Topical Drug Delivery Systems : A Review

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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 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, various excipients, 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 to human 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 to cover the affected area.
  • Internal topicals that are applied to the mucous membrane orally, vaginally  or on  anorectal tissues for local activity2.

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

  • 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/or excipients.
  • 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
  • Paste
  • Gel
  • Jelly
  • Suppository

Topical dosage form for dermatological application

Figure 1 -Topical dosage form for dermatological application

Permeation through skin

Most of topical preparations are meant to be applied to 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.

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.

Cross section of human skin

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 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

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 epidermis is 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 substances diffuse 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 diffusionally squeeze through. Thus, permeation requires frequent crossings of cell membranes, each crossing 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 skin’s appendages offer only secondary avenues for permeation. Sebaceous and eccrine glands are 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 body’s 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 hair follicle 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

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.

Scheme of Events for Percutaneous absorption

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

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 of skin 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 enhancer 21-26

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:

  • Solvents: These compounds increase penetration possibly by swelling the  polar pathway and/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 of hydrophilic 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, calcium thioglycolate etc.

Physical method of topical drug delivery

  • Intophorosis: Intophorosis is a process or a technique involving the transport of ionic or charged 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 pulse to 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. The ultrasound 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.
  • Phonophoresis: The movement of drugs through living intact skin and into soft tissues under the 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 are used 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 needales made 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 topicals 15

  • Release characteristics: The mechanism of drug release depends on Whether the drug molecules 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 weight decrease permeation.
  • Nature of vehicle : Liphophilic vehicle increase permeation where as lipophobic vehicle decrease permeation.

Physiological and Pathological Condition of Skin27-30

  • Reservoir effect of horny layer: The horny layer, depot and modify the transdermal permeation characteristics 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 of moisture from the skin and helps in maintaining the barrier function of the stratum corneum.       
  • Skin hydration: Hydration of stratum corneum can enhance transdermal permeability. Covering or 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.
  • Regional Variation: Differences in the nature and thickness of barrier layer of skin causes variation 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 increase permeability
  • Cutaneous Drug Metabolism: Catabolic Enzymes present in the viable epidermis may render a drug 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 lanolin’s

  • Carboxylic acids:

Lauric acid, Myristic acid, palmitic acid, stearic acid, oleic acid

  • Esters; polyesters:

Cholesterol esters (stearate), Ethylene glycol monoesters, Propylene glycol monoesters, Glyceryl monoesters, Glyceryl monostearate, Sorbitol monoesters, Sorbitain  monoesters, Sorbitol diesters, 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)

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 lanolin’s

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 lanolin’s

Carboxylic acids

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 (E 1520), glyceryl triacetate (E1518), sorbitol (E420), xylitol and maltitol (E965), polydextrose (E1200), quillaia (E999), lactic acid, urea, lithium Chloride.

Sequestering antioxidant:38, 39

Citric acid and salts

Ethylenediaminetetraacetic acid (Versene, EDTA)L

Topical Dosage Form

Ointment:1,3,11,40

Definition

Ointments are semisolid preparation intended for external application to the skin or mucous membranes. 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 the USP into 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 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

Spermaceti…………………………12.5%

White wax…………………………12.0%

Almond oil………………………..55.58%

·  Aqueous phase

Sponsored Links

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)

·  Oleaginous phase

Steryl alcohol………………………15%

Beeswax…………………………….8%

Sorbitan monooleate…………….1.25%

·  Aqueous phase

Sorbitol solution, 70% USP………7.5%

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

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 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 formulator’s 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 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. 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 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 600 C for a few hours and then to o to 400 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

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

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.

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

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 in weigh 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 not indicated 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

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 of carbopol gels ofTN were determined by digital pH meter. One gram of gel was dissolved in 100ml of distilled water and stored at 4°C 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 slide fixed 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

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 (370C) 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 37°C 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

Dissolution test

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 the dissolution medium. 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:

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, 132–41.

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.

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.

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.

About Authors:

Mr.J.P.Goswami

Mr.J.P.Goswami  is a M.Pharm. final year (Pharmaceutics) student of ASBASJSM College of Pharmacy, Bela, Ropar, India. He had completed his graduation from B.N.College of Pharmacy, Udaipur, Raj. He has great intrest in tablet technology and its reproducibility.

Shailesh Sharma

Shailesh Sharma is working a lecturer cum research scholar in department of pharmaceutics in ASBASJSM College of Pharmacy, Bela, Ropar, India. He had completed his graduation from B . R. Nahata Collegeof pharmacy, Mandsaur, (MP) and  post graduation from B.N.College of pharmacy, Udaipur, Raj. He has very good academic and extra circular record. He has more than 20 articles in reputed peer reviewed journals. He has great intrest in tablet technology and its reproducibility.

Dr.G.D.Gupta

Dr.G.D.Gupta is working as a professor and principal in ASBASJSM College of Pharmacy, Bela, Ropar, India. Dr. Gupta has author of number of books and published more than 100 Research Paper / Abstract in National and International conferences.

Mr.Anis Mustafa

Mr.Anis Mustafa is a M.Pharm. final year student of ASBASJSM College of Pharmacy, Bela, Ropar , India.

Mr.Deepak Chaudhary

Mr.Deepak Chaudhary is a M.Pharm. final year student of ASBASJSM College of Pharmacy, Bela, Ropar, India.

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Comments

Lakshya's picture

Dear Sir, I should really appreciate the efforts you should have taken for preparing such an exhaustive presentation. It definitely provides good insight on the topical route of drugs. The flow charts given are very good & make it act as a decision tree for selection of the appropriate form the topical should be formulated.

Hemangi Purarkar's picture

hello,
You people had done a very good informative work as including all aspects of the topical drug delivery system but can u tell me one thing that the recently developed all the transdermal patch systems also come under the same delivery system or not?