PENETRATION ENHANCEMENT THROUGH OPTIMISATION OF DRUG AND VEHICLE PROPERTIES⁴

Penetration of drug through the skin across the stratum corneum that obeys Fick’s first law equation is

Where,

J= steady-state flux (J)

D= the diffusion coefficient of the drug in the

stratum corneum

h= path length or membrane thickness

p= partition coefficient between the stratum

corneum and the vehicle,

c₀= applied drug concentration (C₀) which is

assumed to be constant:

Fick’s first law equation aids in identifying the ideal parameters for drug diffusion across the skin. Katz and Poulsen described tha the influence of solubility and partition coefficient of a drug on diffusion across the stratum corneum. Molecules showing intermediate partition coefficients (log Poctanol/water of 1-3) have adequate solubility within the lipid domains of the stratum corneum to permit diffusion through this domain whilst still having sufficient hydrophilic nature to allow partitioning into the viable tissues of the epidermis. For example a parabolic relationship was obtained between skin permeability and partition coefficient for a series of salicylates and nonsteroidal anti-inflammatory drugs. The maximum permeability measurement being attained at log P value 2.5, which is typical of these types of experiments. Optimal permeability has been shown to be related to low molecular size (ideally less than 500 Da) as this affects diffusion coefficient, and low melting point which is related to solubility. When a drug possesses these ideal characteristics (as in the case of nicotine and nitroglycerin), transdermal delivery is feasible. However, where a drug does not possess ideal physicochemical properties, manipulation of the drug or vehicle to enhance diffusion, becomes necessary.

Properties of Penetration Enhancers:

Desirable properties for penetration enhancers acting within the skin have been given as

Ø They should be non-toxic, non-irritating and non-allergenic.

Ø They would ideally work rapidly, and the activity and duration of effect should be both predictable and reproducible.

Ø They should have no pharmacological activity within the body.

Ø The penetration enhancers should work unidirectional i.e. should allow therapeutic agents into the body whilst preventing the loss of endogenous material from the body.

Ø The penetration enhancers should be compatible with both excipients and drugs.

Ø They should be cosmetically acceptable with an appropriate skin ‘feel’.

MECHANISM OF PENETRATION ENHANCEMENT BY STRATUM CORNEUM MODIFICATION ⁵:-

Chemicals reduce the barrier capability of the stratum corneum in order to promote skin penetration. The enhancer activity of many classes of chemicals has been tested including water, surfactants, essential oils and terpenes, alcohols, dimethyl sulfoxide (DMSO), azone analogues. In addition some chemicals have been identified as penetration retarders. The activity of penetration enhancers may be expressed in terms of an enhancement ratio (ER):

ER = Drug permeability coefficient after enhancer treatment/Drug permeability coefficient before enhancer treatment

Penetration enhancement may takes place by any one of the following mechanism:

1. Hydration

Water is the most widely used and safest method to increase skin penetration of both hydrophilic and lipophilic permeants. The water content of the stratum corneum is around 15 to 20% of the dry weight but can vary according to humidity of the external environment. Additional water within the stratum corneum could alter permeant solubility and thereby modify partitioning from the vehicle into the membrane. In addition, increased skin hydration may swell and open the structure of the stratum corneum leading to an increase in penetration, although this has yet to be demonstrated experimentally. For example, Scheuplein and Blank showed that the diffusion coefficients of alcohols in hydrated skin were ten times that observed in dry skin. Hydration can be increased by occlusion with plastic films; paraffin, oils, waxes as components of ointments and water-in-oil emulsions that prevent transepidermal water loss; and oil-in-water emulsions that donate water. Of these, occlusive films of plastic or oily vehicle have the most profound effect on hydration and penetration rate. A commercial example of this is the use of an occlusive dressing to enhance skin penetration of lignocaine and prilocane from EMLA cream in order to provide sufficient local anesthesia within about 1 hour. Also drug delivery from many transdermal patches benefits from occlusion.

2. Lipid Disruption/ Fluidisation by Chemical Penetration Enhancers

Many enhancers, such as Azone, DMSO, alcohols, fatty acids and terpenes, have been shown to increase permeability by disordering or ‘fluidising’ the lipid structure of the stratum corneum. The diffusion coefficient in of a drug is increased as the enhancer molecules form microcavities within the lipid bilayers hence increasing the free volume fraction. In some cases the enhancers penetrate into and mix homogeneously with the lipids. However, others such as oleic acid and terpenes, particularly at high concentration, pool within the lipid domains to create permeable ‘pores’ that provide less resistance for polar molecules. These effects have been demonstrated using differential scanning calorimetry (DSC) to measure the phase transition temperature electron spin resonance (ESR) studies fourier transform infrared (FTIR), Raman spectroscopy and x-ray diffractometry . These enhancer compounds consist of a polar head group with a long alkyl chain and are more effective for hydrophilic permeants, although increased delivery of lipophilic permeants has also been reported. It has been hypothesised that the enhancement effect of Azone is related to its ability to exist in a ‘bent spoon’ conformation with the ring at a right angle to the hydrocarbon chain. Permeability enhancement would result from its ability to intercalate between stratum corneum ceramides to create spatial disruption.

3. Interaction with Keratin

In addition to their effect on stratum corneum lipids, chemicals such as DMSO, decylmethylsulphoxide, urea and surfactants also interact with keratin in the corneocytes . It has been suggested that penetration of a surfactant into the intracellular matrix of the stratum corneum, followed by interaction and binding with the keratin filaments, may result in a disruption of order within the corneocyte. This causes an increase in diffusion coefficient, and hence increases permeability. However in many studies of surfactants, a close relationship between permeation enhancement and lipid bilayer fluidisation has been observed suggesting that the lipid lamellae of the stratum corneum rather than the keratin of the corneocytes is the main site of action Barry suggested that these molecules may also modify peptide/protein material in the lipid bilayer domain to enhance permeability. Again, there are problems with skin irritancy associated with many of these chemicals.

4. Increased Partitioning and Solubility in Stratum Corneum

A number of solvents (such as ethanol, propylene glycol and N-methyl pyrrolidone) increase permeant partitioning into and solubility within the stratum corneum, hence increasing P in Fick’s equation. Indeed, ethanol was the first penetration enhancer-cosolvent incorporated into transdermal systems. It has been shown that a solvent capable of shifting the solubility parameter of the skin closer to that of the permeant will increase permeant solubility in the stratum corneum and hence flux.

5. Combined Mechanisms

Fick’s law shows that a combination of enhancement effects on diffusivity (D) and partitioning (K) will result in a multiplicative effect. Synergistic effects have been demonstrated for many combinations, such as Azone and propylene glycol , Azone and Transcutol , oleic acid and propylene glycol , terpenes and propylene glycol , various combinations and alcohols eg. N-methylpyrrolidone and propylene glycol , urea analogues and propylene glycol , supersaturation and oleic acid . In these cases, synergism results from the combined effects of the enhancer and solvent acting by different mechanisms. It is likely that the cosolvent, such as propylene glycol, acts to increase the concentration of both the permeant and the enhancer in the stratum corneum. In addition, the lipid fluidising effect of the enhancer will increase the free volume within the lipid bilayers thereby facilitating partitioning of both the permeant and solvent. Harrison and coworkers used attenuated total reflectance-fourier transform infra-red (ATR-FTIR) spectroscopy to deconvolute the effects of Azone and Transcutol on the skin. Using cyanophenol as a model permeant, they showed that Azone acted on lipid fluidity to increase diffusivity by a factor of whilst Transcutol had a similar effect by increasing solubility in the stratum corneum. Some enhancers act inherently by multiple mechanisms. For example, high concentrations of DMSO (above 60%) disturb intercellular organisation, extract stratum corneum lipids, interact with keratin and facilitate lipid drug partitioning .

TYPES OF PENETRATION ENHANCERS:-

There arethree types of penetration enhancers.

I. Physical and electrical enhancers.

II. Chemical enhancers.

III. Miscellaneous enhancers.

I. Physical and electrical enhancers ⁶:-

a) Structure-Based Enhancement Techniques:

i) Microfabricated Microneedles: Microfabricated microneedles are devices which are hybrids of the hypodermic needle and transdermal patch through the use of microscopic needles that can deliver the drug effectively (like a hypodermic needle). Their small size offers the potential advantages of delivering large molecules across the stratum corneum without extreme pain to the patients.The first microneedles systems consisted of a drug reservoir and a plurality of projections (microneedles) extending from the reservoir, which penetrate the stratum corneum and epidermis to deliver the drug.

ii) Macroflux®:Macroflux® technology is another novel transdermal drug delivery system that ALZA Corporation has developed to deliver biopharmaceutical drugs in a controlled reproducible manner that optimizes bioavailability and efficacy without significant discomfort for the patient.16 The system incorporates a titanium microprojection array that creates superficial pathway through the skin barrier layer to allow transportation of therapeutic proteins and vaccines or access to the interstitial fluids for sampling.

iii) Metered-Dose Transdermal Spray: It is a topical solution made up of a volatile cum nonvolatile vehicle containing the drug dissolved as a single-phase solution. A finite metered - dose application of the formulation to intact skin results in subsequent evaporation of the volatile component of the vehicle, leaving the remaining nonvolatile penetration enhancer and drug to rapidly partition into the stratum corneum during the first minute after application, resulting in a stratum corneum reservoir of drug and enhancer.

b) Velocity Based Enhancement Techniques:

i) Needle-Free Injections: The highest value, least developed and most technically challenging group of needle-free technologies is prefilled, disposable injectors. The development of such technologies is primarily driven by the demand for a convenient, non-invasive alternative to the conventional needle and syringe injection. The outer layers of the skin using a suitable energy source, usually a compact gas source, is used to propel a pre-measured quantity of liquid medicine through the skin and into the underlying subcutaneous tissue, without the use of a needle. The needle-free devices have been developed for the delivery of drugs such as insulin, sumatriptan and human growth hormone.

ii) Powderject Device: The core technology involves the high velocity injection of particle formulated drugs and vaccines into any physically accessible tissue. These may be for therapy or prevention of disease and may be small molecules, peptides, proteins and genes. The Powderject system involves the propulsion of solid drug particles into the skin by means of high-speed gas flow. This needle-free method is painless and causes no bleeding and damage to the skin.

c) Electrically-Based Enhancement Techniques:

i) Iontophoresis: Iontophoresis may be defined as the facilitation of ionizable drug permeation across the skin by an applied electrical potential, the driving force of which may be simply visualized as electrostatic repulsion.²²A typical iontophoresis device consists of a battery, microprocessor controller, drug reservoir and electrodes. The technique involves the application of a small electric current (usually 0.5 mA/cm2) to a drug reservoir on the skin, with the similarly charged electrodes (on the surface of the skin) placed together in the drug reservoir producing a repulsion effect that effectively drives the solute molecules away from the electrode and into the skin.

ii) Ultrasound: Ultrasound (sonophoresis, phonophoresis and ultraphonophoresis) is a technique for increasing the skin permeation of drugs using ultrasound (20 KHZ to 16 MHZ) as a physical force. It is a combination of ultrasound therapy with topical drug therapy to achieve therapeutic drug concentrations at selected sites in the skin. In this technique, the drug is mixed with a coupling agent usually a gel but sometimes a cream or ointment is used which transfers ultrasonic energy from the device to the skin through this coupling agent.

iii) Photomechanical Waves: Photomechanical waves are the pressure pulses produced by ablation of a material target (polystyrene) by Q-switched or mode-locked lasers. Photomechanical waves are able to render the stratum corneum more permeable to macromolecules via a possible transient permeabilisation effect due to the formation of transient channels.

Iv) Electroporation: This method involves the application of high voltage pulses to the skin, which has been suggested to induce formation of transient pores. High voltages in the form of direct current [DC (100 volts)] caused by electrical pulses with short treatment durations (milliseconds) are most frequently employed. The mechanism of penetration is the formation of transient pores due to electric pulses that subsequently allow the passage of macromolecules from the outside of the cell to the intracellular space via a combination of possible processes such as diffusion and local elctrophoresis.

v) Electro-Osmosis: If a charged porous membrane is subjected to a voltage difference, a bulk fluid or volume flow, called electro osmosis occurs without concentration gradients, suggesting that this flow is not diffusion. This bulk fluid flow by electro osmosis was found to be of the order of micro liters per hour per square centimeter of hairless mouse skin. The electro – osmotic flow occurs from anode to cathode, thus enhancing the flux of positively charged (cationic) drugs and making it possible to deliver neutral drugs.

II. Chemical enhancers:-These are also called as absorption promoters and inert themselves directly between the hydrophobic lipid tails and change lipid fluidity and increase the drug permeation.

Chemical enhancers are two types

1. Natural penetration enhancers

2. Syntehtic penetration enhancers

1. NATURAL PENETRATION ENHANCERS⁷:-

a) Terpenes:-

Terpenes are the naturally occurring volatile oils, are considered as clinically acceptable penetration enhancers as indicated by high percutaneous enhancement ability reversible effect on the lipids of stratum corneum and low cutaneous irritancy at lower concentrations (1– 5%). Moreover, terpenes have been shown to increase the skin permeation of a number of drugs .A number of terpenes are camphor, Eugenol, Menthol, Cineole, D-limonene and farnesol.

i) Camphor:- Camphor is a waxy, white or transparent solid with a strong, aromatic odour. It is a terpenoid with the chemical formula C₁₀H₁₆O. It is found in wood of the camphor laurel (Cinnamomum camphora). It also occurs in some other related trees in the laurel family, notably Ocotea usambarensis. It can also be synthetically produced from oil of turpentine. It is also used in medicinal purposes. Camphor is readily absorbed through the skin and produces a feeling of cooling.

ii) Eugenol: Eugenol is an allyl chain-substituted guaiacol. Eugenol is a member of the allylbenzene class of chemical compounds. It is a clear to pale yellow oily liquid extracted from certain essential oils especially from clove oil, nutmeg, cinnamon, and bay leaf. It is slightly soluble in water and soluble in organic solvents. It has a pleasant, spicy, clove-like odour. Cloves are the aromatic dried flower buds of a tree in the family Myrtaceae. It is native to Indonesia and used as a spice in cuisines all over the world. Eugenol, a component of clove, may reduce the ability to feel and react to painful stimulation. Therefore, use of clove products on the skin with other numbing or pain-reducing products such as lidocaine / prilocaine cream, theoretically it may increase effects. FT-IR and partitioning studies reveal that the enhancement in the permeability coefficient of drug by Eugenol is due to lipid extraction and improvement in the partitioning of the drug to the SC.

iii) Cineole:Eucalyptol is a natural organic compound which is a colourless liquid. It is cyclic ether and a monoterpenoid. Eucalyptol is also known by a variety of synonyms: 1,8-cineol,1,8- cineole, limonene oxide, cajeputol, 1,8-epoxy-pmenthane, 1,8-oxido-p-menthane, eucalyptol, eucalyptole, 1,3,3-trimethyl-2- oxabicyclo[2,2,2]octane, cineol, cineole. Eucalyptol suppository is used for the treatment of some respiratory ailments. Because of its pleasant spicy aroma and taste, eucalyptol is used in flavourings, fragrances, and cosmetics. It is also an ingredient in many brands of mouthwash and cough suppressant. 1, 8- Cineole has been used to promote the percutaneous absorption of several lipophilic drugs through hairless mouse skin. 10%Eucalyptol is needed to increase the permeation of low molecular weight heparin-enoxaparin sodium across human skin.

iv) D-Limonene:D-Limonene is obtained as a by-product of the citrus juice industry. It is the major component of the oil extracted from the rinds of citrus fruits. There are two main grades of d- Limonene which are called food grade and technical grade. When citrus fruits are juiced, the oil is extracted out of the rind. The juice is separated from the oil and the oil is distilled to recover certain flavour and fragrance compounds. This is called food grade dlimonenewhich is 96% to 97% pure and has amild orange aroma.it is a possible candidate for a variety of medical applications including cancer and aids research.

v) Menthol: Menthol is obtained from flowering tops of Mentha piperita .the active form of menthol occurring in the form of (-)-menthol. it is frequently used in antippruritic creams and as an upper respiratory tract decongestant. Menthol having the ability to chemically trigger the cold-sensitive TRPM8 receptors in the skin which is responsible for the well known cooling sensation provokes when inhaled, eaten, or applied to the skin. It has been used as an enhancer for transdermal drug delivery of variety drugs including imipramine hydrochloride, caffeine, hydrocortisone, triamcinolone, propranolol hydrochloride etc. Menthol is used along with iontophoresis have been shown to increase the influx of buspirone hydrochloride by more than 200-fold compared to a 15-fold increase using iontophoresis alone.

vi) Farnesol: Farnesol is a sesqiterpene alcohol, present in many essential oils, such as citronella, neroli, cyclamen, lemongrass, tuberose, balsam and tolu.0.25%v/v farnesol enhances the permeation of diclofenac sodium compared to terpenes, in the following order is farnesol> carvone>nerolidol>menthone>limonenoxide.0.25%(v/v) cocentration farnesol was found to be a 78-fold increase in permeability coefficient of diclifenac sodium.

b) Essential oils: The effect of three essential oils (eucalyptus, peppermint, turpentine oil) on the permeation of 5-fluorouracil (5-FU) were studied using excised rat skin. Although all three oils enhanced the permeation of drug, their effect was less than that of azone. Eucalyptus oil was found to be the most active, causing a 60-fold increase, while peppermint and turpentine oil showed 48- and 28-fold increases, respectively. Mode of action of these enhancers may be due to a combined process of partition and diffusion, the latter being dominant.

2) SYNTHETIC PENETRATION ENHANECRS:-

i) Pyrrolidones: Pyrrolidones and their derivatives have great potential to be used as transdermal permeation enhancers. The most common N-methyl-2-pyrrolidone (NMP) has been used widely to enhance the skin absorption of many drugs, for example, insulin, ibuprofen, and flurbiprofen. By the use of NMP, the flux of the antiinflammatory drug ibuprofen increased 16 times and that of flurbiprofen increased 3 times through cadaver skin^8-9. 2-Pyrrolidone and NMP were assessed in enhancing the topical bioavailability of a model steroid betamethasone- 17-benzoate, using dimethylisosorbide (DMI) as the standard solvent. pyrrolidones produced higher stratum corneum reservoirs compared with DMI, but because of their irritation potential, they are less preferred clinically.

ii) Azones: Azone (1-dodecylazacycloheptan-2-one) forms one of the major classes of percutaneous permeation enhancers. It has been reported that the choice of solvent is very important while using azone as a permeation enhancer. When azone was used in combination with PG, the flux of methotrexate and piroxicam increased significantly. Patches containing 0.05% w/v of cyclosporin A, an otherwise nonimmunosuppressive concentration, also showed good immunosuppression when azone was included in PG . Azone increase penetration through the stratum corneum by affecting both the hydrophilic and lipophilic routes of penetration. Compared with terpenes, azone is the most effective penetration enhancer for low molecular weight heparin across human skin. Azone alone enhances the skin permeation of a wide variety of drugs, like indomethacin, urea, methadone, 5- FU, propranolol hydrochloride^{10-11 .}

iii) Fatty acids and Esters: A large number of fatty acids and their esters have been used as permeation enhancers. A general trend has been seen that unsaturated fatty acids are more effective in enhancing percutaneous absorption of drugs than their saturated counterparts. Chi et al. reported an increase of 6.5-fold to 17.5-fold in the permeation rate of flurbiprofen through rat skin by unsaturated fatty acids, while no significant increase was observed with saturated fatty acids. Moreover, they have a greater enhancing effect on lipophilic drugs.Oleic acid is a mono-unsaturated fatty acids and is reported to increase the permeation of lipophilic drugs through the skin and buccal mucosa by transdemal cellular pathway⁴⁴. 10% oleic acid produced maximum flux through full-thickness human skin. Moreover, oleic acid proved to be the best enhancer among azone, NMP, and PG for the permeation of ketoprofen^12-13.

iv) Sulfoxides and similar compounds: Dimethyl sulfoxide (DMSO), the most important compound belonging to the category of sulfoxides and similar compounds, enhances the transdermal permeation of a variety of drugs, like b-blockers, ephedrine hydrochloride, and papaverine hydrochloride. It also enhances the release of azapropazone from its ointments. Fourier transform Raman spectroscopic studies revealed that DMSO changes the stratum corneum keratin from alpha-helical to b-sheet conformation. At concentrations greater than 60% v/v, at which DMSO enhances the flux, there was evidence of its interaction with stratum corneum lipids. It also produces alteration in protein structure, but may also be related to alterations in stratum corneum organization besides any increased drug-partitioning effect. In a study by Clancy et al. using attenuated total reflectance–Fourier transform infrared (ATR-FTIR) and DSC, it was confirmed that DMSO treatment (of human skin) causes extensive lipid extraction and stratum corneum protein denaturation. DMSO showed a negligible enhancing effect on the diffusion of piroxicam. It was also found to be less effective than lauryl chloride in increasing the flux of timolol maleate through human skin. Decylmethyl sulfoxide (DCMS) in combination with ethanol increased the flux of oxymorphone hydrochloride. A 4% aqueous solution of DCMS increased the permeation of 5-FU 35 times across human skin, but it was rapidly washed out of the tissues.¹⁴

v) Urea: Cyclic urea permeation enhancers are biodegradable and non-toxic molecules consisting of a polar parent moiety and a long chain alkyl ester group. As a result, enhancement mechanism may be a consequence of both hydrophilic activity and lipid disruption mechanism¹⁵.

vi) Oxazolidinones:

They have ability to localize co-administered drug in skin layers, resulting in low systemic Permeation. Oxazolidinones such as 4- decyloxazolidin-2-one has been reported to localize the delivery of many active ingredients such as retinoic acid and diclofenac sodium in skin layers^16-17.

vii) Alcohols, Glycols and Glycerids: Alcohols promote skin permeation of drugs by causing lipid extraction from the stratum corneum ¹⁸. Flux of propranolol hydrochloride was increased 8.2-fold by 1-nonanol , and octyl alcohol was efficient in increasing the permeation of urea . Ethanol is the most commonly used alcohol as a transdermal penetration enhancer by extracting large amounts of stratum corneum lipids. It also increases the number of free sulphydryl groups of keratin in the stratum corneum proteins. Usually, pretreatment of skin with ethanol increases the permeation of hydrophilic compounds, while it decreases that of hydrophobic ones. It increases the permeation of ketoprofen from a gel-spray formulation and triethanolamine salicylate from a hydrophilic emulsion base. It also acts as a vehicle for menthol in the permeation of urea. Of the fatty alcohols tested, lauryl alcohol increased the transdermal permeation of propranolol hydrochloride, timolol maleate, ibuprofen, acetaminophen, and 5-FU.

viii) Alkyl-n ,n-disubstituted amino acetates : Dodecyl-N,N bimethylaminoacetate and dodecyl-2-methyl-2-(N, N=dimethylaminoacetate) are the skin penetration enhancers.The penetration enahanceing activity is decreased by increasing the N, N-dialkylcarbon chain.Aminoacetates having less skin irritation property duo to biological decomposition of these enhancers by skin enzymes to N,N-dimethyl glycine and the corresponding alcohols.Skin penetration is increased by the interaction with stratum corneum keratin and is increased by hydration efficiency resulting from these interactions¹⁹.

ix) Surfactants: Surfactants are added to formulation in order to solubilise lipophilic active ingredients ,and so they have potential to solubilise lipids within the stratum corneum. surfactants are often described in terms of hydrophilic moiety. Anionic surfactants are Sodium laryl sulphate(SLS) is a powerful irritant and increased the transdermal water lossin human volunteers invivo.cationic surfactants are cetyl trimethyl ammonium bromide and non-ionic surfactants are dodecyl betaine. Both anionic and cationic surfactants swell the stratum corneum and interact with intercellular Keratin²⁰.

III) MISCELLANEOUS ENHANCERS ^21-23:

i) Phospholipids:Phosphatidyl glycerol derivative increased the accumulation of bifonazole in skin and the percutaneous penetration of tenoxicam; phosphatidyl choline derivatives promoted the percutaneous penetration of erythromycin. Six phosphatidyl glycerol derivatives (PGE [from egg yolk], PGS [from soyabean], dimyristyl phosphatidyl glycerol [DMPG], dipalmityl phosphatidyl glycerol [DPPG], distearyl phosphatidyl glycerol [DSPG], dioleyl phosphatidyl glycerol [DOPG] derivatives); five phosphatidyl choline (PC) derivatives (PCS [from soyabean], PCE [from egg yolk], dioleyl PC [DOPC], dilinoleoyl PC [DLPC], hydrogenated PC [HPC]); and two phosphatidyl ethanolamine derivatives were studied using indomethacin. Results suggest that phospholipids containing unsaturated fatty acids in the hydrophobic group are strong permeation enhancers for percutaneous delivery of some topically applied drugs.

ii) Lipid Synthesis Inhibitors : The barrier layer (i.e., stratum corneum) consists of a mixture of cholesterol, free fatty acids, and ceramides, and these three classes of lipids are required for normal barrier function. Addition of inhibitors of lipid synthesis enhances the delivery of some drugs like lidocaine and caffeine. Fatty acid synthesis inhibitors like 5-(tetradecyloxy)- 2-furancarboxylic acid (TOFA) and the cholesterol synthesis inhibitors fluvastatin (FLU) or cholesterol sulfate (CS) delay the recovery of barrier damage produced by prior application of penetration enhancers like DMSO, acetone, and the like. It was concluded that of lipid biosynthesis following the application of conventional chemical penetrant enhancers causes a further boost in the transdermal permeation.

iii) Cyclodextrin Complexes: Cyclodextrin complexes of a number of drugs have been formed, and such a combination usually enhances the permeation of drugs. For instance, an inclusion complex of piroxicam with ß-cyclodextrin increased the drug flux three times across hairless mouse skin (31), and a similar complex of clonazepam with methyl- ß -cyclodextrin improved its release profile from Carbopol hydrogel through cellulose nitrate membrane. In solution, cyclodextrin forms a complex with enhancers like quaternary ammonium salts and shifts their critical micellar concentration to higher values, thereby decreasing the toxic effect of such enhancers . Transdermal absorption of alprostadil (AP) from its ß -cyclodextrin complex and O-carboxymethyl-O-ethyl- ß -cyclodextrin (CME- ß -CD) complex was compared across hairless mouse skin. HPE-101 (1-[2-(decylthio)ethyl] azacyclopentan-2 one) was included as a permeation enhancer in both cases. Flux from the latter complex was 10 times higher than from the former one. It was concluded that a combination of CME- ß -CD and HPE-101 enhances the topical bioavailability of the drug.

iv) Amino Acid Derivatives: Various amino acid derivatives have been investigated for their potential in improving percutaneous permeation of drugs. N-Dodecyl-l-amino acid methyl ester and npentyl- N-acetyl prolinate were studied. Application of these two enhancers on excised hairless mouse skin 1 hr prior to drug treatment produced greater penetration of hydrocortisone from its suspension . n-Pentyl-Nacetyl prolinate also enhances the flux of benzoic acid across human cadaver skin; it is nontoxic at low doses, but at higher doses produces dose-dependent central nervous system toxicity . Esters of omega amino acids like octyl-6-aminohexanoate and decyl-6-aminohexanoate enhanced the transdermal permeation of theophylline in aqueous and oily vehicles, respectively. The effectiveness of the biodegradable penetration enhancer dodecyl N,N-dimethylamino isopropionate (DDAIP; dodecyl-N,N-dimethyl-l-alanine) was compared to dodecyl-N,N-dimethylamino acetate (DDAA), azone, and other known permeation enhancers. DDAIP showed a dose-dependent increase in the flux of 5-FU. Also, DDAIP produced better enhancement than DDAA and azone . It increased the transdermal flux of indomethacin . Hydrogen bonding and dipole-dipole interactions were reported between the drug and DDAIP.

v) Clofibric Acid: Esters and amides of clofibric acid were studied for their permeation-enhancing property using nude mice skin. The best enhancement of hydrocortisone-21 acetate and betamethasone-17-valerate was observed with clofi- bric acid octyl amide when applied 1 hr prior to each steroid. Amide analogues are generally more effective than ester derivatives of the same carbon chain length .

vi) Dodecyl-N,N-Dimethylamino Acetate: DDAA increased the transdermal permeation of a number of drugs, like propranolol hydrochloride and timolol maleate. It was found to be as effective an enhancer as azone, but it possesses an advantage over azone: Skin irritation with DDAA is reversed in a short time compared to azone . DDAA also increased the transdermal flux of 5-FU through snakeskin. Moreover, substitution of one of the hydrogen atoms of the acetate moiety with a methyl group greatly increased its penetration power . The increase in the flux of tetrapeptidehisetal by DDAA was 1.5-fold more than azone across hairless mouse skin. The permeability-enhancing effect was due to changes in the lipid structure of the stratum corneum, like azone and oleic acid. The improvement in transdermal permeation of sotalol by DDAA was the same as that produced by iontophoresis. DDAA causes the disruption of the lipoidal bilayer of the stratum corneum. Its duration of action is shorter than that of azone and dodecyl alcohol because of the presence of hydrophilic groups. So, there is faster recovery of the skin structure and hence less irritation potential. It also exerts a hydrating effect on the skin.

vii) Enzymes: Due to the importance of the phosphatidyl choline metabolism during maturation of the barrier lipids, the topical application of the phosphatidyl choline–dependent enzyme phospholipase C produced an increase in the transdermal flux of benzoic acid, mannitol, and testosterone. Three epidermal enzymes (triacylglycerol hydrolase [TGH], acid phosphatase, phospholipase A2) were also studied for their effect. Acid phosphatase was ineffective, TGH increased the permeation of mannitol, while phospholipase A2 increased the flux of both benzoic acid and mannitol. Pretreatment of skin with papain produced reversible alterations in the protein structure of the stratum corneum. These alterations resulted in increased permeation of proteins of various molecular weights, with the effect decreasing with increasing molecular weight.

CONCLUSION:

Skin permeation enhancers are increases the number of drugs suitable for transdermal drug delivery,with the result that skin will be become one of the major routes of drug administration skin into systemic circulation has limitations, use of Natural penetration enhancers as sorption promoters appears to be very promising and may include biphasic, feedback loops and user activated TDDS. Synthetic penetration enhancers are penetrating into the deeper layers of the skin to viable epidermal cells and induce skin irritation responses. Potential substances have been used for drug penetration-Promoting effects with a low or no skin irritating potentials. The advances achieved in these areas certainly are encouraging and may result in the development of therapeutically and commercially acceptability in times to come.

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Received on 08.10.2012

Modified on 17.10.2012

Accepted on 25.10.2012

Research Journal of Pharmaceutical Dosage Forms and Technology. 4(6): November–December, 2012, 300-308