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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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21.4.2 Finished Product Quality Control Tests
21.4.2.1 Permeability and Sealing
Pharmaceutical Dosage Forms and Drug Delivery
21.4.2.2 Potency and Impurity Content
batch to be acceptable.
21.4.2.3 Average Weight and Weight Variation
content in the formulation for high drug load formulations.
in the formulation.
capsules.
21.4.2.4 Uniformity of Content
content is assured if predetermined criteria for the range and variation in the content of the active ingredient are met.
21.4.2.5 Disintegration
21.4.2.6 Dissolution
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Capsules
21.4.2.7 Moisture Content
387
capsules.
21.4.2.8 Microbial Content
21.5 Shelf- Life Tests
Review Questions
21.1
A
B
C
D
21.2
A
B
C
D
E
21.3
A
B Addition of surfactants
C
D All of the above
21.4
A
B Poor lubrication
C
D
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Pharmaceutical Dosage Forms and Drug Delivery
A
B
C
D
21.6
A
B
C
D Sorbitol
FURTHER READINGS
Ansel’s Pharmaceutical Dosage Forms and Drug Delivery
Systems
Modern
Pharmaceutics
Theory and Practice of Contemporary Pharmaceutics,
Pharmaceutics: The
Science of Dosage Form Design
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Parenteral Drug Products
On completion of this chapter, the students should be able to
1. Enlist the common parenteral routes of drug administration and discuss circumstances where
one route may be preferred over another.
2. Identify different types of parenteral dosage forms.
3. Identify key quality attributes of parenteral drug products.
4.
22.1 Introduction
Parenteral drug products are the dosage forms intended for administration by a route that does not involve
Parenteral dosage forms are preferred for one or more of the following reasons:
• Low oral bioavailability and/ or high variability in oral drug absorption.
• Instability of the drug in the GI tract. For example, most protein drugs are highly unstable.
• Rapid onset of drug action is desired.
• The ability to immediately stop drug administration is important. For example, most emergency
room medications and anesthetics.
•
response is needed. For example, emergency medications such as analgesics, anticancer drugs, and
fertility medications.
LEARNING OBJECTIVES
Many drugs are available only in parenteral dosage forms. These include most protein and peptide
drugs, some antibiotics, heparin, lidocaine, protamine, glucagon, and many anticancer compounds.
Certain drugs, on the other hand, are available both as parenteral and oral dosage forms for different
clinical settings. For example, analgesics and antihistamine drugs for patient self- administration may
emergency room or hospital setting where rapid onset of drug action may be desired. Similarly, hormonal
drugs, such as progestins and antiprogestins, are available as tablets for use in contraception and are also
DOI: 10.1201/9781003389378-25
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22.2 Parenteral Routes of Administration
Pharmaceutical Dosage Forms and Drug Delivery
intravenous, IV), into a muscle (intramus-
cular, IM), into the skin (intradermal, ID), or under the skin (subcutaneous, SC). Nevertheless, drugs
intraarticular
intrasynovial), spinal column (intraspinalintrathecal), arteries (intraarterial),
and in the heart (intracardiac). In addition, parenteral routes of administration include dosage forms such
as sublingual tablets, transdermal patches, and inhalers— which will not be discussed in this chapter.
22.2.1 Intravenous Route
The IV administration provides immediate access to the drug to the systemic circulation, resulting in the
or an infusion. A bolus
used to administer a relatively small volume and is often written as IV push (IVP). An infusion refers to
the introduction of larger volumes (100– 1000 mL) of the drug over a longer period of time. A continuous
infusion is used to administer a large volume of drug at a constant rate. Intermittent infusions are used to
IV infusion can be administered through peripheral veins, typically in the forearm or the peripherally
inserted central catheter. The commonly administered IV infusion products include Lactated Ringers
combinations of dextrose and saline. Other solutions of essential amino acids or lipid emulsions are also
used as infusions.
22.2.2 Intramuscular Route
are less rapid but generally longer lasting than those obtained from IV administration. Aqueous or oleaginous solutions or suspensions of drugs may be administered intramuscularly. Drugs in aqueous solution are absorbed more rapidly than those in oleaginous preparations or suspensions. An IM medication is
Numerous dosage forms are administered through this route of administration, including solutions
(aqueous- or oil- based), emulsions (o/ w or w/ o), suspensions (aqueous- or oil- based), colloidal
suspensions, and reconstitutable powders. Slow drug absorption leading to a sustained- release (SR)
effect can be achieved with highly insoluble drugs or formulations that are oleaginous or particulate.
needed. Antibiotics are often administered by this route.
22.2.3 Subcutaneous Route
beneath the surface of the skin, between the dermis and muscle. Medications administered by this route
are slowly absorbed and consequently have a slower onset of action than medications given by IV or
IM routes. Drugs often given by this route include epinephrine, insulin, heparin, scopolamine, and
route. For example, high- dose drugs that tend to become highly viscous at high concentrations, such
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Parenteral Drug Products
22.2.4 Other Routes
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• Intradermal
can be administered intradermally is limited to 0.1 mL. The onset of action and the rate of absorp-
• Intrathecal
needed if CSF is the desired site of drug action because most drugs do not reach the CSF from the
systemic circulation. Drugs administered intrathecally include antineoplastics, antibiotics, anti-
• An intraarticular
• An intraarterial
necessary to deliver a high concentration of drug to a diseased organ, such as a kidney, with minimal distribution to other systemic locations.
• An intraocular
humor provides access to the drug to the rear regions of the eye, such as the retina, which does not
receive high drug concentration on topical administration.
22.2.5 Rate and Extent of Absorption
drug absorption. The rate of drug absorption from the site of administration to the systemic circulation
the ECM, increases drug diffusion and absorption. The extent of drug absorption from a parenteral route
22.2.6 Factors Affecting Selection of Route
Selection of a parenteral route of administration for a new therapeutic moiety depends on several considerations, such as
• Desired rate of onset of action: The IV route provides the most rapid onset of action, whereas
the SC, IM, and IP routes have a slower rate of drug absorption into the systemic circulation. SC
route is often preferred for SR dosage forms when slow drug absorption over a prolonged period
is desired.
• Location of drug action
whereas the IP route is preferred if drug action is desired in the lymphatic system.
• Tissue irritability
• Injection volume
high doses.
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22.3 Types of Parenteral Dosage Forms
22.3.1 Small- Volume Parenteral Versus Large- Volume Parenteral
Pharmaceutical Dosage Forms and Drug Delivery
closure systems and volumes. Small- volume parenterals (SVPs) are available in volumes of less than 1
ml and up to 50 ml. Large- volume parenterals (LVPs) are usually packaged in volumes up to 1,000 mL.
-
containers, on the other hand, are usually rubber- stoppered and sealed glass vials that are intended for
stopper, which self- seals after the needle is withdrawn.
However, hypertonic solutions tend to be tissue irritants. The pH of SVPs can also vary from the physio-
SVPs for single- dose administration may be free of antimicrobial preservatives, but multidose vials usually have the preservatives to ensure sterility over multiple uses over a certain period of time.
22.3.2 Injections Versus Infusions
with a short plasma half- life, and/ or dilution of a drug immediately before administration.
22.3.3 Types of Formulations
22.3.3.1 Immediate Release
(solid) for reconstitution immediately before use.
22.3.3.2 Solutions
such as glycols (e.g., polyethylene glycol [PEG] or propylene glycol), alcohols (e.g., ethanol), or other
22.3.3.3 Suspensions
Parenteral suspensions should be easily resuspended and passed through an 18- to 21- gauge needle
throughout their shelf lives. To achieve these properties, it is necessary to select and carefully maintain
often consist of the active ingredient suspended in an aqueous vehicle containing an antimicrobial preservative, a surfactant, a suspending agent, a buffer, and/ or a salt.
Due to the inherent long- term physical instability of suspensions, parenteral suspension dosage
forms are formulated as dry powders for reconstitution immediately before administration. The sterile
suspensions are prepared by mixing dry powders in sterile vehicles immediately before administration.
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Parenteral Drug Products
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before administration. It has inherent advantages over other methods of preparation of dry powders,
such as
• Water is removed at low temperatures, avoiding damage to heat- sensitive drugs.
•
•
disaccharides, and monosaccharides.
22.3.3.4 Emulsions
addition to their inherent physical instability, their use as IV dosage forms has been limited. Total body
nutrition is often administered as an IV emulsion to enable the coadministration of water- soluble and
provide essential fatty acids and calories during total parenteral nutrition of patients who cannot absorb
nutrients through the GI tract. IV lipid emulsions are usually administered in combination with dextrose
and amino acids in the aqueous phase.
22.4 Extended Release
Long- acting formulations (LAFs) are drugs designed to release their active ingredients slowly over a
longer period, and they are used in pharmacotherapy for prolonged durations. These treatments pro-
illnesses and other prevalent medical conditions, consequently resolving the demand for long- lasting
treatments.
Chronic diseases like HIV/ AIDS, psychiatric illnesses, cancer, and diabetes often require long- term
prescriptions of medicine. However, patients often struggle to adhere to a frequent and prolonged dosing
schedule. Long- acting parental formulations (LAPFs) are preferred for these conditions due to their
longer release duration, which may improve patient adherence and therapeutic outcomes. For instance,
a subcutaneous implantation of antiviral LAPFs can provide a protective drug concentration for months
or even longer. Long- acting anti- infective drugs have proven effective in eliminating hepatitis B and C
viruses, and long- acting antipsychotics can reduce relapse and improve long- term prognosis due to consistent plasma drug concentration. Efforts have been made to improve the pharmacokinetics of drugs with
short half-life, such as PEGylation of methotrexate or albumin- bound nanomedicines (nab) of paclitaxel
to achieve long- term effectiveness of vincristine. Furthermore, combining small molecular drugs with
ligands (such as long- chain fatty acids) or albumin prolongs the half- life of the drugs. Diverse strategies
are divided into two categories according to the mechanisms underlying them: manipulation of drug
release from delivery systems and manipulation of in vivo clearance.
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22.4.1 Strategies to Manipulate Drug Clearance In vivo
22.4.1.1 Chemical Modification
Pharmaceutical Dosage Forms and Drug Delivery
reduce the renal clearance of drugs in clinical practice due to their structure, lack of impurity, and welldeveloped methods. These strategies aim to prolong the drug’s half- life without affecting bioactivity.
22.4.1.2 PEGylation and Alternatives to PEGylation
Poly(ethylene glycol) (PEG) is nontoxic and biodegradable and, hence, a Food and Drug Administration
small molecular- weight therapeutic drugs, peptides, proteins, and nanobodies. PEGylation increases the
“stealth” properties. The hydration layer produced by PEG prevents plasma proteins from interacting
with the drug moiety and recognition by the reticuloendothelial system (RES). Further, PEGylation can
be immunogenic, which restricts its usage on a frequent basis. Further, PEGylation can affect the interaction of drug moiety with target receptors or cells and limits endosomal escape, resulting in poor bio-
a relatively new method, integrates established biology with the advantages of prodrug and sustained-
parathyroid hormone (PTH), TransCon hGH, and TransCon CNP (C- type natriuretic peptide), have been
designed and are undergoing clinical trials.
Certain less immunogenic and completely biodegradable polymers, such as hyaluronic acid (HA),
polysialic acid (PSA), hydroxyethyl starch (HES), and poly(2- methyacryloyloxyethyl phosphorylcholine)
(PMPC), have also been used as alternatives to PEG to extend the half- life of drugs. In one example,
Factor VIII,” “PSA- rFVIII”) is being developed as a long- acting therapy for the treatment of hemophilia
A. Human serum albumin (HSA), the most abundant plasma protein, has a 19- day average half- life and
tein can enhance its non- covalent binding to albumin, resulting in a prolonged half- life. The FDA has
Levemir, an insulin analog with myristoylated Lys29, allows reversible binding with albumin for once- a-
-
tion. Lipidation strategies offer the potential for the clinical translation of Lipid Accumulation Products
(LAPs). Still, they may not be suitable for all drug molecules, particularly those lacking hydroxyl and
22.4.1.3 Fc/ HSA Fusion
Proteins and peptides have achieved enhanced functionality, targetability, stability, and product purity.
Consequently, the application of proteins and peptides in the treatment of numerous conditions such as
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oncology, endocrinology, and metabolic, cardiovascular, and bone diseases have increased. However,
these drugs present numerous obstacles when administered in vivo, owing to their substantial molecular
weight, hydrophilic characteristics, inherent instability, and inadequate permeation across cellular and
PEGylation, Fc- fusion, chitosan nanoparticles, and liposomes, have increased the therapeutic potential of
One of these strategies is Fc fusion, which involves fusing a therapeutic protein with the Fc domain
in 1998 was Enbrel (etanercept), which is used in treating rheumatoid arthritis. Over ten products based
on Fc fusion proteins have been approved. The binding of the Fc- domain makes the therapeutic protein’s
Fc- domain can prolong circulation time through the neonatal Fc receptor (FcRn) mediated recycling
procedure. Most Fc fusion proteins have a drug- Fc homodimer structure, represented as (drug- Fc)2.
decreased bioactivity. To address this, drug- Fc2 containing a protein linked two Fc domains has been
developed as Eloctate and Alprolix, and clinically approved. However, this technology cannot be used
for all protein drugs due to impurity and low production yields.
HAS is the most abundant of all plasma proteins present in the blood. HSA has an MW of approxi-
fusion protein. In contrast to native GLP- 1, which shows a half- life of 1- 2 minutes, albigutide has a
22.4.1.4 Cell- Mediated Biomimetic Strategies
Drug delivery by nanocarriers (NCs) to non- liver organs has been hampered even when NCs are targeted
used to enhance the properties of NCs by prolonging circulation time, evading immune responses, and
-
portation is called RBC- hitchhiking (RH). RBCs, which are approximately 7 mm in diameter and have
gaseous exchange. The plasma membrane from RBCs contains over 300 proteins, including CD47, which
acts as a self- recognition protein to help cells avoid the immune system. The mechanism involves mixing
NCs with RBCs ex vivo-
the NCs to the pulmonary capillary endothelial cells. The target organ accumulation of NCs can be sig-
accumulate in the organ immediately downstream. In case of heart attack and stroke treatment, RH could
22.5 Strategies to Manipulate Drug Release From the Delivery
22.5.1 Microencapsulation
Drugs can be encapsulated in various polymeric or lipid nanoparticles/ microspheres to control their
micro/ nanospheres, including natural (e.g., gelatin, alginate chitosan), seminatural (e.g., cellulose acetate
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