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Transdermal info!!!

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    Transdermal info!!!


    Electrocution Aids in skin Permiability.
    Record: 1

    Title: Electric pulses pour drugs through skin.
    Author(s): Raloff, J.
    Source: Science News; 11/20/93, Vol. 144 Issue 21, p327, 1/3p

    Document Type: Article
    Subject(s): SKIN -- Permeability
    Abstract: States that researchers at the Massachusetts Institute
    of Technology have come up with a unique approach for temporarily
    increasing the permeability of the skin. Use of electric current;
    Implications for the administration of drugs; Report in the November 15,
    1993 issue of `Proceedings of the National Academy of Sciences'; More.

    Full Text Word Count: 407
    ISSN: 00368423
    Accession Number: 9311237688
    Database: Academic Search Premier
    Section SCIENCE NEWS of the week
    ELECTRIC PULSES POUR DRUGS THROUGH SKIN



    The skin's outer surface - a layer of dead, flattened cells - provides a
    barrier to microbes, chemicals, and other potentially toxic agents. But
    at times physicians would like to breach that barrier, because
    administering drugs through the skin potentially offers several
    therapeutic advantages.

    Now, researchers at the Massachusetts Institute of Technology have come
    up with a novel approach for temporarily increasing the permeability of
    skin. They administer a series of very short, up-to-100-volt pulses of
    electric current. The resulting rearrangement of fatty layers in the
    dead, outer skin appears to create temporary pores, or channels,
    explains Robert Langer.

    Using fluorescent dyes to represent drugs, Langer's team delivered
    millisecond pulses of current every 5 seconds for an hour and monitored
    the dyes' passage through skin. Some tests used skin from human
    cadavers; others involved live rats. In the Nov. 15 PROCEEDINGS OF THE
    NATIONAL ACADEMY OF SCIENCES, Langer's group reports that the technique,
    electroporation, achieved a reversible, 1,000-fold increase in skin
    permeability

    The idea of using an electric current to pass drugs through the skin is
    not new It forms the basis of iontophoresis - a process that "uses very
    low voltages for very long periods to drive a charged molecule [such as
    a drug] through a barrier," notes Langer. Electroporation, by contrast,
    not only employs much higher voltages for far shorter periods of time,
    but also works on the barrier - here, the skin - not on the drug.

    Langer emphasizes that before the technique can find use in drug
    delivery, many nagging questions must be answered, including how safe
    and effective it would be for long-term use.

    A lack of imaging data to confirm mechanistically what's happening to
    the skin surface leaves open the question of whether Langer's team
    achieved electroporation - at least in the classic sense - says Bruce M.
    Chassy A microbiologist at the University of Illinois at
    Urbana-Champaign, Chassy uses electroporation to move materials into
    bacteria.

    However, he adds, 'whether it's electroporation is not really important"
    - as long as the technique delivers a drug without permanently damaging
    the skin. Indeed, he described the new MIT results as "exciting.' In
    fact, he said, it may possess as much potential to transport samples out
    of the body - perhaps for noninvasive blood sampling-as it has to move
    small samples inside.

    ~~~~~~~~

    By J. Raloff

    _____

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    use.
    Source: Science News, 11/20/93, Vol. 144 Issue 21, p327, 1p
    Item: 9311237688
    _____

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    Another interesting one.


    Yipeeeeeee
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    And another.


    For the inquiring minds.
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    Again.


    Title: Dependence of Skin Permeability on Contact Area.
    Author(s): Karande, Pankaj

    Mitragotri, Samir
    Source: Pharmaceutical Research; Feb2003, Vol. 20 Issue 2, p257,
    7p, 1 chart, 2 diagrams, 5 graphs
    Document Type: Article
    Subject(s): SKIN -- Permeability

    HYDRATION

    DRUG delivery systems
    Abstract: Purpose. We report that experimentally measured skin
    permeability to hydrophilic solutes increases with decreasing contact
    area between the formulation and the skin. Our results suggest that an
    array of smaller reservoirs should thus be more effective in increasing
    transdermal drug delivery compared to a large single reservoir of the
    same total area. Methods. Experimental assessment of the dependence of
    skin permeability on reservoir size was performed using two model
    systems, an array of liquid reservoirs with diameters in the range of 2
    mm to 6 mm and an array of gel disk reservoirs with diameters in the
    range of 3 mm to 16 mm. Full thickness pig skin was used as an
    experimental model. Two molecules, sodium lauryl sulfate (SLS) and oleic
    acid, were used as model penetration enhancers. Results. Mannitol
    transport per unit area into and across the skin increased with a
    decrease in the contact area between the skin and the formulation.
    Mannitol permeability increased approximately 6-fold with a decrease in
    the reservoir size from 16 mm to 3 mm in presence of 0.5% SLS in PBS
    (phosphate buffered saline) as a permeability enhancer. Similar results
    were obtained when oleic acid was used as an enhancer. Conclusions. To
    explain the observed dependence of transdermal transport on contact area
    a simple mathematical model based on skin geometry in the reservoir was
    developed. The model predicts a lateral strain in the skin due to
    preferential swelling of skin upon penetration of water. We propose that
    this lateral strain is responsible for the increased skin permeability
    at lower reservoir sizes. [ABSTRACT FROM AUTHOR]
    ISSN: 07248741
    Accession Number: 9719933
    Database: Academic Search Premier
    _____

    Record: 2

    Title: The 500 Dalton rule for the skin penetration of chemical
    compounds and drugs.
    Author(s): Bos, Jan D.

    Meinardi, Marcus M. H. M.
    Source: Experimental Dermatology; Jun2000, Vol. 9 Issue 3, p165,
    5p
    Document Type: Article
    Subject(s): SKIN -- Diseases -- Treatment

    DERMATOLOGIC agents

    TRANSDERMAL medication
    Abstract: Human skin has unique properties of which functioning as
    a physicochemical barrier is one of the most apparent. The human
    integument is able to resist the penetration of many molecules. However,
    especially smaller molecules can surpass transcutaneously. They are able
    to go by the corneal layer, which is thought to form the main deterrent.
    We argue that the molecular weight (MW) of a compound must be under 500
    Dalton to allow skin absorption. Larger molecules cannot pass the
    corneal layer. Arguments for this "500 Dalton rule" are; 1) virtually
    all common contact allergens are under 500 Dalton, larger molecules are
    not known as contact sensitizers. They cannot penetrate and thus cannot
    act as allergens in man; 2) the most commonly used pharmacological
    agents applied in topical dermatotherapy are all under 500 Dalton; 3)
    all known topical drugs used in transdermal drug-delivery systems are
    under 500 Dalton. In addition, clinical experience with topical agents
    such as cyclosporine, tacrolimus and ascomycins gives further arguments
    for the reality of the 500 Dalton rule. For pharmaceutical development
    purposes, it seems logical to restrict the development of new innovative
    compounds to a MW of under 500 Dalton, when topical dermatological
    therapy or percutaneous systemic therapy or vaccination is the
    objective. [ABSTRACT FROM AUTHOR]
    ISSN: 09066705
    Accession Number: 5237096
    Database: Academic Search Premier
    _____

    Record: 3

    Title: Transdermal drug delivery: Vehicle design and formulation.

    Author(s): Pefile, Sibongile

    Smith, Eric W.
    Source: South African Journal of Science; Apr97, Vol. 93 Issue
    4, p147, 4p, 2 charts, 2 diagrams
    Document Type: Article
    Subject(s): TRANSDERMAL medication
    Abstract: Describes the properties of the delivery system most
    desirable for the formulation of transdermal drug delivery preparations.
    Rate of diffusion; Bioavailability of the drug under different
    physiological conditions; Factors to be taken into account for the
    formulation of semi-solids.
    Full Text Word Count: 4109
    ISSN: 00382353
    Accession Number: 9710054042
    Database: Academic Search Premier
    TRANSDERMAL DRUG DELIVERY: VEHICLE DESIGN AND FORMULATION



    Until recently, administration methods for the transportation of drugs
    across the skin have remained virtually unchanged. The ability to
    produce the desired pharmacological response, however, has rarely
    achieved satisfactory results when conventional topical drug delivery
    formulations have been used to convey the desired amount of drug to a
    specific site. As a result, many investigators are currently engaged in
    the research, development and optimization of topical drug delivery
    systems. The ability to deliver an efficacious quantity of a medicament
    transdermally and the advantages of this form of application have made
    it possible to minimize side-effects, enhance the accuracy of delivers'
    and regulate the rate of drug release. From the patient's viewpoint,
    topical drug delivery is a popular method of dosing as it is a
    noninvasive and painless way of administering active drugs.[ 1] The main
    problem facing the pharmaceutical formulator is devising a delivers'
    system that will satisfy the need for optimal drug delivery, negligible
    toxicity, drug and excipient stability and aesthetic acceptability. The
    main purpose of this article is to describe those properties of the
    deliver, system most desirable for the formulation of transdermal drug
    delivery preparations.


    The skin


    The skin is one of the most readily accessible organs of the human body.
    It is composed of three main layers: the epidermis, the dermis, and the
    hypodermis or subcutaneous fat.[ 2] The outermost layer of the epidermis
    consists of two principal layers: the stratum corneum and the viable
    epidermis.[ 1] The stratum corneum is made up of flattened keratinized
    cells which form the principal barrier to the ingress of exogenous
    substances. The stratum corneum functions as a protective physical and
    chemical barrier and is only slightly permeable to water. Below the
    epidermis lies the dermis, a region highly perfused by blood and lymph
    vessels. This microcirculatory network provides an efficient means of
    drug removal into the systemic pool.[ 3] The deepest layer, the
    hypodermis, contains adipose ceils which serve principally as an energy
    source. Additionally, the tissue cushions the outer skin layers from
    impact and its insulating properties contribute to the temperature
    regulation of the skin.[ 4]

    For many decades, the skin has been used as the site for the
    administration of dermatological drugs, either to achieve a localized
    pharmacological action in the skin tissues or a systemic effect in the
    body. In the former case, the drug molecule diffuses to a target tissue
    in the proximity of drug application to produce its therapeutic effect,
    before it is distributed to the systemic circulation for elimination. A
    few examples of localized drug application include the use of
    hydrocortisone for dermatitis, benzoyl peroxide against ache and
    neomycin for superficial use. When the skin serves as the portal of
    administration for systemically active drugs, the drug applied topically
    is distributed in the blood, following absorption, to achieve
    therapeutic action. Substances that pass through the stratum corneum
    move freely through the lower epidermal strata and into the dermis. From
    here the compound reaches the systemic circulation by diffusion through
    the walls of blood vessels or lymphatic vessels. This fairly new
    application is exemplified by the transdermal controlled delivery of
    nitroglycerin to the myocardium for the treatment of angina pectoris,[
    3] of scopolamine to the central emetic centre for the prevention of
    motion-induced sickness, and of oestradiol to the various
    steroid-receptor sites for the relief of postmenopausal syndromes.

    The transfer of a drug across the stratum corneum is by passive
    diffusion and, because of barriers imposed by the skin, this process
    occurs very slowly. The tissue consists of aggregates of closely packed
    cells and contains both lipid and aqueous regions (see Fig. 1).[ 4]
    Lipid-soluble substances readily pass through the intercellular lipid
    bilayers of the cell membranes whereas water-soluble drugs are able to
    pass through the skin because of hydrated intracellular proteins.[ 4-6]
    Further drug diffusion through the skin can occur by means of the skin
    appendages. In this case, the barrier afforded by the stratum corneum is
    circumvented, thus resulting in rapid drug ingress via eccrine sweat
    glands and hair follicles. There is some evidence that compounds with
    both lipophilic and hydrophilic properties, that is, with an oil-water
    partition coefficient close to unity, are best able to pass through the
    stratum corneum. Water-soluble ions, unless very small, do not normally
    pass through the surface skin layer unless iontophoresis is used.


    Factors influencing the rate of diffusion


    During the development of a drug formulation, it is important to
    determine whether the active ingredient will react with the excipients
    (vehicle) used in drug compounding or with the substances normally
    present in the stratum corneum. Unexpected complexes which may be formed
    within the formulation can exert an adverse effect on the absorption of
    the drug through the skin. The physical and chemical characteristics of
    each excipient with respect to the active ingredient, other components
    in the formulation and the skin must be taken into account with respect
    to transdermal drug delivery.

    Diffusant solubility. The thermodynamic activity of a drug in a
    particular vehicle indicates the potential of the active substance to
    become available for therapeutic purposes. A saturated solution is,
    therefore, preferable for a topical drug delivery system as it
    represents maximum thermodynamic activity (leaving potential).[ 7] The
    level of saturation is dependent on the solubility of the drug in the
    delivery formulation.[ 1] Less drug is released from sub-saturated
    solvents than from saturated ones.

    The diffusant solubility of a drug can also be affected by the presence
    of a cosolvent in the formulation. Co-solvents that increase the
    solubility of the active drug can produce greater concentrations across
    the vehicle-skin interface.[ 8] However, enhanced solubility of the drug
    in the solvent may result in reduced partitioning of the drug between
    the membrane and the vehicle.[ 1] As a result, there is a need to keep
    the solubility of the drug in the vehicle as near to the saturation
    point as possible. It is therefore undesirable to use a drug that is
    highly soluble in the base as the release of the drag will be retarded.
    Pre-formulation studies on the solubility of the drug in the solvents
    used in the preparation are essential for ensuring optimal drug release
    from the topical base. There are several semi-empirical methods for
    estimating the diffusion coefficient in terms of solute and solvent
    properties. In addition, diffusivity data for many sob vents have been
    compiled. Such information can assist the formulator in determining the
    conditions necessary for both optimum drug solubility as well as
    achieving maximum drug absorption.

    Partition coefficient. The greater the partition coefficient of the drug
    for the membrane it is to diffuse through, the greater the concentration
    of drug in the proximal lamina of the membrane.[ 1] The vehicle to
    stratum corneum partitioning often contributes to the rate-limiting step
    in transdermal drug delivery.[ 1, 5] Partitioning of the drug to the
    stratum corneum is dependent upon the affinity of the drug for the base
    formulation and the absorption of the drug through the skin.[9]
    Determination of drug solubility in the solvent systems used in
    formulations can help establish the extent of drug binding to the
    vehicle,[ 6] and thereby avoid a situation where minimal drug diffusion
    takes place due to low partitioning of the drug into the stratum
    corneum. For example, the absorption of chloramphenicol may be inhibited
    by the formation of molecular complexes with agents containing amide
    groups present in the topical base.

    Furthermore, the extent of interaction between drug and vehicle plays a
    significant role in determining the partition coefficient of a drug. The
    nature of the vehicle controls drug activity, the rate of diffusion in
    the vehicle, and the partition coefficient between the vehicle and the
    skin. A high affinity of the base for the drug is not desirable.[ 1]
    Drugs that complex with or bind to components of the vehicle are
    released into the skin relatively slowly.[10] Hence, the release of a
    drug is favoured by using a vehicle with relatively low affinity for it.


    pH variation. Unionized molecules pass more readily across lipid
    membranes than ionized molecules.[ 1] This is because unionized drugs
    are more soluble in lipids whereas their ionized forms are more soluble
    in aqueous media. The ionization of a drug is dependent upon the pH of
    the vehicle in which the drug has been formulated.[ 1] An understanding
    of pH effects is important in that their influence on the degree of
    ionization may result in changes on both the activity and release of a
    drug from its delivery system. Most drugs are either weak acids or weak
    bases whose solubility in a given vehicle is determined by the pH of the
    medium. When changing the pH of a formulation, the stability of the drug
    as well as the stability of the preparation must be considered. The
    formulator needs to be aware that the pH of optimum solubility is not
    always the pH of maximum stability of the compound and therefore a
    balance must be struck between optimum solubility and maximum stability.


    Diffusion coefficient. The diffusion coefficient of a drug, either in a
    topical vehicle or in the skin, depends on the properties of the drug,
    the diffusion medium and the interaction between the two.[11] Diffusion
    decreases as the viscosity of the vehicle increases. Of concern to the
    formulator of a topical drug delivery system are the physical
    interactions which the active ingredient may undergo when in solution.
    If such interactions between the drug and the solvent are high then the
    diffusion coefficient will be low and, hence, the release of the active
    substance to the stratum corneum will be decreased, and vice versa. In
    order to obtain maximum bid availability from a topical formulation, it
    is necessary to have the relevant information relating to the
    transdermal kinetics of the drug concerned before it is formulated.


    Biological factors influencing transdermal delivery


    In order to provide optimum bioavailability of a topical drug one must
    take into account that disease, the age of the skin and the site of drug
    application usually violate the constraints of the simple diffusion
    theory. Investigation of the physicochemical nature of the different
    formulation bases and of those components in the topical product which
    will influence the bidavailability of the drug under different
    physiological conditions is essential for achieving suitable drug
    design.

    Skin age. The design of a topical drug delivery system must be adapted
    to suit the physiological conditions under which it may be used. With
    increasing age, the elasticity and hence the permeability of the skin
    decreases.Care must, therefore, be exercised in administering topical
    preparations to young children as their skins are more permeable and one
    runs the risk of overdosing paediatric patients and underdosing
    geriatric ones. This means that the concentration of the active
    ingredient in a paediatric formulation may need to be less than that
    used for an elderly patient.

    Skin condition and sites. Intact skin presents a barrier to absorption
    that can be reduced considerably when the skin is damaged or is in a
    diseased state. Broken, damaged and inflamed skin has increased
    permeability,[12] whilst calluses and corns, on the other hand, have
    reduced permeability. Transdermal absorption is not only influenced by
    the physical state of the skin but also by the area to which the
    preparation is applied. The size of the ceils and bilayer lipid
    composition in the stratum corneum will affect the extent of transdermal
    drug delivery. In addition, the diffusion of a substance across the skin
    is inversely proportional to the thickness of the stratum corneum. The
    thinner the epidermal layer, as found on the abdomen, for example, the
    greater the permeability of the drug through the skin's surface. To
    produce an effective dermatological preparation the formulator must
    consider how the site and condition of the skin will affect drug
    absorption through the stratum corneum. An attempt can be made to assess
    the effect of regional and physiological variations in permeability by
    measuring a pharmacological response such as the erythema reaction
    produced by vasodilators like histamine.

    Skin metabolism and circulatory effects. The skin is a metabolically
    active organ which has the ability to metabolise many drugs such as
    steroids, and therefore reduces their therapeutic efficacy and
    absorption. Below the stratum corneum lies the viable epidermis, the
    most metabolically active layer in the skin. Percutaneous metabolism in
    the viable epidermis (see Fig. 2) may reduce the pharmacological
    potential of the active drug through cutaneous first-pass effects.[13]
    It is essential to inquire into the extent of percutaneous absorption
    which a topical drug undergoes as this will determine the deposition of
    the substance in other parts of the skin and delivery to the capillaries
    in the dermis.[l3]

    Drug absorption from the dermis into the systentic circulation is
    enhanced by good circulation in the dermis. This is because enhanced
    blood flow at the absorption site increases the concentration gradient
    to the dermis through constant removal of the drug from the site.
    Certain drugs, such as topical steroids, have a vasoconstriction effect
    on the skin. These agents will reduce their own clearance from the skin
    due to decreased blood flow at the absorption site. Once again, the
    formulator must bear in mind that the skin is a physiologically active
    region which can influence the extent of drug delivery into the systemic
    circulation.


    Physicochemical factors affecting transdermal drug delivery


    Skin hydration and temperature. Compounds that hydrate the skin cause it
    to swell and, therefore, increase its permeability; lipids in ointment
    formulations and in water-in-oil emulsions, for example, prevent water
    loss and therefore keep the skin hydrated. Many topical formulations
    cause increased skin hydration by reducing evaporation with an occlusive
    layer. Careful selection of the topical base can influence the degree of
    skin hydration so as to obtain the desired conditions. For instance,
    topical bases containing paraffin retard moisture loss from the skin
    whilst those which contain propylene glycol are hygroscopic. That is,
    they withdraw water from the skin especially when in high
    concentrations.

    The penetration rate of compounds through human skin can also be
    accelerated by raising its surface temperature.[14] As the surface
    temperature rises, the kinetic activity of the skin increases, thus
    resulting in enhanced drug permeability across the stratum corneum. This
    is because, with temperature rise, the lipid layer of the stratum
    corneum becomes less viscous and thus the activation energy for
    diffusion is decreased. Consequently, there is an increase in kinetic
    energy leading to enhanced drug permeability. Clinically, skin
    temperature increases under occlusive bases or in diseased states. Under
    occlusion, sweat cannot evaporate nor can heat radiate as readily from
    the skin surface and, therefore, skin temperature may rise by a few
    degrees. The penetration rate of a material through the skin can be
    altered by the type of topical base used (occlusive or nonocclusive) and
    the physical state of the skin.

    Drug-to-skin binding. Prolonged binding of the drug to the molecules in
    the stratum corneum, such as when using sun screens and topical
    corticosteroids, reduces the absorption of the drug into the viable
    epidermis and dermis.[ 1] Recent studies have demonstrated that
    drug-skin binding has given rise to the so-called reservoir effect in
    which topically applied agents form a depot or reservoir in the stratum
    corneum. The mechanism of reservoir formation most probably arises from
    the physicochemical nature of drug solubility and diffusion within the
    stratum corneum. The therapeutic potential of reservoirs is restricted
    to highly potent compounds because of the relatively small amounts that
    can be retained in the stratum corneum. It is necessary to note that
    reservoir formation takes place on top of or in the upper layers of the
    stratum corneum and loss of this depot effect can occur via evaporation,
    chemical and mechanical removal.[15] Abrasion of the stratum corneum
    leads to mechanical removal whilst solvation of the compound and
    subsequent rinsing leads to chemical removal of the reservoir
    effect.[15] The mechanism of the surface reservoir must be taken into
    account to understand the processes of skin evaporation and topical
    absorption of certain drugs.

    Vehicle formulation. Factors such as drug stability, specific product
    use, site of application and product type must be considered in the
    formulation of a vehicle for topical drug application. These varying
    properties must be combined in a dosage form which will readily release
    the drug when placed in contact with the skin. Further, the release
    characteristics of the vehicle are dependent on the physicochemical
    properties of the specific drug to be delivered to the skin. The
    formulator needs to develop a total composition in which the drug is
    stable and safe and able to achieve optimum drug delivery.[10] Table 1
    presents a list of the general factors which a manufacturer evaluates
    for a new semi-solid (as these formulations are known), both during
    developmental studies and as a function of storage time.

    However well a topical vehicle may be designed to maximize drug
    bioavailability, it is still important to ensure that the preparation is
    aesthetically acceptable to the patient. A product that is unappealing
    to the user for whatever reason may lead to noncompliance and thereby
    put treatment at risk. Although a consumer may apply less stringent
    acceptability criteria to a dermatological cream than to, say, a
    cosmetic preparation, patients still generally prefer a product which is
    easy to remove from the container and which spreads readily and smoothly
    yet adheres to the treated area while being neither tacky nor difficult
    to take off. Table 2 is a summary of some of the more important cosmetic
    and usage criteria relevant to the formulation of a dermatological
    product.


    Classification of topical semi-solids


    Creams. Creams are viscous semi-solids and are usually oil-in-water
    emulsions (aqueous creams) or water-in-oil emulsions (oily creams). The
    type of cream used depends on the solubility of the drug. Water-soluble
    drugs are dispersed in oilin-water emulsions whereas lipid-soluble drugs
    are incorporated in water-in-oil emulsions.[ 4] Creams are used to apply
    solutions or dispersions of medicaments to the skin for therapeutic or
    prophylactic purposes where a highly occlusive effect is not necessary.[
    4] In common use are creams applied for their emollient, cooling or
    moistening effects on the skin. They are frequently chosen for wet and
    weepy skin conditions. They are more readily spread, are not
    particularly greasy and rub into the skin leaving little or no trace.

    Gels. Gels are transparent or translucent semi-solid or solid
    preparations consisting of solutions or dispersions of one or more
    active ingredients in hydrophilic or hydrophobic bases. As vehicles for
    the presentation of water-soluble medicaments, gels are ideal because of
    their high water content. Gel products tend to be smooth, elegant and
    produce cooling effects because the associated water evaporates; they
    may dry out to form films which adhere well to the skin and are usually
    easily removed by washing. For the presentation of insoluble materials,
    hydrophilic gels have the limitation that the resultant products may
    lack clarity and smoothness. Owing to the nongreasy nature, transparent
    appearance and easy removal of gels, they are ideal for use on hairy
    parts of the body and the face.

    Ointments. Ointments are semi-solid preparations intended to adhere to
    the skin or certain mucous membranes; they are usually solutions or
    dispersions of one or more medicaments in non-aqueous bases. Ointments
    are used as vehicles for medicaments intended to produce a
    pharmacological effect at or near the application site. There is a
    greater emphasis on the emollient and protective functions of ointments
    because of their highly occlusive nature. Ointments prevent water loss
    from the surface of the stratum corneum, resulting in increased skin
    hydration and therefore a marked increase in drug permeability. Due to
    the presence of a continuous lipid phase, ointments are particularly
    suitable for chronic dry skin lesions and disadvantageous in moist skin
    conditions.

    Pastes. Pastes are much stiffer than ointments and usually contain a
    high proportion of finely ground insoluble powders dispersed in a fatty
    or aqueous base. Because of their consistency, they are commonly used as
    adsorbents, antiseptics, protectives or to smooth broken skin surfaces.
    Pastes are, therefore, particularly useful for circumscribed lesions
    such as those associated with psoriasis or chronic eczema as they adhere
    well to the skin and for relatively long periods.

    The objective when selecting a suitable base is to optimize drug
    delivery through the skin. In reality, optimum delivery is rarely
    achieved as one needs to consider the aesthetic appeal of the
    formulation, its conditions of use and the convenience of application.
    This will require that the formulator assess the physical and chemical
    properties of each base. Ultimately, one would like to ensure that the
    drug in the final preparation is stable, safe to administer and
    efficacious.

    Why transdermal delivery? Its benefits may be summarized as follows:[ 3,
    5]

    1. production of a sustained, constant and controlled level of drug
    in the plasma or the subcutaneous site;
    2. avoidance of the degradation of the active drug by the liver if
    ingested by mouth;
    3. patient compliance;
    4. simple, rapid termination of drag therapy should undesirable
    side-effects arise;
    5. adjustment of dosage frequency and magnitude with corresponding
    moderation of side-effects.

    The principal problems with transdermal drug delivery stem from the fact
    that:[ 1]

    1. percutaneous absorption rates are variable and not always
    predictable;
    2. the stratum corneum is an extremely efficient barrier to most
    compounds, therefore curbing the topical route of administration for
    many drugs;
    3. there may be activation of allergic responses.

    In order to overcome these obstacles to optimal transdermal drug
    delivery, scientists have developed techniques and delivery systems to
    increase and control the rate of percutaneous absorption. These new
    approaches, such as transdermal patches, absorption enhancers and
    iontophoretic techniques, have paved the way for the administration of
    many more compounds that were previously unable to be delivered via the
    topical route. Such advances in technique increase the diversity and
    utility of the skin as an effective drug delivery medium.


    Table 1.


    1.Drug stability (chemical and physical)

    2.Stability of the excipient (vehicle)

    3.Rheological (frictional) properties of the preparation

    4.pH effects

    5.Effect of volatility and loss of water

    6.Stability of the vehicle in terms of phase separation and homogeneity

    7.Particle size and particle size distribution of the vehicle

    8.Particulate and microbial contamination.


    Table 2.


    1. Visual appearance

    2. Odour of the formulation

    3. Sampling characteristics of product

    4. Ease of application (e.g. spreadability, penetrability)

    5. Residual impression after application (e.g. ease of application and
    removal)

    ILLUSTRATION: Fig 1. Routes of drug penetration through the skin

    DIAGRAM: Fig. 2. Schematic diagram of the stages in percutaneous
    absorption and the concentration gradient of the drug across the skin
    layers.

    1. Danewarts M.P. (1991). Percutaneous absorption and transdermal
    patches. S. Afr. pharm. J. 58, 314-318.
    2. Chien Y.W. (1987). Development of transdermal drug delivery
    systems. Drug Dev. Ind. Pharm. 13, 589-651.
    3. Guy R.H. and Hadgraft J. (1985). Transdermal drug delivery: the
    ground rules are emerging. Pharm. Int. 6, 112- 116.
    4. Topical semi-solids (1994). In The British Pharmaceutical Codex,
    12th edn, ed. W. Lund, chap. 1, p. 134. The Pharmaceutical Press,
    London.
    5. Lee C.K., Uchida K., Kitagawa K., Yagi Kim N. and Goto S.
    (1993). Skin permeability of various drugs with different lipophilicity.
    J. pharm. Sci. 83( 4), 562-565.
    6. Abraham M.H., Chadha H.S. and Mitchell R.C. (1995). The factors
    that influence skin penetration of solutes. J. Pharm. Pharmacol. 47,
    8-16.
    7. Kemken J., Zilger A. and Muller B.W. (1992). Influence of
    supersaturation on the pharmacodynamic effect of bupranolol after dermal
    administration using microemulsions as vehicle. Pharm. Res. 9( 4),
    554-558.
    8. Pellet M.A., Davis A.E and Hadgraft J. (1994). Effect of
    supersaturation on membrane transport: 2 Piroxicam. Int. J. Pharm. 111,
    1-6.
    9. Watkinson A.C., Joubin H., Green D.M., Brain K.R. and Hadgraft
    J. (1995). The influence of vehicle on permeation from saturated
    solutions. Int. J. Pharm. 121, 27-35.
    10. Epidermal and Transdermal Drug Delivery, Remmington's
    Pharmaceutical Sciences (1985), 17th edn., ed. A. Gennard, chap 88, p.
    1567. Mack Publishing, Easton, Pennsylvania.
    11. Barry B.W. (1983). In Dermatological Formulations, chap. 6, p.
    330. Marcel Dekker, New York.
    12. Bronaugh R.L. and Stewart R.F. (1985). Methods for percutaneous
    absorption studies V: Permeation through damaged skin. J. pharm. Sci.
    74(10), 1062-1066.
    13. Martin R.J., Denyer S.P. and Hadgraft J. (1987). Skin metabolism
    of topically applied compounds. Int. J. Pharm. 39, 23-32.
    14. Ohara N., Takayama K. and Nagai T. (1995). Influence of
    temperature on the percutaneous absorption for lipophilic and
    hydrophilic drugs across the rat skin pretreated with oleic acid. Int.
    J. Pharm. 123, 281-284.
    15. Percutaneous Absorption -- Mechanisms -- Methodology -- Drug
    Delivery (1989), eds R.L. Bronaugh and H.I. Maibach, chap. 19, p. 314.
    Marcel Dekker, New York.

    ~~~~~~~~

    By Sibongile Pefile and Eric W. Smith

    The authors are in the School of Pharmaceutical Sciences, Rhodes
    University, Grahamstown, 6140 South Africa (e-mail:
    paes@giraffe.ru.ac.za).

    _____

    Copyright of South African Journal of Science is the property of South
    African Assn. for the Advancement of Science and its content may not be
    copied or emailed to multiple sites or posted to a listserv without the
    copyright holder's express written permission. However, users may print,
    download, or email articles for individual use.
    Source: South African Journal of Science, Apr97, Vol. 93 Issue 4, p147,
    4p
    Item: 9710054042
    _____
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