Sustained release

This is the name given to the study of the kinetics of drug absorption, distribution, metabolism, and excretion, all of which are rate-controlled. The earliest studies, which were concerned with inhaled anaesthetics (Widmark, 1920 Dominguez, 1933), were not suited for general application. The fundamental equations were introduced by T. Teorell (1937) in his studies of insulin action. He provided simple kinetic formulae to monitor the concentration of 

Even between substances that are chemically closely related, large kinetic differences operate at the various stages of distribution shown in Fig. 3.3, and these differences contribute very much to the selectivity of drugs. Thus the fate of each drug is ordained by the sum of the constants with which its chemical constitution has endowed it. (It should be borne in mind that these figures are constant only for the animal species in which they were determined.) 

The usual difference in times of onset which occur when a dose is given intravenously or orally is shown in Fig. 3.8. It is evident that injection instantly gives the highest attainable blood concentration, whereas oral dosage gives a more delayed and less intense effect however, the intensity of both effects declines at about the same rate. 

The rate of transfer of a drug across a membrane can be best described by the differential d6 /d, where dS is the microscopic amount transferred in dt (a very short time) see Section 3.2. The amount (S) of drug on the outside of the membrane determines the rate of transfer across the membrane, as follows, 

The apparent volume of distribution ( Fd) (see Section 3.1), discloses whether the drug remains in one compartment (usually the bloodstream) or is shared with a second compartment (usually the tissues). Chemotherapeutic agents 

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Cosmetics and Pharmaceuticals. The main use of hexadecanol (cetyl alcohol) is in cosmetics (qv) and pharmaceuticals (qv), where it and octadecanol (stearyl alcohol) are used extensively as emoUient additives and as bases for creams, Hpsticks, ointments, and suppositories. Octadecenol (oleyl alcohol) is also widely used (47), as are the nonlinear alcohols. The compatibiHty of heavy cut alcohols and other cosmetic materials or active dmg agents, their mildness, skin feel, and low toxicity have made them the preferred materials for these appHcations. Higher alcohols and their derivatives are used in conditioning shampoos, in other personal care products, and in ingested materials such as vitamins (qv) and sustained release tablets (see Controlled RELEASE technology). 

Some tablets that provide a sustained period (up to 8—12 h) of therapy may be coated during processing. A portion is released first to bring the dmg to the desired blood concentration (onset of activity), whereas a sustained-release portion maintains an effective level for a prolonged period of time (duration of activity), eg, by coating erosion or diffusion of dmg through it. 

Improvements in asthma treatment include the development of more effective, safer formulations of known dmgs. The aerosol adrninistration of P2-agonists or corticosteroids results in a decrease in side effects. Also, the use of reUable sustained release formulations has revolutionized the use of oral xanthines which have a very narrow therapeutic index (see Controlled release technology). For many individuals, asthma symptoms tend to worsen at night and the inhaled bronchodilatots do not usually last through an entire night s sleep (26,27). 

Common side effects of theophylline therapy include headache, dyspepsia, and nausea. More serious side effects such as lethal seizures or cardiac arrythmias can occur if blood levels are too high. Many derivatives of theophylline have been prepared in an effort to discover an analogue without these limitations (60,61). However, the most universal solution has resulted from the development of reHable sustained release formulations. This technology limits the peaks and valleys in semm blood levels that occur with frequent dosing of immediate release formulations. ControUed release addresses the problems inherent in a dmg which is rapidly metabolized but which is toxic at levels ( >20 7g/mL) that are only slightly higher than the therapeutically efficacious ones (10—20 p.g/mL). Furthermore, such once-a-day formulations taken just before bedtime have proven especially beneficial in the control of nocturnal asthma (27,50,62). 

Pharmaceutical Applications. Sucrose has a long history in the manufacture of pharmaceuticals. It imparts body to symps and medicinal hquids and masks unpleasant tastes. Sucrose also functions as a diluent to control dmg concentrations in medicines, as an ingredient binder for tablets, and to impart chewiness to the latter. Sustained-release medications and protective tablet glazes are prepared using sucrose (41). Sucrose-based sugar pastes are used to promote wound healing (58). 

Polyethers such as monensin, lasalocid, salinomycin, and narasin are sold in many countries in crystalline or highly purified forms for incorporation into feeds or sustained-release bolus devices (see Controlled-RELEASE technology). There are also mycelial or biomass products, especially in the United States. The mycelial products are generally prepared by separation of the mycelium and then drying by azeotropic evaporation, fluid-bed driers, continuous tray driers, flash driers, and other types of commercial driers (163). In countries allowing biomass products, crystalline polyethers may be added to increase the potency of the product. 

Verapamil (Table 1), the first slow channel calcium blocker synthesized to selectively inhibit the transmembrane influx of calcium ions into cells, lowers blood pressure in hypertensive patients having good organ perfusion particularly with increased renal blood flow. Sustained-release verapamil for once a day dosing is available for the treatment of hypertension. Constipation is a prominent side effect. Headache, dizziness, and edema are frequent and verapamil can sometimes cause AV conduction disturbances and AV block. Verapamil should not be used in combination with -adrenoceptor blockers because of the synergistic negative effects on heart rate and contractile force. 

A. Yacobi and E. Halpetin-Walega, eds.. Oral Sustained Release Formulations Design and Evaluation, Pergamon Press, New York, 1988. 

Formation of Hposomal vesicles under controlled conditions of emulsification of Hpids with phosphoHpids has achieved prominence in the development of dmgs and cosmetics (42). Such vesicles are formed not only by phosphoHpids but also by certain nonionic emulsifying agents. Formation is further enhanced by use of specialized agitation equipment known as microfluidizers. The almost spontaneous formation of Hposomal vesicles arises from the self-assembly concepts of surfactant molecules (43). Vesicles of this type are unusual sustained-release disperse systems that have been widely promoted in the dmg and cosmetic industries. 

Ion exchangers are sometimes used on a throwaway basis also. In the laboratoiy, ion exchangers are used to produce deionized water, purify reagents, and prepare inorganic sols. In medicine, they are used as antacid, for sodium reduction, for the sustained release of drugs, in skin-care preparations, and in toxin removal. 

Progestin-only contraceptives (Fig. 4) contain low-doses of progestins (e.g. 350 pg norethindrone or 75 pg norgestrel) that have to be administered daily without interruption. The lowest expected failure rate during the first year of use is 0.5%, while the typical failure rate amounts to 3%. Subdermal implants of norgestrel (216 mg) for sustained release provides for long-term (for up to 5 years) contraceptive effects characterized by failure rates of only 0.05%. Reliable contraception for 3 months can be achieved by an intramuscular injection of a crystalline suspension of 150 mg medroxyprogesterone acetate (Fig. 3) (failure rate 0.3%). 

The oral route is the most frequent route of drug administration and rarely causes physical discomfort in patients. Oral drug forms include tablets, capsules, and liquids. Some capsules and tablets contain sustained-release drag s, which dissolve over an extended period of time. Administration of oral dru is relatively easy for patients who are alert and can swallow. 

If gastrointestinal upset occurs, take the drug with food. Do not chew or crush coated or sustained-release tablets. 

HBr dex-troe-meth- or -fan Liquid Caps, Robitussin Pediatric, SUcrets, Suppress, Trocal of cough mild dizziness, constipation, nausea, Gl upset, skin eruptions, nasal congestion older than 12 years 10-30 mg q4-8h, sustained release (SR) 60 mg ql2h PO children 6—12 years 5 10 mg q4h or 15 mg q6-8h, SR 30 mg ql2h PO children 2—6 years 2.5—7.5 mg q4—8h, SR 15 mg ql2h PO... 

When tiie drug is given orally, the nurse instructs the patient not to chew the capsule or tablet but to swallow it whole For faster absorption, the drug is given with a full glass of water when the patient s stomach is empty, either 1 hour before or 2 hours after meals. If gastrointestinal upset occurs, the nurse can administer the drug with or immediately after meals. Sustained-released tablets should not be crushed or divided. 

Remember that the wax matrix of sustained-release tablets of procainamide (Procan SR only) is not absorbed by the body and may be found in the stool. This is normal. 

Initial dose 5-20 mg PO maintenance dose 10-40 mg BID, TID sustained release ... 

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. 

Do not chew or divide sustained-released tablets. Swallow them whole... 

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