The field of biopharmaceutics involves factors that influence the (1) protection of the activity of a drug within a drug delivery system, (2) the release of drug from a drug delivery system, and (3) the systemic absorption of the drug after it is released. Both in vitro and in vivo methods are used to look at these factors (Shargel and Yu, 1999). Protecting the Activity of a Drug Within a Drug Delivery System. Major stability, release, and manufacturing challenges in developing drug delivery systems have been noted. There are many ways in which a protein can be degraded thus leading to its instability and inactivation.
The degradation mechanisms can be either physical or chemical. Degradation may be facilitated by environmental conditions such as pH, concentration, and temperature. Stability issues need to be taken into account while controlled-release protein formulations are being formulated (Shao and Bailey, 2000) Denaturation, aggregation, chemical degradation, and adsorption onto the polymer surface may result from the creation of an acidic environment within the microspheres during polymer degradation (Shao and Bailey, 2000). Chemical degradation processes are usually preceded by a physical process such as unfolding, which denatures the protein 1.2 describe the key functions of the brain that are affected by dementia.
(Bowen, 1999) During microsphere formulation, the encapsulated protein is often exposed to numerous unfavorable conditions such as organic solvents and high-speed vortexing to emulsify the internal aqueous phase (Shao and Bailey, 2000). High performance liquid chromatography, HPLC, can be used to determine the chemical integrity of insulin after the fabrication process. Determining the Release of Drug From Drug Delivery Systems. In many release studies using microspheres, protein release kinetics are often unpredictable and uncontrollable.
The microspheres commonly exhibit an initial burst release followed by a very slow release over an extended period, and demonstrate incomplete release profiles at the end (Shao and Bailey, 2000). The initial release phase of a polymeric drug delivery system is affected by factors such as drug loading, drug particle size, drug solubility, microsphere diameter, and porosity. The sustained-release phase is controlled by polymer erosion, and this phase is therefore controlled by the factors that affect polymer degradation. The Systemic Absorption Of Drug After Release From the Delivery System.
After release, the systemic absorption of drug is dependent upon (1) the physicochemical properties of the drug, (2) the nature of the drug product, and (3) the anatomy and physiological functions at the site of drug absorption (Shargel and Yu, 1999). Insulin molecules have a tendency to form dimers in solution due to hydrogen bonding between the C-termini of B chains. Additionally, in the presence of zinc ions, insulin dimers associate into hexamers. These interactions have important clinical ramifications. Monomers and dimers readily diffuse into blood, whereas hexamers diffuse very poorly.
Hence, absorption of insulin preparations containing a high proportion of hexamers is delayed and slow (Bowen, 1999). Insulin is a large hydrophilic protein that has poor absorption across the cell membrane. Systemic drug availability may also differ according to the route of administration. In addition, the bioavailability (an in vivo measure of systemic availability of a drug) may differ according to the route of administration, and from one drug product to another, even if they contain the same drug (Shargel and Yu, 1999).
Pharmacokinetics and Pharmacodynamics Pharmacokinetics involves the kinetics of drug absorption, distribution, and elimination (excretion and metabolism) (Shargel and Yu, 1999), see Figure 1. Pharmacodynamics refers to the relationship between the drug concentration at the cell receptor and pharmacologic response, including biochemical and physiologic effects that influence the interaction of drug with the receptor (Shargel and Yu, 1999). Figure 1. PHARMACOKINETICS: Involves the kinetics of drug absorption, distribution, metabolism, and elimination. Taken from Dr. David Bourne's website located at www. boomer. org/c/pl.
Plasma perfuses all the tissues of the body including the cellular elements in the blood. Assuming that a drug in the plasma is in dynamic equilibrium with the tissues, then changes in the drug concentration in plasma will reflect changes in tissue drug concentrations. There are several methods for assessing bioavailability. The most reliable method of determining bioavailability requires analysis of plasma concentrations of the drug at various times after administration. A good analytical procedure that accurately detects very small quantities of drug in plasma is essential to this type of testing.
HPLC and radioimmunoassay (RIA) have been developed to detect drug and drug metabolite concentrations in micro, nano, and even pico quantities. (Shargel and Yu, 1999) By carefully choosing the route of drug administration and properly designing the drug product, the bioavailability of the active drug can be varied from rapid and complete absorption to a slow, sustained rate of absorption, or, even, virtually no absorption, depending on the therapeutic objective. The rate of drug release from the product and the rate of drug absorption are important in determining the distribution, onset, intensity, and duration of the drug action.
The plasma level vs. time curve is generated by measuring the drug concentration in plasma samples taken at various time intervals after a drug product is administered. The plasma level vs. time curve can give us useful information on bioavailability, including, peak-plasma level, time for peak plasma level, and area under the curve (AUC). The time of peak plasma level is the time of maximum drug concentration in the plasma and is a rough marker of average rate of drug absorption. The peak plasma level or maximum drug concentration is related to the dose, the rate constant for absorption, and elimination constant of the drug.
The AUC is related to the total amount of drug absorbed systemically. (Shargel and Yu, 1999) Alternative Insulin Delivery Systems Insulin remains the mainstay of treatment for Diabetes Mellitus. However, the convectional injectable insulin preparations suffer from problems such as poor patient compliance, sub-optimal glycemic control, etc. Tremendous efforts have been invested in developing new approaches for insulin therapy, which could mainly be categorized into three types: invasive, non-invasive delivery and controlled release delivery systems. (Beals and Kovach, 1997).
Dermal delivery - invasive Pen injectors and jet injectors don't use hypodermic needles. However, they are still invasive administration methods. There are various insulin pen injectors on the market. Most pen injectors are small disposable devices using small gauge needle. The injectors could be pre-loaded with insulin or use insulin cartridges. Injection by pen injectors is less painful than by the conventional needles and the dose can be precisely selected with a dial (Beals and Kovach, 1997).
Jet injectors are needle-less devices that administer insulin by forcing insulin through the skin with high pressure. However, the discomfort associated with jet injectors is not less than that with needles. Jet injectors have received limited acceptance for insulin delivery since they were first proposed 40 years ago. (Beals and Kovach, 1997) Non-invasive insulin delivery Despite the conclusively demonstrated clinical benefit from intensive insulin therapy, along with the variety of insulin preparations available that allow clinician and patients to choose different regimen, insulin therapy often receives poor patient compliance.
Since the only viable administration route of insulin is injection, the patients have concerns about fear, inconvenience, pain and anxiety of insulin injections (Saudek, 1997). Insulin delivery without injections could eliminate the problems associated with injection, thus improve patient compliance. Research has been conducted on insulin delivery via dermal, nasal and oral routes. Iontophoresis Iontophoresis is an electronic transdermal approach for insulin delivery. It enhances transdermal delivery of insulin ions into the skin by low-level electrical current.
The concept of iontophoresis has found its clinical feasibility and there are products on the market, such as IontoPatch (dexamethasone) by Lead-Lok, Inc. (Sandpoint, Idaho). It was (Saudek, 1997) demonstrated that bovine insulin could be effectively delivered by iontophoresis into streptozotocin-induced diabetic rats only if the rat skin was pretreated by depilatory cream, while monomeric human insulin formulation could be delivered without such pretreatment. This proof-of-concept study suggested the possibility of iontophoretic delivery of insulin.
Nevertheless, more research needs to be done before this approach becomes a clinical reality. Low frequency ultrasound Ultrasound (also referred to as sonophoresis or phonophoresis) (Smith et al. , 2003), especially low-frequency ultrasound was shown to increase the permeability of human skin to macromolecules by several orders of magnitude. Smith et al. (2003) studied the effect of 20 KHz ultrasound on the delivery of human insulin through the skin in normal Sprague-Dawley rats.
Exposure of skin to ultrasound operating at ISPTP = 100 mW/cm2 (spatial peak-temporal peak intensity) for 20 or 60 minutes facilitated the permeation of insulin, to a similar extent, resulting in significant blood glucose drop in the treated rats compared to the control groups. Low frequency ultrasound mediated transdermal insulin delivery remains to be a potential non-invasive approach, certainly with efficiency and safety issues to be resolved. Transfersomes ® Transfersomes®, similar to liposomes, have a lipid bilayer surrounding an aqueous core.
Transfersomes®, mostly vesicular, consist of natural, amphiphilic compounds suspended in water-based solution. They are different from liposome in that the bilayer contains component(s) that can soften the membrane and make it very flexible. As a result, the vesicles are extremely deformable and can pass through pores much smaller than the average vesicle size. Cevc et al. (1998) showed that insulin-loaded Transfersomes® achieved a bio-efficiency of at least 50% that of subcutaneously injected insulin, when applied to intact human skin.
We just sent you an email. Please click the link in the email to confirm your subscription!
OKSubscriptions powered by Strikingly