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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_54_библиотеки_им_акад_М_И_Перельмана
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Drug delivery through the skin is categorized into two main groups. Drug prod-
ucts which are designed to achieve local action are termed as topical preparations or
dermal drug delivery system whereas those products in which systemic effect is
desired are termed as transdermal medications or transdermal drug delivery system
(TDDS) [5]. Transdermal medications are designed to increase the amount of drug
that can cross the skin barrier using various permeation enhancers and modern tech-
nology potentiate the drug to enter the systemic circulation and show systemic
effects rather local effects where it is applied [6].
To better understand this difference it is important to understand the structure of
the skin and its barrier function.
10.2 Structure oftheHuman Skin
The skin is largest organ of the body. It receives around one third of blood circula-
tion. The skin serves as rst line of defense, i.e., to provide a permeability barrier
that prevents the absorption of certain biological and chemical agents [7]. The skin
is composed of several layers made up of different types of cells (Fig.10.1).
Epidermis is the outermost layer of skin. It consists of several types of cells, such as
keratinocytes, melanocytes (for melanin production), Langerhans cells (antigen-
presenting dendritic cells), and Merkel cells (sensory mechanoreceptors).
Epidermis is divided into various layers (strata) that vary in structure, function,
and barrier properties. The different layers of epidermis are stratum corneum,
stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. All
these layers work together to continuously rebuild skin surface [8].
Dermis lies beneath the epidermis and connected to epidermis by channeled junc-
tion called dermo-epidermal junction. Dermis is composed of many types of
cells, such as broblasts (synthesize extracellular matrix) and mast cells (impor-
tant component of innate immune system). Moreover, sweat glands, sebaceous
glands, hair follicles, lymph vessels, blood vessels, and cutaneous sensory nerves
are also embedded in the dermis [9].
Hypodermis is also called subcutaneous tissue, lies beneath dermis and supports the
dermis and epidermis. Hypodermis stores fats, regulates temperature, and pro-
vides nutritional support and mechanical protection.
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10.3 Dermal andTransdermal Drug Delivery
When drug delivery through the skin is intended for localized effect, it is called
dermal drug delivery to avoid the systemic absorption of drug. Some may be
intended to interact with stratum corneum e.g., moisturizers. Others may be intended
to remain on skin surface e.g., sunscreens or barrier creams. Some products should
reach the dermis or epidermis layers e.g., antimicrobial agents, local anesthetics, or
photodynamic therapy agents [4].
For transdermal drug delivery drug passes through various layers of the skin to
reach systemic circulation. TDDS is fabricated in such a way that it penetrates
Dermal
papilla
Matrix
Bulge
Fibroblasts
Outer root sheath
Arrector pili
muscle
Cycling
segment
Permanent
segment
Sebaceous
gland
Basement
membrane
SB
SG
EpidermisDermisHypodermis
SC
SS
Fig. 10.1 Anatomy of the skin [10]
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through intact skin and reaches systemic circulation in a controlled manner e.g.,
transdermal patches and microneedles [11].
The dermal and transdermal drug delivery is illustrated in Fig.10.2.
10.3.1 Permeation Through theSkin
Drugs’ permeation through the skin is achieved by different pathways, such as inter-
cellular pathway, transcellular pathway, and skin appendages (sweat glands, hair
follicles, etc.) as shown in Fig.10.3 [12].
Fig. 10.2 Dermal and transdermal drug delivery from topically applied products
Fig. 10.3 Passive drug diffusion through three different pathways from stratum corneum (a),
transappendageal pathway (b), and transcellular pathway
©
to intercellular pathway
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The Intercellular Lipid Pathway It is the passage through the lipid matrix present
in the intercellular spaces of the keratinocytes. Polar molecules utilize the free space
between a lamella and the outer membrane of corneocyte [13].
The Transcellular Pathway The transcellular route passes through the skin and
crosses the lipid structures of interlamellar region across the corneocytes; the cor-
neocytes’ cell membrane is highly impermeable due to which the transcellular route
is considered least important although this assumption needs further investiga-
tions [14].
Through Skin Appendages In recent studies, it is considered that skin appendages
provide an efcient route of drug permeation. Drug delivery is achieved across
sebaceous or sweat glands and hair follicles. In the past, this route was ignored as it
provides negligible contribution of skin surface [15, 16]. In topical preparations
containing polymeric nanoparticles, it was reported that permeation of drug is
enabled through the follicle or the follicle blockers by avoiding the penetration of
drug. Therefore, besides other routes of drug delivery, the transappendageal route
acts as a valuable pathway in skin permeation [17].
10.3.2 Dermal Drug Delivery (e.g., Ointments andCreams)
The product selection for dermal drug delivery depends on factors such as intended
therapeutic use, availability of drug at the site of action, and ease of application.
These products are typically semisolids that vary in composition and physical prop-
erties [18] and examples are shown in Table10.1.
In this section we will particularly focus on two of the most common semisolid
products used for dermal drug delivery, i.e., ointments and creams.
Traditionally, ointment is dened very generally. For instance, ointments have
been dened by the USP 31 Chapter 〈1151〉 as “semisolid preparations intended for
external application to the skin or mucous membranes.” However, in pharmaceutics
“ointment” dosage form is considered to provide drug incorporated into an oleagi-
nous ointment base. Therefore, a more specic denition of ointment would be “a
viscous oleaginous or polymeric semisolid dosage form (emulsions or suspensions)
applied over the skin mucous membranes.”
USP 31 Chapter 〈1151〉 denes creams as “semisolid dosage forms containing
one or more drug substances dissolved or dispersed in a suitable base.” According
to this denition, creams can t in the general denition of ointments. However,
they are given special section in USP 31 Chapter 〈1151〉. A more clear and simple
proposed denition for cream is “a dosage form comprised of a viscous semisolid
emulsion for topical application to the skin or mucous membranes.” Hence, creams
could be considered as a subclass of ointments that would fall into two of the four
classes of ointment bases i.e., water-containing absorption bases and water-
removable bases [19].
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Ointments and creams containing drugs (medicated) are clinically indicated to
deliver drugs into the nose, eye, rectum, vagina etc. as an antiseptic, antipruritic,
astringent, keratolytic, and anti-inammatory. However, nonmedicated ointments
and creams are used as emollient. Nevertheless, nonmedicated ointment comprising
of oleaginous bases or anhydrous absorption base can also be used as protectant [20].
Table 10.1 Physical attributes of common semisolid preparations
Classication Typical attributes
Ointments
Ointments are viscous oleaginous or polymeric semisolid dosage
form (emulsions or suspensions) for external application to the skin
or mucous membranes.
Commonly contain 50% hydrocarbons, PEGs, or waxes and less
than 20% water.
Ointment may form occlusive lm on the skin, depending on the
type of ointment base used.
Creams
Creams are “emulsion” class of the ointments. Since, they typically
contain two of the four classes of ointment bases (i.e., water-
containing absorption bases and water-removable bases).
Creams cannot form occlusive lm on the skin.
Mildly greasy or nongreasy depending on hydrocarbon contents.
Pastes Pastes are “suspension” class of the ointment, containing higher
concentration of dispersed particles, i.e., 20–50% w/w (or more) in
ointment bases.
It may form occlusive lm on the skin.
It is less greasy than ointments.
Gel Gels are semisolid suspension of cross-linked small particles or
macromolecules interpenetrated by liquid.
Depending on the interpenetrated liquid, gels may be classied as
hydrogels (interpenetrated liquid is water) or organogel
(interpenetrated liquid organic solvent).
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10.3.2.1 Formulation Considerations
Formulation of stable ointments and pastes requires the following factors to be
considered).
Vehicle (Ointment Bases)
Ointment bases that act as carriers for the drug in formulation also control the
absorption and drug delivery characteristics of the drug. Therefore, the choice of an
appropriate ointment base is determined on one or more of the following factors:
– Characteristics of the site of application (dry vs moist)
– Desired rate of drug release from the base (determined by the drugs’ solubility in
the base)
– Chemical stability of active ingredient in the ointment base (sensitivity vs resis-
tance of drug to hydrolysis)
– Effect of drug on viscosity of ointment base (dependent on the physical param-
eters and desired drug concentration and composition of the ointment base)
– Water uptake capacity of the formulation (hydrophobic vs water-miscible)
– Proposed use or indication of the dosage form
According to the USP 31 Chapter (1151), ointment bases may be categorized
into four classes on the basis of physicochemical properties, i.e., (i) hydrocarbon
bases, (ii) absorption bases, (iii) water-removable bases, and (iv) water-soluble
bases, as summarized in Table10.2.
Additives/Alternative Vehicles
Hydrophobic liquid solvents used either additionally or alternatively in hydropho-
bic and absorption bases include vegetable oils, organic esters, and liquid silicone.
Vegetable oils, such as arachis oil and coconut oil may be employed to enhance
the emollient property of the formulation or in some instances to replace mineral
oil [21].
Organic esters, such as isopropyl myristate may be added either to achieve better
dissolution of the drug in ointment base or to replace mineral oil for improving the
spreadability. Liquid silicone or polydimethylsiloxane may be used when its water-
repellent properties are desired.
Gel formulations may also contain co-solvents like propylene glycol, glycerol,
and polyethylene glycol in order to improve drug solubility in dosage form and/or
to increase drug permeability. Also, in certain cases if the drug is chemically unsta-
ble in aqueous solvent alternative solvent may be used [22].
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Table 10.2
Characteristics of ointment bases
Base and its
characteristics Uses Examples
Hydrocarbon
(oleaginous bases)
Protectant Hard parafn: Colorless or white solid wax
(melts at 47–65°C), mixture of straight-chain
hydrocarbons (C20 to C30) obtained from
petroleum
Greasy Preferred base for
hydrolyzable
drugs
Anhydrous Emollient
(restricts water
loss)
Soft parafn (petroleum jelly): Contain both solid
and liquid hydrocarbons (melts at ≤45°C)
Cannot absorb water Liquid parafn (also called mineral oil): A
mixture of saturated aliphatic (C14–C18) and
cyclic hydrocarbons
Insoluble in water
Not washable with
water
Microcrystalline wax: Mixture of cycloalkanes
(naphthalene), linear alkanes, and branched
alkanes (C41–C57)
Occlusive
Absorption base Protectant Hydrophilic petrolatum USP: A mixture of
petrolatum, cholesterol, stearyl alcohol, and
white beeswax
(a) Anhydrous
absorption base
Emollient
Contain oleaginous
base and w/o
surfactant
Vehicle for solid
and liquid drugs
(also for aqueous
drug solutions)
Lanolin (wool fat) and hydrous lanolin (wool
alcohol): Waxlike material that is derived from
sheep’s wool
Contain no water
(anhydrous)
Beeswax (yellow and white): Natural beeswax
(yellow beeswax) and its beached form (white
beeswax) consists of esters of aliphatic alcohols
(C24–C36) and linear aliphatic fatty acids (up to
C36)
Can absorb water
(limited)
Insoluble in water
Not washable with
water
Occlusive
(b) Water-containing
absorption base
Emollient Oily cream BP: A w/o emulsion ointment base
consisting of wool alcohols (50% w/w),
magnesium sulfate, phenoxyethanol, and water
Contain oleaginous
base and water
(<45% w/w) and
w/o surfactant
Vehicle for solid
and liquid drugs
(also for aqueous
drug solutions)
Cold cream USP: A w/o emulsion ointment base
consisting of beeswax, spermaceti, mineral oil,
borax, and water
Can absorb water
(limited)
Insoluble in water
Not washable with
water
Occlusive
(continued)
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Table 10.2 (continued)
Base and its
characteristics Uses Examples
Water-removable base Emollient Hydrophilic ointment USP: An o/w emulsion.
The oil phase is composed of stearyl alcohol and
soft parafn, while the water phase is composed
of sodium lauryl sulfate, propylene glycol,
methylparaben, and propylparaben dissolved in
water
Contain oleaginous
base, water (>45%
w/w) and o/w
surfactant
Vehicle for solid
and liquid drugs
(also for aqueous
drug solutions)
Can absorb water
(limited)
Insoluble in water
Washable with water
Nonocclusive
Water-soluble base Emollient Polyethylene glycols (PEGs): Lower molecular
weight PEGs (<1000) are colorless viscous
liquids, whereas PEGs of higher molecular
weight are waxy solids. A blend of different
molecular weights is used as a base to attain
desired consistency of ointment
Does not contain
oleaginous base
(lipid free)
Vehicle for solid
and liquid drugs
(also for aqueous
drug solutions)
Can absorb water
(limited)
Soluble in water
Washable with water
Nonocclusive
Preservatives
Addition of antimicrobial preservatives in semisolids or O/W emulsions is essential
to prevent and resist any microbial attack that may affect the physicochemical prop-
erties of the formulation or may also cause toxic effects.
Two or more preservatives may be added in a formulation to broaden the antimi-
crobial spectrum while keeping the compatibility problems in consideration.
In order to maintain the minimum inhibitory concentration of preservative in
aqueous phase of the formulation, which otherwise may be altered owing to its par-
titioning between oil and aqueous phases, it is important to consider pH of the for-
mulation to ensure that preservative retains its undissociated form (active form). It
may also be compensated by using high initial concentration of the preservative [23].
Examples of preservatives used in semisolid preparations are as given in the
Table10.3.
Antioxidants andHumectants
Antioxidants are employed in semisolid preparations (particularly ointments) to
prevent the auto-oxidation of oils, emulsiers, and the active ingredient itself during
the shelf life that may have effect on the stability and physicochemical properties of
the product.
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Hydrophilic or hydrophobic antioxidants may be chosen depending upon the
nature of vehicle being used in the formulation.
Humectants are also added in semisolid preparations (particularly gels) for the
purpose of preventing or minimizing the evaporation of water from the formulation
during shelf life and application. They have been proposed to prevent loss of water
from the surface of skin, thereby enhancing the penetration and solubility of drug as
well as hydration of skin [21]. Commonly used humectants are as given in Table10.3.
Penetration Enhancers
Delivery of drug to its target site depends largely on the penetration of semisolid
formulation through the skin. This rate-limiting process of percutaneous absorption
follows a progression of steps i.e., release of drug from the formulation and its dif-
fusion onto skin surface, the drug partitioning into and diffusion through the stratum
corneum followed by diffusion into other epidermal layers and then nally parti-
tioning into the fat deposits and blood vessels present in dermis [24].
Chemical penetration enhancers function to reversibly reduce and overcome the pri-
mary barrier resistance offered by stratum corneum thereby allowing sufcient concen-
trations of drug to be penetrated into the skin tissues and systemic circulation [25].
Examples of polymeric chemical penetration enhancers are as given in Table10.3.
Table 10.3 Common excipients used in ointments and creams
Excipients Examples
Vehicle Ointment bases (detailed in Table
10.1)
Additives/alternative
vehicles
Liquid silicone or polydimethylsiloxane
Vegetable oils: Coconut oil and arachis oil
Organic esters: Isopropyl myristate
Emulsifying agents Anionic: Sodium oleate, calcium stearate
Cationic: Cetrimide
Amphoteric: Phospholipids
Nonionic: Sorbian esters (called Span series), polyoxyethylene fatty acid
derivatives of the sorbitan esters (called Tween series)
(for detail description see table)
Antimicrobial agents Phenol, chlorocresol, benzyl alcohol, methyl and propyl para-
hydroxybenzoic acid, benzoic acid, etc.
Antioxidants Hydrophilic antioxidants: Sodium sulte, sodium metabisulte,
ethylenediaminetetraacetic acid (EDTA), ascorbic acid, etc.
Hydrophobic antioxidants: Butylated hydroxyanisole (BHA)
Butylated hydroxytoluene (BHT)
Humectants Glycerol, propylene glycol, and sorbitol
Penetration
enhancers
Short-chain alcohols: Ethanol, isopropyl alcohol
Long-chain alcohols: Hexanol, myristyl alcohol, oleyl alcohol
Sulfoxides: Dimethyl sulfoxide, decylmethyl sulfoxide
Terpenes: Eugenol, menthol, D-limonene, etc.
Surfactants: Phospholipids, sodium lauryl sulfate, etc.
Glycols: Propylene glycol, dipropylene glycol, etc.
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10.3.2.2 Preparation ofOintments andCreams
Lab-Scale Manufacturing
Preparation procedures of ointment should ensure absolute uniformity of nal prod-
uct free from grittiness and phase separation of the aqueous and oil phases.
For laboratory-scale and extemporaneous compounding ointments are com-
monly prepared by two techniques.
Fusion Method
It involves melting together all or some ingredients followed by stirring till a homo-
geneous mixture is obtained. This technique is favored for formulation containing
hard fats and/or waxes. Moreover, the solid ingredients of the formulation are solu-
ble in the base. Fusion method is typically employed for incorporation of large
quantities of hydrophobic components [26].
Direct Incorporation Method
This method involves mixing of the solid components with a fraction of base by
trituration or levigation (wet grinding with aid of levigating agent) followed by
stepwise dilution with the base until a uniform preparation is obtained. The method
is used when the base contains liquid components (soft fats and/or oils), and the
solid components of the formulation are insoluble in the base. Liquids and nely
divided insoluble powders are incorporated into base by means of trituration, while
insoluble coarse powders are incorporated into base by means of levigation [27].
Large-Scale Manufacturing
Industrial manufacturing of ointments and creams follows an easy and straightfor-
ward procedure, somewhat similar to the one described for industrial manufacturing
of emulsions in Chap. 5.
For manufacturing of ointments, drug powder is dispersed into preheated oint-
ment base. Heating lowers the viscosity of the base, thus improving mixing of the
ingredients with the base.
Manufacturing of creams involves incorporation of drug as distinct liquid phase
into the vehicle. The hydrophilic and hydrophobic components are dissolved in
water and oil phases respectively with the help of stirring and heating. Subsequently,
the water and oil phases (usually maintained at 70°C) are mixed and homogenized.
For example, the formulation of gentamicin sulfate cream is given in Table10.4.
Preparation of Oil Phase: White soft parafn and liquid parafn are loaded and
melted at 70°C in a stainless-steel vessel.
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