Peroral Delivery Of Peptide Through Superporous Hydrogel : A Review

Peptide and protein drugs have found an important position in therapeutics.

Many protein- and DNA-based drugs exhibit high sensitivity to the surrounding physiological conditions as a result of their delicate physicochemical characteristics and the susceptibility to degradation by proteolytic enzymes in biological fluids. So, they need to be properly protected during administration and their release needs to be precisely targeted and controlled.

The dried hydrogels (also called xerogels) are used nowadays for effective delivery of this drug by over coming various barrier. They are clear, and swelling in water takes a long time. The slow swelling process is due to slow diffusion of water through the compact polymer chains. So they mainly used for controlled drug delivery. Many applications required fast swelling of dried hydrogels. Superporous hydrogels swell in the order of a minute regardless of their size. They can be made to possess high mechanical strength even after swelling by adding composite materials, e.g., Ac-Di-Sol.

Peptide drugs have been administered mostly by the parenteral route, and no peroral formulation has been developed to date. Super porous hydrogels and their composites that increase their volume by about 200-fold deliver the incorporated peptide drug directly to the gut wall.

Introduction:

Peptide and proteins play a key role in physiological activity and also have been used for treatment of various pathological condition such as diabetes etc. proteins delivery through the gastrointestinal (GI) tract remains a highly challenging task. Generally, the peptides and proteins are given through intramuscular or intravenous injection. However, due to the undesirable nature of this method, such as pain, inconvenience and inconsistent pharmacokinetics, other routes have been considered. They include pulmonary, oral, nasal, buccal, rectal, ocular, vaginal, and transdermal delivery ¹⁷,

Among which oral administration is the most convenient and ideal route. General difficulties associated with developing effective oral formulation of peptide drug are following:

1. Poor intrinsic permeability across biomembrane due to hydrophobic nature and large macromolecule
2. Susceptibility to enzymatic attack
3. Rapid post absorptive clearance
4. Chemical instability like oxidation, hydrolysis, disulfide exchange etc.
5. Physical instability like denaturation, aggregation, precipitation etc.

Hydrogel mainly deliver the drug to gut wall and overcome the deleterious effect of gut enzyme that means targeted delivery approach. A hydrogel is a three-dimensional network of hydrophilic polymer chains that are crosslinked through either chemical or physical bonding. Because of the hydrophilic nature of polymer chains, hydrogels absorb water to swell in the presence of abundant water. The swelling process is the same as the dissolution of non-crosslinked hydrophilic polymers. In a chemical hydrogel, all polymer chains are crosslinked to each other by covalent bonds, and thus, the hydrogel is one molecule regardless of its size. For this reason, there is no concept of molecular weight of hydrogels, and hydrogels are sometimes called infinitely large molecules or supermacromolecules. One of the unique properties of hydrogels is their ability to maintain original shape during and after swelling due to isotropic swelling.

Several important properties of SPH :

Fast swelling,
Large swelling ratio,
Surface slipperiness
These properties make them an excellent candidate material to develop gastric retention devices.

Superporous hydrogels can be synthesized in any moulds, and thus, three-dimensional structure of any shape can be easily made. Figure 1 shows a scanning electron microscopic picture of a porous hydrogel showing interconnected pores. The size of pores produced by the gas blowing (or foaming) method is in the order of 100 mm and larger. Because macroporous hydrogels are known to possess pores in the 100-nm to 10-mm range, the new porous hydrogels were named superporous hydrogels. If any portion of a superporous hydrogel is in contact with water, water is absorbed right away through the open channels to fill the whole space. This process makes the dried superporous hydrogels swell very quickly to very large sizes.¹³

Figure 1 (adopted from Drug Delivery Technology - Article Index.htm)

Recently, superporous hydrogels with an elastic property were prepared. The elastic property is useful in making mechanically strong superporous hydrogels more resilient to compression and elongation. The swollen hydrogel can be stretched to almost twice the original length without breaking. No previous hydrogels have shown such an elastic property. One way of making elastic superporous hydrogels is to form interpenetrating networks.¹³

Oral peptide delivery systems through Superporous hydrogels:

Superporous hydrogels are also used in the development of peptide delivery systems via oral administration^6-8. Self-folding miniature hydrogel device has been developed to provide enhanced mucoadhesion, drug protection, and targeted unidirectional delivery of peptides.¹⁵ Superporous hydrogels and their composites can increase their volume by about 200-fold. Such volume increase allowed the gels to mechanically stick to the intestinal gut wall and deliver the incorporated drug directly to the gut wall.¹³ The proper selection of functional groups of the superporous hydrogels, e.g., carboxyl groups, induced the extraction of calcium ions to induce opening of the tight junctions of the gut wall and deactivate the deleterious gut enzymes. After the peptide drugs have been delivered and absorbed across the gut wall, the superporous hydrogels become overhydrated, their structure is broken down by the peristaltic forces of the gut, and the remnants of the delivery systems are easily excreted together with the feces as miniparticulate systems. Superporous hydrogel (SPH) and SPH composite (SPHC)-based drug delivery systems were also developed for the targeted delivery of peptide drugs into the intestinal tract.¹⁴ Human scintigraphic studies also showed the mechanical fixation of the SPHC-based delivery system in the human duodenum and its subsequent breakdown.¹⁴

Figure 2 shows prototype delivery systems. Cores can be either inside or outside of the delivery system (or shuttle), and the additional penetration enhancer, such as trimethylchitosan, can be used. Recently in vivo pig experiments showed that the absolute bioavailability of octreotide was between 8% and 16%.⁹.Intestinal absorption of human insulin in pigs using superporous hydrogel polymers also shows relative bioavalibility values of 1.3+/-0.4 and 1.9+/-0.7% for c.o. and c.i. Administrations.¹⁶

Dorkoosh et al. in 2002 reported Release studies from SPH and SPHC polymers revealed that buserelin, octreotide and insulin were released almost completely from the polymers. Peptide release rates from SPH were faster than from SPHC, due to the more porous structure of SPH polymer.⁸

Figure 2 (adopted from Drug Delivery Technology - Article Index.htm)

Conclusion :

Superporous hydrogels are more efficient than conventional hydrogels. Because of the porous structure, SPHs also possess hundreds of times more surface area and shorter diffusion distance than conventional hydrogels do. These features allow dried SPHs to swell very fast to a very large size on contact with water. It can exert significant expansion force during swelling, despite the fact that the solid content is only a percentage of the total weight. Superporous hydrogels can also be made elastic, and this property can minimize their rupture. The unique properties of superporous hydrogels can also be used for oral delivery of peptide drug, which is still challenge, by other system.

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About Author:

Swarnali Das
S.L.T Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur, C.G.