Sustained-release products, oral

Transition to oral analgesics as the patient improves choose an oral agent based on previous history, anticipated duration, and ability to swallow tablets if sustained-release products are used, a fast-release product is also needed for breakthrough pain... 

The usual goal of an oral sustained-release product is to maintain therapeutic blood levels over an extended period. To achieve this, drug must enter the circulation at approximately the same rate at which it is eliminated. The elimination rate is quantitatively described by the half-life (t /2). Each drug has its own characteristic elimination rate, which is the sum of all elimination processes, including metabolism, urinary excretion, and all other processes that permanently remove drug from the bloodstream. 

Most published examples of IVIVC concern oral administration and sustained release products. ° The following examples demonstrate the application to non-classical formulation and the use of a new in vitro approach for Level A, as well as a classical formulation for Levels B and C. 

A medication available only as a solid dosage form, may be prepared as an extemporaneous liquid (e.g., suspension) or it may be modified for oral use, for example, by crushing. As mentioned previously, a sustained-release product should not be crushed or chewed. For a solid, non-sustained-release medication, the product can be crushed and mixed with a small amount of food just prior to administration. Examples of foods that may be used for mixing include applesauce, yogurt, or instant pudding, but the medication should not be added to an entire dish of food or to infant formula, because the infant or child may not eat/drink the entire portion and thus not receive the total amount of medication. 

Ingestion of sustained-release products is the most common route of both accidental and intentional exposure to theophylline. Theophylline is available in oral and intravenous dosage forms. Aminophylline is available in oral, rectal, and intravenous dosage forms. 

Most of the oral sustained-release products are diffusional layer tablets coated with an insoluble polymer, such as a tablet with a biodegradable matrix or an osmotic controlled tablet. The mechanism involves the drug dissolved within the semipermeable polymeric coating. After water absorption, the tablet matrix generates an osmotic pressure, which drives the drug solution out through a tiny hole in the coated tablet. 

Drug delivery systems of once-daily products (Concerta, Metadate CD, Ritalin LA, Adderall XR) provide 8 to 12 hours of symptom control. Concerta uses an oral osmotic (OROS) controlled-release delivery system, while other preparations use combinations of immediate-release or extended-release beads containing drug. Concerta is a nondeformable tablet and it should not be given to children with gastrointestinal narrowing due to the risk of obstruction. Older wax-matrix sustained-release products (e.g., Ritalin SR)... 

Chow, A.T. Meek, P.D. Jusko, W.J. High-pressure liquid chromatographic assay of theophylline in dog feces fohowing oral administration of sustained-release products. J.Pharm.Sei., 1993, 82, 956-958 Abdel-Hay, M.H. el-Din, M.S. Abuiijeie, M.A. Simultaneous determination of theophylline and guai-phenesin by third-derivative ultraviolet spectrophotometry and high-performance liquid chromatography. Analyst, 1992, 117, 157-160... 

Often it is unnecessary to calculate an exact value for an absorption rate constant. For example, when several oral tablets containing the same drug substance are all found to be completely absorbed, it may be sufficient to merely determine if the absorption rates are similar to conclude that the products would be therapeutically equivalent. In another instance, it would be possible to choose between an elixir and a sustained-release tablet for a specific therapeutic need without assigning accurate numbers to the absorption rate constant for the two dosage forms. 

Methylxanthines are ineffective by aerosol and must be taken systemically (orally or IV). Sustained-release theophylline is the preferred oral preparation, whereas its complex with ethylenediamine (ammophylline) is the preferred parenteral product due to increased solubility. IV theophylline is also available. 

Sustained-release oral preparations are favored for outpatient therapy, but each product has different release characteristics and some products are susceptible to altered absorption from food or gastric pH changes. Preparations unaffected by food that can be administered a minimum of every 12 hours in most patients are preferable. 

There are diverse formulations and delivery systems for macrocylic lactones in ruminants, including injectable, oral, sustained-release bolus and transdermal ("pour on") products. In Europe, it is popular clinical practice to administer injectable solutions of ivermectin intravenously (i.v.) to horses. This constitutes extra-label (unlicensed) use and there are no objective data to support the perceived improved efficacy following administration by this route. Specifically, in relation to hypobiotic cyathostome larvae, Klei et al (1993) reported no increase in efficacy when horses were administered 10 pg/kg, which is five times the recommended dose rate. 

---