Introduction and classification, anatomy of skin and factors affecting absorption, Formulation ,preparation, packaging, labeling and storage of ointments, Formulation, preparation, packaging, labeling and storage of jellies, creams, pastes.
2. The skin is very effective as a selective penetration barrier. The
epidermis provides the major control element.
3. Mechanism of drug penetration through skin
Three potential entry MACRO ROUTES to the viable tissue:
1. Via the sweat ducts
2. Across the continuous stratum corneum
3. Through the hair follicles with their associated sebaceous glands.
5. Low molecular weight molecules penetrate through stratum conium
to some extent.
Skin appendages are main route for Electrolytes, polar steroids,
antibiotics and colloidal particles.
Particles of 3-10 µ penetrate through hair follicle and particles less
than 3µ penetrate through stratum conium.
Hair follicle route may be important for ions and large polar
molecules.
Topically applied agents such as steroids, hexachlorophane,
griseofulvin, sodium fusidate and fusidic acid may form a depot or
reservoir by binding within the stratum corneum.
6. Once drug permeates through horny layer it readily enters living tissue
and systemic circulation.
The average residence time of drug in dermis may be 1 min before it
is washed away by blood.
NSAIDS reach far down to muscles to form depots.
7. Factors influencing dermal penetration of drugs
I. Biological factors:
1. Skin condition
2. Skin age
3. Blood flow
4. Regional skin site
5. Skin metabolism
6. Species difference.
II. Physicochemical
factors:
1. Skin hydration
2. Temperature and pH
3. Diffusion coefficient
4. Drug concentration
5. Partition coefficient
6. Molecular size and
shape.
8. BIOLOGICAL FACTORS:
1. Skin condition
The intact, healthy skin is a tough barrier but acids and alkalis
injure barrier cells and thereby promote penetration.
Mixtures of non-polar and polar solvents, such as chloroform and
methanol, remove the lipid fraction and molecules pass more easily.
Disease alters skin condition, skin inflamed, with loss of stratum
corneum thus permeability increases.
If organ thickened, with corns, calluses and warts, drug permeation
decrease.
2. Skin age
Skin of the young and the elderly is more permeable than adult
tissue.
Children are more susceptible to the toxic effects of drugs and
chemicals, because of their greater surface area per unit body
weight; thus potent topical steroids, Causes severe side-effects and
death.
9. 3.Blood flow:
An increased blood f;low could reduce the amount of time a
penetrant remains in the dermis, and also raise the concentration
gradient across the skin.
In clinically hyperaemic disease damages the skin barrier and
increase absorption.
4. Regional skin sites :
Variations in permeability depend on the thickness and nature of
the stratum corneum and the density of skin appendages.
Absorption changes with substance, volunteer and site.
Permeabilities depend on thickness of stratum corneum and the
overall thickness of the tissue.
Plantar and palmar callus may be 400-600 µm thick compared to
10-20 µm for other sites.
The hyoscine Transderm system employs in postauricular skin (i.e.
behind the ear) because the layers of stratum corneum are thinner
Facial skin in general is more permeable than other body sites
10. 5. Skin metabolism:
The skin metabolizes steroid hormones, chemical carcinogens and
some drugs.
This is advantage to prodrugs.
Skin can metabolize 5% of topical drugs.
6. Species differences:
Mice, rats and rabbits are used to assess percutaneous absorption,
but their skins have more hair follicles than human skin and they
lack sweat glands.
Hairless mouse, monkey and pig skins are most like that of humans.
Hairless rat and fuzzy guinea pig may be better models for humans.
To obtain skin penetration data it is best to use human skin
11. Physicochemical factors
1. Skin hydration:
When water saturates the skin the tissue swells, softens and wrinkles
and hydration of the stratum corneum increases permeability.
Dusting powders or lotions, provide a large surface area for
evaporation and therefore dry the skin
2. Temperature and pH:
The penetration rate of material through human skin can change
tenfold for a large temperature variation.
Occlusive vehicles increase skin temperature and increase
permeability.
According to pH-partition hypothesis, only unionized molecules pass
readily across lipid membranes.
Weak acids and bases dissociate to different degrees, depending on
the pH and their PKa or Pkb values.
Stratum corneum is resistant to alterations in pH, range of 3-9.
12. 3. Diffusion coefficient:
The diffusional speed of a molecule depends mainly on the state of
matter of the medium.
In gases, diffusion coefficients are large than liquids
In skin, the diffusivities reach their lowest values within the
compacted stratum corneum matrix.
The diffusion coefficient of a drug in a topical vehicle depends on
the properties of the drug and the diffusion medium and on the
interaction between them.
4. Drug concentration:
Drug permeation and flux of solute is proportional to the
concentration gradient across the barrier.
drug permeation follows Fick's law, saturated donor solution gives
maximum flux.
pH change, complex formation, or the presence of surfactants,
micelles or cosolvents modify the effective partition coefficient
13. 5. Partition coefficient(K):
The partition coefficient is important in establishing the flux of a drug
through the stratum corneum.
Drug (K<1) are water soluble, (K>1) are oil soluble.
Polar cosolvent mixtures, such as propylene glycol with water,
produce saturated drug solutions and maximize the concentration
gradient across the stratum corneum.
Surfactants disruption of intercellular lipid packing in the stratum
corneum, act as penetration Enhancers.
Complex formation of drug increases the apparent partition
coefficient may promote drug absorption.
6. Molecular size and shape:
Absorption is apparently inversely related to molecular weight.
Small molecules penetrate faster than large ones.
It is more difficult to determine the effect of molecular shape, as it is
related to partition coefficient.
14. Ointments
DEF: these are semisolid preparations meant for external application to
skin or mucous membrane.
OINTMENT BASES:
Selected after Toxity & Irritability test.
It is one of the most important ingredient used in the formulation of
semisolid dosage form
Ointments and suppository base do not merely acts as the carrier of
the medicaments, but they also control the extent of absorbtion of
medicaments incorporated with them
USFDA- list of ointment bases and their concentrations used.
15. They should be:
Compatible with skin pH and drug
Inert ,non irritating and non sensitizing
Good solvent and/or emulsifying agent
Emollient , protective , non greasy and easily
removable
Release medicaments easily at the site of
administration
Pharmaceutical elegant and possess good stability.
17. 1. Oleaginous ( hydrocarbon) bases:
They consist of a combination of more than one oleaginous material such as
water insoluble hydrophobic oils and fats
Disadvantages:
• Greasy, sticky-non washable
• Retain body heat
• Do not increase absorption
• Prevent drainage on oozing area.
• They are anhydrous, do not absorb water & insoluble in water.
1. Hydrocarbons: Paraffin wax, Soft paraffin, Liquid paraffin
2. Vegetable oils and animal fats: Peanut oil, Coconut oil, Lanolin, Bees wax
3. Hydrogenated & sulfated oils: Hydrogenated castor oil, Hydrogenated &
sulfated castor oil.
4. Acids, Alcohols & Esters: Stearic acid, Stearyl alcohol, Isopropyl Myristicate.
5. Silicones: Dimethyl polysiloxanes
18. A) Soft paraffin (Petrolatum):
This is purified mixture of semisolid hydrocarbons obtained from
petroleum.
Types
1. Yellow soft paraffin – M.pt=380C, used in ophthalmic ointments.
2. White soft paraffin- M.pt=560C, obtained from bleaching Yellow
soft paraffin.
B) Hard paraffin:
purified mixture of solid hydrocarbons obtained from petroleum.
USE- harden/soften ointment base
c) Liquid paraffin (white mineral oil/ liquid petroleum):
mixture of liquid hydrocarbons obtained from petroleum by
distillation.
USE- Combine with hard/ soft paraffin to harden/soften ointment
base.
19. 2. Absorption (Emulsifiable) base:
Qualities :
•Anhydrous
•Forms w/o emulsion
•Absorbs 50% water
•Due to the presence of sterol emulgent
•Easily removable by water
Classification
1. Non-emulsified bases:
Absorb water and aqueous solutions to produces w/o emulsions
Eg. wool fat, wool alcohol, beeswax, cholesterol.
2. W/0 emulsions:
Absorb more water than non-emulsified bases.
Eg. Hydrous wool fat (lanolin)
20. 1. Wool fat(Anhydrous lanolin):
This is fat from wool of sheep.
Can absorb 50% water of its weight.
USE: ointment base preparation, ophthalmic ointments.
2. Wool alcohol:
Wool fat is alkalized to obtain cholesterol & alcohol.
USE: Emulsifying agent in preparation of W/O emulsions.
3. Bees wax:
Wax from honey comb of bees.
2 types- yellow & white bees wax
USE: stiffening agent in paste & ointments.
4. Hydrous wool fat:
Purified fat from wool of sheep.
Insoluble in water, soluble in ether, chloroform.
Contains 70% wool fat+ 30% water.
USE: Emollient.
21. Advantages of Absorption bases
Compatible with most of the medicaments
Absorb large quantity of water or aqueous substances
Relatively heat stable
Easily spreadable
Less occlusive and good emollients
Aqueous substances can be incorporated
Disadvantages
Undesirable due to greasy nature
Chances of microbial contamination.
22. 3. Emulsion bases:
Ability to absorb water, serum discharges and forms o/w and w/o
emulsions.
According to the type of emulsion these bases are classified as
either W/O or O/W.
1. W/O- greasy, sticky. Ex: Sulfur & zinc ointments
2. O/W- easily removed from skin. Ex: vanishing cream.
Emulsifying ointment:
Anionic, cationic or non-ionic Emulsifying wax 30%
White soft paraffin 50%
Liquid paraffin 20%
*When applied on skin leaves behind a layer of fat.
23. Advantages Of Emulsion bases
Miscible with exudates from lesions
Does not interfere with skin function
Good contact with skin because of surfactant content
High cosmetic acceptability.
Easy removable from the hair.
Disadvantages of Emulsion bases
W/o emulsion greasy and sticky
Its acceptance is less
Difficult to remove from body and clothing.
25. Carbo waxes (Macrogols/ Polyethylene glycols)
General formula CH2OH. (CH2OCH2)n . CH2OH
These are mixtures of polycondensation products of ethylene oxide
and water
•Average Molecular weight is represented by numbers
Macrogols 200, 300, 400 -- viscous liquids
Macrogol 1500 -- greasy semi solid
Macrogols 1540, 3000,4000, 6000 -- waxy solids
Liquids
• Clear and colourless
• Faint characterisitic odour
• Miscible with water, alcohol and other glycols
26. Solids
• White or cream in colour
• Hard lumps or flakes
• Soluble 1 in 3 in water and 1 in 2 in alcohol
• Solidifying points range from 40 to 60°c
Macrogols Properties:
• Non-toxic and non-irritating
• pH – 4 to 7.5
• Can be sterilised by heat (solids – dry heat, liquids – autoclave)
• water soluble, non-volatile and inert substances.
Different carbowax mixture produces different consistency.
28. Methods of Preparation of ointments
1. Trituration
2. Fusion
3. Chemical reaction
4. Emulsification
Objectives:
•Free from lumps of separated high M.P ingredients of the base
•No tendency of separation of liquid constituents from the bulk
•Even distribution of insoluble powders
•To obtain ointment free from grittiness
•To obtain uniform ointment
29. 1. Trituration Method
Widely used method
For extemporaneous preparation of ointments.
When the base is soft and medicament is solid insoluble
Small amount of liquid to incorporated in the base
Advantage
Involves mixing as well as size reduction
Procedure:
1. Reduce the solid medicament to fine powder
2. Medicament is mixed with small amount of base on ointment slab
with a stainless steel spatula until a homogeneous product is
formed.
30. 3. Add remaining quantities of base with uniform mixing
4. Incorporate any liquid ingredient if present
(mortar and pestle to be used in case of large quantity of liquid)
Eg: Prepare and dispense 100 g of sulphur ointment
Rx
Sublimed sulphur, finely sifted - 10 g
Simple ointment - 90g
Prepare an ointment
Direction - Apply the ointment to the affected area as directed.
31. 2. Fusion method:
Suitable when ointment base contains number of solid ingredients
of different melting points.
Procedure:
1. Ointment base are melted in decreasing order of their melting
point.
2. Highest melting point should be melted first, low melting point
next.
3. This avoids over heating of substances of low melting point
4. Incorporate medicament slowly to the melted mass
5. Stir thoroughly until mass cools down and homogeneous
product is formed.
32. 6. Liquid ingredients or aqueous substance should be heated to the
same temperature as the melted bases before addition.
7. If not, wax or solids will cool down quickly and get separated
Precautions:
Strring is done continously- homogeneous mass
Vigorous stirring should be avoided to prevent entrapment of air
Rapid cooling should be avoided to get a uniform product.
To remove the dust or foreign particles strain through muslin cloth
33. Eg: Prepare and dispense 100 g of Citrimide ointment
Rx
Cetrimide - 1 g
Cetostearyl alcohol – 10 g
White soft paraffin – 10 g
Liquid paraffin – 29 g
Pure water – 50 g
Procedure:
1. Melt ointment bases in decreasing order of M.Pt.
2. Dissolve cetrimide in water and heat the solution
3. Mix cetrimide solution to hot molten mass and stir.
34. 3. Chemical reaction method
Preparation of some ointment involves chemical reactions
Eg – (a)Iodine ointment (iodine free form)
(b)Iodine ointment (iodine combined form with ointment base)
(a)Ointments containing free iodine
Iodine is slightly soluble in fats and vegetable oils.
Readily soluble is potassium iodide solution in water due to
formation of polyiodides (KI. I2, KI. 2I2 ,KI.3I2)
Poly iodides are readily soluble in water, alcohol and glycerin.
These solutions may be incorporated with the molten absorption
type ointment base.
35. (b) Ointments containing combined iodine
Fixed oils and many fats obtained from vegetable and animal sources
contain unsaturated constituents
Iodine combines with double bonds
CH3 (CH2)7 CH=CH (CH2)7 COOH + I2 (Oleic acid)
CH3 (CH2)7 CHI.CHI (CH2)7 COOH (Di-iodo stearic acid)
Free iodine is not available, So ointments appear dark, greenish black
in colour
Leaves no stain when rubbed into the skin, Hence known as non-
staining iodine ointment
36. 4. Emulsification method
1. Facts, oils and waxes an melted together to a temperature and 700c.
2. Aqueous solution of the heat stable, water soluble compounds is
also heated to the same temperature.
3. Solution is slowly added to the melted bases, with continuous
stirring until cool.
Emulsifying agent is needed to make a stable emulsion
Water soluble soaps are commonly used as emulsifier for semisolid o/w
emulsions.
Combination of triethanolamine stearate soap and cetyl alcohol is used
in o/w emulsion
Bees wax and divalent calcium ions used in w/o emulsion.
39. Packing of ointment:
•Ointment jars
•Made of colorless or colored glass
•Amber colored for light sensitive preparation
• with screw caps
• with impermeable liners
•Collapsible tubes
•Made of tin or plastic
•Supplied with the applicator
40. Storage:
Store in a well closed container and in cool place
Protect from high temperature/ direct sunlight.
Prevent the loss of volatile constituents
High temperature soften or melt base
Separation of phases may take place
Labeling:
“ FOR EXTERNAL USE ONLY ”
41. JELLIES
Def:
jellies are transparent/ translucent, non-greasy, semisolid
preparations meant for external application to skin/ mucous
membrane.
Characteristics:
• Easy to apply
• Evaporation of water- Produces a cooling sensation to skin
• Contents remaining stick to the applied area gives protection
• Can be easily removed by washing with water after treatment.
42. Types of Jellies
Based on its application classified into
(1) Medicated, (2) Lubricating, (3) miscellaneous jellies
1. Medicated jellies:
• Used on mucous membrane/ skin
• Actions-Lubrication, antiseptic, Vasoconstrictor, Contraceptive.
• Mechanism:
Evaporation of water Produces a cooling sensation to skin
Contents remaining stick as film to the applied area gives protection
Ex: Ephedrine sulphate Jelly- Vasoconstrictor
Phenyl mercuric Nitrate- Contraceptive (spermicidal)
43. 2.Lubricating Jellies:
Properties:
Should be thin, transparent & water soluble.
Must be sterile when inserted into sterile regions of the body.
Used for lubrication in:
• Rectal Thermometers
• Urinary Bladders
• Fingerstalls
• Cystoscopes
• Surgical gloves
• Catheters
44. 3.Miscellaneous jellies:
• Patch testing
Used as vehicle for allergens applied on skin in allergy test
• Electrocardiography
Jellies contain Nacl, pumice powder & glycerin.
To reduce electrical resistance between skin and electrode
Formulation of Jellies
(1) Medicament, (2) Gelling Agents, (3) Preservatives
(4) Anti-dehydrating agents, (5) Other stabilizing agents
45. Gelling agents :
• Are usually hydrocolloids, which forms gel like matrix
1. Tragacanth
2. Sodium alginate
3. Pectin
4. Starch
5. Gelatin
6. Cellulose derivatives
46. 1.Tragacanth :
Used for preparations of Lubricating, Medicated & Contraceptive Jellies.
Concentrations used for Lubricating (2 to 3%) &
Dermatological vehicle (5%).
Tragacanth is poorly wettable
On addition to water lumps are formed which is difficult to disperse
Dispersing agent is generally used to get a homogenous product
Alcohol, glycerol or volatile liquids are used as dispersing agent
47. Disadvantages :
• Obtained from natural sources, so vary in viscosity
• After evaporation, the film left on the skin tends to flake
• Loss viscosity outside the pH range of 4.5 – 7
• Can’t be stored for longer time
• Prone to microbial growth
48. 2. Sodium aliginate :
• Used as Lubricant 1.5 to 2% & Dermatological vehicle 5 To 10%
• Viscosity can be increased by adding soluble calcium salt
• Salting out is observed with high conc.
• 2-4% alcohol, glycerine, propylene glycol are used as dispersing agent
Advantages over tragacanth
• Available in several grades of standard viscosity
49. 3. Pectin :
• Good gelling agent suitable for acid products
• Used in many preparations including edible Jellies
• Glycerine is used as dispersing agent & humectant
• Pectin jelly is good medium for bacterial growth, add preservative
Storage:
Well closed container to prevent loss of moisture by evaporation
50. 4. Starch :
Used in combination with other Jelling agent
Provides a water soluble dermatological base
Starch + Gelatin + Glycerin jelly product is still used
Glycerin (up to 50%) may be added which acts as preservative
and humectant
Note:
• Must be freshly prepared
• Well closed container to prevent loss of moisture by evaporation
51. 5. Gelatin :
Insoluble in cold water (swells and soften)
Soluble in hot water
2% gelatin forms jelly on cooling
Stiff medicated Jellies can be prepared (15%)
Melted before use and after cooling to desired temperature,
applied with a brush.
Affected area covered with bandage and left in place for several
weeks
Suitable preservative is required
52. 6. Cellulose derivatives :
Produce neutral jellies of very stable viscosity
Afford good resistance against microbial growth
High clarity & produce a soft film after drying
Sodium CMC
• Used for preparation of lubricating & sterile jellies
• Withstand autoclaving temperature without deterioration
Example
• Methyl cellulose - 3%
• Sodium carboxy methyl cellulose
1.5 - 5% - lubricant, 5% - Dermatological
• Carbomer
0.3 – 1% - Lubricant, 0.5 – 5% - Dermatological
53. Preservation of Jellies :
• Jellies are aqueous preparation-microbes grow
• Cellulose derivative & clays are used as jelling agents to resist the
microbial attack
• Still preservative must be added to avoid incompatibilities with
gelling agent
Examples:
Methyl paraben(0.2%) with propyl paraban(0.05%)
Methyl paraben(0.1 - 0.2%)
Chlorocrerol (0.1%)
Benzoic acid (0.2%)
Phenyl mercuric nitrate (0.001%)
Benzalkonium chloride solution (0.02%)
Chlorhexidine acetate (0.02%)
54. Stabilizers for Jellies :
• Anti-dehydrating agent:
Hygroscopic substance prevent drying of jellies.
ex: Glycerol, propylene glycol, sorbitol solution
• Chelating agents to prevent the sensitivity to heavy metals EDTA
Preparation of jellies:
1. Usually prepared by adding thickening agent
ex:Tragacanth,Carboxymethyl cellulose
2. Thickening agent is added to aqueous solution in which drug has
to be dissolved
3. Mass is triturated in a mortar until a smooth product is obtained
4. When coloured drug to be incorporated glass mortar is used
5. Whole gum is preferred to powdered gum gives clear preparation
of uniform consistency
55. Storage :
• Container should be well filled & well closed to minimize
evaporation of water.
• Cool place (prevent drying of Jellies)
Containers :
• Best is collapsible tube
• Used for all types (sterile & non-sterile)
• Does not allow air spaces in the container for microbial growth
• Wide mouthed screw capped jar
• Other than collapsible tube
• Should have plastic wads instead of cork
• To discourage the mould growth
• Closure must be tightly fixed to avoid leakage
56. Example:
Rx
Icthammol -20g
Tragacanth -5g
Alcohol (90%) -10g
Glycerine -2g
Water -qs 100g
Send 100g Icthammol jelly
Procedure:
1. Tragacanth + alcohol motor mucilage.
2. Icthammol + glycerine + water Drug solution
3. Drug solution + mucilage triturate
4. Add water qs 100g
5. Transfer into container, label & dispense.