INTRODUCTION:

Cardiac arrest occurs when the heart suddenly stops beating. When this happens, blood flow to the brain and the rest of the body also stops. Cardiac arrest is the abrupt loss of heart function in a person who may or may not have been diagnosed with heart disease. Cardiac arrest is a medical emergency. If it is not treated within a few minutes, cardiac arrest most often causes death.

Cardiac arrest is caused by a problem with the heart's electrical system, such as:

a) Ventricular fibrillation (VF) -- When VF occurs, the lower chambers in the heart quiver instead of beating regularly. The heart cannot pump blood, which results in cardiac arrest. This can happen without any cause or as a result of another condition.

b) Heart block -- This occurs when the electrical signal is slowed or stopped as it moves through the heart. Most cardiac arrests are caused by arrhythmias (abnormal heart rhythms) that may not be diagnosed ahead of time. Other causes include:

c) Coronary heart disease

d) Congenial heart disease

e) Heart attack

f) Electrocution, drowning, choking, trauma, respiratory distress

Symptoms of Cardiac Arrest:

Cardiac Arrest Symptoms are very immediate and drastic, and come without any warning:

· Sudden collapse

· No pulse

· No breathing

· Loss of consciousness

· Fatigue and weakness

· Fainting, blackouts, dizziness

· Chest pain, shortness of breath and palpitations

· Vomiting

Skin is the major and most reachable organ of the body, which serves as a prospective way of drug administration for systemic effects. It also acts as a shielding obstacle against the entrance of foreign substances and probable infiltration of pathogens. For a better understanding of the transdermal delivery of drugs, it is essential to know the physiological status of the skin. Anatomically it consists of 3 layers: epidermis, dermis, and hypodermis [1]. Epidermis represents the percutaneous segment constituting different strata like stratum corneum (SC), stratum lucidum, stratum granulosum, stratum spinosum, and stratum germinativum [2]. The SC is a heterogeneous and outermost layer of the epidermis having a thickness of approximately 10-20 μm . There are two diverse forms of cells within the epidermis: keratinocytes and dendritic cells. This SC layer, along with the surface lipid film, forms the interface, which further offers as an application site for topically administered medicines. The dermis is another layer of skin, which is 10-40 times thicker in comparison to the epidermis, depending upon the body area [3]. It is usually made up of loose connective tissue matrix constituting protein and polysaccharides and is less dynamic than the epidermis in terms of metabolism. Blood vessels, nerves, hair follicles, sebaceous glands, sweat glands, mast cells, macrophages, etc. are situated in the dermis [4][5]. The main role of the dermis is to nurture the epidermis. Hypodermis or subcutaneous tissue acts as a fastener for the skin to the underlying surface and fat storage [6]. The determination of release kinetics from therapeutic agent loaded transdermal drug delivery systems is initiated from the estimation of drug substances flux transversely through the skin. Transdermal flux is usually expressed in μg/cm²/h. Mostly a drug follows a passive diffusion process for percutaneous absorption, which can be explained by Fick’s first law of diffusion .According to this flux (J) is a product of the skin diffusion coefficient (D), partition coefficient (K), and drug concentration (C), which is divided by the overall thickness of the skin (h).

J=DKC/h

Transdermal drug delivery involves drug diffusion through distinct layers of the skin into systemic or blood circulation to provoke therapeutic effect. Conventional marketed transdermal products are basically of three types: reservoir, matrix with a rate controlled membrane, and matrix without a rate-controlled membrane [7][8]. Transdermal patches are an effective alternative route to deliver a small drug molecules through the skin into the systemic blood circulation and finally to the target organ [9][10]. It will also be necessary for the delivered drug to reach its target sites and maintain a concentration at the target in therapeutic level [11][12]. However, during this transport process, the drug can undergo severe biochemical degradations and the end products may ineffective and even toxic. Therefore, the drug substances that are used in their controlled release system should not easily degraded during administration and the drug can release as a plateau state in the range between the toxic level and the effective level [13]. The drug in matrix type patch has been increasing in popularity as effective transdermal delivery systems. The drug is dissolved or dispersed in the polymer matrix containing high concentrations of the drug are generally preferred and required that deliver therapeutic agents at a constant rate to the human body. The rate of the drug release from the matrix devices falls off with time, as the drug in the skin-contacting side of the matrix is depleted. Many classes of polymers such as cellulose derivatives, polyvinyl alcohol, carbopol, chitosan, and polyacrylates, have been used for transdermal patches [14][15].

The presence of stratum corneum as the outermost layer produces great challenge for investigators thus making topical delivery a little tedious task [16]. Despite the fact the system is uttermost favorite due to the significant clinical benefits including controlled release rate, no pain, maintaining steady state plasma level and uppermost is avoidance of hepatic first pass metabolism [17]. The aforesaid effects can be advanced by making use of various penetration enhancers (thereby to make upper stratum corneum permeable) for lipophilic drug exhibiting high potency despite of low molecular weight. Iontophoresis (IP) is recently accepted and implemented physical technique showing its effects on direct stratum corneum [18]. The technique deals with the transferring charged molecules into/ through biological membranes or tissues with slight electric current. These current aids in movement of ion across biological membrane using externally applied potential difference [19]. The application of very low voltage (approx. 0.1-5 V) and constant current (0.5mA/cm²) for specifies period of time induces transportation of drug molecule and/or salt of drug molecule through skin. The availability or distribution of drug after treatment depends upon the factors like charge of ion, current intensity, surface of electrode exposed, concentration of drug etc [19,20]. When the membrane involved in this is skin then the process usually referred as transdermal iontophoresis [21].

The technique requires the application of two oppositely charged electrode across skin so as to drive drug molecule with similar charge as electrode by repulsion [22]. The medicated or transdermal patch is a unique device which is meant to be placed over treatment surface with intention to deliver medication into blood stream and to provide advantage of controlled release of drug for longer period of time and marked reduction in dosing of potent drug. The applied patch can be either porous or reservoir type of membrane [23]. Local anaesthetic when applied triggers the chain of sequences initiating many actions on muscles and nerves with marked increase or decrease in circulation to remove drug from site of action. The total plasma level (of local anaesthetic) can be lowered by reversing blood flow patterns to decrease local body distribution of drug. The vasomotor effects of the Lignocaine are concentration dependent [69][70].

Basic Components of TDDS:

a. Polymer matrix / Drug reservoir

b. Drug

c. Permeation enhancers

d. Pressure sensitive adhesive (PSA)

e. Backing laminates

f. Release liner

g. Other excipients like plasticizers and solvents

a. Polymer matrix / Drug reservoir:

Polymers are the heart of TDDS, which control the release of the drug from the device. Polymer matrix can be prepared by dispersion of drug in liquid or solid state synthetic polymer base. Polymers used in TDDS should have good stability and compatibility with the drug and other components of the system and they should provide effective released of a drug throughout the device with safe status [41][68]

The polymers used for TDDS can be classified as:

1 Natural polymers: e.g. cellulose derivatives, zein, gelatine, shellac, waxes, gums, natural rubber and chitosan etc [66].

2 Synthetic elastomers: e.g. polybutadiene, hydrin rubber, polyisobutylene, silicon rubber, nitrile, acrylonitrile, neoprene, butylrubber etc [67].

3 Synthetic polymers: e.g. polyvinyl alcohol, polyvinylchloride, polyethylene, polypropylene, polyacrylate, polyamide, polyurea, polyvinylpyrrolidone, polymethylmethacrylate etc.

The polymers like polyethylene glycol, eudragits, ethylcellulose, polyvinylpyrrolidone 19 and hydroxypropyl methylcellulose are used as matrix type TDDS [42][43][44].

The polymers like EVA, silicon rubber and polyurethane are used as rate controlling TDDS [45][46].

b. Selection of drugs:

The selection of drug for TDDS is based on physicochemical properties of drug. Transdermal drug delivery system is much suitable for drug having [47][48]:

· Extensive first pass metabolism.

· Narrow therapeutic window.

· Short half-life which causes non-compliance due to frequent dosing.

· Dose should be less (mg/day)

· Low molecular weight (less than 500 Daltons).

· Adequate solubility in oil and water (log P in the range of 1-3).

· Low melting point (less than 200°C) [49]

c. Permeation enhancers:

These compounds are useful to increase permeability of stratum corneum by interacting with structural components of stratum corneum i.e., proteins or lipids to attain higher therapeutic levels of the drug [50]. They alter the protein and lipid packaging of stratum corneum, thus chemically modifying the barrier functions leading to increased permeability.

d. Pressure sensitive adhesives:

The pressure-sensitive adhesive (PSA) affixes the Transdermal drug delivery system firmly to the skin. It should adhere with not more than applied finger pressure, be aggressively and permanently tachy and exert a strong holding force. Additionally, it should be removable from the smooth surface without leaving a residue [52][53]. Adhesives must be skin-compatible, causing minimal irritation or sensitization, and removable without inflicting physical trauma or leaving residue. In addition, they must be able to dissolve drug and Excipient in quantities sufficient for the desired pharmacological effect without losing their adhesive properties and skin tolerability. PSAs used in commercially available Transdermal systems include polyacrylate, polyisobutylene, and polysiloxane [54].

e. Backing laminate:

Backing materials must be flexible while possessing good tensile strength. Commonly used materials are polyolefin’s, polyesters, and elastomers in clear, pigmented, or metallized form. Elastomeric materials such as low-density polyethylene conform more readily to skin movement and provide better adhesion than less compliant materials such as polyester. Backing materials should also have low water vapour transmission rates to promote increased skin hydration and, thus, greater skin permeability. In systems containing drug within a liquid or gel, the backing material must be heat-sealable to allow fluid-tight packaging of the drug reservoir using a process known as form-fill-seal. The most comfortable backing will be the one that exhibits lowest modulus or high flexibility, good oxygen transmission and a high moisture vapour transmission rate [55][56].

f. Release Liner:

During storage the patch is covered by a protective liner that is removed and discharged immediately before the application of the patch to skin. It is therefore regarded as a part of the primary packaging material rather than a part of dosage form for delivering the drug. However, as the liner is in intimate contact with the delivery system, it should comply with specific requirements regarding chemical inertness and permeation to the drug, penetration enhancer and water. Typically, release liner is composed of a base layer which may be non-occlusive (e.g. paper fabric) or occlusive (e.g. polyethylene, polyvinylchloride) and a release coating layer made up of silicon or teflon. Other materials used for TDDS release liner include polyester foil and metalised laminates [57].

The Epinephrine, a hormone, neurotransmitter and a sympathomimetic amine interacts with adrenergic receptors (while action varies from tissue type and expression of adrenergic receptors) shows unequivocal relationship between concentration and pain after surgery. The hormone when added exogenously induces pain but prolongs the action (via vasoconstriction effect) results in perfusion of tissue and oxygen availability [51].

Mechanism of action:

Epinephrine augments coronary blood flow generated by chest compressions during cardiopulmonary resuscitation (CPR). Coronary perfusion pressure, operationally defined as the difference between aortic blood pressure and the right atrial pressure, is the major determinant of coronary blood flow. When CPR does not generate coronary perfusion pressure of more than 15–20 mmHg, return of spontaneous circulation (ROSC) rarely or never occurs [25]. After more than a few minutes of cardiac arrest, arterial tone collapses and epinephrine or another vasoconstrictor is essential for restoration of cardiac activity [26][27]. Epinephrine increases aortic pressure during chest compressions via alpha-adrenergic constriction of arterioles, which increases pressure in the proximal aorta [28].

There are no convincing dose–response data for epinephrine use during cardiac arrest and long-term outcome. The original studies used a 1-mg dose of epinephrine, which has been the standard for adult patients ever since.

MATERIALS AND METHOD:

Materials:

Epinephrine, Lignocaine, HPMC, PVA, Ethanol and PVP taken from pharmaceutical laboratory of Shri Shankaracharya Group of Institution, SSGI (Faculty of Pharmaceutical Sciences), Junwani, Bhilai.

Table 1: Formulation table of epinephrine transdermal patches

S. No.	Ingredients	P1	P2	P3	P4
1	Epinephrine (mg)	10	10	10	10
2	Lignocaine (mg)	5	5	5	5
3	HPMC (mg)	10	9	8	7
4	PVA (mg)	10	10	10	10
5	Ethanol (ml)	10	10	10	10
6	PVP (mg)	10	10	10	10

Preparation of patch:

The polymers of HPMC, PVA and PVP were accurately weighed and dissolved in ethanol to prepare 5% solution of Polymer (Polymeric solution). The drug solutions (Lignocaine + Epinephrine) were prepared by dissolving the predetermined amount of drugs in methanolic solution. Thus prepared polymeric solution was poured in glass petri dish (whose diameter was previously measured) to form the backing membrane of the patch. The dish was then dried in hot air oven at 50°C. To the drug solution (Solution A) plasticizer of glycerol was added and thus prepared solution was poured onto the polymeric backing membrane. The prepared plate was dried at 55°C for 4-5 h. After drying the patch was removed and cut into small pieces and evaluated for various parameters.

The polymers of HPMC, PVA and PVP were accurately weighed and dissolved in ethanol to prepare 5% solution of Polymer. The drug solutions (Lignocaine+ Epinephrine) were prepared by dissolving the predetermined amount of drugs in methanolic solution. Thus prepared polymeric solution was poured in glass petri dish (whose diameter was previously measured) to form the backing membrane of the patch. The prepared plate was dried at 55°C for 4-5 h. The dish was then dried in hot air oven at 50°C. To the drug solution (Solution A) plasticizer of glycerol was added and thus prepared solution was poured onto the polymeric backing membrane. After drying the patch was removed and cut into small pieces and evaluated for various parameters.

Characterization:

1. Appearance: The general appearance of tablet is its visual identity and all over elegance, shape, color, surface textures. These all parameters are essential for consumer acceptance.

2. Measurement of Folding Endurance:

The folding endurance was determined manually for the prepared ﬁlms by repeatedly folding the ﬁlm at the same place until it broke. The number of times the ﬁlm could be folded at the same place without breaking or cracking gave the value of folding endurance.[31]

3. Measurement of Weight Variation and Thickness:

The thickness of the patches was assessed at six different points of the patch using a thickness gauze. For each formulation, three randomly selected patches were used. Six ﬁlms from each batch, as a whole, were weighed individually, and the average weights were calculated [32].

4. Determination of Drug Content:

The drug contents in the patches were determined by dissolving 1 cm²patch in 100ml phosphate buffer saline (pH=6.8) and shaken vigorously for 24 h at room temperature. These solutions were ﬁltered through Whatman ﬁlter paper (No. 42). After proper dilution, optical density was measured spectrophotometrically using a UV–VIS spectrophotometer at 274nm against a blank. The drug content was estimated from the calibration curve, which was constructed between 2 and 10µg/ml concentration ranges. The method was validated for linearity, accuracy, and precision.

5. Determination of Moisture Content and Moisture Absorption:

The buccal patches were weighed accurately and kept in desiccators containing anhydrous calcium chloride. After 3 days, the patches were taken out and weighed [33]. The moisture content (%) was determined by calculating moisture loss (%) using the formula:

The buccal patches were weighed accurately and placed in the desiccators containing 100 ml of saturated solution of aluminum chloride, which maintains 76% and 86% relative humidity (RH). After 3 days, the films were taken out and weighed. The percentage moisture absorption was calculated using the formula:

6. Uniformity of dosage unit test:

An accurately weighed portion of the patch is to be cut into small pieces and transferred to a specific volume volumetric flask, dissolved in a suitable solvent and sonicate for complete extraction of drug from the patch and made up to the mark with same. The resulting solution was allowed to settle for about an hour, and the supernatant was suitably diluted to give the desired concentration with suitable solvent. The solution was filtered using 0.2µm membrane filter and analysed by suitable analytical technique (UV or HPLC) and the drug content per piece will be calculated [37].

7. Ex vivo studies:

7.1: Determination of release rate using franz diffusion cell:

The Vertical Franz Diffusion Cell is a simple, reproducible test for measuring the in vitro drug release from creams, ointments and gels. The Franz Cell consists of two primary chambers separated by a membrane. The test product is applied to the membrane via the top chamber- donor compartment. The bottom chamber- receptor compartment contains fluid from which samples are taken at regular intervals for analysis. This testing determines the amount of active drug that has permeated the membrane at each time point. Franz Cells are a widely used methodology to evaluate in vitro drug permeation which has advantages, such as (i) few handling of tissues, (ii) no continuous sample collecting and (iii) low amount of drug required for analysis. With the rise of personalized medicine, it is necessary to develop various pharmaceutical dosage forms for the same active molecule allowing the variability of administration and dosage [58][59][60].

8. Stability studies:

Stability studies are to be conducted according to the ICH guidelines by storing the TDDS samples at 40±0.5°c and 75±5% RH for 6 months. The samples were withdrawn at 0, 30, 60, 90 and 180 days and analyze suitably for the drug content.

RESULTS AND DISCUSSION:

1. Appearance:

The physical appearance test of the patches is done by observing it through sensory organ and following observation is made.

Table 2: Organoleptic properties of transdermal patches

S. No.	Particulars	Result
1	Color	Orangish brown
2	Odour	Aromatic
3	Surface texture	Smooth
4	Shape	Square

2. Folding endurance:

The folding endurance of the prepared transdermal patches was found and given in the table 3:

Table 3: Folding endurance of the transdermal patches

S. No.	Sample	Folding endurance
1	P1	146.2
2	P2	163.3
3	P3	169.2
4	P4	159.9

3. Weight variation:

The weight variation of the prepared transdermal patches was found and given in the table 4:

Table 4: Weight variation of the transdermal patches

S. No.	Sample	Weight variation
1	P1	0.167
2	P2	0.156
3	P3	0.159
4	P4	0.169

4. Thickness:

Thickness of the transdermal patches were measured and given in the table 5:

Table 5: Thickness of the different prepared transdermal patches

S. No	Sample	Thickness
1	P1	0.030
2	P2	0.045
3	P3	0.051
4	P4	0.034

5. Drug content uniformity (%):

The drug content uniformity was measured and given in the table 6:

Table 6: Drug content uniformity of prepared transdermal patches

S. No	Sample	Drug content uniformity (%)
1	P1	98.8
2	P2	94.5
3	P3	91.9
4	P4	97.9

6. Moisture absorption (%) and Moisture loss (%):

The moisture absorption and moisture loss was measured and given in the table 7:

Table 7: Moisture absorption and moisture loss of transdermal patches

S. No	Sample	Moisture absorption	Moisture loss
1	P1	1.4	1.2
2	P2	1.8	1.3
3	P3	2.1	1.7
4	P4	1.5	1.1

7.1 Franz Diffusion Cell Release Rate:

The results of the absorption by the UV spectrospectroscopy by analyzing the concentration of absorption with different time intervals is given in table 8:

Table 8: Absorption rate

S. No	Time	Absorption
1	0min	0.00
2	1min	0.101
3	2.5min	0.301
4	5min	0.426
5	10min	0.501
6	15min	0.714
7	30min	0.919

8. pH:

pH values of the sample is measured by using pH meter. The graph indicates that all the resulted pH values are in range between 4.2–5.4. These values (table 9) indicates that transdermal patch is suitable for topical administration.

Table 10: pH of the different patches

S. No	Sample	pH
1	P1	4.2
2	P2	4.6
3	P3	4.5
4	P4	5.2

9. Stability:

Table 11: Stability data after 7 days

S. No.	Sample		Temperature (⁰C)
		14-21	21-25	25-30
1	P1	Stable	Stable	Stable
2	P2	Stable	Stable	Stable
3	P3	Stable	Not stable	Not stable
4	P4	Stable	Stable	Not stable

Table 12: Stability data after 14 days

S. No.	Sample	Temperature (⁰C)
		14-21	21-25	25-30
1	P1	Stable	Stable	Stable
2	P2	Stable	Stable	Stable
3	P3	Stable	Not stable	Not stable
4	P4	Stable	Stable	Not stable

Table 13: Stability data after 21 days

S. No.	Sample	Temperature (⁰C)
		14-21	21-25	25-30
1	P1	Stable	Stable	Not stable
2	P2	Stable	Stable	Stable
3	P3	Not stable	Not stable	Not stable
4	P4	Stable	Not stable	Not stable

Table 14: Stability data after 28 days

S. No.	Sample	Temperature (⁰C)
		14-21	21-25	25-30
1	P1	Stable	Not stable	Not stable
2	P2	Stable	Not stable	Not stable
3	P3	Not stable	Not stable	Not stable
4	P4	Not stable	Not stable	Not stable

10. Calibration and Absorption of Epinephrine:

The lambda max of the Epinephrine was found to be 196 nm. After the determination of lambda max the calibration curve and absorption are to be evaluated by the UV spectroscopy. The results of the absorption and concentration was given below in the table 15. The regression equation for the calibration curve was

Y=0.1731 X, R2=0.9908.

Table 15: Concentration and absorption of Epinephrine

S. No.	Concentration(ug/ml)	Absorption
1	2	0.050
2	4	0.167
3	6	0.214
4	8	0.494
5	10	0.690
6	12	0.898

DISCUSSION:

The important criterion for selection of components for patches formulation is their compatibility with other component. It has been demonstrated that only few excipients combinations lead to effective transdermal patch formulations.

Maintaining the pH value is significant for determining the stability of the patch because change in pH specifies the occurrence of chemical reactions in the formulation. The resulting pH of sample P1, P2, P3 and P4 is found as 4.2, 4.5, 4.6 and 5.2 respectively.

ACKNOWLEDGEMENT:

Authors want to acknowledge the facilities provided by the Shri Shankracharya Technical Campus, Faculty of Pharmaceutical sciences, Junwani, Bhilai, Chhattisgarh.

CONCLUSION:

Transdermal patch of Epinephrine for cardiac arrest is successfully prepared with different polymers by solvent evaporation method. The present studies were helped in understanding the effect of formulation process variables especially the concentration of different polymers on the drug release profile.

This study is further aimed to perform in vivo studies for analyzing the concentration of Epinephrine reaching into the body and to study its effect, which will help to reduce the dose of Epinephrine transdermal patches and to make its dosage form for treatment of Cardiac Arrest.

REFERENCES:

1. Losquadro WD. Anatomy of the Skin and the Pathogenesis of Nonmelanoma Skin Cancer. Facial Plastic Surgery Clinics. 2017 Aug 1;25(3):283-9.

2. Som PM, Laitman JT, Mak K. Embryology and Anatomy of the Skin, Its Appendages, and Physiologic Changes in the Head and Neck. Neurographics. 2017 Oct 1;7(5):390-415.

3. Somagoni J, Boakye CH, Godugu C, Patel AR, Faria HA, Zucolotto V, Singh M. Nanomiemgel-A novel drug delivery system for topical application-in vitro and in vivo evaluation. PLoS One. 2014 Dec 29;9(12): e115952.

4. Stojic M, Lopez V, Montero A, Quílez C, de Aranda Izuzquiza G, Vojtova L, Jorcano JL, Velasco D. Skin tissue engineering 3. Biomaterials for Skin Repair and Regeneration. 2019 Jun 18:59.

5. Bouwstra JA, Ackaert O, Eikelenboom J, Wolff HM, inventors; UCB Pharma GmbH, assignee. Pharmaceutical composition comprising rotigotine salts (acid or Na), especially for iontophoresis. United States Patent US 8,754,120. 2014 Jun 17.

6. El Maghraby GM. Occlusive Versus Nonocclusive Application in Transdermal Drug Delivery. In Percutaneous Penetration Enhancers Drug Penetration Into/Through the Skin 2017 (pp. 27-33). Springer, Berlin, Heidelberg.

7. Zheng Y, Ouyang WQ, Wei YP, Syed SF, Hao CS, Wang BZ, Shang YH. effects of carbopol® 934 proportion on nanoemulsion gel for topical and transdermal drug delivery: a skin permeation study. International Journal of Nanomedicine. 2016; 11:5971

8. Barry BW. Novel mechanisms and devices to enable successful transdermal drug delivery. European Journal of Pharmaceutical Sciences. 2001 Sep 1;14(2):101-14.

9. Valenta C, Auner BG. The use of polymers for dermal and transdermal delivery. European Journal of Pharmaceutics and Biopharmaceutics. 2004 Sep 1;58(2):279-89.

10. Tracton AA. Coatings Materials and Surface Coatings. CRC Press; 2006 Nov 7.

11. Sanghai P, Nandgude T, Poddar S. Formulation of bilayer benzydamine HCl patch targeted for gingivitis. Journal of Drug Delivery. 2016;2016.

12. Gupta R, Mukherjee B. Development and in vitro evaluation of diltiazem hydrochloride transdermal patches based on povidone–ethylcellulose matrices. Drug Development and Industrial Pharmacy. 2003 Jan 1;29(1):1-7.

13. Kandavilli S, Nair V, Panchagnula R. Polymers in transdermal drug delivery systems. Pharmaceutical Technology. 2002 May;26(5):62-81.

14. Sachan R, Bajpai M. Transdermal Drug Delivery System: A Review. Int J Res Dev Pharm Life Sci 2013; 3: 748-765

15. Dedakia A, Matholiya C, Koyani V, Bhimani D. Three generations: pimary, secondary and tertiary generations of transdermal drug delivery systems: A review. Int J Pharm Sci Res. 2013 Jun 1;4(6):2159-73.

16. Shingade GM, Aamer Q, Sabale PM, Grampurohit ND, Gadhave MV. Review on: recent trend on transdermal drug delivery system. J Drug Deliv Ther 2012; 1: 66-75

17. Wallace SM, Ridgeway B, Jun E. Topical delivery of Lodocaine in healthy volunteers by Electroporation, Electroincorporation, or Iontoporesis: An evaluation of skin Anesthesia. Reg Anesth Pain Med 2001; 26: 229-238.

18. Patel D, Chaudhary SA. Transdermal Drug Delivery System: A Review. Pharma Innovat 2012; 1: 66-75.

19. Rawat S, Vengurlekar S, Rakesh B, Jain S, Srikarti G. Transdermal delivery by iontophoresis. Indian J Pharm Sci 2008; 70: 5-10

20. Menegazzi JJ, Callaway CW, Sherman LD, et al. Ventricular fibrillation scaling exponent can guide timing of defibrillation and other therapies. Circulation 2004; 109:926–931

21. Attama A, Akpa PA, Onugwu LE, Igwilo G. Novel buccoadhesive delivery system of hydrochlorothiazide formulated with ethylcellulose hydroxypropyl methylcellulose interpolymer complex. Scientiﬁc Res Essay. 2008;3(6):26–33

22. Nafee NA, Ahemed F, Borale A. Preparation and evaluation of mucoadhesive patches for delivery of cetylpyridinium chloride (CPC). Acta Pharma. 2003; 199–212

23. Verma N, Wahi AK, Verma A, Chattopadhayay P. Evaluation ofa mucoadhesive buccal patch for delivery of atenolol: in vitroscreening of bioadhesion. J Pure Appl Microbiol. 2007; 1:115–8

24. Attama A, Akpa PA, Onugwu LE, Igwilo G. Novel buccoadhesive delivery system of hydrochlorothiazide formulated with ethyl cellulose hydroxypropyl methylcellulose interpolymer complex. Scientific Res Essay. 2008; 3(6):26–33.

25. Pandit V, Khanum A, Bhaskaran S, Banu V. Formulation and evaluation of transdermal films for the treatment of overactive bladder. Int J Pharm Tech Res. 2009;1: 799–804.

26. Shaila L, Pandey S, Udupa N. Design and evaluation of matrix type membrane controlled Transdermal drug delivery system of nicotin suitable for use in smoking cessation. Indian. Jour. Pharm. Sci. 2006; 68: 179-84.

27. Aggarwal G, Dhawan S. Development, fabrication and evaluation of transdermal drug delivery system - A review. Pharmainfo.net. 2009.

28. Vyas SP, Khar RK. Controlled drug delivery concepts and advances. Vallabh Prakashan. 2002; 1:411-47.

29. Verma PRP, Iyer SS. Transdermal delivery of propranolol using mixed grades of Eudragit: Design and in vitro and in vivo evaluation. Drug. Dev. Ind. Pharm. 2000; 26: 471-6.

30. Gannu R, Vamshi VY, Kishan V, Rao MY. Development of nitrendipine transdermal patches: In vitro and ex vivo characterization. Current. Drug. Delivery. 2007; 4: 69-76.

31. Gordon RA, Peterson TA. Four myths about transdermal drug delivery. Drug Delivery Technology. 2003; 3: 1-7.

32. Williams AC, Barry BW. Penetration enhancers, Advanced drug Delivery Reviews. 2004; 56: 603-18

33. Karande P, Jain A, Ergun K, Kispersky V, Mitragotri S. Design principles of chemical penetration enhancers for transdermal drug delivery, Proceedings of the national academy of sciences of the United States of America. 2005; 102: 4688-93.

34. Foco A, Hadziabdic J, Becic F. Transdermal drug delivery systems. Med. Arch 2004; 58: 230-4.

35. Khengar R.H., Jones S.A., Turner R.B., Forbes B., Brown M.B. Nail swelling as a pre-formulation screen for the selection and optimisation of ungual penetration enhancers. Pharm. Res. 2007; 24:2207–2212.

36. Simon A., Amaro M.I., Healy A.M., Cabral L.M., de Sousa V.P. Comparative evaluation of rivastigmine permeation from a transdermal system in the Franz cell using synthetic membranes and pig ear skin with in vivo-in vitro correlation. Int. J. Pharm. 2016; 512:234–241.

37. Kulkarni K.N., Datta-Gupta A. Estimating Relative Permeability from Production Data: A Streamline Approach. SPE J. 2000; 5:402–411.

38. Sahu GK, Sharma H, Gupta A, Kaur CD. Advancements in microemulsion based drug delivery systems for better therapeutic effects. Int J Pharm Sci Dev Res 1 (1): 008. 2015;15(008).

39. Wahane AR, Karankal S, Sharma P, Khutel D, Singh O, Shardul V, Sabha N, Dewangan J, Dewangan A, Jangde A, Rani C. Pharmaceutical Aspects on the Formulations of Hydrogel: An Update. Research Journal of Pharmaceutical Dosage Forms and Technology. 2018 Jun 20;10(2):79-84.

40. Dapurkar KV, Sahu KG, Sharma H, Meshram S, Rai G. Anti-arthritic activity of roots extract of Boerhaavia diffusa in adjuvant induced arthritis rats. Sch Acad J Pharm. 2013;2(2):107-9.

41. Gupta SS, Sahu G, Sharma M, Chandrakar S, Sahu VD, Sharma G, Dewangan K, Solanki H, Majumdar M, Tripathi DK, Alexander A. Preparation and Optimization of floating microbeads of ciprofloxacin HCl. Research Journal of Pharmacy and Technology. 2016 Jul 1; 9(7):848.

42. Tripathi S, Kumar Sahu U, Tripathi DK, Alexander A, Sharma H, Sahu GK. Formulation and characterization of Virgin Coconut Oil Emulsion (VCOE) for treatment of Alzheimer’s disease. Research Journal of Pharmaceutical Dosage Forms and Technology. 2018 Jun 20;10(2):49-54.

43. Agrawal OP, Agrawal S. An overview of new drug delivery system: microemulsion. Asian J Pharm Sci Tech. 2012; 2(5-12).

44. Sahu GK, Sharma H, Kaur CD. Evolving Concepts and Targeting of Arthritis.

45. Sahu G, Sharma H, Kaur CD. A Novel Approach of Magnetic Modulated Microspheres. science. 2013; 2:5.

46. Sahu G, Sharma H, Dapurkar V, Rai G. Research article; Development and Evaluation of Methotraxate Loaded BSA Microspheres; Int. Res J Pharm. App Sci.; 2012, 2(5): 9-12

47. Bhandarkar A, Sahu SK, Yadav P, Sahu K, Dewangan D, Thapa H, Verma VS, Sharma M, Tripathi DK, Alexander A, Bhatt A. Formulation and Evaluation of Ascorbic acid Lozenges for the treatment of Oral Ulcer. Research Journal of Pharmacy and Technology. 2018 Apr 1;11(4):1307-12.

48. Sharma H, Dapurkar VK, Rai G, Sahu GK. Microemulsions for the Topical Administration of 5-Fluorouracil: Preparation and Evaluation. Research Journal of Pharmacy and Technology. 2012 Aug 1;5(8):5.

49. Tripathi S, Kumar Sahu U, Tripathi DK, Alexander A, Sharma H, Sahu GK. Formulation and characterization of Virgin Coconut Oil Emulsion (VCOE) for treatment of Alzheimer’s disease. Research Journal of Pharmaceutical Dosage Forms and Technology. 2018 Jun 20;10(2):49-54.

50. Jadhav RT, Kasture PV, Gattani SG, Surana SJ. Formulation and evaluation of transdermal films of diclofenac sodium. International Journal of Pharm Tech Research. 2009 Oct;1(4):1507-11.

51. Yairi MB, inventor; Los Gatos Research Inc, assignee. Transdermal patch system. United States patent application US 12/100, 250. 2009 Oct 15.

52. Prausnitz MR, Mitragotri S, Langer R. Current status and future potential of transdermal drug delivery. Nature Reviews Drug Discovery. 2004 Feb;3(2):115.

53. Prausnitz MR. Microneedles for transdermal drug delivery. Advanced Drug Delivery Reviews. 2004 Mar 27;56(5):581-7.

54. Aubin HJ, Bobak A, Britton JR, Oncken C, Billing CB, Gong J, Williams KE, Reeves KR. Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial. Thorax. 2008 Aug 1;63(8):717-24.

55. Lee JW, Park JH, Prausnitz MR. Dissolving microneedles for transdermal drug delivery. Biomaterials. 2008 May 1;29(13):2113-24.

56. Thomas BJ, Finnin BC. The transdermal revolution. Drug Discovery Today. 2004 Aug 1;9(16):697-703.

57. Cormier M, Johnson B, Ameri M, Nyam K, Libiran L, Zhang DD, Daddona P. Transdermal delivery of desmopressin using a coated microneedle array patch system. Journal of Controlled Release. 2004 Jul 7; 97(3):503-11.

58. Yairi MB, inventor; Los Gatos Research Inc, assignee. Transdermal patch system. United States Patent Application US 12/100,250. 2009 Oct 15.

59. Kusum Devi V, Saisivam S, Maria GR, Deepti PU. Design and evaluation of matrix diffusion controlled transdermal patches of verapamil hydrochloride. Drug Development and Industrial Pharmacy. 2003 Jan 1;29(5):495-503.

60. Winblad B, Cummings J, Andreasen N, Grossberg G, Onofrj M, Sadowsky C, Zechner S, Nagel J, Lane R. A six‐month double‐blind, randomized, placebo‐controlled study of a transdermal patch in Alzheimer's disease––rivastigmine patch versus capsule. International Journal of Geriatric Psychiatry: A Journal of The Psychiatry of Late Life and Allied Sciences. 2007 May;22(5):456-67.

61. George TP, Ziedonis DM, Feingold A, Pepper WT, Satterburg CA, Winkel J, Rounsaville BJ, Kosten TR. Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia. American Journal of Psychiatry. 2000 Nov 1;157(11):1835-42.

62. Audet MC, Moreau M, Koltun WD, Waldbaum AS, Shangold G, Fisher AC, Creasy GW, ORTHO EVRA/EVRA 004 Study Group. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a randomized controlled trial. JAMA. 2001 May 9;285(18):2347-54.

63. Barry BW. Novel mechanisms and devices to enable successful transdermal drug delivery. European Journal of Pharmaceutical Sciences. 2001 Sep 1;14(2):101-14.

64. Wick JJ, Weimann LJ, Pollock WC, inventors; Mylan Technologies Inc, assignee. Transdermal patch incorporating a polymer film incorporated with an active agent. United States Patent US 6,010,715. 2000 Jan 4.

65. Mutalik S, Udupa N. Glibenclamide transdermal patches: physicochemical, pharmacodynamic, and pharmacokinetic evaluations. Journal of Pharmaceutical Sciences. 2004 Jun 1; 93(6):1577-94.

66. Arora P, Mukherjee B. Design, development, physicochemical, and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethylammonium salt. Journal of Pharmaceutical Sciences. 2002 Sep;91(9):2076-89.

67. Lee JW, Choi SO, Felner EI, Prausnitz MR. Dissolving microneedle patch for transdermal delivery of human growth hormone. Small. 2011 Feb 18;7(4):531-9.

68. Tiffany ST, Cox LS, Elash CA. Effects of transdermal nicotine patches on abstinence-induced and cue-elicited craving in cigarette smokers. Journal of Consulting and Clinical Psychology. 2000 Apr;68(2):233.

69. Evans HC, Easthope SE. Transdermal buprenorphine. Drugs. 2003 Oct 1;63(19):1999-2010.

70. Eppstein J, McRae S, Smith A, inventors; Altea Therapeutics Corp, assignee. Transdermal drug delivery patch system, method of making same and method of using same. United States Patent US 7,392,080. 2008 Jun 24.

Received on 28.07.2019 Modified on 23.10.2019

Research J. Pharm. and Tech. 2020; 13(4):1684-1692.

DOI: 10.5958/0974-360X.2020.00305.4