Different Approaches for Transdermal Nano-Carrier Delivery System

 

Zohra Firdous*, Pankaj Dhapake, Nitin Padole, Nilakshi Dhoble, Jagdish Baheti

Department of Pharmaceutics, Kamla Nehru College of Pharmacy,

Butibori, Nagpur 441108, Maharashtra, India.

*Corresponding Author E-mail: zohrafirdous.143@gmail.com

 

ABSTRACT:

Transdermal drug delivery is a validated technology that makes a significant contribution to global pharmaceutical care. Since 1980, the sector has seen impressive growth with several commercial successes. The term transdermal drug delivery refers to the delivery of a drug across the layers of skin with the intention of allowing the drug to be absorbed through the skin in a predetermined and controlled rate manner. Skin is one of the largest organs that act as an efficient barrier for drug delivery. The present study focuses on the different approaches of nano-carrier system that delivers the nano-carrier drug across the skin barrier with the help of transdermal delivery system. Nano-carrier drug delivery systems are one of the biggest challenges to deliver drug into systemic circulation by crossing the skin barrier providing a passive drug delivery strategy that is known to be safer and faster than the conventional method. In this review, we describe the diverse types of nano-carriers approaches that have been synthesized for transdermal delivery system includes liposomes, niosomes, ethosomes, solid lipid nanoparticles (SLN), nanostructured lipid carrier (NLC), polymeric nanoparticles, nanocrystals, nanofibers and nanosuspension/nanoemulsion. Several characterization methods of transdermal delivery system have been proposed to control the behavior of nano-carriers, along with in-vitro and in-vivo and other evaluation parameters. It was concluded that the compatibility of nano-carriers with the skin structure should be considered for transdermal nanocarrier delivery systems, which will be the most preferred route for drug delivery in the future as it offers high patient compliance, controlled dosing, low frequency of dosing, high physico-chemical stability and better dermal bioavailability, etc.

 

KEYWORDS: Transdermal Delivery, Skin, Nano-carrier Approaches, Evaluation Parameters, Future Perspectives.

 

 


INTRODUCTION:

Transdermal Drug Delivery System                                                                                                                         

The term transdermal drug delivery refers to the delivery of a drug across the skin through the layers of the skin with the intention of allowing the drug to be absorbed through the skin and exert a systemic effect1. Transdermal drug delivery is a validated technology that makes a significant contribution to global pharmaceutical care. Since 1980, the sector has seen impressive growth with several commercial successes2.

 

 

Transdermal route is the major route for systemic effects3. Although the transdermal route is an attractive alternative to oral and hypodermic administration, a limited number of drugs are available as transdermal products. A drug molecule released from a variety of dosage forms such as semisolid, gel, cream, suspension, microemulsion and patch has to pass through the stratum corneum layer of the skin by a multistep sequential process before reaching the systemic circulation4. Transdermal delivery is one of the highly successful alternative delivery methods. The drug is delivered to the body through the transdermal layer of the skin5. The skin is one of the largest organs that offers multiple sites for drug delivery and serves as a "reservoir" for sustained delivery of drugs. However, the penetration of drugs through the skin is hindered due to the stratum corneum, which acts as an efficient barrier. To overcome this obstacle, nanocarriers such as liposomes, nanoparticles, ethosomes, dendrimers, etc. have emerged as an efficient tool to deliver a range of drugs through the stratum corneum6. Therefore, transdermal delivery systems help the drug to be absorbed into the blood circulation through the stratum corneum layer of the skin. Transdermal drug delivery uses the human skin as a port of entry for systemic delivery of drug molecules. It is one of the systems falling under the category of controlled drug delivery in that they aim to deliver the drug through the skin in a predetermined and controlled rate manner7. Transdermal delivery provides a leading edge over the injectable and oral routes by increasing patient compliance and avoiding first-pass metabolism, respectively8. Transdermal drug delivery overcomes some of the problems associated with other routes of administration. Transdermal delivery is suitable for drugs that have the following properties i.e. the polarity of the molecule should allow diffusion through both the hydrophobic stratum corneum and lipophobic epidermal layers, the drug should not be significantly bound to skin proteins, the drug Must have the correct molecular weight (<500 Da) and the drug must be relatively potent as only small amounts are absorbed through the skin9.

 

Skin Anatomy: Skin is one of the most extensive organs of the human body covering an area of approximately 2m² in the average human adult10. This multilayered organ receives about a third of all blood circulating through the body. It has various functions and properties. Skin separates the underlying blood circulation network from the external environment Acts as a barrier against physical, chemical and microbial attacks Acts as a thermostat in maintaining body temperature Protects against harmful ultraviolet rays of the sun Protects and plays a role in regulating blood pressure11. It is described as having three major tissue layers: the epidermis, the dermis, and the hypodermis as shown in Figure 1.

 

Figure 1: Structure of Skin and Layer of Epidermis

 

Epidermis: The epidermis is the outermost and thinnest area of the skin. Epidermis is composed of keratinized stratified squamous epithelium with surface dead cells filled with tough protein keratin and is divided into several layers and they are hair shaft, sweat gland duct orifice, stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, Stratum is basal12,13,14.

 

Dermis: The dermis is a connective tissue layer sandwiched between the epidermis and the subcutaneous tissue. The dermis is a fibrous structure composed of collagen, elastic tissue, and other extracellular components that include vasculature, nerve endings, hair follicles, and glands. The role of the dermis is to support and protect the skin and deeper layers, aid in thermoregulation, and aid in sensation15. The dermis consists of two layers: the thin and superficial papillary dermis, and a thicker and deeper reticular dermis16,17.

 

Hypodermis: The hypodermis is also known as the subcutaneous layer that lies beneath the dermis. It connects the skin to the underlying tissues and organs. It consists of adipocytes and is attached to the dermis in a deeper structure, increasing the uptake of drugs delivered to this layer because it is replete with vasculature. It is a sheet of fat containing areolar tissue known as the superficial fascia, which connects the dermis to the underlying structure18.

 

Skin Target for TDDS: Transdermal drug delivery systems are used for various purposes to target drug into the skin, given below:19,20.

 

Surface of skin: The skin surface is targeted for locally active substances such as disinfectants, cosmetics, insect repellents etc. in which the drug acts only on the surface of the skin and there is no penetration of the drug or chemicals into the skin.

 

Skin layers itself: Delivery of drug substances within the layers of the skin is also known as topical delivery and is targeted to the layers of the skin when disease or infection is present in the skin itself such as microbial infections, dermatitis and neoplasms etc.

 

Systemic Circulation: It is considered as an alternative to oral and other conventional delivery routes for systemic delivery of drugs. The drug has to enter the blood circulation through various skin layers for it to have a systemic effect.

 

Drug Permeation through Skin: The drug potentially enters the blood vessel through the epidermis and circulates through the shunt pathway, mainly to the hair follicles with their associated sebaceous glands and sweat ducts21. The drug can be penetrated through the skin by various routes in which lipophilic and hydrophilic drug absorption occurs through this route, the stratum corneum of the skin prevent the absorption of the drug but the presence of different permeation routes helps in drug penetration Which is then taken to the systemic circulation as shown in the Figure 2.

 

Figure 2: Drug Permeation through Skin

 

a)    Transfollicular route: Appendages of the skin (hair follicles, sweat ducts) offer openings that bypass the barrier of the stratum corneum. These openings on the surface of the skin occupy only about 0.1% of the total surface. Eccrine sweat glands can be numerous in many areas of the body (such as the palms and soles). The opening of the follicular pores of the skin surface is larger than that of the eccrine glands, although they are less in number22. Transappendageal transport (transfollicular route) may also be important for large polar molecules and ions that would translocate poorly into the bulk of the stratum corneum as shown in          Figure 2.

 

b)   Intracellular route: The intracellular route is one of the types of transepidermal route mainly responsible for diffusion in the skin as shown in Figure 2. The stratum corneum is the main resistance to absorption via this route. Permeability through the skin depends on the O/W distribution tendencies of the drug. Transit by the transepidermal route first involves partitioning into the stratum corneum, then diffusion along this route. Permeation through the dermis occurs through interlocking channels of the ground substance. The route through the dermal region represents a final barrier to systemic entry. Since the viable epidermis and dermis lack major physico-chemical distinctions, they are generally treated as a zone of diffusion, except when extreme polarity entrainment is involved, as the epidermis is the average for such species. Provides graded resistance23.

 

c)    Intercellular route: The intercellular route is also one of the types of transepidermal route, which involves solute diffusion through the intercellular lipid domain via a curved route (through the stratum corneum, viable epidermis, and cornified cells of the dermis), as shown in Figure 2. Has gone. The intercellular route was initially ruled out as a major skin permeation mechanism due to its small volume occupancy. However, the intercellular volume fraction was later found to be much larger than originally estimated. Tracer studies provided evidence that intercellular lipids, not corneocyte proteins, were the main epidermal permeability barrier. These studies suggest that the intercellular route confers a major resistance to skin permeation24.

 

Types of TDDS:

 

Table 1: Types of Transdermal Drug Delivery System

 

1.     Membrane Moderated System:

In reservoir systems the drug is encapsulated between a rate controlling microporous or non-porous membrane and an impermeable backing laminate. The drug is uniformly dispersed in a solid polymer matrix and suspended in a viscous liquid medium forming a paste. The release rate of the drug is determined by the friction rate, permeability, diffusion, and thickness of the membrane. The release rate from the reservoir system is a zero order process. The entire system is supported on an impermeable metallic backing25 as shown in Figure 3.

 

 

Figure 3: Membrane Moderate

 

2.     Adhesion-Diffusion Controlled System:

In this system the medicine is dispersed in the adhesive layer of the patch. The adhesive layer not only adherence the components of the patch to the skin but also controls the rate of drug delivery to the skin. The adhesive layer is surrounded by the liner. In single layer patch a single drug is present in the adhesive layer but in multilayer patch one layer is for immediate release of drug and the other layer is for controlled release of drug26 as shown in figure 4.

 

Figure 4: Adhesion-Diffusion Controlled

 

3.     Matrix Dispersion System:

The matrix dispersion is also known as a monolithic system (Figure 5). In matrix diffusion system the drug is uniformly dispersed in the hydrophilic or lipophilic polymeric material. The adhesive layer extends around the perimeter of the polymer disc rather than spreading over the surface of the patch. The matrix system of drug delivery can be modified by adding drug directly to the adhesive layer. It can be formulated into single layer drug in adhesive system or multilayer drug in adhesive system. The rate of degradation of the polymer, the thickness of the layer and the surface area of the film determine the release rate of the drug. No other rate controlling membrane is present in the matrix system27,28.

 

 

Figure 5: Matrix Dispersion system

 

4.     Micro Reservoir System:

The micro reservoir system (Figure 6) is a combination of matrix and reservoir system. In the micro reservoir system the drug is first suspended in an aqueous solution of a hydrophilic polymer (eg, PEG) and then the above suspension is mixed with a lipophilic polymer (eg, silicone) by high shear mechanical agitation. Cross linking of the in-situ produced polymer chains stabilizes the micro-reservoir system and a medicated polymer disc of specific area and thickness is formed29.

 

Figure 6: Micro Reservoir System

Nano-carriers Approaches for TDDS:

Nanocarriers are classified as colloidal structures with an average particle diameter and droplet size of 1–500 nanometers30. Nanotechnology applied to health science includes new tools used in surgery, new chips for better diagnosis, new materials to replace body structures and some structures capable of carrying drugs through the body to treat diseases are included. These structures can be made from a variety of materials that differ in composition and chemical nature. Hence all these nanostructures are called nanocarriers which can be administered into the skin by transdermal route31. Nanocarriers deliver the drug to the target site. Nanocarriers are a powerful weapon against many diseases because they are small enough to be detected by the immune system. Compared to conventional drug delivery approaches, nanocarriers provide a passive drug delivery strategy that is considered to be safer and faster than conventional method32. Nanocarriers approaches for transdermal drug delivery system includes liposomes, niosomes, ethosomes, solid lipid nanoparticles (SLN), nanostructured lipid carrier (NLC), polymeric nanoparticles, nanocrystals, nanofibers and nanosuspension/ nanoemulsion, as shown in Figure 7.

 

 

Figure 7: Different Types of Approaches for Transdermal Nanocarriers Delivery System

 

1.     Liposomes:

Liposomes are vesicles in which one or more lipid bilayers trap an aqueous volume. Liposomal vesicular systems can incorporate both lipophilic and hydrophilic drugs to aid in the penetration of agents involved. Liposomes are phospholipid-based vesicular structures composed of anionic, cationic and neutral lipids and cholesterol that improve the encapsulation of lipophilic, hydrophilic and amphiphilic drugs. Lipophilic drugs are placed in the interior of the lipid bilayers, hydrophilic drugs in the aqueous core, and amphiphilic types in the interlayer of vesicles. Their major constituents are usually phospholipids with or without cholesterol. Phospholipids are the major components in liposomes but an additional surfactant acts as an edge activator to modify elasticity and enhance deformability. Liposomes as vesicular nanocarriers have several advantages for transdermal drug delivery such as controlled drug release, local drug deposition in the skin layers, decreased systemic absorption and fewer drug side effects33. Local skin deposition of active pharmaceuticals loaded liposomes was evidenced by low serum concentration and urinary excretion of the drug. Liposomes can also enhance transdermal drug delivery and increase systemic drug concentrations34.

 

2.     Niosomes:

Niosomes are a new drug delivery system in which the drug is encapsulated in a vesicle. The vesicles are composed of a double layer of non-ionic surface active agents and are therefore named niosomes. Niosomes are bio-degradable, non-carcinogenic and non-immunogenic35. Structurally, niosomes are similar to liposomes in that they are also composed of bilayers. However, in the case of niosomes the bilayers is composed of non-ionic surface active agents instead of phospholipids as seen in the case of liposomes36. The increased permeability through these vesicles is due to the fact that these vesicles interact with the stratum corneum by aggregation, fusion, and adhere to the cell surface, allowing high-thermodynamic binding of the drug to the surface of the vesicle and the stratum corneum activity is gradient. It serves as a driving force for the penetration of drugs into the stratum corneum. Niosomes also modify the structure of the stratum corneum by increasing the permeability of the stratum corneum and loosening the intercellular lipid barrier of the stratum corneum. The non-ionic surfactant present in niosomes acts as a permeability enhancer and plays an important role in increasing the permeability37.

 

Niosomes are a novel drug delivery system, in which the medication is encapsulated in a vesicle. The vesicle is composed of a bilayers of non-ionic surface active agents and hence the name niosomes. Structurally, niosomes are Similar to liposomes, in that they are also made up of a bilayer. However, the bilayers in the case of niosomes is made up of non-ionic surface active agents rather than phospholipids as seen in the case of liposomes.

 

3.     Ethosomes:

Ethosomes are vesicular carriers composed of hydroalcoholic or hydrolyglycolic phospholipids, which have high water and alcohol content. The high concentration of ethanol makes ethosomes unique. Vesicular systems are the most extensively investigated method for transdermal drug delivery. Ethosomes are non-invasive delivery vehicles that release the drug deep into the systemic circulation. Ethosomes have been developed for transdermal delivery of a drug38. Ethosomes increase drug permeability through the stratum corneum skin barrier, it can be used to administer drugs that have poor skin permeability, low oral bioavailability, suppress first pass metabolism and transdermal route of infection. Ethosomes are interesting and innovative vesicular systems that have appeared in recent years in the fields of pharmaceutical technology and drug delivery. This carrier presents interesting characteristics related to its ability to persist through human skin due to its high virulence39,40.

 

4.     Solid lipid nanoparticle (SLS):

Topical application of drugs to pathological sites offers the potential advantage of delivering the drug directly to the site of action and thus producing higher tissue concentrations of the drug41. The selection of an appropriate dosage form/formulation base is essential to enhance the ease of use and cutaneous and transdermal delivery of SLN. Upscaling and regulatory approval are other challenges that may hinder the clinical translation of SLN. Therefore, this review focuses on the various mechanisms involved in the skin penetration and cellular uptake of SLN. This is followed by a comprehensive discussion on the physico-chemical properties of SLN, including various formulation and dosage form factors that may affect the absorption of SLN through the skin42.

 

5.     Nanostructured lipid carrier:

Nanostructured lipid carriers (NLCs) emerge as the second generation of lipid nanoparticles to overcome the shortcomings of the first generation i.e. SLN. Biodegradable and compatible lipids (solid and liquid) and emulsifiers are used for the preparation of NLC. Liquid lipid (oil) incorporation causes structural defects of solid lipids leading to a less ordered crystalline arrangement that inhibits drug release and presents higher drug loads43,44. NLCs are made from biologically active and biodegradable lipids that show low toxicity and provide several favorable properties such as adhesion, occlusion, skin hydration, lubrication, lubricity, softness, skin penetration enhancement and modified release, improvement in formulation appearance which provide a whitening effect and offer protection of the actives against degradation. NLCs are chemically and physically stable systems with improved drug absorption and increased bioavailability. The key features of NLCs that make them a promising drug delivery system are ease of preparation, biocompatibility, large-scale feasibility, non-toxicity, improved drug loading and stability45.

 

6.     Polymeric Nanoparticles:

Polymeric nanoparticles (NPs) are particles within the size range of 1 to 1000nm and can be loaded onto the polymeric core with active compounds within or by surface-adsorption. The term "nanoparticle" refers to both Nanocapsules and nanospheres, which are distinguished by morphological structure46. They have shown great potential for targeted delivery of drugs for the treatment of many diseases. Advantages of polymeric NPs as drug carriers include their potential use for controlled release, their ability to protect drugs and other molecules with biological activity against the environment, improve their bioavailability and therapeutic index47. Nanocapsules are composed of an oily core in which the drug is typically dissolved, surrounded by a polymer shell that controls the release profile of the drug from the core. The nanospheres are based on a continuous polymer network in which the drug can be encapsulated or adsorbed on their surface. These two types of polymeric NPs, identified as reservoir system (nanocapsule), and matrix system (nanosphere)48 are shown in Figure 8. In the field of TDDS, polymeric NPs are attracting more attention because they can overcome the limitations of other lipid-based systems, such as by providing protection to volatile drugs against degradation and denaturation, and to reduce side effects by providing sustained drug release that will improves the transdermal penetration of drug by increase in the concentration gradient. Widely used polymeric nanoparticles includes polylactic acid, poly (D, L-lactide-co-glycolide) (PLGA), polycaprolactone, polyacrylic acid and natural poly esters (including chitosan, gelatin and alginate). Therefore, it may be difficult to break down the NPs, which means that drugs can be stored for longer periods of time, followed by its release from the NPs and diffusion into the deeper layers of the skin49.

 

Figure 8: structure of nanocapsule and nanospheres (arrow stands for the presence of drug/bioactive within the nanoparticles)

 

7.     Polymeric Nanofibers:

Polymer nanofibers are fibers with very small fiber diameters of less than 1000nm. They have many unique properties because fibers have very large surface area per unit mass as well as small pore sizes. Nanofibers are designed and they are typically manufactured using a technique called electrospinning. If electrostatic forces overcome the surface tension of a polymer solution, a charged jet shoots out and moves towards a grounded electrode. The electrospun nanofibers can be collected on a substrate located on the counter electrode. Polymer nanofibers present a unique structure for drug delivery applications due to their large loading capacity and ease of manipulation and functionalization. Nanofibers suitable for transdermal drug delivery can be produced using several polymer blends for electrospinning. Both natural-based polymeric nanofibers and synthetic polymeric nanofibers can be used for transdermal drug delivery. Due to their favorable characteristics, such as good biocompatibility, biodegradability and low toxicity, natural polymer nanofibers have attracted considerable interest over synthetic-based nanofibers50,51,52.

 

8.     Nanosuspension/Nanoemulsion:

Biphasic, dispersed, very thin colloidal, solids with a size range below 1μm using polymers and surfactants as a stabilizer to prepare a pharmaceutical nanosuspension either for oral and topical use or in an aqueous vehicle for parenteral and pulmonary administration. In nanosuspension technology, the drug is maintained in the required crystalline state with reduced particle size (i.e. increased surface area) thereby increasing the dissolution rate and hence improving bioavailability.The preparation of nanosuspension can be done using various techniques such as precipitation, high pressure homogenization, emulsion/microemulsion template, media milling and dry co-grinding. All statin drugs have poor aqueous solubility and low oral bioavailability. To overcome such criteria, efforts have been made to improve bioavailability by formulating nanosuspension and delivering them through transdermal systems53,54. Nanoemulsion is thermodynamically stable transparent (translucent) dispersions of oil and water stabilized by an interfacial film of surfactant and cosurfactant. The size of the molecules is less than 100nm55. Nanoemulsion technology has been recognized as the best technology due to its fluid nature, predominant contact with skin cells, small droplet size, efficient permeation capability, even irritation, safety capability to deliver volatile and high molecular weight molecules has been anticipated. The nanoemulsion interacts rapidly with skin cells due to its fluid nature and surfactant/emulsifier interface56. Preparation of nanoemulsion is done using different techniques which are similar to those of nanosuspension. Nanoemulsion based carriers are the most suitable delivery systems for poorly soluble drugs to improve drug solubility, drug permeability and ultimately bioavailability by transdermal therapeutic systems57.

 

9.     Nanocrystals:

Nanocrystals are pure drug particles, with particle sizes ranging from 1 to 1000nm, stabilized by stabilizers that are either polymer or surfactant based. The nanocrystals have the highest drug loading compared to other nanotechnology-based formulations and require less amount of surfactant for stabilization58. There are three types of stabilizers used for nanocrystals formation; Belonging to the first group are ionic stabilizers such as sodium lauryl sulfate (anionic surfactants), second non-ionic stabilizers such as poloxamers and tweens (non-ionic surfactants) and third to polymeric stabilizers such as hydroxyl propyl methylcellulose, polyvinyl alcohol. Polyvinyl Povidone, Hydroxyl Propyl Cellulose, etc. Nanocrystals can enhance the solubility and dissolution rate of poorly water-soluble drugs (especially BCS class II); therefore they are considered as promising novel topical drug delivery systems for dermal applications. They can improve skin coagulation and increase skin permeability and achieve faster skin penetration than conventional topical formulations59,60.The most important mechanism of enhancing nanocrystals skin penetration is an increase in saturation solubility and, therefore, an increase in the concentration gradient leading to higher passive diffusion of active pharmaceuticals through the layers of the skin61. Nanocrystals have a unique characteristic as drug delivery systems, i.e. the ability to load nearly 100% drug because they are formed from pure active pharmaceuticals. They are suitable for dermal delivery of practically insoluble drugs with low dissolution rates, but they have more stability problems such as flocculation and agglomeration which may restrict its application. This problem can be solved by the use of nanosuspension stabilizers62.

 

Evaluation Parameters for TDDS:

Transdermal patches have been developed to improve clinical efficacy of the drug and to enhance patient compliance by delivering smaller amount of drug at a predetermined rate. This makes evaluation studies even more important in order to ensure their desired performance and reproducibility under the specified environmental conditions63. There are evaluation parameters for transdermal dosage forms that can be classified into following types:

·       Physicochemical evaluation

·       In-vitro evaluation

·       In-vivo evaluation

 

Physicochemical evaluation:

1.     Thickness:

The thickness of the transdermal film is determined by a traveling microscope, dial gauge, screw gauge or micrometer at various points on the film and the mean thickness and standard deviation are determined to ensure the thickness of the finished film64,65.

 

 

 

2.     Drug Content:

An accurately weighed portion of the film (approximately 100mg) is dissolved in 100mL of the appropriate solvent in which the drug is soluble and the solution is then incubated in a shaker incubator with constant stirring for 24h. Then the whole solution is sonicated. After sonication and subsequent filtration, the drug in solution is estimated spectrophotometrically by appropriate dilutions66.

 

3.     Tensile Strength:

Tensile strength determined using a modified pulley system. The weight was gradually increased so as to increase the pulley force until the film broke. The percentage elongation before rupture of the film was noted on a graph paper with the help of a magnifying glass and the tensile strength was calculated as kg/mm2. 67

 

4.     Weight Uniformity:

The prepared films are to be dried at 60°C for 4 hr before testing. A specified area of the film is to be cut in different parts of the film and weighed in a digital balance. Average weight and standard deviation values are to be calculated from individual weights68.

 

5.     Folding Endurance:

A strip of specific area is to be cut uniformly and repeatedly folded at the same place till it breaks. The folding endurance value is given by the number of times the film can be folded in one place without breaking69.

 

6.     Shear Adhesion Test:

This test is intended to measure the cohesive strength of an adhesive polymer. This can be affected by the molecular weight, degree of cross-linking, structure of the polymer and type and amount of tack added. An adhesive coated tape is applied to a stainless steel plate. A specified weight is hung from the tape to affect it by pulling in a direction parallel to the plate. The shear adhesion strength is determined by measuring the time it takes to pull the tape from the plate. The longer the removal time, the greater the shear forces70.

 

7.     Water Vapour Permeability (WVP) evaluation:

Water vapor permeability can be determined with the foam dressing method; the air forced oven is replaced by a natural air circulation oven. The WVP can be determined by the following formula

 

WVP = W/A

 

 

 

Where, WVP is expressed in gm/m2 per 24hrs, W is the amount of vapour permeated through the patch expressed in gm/24hrs and A is the surface area of the exposure samples expressed in m2.71

 

8.     Percentage Moisture Content:

The prepared films should be weighed separately and placed in desiccators containing fused calcium chloride at room temperature for 24 hr. films to be re-weighed after 24 hr. The determine the percentage moisture content from the below mentioned formula72,

 

                                   Initial weight – Final weight

% Moisture content = ––––––––––––––––––––––––––––– Χ 100

                                                          Final weight

 

 

9.     Percentage Moisture Uptake:

The weighed films are placed in desiccators at room temperature for 24 h. These are then taken out and exposed to 84% relative humidity using a saturated solution of potassium chloride in desiccators until a constant weight is attained. % moisture uptake is calculated as given below73,74,

 

                                         Final weight – Initial weight

% Moisture uptake = –––––––––––––––––––––––––––– Χ 100

                                                     Initial weight

 

10. Polariscopic examination:

This test is to be done to check for drug crystals from the patch by a polariscope. A specific surface area of ​​the fragment is to be placed on the object slide of a polariscopic and inspected for crystals of the drug to ascertain whether the drug is present in the patch in crystalline form or amorphous form75.

 

11. Flatness Test:

Three longitudinal strips are to be cut from each film in different parts such as one from the centre, the other from the left side and the other from the right side. The length of each strip was measured and variation in length due to uneven flatness was quantified by determining the percentage constriction, with 0% constriction equal to 100% flatness76,

                                     I1 – I2

% Constriction = –––––––––––– Χ 100

                                        I1

 

Where, I1 = Initial length of each strip and I2 = final length of each strip.

 

12. Peel Adhesion Test:

Peel adhesion is the force required to remove an adhesive coating from a substrate. A single tape is applied to the stainless steel plate, then the tape is pulled from the substrate at an angle of 180°, and the required measurement is taken to pull the tape77.

 

13. Rolling ball tack test:

The rolling ball tack test is a measure of polymer softness that is related to interaction. A 7/16 inch diameter stainless steel ball rolled on the inclined track and came into contact with the patch horizontally on the plane. The adhesive layer of the patch is placed on a plane with the top side facing up. Then measure the distance traveled by the ball on the track in inches78.

 

14. Swelling Property:

Patches of 3.14 cm² were weighed and placed in petridishes containing 10 ml of double distilled water and allowed to assimilate. The increase in patch weight was determined at predetermined time intervals, until a stable weight was observed. The degree of swelling (S) was calculated using the formula79,

 

                  Wt – Wo

% S = ––––––––––––––– Χ 100

                       Wo

 

Where, S = Percent swelling, Wt = Weight of patch at time t and Wo = Weight of patch at time zero.

 

15. Skin Irritation Study:

Skin irritation and sensitization tests can be performed on healthy rabbits (average weight 1.2 to 1.5kg). The dorsal surface (50cm2) of the rabbit is to be cleaned and hair is removed from the cleaned dorsal surface by shaving and the surface is cleaned using rectified spirit and the representative formulations can be applied to the skin. The patch is to be removed after 24 hours and the skin is to be inspected and classified into 5 grades depending on the severity of the skin injury80,81.

 

16. In-Vitro Diffusion Study:

A Franz diffusion cell was used for drug release studies from the adhesive matrix. Phosphate buffered saline (PBS; 20ml, pH 7.4) was used as the receptor fluid. The receptor fluid was agitated at 100rpm by a Teflon-coated magnetic stirrer. A 3.14cm section of whole human skin (thickness, 0.2±0.03cm) was cell-mounted with the stratum corneum facing the donor stage. The adhesive matrix was placed on the skin and the cell was maintained at 37±0.5°C during drug release studies. Samples were collected every hour from the sampling port and analyzed at 298nm using a UV/Vis spectrophotometer (Shimadzu). An in-vitro release study was also performed in a similar fashion by omitting the skin for a 12.56cm2 area patch, using a Franz diffusion cell of 50ml capacity82,83.

 

17. In-Vivo Study:

In vivo evaluation is a true depiction of drug performance. Variables that cannot be taken into account during in vitro studies can be fully explored during in vivo studies. In vivo evaluation of TDDS can be done using:

 

a.     Animal Model:

Human studies require considerable time and resources, so small-scale animal studies are preferred. The most common animal species used for evaluating transdermal drug delivery systems are mouse, hairless rat, hairless dog, hairless rhesus monkey, rabbit, guinea pig, etc. Various experiments conducted lead us to a conclusion that hairless animals are preferred over hairy animals in both in vitro and in vivo experiments. The rhesus monkey is one of the most reliable models for in-vivo evaluation of transdermal drug delivery in humans.

 

b.    Human Model:

Clinical trials have been conducted to assess the efficacy, risks involved, side effects, patient compliance etc. The final phase of development of the transdermal device involves the collection of pharmacokinetic and pharmacodynamic data following application of the patch to human volunteers. Therefore, phase I clinical trials are conducted primarily to determine safety in volunteers and Phase II clinical trials determine short-term safety and primarily effectiveness in patients. Clinical trial phase III indicates safety and effectiveness in a large patient population and phase IV clinical trial in post marketing surveillance is carried out for the marketed transdermal film to detect adverse drug reactions84.

 

18. Stability Study:

Stability studies are to be carried out as per ICH guidelines by storing TDDS samples at 40±0.5°c and 75±5% RH for 6 months. Samples withdrawn at 0, 30, 60, 90 and 180 days appropriate to analyzed the drug content85,86.

 

The Future Perspectives of the TDDS:

Future development of TDDS will focus on the increased control of therapeutic regulations and the continued expansion of drugs available for use. In recent years, there has been an increase in the scale of TDDS in the domestic and foreign drug delivery systems market, as confirmed through increasing research studies, patents, and commercially available products from several companies and research institutes87. Expanding the use of novel permeation enhancement techniques with macromolecules and other conventional molecules to a wider range of indications is highly desirable for the transdermal industry. One can also expect that the first transdermal prodrugs products will emerge on the market in the near future88. New prodrugs will not only help reach therapeutic levels of certain drugs, but may also help reduce skin irritation. Physical enhancement methods have greatly improved the rate of delivery of therapeutic agents into the skin and reduced skin irritation response with the increase in availability of physical permeation enhancement methods such as iontophoresis, electroporation and sonophoresis. Currently, many of them are under extensive investigation and new tools based on TDDS can be expected in the near future.

 

CONCLUSION:

Transdermal drug delivery systems are a painless, convenient, and potentially effective method of delivering regular doses of medication. Drugs that show hepatic first pass effect and are unstable under GI conditions are suitable candidates for TDDS. In the present scenario skin was found to be the safest and most acceptable route of drug delivery for systemic circulation as compared to oral route. The aim of this study is to deliver drug across the skin barrier with the help of transdermal nanocarrier delivery system. The skin is a natural barrier that restricts the penetration of drugs. Therefore, transdermal nanocarrier delivery systems are one of the biggest challenges to deliver drug into the systemic circulation by crossing the skin barrier. According to this study, various types of nanocarriers have been investigated for transdermal drug delivery systems in terms of enhancing skin permeability. The selection of a suitable nanocarrier for transdermal delivery purposes depends on studies such as extreme permeability enhancement, targeted delivery across the skin and the nature of the active pharmaceuticals that can be encapsulated. The compatibility of the nanocarrier nature with the skin structure should be considered in transdermal nanocarrier delivery systems. Transdermal route will be most preferred for drug delivery in future due to higher patient compliance, controlled dosage, less frequency of dosing, high physico-chemical stability, improved dermal bioavailability, etc.

 

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Received on 06.04.2023         Accepted on 12.06.2023        

Accepted on 04.07.2023        ©A&V Publications all right reserved

Research J. Topical and Cosmetic Sci. 2023; 14(2):94-104.

DOI: 10.52711/2321-5844.2023.00015