Sustained-release preparations

Because of its excellent solubility, povidone normally have no delaying effect on the dissolution of active substances. Though a substance embedded in povidone K 90 dissolves slightly more slowly than it would in povidone K 30, this minor difference cannot be described as a controlled-release effect. On the contrary, the dissolution rate is frequently higher than that of the pure drug (see Sections 2.4.3 and 2.4.5). However, in the case of papaverine tablets, a pH-independent sustained release was found [495]. 

A number of publications appeared since 1981, in which it was reported that povidone forms insoluble flocculates with polyacrylic acid and that these can be used to control release by enveloping crystals or tablet cores in the flocculate [407-410,520,583]. 

Povidone can also be used as a hydrophilic component or pore former in preparations that contain sustained-release auxiliaries like polyvinyl acetate, cellulose derivatives like HPMC [490, 509, 660], alginate [461], cetylacohol [600], polylactic acid [5o6],Gelucire [510],polyvinyl alcohol [522],ceresine wax [523], stearic acid [606] or methacrylate copolymers [491] to control or regulate the release of active substances, as binders and/or sometimes as plasticizers. They can also be extruded together with the active substance in melted stearyl alcohol and filled into hard gelatin capsules to achieve the same effect [471]. Ocular delivery systems are also described [598]. 

Spray-dried polyvinyl acetate/povidone mixture 8+2 

Recently a spray-dried mixture of 8 parts of polyvinyl acetate (PVAc) and 2 parts of povidone K 30 can be found in the market. It is recommended as matrix for sustained-release tablets obtained by direct compression. In this product povidone has two functions to get a free-flowing polyvinyl acetate powder and to form pores in the tablets. 

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Administering Oral Nitroglycerin. Nitroglycerin is also available as oral tablets tiiat are swallowed. The nurse gives tiiis form of nitroglycerin to die patient whose stomach is empty, unless the primary health care provider orders otherwise. If nausea occurs after administration, die nurse notifies die primary healdi care provider. Taking die tablet or capsule widi food may be ordered to relieve nausea The sustained released preparation may not be crushed or chewed. 

Because of die risk of tolerance to oral nitrates developing, die primary care provider may prescribe die short-acting preparations 2 to 3 times daily, witii die last dose no later than 7 pm and die sustained release preparations once daily or twice daily at 8 AM and 2 PM. 

Schweizer E, Patterson W, Rickels K, et al Double-blind, placebo-controlled study of a once-a-day, sustained-release preparation of alprazolam for the treatment of panic disorder. Am J Psychiatry 150 1210-1215, 1993 Seivewright N Benzodiazepine misuse by illicit drug misusers. Addiction 96 333—334, 2001... 

Chiang, C. N., Hollester, L. E., Kishimoto, A., and Barnett, G., Kinetics of a naltrexone sustained-release preparation,... 

SUSTAINED-RELEASE PREPARATIONS. Robert Willette. Ph.D., and Gene Barnett, Ph.D., eds. NCDAI out of stock... 

Potentially important laboratory abnormalities occurring with niacin therapy include elevated liver function tests, hyperuricemia, and hyperglycemia. Niacin-associated hepatitis is more common with sustained-release preparations, and their use should be restricted to patients intolerant of regular-release products. Niacin is contraindicated in patients with active liver disease, and it may exacerbate preexisting gout and diabetes. 

Controlled- and sustained-release preparations dosed every 12 hours are bioequivalent to immediate-release preparations dosed every 6 hours. These dosage forms, compared with immediate-release preparations, have lower peaks and higher troughs. 

Sustained-release theophylline preparations improve patient compliance and achieve more consistent serum concentrations than rapid-release theophylline and aminophylline preparations. Caution should be used in switching from one sustained-release preparation to another because there are considerable variations in sustained-release characteristics. 

Lithium salts, generally in the form of the carbonate or bicarbonate, are rapidly absorbed from the gastrointestinal tract and reach a peak plasma concentration after 2- hours. Extreme fluctuations in blood lithium levels, which are associated with side effects such as nausea, diarrhoea and abdominal cramp, are reduced by using sustained release preparations. Lithium is not protein bound and therefore is widely distributed throughout the body water, which accounts for the adverse effects it has on most organ systems should it reach toxic levels. To avoid toxicity, and ensure optimal... 

Indications for nifedipine include angina pectoris (p. 308) and, — when applied as a sustained release preparation,... 

Drug/Food interactions Theophylline elimination is increased (half-life shortened) by a low carbohydrate, high protein diet, and charcoal broiled beef (due to a high polycyclic carbon content). Conversely, elimination is decreased (prolonged half-life) by a high carbohydrate low protein diet. Food may alter the bioavailability and absorption pattern of certain sustained-release preparations. Some sustained-release preparations may be subject to rapid release of their contents when taken with food, resulting in toxicity. It appears that consistent administration in the fasting state allows predictability of effects. 

PROCHLORPERAZINE Do not crush or chew sustained release preparations. 

Brown, G.L., Ebert, M.H., Mikkelsen, E.I., and Hunt R.D. (1980) Behavior and motor acitivity response in hyperactive children and plasma amphetamine levels following a sustained release preparation. J Am Acad Child Adolesc Psychiatry 19 225—239. 

Bupropion is an aminoketone that exerts its therapeutic effect through the inhibition of norepinephrine and dopamine reuptake. Bupropion s receptor occupancy profile shows an absence of anticholinergic and antihista-minic effects (Cusack et ah, 1994). Bupropion is absorbed rapidly from the gastrointestinal tract, and peak blood levels are achieved within 2 hours for regular release and 3 hours for sustained-release preparations = 10 hours). Bupropion undergoes extensive first-pass metabolism in the liver, yielding three active metabolites hydrobupropion, threohydroxybu-propion, and erythrohydrobupropion. The half-lives of the active metabolites are approximately 20 + hours (Preskorn, 1993). 

Methylphenidate and D-amphetamine are both short-acting compounds, with an onset of action within 30 to 60 minutes and a peak clinical effect seen usually between 1 and 2 hours after administration, lasting 2 to 5 hours. Therefore, multiple daily administrations are required for a consistent daytime response. The amphetamine compound Adderall, the sustained-release preparations of methylphenidate and dextroamphetamine, and pemoline are all intermediate-acting compounds with an onset of action within 60 minutes and a peak clinical effect seen usually between 1 and 3 hours after administration and maintained for up to 8 hours (8 hours with metadate C.D. and Ritalin LA 12 hours with Concerta), allowing for a single dose for the entire school day. Adderall XR is a 12 hour preparation. 

Nausea and diarrhea are common early side effects. Gastrointestinal symptoms may improve with dose reduction or with ingestion of lithium at meals. Slow-release formulations are more often associated with nausea, whereas sustained-release preparations are more commonly associated with diarrhea. 

Yoshizawa, H., Koishi, M. (1990). The coating and the encapsulation of an interactive powder mixture and its application to sustained release preparations. J. Pharm. Pharmacol., 42(10), 673-678. 

The cost of generic substitutes is usually considerably less than that for the trade name psychotropic drugs, but issues of bioequivalence must also be considered (see the section The Four Primary Pharmacokinetic Phases in Chapter 3). Using the fewest tablets to achieve a targeted dose level is always less expensive. Unit dose systems, sustained release preparations, and concentrate forms all increase the cost ( 26). 

Lithium preparations include lithium carbonate, sustained-release preparations, and the liquid form, lithium citrate. The sustained-release preparations allow for a more gradual absorption of the drug, leading to blunted peak plasma levels. Because lithium has a slow onset of action, it can take weeks, and occasionally longer, to obtain an optimal clinical response. Thus, it is important to avoid a premature abandonment in those who are simply slower to respond. 

Lithium is an alkali metal in group lA and shares many properties with similar elements such as sodium and potassium. As a compound it is rapidly absorbed and reaches peak blood levels in approximately 1 to 3 hours (6 to 8 hours with sustained release preparations), with absorption being completed in approximately 8 hours. Unlike other psychotropics, it is not protein-bound and steady-state levels are usually achieved after 4 to 6 days on a fixed dose. Table 10-16 lists the pharmacokinetic properties of lithium, as well as those of the other two commonly used mood stabilizers, VPA and CBZ. 

At one time, sustained-release preparations were thought to reduce renal toxicity, but more recent evidence has cast doubt on this assumption ( 313). A patient on long-term maintenance lithium should have renal function monitored periodically (i.e., every 12 months) with a urinalysis, BUN, and creatinine. If abnormal, a more intensive evaluation should include 24-hour urine osmolality and creatinine clearance. It is advisable to reduce maintenance lithium to optimal minimal dose-blood levels and, if possible, to avoid concomitant antipsychotics, which may enhance toxicity. Some data support the use of a once-a-day dose schedule to minimize peak lithium concentrations over a 24-hour period (314). 

The most frequent early complaints involve this organ system. Nausea, which typically occurs shortly after a dose, can be controlled by taking the drug with meals, and although sustained-release preparations can also help in this regard, they may lead to diarrhea because of the unabsorbed drug s local irritation to the bowel. 

Sustained release preparations of potassium chloride have been widely used to overcome the gastrointestinal side effects following medication with enteric coated tablets. Such formulation techniques delay the rate of absorption and produce a slow release of potassium chloride during the passage through the gastrointestinal tract [1,2]. 

Most of the drugs in this class are well absorbed after oral administration peak concentrations occur 1-3 hours after ingestion. Sustained-release preparations of propranolol and metoprolol are available. 

Improvements in theophylline preparations have come from alterations in the physical state of the drugs rather than from new chemical formulations. For example, the increased surface area of anhydrous theophylline in a microcrystalline form facilitates solubilization for complete and rapid absorption after oral administration. Numerous sustained-release preparations (see Preparations Available) are available and can produce therapeutic blood levels for 12 hours or more. These preparations offer the advantages of less frequent drug administration, less fluctuation of theophylline blood levels, and, in many cases, more effective treatment of nocturnal bronchospasm. 

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