Penetration enhancers (also called chemical penetration enhancers, absorption enhancers or sorption promotors) are chemical compounds that can facilitate the penetration of

active pharmaceutical ingredients An active ingredient is any ingredient that provides biologically active or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals. ...

(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 Transdermal drug delivery techniques include: * Cream (pharmaceutical), Cream * Dimethyl sulfoxide, DMSO solution * Hydrogel * Iontophoresis (using electricity) * Jet injector * Liniment * Lip balm * Liposomes * Lotion * Medicated shampoo * Ointme ...

and transmucosal drug delivery (for example, ocular, nasal, oral and buccal). They typically penetrate into the biological membranes and reversibly decrease their barrier properties.

Transdermal drug delivery

Human skin 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 (biology), tissue guarding Skeletal muscle, muscles, bones, ligaments and organ (anato ...

is a very impermeable membrane that protects the body from ingress of harmful substances and prevents water loss from underlying organs. However, this seriously limits the use of skin as a site for drug administration. One of the approaches to facilitate

is the use of penetration enhancers. Many different compounds have been explored as potential penetration enhancers to facilitate transdermal drug delivery. These include dimethylsulphoxide,

azone Azone () is a term in mythology anciently applied to gods and goddesses that were not the private divinities of any particular country or people. Azones were acknowledged as deities in every country, and worshipped in every nation. The word is etym ...

s (such as laurocapram), pyrrolidones (for example

2-pyrrolidone 2-Pyrrolidone, also known as 2-pyrrolidinone or butyrolactam, is an organic compound consisting of a 5-membered lactam, making it the simplest γ-lactam. It is a colorless liquid that is miscible with water and most common organic solvents. 2-Py ...

), alcohols (

ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

and

decanol 1-Decanol is a straight chain fatty alcohol with ten carbon atoms and the molecular formula C10H21OH. It is a colorless to light yellow viscous liquid that is insoluble in water and has an aromatic odor. The interfacial tension against water at 20 ...

glycol A diol is a chemical compound containing two hydroxyl groups ( groups). An aliphatic diol may also be called a glycol. This pairing of functional groups is pervasive, and many subcategories have been identified. They are used as protecting gro ...

s (for example

propylene glycol Propylene glycol ( IUPAC name: propane-1,2-diol) is a viscous, colorless liquid. It is almost odorless and has a faintly sweet taste. Its chemical formula is CH3CH(OH)CH2OH. As it contains two alcohol groups, it is classified as a diol. An al ...

), surfactants,

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

, various hydrocarbons and terpenes. Different potential skin site and modes of action were identified for penetration enhancement through the skin. In some cases, penetration enhancers may disrupt the packing motif of the intercellular lipid matrix or

keratin Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. It is the key structural material making up Scale (anatomy), scales, hair, Nail (anatomy), nails, feathers, horn (anatomy), horns, claws, Hoof, hoove ...

domains. In other cases, drug penetration to the skin is facilitated because the penetration enhancer saturates the tissue and becomes a better system to dissolve the molecules of API.

Ocular drug delivery

Topical administration to the eye is usually characterised by very poor drug bioavailability due to several natural defence mechanisms, including nasolacrymal drainage,

blink Blinking is a bodily function; it is a semi-autonomic rapid closing of the eyelid. A single blink is determined by the forceful closing of the eyelid or inactivation of the levator palpebrae superioris and the activation of the palpebral por ...

ing, and poor permeability of the

cornea The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...

. Enhancement of the corneal permeability to drug molecules is one of the strategies to improve the efficiency of topical drug delivery to the eye. Several classes of compounds have been researched as potential penetration enhancers through ocular membranes. These include

chelating agent Chelation () is a type of bonding of ions and their molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These l ...

cyclodextrin Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocycle, macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds. Cyclodextrins are produced from starch by enzyme, enzymatic conversion. They are used in ...

s, surfactants,

bile acid Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver in peroxisomes. Bile acids are conjugated with taurine or glycine residues to give anions called bile ...

s and salts, and

crown ether In organic chemistry, crown ethers are cyclic chemical compounds that consist of a ring containing several ether groups (). The most common crown ethers are cyclic oligomers of ethylene oxide, the repeating unit being ethyleneoxy, i.e., . Impor ...

s. There are also reports on the use of cell penetrating peptides and chitosan as penetration enhancers in ocular drug delivery. The most commonly used penetration enhancers in ocular formulations are benzalkonium chloride and

ethylenediamine Ethylenediamine (abbreviated as en when a ligand) is the organic compound with the formula C2H4(NH2)2. This colorless liquid with an ammonia-like odor is a basic amine. It is a widely used building block in chemical synthesis, with approximately ...

tetraacetate (EDTA).

Benzalkonium chloride Benzalkonium chloride (BZK, BKC, BAK, BAC), also known as alkyldimethylbenzylammonium chloride (ADBAC) is a type of cationic surfactant. It is an organic salt classified as a quaternary ammonium compound. ADBACs have three main categories of use: ...

is often used as an antimicrobial preservative in eye drops and EDTA is used as a chelating agent.

Nasal drug delivery

Cyclodextrins,

chitosan Chitosan is a linear polysaccharide composed of randomly distributed β-(1→4)-linked D-glucosamine (deacetylated unit) and ''N''-acetyl-D-glucosamine (acetylated unit). It is made by treating the chitin shells of shrimp and other crusta ...

, some

surfactant Surfactants are chemical compounds that decrease the surface tension or interfacial tension between two liquids, a liquid and a gas, or a liquid and a solid. The word ''surfactant'' is a Blend word, blend of "surface-active agent", coined in ...

s and salts, sodium tauro-24,25-dihydro-fusidate, and

phospholipid Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

s were reported as penetration enhancers in nasal drug delivery both for humans and equines. Chitosan is one of the most widely researched penetration enhancers in nasal drug delivery and it enhances the penetration of drugs by opening the

tight junction Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein Cell junction, junctional complexes between epithelial cells, sealing and preventing leakage of solutes and water. Th ...

s in the cell membranes.

Oral drug delivery

Penetration enhancers have been applied to improve the absorption of poorly permeable, hydrophilic drugs or macromolecules.

Permeation In physics and engineering, permeation (also called imbuing) is the penetration of a wikt:permeate#English, permeate (a fluid such as a liquid, gas, or vapor) through a solid. It is directly related to the concentration gradient of the permeate, ...

enhancers that have been used successfully for oral drug development include

medium-chain fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...

s such as

caprylic acid Caprylic acid (), also known under the systematic name octanoic acid or C8 Acid, is a saturated fatty acid, medium-chain fatty acid (MCFA). It has the structural formula , and is a colorless oily liquid that is minimally soluble in water with ...

(caprate) or one of its amino acid esters such as

salcaprozate sodium Salcaprozate sodium (SNAC) is an intestinal permeation enhancer that is used in drug formulations particularly for macromolecules and poorly permeable compounds. SNAC has been used in formulations of drugs that have undergone clinical trials and ...

(SNAC). The above-mentioned permeation/penetration enhancers have a surfactant-like activity where they perturb the intestinal epithelium, promoting transcellular or paracellular absorption.

References

{{reflist Pharmacology