Arunn Narasimhan

Arunn Narasimhan

Drug Delivery in Human Organs

Created Last modified 7 min read

About this note

A plain-language summary of the 6 publications listed under this topic on Academic Publications (Topic-wise). Full citations are under References.

Why this matters

A drug only works if enough of it reaches the right tissue for long enough. Between the point of application and the target lie layers of tissue that slow it down, and flows that either help it along or carry it away.

Our approach across these studies is to treat tissue as a porous medium: a solid matrix of cells and fibres with fluid-filled spaces between them, described by averaged properties such as porosity (the open fraction of the volume), permeability (a measure of how easily fluid passes through) and an effective diffusivity for the drug. Two organs have been the testing ground, the eye and the skin, and in both the story turns on the same contest: slow diffusion of the drug through tissue against faster convection by some flow.

What we did

The eye: blood flow as a sink, vitreous flow as a helper

With Ramanathan Vishnampet, we modelled the sclera (the white outer coat of the eye) and the choroid (the blood-rich layer beneath it) as porous media to follow a drug placed outside the eye on its way to the retina (Narasimhan and Ramanathan, 2012). The porosity of the sclera was measured from electron microscope images, the drug’s effective diffusivity came from experimental permeability data, and the blood flowing through the choroid was computed as flow through a porous layer.

With C. Sundarraj we first showed that a liquefied or surgically replaced vitreous humour circulates by natural convection when the retina is heated by a laser, and that choroidal blood perfusion cools the retina (Narasimhan and Sundarraj, 2013). We then proposed using that laser-driven circulation to carry an injected drug to the retina (Narasimhan and Sundarraj, 2015), and with Shrinivas Vibhute tested the idea in a glass model eye (Shrinivas and Narasimhan, 2023). The details of these eye studies are in Drug Delivery in Human Eye and Bio-Fluid Dynamics of Human Eye.

The skin: a porous medium that moves

Transdermal patches deliver drug through the skin without needles or pills, and give steadier levels in the blood. The main barrier is the outermost skin layer, the stratum corneum: 10 to 15 layers of dead, flattened cells (corneocytes) packed like bricks in a mortar of lipids. Two features of this layer are usually ignored. First, it is continually renewed: new cells are added from below and old ones shed from the surface, so the whole layer is replaced every 10 to 15 days and slowly migrates outwards, against the inward-moving drug. Skin conditions such as psoriasis or eczema can speed this up five to six times. Second, its diffusivity is anisotropic: a drug spreads about twice as easily sideways, along the layers, as it does across them through the winding lipid paths.

With Ajith Joseph, we built a model that treats the skin as a composite, dynamic porous medium, with the stratum corneum, epidermis and dermis as separate layers, cell migration represented as a slow outward “virtual” flow, direction-dependent diffusivity in the stratum corneum, and blood flow in the dermis as Darcy flow through a porous bed (Narasimhan and Joseph, 2015). It agreed well with in vivo measurements of the drug terbinafine.

Building on what this model revealed about sideways spreading, we then designed a new kind of patch (Joseph and Narasimhan, 2020). Instead of covering the skin completely with drug, it uses many small drug heads arranged periodically with drug-free gaps between them. We studied strips, a matrix of squares and a chessboard-like staggered layout, in two and three dimensions, using the effective area ratio (the fraction of skin actually in contact with drug) as the key design variable.

What we found

The common thread is that flows, real or virtual, decide where the drug goes. In the eye, choroidal blood flow is the dominant route of drug loss inside the eye over the normal range of blood speeds, and the peak drug level in the choroid fell by about 70% between the low and high ends of that range (Narasimhan and Ramanathan, 2012). The vitreous flow, by contrast, can be harnessed to speed delivery, raising the steady drug level at the retina 56.25 times in the glass-eye experiments (Shrinivas and Narasimhan, 2023).

In the skin, cell migration reduced the average drug flux entering the skin by up to 20%, and because this shortfall stays constant over time it adds up to a large loss over a long application. Migration also pushed the drug sideways, increasing its lateral spread by 11%, while anisotropy alone increased lateral spread by 104%. Together they divide the stratum corneum into four regions: directly under the patch only cell migration matters; just inside the patch edge both effects matter; just beyond the edge only anisotropy matters; and further out neither, because the drug does not reach that far (Narasimhan and Joseph, 2015). Because the drug spreads well beyond the patch edge, the paper suggested that several smaller, separated patches could replace one large patch.

The distributed patch turned that suggestion into a design. Flux concentrates at the boundaries between patched and unpatched skin, where local flux can be ten times that of a conventional patch. The new design delivered twice the average flux per unit of drug head area and reached steady state up to 50% sooner. An effective area ratio of 50% emerged as a good balance, and the staggered layout at that ratio was 95% as effective as a conventional fully covered patch in average flux while leaving half the skin free to breathe. This matters because skin irritation and allergy from patches affect 20% to 50% of patients. Matrix and staggered layouts raised flux by a further 5% to 40% over simple strips, and choosing the area ratio can set the dose without the rate-limiting membrane used in current patches (Joseph and Narasimhan, 2020).

References

  1. Shrinivas, V. and Narasimhan, A., (2023) “Convection-assisted intra-vitreous drug delivery in human eye: An experimental investigation,” Heat Transfer May 2023, 1-13. [ DOI: 10.1002/htj.22899 | Abstract | IITM Tech Talk News | BioVoice News ]
  2. Joseph, A. and Narasimhan, A., (2020) “Enhanced design for microscale distribution of drug heads for transdermal patches,” Int. J. Heat Mass Transfer Apr 2020, 151, 119397. [ DOI: 10.1016/j.ijheatmasstransfer.2020.119397 | Abstract ]
  3. Narasimhan, A. and Sundarraj, C., (2015) “Convection-Enhanced Intravitreous Drug Delivery in Human Eye”   ASME J. of Heat Transfer 137(12), 121003 (Aug 11, 2015) (7 pages) [DOI: 10.1115/1.4030916 | Abstract ]
  4. Narasimhan, A. and Joseph, A., (2015) “Porous Medium Modeling of Combined Effects of Cell Migration and Anisotropicity of Stratum Corneum on Transdermal Drug Delivery”   ASME J. of Heat Transfer 137(12), 121007 (Aug 11, 2015) (8 pages) Paper No: HT-14-1277 [ DOI: 10.1115/1.4030923 | Abstract ]
  5. Narasimhan, A. and Sundarraj, C., (2013), “Effect of choroidal blood perfusion and natural convection in vitreous humor during transpupillary thermotherapy (TTT),”  Int. J. Numer. Meth. Biomed. Engng., 29 (4), 530–541. [DOI: 10.1002/cnm.2538 | Abstract]
  6. Narasimhan, A. and Ramanathan, V. G., (2012), “Effect of choroidal blood flow on transscleral retinal drug delivery using a porous medium model,”  Int. J. Heat and Mass Transfer, 55 (21), 5665–5672.[DOI: 10.1016/j.ijheatmasstransfer.2012.05.060].

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