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TABLE 12.11
Formulation of Biopharmaceuticals
General Ranges of Formulation Components
Component General Range
Buffer 5– 100 mM
Component General range
pH 4– 8
Salts 0– 300 mM
Stabilizers 1%– 10%
Surfactants 0.01%– 0.1% (w/ v)
Dosing criteria determine the quantity of the active ingredient in a formulation, with concentration linked to the product’s solubility. Protein solubility refers to the average amount of protein
soluble in co- solvents, yielding a visibly transparent solution without precipitated proteins, crystals,
or gels. Factors such as ionic strength, salt form, pH, temperature, and specic excipients inuence
protein solubility, impacting bulk water surface tension and protein binding to water and ions or
self- association. Protein binding to certain excipients or salts alters the protein’s conformation or
masks specic amino acids involved in self- interaction, inuencing solubility. Some salts, amino
acids, and sugars preferentially hydrate proteins, leading to altered solubility by stabilizing more
compact conformations.
A variety of excipients are used to stabilize protein formulations. To improve the product’s safety
and efcacy, excipients, and buffers for formulation (Table 12.8) are used.
The most common ingredients in biopharmaceutical drug formulations, according to an analysis, are:
• Buffering agents such as phosphates, citrates, and acetates ensure that the pH remains as
stable as possible.
• Stabilizers such as surfactants and sugars include polysorbates, albumin, mannitol, sucrose,
and sorbitol.
• Sugars and electrolytes like sodium chloride are examples of ingredients that change tonicity
and conductivity.
Figure 12.3 shows the percentage of the most common components used in the approximately
200 biopharmaceutical injectable drugs.
12.3.1.1 pH
pH stands out as the most critical among the mentioned formulation variables. Other formulation
methods pose signicant challenges in resolving physical property issues, such as precipitation due
to solubility and stability. pH optimization emerges as a simple yet effective solution to combat these
problems. pH triggers various chemical reactions including deamidation, cyclic imide formation,
disulde scrambling, peptide bond cleavage, and oxidation. Careful evaluation of the properties
of other functional excipients is necessary. For instance, sucrose, used to stabilize proteins during
lyophilization and in solid- state storage, warrants thorough examination.
Adjusting the pH and ionic strength of a protein solution, incorporating sugars, amino acids,
polyols, and utilizing surfactants are effective strategies to prevent oxidation and precipitation. An
in- depth assessment of optimal pH and osmotic conditions stands as a critical element in formulation production to circumvent protein aggregation or precipitation, which is irreversible and is
prevented by surfactants, polyols, or sugars.
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FIGURE 12.3 Percentage occurrence of common formulation components in biopharmaceutical drugs
12.3.1.2 Surface Tension
Surfactants, like sodium polyacrylate, possess both hydrophobic and hydrophilic portions (e.g., an
alkyl chain carboxyl and carboxylate groups).
Nonionic detergents, known as surfactants, are utilized to enhance stability and prevent aggregation. These compounds establish stability by lowering the surface tension of the solution and binding
to hydrophobic sites on the proteins, thereby reducing the likelihood of protein- protein interactions
leading to aggregate formation. Notably, nonionic detergents such as Tween 20 and Tween 80 prevent
the formation of soluble protein aggregates below the critical micelle concentrations (CMC). When
introduced into IgG solutions, polysorbate (Tween) 80 stabilizes small aggregates and prevents their
enlargement into larger particles.
12.3.1.3 Tonicity
The osmotic pressure of an “isotonic” solution mirrors that of human blood, typically ranging
between 250 to 350 mOsmol/ kg. Buffering agents, including phosphate, glycinate, carbonate, and
citrate buffers utilizing sodium, potassium, or ammonium ions as counterions, maintain aqueous
solutions against pH changes resulting from the addition of acid, alkali, or solvent dilution.
12.3.1.4 Protectants
Novel excipients play a crucial role in enhancing protein/ peptide stability, as commonly used
excipients provide only limited stabilization. Examples like resveratrol, a natural phenol,
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Formulation of Biopharmaceuticals
hydroxybutyrate, polyamines, octanoic acid, and quinone- tryptophan derivatives illustrate this
trend. Additionally, hydrophobic salts such as pentane- 1,5- diamine salts and camphor- 10- sulfonic
acid salts reduce the viscosity of mAb solutions by tenfold. However, using uncommon excipients
might necessitate extensive safety testing, potentially including in vivo studies.
Lyoprotectants, when employed alongside a protein of interest, aid in preventing or minimizing
the chemical and physical instability of proteins during lyophilization and subsequent storage.
Preservatives serve to inhibit bacterial activity and can be optional in formulations. For
instance, developing a multi- use formulation becomes easier by incorporating a preservative.
Various preservatives like octadecyldimethylbenzyl ammonium chloride, hexamethonium
chloride, benzalkonium chloride (a mixture of alkyl benzyl dimethylammonium chlorides
with long- chain alkyl groups), benzethonium chloride, and aromatic alcohols such as phenol,
butyl, and benzyl alcohol, alkyl parabens such as methyl or propylparaben, catechol, resorcinol, cyclohexanol, 3- pentanol, and m- cresol, as well as alkyl parabens such as methyl or
propylparaben.
One common method of preventing aggregation is to limit protein mobility is a common
method to prevent aggregation by reducing molecular collisions. Excipients such as surfactants
(e.g., polysorbate 20 and 80), carbohydrates (e.g., cyclodextrin derivatives), and amino acids
(e.g., arginine and histidine) help prevent aggregation by adsorbing to the air- liquid interface and
safeguarding the protein. However, certain excipients such as polysorbate 80 can lead to micelle
formation, heightening the risk of immunogenicity. Cyclodextrin stabilizes commercially available
antibody- based drugs in a hydrogel formulation. Pluronic F68, trehalose, glycine, and amino acids
such as arginine, glycine, glutamate, and histidine, which are found in many commercial protein
therapy products, are all considered safe excipients (GRAS). Avastin® (bevacizumab, 25 mg/ mL)
contains ingredients such as trehalose dehydrates, sodium phosphate, and polysorbate 20. Histidine
hydrochloride, histidine, trehalose dehydrate, polysorbate 20, methionine, and water for injection
are all excipients in subcutaneous Herceptin® (trastuzumab, 600 mg). Chelating agents are used to
prevent metal- induced protein aggregation.
12.3.1.5 Stabilizers
Utilizing large polymeric excipients allows for protein stabilization, where neutral polymers
function as crowding agents to stabilize proteins by eliminating steric repulsion. Examples
include PVP, Ficoll70, hydroxyethyl (heta) starch, or PEG 4000. Recent compositions involving
functionalized trehalose- containing dextrans and glycopolymers aim to enhance process and storage
stability. Additionally, polyanions/ polycations like heparin, dextran sulfate, pentosan polysulfate,
polyphosphoric acid, poly- L- glutamic acid, and poly(acrylic acid) or poly(acrylamide) are potential stabilizers due to their role in protein- polyion interactions (methacrylic acid). Activity between
polycationic chitosan and negatively charged lactate dehydrogenase (LDH) results in signicant
stabilization during air- jet nebulization. When agitated, however, negative heparin and keratinocyte
growth factor 2 (KGF- 2) activity promotes protein aggregation.
Strong interactions can lead to protein destabilization, exemplied by the preferential interaction mechanism. The brillation process, responsible for the formation of amyloid brils linked
to various human diseases, involves interactions between crystalline and non- native protein species.
(Under certain conditions and over time, proteins lose their native folded state and form amyloid
brils, a mechanism linked to a variety of human diseases. Foreign surfaces, such as nanoparticles
with different surface properties, can disrupt this brillation process.)
Utilizing recombinant hyaluronidase enzyme in protein formulation facilitates rapid tissue distribution, allowing for larger- than- normal injection volumes. However, incorporating polymers or
proteins in protein formulations increases complexity, posing challenges in formulation characterization and stability studies.
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12.3.2 liQuid foRMulations
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When designing liquid formulations, various interactions like electrostatic, Van der Waals, hydrogen
bonding, and hydrophobicity are taken into account. High concentrations of saccharides such as
sucrose, trehalose, and lactose, along with polyhydrated alcohols like sorbitol, mannitol, and polyethylene glycol, aid in maintaining the native conformation of biologics. This prevents their interaction with the protein surface. Saccharose isn’t used due to increased surface tension. The process
of “salting in” enhances protein solubility by adding small salt amounts. While salts serve as tonicity regulators, they can sometimes negatively impact conformational stability. Consequently,
counterions and their concentrations, as per the Hofmeister series, are employed to alter the stability
prole— a critical consideration in pre- formulation screening. For instance, different buffer species
at varying concentrations affecting ionic strength can achieve identical pH states, thereby inuencing protein stability. The binding of Zn2+ to human growth hormone illustrates how ligand binding
preserves the native protein state.
Surface- active agents prevent protein adsorption, denaturation, and aggregation at interfaces (airwater and solid- water). They affect protein stability by binding differently to native and denatured
protein states. Surface denaturation can also result from agitation, freeze- thaw stress tests, or low
surfactant concentrations like Polysorbate 20, Polysorbate 80, Pluronic F68, or others adept at reducing both soluble and insoluble aggregates. Addressing issues like metal ions, barium from glass
vials, vulcanizing agents from stoppers, tungsten oxide from prelled syringes, and silicone oil
penetration is crucial. EDTA removes metal leachates from stoppers. Similar to pre- formulation,
counterions and their concentrations based on the Hofmeister series critically impact the stability
prole. Varying buffer species at different concentrations affecting ionic strengths can yield the
same pH state, thereby impacting protein stability. Binding ligands such as Zn
2+
to human growth
hormone also aid in maintaining native protein structure.
Antimicrobial preservatives are commonly used in multi- dose biopharmaceuticals, constituting a third of all such products. They can induce protein aggregation, complicating biopharmaceutical stabilization. Commonly used preservatives include m- cresol, benzyl alcohol or phenol,
phenoxyethanol, and chlorobutanol. Screening various preservatives before their standalone or
combined usage is advisable.
12.3.3 lyoPhilized foRMulations
Lyophilization with suitable excipients enhances protein stability by reducing protein mobility
and limiting conformational exibility. This process minimizes hydrolytic reactions due to water
removal. Proper excipients, like lyoprotectants, prevent aggregate formation during lyophilization and nal product storage. Achieving adequate stability depends on the lyoprotectant- to-
protein molar ratio. Ratios of 300:1 or higher are necessary, especially for room temperature storage.
However, such ratios can cause undesirable viscosity increases.
Lyophilization may be necessary due to protein instability in an aqueous solution without
preservatives. When stability, storage, and shipping requirements align with the target product prole,
lyophilization becomes an important alternative to liquid formulation, especially for highly thermolabile products and live virus vaccine items. Freezing is a prerequisite for lyophilization, followed
by vacuum- assisted primary and secondary drying. The drying process, however, presents its unique
challenges. Denaturation can occur during freezing, caused by freeze- concentrate conditions,
frozen surface interfaces, or cold- denaturation. Formulations during the freeze- concentrate phase
should consider local salt and buffer concentrations’ effects, along with increasing trapped oxygen
concentrations.
Similarly, in lyophilized products, changes in pH due to buffer crystallization must be factored
into the formulation design space. Buffering at physiological pH with a low concentration of
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potassium phosphate buffer (including ten mM) is preferable to sodium phosphate buffer due to
the signicant pH shift during freezing for sodium phosphate. Citrate, Tris, and Histidine are good
buffer choices if the pH range is appropriate. To minimize oxidation, antioxidants (e.g., ascorbic
acid) and scavengers (e.g., thiourea) can be utilized.
Lyoprotectants, external stabilizers, might be necessary in addition to cryoprotectants. For
instance, sorbitol may appear as a good stabilizer during liquid pre- formulation screening, but it’s
not favored in dried formulations due to its low glass transition temperature. Lyoprotectants, such
as sucrose and trehalose, with high glass transition temperatures, act as solid water substitutes, preserving the native state in the dry state. However, the use of reduced sugars (e.g., lactose) requires
careful assessment in risk evaluation. Excipient combinations, especially in a multi- stabilizer
system, can be limited due to the possibility of phase separation (e.g., PEG- Dextran). Trehalose is
preferred over sucrose due to its acid hydrolysis ability at a lower pH.
To prevent “blowout” of low- concentration products, bulking agents (1 percent solid) are added
to lyophilized products. Examples include amorphous bulking agents like sucrose, trehalose, lactose, rafnose, dextran, hydroxyethyl starch (HES), or crystalline ones like glycine and mannitol,
for amorphous or high eutectic temperature (Teu) crystalline excipients. Mannitol’s selection is
limited due to mannitol hydrate presence, posing risks of glass breakage during manufacturing (due
to high ll volume, incorrect freezing procedure, and high concentration).
Isotonicity plays a role in pain relief. Achieving isotonicity in a lyophilized product is challenging due to the concentration of both protein and excipients during reconstitution. A 500:1
protein molar ratio may result in hypertonic preparations if the protein concentration exceeds
100 mg/ mL.
While freeze- drying is extensively used for protein drugs, it has drawbacks, leading to the
development of alternative drying methods (e.g., spray- drying, spray- freezing, supercritical uid
drying, foam drying) for proteins like insulin, trypsin, human growth hormones, and monoclonal
antibodies.
12.3.4 higheR- concentRation foRMulations
Higher concentrations are often needed for subcutaneous administration’s lower volume. Yet, as
protein concentrations increase, their physical properties can drastically change, affecting opalescence, viscosity, and protein aggregation/ immunogenicity. Manufacturing, administration, and marketability of biotherapeutic products are at risk due to these altered properties.
Subcutaneous routes have a limited volume of 1.5 mL. Formulations requiring large doses, over
1 mg/ kg or 100 mg per dose, are formulated at concentrations exceeding 100 mg/ mL. Developing
high concentration formulations for proteins prone to aggregation is challenging. At higher
concentrations, protein interactions can induce reversible self- association, leading to the formation
of insoluble aggregates. Increased concentration heightens the probability of reversible oligomers,
such as dimers and tetramers, due to enhanced molecular collisions. Aggregates can form through
mechanisms like covalent linkages, for instance, disulde exchange, even with minor native structure conformational changes, particularly at higher concentrations.
A high- concentration solution entails solutes occupying a substantial space. Another denition
is when molecular size aligns with the distance between Van der Waals’ surfaces, termed “high
concentration” due to molecular proximity. The primary hurdle in achieving high concentration
formulations is the solubility of the target protein, inuenced by molecular properties (sequence,
charge distribution) and solution conditions (pH, ionic strength, etc.). Solubility denes the maximum protein amount in a solution without visible particles, precipitates, or clumps after 30 minutes
of centrifugation at 30,000 g with a co- solute. Besides solubility, factors like opacity, viscosity, and
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aggregation are vital in mAb formulation. Opacity, expressed in turbidity units in nephelometry,
results from reversible protein- protein and liquid- liquid phase separations. Protein- protein interaction signicantly impacts opalescence and viscosity at high concentrations, potentially leading
to reversible self- association, increased viscosity, opalescence, and aggregation in closely packed
molecules.
Viscosity escalation directly impacts manufacturability and injectability in high concentrations.
Tangential ow ltration (TFF) is a common technique for buffer exchange and protein concentration in large- scale manufacturing (clinical and commercial). Elevated viscosity induces back
pressure surpassing the pump’s capacity due to cavitation and shear stress from rapid pumping
through narrow tubing. This high pressure stresses the mAb, elevating manufacturing costs by
prolonging production time at the very least.
Elevated viscosity signicantly affects subcutaneous dosage administration. Glide force, determining the ease of subcutaneous injection by measuring the force to propel liquid through the
syringe, is predominantly inuenced by viscosity. As viscosity increases, injection site pain rises,
potentially reducing patient compliance.
An emerging concept to tackle protein stability and high viscosity involves “nanoclusters” –
densely packed protein molecules developed in the presence of a crowder like trehalose. At extremely
high concentrations (up to 320 mg/ mL), these form colloidally stable dispersions of nanoclusters
(35– 80 nm). Nanoclusters have protein molecules packed more closely than in bulk solution. While
shorter distances between proteins may enhance interactions, they could compromise protein stability. The nanocluster concept requires further development.
12.3.5 exaMPles of foRMulations
The following is a list of a few commercial product compositions.
• Oprelvekin injection (interleukin [IL]- 11).
Bill of Materials (Batch Size 1 L):
Scale/ mL Item Material Quantity UOM
1.00 mg 1 Oprelvekin (interleukin [IL]- 11) 1.00 g
4.60 mg 2 Glycine 4.60 g
0.32 mg 3 Dibasic sodium phosphate heptahydrate 0.32 g
0.11 mg 4 Monobasic sodium phosphate monohydrate 0.11 g
qs mL 5 Water for injection, qs to 1.00 L
• Interleukin injection (IL- 2).
Bill of Materials (Batch Size 1 L):
Scale/ mL Item Material Quantity UOM
0.25 mg 1 IL- 2 0.25 g
0.70 mg 2 Sodium laurate 0.70 g
10.00 mM 3 Disodium hydrogen phosphate 10.00 M
50.00 mg 4 Mannitol 50.00 g
Qs mL 5 Hydrochloric acid for pH adjustment 1 M qs
qs mL 6 Water for injection, qs to 1.00 L
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• Interferon Alfa- 2a injection.
Bill of Materials (Batch Size 1 L):
Scale/ mL Item Material Quantity UOM
3MM IU 1 Interferon alfa- 2a 3B IU
7.21 mg 2 Sodium chloride 7.21 g
0.20 mg 3 Polysorbate 80 0.20 g
10.00 mg 4 Benzyl alcohol 10.00 g
0.77 mg 5 Ammonium acetate 0.77 g
qs mL 6 Water for injection, qs to 1.00 L
• Interferon Beta- 1b.
Bill of Materials (Batch Size 1 L):
Scale/ mL Item Material Quantity UOM
0.30 mg 1 Interferon beta- 1b 0.30 g
15.00 mg 2 Albumin human 15.00 g
15.00 mg 3 Dextrose 15.00 g
5.40 mg 4* Sodium chloride 5.40 g
qs mL 5 Water for injection, qs to 1.00 L
This item is packaged separately as 0.54% solution (2 mL diluent for lyophilized product).
• Interferon Beta- 1a injection.
Bill of Materials (Batch Size 1 L):
Scale/ mL Item Material Quantity UOM
*33.00 mcg 1 Interferon beta- 1a 33.00 mg
15.00 mg 2 Albumin (human) 15.00 g
5.80 mg 3 Sodium chloride 5.80 g
5.70 mg 4 Dibasic sodium phosphate 5.70 g
1.20 mg 5 Monobasic sodium phosphate 1.20 g
qs mL 6 Water for injection, qs to 1.00 L
• Interferon Alfa- n3 injection.
Bill of Materials (Batch Size 1 L):
Scale/ mL Item Material Quantity UOM
5 MM U 1 Interferon alpha- n3 5B U
3.30 mg 2 Liqueed phenol 3.30 g
1.00 mg 3 Albumin (human) 1.00 g
8.00 mg 4 Sodium chloride 8.00 g
1.74 mg 5 Sodium phosphate dibasic 1.74 g
0.20 mg 6 Potassium phosphate monobasic 0.20 g
0.20 mg 7 Potassium chloride 0.20 g
qs mL 8 Water for injection, qs to 1.00 L
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• Interferon Alfacon- 1 injection.
Bill of Materials (Batch Size 1 L):
Scale/ mL Item Material Quantity UOM
0.03 mg 1 Interferon Alfacon- 1 0.03 g
5.90 mg 2 Sodium Chloride 5.90 g
3.80 mg 3 Sodium Phosphate 3.80 g
qs mL 4 Water for Injection, qs to 1.00 L
• Interferon Gamma- 1b injection.
Bill of Materials (Batch Size 1 L):
Scale/ mL Item Material Quantity UOM
200.00 mcg 1 Interferon Gamma- 1b* 200.00 mg
40.00 mg 2 Mannitol 40.00 g
0.72 mg 3 Sodium Succinate 0.72 g
0.10 mg 4 Polysorbate 20 0.10 g
qs mL 5 Water for Injection, qs to 1.00 L
• Iniximab for injection.
Bill of Materials (Batch Size 1 L):
Scale/ mL Item Material Quantity UOM
10.00 mg 1 Iniximab 10.00 g
50.00 mg 2 Sucrose 50.00 g
0.05 mg 3 Polysorbate 80 0.05 g
0.22 mg 4 Monobasic Sodium Phosphate Monohydrate 0.22 g
0.61 mg 5 Dibasic Sodium Phosphate Dihydrate
qs mL 6 Water for injection, qs to 1.00 L
• Daclizumab for injection.
Bill of Materials (Batch Size 1 L):
Scale/ mL Item Material Quantity UOM
5.00 mg 1 Daclizumab 5.00 g
3.60 mg 2 Sodium Phosphate Monobasic Monohydrate 3.60 g
11.00 mg 3 Sodium Phosphate Dibasic Heptahydrate 11.00 g
4.60 mg 4 Sodium Chloride 4.60 g
0.20 mg 5 Polysorbate 80 (Tween®) 0.20 G
qs mL 6 Water for injection, qs to 1.00 L
Qs mL 7 Sodium Hydroxide for pH adjustment qs
Qs mL 8 Hydrochloric acid for pH adjustment qs
Qs Cu ft 9 Nitrogen gas qs
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• Coagulation factor VIIa (recombinant) injection.
Bill of Materials (Batch Size 1000 vials):
Scale/ vial Item Material Quantity UOM
*1.20 mg 1 rFVIIa 1.20 g
5.84 mg 2 Sodium chloride 5.84 g
2.94 mg 3 Calcium chloride dihydrate 2.94 g
2.64 mg 4 Glycylglycine 2.64 g
0.14 mg 5 Polysorbate 80 0.14 g
60.00 mg 6 Mannitol 60.00 g
• Reteplase recombinant for injection.
Bill of Materials (Batch Size 1000 vials):
Scale/ vial Item Material Quantity UOM
18.10 mg 1 Reteplase 18.10 g
8.32 mg 2 Tranexamic acid 8.32 g
136.24 mg 3 Dipotassium hydrogen phosphate 136.24 g
51.27 mg 4 Phosphoric acid 51.27 g
364.00 mg 5 Sucrose 364.00 g
5.20 mg 6 Polysorbate 80 5.20 g
• Alteplase recombinant injection.
Bill of Materials (Batch Size 1000 vials):
Scale/ vial Item Material Quantity UOM
58MM IU 1 Alteplase 100.00 g
3.50 g 2 L- arginine 3.50 kg
1.00 g 3 Phosphoric acid 1.00 kg
11.00 mg 4 Polysorbate 80 11.00 g
qs mL 5 Water for injection, qs to 1.00 L
12.4 ROUTES OF ADMINISTRATION
Each administration route has its own set of limitations based on anatomical size and location,
microclimate, complex physiological conditions, and formulations. The volume and viscosity of the
uid in the rectum affect drug absorption.
pH conditions in various biological environments affect the ionization, chemical stability, and
absorption of protein- based drugs and their delivery mechanisms. For instance, protein drugs
become unstable at physiological pH. The highly acidic gastric environment (pH 1– 3) causes protein drug destabilization in the stomach, while higher pH reduces chemical degradation in the
ileum and colon. Therefore, the buffering agent in an ocular delivery system plays a critical role,
as hyperosmotic solutions cause transient dehydration of anterior chamber tissues, and hypotonic
solutions can cause edema.
Oral protein delivery and bioavailability face challenges due to enzyme degradation in the gastrointestinal tract. Protease activity is higher in the small intestine but much lower in the colon. Hence,
colon- targeted delivery systems have garnered attention as a viable mechanism for protein drug
delivery. This approach can enhance drug absorption and duration of action. Colon- targeted drug
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delivery systems also prove useful in treating local bowel disorders like colon cancer, ulcerative colitis, Crohn’s disease, and amoebiasis. Despite non- oral routes bypassing the hepatic rst- pass effect,
enzymatic barriers create a “pseudo- rst- pass effect.” For example, low metabolic enzyme activity
can impede protein drug delivery through nasal and pulmonary routes.
Mucus and epithelial cell membranes act as major absorption barriers for non- injectable drugs.
Mucus, coating all mucosal epithelia, acts as the rst line of defense against mechanical damage and
the entry of harmful substances into the eye, respiratory tract, and gastrointestinal tract. It physically
shields large molecules and, due to its hydrophilic nature and negative charge, interacts with the
drug, slowing drug diffusion and limiting absorption in the intestine (Figure 12.4).
Mucus comprises mucin- type glycoproteins and varies greatly in thickness throughout the body.
For example, airway mucus ranges from 5 to 55 microns thick, while nasal tract mucus is very thin,
creating a porous surface. In the eye, the precorneal mucin gel covering the conjunctiva measures
30– 40 um thick. The thickness of the gastrointestinal mucus layer varies signicantly by location
and digestive system activity, being thickest in the stomach and colon, ranging from 10 to over 170
µm. Despite the colon’s lack of proteolytic activity, drugs must penetrate this thicker mucus layer,
making it an advantageous site for protein absorption.
Parenteral routes, excluding the mouth and alimentary canal (e.g., rectal), commonly deliver
biopharmaceuticals via intravenous bolus, intravenous infusion, subcutaneous injection, and intramuscular injection. Despite its precision, parenteral injection faces challenges due to invasiveness,
discomfort, infection risks, high cost, and low patient compliance.
Developing noninvasive drug delivery routes like oral, nasal, pulmonary, ophthalmic, rectal,
or transdermal proves challenging due to biopharmaceuticals’ large molecular size, hydrophilicity,
low permeability, and chemical/ enzymatic instability. Alternative drug delivery approaches
have two major drawbacks. First, the drug’s route of administration is hostile to polypeptides; for
example, orally administered proteins are subjected to harsh conditions before absorption through
FIGURE 12.4 Barriers to absorption in various routes of administration
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