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Differences Between Biologics and Small Molecule Drugs

Let’s first look at the differences between biologics and small molecule drugs. Pharmacologically. Biologics have higher target specificity. And because of the specificity, they have greater therapeutic potency. And usually, they have fewer side-effects. And unfortunately, also short duration of action if without a molecular modification.
Biochemically. Biologics have large molecular weight and because of that, they have low membrane permeability. And also low renal filtration. They are subject to non-specific metabolism. They’re also subject to biofeedback particularly if they are endogenous proteins.
In terms of formulation, what’s the difference between biologics and drugs? pH, buffer capacity, osmoticity, molecular aggregation, concentration dependent precipitation, interfacial adsorption, and short shelf-life. All these, pH, buffer, osmoticity, aggregation, precipitation, adsorption, all of these affect the formulation, the quality of the formulation.
Let’s look at absorption of biologics. Generally speaking, they have poor absorption, again because of the large molecular size. Low permeability, for example to the GI membrane.
There’re high enzymatic activities in the GI tract because of the digestive enzymes, such as protease and peptidase. There’re also possible intramuscular or subcutaneous site metabolism. Therefore the bioavailability is generally low.
Parenteral administration doesn’t fair that much better either plus that the effects vary with the route of administration. IV or intravenous injection is the least effective. IM is subject to possible site metabolism. And subcutaneous usually becomes the route of choice.
In addition, the effect of parenteral administration vary with the rate of drug input, for example, Leuprorelin, is an LH-RH agonist. When given intravenously as a bolus, it actually stimulates FSH and LH production. When given as an intravenous infusion, it suppresses hormone production. And the IM injection or depot injection is actually used for prostate cancer, endometriosis, and also had been used for chemical castration, taking advantage of its suppression of hormone secretion or production.
Another example, Epoetin-alpha, when it’s given subcutaneously, it maintains better hematocrit than when it’s given intravenously.
Absorption enhancement. And we look at this before so I would not repeat the whole thing again. But we can use surfactant, liposome, iontophoresis, nanotechnology, that is to make the nanoparticles out of the biological product, structure modification. All those approaches we can use to improve the absorption of biologics. Here is one example, the surfactant effect on nasal bioavailability. And if you remember, we went over this before. Surfactant, in this case, a glycocholate can improve the nasal bioavailability of five or four biological molecules. And this is another example that we look at before and this is the iontophoretic transdermal absorption.
And the principle that we use is that proteins or peptides are charged molecules that migrate under the influence of electric field and therefore you can if we can establish an electric field between the positive electrode and the negative electrode, and will be able to deliver the biologics through the skin.

Biologics and small molecule drugs differ biochemically and pharmacologically, therefore, formulation requirements are inherently different. Poor permeability and nonspecific enzyme degradation rule out oral administration for biologics. Commonly accepted routes of biologic administration are IV and subcutaneous. Potential alternative routes include nasal, buccal and transdermal. Several absorption-enhancing approaches have been attempted and will be discussed.

Biologics and small molecule drugs differ significantly in biochemistry, pharmacology and formulation. Pharmacological attributes include target specificity, therapeutic potency, biochemical attributes include membrane permeability and non-specific metabolism, and formulation attributes include pH, buffer, osmoticity, polymerization and interfacial adsorption. Each and every variable will be examined.

Poor oral absorption leaves IV and SC as the choice of administration. Several absorption- enhancing approaches including surfactant, nanoparticles, iontophoresis for transdermal delivery, and liposome for targeted delivery will be reviewed.

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Pharmacotherapy: Understanding Biotechnology Products

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