QbD Considerations for Topical and Transdermal Product Development

CHAPTER 7

QbD Considerations for Topical and Transdermal Product Development Sadaf Jamal Gilani*, Md. Rizwanullah†, Syed Sarim Imam‡, Jayamanti Pandit§, Mohd. Aqil†, Meraj Alam†, Sarwar Beg¶ *

Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Sakaka, Saudi Arabia Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India ‡ Department of Pharmaceutics, School of Pharmacy, Glocal University, Saharanpur, India § Department of Pharmaceutics, School of Pharmacy, KR Manglam University, Gurgaon, India ¶ Department of Pharmaceutics, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard (Hamdard University), New Delhi, India †

1 INTRODUCTION From the last five decades, the application of optimization process using the design of experiments (DoE) approaches in the field of different pharmaceutical product/process development. In 1967, the first literature reported on the rational use of the optimization process [factorial design (FD)] in a sodium salicylate tablet.1, 2 In another development, Juran invented the term “quality by design (QbD)” in the 1970s and popularized it in the 1990s.3, 4 The typical five-step optimization methodology employed for the formulation development with a complete understanding of the processes was shown in Fig. 1.5, 6 However, quality of this approach was actually suggested by the regulatory authorities (FDA, EMA) at the beginning of the new millennium, recognizing that “quality cannot be tested into products, that is, quality should be built in by design”.7 The systematic experimental optimization of delivery systems includes a careful “screening” of significant variables and subsequent response surface analysis using experimental designs. There are different types of experimental design has been widely used for the optimization of delivery systems. Among all of the experimental designs, factorial and central composite designs (CCDs) have extensively been used for optimization of different formulations.8 The different experimental design approaches like the fractional design, central composite design, and fractional factorial design have been most frequently used for systematic optimization (Fig. 2). Pharmaceutical Quality by Design https://doi.org/10.1016/B978-0-12-815799-2.00008-3

© 2019 Elsevier Inc. All rights reserved.

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Fig. 1 Five-step theory involved for developing optimized drug delivery systems.

Fig. 2 Different experimental designs involved in development of TDDS.

2 QbD-BASED NANOCARRIERS FOR TRANSDERMAL DRUG DELIVERY Transdermal drug delivery systems (TDDS) are sustained and controlled release delivery systems of drugs or other therapeutic agents for local as well as systemic effects via application over the skin surface.9 There are wide ranges of transdermal and topical formulations containing different drugs have been formulated and statistically optimized using the different

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optimization process to get the best formulation. The different formulations have been widely published in the literature using the different QbD approach [Box-Behnken design (BBD), Taguchi design (TD), PlackettBurman design (PBD) for optimization. It provides an understanding of the plausible interaction(s) among the different levels of variables and helps in selecting “the best” formulation with minimal expenditure of time, effort, and developmental cost vis-a`-vis the traditional one factor at a time (OFAT) approach.2 The formulation was optimized using the different independent variables and their effects were observed on the dependent variables.10 The QbD approach was particularly selected because it needs fewer runs and may take three or four independent variables for the optimization. The collected data for each response in each run were statistically analyzed and fitted into the different regression model. The numerical point prediction procedure was applied to optimize the formulation using the desirability function. All the values for formulations of responses were fitted to different kinetic order like first order, second order, and quadratic models. There are many lipid-based formulations (vesicles, colloidal particle, nanoparticles) have been widely optimized using different formulation design approach for the optimization. These TDDS reported for their better applicability for the local and systemic absorption of drugs across skin.10–13 In this chapter, an attempt was made to provide an overall overview of information about QbD-based transdermal delivery systems and to summarize the different major QbD approach used in transdermal/topical drug delivery systems (Table 1).

2.1 Liposomes Liposomes are one of the most famous and extensively studied lipid vesicles, which are typically composed of phospholipids, cholesterol, and an aqueous medium. The phospholipids bilayer membrane structure of liposomes encapsulates both hydrophilic and/or hydrophobic drugs.39 The QbD approach has been used meticulously in developing liposomes by critically analyzing the material attributes influencing the product performance. In this context, Shi et al.14 used three-factor three-level BBD approach for the formulation and optimization of paeonol-loaded liposomes to improve transdermal delivery. The three factors taken for the study were cholesterol concentration (1%–2%, w/w), molar ratio of lipid/drug (1:12–1:8), and carbopol concentration (2%–3%, w/w) and their responses were studied on entrapment efficiency (%), flux, and viscosity (cP) of liposomal gel. Their

Reference

Liposomes Liposomes Niosomes Niosomes Niosomes Niosomes Niosomes Niosomes Transfersomes Transfersomes

Paeonol Alprazolam Lacidipine Pioglitazone Lacidipine Simvastatin Sumatriptan Succinate Diacerin Sildenafil Diclofenac diethylamine, Curcumin

BBD (3-factor 3-level) CCD (4-factor 5-level) FFCD (2-factor 3-level) BBD (3-factor 3-level) BBD (3-factor 3-level) PBD (8-factor 2-level) TD (5-factor 2-level) BBD (3-factor 3-level) PBD (6-factor 2-level) BBD (3-factor 3-level)

14 15 16 17 18 19 20 21 22 23

Transfersomes Trnasfersomes Ethosomes Ethosomes NLCs NLCs NLCs Nanoemulsion Nanoemulsion

Raloxifene hydrochloride Buspirone hydrochloride Tropisetron HCl Ropinirole hydrochloride Pioglitazone Nimesulide Aceclofenac Olmesartan lidocaine prilocaine

Alzheimer’s disease Anxiety Hypertension Diabetes Hypertension Hyperlipidemia Migraine Psoriasis Erectile dysfunction Musculoskeletal disorders, arthritis, Osteoporosis Anxiety Antiemetic Parkinsonian drug Diabetes Inflammation Inflammatory disorder(s) Hypertension Local anaesthetic

24 25 26 27 28 29 30 31 32

Nanoemulsion Nanolipid vesicular Microemulsion gel Nanostructured lipid carriers Microemulsion based hydrogel Pluronic lecithin organogels

β-D-glucan Phosphatidylcholine Agomelatine Silymarin

Antioxidant Osteoarthritis Depression Skin cancer

BBD (3-factor 3-level) FFCD (2-factor 3-level) FFCD (2-factor 3-level) 3(2) FFCD BBD (3-factor 3-level) BBD (3-factor 2-level) BBD (3-factor 3-level) BBD (3-factor 3-level) BBD (3-factor 3-level), PBD design CCD Two-level FD MD 2(3) FFCD

Sertaconazole

Antifungal

FFCD

37

Sinomenine

—

BBD

38

BBD, Box Behnken design; CCD, Central composite design; FFCD, Full factorial design; PBD, Plucketburman design; TD, Taguchi design.

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Formulation design

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Table 1 QbD-based optimized transdermal/topicalnano lipid based delivery Formulation Drug Disease

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results of the study concluded that the developed optimized liposome formulation using cholesterol (2%), lipid/drug (1:12 molar ratio), and carbopol (2.5%) fulfills the criteria of the optimized formulation. The optimized liposomal gel formulation showed entrapment efficiency (68.83%), flux (26.93 μg/cm2/h), and viscosity (2033 cP).14 Hashemi et al.15 developed and optimized alprazolam-loaded nanoliposomes by taking four-factor five-level CCD design for the improved transdermal delivery. The different variables used for the CCD design were the solvent/nonsolvent volume ratio (0.2–0.5), phospholipid concentration (mg/mL), alprazolam concentration (mg/mL), and cholesterol content (2.5%–10%, w/w). These formulations variables were assessed on the responses vesicle size (nm) and entrapment efficiency. The results indicated that CCD design showed the optimized nanoliposomes formulation composition of solvent/nonsolvent volume ratio (0.425), phospholipid (15.87 mg/ mL), alprazolam (0.875 mg), and cholesterol (7.5%). The optimized liposomal formulation exhibited vesicle size and entrapment efficiency of 121.63 nm and 93.08%, respectively. The results indicated that increase in phospholipid, alprazolam, and cholesterol concentration leads to an increase in the vesicle size as well as entrapment efficiency shown by the CCD design. In another research Duangjit et al.40 used nonlinear response surface method incorporating multivariate spline interpolation (RSM-S) is used for the optimization transdermal formulations. The formulation characteristics (Xn), including vesicle size (X1), size distribution (X2), zeta potential (X3), elasticity (X4), drug content (X5), entrapment efficiency (X6), release rate (X7), and the penetration enhancer (PE) factors as formulation factors (Zn), with the type of PE (Z1) and content of PE (Z2) were used as causal factors of the response surface analysis. The intended responses were high skin permeability (flux, Y1) and high stability formulation (drug remaining, Y2). Based on the dataset obtained, the simultaneous optimal solutions were estimated using RSM-S. The analysis and simulation indicated that X4, X5, and Z2 were the prime factors affecting Y1 and Y2. These findings suggest that this approach could be useful for evaluating the reliability of an optimal transdermal liposome formulation predicted by RSM-S.40 Madecassoside (MA) liposomes were optimized by response surface methodology to enhance wound healing effects. In this study, the design was adopted to yield the optimal preparation conditions of MA double-emulsion liposomes with an average particle size of 151 nm and encapsulation efficiency of 70.14%. The transdermal property and wound cure effect of MA double-emulsion liposomes were superior to those of MA film dispersion liposomes.41

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2.2 Niosomes Niosomes are self-assembling nonionic vesicle systems also called as nonionic liposomes formed from nonionic surfactants in an aqueous environment. It has high potential to act as carriers for poorly soluble drugs.42, 43 Niosomes are vesicular nanocarriers and have gained much attention as novel drug delivery systems in the last three decades due to their unique characteristics for providing the enhanced solubility and bioavailability for poorly soluble drugs.44, 45 Imam et al.11 fabricated and optimized four-factor three-level QbD-based proniosome for transdermal delivery of risperidone. The factors used for the optimization study were span 60 (70–110 mg), cholesterol (5–15 mg), phospholipon 90 G (90–110 mg), and risperidone concentration (15–25 mg). The responses studied were the vesicle size (nm), encapsulation efficiency (%), and flux (μg/cm2/h). The selection of optimized risperidone niosome formulation was done on the criteria of attaining the minimum vesicles size and maximum % encapsulation efficiency and flux, by applying the point prediction method. The results showed the optimized niosomes formulation exhibited the vesicles size of 498.43  1.27 nm, entrapment efficiency of 90.43%  1.21%, and the flux across rat skin was 117.42  8.61 mg/cm2/h. Further, the data were fitted to various models and was observed that the best-fitted model for all the four-dependent variables was the quadratic model. The regression equation given by design showed positive value in the equation for a response represents an effect that favors the optimization (synergistic effect), whereas a negative value indicates an inverse relationship (antagonistic effect) between the factor and the response.46 Soliman et al.16 were prepared lacidipine encapsulated proniosomes and optimized using 23 full FD for improved transdermal delivery. The independent variables used in the study were the cholesterol (10–20 mg), soya lecithin (40–80 mg), and cremophor RH 40 (180–270 mg) and their effects were observed on the vesicle size (nm), entrapment efficiency, (%) and release efficiency (%). The results indicated that the optimized niosomal formulation composition developed using cholesterol (10 mg), soya lecithin (80 mg), and cremophor RH 40 (270 mg) exhibited the low vesicles size (162.43  0.77 nm), high entrapment efficiency (98.01%  0.68%), and release efficiency (88.33%  2.43%). The in vitro permeation through excised rabbit skin study revealed significantly higher flux (6.48  0.45) for lacidipine from the optimized proniosomal gel in compare to the emulgel (EG) (3.04  0.13) mg/cm2/h. Moreover, the optimized formulation

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exhibited significantly improved AUC0-t was evaluated for its bioavailability compared with the commercial product.16 Other research group developed methotrexate (MTX)-loaded niosomes for dermal drug delivery system in treatment of psoriasis. Box-Behnken (BB) design was used to optimize MTX proniosome gels using span 40, cholesterol (Chol-X1) and tween 20 (T20-X2), and short-chain alcohols (X3) [namely ethanol (Et), propylene glycol (Pg), and glycerol (G)]. The responses showed a significant effect on vesicles size (Y1), entrapment efficiency (Y2), and zeta potential (Y3). MTXloaded niosomes were formed immediately upon hydration of the proniosomes gels with the employed solvents. Addition of Pg resulted in a decrease of vesicular size from 534 to 420 nm as Chol percentage increased from 10% to 30%, respectively. The use of Et in proniosomal gels abolish Chol action to increase the zeta potential value and hence less stable niosomal dispersion was formed. The optimized formula of MTX-loaded niosomes showed vesicle size of 480 nm, high EE% (55%), and zeta potential of –25.5 mV, at Chol and T20 concentrations of 30% and 23.6%, respectively.47 In another study, Aziz et al.48 prepared diacerein niosomes as a transdermal delivery system and using film hydration technique. The formulation was optimized by employing CCD using three-level three-factor for attaining optimal niosomes formulation with the desired characteristics. The formulation was optimized by taking three formulation variables amount of salt in hydration medium (X1), lipid amount (X2), and number of surfactant parts (X3) and their effects were assessed on entrapment efficiency percent (Y1), particle size (Y2), polydispersity index (PDI) (Y3), and zeta potential (Y4). The values of the independent variables (X1, X2, and X3) in the optimized niosomes formulation were 0 g, 150 mg, and five parts, respectively. It showed high entrapment efficiency (95.63%), low particle size (436.65 nm), and PDI (0.47) with optimum zeta potential (–38.80 mV). The results revealed that a transdermal niosomal system was successfully prepared and evaluated using CCD which will result in delivering diacerein efficiently.48 In another study by Kumar and Goindi49 statistically optimized itraconazole hydrogel using nonionic surfactant vesicles (NSVs). The formulations were screened using first-order TD and further optimized via D-optimal design involving factors (surfactant type, content, and molar ratio of cholesterol:surfactant). The used screened response factors were investigated as percent drug entrapment, vesicle size, drug skin retention, and skin permeation in 6 h. The ex vivo studies in rat skin depicted that optimized formulation augmented drug skin retention and permeation in 6 h compared to conventional cream and oily solution. The rapid alleviation of infection

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in animals treated with optimized hydrogel was observed in comparison to commonly used formulation.49 Abdelbary et al.12 reported BBD using Design-Expert software to statistically optimize formulation variables for the development of MTX niosomes for management of psoriasis. MTX niosomes were prepared by thin-film hydration technique using three independent variables as MTX concentration in hydration medium (X1), total weight of niosomal components (X2), and surfactant:cholesterol ratio (X3). The effects of variables were observed on the encapsulation efficiency (Y1) and particle size (Y2) as dependent variables. The optimized formulation displayed spherical morphology under transmission electron microscopy (TEM), particle size of 1375 nm and high EE% of 78.66%. In vivo skin deposition study showed that the highest value of percentage drug deposited (22.45%) and AUC0–10 (1.15 mg h/cm2) of MTX from niosomes was significantly greater than that of drug solution (13.87% and 0.49 mg h/cm2), respectively. Concisely, the results showed that the optimized MTX delivery using QbD approach might be used topically applied niosomes for enhanced treatment of psoriasis.12

2.3 Transfersomes Transfersomes also comes under lipid vesicle composed of several phospholipid bilayers with an additional component, that is, the edge activator (EA). This concept has been described for the first time by Cevc et al. in 1992 who named this type of ultra-deformable liposome “transfersomes”.50 Ahmad et al.22 developed sildenafil transfersomes using six-factor two-level PBD to improve transdermal delivery. They used independent variables were the drug to phospholipid molar ratio as X1 (1:10–1:6), phospholipid to surfactant ratio as X2 (75:25–95:5), surfactant HLB as X3 (4.3:15), hydration medium pH as X4 (5.5–7.5), hydration time as X5 (30–120 min), and hydration temperature as X6 (2–20°C). The effect responses were studied on the vesicle size (nm) and entrapment efficiency (%) and the optimized transfersomal formulation was composed of 1:2 95:5, 4.3, 7.5, 120, and 20 of X1, X2, X3, X4, X5, and X6, respectively and exhibited the vesicles size of 602 36 nm and entrapment efficiency of 92.16%  3.15%. The PBD assessed that surfactant HLB value and hydration medium pH showed was found to be more influential factors on vesicle size and entrapment efficiency. Further, in vitro permeation result of the sildenafil transfersomes showed more than fivefold higher permeation rate compared with sildenafil

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suspension.22 In another study, Ahad et al.51 developed valsartan nanotransfersomes and optimized using four-factor three-level BBD. They have taken phospholipon 90 G (75–95 mg), sodium deoxycholate (5–25 mg), valsartan (40–80 mg), and sonication time (15–35 min) as independent variables for the study and their effects were observed on vesicle size (nm), entrapment efficiency (%), and flux (μg/cm2/h). The point prediction results showed by design indicated that optimized nanotransfersome condition was observed with phospholipon 90G (85 mg), sodium deoxycholate (15 mg),valsartan (60 mg), and sonication time of 25 min. The optimized formulation showed the greater entrapment efficiency (85.77%  2.97%), transdermal (627.47  30.45 μg/cm2/h), and low vesicles size (130  10 nm). The BBD optimized valsartan nanotransfersomes exhibited significantly improved antihypertensive efficacy compared to conventional liposome.51 The applicability of BBD design was further used by Chaudhary et al.52 by formulating nano-transfersomes of diclofenac diethylamine (DDEA) and curcumin (CRM). They have taken 33 FD (BB) to derive a polynomial equation (second order) to construct two-dimensional (2D) (contour) and three-dimensional (3D) (response surface) plots for prediction of responses. The independent variables used for this study were ratio of lipid to surfactant (X1), weight of lipid to surfactant (X2) and sonication time (X3), while entrapment efficiency of DDEA and CRM (Y1 and Y2), effect on particle size (Y3), flux of DDEA and CRM (Y4 and Y5) were taken as the dependent variables. The design established the role of the derived polynomial equation, 2D and 3D plots in predicting the values of dependent variables for the preparation and optimization of nanotransfersomes for transdermal drug release.52 Timolol maleate-loaded transdermal protransfersomal system was developed by film deposition using two 23 full FDs to investigate the influence of three formulation variables. The variables used were phosphatidyl choline: surfactant molar ratio, carrier:mixture and the type of SAA and their effect observed on particle size, drug entrapment efficiency, and release rate. The optimized protransfersomal system had excellent permeation rate through shaved rat skin (780.69 μg/cm2/h) and showed 6 times increase in relative bioavailability with prolonged plasma profile up to 72 h. A potential protransfresomal transdermal system was successfully developed and FD was found to be a smart tool in its optimization.53 Mahmood et al.24 formulated and statistically optimized raloxifene hydrochloride transfersomes delivery. The formulation was optimized using response surface methodology (BB experimental design) by taking independent variables phospholipon 90G, sodium deoxycholate, and sonication

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time at three levels, while entrapment efficiency, vesicle size, and flux were identified as dependent variables. The optimized transfersomes has shown particle size of 134  9 nm, entrapment efficiency of 91.00%  4.90%, and flux of 6.5 1.1 μg/cm2/h with spherical, unilamellar structures, and low PDI (0.08). The statistically optimized transfersomes proved significantly superior in terms of drug permeated and deposited in the skin, with enhancement ratios of 6.25  1.50 and 9.25  2.40, respectively, when compared with drug-loaded conventional liposomes, and ethanolic phosphate buffer saline. These findings proved that a statistically optimized transfersome formulation found to be a superior alternative to conventional optimization process.24

2.4 Ethosomes Ethosomes are vesicles composed of water, high content of ethanol (up to 45%), and phospholipids.54, 55 The high concentration of ethanol provides soft, flexible vesicles, which easily penetrate into the deeper skin layers enabling enhanced drug delivery. It has the ability to improve the access for both highly hydrophobic and highly hydrophilic drugs to the skin deep layers.56 Ahad et al.13 developed and optimized valsartan nanoethosomes using four-factor three-level BBD for enhanced bioavailability via transdermal delivery. The phospholipon 90 G (50–80 mg), ethanol (20–50 mL), valsartan (40–80 mg), and sonication time (2–8 min) were taken as independent variables and their result of the study indicated that optimized nanoethosome made up of mid-value of all independent variables showed the entrapment efficiency of 89.34%  2.54% with vesicles size and transdermal flux across rat skin of 103  5.0 nm and 801.36  21.45 μg/cm2/h, respectively. The 3D graph shown by BBD explained that increase in phospholipon 90 G concentration and significantly increased vesicle size, entrapment efficiency, and flux. Increase in sonication time resulted in the decrease in vesicle size and entrapment efficiency while the increase in flux. In vivo pharmacokinetic study using Wistar rats showed that nanoethosomal formulation exhibited 3.03 fold improved bioavailability compared to the oral suspension of valsartan.13 In our laboratory, another study based on BBD applied fisetin transethosomes formulation for dermal delivery using Lipoid S 100, ethanol, and sodium cholate as independent variables. The results demonstrated that the optimized formulation presented vesicle size of 74.21  2.65 nm, entrapment efficiency of 68.31%  1.48%, and flux of 4.13  0.17 mg/cm2/h.

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The present study data revealed that the optimized transethosomes vesicles formulation was found to be a potentially useful drug carrier for fisetin dermal delivery.57 In another study CCD was used to optimize piroxicam transethosomal gel using the concentration of lipids and ethanol was kept in the range of 2%–4%, w/v and 0%–40%, v/v, respectively. The optimized formulation was incorporated in hydrogel and compared with other analogous vesicular (liposomes, ethosomes, and transfersomes) gels for the aforementioned responses. The polynomial equation of CCD showed that soya phosphatidylcholine (SPL 70) and ethanol in different percentage was found to affect drug retention in the skin, drug permeation, vesicle size, and entrapment efficiency. It was observed that the CCD optimized transethosomes were found superior in all the responses compared to other vesicular formulations with improved stability and highest elasticity.58 Ahmed et al.59 developed and optimized transdermal tramadol nanoethosomes using three-factor three-level BBD for improved analgesic efficacy. The independent variables phospholipon 90 G (40–70 mg), ethanol (15–45 mL), and sonication time (3–9 min) were used for the optimization. The optimized nanoethosome formulation showed the entrapment efficiency of 65.87%  3.24% with vesicles size and flux across rat skin of 108.6  4.45 nm and 129.65  15.87 μg/cm2/h, respectively. As per 3D graph generated by the BBD concluded that increase in phospholipon 90 G concentration significantly increased the vesicle size and entrapment efficiency with the reduction in flux. The ethanol concentration and sonication time increased, vesicle size, entrapment efficiency, and flux decreased proportionally.59 Jain et al.60 formulated diclofenac ethosomal formulations for enhanced antiinflammatory activity using QbD approach. The ethosomal formulations were prepared using 4  5 full FD with phosphatidylcholine:cholesterol (PC:CH) ratios ranging between 50:50 and 90:10, and ethanol concentration 0%–30% as formulation variables. The results of multivariate regression analysis illustrated that vesicle size and elasticity of ethosomes was dominating physicochemical properties affecting skin permeation. The interaction of formulation variables had a significant effect on both physicochemical properties and permeation kinetics. The optimized formulation showed permeation flux 12.91.0 μg/cm2/h, which was significantly higher than the drug-loaded conventional liposome, ethanolic or aqueous solution.60 In another study, methoxsalen ethosomes-based hydrogel formulations were formulated and optimized by CCD for effective topical treatment against vitiligo. The optimized ethosomes have shown

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nanometric size, high encapsulation efficiency and significant skin permeation, and accumulation in the epidermal and dermal layers. In a nutshell, the CCD-based statistically optimized ethosomes hydrogel formulation was found to be a promising drug delivery system demonstrating reduced phototoxicity and erythema, thus leading to improved patient compliance for the treatment against vitiligo.61 Another CCD-based raloxifene hydrochloride ethosomes was developed and optimized for transdermal delivery.62 The influence of lipid and ethanol concentration on vesicle size and entrapment efficiency was extensively investigated using response surface methodology. The CCD-based optimization was done and validated using check point analysis and the optimized batch possessed 403 nm size and 74.25% drug entrapment. The ex vivo skin permeation study revealed a flux of 4.621 μg/cm2/h through the intact pig ear skin which was further enhanced through the microporated skin (flux, 6.194 μg/cm2/h) with a 3.87-fold rise when compared to drug permeation from plain solution applied over intact skin (flux, 1.6 μg/cm2/h).

2.5 Invasomes Invasomes are terpene-based lipid vesicular delivery system having a size range <150 nm. They are composed of phosphatidylcholine, ethanol, and terpenes (alone or blend of terpenes). The terpenes are the most important constituents, which act as potent PEs.63 Imam et al.10 developed terpeneloaded risperidone invasomes with phospholipid, safranal, and ethanol. The three-factor three-level BBD was used to statistically optimize soft lipid vesicle using safranal, ethanol, and phospholipid as independent variable, while their effect was observed for vesicle size (81.28–153.87 nm), entrapment efficiency (70.43%–89.74%), and flux (97.43–182.65 μg/cm2/h). The optimum values of safranal (0.85%, w/v), ethanol (5.78%, w/v), and phospholipid (8.65 mg) were selected and were found to fulfill requisites of an optimized risperidone soft lipid vesicle. The extent of absorption from BBD optimized formulation was greater when compared to oral risperidone suspension with the relative bioavailability of 177%. All the developed formulations responses were fitted to different kinetic order like first order, second order and quadratic models and the best-fitted model was found to be quadratic.63 In another study, research group studied another work on development and optimization using BBD design of terpene-loaded ethosomes (invasomes) carrier for isradipine using phospholipon 90G, b-citronellene (terpene), and ethanol. The results of the study revealed that

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prepared isradipine-loaded invasomes deliver ameliorated flux (22.80  2.10 mg/cm2/h through rat skin), reasonable entrapment efficiency (88.46%), and more effectiveness for transdermal delivery. The isradipine invasomes formulation was found to be effective, with a 20% reduction in blood pressure by virtue of better permeation through Wistar rat skin. The study concluded that the BBD optimized isradipine invasomes accentuate the flux and the results obtained encouraged the use as the formulation for the potential management of hypertension.64 In our lab, we have formulated, optimized, and evaluated the transdermal potential of olmesartan novel vesicular nano-invasomes using BBD. The optimized olmesartan invasomes formulation showed vesicles size of 83.35  3.25 nm, entrapment efficiency of 65.21%  2.25%, and flux of 32.78  0.703 (μg/cm2/h) which were found in agreement with the predicted value generated by BBD. It was concluded that the response surfaces estimated by Design-Expert illustrated an obvious relationship between formulation factors and response variables and nano-invasomes were found to be a proficient olmesartan transdermal carrier.65

2.6 Nanoemulsion Nanoemulsion (NE) is a thermodynamically stable isotropically clear dispersion of two immiscible liquids (oil and water), and stabilized by an interfacial film of surfactant molecules.31 Ngan et al.66 also developed and optimized NE containing fullerene for transdermal delivery. The optimization of fullerene NEs was done by employing response surface methodology (BBD and CDD), which involved statistical multivariate analysis. The variables were the effect of the homogenization rate, sonication amplitude, and sonication time on the particle size, ζ-potential, and viscosity. The central composite rotatable design model and BBD model suggested that the response variables for particle size, ζ-potential, and viscosity of the fullerene NE were 152.5 nm, –52.6 mV, and 44.6 pascal seconds, and 148.5 nm, –55.2 mV, and 39.9 pascal seconds, respectively. The suggested process parameters to obtain optimum formulation by both models yielded actual response values similar to the predicted values with the residual standard error of <2%.66 Another transdermal NE-based delivery system was developed and optimized containing ceramide IIIB using phase-inversion composition. The RSM was employed to study the effect of water content (30%–70%, w/w), mixing rate (400–720 rpm), temperature (20°C–60°C), and addition rate (0.3–1.8 mL/min) on droplet size

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and PDI. The mathematical model of RSM showed that the optimum formulation conditions for ceramide IIIB NE with desirable criteria were a temperature of 41.49°C, addition rate of 1.74 mL/min, water content of 55.08 w%, and mixing rate of 720 rpm. Under optimum formulation conditions, the corresponding predicted response values for droplet size and PDI were 15.51 nm and 0.12, respectively, which showed excellent agreement with the actual values (15.8 nm and 0.108), with no significant differences.67 De mattos et al.68 used application of full FD in cutaneous chalcone NEs as drug delivery systems for enhanced topical effect. The formulations were optimized by experimental design approach to check the influence of two independent variables (type of surfactant-soybean lecithin or sorbitan monooleate and type of co-surfactants—polysorbate 20 or polysorbate 80) on the physicochemical characteristics and skin permeation/retention of the synthetic chalcone in porcine skin. The formulation composed of soybean lecithin and polysorbate 20 showed droplet size 171.9 nm; zeta potential –39.43 mV; viscosity 2.00 cP), and the highest retention in dermis (3.03 μg g( 1)).68 Aqil et al.31 developed olmesartan-loaded NE and optimized using three-factor three-level BBD for improved bioavailability via transdermal delivery. The independent variables under study were the concentration of oil (3%–10%, v/v), Smix (mixture of surfactant and co-surfactant; 25%– 40%, v/v), and water (45%–60%, v/v) and their effects studied on droplet size (nm), PDI, and flux (μg/cm2/h). Their results indicated that this optimized NE showed droplet size, PDI, and flux 53.11  3.13 nm, 0.335  0.008, and 12.65  1.60 μg/cm2/h, respectively.31 In another study NE-based EG formulation was developed and optimized as a potential vehicle for topical delivery of tea tree oil (TTO) using CCD. The optimized NE shown particle size and zeta potential of 16.23  0.411 nm with efficient permeation (79.58 μL/cm2) and flux value (JSS) of 7.96 μL/cm2/h through the skin in 10 h. The antimicrobial evaluation of EG with same the amount of TTO as conventional gel revealed broader zones of growth inhibitions against all the selected microbial strains.69

2.7 Lipid Particulate Carriers The lipid-based drug delivery systems (SLN, NLCs, LDC) are the most promising areas of research in drug delivery system and have shown better encapsulation efficiency and drug loading. It has the capability to improve

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the solubility and bioavailability of poorly water-soluble and/or lipophilic drugs.70–73 It can accommodate more drug molecules, minimize drug expulsion, and modify the drug release profile by varying the lipid matrix.74–77 Diflunisal phospholipid complex (DIF-PL complex) was prepared by the solvent-evaporation method and incorporated into supramolecular nanoengineered lipidic carriers (SNLCs) for transdermal delivery.78 The optimization exercise was done using face centered cubic design (FCCD) after the screening of variables by L8 Taguchi orthogonal array design. The optimized SNLC formulation depicted average particle size (188.1 nm), entrapment efficiency (86.77%  3.33%), permeation flux (5.47  0.48 μg/cm2/h), and skin retention (17.72  0.68 μg/cm2). The results of mice ear edema depicted significant inhibition of ear edema (76.37%  12.52%; P < .05). Hence, it can be concluded that QbD applied dual formulation strategybased SNLCs were promising in the treatment of pain and inflammation associated with rheumatoid arthritis. The QbD-oriented aceclofenac-loaded nanostructured lipid carriers (NLCs) were evaluated using different lipids and surfactants components. A 33 FD was used for optimization of NLCs and evaluating them for different critical quality attributes (CQAs), viz., particle size, PDI, zeta potential, in vitro drug release, and entrapment efficiency. The optimized ACE-NLCs were found to be spherical, nanometric in size with higher drug loading and entrapment efficiency and showed better cell uptake efficiency on hyperkeratinocytic cells (HaCaT cell lines) with higher ex vivo skin permeability efficiency visa`-vis marketed formulation.30 Keshari and Pathak79 developed topical econazole nitrate NLCs by solvent injection technique and further optimized using CCD. The design guided the selection of five NLC formulations which were converted to hydrogels (G1–G5) using Carbopol 934. The permeation studies of gels demonstrated G3 with flux rate of 3.21  0.03 μg/cm2/min as the best formulation that exhibited zero-order permeation. The amount of drug/unit area demonstrated linear dependency on flux rate. In another study, Alam et al.28 optimized pioglitazone transdermal NLCs using three-factor three-level BBD to treat diabetes. The independent variables under study were the total lipid (1%–3%), ratio of liquid lipid:total lipid (0.9–1), and pioglitazone (30–50 mg). The point prediction data revealed that the optimized NLC shown particle size (166.05 nm), drug loading (10.41%), and flux (47.36 mg/cm2/h). The polynomial equation generated from DesignExpert software depicted that as the concentration of all independent variable increased there was significant increase in the values of all the dependent

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variables. The three-factor two-level BBD is used for the optimization of nimesulide NLCs for improved transdermal delivery.29 The independent variables under study were the ratio of stearic acid:oleic acid (7:3–9:1), poloxamer 188 (1%–2%, w/w), and lecithin (0.5%–1.5%, w/w) and their results revealed that the optimized formulation showed nanoparticle size, high entrapment efficiency, and flux. The 3D plots were prepared for all the three responses and were shown for all three responses. These plots are known to study the interaction effects of the factors on the responses as well as are useful in studying the effects of two factors on the response at one time.

3 CONCLUSION Pharmaceutical QbD widely used in the optimization of transdermal and topical delivery systems. These approaches mainly depend upon the understanding of both the product and the process. The purpose of this chapter is to provide a background of different QbD approach in different TDDS. The optimization processes is required for an accurate research in these fields and therefore, the right implementation is carried out for different design approach at industrial scale. This chapter overviews the use of the QbD in transdermal and topical research areas. The perspectives and development priorities are drawn to improve the implementation of this integrative approach of quality and safety in transdermal delivery systems.

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