| Oral Peptide Drug Delivery Systems and Methods |
 | |  |
July 12, 2014
There are about 60-70 approved peptide drugs in the global market. Most peptide products are injectable, for infusion
or used in implant. Only a limited amount is formulated in oral dosage forms. It is because most peptides degrade at low
pHs and in the presence of enzymes; their large molecular weight further limits the absorption.
There are two aspects for developing oral peptide delivery systems. The first one is chemical modification and other
one is formulation.
Chemical Modifications
Chemical modification is mainly for improving enzyme stability, membrane penetration and minimizing the
immunogenicity.
L-amino acid is commonly substituted with D-amino acid as to achieve such purposes, for example vasopressin.
Peptides are often modified to increase the hydrophobicity for better membrane penetration, better transcellular
passive or active absorption.
For example, Nobex bonded a small polymer to insulin to form a hyexyl-insulin monoconjugate. This conjugate can
resist enzyme degradation. This conjugate can also be absorption into the portal vein and reach the liver. Since the
liver is a significant participant in controlling blood glucose, the insulin absorbed may activate the liver to reestablish
normal glucose level in diabetic patients.
Formulation - functional excipients
In formulation, enzyme inhibitors, such as soybean trypsin inhibitor, can be used to inhibit the action of trypsin and
chymotrypsin. It was found that a combination of sodium cholate and a protease inhibitor can increase 10% of insulin
absorption in rat intestine. Sodium cholate is an enhancer. (However, not all are FDA approved, we need to select
carefully).
Carbomer and polycarbophil (a drug for losing stool) were also found to be useful to inhibit the activity of chymotrypsin
and carboxypeptidases.
Another approach to enzyme inhibition is to put acids in the formulations, as to lower the local pH, this can help to
inactivate the digestive enzymes. However, this may also degrade the peptide drugs.
The absorption enhancers include detergents, surfactants, bile salts, Ca2+ chelating agents, fatty acids, medium chain
glycerides, acyl carnitine, alkanoyl cholines, N-acetylated α-amino acids, N-acetylated non-α-amino acids, chitosans,
mucoadhesive polymers, and phospholipids.
Many of these absorption enhancers increase the transcellular transport of drugs by disrupting the structure of the lipid
bilayer rendering the cell membrane more permeable and/or by increasing the solubility of insoluble drugs. The
chelators are believe to exert their action by complex formation with calcium ions, thus they may rupture the tight
junctions and facilitate paracellular transport of hydrophilic drugs. However, permeation enhancers often come with
toxic side effects, for e.g.calcium ion depletion and eventually diminishing the cell adhesion. Enhancers, such as fatty
acid, sodium caprate and long chain acyl carnitines, improve absorption without obvious harmful effects to the intestinal
mucosa. Researchers may consider to use these types of enhancers.
Emisphere Technologies developed a series of “transport carriers” to form a complex with polypeptides, to alter the
polypeptide structure to a ‘transportable’ conformation. These molecules promote protein and peptide drug absorption.
It was found that more lipophilic compounds (i.e., high log P values) had better ability to promote protein such as
human growth hormone absorption.
Chitosan is another option. N-trimethyl chitosan chloride is a better soluble than chitosan salts, it increases peptide
transport. The increases in peptide drug transport are in agreement with a lowering of the transepithelial electrical
resistance. No deleterious effect to the cell monolayers could be detected in cell studies.
Dosage Forms (Delivery Systems)
The primary objective of oral delivery systems for peptides is to protect the protein and peptide drugs from acid and
enzyme degradation in the GI tract.
Different types of formulation approaches have been used for the oral peptide delivery – including emulsion,
microspheres, liposomes, and nanoparticles.
Emulsion protects drug from degradation in the GI tract but also it helps the peptide absorption. But, the type of
surfactant, particle size of the dispersed phase, pH, solubility of drug, type of lipid phase used are critical for the
success. Usually, medium chain fatty acids triglycerides help increase the bioavailability of muramyl dipeptides analog.
One example is Torisaka’s emulsion delivery system. They first formed a (lipophilic) surfactant –insulin complex and
then dispersed it into an oil phase. And, then disperse it into an aqueous phase. The emulsion showed hypoglycemic
activity over a few hours in diabetic rats. However, this preparation is not stable during long-term storage. Then, dry
o/w emulsion is developed to solve the issue. (They spray-dry an O/W emulsion, then, put the dry emulsion into a
capsule or tablet. They may further coat the dry emulsion with an enteric polymer. Anyway, the release becomes pH
dependent and also affected by lipase.
Some people use pH-sensitive microsphere to protect the peptide and protein drugs from degradation in the stomach
and the upper GI tract. One example of the polymers commonly used is poly (methacrylic-g-ethylene glycol). In the
basic and neutral environments of the intestine, the peptide-polymer complexes dissociated which resulted in rapid
microspheres swelling and insulin release. And, hypoglycemic effect was noticed.
Nanoparticles have also been used to carry peptides through peyer’s patches to the liver, the spleen and other tissues.
Peyer’s patches are aggregations of lymphoid tissue that are usually found in the lowest portion of the small intestine.
Nanoparticles protect the peptides with polymer – peptide association. The particle size, surface charge, surface
ligands and the particle-gut interaction of the nanoparticles are important for the absorption.
Nanoparticles made of chitosans were found in both epithelial cells and peyer’s patches. And further, insulin
encapsulated in nanoparticle was found to have about 11% efficacy of the intraperitoneally delivered insulin. However,
the absorption of intact particles is generally below 5%.
Liposome? it faces acid and lipase degradation and bile salts alteration.
Mucoadhesive polymeric systems:
Theoretically, mucoadhesive polymeric system a promising approach among several approaches, because it can
provide an intimate contact with the mucosa at the site of drug uptake preventing a presystemic metabolism of peptides
on the way to the absorption membrane in the gastrointestinal tract. Additionally, the residence time of the delivery
system at the site of drug absorption is increased. Thus, this system can increase the peptide absorption. However, my
question is “how do we attach the system to a specific site in the small intestine?
_____________________________________________________________________________________
NOTE The above article is for reference use only, it is not a scientific publication. Though I put my best effort in the
preparation, this article may contain mistakes or out-of-date information. One should review recent publications from
scientific journals for details. All rights reserved. Thanks.
Reference Jessy Shaji* and V. Patole, Protein and Peptide Drug Delivery: Oral Approaches, Indian J Pharm Sci. 2008
May-Jun; 70(3): 269–277.
Keywords: peyer's patches, presystemic metabolism, chitosan, Emulsion, Sodium cholate, acyl carnitines, alkanoyl
cholines, hyexyl-insulin monoconjugate, Luteinizing-hormone-releasing hormone, guar gum
There are about 60-70 approved peptide drugs in the global market. Most peptide products are injectable, for infusion
or used in implant. Only a limited amount is formulated in oral dosage forms. It is because most peptides degrade at low
pHs and in the presence of enzymes; their large molecular weight further limits the absorption.
There are two aspects for developing oral peptide delivery systems. The first one is chemical modification and other
one is formulation.
Chemical Modifications
Chemical modification is mainly for improving enzyme stability, membrane penetration and minimizing the
immunogenicity.
L-amino acid is commonly substituted with D-amino acid as to achieve such purposes, for example vasopressin.
Peptides are often modified to increase the hydrophobicity for better membrane penetration, better transcellular
passive or active absorption.
For example, Nobex bonded a small polymer to insulin to form a hyexyl-insulin monoconjugate. This conjugate can
resist enzyme degradation. This conjugate can also be absorption into the portal vein and reach the liver. Since the
liver is a significant participant in controlling blood glucose, the insulin absorbed may activate the liver to reestablish
normal glucose level in diabetic patients.
Formulation - functional excipients
In formulation, enzyme inhibitors, such as soybean trypsin inhibitor, can be used to inhibit the action of trypsin and
chymotrypsin. It was found that a combination of sodium cholate and a protease inhibitor can increase 10% of insulin
absorption in rat intestine. Sodium cholate is an enhancer. (However, not all are FDA approved, we need to select
carefully).
Carbomer and polycarbophil (a drug for losing stool) were also found to be useful to inhibit the activity of chymotrypsin
and carboxypeptidases.
Another approach to enzyme inhibition is to put acids in the formulations, as to lower the local pH, this can help to
inactivate the digestive enzymes. However, this may also degrade the peptide drugs.
The absorption enhancers include detergents, surfactants, bile salts, Ca2+ chelating agents, fatty acids, medium chain
glycerides, acyl carnitine, alkanoyl cholines, N-acetylated α-amino acids, N-acetylated non-α-amino acids, chitosans,
mucoadhesive polymers, and phospholipids.
Many of these absorption enhancers increase the transcellular transport of drugs by disrupting the structure of the lipid
bilayer rendering the cell membrane more permeable and/or by increasing the solubility of insoluble drugs. The
chelators are believe to exert their action by complex formation with calcium ions, thus they may rupture the tight
junctions and facilitate paracellular transport of hydrophilic drugs. However, permeation enhancers often come with
toxic side effects, for e.g.calcium ion depletion and eventually diminishing the cell adhesion. Enhancers, such as fatty
acid, sodium caprate and long chain acyl carnitines, improve absorption without obvious harmful effects to the intestinal
mucosa. Researchers may consider to use these types of enhancers.
Emisphere Technologies developed a series of “transport carriers” to form a complex with polypeptides, to alter the
polypeptide structure to a ‘transportable’ conformation. These molecules promote protein and peptide drug absorption.
It was found that more lipophilic compounds (i.e., high log P values) had better ability to promote protein such as
human growth hormone absorption.
Chitosan is another option. N-trimethyl chitosan chloride is a better soluble than chitosan salts, it increases peptide
transport. The increases in peptide drug transport are in agreement with a lowering of the transepithelial electrical
resistance. No deleterious effect to the cell monolayers could be detected in cell studies.
Dosage Forms (Delivery Systems)
The primary objective of oral delivery systems for peptides is to protect the protein and peptide drugs from acid and
enzyme degradation in the GI tract.
Different types of formulation approaches have been used for the oral peptide delivery – including emulsion,
microspheres, liposomes, and nanoparticles.
Emulsion protects drug from degradation in the GI tract but also it helps the peptide absorption. But, the type of
surfactant, particle size of the dispersed phase, pH, solubility of drug, type of lipid phase used are critical for the
success. Usually, medium chain fatty acids triglycerides help increase the bioavailability of muramyl dipeptides analog.
One example is Torisaka’s emulsion delivery system. They first formed a (lipophilic) surfactant –insulin complex and
then dispersed it into an oil phase. And, then disperse it into an aqueous phase. The emulsion showed hypoglycemic
activity over a few hours in diabetic rats. However, this preparation is not stable during long-term storage. Then, dry
o/w emulsion is developed to solve the issue. (They spray-dry an O/W emulsion, then, put the dry emulsion into a
capsule or tablet. They may further coat the dry emulsion with an enteric polymer. Anyway, the release becomes pH
dependent and also affected by lipase.
Some people use pH-sensitive microsphere to protect the peptide and protein drugs from degradation in the stomach
and the upper GI tract. One example of the polymers commonly used is poly (methacrylic-g-ethylene glycol). In the
basic and neutral environments of the intestine, the peptide-polymer complexes dissociated which resulted in rapid
microspheres swelling and insulin release. And, hypoglycemic effect was noticed.
Nanoparticles have also been used to carry peptides through peyer’s patches to the liver, the spleen and other tissues.
Peyer’s patches are aggregations of lymphoid tissue that are usually found in the lowest portion of the small intestine.
Nanoparticles protect the peptides with polymer – peptide association. The particle size, surface charge, surface
ligands and the particle-gut interaction of the nanoparticles are important for the absorption.
Nanoparticles made of chitosans were found in both epithelial cells and peyer’s patches. And further, insulin
encapsulated in nanoparticle was found to have about 11% efficacy of the intraperitoneally delivered insulin. However,
the absorption of intact particles is generally below 5%.
Liposome? it faces acid and lipase degradation and bile salts alteration.
Mucoadhesive polymeric systems:
Theoretically, mucoadhesive polymeric system a promising approach among several approaches, because it can
provide an intimate contact with the mucosa at the site of drug uptake preventing a presystemic metabolism of peptides
on the way to the absorption membrane in the gastrointestinal tract. Additionally, the residence time of the delivery
system at the site of drug absorption is increased. Thus, this system can increase the peptide absorption. However, my
question is “how do we attach the system to a specific site in the small intestine?
_____________________________________________________________________________________
NOTE The above article is for reference use only, it is not a scientific publication. Though I put my best effort in the
preparation, this article may contain mistakes or out-of-date information. One should review recent publications from
scientific journals for details. All rights reserved. Thanks.
Reference Jessy Shaji* and V. Patole, Protein and Peptide Drug Delivery: Oral Approaches, Indian J Pharm Sci. 2008
May-Jun; 70(3): 269–277.
Keywords: peyer's patches, presystemic metabolism, chitosan, Emulsion, Sodium cholate, acyl carnitines, alkanoyl
cholines, hyexyl-insulin monoconjugate, Luteinizing-hormone-releasing hormone, guar gum