H|||||||||I|| USOOSO91 189A United States Patent (19) 11 Patent Number: 5,091,189 Heafield et al. l 45) Date of Patent: Feb. 25, 1992 54 CONTROLLED RELEASE DOSAGE FORMS (56) References Cited HAVING A DEFINED WATER CONTENT U.S. PATENT DOCUMENTS 3,965,256 6/1976 Leslie.................................... 424/22 75 Inventors: Joanne Heafield; Stewart I. Leslie; 4,743,247 5/1988 Wong .................................. 424/468 Sandra T. A. Malkowska; Philip J. Neale, all of Cambridge, United 4,753,800 6/1988 Mozda ................................. 424/440 Kingdom 4,844,910 7/1989 Leslie et al. ......................... 424/470 FOREIGN PATENT DOCUMENTS 73) Assignee: Euroceltique S.A., Luxembourg, 97523 1/1984 European Pat. Off. Luxembourg 109320 6/1986 European Pat. Off. 251459 1/1988 European Pat. Off. 21 Appl. No.: 704,714 270305 6/1988 European Pat. Off. Primary Examiner-Thurman K. Page (22 Filed: May 17, 1991 Assistant Examiner-Leon R. Horne Attorney, Agent, or Firm-Nixon & Vanderhye Related U.S. Application Data (57) ABSTRACT A controlled release, solid, oral dosage form containing 63 Continuation of Ser. No. 355,417, May 23, 1989, aban a 3-alkylxanthine, preferably theophylline, at least one doned. hydrophilic or hydrophobic polymer, at least one wax having a melting point between 25' and 90° C. and (30) Foreign Application Priority Data between 3% and 10% (by weight) water. Jun. 2, 1988 GB) United Kingdom ................. 88.3064 Preferably the dosage form is a tablet and the water content is between 4% and 9% (by weight). The 51) Int. Cl................................................. A61K 9/52 amount of water present in the dosage form determines 52 U.S. C. .................................... 424/457; 424/455; the rate of release of the 3-alkylxanthine. 424/459; 424/468 58) Field of Search ................ 424/457, 458, 459, 468 23 Clains, No Drawings 5,091, 189 1 2 preferred. Theophylline (anhydrous or hydrate) is the CONTROLLED RELEASE DOSAGE FORMS most preferred. HAVING A DEFINED WATER CONTENT When theophylline is the 3-alkylxanthine, the in vitro dissolution rate of the theophylline from the present This is a continuation of application Ser. No. 5 oral dosage form, when measured by the USP Paddle 07/355,417, filed May 23, 1989, now abandoned. Method at 100 rpm in 900 ml aqueous buffer (pH 6.5) at The present invention relates to a controlled release, 37 C. is preferably oral dosage form, especially a tablet, containing a 3 between 5% and 30% (by wt) release after 2 hours, alkylxanthine. between 15% and 40% (by wt) release after 4 hours, It is one object of the present invention to provide a O between 20% and 55% (by wt) release after 6 hours, 3-alkylxanthine containing controlled release, oral dos between 25% and 65% (by wt) release after 8 hours, age form having a narrow range of in-vitro dissolution and rates over a wide pH range (pH 1.6 to 7.2). Other ob between 40% and 90% (by wt) release after 12 hours. jects and advantages of the present invention will be Preferred doses of the 3-alkylxanthines in a con come apparent from the following detailed description 15 trolled release dosage form according to this invention thereof. are as follows: According to the present invention, there is provided a controlled release, solid, oral dosage form comprising a 3-alkylxanthine, at least one hydrophilic or hydropho Acepifylline 125-1000 mg Aninophylline 50-450 mg bic polymer, at least one wax having a melting point 20 Bamifylline HCl 150-600 mg between 25 C. and 90' C. and between 3% and 10% Bufylline 30-120 mg (by weight) water. Choline Theophyllinate 50-400 mg Oral dosage forms according to the present invention Diprophylline 50-400 mg Enprofylline 50-600 mg are preferably tablets but are not spheroids, film coated Etamiphylline cannsylate 50-600 mg spheroids or unit dosage forms (e.g. capsule, sachet, 25 Etofylline 100-600 mg cachet) containing spheroids or film coated spheroids. Proxyphylline 100-600 mg. In the present specification "per cent (by weight) Theobromine 50-600 mg Theophylline 50-600 mg water" refers to the water content of the oral dosage Theophylline Monoethanolamine 30-400 mg form as measured using a Karl Fischer titration method. Theophylline Na Glycinate 50-600 mg Preferably the water content of the oral dosage form 30 is between 4% and 9% (by weight), most preferably between 4% and 8% (by weight), especially between The concentration of 3-alkylxanthine in the present 5% and 7% (by weight). A particularly preferred oral dosage forms will depend, amongst other factors, on the dosage form according to this invention has a water amount of xanthine to be administered. In the case of content of about 6% (by weight). 35 theophylline, the dosage forms preferably contain be The present inventors have surprisingly found that tween 40% and 85% (by wt), especially between 50% the water content of the present dosage forms has a and 80% (by wt), of the active ingredient. The at least dramatic effect on the in-vitro release rate of the active one hydrophilic or hydrophobic polymer may be ingredient. When the water content of the dosage forms chosen from such materials as gums, cellulose ethers, is below 3% (by wt), the release rate is too slow. When acrylic resins and protein derived materials. Of these the water content of the dosage forms is above 10%, the polymers, the cellulose ethers, especially hydroxyalkyl release rate is too fast. celluloses and carboxyalkylcelluloses, are preferred. Furthermore, when the dosage forms have a water The oral dosage form may contain between 1% and content between 3% and 10% (by wt) they (the dosage 20%, especially between 2% and 12% (by weight) of forms) are more stable over a 1-2 year period (with 45 the at least one hydrophilic or hydrophobic polymer. regard to rate of release of the active ingredient) than The at least one wax of the present invention must other equivalent dosage forms having water contents have a melting point between 25 C. and 90' C., prefera Outside this range. bly between 40' and 70". The at least one wax may be, It is a particular advantage of the present dosage for example, a polyalkylene glycol, a fatty (aliphatic) forms that the in-vitro dissolution rate is substantially acid, a fatty (aliphatic) ester or, which is preferred, a independent of pH over a wide range (1.6 to 7.2). fatty (aliphatic) alcohol, particularly a C1-C36 fatty The present controlled release dosage forms contain a alcohol, especially a C14-C22 fatty alcohol such as my 3-alkylxanthine. The phrase "3-alkylxanthine' in the ristyl alcohol, cetyl alcohol, stearyl alcohol or cetostea present specification incorporates ryl alcohol. The present dosage forms preferably con (i) Any xanthine substituted at the 3 nitrogen by an alkyl 55 tain between 4% and 40%, especially between 8% and group, and 36%, by weight of the at least one wax. (ii) Any salt or derivative of such a 3-alkyl substituted One particularly suitable dosage form according to Xanthine. this invention comprises a 3-alkylxanthine, a water-solu Thus, the 3-alkylxanthine may be, for example, em ble hydroxyalkyl cellulose, at least one C1-C36, prefer profylline or theobromine. Preferably, however, the ably C4-C22, fatty alcohol and, optionally, at least one 3-alkylxanithine is a 1,3-dimethylxanthine, such as polyalkylene glycol. acepifylline, bamifylline, bufylline, diprophylline, eta The at least one hydroxyalkyl cellulose is preferably miphylline, etofylline, proxyphylline or theophylline. a hydroxy (C1 to C6) alkyl cellulose, such as hydroxy Of these 1,3-dimethyl xanthines, theophylline (anhy propycellulose, hydroxypropylmethylcellulose and es drous or hydrate) or a salt or derivative of theophylline, pecially, hydroxyethyl cellulose. The amount of the at Such as aminophylline, choline theophyllinate, theoph least one hydroxyalkyl cellulose in the present dosage ylline monoethanolamine, theophylline sodium glyci form will be determined, interalia, by the precise rate of nate or theophylline calcium salicylate is particularly drug release required. Preferably, however, the dosage 5,091,189 3 4. form contains between 1% and 20%, especially be The present controlled release dosage form and pro tween 2% and 12% (by weight) of the at least one hy cesses for the preparation of such dosage forms will droalkyl cellulose. now be described by way of example only: The at least one fatty alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In 5 DETERMINATION OF WATER CONTENT BY particularly preferred embodiments of the present dos THE KARL FISCHER METHOD age form, however, the at least one fatty alcohol is cetyl 1. A Karl Fischer Autotitration unit (Baird and Tat alcohol or cetostearyl alcohol. The amount of the at lock) was set up according to the manufacturer's least one fatty alcohol in the present dosage form will be instructions. determined, as above, by the precise rate of drug release 10 2. A sample volume of Karl Fischer reagent (Fisons) required. It will also depend on whether at least one was standardised. polyalkylene glycol is present in or absent from the 3. A predetermined quantity of tablets was ground to a dosage form. In the absence of at least one polyalkylene fine powder in a mortar and pestle. glycol, the dosage form preferably contains between 4. Approximately 0.5 g of the powdered tablets was 4% and 40%, especially between and 8% and 36%, (by 15 weighed into the sample vessel. weight) of the at least one fatty alcohol. When at least 5. The Karl Fischer reagent was neutralised in the reac one polyalkylene glycol is present in the dosage form tion vessel and then the sample was added. The mix then the combined weight of the at least one fatty alco ture was stirred for 3minutes.