INTRODUCTION:

A wound can be defined as a defect on the epidermal layer of the skin due to the thermal physical or any external foraging material that damage the skin result of the existence of a medical or physiological situation.¹ Topical route is one of the most sophisticate and common route of administration of drug delivery. It is generally recognized as a first line therapy in case of skin condition. Most of drugs are given either oral route or parental rout, even when disease sites are on surface of the skin or in its layer. However when any reason both oral and parental rout are not possible then apply to topical route for drug administration.²

When the drug is given through the oral route they may be cause to poor absorption, irritation of the GIT track either decrease the potency of the drug at the site of action although the same of the parental route are also produce some unwanted and toxicity effect on multiple orange of the body. Hence not vary use until and unless for the clinical purpose topical route are used.³ Primary and vital advantage of topical route that it’s avoids the exposure of drug molecules from the skin surface. While when the drug is direct apply to the affected areas they produce the batter bioavaibility and instate of the action of drugs. But inability to attained the desired concentration of the local of the disease. However make the topical dosage form ineffective and they should be not irritant to skin.^3,4

The key challenge of prepare to topical drug is the tough keratinized upper layer of the skin especially in case of disease condition which make the delivery of drug is extremely difficult. Beside the other specific problem are stability, permeability and solubility of the drug.

Merits and Demerit of topical drug delivery:⁵

Merits:

1. Convenient and easy to apply.

2. Avoidance of first pass metabolism.

3. Drug delivery is more selectively of the specific site.

4. Reduce the frequency and cost of treatment.

5. Improve the patient compliance and reduce the specialized healthcare personnel in hospital.

Demerits:

1. Poor permeability of drugs to penetrate through skin.

2. Can cause allergic reaction on targeted site

3. Limited suitability of drug molecule.

4. Manufacturing problem such as packaging of finished product. Etc

Human skin: human skin is the outer most layer of the body it is approx 1.5 to 2 M² length in adults person hence it is the largest organ in human body. Human skin contains some sensory organ such as sweat gland, sebum gland, hair follicles, veins and cutaneous nerve. Skin is also protected our internal organ from physical pathogen. Generally skins are divided into two parts epidermis and dermis layer.⁶

Figure No. 1: Structure of Skin

Epidermis: Epidermis is the superficial layer of the skin it is consist of stratified keratinized squamous epithelium cell. Thickness of the epidermis layer are varies on the different position of the skin due to deposing of adipose tissue and its help to storage of oxygen and energy.^6,7

Epidermis can be divided into the following 5 sub layers:

· Stratum corneum

· Stratum lucidum

· Stratum granulosum

· Stratum spinosum

· stratum basal

· Stratum corneum: stratum corneum is the uppermost layer of the epidermis skin, generally stratum carneum is 20-30 layers of cells and made of dead keratinocytes and horny scales thickness of the stratum corneum is varies on different site of body organ. The dead keratinocytes secrete defenses which is the part of our immune system.^6,7

· Stratum lucidum: stratum lucidum are consisting of 2-3 cells layer. these types of cell are generally found in palm and soles of foot.

· Stratum granulosum: it is consist approx 3-5 layers of cell. These are the diamond shaped cell with the karatohyallin granules and lamellar granules. Lamellar granules consist of glycolipid’s which act as glue thus keeping the cells stuck together.

· Stratum spinosum: 8-10 cells layers are found in these parts of epidermis cell it’s also know as prickle cell layer contain irregular polyhedral cell with cytoplasmic cell. Sometime is also called “spines”.

· Stratum basal: stratum basal is the lasted and deepest layer of epidermis cell it is also known as stratum germinativum. it is separated from the dermis layer and attached with basement membrane by hemidesmosomes. The cells found in this layer are cuboidal and columnar. This layer is also consisting of monocytes.

Dermis:

Dermis is the second layer of the skin and it is situated below of stratum basal. Thickness of the dermis is 3-5mm. It is also called corneum layer dermis is comprise of fibrous filamentous and amorphous connective tissue sweat gland appocrine gland lymphatic vassal and blood vessel that stimulate- induce nerve and vascular network impulse The dermis consist of the bulk of skin and that provides its elasticity, and tensile strength. It’s also including other blood borne cell like lymphocyte, plasma cell and leukocyte. dermis are structurally divided into two parts superficial area of epidermis called as papillary region and deep thicker area called as reticular region. Dermis help to protect the body from mechanical injury, binds water, aids thermal regulation, and includes receptors of sensory stimuli. The main component of the dermis is collagen, fibrous protein with at least 15 genetically distinct types in human skin. A collagen is found in the form of tendons, ligaments, and ligning of bones.^7,9

Hypodermis:

The hypodermis is also called as subcutaneous layer or superficial fascia this layer found to the below of the dermis layer and serve to connect the skin to the underlying fascia of the bone and muscle. Generally hypodermises consist of adipose tissue, vascular connective tissue which helps to storage of fat and deposing of energy.

Drug transport across skin: Penetration pathways.^8,10

Figure No. 2: Drug transport pathway

Drug transport through the skin is challenging and difficult task because skin is the primary barrier .skin is consist of mainly two layer outer most layer is the epidermis which consist of stratum carneum and they are almost act as ret limiting step and second layer is the dermis. Drug is penetrated through the skin are mainly two routes, namely are transepidermal route and Transappendageal pathway. This has been shown in fig. no -2. In transepidermal route the drug molecule are passages through the stratum cranium, transepidermal route also called as intracellular (through the cell) or inter-cellular (pores of cell) pathway. The intra-cellular pathway through corneocytes, terminally differentiated keratinocytes, allows to the transport of hydrophilic or polar solute. Polar (lipophillic) or non-polar (hydrophilic) drug molecule are transported through inter-cellular pathway while the Transappendageal route involve to hair follicles and sweat gland.^10,11

According to Kalia and Guy (2001), drug transport in the skin is a process involves several step such as:¹²

1. Dissolution and release of drug from the formulation

2. Drug partitioning into the stratum corneum

3. Drug diffusion across the stratum corneum

4. Drug partitioning from the stratum corneum into viable epidermis layer

5. Diffusion across the viable epidermis layer into the dermis and

6. Drug absorption by the capillary vessels, which achieved by systemic circulation.

Factor affecting of drug absorption:¹³

a. Particle size

b. Solubility of drug

c. Molecular size

d. Concentration of drug

e. Formulation and preparation method

f. Chemical nature

g. Age related factor

h. Sex

i. Disease condition etc

a. Particle size: particle size of the drug is play major role of drug absorption, bigger particle size have slow diffusion and lower absorption while the smaller particle have fast and optimizing diffusion and shown vise versa absorption rate.

b. Solubility of drug: water lipid solubility is also a important factor for drug penetration on the skin, our skin membrane is made of lipid bilayer hence the lipid soluble drug have more penetration powersacompair to water soluble drug. but both lipid and water soluble drug is important for preparation of drug formulation.

c. Molecular size: molecular size and weight are also important factor for drug penetration smaller molecule size easily penetration while big molecule are cause to dificultety.

d. Concentration of drug: according to the ficks low higher concentration of drug form more flukes hence low absorption while less concentration are not form flucks and easy to absorbed.

e. Formulation and preparation method: drugs are prepared by various formulation methods hence alter their disintegration time, dissolution time, types of dosage form and storage condition. All these factors are affected the drug penetrating power.

f. Chemical nature: most of drug molecules are either acidic or basic in nature; selection of drug administrating of drug is responsible of nature of drug those drug who degraded in stomach not given through oral route such as insulin.

g. Age related factor: Age related factor are generally patient related factor. In infant, gastric ph is high and intestinal surface and blood flow is low hence lower absorption rate while an adult has proper absorption as compare to old age person because old person has lower the blood flow and poor digestion as well as most of epidermis skin cells are death hence lower the absorption and drug penetration.

h. PH of drug: Acidic drug fever to acidic ph while the basic drugs fever to basic pH of drug

i. Disease condition: in case of patent suffering various diseased condition such asdiarrhea, lipodystrophy, ulcerative colitis, colon cirrhosis, and diabetics the drug absorption and penetration are reduced because the contact time of drug to the stochmach and skin are less hence reduced the activity of the drug.

Goods of drug penetration enhancer:^14,15

· They have not any pharmacological activity with receptor.

· They should be not toxic, not irritant and non allergic activity.

· It should be well spread on the skin and produce soothing effect.

· It should be prepared as skin adhesive device.

· When the skin is removed, barrier properties should return rapidly and fully.

· It should be compatible with all drugs.

Drug penetration enhancer:¹⁶

1. Chemical compound:

several chemical compound which help to increase or enhance the drug penetration trough the skin by using various mechanism of action such as either disruptions of stratum corneum or by improving portions coefficient of drug and stratum corneum layer.⁹

Table 1: Chemical Drug penetration Enhancers

SN.	Name of chemicals	Mechanism of action	Structure and IUPAC name	Application	Ref. No.
1	Sulphaoxide	Enhancing the drug permeability by denaturing Protein	methylsulfinylmethane	1. Decrease pain 2. Healing of wound 3. inflammation,	17
2	Dimethyl Sulphaoxide	Enhancing the drug permeability by denaturing protein	Methylsulfinylmethane Methyl sulfoxide	1. Antiinflametry 2. Diuretics 3. Local analgesic	18
3	Dimethyl formamide and Dimethyl acetamide	Denaturing the protein and cleavage chain A and B chain	N,N-dimethylformamide	1. stabilizer 2. pesticide	19
4	Piroxicam	Improve the drug dissolution properties	4-hydroxy-2-methyl-N-pyridin-2-yl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide	1. Pain relief 2. artherities 3. anti-inflametory	21
5	Laurocapram (Azone)	Azone molecules may exist dispersed within the barrier lipoid or separate domains within the bilayer	1-dodecylazepan-2-one	1. Antiinflametry 2. Drug carrier	18
6	Pyrrolidones	It generate reservoirs within the skin membrane and act by altering the solvent nature	Pyrrilodone-2-one	1. solubilizer 2. Act as reducing, and oxidizing agent	20
7	Oxazolidine	It act as co-administered drug in skin layers, hence cause low systemic permeation	1,3-oxazolidine	1. wet white tanning 2. Bacteriostatic and bactericidal activity. 3. used in UTI treatment	22

Table 2: Natural Drug penetration Enhancers

S. No.	Terpines	Mechanism of action	Structure and IUPAC name	Application	Ref. No.
1	Methanol	Methanol is effective for hydrophilic drug and act by changing the solvent nature of stratum corneum or disturbing the lipid bilayer hence improve the drug penetration.	5-methyl-2-propan-2-ylcyclohexan-1-ol	1. used with Corticosterone 2. topical analgesic 3. used in oral hygiene	25
2	Linalool	Increasing the fluidity of SC lipids and causing disorder of the stacking arrangement of the lipid bilayer.	3,7-dimethylocta-1,6-dien-3-ol	1. Used as hygiene in product. 2. Used with Lomerizine dihydrochloride drug.	23
3	Limonene	It is effective of lipophillic drug and act by modifying the solvent nature of stratum corneum it improves drug partitioning.	1-methyl-4-prop-1-en-2-ylcyclohexene	1. used as obesity, flavoring andcancer, agent 2. use in Ferulic acid drug	26
4	Carvacrol	Fluidized to stratum carneum intracellular lipid bilayer.	2-methyl-5-propan-2-ylphenol	1. Antitumor, analgesic, anti-inflammatory activity. 2. Used with Corticosterone drug. 3. Antihepatotoxic and hepatoprotective.	27
5	Geraniol	Disrupting the hydrophobic lipid packing of the SC	3,7dimethylocta-2,6-dien-1-ol	1. Insecticidal and natural pest controller. 2. Antimicrobial, anti-oxidant, anti-inflammatory. 3. Used in Propranolol hydrochloride drug.	23
6	Basil oil	Basil oil suggests creation of new polar pathways in the skin for enhanced permeation of LHCl(labetolol hydrochloride)	(Estragole) methyl (E)-3-phenylprop-2-enoate	1. Used in anxiety.bronchitis.colds and coughs etc. 2. Anti-inflammatory, immune modulator. 3. Ibuprofen, Salicylic acid	25
7	Clove oil	Enhance the permeability of drug across the skin and loosing the hydrogen bond between the stratum carneum.	(Eugenol) 2-methoxy-4-prop-2-enylphenol	1. Analgesic, antimicrobial and anti-inflammatory activity. 2. Used with Valsartan drug. 3. Toothache and muscle pain killer.	23
8	Eucalyptus oil	Eucalyptus modifying the skin barrier without changing the structure .hence drug are easily penetrated	(Eucalyptol) 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane	1. Nasal congestion, asthma, ulcer treatment. 2. antiseptic, antimicrobial and antioxidant activity 3. used with Lomerizine dihydrochloride drug	23
9	Chenopodium oil	Increase the permeability coefficient of the drug.	(Ascradiol) 1-methyl-4-propan-2-yl-2,3-dioxabicyclo[2.2.2]oct-5-ene	1. Anti-inflammatory, anticancer, anthelmintic and insecticidal activity. 2. Analgesic and antioxidant.	27
10	Ylang-ylang	three-fold increase in the drug permeability coefficient, respectively	benzyl acetate	It have found be effective on 5-flouorouracil transversing human skin in vivo	25

4. Surfactants:

Surfactants are used in many pharmaceutical preparation, cosmeceutical and agrochemical industries usually, they are added to formulations to stabilize emulsions and suspensions or to solubilizer lipophillic active ingredients, and so they have the potential to dissolve lipids within the stratum corneum. Anionic surfactants include sodium lauryl sulfate (SLS), cationic surfactants encompass cetyltrimethyl ammonium bromide, the nonoxynol surfactants are nonionic surfactants and zwitterionic surfactants include Dodecyl betaine. Anionic and cationic surfactants swell the stratum corneum and interact with intracellular keratin. Nonionic surfactants are much less damaging, but are also less potent as enhancers.

5. Physical enhancer: these are the techniques which help to enhance the drug penetration by physical method such as:^24,29,30

Ionophoresis: these method help to enhancing the drug penetration on the topical drug of the low level of electric current either directs applied on the skin or dosage form. Ionophoresis is the electrodynamics method of drug delivery in these the drug must be ionized (+,-). In these drugs are penetrated through electrorepulsion, electroosmosis or diffusion method.

Example: Dexamethasone shows the penetration on hip and soldier joint.

Sonophoresis: this was first introduced by Fellinger and Schmidtthese in 1950s. These are similar to phonophoresis method in this method low frequency (55 KHz) of ultrasound is used for drug penetration. Main mechanisms behind this process that formation of gaseous cavities within the intracellular lipid or disruption of the stratum carneum layer of the skin.

Example: hydrocortisone is used for sonophoresis method.

Phonophoresis: phonophoresis is the physical method to enhance the drug penetration by increasing the diameter of the skin pore, hair follicle pores, or sweat gland. In phonophoresis generally 1-3MHz ultrasound can be used for drug penetration. When medications are applied directly to the skin, then the ultrasound works to help pass the medicine through the skin into the affected areas of the body.

Megnetophoresis: magnetic having two pole (Dielectrone nature) which create magnetic field thus the drug molecule are migrate and drug molecule passing the biological barrier hence reach in the site of action to produce the desirable effect.

Thermophoresis: In thermophoresis heat energy involve to drug penetration through the biological barriers generally thermophoresis occurs to the difference between the movement of gases particle through high thermal velocity to low thermal velocity. When the drug is applied topical surface and give to thermal energy pores of skin is open hence drug is easily penetrated through stratum carneum.

Example: Lidocain and tetracycline

Electroporation: Electrophoresis may be defined as migration of charged particles through the solution under the influence of external electric field. These charge particles will migrate either cathode or anode side depending on the nature of their net charge. Hence drugs are penetrated to inside depth of skin.

Example: Delivery of physostigmine for organophosphate poisoning.

Radiofrequency: Radiofrequency is one of the important and challenging method for drug delivery in these method approx 100 radio electrodes are placed on the surface of skin which Emits 100-500 KHz radiofrequency which cause vibration within the tissue hence thus ablate the cells in that region and drugs are penetrated.

Hydration of stratum corneum: Water is one of the common and important vehicles and penetration enhancer. It found any ware and it’s compatible with most of chemical components hence it is also used as diluents. Water cause hydration on skin hence increased permeability of solvent as well as swelling the corneocytes and loosening the intercellular lipid packing. Thus causes to increased movement of the solvent and stimulates the skin and dilated the pore of skin which help to penetrated drug molecule by the diffusion

6. Biochemical Approach:

Most of biochemical product such as bio-convertible prodrugs and metabolite inhibiters are also act as drug penetration enhancer. They are modifying the substance by converting into suitable forms which are easily penetrated to skin by interdermal routes.²⁵

7. Fatty acid:

There are number of fatty acid are available which help to penetration of drug. They are mainly helpful for lipid soluble drug .oleic acid one of the great example of lipid drug penetration enhancer .fatty act by paracellular and Transcellular route or increase fluidity of phospholipids domains.²⁷

8. Miscellaneous:

Lipid synthesis inhibiters, Phospholipids, clofibric acid and Dodecyl-N, N-Dimethyl are another penetration enhancer and they are act by various mechanism of action as well as they are compatible with specific drugs.²⁸

CONCLUSION:

The article was focused on review of skin penetration enhancer in recent. Transdermal delivery of therapeutically agents has been studied for the many years and still challenge for pharmacy professionals. Despite the strong efforts, new formulaton development of drug molecules is a rigorous experience. In this article reviewed diverse techniques to overcome the barrier role of skin through physical- chemical agents have been broadly studied. In this review, we have study various physical and chemical penetration enhancer, including Azone, Oxazolidine, Pyrrolidones, Pyrrolidones, ion pair and complex coacervates, chemical potential adjustment, methanol, linalool, limonene, carvacrol, Essential oil, basil oil, neem oil, eucalyptus oil, chenopodium and ylang-ylang. Factors affecting skin penetration, particularly for drug transport, patient related factors, skin perfusion, etc., are also discussed.

ACKNOWLEDGEMENTS:

The authors are thankful to Managing Director, School of Pharmacy, Chouksey Engineering College, Bilaspur, Chhattisgarh, India, 495001 for providing necessary infrastructure.

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Received on 04.12.2021 Modified on 26.12.2021

Res. J. Pharma. Dosage Forms and Tech.2022; 14(1):55-62.

DOI: 10.52711/0975-4377.2022.00010