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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5640_Библиотеки_им_академика_М_И_Перельмана.pdf
Transdermal Drug Delivery: Technology and Applications 189
transdermal drug delivery are complex and multifaceted and
involve numerous physiological and physicochemical processes.
1. Passive diffusion represents the primary and most prevalent
mechanism, relying on the concentration gradient between
the drug formulation and the skin. This process involves the
movement of molecules from an area of high concentration to
an area of low concentration, without energy expenditure. The
rate of passive diffusion is influenced by several factors, including molecular weight, lipophilicity, and thickness of the stratum corneum of the drug. Molecules with lower molecular
weights and higher lipophilicities tend to diffuse more readily
through the lipid-rich intercellular spaces of the stratum corneum. The stratum corneum, the outermost layer of the epidermis, serves as the primary barrier to drug penetration and
plays a crucial role in determining the rate and extent of passive
diffusion.
Passive diffusion can be further subdivided into transcellular
and intercellular pathways. In the transcellular pathway, drug molecules traverse through corneocytes and the lipid matrix surrounding them. This route is generally favored by small hydrophilic
molecules. Conversely, the intercellular pathway involves the movement of molecules through the continuous lipid domains between
corneocytes. Lipophilic drugs typically prefer this route because of
their affinity for lipid-rich environments.
2. In c
ontrast t
o passive diffusion, active transport involves the
utilization of energy-dependent carrier proteins to transport
drugs across the skin barrier against a concentration gradient.
Although less common in transder mal deliver y, this mechanism
can be exploited for specific molecules that serve as substrates
for naturally occur ring transporters in the skin. Active transport
has the potential to enhance the delivery of larger or more
hydrophilic molecules, which would otherwise encounter difficulties in passively penetrating the skin. This mechanism is
particularly relevant for peptides and proteins, which are typically too large to passively diffuse through the stratum
corneum.
Active transpor
t in the skin can occur through various transporters, including ATP-binding cassette (ABC) and solute carrier
(SLC) transporters [
14]. These transporters are found in different
layers of the skin and can facilitate the movement of specific molecules across cellular membranes. The expression and activity of
these transporters can vary depending on factors such as skin condition, age, and disease state, potentially influencing the efficacy of
transdermal drug delivery systems that rely on active transport
mechanisms.
190 Pabbathi Shivakumar et al.
3. Facilitated diffusion represents an intermediate mechanism
wherein specific carrier proteins or channels assist in the movement of drugs across the skin without direct energy expenditure. This process can accelerate the transport of certain
molecules compared to passive dif fusion alone, particularly
for drugs that bear a close resemblance to endogenous substances recognized by these facilitator proteins. Facilitated diffusion can be especially beneficial for polar molecules that
would otherwise struggle to penetrate the lipophilic stratum
corneum.
The facilitated diffusion process involves the binding of drug
molecules to specific carrier proteins or channels, which then
undergo conformational changes to transport molecules across
the membrane. This mechanism is saturable and exhibits selectivity
based on the structural characteristics of the drug molecules. Examples of facilitated diffusion in transdermal drug delivery include the
transport of glucose and amino acids through specific carrier proteins in the skin.
In addition to these primary mechanisms, several other factors
can influence transdermal drug delivery. For instance, the hydration
state of the stratum corneum can significantly affect drug penetration. Increased hydration can lead to swelling of corneocytes and
disruption of lipid bilayers, potentially enhancing drug permeation.
Temperature changes can also affect drug delivery by altering the
fluidity of lipid bilayers and increasing skin blood flow, which can
enhance drug absorption.
Various enhancement techniques have been developed to
improve transdermal drug delivery. These include chemical enhancers that can disrupt the structure of the stratum corneum or alter
its lipid organization to increase permeability. Physical methods
such as iontophoresis, which uses a small electric current to drive
charged drug molecules across the skin, and microneedles, which
create temporary microchannels in the skin, have also shown promise in enhancing transdermal drug delivery [
A comprehensive understanding and manipulation of these
mechanisms are essential for optimizing transdermal drug delivery
systems and expanding the range of therapeutics that can be effectively administered. This may involve selecting appropriate drug
candidates based on their physicochemical properties, developing
novel carrier systems that can interact with skin transporters, or
incorporating enhancers that can modulate skin barrier function.
15].
4 Formulation Strategies for Transdermal Drug Delivery
Transdermal drug delivery systems aim to overcome the limitations
of oral and injectable routes by providing controlled release,
Transdermal Drug Delivery: Technology and Applications 191
improved bioavailability, and reduced side effects. Formulation
strategies play a crucial role in enhancing drug permeation through
the skin barrier and optimizing therapeutic outcomes.
4.1 Drug Selection Criteria
The selection of appropriate drugs for transdermal delivery is critical for the efficacy of a transdermal drug delivery system (TDDS).
Several key parameters must be evaluated when assessing the suitability of a drug for transdermal administration. Primarily, the
molecular weight of the drug should preferably not exceed
500 Da, as larger molecules encounter difficulties in penetrating
the stratum corneum. Additionally, the drug should possess balanced lipophilicity, with an octanol-water partition coefficient (log
P) ranging between 1 and 3, to ensure adequate solubility in both
lipid and aqueous environments [
16]. This equilibrium facilitates
efficient partitioning into the stratum corneum and subsequent
diffusion into the deeper skin layers.
Drug potency is another crucial factor, as transdermal delivery
is constrained by the available application surface area. Drugs with
high potency that require daily doses below 10 mg are generally
more appropriate for transdermal delivery [
17]. The melting point
of the drug is also significant, with lower melting points (<200 °C)
being preferable, as they often correlate with enhanced solubility
and skin permeability [
18]. Furthermore, the drug should exhibit a
favorable therapeutic index to minimize the toxicity risks associated
with potential variations in absorption rates.
The pharmacokinetic profile of the drug warrants consideration
as well. Drugs with short half-lives or those requiring frequent
dosing are often suitable candidates for transdermal delivery, as
this route can provide sustained release and reduce dosing frequency [
19]. Lastly, the drug should not induce significant skin
irritation or sensitization, as these effects can compromise patient
compliance and diminish the efficacy of TDDS.
4.2 Vehicle and Excipient Considerations
The selection of appropriate vehicles and excipients is fundamental
for the formulation of effective transdermal drug delivery systems.
The vehicle serves as a carrier for the drug and influences its release
characteristics, whereas excipients enhance its solubility, stability,
and permeation through the skin [
When choosing
a vehicle, formulators must evaluate its com-
20].
patibility with the drug, capacity to maintain drug stability, and
ability to facilitate drug release and skin penetration. Common
vehicles for transdermal formulations include hydrophilic and
lipophilic bases, such as creams, gels, ointments, and patches.
Hydrophilic vehicles, such as hydrogels, are frequently employed
as water-soluble drugs and can provide a cooling effect upon application [
21].
Lipophilic vehicles such as mineral oil-based ointments
are suitable for lipophilic drugs and can enhance skin occlusion,
potentially improving drug penetration [
22].
192 Pabbathi Shivakumar et al.
Excipients in transdermal formulations have various functions.
Solubilizers, such as propylene glycol or ethanol, can enhance drug
solubility in the vehicle. Preservatives are often required to inhibit
microbial growth, particularly in water-containing formulations.
Antioxidants may be incorporated to protect drugs that are susceptible to oxidation. Viscosity modifiers such as cellulose derivatives
can optimize the rheological properties of a formulation, affecting
its spreadability and retention on the skin [
Adhesives are critical components in transdermal patch formulations that ensure proper contact between the drug-containing
matrix and skin. Common adhesives include acrylic polymers, silicone adhesives, and polyisobutylene. The selection of an adhesive
depends on its compatibility with the drug and other for mulation
components, as well as its ability to maintain adhesion over the
intended duration of use.
23].
4.3 Permeation Enhancers
Permeation enhancers temporarily and reversibly alter the structure
of the stratum corneum, facilitating drug penetration through the
skin. These compounds play a vital role in overcoming the natural
barrier function of the skin and improving the bioavailability of
transdermally delivered drugs. Permeation enhancers can act
through various mechanisms, including disruption of the ordered
structure of stratum corneum lipids, interactions with intercellular
proteins, and increased drug partitioning into the skin [
24].
Chemical permeation enhancers are widely used in transdermal
formulations. Alcohols and polyols, such as ethanol and propylene
glycol, can increase drug solubility and extract lipids from the
stratum corneum, creating diffusion pathways. Fatty acids such as
oleic acid can disrupt lipid packing in the stratum corneum, thereby
enhancing drug penetration. Surfactants, including sodium lauryl
sulfate, can solubilize lipids and denature keratin, thereby facilitating drug passage through the skin.
rpenes d
Te
erived from natural sources have garnered attention
as effective and relatively safe permeation enhancers. Compounds
such as menthol and limonene can interact with intercellular lipids,
increasing their fluidity and improving drug diffusion. Dimethyl
sulfoxide (DMSO) is a potent permeation enhancer that can denature proteins and alter keratin conformation in the stratum corneum, although its use is limited owing to potential irritation.
Recently,
physical permeation enhancement techniques have
been developed to complement or replace chemical enhancers.
These include iontophoresis, which employs a small electric current
to drive ionized drug molecules through the skin, and microneedle
technology, which creates temporary microchannels in stratum
corneum for drug delivery. These physical methods can provide
more controlled and targeted drug delivery while minimizing skin
irritation associated with some chemical enhancers.
Transdermal Drug Delivery: Technology and Applications 193
Table 2
Therapeutic applications of transdermal drug delivery systems
Therapeutic area Examples of drugs Benefits of transdermal delivery
Cardiovascular Nitroglycerin, clonidine Controlled release, avoid first-pass
metabolism
Hormonal
therapy
Pain management Fentanyl, lidocaine Sustained pain relief, reduced systemic
Neurological
disorders
Smoking
cessation
Estradiol, testosterone Mimic physiological hormone levels
side effects
Rotigotine (Parkinson’s), rivastigmine
(Alzheimer’s)
Nicotine Controlled nicotine delivery, behavioral
Steady drug levels, improved adherence
support
Table 3
Comparison of transdermal drug delivery
Technology Mechanism Advantages Limitations
Passive
patches
Iontophoresis Electric current drives
Microneedles Create microchannels in
Nanocarriers Encapsulate drugs in
Diffusion through skin Simple, non-invasive Limited to small, lipophilic drugs
charged drugs
skin
nanoparticles
Enhances delivery of ionic
drugs
Enables delivery of larger
molecules
Improves drug stability
and penetration
Requires power source, potential
skin irritation
Manufacturing complexity,
potential skin reactions
Complex formulation, potential
toxicity concerns
Sonophoresis Ultrasound enhances
skin permeability
When incorporating permeation enhancers into transdermal
formulations, it is crucial to balance their efficacy with potential
skin irritation or long-term effects on skin barrier function
(Table
should consider their compatibility with the drug and other formulation components, as well as their safety profile for long-term use.
4.4 Transdermal Drug Delivery Technologies
Transdermal drug delivery technologies have revolutionized medication administration, offering noninvasive methods to deliver
drugs through the skin. Transdermal delivery systems can be
broadly categorized into passive, active, and nanocarrier-based systems, each with distinct mechanisms and applications (Table
Increases delivery of
various molecules
Requires specialized equipment,
limited clinical data
2). The selection of appropriate permeation enhancers
3).
194 Pabbathi Shivakumar et al.
1. Passive systems, including patches, gels, and creams, rely on the
natural permeability of the skin for drug delivery. Transdermal
patches are adhesive systems that contain a drug reservoir that
releases the medication at a controlled rate [
have gained widespread acceptance and are used for various
treatments such as nicotine replacement therapy for smoking
cessation, hormone replacement therapy for menopausal symptoms, and pain management with opioid analgesics. The controlled-release mechanism of the patches allows for sustained
drug delivery over extended periods, enhancing patient compliance and reducing dosing frequency. Gels and creams are
topical formulations that en able drugs to penetrate the skin
through diffusion and are particularly useful for localized treatments such as topical analgesics or anti-inflammatory agents.
While passive systems are user-friendly and generally well tolerated, they may have limitations regarding the size and type of
molecules that can be effectively delivered, often restricted to
small, lipophilic compounds.
2. Active s
methods to enhance drug penetration through the skin,
thereby addressing some of the limitations of passive delivery.
Iontophoresis utilizes a small electric current to drive charged
drug molecules across the skin barrier, which is particularly
useful for delivering water-soluble, charged medications, such
as certain pain medications or anti-inflammatory drugs. Electroporation involves the application of high-voltage electrical
pulses to create temporary pores in the skin, thereby allowing
the passage of larger molecules. This method has demonstrated
potential for the delivery of macromolecules, including proteins and nucleic acids, which are typically challenging to
administer transdermally [
waves to increase skin permeability, enabling the delivery of
both small and large molecules. Ultrasound energy temporarily
disrupts the skin’s structure, creating pathways for drug penetration. This technique has been explored for various applications, including insulin and vaccine delivery [
ystems e
25]. These patches
mploy external energy sources or physical
26]. Sonophoresis uses ultrasound
27].
Microneedles represent
another innovative approach for active
transdermal delivery systems. These minimally invasive devices consist of arrays of microscopic needles that create small channels in the
skin for drug delivery. Microneedles can be solid and coated with
drugs, dissolving types that release the drug as they dissolve in the
skin, or hollow for direct drug administration. The small size of
these needles (typically less than 1 mm in length) allows painless
a
pplication
while effectively bypassing the stratum corneum, which
is the main barrier to transdermal drug delivery. Microneedle technology has shown promise in vaccine delivery, insulin
Transdermal Drug Delivery: Technology and Applications 195
administration, and delivery of large molecules that are typically
challenging to administer through the skin.
3. Nanocarrier-based systems represent an advanced approach to
transdermal drug delivery that leverages the unique properties
of nanoscale materials. These systems use nanoparticles, liposomes, dendrimers, and other nanostructures to encapsulate
and transport drugs across the skin barrier. Nanocarriers offer
several advantages in transdermal delivery, including protection
of drugs from degradation, enhanced stability during storage
and application, improved solubility of poorly water-soluble
drugs, and enhanced penetration through skin layers, potentially improving drug bioavailability [
28].
One of the key benefits of nanocarrier-based systems is their
potential for targeted delivery and controlled release of medications. By modifying the surface properties of nanocarriers, it is
possible to direct them to specific skin layers or particular cell
types within the skin, thereby enhancing their therapeutic efficacy
while minimizing systemic side effects. Controlled release mechanisms can be incorporated into nanocarrier designs, allowing for
sustained drug delivery over extended periods, which is particularly
beneficial for drugs requiring consistent blood levels or for reducing dosing frequency to improve patient compliance.
The versatility of nanocarrier systems allows the delivery of a
wide range of therapeutic agents, including small molecules, proteins, and nucleic acids. Lipid-based nanocarriers, such as liposomes
and solid lipid nanoparticles, have shown promise in delivering
both hydrophilic and hydrophobic drugs. Polymeric nanoparticles
offer tunable release profiles and can be designed to respond to
specific stimuli, such as pH changes or temperature. Dendrimers,
with their highly branched structures, provide a unique platform
for drug encapsulation and controlled release.
Each t
ransderm
al drug delivery technology offers unique
advantages and faces specific challenges. Passive systems are generally simpler and more cost-effective but may be limited in their
ability to deliver larger or hydrophilic molecules. The development
of new patch designs and formulation techniques continues to
expand the range of drugs that can be delivered passively. Active
systems can overcome many of the limitations of passive delivery
but may require more complex devices and careful consideration of
safety aspects. The integration of active delivery methods with
smart technologies and wearable devices is an area of ongoing
research that promises more precise and patient-friendly drug
delivery.
Nanocarrier
-based systems offer great potential for enhancing
drug delivery but require sophisticated formulation techniques and
thorough evaluation of their long-term safety and efficacy. The
196 Pabbathi Shivakumar et al.
Table 4
Physicochemical properties ideal for transdermal drug
Property Ideal range Rationale
Molecular weight <500 Da Facilitates skin penetration
Log P (octanol-water partition coefficient) 1–3 Balances skin penetration and solubility
Melting point <200 °C Correlates with solubility
Aqueous solubility >1 mg/mL Ensures adequate concentration gradient
Dose <10 mg/day Feasible for limited patch size
behavior of nanoparticles in biological systems, including their
potential toxicity and long-term accumulation, remains an area of
active investigation. Regulatory considerations for nanomedicine
products also present challenges for bringing these advanced delivery systems to the market.
The selection of transdermal delivery technology depends on
various factors, including the physicochemical properties of the
drug, desired therapeutic effect, patient compliance considerations,
and specific requirements of the treatment regimen (Table
4). For
instance, drugs with a narrow therapeutic window may benefit from
the controlled release offered by patches or nanocarrier systems.
Vaccines or large-molecule drugs may be better suited for delivery
via microneedles or advanced nanocarrier formulations. Patient
factors such as skin condition, age, and lifestyle also play a role in
selecting the most appropriate delivery system.
5 Evaluation Methods for Transdermal Drug Delivery Systems
1. In vitro permeation studies are essential for evaluating transdermal drug delivery systems (TDDS) before in vivo testing.
These studies typically employed Franz diffusion cells or similar
apparatus to assess drug permeation through excised human or
animal skin or synthetic membranes [
brane is critical because it can significantly impact the results
and their relevance to in vivo conditions. Excised human skin is
considered the gold standard; however, its limited availability
often necessitates the use of animal skin or synthetic
alternatives.
The donor
compartment contains the TDDS or drug formulation, whereas the receptor compartment is filled with a physiologically relevant medium. The receptor medium was carefully selected
to maintain sink conditions and to mimic the physiological environment. Factors such as pH, temperature, and stirring rate were
tightly controlled to ensure reproducibility and physiological
relevance.
29]. The choice of mem-
Transdermal Drug Delivery: Technology and Applications 197
Samples were collected from the receptor compartment at predetermined intervals and analyzed using validated analytical methods, such as HPLC or LC-MS/MS. The sampling frequency and
duration were optimized to capture the drug’s permeation profile
accurately. These analytical techniques offer high sensitivity and
specificity, allowing for precise quantification of drug concentrations, even at low levels.
Key parameters derived from these studies include the steadystate flux, lag time, and permeability coefficient. Steady-state flux
represents the rate of drug permeation across a membrane under
equilibrium conditions. Lag time indicates the time required for
the drug to establish a concentration gradient across the membrane. The permeability coefficient provides a measure of the membrane’s resistance to drug permeation, accounting for both the
drug’s physicochemical properties and membrane characteristics.
Advanced techniques such as confocal laser scanning microscopy and ATR-FTIR spectroscopy can provide insights into drug
distribution within skin layers and potential interactions with skin
components. Confocal microscopy allows for three-dimensional
visualization of fluorescently labeled drugs within the skin, revealing their penetration pathways and accumulation in specific skin
structures. ATR-FTIR spectroscopy enables noninvasive analysis of
molecular interactions between the drug and skin components,
offering valuable information on the behavior of the drug at the
molecular level.
Furthermore, these advanced techniques can be complemented
by emerging technologies, such as Raman spectroscopy and multiphoton microscopy. Raman spectroscopy provides chemicalspecific information on drug distribution and potential structural
changes in skin lipids or proteins. Multiphoton microscopy offers
high-resolution, three-dimensional imaging of the skin structure
and drug penetration with minimal photodamage, allowing for
real-time monitoring of drug permeation in intact skin samples.
2. In v
harmacokinetic studies are crucial for assessing the
ivo p
performance of TDDS in living organisms. These studies typically involve administering TDDS to animal models or human
volunteers and collecting blood samples at specified time
points. The choice of animal model is critical, considering
factors such as skin per meability, metabolic pathways, and
physiological similarities to humans. In human studies, careful
selection of subjects and adherence to ethical guidelines is
paramount.
Plasma dr
ug concentrations were then determined using sensitive analytical techniques. The analytical methods employed must
be validated for selectivity, accuracy, precision, and stability to
ensure reliable quantification of drug levels in complex biological
198 Pabbathi Shivakumar et al.
matrices. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is often the method of choice owing to its
high sensitivity and specificity.
The key pharmacokinetic parameters evaluated included maximum plasma concentration (Cmax), time to reach Cmax (Tmax),
area under the curve (AUC), and elimination half-life. These parameters provide crucial information regarding the rate and extent of
drug absorption, distribution, and elimination. Cmax and Tmax
offer insights into peak drug exposure and the time required to
achieve it, respectively. AUC serves as a measure of overall drug
exposure, while the elimination half-life indicates the persistence of
the drug in the body.
Advanced approaches may incorporate microdialysis techniques to measure drug concentrations in the extracellular fluid of
target tissues. This method allows for continuous, real-time monitoring of drug levels in specific tissue compartments, providing a
more detailed understanding of drug distribution and local pharmacokinetics. Microdialysis is particularly valuable for assessing
drug concentrations at the site of action, which may not always
correlate directly with plasma levels.
Additionally, positron emission tomography (PET) imaging
with radiolabeled drugs can provide real-time, noninvasive insights
into drug distribution and kinetics across various organs and tissues. PET imaging offers unique advantages for visualizing drug
biodistribution, penetration into target tissues, and potential
off-target accumulation. This technique can be combined with
other imaging modalities, such as computed tomography (CT) or
magnetic resonance imaging (MRI), to provide an anatomical context and enhance data interpretation.
Population phar
based pharmacokinetic (PBPK) modeling are increasingly
employed to analyze and interpret in vivo pharmacokinetic data.
These noninvasive approaches can account for inter-individual
variability, predict drug behavior in different patient populations,
and facilitate the optimization of dosing regimens. They also play a
crucial role in extrapolating data from animal studies to humans
and in predicting drug-drug interactions.
macokinetic
modeling and physiologically
3. Safety and
irritation assessments are critical for ensuring the
biocompatibility and tolerability of TDDS. In vitro methods
include cytotoxicity assays using relevant cell lines and
3D-reconstructed human skin models to evaluate potential
skin irritation and corrosion. These models, such as EpiSkin
and EpiDerm, mimic the structure and function of human skin
and provide a more physiologically relevant platform for assessing the effects of TDDS components on skin viability and
barrier function [
30].