Theophylline formulations

TABLE 4 Theophylline Formulation by Direct Compression and Wet Granulation (mg/tablet)... 

Macheras, P. Koupparis, M. Apostolelli, E. Dissolution of 4 controlled-release theophylline formulations in milk. Int. 

Koritz, G.D. McKiernan, B.C. Neff-Davis, C.A. Munsiff, I.J. Bioavailability of four slow-release theophylline formulations in the beagle dog. J. Vet. Pharmacol Ther. 1986, 9, 293-302. 

Lu ME, Woodward L, Borodkin S. Xanthan gum and alginate based controlled release theophylline formulations. Drug Dev Ind Pharm 1991 17 1987-2004. 

Macheras P, Koupparis M, and Apostolelli E. Dissolution of 4 Controlled-Release Theophylline Formulations in Milk. Int J Pharm 1987 36 73-... 

FIGURE 10.1 Relationship between serum theophyUine concentration and improvement in pulmonary function, measured as increase in PEFR, among 31 adult subjects with asthma given 7.5 mg/kg of a rapidly absorbed theophylline formulation. (From Richer, C. et al., Clin. Pharmacol. Then, 31(5) 579-586, 1982. With permission.)... 

For many years oral xanthines, shown in Table 2, were the preferred first-line treatment for asthma in the United States, and if the aerosol and oral formulations of P2" go sts are considered separately, as they are in Table 1, this was still the case in 1989. Within this class of compounds theophylline (8), or one of its various salt forms, such as aminophylline [317-34-0] (theophylline ethylenediamine 2 l), have been the predominant agents. Theophylline, 1,3-dimethylxanthine [58-55-9], is but one member of a class of naturally occurring alkaloids. Two more common alkaloids are theobromine (9), isomeric with theophylline and the principal alkaloid in cacao beans, and caffeine, (10), 1,3,7-Trimethylxanthine [58-08-2], found in coffee and tea. 

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). 

In a series of papers, personnel from Novartis and the University of Basel in Switzerland have highlighted the pros and cons of neural networks for immediate release tablets [37-40]. In other studies neural networks have been found useful in modeling tablet formulations of antacids [41], plant extracts [42], theophylline [43], and diltiazem [44]. In a recent paper Lindberg and Colbourn [45] have used neural networks, genetic algorithms, and neurofuzzy to successfully analyze historical data from three different immediate-release tablet formulations. 

Other Formulations. Neural networks have been applied to the modeling of pellet formulations to control the release of theophylline [63] and to control the rate of degradation of omeprazole [64]. They have also been applied to the preparation of acrylic microspheres [65] and to model the release of insulin from an implant [66]. In arecent study from Brazil, the release of hydrocortisone from a biodegradable matrix has been successfully modeled [67]. 

Methylxanthine Theophylline Oral 0.5-2 hours Up to 24 hours, depending on formulation 6-24 hours 400-600 mg/day divided every... 

Accelerated aging and crystal transformation rates have also been traced to high residual moisture content. Ando et al. studied the effect of moisture content on the crystallization of anhydrous theophylline in tablets [9]. Their results also indicate that anhydrous materials convert to hydrates at high levels of relative humidity. In addition, if hygroscopic materials (e.g., polyethylene glycol 6000) are also contained in the formulation, needle-like crystals form at the tablet surface and significantly reduce the release rate of the theophylline. 

Sustained-release formulations can produce stable serum concentrations with once or twice daily dosage. Therapeutic effects occur at blood levels > 5 mg/1, and side effects increase considerably at levels > 15 mg/1. Smoking, alcohol, anticonvulsants, and rifampicin induce the drug-metabolizing enzyme system in liver and reduce the half-life of theophylline. On the other hand, heart and liver failure, sustained fever, old age and drugs such as cimeti-dine, ciprofloxacin, and oral contraceptives reduce theophylline clearance and thereby increase serum concentrations. 

Cholestatic hepatitis may occur when drug therapy lasts longer than 10 days or repeated courses are prescribed. The hepatitis is characterized by fever, enlarged and tender liver, hyperbilirubinemia, dark urine, eosinophilia, elevated serum bilirubin, and elevated transaminase levels. Hepatitis has been associated with the estolate salt of erythromycin but not with other formulations. Although the hepatitis usually occurs 10 to 20 days after the initiation of therapy, it can occur within hours in a patient who has had such a reaction in the past. The hepatitis is believed to be the result of both a hepatotoxic effect and a hypersensitivity reaction this latter effect is reversible on withdrawal of the drug. Erythromycin and derivatives induce hepatic microsomal enzymes and interfere with the actions of various drugs, including theophylline and carbamazepine. 

Dissolution studies were also conducted on tablets containing high molecular weight PCL-300 and PCL-700 (Fig. 4). As with the high molecular weight DL-PLA formulations, there was a significant retardation in release rate of theophylline from thermally treated tablets when compared with the non-thermally treated tablets. 

If the asthma attack is relieved, the clinician might want to maintain this plasma level using oral theophylline, which might be given every 12 hours using an extended-release formulation to approximate a continuous intravenous infusion. According to Table 3-1, Fora is 0.96. When the dosing interval is 12 hours, the size of each maintenance dose would be ... 

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. 

Theophylline improves long-term control of asthma when taken as the sole maintenance treatment or when added to inhaled corticosteroids. It is inexpensive, and it can be taken orally. Its use, however, also requires occasional measurement of plasma levels it often causes unpleasant minor side effects (especially insomnia) and accidental or intentional overdose can result in severe toxicity or death. For oral therapy with the prompt-release formulation, the typical dose is 3-4 mg/kg of theophylline every 6 hours. Changes in dosage result in a new steady-state concentration of theophylline in 1-2 days, so the dosage may be increased at intervals of 2-3 days until therapeutic plasma concentrations are achieved (10-20 mg/L) or until adverse effects develop. 

Caffeine is used medicinally as a CNS stimulant, usually combined with another therapeutic agent, as in compound analgesic preparations. Theobromine is of value as a diuretic and smooth muscle relaxant, but is not now routinely used. Theophylline is an important smooth muscle relaxant for relief of bronchospasm, and is frequently dispensed in slow-release formulations to reduce side-effects. It is also available as aminophylline (a more soluble preparation containing theophylline with ethylenediamine) and choline theophyllinate (theophylline and choline). The alkaloids may be isolated from natural sources, or obtained by total or partial synthesis. 

Karim, A., Burns, T., Janky, D., and Hurwitz, A. Food-induced changes in theophylline absorption from controlled-release formulations II. Importance of meal composition and dosing time relative to meal intake in assessing changes in absorption. Clin. Pharmacol. Ther. 38 642—647, 1985. 

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