Transcript semisolid dosage forms

DEFINATION
Semisolid dosage forms are products of semisolid consistensy and
applied to skin or mucous membranes for therapeutic or protective action
or cosmetic function
SEMISOLID DOSAGE FORMS INCLUDE
1.Ointments
2.Creams
3.Pastes
4.Jellies
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IDEAL PROPERTIES OF SEMISOLID DOSAGE FORMS
1.Smooth texture
2.Elegant in appearance
3.Non dehydrating
4.Nongritty
5.Non greasy and non staining
6.Non hygroscopic
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PHYSIOLOGICAL PROPERTIES
1.Non irritating
2.Do not alter membrane/skin functioning
3.Miscible with skin secretions
4.Have low sensitization effect
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APPLICATION PROPERTIES
1.Easily applicable with efficient drugs release
2.High aqueous washability
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PHYSIOLOGICAL FACTORS
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SKIN CONDITION:
Intact skin is a barrier
Damaged skin more permeable
Diseased skin usually more permeable
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SKIN AGE:
Babies and childern greater area/weight than adult obsorb more drug
eg:steriod
Premature infants-no stratum cornea
e.g. The use of topical caffeine for breathing difficulties
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REGIONAL SKIN SITE:
Wide variation eg: face to foot
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AREA OF APPLICATION
There is a direct relationship between the area of application of the drug and rate
of absorption .as the area of application increases the rate of absorption also
increases .
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AFFINITY OF THE DRUG:
The affinity of the drug for the skin should more than that for the base. Only then
the drug leaves the base and penetrates the skin rapidly
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CONTACT TIME:
The more the time between the dosage form and the skin, the larger is the amount
of drug absorbed . Sufficient time should be allowed between the application of the
dosage form and its washing.
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PHYSICOCHEMICAL FACTORS
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TEMPERATURE AND pH
Diffusion depends temperature
Partition theory applies i.e. nonionic molecules is more permeable
than ionic
Stratum cornea pH=4.5-6
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DRUG CONCENTRATION
As the amount of drug applied increases, the amount absorbed per
unit surface of the skin in unit time also increases.
Obeys ficks law –dQ/dt=KDC/h
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PARTITION COFFICIENT
Drugs with more oil-water partition coefficients can cross the layer
of skin easily and get absorbed .
Also obeys ficks law.
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MOLECULAR SIZE:
Drugs with molecular weight in between 100-800 Daltons can only
penetrate the skin .for trandermal drug delivery, molecular weight
of less than or equal to 400 Dalton is required.
Absorption should be inversely proportion to size (M.Wt)
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SKIN STRUCTURE:
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STRUCTURE OF THE SKIN:
PROPERTIES
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The skin is the largest organ of the body and acts as a
protective barrier with sensory and immunological functions.
Human skin is, on average, 0.5 mm thick (ranging from 0.05
mm in eye lid to 2 mm).
Classification of skin based on the epidermis alone especially
the surface layer (stratum corneum):
thick: palms of hand, soles of feet
thin: rest of the body
SKIN STRUCTURE
Skin consist of 3 major layers
1. Epidermal layer:
- Stratum Corneum (SC) or horny layer
- Viable epidermis
2.Dermis and
3.Sub cutaneoustissue
Stratum corneum (SC) = horny layer
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The stratum corneum (10-20-μm) is the outermost horny layer
of skin,comprising about 15-20 rows of flat, partially
desiccated, dead, keratinized epidermal cells (corneocytes),
which are constantly shed and renewed.
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Its organization can be described by the brick and mortar
model, in which extra cellular lipid accounts for ~10% of the
dry weight and arranged in a bilayer format and form so called
lipid channels
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It represent the main barrier function of the skin.
Viable epidermis
 The viable epidermis consists of multiple layers of keratinocytes at various
stages of differentiation.
 Does not contain blood vessel but contain nerve ending for touch and pain.
 The role of the viable epidermis in skin barrier function is mainly related
to the intercellular lipid channels.
Cell types:
 Keratinocytes: produce keratine
 Melanocytes: produce melanine
 Langrhans cells: immune cells, defense mechanism
2.Dermis = layer beneath epidermis (3-5 mm)
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Composed of collagen fibril and elastic tissue providing elasticity and
flexibility.
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Connective tissue
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Nerves
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Blood vessels
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Lymphatics
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Supports and nourishes skin
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Minimal barrier to drug penetration
3.Subcutaneous tissue = layer beneath dermis
Insulate the body, protect against physical shock and source of
 energy supply
 Absent in eyelid
 Skin appendages
 There are three main appendages:
A Hair . follicles;
 found all over the body except load bearing
 feet and palms of hands and lips.
B. Sebaceous glands;
 secret sebum (mix. of fatty acids and waxes) which help to lubricate
skin surface and maintain surface pH of around .
Sweat gland;
 Apocrine glands less in number and limited to certain area of the
skin e.g. armpit, nipples and per anal region.
Pathways of drug penetrationthrough skin
Penetration through SC could be:
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- Trans-cellular pathway
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- Inter-cellular pathway
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Any greasy or oily semi-solid preparation, usually medicated,
that can be applied externally to the skin in order to heal,
soothe or protect it.
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It is a viscous semisolid preparation used topically on a
variety of body surfaces.
OINTMENT BASES:
There is no single ointment bases which possesses all the qualities
of an ideal ointment base. So it become necessary to use more than
one ointment base in the preparation of ointments.
Ointment bases are classified in to 4 types
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1.Oleginous bases
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2.Absorption bases
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3.Emulsion bases
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4.Water soluble bases
OLEGINOUS BASES:
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The bases consist of water soluble hydro cabons , vegetable oils,
animal fats and waxes.
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The constituents of hydrocarbon bases are soft paraffin , hard
paraffin and liquid paraffin.
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The animal fat includes lard.
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The vegetable oils are used chiefly in ointments to lower the
melting point or to soften bases of higher consistency.
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These bases serve to keep the medicaments in prolonged contact
with the skin and also act as occlusive dressings.
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These bases are losing their importance now a days for the
following reasons
1. They are greasy
2. They are sticky and are difficult to remove both form skin and
clothing.
They do not help in the absorption of medicaments.
Examples: Vaseline, hard paraffin, liquid paraffin,
white ointment,whitepetrolatum.
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ABSORPTION BASES:
 These bases are generally anhydrous substances which have
the property of absorbing considerable quantities of water but
still retaining their ointment like consistency.
 The absorption bases are of two types
1.Non emulsified bases
2.water in oil emulsions
Example: Hydrophilic Petrolatum, Anhydrous Lanolin,
Aquabase™, Aquaphor®, Polysorb®
Non emulsified bases:
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These bases absorb water and aqueous solutions producing w/o
emulsions
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Examples:-
1. wool fat
2.Wool alcohol
3.bees wax and
4.cholesterol
Used as vehicles for aqueous liquids or as solutions of medicaments.
EMULSION BASES:
 These bases are semisolid or have a cream like consistency.
 Both o/w and w/o emulsions are used as ointment bases.
 The o/w type emulsions bases are more popular because these
can be easily removed from the skin or clothes by washing
with water.
 The w/o type of bases are greasy and sticky
 Examples
 o/w:- derma base, vanishing cream
 w/o:-cold cream,lanolin,hydrocream
WATER SOLUBLE BASES:
 These are commonly known as greaseless ointment bases.
 The water soluble bases consist of water soluble ingredients
such as polyethylene glycol polymers which are popularly
known as carbowaxes.
 The carbowaxes are water soluble ,non-volatile ,and inert
substances.
 These are available in varying consistencies depending upon
their molecular weights .
Examples
 The poly-ethylene glycols 400,1500,4000,6000 are commonly
used in pharmacy.
Types ointments:
Simple ointment
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sulpher ointment
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compund benzoic acid ointment
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Calamine and coal tar ointment
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Zinc ointment
SELECTION OF THE APPROPRIATE BASE BASED ON:
1 .Desired release rate.
2. Desirability for enhancement of percutaneous absorption.
3. Advisability of occlusion.
4 .Short-term or long-term stability.
5 .Influence of drug on consistency or other features of ointment
base.
6 .Patient factor - dry or weeping (oozing) skin.
7 .Compatible with common medicaments.
8. Efficient release of medicament at site of application.
9. Washability (easily removed with water).
10. Minimum number of ingredients.
11 Ease of compounding.
12.Neutral in reaction
13Good keeping qualities
14.Low sensitization index
15.Pharmaceutical elegance
16.A low index of irritation
17.Non dehydrating
18.Non greasy
Preparation of the Ointments
1.BY TRITURATION:(incorporation).
When base contain soft fats and oils or medicament is insoluble or liquid,
then this method is use with spatula or mortar and pestle.
2 BY FUSION:
Used for large quantities or for ointments in which waxes or solids of
high melting points are to be mixed with semisolid or oils. Constituents
are melted successively in decreasing order of melting point.
3 BY OINTMENT MILLS:
It is used for large scale production where triple roller mill is utilized
which is faster then others .
Electric Mortar and Pestle
Ointment Mill
PACKAGING AND STORAGE
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(jars and tubes)
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Prepare the ointment. Select an ointment jar that will just hold
all of the formulation.
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Begin by taking some ointment and fill the bottom the
ointment jar. Use the spatula to put ointment into the crevices.
Medicinal application of the Ointment
1. Ointments are used topically for several purposes, e.g., as
protectants, antiseptics, emollients, antipruritics, kerotolytics,
and astringents.
2.
In the case of a protective ointment, it serves to protect the
skin against moisture, air, sun rays and other external factors.
CREAMS
These are viscous semi-solid emulsions which are meant for
external use
 The creams are of two types
1.o/w type (aqueous creams)
2.w/o type (oily creams)
 O/w type creams are relatively non –greasy
 In aqueous creams the emulsifying anionic, cationic and nonionic waxes, polysorbates and tri ethanolamine soaps are used
as emulsifying agents
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The oily creams are generally prepared with emulsifying
agents such as wool fat, wool alcohol beeswax and calcium
soaps.
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E g: hydrocortisone cream B.P.C
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Hydrocortisone -10g
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cetomacrogol-300g
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chlorocresol-1g
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Purified water-689g
NEOMYCIN CREAM B.P.C
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Neomycin sulphate - 5.0g
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Cetomacrogol-300g
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Chorocresol-1.0g
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Disodium edetate-0.1g
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Purified water -693.9g
STORAGE:Creams should be stored and supplied in well
closed container which prevent evaporation and
contamination
TYPES OF CREAMS:
Depending on formulation are as follow,
1) Sterol Creams (water in oil emulsions)
2) Anionic Emulsifying Wax Creams(oil in water type)
3) Vanishing Creams(oil in water type)
4) Cationic Emulsifying Wax Creams:(water in oil type.)
FORMULATION OF A CREAM:
1)
Active ingredient: Drug or raw materials are used as active ingredient
2)
Base: Base is used as carrier of the drug.
Bases that are usually used in the cream preparations are water removable
bases. Stearyl alcohol, white petrolatum is the usual oleaginous bases. It
melts at 38 to 600c which indicates that it melts easily in the body
temperature.
3)
Preservative: Preservatives are used to protect the drug from microbial
content.
4)
Surfactant: Used to prevent surface tension of two immiscible phases.
5) Antimicrobial agents: Among the microbial
preservatives used to prevent microbial growth in topical
preparations are
a)
Methylparaben
b)
Propylparaben
c)
Phenols
d)
Benzoic acid
e)
Sorbic acids and
f)
Quaternary ammonium salts
6) Emulsifier :
Na-lauryl sulfate are usually used as emulsifying agents.
7) Complexing agents:
It enhances the stability and prolongs action.
EDTA is the mostly used complexing agents that produce complex with
active drug to produce more stability and to prolong the duration of action.
8) Antioxidants:
It is used to prevent oxidation of the drug that causes degradation.
Na-benzoate, benzoic acid, ascorbic acid are the common antioxidants
used in extended amounts in pharmaceutical industries.
9)Viscosity enhancer: Decrease the flow property of creams.
10) Humectants: Protect the drug from moisture.
PASTES:
Pastes are semisolid preparations intended for External
application to skin
They differ from ointment as they contain a highproportion of
freshly powdered medicaments .
Such as zinc oxide ,calcium carbonate , starch.
These substance make the pastes very thick and stiff.
Pastes are less greasy than ointments .
The stiffness property of pastes make them useful as protective
coatings.
They are used mainly as antiseptics ,protectives
Examples :Triamcinolone dental Pastes-anti inflamatory
Titanium dioxide paste
zincoxide paste
Carboxy methyl cellulose sodium paste
Storage:
Pastes should be stored and supplied in containers made of materials
which do not allow absorption or diffusion of the contents.
GELS:
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Jellies are transparent or transulent , nongreasy ,semisolid
preparations mainly used for external application to the skin.
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There are also used for lubricating catheters,surgical gloves
and rectal thermometers
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The substance like gelatin ,starch,tragacanth,sodium alginate
and cellulose derivatives are used in the preparation of jellies.
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These are now becoming popular for contraceptive purposes
and contain surfactants to enhance the spermicidal properties
of the jelly.
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The majority of gels are formed by aggregation of colloidal sol
particles, the solid or semisolid system so formed being
interpenetrated by a liquid.
The particles link together to form an interlaced network, thereby
imparting rigidity to the structure; the continuous phase is held
within the meshes.
Often only a small percentage of disperse phase is required to
impart rigidity, for example 1 % of agar in water produces a firm
gel.
A gel rich in liquid may be called a jelly; if the liquid is removed
and only the gel framework remains this is termed a xerogel.
Ex.-Sheet gelatin, acacia tears and tragacanth flakes are all
xerogels.
TYPES OF GELS:
Gels may be classified into two primary types:
1. Hydrogels, which have an aqueous continuous phase, and
2.Organogels, which have an organic solvent as the liquid continuous medium.
Gels may also be classified based on the nature of the bonds involved in the threedimensional solid network.
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Chemical gels and
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Physical gels.
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Chemical gels form when strong covalent bonds hold the network together.
physical gels form when hydrogen bonds and electrostatic and vander Waals
interactions maintain the gel network.
Gels may also be classified as, Two-phase systems and, Single-phase systems.
TWO PHASE SYSTEM: A two-phase gel system consists of floccules of small
distinct particles rather than large molecules, thus called a two-phase system often
referred to as a magma. The gel structure in the two-phase systems is not always
stable and thus may thicken on standing, forming a thixotrope, and must be shaken
before use to liquefy the gel and enable pouring.
Examples: Milk of magnesia (or magnesia magma), which comprises a gelatinous
precipitate of magnesium hydroxide, is an example of such a system.
SINGLE PHASE SYSTEM : Single-phase systems are gels in which the
macromolecules are uniformly distributed throughout a liquid with no apparent
boundaries between the dispersed macromolecules and the liquid.
Examples of Single phase system gels include, Tragacanth and,
Carboxymethylcellulose.
Formulation of pharmaceutical gels.
These include:
(1) The choice of vehicle;
(2) The inclusion of buffers;
(3) Preservatives;
(4) Chelating agents
(5) Antioxidants;
(6) Emulsifying agents
(7) Permeation enhancers
(8) Thickaning agents
(9) Gelling agents
(10) Flavours/sweetening agents; and
(11) Colours.
THE CHOICE OF VEHICLE
 Purified water is the normal solvent/vehicle used in the formulation of
pharmaceutical gels.
 However, co-solvents may be used, e.g. alcohol, propylene glycol,
glycerol, polyethylene glycol (usually polyethylene glycol 400) to enhance
the solubility of the therapeutic agent in the dosage form and/or (in the
case of ethanol) to enhance drug permeation across the skin.
 If the drug has poor chemical stability and/or poor solubility in water or
water-based vehicles, pharmaceutical gels may be formulated using
polyhydroxy solvents,
e.g. propylene glycol,
 glycerol,
 polyethylene glycol 400 and
polyacidic polymers,
 e.g. poly(acrylic acid).
BUFFERS
E.g citrate buffer ,phosphate buffer
HUMECTANTS Prevent H20 loss from gel
E.g glycerol (up to 30%)
propylene glycol (approx 15%)
sorbitol (3-15%)
ANTIOXIDANTS:
E.g EDTA,CITRIC ACID
EMULSIFYING AGENTS:
E,g glycerin ,P.G,PEG
PRESERVATIVES
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Important ingredient as gels has ↑ H20 content thus
susceptible to microbial contamination Choice of preservative
depends on the gelling agent used.
CHOICE OF PRESERVATIVE
PRESERVATIVE AND GELLING AGENT
1.Benzalkonium chloride(0.01%w/v)
2.Benzoic acid (0.2%)
3.Chlorhexidine acetate (0.02%)
4.Chlorocresol (0.1-0.2%)
5.Methyl Hydroxybenzoates
6.Phenylmercuric nitrate
HypromelloseMethylcellulose
AlginatesPectin
Polyvinyl alcohols
Alginates, Pectin
Carbomer, Hypromellose, Pectin
Methylcellulose
GELLING AGENTS
• TRAGACANTH
• ALGINATES
• PECTIN
• GELATIN
• CELLULOSE DERIVATIVES
• CARBOMER
• POLYVINYL ALCOHOL
• CLAYS
EVALUATION OF SEMISOLIDS:
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Test of rate of absorption
Test of non-irritancy
Test of rate of penetration
Test of rate of drug release
Test of rheological properties
Test of content uniformity
Microbial test
REFERENCES
 Ansel HC, pharmaceutical dosage forms and drug delivery
system,8th ed.(page276)
 Lachman L, the theory and practice of industrial pharmacy, 3rd
ed.(page534)
 Mehta RM, dispensing pharmacy.(page226)
 www.pharmainfo.net
 www.pharmaworld.com
 www.docstoc.com
 www.wikipedia.com
 www.medlink.com