for bioequivalence studies when pre-approval and post-approval changes are
`required (e.g. formulation composition, as well as manufacturing process, equipment and
`site) [6–8]. Through the successful development and application of a meaningful IVIVC, the
`in vivo performance may be accurately predicted from the in vitro performance of drug
`products and therefore, human or animal studies can be minimized and the regulatory
`burden can be reduced [9, 10].
`
`Despite the publication of the FDA IVIVC guidance on ER oral dosage forms nearly two
`decades ago, only 14 ANDA submissions had IVIVC data, most of which were deficient and
`thereby, not acceptable [11]. Compared to the ER oral dosage forms, the establishment of an
`IVIVC for non-oral drug products (e.g. parenteral microspheres and implants, as well as
`transdermal and ophthalmic products) has been even more challenging due to their complex
`characteristics as well as the lack of standardized, compendial in vitro release testing
`methods [10]. In recent years, there has been significant interest within the pharmaceutical
`industry, academia, and regulatory agencies in developing suitable in vitro release testing
`methods as well as establishing IVIVCs for complex non-oral drug products. Notably, the
`U.S. FDA has funded over 20 research grants to advance in vitro equivalence methods for
`complex non-oral drug products and drug-device combinations in the past two years.
`Through collective and collaborative efforts in the field of pharmaceutics and drug delivery,
`some “ground-breaking” progress has been achieved. This review highlights recent advances
`in the development of IVIVC for complex non-oral dosage forms and briefly summarizes
`the knowledge gained over the past two decades. Lastly this review discusses possible
`directions for future development of IVIVC for these complex dosage forms.
`
`2. Current State-of-the-Art
`To date, there is no regulatory IVIVC guidance available for complex non-oral drug
`products. The same principles of developing IVIVC for ER oral dosage forms as detailed in
`the FDA IVIVC Guidance have been applied to develop IVIVC for various complex non-
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`oral dosage forms such as parenteral polymeric microspheres and implants [12–17],
`transdermal patches/gels [18, 19], as well as ocular inserts [20].
`
`2.1. Approaches to develop IVIVCs
`A Level A IVIVC is generally considered the highest level of correlation and is desirable
`from a regulatory point of view. Typically, developing a Level A IVIVC involves the
`following procedures (Figure 2): 1) obtaining formulations (preferably, three or more) with
`different release rates (e.g. slow, medium, and fast) or using one formulation if its in vitro
`dissolution is independent of dissolution testing conditions (e.g. pH, media, and agitation);
`2) obtaining in vivo plasma concentration profiles or in vivo dissolution profiles of the
`selected formulations; 3) estimating in vivo absorption or dissolution time course of each
`formulation using an appropriate deconvolution technique (e.g. model-dependent, and
`model-independent numerical) (Table 1); 4) establishing a correlation/relationship between
`the estimated fraction in vivo release/absorption and the faction in vitro release, using a
`linear (preferably) or non-linear model (e.g. Sigmoid, Hixon-Crowell, Weibull, Higuchi, and
`Logistic) [21]; and 5) evaluating the predictability of the developed IVIVC internally and/or
`externally. Based on the FDA IVIVC Guidance, an average percentage prediction error (%,
`PE) of 10% or less for pharmacokinetic parameters of interest (e.g. Cmax or AUC)
`establishes the predictability of a developed IVIVC. When developing a Level A IVIVC,
`there may be disparity between deconvoluted in vivo and in vitro dissolution profiles due to
`the intrinsic difference between in vitro and in vivo dissolution conditions. Accordingly,
`time shifting/scaling may be utilized to allow the deconvoluted in vivo data to be on the
`same time scale as the in vitro dissolution data, which in turn makes it possible to establish a
`correlation/relationship between in vitro and in vivo release data.
`
`Although a Level A IVIVC is most informative and recommended by the U.S. FDA, other
`levels of IVIVC (e.g. multiple Level C, and Level B) can be helpful to assure product
`quality, and to assist in formulation development. When developing a Level B IVIVC, at
`least three formulations are required. Based on the principles of statistical moment analysis,
`a mean residence time (MRTin vivo), mean absorption time (MATin vivo), or mean in vivo
`dissolution time (MDTin vivo) is calculated and related to a mean in vitro dissolution time
`(MDTin vitro) (Figure 3A). All parameters determined are model-independent. In the case of
`developing a multiple Level C correlation, one or more pharmacokinetic parameters (e.g.
`Cmax, Tmax or AUC) are correlated with at least three dissolution time points covering the
`early, middle, and late stages of the dissolution profile. Based on the U.S. FDA IVIVC
`Guidance, the recommendations for assessing the predictability of Level C correlations
`depend on the type of application for which the correlation is to be used. The methods and
`criteria for assessing the predictability are the same as that for Level A correlations
`described above.
`
`The development of IVIVCs for non-oral drug products is a complicated process, due to not
`only their complex characteristics (e.g. multi-phasic release) but also the lack of suitable in
`vitro release testing methods. Despite that extensive efforts have been devoted in this area,
`there are only a few literature reports on the establishment of IVIVCs for these drug
`products based on multiple formulations, albeit with different in vitro release testing
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`methods such as USP apparatus 4 methods [15, 16], dialysis membrane methods [14, 22],
`and Franz diffusion cells [18–20] (Table 2).
`
`2.2. IVIVCs for parenteral polymeric microspheres/implants
`Parenteral polymeric microspheres/implants, particularly poly(lactic-co-glycolic acid)
`(PLGA)/poly(lactic acid) (PLA)-based microsphere/implant drug products have been one of
`the most successful complex non-oral polymeric drug products on the market. The PLGA/
`PLGA-based microsphere/implant drug products are biodegradable, biocompatible, and
`possess the capability of delivering a variety of therapeutics (e.g. small molecules and
`biologics) in a controlled manner over periods of days to several months [33–36]. These ER
`parenteral drug products normally contain substantial amounts of potent therapeutics.
`Therefore, it is critical to assure consistent product performance and safety through in vitro
`quality control tools such as discriminatory in vitro release testing methods, as well as
`reliable IVIVCs or in vitro-in vivo relationship (IVIVR) in the event that an IVIVC is not
`feasible. Over the past two decades, the development of IVIVCs for polymeric
`microspheres/implants has received the most attention, as a result of which considerable
`progress has been achieved (Table 2). However, most reported literature are “proof-of-
`concept” research that only demonstrated the possibility of developing point-to-point linear
`correlations or Level B correlations based on one formulation. Encouragingly, Level A
`IVIVCs established using two or more microsphere formulations with different release
`characteristics have recently be presented [14, 16, 22, 23]. It should be noted that multiple
`formulations with different release characteristics are essential to develop a reliable IVIVC.
`
`One of the most challenging aspects of developing IVIVCs for complex microsphere/
`implant drug products is to design in vitro release studies in such a way that the in vivo
`behavior of these products is reflected as much as possible. PLGA/PLA-based polymeric
`microspheres/implants are normally administrated into subcutaneous or muscular tissues or
`directly injected into local areas (e.g. knee joints). Following injection/implantation,
`therapeutics are slowly released from microspheres/implants into the tissue fluids via
`complex release mechanisms (e.g. diffusion, polymer erosion or a combination thereof) [37,
`38], and are subsequently transported into the systemic blood circulation system via
`diffusion and/or convective processes [39–41]. Due to the lack of compendial in vitro
`release methods, various in vitro release methods (e.g. sample-and-separate [23, 26, 27],
`membrane dialysis [14, 22], and flow through [15, 16]) have been utilized to determine in
`vitro drug release characteristics and to develop IVIVCs. Although it is feasible to develop
`IVIVCs for parenteral microspheres/implants based on a simple sample-and-separate
`method [17, 23–25], there are limitations associated with this method such as poor
`hydrodynamic conditions, loss of product (e.g. microspheres) during sampling as well as
`inability to mimic different in vivo drug release conditions. For example, the presence of the
`in vivo boundary layers as well as the small interstitial fluid volume available for drug
`release at the administration sites. It has been reported that the correlation/relationship
`between the in vitro and in vivo data of huperzine microspheres was sensitive to the route of
`administration. Additionally, the sample-and-separate method appeared to better reflect drug
`release from PLGA microspheres in muscular tissues compared to that in subcutaneous
`tissues, thus a better correlation was obtained for the intramuscular route [23]. Compared to
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`the sample-and-separate method, membrane dialysis and flow though (USP apparatus 4)
`methods have more complex apparatus setup. However, they appear to be more capable of
`mimicking in vivo drug release conditions of parenteral microspheres/implants (e.g.
`microspheres/implants are exposed to a limited volume of release media at a time).
`Accordingly, these two release methods may be more suitable to develop a Level A IVIVC
`for parenteral microspheres/implants. A Level A IVIVC based on three olanzapine
`microsphere formulations with different release rates (i.e. fast, medium, and slow) has been
`recently reported using a membrane dialysis method [13]. In our ongoing research, we have
`successfully developed a Level A IVIVC using different combinations of three risperidone
`microsphere formulations that are compositionally equivalent but prepared using different
`manufacturing processes. Notably, both external predictability and robustness (IVIVCs not
`affected by the formulation combinations) of the developed IVIVC have been validated.
`Compared to the sample-and-separate method, the USP apparatus 4 method demonstrated
`not only better discrimination against compositionally equivalent microsphere formulations
`with manufacturing differences, but also better predictability of the in vivo PK profiles
`obtained from the animal study using a rabbit model. More importantly, the USP apparatus 4
`method demonstrated better predictability of the in vivo initial burst release phase, whereas
`the sample-and-separate method was not able to discriminate the initial burst release phase.
`Reliable detection of the in vitro initial burst can be important, especially in regulatory
`applications when two formulations are being evaluated for equivalence.
`
`To help understand drug release mechanisms and guide the establishment of IVIVCs for
`polymeric microspheres/implants, different mathematical models (e.g. Higuchi, and
`Weibull) have often been used (Table 3). These mathematical models assume zero
`dissolution at time zero and complete dissolution at sufficient time t. By introducing a
`parameter that represents the degree of dissolution, these mathematical models can easily be
`modified to account for incomplete dissolution (if any). For example, a Level A IVIVC was
`established for buserelin implants, from which drug release can be described using the
`Higuchi model [17]. Interestingly, when buserelin release from implants was governed by a
`combination of diffusion, dissolution as well as erosion, a Level B IVIVC appeared more
`suitable [17].
`
`Another challenging aspect of developing IVIVCs for complex microspheres/implants is
`how to deconvolute in vivo data and correlate that with in vitro release data. Due to their
`complex release characteristics (e.g. bi- or tri-phasic release profiles), it may be very
`difficult to correlate deconvoluted in vivo data with multi-phasic in vitro release data using a
`simple mathematical model. In some cases, it may not be possible to predict the initial in
`vivo drug release based on the in vitro release data from the burst release phase, since the
`rate-limiting step for the initial in vivo drug availability may actually be drug permeation
`across the tissue barriers. Although an IVIVC may still be developed using post-burst in vivo
`and in vitro release data, the “post-burst” IVIVC may have limited prediction capability
`[26]. Furthermore, pharmacokinetic parameters of testing dosage forms are normally needed
`when using the deconvolution approach. For drugs that fit into a two-compartment model,
`an extra in vivo study (intravenous administration) is required in order to perform
`deconvolution. Accordingly, in order to simplify the development of IVIVCs and avoid the
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`use of pharmacokinetic parameters, other approaches (e.g. fractional AUC) have been
`reported [13, 14, 23, 29]. The factional AUC is determined by dividing cumulative AUC at
`time “t” with cumulative AUC0-t and plotting along with the percent drug release in vitro. In
`a manner similar to the deconvolution approach, the in vitro and in vivo drug release data are
`then compared. It has been demonstrated that in vivo profiles of PLGA microspheres
`obtained using both the Wagner-Nelson and fractional AUC methods were nearly
`superimposable, suggesting that fractional AUC could be used as an alternative to the
`commonly used Wagner-Nelson method [14, 22]. However, it should be noted that these
`methods are not adopted in the FDA IVIVC Guidance and therefore, may not be useful for
`regulatory purposes. In addition to comparing the drug absorption percentage with the
`amount of drug released at different time points, the time for 0% to 90% absorbed in vivo
`with the time for releasing the same amounts of the drug in vitro (Levy plot, Figure 3B) has
`been compared and good linear correlation was shown [17, 30].
`
`Considering that real-time in vitro release testing of parenteral microspheres/implants
`normally requires extended periods of time, it may be necessary to develop IVIVCs based
`on discriminatory accelerated in vitro release tests. To this end, a relationship between
`accelerated and real-time in vitro release data should be established such that the accelerated
`in vitro test could maintain “bio-relevance”. Ideally, drug release from real-time and
`accelerated tests should follow the same release mechanism with a one-to-one correlation
`between the release profiles [42]. However, it is possible that the drug mechanism(s) may
`change since accelerated release tests are typically performed under extreme conditions (e.g.
`high temperatures, extreme pH conditions) [43]. Nevertheless, developing an IVIVC based
`on accelerated testing may still be feasible as long as all microsphere/implant formulations
`experience similar changes and their release characteristics can be differentiated. The
`possibility of developing an IVIVC based on accelerated testing for PLGA microspheres has
`recently been demonstrated using commercial Risperdal® Consta® [15]. Despite that the
`accelerated in vitro release profiles obtained at elevated temperatures (50°C and 54.5°C) did
`not show a good linear correlation with the real-time in vitro release profile, a one-to-one
`linear correlation between the accelerated in vitro data and the time scaled in vivo data of
`Risperdal® Consta® was shown [15].
`
`Physiologic responses (e.g. foreign body response) to biomaterials is another important issue
`that must be considered when developing a reliable IVIVC as they may result in polymer
`degradation mechanism changes in vivo. For instance, acidic PLGA degradation products
`may accumulate at the local sites and hence lower the pH in the interstitial space
`immediately surrounding the microspheres. This may result in a change in the degradation
`mechanism of PLGA microspheres from bulk erosion to surface erosion, thus accelerating
`polymer degradation with subsequent increased drug release in vivo [16, 44]. On the other
`hand, chronic inflammation in response to the presence of microspheres in the interstitial
`site, and fibrosis may form and isolate microspheres, thus slowing down drug absorption/
`drug release in vivo [45]. The formation of fibrosis was speculated to be responsible for the
`slower in vivo release/absorption of Risperdal® Consta® 30 days following administration to
`humans [15]. Interestingly, it was noted in our recent research that Risperdal® Consta®
`demonstrated faster drug release in rabbits compared to in vitro real time release. This
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`suggests that differences in drug absorption and drug release between animals and humans
`must be taken into consideration, and an IVIVC study based on animal data may not be fully
`extrapolated to humans.
`
`2.3. IVIVCs for transdermal dosage forms
`Transdermal drug delivery systems (TDDS) are one of the first generation controlled release
`drug products that appeared on the market [47, 48]. Since the first transdermal drug product
`(Transdermal Scop®) was approved by the U.S. FDA in 1979, there have been different
`generations of transdermal drugs products (e.g. passive transdermal patches, and
`iontophoretic transdermal devices) developed and commercialized [48, 49]. Unfortunately,
`unlike parenteral microspheres/implants, the development of IVIVCs for TDDS has not yet
`been given substantial attention. To date, there are only very few literature reports on
`IVIVCs for TDDS (Table 2).
`
`Transdermal drug delivery involves a few consecutive steps: i) drug release from the
`formulation; ii) drug penetration/diffusion into/through skin; and iii) drug arriving at the site
`of action to trigger a pharmacological response. In most cases, drug penetration/diffusion
`through the skin is the rate-limiting step, which can be described using different
`mathematical models (Table 4). The development of IVIVC for TDDS is somewhat
`different compared to that of parenteral microspheres/implants. One of challenges to
`develop an IVIVC for TDDS is to mimic the process of drug permeation across human skin
`as much as possible. Various in vitro dissolution methods (e.g. apparatus 5 (paddle over disk
`method), apparatus 6 (rotating cylinder method), and apparatus 7 (reciprocating holder
`method)) have been recommended as quality control tools for transdermal/topical drug
`products (such as transdermal patches and films) [50]. However, these dissolution methods
`may not reflect complex mechanism(s) of drug permeation/diffusion across skin.
`Accordingly, instead of in vitro dissolution, in vitro skin permeation is more often used for
`the development of IVIVCs for TDDS [18, 19].
`
`Franz diffusion cells are the most widely used apparatus for determining in vitro drug
`permeation of TDDS and for the development of IVIVCs. Franz diffusion cells consist of a
`donor compartment and receptor compartment with the membrane of interest (e.g. excised
`human or animal skin) mounted as a barrier between the two compartments. Due to the
`inherent variability in absorption between individuals and between anatomical sites (e.g.
`abdominal vs forearm skin), it is important to control for skin source and viability, as well as
`to evaluate in vitro permeability across skin from several donors in cases where in vitro skin
`permeation data is correlated [51]. Excised human skin has been demonstrated to be the
`most appropriate in vitro skin model that may potentially be used as a surrogate for more
`costly and time-consuming in vivo bioequivalence studies [52]. Other skin models (such as
`excised porcine skin [19] and rat skin [32]) have also been used for in vitro drug permeation
`testing, and for the development of IVIVCs.
`
`Generally IVIVCs for transdermal drug products could be categorized into the same levels
`as those described in the FDA IVIVC Guidance for extended release oral dosage forms (i.e.
`Levels A, B, C, and multiple C). However, since in vitro dissolution is not commonly used
`for the development of IVIVCs, Level B (which uses mean dissolution time) and Level C
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`IVIVCs may not be applicable for TDDS [51]. A Level A IVIVC that correlates in vitro
`drug permeation across skin with in vivo drug permeation or absorption is more desirable.
`Similar to parenteral microspheres/implants, different deconvolution techniques (Table 1)
`can be utilized to deconvolute in vivo data and correlate with in vitro drug permeation data.
`In some cases, the steady state flux in vitro is extrapolated to determine the in vivo plasma
`concentration using pharmacokinetic modeling [53]. Most recently, a Level A IVIVC (a
`second order polynomial correlation) between the in vitro permeation percent and the
`deconvoluted in vivo absorption percent was established using three estradiol TDDS [18]. In
`this study, the Wagner-Nelson method was used to deconvolute human pharmacokinetic
`data obtained from the literature. The developed Level A IVIVC was validated internally
`and externally and showed less than 15% PE for both Cmax and AUC.
`
`In order to facilitate the development of a good in vitro predictive model for TDDS, some
`improvements on current in vitro testing apparatus and in vivo analytical techniques have
`been reported. An inherent problem with Franz diffusion cells is the lack of
`microvasculature, which is present in the in vivo environment and helps in rapid clearance of
`the drug. To overcome this, flow-through diffusion cells have been designed in such a way
`that the receptor buffer is continuously removed to help maintain the sink conditions in vitro
`[54], which may be more relevant to the actual in vivo conditions and hence, could
`potentially benefit the development of IVIVCs for TDDS. In addition, new technologies
`(e.g. microdialysis and Confocal Raman Spectroscopy (CRS)) have been implemented to
`obtain in vivo drug adsorption data in a continuous fashion [31, 32]. For example, the real-
`time drug disposition in skin was monitored using CRS and correlated with in vitro human
`skin permeation data obtained using Franz diffusion cells. In this “proof-of-concept” study,
`a good correlation was obtained between the in vitro flux of niacinamide and signal intensity
`of niacinamide permeated into the mid ventral forearm at 4 µm in vivo after a 30 min
`application [31].
`
`3. Future perspectives
`Despite the encouraging progress that has been made over the past two decades, the
`development and application of IVIVCs for complex non-oral dosage forms still remains at
`an infant stage. At present, there is sparse or no literature reports on IVIVC for most
`complex non-oral dosage forms (e.g. parenteral nanoparticulate systems, and ophthalmic
`dosage forms). With the ongoing commercialization of novel and generic complex non-oral
`drug products, it is essential to initiate the development of IVIVCs to help assure the product
`performance and safety, as well as to assist in product development in a timely and cost-
`effective fashion.
`
`One of the biggest hurdles yet to conquer in developing IVIVCs for complex non-oral drug
`products is the dearth of bio-relevant in vitro dissolution methods that are capable of
`reflecting the complex and dynamic in vivo environment these dosage forms are
`encountered. This is particularly the case for nanoparticulate systems such as liposomal
`products, as well as ophthalmic drug products. Liposomal formulations have often showed a
`poor correlation between their in vitro and in vivo performance, due to their possible
`multiple fates in the blood circulation [55]. For example, “stealth” liposomal drug products
`
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`are designed to be stable with no (or very little) drug release prior to reaching their target
`organs and cells (e.g. Doxil®), while other liposomal drug products are designed to provide
`