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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5320_Библиотеки_им_академика_М_И_Перельмана
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Pharmaceutical Dosage Forms and Drug Delivery
routes may not be suitable. Vaginal or rectal suppositories are sometimes also termed as pharmaceutical
pessaries (singular, pessary).
24.2.2.1 Types of Suppositories
Based on their route of administration, suppositories can be rectal, vaginal, or urethral.
• Rectal suppositories are cylindrical or conical in shape. Suppositories containing a mois mation associated with hemorrhoids. Glycerin or bisacodyl suppositories are used as a
laxative. They may also be used for systemic administration of drugs, such as opiate analgesics.
Rectal suppositories are often intended for systemic drug action. Examples of such rectal supposi-
®®
dissolves at body temperature and gradually spreads over the lining of the lower bowel (rectum),
from where it is absorbed into the bloodstream. The medicine is easily absorbed from the rectum
because there is a rich supply of blood vessels in this area. The addition of surfactants may increase
the wetting and spreading of the molten mass, which tends to increase the extent of drug absorption. Surfactants, such as polyoxyethylene sorbitan monostearate and sodium lauryl sulfate, may
in drug absorption.
• Vaginal suppositories are available in ovoid, globular, or other shapes. They are employed as
contraceptives, antiseptics in feminine hygiene, treatment of local vaginal infections (e.g., candidiasis), or for systemic delivery of hormones (e.g., progesterone), with high local concentration,
especially in the uterus.
• Urethral suppositories are sometimes used for the treatment of severe erectile dysfunction. For
example, alprostadil pellets that contain the vasodilator prostaglandin E1 are marketed under the
® (medicated urethral suppository for erection).
24.2.2.2 Suppository Bases
Most suppositories consist of a drug substance dissolved or dispersed in a matrix, termed as a supposi-
bases can be either oleaginous or water- soluble bases.
• Oleaginous bases
such as hydrogenated vegetable oils.
•
regions. Addition of certain drugs can change (lower) the melting point. Melting point may also be
into a lower melting metastable morph. These considerations limit the manufacturability of cocoa
butter bases. Synthetic triglyceride bases, such as Fattibase®, Wecobee®, Suppocire®, Witepsol®,
Hydrokote®, or Dehydag®, do not exhibit polymorphism.
• Water- soluble or water- miscible suppository bases
polyethylene glycols (PEGs). PEG suppository bases do not melt at body temperature but rather
The higher the molecular weight, the higher the melting point. A combination of lower and higher
melting PEGs is typically used to make a suppository base.
• Factors affecting the bioavailability of suppository dosage forms include the retention time of the
and the onset of drug action also depend on the liquefaction of the suppository base, dissolution of
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24.2.2.3 Manufacturing Process and Formulation Considerations
417
Drugs are usually dissolved or dispersed in a suitable suppository base. Other excipients that may be used
include surfactants and preservatives. Hand rolling, compression molding, or fusion molding are the three
processes commonly used to manufacture suppositories.
• Hand rolling is typically employed for cocoa butter- based suppositories. The base is triturated with
the drug in a mortar. The mass is formed into a ball in the palm of the hands. The ball is rolled on a
of pieces, one end of each of which is rolled to produce a conical shape.
• Compression molding
compression mold. The quantity of the formulation is calculated based on the prior determination
of the volume of molds and the density of the formulation.
• Fusion molding involves melting the suppository base, followed by dissolving or dispersing the
drug in the base, and pouring the molten mixture into a metallic suppository mold— where the mixture is allowed to congeal into shape.
Formulation considerations for suppository manufacturing include a careful consideration of density,
possible variation in drug loading that can result from the manufacturing process and potential variability
be suitable for delivery via a suppository. Suppository quality control involves testing the melting range,
liquefaction or softening time, physical integrity or breaking test, drug release rate testing, and stability
determination for the physical (appearance and odor) and chemical (pH and drug degradation) attributes.
24.2.3 Vaginal Rings
Vaginal rings, also known as V- rings or intravaginal rings, are doughnut- shaped polymeric drug delivery
devices designed to provide controlled release of drugs to the vagina. They are manually placed in the
vagina and are held in place by the anatomy, usually close to the cervix.
• Nuvaring® is a contraceptive vaginal ring that contains etonogestrel (progestogen) and ethinyl
estradiol (estrogen). It is made using poly(ethylene- co- vinyl acetate) polymer and provides a slow
release of hormones over a period of three weeks.
• Estring® is a low- dose estradiol- releasing ring for treating vaginal atrophy.
• Femring® is a low- dose estradiol acetate- containing ring. It is used for vaginal atrophy and hot
24.3 Implants
into the body. Most of
the implants are surgically placed inside the body. A drug- containing implant is usually a sterile, solid dosage
form prepared by compression or melting for drug delivery at a desired rate over a prolonged period of time.
24.3.1 Types of Implants Based on Drug Release Mechanism
1. Diffusion- controlled implants
2. Osmotic minipumps
These implants differ in the mechanism of control of drug release.
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24.3.1.1 Diffusion- Controlled Implants
Pharmaceutical Dosage Forms and Drug Delivery
The rate of drug delivery from polymeric systems may be controlled by (a) drug diffusion and dissolution through an insoluble matrix and/ or (b) the use of a rate- controlling membrane. Devices that use a
rate- controlling membrane achieve a controlled rate of drug delivery through diffusion across the membrane. These membrane systems contain a reservoir, which is in contact with the inner surface of the
rate- controlling membrane. The reservoir contains the drug in a liquid, gel, colloid, semisolid, or solid
drug release rate, the matrix could be composed of hydrophilic or hydrophobic polymers or a combination of the two to obtain optimum drug release. Depending on the nature of the polymers used, the
matrix implants could be biodegradable or nonbiodegradable. Drug release from biodegradable implants
is a function of both the rate of drug diffusion and the rate of polymer degradation.
diffuse from a concentrated solution in the core. A matrix system usually provides a square root of the
ation is slow compared to the rate of drug diffusion, drug release kinetics obtained with a biodegradable
implant can become diffusion limited from a concentrated core and thus similar to nonbiodegradable
implants.
• Zoladex® is an implant that contains goserelin acetate dispersed in a matrix consisting of ,- lactic
and glycolic acid copolymer. Goserelin acetate is a potent synthetic decapeptide analog of lutein-
agonist. Zoladex is implanted subcutaneously into the upper abdominal wall. It is used for palliative treatment of advanced carcinoma of the prostate, endometriosis, and advanced breast cancer.
• Vantas® implant contains histrelin, which is a synthetic analog of GnRH agonist. It is a diffusioncontrolled device that provides drug release for up to 12 months. It is used for treating prostate
cancer by decreasing the production of certain hormones, which reduces testosterone levels.
24.3.1.2 Osmotic Minipumps
In contrast to rate- controlling membranes (that use a porous membrane), osmotic minipumps use a mem-
together with an osmotic agent, usually a salt. The membrane is permeable to solvent (water) but impermeable to solute (drug). Such a membrane is called semipermeable membrane. Penetration of water
inside the device through the semipermeable membrane allows the dissolution of salt (osmotic agent)
and the creation of high osmotic pressure inside the membrane (highly concentrated salt solution). This
rate until the entire solid agent has been dissolved. The drug release rate is usually unaffected by the pH
of the environment and essentially remains constant as long as the osmotic gradient remains constant.
Thus, the kinetics of drug release is governed by the salt concentration and dosage form volume— which
Polymers, such as cellulose acetate, ethylcellulose, polyurethane, polyvinyl chloride, and PVA,
are used to prepare semipermeable membranes to regulate the osmotic permeation of water. A waterinsoluble polymer impregnated with a small quantity of a water- soluble polymer allows the formation of
micropores that allow solvent diffusion across the membrane, thus making a semipermeable membrane.
An oral osmotic pump is one of the commonly used devices. It is composed of a core tablet surrounded
by a semipermeable coating. The coating membrane has a 0.3– 4 mm diameter hole, which is produced by
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FIGURE 24.2 (a) An illustration of design elements of osmotic minipump devices. (b) different components of an osmotic pump.
a laser beam, for drug exit. This system requires only osmotic pressure to be effective. The drug release
rate is dependent on the surface area, the nature of the membrane, and the diameter of the hole. When the
controlled rate driven by the resultant osmotic pressure of the core.
• ® miniosmotic pump (illustrated in Figure 24.2a) permits easy manipulation of drug release
rate over a range of time periods (from one day to six weeks). These miniature infusion pumps are
designed for continuous dosing of unrestrained laboratory animals.
• ®® technology
(illustrated in Figure 24.2b). A nondegradable, osmotically driven system is intended to enable
These implants are used for continuous therapy for up to one year. Viadur is a leuprolide acetatecontaining implant, once yearly, for the palliative treatment of advanced prostate cancer.
24.3.2 Types of Implants Based on Clinical Use
be drug- containing or nondrug- containing devices. Drugs may also be incorporated into or on the surface
of devices used in routine clinical medicine, such as cardiac stents.
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24.3.2.1 Cardiac Implants
Pharmaceutical Dosage Forms and Drug Delivery
Cardiac implants are devices that are surgically placed in the heart for restoring and assisting regular heart
® and CardioSEAL®, are used to
close a hole or an opening between the right and the left side of the heart to correct birth defects located
Drug loading into conventional cardiac implants can improve their clinical outcome. For example,
drug- eluting stents
blockade of the stented artery). These stents contain drugs, such as sirolimus (Cypher®), paclitaxel
(Taxus®®®). In addition, an iontophoretic cardiac
drug delivery system allows cardiac electrical pulse- induced drug release to treat arrhythmias.
24.3.2.2 Dental Implants
tistry. Antibiotics and analgesic drugs are commonly used in medicated dental implants. Prophylactic
Atridox® is a FDA- approved product designed for controlled delivery of the antibiotic doxycycline to
delivery depot that delivers the antibiotic to the cavity.
24.3.2.3 Urological and Penal Implants
Penile implants are surgically placed inside the penis for male infections and impotence.
Surface deposition of ionic and organic components (encrustation) can affect drug release from these
devices. Encrustation is promoted by high urinary pH, which is common with urinary infections, and due to
their prolonged contact with urine. Encrustation also leads to a higher risk of infection. Glycosaminoglycans
can act as crystal growth inhibitors. Therefore, surface coating of the glycosaminoglycan heparin on the
Infection of the implants is a relatively common problem that requires expensive and invasive replacement of the prosthesis. The use of antibiotic- releasing implants can overcome this problem. An antibiotic-
®
release of antibiotics, such as minocycline and rifampin, in the microenvironment surrounding the
implant.
24.3.2.4 Breast Implants
Cosmetic breast enhancement implants are fairly common. Pain management with the implant involves
the use of oral medication, including narcotic analgesics. Intraoperative administration of analgesics into
the implant pocket facilitates early postoperative recovery and reduces the incidence of pain in patients
undergoing surgery.
24.3.2.5 Ophthalmic Implants
Local drug delivery using ophthalmic implants provide higher local drug concentration and improves
patient response compared to intravenous (IV) therapy. Vitrasert® is a ganciclovir intravitreal implant for
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(CMV) retinitis. Vitrasert contains ganciclovir embedded in a polymer matrix, which releases the drug
over a period of 5– 8 months.
Retisert®
insert contains 0.59 mg of drug, which is released over a period of about 30 months.
Intravitreal- controlled drug delivery can be achieved with the use of implantable devices. For
example, the I- vation® intravitreal implant is made of a nonferrous metal alloy, which is placed inside
the vitreous humor of the eye using a 25 gauge needle. Drugs are delivered by coating onto its surface.
six months to two years.
24.3.2.6 Dermal or Tissue Implants
Drug implants in the SC region or within certain tissues are used for controlled/ prolonged drug release
• SC contraceptive implants provide slow drug release over a prolonged period of time. Most of
these implants contain a progestogen, such as levonorgestrel, etonogestrel, nestorone, elcometrine,
7 years.
• Gliadel® wafer, which contains the antitumor agent carmustine in a biodegradable polyanhydride
copolymer, is used for the treatment of malignant glioma (brain tumor) and recurrent glioblastoma
multiforme by implantation in or close to the tumor site. Each wafer contains 7.7 mg carmustine
• Vantas® SC implant contains histrelin acetate and is indicated for palliative treatment of advanced
prostate cancer by suppressing testosterone levels while requiring less frequent administration than
other LHRH agonists. It releases 50 mg of the drug over a period of 12 months.
24.4 Devices
targeting are achieved with the aid of the packaging container. Pulmonary delivery devices, transdermal
24.4.1 Inhaler Devices for Pulmonary Drug Delivery
designed to deliver the containing solution or suspension of the drug(s) to the lung by forming an aerosol
-
ator is pressed, and a dip tube that conveys the formulation from the bottom of the container to the valve
driving force for the delivery of the contents.
Formulation factors
lung deposition). Particle shape and density determine the proportion of inhaled particles deposited
Device factors affecting pulmonary drug delivery include
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FIGURE 24.3
powder inhaler.
Pharmaceutical Dosage Forms and Drug Delivery
User or patient factors impacting
drug delivery to the lung include coordination of inspiration time with device actuation and the strength,
quantity, and consistency of air intake for breath- actuated devices.
Formulation considerations important for the development of aerosol dosage forms include uniformity
formulations, metered- dose inhalers (MDIs), and dry powder inhalers (DPIs). Figure 24.3 shows a schematic of these inhalation devices. These devices vary as much in their sophistication as they do in their
effectiveness. Each type of device has its own advantages, disadvantages, and limitations. The choice of
device depends on the drug (such as solubility and stability in aqueous medium), the formulation (e.g.,
dry powder or aqueous solution), the pathophysiology of the lungs (e.g., lung capacity), and the status of
the patient (e.g., inpatient or ambulatory self- use).
24.4.1.1 Nebulizers
using compressed air (usually through a pump) and device design. The patient inhales normally, while the
patient coordination of breathing but are cumbersome, nonportable, and time consuming to use.
•
•
compressed gas
approximately two- thirds of the aerosol during the expiration and breath- holding phases.
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breath- enhanced and dosimetric
-
ation phase and release aerosol exclusively during the inhalation phase, respectively.
on the solubility and stability of the drug in aqueous media. For protein and peptide drugs, the stability
stress on these macromolecules, which can lead to their denaturation. This problem gets exacerbated
next dosing cycle. Furthermore, the physical properties of drug solutions (e.g., ionic strength, viscosity,
the lower respiratory tract. They often require several minutes of use to administer the desired dose of
such as the trachea, than deep lung alveoli. Thus, adrenergic agonists such as albuterol and steroids
®
Germany), generate an aerosol mechanically and reduce the shear forces on the drug. In addition,
vibrating mesh technologies such as AeroDose (Aerogen Inc., Mountain View, CA) have been used successfully to deliver proteins to the lungs.
24.4.1.2 Metered- Dose Inhalers
aerosol devices today. A typical MDI comprises a canister, metering valve, actuator, spacer, and holding
chamber. In addition, they may also have dose counters and content indicators. During MDI manufac-
20– 30 sprays. However, the last doses from the container are inconsistent and unpredictable. Therefore,
the dose counter feature allows patients to track the number of actuations and avoid using the product
beyond the recommended number of doses.
-
metrically. The high velocity of the generated aerosol spray causes substantial oropharyngeal deposition
by impaction, which results in poor drug delivery to the lung. This can be avoided by adding a spacer
device
inhalation and actuation, especially for pediatric patients, resulting in improved dosing reproducibility.
mouth coordination. An increase in tidal volume (volume of air moved into or out of the lungs during
normal breathing) and a decrease in respiratory frequency increase peripheral drug deposition in the lung.
Most patients need to be trained for the proper use of the MDI.
24.4.1.3 Dry Powder Inhalers
DPIs are one of the most popular methods of protein delivery to the lungs. DPIs generate aerosols by
drawing air through the loose dry powder of a drug formulation. These are usually capsule- based devices,
of its contents through the piercing. The drug particles form an aerosol in the inspired air upon breathing
by the patient. DPIs are generally easier to use compared to MDIs. However, DPIs require a rapid rate
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Pharmaceutical Dosage Forms and Drug Delivery
distressed patients and in certain disease states such as asthma or chronic obstructive pulmonary disease
(COPD). DPIs range from unit dose systems, employing only the patient’s breath to generate the aerosol,
to multiple- dosing reservoir devices, which actively impart energy to the powder bed to introduce aerosol
unit- dose devices are preferred for
®).
Lung deposition of drug particles varies among different DPIs. DPIs are complex systems, and their
performance depends on effective powder deagglomeration. Drugs in low doses are often combined with
excipients that provide drug- binding sites on the surface while serving as bulking agents. These help with
uniformity of drug content and consistency of emitted dose. Carrier particles, such as lactose, are com-
-
ance of both the device and the formulation is critical to ensuring high and consistent lung deposition.
Most of the therapeutic dry powders for DPIs are currently made with particles of small aerodynamic
3. Increased porosity of
particles, such as when produced by spray drying, helps with deep lung penetration by improving the
Drugs administered by inhalation are mostly intended to have a direct effect on the lungs. Inhaled drugs
parenteral administration because lipid- soluble compounds are rapidly absorbed across the respiratory
tract epithelium. Bronchodilators and corticosteroids are commonly used for treating asthma and COPD.
® (triamcinolone acetamide), Ventolin® HFA (albuterol sulfate), and Serevent® (salmeterol) are
examples of commercially available aerosols for the treatment of asthma.
Proteins, oligonucleotides, and genes demonstrate poor oral bioavailability due to the harsh environ-
the pulmonary route enables higher rates of passage into systemic circulation than oral administration.
24.4.2 Intrauterine Devices
or preventing the implantation of the blastocyst into the uterine endometrium. The hormone- containing
devices can be used for other hormonal effects, such as in menorrhagia.
they are held in place in the uterus by the arms of the T
allows the release of copper in the uterine mucosal microenvironment, which aids contraception. A side
progestogen. These devices can provide much lower systemic and high local progestogen levels.
• Progestasert®
progesterone per day to provide contraception for 1 year.
• Mirena®
for up to 5 years.
24.4.3 Subcutaneous Devices
Parenteral drug administration is indicated for several drugs, especially the new biotechnology- based
drug products such as monoclonal antibodies, and protein and peptide therapeutic agents. During the initial clinical development of these therapies, the IV route of drug administration is adopted to allow dose
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administration is not preferred for commercial use of these drugs by patients because IV drug administration requires the intervention of a health care professional and the use of a health care facility. In contrast,
administered in the SC space (usually about 1 mL, maximum 1.5 mL), the required dose of the drug, and
volume in the SC space. In these cases, the use of a device for SC drug delivery can facilitate SC delivery
of a drug that would otherwise not be possible.
The devices that can be used for SC delivery of a drug could be a syringe pump in an inpatient setting or
a patch pump in an outpatient setting. A syringe pump is a mechanical device that pumps the drug product
This allows a higher volume of drug to be administered subcutaneously over a prolonged period of time.
for the duration of drug administration. Also, the operation and calibration of the syringe pump usually
require the expertise of a healthcare professional. Thus, although syringe pumps can generally be used in
an inpatient setting in a hospital and during clinical trials, their use is limited for outpatient clinical use.
SC devices for outpatient clinical use are generally smaller, battery- operated pumps that can be attached
to the abdominal cavity and worn under the clothing. These allow patient self- administration, and the patient
® device
and West’s SmartDose®
associated with these devices provide better patient compliance and satisfaction with the therapy.
Review Questions
24.1
A Rectal and vaginal drug delivery
B Oral drug delivery
C Nasal drug delivery
D Skeletal drug delivery
E All of the above
24.2 The rate of drug release from an aerosol depends on
A
B
C The type of drug
D The type of container
E All of the above
24.3
A Dry powders can be dispensed.
B Contamination is avoided.
C Emulsions cannot be dispensed.
D
E None of the above
24.4
24.5 Enlist factors that affect drug bioavailability from a suppository. What are the different kinds
Identify clinical considerations important to the development of all implantable drug delivery
systems. What are the differences in the principle of drug delivery between an osmotic minipump
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