MXPA01006529A - Controlled release galantamine composition - Google Patents

Abstract

The present invention is concerned with controlled release compositions for oral administration comprising galantamine;and with processes of preparing such controlled release compositions.

Description

COMPOSITION OF CONTROLLED LIBERATION GALANTAMINE DESCRIPTIVE MEMORY The present invention relates to controlled release compositions for oral administration comprising galantamine; and with its procedures for the preparation of said controlled release compositions. Galanthamine (I), a tertiary alkaloid, has been isolated from the bulb of the Caucasian glabella, Galanthus woronowi (Proskumina, NF and Yakoleva, AP 1952, Alkaloids of Galanthus 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 Galanthus nivalis (Boit, 1954).

The chemical name of galantamine is [4aS- (4aa, 6ß, 8aR *)] - 4a, ,9,10,11, 12-hexahydro-3-methoxy-11-methyl-6H-benzofuro [3a, 3,2-ef] [2] benzazepin-6-ol; both the base compound and its hydrobromide are levorotatory. Galantamine is a well-known acetylcholine esterase inhibitor, which is active at nicotinic receptor sites but not at muscarinic receptor sites. It is capable of passing the cerebral blood barrier in humans, and does not present severe side effects in therapeutically effective dosages. Galantamine has been used extensively as a curare investment agent in anesthetic practice in Eastern bloc countries (see review by Paskow, 1986) and also experimentally in the West (see Bretagne and Valetta, 1965; Wlslicki, 1967; Consanitis, 1971). Galantamine 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 galantamine or an analog or a pharmaceutically acceptable acid addition salt thereof, for the preparation of a medicament for the treatment of Alzheimer's Dementia (AD) and related dementias, has been described in EP-0,236,684 (US-4,663,318 ). This patent has only a generic description of possible dosage forms of galantamine. CA-1, 326,632 generically describes slow release formulations of galantamine. The use of galantamine for the treatment of alcoholism and administration by means of a transdermal therapeutic system (TTS) or patch is described in EP-0,449,247 and in WO 94/16707. Likewise, the use of galantamine in the treatment of nicotine dependence using the administration by means of a transdermal therapeutic system (TTS) or patch, is described in WO-94/16708. The treatment of nerve gas poisoning is described in DE-4,342,174. A number of applications by E. Snorrason disclose the use of galantamine, analogs thereof and pharmaceutically acceptable salts thereof, for the preparation in medicaments for the treatment of mania (EUA-5,336,675), chronic fatigue syndrome (CFS) ( EP-0,515,302; US-5,312,817), the negative effects of the benzodiazepine treatment (EP-0,515,301) and the treatment of schizophrenia (US-5,633,238). In these applications and patents, for example, in EUA-5,312,817, a number of immediate-release tablet formulations of galantamine hydrobromide are provided. WO-97/47304 (equivalent to the patent application Agentina No. P97 0102615) describes tablets of immediate release or rapid dissolution of galantamine, prepared by direct compression. These and other immediate release tablets well known in the art are administered twice (b.i.) daily, with an interval of 8 hours. The plasma levels of the active ingredient typically rise acutely (early Tmax and relatively high Cmax) and fall rapidly (deep depression after approximately 6 to 8 hours). Galantamine therapy can be considered optimal when effective plasma levels are reached when required. In addition, the peak values (Cmax) should be as low and even as possible, way to reduce the incidence and severity of possible side effects. The preceding requirements apply not only to the administration of a single dose, but also to the administration of repeated doses (until a steady-state condition is reached). In particular, when treating a patient suffering from Alzheimer's disease, optimal efficacy is expected when plasma levels are maintained effective during the day; During the night, the galantamine plasma levels can probably go down. For the treatment of other conditions, for example for the treatment of disordered sleep breathing, such as snoring and apnea (WO-97/22339), one may wish to achieve the inverse situation, say, having effective plasma levels during night, and lower levels during the day. For the benefit of the patient and the dependents, a pharmaceutical dosage form that has to be administered once a day only and that produces effective plasma levels for eight hours (night) to 16 hours (day) would be highly desirable. The present invention relates to 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; a pharmaceutically acceptable excipient soluble in water, and optionally other excipient; pharmaceutically acceptable, said particles are coated by a membrane coating controlling the release index. Dosage forms that comprise an amount therapeutically effective of said controlled release formulations can be administered orally to a patient once a day. In preferred dosage forms, part of the galantamine is present in an immediate release form, for example, as particles lacking a membrane coating controlling the release index, or as an immediate-release mini-tablet, or as a top cover about the controlled release formulation. Preferably, the formulation according to the present invention comprises galantamine in the form of galantamine hydrobromide (1: 1). Water-soluble excipient may conveniently be a film-forming polymer. Useful water-soluble film-forming polymers are polymers having 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 may be selected from the group consisting of alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcelluloses, hydroxypropylcellulose and hydroxybutylcellulose, hyoxyalkyl alkylcelluloses, such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose, carboxyalkylcelluloses such as carboxymethylcellulose. , alkali metal salts of carboxyalkylcelluloses, such as sodium carboxymethyl cellulose, carboxyalkyl alkyl celluloses such as carboxymethyl ethyl celluloses, carboxyalkyl cellulose esters, starches, pectins such as sodium carboxymethylammylopectin, chitin derivatives such as chitosan, polysaccharides such as alginic acid, ammonium salts and alkaline metals thereof, carrageenins, galactomannanes, tragacanth, agar-agar, gummi arabicum, guar gum and xanthan gum, polyacrylic acids and their salts, polymethacrylic acids and the salts thereof, copolymers of methacrylate, polyvinylalcohol , polyvinylpyrrolidine, copolymers of polyvinylpyrrolldone with vinyl acetate, polyalkylene oxides, such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide. Polymers not listed that are pharmaceutically acceptable and have appropriate physicochemical properties as defined above are equally suitable for the preparation of particles according to the present invention.

Preferred water soluble polymers are for example hydroxypropyl methylcellulose (Methocel ®, Pharmacoat ®, polymethacrylate (Eudragit E: ®), hydroxypropylcellulose (Klucel ®) or a polyvidone The particularly preferred water - soluble polymers are hydroxypropyl methylcelluloses or HPMC. it 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 molar substitution of hydroxypropyl from about 0.05 to about 3.0 are generally soluble in water. refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule The molar substitution of hydroxy Dropyl refers to the average number of moles of propylene oxide that have reacted with each anhydroglucose unit of the cellulose molecule Hydroxypropyl methylcellulose is the name adopted by the United States for hypromellose (see Matindale, The Extra Pharmacopoeia, 29th edition, page 1435). Preferably, hydroxypropyl methylcellulose with low viscosity, ie about 5 mPa.s, for example, hydroxypropyl methylcellulose 2910 5 mPa.s. In the four-digit number "2910", the first two digits represent the approximate percentage of methoxyl groups, and the third and fourth digits represent the approximate percentage of hydroxypropyl group composition. 5 mPa.s is a value indicative of the apparent viscosity of a 2% aqueous solution at 20 ° C.

Suitable HPMCs include those having a viscosity from about 1 to about 100 mPa.s, in particular from 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 commercially available HPMC 2910 5 mPa.s. An equally preferred type of HPMC is in admixture with polyethylene glycine 400, commercially available from Colorcon (R.U.) as Opadry ™ OY-7240 Clear. The weight ratio of drug: polymer weight is in the range of 17: 1 to 1: 5, preferably 10: 1 to 1: 3. In the case of (galantamine, HBr): (HPMC 2910 5 mPa.s), said ratio can vary from about 10: 1 to about 1: 3, and optimally is from 7: 1 to 1: 2. The weight-for-weight ratio of galantamine. HBr to other water-soluble polymers can be determined by a person skilled in the art, by direct experimentation. The lower limit is determined by practical considerations. In particular the present invention relates to particles comprising (a) a central rounded or spherical center, (b) a layer or a coating film of a water soluble polymer and galantamine hydrobromide (1: 1), (c) optionally a polymeric layer of sealing coating and (d) a membrane coating controlling the release index. The center has a diameter of approximately 250 a about 1180 μm (16-60 mesh network), preferably about 600 to about 1180 μm (16-30 mesh). The pellets, beads or centers of the dimensions mentioned herein can be obtained by sifting through nominal standard rating screens, as described in the CRC Handbook, 64th ed., Page F-114. Nominal standard screens are characterized by standard network / hole width (μm) values, DIN 4188 (mm), ASTM E 11-70 (No.), Tyler® (network). Throughout this description and in the claims, the particle sizes are designated by reference to the network / hole width in μm, and to the corresponding No. screen in the ASTM E11 -70 standard. Materials suitable for use in the particles according to the present invention take many forms, provided that said materials are pharmaceutically acceptable and have appropriate dimensions (approximately 16-60 mesh) and firmness. Examples of said materials are polymers, for example plastic resins; inorganic substances, for example silica, glass, hydroxyapatite, salts (sodium or potassium chloride, calcium or magnesium carbonate) and the like; organic substances, for example activated carbon, acids (citric, fumaric, tartaric, ascorbic and similar acids) and saccharides and derivatives thereof. Particularly suitable materials are saccharides such as sugars, oligosaccharides, polysaccharides and their derivatives, for example, glucose, rhamnose, galactose, sucrose, mannitol, sorbitol, dextrin, maltodextrin, cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, starches (corn, rice, potato, wheat, tapioca) and similar saccharides. A particularly preferred material suitable for use as centers in the particles according to the present invention is represented by sugar spheres of 16-60 mesh (USP 22 / NF XVII, p.89), consisting of 62.5% -91.5 % (w / w) sucrose, the rest being starch and possibly also dextrins, and which are pharmaceutically inert or neutral. Accordingly, these centers are also known in the art as neutral pellets. In accordance with the weight ratio of drug: polymer, it is stated herein that the water-soluble polymer and galantamine form either a stratum (ratio> 10: 1) or a coating or coating film (ratio < 10: 1). As an alternative to the inert pellets coated with drug or with stratum or drug described so far, the suitable particles that buy galantamine can also be formed of granules or spheroids (spherical granules) prepared according to methods known in the granulation technique. and spheronization. The membrane coating controlling the release index comprises a water insoluble polymer and optionally a plasticizer. Said polymer is ethylcellulose and the plasticizer is selected from the group comprising dibutyl sebacate, diethyl phthalate and triethyl citrate. It is useful to modify the properties of the water insoluble polymer by means of the addition of particular amounts of a water-soluble polymer, as described above, preferably HPMC. The addition of the water-soluble polymer is especially useful for increasing the onset of action. For the particles according to the present invention, the ratio ethylcellulose: HPMC can vary from 100: 0 to approximately 70:30, in particular from approximately 80:20 to approximately 72.5: 27.5, more in particulate from approximately 75:25 to approximately 72.5: 27.5. The controlling membrane coating of the release index can be applied to the drug coated centers in an aqueous dispersion (Aquacoat ™, Surelease ™), or as a solution in an organic solvent system. A useful organic system comprises an alcohol, for example, methanol or ethanol, and optionally a chlorinated hydrocarbon such as, for example, dichloromethane. The weight of the controlling membrane coating of the release index 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 to the thickness of the controlling membrane coating of the liration index. A sealant liner is optionally located between the drug center and the controlling membrane liner of the release index. The polymeric layer of sealant coating is applied to the drug coated centers to avoid sticking of the particles during the procedure, and to prevent migration of the drug to the controlling membrane of the release index. Preferably, a thin layer of HPMC 2910 5 mPa.s and polyethylene glycol (PEG), in particular polyethylene glycol 400, is used as a polymeric layer of sealant coating. In addition, the particles according to the present invention may also contain various additives, such as thickening agents, lubricants, surfactants, preservatives, chelating and complexing agents, electrolytes or other active ingredients. Hard gelatin capsules can be filled with the particles so that a therapeutically effective amount of, for example, 8 to 32 mg of the active ingredient is available per dosage form. A convenient pharmacokinetic profile (rapid onset, even depression and peak 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 a immediate release form; preferably the amount of controlled release particle to 75% of the galantamine, and the immediate release form to 25%. To achieve the desired pharmacokinetics, the dosage forms can be filled with particles that release the active ingredient at different rates, at least one class that releases the active ingredient slowly, and at least one class that releases the active ingredient in a faster; in particular, a class that releases the active ingredient immediately, for example, particles as described that lack the controlling membrane of the release index. With the different particles the capsules can be filled consecutively, or they can be pre-mixed and with the mixture thus obtained the capsules can be filled (taking into account possible segregation). Alternatively, the controlled release particles of the present invention may also comprise an upper coating of a water soluble polymer as described above, and galantamine which is practically released immediately upon ingestion, and thus ensures a rapid onset of action. Another alternative solution for providing a dosage form with a pharmaceutical profile as described, ie, with a rapid onset, depression values and even peaks, comprises filling a capsule with controlled release particles., as described above (70 to 80%, preferably 75% of the dose of galantamine), together with one or more minitablets comprising the remaining 20 to 30%, preferably 25% galantamine. Suitable immediate release tablet formulations of galantamine have been previously described in WO 97/47304. The present invention furthermore relates to processes for the preparation of formulations as described above, comprising galantamine mixtures or a pharmaceutically acceptable salt form thereof, as a water-soluble excipient to form a drug center, optionally applying a coating sealant to the center drug, and then apply the controlling membrane coating of the release index. The particles according to the present invention are conveniently prepared in the following manner. A drug coating solution is prepared by dissolving in an appropriate suitable solvent system amounts of galantamine.HBr and a water soluble polymer. A suitable solvent system comprises purified water or an alcohol, preferably ethanol, which can be denatured, for example, with butanone. The amounts of solids, ie, galantamine.HBr and water-soluble polymer, in the drug coating solution can vary from 10 to 30% (w / w) and is preferably approximately 25%. The solution is preferably stirred during the coating process. The drug coating process (on an industrial scale) is conveniently conducted in a fluidized bed pelletizer (eg Glatt type WSG-30 or GPCG-30) equipped with a Wurster base spray insert (eg, a Wurster insert). 45.71 cm (18 inches)). The development of the laboratory scale procedure can be performed on a Glatt type WSG-1 with a Wurster base insert of 15.23 cm (6 inches). Obviously the parameters of the procedure depend on the equipment using. The spray rate should be carefully regulated. A too low spray rate can cause some spray drying of the drug coating solution, and result in a loss of product. A too high spray rate can cause excessive wetting and subsequent agglomeration. With agglomeration being the most serious problem, lower spray rates can initially be used to be increased as the coating process proceeds and the particles become larger. The atomizing air pressure with which the drug-coating solution applies also influences the performance of the coating. The low atomizing air pressure causes the formation of larger droplets and an increased tendency towards agglomeration. The 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, the atomizing air pressure can be established at almost maximum levels. The fluidizing air volume can be monitored by operating the exhaust air valve of the apparatus, and should be set in such a way as to obtain an optimum pellet circulation. Too low a volume of air will cause insufficient fluidization of the pellets; too high a volume of air will interfere with the circulation of the pellets due to countercurrent air currents that develop in the apparatus. In the present process, optimal conditions were obtained by opening the exhaust air valve to approximately 50% of its maximum, and gradually increasing the opening thereof to approximately 60% of the maximum as the coating process proceeded.

The coating process is conveniently conducted using an air inlet temperature ranging from about 50 ° C to about 55 ° C. Higher temperatures can accelerate the process, but have the disadvantage that evaporation of solvent is so rapid that the coating liquid does not spread uniformly on the surface of the pellets, resulting in the formation of a drug coating layer. with high porosity. As the overall volume of the coated pellets increases, the drug solution can significantly decrease to unacceptable levels. Obviously, the optimum process temperature will also depend on the equipment used, the nature of the center, the volume of the batch, the solvent and the spray rate. Setting the parameters for optimal coating results is described in more detail in the example below. It was found that carrying out the coating procedure under those conditions produced very reproducible results. To reduce the levels of residual solvent in the pellets after the application of the controlling membrane of the index of an organic solution, the pellets can be conveniently dried in any suitable drying apparatus. Good results can be obtained by using a vacuum drum dryer operated at a temperature from about 60 ° C to about 90 ° C, preferably about 80 ° C; a reduced pressure that varies from about 15-40 kPa (150-400 mbar), preferably 20-30 kPa (200-300 mbar), for at least 24 hours, preferably about 36 hours. Eil vacuum drum dryer is conveniently rotated at its minimum speed, for example, 2 to 3 rpm. After drying, drug-coated centers can be screened. The sealant coating layer is applied to the drug coated centers in the Wurster base spray fluidized bed granulator or in a powder coater. The sealant coating solution can be prepared by dissolving an appropriate amount of a sealant coating polymer in a suitable solvent system. Said system is, for example, purified water or an alcohol, preferably ethanol, which can be denatured with, for example, butanone. The amount of sealant coating polymer in the sealant coating spray solution can vary from 5 to 10% (w / w), and is preferably about 6.6%. The sealant coating spray solution is conveniently agitated during the sealant coating process. The appropriate conditions are described in more detail in the example below. An additional drying step may be required after the application of the polymeric sealant coating layer. Excess solvents could be easily removed while operating the apparatus at the parameter settings used for approximately 5 to 15 minutes after the spray is complete.

The membrane layer polymer layer controlled by the release index is applied to the drug coated (or sealed) centers in a fluidized bed granulator with Wurster base spray insert. The release-controlling membrane coating solution or suspension can be prepared by suspending or dissolving an appropriate amount of a controlled membrane coating polymer of the release index in a suitable solvent system. Said system is, for example, purified water or an alcohol, preferably ethanol, which can be denatured with, for example bulanone, dichloromethane which can be mixed with an alcohol, preferably methanol or ethanol. The amount of membrane coating polymer controlling the release rate in the spray solution or suspension may vary from 5 to 40% (w / w), and is preferably approximately 30%. The spraying solution or suspension of membpane coating controlling the release index is conveniently agitated during the spraying process. The establishment of parameters to conduct this last step is essentially similar to that used in the previous coating processes. The appropriate conditions are described in more detail in the example below. All coating processes are preferably conducted under an inert atmosphere of, for example, nitrogen. The cladding equipment should preferably be supported and equipped with a Appropriate solvent recovery system that contains an efficient condenser system. With the particles, hard gelatin capsules can be filled using standard automatic capsule filling machines. Designation equipment and proper grounding can conveniently prevent the development of electrostatic charges. Capsule filling can influence the weight distribution, and should be monitored. Good results are obtained when the equipment is operated at approximately 75% to 85% of the maximum speed, and in many cases when operating at full speed. Dosage forms according to the present invention, which have a convenient pharmacokinetic profile as described, ie, a rapid onset of action and even peak and peak values, are capable of releasing in 500 ml USP buffer (pH 6.8) at 37 ° C in an Apparatus 2 (USP 23, <; 711 > Disiolutíon, pages 1791-1793, pallet, 50 rpm) from 20 to 40% of the tctal amount of galantamine.HBr in 1 hour, and more than 80% of the total amount of cjalantamine.HBr in 10 hours. Said dosage forms provide a mean maximum plasma concentration of galantamine from 10 to 60 ng / ml, and an average minimum plasma concentration from 3 to 15 ng / ml after repeated administration every day through steady-state conditions . The formulations according to the present invention deliver a therapeutically effective amount of galantamine to a patient during 24 hours after a simple administration once a day. The present invention further relates to pharmaceutical packages suitable for commercial sale, comprising a container, a galantamine formulation as set forth in claim 1, and associated with said package, written material specifying how said formulation should be administered. Said pharmaceutical packets can be adapted to treat a patient unaffected by "acetylcholine esterase inhibitor", that is, a patient who has not previously been exposed to an acetylcholine esterase inhibitor, and who should start with small doses, either tolerated, before being exposed to permanent higher doses until the optimal dose is reached. Such packages typically comprise 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 packets may be adapted for the treatment of a patient who is tolerant to "acetylcholine esterase inhibitor", ie, a patient who has been previously exposed to an acetylcholine esterase inhibitor, and who tolerates an optimal dose . Such packages typically comprise daily dosage units comprising from 15 to 30 mg galantamine. A method for the treatment of Alzheimer's dementia and related dementias in a human, while substantially reducing (avoiding) the concomitant disadvantages of adverse effects associated with acetylcholine esterase inhibitors, comprises administering to a human in need of such treatment, a therapeutically effective amount of galantamine in a controlled release formulation as set forth in claim 1; said amount is sufficient to alleviate said Alzheimer's dementia and related dementias, but insufficient to cause said adverse effects. Related dementia belongs to the group consisting of vascular dementias, Lewy body disease, autism, mental retardation, psychiatric conditions of bipolar disorder, altered behavior, hyperactivity disorder, attention deficit, substance abuse, extreme aggression, especially behavior disorder , cessation and withdrawal of nicotine. Adverse effects belong to the group that includes nausea, vomiting, sweating, restlessness and insomnia.

EXPERIMENTAL PART EXAMPLE 1 Oral Capsule LC qalantamine 8 mg (F1) Ingredients: galantamine hydrobromide 10.253 mg (8 mg galantamine base) sugar spheres (18-20 network) 63.283 mg HPMC 2910 5 mPa.s 1465 mg purified water 37.105 μl * HPMC 2910 5 mPa.s 1,500 mg polyethylene glycol 400 0.150 mg purified water 23,350 μl * aqueous dispersion of ethylcellulose 10,220 mg (30%) dibutyl sebacate 0.736 mg purified water 10,220 μl * capsule n. 4 *: these ingredients do not appear in the final product preparation: a) Drug coating suspension Galantamine hydrobromide (123 g) was suspended in 297 ml of purified water and heated to 70-80 ° C. HPMC 2910 5 mPa.s (17.58 g) was dissolved in the heated suspension while stirring. b) Sealant coating 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). c) Dispersion of controlling meme coating of the release index To a moderately stirred aqueous dispersion of ethylcellulose (122.6 g, 20%) was added dibutyl sebacate (8,832 g). The dispersion was diluted with purified water (122.6 g). d) Coating procedure A fluidized bed granulator (Glatt, type WSG 1) equipped with a Wurster insert (base spray) of 15.23 cm (6 inches), with 18-20 net sugar spheres (759.4 g) was loaded. ). The spheres were warmed with dry air of approximately 50 ° C. The volume of fluidizing air was controlled by opening the exhaust air valve to approximately 45% of its maximum. The drug coating suspension was sprayed on the spheres that moved in the apparatus. The suspension was sprayed at a feed rate of about 5 to 30 g.min -1 at an atomizing air pressure of about 0.16-0.4 MPa (1.6 to 4.0 bar) .When the spraying procedure was completed, the coated spheres were dried by additionally supplying dry air of 60 ° C during approximately 2 minutes. The coated spheres were then coated with the sealant coating solution, using the same parameters used in the drug coating process. After drying for about 2 minutes, the sealant-coated spheres were allowed to cool to room temperature and filled in a stainless steel drum. The fluidized bed granulator (Glatt, type WSG1) equipped with a 15.23 cm (6 inch) Wurster base insert was reloaded with the sealant-coated spheres. The spheres were warmed with dry air of approximately 50 ° C. The volume of fluidizing air was controlled by opening the exhaust air valve at approximately 45% of its maximum. The release-rate-controlling membrane coating suspension was sprayed onto the spheres that moved in the apparatus. The suspension was sprayed at a delivery rate of approximately 5 to 30 g. min "1, at an atomizing air pressure of approximately 0.16 - 0.4 MPa (1.6 to 4.0 bar) After drying for about 2 minutes, the controlled release membrane coated beads were allowed to cool to room temperature and filled in a stainless steel drum. e) Drying and curing process To remove the agglomerates, the coated spheres were sieved using a screen having a net width of 1.2 mm. The particles were placed in a drying oven at 60 ° C for 2 hours, so as to cure the release-rate controlling membrane. f) capsule filling Hard gelatine capsules filled with the particles (size 4) using standard automatic capsule filling machines (e.g., Model GFK-1500, Hoffiger and Karg, Germany). To obtain capsules with good weight distribution, the filling speed of the capsules was reduced to approximately 75-85% of the maximum speed. Each capsule received approximately 87.6 mg of particles, equivalent to approximately 8 mg of galantamine.

EXAMPLE 2 Oral capsule LC galantamine 8 mg (F2) Ingredients: galantamine hydrobromide 10.253 mg (8 mg galantamine base) sugar spheres (18-20 network) 63.283 mg HPMC 2910 5 mPa.s 1465 mg purified water each 37.105 μl HPMC 2910 5 mPa.s 1,500 mg polyethylene glycol 400 0.150 mg water Purified 23,350 μl aqueous dispersion of ethyl cellulose 25,550 mg (30%) dibutyl cate 1,840 mg purified water 25,550 μl capsule no. 4 *: these ingredients do not appear in the final product Preparation: The preparation was identical to that described in example 1, except for the preparation of the membrane dispersion controlling the release index. c) Dispersion of controlling membrane coating of the release index To a moderately stirred aqueous dispersion of ethylcellulose (306.6 g, 30%) was added dibutyl cate (22.08 g). The dispersion was diluted with purified water (306.6 g).

EXAMPLE 3 Bioavailability The bioavailability of a simple 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 two times a day with an interval of 8 hours. The plasma levels of galantamine in healthy volunteers (12) were determined by HPLC, and the mean values calculated from the individual measurements are reported in the following table. nd: not detectable (< 1 ng / ml) EXAMPLE 4 Oral capsule (F4) comprising 8 mg galantamine (75% LC pellets and 25% Ll tablet) Ingredients: sugar spheres (network 18-20) 63,482 mg galanamine hydrobromide 7.69 mg (6 mg galantamine base) HPMC 2910 5 m Pa.s 0.641 mg water made 42,932 μl HPMC 2910 5 mPa.s 1,436 mg polyethylene glycol 400 0.145 mg chloride methylene 12,385 μl ethane 96% (v / v) 10,858 mg HPMC 2910 5 mPa.s 1,101 mg ethyl cellulose 20 mPa.s 3,308 mg Diethyl phthalate 0.881 mg Methylene chloride 31.077 μl Ethanol 9 (5% (v / v) 27.244 mg Galantarnin hydrobromide 2,563 mg (2 mg powder dried mixture of galantamine base lactose) monohydrate and microcrystalline cellulose (72:25) 49.302 mg Silica colloidal anhydrous 0.11 mg Crospolividone 2.750 mg Magnesium stearate 0.275 mg these ingredients do not appear in the final product preparation: a) Drug stratum suspension Galantamine hydrobromide was suspended in purified water and heated to 70-80 ° C. HPMC 2910 5 mPa.s was dissolved in the heated suspension while stirring. b) Sealant coating solution Methylene chloride and ethanol were mixed together, and polyethylene glycol and HPMC 2910 5 mPa.s were dissolved therein. c) Release rate controlling membrane coating solution Methylene chloride and ethanol were mixed and ethyl cellulose 20 mPa.s, HPMC 2910 5 mPa.s and diethyl phthalate were added while stirring the solution d) Stratification and coating process A fluidized bed granulator (Glatt) equipped with a Wurster insert (base spray) was charged with 18-20 mesh sugar spheres. The spheres were warmed with dry air of approximately 50 ° C.

The volume of fluidizing air was controlled by opening the exhaust air valve to approximately 45% of its maximum. The suspension of the stratum of drug was sprayed on the spheres that were moving in the apparatus. When the spraying procedure was completed, the layered spheres were dried by additionally supplying dry air of 60 ° C for about 2 minutes. The layered spheres were then coated with the sealant coating solution, using the same parameters used in the drug coating process. After drying for about 2 minutes, the sealant-coated spheres were allowed to cool to room temperature and filled in a stainless steel drum. The fluted bed granulator (Glatt) equipped with an insert (base spray) Wurster was again charged with the beads coated with sealant. The spheres were warmed with dry air of approximately 50 ° C. The volume of fluidizing air was controlled by opening the exhaust air valve to approximately 45% of its maximum. The controlled membrane coating suspension of the release index was sprayed onto the spheres that moved in the apparatus. After drying for about 2 minutes, the controlled release membrane coated spheres were allowed to cool to room temperature and filled in a stainless steel drum. e) Immediate release mini-tablet Galantamine hydrochloride, spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), silica were mixed colloidal anhydrous, crospolividone and magnesium stearate, in a planetary mixer, and compressed in a tableting machine, preparing minitabletas of 55 mg of weight. f) Capsule filling With the coated spheres and the minitabletas of liberation Immediate hard gelatin capsules (size 0) were filled using standard automatic capsule filling machines (eg, Model GFK-1500, Höffiiger and Karg, Germany).

EXAMPLE 5 Oral Galantamine Capsule (F5, F6, F7, F8) (75% LC pellets 25% upper cover Ll) Ingredients sugar spheres (18-20 of 63,624 mg red) galantamine hydrobromide 7.69 mg (6 mg galantamine base) HPMC 2910 5mPa.s and PEG 12,687 mg (Opadry ™ OY- 400 7240 Clear, Colorcon) purified water 267,693 μl HPMC 2910 5mPa.s 1,260 mg ethylcellulose 20 mPa.s 3,780 mg diethyl phthalate 1,008 mg methylene chloride 46,772 μl 96% ethanol (v / v) 31,184 mg galantamine hydrobromide 2,563 mg (2 mg galantamine base) HPMC 2910 5mPa.s and PEG 4.229 mg (Opadry OY-7240 400 Clear) purified water 89.321 μl capsule size n. 4, 2, 1 and 0 *: these ingredients do not appear in the final product preparation: a) Drug coating solution Galantamine hydrobromide and Opadry OY-7240 Clear were dissolved in purified water at room temperature. b) Release rate controlling membrane coating solution Methylene chloride and ethanol were mixed and ethyl acetate 20 mPa.s, HPMC 2910 5 mPa.s and diethyl phthalate were added while stirring the solution. c) Drug top coat solution Galantamine hydrobromide and Opadry ™ OY-7240 Clear were dissolved in purified water at room temperature. d) Coating procedure A fluidized bed granulator (Glatt) equipped with a Wurster insert (base spray) was charged with 18-20 mesh sugar spheres. The spheres were warmed with dry air of approximately 50 ° C. The volume of fluidizing air was controlled by opening the exhaust air valve to approximately 45% of its maximum. The drug coating solution was sprayed onto the spheres that moved in the apparatus. When it was completed the spraying process, the coated spheres were dried by further supplying dry air of 60 ° C for about 2 minutes. The release-controlling membrane coating solution was sprayed onto the spheres that moved in the apparatus. After drying for about 2 minutes, the controlled release membrane coated spheres were sprayed with the drug topcoat solution. After drying for about 2 minutes, the top-coated spheres were allowed to cool to room temperature, sieved / filled in a stainless steel drum. e) Capsule filling With the top-coated spheres (96.841 mg, 193.683 mg, 290.524, 387.365 mg) hard gelatin capsules (size numbers 4, 2, 1, 0) were filled using standard automatic capsule filling machines ( for example, Model GFK-1500, Höffiiger and Karg, Germany), producing oral capsules containing respectively 8 mg, 16 mg, 24 mg and 32 mg galantamine base.

EXAMPLE 6 Oral caplets of qalantamine (F9) (75% LC pellets and 25% upper cover Ll) Spheres were made that have a slightly faster release, decreasing the ratio of ethyl cellulose 20 mPa.s to HPMC 2910 5 mPa.s, to 72.5: 27.5 (compared to the ratio 75:25 in the previous example).

EXAMPLE 7 In vitro dissolution of the spheres with top cover Comparative in vitro dissolution studies were carried out on the formulations of spheres with top cover F5 to F8 and F9. The medium was 500 ml USP buffer pH 6.8 at 37 ° C in Apparatus 2 (USP 23, <711> Dissolution, pages 1791-1793) (paddle, 50 rpm). The following results were obtained: F5 to F8

Claims (29)

NOVELTY OF THE INVENTION CLAIMS

1. 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 pharmaceutically acceptable excipient soluble in water and optionally other pharmaceutically acceptable excipients; said particles are coated by a membrane coating controlling the release index.

2. The formulation according to claim 1, further characterized in that galantamine is in the form of galantamine hydrobromide (1: 1).

3. The formulation according to claim 1, further characterized in that the water-soluble excipient is a film-forming polymer.

4. The formulation according to claim 3, further characterized in that the water-soluble film-forming polymer is a polymer having an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution at 20 °. C solution.

5. The formulation according to claim 4, further characterized in that the water-soluble polymer is selected from among the group comprising 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, carboxyalkyl alkylcelluloses such as carboxymethyl ethylcellulose, carboxyalkylcellulose esters, starches, pectins such as carboxymethylamylopectin sodium, chitin derivatives such as chitosan, polysaccharides such as alginic acid, ammonium and alkali metal salts thereof, carrageenins, galactomannanes, tragacanth, agar agar, gummi arabicum, guar gum and xanthan gum, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts thereof, copolymers of methacrylate, 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.

6. The formulation according to claim 5, further characterized in that the water-soluble polymer is hydroxypropyl methylcellulose HPMC 2910 5 mPa.s.

7. The formulation according to claim 6, further characterized in that the weight ratio of hydroxypropyl HPMC 2910 methylcellulose 5 mPa.s to galantamine is in the range of 17: 1 to 1: 5.

8. The formulation according to claim 2, further characterized in that with the galantamine hydrobromide (1: 1) and the water-soluble film-forming polymer, an inert sphere is laminated or coated.

9. The formulation according to claim 8, further characterized in that the inert spheres are sugar spheres of 16-60 mesh (1, 180-250 μm) (NF XVII, page 1989).

10. The formulation according to claim 1, further characterized in that the membrane coating controlling the release index comprises a polymer insoluble in water and optionally a plasticizer.

11. The formulation according to claim 10, further characterized in that the water-insoluble polymer is ethylcellulose, and the plasticizer is selected from the group comprising dibutyl sebacate, diethyl phthalate and triethyl citrate.

12. The formulation according to claim 11, further characterized in that the weight of the membrane coating controlling the rate of release varies from 3% to 15% of the uncoated particle.

13. The formulation according to claim 1, further characterized in that a sealing coating is found between the drug center and the membrane coating controlling the release index.

14. The formulation according to any of claims 1 to 13, further comprising a top cover comprising galantamine and water soluble polymer.

15. The formulation according to claim 14, capable of releasing in USP buffer pH 6.8 at 37 ° C, in an Apparatus 2 (USP 23, < 711 > Dissolution, pages 1791-1793, pallet, 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.

16. A dosage form comprising a therapeutically effective amount of the controlled release formulation of any of claims 1 to 15.

17. The dosage form according to claim 16 which delivers a therapeutically effective amount of galantamipa to a patient for 24 hours after a simple administration once a day.

18. The dosage form according to claim 16, further characterized in that part of the galantamine is present in an immediate release form.

19. The dosage form according to claim 18, further characterized in that said release form Immediate comprises particles as described in claim 1, which lack the controlling membrane of the release index.

20. The dosage form according to claim 18, further characterized in that said immediate release form comprises minitablets of immediate release.

21. The dosage form according to claim 18, further characterized in that said immediate release form comprises a controlled release formulation of claim 14.

22. The dosage form according to claim 16, which provides a average maximum plasma concentration of galantamine from 10 to 60 ng / ml, and an average minimum plasma concentration from 3 to 15 ng / ml, after administration every day through steady-state conditions.

23. A pharmaceutical package suitable for commercial sale, comprising a container, a formulation of galantamine as stipulated in claim 1, and associated with said package, written material specifying how such formulation should be administered.

24. The pharmaceutical package according to claim 23, adapted for the treatment of a patient not affected by "acetylcholine esterase inhibitor", characterized in that said package comprises 21-35 daily sequential dosage units of (a) a first group of 7 to 14 dosage units ranging 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 group room of 7 dosage units comprising from 20 to 40 mg galantamine.

25. The pharmaceutical package according to claim 23, adapted for the treatment of a patient that is tolerant to "acetylcholine esterase inhibitor", characterized in that said package comprises daily dosage units comprising from 15 to 30 mg galantamine.

26. A process for the preparation of a formulation according to claim 1, comprising mixing galantamine or a pharmaceutically acceptable salt form thereof with a water-soluble excipient, to form a drug center, optionally applying a coating Sealer to the drug center, and then apply the membrane coating controlling the release index.

27. The use of galantamine or a pharmaceutically acceptable acid addition salt thereof, for the manufacture of a controlled release formulation for the treatment of Alzheimer's dementia and related dementias in a human, while substantially reducing (avoiding ) the concomitant disadvantage of adverse effects associated with acetylcholinesterase inhibitors

28. - The use according to claim 27, further characterized in that the related dementia belongs to the group consisting of vascular dementia, Lewy body disease, autism, mental retardation, psychiatric conditions of bipolar disorder, altered behavior, attention deficit, hyperactivity disorder , substance abuse, extreme aggression, especially conduct disorder, cessation and nicotine withdrawal.

29. The use according to claim 27, further characterized because the adverse effects belong to the group comprising nausea, vomiting, sweating, restlessness and insomnia.