The biological active macromolecular substances in drugs, which are mainly composed of polypeptide, protein, nucleic acid, carbohydrate and lipid. Among them, polysaccharide, protein and nucleic acid molecule is composed of many small molecular weight is very high, known as molecular macromolecular compounds; lipid directly composed of many atoms, called atom type compounds. In this chapter, we describe the typical dosage forms (dosage form design) of representative peptides and protein drugs in the treatment and prevention of diseases. The problem for both the preparation and the pharmaceutical industry is how to design a drug delivery system that is safe, stable and effective in the delivery of peptides and protein drugs. Therefore, the research on the preparation technology of peptide and protein drugs is becoming more and more urgent and important.

First, the pre Prescription Research

The design of the drug delivery system for peptides and proteins depends on the physical and chemical properties and biological properties of the drug. Including the molecular size, biological half-life, immunogenicity, conformational stability, dose requirements, delivery location and rate as well as the pharmacokinetic and pharmacodynamic properties, physiological, pharmacological and toxicological research is also very important, must also consider any impurities or drugs potentially immunogenicity. Because these drugs are very potent, the rate of delivery must be very precise. The effect of drug delivery methods on the drug was also great. For some biological drugs regularly adjusting human body functions, such as leaf pressure cable, calcitonin and luteinizing hormone releasing hormone (LHRH), must be designed to pulse dosage forms instead of the ordinary stable sustained release drug formulations.

Several key contents of preformulation study are: drug stability and solubility in common solvents, light, heat, temperature, pH value and other factors on the possible sensitivity of drug degradation, excipients (such as preservative, antioxidant, stabilizer and dispersant) of protein and polypeptide drugs stability and compatibility. The crystallization trend many peptide drugs have a strong, often exist in amorphous powder form, so the differential thermal analysis may not provide a lot of information, and the amorphous powder can absorb a large amount of water, resulting in between batches of different moisture content. Polypeptide and protein drugs have the characteristics of both the ionization and isoelectric point, and the lowest solubility of the drug at the isoelectric point.

Two, drug self aggregation and its adsorption properties on the surface of the container

Protein molecules, such as insulin themselves, can form a two - dimer, a dimer, or even a poly (). The aggregation of insulin molecules is a major obstacle to the long-term use of the infusion pump system. Many researchers have found. Suitable additives can reduce the aggregation of insulin, these substances include urea, acidic amino acids (such as aspartic acid and glutamic acid), glycerol, EDTA, lysine, Tris buffer and carbonate buffer etc.. In addition, 60 kinds of additives and

Further studies of the 1125 prescriptions showed that nonionic surfactant Pluoronic F68 can effectively prevent the aggregation of insulin. Other studies have suggested that human insulin is easier to accumulate than pig or bovine insulin, and that phenolic preservatives accelerate the accumulation of insulin, which is more stable than zinc free insulin.

Peptides and proteins have a tendency to adsorb on glass or plastic containers. Low concentration of drug activity is particularly serious. If the adsorption is due to the ionic interaction between the peptide molecules and the silanol groups on the glass surface, the glass can be synthesized by a silane. Other measures include adding carrier protein such as gelatin, surfactants such as cinnamyl alcohol and sodium sulfate, sodium chloride, amino acids, but the quantity of electrolyte, and make it possible for protein precipitation and inactivation.

Three, stability

The stability problem is more prominent than that of chemical drugs in biological medicine preparation. Taking insulin as an example, the one or two and the three or four structures of proteins can change the biological function of proteins. Figure 6-1 is the primary structure of insulin.

Trypsin Hydrolysis of insulin, can remove the B C terminal 8 peptide chain, 43 peptide remaining only the original insulin activity 1%, if the two disulfide bond reduction, insulin A, B two chain separately, the complete loss of biological activity. It can be seen that some amino acid residues and two disulfide bonds in the C terminal of the B chain are necessary for the performance of insulin ().

The relationship between functional groups and show that the activity of the insulin molecule, B22 arginine guanidino was combined, leaving only about 1% of energy. Arginine is replaced by other alkaline amino acids, there is still a certain vitality. Therefore, it is very important for the biological function of insulin to B22 basic side chain.