Post on 03-Apr-2018
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Topical Drug Delivery Systems : A ReviewMr.J.P.GoswamiShailesh SharmaDr.G.D.GuptaMr.Anis Mustafa
Topical preparations are used for the localized effects at the site of their application by virtue of
drug penetration into the underlying layers of skin or mucous membranes.
The main advantage oftopical delivery system is to bypass first pass metabolism. Avoidance of the
risks and inconveniences of intravenous therapy and of the varied conditions of absorption, like pH
changes, presence of enzymes, gastric emptying time are other advantage of topical preparations.
Semi-solid formulation in all their diversity dominate the system for topical delivery, but foams,
spray, medicated powders, solution, and even medicated adhesive systems are in use. The topical
drug delivery system is generally used where the others system of drug administration fails or it is
mainly used in pain management, contraception, and urinary incontinence. This review describes the
various formulation aspects, variousexcipients, evaluation tests, challenges and drugs explored in
the field of topical drug delivery.
Introduction
Over the last decades the treatment of illness has been accomplished by administrating drugs tohuman body via various routes namely oral, sublingual, rectal, parental, topical, inhalation etc.
Topical delivery can be defined as the application of a drug containing formulation to the skin to
directly treat cutaneous disorders (e.g. acne) or the cutaneous manifestations of a general disease
(e.g. psoriasis) with the intent of containing the pharmacological or other effect of the drug to the
surface of the skin or within the skin. Semi-solid formulation in all their diversity dominate the
system for topical delivery, but foams, spray, medicated powders, solution, and even medicated
adhesive systems are in use1.
Topical delivery includes two basic types of product:
External topicals that are spread, sprayed, or otherwise dispersed on to cutaneous tissues tocover the affected area.
Internal topicals that are applied to the mucous membrane orally, vaginally or on anorectaltissues for local activity
2.
For the most part topical preparations are used for the localized effects at the site of their application
by virtue of drug penetration into the underlying layers of skin or mucous membranes. Although
some unintended drug absorption may occur, it is sub therapeutics quantities and generally of minor
concern3.
Advantages of Topical Drug Delivery Systems:4-7
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Avoidance of first pass metabolism. Convenient and easy to apply. Avoidance of the risks and inconveniences of intravenous therapy and of the varied conditions
of absorption, like pH changes, presence of enzymes, gastric emptying time etc.
Achievement of efficacy with lower total daily dosage of drug by continuous drug input. Avoids fluctuation in drug levels, inter- and intrapatient variations. Ability to easily terminate the medications, when needed. A relatively large area of application in comparison with buccal or nasal cavity Ability to deliver drug more selectively to a specific site. Avoidance of gastro-intestinal incompatibility. Providing utilization of drugs with short biological half-life, narrow therapeutic window. Improving physiological and pharmacological response. Improve patient compliance. Provide suitability for self-medication.
Disadvantages of Topical Drug Delivery Systems:8-10
Skin irritation of contact dermatitis may occur due to the drug and/orexcipients. Poor permeability of some drugs through the skin. Possibility of allergenic reactions. Can be used only for drugs which require very small plasma concentration for action Enzyme in epidermis may denature the drugs Drugs of larger particle size not easy to absorb through the skin
Classification ofTopical Drug Delivery Systems:11
Classification of Topical Drug Delivery Systems based on physical state
(A) Solid:
Powder Aerosol Plaster
(B)Liquid :
Lotion Liniment Solution Emulsion Suspension Aerosol
(c) Semi-solid :
Ointment Cream
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Paste Gel Jelly Suppository
Figure 1 -Topical dosage form for dermatological application
Permeation through skin
Most of topical preparations are meant to be appliedto the skin. So basic knowledge of skin and its
physiology, function and biochemistry is very important for designing topicals. The skin is the
heaviest single organ of the body, combines with the mucosal lining of the respiratory, digestive and
urogenital tracts to from a capsule, which separates the internal body structures from the external
environment. The pH of the skin varies from 4 to 5.6. Sweat and fatty acids secreted from sebum
influence the pH of the skin surface. It is suggested that acidity of the skin helps in limiting or
preventing the growth of pathogens and other organisms11.
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Physiology of the skin:11-14
The skin has several layers. The overlaying outer layer is called epidermis, the layer below epidermis
is called dermis. They dermis contain a network of blood vessels, hair follicle, sweat gland &
sebaceous gland. Beneath the dermis are subcutaneous fatty tissues. Bulbs of hair project in to these
fatty tissues.
Figure 2 -Cross section of human skin
The layers of epidermis are:
Stratum Germinativum (Growing Layer) Malpighion Layer (pigment Layer) Stratum Spinosum (Prickly cell Layer) Stratum Granulosum (Granular Layer) Stratum Lucidum Stratum Corneum (Horny Layer)
Epidermis
It is the outermost layer of the skin, which is approximately 150 micrometers thick. Cell from lowers
layers of the skin travel upward during their life cycle and become flat dead cell of the corneum. The
source of energy for lower portions of epidermis is also glucose, and the end product of metabolism,lactic acid accumulates in skin.
Stratum Germinativum: Basal cells are nucleated, columnar. Cells of this layer have high mitotic
index and constantly renew the epidermis and this proliferation in healthy skin balances the loss of
dead horny cells from the skin surface.
Malpighion Layer: The basal cell also include melanocytes which produce the distribute melanin
granules to the keratinocytes required for pigmentation a protective measure against radiation.
Stratum Spinosum: The cell of this layer is produced by morphological and histochemical alteration
of the cells basal layers as they moved upward. The cells flatten and their nuclei shrink. They are
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interconnected by fine prickles and form intercellular bridge the desmosomes. These links maintain
the integrity of the epidermis.
Stratum Granulosum: This layer is above the keratinocytes. They manufacturing basic staining
particle, the keratinohylline granules. This keratogenous or transitional zone is a region of intense
biochemical activity and morphological change.
Stratum Lucidum: In the palm of the hand and sole of the foot, and zone forms a thin, translucent
layer immediately above the granule layer. The cells are non-nuclear.
Stratum corneum: At the final stage of differentiation, epidermal cell construct the most superficial
layer of epidermis, stratum corneum. At friction surface of the body like palms and soles adapt for
weight bearing and membranous stratum corneum over the remainder of the body is flexible but
impermeable. The horny pads (sole and palm) are at least 40 times thicker than the membranous
horny layer
Dermis
Non-descriptive region lying in between the epidermis and the subcutaneous fatty region. It consist
mainly of the dense network of structural protein fibre i.e. collagen, reticulum and elastin, embedded
in the semigel matrix of mucopolysaccaridic 'ground substance'. The elasticity of skin is due to the
network or gel structure of the cells. Beneath the dermis the fibrous tissue open outs and merges
with the fat containing subcutaneous tissue. Protein synthesis is a key factor in dermal metabolism.
Subcutaneous tissue
This layer consist of sheet of fat rich areolar tissue, know as superficial fascia, attaching the dermis
to the underlying structure. Large arteries and vein are present only in the superficial region.
Skin Appendages
The skin is interspersed with hair follicle and associated sebaceous gland like regions two types of
sweat glands eccrine and apocrine. Collectively these are referred to as skin appendages.
Functions of skin:15
Containment of body fluids and tissues. Protection from external stimuli like chemicals, light, heat, cold and radiation. Reception of stimuli like pressure, heat, pain etc. Biochemical synthesis. Metabolism and disposal of biochemical wastes. Regulation of body temperature. Controlling of blood pressure. Prevent penetration of noxious foreign material & radiation. Cushions against mechanical shock. Interspecies identification and/ or sexual attraction.
Biochemistry of skin:
15-16
Epidermis
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The source of energy for the lower portion of epidermis is also glucose and the end product of
metabolism; lactic acid accumulates in the skin, which result in a drop in tissue pH from the usual 7
to less then 6. During differentiation from basal cells to stratum corneum by degradation of the
existing cellular components, the entire cellular make-up changes. Specialized cellular organelles
called lysosomes contain a host lytic enzyme, which they release for intracellular lysis. The epidermisis reservoir of such lytic enzymes. Many of these enzymes are inactivated (probably by auto catalytic
processes) in upper granular layer; however, many also survive into the stratum corneum. The
stratum corneum also has proteolytic enzymes involved in this desquamation.
Dermis
Despite its greater volume, the dermis contains far fewer cells than the epidermis and instead much
of its bulk consists of fibrous and amorphous extra cellular matrix interspersed between the skin's
appendages, nerves, vessels, receptors and the dermal cells. The main cell type of the dermis is the
fibroblast, a heterogeneous migratory cell that makes and degrades extracellular matrix extracellular
matrix components. There is significant current interest in the factors that control the differentiation
of the dermal fibroblast, particularly in the context of their increased synthetic and proliferative
activity during wounding healing. The dermis is home to several cell types including multi-functional
cells of the immune system like macrophages and mast cells, the latter which can trigger allergic
reactions by secreting bioactive mediators such as histamine.
Skin surface
The skin surface has a population of microorganisms. They can contribute to the skin enzymology.
Their diversity and abundance can vary considerabely among individuals and body sites. They can
also effect skin surface lipid composition via hydrolysis of secreted sebum.
Absorption through skin:16-18
Two principal absorption route are identified:
Transepidermal absorption
It is now generally believed that the transepidermal pathway is principally responsible for diffusion
across the skin. The resistance encountered along this pathway arises in the stratum corneum.
Permeation by the transepidermal route first involves partitioning into the stratum corneum.
Diffusion then takes place across this tissue. The current popular belief is that most substancesdiffuse across the stratum corneum via the intercellular lipoidal route. This is a tortuous pathway of
limited fractional volume and even more limited productive fractional area in the plane of diffusion.
However, there appears to be another microscopic path through the stratum corneum for extremely
polar compounds and ions. Otherwise, these would not permeate at rates that are measurable
considering their o/w distributing tendencies. When a permeating drug exits at the stratum corneum,
it enters the wet cell mass of the epidermis and since the epidermis has no direct blood supply, the
drug is forced to diffuse across it to reach the vasculature immediately beneath. The viable epidermis
is considered as a single field of diffusion in models. The epidermal cell membranes are tightly joined
and there is little to no intercellular space for ions and polar nonelectrolyte molecules to diffusionallysqueeze through. Thus, permeation requires frequent crossings of cell membranes, each crossing
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being a thermodynamically prohibitive event for such water-soluble species. Extremely lipophilic
molecules on the other hand, are thermodynamically constrained from dissolving in the watery
regime of the cell (cytoplasm). Thus the viable tissue is rate determining when nonpolar compounds
are involved.
Passage through the dermal region represents a final hurdle to systemic entry. This is so regardless of
whether permeation is transepidermal or by a shunt route. Permeation through the dermis is
through the interlocking channels of the ground substance. Diffusion through the dermis is facile and
without molecular selectivity since gaps between the collagen fibers are far too wide to filter large
molecules. Since the viable epidermis and dermis lack measure physiochemical distinction, they are
generally considered as a single field of diffusion, except when penetrants of extreme polarity are
involved, as the epidermis offers measurable resistance to such species.
Transfollicular (shunt pathway) absorption
The skins appendages offer only secondary avenues for permeation. Sebaceous and eccrine glandsare the only appendages, which are seriously considered as shunts bypassing the stratum corneam
since these are distributed over the entire body. Though eccrine glands are numerous, their orifices
are tiny and add up to a miniscule fraction of the bodys surface. Moreover, they are either
evacuated or so profusely active that molecules cannot diffuse inwardly against the glands output.
For these reasons, they are not considered as a serious route for percutaneous absorption. However,
the follicular route remains an important avenue for percutaneous absorption since the opening of
the follicular pore, where the hair shaft exits the skin, is relatively large and sebum aids in diffusion of
penetrants. Partitioning into sebum, followed by diffusion through the sebum to the depths of the
epidermis is the envisioned mechanism of permeation by this route. Vasculature sub serving the hairfollicle located in the dermis is the likely point of systemic entry. Absorption across a membrane, the
current or flux is and terms of matter or molecules rather then electrons, and the driving force is a
concentration gradient (technically, a chemical potential gradient) rather then a voltage drop. A
membranes act as a diffusional resistor. Resistance is proportional to thickness (h), inversely
proportional to the diffusive mobility of matter within the membrane or to the diffusion coefficient
(D), inversely proportional to the fractional area of a route where there is more than one (F), and
inversely proportional to the carrying capacity of a phase.
R = h/FDK
R =Resistance of diffusion resistor
F = Fractional area
H = Thickness
D = diffusivity
K = Relative capacity
Basic principle of permeation:9
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In the initial transient diffusion stage, drugs molecules may penetrate the skin along the hair follicles
or sweat ducts and then be absorbed through the follicular epithelium and sebaceous glands. When
a steady state has been reached diffusion through stratum corneam becomes the dominant pathway.
The membrane-limited flux (J) under steady condition is described by expression.
DAKO/W r C
J = ---------------------
h
Where:
J = Amount of drug passing through the membrane system per unit area, per unit area per unit time.
D= Diffusion coefficient
A= Area of the membrane
C= Concentration gradient
Ko/w= Membranes / vehicle partition coefficient
h= Thickness of the membrane.
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Kinetics of permeation:16-18
Knowledge of skin permeation is vital to the successful development of topical formulation.
Permeation of a drug involves the following steps,
Sorption by stratum corneum, Penetration of drug though viable epidermis, Uptake of the drug by the capillary network in the dermal papillary layer.
This permeation can be possible only if the drug possesses certain physicochemical properties. The
rate of permeation across the skin (dQ/dt) is given by:
dQ
----- = Ps(cd-cr)
dt
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Where Cd and Cr are, the concentrations of skin penetrant in the donor compartment (e. g., on the
surface of stratum corneum) and in the receptor compartment (e.g., body) respectively. Ps is the
overall permeability coefficient of the skin tissues to the penetrant. This permeability coefficient is
given by the relationship:
Ks Dss
Ps = --------------
Hs
Where Ks is the partition coefficient for the interfacial Partitioning of the penetrant molecule form a
solution medium on to the stratum corneum, Dss is the apparent diffusivity for the steady state
diffusion of the penetrant molecule through a thickness of skin tissues and hs is the overall thickness
ofskin tissues. As Ks, Dss and hs are constant under given conditions, the permeability coefficient (Ps)
for a skin penetrant can be considered to be constant.
From equation (1) it is clear that a constant rate of drug permeation can be obtain when Cd >> Cr i.e.,
the drug concentration at the surface of the stratum corneam (Cd) is consistently and substantially
greater than the drug concentration in the body (Cr). The equation (1) becomes:
And the rate of skin permeation (dQ/dt) is constant provide the magnitude of Cd remains fairly
constant throughout the course of skin permeation. For keeping Cd constant, the drug should be
released from the device at a rate (Rr) that is either constant or greater than the rate of skin uptake
(Ra) i.e., Rr >> Ra.
Factor affecting topical permeation:
Physicochemical properties of drug substances19-20
Partition coefficient pH-condition Drug solubility Concentration Particle size Polymorphism Molecular weight
Penetration enhancer21-26
Percutaneous absorption can be enhancing in two ways either by chemical enhancer or by physical
method.
Chemical penetration enhancer: By definition, a chemical skin penetration enhancer increase skin
permeability by reversibly damaging or by altering the physicochemical nature of the stratum
corneam to reduce its diffusional resistance. Among the alterations are increased hydration of
stratum corneam and / or a change in the structure of the lipids and lipoproteins in the intercellular
channels through solvent action or denaturation. These may conveniently be classified under the
following main heading:
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Solvents: These compounds increase penetration possibly by swelling the polar pathwayand/or by fluidizing lipids. Examples include water, alcohols, methanol and ethanol; alkyl methyl
sulfoxide, dimethyl sulfoxide, alkyl homologs of methyl sulfoxide, dimethyl acetamide and
dimethylformamide; pyrrolidones- 2 -pyrrolidone, N-methyl, 2- pyrrolidone; laurocapram
(Azone), miseellancous solvents- propnylene glycol, glyeerol, silicone fluids, isopropyl palmitate.
Surfactant: These compounds are proposed to enhance polar pathway transport, especially ofhydrophilic drugs. The ability of the surfactant to alter penetration is a function of polar head
group and the hydrocarbon chain length. Commonly used surfactant are as follow
Anionic surfactant: can penetrant and interact strongly with skin. Examples include are Dioctyl
sulphosuccinate, Sodium lauryl sulphate, Decodecylmethyl sulphoxide etc.
Cationic surfactant: Cationic surfactants are reportedly more irritating than anionic surfactants and
they have not been widely studied as skin permeation enhancer.
Nonionic surfactant: Nonionic surfactants have least potential for irritation. Example includes are
Pluronic F127, Pluronic F68 etc.
Bile salts: Sodium taurocholate, Sodium deoxycholate, and Sodium tauroglycocholate. Binary system: These systems apparently open the heterogeneous multilaminated pathway
as well as the continuous pathways. Examples include are Prolylene glycol -oleic acid and 1,4-
butane diol- linoleic acid.
Miscellaneous chemicals: These includes urea, N,N-dimethyl-m-toluamide, calciumthioglycolate etc.
Physical method of topical drug delivery
Intophorosis: Intophorosis is a process or a technique involving the transport of ionic orcharged molecules into a tissue by the passage of direct or periodic electric current through an
electrolyte solution containing the ionic molecules to be delivered using an appropriate
electrode polarity.
Electroporation: The process involves the application of transient high voltage electrical pulseto cause rapid dissociation of the stratum corneam through which large and small peptides,
oligonucleotides and other drugs can pass in significant amounts. Electroporation or elecro-
permeabilization involves changes in membrane cells due to application of large
transmembrane voltage. The change in the membrane involves structural arrangement and
conductance leading to temporary loss of semi-permeability of cell membranes suggesting
formation of pores.
Sonophoresis: Sonophoresis involves the usage of the frequency ultrasound waves. Theultrasound application has resulted in permeation of low frequency ultrasound was shown to
increase the permeability of human skin to many drugs including high molecular weight protein
by several orders of magnitude.
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Phonophoresis: The movement of drugs through living intact skin and into soft tissues underthe ultrasound perturbation is called phonophoresis. The technique involves placing an
ultrasound-coupling agent on the skin over the area to be treated and massaging the area with
an ultrasound source.
Vesicular concept: Drug enclosed vesicle made from phospholipids and nonionic surfactants areused for transport of drug into and across the skin. The various vesicles used for this purpose
are liposomes, niosomes and transferosome. The lipid vesicle serve as a rate limiting membrane
barrier for system absorption of drug, non-toxic penetration enhancers for drug, organic
solvents for solubilization of poorly soluble drugs and can incorporate both hydrophillc and
lipophillic drugs.
Microfabricated microneedles technology: This technology employed micron-sized needalesmade silicon. These microneedles after insertion into the skin create conduits for transfer of
drug through the stratum corneum. The drug after crossing stratum corneum diffuses rapidly
through deeper tissues and taken up by capillaries for systemic adminitration.
Physicochemical properties of topicals15
Release characteristics: The mechanism of drug release depends on Whether the drugmolecules are dissolved or suspended in the delivery system. The interfacial partition
coefficient of drug from delivery systems to the skin pH of the vehicle
Composition of drug delivery system: Example polyethylene glycols of low molecular weightdecrease permeation.
Nature of vehicle : Liphophilic vehicle increase permeation where as lipophobic vehicledecrease permeation.
Physiological and Pathological Condition of Skin27-30
Reservoir effect of horny layer: The horny layer, depot and modify the transdermal permeationcharacteristics of some drugs. The reservoir effect is due to irreversible binding of a part of the
applied drug with the skin. This binding can be reduced by pretreatment of skin surface with
anionic surfactants.
Lipid film: The lipid film on the skin surface acts a protective layer to prevent the removal ofmoisture from the skin and helps in maintaining the barrier function of the stratumcorneum.
Skin hydration: Hydration of stratum corneum can enhance transdermal permeability. Coveringor occluding the skin with plastic sheet leading to sweet and condensed water vapor can
achieve skin hydration.
Skin temperature: Raising skin temperature results in an increase in rate of skin permeation.This may be due to.
Thermal energy required diffusivity.
Solubility of drug in skin tissues.
Increased vasodilatation of skin vessels.
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Regional Variation: Differences in the nature and thickness of barrier layer of skin causesvariation in permeability. Rate of permeation increase in an atomic order: Plantar anterior fore
arm, scalp, ventral thigh, scrotum and posterior auricular area.
Pathologic injuries to the skin: Injuries that disrupt the continuity of stratum corneum increasepermeability
Cutaneous Drug Metabolism: Catabolic Enzymes present in the viable epidermis may render adrug inactive by metabolism and thus affect topical bioavailability of the drug. Example.
Testosteron is 95% metabolized.
Common Topical Ingredients
Vehicle:1,3,11
Hydrophobic vehicle
Hydrocarbons:Liquid petrolatum (mineral oil, liquid paraffin, paraffin oil)
White petrolatum (petroleum jelly, Vaseline)
Yellow petrolatum (petroleum jelly)
Squalane (perhydrosqualene, spinacane)
Silicones:Liquid polydimethylsiloxanes (dimethicone, silastic, medical grade silicone oil)
Alcohols:Lauryl alcohols (1-dodecanol, dodecyl alcohols)
Myristyl alcohols (tetradecanol, tetradecyl alcohols)
Cetyl alcohols (hexadecanol, ethal, palmityl alcohols)
Stearyl alcohols (stenol, cetosteryl alcohols)
Oleyl alcohols (ocenol)
Sterols; sterol esters:Lanolin (hydrous wool fat, lanum)
Anhydrous lanolin (wool fat, anhydrous lanum, agnin)
Semi synthetic lanolins
Carboxylic acids:Lauric acid, Myristic acid, palmitic acid, stearic acid, oleic acid
Esters; polyesters:Cholesterol esters (stearate), Ethylene glycol monoesters, Propylene glycol monoesters, Glycerylmonoesters, Glyceryl monostearate, Sorbitol monoesters, Sorbitain monoesters, Sorbitol diesters,
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Sorbitan polyesters (spans, arlacels), Glyceryl tristearate, Lard, Almond oil, Corn oil, Caster oil,
Cottonseed oil, Olive oil,Soyabean oil,Hydrogenated oils, Sulfated oils, Isopropyl myristate, Isopropyl
palmitate.
Ethers; polyethers:Polyethylene-polypropylene glycols (pluronics)
Water-miscible vehicle, co solvent
Polyols; polyglycols:Propylene glycol (1,2-propanediol)
Glycerin (glycerol)
Liquid polyethylene glycol
Solid polyethylene glycol (hard macrogol, carbowax)
1,2,Phenols-hexanetriol, Sorbitol solution 70%
Esters; polyesters:Polyoxyethylene sorbitain monoesters (stearate- tweens)
Polyoxy ethylene sorbitan polyesters (tweens)
Ethers; polyethers:Polyethylene glycol monocetyl ether (cetomacrogol 1000)
Polyethylene-polypropylene glycols (pluronics)
Structural matrix former:11
Hydrocarbons
White petrolatum (petroleum jelly, vaseline)
Yellow petrolatum (petroleum jelly)
Paraffin (paraffin wax, hard paraffin)
Microcrystalline wax
Ceresin (mineral wax, purified ozokerite)
Silicones
Fumed silica (cab-O-sil)
Bentonite (colloidal aluminum silicate)
Veegum (colloidal magnesium aluminum silicate)
Polyols, polyglycols
Solid polyethylene glycol (hard macrogol, carbowax)
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Alcohols
Cetyl alcohols (hexadecanol, ethal, palmityl alcohols)
Stearyl alcohols (stenol, cetosteryl alcohols)
Sterols; sterol esters
Cholesterol (cholesterin)
Lanolin (hydrous wool fat, lanum)
Anhydrous lanolin (wool fat, anhydrous lanum, agnin)
Semi synthetic lanolins
Carboxylic acids
Lauric acid, Myristic acid, palmitic acid, stearic acid, oleic acid
Esters; polyesters
Bees wax, White bees wax (bleached bees wax), Carnauba wax,
Myricin, Cholesterol esters (stearate), Polyoxyethylene sorbitain
Monoesters (stearate- tweens), Lard, Hydrogenated oils.
Suspending, jelling, or viscosity inducing agents:31-34
Silicones
Fumed silica (cab-O-sil)
Bentonite (colloidal aluminium silicate)
Veegum (colloidal magnesium aluminium silicate)
Polycarboxylates; polysulfates; polysaccharides
Agar, Alginates, Carragen, Acacia, Tragacanth, Methylcellulose, Carboxy methylcellulose, Hydroxy
ethyl cellulose, Carboxy vinyl polymer, gelatin, pectin, xanthan, polyacrylic acid.
Others
Ethanolamin, Triethanolamin.
Water-in-oil(w/o) emulsifier:15,34-36
Sterols; sterol esters
Cholesterol (cholesterin)
Lanolin (hydrous wool fat, lanum)
Anhydrous lanolin (wool fat, anhydrous lanum, agnin)
Semi synthetic lanolins
Carboxylic acids
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Na+, K+, ethanolamin salts of Lauric acid, Myristic acid, palmitic acid, stearic acid, oleic acid.
Ethers; polyethers
Polyethylene-polypropylene glycols (pluronics)
Oil-in-water (o/w) emulsifier:15,34-37
Esters;polyesters
Polyoxyethylene sorbitain monoesters (stearate- tweens)
Polyoxy ethylene esters (stearate-polyethylene glycol monoesters, Myrj).
Polyoxy ethylene sorbitan polyesters (tweens)
Ethers; polyethers
Polyethylene glycol monocetyl ether (cetomacrogol 1000)
Polyethylene-polypropylene glycols (pluronics)
Others
Sodium lauryl sulfate, Borax (sodium borate), Ethanolamine, Triethanolamine.
Preservative:1,27
Antimicrobial
Benzalkonium chloride, Benzoic acid, Benzyl alcohol, Bronopol, Chlorhexidine,
Chlorocresol, Imidazolidinyl urea, Paraben esters, Phenol, Phenoxyethanol, Potassium sorbate,Sorbic acid
Antioxidants
a-Tocopherol, Ascorbic acid, Ascorbyl palmitate, Butylated hydroxyanisole, sodium ascorbate,
sodium metabisulfite
Chelating agents, Citric acid, Edetic acid
Buffer:1
Citric acid and salts, Phosphoric acid and salts, H3PO4 / NaH2PO4, Glycine, Acetic acid,
Triethanolamine, Boric acid.
Humectant:15,35
Glycerin (glycerol),propylene glycol(E1520),glyceryl
triacetate(E1518),sorbitol(E420),xylitolandmaltitol(E965),polydextrose(E1200),quillaia(E999),lac
tic acid,urea, lithium Chloride.
Sequestering antioxidant:38, 39
Citric acid and salts
Ethylenediaminetetraacetic acid (Versene, EDTA)L
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Topical Dosage Form
Ointment:1,3,11,40
Definition
Ointments are semisolid preparation intended for external application to the skin or mucousmembranes. Typical ointments are based on petrolatum. An ointment does not contain sufficient
water to separate into a second phase at room temperature. Water-soluble ointments may be
formulated with polyethylene glycol. Ointments are ideal emollients with good skin penetration and
adherence to surfaces. We prepare ointments of smooth consistency, non-grittiness, and
pharmaceutical elegance. We use geometric dilution when manually compounding with a spatula or
mortar and pestle. For larger quantities, a mixer is utilized. The final procedure involves a brass mill
to reduce particle size and to produce a non-irritating ointment. Ointments are packaged in
convenient containers such as tubes or jars.
Ointment bases
Ointment bases are classified by theUSPinto four general groups
(a)Hydrocarbon bases: Hydrocarbon bases are also termed oleaginous bases. On application to the
skin, have an emollient effect, as occlusive dressing, can remain on the skin for prolonged periods of
time without drying out.
Petrolatum,USP
White petrolatum, USP
Yellow petrolatum, USP
White petrolatum, USP
(b)Absorption bases: Absorption bases are of two types:
(1) Those that permit the incorporation of aqueous solutions resulting in the
formation of water-in-oil emulsions
Hydrophilic Petrolatum
(2) Those that are water-in-oil emulsions (syn: emulsion bases) and permit the
incorporation of additional quantities of aqueous solutions
Lanolin
(c)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.
Hydrophilic Ointment,USP
(d)Water-soluble Bases: Water- soluble bases do not contain oleaginous components. They are
completely water-washable and often referred to as greaseless Because they soften greatly with
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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.
Polyethylene Glycol Ointment, NF
Cream :15,16
Definition
Creams consist of medicaments dissolved or suspended in water removable or emollient bases.
Creams are classified as water-in-oil or oil-in-water. Therefore, combining immiscible compounds is
possible by mechanical agitation or heat. The wet gum, dry gum, bottle, and beaker methods are
employed. More recently, the term has been restricted to products consisting of oil-in-water
emulsions or aqueous microcrystalline dispersions of long chain fatty acids or alcohols that are water
washable and more cosmetically and aesthetically acceptable.
Types
Most commonly available creams classified on the basis of their function.
Cleansing & cold cream or lotion
Vanishing & Foundation cream
Night & massage cream
Hand &body cream
All purpose cream
Moisturizing cream
Cream bases
(a) Cream base, w/o (rose water ointment, MF 14)
Oleaginous phase
Spermaceti12.5%
White wax12.0%
Almond oil..55.58%
Aqueous phase
Sodium borate..0.5%
Stronger rose water, NF...2.5%
Purified water, USP..16.5%
Aromatic
Rose oil, NF.0.02%
(b) Cream base, o/w (general prototype)
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Oleaginous phase
Steryl alcohol15%
Beeswax.8%
Sorbitan monooleate.1.25%
Aqueous phase
Sorbitol solution, 70% USP7.5%
Polysorbate 80.3.75%
Methyl paraben.0.025%
Purified water, qs.100%
(c) Cream base, o/w (vanishing cream)
Oleaginous phase
Stearic acid.13%
Stearyl alcohol..1%
Cetyl alcohol.1%
Aqueous phase
Glycerin..10%
Methyl paraben..0.1%
Propyl paraben.0.05%
Potassium hydroxide.0.9%
Purified water, qs.100%
Paste:41,42,48
Pastes are basically ointments into which a high percentage of insoluble solids have been added-as
much as 50% by weight in some instances. They much stiffer then ointment due to presence of
solids, which contribute a particulate matrix over and above the ointment structure already present.
Ingredients such as starch, zinc oxide, calcium carbonate, and talc are used as the solid phase. Paste
make particularly good protective barrier on skin, for in addition to the formation of an unbroken
film, the high-surface area they contain absorb noxious chemicals before they reach the skin. This
explains their use in diaper rash, as they absorb irritating ammonia formed by bacterial action on
urea. Like ointment, paste form an unbroken, relatively water impermeable film on the skin surface;
unlike ointment the film is opaque and therefore an effective sun filter. Thus pastes are often by
skiers around the nose and lips, for the solids block out the suns rays and formed film prevent
excessive wind dehydration (windburn). Pastes are less greasy than ointments by reason of the fact
that much of the fluid hydrocarbon fraction is molecularly associated with the particulates.
Gels:31,34,44-48
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Definition
Gels are semisolid systems consisting of dispersions of small or large molecules in an aqueous liquid
vehicle rendering jelly-like through the addition of gelling agent. Among the gelling agents used are:
Synthetic macromolecules: Carbomer 934
Cellulosederivatives:Carboxymethylcellulose, Hydroxypropylmethyl-cellulose
Gels are compatible with many substances and may contain penetration enhancers for anti-
inflammatory and anti-nauseant medications.
Types
Single phase gels: Gels in which the macromolecules are uniformly distributed throughout a liquid
with no apparent boundaries between the dispersed macromolecules and the liquid.
Double phase gels: Gel mass consists of floccules of small distinct particles, often referred to as a
magmas. Milk of magnesia (or magnesia magmas)
Jelly:48
Jellies are water-soluble bases prepared from natural gums such as tragacanth, pectin, alginate, and
boroglycerin. Or from synthetic derivatives of natural substance such as methylcellulose and
carboxymethylcellulose.
Lotion:15
Definition
The lotions are clear solution containing 25-50% alcohol. Additionally they may contain antiseptic,
emollient, and haemostypic substance. Also they may contain extract of witchhazel, menthol,
glycerin, boric acid, alum, potassium oxyquinoline sulfate & chloro form. Most of the lotions are used
as after-shave preparation. Lotions are not rubbed when applied.
Types
Hand lotion
Face lotion
Body lotion
After shave lotion
Antiperspirants lotion
Liniment: 15
Liniments are same as lotion but they are rubbed when applied.
Suppository:48
Suppositories are solid dosage forms intended to deliver medicine into the rectal, vaginal, or urethral
orifice. Suppositories may prepare by the cold compression or fusion technique. An appropriate base
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is selected for its compatibility, stability, melting point, and esthetics. Commonly used bases are
cocoa butter, glycerin, hydrogenated vegetable oils, and polyethylene glycol.
Powder:15,48
Powder differs from liquid skin care preparation in their physical characteristics. Very fine particle
size produces large surface area per unit weight, which covers a large surface area of the body &
result in strong light dispersion. There are body powders, which are also known as dusting powder or
talcum powder, face powder and compact. Medicated powders are used for prickly heat or
preventing microbial growth on skin.
Solution:3,49
Solutions are liquid preparations of soluble chemicals dissolved in solvents such as water, alcohol, or
propylene glycol.
Aromatic waters
Tinctures
Tincture of iodine
Sterile Indian ink for surgical procedures
Emulsion:35,36,48,50
Emulsions are two-phase preparations in which one phase (the dispersed or internal phase) is finely
dispersed in the other (continuous or external phase). The dispersed phase can have either a
hydrophobic-based (oil-in-water), or be aqueous based (water-in-oil). Because there are two
incompatible phases in close conjunction, the physical stabilizing system. In most pharmaceutical
emulsions, the stabilizing system comprises surfactant (ionic or nonionic), polymers (nonionic
polymers, polyelectrolytes, or biopolymers), or mixtures of these.
Types
Water-in-oil emulsion
Oil-in-water emulsion
Water-in-oil-in-water emulsion
Oil-in-water-in-oil emulsion
Suspension:31-34,48
Suspensions are heterogeneous system consisting of two phases. The continuous or external phase is
generally a liquid or semisolid and the disperse or internal phase is made up of particulate matter
that is essentially insoluble in, but dispersed throughout, the continuous phase; the insoluble matter
may be intended for physiologic absorption or for internal or external coating function. The dispersed
phase may consist of discrete particle, or it may be a network of particles resulting from particle-
particle interactions. Almost all suspension system separated on standing. The formulators main
concern, there fore, is not necessarily to try to eliminate separation, but rather to decrease the rate
of settling and to permit easy resuspendability of any settled particulate matter. A satisfactory
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suspension must remain sufficiently homogenous for at least the period of time necessary to remove
and administered the required dose after shaking its container.
Types
Flocculated suspension
Deflocculated suspension
Aerosol:48
A system that depends on the power of compressed or liquefied gas to expel the contents from the
container. The propellants responsible for developing the proper pressure within the container, and
it expel the product when the valve is opened and aids in the atomization or foam production of the
products. Topical pharmaceuticals aerosols utilize hydrocarbon (propane, butane, and isobutene)
and compressed gases such as nitrogen, carbon dioxide, and nitrous oxide.
Evaluation Of Topical Dosage Form
Evalution of patch:27
21-day cumulative irritancy patch test:
In this test the test compound is applied daily to the same on the back or volar forearm. Test
materials are applied under occlusive tape, and scores are read daily. The test application and scoring
are repeated daily for 21 days or until irritation produces a predetermined maximum score. Typical
erythema scores range from 0 (no visible reaction) to 4 (intense erythema with edema and vesicular
erosion). Usually, 24 subjects are used in this test
Draize-shelanski repeat-insult patch test
This test is designed to measure the potential to cause sensitization. The test also provides a
measure of irritancy potential. In the usual procedure the test material or a suitable dilution is
applied under occlusion a 7-day rest period, the test material is applied again to a fresh site for 24
hours. The challenge sites are read on removal of the patch and again 24 hours later. The 0-4
erythema scale is used. A test panel of 100 individuals is common.
Kligman maximization test
This test is used to detect the contact sensitizing potential of a product or material. The test material
is applied under occlusion to the same site for 48-hr periods. Prior to each exposure the site may be
pretreated with a solution of sodium lauryl sulfate under occlusion. Following a 10-day interval the
test material again is applied to a different site for 48 hours under occlusion. The challenge site may
be treated briefly with a sodium lauryl sulfate solution. The maximization test is of shorter duration
and makes use of fewer test subjects than the Draize-Shelanski test.
Evaluation of ointments:3,48
Penetration
For assessing the penetration some very simple experiments have been suggested. Weighed
quantities of the ointments are rubbed over definite areas of the skin for a given length of time.
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Thereafter the unabsorbed ointment is collected from the skin and weighed. The difference between
the two weights roughly represents the amount absorbed.
Rate of release of medicaments
To assess the rate of release of a medicament small amount of the ointment can be placed on the
surface of nutrient agar contained in a petry dish or alternately in a small cup cut in the agar surface.
If the medicament is bactericidal the agar plate is previously seeded with a suitable organism like S.
aureus. After a suitable period of incubation the zero of inhibition is measured and correlated with
the rate of release. Another method for finding out release rate is to smear internal surface of test
tubes with thin layers of ointment, fill the tubes with saline or serum and after a gap of time
estimating the amount of drug present in the serum/saline.
Absorption of medicaments into blood stream
The diadermatic ointments should be evaluated for the rate of absorption of drug into the blood
stream. This test can be in vivo only. Definite amounts of ointments should be rubbed the skin under
standard conditions and medicaments estimated in the blood plasma or urine.
Irritant effect
In general no ointment should possess irritant effect on the skin or the skin or mucous membranes.
The tests for irritancy can be carried out on the skin and eyes of rabbits or the skin in rats. Reactions
are noted at intervals of 24, 48, 72 and 96 hours. Lesions on cornea, iris, conjunctiva are used for
judging the irritancy to the eyes. Presence of patches on the skin within 2 weeks indicate irritancy to
skin.
Evaluation of cream:15
Rheology
Rheology is very important as these creams are marketed in tubes or containers. The rheology or
viscosity should remain constant. As these products are normally non-newtonian in nature, the
viscosity can be measured using viscometers used for such liquids.
Sensitivity
As various types of ingredients are used with occasional use of antiseptic, hormones. etc., there is a
possibility of sensitization or photosensitization of the skin. This should be tested beforehand. This
test is normally done by patch test on skin and can be either open or occlusive. The test sample is
applied along with a standard market product at different places and effect is compared after a
period of time.
Biological testing
This is particularly essential for products containing antiseptics, hormones, vitamins, etc.
Evaluation of emulsions:35,36,48
Phase separation
The rate and degree of phase separation in an emulsion can be easily determined by keeping a
certain amount in a graduated cylinder and measuring the volume of separated phase after definite
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time intervals. The phase separation may result from creaming or coalescence of globules. The phase
separation test can be accelerated by centrifugation at low/moderate speeds. One can at best expect
a mixture of creamed and coalesced particles and in such a situation it may be difficult to make
correct interpretations.
Globule size
Growth in the globule size after the preparation of an emulsion is an indication of its physical
instability. The globule size is measured by microscopic methods or by electronic devices such as
coulter counter. In either of these two techniques the original product has to be suitable diluted
before estimation. The dilution may introduce errors because of incomplete deflocculation or new
patterns of flocculation.
Rheological properties
The rheological characteristics of an emulsion system depend upon globule size, emulsifier and its
concentration, phase volume ration etc. Use of a heliapath attachment with Brookfield viscometer
helps in detection of creaming tendency and hence it is advisable to study rheological properties over
extended periods of time, which can help in prediction of their long-term behaviour. Many emulsion
show change in consistency with time which follows linear relationship when plotted on a log-log
scale over a number of ten fold time intervals.
Effect of thermal stresses
It is usual to evaluate thew stability of an emulsion by subjecting it too high and low temperatures in
alternating cycles. The samples are first exposed to 60 C for a few hours and then to o to 40 C. Such
exposures are repeated a number of times and emulsion stability assessed after each cycle.
Evaluation of paste:15,41,42
Abrasiveness
The teeth were mechanically brushed with pastes or powders and then the effects were studied by
observation, mechanical or other means. Abrasive character normally depended on the particle size
Particle size
This can be determined by microscopic study of the particles or other means.
Cleansing property
This is studied by measuring the change in the reflectance character of a lacquer coating on a
polyester film caused by brushing with a tooth cleanser (paste or power). Also an in vivo test has
been suggested in which teeth were brushed for 2 weeks and condition of teeth was assessed before
and after use with the help of photographs.
Consistency
It is important that the product, paste, should maintain the consistency to enable the product press
out from the container. Study of viscosity is essential for these powders from the container.
pH of the product
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pH of the dispersion of 10% of the product i9n water is determined by pH meter.
Foaming character
This test is specially required for foam-forming tooth pastes or tooth pastes or tooth powers.
Especially amount of product can be mixed with specific amount of and water to be shaken. The
foam thus formed is studies for its nature, stability, washability.
Limit test for arsenic and lead
This is very important, as these are highly toxic metals. Specific tests are there to estimate these two
metals. However, if the raw materials are tested for the limit of these two metals, products
may not have excess of such metals.
Volatile matters and moisture
A specific amount of the product required to be taken in a dish and drying is to be done till constant
weigh. Loss of weigh will indicate percentage of moisture and volatile matters.
Effect of special ingredients
Special tests should be done for the special ingredients if any like antiseptic, enzymes, etc. For each
one special and specific test are to be done.
Evaluation of powder:15
Shade control and lighting
This is to control and determine the variation of color shade from batch to batch and with the
stander, Proper test is to be done to prevent in shades. One such method is comparison of the
appearance of the body of the power with a standard when it is spread out and flattened on a white
paper background. The other method of evaluation is comparison of the sample with the standard by
skin tone or undertone. Powers should be applied by the same puff that is to be used for finished
pack. This is the final judgement for the shade test. Artificial lighting is used for color evaluation.
Dispersion of color
Color should be homogeneously distributed in the power base. There should not be segregation or
bleeding of color. This can be tested by spreading the power on a white paper and checking if with a
magnifying glass.
Pressure testing
Pressure applied to compact powder should be uniform to the hardness can be tested by
penetrometer. Reading on hardness is checked at various points of compact tablet to see the
uniformity of hardness.
Breakage test
This is carried out by dropping the compact tablet of powder on a wooden surface several times from
a height of 8 to 10 inches and checking the breakage or clipping of the resistance against travel and
normal handling.
Flow property
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This is very important, particularly for body powders, as they should come out easily from the
container for easy application. This can be studied by measuring angle of repose of powder product
by allowing to fall on a plate from a funnel and measuring the height and radius of heap formed.
Particle size and abrasiveness
Particle size can be determined by microscope, sieve analysis or by using sophisticated instrument
and techniques. Abrasiveness can be studied by rubbing the powers on a smooth surface and then
studying the effect on the surface using microscope.
Moisture content and limits for color
These can be estimated by using suitable analytical methods.
Evaluation suspension:48
Sedimentation volume
Measurement of the sedimentation volume and its ease of redispersion from of the most common
basic evaluative procedures. The concept of sedimentation volume is simple. In short, it
considers the ratio of the ultimate height (Hu) of the sediment to the initial height (Ho) of the total
suspension as the suspension settles in a cylinder under standard conditions. The larger this fraction,
the better is the suspendability. First obtain the Hu /Ho ratios and plot them as ordinates with time as
the abscissa. Note that although the height at any particular time. The plot just described will at time
zero start at 1.0, with the curve then being either horizontal or gradually sloping downward to the
right as time goes on. One can compare different formulation and choose the best by observing the
lines, the better formulations obviously producing lines that are more horizontal and/or less steep.
The evaluation of redispersibility is also important. To help quantitate this parameter to some extent,
a mechanical shaking device may be used. It simulates human arm motion during the shaking process
and can give reproducible results when used under controlled conditions.
Rheologic methods
Rheologic methods can be used to help determine the setting behavior and the arrangement of the
vehicle and particle structural features for purpose of comparison. A practical rheologic method
involves the use of the Brookfield viscometer mounted on a helipath stand. The T-bar spindle is made
to descend slowly into the suspension, and the dial reading on the viscometer is then a measure of
the resistance the spindle meets at various levels in a sediment. In this technique, the T-bar is
continually changing position and measures undisturbed samples as it advances down into the
suspension. This technique also indicates in which level of the suspension the structure is greater,
owing to particle agglomeration, because the T-bar descends as it rotates, and the bar is continually
entering new and essentially undisturbed material.
Electrokinetic techniques
Instrumentation permitted measurement of the migration velocity of the particles with respect to
the surface electric charge or the familiar zeta potential; the latter has units of viscosity times
electrophoretic mobility, or more familiarly, volts.
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Particle size changes
The freeze-thaw cycling technique is particularly application to stressing suspension suspension for
stability testing purposes. This treatment promotes particle growth and may indicate the probable
future state of affairs after long storage at room temperature. Thus, it is of prime importance to be
alert for changes in absolute particle size, particle size distribution, and crystal habit. Particle size
distribution is sometimes determined by microscopic means. This method of necessity requires dilute
suspensions that are counted with the aid of an ocular grid. In some instances, photomicrographs
may to take for permanent records.
Evaluation of aerosol:48
Flame projection
This test indicates the effect of an aerosol formulation on the extension at an open flame. The
project is sprayed for about 4 sec into a flame. Depending on the nature of the formulation, the
flame is extended, the exact exact length being measured with a ruler.
Flash point
This is determined by use of the standard Tag Open Cup apparatus. The aerosol product is chilled to a
temperature of about -250
F and transferred to the test apparatus. The test liquid is allowed to
increase slowly in temperature, and the temperature at which the vapors ignite is taken as the flash
point obtained is usually the flash point of the most flammable component, which in the case of
topical pharmaceuticals is the hydrocarbon propellant.
Vapor pressure
The pressure can be measured simply with a pressure gauge or elaborately through use of a water
bath, test gauges, and special equipment. Methods are available for aerosols packaged in both metal
and glass containers.
Density
The density of an aerosol system may be accurately determined through the use of a hydrometer or
a pycnometer. These methods, which have been modified to accommodate, liquefied gas
preparations. A pressure tube is fitted with metal flanges and a Hoke valve, which allow for the
introduction of liquids under pressure. The hydrometer is placed into the glass pressure tube.
Sufficient sample is introduced through the valve to cause the hydrometer to rise halfway up the
length of the tube. The density can be read directly. Specific gravity can be determined through the
use of a high-pressure cylinder of about 500-ml capacity.
Moisture
Many methods have proven useful for this purpose. The Karl Fischer method has been accepted to a
great extent. Gas chromatography has also been used.
Aerosol valve discharge rate
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This is determined by taking an aerosol product of known weight and discharging the contents for a
given period of time using standard apparatus. By reweighing the container after the time limit has
expired, the discharge rate, which can then be expressed as grams per second.
Spray patterns
The method is based on the impingement of the spray on a piece of paper that has been treated with
a dye-talc mixture. Depending on the nature of the aerosol, an oil-soluble or water-soluble dye is
used. The particles that strike the paper cause the dye to go into solution and to be absorbed onto
the paper. This gives a record of the spray, which can then be used for comparison purposes. To
control the amount of material coming into contact with the paper, the paper is attached to a
rotating disk that has an adjustable slit.
Dosage with metered valves
Method that can be used involves accurate weighing of filled container followed by dispensing of
several doses. The container can then be reweighed, and the difference in weigh divided by the
number of doses dispensed gives the average dose. This must then be repeated and the results
compared. Determination of the does received by a patient is a rather difficult procedure, since all of
the respiratory system has been developed and is satisfactory for this purpose.
Net contents
The tared cans that have been placed onto the filling line are reweighed, and the difference inweigh is equal to the vet contents.
Method is a destructive method and consists of weighing a full container and then weighed,with provision being made for the amount retained in the container.
Opening the container and removing as much of the produce as possible. These tests are notindicated in determining the actual net weight of each container as related to the amount that
can actually be dispensed.
Foam stability
The life of a foam can range from a few seconds (for some quick breaking foams) to one hour or
more depending on the formulation. Several methods have been used, which include a visual
evaluation, time for a given rod that is inserted into the foam to fall, and the use of rotational
viscometers.
Particle size determination
Cascade impactor and light scatter decay. The cascade impactor operates on the principle that in a
stream of particles projected through a series of nozzles and glass slides at high velocity, the larger
particles become impacted first on the lower velocity stages, and the smaller particles pass on and
are collected at higher velocity stages. Light scatter decay method as the aerosol settles under
turbulent conditions, the change in light intensity of a Tyndall beam is measured.
Evaluation of lotion:15
Antiseptic property
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As these preparations contain antiseptics, it is necessary to evaluate antiseptic property by in-vitro
test.
Determination of alcohol content
This can be determining by any suitable method as these preparations contain alcohol it is necessary
to estimate the alcohol content.
Evaluation of gel:44-48
Drug content
1gm of gel was accurately weighed in a 50ml of volumetric flask to which 20ml purified water was
added with continuous shaking. Volume was adjusted with a mixture of 10% methanol in water. Plain
bases were also treated in similar manner for blank determination. Absorbance of the solution with
the blank was measured at 360nm using UV-spectrophotometer.
Homogeneity of drug content
For homogeneity of drug contents, six tubes weretaken randomly and assayed for the drug content
as stated above. Studies were performed in triplicate and mean values were used for the analysis of
data.
Measurement of pH
The pH ofcarbopolgels ofTN were determined by digital pH meter. One gram of gel was dissolved in
100ml of distilled water and stored at 4C for two hours. The measurement of pH of each
formulation was in triplicate and the average values are presented.
Viscosity
Brookfield synchrolectric viscometer model RVT attached with spindle D was used for determination
of viscosity. Gels were filled in jar andspindle was lowered perpendicularly taking care that spindle do
not touch bottom of the jar. The spindle was rotated in the gel at increasing shear rates 0.5, 1, 2.5
and 5rpm. At each speed, the corresponding dial reading was noted. The reverse reading were also
noted and average was taken for these two readings.The viscosity of the gel was obtained by the
multiplication of the dial readings with the factors given in the Brookfield viscometer catalogues.
Spreadability
A modified apparatus consisting of two glass slides containing gel in between with the lower slidefixed to a wooden plate and the upper one attached to a balance by a hook was used to determine
spreadability.
Extrudability
A simple method was adopted for determination of extrudability in terms of weight in grams
required to extrude a 0.5cm ribbon of gel in 10 seconds from the collapsible tube.
Evaluation of suppository:48-54
Melting range test
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This test is also called the macro melting range test and is a measure of the time it takes for the
entire suppository to melt when immersed in a constant-temperature (37C) water bath.
Liquefaction or softening time test
It consists of a U-tube partially submersed in a constant temperature water bath. A constriction on
one side holds the suppository in place in tube. A glass rod is placed on top of the suppository, and
the time for the rod to pass through to the constriction is recorded as the softening time.
Breaking test
The apparatus used for the test consists of a double-wall chamber in which the test suppository is
placed. Water at 37C is pumped through the double walls of the chamber, and the suppository,
contained in the dry inner chamber, supports a disc to which a rod is attached. The other end of the
rod consists of another disc to which weights are applied. The test is conducted by placing 600 g on
the platform. At 1-min intervals, 200-g weights are added, and the weight at which the suppository
collapses is the breaking point, or the force that determines the fragility or brittleness characteristics
of the suppository
Dissolutiontest
Testing for the rate of in vitro release of drug substances from suppositories has always posed a
difficult problem, owing to melting, deformation. and dispersion in thedissolutionmedium. Early
testing was carried out by simple placement in a beaker containing a medium. In an effort to control
the variation in mass/ medium interface, various means have been employed, including a wire mesh
basket, or a membrane, to separate the sample chamber from the reservoir. Samples sealed in
dialysis tubing or natural membranes have also been studied. Flow cell apparatus have been used,holding the sample in place with cotton, wire screening, and most recently with glass beads.
Summary And Conclusion
Topical delivery can be defined as the application of a drug containing formulation to the skin to
directly treat cutaneous disorders (e.g. acne) or the cutaneous manifestations of a general disease.
Topical preparations are used for the localized effects at the site of their application by virtue of drug
penetration into the underlying layers of skin or mucous membranes. The main advantage of topical
delivery system is to bypass first pass metabolism. Avoidance of the risks and inconveniences of
intravenous therapy and of the varied conditions of absorption, like pH changes, presence of
enzymes, gastric emptying time are other advantage of topical preprations.
The topical drug delivery system is generally used where the others system of drug administration
fails or it is mainly used in pain management, contraception, and urinary incontinence. Iontophoresis,
Electroporation, Sonophoresis, Phonophoresis, Vesicular concept and Microfabricated microneedles
technology are some advanced technique which are widely being used to increase delivery through
skin.
Semi-solid formulation in all their diversity dominate the system for topical delivery, but foams,
spray, medicated powders, solution, and even medicated adhesive systems are in use.
References:
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1.Surver, C. and Davis, F.A., Bioaviability and Bioequivalence, In Walter, K.A..(Ed. ) , Dermatological
and Transdermal Formulation, Marcal Dekker, INC. NewYork , 119,2002,pp. 403,323,326,327,403.
2.Stan-posthumd J.J., Vink J., Lecessies, Bruijn J.A., Et.al., Topical Tretinoin Under Oocclusion on a
Typical Navei, 1998, 548.
3.Ansel H.C., Allen L.V., Pharmaceutical Dosage Forms and Drug Delivery System, 7th
edition,
Lippincott Willams and Wilkens, Baltimore, 2000, 244-246,249-251, 253-255,264-265.
4.Nayank S.H., Nkhat P.D., and Yeole P.G., The Indian Pharmacist, Vol. III, No. 27, Sept. 2004, 7-14.
5.Jain N.K., Et. al., Pharma Times, May 2000, 21.
6.Misra A.N.,Controlled and Novel Drug Delivery, CBS Publishers and Distributors, New Delhi,1997,
107-109.
7.Nandu S., Et.al.., Ind. J.Pharm. Sci., Vol. 60. No.4., 1998, 185-188.
8.Mishr B., Et.al., Ind.J. Exp. Biol, 1990, 28,1001.
9.Kumari P., Shankar C. and Mishra B., The Indian Pharmacist, Vol III., No. 24, June 2004, 7-16.
10.Lee V.H.L., and Robinson J.R., J. Pharm. Sci. 1979, 68, 673.
11.Banker G.B.S., Rodes C.T., Modern Pharmacist, 2nd
edition, Vol. 40, Marcel Dekker, New York,
1979, 263-273, 283,286-287,299-311.
12.Lemberger A.P., A Hand Book of Non Prescription Drug, American Pharmaceutical Association,
Washington, 1973, 161.
13.Wilkes G.L., Brown I.A. and Wilnauer R.H., CRC Crit Rev. Bioeng., Aug. 1973, 453.
14.Rushmer R.F., Buettner K.J.K., Short J.M., Odland, Science, 1966, 154,343.
15.Mithal B.M., and Saha R.N., A Hand Book of Cosmetics, Ist
edition, Vallabh Prakashan Delhi,
2003, 11-17,21-22,37-38,61-89,90-93,177,214-215.
16.Jain N.K., Controlled and Novel Drug Delivery, Ist
edition, CBS Publishers and Distributors, Delhi,
1997,100-106.
17.Storm J.E., Collier S.W., Stewart S., Mtabolism of Xenobiotics During Percutaneous Penetration:
Role of Absorption Rate and Cutaneous Enzyme Activity, Fundam. Appl. Toxicol, 1990, 13241.
18.Banker G.S., Chalmers R.K., Pharmaceutics and Pharmacy Practice, Ist
edition, Lippincott
Company, 1982, 28-294.
19.Vyas S. and Khar R.K., Controlled Drug Delivery- Concept and Advances, Vallabh Prakashan,
2002, 418-422.
20. Kaur I.P., Smith L.I., Percutaneous Absorption-Penetration Enhancers, 1998, 34-33.
21.Shah V.P., Williams R.L.,Skin Penetration Enhancement Clinical Pharmacological and Regulatory
Considerations, 1993, 27-35.
7/28/2019 Topical Drug Delivery Systems
32/33
22.Osborne D.W., Henke J.J., Skin Penetration Enhancers Cited in the Technical Literature, Pharm.
Tech., 1997, 21,50-66.
23. Stillwell G.K., Electrical Stimulation and Iontophoresis in Krussen F.H., Saunders Company,
1971, 14.
24.Sloan J.B. and Soltani K., J.Amer Acad. Dermatol., 1986, 30-72.
25.Prausnitz M.R. and Bose V.G., Electroporation: In Percutaneous Penetration Enhancers, CRC
Press, Bocaraton. 1995, 393-405.
26.Shyamala B., Kumari L.P. and Harish C.G., Ind. J. Pharm. Sci., 64(4), July-Aug 2005, 475-476.
27.Block L.H. Remington -The Science and Practice of Pharmacy, I volume, 21st
edition,
Lippincott Williams and Wilkins, 2006, 875-877.
28.Ghosh T.K., Banga A.K, Pharma Technol, 1993, 62, 68. Sloan K.B., Bodor N., Int J. Pharm ,
1982,299.
29.Bottger W.M., Et.al., J. Pharmacokinetic Biopharma,1997, 23,24.
30.Sloan K.B., Bodor N., Int J. Pharm , 1982, 299.
31.Amin P.D., Tayade P.T. and Dhavse V.V., Estern Pharmacist, 1998, 486, 127.
32.Saeftone M.F., Giannaccini B., Savigni P. and Wirth A., Pharm. Pharmacol, 1980, 32, 519.
33.Chrai S.S. and Robinson J.R., J. Pharm. Sci., 1974, 63,1219.
34.Kibbe H.A., Hand Book of Pharmaceutical Excipients, 3rd
edition, Pharmaceutical Press London,
2000, 41.
35.Tamilvanan S., Ind. J. Pharm. Edu, 38 (02), Apr-June 2004, 73-80.
36.Myers D., Surfactant Science and Technology, VCH Publishers, 1992, 209-247.
37.Eccleston G.M., Encyclopedia of Pharmaceutical Technology, 9th
Vol. Marcel Dekker, New
York,1992, 375-421.
38.Matillha, Antioxidants, Annu. Rev. Biochem., 1947, 177-192.
39.Walfg, The Discovery of the Antioxidant Function of Vitamin E, J. Nutr. 135(3), 2005, 358-366.
40.Walters K.A., Percutaneons Absorption and Transdermal Therapy, Pharm. Tech., 1986, 30-42.
41.Jessy S, and Reddy S., Pharma Times, 36(7), July 2004, 17-25.
42.Chanderasekar S.K., Et.al.,Ind. J. Pharm. Sci., 38(02), July-Aug.2005, 404-408.
43.Shankas V.,Chandrasekaran A.K., Durga S., Ind. J. Pharm. Sci., 67(4), 2005, 473-76.
44.Gupta G.D., Gaud R.S., The Indian Pharmacist, May-2005, 69-76.
45.Mutimar M.N., Reftkin C., Hill J.A. and Cyr G.N., J. Am. Pharm. Assoc. Sci., 1956, 45,101.
46.Hatanaka T., Inuma M., Sugibayacki K., Chem. Pharm. Bull., 1990, 38, 345.
7/28/2019 Topical Drug Delivery Systems
33/33
47.Reddy M.S., Mutaliks, Rao G.V., Preparation and Evalution of Minoxidil Gels for Topical
Application in Absorption, Ind.J. Pharm. Sci., 68(4), 2006, 432-436.
48.Lachman L., Lieberman H.A., Kanig J.C. The Theory and Practice of Industrial Pharmacy,
3rd
edition, 1991, Varghnese Publishing House, Bembay, 479,492-494, 502,526-531, 548,564,584-
585,589,615-618.
49.Martin A., Physical pharmacy, 4th
edition, 1996, 423-431.
50.Ecleston G.M. Encyclopedia of Pharmaceutical Technology, Vol 9, Marcel and Dekkes, New York,
1992, 375-421.
51.Young J., Porush I., J. Am. Pharm. Assoc. Sci., IInd
edition,1960, 49-72.
52.Kanig J. and Mintzer H, Measurement of Particulars Solid in Aerosal Systems Aerosal
Technicoment, Vol III (2), 1960, 1.
53.Johnson M.A., Darland W.E., Dorland E.K. The Aerosal Handbook, 1972, 377.
54.Leede D., J. Pharmacokin, Bropharma., Vol 10, 1982, 525.