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					Transdermal Drug Delivery




                            1
Structure, Function & Topical
  treatment of Human Skin

Anatomy & Physiology




                                2
Drugs enter different layers of skin via intramuscular, subcutaneous, or transdermal
delivery methods.                                                                    3
• 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)4
• 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)


                                              5
An eccrine sweat gland: most of the body's sweat production is the
result of eccrine gland activity




                                                                     6
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.

                                                 7
An apocrine gland, which produces little sweat but is responsible
for the body's natural 'scent '




•Hair follicles
•Nails




                                                                    8
Function of the Skin:
I.   Mechanical function
This 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.




                                                     9
II. Protective function:
a. Microbiological barrier
Acid mantle …………………...

The following gland secretion have antibacterial
    activity:
1. …………………..;
2. …………………...



                                              10
b. 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:
1. …………………..;

2. …………………..;

3. …………………...                                11
• Chronic irradiation produces:
1. …………………..;

2. …………………..;

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

2. …………………..;

3. …………………..;

4. …………………..;
                                  12
5. …………………...
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
                                                  13
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.




                                                     14
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


                                               15
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
                                             16
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
                                                       17
  (photodynamic therapy) …………………...
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 …………………….

                                             18
Drug Transport Through the Skin
Basic principles of diffusion through membranes:
The diffusion process:               dC
                             J D
                                    dX



                             D  cm 2 / s
Fick’s Law of Diffusion:
                            dm DK
Fig 33.3                            C0
                            dt     h
                                 h2
                             L
                                6D
                                 KD
                              P
                                  h          19
• Complex Diffusional Barrier


         1   h1     h2     h3
    RT                
         PT D1 K 1 D2 K 2 D3 K 3


• Skin Transport
Relate the intrinsic properties of the skin with the
  properties of the drug.

• Routes of Penetration:
                                                 20
Figure 33.1
21
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.




                                              22
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 …………………….                           23
3.   Epidermal Route (stratum corneum):




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

b.   Intercellular -route (mortar) composed of: Lipid; cholesterol;
                                                                24
     ceramide; ..etc.
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)
  ……………………
                                                           25
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
                                                 26
   properties of the S.C.
Properties That influence Transdermal Delivery:
1. Release of the drug ……………………;

2. Penetration through ……………………;

3. Activation of the …………………….



Figure 33.4


                                             27
Factors that complicate drug penetration:

1. The non homogeneity of tissue;

2. ……………………;

3. ……………………;

4. ……………………;

5. ……………………;


                                            28
6. ……………………;

7. Cell transport to & through S.C;

8. ……………………;

9. ……………………;

10. The drug & emulsion components may modify
    progressively the skin.
                                          29
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.                     30
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. 31
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.
                                                 32
5. Skin metabolism
About 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                              33
34
2. Temperature & pH:
DT
Occlusive vehicles →↑ T (few degree)
Regarding pH, …………………….

                          2              2
                     h      h
                  L    D
                     6D     6L
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:
                                                          35
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

                                                                             36
4. Drug Concentration
Eq. 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 …………………….                                   37
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 ……………………;

                                                                    38
3. Disruption of intercellular lipid packing in the s.c.
39
6. Molecular size & shape
Absorption 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; …………………….                          40
Nicotine Patches has all the above mentioned.
• 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                                41
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,
                                                     42
    & skin secretions do not dilute the vehicle;
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.                    43
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;

                                                        44
b. Only the drug diffuses out of the vehicle.
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.




                                                45
Under these limitation eq. 33.9 represents the
relationship between:

                            Dvt
              m  2Co                     eq.33.9
                             
              dm      Dv
                  Co                     eq.33.10
              dt      t
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, &
                                                          46
t, the time after application. Fig 33.5, 33.6
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;

      dm
          Dv t (2 A C s )C s                    eq.33.11
      dt                                                       47
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.



                                                 48
Methods for studying transdemal drug delivery
1. 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?
                                                     49
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?
                                                        50
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.
                                                       51
I. In vitro methods:
1. Excised skin
Fig: 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
                                              52
   for human studies.
II. In vitro method
Differences between human & animal skins:
1. …………………….;

2.   ……………………;

3.   ……………………;

4.   The papillary blood supply & biochemical
     aspects.

                                                53
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. ……………………;

                                             54
d. Preliminary biopharmaceutical investigations.
I. Histology:
Exper. To locate skin penetration of the drug:
• Microscopic section
But;
The cut, handling & development of skin section
   encourage:
1. Leaching, &;

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

Drug which produce colored end products after
                                            55
   chemical reaction.
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 ……………………
                                            56
Not Useful:
Β-emitters because darken areas up to 2 or 3 mm
    away (……………………)

3. Confocal Microscopy:
…………………….




                                           57
II. Microdialysis
Also needs very sensitive analytical techniques:
Especially when protein-binding occurs.




                                              58
59
Schematic drawing of the principle of microdialysis   60
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].
                                                       61
IV. Observation of Pharmacological or
     Physiological response
Like:
1. Allergic Response (……………………);

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

V. Physical properties of the skin
To evaluate the skin using:
1. …………………….;
                                        62
2.   …………………….
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.).



                                                      63
Maximizing Bioavailabilty of Drugs Applied to Skin
1. Drugs or prodrugs selection;

                                           dm DK
                                                 Co
……………………                                   dt   h
2.   Chemical Potential Adjustment;

3.   ……………………;

4. Ultrasound
Disturbs the lipid-Packing in the intercellular spaces of s.c.
     [……………………]
 Disadvantage:
•    ……………………;
                                                                 64
•    …………………….
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 .                                                      65
5. Iontophoresis:
Disadvantages:
a. ……………………;        Basic principle
                    of
b. …………………….        iontophoresis.
                    A current
                    passed
                    between the
                    active electrode
                    and the
                    indifferent
                    electrode
                    repelling drug
                    away from the
                    active electrode
                    and into the
                    skin .

                                66
6. Electrophoresis:
Creation of Aqueous-Pores ins.c. by Application of
   currents for m. seconds (100-1000 v/cm)
   ……………………

Disadvantages:
• ……………………
Electroporation + Iontophoresis  …………………….




                                                     67
Basic principle of electroporation. Short pulses of high voltage current are applied
to the skin producing hydrophilic pores in the intercellular bilayers via momentary
                                                                               68
realignment of lipids .
7. Stratum corneum removal
1. 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;
                                           69
 …………………….
Photomechanical wave




                  70
8. Needle array
400 needles
Flux ↑↑ to 100,000 folds
There is needle array + Iontophoresis technique
    combination.




                                                  71
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 .                                     72
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;
                                              73
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.                               74
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.                     75
Chemical structure of typical chemical penetration   76
enhancers
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:
……………………;                                       77
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.
                                                      78
Structure of nanodispersed vehicle systems
                                             79
• Transfersomes
A 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.



                                                    80
Penetration of these colloidal particles works
   best:
1. ……………………&;

2. …………………….

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




                                                 81
• 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.


.
                                                   82
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:
• ……………………,
• ……………………,
• ……………………


                                              83
Figure 33.12


               84
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.




                                           85
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
                                                                  86
87
Advantages:
1. ……………………

2. ……………………;

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

4. ……………………;

5. ……………………;
                                               88
6. ……………………;

7. ……………………;

8. Safety - the device avoids-:
• ……………………

•   ……………………;

•   Splash back of body fluids (……………………)
                                      89
Disadvantages
• No home use;

• Problems arising with:
1. Bruising of the skin;

2. Bouncing off the skin surface.



                                    90
Transdermal Therapeutic Systems (TTS) or
   (TDDS)
• Advantages:
1. Eliminate variables in the G.I.T. absorption;

2. ……………………;

3. Controlled release  improves patient;
   compliance;

4. ……………………;
                                               91
5. Can use drug with low therapeutic index

6. ……………………

•   Disadvantages

1. ……………………;

2. Drugs must be stable & have correct
   physichochemical properties.
                                             92
Device Design
Types of TTS Devices:
1. Monolith or matrix system
                                            (Higuchi eq.)
                m  2Dv Cs At
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.            93
2. Rate-Limiting Membrane



                                     (Fick’s law)
       dm DK
             .C 0
       dt   h

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

                                                    94
• Fig. 33.13+33.14+33.15+33.16




                                 95
96
97
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
                                             98
   matrix patch ( figure 33.17)
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:
• ……………………;

•   ……………………;

•   …………………….                                        99
100
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;
                                              101
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.
                                                                  102
5. Transdermal Nicotine
TTSs 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.
                                                      103
TTS Testosterone
a. Hypogonadism (due to testicular or pituitary
    disorder)

b.   Testosteron deficiency due to orchidectomy.




                                            104
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:
• ……………………;

•   ……………………;

•   …………………….                                        105
5. There is a need to solve problems relating to, e.g.:
• ……………………,

•   ……………………,

•   ……………………,

•   ……………………,




                                                    106
• Wearability of the patch for up to 7 days; the
  device must:
a. ……………………,

b. ……………………,

c.……………………;

d. ……………………


                                               107
Formulation of Dermatological vehicles
1. Old Formulator developed formulations for:
• Stability,

•   Compatibility,

•   Patient acceptability.

2. Modern Formulator developed formulations
   for:
• ……………………
                                            108
•   …………………….
Dermatological formulations
1. Liquid preparations:
a. Liniments;
b. Lotions;
c. Paints;
d. Varnishes;
e. Tinctures;
f. Ear drops
g. 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..                                             109
2. Gels (Jellies)
Are two- component semisolid systems rich in liquid.
    (water & polymer)  TD structures.
3. Powders
4. Ointments:
a. Hydrocarbon bases;
b. Plastibases (Polyethylene in paraffin oil)
Advantages:
 ……………………,
 ……………………,
 ……………………,
 ……………………,
 ……………………,
 ……………………,
                                                   110
……………………,
……………………,
compatible with most medicaments &
 maintain their consistency event at ↑ temp.

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

……………………

…………………….
                                            111
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)
                                           112
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.                                           113
I.   Cosmetic or aesthetic criteria for
     dermatological formulations:
1.   ……………………;
2.   ……………………;
3.   ……………………;
4.   ……………………;
5.   ……………………;
6.   …………………….




                                          114
Physiologic criteria for dermatological
  formulations:
   ……………………;

   ……………………;

   Rheological properties-consistency, visco-elasticity,
    extrudability;
   115115
   ……………………;

   Phase changes-homogeneity, bleeding, cracking;

   Particle size distribution of dispersed phase;

   ……………………;                                               115
Microbial Contamination & Preservation:
Rancidity & Antioxidants




                                          116

				
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