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TABLE 23.2
Pharmaceutical Dosage Forms and Drug Delivery
A Typical Composition of Hydrophilic Ointment
S. No. Component Function Content (% w/ w)
1. White petrolatum Oil base of o/ w emulsion 25
2. Stearyl alcohol Hydrophobic, oil soluble component, used as an
3. Propylene glycol Hydrophilic viscous liquid used in the aqueous
phase to increase viscosity
4. Sodium lauryl sulfate 1
5. Water Aqueous base of o/ w emulsion 37
TABLE 23.3
25
12
A Typical Composition of Vanishing Cream
S. No. Component Function Content (% w/ w)
1. Stearyl alcohol Oil base of o/ w emulsion 14
2. Other hydrophobic ingredients, for
example, cetyl esters wax, glyceryl
monostearate, and polyoxyethylene
stearyl ether
3. Surfactant 1
4. Water Aqueous base of o/ w emulsion
5. Sorbitol Water- soluble component, used
thickener
as a humectant and thickener
10
10
Emulsion bases are of the following types:
• Hydrophilic ointment is an o/ w emulsion that uses sodium lauryl sulfate as an emulsifying agent.
It is readily miscible with water and is easily removed from the skin. A typical composition of
hydrophilic ointment is listed in Table 23.2. In addition to these basic components, this base may
contain preservatives to control microbial growth. The preservative(s) could be methylparaben,
phase contains the water- soluble components of the emulsion system, together with any additional
• Vanishing cream is an o/ w emulsion that contains a large percentage of water as well as a humec-
tant (e.g., sorbitol, glycerin, or propylene glycol) that retards surface evaporation of water. A typical composition of vanishing cream is listed in Table 23.3. It is a cosmetic product that is colorless
evaporates.
23.2.1.4 Water- Soluble Bases
Water- soluble bases absorb water to the point of solubility. They are water washable and may be anhydrous, or contain some water. Water- soluble bases are made of carbowax or polyethylene glycol (PEG) as
the base. They are oil/ lipid free and non/ less occlusive. However, they may absorb water from the skin,
thus dehydrating the skin and may hinder percutaneous absorption.
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Semisolid Dosage Forms
TABLE 23.4
407
A Typical Composition of Water- Soluble Base
S. No. Component Function Content (% w/ w)
Base With Low (<5% w/ w Water Incorporation Capacity)
1. PEG 400 Nonaqueous, hydrophilic base that is liquid at
room temperature
2. PEG 4,000 Nonaqueous, hydrophilic base that is solid at
room temperature
Base With Higher (>5% w/ w Water Incorporation Capacity)
1. PEG 400 Nonaqueous, hydrophilic base that is liquid at
room temperature
2. PEG 4,000 Nonaqueous, hydrophilic base that is solid at
room temperature
3. Cetyl alcohol Hydrophobic component 5.0
40
47.5
47.5
PEGs are water soluble, nonvolatile, stable, and do not support the growth of mold. PEGs are
polymers of oxyethylene units with different molecular weights. The number at the end of PEGs
indicates their average molecular weight. Their melting point increases with increasing molecular
solid at room temperature.
A typical composition of a water- soluble base is listed in Table 23.4. The ointment is a blend of watersoluble PEG that forms a semisolid base. The base of PEGs alone is highly water soluble and does not
action of the nonaqueous hydrophilic polymers present in the base. These bases are compatible with a
wide variety of drugs.
Another water- soluble base is the ointment prepared with propylene glycol and ethanol, which form
dermatologic vehicle.
23.2.2 Selection of Ointment Bases
An ointment base is chosen depending on
• The solubility characteristics of the drug and the desired rate of drug release. For example, a hydrophilic drug incorporated in an o/ w base would be released immediately, whereas incorporation in a
w/ o emulsion would lead to slower drug release.
• tion) or not (topical application).
• Typical properties of various ointment bases, such as water washability and the tendency for skin
occlusion.
• Intended usage of the ointment, for example, cosmetic use, would require due attention to customer
convenience factors such as water washability and nonstaining on the clothing. On the other hand,
usage in a clinical setting, such as occlusive barriers to wounds that would be bandaged, might not
require such considerations.
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408
23.2.3 Methods of Incorporation of Drugs into Ointment Bases
Pharmaceutical Dosage Forms and Drug Delivery
In addition to the active drug, ingredients in ointment preparations can include oleaginous components,
aqueous components, emulsifying agents, stiffeners, penetration enhancers, preservatives, and
antioxidants. Oleaginous ointments may be prepared by levigation and fusion.
• Levigation involves dispersing and/ or grinding an insoluble drug into small particles while wet.
Mixing a base and other components over an ointment slab using a spatula can carry it out.
Components such as liquid petrolatum serve as levigating agents by promoting the wetting of
powders for incorporation into bases. Hydrophobic ointments w/ o emulsions and suspensions are
typically prepared by a levigation process to incorporate a powder and/ or a small quantity of water
or hydrophilic component into an oil base.
• Fusion
wax, and high molecular weight PEGs) together to form a homogeneous solution. The fusion
method is used when the base contains solids that have higher melting points (e.g., waxes, cetyl
alcohol, or glyceryl monostearate). This process is employed only when the components are
stable at fusion temperatures. Hydrophilic o/ w emulsions (such as water- removable ointments and
creams) are typically prepared by the fusion process. The hydrophobic components are melted
together and added to the aqueous phase/ water- soluble components containing an emulsifying
agent with constant mixing until the mixture congeals.
of powders into a small portion of the base may be facilitated by the use of a melted base or a small
quantity of compatible levigation aid, such as mineral oil or glycerin. Water- soluble salts of drugs are
incorporated by dissolving them in a small volume of water and incorporating the aqueous solution into
a compatible base.
23.3 Creams
Creams are semisolid dosage forms containing one or more drug substances dissolved or dispersed in
such as ointments and pastes. Creams have a whitish, creamy appearance, which is a result of scattering
of light from their dispersed phases, such as oil globules. This distinguishes them from simple ointments,
which are translucent.
Creams based on o/ w emulsions are useful as water- washable bases, whereas w/ o emulsions have
emollient and cleansing action. As described earlier, an o/ w cream with high water content is also known
as a vanishing cream
to the skin. This increase in the concentration gradient of the drug across the stratum corneum promotes
percutaneous absorption.
Creams based on w/ o emulsions, such as cold cream, are useful as softening and cleansing agents.
Cold cream refers to the cooling sensation associated with the slow evaporation of the dispersed aqueous
phase. A cold cream, typically, also contains scents and is used to remove makeup. Other common cold
microbial preservatives such as methylparaben and propylparaben.
The use of creams as drug delivery systems is associated with good patient acceptance. In addition to
the general requirements for semisolid dosage forms, incorporation of the drug in a cream requires that
the drug should
• Be soluble in the desired concentration.
•
•
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Semisolid Dosage Forms
23.4 Gels and Jellies
23.4.1 Gels
409
Gels are semisolid systems consisting of dispersions of small or large molecules in an aqueous liquid
vehicle, which has been thickened with a gelling agent. Gels can be a single phase or a biphasic system.
• Single- phase gels use high molecular weight hydrophilic polymers as gelling agents. Examples of
such polymers include carbomers (cross- linked acrylic acid polymers). These gels are considered to
and the liquid.
• Biphasic gels could contain a gelatinous, cross- linked precipitate of one substance in the aqueous
phase. For example, magma or milk of magnesia consists of a gelatinous precipitate of magnesium
hydroxide.
Carbomers are high molecular weight water- soluble polymers of acrylic acid cross- linked with allyl
ethers of sucrose and/ or pentaerythritol. Their viscosity depends on their polymeric composition. They
In addition to the gelling agent and water, gels may also contain a drug substance, cosolvents (such as
alcohol and/ or propylene glycol), antimicrobial preservatives (such as methylparaben and propylparaben,
precipitates of inorganic salts, such as magnesium hydroxide, as gelling agents, whereas organic gels generally use a carbon- based hydrophilic polymer. Inorganic gels are generally two- phase systems, whereas
organic gels are generally single- phase systems.
contain water as the main continuous- phase solvent, whereas organogels may contain an organic liquid.
The diffusion rate of a drug from a gel depends on the physical structure of the polymer network and
its chemical nature. If the gel is highly hydrated, diffusion occurs through the pores. In gels of lower
hydration, the drug dissolves in the polymer and is transported between the chains. Polymer cross- linking
increases the hydrophobicity of a gel and reduces the diffusion rate of the drug.
be thixotropic, displaying higher viscosity and a semisolid state on standing and becoming low- viscosity
liquids on agitation.
23.4.2 Jellies
and contain a high proportion of liquid, usually water, hydrogen- bonded and associated with the hydrophilic polymer chains. Adding a thickening agent to an aqueous solution of a drug substance forms a
derivatives of natural substances, such as sodium carboxymethyl cellulose (CMC) and methylcellulose
bacterial growth. Thus, antimicrobials are usually added as preservatives.
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410
23.5 Lotions
Pharmaceutical Dosage Forms and Drug Delivery
A lotion is a low- to medium- viscosity medicated or nonmedicated topical preparation, intended for
application to unbroken skin. Lotions are usually applied to external skin with bare hands, a clean cloth,
grittiness.
Most lotions are o/ w emulsions, but w/ o lotions are also formulated. The key components of a lotion
are the aqueous and oily phases, an emulsifying agent to prevent separation of these two phases, and, if
used, the drug substance or substances. A wide variety of other ingredients, such as fragrances, glycerol,
organoleptic and preservation characteristics.
Lotions can be used for the topical delivery of medications such as antibiotics, antiseptics, antifungals,
corticosteroids, antiacne agents, and soothing/ protective agents (such as calamine). Aside from medical use and skin care, lotions are often used as accessories to aid massage, masturbation, or sex.
Noncomedogenic lotions, products that do not block the natural pores of the skin, are recommended for
use on pimples or acne- prone skin. These lotions are also termed as nonocclusive. Thus, they may reduce
acne and/ or reduce the incidence of pimples.
The same drug substance can be formulated into a lotion, cream, and ointment. Creams are the most
convenient of the three but are inappropriate for application to regions of hairy skin such as the scalp,
whereas a lotion is less viscous and may be readily applied to these areas. Many medicated shampoos
are, in fact, lotions. Lotions also have an advantage that they may be spread thinly compared to a cream
or ointment and may economically cover a larger area of skin.
23.6 Pastes
Pastes are semisolid dosage forms that contain a large proportion of solid components. They differ from
ointments in their consistency, as they contain larger amounts of solids and consequently are thicker and
stiffer. Pastes can be made of fatty bases, such as petrolatum and hydrophilic petrolatum, or aqueous
gels, such as celluloses. Pastes may contain one or more drug substances intended for topical application.
Pastes are well adsorbed on the skin. Pastes can absorb watery solutions so that they can be used
Pastes that contain hydrophobic components can be water impermeable and prevent dehydration.
Pastes can be formed from several bases, such as gelatin, starch, tragacanth, PEG, pectin, or cellulose
derivatives.
23.7 Foams
matrix with a large surface area of the liquid. Foams are sometimes used for topical application to areas
For example, Luxiq®
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Semisolid Dosage Forms
411
butane) propellant. The foam melts upon contact with warm skin and is intended for application to the
use in acne.
solution. The drug is dissolved in a low boiling point vehicle, such as the one containing a high proportion of ethanol, which also has a surfactant and a base to dissolve the drug. The vehicle may also contain
liquid droplets and the formation of foam by entrapment of air.
23.8 Manufacturing Processes
23.8.1 Laboratory Scale
Preparation of semisolid dosage forms on a laboratory or compounding pharmacy scale can be
accomplished using one or more of the following techniques and principles:
• Geometric mixing using a spatula on a plate. This allows uniform incorporation of a small quantity
of an ingredient into a large quantity of the other ingredient(s). Geometric mixing involves mixing
a small quantity of ingredients with the same volumetric or weight quantity of a larger quantity of
ingredients. This is followed by repeating this procedure with the small component mix until all the
large quantity ingredients have been incorporated.
•
• Levigation by grinding the powder in a small quantity of suitable levigation aid in a pestle and
mortar, followed by geometric mixing with the base using a spatula on a plate.
• Fusion by melting the components together in a water bath.
• Pestle and mortar are used to prepare an emulsion concentrate using a lower quantity of the external
or continuous phase, followed by dilution of the emulsion concentrate to volume.
23.8.2 Industrial Scale
Manufacture of semisolid dosage forms on a large scale presents challenges with respect to the inherent
tribution within a vessel, variation in the volume of liquid components with changes in operating or
On a pilot plant to a production scale, semisolid formulations are manufactured using one or more of
the following equipment and techniques:
1. Electrically operated propeller mixer in a suitable mixing vessel.
2.
water or steam. The mixing vessel also often has a mixer that sweeps close to the wall to prevent overheating and allow the mixing of semisolid mass, which otherwise has a low convective
mixing rate.
3.
4.
5. Transfer the semisolid material from one unit operation to another, or the packaging line, in a
container, gravity- facilitated, if feasible, or pumping through a tube.
The choice of technique depends on rheological properties of the formulation in addition to plant
design and feasibility of equipment.
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412
23.9 Analysis of Semisolid Dosage Forms
Pharmaceutical Dosage Forms and Drug Delivery
The following quality attributes of semisolid dosage forms of drugs, such as ointments and creams, are
evaluated:
1. Physical stability, in terms of nonseparation of emulsion phases, when applicable, and homogeneity of appearance/ color.
2. Drug identity, purity, content, and uniformity of content. The content of drug per unit mass of
the dosage form and impurities/ related substances of the drug substance indicate its potency and
purity.
3. Drug release rate using an in vitro test.
4. Viscosity of the formulation.
5.
Although these dosage forms are not required to be sterile, the microbial content of certain bac-
terial species, such as Staphylococcus aureus and Pseudomonas aeruginosa, is controlled.
Review Questions
23.1 The following are semisolid topical preparations:
A Ointments
B Creams
C Lotions
D All of the above
23.2 The main difference between creams and ointments is
A Creams are thicker than ointments.
B Ointments are thicker than creams.
C Creams are emulsions, whereas ointments are suspensions.
D None of the above.
23.3 The presence of petrolatum- like bases renders them:
A Occlusive
B Greasy
C Water washable
D Occlusive and greasy
E All of the above
23.4 Select none, one, or more correct answers from the following for the subset of questions:
A Cold cream
B Vanishing cream
C Vaseline
D Calamine lotion
E Lanolin
F Hydrophilic ointment
G
i
ii
iii
iv
23.5 Select the most appropriate answer from the following for the subset of questions:
A An o/ w emulsion
B A w/ o emulsion
C A suspension
D An aqueous solution
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Semisolid Dosage Forms
E An oily solution
F Mixture of PEG 400 and PEG 4,000
i
ii Which of these would lead to a water- soluble drug deposition on the skin in a
iii
iv
Which of the following ointment bases would be considered as the most suitable for the subset
A A hydrocarbon/ oleaginous base
B An absorption base
C An emulsion base
D A water- soluble base
i
ii Which base should be selected for formulating a hydrophobic drug for transcutaneous
iii
iv
v
23.7
A Pseudoplastic
B Dilatant
C Thixotropic
D All of the above
413
FURTHER READINGS
The Art, Science, and Technology of Pharmaceutical Compounding, 2nd ed., Washington,
DC: American Pharmaceutical Association.
Allen L.V., Popovich N.G., and Ansel H.C. (2005) Ansel’s Pharmaceutical Dosage Forms and Drug Delivery
Systems
The Theory
and Practice of Industrial Pharmacy
Shah V.P., Behl C.R., Flynn G.L., Higuchi W.I., and Schaefer H. (1992) Principles and criteria in the develop-
Pharm Res 9: 1107– 1112.
Pharmaceutics: Basic Principles and Application to Pharmacy Practice. San Diego,
CA: Elsevier: 241– 270.
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24
Inserts, Implants, and Devices
LEARNING OBJECTIVES
On completion of this chapter, the students should be able to
1. Differentiate between inserts and implants.
2.
3.
4.
5. Exemplify various types of implants based on drug release mechanism and clinical use.
Differentiate different types of inhalation devices.
24.1 Introduction
Inserts, implants, and devices represent pharmaceutical interventions in healthy and/ or disease states
that may be used to improve health and/ or promote quality of life. Inserts, as the name implies, are drug
delivery systems that are designed for insertion into one or the other body cavity, such as the vagina,
rectum, buccal cavity, or the cul- de- sac of the eye, in the patient. Suppositories are solid dosage forms
that are used to administer drugs through the rectum or vagina. Implants, on the other hand, are designed
for surgical placement inside the body, such as in the subcutaneous (SC) tissue, breast, penis, heart,
bones, teeth, eye, or the ear.
-
insulin pumps and pens. Transdermal patches are used for drug delivery across the skin. Aerosols and
inhalation drug delivery devices are used for pulmonary drug delivery.
Inserts, implants, and devices may or may not be loaded with drug(s). Drug- containing inserts,
drug release is controlled. In such cases, the drug may embed into biodegradable or nonbiodegradable
materials forming a uniform matrix that allows slow release of the drug.
24.2 Inserts
24.2.1 Ocular Inserts
Drug administration to the eye commonly involves the use of eye drops, which can be formulated as
a drug solution, suspension, or semisolid ointments. Tear turnover and drainage can quickly eliminate
applied dose is usually absorbed into the eye. A part of the dose also passes into the nasal sinus and is
absorbed through the highly vascular nasal mucosa into the bloodstream. This may result in unwanted
®) eye drops, a prosta
DOI: 10.1201/9781003389378-27
414
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Inserts, Implants, and Devices
415
such as hypotension and bradycardia.
These safety concerns are addressed by the use of inserts that stay on the cornea for a long duration of
time. Inserts can be biodegradable or non-biodegradable. Inserts can also be designed for immediate or
controlled drug release. Drug- containing inserts are placed on the cornea, sometimes hidden below the
at relatively steady levels over a prolonged period of time and allow drug diffusion across the cornea.
inserts (e.g., medicated contact lenses, collagen shields, and minidiscs) also reduce systemic absorption
of topically applied drugs as a result of decreased drainage into the nasal cavity. In addition, contact
lenses are becoming increasingly useful as potential drug delivery devices by presoaking them in drug
solutions. The use of contact lenses can simultaneously correct vision and release drugs.
The ophthalmic inserts can be insoluble or soluble. Insoluble inserts may or may not be erodible/ bio-
inserts consist of degradable polymers such as polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC),
polyvinylpyrrolidone (PVP), and hyaluronic acid. Nonbiodegradable inserts are prepared from insoluble
materials such as ethylene– vinyl acetate copolymers and styrene– isoprene– styrene block copolymers.
• Ocusert® consists of a drug reservoir (e.g., pilocarpine HCl in an alginate gel) sandwiched on both
sides by a release- controlling membrane, which is made of ethylene– vinyl acetate copolymer. This
system is encased in the periphery by a white ring, which allows positioning of the system in the
eye (Figure 24.1). Ocusert provides a slow release of pilocarpine HCl for the control of increased
intraocular pressure in glaucoma.
• Lacrisert® is a soluble insert composed of HPC. It is useful in the treatment of dry eye syndrome.
The device is placed in the lower fornix (below the lower eyelid), where it slowly dissolves over
24.2.2 Suppositories
urethra. Once inserted, the suppository base melts, softens, or gets dissolved at body temperature, distributing its medication to the tissues of the region. Suppositories are used for local or systemic effects.
Suppositories are also used to administer drugs to infants and small children, severely debilitated patients,
geriatric patients who cannot take medications orally, and those for whom both the oral and the parenteral
FIGURE 24.1 An illustration of design elements of an ocular insert device.
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