Application Of Enzyme Inhibitors In Oral Preparation Of Protein And Peptide Drugs

With the rapid development of genetic engineering technology, protein and peptide drugs produced by biotechnology are emerging. However, the oral bioavailability of such drugs is very low and the half-life is generally short, so the treatment of chronic diseases must be injected frequently for a long time, which brings inconvenience to patients. Recent studies have shown that, after appropriate modification, insulin and other biological macromolecules can also be absorbed orally to play biological functions, thus stimulating the research interest in non-injectable delivery of protein and peptide drugs, among which oral delivery is favored by convenient and physiological absorption mode.

Conventional types of enzyme inhibitors

1. Non-amino acids

Although the effects of these inhibitors are very strong, they are more theoretical as human oral protein and peptide drugs, because most of these inhibitors are highly toxic. However, if it can be chemically fixed in a non-absorbable matrix, or its structure can be chemically modified to develop congeners, the toxicity can be reduced or even eliminated, and it is still possible to apply it in protein and peptide drugs.

2. Amino acids and their derivatives

Amino acids are a class of low-toxic or non-toxic compounds with small molecular weights, which are highly soluble in the intestinal tract and are over-diluted and quickly absorbed after entering the intestinal tract. To achieve inhibition of intestinal enzymes, the dose must be very high, which is unrealistic. In addition, its inhibitory activity against exopeptidase such as aminopeptidase is not high, and this kind of inhibitor is more suitable for application in transmucosal route such as nasal cavity. The modified amino acid derivatives have stronger inhibitory effect. There is a modified amino acid inhibitor called "transition state". The transition state configuration is similar to the substrate structure, but has a stronger affinity with the enzyme binding site, and is a strong reversible inhibitor of aminopeptidase.

3. Peptides and modified peptides

Bacitracin is a typical peptidase inhibitor obtained from Bacillus licheniformis and can strongly resist the hydrolysis of pepsin and trypsin. It has been reported that bacitracin can inhibit the degradation of peptide drugs such as insulin in the intestinal tract. However, due to its nephrotoxicity, it has been used as a veterinary drug or as an antibiotic for the treatment of human infectious diseases. Pepstatin is a modified decapeptide that has a strong inhibitory effect on pepsin. Although anti-gastric capsules have been developed to prevent protein and peptide drugs from being degraded by pepsin, some protein and peptide drugs, such as epithelial cell growth factor, for the treatment of gastric ulcers must be released in the lesions in the stomach, so use pepsin inhibition Drugs such as gasstatin are the only option, but they can cause some side effects when taken orally. In addition, there are modified peptides with an aldehyde group at the end of the structure, which are reversible inhibitors of chymotrypsin.

4. Polypeptides

Aprotinin is one of the most basic and earliest peptide tryptase inhibitors. Aprotinin can improve the oral bioavailability of protein and peptide drugs by inhibiting trypsin and chymotrypsin. The results of in vivo experiments show that the drug delivery system containing polypeptide enzyme inhibitors can improve the bioavailability of drugs. Due to their low toxicity and high inhibitory activity, these inhibitors have been widely studied as adjuvants for protein and peptide oral drugs.

Novel enzyme inhibitors

Current studies have shown that the mucoadhesive polymer-inhibitor conjugate is a promising compound enzyme inhibitor, which has been paid more and more attention in the drug delivery system of protein and peptide drugs, and the conjugate can be used as a drug carrier , has several advantages:①Due to the mucoadhesion of the carrier, the distance between the drug release system and the absorption mucosa is reduced, which reduces the degradation of protein and peptide drugs there;②The enzyme inhibitor is combined with the matrix;③Reduce the impact on the digestion of intestinal protein nutrients and reduce systemic side effects;④Avoid intestinal dilution and reduce the dosage of enzyme inhibitors;⑤Adhesive polymers can inhibit both protein secretases and brush border membrane-associated enzymes in the gut.

Although such conjugates are still in the stage of in vitro research, it is foreseeable that through the development of new dosage forms, the application of enzyme inhibitors in the oral drug delivery system of protein and peptide drugs has great prospects for development.