MXPA01002365A - New sustained release oral formulations - Google Patents

Abstract

Pharmaceutical composition capable of releasing a therapeutically effective dose of active agent, e. g., rivastigmine, in a time-controlled manner.

Description

NEW ORAL FORMULATIONS This invention relates to a controlled release oral pharmaceutical composition, and more particularly, to a unit dosage which, after administration, releases an active agent in a controlled mode as a function of time.

The controlled release formulations can be formulated with the following aspects in mind: = a) the time until the release of the active agent (delay time or delay time). b) the rate of release of the active agent (fast or slow). c) the duration of release of the active agent (long or short). These aspects can be observed in tests of conventional dissolution in vi tro, for example in water, or if desired in body fluids, for example the artificial gastric juices. Little has been published on reliable controlled release formulations that allow a predetermined time release of a single dose or repeated doses of active agents. There is a need for these formulations to be commercially acceptable. After extensive testing, we have now found that it is possible to produce a pharmaceutical composition capable of releasing, at a specific time, ie, with a delay of time or a lag time, an active pharmaceutical agent or a mixture of active agents, by example in a manner substantially independent of the concentration and type of ions present in the gastrointestinal environment, for example, hydrogen ions and hydroxyl ions, ie, independently of the pH, of the phosphate ions, and also independently of the enzymes present in the surrounding body fluid. The present invention provides, in one aspect, a pharmaceutical composition comprising: a first component comprising a first dose of active agent, wherein, upon contact with water (or with body fluid), it is released from 70 to 95 by hundred of this dose in Water within 3 to 4 hours, and a second component comprising a second dose of active agent, a water-soluble osmosis-inducing agent, and a water-swellable excipient, this second component having a water-permeable (or body fluid) Which, in use after water penetrates it, is broken after a certain delay, for example due to swelling of the inflatable excipient, and releases (in a predetermined time) the active agent (hereinafter additionally referred to herein) as the pharmaceutical compositions of the present invention).

The present invention also provides a pharmaceutical composition comprising: a first component comprising an active agent, wherein from 70 to 50% by weight, 95 percent of the active agent in the first component, released in water within 3 to 4 hours, and a second component comprising the active agent, a water-soluble osmosis inducing agent, and a water-swellable excipient, having the second component a coating that, after being penetrated by aqueous fluids, breaks after a certain period due to swelling of the inflatable excipient, and releases the active agent at a predetermined time. "Within 3 to 4 hours" means that at the end of a period of 3 to 4 hours, the specified dose of the active agent has been released, for example > 80 percent or > 85 percent. The active agent can be a single active agent or can be a mixture. The active agent can be the same in the first and second doses, or different in each dose. Preferably, the active agent is the same. In one embodiment, the coating for the second component is a film, for example a semipermeable membrane. The inflatable excipient swells in the presence of water or body fluid, which penetrates through the coating, and creates mechanical pressure inside the second component, thus causing the coating to break and the system to open, for example as the lid of a box. Also, the inflatable excipient can act as an osmotic agent that draws the water towards the second component. The thickness of the coating is one of the parameters that controls the time delay, resulting in more coating a longer time delay. It will be appreciated that the term "rupture" refers preferably to the violation, but it can also refer to any film system that dissolves or disappears quickly (for example, for 30 minutes or less) or changes its properties to allow the release of the film. active agent In another aspect, a controlled release formulation, for example the second component, is provided for releasing a dose of the active agent after a delay time, wherein the active agent is released from 6 to 12 hours, for example 8 hours. hours, after ingestion. The second component can be coated with two films. A first film is contacted directly with the second component, and preferably is a semipermeable membrane. The second film can be semipermeable (for example, allowing the passage of, for example, water or active agent in one direction), or permeable. The films used in this embodiment can be, for example, 2 to 5 times thinner than that used in one embodiment of a film. This composition can provide, if desired, delay time t-jÉ-k longer for the second component, with a good release of the second dose of the active agent. It also provides certain advantages such as reducing the amount of coating used. "First component" means a component capable of releasing immediately, or in a controlled manner, for example sustained release, a first therapeutically effective dose of the active agent, when this first component is contacted with water or body fluids. "Second component" means a component capable of releasing immediately or in a controlled manner, for example sustained release, a second therapeutically effective dose of the active agent, when the second component is brought into contact with water or body fluids. "Semipermeable membrane" means a membrane suitable for the passage of water (or body fluid) into a core containing the active agent, which is coated with this membrane and prevents the discharge of a dissolved active agent outwardly. of the nucleus. "Film", "film coating", or "membrane" means, unless otherwise reported, a coating that is applied over a core component, for example the first or second component. "Delay time or delay time" means the length of time between the administration of the composition and the release of an effective dose of the active agent from the first or second components. A person skilled in the art will appreciate that different plasma profiles can be obtained by varying, for example: the composition of the first and / or second components, for example the nature and amount of the excipients and / or active agents, the time of delay, - the type of semi-permeable and / or non-semipermeable membrane, the speed and nature of the establishment of the release of the active agent (eg, fast, slow, exponential, logarithmic, linear), which may depend on the rate of breakdown of the the membrane. The composition according to the invention can be used to administer a wide variety of active agents. The composition according to the invention is suitable, for example for water-soluble and also water-insoluble solid pharmaceutical active ingredients, which may be inorganic, or in particular organic active substances, and are to be used according to their indication as analgesics. , antipyretics, antirheumatics, sedatives, hypnotic agents, antiepileptics, depressants and stimulants, anesthetics, neuroleptic analgesics, antihistamines, antihypertensive agents, anticoagulants, antithrombotic agents, psychoactive agents ^^ a ^^^^ 4 ^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Pharmacological, psycholeptic, chemotherapeutic agents, for example antibiotics, sulfonamides, antituberculosis agents (tuberculostatic agents), or also chemotherapeutic agents against tropical infections, diuretics, spasmolytics, cardiovascular agents, for example sympathomimetics, agents antihypertensives, cardiac stimulants, for example cardiac and digitalis glycosides, parenteral sugar therapeutics, analeptics acting on the central nervous system, geriatric, tonolitic agents (of striated muscles), anti-Parkinson's agents, cytostatic agents, immunosuppressants, tonics and vitamins, according to B. Helwig (Moderne Arzneimittel), 1980. As antibiotics, penicillin, tetracycline, chlorotetracycline, bacitracin, nystatin, streptomycin, neomycin, polymycin, gramicidin, oxytetracycline, chloramphenicol, thromycin, rifampicin, cefazolin, cefoxitin, cefsu- lodin, cefotiam and mefoxin, and as chemotherapeutic agents sulfametrazine, sulfamerazine, sulfametizole and sulfisoxazole may be used as solid active ingredients for the preparation according to the invention. In addition, for example, as sedatives and hypnotic agents, doral hydrate, pentobarbital, phenobarbital, secobarbital, codeine, and carbromal can be used, and as cardiac glycosides and digitalis, digitoxin and digoxin can be used, and as sympathomimetics can be used epinephrine as the active solid substance in a form soluble in water or in a more water soluble form. In particular, antipyretics, analgesics, and antirheumatics may be used as the active solid ingredient in the presentation according to the invention, in a water-soluble form or in a suitable water-insoluble form, for example propifenazone, aminophenazone, aspirin ( AAS), antipyrine, methylnifrazine, melaminsulfone, sulfenazone, phenacetma, pentazocine, lactophenine, paracetamol, quinine, flufenamic acid, mefenamic acid, tolfenamic acid, meclofenamic acid, acid niflumic, clonixin or clonixidine, flunixin, ibuprofen, supephen, ketoprofen, fenoprofen, pirprofen, diclofenac, ibufenac, procticic acid, naproxen, cycloprofen, tolmetin, clopy, thiaprofenic acid, oxaprozin, fenclonic acid, fentiazac, clidanaco, fenclonaco, fenoprofen, flurbipro-15-pheno, carprofen, sulindaco, cinmetacin, fenbutene, ethodolac, butifufen. In a more convenient manner, psychopharmacological agents can be used as the active solid ingredient in the presentation according to the invention, for example neuroleptics, antidepressants, thymolleptics, thimeric drugs and tranquilizers in a water soluble form or in a insoluble in water, such as thioridazine, imipramine, desipramylamine, clomipramine, cetimipramine, opipramol, amitriptyline, nortriptyline, reserpine, aromazine, chlorpromazine, fluoproma- zina, metopromazine, trimeprazine, dietzine, promethazine, amidopromazine, mepazine, pipamazine, and maprotiline. In addition, antihypertensive agents, such as oxprenolol and metoprolol, can be used as the active solid ingredient in the presentation. In a preferred embodiment, a composition according to the invention is used to administer Rivastigmine (Exenon®) which is useful in the treatment of patients with mild to moderately severe dementia of the Alzheimer's type, also known as Alzheimer's Disease. Rivastigmine can be administered as the hydrogen tartrate (hta) in a unit dosage form, for example an immediate-release capsule, in a dose of 0.5 milligrams to 6 milligrams twice a day. Little has been published in detail about the biopharmaceutical properties of Rivastigmine in humans. It is quickly and completely absorbed. We have found that it is metabolized primarily through hydrolysis by esterases, for example acetyl- and butyryl cholinesterase and has a plasma half-life of one hour. It is subject to pre-systemic and systemic metabolism. We have now found that sustained release formulations of Rivastigmine can be produced with convenient properties, for example better tolerability. An adequate test can be done in beagle dogs in ayu-ñas. ugly * ... aA,. «J¡?? Tis * &amp? Ír'l?,.

In accordance with the present invention, Rivastigmine can be used in the form of the free base or a pharmaceutically acceptable salt thereof. Preferably hydrogen tartrate (hta) is used. The composition of the invention allows, for example, the manufacture of oral pharmaceutical forms once a day for patients who have to take more than one dose of an active agent per day, for example at specific times, so that their treatment. With these compositions, tolerability can be improved, for example with Rivastigmine, and this may allow a higher initial dose, and a reduced number of titration steps of the dose. In a further aspect, the invention relates to a pharmaceutical composition comprising adapted Rivastigmine, such that, in use after oral administration, a therapeutically effective dose of Rivastigmine is released only after 6 hours (subsequently further referred to as The pharmaceutical compositions of the present invention In a further aspect, the invention relates to a pharmaceutical composition capable of releasing twice the dose after administration, a therapeutically effective dose of Rivastigmine at different intervals after oral administration (referred to later in the present further as the pharmaceutical compositions of the present invention).

In a preferred pharmaceutical composition of the invention, a first therapeutically effective dose of Rivastigmine is released within 3 to 4 hours after ingestion, and subsequently, a second therapeutically effective dose of Rivastigmine is released from 6 to 12, preferably 8 to 10 hours after ingestion. The first component can be produced, for example, by any conventional methods, to provide the desired controlled release characteristics. It can be produced in solid form, for example a tablet (for example, a matrix tablet), coated particles (for example, not identical) or granules, for example coated granules. In one embodiment of the first component, the active agent is incorporated into a hydrophilic substance which forms a gel substance on contact with water, for example, which may be present in a proportion of 10 to 50 percent, for example 15 to 50%. 45 weight percent of the first component, for example in the form of a controlled release tablet formulation, for example a matrix tablet. Hydrophilic gel-forming substances commonly used in tablet formulations can be used, and reference is made to the extensive literature on suitable substances, see in particular Fiedler's "Lexicon der Hilfstoffe", 4th edition, ECV Eulendorf 1996 and "Handbook of Pharmaceutical Excipients "Wade and Weller editors (1994), whose The content is incorporated herein by reference. Preferred hydrophilic gel-forming substances that can be used for the first component include one or more natural, partially or fully synthetic, anionic, or preferably non-ionic hydrophilic gums, modified cellulose substances or aqueous protein substances, such as , for example, acacia, tragacanth gum, locust bean gum, guar gum, karaya gum, agar, peptin, carrageenan, soluble and insoluble alginates, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, carboxypolymethylene , jelly. Cellulose, including methylcellulose, hydroxypropylcellulose, and especially hydroxypropylmethylcellulose, and sodium carboxymethylcellulose are preferred. Particularly preferred hydrophilic gel-forming substances which can be used for the first component comprise high viscosity, hydrophilic, swellable substances, for example substances having a viscosity in the range of 10,000 to 200,000 mPa-s, for example 50,000 to 150,000 mPa-s. s, for example 100,000 mPa-s. A preferred inflatable substance that can be used is hydroxypropylmethylcellulose, for example Methocel, for example, K100M (100,000 mPa-s / 2% solution in water at 20 ° C), with a methoxyl content of, for example, 15%. at 30 percent, for example from 19 to 24 percent, and a hydroxypropoxyl content of, for example, 5 to 15 percent, for example 7 to 12 percent. Inflatable substances with various viscosities can be prepared as disclosed in "Handbook of Pharmaceutical Excipient" Wade and Weller editors (1994). The weight portion of the gel-forming hydrophilic substances in the formulation can be 10 to 50 percent, for example 25 to 50 percent, preferably 40 percent. The first component can comprise from 3 to 20 percent, for example from 5 to 15 percent, for example from 6 to 13 percent by weight of the active agent, for example, hydrogen tartrate (hta) of rivastigmine. It may also be convenient to incorporate in the first component at least one of other soluble or insoluble pharmaceutical excipients such as tablet diluents, such as calcium sulfate, calcium phosphate, lactose, mannitol, sucrose. For example, microcrystalline cellulose may be incorporated in a granular powder and / or in a fine powder, for example 10 to 50 percent. For example, fine powder of microcrystalline cellulose may be present in the range of 20 to 50 percent, for example 30 to 40 weight percent of the first component, and granular microcellulose powder in the range of 10 to 40 percent, for example from 20 to 30 weight percent of the first component. There may be at least one rinse aid, for example Vta ^ &. ^ JiM ^^ i ^. dispersed silicon oxide, talc, present in the scale from 0.1 to 1 weight percent of the first component, and at least one tablet lubricant, for example magnesium stearate, stearic acid, hydrogenated castor oil, polyethylene glycol, also present in the scale of 0.1 to 1 percent by weight of the first component, preferably 0.5 percent. For example, the first component in this specific embodiment may have the following characteristics of release of the active agent, for example rivastigmine, in water or in artificial stomach juices (eg 0.1 N HCl): time (minutes) amount (percentage) 30 28-35 60 40-55 120 58-75 180 70-90 240 80-95 300 88-98 360 > In a further embodiment of the first component, the active agent is incorporated into coated particles comprising a diffusion coating. The coating can be adapted to provide controlled release of the active agent. Coating auxiliaries, conveniently used in the coating formulation, can be used. These coatings may include additional binders, lubricants, brighteners, stabilizing agents, fillers or diluents, surfactants, and the like. As disintegrants, mention may be made in particular of CMC-Ca, CMC-Na, crosslinked PVP (Crospovidone, Kollidon XL Poliplasdone), alginic acid, sodium alginate, and guar gum, more preferably crosslinked PVP, Crospovidone, cross-linked CMC, and Ac -Di-Sol As the binders that can be used in these coatings, mention may be made in particular of polysaccharides, for example potato starch, wheat starch, corn starch, hydroxypropylmethylcellulose, for example products known under the trademarks Avicel®, Filtrak®, Heweten. ® or Pharmacel®. Preferably, the cores that can be used for the first component are inert and soluble in water. Normally the diameter is approximately 0.5 to 1.5 millimeters. The coatings that can be used for the first component can comprise, for example, a cellulose derivative, for example that can be applied as a film. Common cellulose coatings can be used, and reference is made to the extensive literature on the appropriate diffusion control substances. As a preferred cellulose coating for the first component, a coating comprising ethylcellulose and hydroxypropylmethylcellulose (subsequently in the present HPMC). The ethylcellulose preferably has a molecular weight of 10,000 to 15,000,000, for example 50,000 to 1,000,000, for example 75,000 to 80,000 Daltons. Preferably it is cellulose substituted by approximately 2 to 3 ethoxy groups per saccharide unit. It preferably has an ethoxy content of 44 to 51 percent. Ethylcellulose, as used in the examples, is preferably N10 ethylcellulose Trademark Aqualon® N10 (available from Dow Chemicals Company). The hydroxypropylmethylcellulose preferably has a viscosity of 1 to 10 cps, for example 2 to 8 cps. Preferably it has a molecular weight of 10,000 to 1,500,000 Daltons, for example 100,000 to 1,000,000, for example 300,000 to 800,000. Preferably it is cellulose substituted by ethyl and hydroxypropyl groups. The hydroxypropylmethylcellulose preferably has a viscosity of 3 cps or 5 cps. The particles may have a diffusion coating preferably comprising ethylcellulose and hydroxypropylmethylcellulose, for example in a ratio of 15: 1 to 1: 1, for example 9: 1 to 1: 1, for example 8: 1 to 2: 1, for example from 7: 1 to 3: 1. The particles may have a drug coating (active agent) preferably comprising hydroxypropylmethylcellulose. The drug coating may contain from about 50 to 90 weight percent of the active agent, for example rivastigmine, for example from 50 to 80 weight percent of rivastigmine. The amount of drug can comprise, for example, from 3 to 15 percent of the nucleus. Typically, the ratio of the drug coating to the diffusion coating is from 3: 1 to 1: 1. If desired, there may be a protective coating pre- sented between the diffusion coating and the drug coating. It may comprise hydroxypropylmethylcellulose or ethylcellulose. The proportion of the protective coating / diffusion coating can be, for example, from 1: 1 to 1:10, for example from 1: 2 to 1: 8. There may be silica present, for example 10 to 70 per 15 weight percent of the film coating. For example, the first component in this specific embodiment may have one or more, for example all of the following release characteristics of the active agent, for example rivastigmine, in water or in artificial stomach juices (for example, 0.1 N HCl): time (minutes) amount (percentage) 30 25-40 60 45-65 120 65-85 5 180 75-95 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^ fe ^^^ g ^ - ^^^^^^^^ t ^ g 240 75-96 300 85-97 360 87-98 420 90-98 480 90-99 As an additional example, the first component in this modality specific can have the following characteristics of release of the active agent, for example rivastigmine, in water or in artificial stomach juices (eg 0.1 N HCl): time (minutes) amount (percentage) 30 5-25 60 25-45 120 50- 70 180 65-80 240 70-90 300 75-95 360 80-90 420 85-95 480 85-95 In a further embodiment of the first component, the active agent is incorporated into granules, for example extruded granules, which can be coated with a diffusion coating as described above. The granules may comprise the active agent, for example rivastigmine, in the same sk ± »* ..- .. aa-teafc i * éikJi-? - > , ^^ S- ^ A%. »K« ¿nárffceM .. ¿&amp? Afc & ? - form that for the particles. It may further comprise binders, such as those mentioned above, and diluent, such as calcium sulfate, calcium phosphate, lactose, mannitol, or sucrose. For example, the first component in this specific embodiment may have one or more, for example all of the following release characteristics of the active agent, for example rivastigmine, in water or in artificial stomach juices (eg, 0.1 N HCl): time ( minutes) quantity (percentage) 30 1-40 60 10-60 120 40-80 180 60-90 240 65-95 300 70-99 360 75-99 420 > 80 It can preferably have the following release characteristics: time (minutes) amount (percentage) 30 1-8 60 15 - 25 120 45 - 70 180 75 - 90 ^^^^^^^^^^^^^ 240 92-95 300 95-98 360 97-99 420 > The present invention further relates to a controlled release oral pharmaceutical composition comprising a therapeutically effective dose of rivastigmine and pharmaceutically acceptable excipients, for example the first component (hereinafter referred to herein further as the pharmaceutical compositions of the present invention). The present invention further relates to a controlled release oral pharmaceutical composition comprising a therapeutically effective dose of rivastigmine, wherein, in use, it is released from 50 to 95 percent, for example 50 to 80 percent, of the at 90 percent, from 70 to 95 percent of rivastigmine in water or in body fluids, for example artificial stomach juices, within 3 hours (hereinafter referred to herein further as the pharmaceutical compositions of the present invention). The delay time for the second component can be precisely determined, for example: by the type and amount of water-soluble excipients in the core, by the water permeability and the number of films re-coated on the second component, by the mechanical strength, that is, the elasticity and tear resistance of the film, by the type and amount of inflatable excipients incorporated in the core. 5 an appropriate coating for the second component can be a semipermeable membrane that is adapted to allow, in use, the passage of water (in use, gastrointestinal juices) to the core, and prevent the egress of the active agent dissolved out of the nucleus. Water is drawn through the semipermeable membrane at a rate that can be controlled by the composition of the membrane. The water that has penetrated the nucleus dissolves at least part of the active agent. In this way the osmotic pressure is produced. The higher the pressure, the more molecules or ions come into solution, until, under normal circumstances, a saturated solution is produced. In one embodiment, after penetration by water or body fluid, the osmotic pressure, which consequently also induces swelling of the inflatable excipient, can be produced by the active agent, for example rivastigmine, itself. However, a vehicle that is soluble in water can be added in order to produce the necessary osmotic pressure. In this way, the osmotic pressure necessary to induce the operating principle of the second component can be obtained, in such a way that the body fluid that enters into • > "Al; ft -«? At- ^ j ^ -fe «^. ^ &«. «- ^^ srij -» ---! - ^^ Balancing the osmotic gradient produces the desired swelling of the inflatable excipient (disintegrant ), and after a certain delay time, the rupture or breaking of the film coating allows the release of the active agent.With the optional addition of a water soluble carrier in the core of the tablet, the second component can be produced in a almost independent form of pH, that is, independent of the concentration of hydrogen ions and hydroxyl ions, and / or independent of other ions, such as phosphate ions, and also enzymes, for example in the alimentary tract.Semipermeable membranes Suitable for the film layer include the semipermeable membranes described in the literature, for example, in U.S. Patent Nos. 3,916,899 and 3,977,404, which are suitable for the passage of water (body fluid), and not of the active agent. ivo dissolved, and therefore, are suitable to cause osmosis. For example, artificially produced membranes, consisting of cellulose acetate, cellulose triacetate, agar acetate, amylose acetate, cellulose acetate ethylcarbamate, cellulose acetate phthalate, cellulose acetate methylcarbamate, may be used. , cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethylcarbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, methyl cellulose acetate ux? * Aí¿ ^ 0? £? gllÍ cellulose acetate, cellulose acetate butylsulphonate, cellulose ether, cellulose acetate propionate, cellulose acetate dimethylaminoacetate, cellulose acetate octate, cellulose acetate laurate , methyl cellulose, cellulose acetate p-toluenesulfonate, hydroxylated ethylene vinyl acetate, cellulose acetate butyrate, and other cellulose acetate derivatives. Other suitable semipermeable membranes are also hydroxypropylmethylcellulose and polymeric epoxides, copolymers of alkylene oxide and alkyl glycidyl ether, polyglycols or polylactic acid derivatives, and other derivatives thereof. In addition, mixtures can also be used, for example of water-insoluble acrylates, for example copolymer of ethyl acrylate and methyl methacrylate. In general, all semipermeable membranes that are known in the literature, and having water-permeable properties, are suitable for producing the film for the second component. The coating of, for example, tablets, for example compressed tablets, core particles or granules, with a film comprising, for example, a semipermeable membrane of required thickness, can be carried out in fluidized beds, coating trays, or the coating it can be done using, for example, tablet-forming machines (dry-coated ta-bleta).

^^^ MBig ^ ^^^^ s ^^^^^^^^^^^ The second component, for example, may also be contained in a capsule, for example a gelatin capsule, containing the active agent, for example rivastigmine, an inflatable excipient, optionally a water soluble vehicle and other excipients, such as lubricants and sustained release agents in a powder form, and coated with the semipermeable membrane as a film. Suitable films that can be used as a second coating for the second component include membranes that can be permeable or semipermeable to water or body fluid, for example sustained release membranes, as described in the literature. This second film coating can be applied in the same manner as for the first film. A second preferred film coating for the second component comprises ethylcellulose, e.g. Aqualon® NIO Ethylcellulose (available from Dow Chemicals Company). It can be applied, for example, by spraying a solution comprising ethylcellulose and HPMC, 5 cps, in a proportion by weight, for example, from 15: 1 to 1: 1, for example from 9: 1 to 1: 1, for example from 8: 1 to 2: 1, for example from 7: 1 to 3: 1. The ethyl cellulose preferably has a molecular weight of ,000 to 15,000,000, for example 50,000 to 1,000,000, for example 75,000 to 80,000 Daltons. Preferably it is cellulo-sa substituted by approximately 2 to 3 ethoxy groups per unit & - &,. saccharide. It preferably has an ethoxy content of 44 to 51 percent. The hydroxypropylmethyl cellulose preferably has a viscosity of 1 to 10 cps, for example 2 to 8 cps, preferably 3 cps to 5 cps. Preferably it has a molecular weight of 10,000 to 1,500,000 Daltons, for example 100,000 to 1,000,000, for example 300,000 to 800,000. Preferably it is cellulose substituted by ethyl and hydroxypropyl groups. In a preferred embodiment, the weight ratio between the first and the second film applied on the second component is from 20: 1 to 1: 5, for example from 15: 1 to 1: 1, for example from 10: 1 to 2 :1. In a preferred embodiment of the invention, the film thickness for the second component can be in the range of 50 to 800 microns (μm), for example 100 to 600 microns. For a second component having a film, a preferred thickness is in the range of 300 to 500 microns, for example 350 to 400 microns. For a second component having two films, a preferred thickness is in the range of 100 to 300 microns, for example 150 to 200 microns. The nature and quantity of the excipients and the active agent of the second component (excluding the film coatings to be broken) may or may not be the same as those of the first component. The inflatable excipients or disintegrating agents suitable for the second component may be inert substances that swell rapidly after their contact with aqueous liquids, for example alginic acid and derivatives, agar-agar, cellulose, such as microcrystalline or microfine cellulose, methylcellulose. , crosslinked carboxymethylcellulose, carboxymethyl starch, modified starch, cross-linked polyvinylpyrrolidone, colloidal silicon dioxide, high molecular weight polymers comprising ethylene oxide, bentonite, Veegum, montmorillonite, dried citrus pulp, xylans, and also cationic and anionic exchangers, such as cholestyramines. Additional excipients can be used to produce or induce osmosis in the swelling process in the second component, such as water-soluble carriers (osmosis-inducing substances), for example substances that do not irritate the gastric or intestinal mucous membranes, for example salts inorganic or organic, such as sodium chloride, sodium acid phosphate, sodium nitrate, and sodium acetate, or also acids, such as tartaric, citric, or succinic acid, and also sugars, especially, for example, mannitol, glucose, fructose, lactose and dextran compound with different molecular weights. The amount of vehicle can vary from a fragment to many times the amount of rivastigmine used. Lubricants which may be an additional optional excipient for the second component may be, for example, magnesium stearate, silicon airgel, talc, stearic acid, hydrogenated castor oil, polyethylene glycol (PEG). The optional additives for the second component can be, for example, antioxidants, for example α-tocopherol or butylated hydroxytoluene (BHT). The optional additives in the film coating for the second component can be, for example, pigments, such as colored iron oxides or titanium dioxide, and / or flavorings, for example sweeteners, for example saccharin, Na cyclamate, or sugar. A second preferred component comprises, for example (% by weight): Rivastigmine hta core 0.5 to 25% Sodium chloride 10 to 35% Avicel PH 102 5 to 25% PVPP-XL 20 to 70% α-tocopherol 0.01 to 5% Aerosil 200 1 to 15% Magnesium stearate 0.1 to 5% First coating: Cellulose acetate 1 to 20% HPMC 0.1 to 1% Second coating: Ethylcellulose 0.5 to 10% JßB & ampThe invention relates to olefins to a pharmaceutical composition comprising a core coated with two films, the first internal film being a semi-permeable film 5 to water or body fluids. applied directly on the core and comprising cellulose acetate, for example cellulose acetate E320 or 398-10, the second outer film being a film permeable to water or body fluids comprising ethylcellulose, for example ethylcellulose NIO. The nuclei in question comprising the active agent, for example rivastigmine, and excipients, for example, can be the compressed tablets, capsules, and granules which are customary in the galenic art, and can be produced by known processes. For example, the tablet dough can be produced by mixing the active agents, the disintegrant, and additional optional excipients, such as vehicles, lubricants, and if desired, also sustained release excipients, as required. The production of the compressed tablets and granules can be effected, for example, by using the tablet-forming machines known for the preparation of, for example, compressed tablets round or in the form of canes and granules, and the capsules are they fill using known capsule filling machines. The sustained-release excipients that are used can be excipients essentially insoluble in water or mixture.

JE - ^ - "'** ^^« ^ aai »-, ---»., »Jies of the same, for example lipids, among others, fatty alcohols, for example cetyl alcohol, stearyl alcohol, and alcohol keto stearyl, glycerides, for example glycerin monostearate, or mixtures of mono-, di-, and triglycerides of vegetable oils; hydrogenated oils, such as hydrogenated castor oil or hydrogenated cottonseed oil; waxes, for example waxes; bees or carnauba wax, solid hydrocarbons, for example paraffin or mineral wax, fatty acids, for example stearic acid, certain cellulose derivatives, for example ethylcellulose or acetylcellulose, polymers or copolymers, such as polyalkylenes, for example polyethylene, compounds of polyvinyl, for example polyvinyl chloride or polyvinyl acetate, thus copolymers of vinyl chloride-vinyl acetate, and copolymers with crotonic acid, or polymers and copolymers of acrylates and methacrylates, for example copolymer s of ethyl acrylate and methyl methacrylate. A person skilled in the art can use other excipients than those disclosed above to obtain the desired effect. Reference is made to the extensive literature on suitable excipients provided in the art, in particular Fiedler's "Lexicon der Hilfstoffe", 4th edition, ECV Aulendorf 1996, and "Handbook of Pharmaceutical Excipient" Wade and Weller editors (1994), whose The content is incorporated herein by reference. As already mentioned initially, the release that is going ..- * ''? A £ ¡£ ¡S & *,. ?? .. -JÜ. -. It can be controlled precisely by the composition and the thickness of the coating layer (film) used for the second component, to perform at different time intervals. the mechanical strength and elasticity, and optionally through the amount and swelling property of the swelling or disintegrating agent. The second component, for example with a film, according to the invention, may have one or more, for example all of the following water release characteristics: time (minutes) amount (percentage) 0 0-1 120 0-1 180 0-1 240 0-85 300 0-97 360 > 99.5 The second component, for example with two films, according to the invention, may have one or more, for example all of the following water release characteristics: time (minutes) amount (percentage) 0 0-1 120 0-1 180 0-1 240 0-85 360 0-99.5 420 0-100 480 70-100 540 75-100 600 85-100 660 90-100 720 > fifty The time of rupture can lead to the release of 85 percent or more, for example 90 percent of the active agent of the second component, within 30 minutes. The pharmaceutical composition according to the invention preferably comprises from 0.5 to 25 percent, for example from 1 to 10 percent, for example from 2 to 5 percent by weight of rivastigmine of the total composition. The pharmaceutical compositions of the present invention are useful in the known indications of the particular active agent incorporated therein. The exact amounts of the doses of active agent and of the formulation to be administered depend on a number of factors, for example the condition to be treated, the desired duration of treatment, and the rate of release. of the active agent. For example, the amount of the active agent required and its rate of release can be determined based on known in vitro or in vivo techniques, determining how long a particular concentration of active agent remains in the blood plasma at an acceptable level for a therapeutic effect. For example, for rivastigmine, dosages in the range of 1 milligram to 12 milligrams of active agent per day can be used for a 70 or 75 kilogram mammal, for example humans, and in conventional animal models. A surprisingly in- creased tolerability of the rivastigmine provided by the compositions in conventional animal tests and in clinical trials can be observed. The pharmaceutical compositions of the invention, for example, they are administered, for example orally once a day, if 2 doses of the active agent are present, and twice a day if a second dose of the active agent is present. In a further aspect, the present invention provides the use of an active agent, for example rivastigmine, and excipients as defined above, in the manufacture of a medicament for a once a day treatment of patients with, for example , mild to moderately severe dementia of the Alzheimer's type, by oral administration. In the following non-limiting examples, the invention is more fully elucidated. If not otherwise reported, the parts are parts by weight. Temperatures are given in degrees 25 Celsius.

Preparation of the first component The first component can be produced in a conventional manner by mixing the components. Below are examples of specific forms of the first component, which allow different release profiles of the active agent contained therein.

Example 1: First component in the form of a matrix tablet 10 The resulting mixture can be in powder form, which can be compressed to form a tablet in conventional tablet-forming machines, at compression pressures, for example, from 140 to 1,120 kg / cm2.

A. Preparation of a granulate: Rivastigmine ingredients, for example, microcrystalline cellulose, for example fine powder, purified water to dissolve the drug substance. The rivastigmine is dissolved from 10 to 20 percent, for example 16.3 percent by weight of purified water from the total granulate, and the solution is stirred until it becomes clear. A crossbar stirrer can be used, for example, at 150-200 rpm, for example at 180 rpm, for 10 to 20 minutes, for example 15 minutes.

The fine powder of microcrystalline cellulose is screened, for example through a manual or vibrating sieve adapted with a mesh, and having a mesh width, for example, 1,600 microns, and a diameter of the wire, for example, of 500 microns, in a container, for example, a high shear mixer Collette Gral® 10. In position I of the mixer and in position I of the chopper, the powder is wet granulated in the high shear mixer with the aqueous solution of drug substance (granulation liquid), which is added at a rate of 0.5 to 1 liter / minute, for example at 0.75 liters / minute. The dissolution container (used for the preparation of the granulation liquid) is rinsed with the purified water, and the rinse liquid is added in the position I of the ez-giver and in position I of the chopper, at a speed of 0. 5 to 1 liter / minute, for example at 0.75 liters / minute. Then the position of the chopper is increased to II, and mixing is applied for approximately 1 minute. The granulation stops, and the wall of the Collette Gral® container is cleaned. The wet granulate is mixed for an additional minute in position I of the mixer and in position II of the chopper. Then the wet granulate is dried, for example, by transferring it from the high shear mixer to a fluidized bed dryer vessel, and applying an inlet air temperature of 40 ° C to 60 ° C, for example 50 ° C, until J3 & ? B =. that an LOD (density loss) of 2.5 to 5.0 percent (corresponding to a product temperature of approximately 31 ° C) is reached. The dried granulate is then broken, for example, by passing it through an oscillator with a mesh (for example, a mesh width of 800 microns, and a wire diameter of 320 microns) to the container of a mixer. Free fall (for example, Turbula® T10A). B. Preparation of the mixture for tablets: Ingredients _ hydroxypropylmethylcellulose K100M, microcrystalline cellulose, for example granular powder, highly dispersed silicon dioxide. Granular microcrystalline cellulose powder (MCC), hydroxypropylmethylcellulose, and highly dispersed silicon dioxide can be manually mixed in a plastic bag or in a free fall mixer for approximately 2 minutes. The silicon dioxide can be dispersed in the HPMC and in the MCC, in order to reduce any dusting during the subsequent screening step. The premix can be sifted by passing it through a screen (or vibration screen). The mesh width used can be, for example, 800 microns, and the diameter of the wire 25 of 320 microns.

The dry premix can be transferred to the free fall mixer container (for example, Turbula® T10A), and mixed with the granulate until 100 rotations are achieved, for example 20 rpm for 5 minutes. The magnesium stearate can be pre-mixed in a manual manner with approximately 10 parts of the dry premix in a plastic bag or free fall mixer for about 2 minutes. The magnesium stearate can be dispersed in order to prevent any reagglomeration after the subsequent sieving step. The premix can be sifted, for example, by manually passing it through a screen (or vibrating screen). The mesh width used can be, for example, 800 microns, and the diameter of the wire of 320 microns. The premix of magnesium stearate is transferred, for example, to the container of a free-fall mixer (for example, Turbula® T10A) containing the remainder of the premix, and the entire mixture for tablets is mixed until they are reached 100 rotations, for example at 20 rpm for 5 minutes. C. Tableting Tablets are formed by compression, for example, in a single-eccentric perforating tablet machine (eg, Comprex®), or in a rotary tablet press (eg, Betapress®, Korsch® PH250) using, for example, 6 mm drills (round, convex, beveled edges). Non-limiting examples of the first component that can be prepared by the process disclosed above, are provided in the following table: The compositions Numbers 1, 2, and 3 provide the si¬ next release profile when dissolved in water: Composition 1 Time (min.) 30 60 120 180 240 300 360 420 480 Drug Release (%) 29.3 42.6 60.5 73.3 82.6 89.4 93.5 96.4 97.8 15 Composition 2: Time (min.) 30 60 120 lüu 240 300 360 420 480 Release of the drug (%) 33 51.9 72.6 84.5 92.3 96.8 98.9 99.9 100 Composition 3: Time (min.) 30 60 120 180 240 300 360 420 480 Release of the drug (%) 32.1 46 64.3 77.6 85.5 91.7 95.1 97.2 97.8 10 Example 2: First component in the form of coated particles The preparation protocol of the Film solutions are given later in the present. A non-limiting example of a composition obtained according to this protocol will illustrate the invention. A / INGREDIENTS: The ingredients for the preparation of the film solutions are provided in the following Table: 20 B / PREPARATION OF FILM SOLUTIONS The percentage is expressed as the weight of the prepared solution (sufficient quantity of purified water for 1, 2, and 3). 1. Preparation of the aqueous solution of HPMC- (5%) HPMC 3 cps is dispersed in purified water in a stainless steel vessel with stirring for about 2 minutes at 500 rpm with a cross-bar stirrer. The solution is stirred until transparent (30 minutes) at a speed of 250 rpm. The solution is left standing still for 12 hours in a stainless steel container. 2. Preparation of Rivastigmine Aqueous Solution / HPMC Film Dissolve rivastigmine (15 to 25 percent) in the HPMC solution (3 to 5 percent) with shaking (Rivastigmine / HPMC Solution) . The solution obtained is stirred until it becomes clear (approximately 15 minutes) in a stainless steel vessel (speed of the crossbar stirrer: 250 rpm). Silicon dioxide (1 to 3 percent) is then dispersed in the rivastigmine / HPMC solution with stirring in a stainless steel vessel (crossbar stirrer speed: 250 rpm). The obtained solution is stirred for about 10 minutes. If necessary, silicon dioxide can be dispersed in two parts of the rivastigmine / HPMC solution using mortar and pestle, before adding the rest of the solution. 3. Preparation of aqueous HPMC film solution Silicon dioxide (1.0 to 3 percent) is dispersed in the HPMC solution 3 cps (3 to 7 percent) with stirring in a stainless steel vessel (speed of crossbar stirrer: 250 rpm). The solution is stirred for about 10 minutes. If necessary, the silicon dioxide is dispersed in two parts of the rivastigmine solution. «-aAsfei--, a - fc. * • «-? .- ta» g-Ma na / HPMC using mortar and pestle, before adding the rest of the solution. 4. Preparation of organic solvent 5 Ethanol 94 percent (w / w) and acetone are mixed (see proportions in paragraph 5) for approximately 2 minutes in a stainless steel container with acetone (crossbar stirrer speed: 250 rpm). 5. Preparation of the organic polymer film solution 10 Ethylcellulose NIO (5 to 10 percent) and HPMC 5 cps (0.5 to 2 percent) are dispersed in a stainless steel vessel in the organic solvent (acetone ( 45 to 65 percent) and 94 percent ethanol (35 to 45 percent)) with stirring for about 1 minute, at a cross-bar agitator speed of 500 rpm, and the solution is stirred until it becomes clear during about 30 minutes (speed: 250 rpm) in a stainless steel container. The solution is allowed to stand still for 12 hours. 20 C. COATING 1. Aqueous coating A Glatt WST5 fluid bed dryer (batch size: approximately 1.5 kilograms) is adjusted to the required inlet air temperature (60 ° C), and the speed of rotation to 25 ° C. grams / minute (pressure: 2.5 bar) by means of the of the peristaltic pump with a silicon tube (internal diameter of 4.0 millimeters). The Wurster column (15.24 centimeters) with a binary spray nozzle (1.0 to 1.2 millimeters in diameter) in the center of the base plate that sprays in line with the air stream, is preheated to 45 ° C. The non-similar ones are added, and the air fin is adjusted to the air flow required for a smooth fluidization of the amount of unpaired inlet air of approximately 325 m3 / h. The Rivas-tigmine / HPMC solution from step A is then immediately sprayed in order to minimize abrasion of the resemblances of the stainless steel container. The temperature of the product is approximately 45 ° C. The stainless steel container and the silicon tubing are then rinsed with the HPMC solution 3 cps (approximately 25 grams). For the protective coating, the aqueous HPMC solution is sprayed (rinse-first, the rest of the HPMC-second solution). The stainless steel container and the silicon pipe are then rinsed with purified water (approximately 25 grams), and then the rinse water is sprayed. 2. Organic Coating A Glatt WST 5 fluid bed dryer (batch size: approximately 1.5 kilograms) is adjusted to the inlet air temperature (50 ° C), and the spray rate to 25 grams / minute (pressure: 2.5) bar), by means of the variation of the peristaltic pump with the silicone tube (internal diameter of 4.0 millimeters). The Wurster column (15.24 centimeters) is used with a binary spray nozzle (1.0 to 1.2 millimeters in diameter) in the center of the base plate that sprays in line with the air stream. The organic solvent is sprayed to remove the remaining purified water from the nozzle piping system (to prevent the crystallization of ethylcellulose (organic polymer film solution) in the tubes). The temperature of the product is approximately 40 ° C. The organic polymer film solution is then sprayed. The stainless steel container and the silicon pipe are rinsed with approximately 50 grams of the organic solvent of ethanol / acetone, and the rinse liquid is sprayed. The uncoated coated ones are dried at an inlet air temperature of 50 ° C, until the temperature of the product is increased by 2 ° C. The uncoated coated ones are manually dried in a Waldner tray dryer (inlet air temperature: 30 ° C) for 6 hours to remove any organic solvent residue from the coating, and passed through a sieve (sieve size). 1,250 millimeters, and wire diameter of 400 millimeters) to remove the agglomerates. 3. Preparation of the mixture for filling capsules. Magnesium stearate is manually passed through a g ^^^^ j sieve that has a width of mall? F'of 800 millimeters, and a wire diameter of 320 millimeters. The sifted magnesium stearate is then mixed with the coated granules in a free fall mixer (Turbula 101) at 20 rpm for 5 minutes, ie 100 rotations. Four . Capsule filling Capsule filling is filled into an automatic capsule filling machine (Zanasi LZ 5) in empty hard gelatin capsules (CONI-SNAP, dimple 6, size 3). The nominal filling weight is as mentioned above. The parameters of the process are as follows: speed: 3000 HK / h dosing / piston: - size: # 4 height: 12 - 14 mm vacuum: 0.7 bar feed hopper: none D / PREP7ARACI N OF A COMPOSITION OF EXELON MR BID 4.5 MG HKP The composition is prepared according to the process described above. The ingredients are given in the following table: % HPMC solution 2 10% polymer solution / organic solvent (60% acetone, 40% 94% (w / w) ethanol) 3% excess (loss after spraying) Composition of an Exelon MR BID 4.5 mg HKP capsule Amount of total film (% of the theoretical content of the capsule (= 150 milligrams)) 3.0 Diffusion coating (ethylcellulose: hydroxypropylmethylcellulose) 90:10 70:30 Phase Component i) ii) unlike nucleus (placebo) 134.40 129.15 coating 1 hta rivastigmine 7.20 7.20 (drug loading) hydroxypropylmethylcellulose 3 cps 1.50 1.50 highly dispersed silicon dioxide 0.75 0.75 Coating 2 hydroxypropylmethylcellulose 3 cps 1.50 1.50 (high-protection silicon dioxide coating) dispersed 0.75 0.75 Coating 3 ethylcellulose N10 4.05 7.35 (coating of hydroxypropylmethylcellulose) slab 5 cps 0.45 3.15 lubricant magnesium stearate 0.15 0.15 Total filling weight 150.75 151.50 capsules CONISNAP size 3 49.00 49.00 TOTAL (mg) 199.5 200.50 The following release profile is obtained: Time (min) 30 60 120 180 240 300 360 420 480 Drug release i) 32.5 55.1 76.4 84.1 88.0 90.6 92.4 93.8 94.9 (% in HCl 0.1) ii) 15.5 36.3 61.2 72.9 79.7 83.4 86.5 89.1 90.6 E / DOSAGE CONCENTRATIONS: For all dosing concentrations, the same ones are used coated (with the same drug load). Different dosage concentrations are obtained (from 1.5 milligrams to 9 milligrams) varying the weight of the filling the capsule, as illustrated in the following table.

For dosing concentrations of 6.0 milligrams, 3.0 milligrams, and 1.5 milligrams, non-placebo comparisons could be added to optimize the degree of filling of the capsules if necessary.

"JS ^ ^ -:? - J ^ ?? ^. ^^? T ^ Example 3: First component in the form of coated granules A / Ingredients: - Hydrogenated tartrate of Rivastigmine Microcrystalline cellulose Avicel® PH-101 (FMC) Corporation, Philadelphia, USA) Lactose 200 Mesh (DMV, Vehgel, The Netherlands) _ i Ethylcellulose NIO (Dow Chemicals Company, USA) - Hydroxypropylmethylcellulose 5 cps (Dow Chemicals Company, USA) Magnesium Stearate Hard Gelatin Capsules: size 3, Lid + Body: opaque rich yellow, CONISNAP® dimple 6 (Capsulgel NV) The quantities of the ingredients to be used are given in the description of the protocol or in the following paragraph G / .B / Preparation of the drug and film solutions The percentage mentioned below in 1, 2, and 3 is expressed by weight of the prepared solution: 1. Preparation of the aqueous solution of rivastigmine. Rivastigmine is dissolved in water, for example, in a stainless steel vessel, with stirring, and the sun The mixture is stirred transparent for approximately 15 minutes at 250 rpm, for example, in a crossbar stirrer.

The amount of water is approximately 39 percent of the dry weight of the core, which is prepared as described below. 2. Preparation of the organic solvent 94 percent (w / w) ethanol and acetone (acetone (60 percent) / 94 percent ethanol (40 percent)) are mixed for about 2 minutes in a stainless steel vessel ( speed of the crossbar stirrer: 250 rpm). 3. Preparation of the organic polymer film solution Nio ethylcellulose (8 percent) and HPMC 5 cps (2 percent) are dispersed in a stainless steel vessel in the organic solvent (90 percent) with stirring for about 1 minute on a crossbar stirrer (speed: 500 rpm). The solution is stirred until clear for about 30 minutes (speed: 250 rpm), for example, in a stainless steel container. The solution is left to stand for 12 hours. C / Preparation of the granules The lactose and the Avicel® are loaded in a Collette Gral® (10 or 25 liters), and mixed for 2 minutes (slow furrow, slow chopper). The rivastigmine solution is added to the mixture of Avicel® and lactose in the Collette Gral®, with the groove at slow speed (chopper off). After the drug solution is pumped into the Co- lleral Gral®, water is added adi-g || Eal to the same container for rinsing. The amount of additional water is 18.5 percent of the dry weight of the core. This additional water is pumped into the mixture from above with the furrow at slow speed (chopper turned off). The mixture from above is granulated in the Collette Gral® for approximately 15 minutes (slow furrow, chopper off). The machine stops at 5 minute intervals, and the walls of the container are scraped. The chopper is reactivated at slow speed during the last 2 to 3 minutes. The wet mass from above is extruded into thin strands (parameters: Gabler® twin screw extruder, mesh size: 1 millimeter, screw speed: 50 rpm, dosing machine position: 1.8, mass pressure: 10 Pub) . 15 The extruded mass is spheronized, that is, it is formed into granules, using a load of 3 kilograms at a time (parameters: Wyss Pharmex® spheronizer, spheronizer load: 3 kilograms, rotating speed: 870 rpm, time of speronization: 6 minutes). 20 Wet granules are dried (parameters: Aeromatic® fluid bed dryer, inlet air temperature: 60 ° C, extraction temperature: 47 ° C to 49 ° C, drying to an LOD (loss on drying) of 2.5 at 3.0 percent). The dry granules are sifted manually to exclude agglomerates. Everything that passes through the sieve is collected for coating (sieve size: 1600 microns). D / Coating 1. Organic Coating A Glatt® WST 5 fluid bed dryer (batch size: approximately 1.5 kilograms) is adjusted to the inlet air temperature (50 ° C-325 cubic meters / hour), and the speed of sprayed at 25 grams / minute (pressure: 2.5 bar) by means of the variation of the peristaltic pump with silicone tube (internal diameter of 4.0 millimeters). The Wurster column (15.24 centimeters) is used with a binary spray nozzle (1.0 to 1.2 millimeters in diameter) in the center of the base plate that sprays in line with the air stream. The organic solvent is sprayed to remove the remaining purified water from the pipe system and nozzles (to prevent the crystallization of ethylcellulose (organic polymer film solution) in the tubes). The temperature of the product is approximately 40 ° C. Then the organic polymer film solution is sprayed. The stainless steel container and the silicon pipe are rinsed with approximately 50 grams of the organic solvent of ethanol / acetone, and the rinse liquid is sprayed. The coated granules are subsequently dried at an inlet air temperature of 50 ° C, until the temperature of the product is increased by 2 ° C. The coated granules are dried manually in a dry Tray Waldner® of the ti ^ »HW 15 / 2N (inlet air temperature: 30 ° C) for 6 hours to remove any residue of the organic solvent from the coating, and then pass through a sieve (sieve size) 1,600 microns, and diameter of the wire of 400 microns) to remove the agglomerates. E / Preparation of the mixture to fill capsules: Magnesium stearate is passed through a sieve having a mesh width of 800 microns, and a wire diameter of 320 microns. Then sieved magnesium stearate 10 is mixed with the coated granules in a free fall mixer (Turbula® 101) at 20 rpm for 5 minutes, ie, 100 rotations. F / Capsule filling The capsule filling mixture is filled in an automatic capsule filling machine (Zanasi® LZ5), in empty hard gelatin capsule covers (CONI-SNAP®, dimple 6, size 3). The nominal filling weight is as mentioned above (recoil parameters: speed: 3,000 HK / hour, doser / piston: size # 4, and height 12-14 millimeters, vacuum: 20 0.7 bar, feed hopper: none). G / Composition of Exelon MR BID 4.5 mg HKP The composition is prepared according to the process described above. Amount of total film (% of the theoretical content 25 of the capsule (= 150 mg)) 3.0 ^ S Diffusion coating (ethylcellulose: hydroxypropylmethylcellulose) 80:20 Phase Component Weight (mg) Core hta, rivastigmine 7.20 lactose 200 mesh 60.30 microcrystalline cellulose (Avicel®) 67.5 i Ethylcellulose coating NIO 3.24 diffusion hydroxypropylmethylcellulose 5 cps 0.81 lubricant magnesium stearate 0.15 Total filling weight 139.20 capsules CONISNAP® Size 3 49.00 TOTAL 188.20 The following release profile is obtained: Time (min.) 30 60 120 180 240 300 360 420 drug release 4.2 21.9 57.8 84.8 94.5 97.9 99.4 99.9 (% in HCl 0 . ÍN) H / Dosing Concentrations: For all dosing concentrations, the same granules are used (with the same drug loading). Different dosage concentrations are obtained (from 1.5 ml- £! Tí¡k ^ -, Si ttáim ^ M ^ i¿ £ &rr: .. ^^^^ -. ^^ a-SMiM ------ *. »-. - »-. * .iS &? 3¡íß? I ** íií¿á we link to 9 milligrams) by varying * tel filling weight of the capsule, as illustrated in the following table For the dosing concentrations of 6.0 milligrams, 3.0 milligrams, and 1.5 milligrams, placebo granules could be added to optimize the degree of filling of the capsules, if necessary. Preparation of the second component 10 The second component can be produced in a conventional manner by mixing the components, for example, in order to obtain coated particles or granules as for the first component, and then applying one or more film coatings, as described previously. fifteen ^^^ Example 4: Second component in the form of a matrix tablet coated with a film A second component containing 4.8 milligrams of the enzyme, rivastigmine as the rivastigmine in the compressed core, for example the compressed tablet, is coated with a film appropriate This system, which releases the rivastigmine after a previously determined time when placed in an aqueous fluid, can be produced as follows: A. Core preparation: The mass for 5,000 cores is prepared as follows. Dissolve 24 grams of rivastigmine in 1,000 grams of purified water. 400 grams of polyplasdone (cross-linked polyvinylpolypyrrolidone) and 221 grams of sodium chloride are placed in a granulation machine with a mixer, for example Diosana®. This mixture is combined for 5 minutes, and slowly added to rivastigmine and wet granulated. The wet mass is then passed through a 2-millimeter sieve and dried using a fluid bed dryer at 60 ° C. After drying, the granules are passed through a 1 mm sieve. The granules are weighed and mixed with the appropriate amounts of silica gel, for example Aerosil 200®, and microcrystalline cellulose for 20 minutes in a tumble mixer (Turbula® mixer), and compressed as indicated above into cores, each one of 178 milligrams of total weight. A 8-mm concave drilling machine (R = 12) can be used in a dam D & X tablets having only one drilling machine, for example Kilian EKO®. B. Film coating preparation: 4,000 cores are coated with a semistripe film (or membrane) of the following composition using the fluidized bed process in an air stream, for example Glatt-wurster: acetyl-containing cellulose acetate to 32% 139.5 g cellulose acetate containing 39.8% acetyl 145.5 g hydroxypropylmethylcellulose (HPMC) 15.0 g methylene chloride 6.750. g methanol 750 g The film coating (semi-permeable membrane coating) is carried out with the aforementioned organic lacquer, which contains 4 percent solid film constituent, in a solvent mixture of methylene chloride-methanol. However, another solvent mixture, such as acetone / alcohol / water, can also be used in place of methylene chloride / methanol. The cores are coated with film layer of different thicknesses, ie different weights, for example, with approximately 55 milligrams, 70 milligrams, 80 milligrams / core, or more to obtain delay times of, for example, 3 to 4, 5 to 6, or 7 to 8 hours, and dried in the air stream of a fluidized bed seperator for 48 hours at 40 ° C. -to"-. -JNr », - mJ _ ^ ---_» - ^ », -« ,, ™, .. * »-.,., ^,« »U -» - »- ...« ...- -.-------- Ba ----- ^ »--- ^^? E¡J6 ^" _ ^^ m ^ j C. Compositions 1 / Ingredients Quantity / tablet (mg) Polyplasdone XL or crosspovidone 80.0 Colloidal silicon dioxide 5.0 5 Sodium chloride 44.2 hta, rivastigmine 4.8 Polyplasdone-XL or crosspovidone 20.0 Avicel PH 102 23.0 Magnesium Stearate 1.0 Core weight 10 178.0 Cellulose Acetate E320 25.52 Cellulose acetate 398-10 26.74 HPMC 603 2.74 Total Weight 233.0 February 15 / ingredients Quantity / tablet (mg) Polyplasdone XL or crosspovidone 80.0 colloidal silicon dioxide 5.0 sodium chloride 44.2 20 hta, rivastigmine 4.8 Polyplasdone XL or crosspovidone 20.0 Avicel PH 102 23.0 magnesium stearate 1.0 Weight core 178.0 25 Cellulose acetate E320 32.48 Cellulose acetate 398-10 34.03 HPMC 603 3.49 Total weight 248.0 D. Determination of rivastigmine release: The film-coated tablets as described above, having two different film thicknesses (coated with a different weight film) are placed in a beaker containing 200 milliliters of deionized water ( desalted) at 37 ° C, and the time needed for the breaking of the film (semipermeable membrane) of the two tablets is determined. The details are given in Tables 1 and 2: Table 1: DR Drug Release (%) in water, 50 rpm, film thickness: 55 milligrams minutes aelda 1 cell 2 cell 3 cell 4 cell 5 cell 6 0 0.0 0.0 0.0 0.0 0.0 0.0 120 0.8 0.7 0.9 0.9 0.7 0.7 150 0.7 0.8 0.7 0.7 0.6 0.7 180 0.7 0.8 0.7 0.7 0.6 0.7 210 53.4 1.4 0.9 0.7 46.9 0.6 240 64.0 64.4 67.0 0.7 57.5 0.7 300 76.6 81.7 89.5 69.8 69.7 82.1 360 83.1 92.2 94.5 77.7 78.4 86.8 Table 2: drug release DR (%) in water, 50 rpm, film thickness: 70 milligrams rriputos aelda 1 cell 2 cell 3 cell 4 cell 5 cell 6 0 0.0 0.0 0.0 0.0 0.0 0.0 240 0.6 0.4 0.3 0.3 0.3 0.2 270 0.5 1.0 1.3 0.8 0.5 0.6 300 45.6 0.3 42.9 46.8 0.5 2.2 330 63.7 59.1 61.8 61.0 33.0 45.1 _ I 360 72.7 71.2 69.8 70.1 51.2 56.0 420 84.7 84.0 81.6 81.8 65.7 69.5 Example 5; Second component in the form of a coated matrix tablet with two films: A. Nucleus Preparation: The mass for 70,000 cores is prepared as follows. 336 grams of rhamstigmine are dissolved in approximately 6,400 grams of purified water, and 12 grams of α-tocopherol are dissolved in about 388 grams of ethanol (in the case of BHT a similar solution would also be prepared). 6.939 grams of Polyplasdone-XL, 1660 g of microcrystalline cellulose, 3.094 grams of sodium (previously milled) chloride, and 350 grams of colloidal silicon dioxide (Aerosil 200) are sieved through a sieve of 1.600 microns, and they are transferred to a 75-liter Collette Gral high shear mixer. In the Collette Gral, the dry powders are mixed for 1 minute with the furrow at slow speed and the chopper off. After that, the alpha-tocopherol solution and the rivastigmine solutions are slowly agitated with the groove and the chopper both operating at a slow speed. Additional purified water is added for the granules. After that, the Collette Gral is operated for 2 minutes with the furrow at slow speed and the chopper at high speed. The granules are then dried in the fluid bed dryer with an inlet air temperature of about 70 ° C, until a loss on drying of less than 4 percent is achieved. After that, the dried granules are sieved through a sieve of 800 microns, and mixed with the magnesium stearate (previously sieved) for 5 minutes in a free fall mixer. Then this mixture is compressed into 178 milligram tablets using oblong tool of a size of 10 x 5.2 millimeters, using a suitable tablet press. B. Film coating: First, the two solutions are prepared for the two films. Dissolve 499 grams of cellulose acetate 398-10, 499 grams of cellulose acetate 320S, and 53 grams of HPMC 3 cps, in a solvent mixture of 70 percent acetone, 20 percent ethanol, and 10 percent purified water, to form a solution 7.5 percent by weight of solid components. 441 grams of ethylcellulose are dissolved N10, and 49 grams of HPMC 5 cps in a solvent mixture of ^. ^ k?? ¡jk¡. ¿^ 1 60 percent acetone and 40 percent ethanol, to form a 5 percent by weight solution of the solid components. Up to 5 percent extra solution can be prepared to account for the loss from spray drying during the coating process. The tablets prepared above are coated in a suitable perforated coating pan, by first spraying the cellulose acetate solution, and then the ethyl cellulose solution, to reach the weight of the films. You can also use other systems more solvents, such as methylene chloride / methanol.

C. Compositions. Ingredients Amount / tablet (mg) hta, rivastigmine 4.8 4.8 15 Sodium chloride 44.2 44.2 Avicel PH 102 23,712 23,712 PVPP-XL 99.11 99. li a-tocopherol 0.178 0.178 Aerosil 200 5.0 5.0 20 Magnesium stearate 1.0 1.0 Core weight 178.0 178.0 Cellulose acetate 398-10 7.125 7.125 Cellulose acetate E320 7.125 7.125 HPMC 603 0.750 0.750 25 Ethylcellulose N10 4.5 6.3 HPMC 5 cps 0.5 0.7 Total weight 198 200 In a further composition, α-tocopherol can be replaced by BHT (butylated hydroxytoluene): Ingredients Amount / tablet (mg) tta, rivastigmine 4.8 Sodium chloride 44.2 __ i Avicel PH 102 23.0 10 PVPP-XL 99.11 BHT 0.890 Aerosil 200 5.0 Magnesium stearate 1.0 Core weight 178.0 15 Cellulose acetate 398-10 9.5 Cellulose acetate E320 9.5 HPMC 603 1.0 Ethylcellulose N10 2.7 HPMC 5 cps 0.3 20 Total weight 201 D. Determination of the release of rivastigmine: Table 1: Release of DR drug (%) in water. 50 rpm, oblong tablet (approximate size of 10.25 mm (millimeters) x 5.5 mm x 25 4.80-4.85 mm) * minutes cell 1 cell 2 cell 3 cell 4 * 0ligh 5 cell 6 240 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 58.8 0.0 0.0 59.8 0.0 0.0 420 89.6 62.4 58.9 83.4 0.0 60.6 480 92.0 96.0 85.4 97.2 97.1 85.5 540 99.0 97.9 95.2 100.9 95.8 97.6 600 99.4 100.2 102.7 101.0 100.2 99.9 660 100.4 100.9 103.0 102.3 102.1 102.5 720 102.1 101.8 103.2 99.4 104.2 101.6 Table 2: Drug DR release (%) in water, 50 rpm. round tablet (approximate size: 8.57x 5.58 mm) mipu-tos cell 1 cell 2 cell 3 cell 4 cell 5 cell 6 240 0.0 0.0 0.0 0. 0.0 0.0 300 0.0 0.0 0.0, 0.10 96.5 0.0 360 92.5 0.0 0.0 0. .0 99.4 0.0 420 100.9 0.0 0.0 0. .0 99.8 0.0 480 101.6 89.5 0.0 0. 100.3 0.0 540 101.5 98.0 0.0 0. 100.2 88.7 600 100.9 100.1 94.4 0 0 ... 99.4 97.0 660 101.7 101.7 100.1 0.0 98.8 101.0 720 102.1 100.7 101.8 76.2 99.2 102.1 Example 5: Capsule filling The mixture for filling capsules comprising the first and second components together (or alone, if desired) is filled in an automatic capsule filling machine (Zanasi ® LZ 5) in 5 caps of empty hard gelatine capsules (CONISNAP® dimple 6, size 3). The nominal filling weight is as mentioned above. The process parameters are as follows: speed: 3,000 HK / h _ I doser / piston: 10 - size: # 4 height: 12-14 mm vacuum: 0.7 bar feed hopper: none

Claims (31)

1. A pharmaceutical composition comprising: a first component comprising a first dose of active agent, wherein, after its contact with water, 70 to 95 percent of this dose is released within 3 to 4 hours, and a second component comprising a second dose of active agent, a water-soluble osmosis-inducing agent, and a water-swellable excipient, the second component having a water-permeable coating which, in use after contact with water, is broken after a delay, and free the active agent.

2. A pharmaceutical composition according to claim 1, wherein the coating on the second component is a semipermeable membrane.

3. A pharmaceutical composition according to claim 1 or 2, wherein the second component releases an effective dose of the active agent from 6 to 12 hours after ingestion.

4. A pharmaceutical composition according to any of claims 1 to 3, wherein the first component comprises a coating of a cellulose derivative.

5. A pharmaceutical composition according to claim 4, wherein the coating of the cell derivative .. js-a? gfc «fo.y- ^ AifeAlteategtefe, * '.» »slab comprises ethylcellulose and hi | K K? xipropylmethylcellulose.

6. A pharmaceutical composition according to any of claims 1 to 3, wherein the first component comprises the active agent in a matrix.

7. A pharmaceutical composition according to claim 6, wherein, in the first component, the active agent is in a hydrophilic gel-forming substance.

8. A pharmaceutical composition according to claim 7, wherein the hydrophilic gel-forming substance is present in a proportion of 10 to 50 weight percent of the first component.

9. A pharmaceutical composition according to claim 7 or 8, wherein the hydrophilic gel-forming substance comprises hydroxypropylmethylcellulose having a viscosity of 100,000 mPa-s.

10. A pharmaceutical composition according to any of claims 1 to 9, wherein the second component has the following release characteristics in water: time (minutes) amount (percentage) 0 0-1 120 0-1 180 0-1 240 0 - 75 300 0 - 95 360 > 99

11. A pharmaceutical composition according to any of claims 1 to 10, wherein the active agent is rivastigmine.

12. A pharmaceutical composition according to any of claims 1 to 11, which comprises 0.5 to 25 weight percent of rivastigmine as the active agent of the total composition.

13. A pharmaceutical composition according to any of claims 1 to 12, wherein the second component comprises a second coating.

14. A pharmaceutical composition comprising rivastigmine adapted in such a way that, in use after oral administration, a therapeutically effective dose is released

15 of rivastigmine only after 6 hours. 15. A pharmaceutical composition capable of delivering, after dosing twice, a therapeutically effective dose of rivastigmine at different intervals after oral administration.

16. An oral pharmaceutical composition for controlled release tablets comprising rivastigmine.

17. A pharmaceutical composition comprising rivastigmine, having the following release characteristics in water: , .J -, É ^, "- * -.- | ^ ¡^^ ^, ¿j¡ time (mi.ñuto) ^ jj, quantity (percentage 30 1-40 60 10-60 120 40-80 180 60-90 240 65-95 300 70-99 360 75-99 420> 80

18. A controlled-release oral pharmaceutical composition containing rivastigmine, which has the following release characteristics in water or in artificial stomach juices: time (minutes) amount (percentage) 30 1-8 60 15-25 120 45-70 180 75-90 240 92-95 300 95-98 360 97-99 420 > 99

19. An oral pharmaceutical composition of controlled release containing rivastigmine, which has the following characteristics of release in water or in artificial stomach juices: time (minutes) amount (percentage) 30 5-25 60 25-45 120 50-70 180 65 -80 240 70-90 300 75-95 360 80-90 420 85-95 480 85-95

20. A controlled-release oral pharmaceutical composition containing rivastigmine, which has the following release characteristics in water or in artificial stomach juices: time (minutes amount (percentage) 30 25 -40 60 45 - 65 120 65 - 85 180 75 - 95 240 75 - 96 300 85-97 360 87-98 420 90-98 480 90-99

21. A controlled-release oral pharmaceutical composition containing rivastigmine, where, in use, 50 to 80 percent of the rivastigmine in the juices is released | Artificial stomachs within 3 hours.

22. A composition according to any of claims 16 to 21, which comprises coated particles.

23. A composition according to any of claims 16 to 22, which comprises coated granules.

24. A composition according to claim 22 or 23, wherein the coating comprises a cellulose derivative.

25. A composition according to claim 24, wherein the cellulose derivative comprises ethylcellulose and hi-droxypropylmethylcellulose.

26. A pharmaceutical composition according to claim 16 or 17, wherein the rivastigmine is in an inflatable hydrophilic substance.

27. A pharmaceutical composition according to claim 26, wherein the hydrophilic, swellable substance comprises hydroxypropylmethylcellulose 100,000 cps.

28. An oral pharmaceutical composition for controlled release tablets, which comprises rivastigmine, which has the following release characteristics in water or in artificial stomach juices: time (minutes) amount (percentage) 30 30 28-35 60 40-55 120 58-75 180 70-90 240 80-95 300 88-98 360 > 92

29. An oral pharmaceutical composition for controlled release tablets comprising rivastigmine, wherein, in use, 60 to 90 percent of rivastigmine is released in artificial stomach juices within 3 hours.

30. The use of rivastigmine and excipients as defined in any of claims 1 to 29, in the manufacture of a medicament for the treatment of patients with mild to moderately severe dementia of the Alzheimer's type, by oral administration.

31. A pharmaceutical composition comprising a core coated with two films, the first inner film being a film semipermeable to water or body fluids applied directly on the core, and comprising cellulose acetate, the second outer film being a film permeable to water or body fluids comprising ethylcellulose.