Invasomes

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Invasome Invasome.png
Invasome

An invasome are a type of artificial vesicle nanocarrier that transport substances through the skin, the most superficial biological barrier. Vesicles are small particles surrounded by a lipid layer that can carry substances into and out of the cell. Artificial vesicles can be engineered to deliver drugs within the cell, with specific applications within transdermal drug delivery. However, the skin proves to be a barrier to effective penetration and delivery of drug therapies. Thus, invasomes are a new generation of vesicle with added structural components to assist with skin penetration. [1]

Contents

Transdermal drug delivery

Transdermal drug delivery (TDD) systems aim to deliver drug therapies topically for local and systemic delivery. They have been gaining increasing attention within the field of drug delivery because of their potential to improve bioavailability, reduce side effects, and avoid first pass metabolism, compared to oral medications. However, TDD systems face the challenge of overcoming the barrier of the topmost skin layer, the stratum corneum. [2]

Skin barrier

Anatomy of the skin, including the stratum corneum (SC) layer Anatomy of the skin de.jpg
Anatomy of the skin, including the stratum corneum (SC) layer

Transdermal drug delivery systems are methods to transport drug therapies across the skin barrier. The skin is the largest organ of the body and its primary aim is to protect the body against chemical, thermal, radiation, and microbial threats. However, it is not completely waterproof, allowing some exchange of gas, heat, and fluids from its external environment. [3]

To effectively shield against external injuries, the skin is composed of several layers: the three distinguishing layers are the epidermis, the dermis, and the subcutaneous layer, or hypodermis. The bottommost layer is the hypodermis. It is primarily composed of adipose tissue. Next is the dermis, a 3-5 mm thick layer made up of fibrous proteins, an interfibrillar gel, salts, and water. The epidermis is the topmost layer of skin and where vascularization ends. Due to the lack of vascularization, the transfer of fluids, nutrients, and waste across the epidermis occurs through the epidermal-dermal junction. [4] [5] The epidermis is further divided into five layers. From innermost to outermost is the germinative stratum, the spinous stratum, the granular stratum, the lucid stratum, and the stratum corneum. The majority of the epidermis is composed of corneocytes, which develop from the proliferation, differentiation, and keratinization of keratinocytes. These fundamental skin cells continually renew as they move upwards toward the surface of the skin. [3] [5] The stratum corneum is a 10-15 μm thick layer of dead keratin-rich corneocytes tightly packed within a lipid-rich matrix, often described and depicted as a brick-and-mortar structure. [5]

Penetration routes for transdermal drug delivery

Intercellular and transcellular penetration routes through the stratum corneum Transdermal penetration routes.png
Intercellular and transcellular penetration routes through the stratum corneum

Penetration of the stratum corneum is recognized as the largest challenge of TDD. Due to its tight cell structure, it is the rate limiting barrier for drug absorption. Thus, several methods of penetrating the stratum corneum have been explored. A couple of common methods include delivery through the intercellular route and the transcellular route. The roundabout, intercellular route seeks to bypass the corneocytes by transporting molecules through the lipid-rich intercellular space between the cells. The transcellular route seeks to transport molecules directly through the cells of the stratum corneum. In this method, molecules must travel through both corneocytes and the intercellular lipid space. The method of choice is dependent on physical and chemical properties of the transporting compounds; however, the intercellular route is the most common. Thus, the intercellular lipid barrier has been a subject of investigation to allow for greater understanding of how to develop transportation mechanisms of molecules through the stratum corneum. [3] [5]

Methods for increased transdermal penetration

In recent decades, due to the increasing use of therapeutic medications through transdermal pathways, techniques for improving permeation through the stratum corneum have been explored. The primary two routes of exploration have been chemical and physical penetration-enhancing mechanisms. [6]

A brief overview of physical penetration methods are summarized in the table below.

MethodDescription
Iontophoresis Application of an electrical charge to the skin to allow percutaneous penetration of charged particles. [7]
Electroporation Application of a voltage to the skin that surpasses the cell membrane barrier for drug permeation. [8]
Sonophoresis Application of an ultrasound at the skin to overcome the skin barrier. [9]
Microneedles Application of micro-sized needles to bypass the stratum corneum for drug delivery, with the intention of decreasing pain and improving patient compliance. [10]
MagnetophoresisApplication of a magnetic field to increase skin permeability. [11]
Stratum corneum ablationRemoval of the stratum corneum through various techniques. These include through radiofrequency, laser, microwave, ultrasound, cryoablation, and chemical ablation. [12]

Chemical characteristics to enhance drug delivery include incorporating salt formations, drug-ion pairs, eutectic mixtures, chemical penetration enhancers, and utilizing liposomal vesicles. [13] Vesicles have shown the ability to be paired with current physical penetration techniques to synergistically improve drug penetration. [2] [14] [15]

Invasome characteristics

Other vesicular systems, such as liposomes and ethosomes, have already been extensively researched and utilized as drug transporters, but the penetration barrier has resulted in studies to modify current vesicles to add characteristics for improved penetration of the stratum corneum. [1]

Invasome vesicular systems are artificial vesicles composed of phospholipids, terpene, and ethanol. [1] A phospholipid bilayer creates the external structure of the spherical particle. Within the bilayer are terpenes. Terpenes are naturally-occurring hydrocarbon chains that are commonly used in aromatics and scent products, but also have been used for the development of pharmaceuticals. Within the center of the terpene-and-phospholipid bilayer is a core that contains an aqueous hydroethanolic solution, along with the relevant drug. [1] [2]

Invasome penetration

Compared with other vesicular systems, the terpenes and ethanol function synergistically to increase the flexibility of invasomes, which allows for a softer, fluidic structure that increases penetration efficacy of the skin barrier.[ citation needed ]

Terpenes

Terpenes are known to be effective penetration enhancers. They function in invasomes by breaking apart the tight phospholipid structure of the stratum corneum, increasing the permeability of the intercellular space. [1]

Ethanol

Like terpenes, ethanol has also been shown to disrupt the lipid structure of the stratum corneum, as well as loosening the invasome phospholipid bilayer. Ethanol also softens the lipids which increases the deformability of invasomes, allowing them to flatten to travel through the tight intercellular spaces of the skin. [16]

Penetration mechanism

The terpenes and ethanol have been shown to loosen the invasome's phospholipid structure, allowing some of the terpenes and ethanolic solution to leak out of the invasome. There, they also separate the lipids of the stratum corneum. The smaller, flexible invasome is then able to travel intercellularly, passing through the stratum corneum to the viable cell layer where the drug is released and reaches systemic circulation. Thus, the terpenes and ethanol work in conjunction to both break up the phospholipids of the invasome they inhabit so they can pass through, as well as loosen the tight cellular matrix of the stratum corneum, giving the already-flexible invasomes an increased penetration ability. [16] [17]

Invasome preparation

Several preparation techniques of invasomes exist, but the most commonly used techniques are mechanical dispersion and thin-film hydration. [18]

Mechanical dispersion

During lipid dispersion, the lipid and organic solvent are added with a drug of choice; then the solution is vortexed and sonicated for five minutes. PBS is added to the solution with additional vortexing, and then an aqueous buffer is used to hydrate the mixture. The spontaneous swelling of the lipids then creates the invasome vesicles, which are finally sonicated, lyophilized, and experience high-pressure extrusion. [18]

Thin-film hydration

During thin-film hydration, also known as the conventional film method, [16] lipids and drugs are added to ethanol and sonicated. A rotary flash evaporator is used to dry the mixture; nitrogen gas is used to remove harmful residual solvent. The resulting thin lipid films are hydrated using a PBS, and after cooling the terpene mixture is added to form the invasomes. Finally, the invasome solution is vortexed and ultrasonicated. [18]

Applications

Pharmaceutical applications

Invasomes have been considered in a range of applications. Apart from cosmetics, they are increasingly becoming a part of pharmaceuticals and drug delivery research. Areas for use include delivery of immunosuppressive, anticancer, antiacne, contraceptive, erectile dysfunction, antihypertensive, alopecia, and antipsychotic drug therapies. [18] [19] [20]

Drug delivery methods

Cream, patch, and microneedles as transdermal drug delivery methods Skhematichnoe izobrazhenie glubiny vvedeniia aktivnoi substantsii.png
Cream, patch, and microneedles as transdermal drug delivery methods

Invasomes can be paired with transdermal delivery methods to target the skin barrier. Examples of these techniques include transdermal patches, microneedles, and creams.

Transdermal patches are medicated adhesives that can be applied to the skin. Compared to conventional hypodermic needles and oral delivery methods, patches allow for controlled release of drugs through the skin using built-in release mechanisms that allow drug reservoirs to discharge. Additionally, patches can be paired with microneedles to increase drug absorption. [21]

Microneedles are minimally invasive arrays of needles that bypass the stratum corneum. They can range in length from a few micrometers up to 2000 μm, with the needles existing in several forms: solid, coated, dissolving, hollow, and hydrogel-forming. [22] [23]

Medical creams have been used for centuries due to their relative simplicity, ease of preparation, and ease of use. They are medically-treated, semi-solid formulations for topical drug delivery. Benefits of creams include increased patient compliance and avoidance of first pass metabolism. [24] [25]

Related Research Articles

<span class="mw-page-title-main">Epidermis</span> Outermost of the three layers that make up the skin

The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water released from the body into the atmosphere through transepidermal water loss.

<span class="mw-page-title-main">Vernix caseosa</span> Waxy white substance found coating the skin of newborn human babies

Vernix caseosa, also known as vernix, is the waxy white substance found coating the skin of newborn human babies. It is produced by dedicated cells and is thought to have some protective roles during fetal development and for a few hours after birth.

<span class="mw-page-title-main">Liposome</span> Composite structures made of phospholipids and may contain small amounts of other molecules

A liposome is a small artificial vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, liposomes can be used as drug delivery vehicles for administration of pharmaceutical drugs and nutrients, such as lipid nanoparticles in mRNA vaccines, and DNA vaccines. Liposomes can be prepared by disrupting biological membranes.

<span class="mw-page-title-main">Transdermal patch</span> Adhesive patch used to deliver medication through the skin

A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. An advantage of a transdermal drug delivery route over other types of medication delivery is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. The main disadvantage to transdermal delivery systems stems from the fact that the skin is a very effective barrier; as a result, only medications whose molecules are small enough to penetrate the skin can be delivered by this method. The first commercially available prescription patch was approved by the U.S. Food and Drug Administration in December 1979. These patches administered scopolamine for motion sickness.

<span class="mw-page-title-main">Stratum corneum</span> Outermost layer of the epidermis

The stratum corneum is the outermost layer of the epidermis. Consisting of dead tissue, it protects underlying tissue from infection, dehydration, chemicals and mechanical stress. It is composed of 15–20 layers of flattened cells with no nuclei and cell organelles.

<span class="mw-page-title-main">Desquamation</span> Medical condition

Desquamation, or peeling skin, is the shedding of dead cells from the outermost layer of skin.

<span class="mw-page-title-main">Drug delivery</span> Methods for delivering drugs to target sites

Drug delivery refers to approaches, formulations, manufacturing techniques, storage systems, and technologies involved in transporting a pharmaceutical compound to its target site to achieve a desired therapeutic effect. Principles related to drug preparation, route of administration, site-specific targeting, metabolism, and toxicity are used to optimize efficacy and safety, and to improve patient convenience and compliance. Drug delivery is aimed at altering a drug's pharmacokinetics and specificity by formulating it with different excipients, drug carriers, and medical devices. There is additional emphasis on increasing the bioavailability and duration of action of a drug to improve therapeutic outcomes. Some research has also been focused on improving safety for the person administering the medication. For example, several types of microneedle patches have been developed for administering vaccines and other medications to reduce the risk of needlestick injury.

Sonophoresis also known as phonophoresis, is a method that utilizes ultrasound to enhance the delivery of topical medications through the stratum corneum, to the epidermis and dermis. Sonophoresis allows for the enhancement of the permeability of the skin along with other modalities, such as iontophoresis, to deliver drugs with lesser side effects. Currently, sonophoresis is used widely in transdermal drug delivery, but has potential applications in other sectors of drug delivery, such as the delivery of drugs to the eye and brain.

<span class="mw-page-title-main">Human skin</span> Organ covering the outside of the human body

The human skin is the outer covering of the body and is the largest organ of the integumentary system. The skin has up to seven layers of ectodermal tissue guarding muscles, bones, ligaments and internal organs. Human skin is similar to most of the other mammals' skin, and it is very similar to pig skin. Though nearly all human skin is covered with hair follicles, it can appear hairless. There are two general types of skin: hairy and glabrous skin (hairless). The adjective cutaneous literally means "of the skin".

<span class="mw-page-title-main">Transdermal</span> Method of drug administration

Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery. The drug is administered in the form of a patch or ointment that delivers the drug into the circulation for systemic effect.

<span class="mw-page-title-main">Phonophoresis</span>

Phonophoresis, also known as sonophoresis, is the method of using ultrasound waves to increase skin permeability in order to improve the effectiveness of transdermal drug delivery. This method intersects drug delivery and ultrasound therapy. By assisting transdermal drug delivery, phonophoresis can be a painless treatment and an alternative to a needle.

Corneocytes are terminally differentiated keratinocytes and compose most of the stratum corneum, the outermost layer of the epidermis. They are regularly replaced through desquamation and renewal from lower epidermal layers and are essential for its function as a skin barrier.

<span class="mw-page-title-main">Niosome</span> Non-ionic surfactant-based vesicle

Niosomes are vesicles composed of non-ionic surfactants, incorporating cholesterol as an excipient. Niosomes are utilized for drug delivery to specific sites to achieve desired therapeutic effects. Structurally, niosomes are similar to liposomes as both consist of a lipid bilayer. However, niosomes are more stable than liposomes during formation processes and storage. Niosomes trap hydrophilic and lipophilic drugs, either in an aqueous compartment or in a vesicular membrane compartment composed of lipid material.

<span class="mw-page-title-main">Ethosome</span>

Ethosomes are phospholipid nanovesicles used for dermal and transdermal delivery of molecules. Ethosomes were developed by Touitou et al.,1997, as additional novel lipid carriers composed of ethanol, phospholipids, and water. They are reported to improve the skin delivery of various drugs. Ethanol is an efficient permeation enhancer that is believed to act by affecting the intercellular region of the stratum corneum. Ethosomes are soft malleable vesicles composed mainly of phospholipids, ethanol, and water. These soft vesicles represent novel vesicles carriers for enhanced delivery through the skin. The size of the ethosomes vesicles can be modulated from tens of nanometers to microns.

<span class="mw-page-title-main">Microneedle drug delivery</span> System for vaccination

Microneedles or Microneedle patches or Microarray patches are micron-scaled medical devices used to administer vaccines, drugs, and other therapeutic agents. While microneedles were initially explored for transdermal drug delivery applications, their use has been extended for the intraocular, vaginal, transungual, cardiac, vascular, gastrointestinal, and intracochlear delivery of drugs. Microneedles are constructed through various methods, usually involving photolithographic processes or micromolding. These methods involve etching microscopic structure into resin or silicon in order to cast microneedles. Microneedles are made from a variety of material ranging from silicon, titanium, stainless steel, and polymers. Some microneedles are made of a drug to be delivered to the body but are shaped into a needle so they will penetrate the skin. The microneedles range in size, shape, and function but are all used as an alternative to other delivery methods like the conventional hypodermic needle or other injection apparatus.

<span class="mw-page-title-main">Topical cream formulation</span>

Topical cream formulation is an emulsion semisolid dosage form that is used for skin external application. Most of the topical cream formulations contain more than 20 per cent of water and volatiles and/or less than 50 per cent of hydrocarbons, waxes, or polyethylene glycols as the vehicle for external skin application. In a topical cream formulation, ingredients are dissolved or dispersed in either a water-in-oil (W/O) emulsion or an oil-in-water (O/W) emulsion. The topical cream formulation has a higher content of oily substance than gel, but a lower content of oily ingredient than ointment. Therefore, the viscosity of topical cream formulation lies between gel and ointment. The pharmacological effect of the topical cream formulation is confined to the skin surface or within the skin. Topical cream formulation penetrates through the skin by transcellular route, intercellular route, or trans-appendageal route. Topical cream formulation is used for a wide range of diseases and conditions, including atopic dermatitis (eczema), psoriasis, skin infection, acne, and wart. Excipients found in a topical cream formulation include thickeners, emulsifying agents, preservatives, antioxidants, and buffer agents. Steps required to manufacture a topical cream formulation include excipient dissolution, phase mixing, introduction of active substances, and homogenization of the product mixture.

Topical drug delivery (TDD) is a route of drug administration that allows the topical formulation to be delivered across the skin upon application, hence producing a localized effect to treat skin disorders like eczema. The formulation of topical drugs can be classified into corticosteroids, antibiotics, antiseptics, and anti-fungal. The mechanism of topical delivery includes the diffusion and metabolism of drugs in the skin. Historically, topical route was the first route of medication used to deliver drugs in humans in ancient Egyptian and Babylonian in 3000 BCE. In these ancient cities, topical medications like ointments and potions were used on the skin. The delivery of topical drugs needs to pass through multiple skin layers and undergo pharmacokinetics, hence factor like dermal diseases minimize the bioavailability of the topical drugs. The wide use of topical drugs leads to the advancement in topical drug delivery. These advancements are used to enhance the delivery of topical medications to the skin by using chemical and physical agents. For chemical agents, carriers like liposomes and nanotechnologies are used to enhance the absorption of topical drugs. On the other hand, physical agents, like micro-needles is other approach for enhancement ofabsorption. Besides using carriers, other factors such as pH, lipophilicity, and drug molecule size govern the effectiveness of topical formulation.

Penetration enhancers are chemical compounds that can facilitate the penetration of active pharmaceutical ingredients (API) into or through the poorly permeable biological membranes. These compounds are used in some pharmaceutical formulations to enhance the penetration of APIs in transdermal drug delivery and transmucosal drug delivery. They typically penetrate into the biological membranes and reversibly decrease their barrier properties.

Laser-assisted drug delivery (LADD) is a drug delivery technique commonly used in the dermatology field that involves lasers. As skin acts as a protective barrier to the environment, the absorption of topical products through the epidermis is limited; thus, different drug delivery modalities have been employed to improve the efficacy of these treatments. The use of lasers in LADD has been shown to enhance the penetration of drugs transdermal, leading to a higher absorption rate, limited systemic effects, and reduced duration of treatment. Although this technique has evolved in the past decade due to its efficacy through scientific research and clinical practice, there remain some limitations regarding the safety aspect that needs to be taken into consideration.

Microneedles (MNs) are medical instruments for the procedure of microneedling that are most commonly used in drug delivery, disease diagnosis, and collagen induction therapy. They are known for being minimally invasive and precise. MNs consist of arrays of micro-sized needles ranging from 25μm-2000μm. The concept of microneedling was first established in the 1970s, but its popularity began to rise as they have been found to be effective in drug delivery and possess cosmetic benefits.

References

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  20. ↑ Teaima, Mahmoud H.; Eltabeeb, Moaz A.; El-Nabarawi, Mohamed A.; Abdellatif, Menna M. (2022-12-31). "Utilization of propranolol hydrochloride mucoadhesive invasomes as a locally acting contraceptive: in-vitro, ex-vivo, and in-vivo evaluation". Drug Delivery. 29 (1): 2549–2560. doi:10.1080/10717544.2022.2100514. ISSN   1071-7544. PMC   9347470 . PMID   35912869.
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  25. ↑ Sahu, T; Patel; Sahu; Gidwani (25 Aug 2016). "Skin Cream as Topical Drug Delivery System: A Review". Journal of Pharmaceutical and Biological Sciences. 4 (5): 149–154.
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