1

Transdermal Drug Delivery

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Structure, Function & Topical treatment of Human Skin

Anatomy & Physiology

3Drugs enter different layers of skin via intramuscular, subcutaneous, or transdermal delivery methods.

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• The epidermis

0.8 mm (Palms & soles)

0.006 mm eyelids.

Stratum Germinativum divide & migrate to produce Stratum corneum or horny layer.

This permit to human to survive.

• The dermis (corium) 3-5 mm thick

• The subcutaneous tissue ( sibcutis, hypoderm) (fat)

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• The skin appendages

The eccrine sweat glands (2-5 million):

1. produce sweat …………………..

2. Secrete drugs, proteins, antibodies & antigens.

Emotional stress increase its secretion (clammy palm syndrome)

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An eccrine sweat gland: most of the body's sweat production is the result of eccrine gland activity

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The aporine sweat glands

Develop at the pilosebaceous follicle in the armpit.

Its milky or oily secretion may be colored & contains:

Proteins, lipids, lipoproteins & saccarides.

Bacteria metabolize this odorless secretion to

give the characteristic human smell.

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An apocrine gland, which produces little sweat but is responsible for the body's natural 'scent'

•Hair follicles•Nails

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Function of the Skin:I. Mechanical functionThis depends on a correct balance of lipids,1. water-soluble hygroscopic substances

(…………………..);

2. Water.The tissue requires 10 -20% of moisture to maintain its

suppleness.

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II. Protective function:

a. Microbiological barrier

Acid mantle …………………...

The following gland secretion have antibacterial activity:

1. …………………..;

2. …………………...

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b. Chemical barrierThe appendageal shunt route provide only a small

fractional area (0.1%).

C. Radiational barrier The UV light 290-400 nm is the most damaging.

• Short irradiation produces:1. …………………..;

2. …………………..;

3. …………………...

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• Chronic irradiation produces:1.…………………..;

2.…………………..;

3.Malignancy.• Sun damaged skin produces:1.…………………..;

2.…………………..;

3.…………………..;

4.…………………..;

5.…………………...

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III. Heat barrier & temperature regulation:

1. To conserve heat; …………………...

2. To lose heat; blood vessel dilate, eccrine sweat glands pour out their dilute saline secretion, water evaporates.

IV. Electrical barrier

Dry skin has low conductivity

V. Mechanical shock

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Rational approach to drug delivery to & via the skin

There are 3 main ways to manipulate the problem of formulating a successful topical dosage form:

1. For epidermal or surface treatment (i.e. …………………..);

2. For viable skin tissue ( without oral drugs);

3. For systemic treatment.

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Dermatologists target the following skin regions:

• Skin surface;

• Horny layer;

1. viable epidermis & upper dermis;

2. Skin glands & systemic circulation. Fig 33.1-33.2

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1. Surface treatment (i.e. camouflage or cosmetic, deodorants, surface

antiseptic or antibiotics).…………………...

2. Stratum corneum (S.C.) treatment(i.e. …………………..)

3. Skin appendages treatment(i.e. …………………...)

4. Viable epidermis& dermis treatment

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Cream & gels:• Topical steroids;

• …………………..;

• …………………..;

• Topical 5-fluorouracil & methotrexate eradicate premalignant & some malignant skin tumors, …………………...

• Psoralens + UVA therapy (PUVA) mitigate psoriasis;

• 5-amino-levulinic acid + visible light irradiation (photodynamic therapy) …………………...

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5. Transcutaneous immunization

Vaccine Antigens developing transcutaneous immunization (……………………)

6. Systemic treatment via ……………………

Problems of this way:

a. The body absorbs drugs ……………………;

b. Drugs are lost by …………………….

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Drug Transport Through the Skin

Basic principles of diffusion through membranes:

The diffusion process:

Fick’s Law of Diffusion:

Fig 33.3

scmD

dX

dCDJ

/2

0Ch

DK

dt

dm

D

hL

6

2

h

KDP

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• Complex Diffusional Barrier

• Skin TransportRelate the intrinsic properties of the skin with the

properties of the drug.

• Routes of Penetration:Figure 33.1

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3

22

2

11

11

KD

h

KD

h

KD

h

PR

TT

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1. Sebum & Surface Material (0.4-10 m)

It hardly affect the Transdermal absorption (TDA)

2. Skin Appendages (0.1% of the total available area)

Acts before the steady state.

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After the steady state is considered neglect.Uses: a. Immunization (i.e. naked DNA in topical application);

b. Anti hair loss of alkaloids of transgenic plant (……………………);

c. Liposomes.Usually:Molecules > 10 m ……………………;

Molecules around 3-10 m ……………………;

Molecules < 3 m …………………….

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3. Epidermal Route (stratum corneum):

a. Intracellular -route (bricks) = s.c. [corneocytes, consisting of hydrated keratin]

b. Intercellular -route (mortar) composed of: Lipid; cholesterol; ceramide; ..etc.

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Topically applied agents (steroids, creseofulvin,..) form a depot by binding within the stratum corneum.

Thus, psoriasis …………………….

• Viable layer (particularly the epidermis) …………………….

• Dermis layer contains capillaries so the residence time of a hydrophilic drug …………………….

• Dermis may bind lypophilic drugs ( testosterone) ……………………

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Conclusions:• S.c. is the rate limiting step.• The fraction of a drug that penetrates the skin via

any route depends on:1. Physicochemical nature of the drug:

(……………………),

2. Timescale of observation,

3. ……………………,

4. ……………………,

5. How vehicle components temporarily change the properties of the S.C.

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Properties That influence Transdermal Delivery:

1. Release of the drug ……………………;

2. Penetration through ……………………;

3. Activation of the …………………….

Figure 33.4

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Factors that complicate drug penetration:

1. The non homogeneity of tissue;

2. ……………………;

3. ……………………;

4. ……………………;

5. ……………………;

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6. ……………………;

7. Cell transport to & through S.C;

8. ……………………;

9. ……………………;

10.The drug & emulsion components may modify progressively the skin.

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Factors that complicate the skin absorption:

I. Biological factors;

II. Physicochemical Factors.

Biological Factors:

1. Skin Conditions:

Chemicals & solvents may open the complex & dense structure of the skin (……………………).

2. Skin Age:

……………………> permeable than adult tissue, but there is no dramatic difference.

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3. ……………………;

4. ……………………:Permeability depends on:a. ……………………;

b. ……………………;

c. …………………….

Plantar & palmar Callus (400-600 m), while other sites (10-20 m),

But permeability of plantar & palmer is > than other sites.

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Why Post Auricular skin was employed for the administration of Hyoscine (scopolamine)?

a. Thinner skin;

b. Less dens skin;

c. ……………………;

d. ……………………;

e. …………………….

Face skin is >> permeability than other sites.

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5. Skin metabolismAbout 5% of topical drugs can be metabolized by the

skin.

6. Species differences.Physicochemical Factors such as:1. Skin Hydration:

Moisturizers such: …………………….

Dryer such as: …………………….

Order of Occlusion:Plastic film of TD patch > lipophilic ointment > W/O >

O/W creams. Table33-1

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2. Temperature & pH:D TOcclusive vehicles →↑ T (few degree)Regarding pH, …………………….

3. Diffusion coefficient (D):D of gases > than D of liquids > than D of molecules in s.c. >

than D of solids.

D depends also on many intrinsic factors like:Binding (depot) of drugs to s.c. ↑ L:

L

hD

D

hL

66

22

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So, binding or gives L, therefore, in order to see m> 0 we have to saturate all binding sites in s.c., thus the remaining drug permeates & starts to increase

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4. Drug ConcentrationEq. 33,3

5. Partition coefficient (K) K varies …………………….

Triamcinolone systemic = …………………….

Triamcinolone topical = …………………….

Triamcinolone acetonide topical = …………………….

Of 23 esters of betamethasone tested, the 17-valerate has …………………….

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In the family of Hydrocortisone:• Side chain lengthens from 0 to 6 C , ↑ K & the anti-

inflammation activity.

• For C > than 6, K ↑, while the anti-inflammations index ↓.

Maximizing solubility ↑ Δ C but ↓ K, so it is better to non over-solubilize the drug, if the aim is to ↑ drug penetration.

Surface activity & Micellization,Effect of surfactant on skin:1. ↓ interfacial tension (……………………);

2. Changes ……………………;

3. Disruption of intercellular lipid packing in the s.c.

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6. Molecular size & shapeAbsorption depends on:1. ……………………

2. ……………………

3. …………………….All the above factors are difficult to be evaluated.

Ideal Molecular Properties for Drug Penetration:1. A low MW (< 600 Da) when D will tend to be ↑;

2. An adequate solubility in oil & water;

3. ……………………;

4. ↓ melting point; …………………….Nicotine Patches has all the above mentioned.

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• The nicotine patch is a type of transepidermal patch designed to deliver nicotine, the addictive substance contained in cigarettes, directly through the skin and into the blood stream.

• The drug leeches slowly out of the reservoir, releasing small amounts of the drug at a constant rate for up to 24 hours

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Drug permeation through SkinS.C. rate Controlling Step:Assumptions:• S.C. → the rate-limiting step;

• Skin is homogenous intact membrane;

• Appendages are unimportant;

• Only a single non-ionic drug species is important, dissolving to form an ideal solution unaffected by pH, & dissolution is not rate limiting;

• Only drug diffuse from the vehicle.

• Formulation components neither diffuse nor evaporate, & skin secretions do not dilute the vehicle;

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6. Diffusion coefficient is constant with time or position in the vehicle or horny layer;

7. Penetrant reaching viable tissue sweeps into the circulation maintaining sink conditions below the S.c;

8. Donor phase depletes negligibly, i.e. constant [drug] in the vehicle;

9. Vehicle doesn't alter skin permeability during an experiment (i.e. changing s.c. hydration or acting as penetration enhancer);

10. Drug remains intact & unaltered;

11. Flux estimates are steady-state value.

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2. S.C. not rate controlling:

This happens in absence of s.c. (i.e. damaged skin) or in the presence of TDS.

Here the release of the drug from the vehicle → the rate-limiting step & the skin act as a sink.

1. Absorption from solution: skin a perfect sink

Assumption:

a. Only a single drug species is important, it is in true solution, & it is initial uniformly distributed through the skin;

b. Only the drug diffuses out of the vehicle.

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b. Other components do not diffuse or evaporate & skin secretion do not pass into the vehicle.

c. The D does not alter with time or position within the vehicle;

d. When the penetrant reaches the skin, it absorbs instantaneously.

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Under these limitation eq. 33.9 represents the relationship between:

m, the quantity of drug released to the sink/unit of area;

Co, the initial concentration of solute in the vehicle;

Dv, the diffusion coefficient of the drug in the vehicle, &

t, the time after application. Fig 33.5, 33.6

10.33.

9.33.2

eqt

DvCo

dt

dm

eqDvt

Com

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2. Absorption from suspensions: skin a perfect sink

Equation 33.11 is derived for a simple model system under the following conditions:

a. The suspended drug is micronized so that particle are << than the vehicle;

b. The particles are uniformly distributed & do not sediment in the vehicle;

c. The total amount of drug, soluble & suspended, /unit volume (A) is much >> than Cs, the solubility of the drug in the vehicle;

11.33.)2( eqCCAtDdt

dmssv

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d. The surface to which the vehicle is applied is immiscible with the vehicle, i.e. skin secretions do not enter the vehicle;

e. Only the drug diffuses out of the vehicle components neither diffuse nor evaporate;

f. The receptor, Which is the skin, operates as a perfect sink.

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Methods for studying transdemal drug delivery1. What is the drug flux through the skin & how do the

apparent D, K, & SARs control it?

2. What is the main penetration route-across the s.c. or via the appendages?

3. Which is > important clinically or toxicologically-transient diffusion (possibly down the appendages) or steady-state permeation (usually across the intact s.c.)?

4. Does the drug bind to the s.c., the viable epidermis?

5. Does it form a depot in the subcutaneous fat or penetrate to the deep muscle layers?

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6. What is the rate limiting step in permeation-drug dissolution or diffusion within the vehicle or patch; partitioning into, or diffusion through, the skin layers; or removal by the blood, lymph or tissue fluids?

7. How do skin condition, age, site, blood flow & metabolism affect topical bioavailability?

8. Are differences between animal species important?

9. How do vehicles modify the release & absorption of the medicament?

10. What is the optimal formulation for a specific drug-an aerosol spray, a solution, suspension, gel, powder, ointment, cream, paste, tape or delivery devices?

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11. Are vehicle components inert, or do they modify the permeability of the s.c., if only by changing its hydration state?

12. To increase the drug flux, should we use stratagems such as penetration enhancer, iontophoresis?

13. Is the formulation designed correctly to treat intact s.c., thickened epidermis or damaged skin?

14. Should the experimental design produce a pharmacokinetic profile, measuring absorption, distribution, metabolism & excretion in vivo?

No single method can answer all questions & provide a full picture of the complex process of TD absorption.

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I. In vitro methods:1. Excised skinFig: 33.7, 33.8, 33.9

2. Artificial membranes

3. Release methods without a rate-limiting membrane:

Fig 33.10, eq 33.9-33.14

However; Exp. With animal cant fully substitute for human studies.

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II. In vitro method

Differences between human & animal skins:

1. …………………….;

2. ……………………;

3. ……………………;

4. The papillary blood supply & biochemical aspects.

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Few techniques produce Anima diseases similar to human afflictions.

The Animal models are important for:

a. Studying the anatomy, Physiology & biochemistry of the skin;

b. ……………………;

c. ……………………;

d. Preliminary biopharmaceutical investigations.

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I. Histology:Exper. To locate skin penetration of the drug:• Microscopic sectionBut; The cut, handling & development of skin section

encourage:1. Leaching, &;

2. Translocation of drug (……………………)Histochemical techniques for:

Drug which produce colored end products after chemical reaction.

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Mistake of the past:

Colour the drug with dye & Examine skin section to locate drug.

Why?

Because each chemical species …………………….

Better to use: Fluorescence Method (…………………….)

Tritium-labeled ……………………

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Not Useful:

Β-emitters because darken areas up to 2 or 3 mm away (……………………)

3. Confocal Microscopy:

…………………….

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II. Microdialysis

Also needs very sensitive analytical techniques:

Especially when protein-binding occurs.

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60Schematic drawing of the principle of microdialysis

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III. Analysis of Body tissue or fluids:1. ……………………Needs calibration of the subject by:A slow I.V. inj. & simultaneous Det. Of blood level.(Gives Pharmacokinetic Information;

2. ……………………;

3. Some drugs have↑↑↑ affinity to animal organs:…………………….

4. Tissue Biopsies & individual sections measured.

Adhesive tape [strip sequential layers of s.c. which should be analyzed].

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IV. Observation of Pharmacological or Physiological response

Like:1. Allergic Response (……………………);

2. Blood Pressure (……………………). Figure 33.11

V. Physical properties of the skinTo evaluate the skin using:1. …………………….;

2. …………………….

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VI. Bioassays

Bioassays are typically conducted to measure the effects of a substance on a living organism.

Bioassays may be qualitative or quantitative .

Many specialized bioassays screen topical formulations prior to clinical trial (i.e. Anti-bacterials, antifungals,…etc.).

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Maximizing Bioavailabilty of Drugs Applied to Skin1. Drugs or prodrugs selection;

……………………

2. Chemical Potential Adjustment;

3. ……………………;

4. UltrasoundDisturbs the lipid-Packing in the intercellular spaces of s.c.

[……………………] Disadvantage:• ……………………;• …………………….

oCh

DK

dt

dm

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Basic principle of phonophoresis. Ultrasound pulses are passed through the probe into the skin fluidizing the lipid bilayer by the formation of bubbles caused by cavitation.

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5. Iontophoresis:

Disadvantages:

a. ……………………;

b. …………………….

Basic principle of iontophoresis. A current passed between the active electrode and the indifferent electrode repelling drug away from the active electrode and into the skin.

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6. Electrophoresis:

Creation of Aqueous-Pores ins.c. by Application of currents for m. seconds (100-1000 v/cm) ……………………

Disadvantages:• ……………………

Electroporation + Iontophoresis …………………….

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Basic principle of electroporation. Short pulses of high voltage current are applied to the skin producing hydrophilic pores in the intercellular bilayers via momentary realignment of lipids.

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7. Stratum corneum removal8. Laser ablation:Disadvantages:• ……………………;

• ……………………2. Adhesive tape;

3. Keratolytic agents.

8. Photochemical wave: A drug solution is placed on the skin;

Covered by a black polysterene target;

…………………….

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Photomechanical wave

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8. Needle array

400 needles

Flux ↑↑ to 100,000 folds

There is needle array + Iontophoresis technique combination.

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Basic design of needle delivery devices. Needles of approximately with or without centre hollow channels are placed onto the skin surface so that they penetrate the stratum corneum and epidermis without reaching the nerve endings present in the upper dermis.

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9. Penetration enhancers

Characteristics of ideal penetration enhancer:

1. ……………………;

2. ……………………;

3. Upon removal of the material, the skin should immediately & fully recover its normal barrier property;

4. Should not cause loss of body fluids, electrolytes, or other endogenous materials;

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5. ……………………;

6. ……………………;

7. Should be cosmetically acceptable (……………………);

8. Should formulate into all the variety of preparations used topically;

9. Should be odourless, tasteless, colourless & inexpensive.

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Some penetration enhancers:1. Water; Sulphoxides (DMSO);

2. Fatty acids & alcohols;

3. Pyrrolides;

4. Azone;

5. Surfactants;

6. Urea & its derivatives;

7. Alcohols & glycols;

8. Essential Oils, Terpenes & derivatives;

9. Synergistic mixtures.

76Chemical structure of typical chemical penetration enhancers

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Mechanism of Penetration enhancers:• The Lipid-Protein-Partitioning theory (is the

most accredited):1. Lipid action:The enhancer interact with the lipid structure of

s.c., ……………………;

2. Solvent action:The enhancer (solvent) extracts lipid from s.c.

……………………;

3. Surfactant action:……………………;

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Formulation approachNanodispersed vehicle systems • Liposomes, Nanoemulsions, & Solid-Lipid

Nanoparticles .

Liposomes are colloidal particles composed mainly of phospholibids & colesterol, to which other ingredients may be added.

Most reports cite a localizing effect whereby the carriers accumulate in s. c. or other upper skin layers.

Generally, these colloidal carriers are not expected to

penetrate into viable skin.

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Structure of nanodispersed vehicle systems

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• TransfersomesA new type of liposomes called transferosomes has

been introduced. Transferosomes consist of phospholipids, cholesterol &

additional surfactant molecules such : ……………………

Transferosomes are ultradeformable (105 > than liposomes) & squeeze through pores < 0.1 of their .

Thus 200 to 300 nm transferesomes are claimed to penetrate intact skin.

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Penetration of these colloidal particles works best:

1. ……………………&;

2. …………………….

e.g. 50% of topical insulin penetrates skin into 30 minutes.

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• Microemulsions.

Such systems consist of water, oil, & amphiphilic compounds (surfactant and co-surfactant) which yield a:

Transparent, single optically isotropic, & thermodynamically stable liquid.

-emulsions can be either oil continuous, water continuous, or bi-continuous.

.

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The main difference between -emulsions & -emulsions lies in ……………………:

The -emulsions ( 10 – 200 nm) are little smaller than the conventional emulsions (1 – 20 µm).

Typical properties of -emulsions include:

• ……………………,

• ……………………,

• ……………………

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Figure 33.12Figure 33.12

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Penetration enhancement from -emulsions is mainly due to an ↑ in [drug] which a ↑ C from the vehicle to the skin.

Also, the surfactants & the oil from the -emulsion interact with the rigid lipid bilayer structure & acts as a chemical enhancer.

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11.High velocity particles

The powder Ject system fires solid particles through the s.c. into the lower skin layers,

using a supersonic shockwave of helium gas traveling at Mach 2-3.

Injections without needles: Dermal PowderJect

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Advantages:

1. ……………………

2. ……………………;

3. Targeting to a specific tissue, such as a vaccine delivered to epidermal cells;

4. ……………………;

5. ……………………;

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6. ……………………;

7. ……………………;

8. Safety - the device avoids-:

• ……………………

• ……………………;

• Splash back of body fluids (……………………)

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Disadvantages

• No home use;

• Problems arising with:

1. Bruising of the skin;

2. Bouncing off the skin surface.

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Transdermal Therapeutic Systems (TTS) or (TDDS)

• Advantages:

1. Eliminate variables in the G.I.T. absorption;

2. ……………………;

3. Controlled release improves patient; compliance;

4. ……………………;

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5. Can use drug with low therapeutic index

6. ……………………

• Disadvantages

1. ……………………;

2. Drugs must be stable & have correct physichochemical properties.

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Device Design

Types of TTS Devices:

1. Monolith or matrix system

(Higuchi eq.)

m is the amount of drug;

A is the volume of the applied vehicle;

Dv is the diffusion coefficient in the vehicle;

Cs is the solubility of the drug (in the vehicle) at time t

The amount of drug released depends meanly on Cs which depends on the equilibrium between the crystals and the dissolved amount.

AtCDm sv2

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2. Rate-Limiting Membrane

(Fick’s law)

The amount of drug released depends on The presence of rate-limiting membrane.

0.Ch

DK

dt

dm

95

• Fig. 33.13+33.14+33.15+33.16

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Future Trend

Why monolith system is the most popular?

Because the trend is to concentrate on simple designs that are:

1. ……………………;

2. ……………………;

3. Less obstructive (……………………)

The result is a move towards the simple adhesive matrix patch ( figure 33.17)

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Clinical Patches:1. Transdermal Scopolamine (hyoscine):• It can control the emetic side-effects of anticancer

drugs;

• ……………………;

• ……………………

This TDDs Patch overcomes the side-effects of hyoscine injection or tablets:

• ……………………;

• ……………………;

• …………………….

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2. Transdermal Nitroglycerin (Glyceryl Trinitrate) (TDDS)

3. Transdermal Oestradiol (TDDS)

Advantages:

1. ……………………;

2. ……………………;

3. Such dosing doesn’t affect the blood levels of proteins produced by the liver;

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3. Transdermal clonidine

4. Transdermal fentanyl

This TTS patch treats chronic intractable pain & last for 72-h.

A TTS gives 25 g of fentanyl /h = 0.6 mg/day = The oral administration of 90 mg of morphine sulphate /day.

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5. Transdermal NicotineTTSs of nicotine provide an alternative route of Nicotine.

Chewing gum; Lozenge; Sublingual tablets; Nasal Sprays ; Inhalers.

Advantages of nicotin TTS:a. ……………………;

b. Maintain labour (……………………);c. ……………………;

d. Improve the activity of anti-Tourette’s syndrome drugs.

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TTS Testosterone

a. Hypogonadism (due to testicular or pituitary disorder)

b. Testosteron deficiency due to orchidectomy.

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General conclusions on the usage of transdermal patches:

1. A vibrant developmental area within the pharmaceutical industry;

2. No marketed patch fully controls the drug flux;

3. Movement from a complex patch structure towards matrix formulation;

4. Future progress will depend on:• ……………………;

• ……………………;

• …………………….

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5. There is a need to solve problems relating to, e.g.:• ……………………,

• ……………………,

• ……………………,

• ……………………,

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• Wearability of the patch for up to 7 days; the device must:

a. ……………………,

b. ……………………,

c.……………………;

d. ……………………

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Formulation of Dermatological vehicles1. Old Formulator developed formulations for:• Stability,

• Compatibility,

• Patient acceptability.

2. Modern Formulator developed formulations for:

• ……………………

• …………………….

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Dermatological formulations1. Liquid preparations:a. Liniments;b. Lotions;c. Paints;d. Varnishes;e. Tinctures; f. Ear dropsg. Soak ( provides drug in aqueous solution or

suspension);

Gums, gelling agents change consistency from mobile liquid to stiff gels.

Oilatum Emolient deposit a layer of liquid paraffin on the s.c..

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2. Gels (Jellies)Are two- component semisolid systems rich in liquid.

(water & polymer) TD structures.3. Powders4. Ointments:a. Hydrocarbon bases;b. Plastibases (Polyethylene in paraffin oil)Advantages: ……………………, ……………………, ……………………, ……………………, ……………………, ……………………,

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……………………,……………………, compatible with most medicaments &

maintain their consistency event at ↑ temp.

The basses apply easily, spread readily & adhere to the skin,

……………………

…………………….

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c. Soap-based greases (Al stearate + mineral oil);

d. Fats & fixed-oil bases;

e. Silicones;

f. Absorption base

g. Emulsifying bases

h. Water soluble bases (PEGs)

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5. Creams:Difficult to predict the role of emulsion in drug absorption

because:a. Partitioning of the drug between the emulsion

phases;

b. ……………………;

c. Determination of a true viscosity for diffusing molecules in the vehicle;

d. …………………….

6. Pastes;

7. Aerosols.

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I. Cosmetic or aesthetic criteria for dermatological formulations:

1. ……………………;

2. ……………………;

3. ……………………;

4. ……………………;

5. ……………………;

6. …………………….

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Physiologic criteria for dermatological formulations:

……………………;

……………………;

Rheological properties-consistency, visco-elasticity, extrudability;

115115 ……………………;

Phase changes-homogeneity, bleeding, cracking;

Particle size distribution of dispersed phase;

……………………;

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Microbial Contamination & Preservation:

Rancidity & Antioxidants