4. Three layers of skin
• Epidermis (Stratum corneum):dead keratinized cells, density 1.55,
palms& soles : 100 micrometer.
Other portions: 10 micrometer in dry state & 40 to 50 micrometer in
hydrated state.
Dermis: consists of proteins in a matrix of muco polysaccharide,
blood vessels, lymphatics, nerves, hair follicles, sebaceous & sweat
glands.
Hypodermis layer
6. Mechanisms of drug permeation
6
Hydrophilic drugs permeates by Intercellular pathway
Lipophilic drugs permeates by Intracellular (Transcellular)
mechanism.
7. Factors affecting skin penetration
Physiochemical
• Properties of drug
• Vehicle
• pH
• pKa
• Concentration
• Partition coefficient
Physiological
• Skin .. Intact/injured
• Skin age
• Area of skin under treatment
• Thickness of skin barriers
• Skin moisture
• Species variation
• Temperature of skin
8. Physiology of skin
• Hydration of stratum corneum is important factor
• Affect rate of passage of all substances
• Hydration result from water diffusing from epidermis from
perspiration
• Under occlusive condition hydration of stratum corneum increases
from 15% to 50%
• This increases penetration of steroids
9. Physicochemical factor
• Solubility of drug determine conc of drug at absorption site,
• Partition coeff. influence rate of transport
• Rate of absorption is inversly proportional to mol. wt. of drug
11. Introduction
• The aim of drug administration via skin can be either the local therapy or
the transdermal drug delivery of the systemic circulation.
• Transdermal system delivers medications through the skin direct into the
blood stream.
• One long standing approach to increase the range of drugs that can
effectively delivered via this route has been to use penetration enhancers:
chemicals that interact with skin constituents to promote drug flux.
12. Percutaneous absorption
▪ It involves passive diffusion
of substance through skin.
▪ Trans-corneal penetration:
▪ Intra cellular
penetration.
▪ Inter cellular
penetration.
▪ Transappendegeal
Penetration.
13. Factors affecting percutaneous absorption
• Solubility in stratum corneum
• Diffusion through stratum corneum
• Partitioning
• Diffusion through viable skin tissue
• Condition of skin (Hydration)
• Effect of vehicles
• Effect of concentration of medicament
• Effect of surfactant
13
14. Techniques to enhance penetration
1. By increasing the diffusion coefficient of the drug.
2. By increasing the effective concentration of the drug in the vehicle.
3. By improving partitioning between the formulation and the stratum corneum.
4. Temporarily disrupting stratum corneum
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15. Penetration enhancement
• Skin penetration enhancement technique have been developed to
improve bioavailability & increase the range of drugs for which topical &
transdermal delivery.
• Penetration enhancers penetrates through skin to decrease the barrier
resistance.
• Alternatively, physical mechanism such as iontophoresis &
phonophoresis can be used for certain cases of drugs.
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16. Penetration enhancers (PE)
• Chemical enhancers or penetration enhancers or absorption promoters are the
agents that interact with skin constituents to promote the drug flux.
• It is difficult to select rationally a penetration enhancer for a given permeant.
• Penetration enhancers tend to work well with co-solvents such as PG or
ethanol.
• Most penetration enhancers have a complex concentration dependent effect.
• Permeation through animal skins & rodent skins are generally considerably
greater than those obtained with human skin.
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17. Direct Effects of PE
1. Act on the stratum corneum intracellular keratin, denature it or modify its
conformation.
2. Affect the desmosomes that maintain cohesion between corneocytes.
3. Modify the intercellular lipid domains to reduce the barrier resistance of the
bilayer lipids.
4. Alter the solvent nature of the stratum corneum to modify partitioning of the
drug.
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18. Indirect Effects of PE
1. Modification of thermodynamic activity of the vehicle.
2. Solvent permeating through the membrane could ‘drag’ the
permeant with it.
3. Solubilizing the permeant in the donor, especially where solubility is
very low so that can reduce depletion effects and prolong drug
permeation.
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19. Ideal Properties of PE
• Non toxic, non irritating, non allergic.
• work rapidly.
• Pharmacologically inert.
• Its duration of action should be predictable & reproducible.
• Should work unidirectionally.
• When removed from skin barrier properties should return both rapidly &
fully.
• Cosmetically acceptable.
• Compatible with both excipients & drug.
10/31/2020PENETRATION ENHANCERS 19
20. Fick’s 2nd Law of diffusion
dC/ dt = D d2C/dx2 ---------- (1)
Where,
C = Conc. Of drug
x = thickness of skin
D = Diffusion coefficient
t = Time
20
21. Classification of PE
1. Surfactants :
a) Ionic: SLS, Na laureate, etc.
b) Non ionic : Tween 80, Polysorbates
2. Bile Salts & Derivatives :
E.g.. Na glyacolate, Na deoxycholate
3. Fatty Acid & Derivatives :
E.g.. Oleic acid, Caprylic acid, etc.
4. Chelating Agents :
E.g.. EDTA, Citric acid, etc.
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22. 5. Sulphoxide :
E.g.. DMSO, DMA, DMF, etc.
6. Polyols :
E.g. : PG, PEG, Glycerol, etc.
7. Monohydric Alcohols :
E.g. : Ethanol, 2- Propanol, etc.
8. Miscellaneous :
E.g. : a) Urea & its derivatives
b) Terpenes & Terpenoids
c) Phospholipids
d) Water
10/31/2020PENETRATION ENHANCERS 22
24. Mechanism of action
• Action on lipid (ex. DMSO)
• Action on Protein (DMSO on corneocytes)
• Partitioning promotion (Ex. ethanol increases partitioning of
nitroglycerin)
26. Water
The water content of human stratum corneum is typically around 15-
20% of tissue dry weight.
Soaking the skin in water, exposing the membrane to high humidities
or, occluding allow the stratum corneum to reach water contents in
equilibrium with underlying epidermal skin cells.
In general, increased tissue hydration appears to increase transdermal
delivery of both hydrophilic & lipophilic permeants
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27. Water present in stratum corneum is in two form, bound & free,
Free form act as solvent for polar permeants to diffuse.
MOA:
- free water act as solvent & alter solubility of permeants & so its
partitioning. .
- The corneocytes take up water and swell, such swelling of cells would
impact upon the lipid structure between the corneocytes causing
some disruption to the bilayer packing.
27
28. Dimethyl sulphoxide (DMSO)
Dimethyl sulphoxide (DMSO), aprotic solvent which form hydrogen bond with itself
rather than with water.
It interact with corneocytes
Open-up denser protein structure to make it permeable.
Promotes both hydrophilic & hydrophobic permeants.
Effect is concentration dependent(> 60% needed for optimum action).
At high concentration – erythema & whales, may denature proteins.
To avoid above side effects researchers have investigated chemically related materials –
DMAC & DMF
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29. MOA:
• - denature protein, changes the keratin confirmation from α -
helical to β – sheet.
• - interacts with the head groups of some bilayer lipids to
distort to the packing geometry.
• - also may facilitate drug partitioning from formulation to this
universal solvent.
DMSO
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30. 30
Azones
• First chemically design molecule as penetration enhancer.
• Promote flux both hydrophilic & lipophilic permeants.
• Highly lipophilic with Log o/w =6.2.
• Effective at low concentration(0.1 – 5%).
• Soluble in & compatible with most organic solvents.
• Enhances permeation of steroids, antiviral & antibiotics.
• MOA:
- Interact with the lipid domains of the stratum corneum.
- Partition into the lipid bilayer to disrupt their packing arrangement.
31. Pyrrolidone
Mostly used member : 2- Pyrrolidone(2P) & N- Methyl -2-
Pyrrolidone(NMP).
NMP & 2P are miscible with most organic solvents.
Used for numerous molecules including hydrophilic (e.g. mannitol, & 5-FU) and
lipophilic ( hydrocortisone and progesterone) permeants.
Greater effect on hydrophilic drugs.
MOA:
- may act by altering the solvent nature of the membrane and pyrrolidones have
been used to generate ‘reservoirs’ within skin membranes.
- Such a reservoir effect offers potential for sustained release of a permeant.
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32. Fatty acid
Oleic acid & other long chain fatty acid are used.
Effective at low concentration(<10%)
Used both for hydrophilic & lipophilic drugs.
Saturated alkyl chain lengths of around C10–C12 attached to a polar head group yields a
potent enhancer.
In unsaturated compounds, the bent cis configuration is expected to disturb intercellular
lipid packing more than trans.
Used for estradiol, acyclovir, 5 FU, Salicylic acid.
MOA:
- Interacts with & modifies the lipid domains of stratum corneum discrete lipid domains is
induced within stratum corneum bilayer lipid on exposure to oleic acid.
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33. Alcohol, Fatty alcohols and Glycol
Ethanol is used most commonly in patches.
Used for levonorgestrol, estrdiol, 5 FU, etc.
Its effect is concentration dependent, at high concentration causes dehydration of
biological membrane & decreases the permeation.
Applied in concentration range from 1 – 10%.
Branched alkanols lower activity
1- Butanol most effective.
1-octanol and 1-propranolol to be effective enhancers for salicylic acid and nicotinamide.
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34. MOA:
- Act as solvent.
- alter solubility property of tissue leads to improvement in drug partitioning.
- volatile nature of ethanol help in modifying thermodynamic activity of drug.
- due to evaporation of ethanol drug concentration increases providing supersaturated
state with greater driving force
- Solvent drag may carry permeant into the tissue.
- As volatile solvent may extract lipid fraction from skin.
34
35. Surfactant
Are made up of alkyl or aryl side chain with polar head group.
Have potential to damage human skin.
Both anionic & cationic surfactant can be used, but non ionic surfactant are safe.
Non ionic – minor effect, anionic – pronounced effect.
MOA:
- Alter behavior of water in skin
- Solubilize the lipophilic active ingredient & also have potential to solubilize lipids within
the stratum corneum.
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36. Essential oils and Terpenes
• Hydrocarbon terpenes less potent, alcohol/ ketone containing terpenes
moderate and oxide & terpenoid shows greatest enhancement .
• Smaller terpenes are more active than larger.
• Non polar(limonene) agents active for lipophilic drugs & polar(menthol) for
hydrophilic drugs.
• MOA:
- Modify the solvent nature of the stratum corneum, improving drug
partitioning.
- Alters thermodynamic activity of the permeant.
- Terpenes may also modify drug diffusivity through the membrane.
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37. Urea
Hydrating agent, have been used in scaling conditions such as psoriasis & other
skin conditions.
It produces significant stratum corneum hydration, produces hydrophilic
diffusion channels.
Has keratolytic properties, usually when used in combination with salicylic acid
for keratolysis.
Urea itself possesses only marginal penetration enhancing activity.
Cyclic urea analogues and found them to be as potent as Azone for promoting
indomethacin.
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38. Phospholipid
• Generally employed as vesicles (liposomes) to carry drugs.
• In a non-vesicular form as penetration enhancers.
• Phosphatidylcholine & hydrogenated soya bean phospholipids have been reported to
enhance penetration of theophylline & diclofenac respectively.
• MOA:
- occlude the skin surface & thus increase tissue hydration.
- phospholipids fuse with stratum corneum lipids.
- this collapse of structure liberates permeant into the vehicle where drug is poorly
soluble and hence thermodynamic activity could be raised so facilitating drug delivery.
10/31/2020
38
40. Compendial (USP) requirements for ointments
• Microbial content
• Tests for absence of Staphylococcus aureus and Pseudomonas aeruginosa
• Minimum fill
• USP’s minimum fill test is determination of the net weight or volume of the
contents of filled containers to ensure proper contents compared with the
labelled amount
• Packaging, Storage, and labeling
• Semisolid preparations must be stored in well-closed containers to protect
against contamination and in a cool place to protect against product
separation in heat.
41. Evaluation of semisolids
• Extrudability and Spreadability
• In vitro permeation
• Irritation test
• In vivo test
43. In vitro skin permeation
Fanz diffusion apparatus
The Franz Cell apparatus consists of two primary
chambers separated by a membrane. Although
animal skin can be used as the membrane,
human skin is preferred. The test product is
applied to the membrane via the top chamber.
The bottom chamber contains fluid from which
samples are taken at regular intervals for
analysis. This testing determines the amount of
active that has permeated the membrane at
each time point. The chamber is maintained at a
constant temperature of 37O C
44. Irritation test
• HET CAM (Hen's Egg Test-
Chorioallantoic Membrane)
• Draize-test (rabbit eye)
47. IDEAL PROPERTIES OF SEMISOLIDS PHYSICAL
PROPERTIES
» Smooth texture
» Non dehydrating
» Non gritty and non greasy
» Elegant in appearance
48. PHYSIOLOGICAL PROPERTIES
◼Non irritating
◼Do not alter membrane or skin functioning
◼Miscible with skin secretion
APPLICATION PROPERTIES
◼ Easily applicable with efficient drug release.
◼High aqueous wash ability.
49. Semisolid preparations
• Topical preparations are used for both local and systemic effects.
• A topical dermatological product is designed to deliver drug into the
skin in treating dermal disorders, with the skin as the target organ.
• A transdermal product is designed to deliver drugs through the skin
(percutaneous absorption) to the general circulation for systemic
effects, with the skin not being the target organ.
• Systemic drug absorption should always be considered when using
topical products if the patient is pregnant or nursing.
50. • Ointments, creams and gels are semisolid dosage forms intended
for topical application.
• They may be applied to the skin, placed onto the surface of the
eye, or used nasally, vaginally or rectally.
Ointments
Creams
Gels
51. I. Ointments
• Ointments are semisolid preparations intended for external
application to the skin or mucous membranes.
• Ointments may be medicated or nonmedicated.
• Nonmedicated ointments are used for the physical effects that they
provide as protectants, emollients or lubricants.
52. 1. Ointment bases
Ointments bases are classified by the USP into four
general groups:
- hydrocarbon bases
- absorption bases
- water-removable bases
- water-soluble bases
53. Hydrocarbon bases are also termed oleaginous bases.
On application to the skin
1) Hydrocarbon bases
protect against the escape of moisture
emollient effect occlusive dressings
54. Petrolatum
is a purified mixture of semisolid hydrocarbons obtained
from petroleum.
• It is an unctuous mass, varying in color from yellowish to
light amber
• It melts at temperatures between 38C and 60 C and
may be used alone or in combination with other agents
as an ointment base.
• A commercial product is Vaseline.
55. White Petrolatum
is a purified mixture of semisolid hydrocarbons from
petroleum that has been wholly or nearly decolorized.
It is used for the same purpose as petrolatum. A
commercial product is White Vaseline.
56. • Bees wax
• -is the mixture (1000g) of yellow wax (50g) and
petrolatum (950g).
• bees wax is the purified wax obtained from the
honeycomb of the bee.
• The ointment is prepared by melting the yellow wax on a
water bath, adding the petrolatum until the mixture is
uniform, then cooling with stirring until congealed.
57. White ointment
This ointment differs from yellow ointment by
substituting white wax and white petrolatum in the
formula.
60. 2) Absorption bases
Absorption bases are of two types:
• Those that permit the incorporation of aqueous solutions
resulting in the formation of water-in-oil emulsions (e.g.,
hydrophilic petrolatum)
• Those that are water-in-oil emulsions and permit the
incorporation of additional quantities of aqueous solutions
(e.g., Lanolin)
61. Absorption bases may be used as emollients;
• are not easily removed from the skin with water washing
since the external phase of the emulsion is oleaginous;
• are useful as pharmaceutical adjuncts to incorporate
small volumes of aqueous solutions into hydrocarbon
bases.
• Emulsified: Lanolin
• Non-emulsified: Anhydrous lanolin
62. Hydrophilic petrolatum
Hydrophilic petrolatum, USP has the following formula
for the preparation of 1000 g:
Cholesterol 30 g
Stearyl alcohol 30 g
White wax 80 g
White petrolatum 860 g
It is prepared by melting the stearyl alcohol and the white wax on
a steam bath, adding the cholesterol with stirring until dissolved,
adding the white petrolatum and allowing the mixture to cool
while being stirred until congealed.
63. Lanolin
obtained from the wool of sheep;
is a purified, wax-like substance that has been
cleaned, deodorized, and decolorized.
It contains not more than 0.25% water.
Additional water may be incorporated into lanolin
by mixing.
Hydrous lanolin is w/oemulsion with ability to
abbsorb
64. Anhydrous Lanolin
It is capable of absorbing 30-40% water
maximum amount of water that can be added to
100g of base at given temp is water no.
65. 3) Water-removable bases
• Water-removable bases are oil-in-water emulsions
resembling 'creams' in appearance.
• Because the external phase of the emulsion is
aqueous, they are easily washed from skin and are
often called ‘water washable’ bases.
• It form semipermeable film on skin
• Vanishing cream after application on skin there is no
visible evidence
66. Hydrophilic ointment
Hydrophilic ointment has the following formula for the
preparation of about 1000 g:
Methylparaben 0.25g
Propylparaben 0.15g
Sodium lauryl sulfate 10g
Propylene glycol 120g
Stearyl alcohol 250g
White petrolatum 250g
Purified water 370g
In preparation the ointment, the stearyl alcohol and white petrolatum are melted together at about 75C. The
other agents, dissolved in the purified water, are added with stirring until the mixture congeals.
67. 4) Water-soluble bases
• Water-soluble bases do not contain oleaginous components.
• They are completely water-washable and often referred to as
‘greaseless’.
• W/O type are less occlusive or greasy
• Because they soften greatly with the addition of water, large amounts
of aqueous solutions are not effectively incorporated into these bases.
• They mostly are used for the incorporation of solid substances.
• No water required for preparation
• Polyethylene glycol/Macrogol
68. Polyethylene glycol ointment
Polyethylene glycol (PEG) is a polymer of ethylene
oxide and water represented by the formula:
H(OCH2CH2)nOH in which n represents the average
number of oxyethylene groups.
PEGs having average molecular weights below 600
are clear, colorless liquids; those with molecular
weights above 1000 are wax-like white materials;
those with molecular weights in between are
semisolids.
69. Selection of the appropriate base
• Desired release rate of the drug substance from the ointment base;
• Desirability for topical or percutaneous drug absorption;
• Desirability of occlusion of moisture from the skin;
• Stability of the drug in the ointment base;
• Effect of the drug on the consistency or other features of the
ointment base
• The desire for a base that is easily removed by washing with water.
70. II. Compendial requirements for ointments
1) Microbial content
• Ointments must meet acceptable standards for microbial
content and preparations which are prone to microbial
growth must be preserved with antimicrobial preservatives.
71. Among the antimicrobial preservatives used to inhibit
microbial growth in topical preparations are:
• methylparaben,
• propylparaben,
• phenols,
• benzoic acid,
• sorbic acid,
• quaternary ammonium salts.
72. 2) Minimum fill
The USP’s minimum fill test involves the
determination of the net weight or volume of the
contents of filled containers to assure proper
contents compared with the labeled amount.
73. 3) Packaging, storage, and labeling
• In large-mouth ointment jars or in metal or plastic tubes;
• In well-closed containers to protect against contamination and
in a cool place to protect against product separation due to
heat;
• In addition to the usual labeling requirements for
pharmaceutical products, the USP directs that the labeling for
certain ointments and creams include the type of base used
(e.g., water-soluble or water-insoluble).
74. 4) Additional standards
In addition to the USP requirements, manufacturers often examine
semisolid preparations
• for viscosity
• for in vitro drug release
In order to ensure intra-lot and lot-to-lot uniformity.
75. III. Creams
• Pharmaceutical creams are semisolid preparations containing one or
more medical agents dissolved or dispersed in either an oil-in-water
emulsion or in another type of water-washable base.
• Creams find primary application in topical skin products and in products
used rectally and vaginally.
• Many patients and physicians prefer creams to ointments because they
are easier to spread and remove than many ointments.
76. IV. Gels
Gels are semisolid systems
consisting of dispersions of small or large
molecules in an aqueous liquid vehicle
rendered jelly-like through the addition
of a gelling agent.
77. In addition to the gelling agent and water, gels may be
formulated to contain a drug substance, co-solvents
as alcohol and/or propylene glycol, antimicrobial
preservatives as methylparaben and propylparaben or
chlorhexidine gluconate, and stabilizers as edetate
disodium
Gelling agent
Water
Preservatives
Stabilizers
78. Medicated gels may be prepared for administration by various routes
including topically to the skin, to the eye, nasally, vaginally, and
rectally.
eye
skin
nasally
vaginally, rectally
79. V. Miscellaneous semisolid preparations
1. Pastes
Pastes are semisolid preparations intended for
application to the skin;
They generally contain a larger proportion of solid
material than ointments and therefore are stiffer.
80. • Pastes are prepared in the same manner as
ointments.
• Because of the stiffness of pastes, they remain in
place after application and are effectively employed
to absorb serous secretions.
• Because of their stiffness and impenetrability, pastes
are not suited for application to hairy parts of the
body.
86. Steps of Emulsification
• Preparation of oil and Aqueous phase
• Mixing of phases (70 0C)
• Simetenious
• Oil to Aq
• Aq to oil
• Cooling of Emulsion
• volatile content added at 450C
87. Operation steps
• All waxes and oils are dissolved in the wax phase vessel separately
• All aqueous phase materials are added in the water phase vessel and processed separately
• Both phase vessels are jacketed and are provided with motor driven propeller type of agitators which
facilitate thorough mixing
• Once the phases are ready, they are transferred to the main Ointment manufacturing vessel by opening
respective valves.
• This transfer takes place through filters and pipelines due to the vacuum created within the main vessel with
the aid of a pump.
• The Ointment Manufacturing vessel is provided with anchor type of stirrer along with Teflon scrapper at the
ends, the agitator is driven by dual speed motor.
• A built-in high speed emulsifier ensures proper emulsification of the ointment,
• The the control panel controls the time of emulsification with the aid of timers.
• The finished product is transferred to storage vessels by means of the bump pump.
• Transfer from storage vessel to the filling hoppers is achieved by means of reciprocating metering pumps at
the required rate.
• Special scrappers are provided for transfer of the complete product and to avoid wastage.
88. Planetary mixer
• Intimate and homogeneous mixing of products is employed by planetary motion of
beaters and centrally located Planetary Mixer.
• Product container provided with jacket to heat and cool for circulation of steam /
cold water. Mixer is also designed to operate under vacuum to remove air
entrapment in product during mixing.
• High speed dispenser suitable for homogenising the product with independent
drive at the center of top dish
• Product bowl mounted on castor wheels for easy portability, washing &
transporting mixed materials.
• Jacketted bowls available for heating or cooling of products during mixing.
• Provision to mix materials under vacuum for de-aeration purpose.
• Double beaters open type to cover full cross section of products in bowl.
• For ointments / paste / cream / lotions etc. high speed emulsifier provided for
homogeneous mixing
92. 1) Filling ointment jars
• Ointment jars are filled on a small scale in the pharmacy by
carefully transferring the weighed amount of ointment into
the jar with a spatula.
• The ointment is packed on the bottom along the sides of the
jar, avoiding entrapment of air.
• In large-scale manufacture of ointments, pressure fillers force
the specified amount of ointment into the jars.
93. 2) Filling ointment tubes
• Tubes are filled from the open back end of the tube,
opposite from the cap end.
• On a small scale, the tube may be filled manually or with a
small scale filling manually.
• After filling, the tube is closed and sealed.
• Industrially, automatic tube-filling, closing, crimping, and
labeling machines are used for the large-scale packaging of
semisolid pharmaceuticals.
• Depending on the model, machines are available which
have the capacity to fill from about 1000 to up to 6000
tubes per hour.