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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