Drug/Vehicle Impacts and Formulation Centered Stratagems For

192 Send Orders for Reprints to [email protected] Current Drug Therapy, 2019, 14, 192-209

REVIEW ARTICLE

ISSN: 1574-8855 eISSN: 2212-3903 Drug/Vehicle Impacts and Formulation Centered Stratagems for Enhanced Transdermal Drug Permeation, Controlled Release and Safety: Unparalleled Past and Recent Innovations: An Overview

Balamurugan Manickam1,*, Rajesh Sreedharan2 and Kumarappan Chidambaram3

1School of Pharmacy, College of Pharmacy and Nursing, University of Nizwa, Initial Campus, Birkat Al Mouz, Nizwa, P.O. Box 33, PC 616, Sultanate of Oman; 2Faculty of Pharmaceutical Sciences, UCSI University, No-1, Jalan Menara Gading, UCSI Heights, Cheras, 56000, Kuala Lumpur, Malaysia; 3College of Pharmacy, King Khalid University, Abha, Asir, 52629, Saudi Arabia

Abstract: Transdermal drug delivery systems (TDDS) are one of the fascinating uncon- A R T I C L E H I S T O R Y ventional drug delivery systems offering plentiful advantages of which patient compli-

ance is of paramount importance. However, as a matter of fact, the transdermal delivery Received: June 26, 2018 of drug molecules is absolutely a tedious job which is precisely influenced by a number of Revised: November 08, 2018 Accepted: December 19, 2018 factors including penetration barrier properties of the skin, drug characteristics formulation allied issues, etc. Over the years, innumerable tremendous efforts have been made in DOI: 10.2174/1574885514666190212113754 transporting the drugs through the skin into the systemic circulation by noteworthy tac- tics. This paper discusses such revolutionary formulation based techniques that have been endeavored in achieving the enhanced skin permeation of drugs, controlled release, and safety. Keywords: Formulation strategies, drug and vehicle impacts, transdermal drug delivery, enhanced drug permeation, controlled release, safety.

1. INTRODUCTION plasma drug concentration [1] obtainable by controlled and prolonged drug delivery, diminished or In fact, the Transdermal Therapeutic Systems thoroughly eliminated systemic side effects, elimi- (TTS) are not a recent concept andhas been delib- nation of first-pass effect by liver [2] and conse- erated comprehensively for almost four decades. quent enhanced efficacy, etc. [3, 4]. Likewise, Since the introduction of the first transdermal with no painful administration procedures [5], it patch for systemic delivery containing scopola- can be easily applied and removed from the skin, mine in the year 1979 approved for use in the adding improved patient compliance [6, 7]. The United States, this particular technology has been apt transdermal drug molecule should possess cer- enduring enormous transformation and contribut- tain attributes including suitable aqueous solubility ing a substantial share in the growing pharma (>1mg/mL) and melting point (<200°C), low mo- market. This distinguished therapeutic system has lecular weight (<400 daltons) [8], appropriate Log proffered profuse clinical advancements over the P (n-octanol/water) partition coefficient (−1.0 to 4) conventional dosage forms such as steady-state [9-11] potent adequate to produce essential pharmacological actions even at low doses

(<20mg/day), short half-life (< 10hrs), etc. The *Address correspondence to this author at the School of Pharmacy, aforementioned qualities are basically needed for College of Pharmacy and Nursing, University of Nizwa, Initial Campus, Birkat Al Mouz, Nizwa, P.O. Box 33, PC 616, Sultanate an aspired drug candidate to be delivered passively of Oman; E-mail: [email protected] into the systemic circulation. Nevertheless, the

Drug/Vehicle Impacts and Formulation Centered Stratagems Current Drug Therapy, 2019, Vol. 14, No. 3 193 skin is also a tough barrier that keeps a tight rein adhesive qualities [19, 20]. The transdermal films on permeation of bioactive agents passively into containing ondansetron using chitosan as film- the systemic circulation. The transdermal drug forming material were studied. The study revealed permeation takes place by way of the stratum cor- the matchless qualities of this versatile polymer neum, which, is composed of lifeless, keratinized such as bio-adhesiveness and physicochemical epidermal cells (approx.10 µm in thickness) limit characteristics. It demonstrated better permeation the permeation of drugs. Apart from the hydro- of included drug along with terpenes as penetra- philic drug molecules, proteins, peptides and mac- tion enhancer [18]. Similarly, pullulan- romolecules including DNA, siRNA contend per- polyacrylamide amalgamation based films were meation through the skin. With the purpose of ac- formulated for the efficient release of metoprolol complishing desired drug permeation transder- succinate through the skin as demonstrated in an in mally, various techniques and principles have been vitro study. Pullulan is a natural, bioadhesive, non- endeavored to enhance the permeation of drugs, toxic, hydrophilic linear polymer obtained from among those use of advanced modified formula- starch by Aureobasidium pullulans. This extra- tions/vehicles for this purpose is also one of the cellular bacterial polysaccharide combined with common procedures. The era of nanotechnology one of the low toxic synthetic acrylic polymers, waved huge improvisations in the effective per- polyacrylamide offered good adhesion. These meation, controlled release, and safety of drugs natural and synthetic polymeric blended transder- through the skin. mal films have evidencedthe fast release of incorporated drug transdermally by way of Fickian 2. FORMULATION MANEUVERS FOR mechanisms [21]. Polycarbophil is a high molecu- IMPROVED TRANSDERMAL PERMEATION, lar weight acrylic acid polymer, which has been CONTROLLED RELEASE, AND SAFETY used in the controlled drug delivery systems. The durable bioadhesive belongings and less adverse 2.1. Incorporation of Drugs in the Bioadhesive reactions laid this pharmaceutical excipient nota- Polymer Matrix ble polymeric carrier for TDDS [13]. Through the earlier published research/review articles, it is well-known that the natural and syn- 2.2. Adhesive Matrix-type Transdermal thetic polymers of organic origin have been used Patches Using Pressure Sensitive Adhesives far and wide in the development of TDDS [12]. (PSAs) Fabrication of transdermal patches using bioadhe- Essentially, the PSAs act as a matrix for the sive polymers was found to have a remarkable drugs, penetration enhancers and rate controlling permeation enhancement tactic for a range of membrane along with its skin adhesive properties drugs through the skin into the systemic circula- [22]. Indeed, the adhesive characteristic of TDDS tion. By prolonging the contact time, attained by is also one of the vital features deciding the thera- pertinent adhesion effect on the stratum corneum peutic efficacy of the drugs [23]. The silicone could advance the skin permeability via chemical PSAs have been widely used alone and/or in blend bonding [13]. For instance, chitosan is one of the with other adhesive type polymers for fabricating naturally obtained cationic polymers preserving TDDS in the pharma industry from 1990 till date. massive, unique pharmaceutical qualities including Lipophilic drugs can make skin permeability easy incredible bioadhesive characteristics. The poten- when it is devised with silicone PSAs. Therefore, tial of chitosan as a suitable bioadhesive carrier for to deliver the hydrophilic drugs, these silicone delivering drugs through the skin has been sup- PSAs could also be improved by combining to- ported in a number of studies [14, 15]. On applica- gether with hydrophilic fillers, copolymers and tion to the skin, this positively charged bioadhe- plasticizers [12]. When compared with other poly- sive polymer-based formulation enables long- mers this class of silicone PSAs indicated less standing contact time on epithelium through elec- interaction with the dispersed drugs, eventually trostatic interaction between its cationic charges marked the high drug release rates. It was also and the cell surface possessing anionic charged verified earlier that the required drug release rates glycoprotein residues [16, 17]. Consequently, could be accomplished by mixing silicone adhe- permeation of drug is enabled [18] through the sives with other non-adhesives and polymers. In a epithelium by passive diffusion due to its strong previous study, the transdermal patches containing 194 Current Drug Therapy, 2019, Vol. 14, No. 3 Manickam et al. buflomedil hydrochloride were developed using physical enhancement techniques. According to different combinations of PSAs with two adhe- the numerous reports, approximately 300-360 sives. The above-stated monolithic transdermal chemical enhancers [29] from different chemical patch presented numerous notable functions com- origins have been tried in the transdermal formula- prising good skin adhesion quality, a congruent tions but agonizing toxic effects of these chemical matrix station for the drugs and enhancers, and compounds limit their use. Some of these classes desirable controlled drug release by means of including surfactants (anionic, cationic, zwitter- unique diffusion pathways was accomplished by ionic and non-ionic surfactants), fatty acid esters, the various combinations of PSAs [24]. The con- amines, amides, various alcohols, hydrocarbons, venience and ecologically compatible qualities of water, etc., which excercise their penetration- hot-melt pressure sensitive adhesives (HMPSAs) enhancing competences adopting different com- made it popular recently. The higher drug release plex mechanisms, have been extensively used in rates have been witnessed in HMPSAs based the transdermal formulations. Usually, the previ- TDDS with highly lipophilic drugs due to the ously itemized cluster of CPEs acts on the skin by compatibility with drugs [25]. Lately, in an atten- disrupting or interacting with the intercellular lip- tion-grabbing research study, a combination of sty- ids and by enhancing thermodynamic activity of rene–isoprene–styrene (SIS) block copolymer, hy- the drugs. In order to achieve the desired permea- drocarbon resin and liquid paraffin was utilized to tion rate and to tail off the setbacks, these CPEs prepare a PSA matrix TDDS. A probe on the per- are used either alone or in combination with one or meation of incorporated model drug capsaicin, more of its kind. This combination pattern of con- magnitude of skin adhesion and the extent of ception is undertaken to enhance the skin permea- safety was also studied. The results of this study tion in the outermost layer of the epidermis with revealed that the efficient adhesion bid prolonged no or least irritation in the subterranean skin tis- application time so that the improved efficacy of sues. It was well-comprehended in a previously permeation of drugs was proven [26]. The published review article stating that approximately HMPSA based on SIS block copolymer TDDS of there were 5000 such combinations achieved after a model drug α-asarone was prepared, evaluated investigating 500 varied sets of CPEs. Such robust for its compatibility and the adhesion potentials. combinations have shown very promising permea- The results of this study showed no skin reactions tion enhancing qualities even in the TDDS con- and good adhesive qualities after the in vivo stud- taining macromolecules [30]. The assured upshots ies on rabbits in addition to the desired amount of exhilarated the pharma industries to work towards drug penetrations [27]. A monolithic drug-in- these approaches. Similarly, the biochemical en- adhesive TDDS for testosterone with a PSA matrix hancers like peptides and magainins, a class of an- based on SIS block copolymer was prepared using timicrobial peptides, have shown that promising hot homogenization technology and evaluated for drug delivery of certain drugs through the targeted percentage drug release, water vapor permeability pathways across the skin further impedes the cuta- and adhesive characteristics. A complete desired neous inflammations [31]. Interestingly, in one of result was reported highlighting the influence of the latest review articles, the research findings of concentration, compatibility and physicochemical the development of ceramide analogs, azone ana- characteristics of the chemical permeation en- logs for the enhanced permeation of various drugs hancers on adhesion, disclosing the distinguished via transdermal route were discussed. The permea- skin permeability and suitable skin adhesion [28]. tion enhancement attributes of the stated analogs were achieved by modifying the chain length and 2.3. Addition of Chemical Permeation En- scheming the polar head groups existing in the hancers (CPEs)/ Biochemical Enhancers azone structures. Additionally, the same article deliberated Tranexamic acid derivatives, menthol A wide range of chemical permeation en- derivatives, Transkarbams, etc. in this context [32]. hancers have been reported so far, exhibiting different mechanisms, penetration enhancing capa- 2.4. Utilization of Essential Oils in the Formula- bilities, together with many pros and cons. In con- tions for Enhanced Transdermal Permeation sideration of its inexpensiveness, flexibility in designing the transdermal formulations, etc., are The use of natural essential oils comprising some of the substantial merits over the other volatile components and its indispensable permea- Drug/Vehicle Impacts and Formulation Centered Stratagems Current Drug Therapy, 2019, Vol. 14, No. 3 195 tion boosting potentials of various drugs in the drophilic matrix consisting of PEG (polyethylene topical and transdermal formulations has been glycol) coated vinyl trimethoxy silane-g-chitosan demonstrated worthy in plentiful past investiga- was developed and dispersed in sodium alginate tions. The multifarious combinations present in (SA), carboxymethyl cellulose (CMC) and polyvi- these natural products holding distinctive chemical nyl alcohol (PVA) matrices. The study was aimed compounds [33] facilitate the penetration en- to assess the economic feasibility, aesthetic appeal hancement of many drugs by different mecha- along with the drug delivery efficacy and showed nisms into the deeper skin layers. The fragmenta- some beneficial results [37]. The TDDS fabricated tion of intercellular lipid structures and increased using chitosan/ hydroxypropyl methylcellulose partitioning of drugs are some of the prominent (HPMC) containing propranolol hydrochloride by mechanisms that facilitate the drug permeation solvent casting systems showed encouraging re- across the skin. However, a comprehensive inter- sults [38]. Etoricoxib transdermal patches were pretation of the mechanism of actions is needed. made using chitosan blended with HPMC which Above all, the safety of these oils is guaranteed by showed good results [39]. The enhanced permea- its precipitous metabolism, excretion and non- tion of the drugs from the blended films was accumulation on application to the skin [34]. In achieved by matrix erosion mechanism and diffu- one of the recent studies, the potentials of angelica sion of drug across the gel layer or of both the oil, chuanxiong oil, cyperus oil, cinnamon oil, and combinations [38, 39]. The patches comprising clove oil were investigated in delivering ibuprofen herbal blends were crafted using chitosan/HPMC transdermally to treat dysmenorrhea. This particu- combinations, which disclosed the superior drug- lar study revealed that the employed essentials oils polymer compatibility, controlled release and skin acted on the intercellular lipid structure, thereby permeation of the incorporated herbal drugs [40]. providing exceptional safety merits than the The transdermal patches of the hydrophilic anti- azones [33]. Owing to their rare qualities, the es- hypertensive drug losartan potassium were formu- sential oils continually sustain the drug delivery lated using various proportions of hydrophilic and scientists to investigate the new of its kind for the hydrophobic polymers such as eudragit RS & RL- efficient transdermal delivery/permeation of both 100, ethyl cellulose, poly vinyl pyrolidine (PVP) lipophilic and hydrophilic drugs. The effect of and PVA. The higher amount of drug release was wintergreen oil on the transdermal permeation of obtained from the hydrophobic polymers [41]. The osthole and geniposide as model drugs was ex- efficiency of the transdermal films made up of chi- perimented. This study disclosed that this oil less- tosan and montmorillonite K 10 clay fusion hold- ened the permeation impediments by means of act- ing curcumin was reported. The combined effects ing on the intercellular lipids, exhibited good per- of the chitosan and clay presented substantial in- meation properties of the previously stated lipo- terfacial interactions resulted in augmented phys- philic and hydrophilic drugs [35]. An amplified icochemical descriptions along with the controlled transdermal permeation quantity of Chuanxiong release characteristics [7]. was accomplished by using Frankincense and Myrrh oil as permeation enhancers by way of in- 2.6. Cross-linking of Polymeric Films for Modi- tensified skin blood flow [36]. Similarly, the capa- fied Permeation Characteristics bilities of a number of essential oils including eucalyptus, tulsi/basil, turpentine, orange, melissa, For the purpose of acquiring upgraded me- myrtle, citronella, mentha, ylang, lavender, nut- chanical properties and to control/modulate the meg, chamomile, peppermint oils, etc., have been drug release characteristics from the films [42], verified in various different studies at different this noteworthy technique has been carried out us- time periods yet again corroborating their promi- ing various cross-linking agents and cross-linking nence in increasing the transdermal permeation of procedures. In a study, TDDS formulated using many drugs. sodium alginate was cross-linked with different dilutions of glutaraldehyde prepared in methanol . 2.5. Blended Films for Enhanced and Con- This research paper divulged that drug diffusion is trolled Transdermal Drug Delivery controlled by cross-linking density as well as the concentration of the polymer. This attribute was In an attempt to deliver diltiazem hydrochloride described based on the point that the increased transdermally intended for sustained release, a hy- concentrations of glutaraldehyde reduce the drug 196 Current Drug Therapy, 2019, Vol. 14, No. 3 Manickam et al. release considerably [43]. On contrary to the for- raised transdermal delivery of apomorphine Liu et merly stated research findings, the addition of suc- al., synthesized diester prodrugs of apomorphine cinic acid as a cross-linking agent in the and gauged for its skin permeation efficiency. The HPMC/Eudragit RL 100 based transdermal transdermal permeation studies using intact and patches increased the drug release. This outcome stripped skins pointed out that the viable der- was justified as follows: addition of 5% w/w cross- mis/epidermis was found to be the stumbling block linking agent changed the film properties then in- for the permeation of prodrugs. Lipid emulsions of fluenced the drug diffusion and thermodynamic nanosize were also used as a carrier for these di- activity within the succinic acid treated films [44]. ester prodrugs of apomorphine which displayed Consumption of genipin, a natural cross-linking impressive skin permeation than their parent drug agent in the drug delivery systems, is very com- [53]. mon [45] in the TDDS as well. Genipin crosslinked chitosan film consisting of curcumin was 2.8. Eutectic Systems formulated and evaluated and showed an excellent release of the curcumin [46]. In another study, this In order to increase the solubility and permea- biocompatible, safe, non-toxic, cross-linking agent tion of drugs, the eutectic mixtures were utilized in was used in the transdermal patches for the con- the expanse of drug delivery systems. These mix- trolled delivery of marker drug, 4,4'-bis(2- tures might contain two or more components sulfostyryl) biphenyl [47]. Polyethylene oxide hy- formed amongst drug and drug or drug and excipi- drogel films for passive transdermal drug delivery ent combinations at particular proportions conse- were fabricated and loaded with some hydrophilic quently yield a system with a depressed melting and lipophilic drugs. These films were cross- point than both of the pure components [54, 55]. linked with pentaerythritol tetraacrylate, one of the For enhanced transdermal drug delivery, the bi- well-recognized safest cross-linkers for the topical nary eutectic systems of ibuprofen and ketoprofen applications. This paper relates the effective cross- were prepared. The prepared binary eutectic sys- linking with elevated drug loading capabilities, tem was then tested for its physicochemical char- beneficial mechanical qualities and ideal drug re- acteristics showed depressed melting points. The lease descriptions of this TDDS [48]. results of in vitro permeation studies performed using shed snake skins as model membrane 2.7. Prodrug Approach for Increased Trans- showed an increased permeation of drugs due to dermal Permeation the improved solubility of drugs in skin lipids which occurred as an effect of the lessened melt- The incorporated enhancers in the transdermal ing point of the eutectic systems [56]. In one more formulations could facilitate the permeation of study, intended for the improved drug delivery drugs along with detrimental components, conse- across the skin, the influence of physicochemical quently leading to the skin mutilation. The prodrug characteristics of enantiomers, racemate, and concept is considered as one of the assuring com- eutectics of Ibuprofen was experimented. The re- plementary techniques in delivering the drugs sults of the in vitro skin permeation studies per- transdermally to combat the formerly stated com- formed in the Franz diffusion cells through the plications. Prodrug strategy requires modification shed snake skin membranes showed heightened of the chemical structure of the parent drugs such percutaneous absorption of eutectic ibuprofen. as alkyl chain lengthening and PEGylation [49]. This finding was also correlated to the reduced This well-known method has been exercised to melting point of eutectic ibuprofen and the im- provide the suitable physicochemical and pharma- proved solubility of the same in skin lipids [57]. cological properties to the drugs [50], therefore TDDS containing glabridin utilizing eutectic mix- facilitates the transdermal permeation [51]. In a ture of menthol and camphor based nanoemulsion recent study, diclofenac ester prodrugs were syn- for the enhanced transdermal permeation was stud- thesized using diclofenac acid and were evaluated ied. Followed by the thorough characterization of for their appropriateness as transdermal drug can- the formulations, an in vitro skin permeation study didates. The use of glycol and glycerol in the deri- conducted using male Sprague Dawley rat’s dorsal vation yield prodrugs possesses favorable trans- skin portion showed increased drug permeation dermal permeation capacities corroborated by the rates. Likewise, the in vivo skin permeation study higher flux rates across the skin [52]. For the findings in rats showing worthy results were also Drug/Vehicle Impacts and Formulation Centered Stratagems Current Drug Therapy, 2019, Vol. 14, No. 3 197 reflected in the drug permeation on the human skin was made by spontaneous emulsification method. performed in three female volunteers. Further- The in vitro skin permeation study results con- more, the enhanced chemical stability, a notable firmed these formulations suitability as a trans- quality of this formulation, was revealed after dermal carrier for the incorporated NSAID [66]. short term stability studies were carried out at An innovative squalane nanoemulsion was com- room temperature for 3 months, which finally con- posed for the transcutaneous delivery of albumin- cluded that this nanoemulsion-based eutectic mix- fluorescein isothiocyanate conjugate used as a ture was suitable for the enhanced transdermal vaccine model. The study showed favorable results permeation of the incorporated drug [58]. of the engineered nanoemulsion in delivering the vaccines transdermally [67]. With the aim of treat- 2.9. Drug Delivery Carriers: Lipid Vesicles, ing oxidative- stress-related diseases, quercetin Micelles, Nanoparticles, etc. in TDDS containing poly (lactic-co-glycolic acid) nanoemulsions was prepared by solvent evaporation Of late, the drug delivery carriers, such as lipid technique. The researchers remarked the transder- vesicles, micelles, nanoparticles, etc., were found mal permeation capabilities of this nanoemulsion to have potential applications in the transdermal system by in vitro and ex vivo examinations. The delivery of biologically active agents. The utiliza- results of this analysis elucidated the safety of the tion of vesicular constructs including modi- formulation, controlled delivery and heightened fied/improved liposomes in TDDS gained im- transdermal drug permeation [68]. mense importance in this field because of their in- spiring transdermal permeation enhancing compe- 2.9.2. Pickering Emulsions tencies of bioactives [59]. Moreover, their is biocompatible, biodegradable, nontoxic, non- These are the category of surfactant-free emul- immunogenic qualities [60, 61] and potentials of sions stabilized by nano/microparticles holding the transporting both hydrophilic and lipophilic drugs particle size <200nm. These particle-stabilized ranging from small molecules to proteins trans- emulsions help in the improved deep penetration dermally [62] further fortified the pharmaceutical of drugs in the skin [69]. One of the shortcomings researches to delve intensely towards this direc- of these emulsions is that the desiccation of the tion. To achieve the desired percentage of encap- skin could be enfeebled by the inclusion of cyclo- sulation, extent of protection and controlled re- dextrins. By reason of the strong adhesion of drop- lease of drugs the different types of nanoparticle- lets of the emulsions onto the skin surface ease the based drug delivery systems have been developed penetration of confined drugs through the skin in recent years. It includes nanovesicles, nanoe- [70]. In a study, the formulated w/o pickering mulsions, lipid nanoparticles polymeric nanoparti- emulsion was stabilized using modified starch and cles, etc [63]. demonstrated their potential as a safe topical drug delivery carrier [71]. An identical study was car- 2.9.1. Nanoemulsions ried out to evaluate the in vitro skin penetration aptitudes of the starch-based o/w pickering emul- These clear, transparent liquid vehicles were sions containing three different oils. This examina- found to be suitable for transdermal drug delivery tion exhibited a raised flux double the times of lipophilic and hydrophilic drugs based on sev- through the skin [72]. eral ins and outs. Most importantly, the effortless- ness formulation involved high solubilization, sub- 2.9.3. Nanovesicles sequently its thermodynamic stability, small glob- ule size, and very low viscosity pulled considera- Nanovesicles containing aceclofenac were con- tion in the construction of promising TDDS utiliz- structed using ceramide-2, cholesterol, palmitic ing nanoemulsions. Carvedilol was used as a acid, and cholesteryl sulfate by thin film hydration model drug in the nanoemulsion formulations. The technique. They were then formulated in carbopol nano-sized globules that offered intimate contact gel for transdermal usage. The results of this ex- on the skin witnessed the enhanced permeation amination showed that the formulation based ce- [64]. Nanoemulsion of diclofenac prepared using ramide and palmitic acid lent superior drug per- argan oil by ultrasonication method was proved to meation characteristics plus improved stability and be a worthy transdermal drug carrier [65]. The skin safety [73]. In the same way, the nanovesicles TDDS of nanoemulsions confining aceclofenac of aceclofenac also formulated using guggul lipid 198 Current Drug Therapy, 2019, Vol. 14, No. 3 Manickam et al. showed boosted stability and drug access inner properties for the transdermal delivery were stud- into the skin [74]. Ex vivo permeation studies ied. Transdermal delivery capacities of these phy- showed that nanovesicles for nitrendipine which tosterol derivatives encompassing 1, 2-dimyristoyl- were developed using ceramide-2 containing oleic sn-glycero-3-phosphocholine liposomes were evalu- acid by film hydration method demonstrated good ated utilizing 3-Dimensional skin models. It was permeation through the human skin. The improved determined that the release of liposomal inside was permeability was due to the incorporation of oleic impelled out by the low pH besides the increased acid on to the vesicle wall and the presence of ce- temperatures than the body temperature. The con- ramide balanced the skin protection even after fined pH-responsive phytosterol esters from the drug permeation [75]. liposomes were transported into the skin networks intensely, which further affirmed the safety as well 2.9.4. Liposomes [81]. Liposomes are the class of smaller vesicular 2.9.5. Ultra-deformable Vesicles structures made-up of cholesterol and phospholip- ids comprising of one or multiple bilayers confin- (i) Elastic Liposomes (EL)/Transfersomes ing an aqueous center [61]. Similar to the biocom- Flexibility/deformability and elasticity of this patibility, biodegradability and toxicity minus biocompatible formulation are noteworthy aspects merits [76, 77], these spherical shaped phosphol- obtained by designing a bilayer structure of lipids ipid vesicles appending hydrophilic and hydro- crafted from the typical liposomes [82]. The inte- phobic characteristics thoroughly substantiated gration of edge activators (usually a single chain this class as a worthy transdermal carrier based on surfactant) hooked on to the lipid bilayer structure its bilayer structures [78]. Lots of investigations imparted elasticity to this groundbreaking formula- done in the past evidenced the exceptional poten- tion [83]. It consists of an inner aqueous portion tial of transdermal liposomes against conventional enclosed within a lipid bilayer capable of encapsu- dosage forms [79]. Use of either unsaturated phos- lating both hydrophilic and lipophilic drugs in the phatidylcholine species or the saturated phosphol- aqueous chamber and lipid bilayer portion, respec- ipids (long acyl chains) in the formulation schemes tively. Due to their distinctive constituents and determines the permeability and stability descrip- structures, the EL possess enhanced efficacy and tions of these lipid constructions. They can be skin permeation potentials [62]. Non-occluded sorted into multi-lamellar vesicles and uni-lamellar skin application of EL leads to skin hydration and vesicles (large and small unilamellar vesicles) osmotic force in the skin, in this way these struc- based on their size and the number of bilayers [60]. Szura, D. et al. studied the efficiency of tures permeate the stratum corneum through diffu- transdermal permeation of liposomes containing sion intervened mechanisms [62, 84]. As it is un- naproxen. The obtained large unilamellar vesicles derscored formerly, the elasticity, stability and were characterized. Transdermal permeation permeation potentials of EL could be uplifted by analysis of naproxen liposomes was conducted in suitable ingredients and an intensive research is the Franz diffusion cell using pig ear skin. The marching towards these implications. Transdermal study displayed increased naproxen transport from delivery of sertraline using transfersomes as ve- the liposomes (formulated using phosphatidylcho- sicular carriers was designed and characterized for line) twice as compared to the reference formula- its enhanced skin permeation rates. The research- tions [77]. Liposomes using various concentrations ers adopted the conventional rotary evaporation of soy lecithin and cholesterol were prepared by sonication method for further dispersing the for- thin film technique for the transdermal delivery of mulation of transfersomes in the gel matrix base a selective COX-2 inhibitor, celecoxib. Thence- (Carbopol 940) in order to form transfersomal gel. forth, these liposomes were probed for their size, The research paper revealed that this TDDS could encapsulation efficiency, percentage drug release be the promising vesicular carriers for enhancing analysis in Franz diffusion cells and in vitro skin skin delivery of the incorporated drug [85]. Trans- permeation studies using male adult Wistar rat ferosomal gel TDDS for insulin was formulated by skins. The findings of this inquiry undraped the the reverse phase evaporation method. The in vitro efficient transdermal permeation of the liposomal permeation study across porcine ear skin showed fenced drug aptly [80]. The liposomes containing beneficial end results. The transdermal application phytosterol derivatives with stimuli-sensitive of optimized transferosomal gel has displayed a Drug/Vehicle Impacts and Formulation Centered Stratagems Current Drug Therapy, 2019, Vol. 14, No. 3 199 stretched out hypoglycemic effect on alloxan- somes which is composed of a high content of induced diabetic albino rats over 24hrs [86]. A re- ethanol (30%) in addition to the edge activators or search on the soft nanovesicles (nano- permeation enhancers [92]. As an effect of its dual transfersomes) for improved skin delivery of epro- characteristics, the mechanism of skin permeation sartan mesylate was carried out. The sizes of these may perhaps adhere to the ways of both transfer- colloidal carriers ranged from 100-200nm, capable somes and ethosomes [88]. In an effort to deliver of traversing the skin barrier free of drug concen- the transethosomes containing voriconazole, the tration. The report disclosed that the prepared researchers prospered in delivering the included nano-transfersomes were of nanosizes, indicating drug transdermally at increased rates. The study enhanced transdermal permeation of the drug after related the influence of ethanol and edge activator in vitro rat skin permeation studies [87]. combinations synergetic effect granted the higher elasticity, permeability and deposition to the for- (ii) Ethosomes mulations. In addition to the previously stated results, increased in vivo depositions of this vesicle These vesicular structures are made up of phos- pholipids, water and ethanol (at high concentra- carriers were mentioned due to the presence of oleic acid [92]. Piroxicam containing transethoso- tion, ranging from 20-45%) [88, 89]. The in- mal gel was formulated and evaluated by in vitro creased concentration of ethanol contents in vesi- and ex vivo studies. The assessment publicized the cles imparted improved stratum corneum permeat- formulations high drug permeation and prolonged ing values by interrupting lipid bilayer assembly of drug release attributes, hence suitable for skin de- the skin. Like EL, these soft nanovesicles (size ranges from 150 to 200 nm) [90] suitable for both livery [93]. The transethosomes transdermal delivery carriers for transporting paeonol were devel- hydrophilic and lipophilic drugs retain elasticity. oped with the aim of enhancing drug stability and Upon application, alcohol contents present in the bioavailability. On comparison with transfer- formulation evaporate [88] and bring about the somes, transethosomes possess improved in vitro formulation integral on the skin under non- and in vivo delivery of paeonol, and supplemen- occlusive conditions. Recently, ethosomal TDDS of an antihypertensive drug valsartan was devel- tary investigation to prove its safety is proposed [94]. oped and evaluated for its skin enhancement properties. This preparation was compared with drug (iv) Cubosomes solutions in water and water-ethanol mixture for the transdermal permeation through an ex vivo These are self-assembled, nanostructured liquid study conducted using rat abdominal skin. In vivo crystalline dispersed colloidal particles formed by studies on Wistar rats revealed the formulation’s involving suitable proportions of particular am- exceptional skin permeation abilities convinced by phiphilic lipids (usually glycerol monooleate) and the extended antihypertensive activity devoid of water mixtures in addition to a stabilizer [95]. The the skin damages [91]. In another innovative properties of cubosomes including biocompatibil- study, these ethanolic liposomes were utilized to ity, bio-adhesiveness, the capability of holding hy- deliver (epigallocatechin gallate) green tea leaves drophilic and hydrophobic drugs, prolonged re- extract transdermally. The ethosomes were formu- lease [96, 97] and skin permeation enhancement of lated by mechanical dispersion method, then the drugs, (owing to the structural configuration of prepared formulations were evaluated for their cubosomes). make them suitable for TDDS. morphology, entrapment efficiency, etc. The pre- Cubosomes comprising capsaicin were prepared pared ethosomes were then mixed in the gel base. with the purpose of attaining skin-targeted and Besides the physicochemical evaluation, an in vitro sustained transdermal delivery of the skin ab- test was done on Sprague-Dawley abdomen rat skin. sorbed drug. In addition to the encapsulation effi- The better penetration of epigallocatechin gallate ciency, stability, particle size, skin safety and in was observed in the ethosomal based gel formulation vitro release studies, in vitro percutaneous permea- ensued by different penetration mechanisms [89]. tion studies were also conducted in a vertical Franz diffusion cell using excised Sprague Dawley (iii) Transethosomes rat abdominal skin as the model skin. The findings of this study accentuated the merits of these for- The formulation of transethosomes possesses- mulations [98]. A momentous attentiveness has the characteristics of both transfersomes and etho- 200 Current Drug Therapy, 2019, Vol. 14, No. 3 Manickam et al. been given towards these nanoparticles as a trans- which works by forming an occlusive film on the dermal carrier is also because of its unmatched surface of the skin [104]. For the improved topical skin adhesiveness abilities. To amplify the skin delivery of an anti-psoriatic drug, thymoquinone delivery of hinokitiol, cubosomes containing this from the lipospheres has been studied. The pre- hair growth promoter were prepared. For the in pared anti-psoriatic drug containing lipospheres vitro permeation studies, dorsal skin of the female (≤70 nm) had shown down reaching skin penetra- hairless mice was used. Finally, this study dis- tion; prolonged release and skin fit advantages closed that the cubosomes prepared with submi- [105]. However, various methods of formulation cron monoolein were stable and showed enhanced of lipospheres have been reported such as solvent skin permeation in vitro [99]. Kwon, T. K., et al. techniques, melt dispersion technique, multiple for the first time tested cubosomes as transdermal microemulsion method, etc. But then again, meth- carriers for enhancing the permeation of water- ods of preparation determine the characteristics of soluble compounds. The cubosomes were prepared lipospheres as reported in a study by Nasr, M., et using liquefied monoolein and water-soluble ex- al. Lipospheres, encompassing aceclofenac formu- tracts of Korean barberry and then studied for lated by melt and solvent procedures, showed ele- theirsize stability in ethanolic solutions followed vated quantities of the drug in the lipid core and in by in vitro skin permeation studies in Franz diffu- the phospholipid bilayers, respectively, providing sion cells using dorsal skin of the female hairless slow release. The results of this research endorsed mice [100]. Very recently for the treatment of the transdermal competence of this formulation rheumatoid arthritis, etodolac transdermal indicating improved entry of the drug into the skin cubosomes were formulated by emulsification and [103]. homogenization procedures. In this thorough investigation, the prepared nanoparticles were char- (ii) Lipid Nanoparticles acterized and examined for their in vitro permea- Like liposomes and emulsions, solid lipid tion potential across fresh skin of young albino nanoparticles (SLN) and nanostructure lipid carri- mice. Subsequently, a bioavailability study in hu- ers (NLC) were also extensively studied for topical man volunteers was also conducted. Altogether and transdermal drug delivery. But the formerly with the appropriate characteristics, the prepared itemized nanoparticles regulated the release of en- monoolein/poloxamer in aqueous solutions of capsulated drugs and intensified the skin hydration poly(vinyl alcohol) based cubosomes showed en- [106]. Constrained drug loading capability, evic- hanced and controlled transdermal permeation in tion of the encapsulated drugs from the carrier dur- rates [101]. ing storage and high water content in the dispersions are all the critical holdups of SLNs tackled 2.9.6. Lipid-based Carriers by the introduction of NLCs. Based on the compo- (i) Lipospheres sitions and preparation techniques, three different structures of NLCs have been developed. Theyin- Lipospheres/Lipid microspheres are the lipid- clude, (i) imperfect type (distinguished by posi- based microparticulate drug delivery systems tioning of drugs amid triglyceride fatty acid chain which consist of hydrophobic solid lipid interior containing an assortment of lipid structures), (ii) (triglycerides, fatty acid derivatives) containing formless type/amorphous form (obtained by mix- the dispersed/dissolved drugs coated with phos- ing of specific lipids i.e. isopropyl myristate etc., pholipid monolayer on the surface [102]. These for prohibiting the formation of crystals) and (iii) water dispersible, crystal lipid particles, due to multiple type (a structure containing nanocubicles their small dimensions (0.01-100 μm in diameter) of oil-soluble drugs surrounded by a solid and solid lipid matrix contents ensure intimate lipid-resembles w/o/w emulsions) [107, 108]. The contact onto the stratum corneum (intensify the nanosized SLNs and NLCs based TDDS of silde- drug penetration) and control the drug release to nafil citrate were prepared using a customized make it available for the extended period of time high-shear homogenization procedure. Detailed [103, 104]. The numerous dedicated research pa- analysis of its stability, entrapment efficiency, par- pers published during yesteryears upheld the worth ticle size analysis, etc. presented appropriate re- of solid microparticles as exceptional TDDS. The sults. At the end of this comparison study, it was skin permeation enhancement of lipospheres for a concluded that a significant amount of drug was variety of drugs has been reported efficaciously Drug/Vehicle Impacts and Formulation Centered Stratagems Current Drug Therapy, 2019, Vol. 14, No. 3 201 permeated in vitro in the permeation studies con- carbon allotropes having a cylindrical shape. The ducted using full-thickness human skin [109]. diameters of these huge cylindrical large molecules are less than 100nm, hence called as nano- 2.9.7. Polymeric Nanocarriers tubes extended up to several millimeters in length. (i) Dendrimers Single-walled nanotubes and multi-walled nanotubes (made up of single or multiple layers of gra- Dendrimers are nano-entities, monodispersed, phene sheets respectively) are the types of these symmetric, hyperbranched macromolecules which seamless cylinders which allow accommodating have been explored in the area of drug delivery small biomolecules interior, whereas the external due to their workable features. The level of aque- surface of these structures can be customized ous solubility, biocompatibility, less toxicity, mo- chemically by inserting gene and proteins for lecular weight, poly-valency due to the branched transdermal delivery [116]. Fullerenes are caged structures and chemical stability of three-D po- spheroidal carbon molecules made up of 60 carbon lymeric distinct structural design encouraged re- atoms (C60 and the higher homologs C70). These searchers to investigate them in the area of drug hydrophobic orbicular structures of 1nm dimen- delivery systems including TDDS [110, 111]. Poly sions possess hollow interior, can be improved as (amidoamine)/PAMAM dendrimers are the most water-soluble segments by appending the hydro- commonly utilized type of dendrimers in the philic moieties through covalent functionalization TDDS for effectual skin permeation properties. In or encapsulation of cyclodextrin or polyvinylpyr- contrast to the larger PAMAM dendrimers, the rolidone, etc. [116, 117]. There were few research smaller of its kind competently penetrate stratum reports in the recent past with reference to the car- of the skin. It was reported that the surface- bon-based nanomaterials as skin drug delivery sys- modified PAMAM dendrimers diffuse across ex- tems which laid emphasis on further exploration. tracellular routes and conjugating oleic acid in Degim, I.T., et al. studied the potentials of carbon these structures gives rise to the skin permeation nanotubes as TDDS of doxorubicin (weak basic, [112]. Based on the conclusions of several preced- hydrophilic drug) and indomethacin (weak acidic, ing reports, PAMAM dendrimers own cationic hydrophobic drug) for enhanced skin permeation. charges which points towards significant dermal From the conclusion of this analysis, it was in- toxicity. On the other hand, apart from its gaining ferred that these carbon nanotubes could be bene- recognition in the ambit of drug delivery research, ficial in enhancing the skin permeation of hydro- there are huge studies in progress to establish its phobic drugs [118]. A research report on the skin safety [113]. Dendrimer-based transdermal patches permeation mechanisms of pristine fullerene C60 of meloxicam were developed by solvent casting across lipid bilayer of skin was published by evaporation technique and probed for the physico- Gupta, R., & Rai, B. This molecular dynamics chemical as well as in vitro drug release character- simulation analysis suggested that the fullerene istics. The findings of this research articulated en- C60 could be benefitted as capable transferors in hanced drug release of meloxicam attributable to the drug delivery systems [119]. its increased solubility and permeation across membranes [114]. In one of the pioneering studies 2.9.9. Quantum Dots [115], the transdermal delivery of DNA plasmids using PAMAM dendrimers conjugated with HIV Quantum dots are inorganic nanoparticles hav- transactivator of transcription (highly cationic cell ing a diameter of few nanometers (2-10nm). They penetrating peptide) was achieved and tested. Easy received considerable attention due to their skin formulation procedures, troughed cytotoxicity and interacting properties. These semiconductor improved skin permeation are the illustrious out- nanocrystals are made up of group II-VI, III-1V comes of this exploration emphasized in vivo vali- and IV-VI elements present in the Periodic Table dations. [120, 121] such as ZnO, ZnSe, InAs [122], CdSe [123], etc. Similar to the formerly stated type of 2.9.8. Carbon Based Nanomaterials quantum dots, the carbon and graphene quantum dots gained consideration for the reason that these (i) Carbon Nanotubes and Fullerenes nanoparticles possessing biocompatible and less- Carbon nanotubes are stable carbon nanoparti- toxic characteristics [121] are deemed as some of cles which fit into the fullerene structural family of the prerequisites of the drug delivery systems. 202 Current Drug Therapy, 2019, Vol. 14, No. 3 Manickam et al. Degim and Kadioglu (2013) researched the up- through transdermal routes of administration. The shots of ZnO quantum dots for the transdermal authors deliberated that the in vitro permeation permeation of ketoprofen and dexketoperofen as studies performed via cadaver skin to measure up model drugs. The ZnO quantum dots coated with the comparative transdermal absorption rates of the stated model drugs were characterized and the micellar nanoparticle-based estradiol marketed es- skin penetration experiments using rat skin on tradiol gel and estradiol ethanolic solutions di- Franz diffusion cell were conducted. These fluo- vulged the improved skin permeation quantities of rescent nanoparticles accommodate the drugs on micellar estradiol. Further human trial data reiter- their surface as confirmed by zeta potential differ- ate the outstanding transdermal permeation quali- ences between blank and drug-coated quantum ties of micellar nanoparticles. The micellar dots. Due to its large surface area, quantum dots nanoparticles of nicotine were also appreciated in adsorb drugs, and the penetration enhancement of this study [127]. drugs is presumed by adsorption and subsequent 2.9.11. Metal-based Nanoparticles for Enhanced liberation of the drugs [124]. The capability of Transdermal Permeation quantum dots in the transdermal delivery during the course of the in vitro and in vivo studies was (i) Silver and Gold Nanoparticles examined. The study concluded that the CdTe It is very well-apprehended from the past pub- quantum dots of certain sizes are permeable across lished reports that the gold and silver nanoparticles mouse skin. However, its extreme distribution in have potentials of augmenting transport of drugs the multiple organs and the time-consuming clear- across the skin. Gold nanoparticles can be formu- ance prompted the investigators to carry on the lated in diverse sizes and shapes at ease, and upon work in vivo for the interpretation of its mecha- addition of polymers, surfactants, etc. the surface nism of adsorption, metabolism and the level of of these nano-scaled particles could be customized toxicity [120]. The toxicity related to the quantum propitiously [128]. Khayrullin, R. M., et al (2013) dots is a serious matter of concern associated with [129] have experimented the permeation capability their chemical composition which can be con- of gold nanoparticles and the permeation en- fronted by functionalizing the surface of quantum hancement means of the same in combination with dots with biocompatible fragments [121]. organosulfur compounds through the intact and contact dermatitis induced skins. From the dis- 2.9.10. Polymeric Micelles/Micellar Nanoparticles semination of this recent research paper, it was Micelles containing arbutin, a natural skin- noticed that the gold nanoparticles in combination lightening agent for the transdermal delivery has with organosulfur compounds evidenced a consid- been formulated and evaluated for its skin penetra- erable increase in the skin permeation caused no tion ability and melanin suppression efficacy. The loss to the skins. There was an in vivo study con- skin permeation capacities of this formulation ducted in the Sprague Dawley rats with the aim of were analyzed in a Franz diffusion cell using fresh investigating the skin permeation enhancement porcine abdominal skin. The study concluded that capabilities of gold nanoparticles functionalized the micelle-based arbutin could be delivered trans- with PEG and PEG-oleylamine. As a result, this dermally as necessitated [125]. The influence of specific study unveiled the remarkable effect of nano-polymeric micelles comprising plasmid the aforesaid organic solvents on the permeation of DNA transdermal permeability was exhaustively gold nanoparticles through the skin [130]. investigated. The results of the in vitro skin permeation studies (conducted in a Franz diffusion 2.9.12. Gel Based TDDS cell using abdominal skin of nude mouse) and the An increased number of scientific reports pub- in vivo studies on nude mice demonstrated en- lished in recent times on the use of numerous gel hanced transdermal permeability of plasmid [126]. formulations in the drug delivery boulevard wit- In one of the book chapters, Lee, R. W., et al re- nessed its efficiency in delivering drugs through viewed the applications of micellar nanoparticles the skin at enhanced rates. These semi-solid prepa- for transdermal delivery and indicated that this rations of 3-D complex macromolecular construc- particular concept (micellar nanoparticle technol- tions can be sorted as organogels and hydrogels ogy) was in fact conceived for transporting drugs when they retain a hydrophobic or hydrophilic

Drug/Vehicle Impacts and Formulation Centered Stratagems Current Drug Therapy, 2019, Vol. 14, No. 3 203 external solvent segment, respectively [131, 132]. hydrogel formulations. These 3-D polymeric net- A study on the TDDS of diltiazem hydrochloride works absorb and grip large quantity of water in its using organogels, hydrogels and bigels for the en- macromolecular structure made these formulations hanced skin permeability was performed. The dif- look a lot like the biological tissues tenders appro- ferent types of prepared gel formulations were priate compatibility [135]. Several drug release characterized and then investigated for in vitro mechanisms from the hydrogels have been re- percentage drug release using cellophane mem- ported involving diffusion and chemical stimula- brane and in vitro drug permeation studies using tion [136]. With the aim of studying the in vivo rabbit skin. Furthermore, an in vivo study con- water exchange and skin compatibility of trans- ducted in male adult albino rats for the anti- dermal hydrogel patch, a research was conducted hypertensive activity of incorporated drug from in eight human volunteers for 100hours. This par- the selected gel formulations ultimately revealed ticular study revealed that the formulation’s im- the capabilities of the assorted gel formulations in proved compatibility was actually due to its water enhancing the drug permeation through the skin. It exchange attributes [137]. The fusion of lipid was also concluded that the drug release was in- nanovesicles such as liposomes, transfersomes, fluenced by the characteristics of both the drug etc. plus hydrogel for the transdermal drug deliv- and other ingredients including the viscosity of the ery of various drugs was discussed widely under- carrier [131]. scoring its transdermal potentials [135]. A composite hydrogel containing Cortex Moutan extract (i) Organogels for the treatment of atopic dermatitis was fabri- These thermoreversible gels belonging to this cated using thermosensitive poloxamer 407 and category are made up of gelating agents (sorbitan sodium carboxymethyl cellulose. Subsequently, monostearate, sterol, sorbitan monopalmitate, this hydrogel was extensively characterized for its etc.), [133] and liquid organic phase can improve viscosity, surface descriptions, in vitro cytotoxicity drug permeation over the stratum corneum owing and drug release experiments using dialysis bag to their lipophilic characteristics. The capacity of followed by in vivo investigations in porcine ear stationing both lipid and water soluble drugs in its skin. The study results showed the appropriate 3-dimensional network structure, easy formulation safety of the formulation, and then the enhanced techniques, intrinsic extended stability [131] and percutaneous performance of this multifarious hy- biocompatibility made this apolar gels popular es- drogel showed an effect on the presence of sodium pecially in the TDDS for the enhanced permeation carboxymethyl cellulose [138]. Arora, R., et al of drugs. Pluronic lecithin organogels containing (2014) [139] studied the outcome of a nanoemul- sumatriptan for the transdermal delivery were pre- sion-based hydrogel (nano-emulgel) containing pared and evaluated. The findings of this study ketoprofen for the skin delivery. These hydrogels clearly indicated that the tested formulations were prepared using carbomer 940 exhibited enhanced found to have suitable textures and better micro- transdermal permeation of ketoprofen twice that of bial endurance. Above all, the system is safe, sta- the permeation of drug solution and marketed for- ble, and economic displaying an increased drug mulations noticed after an in vivo permeation diffusion rate which was verified all the way study carried out across the excised Wistar rat through the results of in vitro drug release studies skins. The effect of oleic acid as skin penetration conducted using rat abdominal skin. The subse- enhancer in a polaxamer gel based drug delivery quent in vivo studies in albino mice emphasize the systems containing lumiracoxib was studied. The efficacy of this formulation by showing a signifi- results of the in vitro permeation studies conducted cant antinociceptive activity [134]. across full thickness porcine skin showed that the existence of high concentrations of oleic acid in (ii) Hydrogels the gel formulations amplified the drug permeation; conversely, the increased strengths of poly- Gels of this category are comprised of ingredi- mer caused the gel formulations more viscous ents which are soluble in water or dispersed into leading to the decreased permeation of drug across colloidal dimensions, prepared using natural or the skin. Followed by the formerly specified in synthetic hydrophilic polymers, gums etc. The vitro permeation studies, to ensure the safety of simple formulation techniques and their adaptable these drug delivery systems a skin irritation study characteristics are the significant features of the performed on the rabbits showed no incidence of 204 Current Drug Therapy, 2019, Vol. 14, No. 3 Manickam et al. serious skin reactions. The study uncovered the ing polar and nonpolar faces. The facial structure suitability of the investigated formulations of this of the bile salts grants the arrangement of micelles kind in the transdermal drug delivery of drugs in water [150]. Enhanced transdermal permeation [140]. of theophylline was witnessed across shed snake skins using bile salts as permeation enhancers such 3. OTHER PRACTICES FOR ENHANCED as sodium tauroglycocholate and sodium deoxy- PASSIVE TRANSDERMAL DRUG cholate revealed the capabilities of bile salts in DELIVERY amplifying the permeation of theophylline [151]. It has been reported that sodium tauroglycocholate (i) Use of Water for Enhanced Skin Permeation enhances drug permeation in causing disruptions Hydration of the stratum corneum is one of the inside the corneocytes by interacting with keratin essential steps in enhancing the permeation of both filaments. In addition to that, it also makes better hydrophilic and lipophilic drugs. Use of water for permeation of drugs as the effect of the modifica- this purpose has been described and discussed far tions of peptide or protein in the lipid bilayers and wide in the past through many notable publi- [152]. In another interesting study, the effects of cations [141, 142]. Water wetted skin absorbs a film composition and permeation enhancers of the substantial quantity of water within the tissues transdermal films containing ketorolac trometh- cause the swelling of the skin opens up the con- amine werestudied. The permeation enhancement densed assembly of the stratum corneum, thereby effect of sodium glycocholate (trihydroxy bile salt) facilitating the enhanced permeation of drugs on ketorolac tromethamine transdermal films was [143]. found to be increased substantially. It was depicted that multifarious mechanisms were involved in the (ii) Supersaturation Systems penetration enhancement of the said model drug including solubilization and micellar entrapment These systems contain higher drug concentra- of intercellular lipids [153]. The bile salts as edge tions than the saturated solutions could be pro- activators in the ultradeformable liposomes have duced by several procedures such as hot-melt ex- shown improved penetration qualities [154]. trusion technology, heating and subsequent cool- ing and evaporation, etc. Addition of polymers (as CONCLUSION anti-nucleants) to stabilize this thermodynamically variable state prevents crystallization and keeps In addition to the studies discussed in this paper the drug to remain in the solution form [144, 145]. regarding formulation approaches utilized to en- The mechanism of penetration enhancement is ac- hance the transdermal permeation of drugs pas- tually based on the thermodynamic activity of sively, there are also a number of other unique drugs with no modification in the configuration of techniques which have been attempted and re- the skin [146]. With the intention of stabilizing the ported by many researchers. As pointed out previ- saturated solutions of diclofenac, the effects of ously, the stern requirements of the drug mole- mixtures of HPMC and β-cyclodextrin as anti- cules and other factors limit the transdermal drug nucleants were studied. The conclusions of this delivery of drugs passively. To circumvent this investigation showed enhancement in the permea- issue, there are notable non-invasive active trans- tion of the included drug [147]. Diffusion of ibu- dermal delivery procedures such as microneedles profen from supersaturated solutions prepared us- are showing promising results.The recent ad- ing HPMC and β-cyclodextrin as stabilizers was vancements and applications of the pharmaceutical studied across the human skin and showed in- nanotechnology have flourished huge accom- creased flux rates [148]. plishment by establishing several contemporary formulation strategies for the enhanced passive (iii) Bile Salts transdermal delivery of drugs, thereby encouraging the researchers to work further towards this In the several preceding investigations, the po- direction. tential of bile salts in enhancing the transdermal drug permeation has been discussed [149]. The CONSENT FOR PUBLICATION bile salts are ionic, amphiphilic surfactants having a rigid, steroidal structural configuration embrac- Not applicable. 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