Transdermal Drug Delivery

1
Transdermal Drug Delivery
2
Structure, Function Topical treatment of Human
Skin

• Anatomy Physiology

3
Drugs enter different layers of skin via
intramuscular, subcutaneous, or transdermal
delivery methods.
4

• 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)

5

• The skin appendages
• The eccrine sweat glands (2-5 million)
• produce sweat ..
• Secrete drugs, proteins, antibodies antigens.
• Emotional stress increase its secretion (clammy
  palm syndrome)

6
An eccrine sweat gland most of the body's sweat
production is the result of eccrine gland activity
7

• 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.

8
An apocrine gland, which produces little sweat
but is responsible for the body's natural 'scent'

• Hair follicles
• Nails

9

• Function of the Skin
• I. Mechanical function
• This depends on a correct balance of lipids,
• water-soluble hygroscopic substances
  (..)
• Water.
• The tissue requires 10 -20 of moisture to
  maintain its suppleness.

10

• Protective function
• Microbiological barrier
• Acid mantle ...
• The following gland secretion have antibacterial
  activity
• ..
• ...

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• Chemical barrier
• The 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
• ..
• ..
• ...

12

• Chronic irradiation produces
• ..
• ..
• Malignancy.
• Sun damaged skin produces
• ..
• ..
• ..
• ..
• ...

13

• Heat barrier temperature regulation
• To conserve heat ...
• To lose heat blood vessel dilate, eccrine sweat
  glands pour out their dilute saline secretion,
  water evaporates.
• Electrical barrier
• Dry skin has low conductivity
• V. Mechanical shock

14

• 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
• For epidermal or surface treatment (i.e.
  ..)
• For viable skin tissue ( without oral drugs)
• For systemic treatment.

15

• Dermatologists target the following skin regions
• Skin surface
• Horny layer
• viable epidermis upper dermis
• Skin glands systemic circulation. Fig
  33.1-33.2

16

• Surface treatment
• (i.e. camouflage or cosmetic, deodorants, surface
  antiseptic or antibiotics).
• ...
• Stratum corneum (S.C.) treatment
• (i.e. ..)
• Skin appendages treatment
• (i.e. ...)
• 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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• Transcutaneous immunization
• Vaccine Antigens developing transcutaneous
  immunization ()
• Systemic treatment via
• Problems of this way
• The body absorbs drugs
• Drugs are lost by .

19

• Drug Transport Through the Skin
• Basic principles of diffusion through membranes
• The diffusion process
• Ficks Law of Diffusion
• Fig 33.3

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• Complex Diffusional Barrier
• Skin Transport
• Relate the intrinsic properties of the skin with
  the properties of the drug.
• Routes of Penetration
• Figure 33.1

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• Sebum Surface Material (0.4-10 ?m)
• It hardly affect the Transdermal absorption (TDA)
• 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
• Immunization (i.e. naked DNA in topical
  application)
• Anti hair loss of alkaloids of transgenic plant
  ()
• Liposomes.
• Usually
• Molecules gt 10 ?m
• Molecules around 3-10 ?m
• Molecules lt 3 ?m .

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• Epidermal Route (stratum corneum)
• Intracellular ?-route (bricks) s.c.
  corneocytes, consisting of hydrated keratin
• 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
• Physicochemical nature of the drug (),
• Timescale of observation,
• ,
• ,
• How vehicle components temporarily change the
  properties of the S.C.

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• Properties That influence Transdermal Delivery
• Release of the drug
• Penetration through
• Activation of the .
• Figure 33.4

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• Factors that complicate drug penetration
• The non homogeneity of tissue

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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
• Biological factors
• Physicochemical Factors.
• Biological Factors
• Skin Conditions
• Chemicals solvents may open the complex dense
  structure of the skin ().
• Skin Age
• gt permeable than adult tissue, but there
  is no dramatic difference.

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• Permeability depends on
• .
• Plantar palmar Callus (400-600 ?m), while other
  sites (10-20 ?m),
• But permeability of plantar palmer is gt 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 gtgt permeability than other sites.

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• Skin metabolism
• About 5 of topical drugs can be metabolized by
  the skin.
• Species differences.
• Physicochemical Factors such as
• Skin Hydration
• Moisturizers such .
• Dryer such as .
• Order of Occlusion
• Plastic film of TD patch gt lipophilic ointment gt
  W/O gt O/W creams. Table33-1

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• Temperature pH
• D ? T
• Occlusive vehicles ?? T (few degree)
• Regarding pH, .
• Diffusion coefficient (D)
• D of gases gt than D of liquids gt than D of
  molecules in s.c. gt than D of solids.
• D depends also on many intrinsic factors like
• Binding (depot) of drugs to s.c. ? L

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So, binding or gives L, therefore, in
order to see mgt 0 we have to saturate all
binding sites in s.c., thus the remaining drug
permeates starts to increase
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• Drug Concentration
• Eq. 33,3
• 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 gt than 6, K ?, while the anti-inflammations
  index ?.
• Maximizing solubility ? ? 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
• ? interfacial tension ()
• Changes
• Disruption of intercellular lipid packing in the
  s.c.

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• Molecular size shape
• Absorption depends on
• .
• All the above factors are difficult to be
  evaluated.
• Ideal Molecular Properties for Drug Penetration
• A low MW (lt 600 Da) when D will tend to be ?
• An adequate solubility in oil water
• ? 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 Skin
• S.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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1. Diffusion coefficient is constant with time or
   position in the vehicle or horny layer
2. Penetrant reaching viable tissue sweeps into the
   circulation maintaining sink conditions below the
   S.c
3. Donor phase depletes negligibly, i.e. constant
   drug in the vehicle
4. Vehicle doesn't alter skin permeability during an
   experiment (i.e. changing s.c. hydration or
   acting as penetration enhancer)
5. Drug remains intact unaltered
6. Flux estimates are steady-state value.

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• 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.
• Absorption from solution skin a perfect sink
• Assumption
• Only a single drug species is important, it is in
  true solution, it is initial uniformly
  distributed through the skin
• Only the drug diffuses out of the vehicle.

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• Other components do not diffuse or evaporate
  skin secretion do not pass into the vehicle.
• The D does not alter with time or position within
  the vehicle
• 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
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• Absorption from suspensions skin a perfect sink
• Equation 33.11 is derived for a simple model
  system under the following conditions
• The suspended drug is micronized so that particle
  ? are ltlt than the vehicle
• The particles are uniformly distributed do not
  sediment in the vehicle
• The total amount of drug, soluble suspended,
  /unit volume (A) is much gtgt than Cs, the
  solubility of the drug in the vehicle

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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 delivery
• What is the drug flux through the skin how do
  the apparent D, K, SARs control it?
• What is the main penetration route-across the
  s.c. or via the appendages?
• Which is gt important clinically or
  toxicologically-transient diffusion (possibly
  down the appendages) or steady-state permeation
  (usually across the intact s.c.)?
• Does the drug bind to the s.c., the viable
  epidermis?
• 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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• In vitro methods
• Excised skin
• Fig 33.7, 33.8, 33.9
• Artificial membranes
• 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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• In vitro method
• Differences between human animal skins
• .
• 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 section
• But
• The cut, handling development of skin section
  encourage
• Leaching,
• 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
• ?-emitters because darken areas up to 2 or 3 mm
  away ()
• Confocal Microscopy
• .

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• Microdialysis
• Also needs very sensitive analytical techniques
• Especially when protein-binding occurs.

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Schematic drawing of the principle of
microdialysis
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• Analysis of Body tissue or fluids
• Needs calibration of the subject by
• A slow I.V. inj. simultaneous Det. Of blood
  level.
• (Gives Pharmacokinetic Information
• 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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• Observation of Pharmacological or Physiological
  response
• Like
• Allergic Response ()
• Blood Pressure ().
• Figure 33.11
• Physical properties of the skin
• To evaluate the skin using
• .
• .

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• 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
  Skin
• Drugs or prodrugs selection
• Chemical Potential Adjustment
• Ultrasound
• Disturbs the lipid-Packing in the intercellular
  spaces of s.c.
• Disadvantage
• .

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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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• Iontophoresis
• Disadvantages
• .

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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• 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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• Stratum corneum removal
• Laser ablation
• Disadvantages
• Adhesive tape
• Keratolytic agents.
• 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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• 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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• Penetration enhancers
• Characteristics of ideal penetration enhancer
• 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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3. Should be cosmetically acceptable ()
4. Should formulate into all the variety of
   preparations used topically
5. Should be odourless, tasteless, colourless
   inexpensive.

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• Some penetration enhancers
• Water Sulphoxides (DMSO)
• Fatty acids alcohols
• Pyrrolides
• Azone
• Surfactants
• Urea its derivatives
• Alcohols glycols
• Essential Oils, Terpenes derivatives
• Synergistic mixtures.

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Chemical structure of typical chemical
penetration enhancers
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• Mechanism of Penetration enhancers
• The Lipid-Protein-Partitioning theory (is the
  most accredited)
• Lipid action
• The enhancer interact with the lipid structure of
  s.c.,
• Solvent action
• The enhancer (solvent) extracts lipid from s.c.?
  
• Surfactant action

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• Formulation approach
• Nanodispersed 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
80

• Transfersomes
• A new type of liposomes called transferosomes has
  been introduced.
• Transferosomes consist of phospholipids,
  cholesterol additional surfactant molecules
  such
• Transferosomes are ultradeformable (105 gt than
  liposomes) squeeze through pores lt 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
• .
• 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 33.12
85

• 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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• 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
• Targeting to a specific tissue, such as a vaccine
  delivered to epidermal cells

89

• 6.
• 7.
• 8. Safety - the device avoids-
• Splash back of body fluids ()

90

• Disadvantages
• No home use
• Problems arising with
• Bruising of the skin
• Bouncing off the skin surface.

91

• Transdermal Therapeutic Systems (TTS) or (TDDS)
• Advantages
• Eliminate variables in the G.I.T. absorption
• Controlled release ? improves patient
  compliance

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• 5. Can use drug with low therapeutic index
• 6.
• Disadvantages
• Drugs must be stable have correct
  physichochemical properties.

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• Device Design
• Types of TTS Devices
• 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.

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• Rate-Limiting Membrane
• (Ficks law)
• The amount of drug released depends on The
  presence of rate-limiting membrane.

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• Fig. 33.1333.1433.1533.16

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• Future Trend
• Why monolith system is the most popular?
• Because the trend is to concentrate on simple
  designs that are
• Less obstructive ()
• The result is a move towards the simple adhesive
  matrix patch ( figure 33.17)

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• Clinical Patches
• 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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• Transdermal Nitroglycerin (Glyceryl Trinitrate)
  (TDDS)
• Transdermal Oestradiol (TDDS)
• Advantages
• Such dosing doesnt affect the blood levels of
  proteins produced by the liver

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• Transdermal clonidine
• 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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• Transdermal Nicotine
• TTSs of nicotine provide an alternative route of
  Nicotine.
• Chewing gum Lozenge Sublingual tablets Nasal
  Sprays Inhalers.
• Advantages of nicotin TTS
• Maintain labour ()
• Improve the activity of anti-Tourettes 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
• A vibrant developmental area within the
  pharmaceutical industry
• No marketed patch fully controls the drug flux
• Movement from a complex patch structure towards
  matrix formulation
• Future progress will depend on
• .

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• 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
• ,
• ,

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• Formulation of Dermatological vehicles
• Old Formulator developed formulations for
• Stability,
• Compatibility,
• Patient acceptability.
• 2. Modern Formulator developed formulations for
• .

109

• Dermatological formulations
• Liquid preparations
• Liniments
• Lotions
• Paints
• Varnishes
• Tinctures
• Ear drops
• 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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• Gels (Jellies)
• Are two- component semisolid systems rich in
  liquid. (water polymer) ? TD structures.
• Powders
• Ointments
• Hydrocarbon bases
• 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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1. Soap-based greases (Al stearate mineral oil)
2. Fats fixed-oil bases
3. Silicones
4. Absorption base
5. Emulsifying bases
6. Water soluble bases (PEGs)

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• Creams
• Difficult to predict the role of emulsion in drug
  absorption because
• Partitioning of the drug between the emulsion
  phases
• Determination of a true viscosity for diffusing
  molecules in the vehicle
• .
• Pastes
• Aerosols.

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• Cosmetic or aesthetic criteria for dermatological
  formulations
• .

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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