SUSTAINED RELEASE TABLETS OF THEOPHYLLINE

Abstract: The present invention relates to a sustained release tablet comprising an admixture of theophylline and de­ naturated egg-albumin. The invention relates also to a process for the preparation of said tablet and to the use of said mixture for the manufacture of a medicament for treating asthma.

Description: The present invention relates to sustained release tab­ lets of theophylline for the treatment of asthma. Theophylline relieves and/or prevents symptoms of asthma by relaxing bronchial smooth muscles. It is rapidly, con­ sistently and completely absorbed from oral solutions and plain uncoated tablets. Absorption may be delayed, slowed or incompleted by the administration of specific formula­ tions which decrease the rate of dissolution in the gut. Formulations having a slow but reliable absorption have a therapeutic advantage, particularly for children in whom elimination is rapid and fluctuations in serum con­ centrations between doses are excessive. Slow release formulations allow longer, better dosing intervals with more stable blood levels. There are known several sustained release formulations comprising theophylline. From FR-A-1 443 063 there is known a coated tablet comprising theophylline and nosco­ pine. From US-A-4 415 547 there is known a sustained re­ lease tablet consisting of an encapsulated drug pellet comprising as active material theophylline. From EP-A-­ 109 320, BE-A-899 293 and JP-A-57-171 918 there are known sustained release matrix tablets comprising as active ma­ terial theophylline. Said tablets require the use of syn­ thetic polymers which are quite expensive. From PCT Application WO 83 00284 there is known a sus­ tained release composition which is being distributed un­ der the name Theo-Dur. In said composition theophylline is coated on sugar beads using poly(vinylpyrrolidone) as adhesive and the micropellets obtained are coated with a mixture of cellulose ethers to give the desired pro­ duct. The dissolution achieved in this composition is quite satisfactory, but the manufacture of said composi­ tion is rather complicated and requires the use of rather expensive materials. All the above known forms are not entirely satisfactory as either their manufacture is complicated and expensive or their sustained release is not easy to control. It has thus been desirable to find a suitable formulation for a sustained release tablet comprising theophylline, which should be easy and cheap to manufacture and wherein the sustained release is easily controlled. From DE-A-31 04 815 there is known a very general method for the preparation of sustained release formulations comprising one or more physiologically active substances and one or more proteins. The protein is denaturated by a physical and/or chemical treatment and the denaturated protein serves, in case that it is admixed with a solid compound, as a matrix encapsulating said active compound. Many physiologically active substances are mentioned in said specification but not theophylline. Moreover, the method described in the examples which comprises mere admixing of powders and direct preparation of pellets there-after is not suitable in the preparation of tablets ac­ cording to the present invention. The process for the manufacture of said tablets requires first the prepara­ tion of granulates of specific size which enables the free flow thereof. The tablets can be prepared only from said granulates. It could therefore not have been foreseen that a formu­ lation comprising theophylline and denaturated egg-albu­ min would give a sustained release tablet having the de­ sired quality. The present invention thus consists in a heat-treated sustained release tablet obtained from a granulated mixture of theophylline and dried egg-albumin. The tablets according to the present invention preferably comprise theophylline and egg-albumin in a ratio of 0.1-­ 10:1. Egg-albumin is commercially available. It is water soluble at ambient temperatures. When heated over 60°C irreversible denaturation occurs resulting in insolubili­ ty in water. Denaturation of native egg-albumin may be obtained be­ sides by heating, by cross-linking or by an interaction with suitable denaturation agents, such as ethanol,acids, polyvalent cations and many other chemicals. The present invention consists also in a process for the preparation of the tablet according to the present inven­ tion in which theophylline and dried egg-albumin are ad­ mixed, the mixture obtained is wetted and dried, the gra­ nulates obtained are thereafter converted into a tablet by methods known per se and the tablets obtained are heated to at least 60°C. The tabletation is suitably performed with a lubricant, e.g. magnesium stearate. The tablet may optionally be coated, in order to obtain suitable form and/or taste, with a suitable coating agent. The present invention is not restricted to heating for the denaturation and any other suitable denaturation method may be utilised. The present invention will now be illustrated with refe­ rence to the following examples without being restricted to them. The tablets described in Examples 1 to 4 were prepared as follows: Anhydrous theophylline and dried egg-albumin were admixed and granulated by wetting the mixture with water. The granulates obtained were heated in an oven to about 50°C and then passed through an adequate sieve (mesh size 1.00 mm; wire diameter 0.63 mm; mesh/cm² 15).Magnesium stea­ rate was then admixed with the granulates. The mixture obtained was passed to a tabletting machine, the tablets obtained were then passed on to an oven and heated there to 130° C±5°C for two hours and then cooled. The tablets were then coated with Opadry® Y-1-7000, a composition manufactured by Colorcon, U.K., and consisting of 62.5% hydroxypropylmethylcellulose, 6.25% Polyethylene Glycol 400 and 31.25% titanium dioxide. EXAMPLE 1 The tablet comprised: (The weight of the tablet was determined by the analysis of the tablet in order that it should comprise the above amount of theophylline.) EXAMPLE 2 The tablet comprised: EXAMPLE 3 The tablet comprised: EXAMPLE 4 The tablet comprised: EXAMPLE 5 The release rate of theophylline from the tablets obtained in Examples 1 to 4 was measured by the following procedure. Equipment and Solutions Standard USP dissolution apparatus was used in all of dissolution rate measurements. Solutions 1. Gastric fluid USP XX (pH 1.5 with pepsin) 2. Intestinal fluid USP XX (pH 6.9 with pancreatine) 3. Standard theophylline solutions. Procedure The tested theophylline tablets were placed in the disso­ solution beaker containing simulated gastric fluid. At suitable intervals samples of the dissolution solutions were withdrawn, centrifuged and the amounts of theo­ phylline released were determined spectrophotometrically at 272 nm. After 2 hours the dissolving medium was totally replaced by the artificial intestinal fluid. The sampling and the theophylline release determination was continued up to 12 hours. The results of said experiments are shown in Table 1. EXAMPLE 6 In a similar manner to that described for the preparation of tablets in Examples 1 to 4 several tablets were pre­ pared. No coating procedure was performed. Each tablet contained 300 mg of theophylline but the amount of dried egg-albumin was varied. There were prepared tablets com­ prising: 75 mg dried egg-albumin 150 mg dried egg-albumin 300 mg dried egg-albumin 600 mg dried egg-albumin 900 mg dried egg-albumin The release rate of theophylline from the tablets ob­ tained was measured in the same manner as described in Example 5. The results of said experiments are given in Table 2. EXAMPLE 7 The pharmacokinetic performance of tablets having the formulation and properties given in Example 3 (hereinaf­ ter called Theotrim) was measured. The experiments were performed as follows: Material and methods Five male volunteers aged between 24 and 32 years, weigh­ ing 65-82 kg were selected on the basis of negative medi­ cal history, physical examination, normal routine chemi­ cal blood analysis and morphology and urine analysis. Each patient received at a separate time one tablet of Theotrim. Each tablet was administered at 8:00 a.m. after an over­ night fast. Food was withheld for 5 hours after the ad­ ministration of each theophylline formulation. Tea, coffee, Coke® and other caffeinated beverages and food were not allowed from two days before, until the end of each study. Various blood samples (10 ml) were taken via an indwel­ ling catheter from the forearm vein at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 30, 38 and 48 hours after the oral administration. The plasma was immediately separated by centrifugation at 7000 rpm for 15 min and stored at -20°. Before assaying, the plasma was allowed to reach room temperature, vortexed, centrifuged and the residual clot removed. Plasma theophylline levels were determined at HPLC at a UV wavelength of λ=275 nm. The assay procedure was a modification of a method published by J.J.Orcid et al.,Clin.Chem. 27 , 2071-2072 (1981). Each sample was assayed in triplicate with an eight point calibration curve (containing plasma from each patient before the administration of the theophylline formulation t=0), spiked with known amounts of theophylline. The linear terminal slope (β) of the log Cb Theophylline serum concentration vs. t (time) plot was calculated by the method of least squares. The half-life of theophyl­ line (t 1/2 β) was calculated for the quotient The AUC (area under the Cb vs. t curve) was calculated using the trapezoidal rule, with extrapolation to infi­ nity by dividing the last experimental point by the li­ near terminal slope. The peak serum concentration of theophylline (Cb max ) and the time to reach Cb max (t max ) were reported. A statistical analysis was conducted for measuring va­ rious pharmacokinetic parameters such as: t 1/2 β, AUC, and Cb max . Results Individual and mean plasma concentrations obtained after the administration of the theophylline formulation are presented in Table 3. The plasma concentrations are ex­ pressed therein in mg/l. Table 4 summarizes the various pharmacokinetic parameters obtained after the administra­ tion of the theophylline formulation. The theophylline half-life obtained was similar to that obtained by L.Hendeles et al., Am.J.Hosp. Pharm. 34 , 525-527 (1977). The various pharmacokinetic parameters presented in Table 4 were calculated individually for each patient. The mean data presented in Table 4 are the average of the various individual pharmacokinetic parameters. The tables mentioned above are given hereinafter. Key: Conclusions From theoretical multiple dose calculations (based on the experimental data obtained in this single dose study) it seems that a daily dose of 600 to 900 mg of Theotrim can maintain steady-state plasma levels of theophylline with­ in its therapeutic window with a relatively small fluc­ tuation percentage. From comparative experiments performed it was found that Theotrim and Theo-Dur are bioequivalent. However, as in­ dicated above the manufacture of the latter is quite comp­ licated and requires the use of rather expensive mate­ rials.

Claims: 1. A heat-treated sustained release tablet obtained from a granulated mixture of theophylline and dried egg-albumin. 2. A tablet according to claim 1 comprising theophylline and egg-albumin in a ratio of 0.1-10:1. 3. A tablet according to claim 1 or 2 comprising a lubri­ cant. 4. A tablet according to claim 3, wherein the lubricant is magnesium stearate. 5. A tablet according to any of claims 1 to 4 comprising a coating agent. 6. A process for the preparation of a tablet according to any of claims 1 to 5, in which theophylline and dried egg-albumin are admixed, the mixture obtained is wetted and dried, the granulates obtained are thereafter converted into a tablet by methods known per se the tablets obtained are heated to at least 60°C. 7. A process according to claim 6, wherein the tablets are prepared with a lubricant, e.g. magnesium stearate. 8. A process according to claim 6 or 7 wherein the tab­ lets are coated with a coating agent. 9. The use of a mixture of theophylline and denaturated egg-albumin for the manufacture of a medicament for treating asthma.

Inventors: BIALER, MEIR, FRIEDMAN, MICHAEL, ZIAD, HUSSEIN
Applicants: YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW UNIVERSITY OF JERUSALEM
Application year: 1986
Main classification: A61K31
IPC codes: A61K9, A61K47, A61K31, A61P11