Topical formulations - · PDF fileLiniments Lotions ... •Disadvantages ... •...
Transcript of Topical formulations - · PDF fileLiniments Lotions ... •Disadvantages ... •...
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Topical formulations
AltonChapter 6 and 38
The skin:its function• Mechanical protection
(dermis) Changes over time The outer layer of skin
should contain 10-20%water to have the properelasticity
• Protection from Bacteria and viruses,
foreign substances Dehydration, radiation
• Temperature regulation• Production of vitamin D
Thick skin
Thin skin
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The skin:Anatomy• The heaviest organ in the
body• Epidermis
Stratum corneum Viable epidermis
• Dermis• Subcutaneous fat tissue• Appendages of the skin
Sweat glands• Eccrine sweat
glands• Apocrine sweat
glands Hair follicles Sebaceous glands
Epidermis
Dermis
Stratum corneum
Sebaceousglands
Sweat glands
Passage through the skin -effects of the route
• The appendages Two types
• hair follicles• sweat ducts
Low available surfacearea 0.1%
Can be important for ionsand large hydrophilicmolecules such as inimmunization through theskin
Colloidal particles suchas liposomes or smallcrystals of 3-10µm sizecan be used to target theappendages
• Epidermis Main transport barrier -
stratum corneum• 10 mm in dry state,
Swells in water• Intracellular matrix of
lipids and proteins The viable layer has some
enzymatic activity The dermis is strongly
vascular and oftenfunctions as a perfectsink
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Stratum corneum• Dead cells: no-active transport• Network of lipids and proteins
giving two possible “transportcanals”
• Organized like a brick wall Bricks (Corneocytes)
• Dense layer of dead cellscontaining keratin (protein)
¬ Mortar• Lipids and some water
(bilayer), ceramides, fattyacids, cholesterol
• The layer where mostsubstances are transported
Passage through the skin-Interactions,reactions and other problems
• Binding of activesubstance to skincomponents such as deadtissue, to cell receptorsand to fat tissue
• Precipitation whenpartitioning from a lipid-rich to a water-richenvironment
• Metabolism by the cells• Fast clearance in the
dermis• Rediffusion
Bindingin depot
DiffusionPartition
Metabolicsite
Bindingin depot
Bindingin depot
Binding toreceptors
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Passage through the skin - effectsof biological factors
• Age of the skin Higher penetration for
children and elderly• Condition of the skin
Disease can causeincreased thickness ordamage to the skin
Damaged skin showenhanced permeability
3 days needed to obtain aprotective layer
• Regional skin sites Hands- feet - eyelids -
scrotum
Evaluation of uptake anddissolution
Dissolution• Release without use of a rate-
limiting membrane• Release with use of a rate-limiting
membrane Types of membrane
• Simulated skin: celluloseacetate, silicone rubber
• Natural skin: stratumcorneum, whole skin
Uptake• No good animal models - pig best
Franz
Bronaugh
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Strategies for delivery
• Local treatment Surface treatment
• Bacteria and fungalcreams
• Deodorants• Insect repellents
Stratum corneum• Moisturizing agents
Skin appendages• Antiperspirants such
as aluminium• Treatment of acne• Antibiotics and
Antifungals
Viable epidermis anddermis
• Anti-inflammatory• Anaesthetics• Antiprutric• Antihistamines
• Transcutaneous immunization(in the development stage)
• Systematic treatmentOften depot formulations
• Testosterone,Estrogens
• Nicotine• Nitroglycerine
Factors affecting development of aformulation
• Patients’ compliance Products that are easy to
transfer from the container tothe skin
Products that spread easilyand evenly
Products that leave no visibleresidues on the skin
Products that do not feeltacky or sticky
Products that do not sting• Safety
Need of dose accuracy Microbiological safety
• Enhancement of drugpenetration Drug properties
• Prodrugs• Ion pairs
Hydration of the skin• Moistering• Occlusion
Chemical activity andsolubility of the drug• Supersaturation• Lipophilic or
hydrophilic drugvehicle
Adding excipients thatenhance penetration
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Penetration enhancers
DefinitionA substance thattemporarily diminishes theimpermeability of the skin
• Example of enhancers DMSO Pyrrolidols Surfactants Azone (Water)
The ideal enhancer• Pharmacologically inert• Non-toxic, non-irritating• Immediate effect• Full recovery• Compatible with the drug• Good solvent for the drug• Not causing loss of water, ions
etc• Having a acceptable look, taste,
texture and odour• Inexpensive
• In reality, it is difficult to findenhancers that are safe and thatare accepted by authorities
Formulations that affect skinhydration
Vehicle Examples Effects on hydration Effects onpermeability
Occlusivedressings
Waterproofplaster
Preventing water loss, fullhydration
++
Lipophilic Waxes, oils Preventing water loss,might give full hydration
++
Absorptionbase
Anh. Lipids +W/O emulsifier
Prevent water loss,marked hydration
++
Emulsionbase
Anh. Lipids +O/W emulsifier
Prevent water loss,marked hydration
++
W/Oemulsions
Oily creams Reduce water loss,increased hydration
+
O/Wemulsions
Aqueous creams May donate water, slightincrease in hydration
(+)
Humecant Glycerol May withdraw water (-)Powders Clay, Topical
powdersAiding evaporation ofwater
-/0
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Requirements on an idealformulation for local treatment• Low penetration of the active substance to
avoid systemic delivery• Non irritating• Broad therapeutic window• Not harming clothes and other things that
comes in contact with the formulation• Good cosmetic properties
Requirements placed onformulations for systemic delivery• Usually a low daily dose, <20 mg/day• An active substance that can penetrate the skin
• Low molecular weight < 600 Daltons• A partitioning coefficient high enough to ensure penetration
through the lipid layers in the stratum corneum but not so highthat it risks precipitation in the dermis
• A non-charged species passes through the skin more easilly• A low melting temperature leads to high intrinsic solubility
• Not causing irritation or sensitisation of the skin• Easy to apply the correct dose - (transdermal patches)
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Special Quality considerations
• Stability of excipients,especially of Preservatives Penetration enhancers Lipids
• Rheology• Water content• Phase changes• Particle and drop size• pH
• Test conditions Problems at elevated
temperatures• Typical problems
Volatile solvents canevaporate
Risk of oxidation of the lipidcomponents
pH measurements aredifficult in complex systems
Tests of dissolutionespecially from plasters
Type of formulations• Solutions (viscose or liquid)
Liniments Lotions Tinctures
• Solution aerosols• Powders• Ointments• Pastes and ointment that
contains as much as than50% solid material
• Gels• Creams and semi solid
emulsions• Depot formulations such as
plasters
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Ointments
• CharacterGreasy, sticky, semisolidproducts normally containinga hydrophobic componentsuch as oil, fat, hydrocarbonsor silicone
• Example of products Bactroban Nasal - local
treatment ofStaphylococcus aureusinfection
Iodosorb® - Treatment ofopen infected wounds,also as a powder
• Advantages Increases hydration of
the skin Good chemical stability
if no water present• Disadvantages
Poor cosmeticproperties
Formulation of ointments
• Base Hydrocarbons
• Paraffin• Plastibases
(polyethylene inhydrocarbons)
Fats and fixed-oils bases• Semisolid vegetable
oils Silicones
• Water-repellent Water-soluble
• Polyethylene glycols• Non-occlusive
Absorption base• Contain excipients that
create o/w emulsionsupon adsorption of water
Emulsifying base• Self-emulsifing systems
that are mixable withwater
• Other Excipients Usually low in water
content thusbacteriosides are onlyneeded in special cases
Antioxidants may beneeded especially for Fatsand fixed-oils bases
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Gels
• CharacteristicsTwo phase semisolids systemrich in liquids containing acontinuous structure
• Examples of products Divigel®- Oestrogen for
systemic treatment Oftagel - tear substitute
local treatment of the eye Crinone - a progesterone
replacement formulatedas a vaginal gel
Basiron® - local treatmentof acne
• Advantages Good cosmetic properties Good release of
substances High water content can
hydrate the skin slightly
• Disadvantages Low chemical stability of
some excipients due tohigh water content
Low microbiologicalstability
What defines a gel
A gel is a two-phasesemisolid product.A gel consists of a networkthat entraps the liquid phase.A gel has viscoelasticproperties and ischaracterised by losing itselastic properties at highstress.There is a has high mobilityof molecules in the liquidphaselow amount of dispersedphase (>1%) still providesrigidity
• Uses of gels Topical formulations Stabilising foams,
emulsions anddispersions
“Cosmetic” factors• Easy to handle• Easy to spread
Entrapment of activesubstances to achievecontrolled release
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Formulation of gels• The gel-forming
component• Lyophilic sols
Entangled networks• Polyvinyl alcohols• Cellulous derivates
Covalent coupled• Carbomers
Ion-birding• Alginic acid
An aggregating structure• Gelatin• Carrageenan
• Flocculated lyophobic sols Clay and Bentonite Magnesium hydroxide
• The solvent Water Additives to increase
vaporization -ethanol Buffers to control pH
• Other additives Antioxidants Perfumes, colour Bactericide and
preservatives Moisterises
Types of networksNetworks can consist of
Flocculated systems• Normal hydrophobic
solids• “Card house” flocks
of special crystalparticles
Polymeric networks• Covalent linked
networks• Entangled networks• Physically linked
networks
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Creams
• CharacteristicsSemisolid emulsions fortopical use. O/W emulsionsand W/O emulsions
• Examples of products Garamycin® for Local
treatment of virusinfection
Daktacort® for Localtreatment of fungalinfection
EMLA- local treatment ofpain
• Advantages Good cosmetic properties Evaporation of the liquid
gives a soothing feeling When O/W emulsions are
rubbed into the skin thewater evaporates
An effective formulationfor hydrophobicsubstances
• Disadvantages Can be unstable systems Show complex release
patterns
Formulation of creams
• Contain all the ingredientsof gels and of emulsions
• It is sometimes notnecessary to stabilize theemulsion by the use of agel. Especially if theformulation contains highamounts of the dispersedphase for example Nivea
• Surfactants are needed tostabilize the emulsioncomponent of the gel
• O/W creams Used for vanishing
creams as the oil isrubbed into the skin
Can increase theamount of water-soluble substances inthe skin
• W/O creams Spread better than
ointments but are notocclusive
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Transdermal Therapeutic systems TTS”Plasters”
• Advantage Possible controlled
release Easy to remove No peak concentration Avoiding the variability
seen in thegastrointestinal systems
• Disadvantages Low permeability Risk of skin irritation Only applicable for potent
drugs < 2 mg/day
Backing membrane
Drug reservoir
Dissolution controlContact adhesive
Occlusive or nonocclusive
Can becombined
“Plasters”- things to consider
• Site of application Buccal plasters Special locations on
the body• Duration of a unit
1-3 days• Types of release control
Polymeric membrane Rate-controlling
adhesive layer Polymeric matrix Microreservoir system
• Interactions with excipientsand the control system Penetration enhancers
• Effect on occlusion of theskin Hydration
• Effect of adhesive on the skin Irritation Easy to remove
• Long-term changes in thematrix system
• Temperature- and light.stability of the matrix system
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Plasters- Example of products• Nicotine plasters
Nicotine passes easilythrough the skin
• Steroid hormones Testosterone - Atmos® Oestrogen - Evorel®
• Motion sickness Scopolamine -
Scopoderm®• Angina pectoris
Nitroglycerine• Hypertension
Clonidine
• Joint formulationdevelopment between bigpharma and drugformulation companies(patent holder) arecommon 3M Alza
Iontophorecic drug delivery• Molecules are transported
through the skin by the meanof an electric current
• Transport mainly through theskin appendages, which havethe lowest impedance of anyof the skin components
• Neutral moleculestransported due to low flow ofwater - electro-osmosis
• Other types of “external”induced uptakes Phonophoresis - Ultrasound Electroporations Needle arrays
+ -
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Terms to know from today'slecture
• Epidermis: the outer layer of the skin contains• Stratum corneum. the protective layer of the, skin containing dead cells
and a lipid matrix• Dermis; the lower parts of the skin which contains blood vessels• The appendages of the sin, sweat glands, hair follicles and sebaceous
glands• Penetration enhancers: excipients that increase penetration of the
epithelial cells or the skin• Ointments: topical formulations containing low amounts of water, often
lipophilic bases• Pasts: ointments with high particle content• Gels: Two phase semisolids system rich in liquid can be used for topical
formulations• Creams: semisolid emulsion for topical use.• Transdermal Therapeutic systems TTS - ”Plasters containing active drug
for slow release formulations