BioTherapi: Bioinformatics for Therapeutic Peptides and Proteins

The main obstacles to delivery of peptides are related to their chemical and physical properties. for example, transdermal delivery of peptides is not feasible due to their relatively large molecular size. The oral route has not been suitable because of their susceptibility to hydrolysis and proteolytic breakdown. The peptide formulation is depend on the route of adminstration and divide according to this.

1. Parenteral delivery system

a) Solution Formulation: Dosage strength/potency, integrity, and stability of peptide drugs are of the utmost concern in the design of parenteral formulations. The most common sources that cause changes in peptide dosage and integrity are adsorption, sterilization, and chemical proper- ties of the peptide. For peptides in solution, it is known that many peptides are absorbed or attached to manufac- turing equipment or delivery devices. The absorption losses are most significant when the peptide concentration is relatively low. The result of loss due to absorption is a reduction in the dose to the patient if the loss is not corrected by some manner such as overage and/or over- fill. A second common source of peptide loss can occur during sterilization.Many peptides cannot undergo ter- minal sterilization because of problems of degradation. To overcome this problem, sterile filtration and aspectic filling must be used to sterilize peptide drugs.In this case, it is possible that the peptide may be retained by membrane filters. Thus, the effect of membrane filtration on retention of peptide needs to be validated by modern analytical methods.Finally, factors that affect the dosage strength of a peptide drug include the physical properties of the peptide itself. For example, when a peptide (e.g., LHRH antagonists) contains a large number of hydrophobic amino acid residues, there is an intrinsic propensity of the peptide to form aggregates,resulting in a lower effective concentration and, therefore, serious safety concerns. Several factors of the peptide in solution that one must consider and often affect adsorption loss and/or gel forma- tion are ionic strength, excipients, pH, temperature, and osmotic pressure.To ensure that any accidentally introduced microorgan- ism cannot grow in the multiple-dose injectable solution,a preservative is added to the formulation. The most commonly acceptable preservatives includes phenolic com- pounds (phenol, m-cresol, and benzyl alcohol). Since these preservatives are susceptible to oxidation and light, care- fully monitoring the phenolic compound in the drug product is highly recommended during storage.

b) Lyophilized Powder Formulation: The stability problem of many peptides in solution is serious enough that peptides are commonly formulated as a solid by lyophilization and reconstituted with a sterile diluent prior to administration. Due to its high potency, often a small amount of peptide provides a sufficient therapeutic dose. Therefore, in this formulation, a bulking agent as a carrier is usually required. For example, lactose and mannitol are added during the formulation of Acthrel and Geref, respectively. The same precautions as described in the liquid formulation should be taken during the manufacture of the lyophilized powder because the manufacturing processes are generally identical between liquid formulation and lyophilized powder formulation, except the final process of lyophilization. After lyophilization, the peptide must also be analyzed for dosage strength as well as physicochemical and biological integrity.

c) Depot Formulation: To alleviate the pain caused by daily injections and to improve patient compliance, there has been interest in the use of biodegradable polymers for controlled release of peptides to be administrated via a parenteral route. In this delivery system, peptide drugs are embedded in polymer matrixes (microspheres) that undergo hydrolysis or enzymatic digestion, resulting in controlled release of the peptide into the human body. Commonly used in this delivery system is poly(lactic-co- glycolic) (PLGA) copolymer. On exposure to water, the copolymer undergoes random chain scission by simple hydrolysis of the ester bond linkage and the drug is released.To date, a number of peptide drug products formulated for depot delivery, including Lupron Depot and Zoladex, have been approved by the FDA for marketing. These depot formulations are designed for steady release of the peptide over a period of 1 to 3 months after administration.

2. Oral delivery system

a) Tablets: The most con- venient route for the systemic delivery of pharmaceuticals is oral; however, attempts to deliver peptides orally have not been widely successful. Bioavailability via this route is poor because peptides are susceptible to hydrolysis and modification at gastric pH levels, and they can be degraded by proteolytic enzymes in the gastrointestinal (GI) tract. One way to overcome the enzymatic barriers is to modify the peptide structure in a way to increase its resistance to enzymatic degradation but not to reduce its biological potency. So far, there have been a few examples of modified peptide drugs with improved oral activity. One example is DDAVP (desmopression) tablets approved in 1995 for the treatment of patients with cranial diabetes insipidus (CDI). DDAVP differs structurally from the naturally occurring peptide, vasopressin, in two positions. DDAVP has â-mercaptopropoinic acid instead of hemicys- tine in position 1 and D-arginine in place of L-arginine in position 8. These modifications lead to enhanced stability against proteolytic degradation and increased membrane penetration.17 However, the peptide dose required for the tablet still is much higher than those needed by parenteral and nasal routes.

3. Nasal delivery system: A promising alternative for delivering peptide drugs is the nasal route. The advantages of intranasal delivery are (1) the large surface area of the nasal mucosa for absorption and (2) the rapid onset of action.The FDA has approved a number of peptide drugs formulated in intranasal dosage form, such as Diapid (lypressin), DDAVP (desmopressin), and nafarelin (Synarel). During formulation of the intranasal dosage for these peptide drugs, a number of important issues need to be considered. (1) Particle Size
(2) Preservatives
(3) Adsorption