Title of Invention	A CONTROLLED RELEASE FORMULATION CONTAINING GALANTAMINE AS THE ACTIVE INGREDIENT
Abstract	A controlled release formulation containing galantamine as the active ingredient, characterized in that it comprises particles comprising galantamine or a pharmaceutically acceptable acid addition salt thereof, a water soluble pharmaceutically acceptable excipient and optionally other pharmaceutically acceptable excipients, said particles being coated by a release rates controlling membrane coating.

Title of Invention

A CONTROLLED RELEASE FORMULATION CONTAINING GALANTAMINE AS THE ACTIVE INGREDIENT

Abstract

A controlled release formulation containing galantamine as the active ingredient, characterized in that it comprises particles comprising galantamine or a pharmaceutically acceptable acid addition salt thereof, a water soluble pharmaceutically acceptable excipient and optionally other pharmaceutically acceptable excipients, said particles being coated by a release rates controlling membrane coating.

Full Text	FORM 2 THE PATENTS ACT 1970 [39 OF 1970] & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See Section 10; rule 13] "A CONTROLLED RELEASE FORMULATION CONTAINING. GALANTAMINE AS THE ACTIVE INGREDIENT" JANSSEN PHARMACEUTICA N.V., of Tumhoutseweg 30, B-2340 Beerse, Belgium The following specification particularly describes the invention and the manner in which it is to be performed: The present invention is concerned with controlled release compositions for oral administration compnsm£ galantamme ; and with processes of preparing such controlled release compositions, Galanrarmne G), :■. tertiarv alkaloid, has been isolated from the bulbs of the Caucasian snowdrops Gaianiiius noronowi (Proskumma. N. F. and Yakoieva. A. P 1952. 10 Alkaloids of Galanihus woronowi. II. Isolation of a new alkaloid. (In Russian.) Zh. Obschchei Khim (J. Gen Chem.) 22, 1899-1902). It has also been isolated from the common snowdrop Galanihus nivalis (BoiL 1954). McO OH The chemical name of galantamme is [4aS-(4aa, 6p\8aR)]-4a, 5, 9,10,11,12-15 hexahydr6-3-methoxy-1 }-methyl-6H-benzofuro[3a, 3,2-ef)[2]benza2epin-6-ol; both the base compound and its hydrobromide are laevorotatory. Gajantamine is a well-known acetylcholinesterase inhibitor which is active at nicotinic receptor sites but not on muscarinic receptor sues. It is capable of passing the blood-brain bamer in humans, and presents no severe side effects in therapeutically effective dosages. 20 Galantamirje has been used extensively as a eurare reversal agent in anaesthetic practice in Eastern bloc countries (cf. review by Paskow/1986) and also experimentally in the West (cf. Bretagne and Valeria, 1965: Wislicki, 1967; Consamtis, 1971). 25 Galantamme has been marketed by Waldheim (Sanochemia Gruppe) as Nivalin™ in Germany and Austria since the 1970s for indications such as facial neuralgia The use of galantamme or an analogue or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for treating Alzheimer"s Dementia 30 (AD) and related dementiai has been described in EP-0.236,684 (US-4.663,318) This patent only has a generic disclosure of possible dosage forms of galantamme WO 00/38686 PCT/EP99/10257 CA-1,326,632 generic ally discloses slow release formulations of galamamme. The use of galantamine for treating alcoholism and the administration via a transdermal therapeutic system (ITS) or patch is disclosed m EP-0,449,247 and WO-94/16707 5 Similarly, the use of gaJaniarmne in the treatment of nicotine dependence using administration via a transdermal therapeutic system (TTS) or patch is disclosed in WO-94/16708. Treatment of nerve gas poisoning is disclosed in DE-4,342,174. A number of applications bv E Snorrason disclose the use of galantamine. analogues 10 thereof and pharmaceutical acceptable salts thereof for the preparation of medicaments for treating mama (US-5,336,675), chronic fatigue syndrome (CFS) (EP-0,515,302 ; US-5,312,817), the negative effects of benzodiazepine treatment (EP-0,515.301) and the treatment of schizophrenia (US-5,633,238). In these applications and patents, e.g. m US-5.312,817, a number of immediate release tablet 15 formulations of galantamine hydrobromide are given. WO-97/47304 discloses fast-dissolving or immediate release tablets of galantamine prepared by direct compression. These and other art known immediate release tablets are administered twice (b.i.d.) or thrice (Li.d.) daily with an interval of 8 hours. The 20 plasma levels of the active ingredient typically raise sharply (early T^ and relatively high CmaX and decline rapidly (deep trough after about 6 to 8 hours). Therapy with galantamine can be considered optimal when effective plasma levels are reached when required. In addition, peak values (CmaX) should be as low and level as 25 possible so as to reduce the incidence and severity of possible side effects. The foregoing requirements not only apply upon single dose administration, but also upon repeated dose administration (until a steady-state condition is reached). In particular, when treating a patient suffering from Alzheimer"s Disease, optimum efficacy is expected when effective plasma levels are maintained during daytime; during nighttime 30 galantamine plasma levels probably may be lower. For the treatment of other conditions, for example for treating sleep disordered breathing such as snoring and apnoea (WO-97/22339), one may wish to attain the reverse situation, namely to have effective plasma levels during the night, and lower levels during daytime. For the benefit of the patient and the caretakers, a pharmaceutical dosage form that has to be 35 administered once daily only and yields effective plasma levels for eight hours-(nighttime) to 16 hours (daytime) would be highly desirable The present invention relates to a controlled release formulation containing galantamine WO 00/38686 PCT/EP99/10257 as the active ingredient, characterized in that it comprises panicles comprising galaniamine or a phamnaceuticaily acceptable acid addition salt thereof, a water soluble pharmaceutically acceptable excipient and optionally other pharmaceutically acceptable excipiems. said panicles being coated by a release rate controlling membrane coating. 5 Dosage forms comprising a therapeutically effective amount of said controlled release formulations can be administered orally to a patient once daily. In preferred dosage forms, part of the galantamine is present in an immediate release form, for example, as particles lacking a release rate controlling membrane coating, or as immediate release minitabiets. or as as a topcoat on the controlled release formulation. 10 Preferably, the formulations according to the present invention compnse galantamine in the form of galantamine hydrobromide (1:1). The water soluble excipient can conveniently be a film forming polymer. Useful water 15 soluble film forming polymers are polymers that have an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2 % aqueous solution at 20°C solution. For example, the water soluble polymer can be selected from the group comprising - alkylcelluloses such as methylcellulose, - hydroxyalkylcelluloses such as hydroxymethylcellulose, 20 hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose, - hydroxyalky] alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose, - carboxyaikylcelluloses such as carboxymeihylcellulose, - alkali metal salts of carboxyaikylcelluloses such as sodium carboxymethyl- 25 cellulose, - carboxyalkyl alkylcelluloses such as carboxymethyl ethykellulose, - carboxyalkylcellulose esters, - starches, - pectines such as sodium earboxymethylarnylopectine, 30 - chuine denvates such aschitosan, - polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans. traganth, agar-agar, gummi arabicum, guar gummi and xanthan gummi, - polyacrylic acids and the salts thereof, 35 poiymethacryiic acids and the salts thereof, methacryiaie copolymers. polyvinylalcohol. - polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate WO 00/38686 PCT/EP99/10257 - polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide. Non-enumerated po.lymers which are pharmaceutically acceptable and have appropriate physico-chemical properties as defined hereinbefore are equally suited for preparing 5 particles according to the present invention. Preferred water-soluble polymers arefor example hydroxypropyl methylcellosee (Methocel®. Pharmacoat®), polymethacrylate (Eudragit E®), hydroxypropylcellulose (Klucel®). or a polyvidune. Especially preferred water-soluble polymers are 10 hydroxypropyl methylcelluloses or HPMC. Said HPMC contains sufficient hydroxypropyl and methoxy groups to render it water-soluble. HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water-soluble. Methoxy degree of substitution refers to the average number of methyl ether groups present per 15 anhydroglucose unit of the cellulose molecule. Hydroxypropyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule. Hydroxypropyl methylcellulose is the United States Adopted Name for hypromellose (see Martindale, The Extra Pharmacopoeia, 29th edition, page 1435). Preferably hydroxypropyl methylcellulose 20 with low viscosity, i.e. about 5 mPa.s, is used, e.g. hydroxypropyl methyJcellulose 2910 5 mPa.s. In the four digit number "2910", the first two digits represent the approximate percentage of methoxy] groups and the third and fourth digits the approximate percentage composition of hydroxypropoxyl groups. 5 mPa.s is a value indicative of the apparent viscosity of a 2 % aqueous solution at 20°C. 25 Suitable HPMC include those having a viscosity from about 1 to about 100 mPa.s, in particular form about 3 to about 15 mPa.s, preferably about 5 mPa.s The most preferred type of HPMC having a viscosity of 5 mPa.s., is the commercially available HPMC 2910 5 mPa.s. An equally preferred type of HPMC is admixed with 30 polyethylene glycol 400, commercially available from Colorcon (UK) as Opadry™ OY-7240 clear. The weight-by-weight ratio of drug : polymer is in the range of 17 : 1 to ] : 5, preferably 10 : 1 to 1 : 3 In the case of (galantamine.HBr): (HPMC 2910 5 mPa.s), 35 said ratio may range from about 10 : 1 to about 1 : 3, and optimally is from 7 : 1 to 1: 2. The weighi-bv-weight ratio of galantamine.HBr to other water-soluble polymers may be determined by a person skilled in the an by straightforward experimentation. The lower limit is determined by practical considerations. WO 00/38686 PCT/EP99/10257 In particular the present invention is concerned with particles which comprise (a) a central, rounded or spherical core, (b) a layer or a coating film of a water-soluble polymer and galantamuneeobromide (1:1), (c) optionally a seal coating polymer 5 layer and (d) a release rate controlling membrane coating The core has a diameter of about 250 to about 1.180 pm(16-60 mesh), preferably of about 600 to about LI 80 urn 116-30 mesh). Pellets, beads or cores of me dimensions mentioned herein can be obtained by sieving 10 throughnominal standard test sieves as descnbed in the CRC Handbook, 64th ed., page F ] 14. Nominal standard sieves are characterized by the mesh/hole width (um), DIN 4188 (mm), ASTM E 11-70 (No), Tyler® (mesh) orBS 410 (mesh) standard values. Throughout this description and the claims, particle sizes are designated by reference to the mesh/hole width in um and to the corresponding Sieve No in the ASTM El1-70 15 standard. Materials suitable for use as cores in the particles according to the present invention are manifold, provided that said materials are pharaceutically acceptable and have appropriate dimensions (about 16-60 mesh) and firmness. Examples of such materials 20 are pplymers e.g. plastic resins; inorganic substances, e.g. silica, glass, hydroxyapatite, salts (sodiumpotassium chloride, calcium or magnesium carbonate) and the like; organic substances, e.g. activated carbon, acids (citric, fumaric, tartaric, ascorbic and the like acids), and saccharides and derivatives thereof. Particularly suitable materials are saccharides such as sugars, oligosaccharides, polysaccharides and their derivatives, 25 for example, glucose, rhamnose, galactose, lactose, sucrose, mantitol, sorbitol, dextrin, maltoextrin, cellulose, microcrystalline cellulose, sodium carbbxyrnethyl cellulose, starches (maize, rice, potato, wheat, tapioca) and the like saccharides A particularly preferred material suitable for use as cores in theparticles according to 30 the present invention is represented by 16-60 mesh sugar spheres (USP 22 / NF XVII p. 1989) which consist of 62.5% - 91.5% (w/w) sucrose, the remainder being starch and possibly also dextrines, and which are pharmaceutically inert or neutral. Consequently, these cores are also known in the art as neutral pellets. 35 Depending on the weight-by-weight ratio of drug : polymer, the water-soluble polymer and galantamme are herein said to form either a layer (ratio > 10 : 1) or a coat or coating film (ratio WO 00/38686 PCT/EP99/10257 As an alternative to the drug layered or drug coated inert pellets descnbed thus far, suitable particles comprising glantarrune may also be formed by granules or by spheroids (spherical granules) prepared according to art-known methods of granulation and spheronization 5 The release rate controlling membrane coating comprises a waiei insoluble polymer and optionally a plasticizer. Said polymer is ethylcellulose and the plasticizer is selected from the group comprising dibutvl sebacate, diethvl phthalate and triethvl citrate. It is useful to modify the properties of the water-insoluble polymer by the 10 addition of particular amounis of a water-soluble polymer as descnbed hereinbefore, preferably HPMC. The addition of the water-soluble polymer is especially useful to increase the onset of action. For the particles according to the present invention, the ratio ethylcellulose : HPMC can vary from 100 : 0 to about 70 : 30, in particular from about 80 : 20 to about 72.5 - 27.5, more in particular from about 75 : 25 to about 72.5 : 15 27.5. The release rate controlling membrane coating may be applied to the drug coated cores in an aqueous dispersion (Aquacoat™, Surelease™), or as a solution in an organic solvent system. A useful organic system comprises an alcohol, e.g. methanol or ethanol, and optionally a chlorinated hydrocarbon such as for example dichloromethane. 20 The weight of the release rate controlling membrane coating ranges from 3 % to 15 % of the uncoated particle, in particular from about 4% to about 12 %. The rate of release of the active ingredient from the particles is approximately inversely proportional with the thickness of the release rate controlling membrane coating. 25 A seal coat lies optionally between the drug core and the release rate controlling . membrane coating. The seal coating polymer layer isappli to thedrug coated cores to prevent sticking of the particles during the process and to prevent migration of the drug into the the release rate controlling membrane. Preferably, a thin layer of HPMC 30 2910 5 mPa.s and polyethylene glycol (PEG), in particular polyethylene glycol 400 is used as a seal coating polymer layer. In addition, the particles according to the present invention may further contain various additives such as thickening agents, lubricants, surfactants, preservatives, complexing 35 and chelating agents, electrolytes or other active ingredients. The particles can be filled in hard-gelatin capsules such that a therapeutically effective amount of, for example, 8 to 32 mg of the active ingredient is available per dosage WO 00/38686 PCT/EP99/10257 form. An advantageous pharmacokinetic profile profile (fast onset, level peak and trough values) is obtained when from 70 to 80 % of the galantamine is comprised " within the controlled release particles and the remaining 20 to 30 % of the galantamine is comprised in an immediate release form, preferaby the controlled releases particle 5 amount to 75 % of the galantamine and the immediate release form to 25 %. In order to achieve the desired pharmacokinetic, the dosage forms may be filled with particles that release the active ingredient ai different rates, at least one kind that releases the active ingredient slowly, and at least one kind that releases the active 10 ingredient more rapidh. m particular one kind that releases the active ingredient immediately, e.g. particles as described thai lack the release rate controlling membrane. The different particles may be filled consecutively in the capsules, or they may be prerruxed and the thus obtained premix may be filled into the capsules (taking into account possible segregation). 15 Alternatively, the controlled release particles of the present invention may further comprise a top-coat of a water-soluble polymer as described hereinbefore and galantamine which is released practically immediately upon ingestion and thus ensures a rapid onset of action. 20 Another alternative solution for providing a dosage form with a pharmacokinetic profile as outlined, nameljy with a fast onset, level peak and trough values, comprises filling a capsule with controlled release particles as described hereinbefore (70 to 80 %, preferably 75 % of the galantamine dose) together with one or more minitablets which 25 comprise the remaining 20 to 30 %, preferably 25 % of galantamine. Suitable ___ immediate release tablet formulations of galantamine have been described previously in WO-97/47304. The present invention also relates to processes of preparing formulations as described 30 hereinbefore comprising admixing galantamine or a phannaceutically acceptable salt form thereof with a water soluble excipient to form a drug core, optionally applying a seal coat to the drug core, and thereafter applying the release rate controlling membrane coating. 35 The particles according to the present invention are conveniently prepared in the following manner. A drug coating solution is prepared by dissolving into a suitable solvent system appropriate amounts of galantamine.HBr and a water-soluble polymer. A suitable solvent system comprises purified water or an alcohol, preferably ethanol 8 WO 00/38686 PCT/EP99/10257 which may be denatured, for example, with butanone. The amounts of solids, i.e. galaniarrune.HBr and water-soluble polymer, in the drug coating solution may range from 10 to 30% (w/w) and preferably is about 25 %. The solution is preferably stirred during the coating process. 5 The drug coating process (on an industrial scale) is conveniently conducted in a fluidized bed granulator (e.g. Glati type WSG-30 or GPCG-30) equipped with a Wurster bottom spray insert (e.g. an 18 inch Wurster insert). Laboratory scale process development can be performed on a Glatt type WSG-1 with a 6 inch Wurster bottom 10 insen. Obviously the process parameters depend on the equipment used. The spraying rate should be regulated carefully. Too low a spraying rate can cause some spray drying of the drug coating solution and result in a loss of product. Too high a spraying rate will cause overwetlmg with subsequent agglomeration. Agglomeration 15 being the most serious problem, lower spraying rates may be used initially, to be increased as the coating process proceeds and the particles grow larger. The atomizing air pressure with which the drug coating solution is applied also influences the coating performance. Low atomizing air pressure results in the\ 20 formation of larger droplets and an increased tendency toward agglomeration. High atomizing air pressure could conceivably carry the risk of spray drying the drug solution, but this was found not to be a problem. Consequently, atomizing air pressure may be set at nearly maximum levels. 25 Fluidizing air volume can be monitored by operating the exhaust air-valve .of the apparatus and should be set in such a manner that optimum pellet circulation is obtained. Too low an air volume will cause insufficient fluidization of the pellets; too high an air volume will interfere with the pellet circulation due to countercurrent air streams developing in the apparatus. In the present process optimum conditions were 30 obtained by opening the exhaust air valve to about 50% of its maximum and gradually increasing the opening thereof to about 60% of the maximum as the coating process proceeded. The coating process is advantageously conducted by employing an inlet-air temperature 35 ranging from about 50°C to about 55°C. Higher temperatures may speed up the process but have the disadvantage that solvent evaporation is so rapid that the coating liquid is not spread uniformly on the surface of the pellets resulting in the formation of a drug coating layer with high porosity. As the bulk volume of the coated pellets increases. WO 00/38686 PCT/EP99/10257 drug dissolunon may decrease significantly to unacceptable levels. Obviously, the optimum process temperature will further depend on the equipment used, the nature of the core, the batch volume, the solvent and the spraying rate. 5 Parameter settings for optimum coating results are described in more detail in the example hereinafter. Running the coating process under those conditions was found to yield very reproducible results. In order to decrease residual solvent levels in the pellets following application of the 10 rate controlling membrane from an organic solution, the pellets can conveniently be dned in any suitable drying apparatus. Good results may be obtained using a vacuum tumbler-drier operated at a temperature from about 60°C to about 90°C, preferably about 80°C, a reduced pressure ranging from about 150-400 mbar (15-40 kPa), preferably 200-300 mbar (20-30 kPa), for at least 24 hours, preferably about 36 hours 15 The vacuum tumbler-drier is conveniently rotated at its minimum speed, e.g. 2 to 3 rpm After drying, the drug coated cores may be sieved. The seal coat layer is applied to the drug coaled cores in the fluidized bed granulator with Wurster bottom spray insert or in a powder coater. The seal coating solution can 20 be prepared by dissolving an appropriate amount of a seal coating polymer into a suitable solvent system. Such a system, is, e.g. purified water or an alcohol, preferably ethanol which may be denatured with, for example, butanone. The amount of seal coating polymer in the seal coating spraying solution may range from 5 to 10% (w/w) and preferably is about 6.6%. The seal coating spraying solution is advantageously 25 stirred during the seal coating process. Appropriate conditions are described in more detail in the example hereihafter. A further drying step may be required after applying the seal, qoating polymer layer. Excess solvents could easily be removed while operating the apparatus at the parameter 30 settings used for about 5 to 15 minutes after the spraying had been completed. The release rate controlling membrane coating polymer layer is applied to the drug (or seal) coated cores in a fluidized bed granulator with Wurster bottom spray insert. The release rate controlling membrane coating suspension or solution can be prepared by 35 suspending or dissolving an appropriate amount of a release rate controlling membrane coating polymer into a suitable solvent system. Such a system, is, e.g. purified water or an alcohol, preferably ethanol which may be denatured with, for example, butanone. dichioromeihane which may be admixed with an alcohol, preferably methanol or 10 WO 00/38686 PCT/EP99/10257 ethanol The amount of release rate controlling membrane coating polymer in the spraying suspension or solution may range from 5 to 40% (w/w) and preferably is about 30%. The release rate controlling membrane coating spraying suspension or solution is advantageously stirred during the spraying process. The parameter setting for 5 conducting this last step is essentially similar to that used in the previous coating processes. Appropriate conditions are described in more detail in the example hereinafter. All coating processes are preferably conducted under an men atmosphere of e.g. 10 nitrogen. The coating equipment should preferably be grounded and provided wuh an appropriate solvent recovery system containing an efficient condensing system. The particles may be filled in hard-gelatin capsules using standard automatic capsule filling machines. Suitable earthing and de-iomsation equipment can advantageously 15 prevent development of electrostatic charges. Capsule filling speed may influence weight distribution and should be monitored. Good results are obtained when operating the equipment at about 75% to 85% of the maximum speed and in many cases when operatingiat full speed. 20 Dosage forms according to the present invention having an advantageous pharmacokinetic profile as outlined, namely a fast onset and level peak and trough values, are capable of releasing in 500 ml USP buffer (pH 6.8) at 37°C in an Apparatus 2 (USP 23, Dissolution, pp 1791-1793, paddle, 50 rpm) from 20 to 40 % of the 25 total amount of galantamine.HBr in 1 hour, and more than he. total amount of galantamincHBr in 10 hours. Said dosage forms provide a mean maximum plasma concentration of galantamine from 10 to 60 ng/ml and a mean minimum plasma concentration from 3 to 15 ng/ml after repeated administration ever day through steady-state conditions. 30 The formulations according to the present invention deliver a therapeutically effective amount of galantamine to a patient during the 24 hours following a single once daily administration. 35 The present invention also concerns pharmaceutical packages suitable for commercial sale comprising a container, a formulation of galantamine as claimed in claim 1, and associated with said package written matter specifying how said formulation should be administered. WO 00/38686 PCT7EP99/10257 Said pharmaceutical packages may be adapted for titrating a patient who is "acetylcholine esterase inhibitor"-nai"ve, i.e. a patient who has not been exposed to an acetylcholine esterase inhibitor before and who should start with small, well-tolerated doses before being exposed to ever higher doses until the optimal dose is reached. Said packages typically comprises 21-35 daily sequential dosage units of (a) a first group of 7 to 14 dosage units comprising from 5 to 10 mg galantamine. (b) a second group of 7 to 14 dosage units comprising from 10 to 20 mg galantamine, (c) a third group of 7 to 14 dosage units comprising from 15 to 30 mg galantamine. and (d) optionally a fourth group of 7 dosage units comprising from 20 to 40 mg galantamine. Alternatively, the pharmaceutical packages may be adapted for treating a pauem who is acetylcholine esterase inhibitor"-tolerant, i.e. a patient who has been exposed to an acetylcholine esterase inhibitor before and who tolerates an optimal dose Said 15 packages typically comprises daily dosage units comprising from 15 to 30 mg galantamine. A method of treating Alzheimer"s dementia and related dementias in a human while substantially reducing (avoiding) the concomitant liability of adverse effects associated 20 with acetyl cholinesterase inhibitors, comprising administering to a human in need of such treatment, a therapeutically effective amount of galantamine in a controlled release formulation as claimed in claim 1, said amount being sufficient to alleviate said Alzheimer"s dementia and related dementias, but insufficient to cause said adverse effects. 25 ;. The related dementia belongs to the group consisting of vascular dementia. Lewy body disease, autism, mental retardation;,l?ipbiar$isorder psychiatric conditions, disruptive behaviour, attention deficit hyperactivity aisbrder\ substance abuse, extreme aggression, especially conduct disorder, nicotine cessation and withdrawal. 30 The adverse effects belong to the group comprising nausea, vomiting, sweating, restlessness, and insomnia. WO 00/38686 PCT/EP99/1025" Experimental part Example I : 8 mg galantamine CR oral capsule (Fl) Ingredients : galantamme hydrobromide 10.253 mg (8 mg galaniamine base) 5 sugar spheres (18-20 mesh) 63.283 mg HPMC 29l0 5mPa.s 1.465 mg purified water 37.105 pi HPMC 2910 5mPa.s 1.500 mg polyethylene glycol 400 0.150 mg 10 punfied water 23.350 pi * ethylcellulose aqueous dispersion 10.220 mg (30%) dibutyl sebacate 0.736 mg punfied water 10.220 pi * capsule nr. 4 15 * : these ingredients do not occur in the end product Preparation : a) Drug coat suspension Galantamine hydrobromide (123 g) was suspended in 297 mJ purified water and heated to 70 -80 °C. HPMC 2910 5 mPa.s (17.58 g) was dissolved in the heated supension 20 whilst stirring. b) Seal coat solution Purified water (93. 4 g) was heated to 70 - 80°C and HPMC 2910 5 mPa.s (18 g) and polyethylene glycol 400 (1.8 g) were dissolved therein. The solution was then further diluted with purified water (186.8 g). 25 c) Release rate controlling membrane coat dispersion To a gently stirred aqueous dispersion of ethylcellulose (122.6 g ; 30 %) was added dibutyl sebacate (8.832 g). The dispersion was diluted with purified water (122.6 g). d) Coating process A fluidized-bed granulaior (Glau. type WSG 1) equipped with a 6.mch Wurster 30 (bottom spray) insen was loaded with 18-20 mesh sugar spheres (759.4 g). The spheres were warmed with dry air of about 50°C. The fluidizing air volume was controlled by opening the exhaust air valve to approximately 45 % of its maximum. The drug coat suspension was spraved on the spheres moving in the apparatus The suspension was sprayed ai a dehver\ rate of about 5 to 30 g.min ai an atomizing air pressure of about 35 1.6 to 4.0 bar (0 16 -0.4 MPs). When the spraying process was completed, the coated spheres were dried by funher supplying dry air of 60°C for about 2 minutes. The WO 00/38686 PCT/EP99/)025^ coated spheres were then seal coated with the sealcoat solution using the same parameters as used in the drug coating process. After drying for about 2 minutes, the seal coated spheres were allowed to cool to room temperature and filled into a stainless steel drum. 5 The fluidized-bed granulator (Glatt. type WSG 1) equipped with a 6 inch Wurster (bottom spray) insert was reloaded with the seal coated spheres. The spheres were warmed with dry air of about 50°C. The fluidizing air volume was controlled by opening the exhaust air valve 10 approximately 45 % of its maximum The release rate controlling membrane coat suspension was sprayed on the spheres moving in the 10 apparatus. The suspension was sprayed at a delivery rate of about 5 to 30 g.min" ■* at an atomizing air pressure of about 1.6 to 4.0 bar (0.16 -0.4 MPa). After drying for about 2 minutes, the controlled release membrane coated spheres were allowed to cool to room temperature and filled into a stainless steel drum. e) drying and curing process 15 In order to remove agglomerates, the coated spheres were sieved usmg a sieve having a mesh width of 1.2 mm. The panicles were placed in a drying oven at 60°C during 2 hours so as to cure the release rate controlling membrane. f) capsule filling The particles were filled into hard-gelatin capsules (size 4) using standard automatic 20 capsule filling machines (e.g. Model GFK-1500, Hoffliger and Karg. Germany). In order to obtain capsules with good weight distribution, capsule filling speed was reduced to about 75-85% of the maximum speed. Each capsule received approximately 87.6 mg particles, equivalent to about 8 mg galantamine. 30 (30 %) 25 Example 2 : 8 mg galantamine CR oral capsule (F2) Ingredients: galantamine hydrobromide 10.253 mg ( sugar spheres (18-20 mesh) 63.283 mg HPMC 2910 5mPa.s 1.465 mg purified water 37.105 fil HPMC 2910 5mPa.s 1.500 mg polyethylene glycol 400 0.150 mg purified water 23.350 jil ethvlcellulose aqueous dispersion 25.550 mg dibutyl sebacate 1.840 mg purified water 25.550 u.1 capsule nr 4 WO 00/38686 PCT/EP99/10257 * : these ingredients do not occur in the end product Preparation . The preparation was identical to that described in Example 1 except for the preparation 5 of the release rate controlling membrane dispersion. c) Release rate controlling membrane coat dispersion To a gently stirred aqueous dispersion of ethyl cellulose (306.6 g ; 30 %) was added dibutyl sebacate (22.08 g) The dispersion was diluted with punfied water (306.6 g). 10 Example 3: Bioavailability The bioavailability of a single oral administration of the two controlled release formulations of examples 1 and 2 was compared with that of an immediate release tablet (F3) [WO-97/47304] comprising 4 mg galantamine which was administered 15 twice daily with an interval of 8 hours. Galantamine plasma levels in healthy volunteers (12) were determined by HPLC and the mean values calculated from the individual measurements are reported in the following table. time (h) Fl F2 F3 0 nd nd nd 0.5 1.6 nd 16.4 1 7.3 nd 24.1 1.5 11.5 nd 203 2 16.3 1,8—--. 18.3 3 23.8 3.7 16.9 4 26.7 6,3 14.5 6 25.2 9.5- 11.3 8 22.5 10.5 9.3 8.5 18 9 24.5 9.5 25.5 10 18.6 11.1 23.7 11 22.7 12 15.1 12.0 19.3 14 13.4 124 15.2 16 10.8 11.7 12.7 24 6.0 1 8.8 6.6 15 WO 00/38686 PCT/EP99/102S" time (h) FI F2 F3 30 3.5 6.1 3.5 36 2.0 4.3 2.0 48 nd 1.6 nd nd " noi deiecinbie ng/ml) Example 4 . oral capsule (F4) comprising 8 mg galantarrune (75 % CR pellets and 25 % IP Tablet) Ingredients 63.482 mg sugar spheres (18-20 mesh) 7.69 mg (6 mg galantamine base) 0.641 mg 42.932 p.1 1.436 mg 0.145 mg 12.385 uJ 10.858 mg * 1.101 mg 3.308 mg 0.881 mg 31.077 jil * 27.244 mg 2.563jng (2 mg galantamine base) galantamine hydrobromide HPMC 29J0 5mPa.s punfied wafer 10 HPMC 2910 5 mPa.s polyethylene glycol 400 methylene chlonde eihanol 96 % (v/v) 15 HPMC29l0 5mPa.s eihylcellulose 20 mPa.s diethyl phthalate methylene chlonde ethanol 96 % (v/v) galantamine hydrobromide spray-dried mixture of lactose monohydrate 20 and microcrysiailme cellulose. (75325) 49.302 mg colloidal anhydrous silica 0.11 mg crospolyvidone 2.750 mg magnesium siearate 0.275 mg 25 * . these ingredients do not occur in the end product Preparation : a) Drug layer suspension Galantamine hvdiobromide was suspended in punfied water and heated to 70 -80 CC 30 HPMC 29)0 5 mPa s was dissolved in the heated supension whilst stirring. WO 00/38686 PCT/EP99/10257 b) Seal coat solution Methylene chloride and ethanoi were mixed together and polyethylene glycol and HPMC 2910 5 mPa.s were dissolved therein. .i Release rate controlling membrane coat solution Methylene chloride and ethanoi were mixed and ethylcellulose 20 mPa.s, HPMC 2910 5 mPa.s and diethyl phthalaie were added while stirring the solution. d) Layering and coating process 10 A fluidized-bed granulaior (Glan) equipped wjih a Wurster (bottom spray) insert was loaded with 18-20 mesh sugar spheres. The spheres were warmed with dry air of about 50°C The fluidizing air volume was controlled by opening the exhaust air valve to approximately 45 % of its maximum. The drug layer suspension was sprayed on the spheres moving in the apparatus When the spraying process was completed, the layered 15 spheres were dried by further supplying dry air of 60°C for about 2 minutes. The layered spheres were then seal coated with the seal coat solution using the same parameters as used in the drug coating process. After drying for about 2 minutes, the seal coated spheres were allowed to cool to room temperature and filled into a stainless steel drum. 20 The fluidized-bed granulator (Glan) equipped with a Wurster (bottom spray) insert was reloaded with the seal coated spheres. The spheres were warmed with dry air of about 50°C The fluidizing air volume was controlled by opening the exhaust air valve to approximately 45 % of its maximum. The release rate controlling membrane coat suspension was sprayed on the spheres moving in the apparatus. After drying for about 2? 2 minutes, the controlled release membrane coated spheres were allowed to^ool to room temperature, sieved and filled into a stainless steel drum. e) immediate release minitablet Galantamine hydrobromide, spray-dried mixture of lactose monohydrate 30 and microcrystalline cellulose (75:25), colloidal anhydrous silica, crospolyvidone and magnesium stearate were mixed in a planetary mixer and compressed in a tabletting machine, thus preparing minitablets of 55 mg weight. f) capsule filling 35 The coated spheres and the immediate release minitab were filled into hard-gelatin capsules (sue 0) using standard automatic capsule filling machines (eg. Model GFK-1500. Hoffhger and Karg- Germany) WO 00/38686 PCT/EP99/10257 Example 5 : galaniamine oral capsules (F5, F6, F7, F8) (75 % CR pellets and 25 % IR topcoat) Ingredients: sugar spheres (18-20 mesh) 63.624 mg 5 galantamine hydrobromide 7.69 mg (6 mg galantamine base) HPMC 2910 5 mPa.s and PEG 400 12.687 mg (Opadry™ OY-7240 Clear, Colorcon) purified water 267.693 ul * HPMC2910 5mPa.s 1.260 ms ethylcellulose 20 mPa.s 3.780 mg 10 diethyl phthalate 1.008 mg methylene chloride 46.772 pi * ethanol 96 % (v/v) 31.184 mg galantamine hydrobromide 2.563 mg (2 mg galantamine base) HPMC 2910 5 mPa.s and PEG 400 4.229 mg (Opadry OY-7240 Clear) 15 purified water 89.321 ul * capsules size nr. 4,2, 1 and 0. *: these ingredients do not occur in the end product 20 Preparation: a) Drug coat solution Galantamine hydrobromide and Opadry OY-7240 Clear were dissolved in purified water at room temperature. 25 b) Release rate controlling membrane coat solution Methylene chloride and ethanol were mixed and ethylcellulose 20 mP-a-S, HPMC 2910 5 mPa.s and diethyl phthalate were added while stirring the solution. -- c) Drug topcoat solution 30 Galantamine hydrobromide and Opadry™ OY-7240 Clear were dissolved in purified wateria room tempeature. d) Goating process A fluiiized-bed granulatbr (Glatt) equipped with a Wurster (bottom spray) insert was 35 loaded with 18-20 mesh sugar spheres. The spheres were warmed with dry air of about 50°C. The fluidizing air volume was controlled by opening the exhaust air valve to approximately 45 % of its maximum. The drug coat solution was sprayed on the WO 00/38686 PCT/EP99/10257 , spheres moving in the apparatus. When the spraying process was completed, the coated spheres were dried by further supplying dry air of 60°C for about 2 minutes. The release rate controlling membrane coat solution was sprayed on the spheres moving in the apparatus. After drying for about 2 minutes, the controlled release membrane coated 5 spheres were sprayed with the drug topcoat solution. After drying for about 2 minutes, the topcoated spheres were allowed to cool to room temperature, sieved and were filled into a stainless steel drum. e) capsule filling 10 The topcoated spheres (96.841 mg ; 193.683 mg : 290.524 ; 387.365 rag) were filled into hard-gelatin capsules (size numbers 4, 2, 1, 0) using standard automatic capsule filling machines (e.g. Model GFK-1500, Hoffliger and Karg. Germany) yielding oral capsules containing respectively 8 mg, 16 mg, 24 mg and 32 mg galantamine base. 15 Example 6 : galantamine oral capsules (F9) (75 % CR pellets and 25 % TR topcoat) Spheres having slightly faster release were made by lowering the ratio of ethylcellulose 20 mPa.s to HPMC 2910 5 mPa.s to 72.5 : 27.5 (as compared to the ratio 75 : 25 in the previous example. 20 Example 7 : In vitro dissolution of the topcoated spheres Comparative in-viiro dissolutions studies were performed on the topcoated spheres formulations F5 to F8 and F9. The medium was 500 ml of USP buffer pH 6.8 at 37°C in Apparatus 2 (USP 23, Dissolution, pp. 1791-1793) (paddle, 50 rpm). 25" The following results were obtained: F5 to F8 Time Calculatec concentration (% w/w) of the active dose sample 1 sample 2 sample 3 sample A sample 5 sample 6 average (min) 0 ..... 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 32.20 30.44 37.47 30.44 30.44 38.05 33.17 120 42.54 41.37 48.39 41.37 42.54 42.54 43.13 240 58.93 60.10 65.96 61.27 61.27 61.27 61.47 480 85.47 80.20 84.30 81.96 81.37 80.79 82.35 720 91.52 90.35 97.37 99 13 92.11 87.42 92.98 1080 96.59 97.18 102.45 102.45 99.52 98.94 99.52 1410 9640 97.57 103.42 103.42 100.5 101.08 100.40 ; 19 WO 00/38686 PCT/EPW/102S7 F9 Calculated concentration (% w/w) of the active dose Time sample 1 sample 2 sample 3 sample 4 sample 5 sample 6 average (min) 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 38.9 36.0 36.5 39.5 33.4 37.2 32.86 120 60.3 55.7 56.9 60.4 60.9 55.1 58.2 240 89.5 81.8 86.2 86.7 91.2 84.0 86.6 480 103.4 103.6 95.9 101.7 100.8 105.8 101.9 720 107.0 99.0 104.0 103.1 109.1 100.8 103.8 WE CLAIM: 1. A controlled release formulation containing galantamine as the active ingredient, wherein it comprises particles comprising galantamine hydrobromide (1:1), and a water soluble film forming polymer wherein the galantamine hydrobromide (1:1) and the water soluble film forming polymer are layered or coated on inert spheres, said particles being coated by a release rate controlling membrane coating wherein the release rate controlling membrane coating comprises a water insoluble polymer and optionally a plasticizer, and wherein the formulation further comprises a topcoat comprising galantamine and water-soluble polymer and wherein the formulation is capable of releasing in USP buffer pH 6.8 at 37° C. in a paddle apparatus operating at 50 rpm, from 20 to 40% of the total amount of galantamine.HBr in 1 hour, and more than 80% of the total amount of galantamine.HBr in 10 hours. 2. A formulation as claimed in claim 1 wherein the water insoluble polymer is ethylcellulose and the plasticizer is selected from the group consisting of dibutyl sebacate, diethyl phthalate and triethyl citrate. 3. A formulation as claimed in claim 2 wherein the weight of the release rate controlling membrane coating ranges from 3% to 15% of the uncoated particle. 4. A formulation as claimed in claim 1 wherein a seal coat lies between the drug core and the release rate controlling membrane coating. 5. A formulation as claimed in claim 1 wherein the water soluble film forming polymer is a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution at 20° C solution. 6. A formulation as claimed in claim 5 wherein the water soluble polymer is selected from the group consisting of alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose, hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose, carboxyalkylcelluloses such as carboxymethylcellulose, alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose, carboxyalkylalkylcelluloses such as carboxymethylethylcellulose, carboxyalkylcellulose esters, starches, pectines such as sodium carboxymethylamylopectine, chitine derivatives such as chitosan, polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, traganth, agar-agar, gummi arabicum, guar gummi and xanthan gummi, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts thereof, methacrylate copolymers, polyvinylalcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide. 7. A formulation as claimed in claim 6 wherein the water soluble polymer is hydroxypropyl methylcellulose HPMC 2910 with an apparent viscosity of 5 mPa.s when dissolved in a 2% aqueous solution at 20° C. 8. A formulation as claimed in claim 7 wherein the weight-by-weight ratio of said hydroxypropyl methylcellulose to galantamine is in the range of 17:1 to 1:5. 9. A formulation as claimed in claim 1 wherein the inert spheres are I8¬60 mesh (1,180 250 .mu.m) sugar spheres. 10. A formulation as claimed in any one of claims 5, 6, 7, 8, 9 or 4 which delivers a therapeutically effective amount of galantamine to a patient during the 24 hours following a single once daily administration. 11. A formulation according to claim 1 providing a mean maximum plasma concentration of galantamine from 10 to 60 ng/ml and a mean minimum plasma concentration from 3 to 15 ng/ml after repeated administration every day through steady-state conditions. EMFRY 8B SAGAR TOR THE APPLICANTS Dated this 15th day of May, 2001

Full Text

FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"A CONTROLLED RELEASE FORMULATION CONTAINING. GALANTAMINE AS
THE ACTIVE INGREDIENT"
JANSSEN PHARMACEUTICA N.V., of Tumhoutseweg 30, B-2340 Beerse, Belgium
The following specification particularly describes the invention and the manner in which it is to be performed:

The present invention is concerned with controlled release compositions for oral administration compnsm£ galantamme ; and with processes of preparing such controlled release compositions,
Galanrarmne G), :■. tertiarv alkaloid, has been isolated from the bulbs of the Caucasian snowdrops Gaianiiius noronowi (Proskumma. N. F. and Yakoieva. A. P 1952. 10 Alkaloids of Galanihus woronowi. II. Isolation of a new alkaloid. (In Russian.) Zh. Obschchei Khim (J. Gen Chem.) 22, 1899-1902). It has also been isolated from the common snowdrop Galanihus nivalis (BoiL 1954).
McO
OH
The chemical name of galantamme is [4aS-(4aa, 6p\8aR*)]-4a, 5, 9,10,11,12-15 hexahydr6-3-methoxy-1 }-methyl-6H-benzofuro[3a, 3,2-ef)[2]benza2epin-6-ol; both the base compound and its hydrobromide are laevorotatory. Gajantamine is a well-known acetylcholinesterase inhibitor which is active at nicotinic receptor sites but not on muscarinic receptor sues. It is capable of passing the blood-brain bamer in humans,
and presents no severe side effects in therapeutically effective dosages.
20
Galantamirje has been used extensively as a eurare reversal agent in anaesthetic practice in Eastern bloc countries (cf. review by Paskow/1986) and also experimentally in the West (cf. Bretagne and Valeria, 1965: Wislicki, 1967; Consamtis, 1971).
25 Galantamme has been marketed by Waldheim (Sanochemia Gruppe) as Nivalin™ in Germany and Austria since the 1970s for indications such as facial neuralgia
The use of galantamme or an analogue or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for treating Alzheimer"s Dementia 30 (AD) and related dementiai has been described in EP-0.236,684 (US-4.663,318) This patent only has a generic disclosure of possible dosage forms of galantamme

WO 00/38686 PCT/EP99/10257
CA-1,326,632 generic ally discloses slow release formulations of galamamme.
The use of galantamine for treating alcoholism and the administration via a transdermal therapeutic system (ITS) or patch is disclosed m EP-0,449,247 and WO-94/16707 5 Similarly, the use of gaJaniarmne in the treatment of nicotine dependence using administration via a transdermal therapeutic system (TTS) or patch is disclosed in WO-94/16708. Treatment of nerve gas poisoning is disclosed in DE-4,342,174.
A number of applications bv E Snorrason disclose the use of galantamine. analogues 10 thereof and pharmaceutical acceptable salts thereof for the preparation of
medicaments for treating mama (US-5,336,675), chronic fatigue syndrome (CFS) (EP-0,515,302 ; US-5,312,817), the negative effects of benzodiazepine treatment (EP-0,515.301) and the treatment of schizophrenia (US-5,633,238). In these applications and patents, e.g. m US-5.312,817, a number of immediate release tablet 15 formulations of galantamine hydrobromide are given.
WO-97/47304 discloses fast-dissolving or immediate release tablets of galantamine prepared by direct compression. These and other art known immediate release tablets are administered twice (b.i.d.) or thrice (Li.d.) daily with an interval of 8 hours. The 20 plasma levels of the active ingredient typically raise sharply (early T^ and relatively high CmaX and decline rapidly (deep trough after about 6 to 8 hours).
Therapy with galantamine can be considered optimal when effective plasma levels are reached when required. In addition, peak values (CmaX) should be as low and level as
25 possible so as to reduce the incidence and severity of possible side effects. The
foregoing requirements not only apply upon single dose administration, but also upon repeated dose administration (until a steady-state condition is reached). In particular, when treating a patient suffering from Alzheimer"s Disease, optimum efficacy is expected when effective plasma levels are maintained during daytime; during nighttime
30 galantamine plasma levels probably may be lower. For the treatment of other
conditions, for example for treating sleep disordered breathing such as snoring and apnoea (WO-97/22339), one may wish to attain the reverse situation, namely to have effective plasma levels during the night, and lower levels during daytime. For the benefit of the patient and the caretakers, a pharmaceutical dosage form that has to be
35 administered once daily only and yields effective plasma levels for eight hours-(nighttime) to 16 hours (daytime) would be highly desirable
The present invention relates to a controlled release formulation containing galantamine

WO 00/38686 PCT/EP99/10257
as the active ingredient, characterized in that it comprises panicles comprising
galaniamine or a phamnaceuticaily acceptable acid addition salt thereof, a water soluble
pharmaceutically acceptable excipient and optionally other pharmaceutically acceptable
excipiems. said panicles being coated by a release rate controlling membrane coating.
5 Dosage forms comprising a therapeutically effective amount of said controlled release
formulations can be administered orally to a patient once daily. In preferred dosage
forms, part of the galantamine is present in an immediate release form, for example, as
particles lacking a release rate controlling membrane coating, or as immediate release
minitabiets. or as as a topcoat on the controlled release formulation. 10
Preferably, the formulations according to the present invention compnse galantamine in
the form of galantamine hydrobromide (1:1).
The water soluble excipient can conveniently be a film forming polymer. Useful water 15 soluble film forming polymers are polymers that have an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2 % aqueous solution at 20°C solution. For example, the water soluble polymer can be selected from the group comprising
- alkylcelluloses such as methylcellulose,
- hydroxyalkylcelluloses such as hydroxymethylcellulose,
20 hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose,
- hydroxyalky] alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose,
- carboxyaikylcelluloses such as carboxymeihylcellulose,
- alkali metal salts of carboxyaikylcelluloses such as sodium carboxymethyl-
25 cellulose,
- carboxyalkyl alkylcelluloses such as carboxymethyl ethykellulose,
- carboxyalkylcellulose esters,
- starches,
- pectines such as sodium earboxymethylarnylopectine,
30 - chuine denvates such aschitosan,
- polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans. traganth, agar-agar, gummi arabicum, guar gummi and xanthan gummi,
- polyacrylic acids and the salts thereof,
35 poiymethacryiic acids and the salts thereof, methacryiaie copolymers.
polyvinylalcohol.
- polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate

WO 00/38686

PCT/EP99/10257

- polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide. Non-enumerated po.lymers which are pharmaceutically acceptable and have appropriate physico-chemical properties as defined hereinbefore are equally suited for preparing
5 particles according to the present invention.
Preferred water-soluble polymers arefor example hydroxypropyl methylcellosee (Methocel®. Pharmacoat®), polymethacrylate (Eudragit E®), hydroxypropylcellulose (Klucel®). or a polyvidune. Especially preferred water-soluble polymers are
10 hydroxypropyl methylcelluloses or HPMC. Said HPMC contains sufficient
hydroxypropyl and methoxy groups to render it water-soluble. HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water-soluble. Methoxy degree of substitution refers to the average number of methyl ether groups present per
15 anhydroglucose unit of the cellulose molecule. Hydroxypropyl molar substitution
refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule. Hydroxypropyl methylcellulose is the United States Adopted Name for hypromellose (see Martindale, The Extra Pharmacopoeia, 29th edition, page 1435). Preferably hydroxypropyl methylcellulose
20 with low viscosity, i.e. about 5 mPa.s, is used, e.g. hydroxypropyl methyJcellulose 2910 5 mPa.s. In the four digit number "2910", the first two digits represent the approximate percentage of methoxy] groups and the third and fourth digits the approximate percentage composition of hydroxypropoxyl groups. 5 mPa.s is a value indicative of
the apparent viscosity of a 2 % aqueous solution at 20°C.
25
Suitable HPMC include those having a viscosity from about 1 to about 100 mPa.s, in particular form about 3 to about 15 mPa.s, preferably about 5 mPa.s The most preferred type of HPMC having a viscosity of 5 mPa.s., is the commercially available HPMC 2910 5 mPa.s. An equally preferred type of HPMC is admixed with 30 polyethylene glycol 400, commercially available from Colorcon (UK) as Opadry™ OY-7240 clear.
The weight-by-weight ratio of drug : polymer is in the range of 17 : 1 to ] : 5, preferably 10 : 1 to 1 : 3 In the case of (galantamine.HBr): (HPMC 2910 5 mPa.s), 35 said ratio may range from about 10 : 1 to about 1 : 3, and optimally is from 7 : 1 to 1: 2.
The weighi-bv-weight ratio of galantamine.HBr to other water-soluble polymers may be determined by a person skilled in the an by straightforward experimentation. The lower limit is determined by practical considerations.

WO 00/38686 PCT/EP99/10257
In particular the present invention is concerned with particles which comprise (a) a central, rounded or spherical core, (b) a layer or a coating film of a water-soluble polymer and galantamuneeobromide (1:1), (c) optionally a seal coating polymer 5 layer and (d) a release rate controlling membrane coating The core has a diameter of about 250 to about 1.180 pm(16-60 mesh), preferably of about 600 to about LI 80 urn 116-30 mesh).
Pellets, beads or cores of me dimensions mentioned herein can be obtained by sieving 10 throughnominal standard test sieves as descnbed in the CRC Handbook, 64th ed., page F ] 14. Nominal standard sieves are characterized by the mesh/hole width (um), DIN 4188 (mm), ASTM E 11-70 (No), Tyler® (mesh) orBS 410 (mesh) standard values. Throughout this description and the claims, particle sizes are designated by reference to the mesh/hole width in um and to the corresponding Sieve No in the ASTM El1-70 15 standard.
Materials suitable for use as cores in the particles according to the present invention are manifold, provided that said materials are pharaceutically acceptable and have appropriate dimensions (about 16-60 mesh) and firmness. Examples of such materials
20 are pplymers e.g. plastic resins; inorganic substances, e.g. silica, glass, hydroxyapatite, salts (sodiumpotassium chloride, calcium or magnesium carbonate) and the like; organic substances, e.g. activated carbon, acids (citric, fumaric, tartaric, ascorbic and the like acids), and saccharides and derivatives thereof. Particularly suitable materials are saccharides such as sugars, oligosaccharides, polysaccharides and their derivatives,
25 for example, glucose, rhamnose, galactose, lactose, sucrose, mantitol, sorbitol, dextrin, maltoextrin, cellulose, microcrystalline cellulose, sodium carbbxyrnethyl cellulose, starches (maize, rice, potato, wheat, tapioca) and the like saccharides
A particularly preferred material suitable for use as cores in theparticles according to 30 the present invention is represented by 16-60 mesh sugar spheres (USP 22 / NF XVII p. 1989) which consist of 62.5% - 91.5% (w/w) sucrose, the remainder being starch and possibly also dextrines, and which are pharmaceutically inert or neutral. Consequently, these cores are also known in the art as neutral pellets.
35 Depending on the weight-by-weight ratio of drug : polymer, the water-soluble polymer and galantamme are herein said to form either a layer (ratio > 10 : 1) or a coat or coating film (ratio
WO 00/38686 PCT/EP99/10257
As an alternative to the drug layered or drug coated inert pellets descnbed thus far, suitable particles comprising glantarrune may also be formed by granules or by spheroids (spherical granules) prepared according to art-known methods of granulation
and spheronization
5
The release rate controlling membrane coating comprises a waiei insoluble polymer and optionally a plasticizer. Said polymer is ethylcellulose and the plasticizer is selected from the group comprising dibutvl sebacate, diethvl phthalate and triethvl citrate. It is useful to modify the properties of the water-insoluble polymer by the
10 addition of particular amounis of a water-soluble polymer as descnbed hereinbefore, preferably HPMC. The addition of the water-soluble polymer is especially useful to increase the onset of action. For the particles according to the present invention, the ratio ethylcellulose : HPMC can vary from 100 : 0 to about 70 : 30, in particular from about 80 : 20 to about 72.5 - 27.5, more in particular from about 75 : 25 to about 72.5 :
15 27.5. The release rate controlling membrane coating may be applied to the drug coated cores in an aqueous dispersion (Aquacoat™, Surelease™), or as a solution in an organic solvent system. A useful organic system comprises an alcohol, e.g. methanol or ethanol, and optionally a chlorinated hydrocarbon such as for example
dichloromethane.
20
The weight of the release rate controlling membrane coating ranges from 3 % to 15 % of the uncoated particle, in particular from about 4% to about 12 %. The rate of release of the active ingredient from the particles is approximately inversely proportional with
the thickness of the release rate controlling membrane coating.
25
A seal coat lies optionally between the drug core and the release rate controlling . membrane coating. The seal coating polymer layer isappli to thedrug coated cores to prevent sticking of the particles during the process and to prevent migration of the drug into the the release rate controlling membrane. Preferably, a thin layer of HPMC 30 2910 5 mPa.s and polyethylene glycol (PEG), in particular polyethylene glycol 400 is used as a seal coating polymer layer.
In addition, the particles according to the present invention may further contain various additives such as thickening agents, lubricants, surfactants, preservatives, complexing 35 and chelating agents, electrolytes or other active ingredients.
The particles can be filled in hard-gelatin capsules such that a therapeutically effective amount of, for example, 8 to 32 mg of the active ingredient is available per dosage

WO 00/38686 PCT/EP99/10257
form. An advantageous pharmacokinetic profile profile (fast onset, level peak and trough values) is obtained when from 70 to 80 % of the galantamine is comprised " within the controlled release particles and the remaining 20 to 30 % of the galantamine is comprised in an immediate release form, preferaby the controlled releases particle 5 amount to 75 % of the galantamine and the immediate release form to 25 %.
In order to achieve the desired pharmacokinetic, the dosage forms may be filled with
particles that release the active ingredient ai different rates, at least one kind that
releases the active ingredient slowly, and at least one kind that releases the active
10 ingredient more rapidh. m particular one kind that releases the active ingredient
immediately, e.g. particles as described thai lack the release rate controlling membrane.
The different particles may be filled consecutively in the capsules, or they may be
prerruxed and the thus obtained premix may be filled into the capsules (taking into
account possible segregation). 15
Alternatively, the controlled release particles of the present invention may further
comprise a top-coat of a water-soluble polymer as described hereinbefore and
galantamine which is released practically immediately upon ingestion and thus ensures
a rapid onset of action. 20
Another alternative solution for providing a dosage form with a pharmacokinetic profile
as outlined, nameljy with a fast onset, level peak and trough values, comprises filling a
capsule with controlled release particles as described hereinbefore (70 to 80 %,
preferably 75 % of the galantamine dose) together with one or more minitablets which
25 comprise the remaining 20 to 30 %, preferably 25 % of galantamine. Suitable ___
immediate release tablet formulations of galantamine have been described previously in
WO-97/47304.
The present invention also relates to processes of preparing formulations as described 30 hereinbefore comprising admixing galantamine or a phannaceutically acceptable salt form thereof with a water soluble excipient to form a drug core, optionally applying a seal coat to the drug core, and thereafter applying the release rate controlling membrane coating.
35 The particles according to the present invention are conveniently prepared in the
following manner. A drug coating solution is prepared by dissolving into a suitable solvent system appropriate amounts of galantamine.HBr and a water-soluble polymer. A suitable solvent system comprises purified water or an alcohol, preferably ethanol
8

WO 00/38686 PCT/EP99/10257

which may be denatured, for example, with butanone. The amounts of solids, i.e. galaniarrune.HBr and water-soluble polymer, in the drug coating solution may range from 10 to 30% (w/w) and preferably is about 25 %. The solution is preferably stirred
during the coating process.
5
The drug coating process (on an industrial scale) is conveniently conducted in a fluidized bed granulator (e.g. Glati type WSG-30 or GPCG-30) equipped with a Wurster bottom spray insert (e.g. an 18 inch Wurster insert). Laboratory scale process development can be performed on a Glatt type WSG-1 with a 6 inch Wurster bottom 10 insen. Obviously the process parameters depend on the equipment used.
The spraying rate should be regulated carefully. Too low a spraying rate can cause some spray drying of the drug coating solution and result in a loss of product. Too high a spraying rate will cause overwetlmg with subsequent agglomeration. Agglomeration 15 being the most serious problem, lower spraying rates may be used initially, to be increased as the coating process proceeds and the particles grow larger.
The atomizing air pressure with which the drug coating solution is applied also influences the coating performance. Low atomizing air pressure results in the\ 20 formation of larger droplets and an increased tendency toward agglomeration. High atomizing air pressure could conceivably carry the risk of spray drying the drug solution, but this was found not to be a problem. Consequently, atomizing air pressure may be set at nearly maximum levels.
25 Fluidizing air volume can be monitored by operating the exhaust air-valve .of the apparatus and should be set in such a manner that optimum pellet circulation is obtained. Too low an air volume will cause insufficient fluidization of the pellets; too high an air volume will interfere with the pellet circulation due to countercurrent air streams developing in the apparatus. In the present process optimum conditions were
30 obtained by opening the exhaust air valve to about 50% of its maximum and gradually increasing the opening thereof to about 60% of the maximum as the coating process proceeded.
The coating process is advantageously conducted by employing an inlet-air temperature 35 ranging from about 50°C to about 55°C. Higher temperatures may speed up the process but have the disadvantage that solvent evaporation is so rapid that the coating liquid is not spread uniformly on the surface of the pellets resulting in the formation of a drug coating layer with high porosity. As the bulk volume of the coated pellets increases.

WO 00/38686 PCT/EP99/10257
drug dissolunon may decrease significantly to unacceptable levels. Obviously, the optimum process temperature will further depend on the equipment used, the nature of the core, the batch volume, the solvent and the spraying rate.
5 Parameter settings for optimum coating results are described in more detail in the
example hereinafter. Running the coating process under those conditions was found to yield very reproducible results.
In order to decrease residual solvent levels in the pellets following application of the 10 rate controlling membrane from an organic solution, the pellets can conveniently be dned in any suitable drying apparatus. Good results may be obtained using a vacuum tumbler-drier operated at a temperature from about 60°C to about 90°C, preferably about 80°C, a reduced pressure ranging from about 150-400 mbar (15-40 kPa), preferably 200-300 mbar (20-30 kPa), for at least 24 hours, preferably about 36 hours 15 The vacuum tumbler-drier is conveniently rotated at its minimum speed, e.g. 2 to 3 rpm After drying, the drug coated cores may be sieved.
The seal coat layer is applied to the drug coaled cores in the fluidized bed granulator with Wurster bottom spray insert or in a powder coater. The seal coating solution can
20 be prepared by dissolving an appropriate amount of a seal coating polymer into a
suitable solvent system. Such a system, is, e.g. purified water or an alcohol, preferably ethanol which may be denatured with, for example, butanone. The amount of seal coating polymer in the seal coating spraying solution may range from 5 to 10% (w/w) and preferably is about 6.6%. The seal coating spraying solution is advantageously
25 stirred during the seal coating process. Appropriate conditions are described in more detail in the example hereihafter.
A further drying step may be required after applying the seal, qoating polymer layer. Excess solvents could easily be removed while operating the apparatus at the parameter 30 settings used for about 5 to 15 minutes after the spraying had been completed.
The release rate controlling membrane coating polymer layer is applied to the drug (or seal) coated cores in a fluidized bed granulator with Wurster bottom spray insert. The release rate controlling membrane coating suspension or solution can be prepared by 35 suspending or dissolving an appropriate amount of a release rate controlling membrane coating polymer into a suitable solvent system. Such a system, is, e.g. purified water or an alcohol, preferably ethanol which may be denatured with, for example, butanone. dichioromeihane which may be admixed with an alcohol, preferably methanol or
10

WO 00/38686

PCT/EP99/10257

ethanol The amount of release rate controlling membrane coating polymer in the spraying suspension or solution may range from 5 to 40% (w/w) and preferably is about 30%. The release rate controlling membrane coating spraying suspension or solution is advantageously stirred during the spraying process. The parameter setting for 5 conducting this last step is essentially similar to that used in the previous coating processes. Appropriate conditions are described in more detail in the example hereinafter.
All coating processes are preferably conducted under an men atmosphere of e.g.
10 nitrogen. The coating equipment should preferably be grounded and provided wuh an
appropriate solvent recovery system containing an efficient condensing system.
The particles may be filled in hard-gelatin capsules using standard automatic capsule filling machines. Suitable earthing and de-iomsation equipment can advantageously 15 prevent development of electrostatic charges.
Capsule filling speed may influence weight distribution and should be monitored.
Good results are obtained when operating the equipment at about 75% to 85% of the
maximum speed and in many cases when operatingiat full speed. 20
Dosage forms according to the present invention having an advantageous
pharmacokinetic profile as outlined, namely a fast onset and level peak and trough
values, are capable of releasing in 500 ml USP buffer (pH 6.8) at 37°C in an Apparatus
2 (USP 23, Dissolution, pp 1791-1793, paddle, 50 rpm) from 20 to 40 % of the
25 total amount of galantamine.HBr in 1 hour, and more than he. total amount of
galantamincHBr in 10 hours. Said dosage forms provide a mean maximum plasma
concentration of galantamine from 10 to 60 ng/ml and a mean minimum plasma
concentration from 3 to 15 ng/ml after repeated administration ever day through
steady-state conditions.
30
The formulations according to the present invention deliver a therapeutically effective amount of galantamine to a patient during the 24 hours following a single once daily administration.
35 The present invention also concerns pharmaceutical packages suitable for commercial sale comprising a container, a formulation of galantamine as claimed in claim 1, and associated with said package written matter specifying how said formulation should be administered.

WO 00/38686 PCT7EP99/10257

Said pharmaceutical packages may be adapted for titrating a patient who is "acetylcholine esterase inhibitor"-nai"ve, i.e. a patient who has not been exposed to an acetylcholine esterase inhibitor before and who should start with small, well-tolerated doses before being exposed to ever higher doses until the optimal dose is reached. Said packages typically comprises 21-35 daily sequential dosage units of
(a) a first group of 7 to 14 dosage units comprising from 5 to 10 mg galantamine.
(b) a second group of 7 to 14 dosage units comprising from 10 to 20 mg galantamine,
(c) a third group of 7 to 14 dosage units comprising from 15 to 30 mg galantamine. and
(d) optionally a fourth group of 7 dosage units comprising from 20 to 40 mg galantamine.
Alternatively, the pharmaceutical packages may be adapted for treating a pauem who is acetylcholine esterase inhibitor"-tolerant, i.e. a patient who has been exposed to an acetylcholine esterase inhibitor before and who tolerates an optimal dose Said 15 packages typically comprises daily dosage units comprising from 15 to 30 mg galantamine.
A method of treating Alzheimer"s dementia and related dementias in a human while substantially reducing (avoiding) the concomitant liability of adverse effects associated 20 with acetyl cholinesterase inhibitors, comprising administering to a human in need of such treatment, a therapeutically effective amount of galantamine in a controlled release formulation as claimed in claim 1, said amount being sufficient to alleviate said Alzheimer"s dementia and related dementias, but insufficient to cause said adverse effects.
25 ;.
The related dementia belongs to the group consisting of vascular dementia. Lewy body
disease, autism, mental retardation;,l?ipbiar$isorder psychiatric conditions, disruptive
behaviour, attention deficit hyperactivity aisbrder\ substance abuse, extreme aggression,
especially conduct disorder, nicotine cessation and withdrawal. 30
The adverse effects belong to the group comprising nausea, vomiting, sweating,
restlessness, and insomnia.

WO 00/38686 PCT/EP99/1025"
Experimental part
Example I : 8 mg galantamine CR oral capsule (Fl)
Ingredients :
galantamme hydrobromide 10.253 mg (8 mg galaniamine base)
5 sugar spheres (18-20 mesh) 63.283 mg
HPMC 29l0 5mPa.s 1.465 mg
purified water 37.105 pi *
HPMC 2910 5mPa.s 1.500 mg
polyethylene glycol 400 0.150 mg
10 punfied water 23.350 pi *
ethylcellulose aqueous dispersion 10.220 mg (30%)
dibutyl sebacate 0.736 mg
punfied water 10.220 pi *
capsule nr. 4 15 * : these ingredients do not occur in the end product
Preparation :
a) Drug coat suspension
Galantamine hydrobromide (123 g) was suspended in 297 mJ purified water and heated to 70 -80 °C. HPMC 2910 5 mPa.s (17.58 g) was dissolved in the heated supension 20 whilst stirring.
b) Seal coat solution
Purified water (93. 4 g) was heated to 70 - 80°C and HPMC 2910 5 mPa.s (18 g) and polyethylene glycol 400 (1.8 g) were dissolved therein. The solution was then further diluted with purified water (186.8 g).
25 c) Release rate controlling membrane coat dispersion
To a gently stirred aqueous dispersion of ethylcellulose (122.6 g ; 30 %) was added dibutyl sebacate (8.832 g). The dispersion was diluted with purified water (122.6 g).
d) Coating process
A fluidized-bed granulaior (Glau. type WSG 1) equipped with a 6.mch Wurster
30 (bottom spray) insen was loaded with 18-20 mesh sugar spheres (759.4 g). The spheres were warmed with dry air of about 50°C. The fluidizing air volume was controlled by opening the exhaust air valve to approximately 45 % of its maximum. The drug coat suspension was spraved on the spheres moving in the apparatus The suspension was sprayed ai a dehver\ rate of about 5 to 30 g.min ai an atomizing air pressure of about
35 1.6 to 4.0 bar (0 16 -0.4 MPs). When the spraying process was completed, the coated spheres were dried by funher supplying dry air of 60°C for about 2 minutes. The

WO 00/38686 PCT/EP99/)025^

coated spheres were then seal coated with the sealcoat solution using the same parameters as used in the drug coating process. After drying for about 2 minutes, the seal coated spheres were allowed to cool to room temperature and filled into a stainless steel drum. 5 The fluidized-bed granulator (Glatt. type WSG 1) equipped with a 6 inch Wurster (bottom spray) insert was reloaded with the seal coated spheres. The spheres were warmed with dry air of about 50°C. The fluidizing air volume was controlled by opening the exhaust air valve 10 approximately 45 % of its maximum The release rate controlling membrane coat suspension was sprayed on the spheres moving in the 10 apparatus. The suspension was sprayed at a delivery rate of about 5 to 30 g.min" ■* at an atomizing air pressure of about 1.6 to 4.0 bar (0.16 -0.4 MPa). After drying for about 2 minutes, the controlled release membrane coated spheres were allowed to cool to room temperature and filled into a stainless steel drum.
e) drying and curing process
15 In order to remove agglomerates, the coated spheres were sieved usmg a sieve having a mesh width of 1.2 mm. The panicles were placed in a drying oven at 60°C during 2 hours so as to cure the release rate controlling membrane.
f) capsule filling
The particles were filled into hard-gelatin capsules (size 4) using standard automatic 20 capsule filling machines (e.g. Model GFK-1500, Hoffliger and Karg. Germany). In order to obtain capsules with good weight distribution, capsule filling speed was reduced to about 75-85% of the maximum speed. Each capsule received approximately 87.6 mg particles, equivalent to about 8 mg galantamine.
30
(30 %)
25 Example 2 : 8 mg galantamine CR oral capsule (F2)
Ingredients:
galantamine hydrobromide 10.253 mg (
sugar spheres (18-20 mesh) 63.283 mg
HPMC 2910 5mPa.s 1.465 mg
purified water 37.105 fil
HPMC 2910 5mPa.s 1.500 mg
polyethylene glycol 400 0.150 mg
purified water 23.350 jil
ethvlcellulose aqueous dispersion 25.550 mg
dibutyl sebacate 1.840 mg
purified water 25.550 u.1
capsule nr 4

WO 00/38686 PCT/EP99/10257
* : these ingredients do not occur in the end product Preparation .
The preparation was identical to that described in Example 1 except for the preparation 5 of the release rate controlling membrane dispersion.
c) Release rate controlling membrane coat dispersion
To a gently stirred aqueous dispersion of ethyl cellulose (306.6 g ; 30 %) was added
dibutyl sebacate (22.08 g) The dispersion was diluted with punfied water (306.6 g). 10
Example 3: Bioavailability
The bioavailability of a single oral administration of the two controlled release
formulations of examples 1 and 2 was compared with that of an immediate release
tablet (F3) [WO-97/47304] comprising 4 mg galantamine which was administered
15 twice daily with an interval of 8 hours. Galantamine plasma levels in healthy
volunteers (12) were determined by HPLC and the mean values calculated from the
individual measurements are reported in the following table.

time (h) Fl F2 F3
0 nd nd nd
0.5 1.6 nd 16.4
1 7.3 nd 24.1
1.5 11.5 nd 203
2 16.3 1,8—--. 18.3
3 23.8 3.7 16.9
4 26.7 6,3 14.5
6 25.2 9.5- 11.3
8 22.5 10.5 9.3
8.5 18
9 24.5
9.5 25.5
10 18.6 11.1 23.7
11 22.7
12 15.1 12.0 19.3
14 13.4 124 15.2
16 10.8 11.7 12.7
24 6.0
1 8.8 6.6
15

WO 00/38686

PCT/EP99/102S"

time (h) FI F2 F3
30 3.5 6.1 3.5
36 2.0 4.3 2.0
48 nd 1.6 nd

nd " noi deiecinbie

ng/ml)

Example 4 . oral capsule (F4) comprising 8 mg galantarrune
(75 % CR pellets and 25 % IP Tablet) Ingredients

63.482 mg
sugar spheres (18-20 mesh)
7.69 mg (6 mg galantamine base) 0.641 mg 42.932 p.1
1.436 mg
0.145 mg
12.385 uJ
10.858 mg *
1.101 mg
3.308 mg
0.881 mg
31.077 jil *
27.244 mg
2.563jng (2 mg galantamine base)
galantamine hydrobromide HPMC 29J0 5mPa.s punfied wafer
10
HPMC 2910 5 mPa.s polyethylene glycol 400 methylene chlonde eihanol 96 % (v/v)
15
HPMC29l0 5mPa.s eihylcellulose 20 mPa.s diethyl phthalate methylene chlonde ethanol 96 % (v/v)
galantamine hydrobromide
spray-dried mixture of lactose monohydrate
20
and microcrysiailme cellulose. (75325) 49.302 mg
colloidal anhydrous silica 0.11 mg
crospolyvidone 2.750 mg
magnesium siearate 0.275 mg
25 * . these ingredients do not occur in the end product
Preparation : a) Drug layer suspension
Galantamine hvdiobromide was suspended in punfied water and heated to 70 -80 CC 30 HPMC 29)0 5 mPa s was dissolved in the heated supension whilst stirring.

WO 00/38686 PCT/EP99/10257
b) Seal coat solution
Methylene chloride and ethanoi were mixed together and polyethylene glycol and
HPMC 2910 5 mPa.s were dissolved therein.
.i Release rate controlling membrane coat solution
Methylene chloride and ethanoi were mixed and ethylcellulose 20 mPa.s, HPMC 2910 5 mPa.s and diethyl phthalaie were added while stirring the solution.
d) Layering and coating process
10 A fluidized-bed granulaior (Glan) equipped wjih a Wurster (bottom spray) insert was loaded with 18-20 mesh sugar spheres. The spheres were warmed with dry air of about 50°C The fluidizing air volume was controlled by opening the exhaust air valve to approximately 45 % of its maximum. The drug layer suspension was sprayed on the spheres moving in the apparatus When the spraying process was completed, the layered
15 spheres were dried by further supplying dry air of 60°C for about 2 minutes. The layered spheres were then seal coated with the seal coat solution using the same parameters as used in the drug coating process. After drying for about 2 minutes, the seal coated spheres were allowed to cool to room temperature and filled into a stainless steel drum.
20 The fluidized-bed granulator (Glan) equipped with a Wurster (bottom spray) insert was reloaded with the seal coated spheres. The spheres were warmed with dry air of about 50°C The fluidizing air volume was controlled by opening the exhaust air valve to approximately 45 % of its maximum. The release rate controlling membrane coat suspension was sprayed on the spheres moving in the apparatus. After drying for about
2? 2 minutes, the controlled release membrane coated spheres were allowed to^ool to room temperature, sieved and filled into a stainless steel drum.
e) immediate release minitablet
Galantamine hydrobromide, spray-dried mixture of lactose monohydrate 30 and microcrystalline cellulose (75:25), colloidal anhydrous silica, crospolyvidone and magnesium stearate were mixed in a planetary mixer and compressed in a tabletting machine, thus preparing minitablets of 55 mg weight.
f) capsule filling
35 The coated spheres and the immediate release minitab were filled into hard-gelatin
capsules (sue 0) using standard automatic capsule filling machines (eg. Model GFK-1500. Hoffhger and Karg- Germany)

WO 00/38686 PCT/EP99/10257
Example 5 : galaniamine oral capsules (F5, F6, F7, F8)
(75 % CR pellets and 25 % IR topcoat)
Ingredients:
sugar spheres (18-20 mesh) 63.624 mg
5 galantamine hydrobromide 7.69 mg (6 mg galantamine base)
HPMC 2910 5 mPa.s and PEG 400 12.687 mg (Opadry™ OY-7240 Clear, Colorcon)
purified water 267.693 ul *
HPMC2910 5mPa.s 1.260 ms
ethylcellulose 20 mPa.s 3.780 mg
10 diethyl phthalate 1.008 mg
methylene chloride 46.772 pi *
ethanol 96 % (v/v) 31.184 mg
galantamine hydrobromide 2.563 mg (2 mg galantamine base)
HPMC 2910 5 mPa.s and PEG 400 4.229 mg (Opadry OY-7240 Clear)
15 purified water 89.321 ul *
capsules size nr. 4,2, 1 and 0.
*: these ingredients do not occur in the end product
20 Preparation:
a) Drug coat solution
Galantamine hydrobromide and Opadry OY-7240 Clear were dissolved in purified
water at room temperature.
25 b) Release rate controlling membrane coat solution
Methylene chloride and ethanol were mixed and ethylcellulose 20 mP-a-S, HPMC 2910 5 mPa.s and diethyl phthalate were added while stirring the solution. --
c) Drug topcoat solution
30 Galantamine hydrobromide and Opadry™ OY-7240 Clear were dissolved in purified wateria room tempeature.
d) Goating process
A fluiiized-bed granulatbr (Glatt) equipped with a Wurster (bottom spray) insert was 35 loaded with 18-20 mesh sugar spheres. The spheres were warmed with dry air of about 50°C. The fluidizing air volume was controlled by opening the exhaust air valve to approximately 45 % of its maximum. The drug coat solution was sprayed on the

WO 00/38686

PCT/EP99/10257

, spheres moving in the apparatus. When the spraying process was completed, the coated spheres were dried by further supplying dry air of 60°C for about 2 minutes. The release rate controlling membrane coat solution was sprayed on the spheres moving in the apparatus. After drying for about 2 minutes, the controlled release membrane coated 5 spheres were sprayed with the drug topcoat solution. After drying for about 2 minutes, the topcoated spheres were allowed to cool to room temperature, sieved and were filled into a stainless steel drum.
e) capsule filling 10 The topcoated spheres (96.841 mg ; 193.683 mg : 290.524 ; 387.365 rag) were filled into hard-gelatin capsules (size numbers 4, 2, 1, 0) using standard automatic capsule filling machines (e.g. Model GFK-1500, Hoffliger and Karg. Germany) yielding oral capsules containing respectively 8 mg, 16 mg, 24 mg and 32 mg galantamine base.
15 Example 6 : galantamine oral capsules (F9)
(75 % CR pellets and 25 % TR topcoat)
Spheres having slightly faster release were made by lowering the ratio of ethylcellulose
20 mPa.s to HPMC 2910 5 mPa.s to 72.5 : 27.5 (as compared to the ratio 75 : 25 in the
previous example. 20
Example 7 : In vitro dissolution of the topcoated spheres
Comparative in-viiro dissolutions studies were performed on the topcoated spheres
formulations F5 to F8 and F9. The medium was 500 ml of USP buffer pH 6.8 at 37°C
in Apparatus 2 (USP 23, Dissolution, pp. 1791-1793) (paddle, 50 rpm).
25" The following results were obtained:

F5 to F8

Time Calculatec concentration (% w/w) of the active dose

sample 1 sample 2 sample 3 sample A sample 5 sample 6 average
(min)
0 ..... 0.00 0.00 0.00 0.00 0.00 0.00 0.00
60 32.20 30.44 37.47 30.44 30.44 38.05 33.17
120 42.54 41.37 48.39 41.37 42.54 42.54 43.13
240 58.93 60.10 65.96 61.27 61.27 61.27 61.47
480 85.47 80.20 84.30 81.96 81.37 80.79 82.35
720 91.52 90.35 97.37 99 13 92.11 87.42 92.98
1080 96.59 97.18 102.45 102.45 99.52 98.94 99.52
1410 9640 97.57 103.42 103.42 100.5 101.08 100.40 ;
19

WO 00/38686 PCT/EPW/102S7
F9

Calculated concentration (% w/w) of the active dose
Time sample 1 sample 2 sample 3 sample 4 sample 5 sample 6 average
(min)
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00
60 38.9 36.0 36.5 39.5 33.4 37.2 32.86
120 60.3 55.7 56.9 60.4 60.9 55.1 58.2
240 89.5 81.8 86.2 86.7 91.2 84.0 86.6
480 103.4 103.6 95.9 101.7 100.8 105.8 101.9
720 107.0 99.0 104.0 103.1 109.1 100.8 103.8

WE CLAIM:
1. A controlled release formulation containing galantamine as the active ingredient, wherein it comprises particles comprising galantamine hydrobromide (1:1), and a water soluble film forming polymer wherein the galantamine hydrobromide (1:1) and the water soluble film forming polymer are layered or coated on inert spheres, said particles being coated by a release rate controlling membrane coating wherein the release rate controlling membrane coating comprises a water insoluble polymer and optionally a plasticizer, and wherein the formulation further comprises a topcoat comprising galantamine and water-soluble polymer and wherein the formulation is capable of releasing in USP buffer pH 6.8 at 37° C. in a paddle apparatus operating at 50 rpm, from 20 to 40% of the total amount of galantamine.HBr in 1 hour, and more than 80% of the total amount of galantamine.HBr in 10 hours.
2. A formulation as claimed in claim 1 wherein the water insoluble polymer is ethylcellulose and the plasticizer is selected from the group consisting of dibutyl sebacate, diethyl phthalate and triethyl citrate.
3. A formulation as claimed in claim 2 wherein the weight of the release rate controlling membrane coating ranges from 3% to 15% of the uncoated particle.
4. A formulation as claimed in claim 1 wherein a seal coat lies between the drug core and the release rate controlling membrane coating.
5. A formulation as claimed in claim 1 wherein the water soluble film forming polymer is a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution at 20° C solution.

6. A formulation as claimed in claim 5 wherein the water soluble polymer is selected from the group consisting of alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose, hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose, carboxyalkylcelluloses such as carboxymethylcellulose, alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose, carboxyalkylalkylcelluloses such as carboxymethylethylcellulose, carboxyalkylcellulose esters, starches, pectines such as sodium carboxymethylamylopectine, chitine derivatives such as chitosan, polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, traganth, agar-agar, gummi arabicum, guar gummi and xanthan gummi, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts thereof, methacrylate copolymers, polyvinylalcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.
7. A formulation as claimed in claim 6 wherein the water soluble polymer is hydroxypropyl methylcellulose HPMC 2910 with an apparent viscosity of 5 mPa.s when dissolved in a 2% aqueous solution at 20° C.
8. A formulation as claimed in claim 7 wherein the weight-by-weight ratio of said hydroxypropyl methylcellulose to galantamine is in the range of 17:1 to 1:5.
9. A formulation as claimed in claim 1 wherein the inert spheres are I8¬60 mesh (1,180 250 .mu.m) sugar spheres.
10. A formulation as claimed in any one of claims 5, 6, 7, 8, 9 or 4 which delivers a therapeutically effective amount of galantamine to a patient during the 24 hours following a single once daily administration.

11. A formulation according to claim 1 providing a mean maximum plasma concentration of galantamine from 10 to 60 ng/ml and a mean minimum plasma concentration from 3 to 15 ng/ml after repeated administration every day through steady-state conditions.

EMFRY 8B SAGAR TOR THE APPLICANTS
Dated this 15th day of May, 2001

Documents:

in-pct-2001-558-mum-cancelled pages(22-5-2007).pdf

in-pct-2001-558-mum-claims(granted)-(22-5-2007).doc

in-pct-2001-558-mum-claims(granted)-(22-5-2007).pdf

in-pct-2001-558-mum-correspondence(15-6-2007).pdf

in-pct-2001-558-mum-correspondence(ipo)-(12-6-2007).pdf

in-pct-2001-558-mum-form 1(15-5-2001).pdf

in-pct-2001-558-mum-form 1(22-5-2007).pdf

in-pct-2001-558-mum-form 18(9-11-2005).pdf

in-pct-2001-558-mum-form 2(granted)-(22-5-2007).doc

in-pct-2001-558-mum-form 2(granted)-(22-5-2007).pdf

in-pct-2001-558-mum-form 3(15-5-2001).pdf

in-pct-2001-558-mum-form 3(22-5-2007).pdf

in-pct-2001-558-mum-form 5(15-5-2001).pdf

in-pct-2001-558-mum-form-pct-iper-409(15-5-2001).pdf

in-pct-2001-558-mum-petition under rule137(23-5-2007).pdf

in-pct-2001-558-mum-petition under rule138(23-5-2007).pdf

in-pct-2001-558-mum-power of authority(2-8-2001).pdf

in-pct-2001-558-mum-power of authority(22-5-2007).pdf

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Patent Number

209167

Indian Patent Application Number

IN/PCT/2001/00558/MUM

PG Journal Number

35/2007

Publication Date

31-Aug-2007

Grant Date

22-Aug-2007

Date of Filing

15-May-2001

Name of Patentee

JANSSEN PHARMACEUTICA N.V.

Applicant Address

TURNHOUTSEWEG 30, B2340 BEERSE

Inventors:

#	Inventor's Name	Inventor's Address
1	JOHN PAUL McGEE	C/O JANSSEN PHARMACEUTICA N.V. TURNHOUTSEWEG 30, B2340 BEERSE
2	PAUL MARIE VICTOR GILIS	C/O JANSSEN PHARMACEUTICA N.V. TURNHOUTSEWEG 30, B2340 BEERSE
3	MARC MAURICE GERMAIN DE WEER	C/O JANSSEN PHARMACEUTICA N.V. TURNHOUTSEWEG 30, B2340 BEERSE
4	VALENTIN FLORENT VICTOR DE CONDE	C/O JANSSEN PHARMACEUTICA N.V. TURNHOUTSEWEG 30, B2340 BEERSE
5	HERMAN JOHANNES CATHERINA DE BRUIJN	C/O JANSSEN PHARMACEUTICA N.V. TURNHOUTSEWEG 30, B2340 BEERSE
6	FREDERIC ANNE RODOLF VAN DYCKE	C/O JANSSEN PHARMACEUTICA N.V. TURNHOUTSEWEG 30, B2340 BEERSE

PCT International Classification Number

A61K 9/50

PCT International Application Number

PCT/EP99/10257

PCT International Filing date

1999-12-20

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	98204447.1	1998-12-24	EPO