New prolonged compositions for peroral administration

FIELD: pharmaceutical agents.

SUBSTANCE: invention relates to solid pharmaceutical formulations for peroral administration useful in treatment of mild and moderately severe dementia such as Alzheimer's disease. Claimed formulation contains Rivastigmin or pharmaceutically acceptable salts thereof. Formulation represent gelatin capsule filled with pellet mixture or mixture of magnesium stearate with nonpareils, or matrix tablet.

EFFECT: preparation with controlled prolonged Rivastigmin release and improved tolerance.

3 cl, 5 ex, 15 tbl

 

The present invention relates to pharmaceutical compositions prolonged action for oral administration and, more specifically, to a standard dosage form after administration releases the active substance controlled time profile.

Compositions with controlled release profile can be prepared, taking into account the following characteristics:

(a) the period of time prior to the release of the active substance (the lag time or delay time),

b) the rate of release of the active substance (fast or slow),

C) the duration of release of the active substance (long or short).

These characteristics can be assessed in vitro in standard tests on the solubility, for example, in water or, if necessary, in a common water body, such as in artificial gastric juice.

There are only a small number of publications devoted to songs with a trusted controlled time release profile that allows you to release at a predetermined time of one or more doses of active substances. There is a need to develop compositions that are acceptable from a commercial point of view.

After extensive trials, the applicants have found that you can create a pharmaceutical composition, oblad the expansion of its ability to release at a certain time, i.e. with a time delay or time lag of the pharmaceutical active ingredient or mixture of active substances, for example, almost regardless of the concentration and type of ions present in the gastrointestinal tract, for example, hydrogen ions and hydroxyl ions, i.e. regardless of the value of pH, phosphate ions, and regardless of the enzymes present in the environment total water body.

One of the objects of the present invention is a pharmaceutical composition containing

the first component includes a first dose of active ingredient, and upon contact with water (or total body water) 70-95% of the dose is released into the water for 3-4 h, and

the second component includes a second dose of the active substance, a water-soluble inducing osmosis agent and swelling in water excipient, and the second component is permeable to water (or to a common water body) coating, which when applied after the water breaks after a certain time delay, for example, due to swelling swelling of excipient, and releases (a predetermined time) active substance (below in the present description is also referred to as the pharmaceutical composition of the present invention).

The object of the present invention also has the pharmaceutical composition, contains

the first component comprising the active substance, and 70-95% of this active ingredient of the first component is released in water for 3-4 hours, and

the second component comprising the active substance, a water-soluble inducing osmosis agent and swelling in water excipient, and the second component has a coating that upon penetration of aqueous liquids is terminated after a certain time due to swelling swelling of excipient and releases the active ingredient at a predetermined time.

The concept of "within 3-4 h" means that after a period of time from 3 to 4 h freed a certain dose of the active substance, for example >80% or >85%.

The active substance may be a single active substance or a mixture. The active substance may be the same in the first and second doses or different at each dose. Preferably the active ingredient is the same.

In one embodiment, the implementation of the floor for the second component is a film, for example a semipermeable membrane. Swelling excipient swells in the presence of water or public water body, which penetrates through the floor and creates a mechanical pressure within the second component, which leads to rupture or breaking of the coating is opening system for example, like the lid of the box. Swelling excipient can also act as an osmotic agent, drawing the water in the second component. The thickness of the coating is one of the parameters controlling the time delay, the greater the thickness of the coating, the longer the delay time.

It should be noted that the concept of "gap" preferably refers to the formation of gaps, but it can also refer to any film system, which quickly (e.g. within 30 min or less) dissolves or disappears or changes its properties, allowing the current substance.

Another object is the composition of controlled release, for example the second component, releasing the dose of the active substance after a lag time where the active substance is released after 6-12 hours, such as 8 h after ingestion.

The second component may have a coating consisting of two films. The first film is directly in contact with the second component and preferably is a semi-permeable membrane. The second film may be semi-permeable (for example, allowing to pass, for example, water or current substance in one direction) or permeable. In this embodiment, the used film can be, for example, 2 to 5 times thinner than the Lenka, used in droplinegnome embodiment. Such a composition can provide, if required, a longer time delay for the second component in combination with a good release of the second dose of the active substance. In addition, it has certain advantages, for example, in this case, can be reduced by the amount of coverage.

The concept of "first component" means a component which is able to release immediately or in a controlled way, for example, to implement a prolonged release of the first therapeutically effective dose of the active substance when said first component comes into contact with water or total body water.

The concept of the "second component" means a component which is able to release immediately or in a controlled way, for example, to implement a prolonged release of the second therapeutically effective dose of the active substance when the second component comes into contact with water or total body water.

The term "semipermeable membrane" means a membrane that allows water to penetrate (or a common water body) in the core containing the active substance coated with the specified membrane and inhibits the release of dissolved active substance out I had RA.

The term "film", "film coating" or "membrane" means, unless otherwise specified, the coating applied to the core component, i.e. in the first or second component.

The concept of "time delay" or "delay time" means the period of time between the introduction of the composition and release of an effective dose of the active substance from the first or second component.

Specialist in this field should be obvious that the different profiles in the plasma can be obtained by varying, for example:

- composition of the first and/or second component (s), such as the nature and quantity of excipients and/or active (it) substances (a)

- delay time,

- type semi-permeable and/or neparprotamas membrane

- speed and characteristics of the initial release of the active substance (e.g., fast, slow, exponential, logarithmic, linear), which may depend on the rate of rupture of the membrane.

The composition of the invention can be used to introduce a wide ranoobrazie active substances.

The composition according to the invention may contain, for example, water-soluble and water-insoluble solid ingredients with pharmaceutical activity, which can be an inorganic or primarily organic ingredients and are intended for use in accordance with the relevant indications, such as analgesics, antipyretics, Antirheumatic agents, sedatives, hypnotic agents, antiepileptic drugs, depressants and stimulants, anesthetics, antipsychotic analgesics, antihistamines, antihypertensive agents, anticoagulants, antithrombotic agents, psychopharmacological agents, Psycholeptics tools, chemotherapeutic agents, such as antibiotics, sulfonamides, anti-tuberculosis agents (tuberculostatic funds) or chemotherapeutic agents against tropical infections, diuretic, antispasmodic, cardiovascular drugs, such as sympathomimetics, anti-hypertensive agents, cardiac stimulants, such as cardiac glycosides and digitality, parenteral therapeutic agent containing sugar, analeptics, acting on the Central nervous system, geriatrics agents, tonalitic (striated muscles), anti-Parkinson's disease, cytotoxic agents, immunosuppressants, tonics and vitamins, specified in B. Helwig has created (Moderne Arzneimittel), 1980.

As a solid active substance used according to the invention, it is possible to use antibiotics, such as penicillin, tetracycline, chlortetracycline, bacitracin, histatin, streptomycin, neomycin, polymycin, gramicidin, oxytetracycline, chloramphenicol, erythromycin, rifampicin, Cefazolin, cefoxitin, cefsulodin, cefotiam and mefoksin, and chemotherapeutic agents, such as sulfamethazine, sulfamerazine, sulfamethizole and sulfisoxazole. In addition, as the solid active ingredient in water-soluble or water-insoluble form, you can use a sedative and hypnotic agents, such as chloralhydrate, pentobarbital, phenobarbital, secobarbital, codeine and carbromal, you can use cardiac glycosides and digitality, such as digitoxin and digoxin, can be used sympathomimetics such as epinephrine.

As a solid active ingredient in water-soluble or water-insoluble form, used according to the invention can, in particular, to use antipyretics, analgesics and Antirheumatic agents, such as, for example, propifenazona, aminophenazone, aspirin (acetylsalicylic acid (ASA), phenazone, methylnitrate, millencolin, sulfinate, phenacetin, pentazocine, lactoferin, paracetamol, quinine, floranova acid, mefenamovaya acid, telenova acid, meclofenamic acid, niflumova acid, clonixin or clonixin, flunixin, ibuprofen, suprofen, Ketoprofen, fenoprofen, pirprofen,diclofenac, ibufenac, practicala acid, naproxen, cicloprofen, tolmetin, clairac, tiaprofenic acid, oxaprozin, fenclova acid, fentiazac, clidanac, fenglong, fenoprofen, flurbiprofen, carboplatin, sulindac, cinmetacin, fenbufen, etodolac, butibufen.

Most preferably as a solid active substance used according to the invention, can be used psychopharmacological agents, for example, neuroleptics, antidepressants, thymoleptic, timerelease drugs and tranquilizers in the water-soluble or water-insoluble form, such as thioridazine, imipramine, desimipramine, clomipramine, ketimipramine, opipramol, amitriptyline, nortriptyline, reserpine, Aromasin, chlorpromazine, fluororesin, melipramin, trimeprazine, detain, promethazine, aminopropanol, maasin, pipamazine and maprotiline.

In addition, as a solid active substance can be used antihypertensive agents, such as oxprenolol and metoprolol.

In a preferred embodiment, the composition according to the present invention used for the introduction of rivastigmine (Exelon®), which is used in the treatment of patients with dementia type Alzheimer's disease from mild to moderate, also known as Alzheimer's disease.

Rivastigmine can be entered in the form of bitartrate (BTA) in VI is e standard dosage forms, for example in the form of capsules with a very quick release, at a dose of from 0.5 to 6 mg twice a day.

There is a limited amount of data on biopharmacological properties of rivastigmine when administered to humans, in particular, it is known that it is rapidly and completely absorbed. In the claimed invention, it was found that it is metabolized mainly by hydrolysis using an esterase, such as acetyl - and butyrylcholinesterase, and its half-life in plasma is 1 o'clock He undergoes dasystemon and systemic metabolism. While the invention has been set, which can be prepared song with slow release of rivastigmine with preferred properties, such as better tolerability. An appropriate test can be conducted on the hungry hound dogs.

According to the present invention rivastigmine can be applied in the form of a free base or its pharmaceutically acceptable salt. Preferably used bitartrate (BTA).

Based on the composition according to the invention can be prepared intended for a single injection parenteral pharmaceutical forms for patients who need to take more than one dose of active ingredient per day, for example, after a certain period of time, which simplifies the treatment. Such compositions POS is enable to improve portability, for example, rivastigmine and consequently to apply a higher initial dose and to introduce a reduced dose fewer times.

The next object of the invention is a pharmaceutical composition containing rivastigmine prepared so that when oral administration of a therapeutically effective dose of rivastigmine was released only after 6 h (these songs below in the present description also referred to as pharmaceutical compositions according to the present invention).

Another object of the invention is a composition which allows a single oral administration twice to release a therapeutically effective dose of rivastigmine over different time intervals (such compositions below in the present description also referred to as pharmaceutical compositions according to the present invention).

In preferred compositions according to the invention, the first therapeutically effective dose of rivastigmine is released after 3-4 h after ingestion, and then the second therapeutically effective dose of rivastigmine is released after 6 to 12 h, preferably 8-10 h after ingestion.

The first component can be prepared, for example, conventional methods, allowing to provide the required characteristics of supervised release. It can be wearable is sponsored in solid form, for example in the form of tablets (e.g., matrix tablets), particles having a coating (for example, nonparallel) or pellets, such as pellets having a coating.

In one embodiment, the first component active substance is enclosed in a hydrophilic substance, which forms a gel-like substance which in contact with water, which, for example, may be from 10 to 50%, for example, 15-45% in recalculation on weight of the first component, for example, in the form of compositions of controlled-release tablets, such as matrix tablets.

Can be applied hydrophilic gel-forming substance, usually used in compositions for tablets, there is an extensive literature devoted suitable for this purpose, the compounds, see, in particular, references Fiedler "Lexicon der Hilfstoffe", 4th ed., ECV, Aulendorf, 1996, and "Handbook of Pharmaceutical Excipients" Wade and Weller (ed) (1994), the contents of which are incorporated into this description by reference.

Preferred gel-forming substances which may be used for the first component are one or more compounds selected from the group comprising natural, partially or fully synthetic anionic or preferably non-ionic hydrophilic resin, modified cellulose derivatives, or water-protein derivatives, such as, for example, the Arabian is Kai gum, tragacanth gum, carob bean gum, guar gum, gum karaya, agar, Patin, carragenin, soluble and insoluble alginates, methylcellulose, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose sodium, carboxypolymethylene, gelatin. Preferred are different forms of cellulose, which include methylcellulose, hydroxypropylcellulose and especially hypromellose and carboxymethylcellulose sodium.

The most preferred hydrophilic gel-forming substances which may be used for the first component include having high viscosity hydrophilic swellable substances, for example substances with a viscosity in the range from 10000 to 200000 MP, for example from 50000 to 150000 MT, for example 100000 MP. The preferred swelling agent which can be used for this purpose is hypromellose, for example metozel, for example KM (having a viscosity of 100,000 MT to 2%solution in water at 20° (C)having a content of methoxyl, for example, from 15 to 30%, for example from 19 to 24%, and the content of hydroxypropoxy, for example, from 5 to 15%, for example from 7 to 12%. Swelling substances with different viscosities can be obtained according to the methods described in "Handbook of Pharmaceutical Excipients" Wade and Weller (ed) (1994).

Mass delegitimising gel-forming substances in the composition may range from 10 to 50%, for example from 25 to 50%, preferably 40%.

The first component may contain from 3 to 20 wt.%, for example from 5 to 15 wt.%, for example from 6 to 13 wt.% the active substance, for example, bitartrate of rivastigmine (BTA).

It may be appropriate to include in the composition of the first component as a diluent for a pill of at least one soluble or insoluble pharmaceutical excipient, such as calcium sulfate, calcium phosphate, lactose, mannitol, sucrose. For example, can be included microcrystalline cellulose in the form of a granulated powder and/or fine powder, for example, in the range from 10 to 50%. For example, fine powder microcrystalline cellulose may be present in an amount of from 20 to 50%, for example from 30 to 40% in recalculation on weight of the first component and the granular powder microcellulose may be present in an amount of from 10 to 40%, for example from 20 to 30% in recalculation on weight of the first component.

May contain at least one substance that improves the slip, for example dispersed silicon dioxide, talc, in an amount of from 0.1 to 1% based on the weight of the first component, and may contain at least one lubricant for tablets, for example magnesium stearate, stearic acid, hydrogenated castor is oil, the polyethylene glycol in an amount of from 0.1 to 1%, preferably 0.5% calculated on the weight of the first component.

For example, in this particular embodiment, the first component may have the following characteristics release of the active substance, such as rivastigmine, in water or in an artificial gastric juice (for example, in 0,1N. HCl):

Time (min)Number (%)
3028-35
6040-55
12058-75
18070-90
24080-95
30088-98
360>92

In another embodiment, the first component active substance include particles having a diffusion coating. The coating can be adapted for a controlled release of the active substance. Can be used coating materials commonly used for coating compositions. In addition, these coating materials may be included binders, sizing, substances that improve slip, stabilizers, fillers or diluents, surfactants, etc. as baking powder trail is t to emphasize CMC-CA, CMC-Na, crosslinked PVP (Crosspovidone, Polyplasdone or Kollidon XL), alginic acid, sodium alginate and guar gum, the most preferred are crosslinked PVP, Crosspovidone, crosslinked CMC and Ac-Di-Sol.

As the binders that can be used in these coatings, it should be noted polysaccharides, such as potato starch, wheat starch, corn starch, hypromellose, for example the products known under the registered trade marks Avicel®, Filtrak®, Heweten®or Pharmacel®.

Kernel that can be used for the first component, preferably are inert and water soluble. Usually the diameter is approximately 0.5 to 1.5 mm

Coatings that can be used for the first component may contain, for example, a derivative of cellulose, which may be, for example, applied in the form of a film. Can be applied to conventional cellulose coating, information about which can be derived from the extensive literature devoted to the substances suitable for control of diffusion.

As the preferred cellulose coating for the first component, it is possible to apply the coating containing ethylcellulose and hypromellose (below in the present description designated as GPMC).

Ethical ulosa preferably has a molecular weight of from 10,000 to 15000000, for example from 50000 to 1000000, for example from 75000 to 80000 Yes. Preferably, the cellulose is substituted by an approximately 2-3 ethoxypropane per unit of the saccharide. Preferably it has a content of taksigrup constituting 44-51%.

Used in the examples ethylcellulose preferably represents ethylcellulose N10 brand name Aqualon®N10 (marketed by the company Dow Chemicals Company).

The hypromellose preferably has a viscosity of from 1 to 10 SP, for example from 2 to 8 SP. Preferably it has a molecular weight of from 10,000 to 1,500,000 Da, such as from 100,000 to 1,000,000 Da, such as from 300,000 to 800000 Yes. Cellulose is preferably substituted ethyl and hydroxypropionate groups.

The hypromellose preferably has a viscosity of from 3 up to 5 SP.

The particles may have a diffusion coating, preferably containing ethylcellulose and hypromellose, for example, in a ratio of 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 particles may have a coating of the drug (active ingredient), preferably containing hypromellose. The cover of medicines can contain from about 50 to 90 wt.% the active substance, such as rivastigmine, for example from 50 to 80 wt.% of rivastigmine. The amount of the drug can be, e.g. the, 3-15% of the mass of the nucleus.

Typically, the ratio of coverage of drugs to diffuse the coating is in the range from 3:1 to 1:1.

If necessary between diffuse coating and a coating of medication may be protective coating. It may contain hypromellose or ethylcellulose. The ratio of protective coating and diffuse coating may, for example, be in the range of from 1:1 to 1:10, for example from 1:2 to 1:8.

In film coating may be silicon dioxide, for example, in the range from 10 to 70 wt.%.

In this particular embodiment, the first component may, for example, have one or more, for example, all of the following characteristics of release of the active substance, such as rivastigmine, in water or artificial gastric juice (for example, in 0,1N. HCl):

Time (min)Number (%)
3025-40
6045-65
12065-85
18075-95
24075-96
30085-97
36087-98
42090-98
48090-99

As the next example in races is motivemag specific embodiment, the first component may have one or more, for example, all of the following characteristics of release of the active substance, such as rivastigmine, in water or artificial gastric juice (for example, in 0,1N. HCl):

Time (min)Number (%)
305-25
6025-45
12050-70
18065-80
24070-90
30075-95
36080-90
42085-95
48085-95

In another embodiment, the first component active substance include pellets, such as extruded pellets, which can be applied diffusion coating according to the above-described method. The pellets may contain the active ingredient, such as rivastigmine, in the same manner that was described for particles. They can additionally enable the above binders and such diluents as calcium sulfate, calcium phosphate, lactose, mannitol or sucrose.

In this particular embodiment, the first component may, for example, have one or more, for example, all of the following characteristics of the release action is the pollutant specific for example, rivastigmine, in water or artificial gastric juice (for example, in 0,1N. HCl):

Time (min)Number (%)
301-40
6010-60
12040-80
18060-90
24065-95
30070-99
36075-99
420>80

Preferably it can have the following characteristics release:

Time (min)Number (%)
301-8
6015-25
12045-70
18075-90
24092-95
30095-98
36097-99
420>99

In addition, the present invention relates to pharmaceutical compositions with controlled release for oral administration containing a therapeutically effective dose of rivastigmine and pharmaceutically acceptable excipients, for example, the first component (below in the present description also referred to as the I and pharmaceutical compositions of the present invention).

Further, the present invention relates to pharmaceutical compositions with controlled release for oral administration containing a therapeutically effective dose of rivastigmine, when 50-95%, for example, 50-80%, 60-90%, 70-95% of rivastigmine is released in water or common water body, such as in artificial gastric juice within 3 h (below in the present description also referred to as pharmaceutical compositions according to the present invention).

The delay time for the second component can accurately be determined, for example:

- type and number of water-soluble excipients in the core,

the permeability to water and the number of film(s) of coverage (s)applied(s) on the second component,

- mechanical strength, such as elasticity and tensile strength of the film,

the type and amount of swelling excipient included in the kernel.

Appropriate floor for the second component may be a semipermeable membrane adapted to, when applied to flowing water (in the environment of the gastro-intestinal juices) in the core and to prevent the release of dissolved active substance from the kernel.

The water passes through a semipermeable membrane at a rate that can be controlled by the composition of the membrane. Water that has penetrated into the core, restoree the at least a portion of the active substance. This results in osmotic pressure. The higher the pressure, the greater the number of molecules or ions go into solution until, while in normal conditions does not form a saturated solution.

In one embodiment, the implementation after the entry of water or public water body's osmotic pressure, the emergence of which also induces swelling swelling of excipient can be created by active ingredient, such as rivastigmine. However, to create the necessary osmotic pressure may be added water-soluble media. Thus, the osmotic pressure required to implement the functions of the second component, can be achieved due to the fact that the total water body coming in order to balance the osmotic gradient, causing the desired swelling swelling of excipient (baking powder) and after a certain time delay leads to rupture or break a film coating that allows the release of the active substance. By optional add in the core tablet of water-soluble media, the second component can be prepared in a form that is practically independent of pH, i.e. independent from the concentration of hydrogen ions and hydroxyl ions and/or independent from the other ion is in, such as phosphate ions, and enzymes that are present, for example, in the digestive tract.

Semi-permeable membranes suitable for film layer include a semi-permeable membrane described in the literature, for example in patents US 3916899 and 3977404, through which water (total water body), but is not dissolved active substance, and which, therefore, suitable for the creation of osmosis. For example, can be applied membrane, created by artificial means, which consist of cellulose acetate, cellulose triacetate, acetate agar, amylose acetate, ethylcarbamate cellulose acetate, phthalate cellulose acetate, methylcarbamate cellulose acetate, succinate cellulose acetate, diethylaminoacetate cellulose acetate, ethylcarbamate cellulose acetate, CHLOROACETATE cellulose acetate, ethylacetate cellulose acetate, methylsulfonate cellulose acetate, butylsulfonyl cellulose acetate, a simple ester of cellulose propionate cellulose acetate, diethylaminoacetate cellulose acetate, octate cellulose acetate, laurate cellulose acetate, methyl cellulose, acetate-para-toluensulfonate cellulose, gidrauxilirovannogo of ethylene vinyl acetate, butyrate cellulose acetate and other derivatives of cellulose acetate. Other suitable semi-permeable membranes are membranes, sostojashie is from hydroxypropylmethylcellulose and polymeric epoxides, copolymers of accelerated and simple alkylglycerol ether derivatives, polyglycols or polymer of lactic acid and other derivatives thereof. In addition, can also be used mixtures, for example water-insoluble acrylates, for example a copolymer of acrylate and methacrylate.

In General, to obtain a film for the second component fit all semi-permeable membrane, known from the literature that has the property of flowing water.

The coating, for example, on tablets, such as pressed tablets, the core particles or pellets, in the form of a film representing a semipermeable membrane thickness, can be carried out in a fluidized bed layers, vats coating or the coating can be applied using, for example, tabletiruemyh machines (tablet coating dry method).

The second component may also be, for example, enclosed in a capsule such as a gelatin capsule containing the active substance, such as rivastigmine, swelling excipient, optionally containing a water-soluble carrier and other excipients, such as sizing agents, and slow release in powdered form, and it can be applied film coating, representing a semipermeable membrane.

The corresponding film, to the which can be applied as a second coating to a second component, include membrane, which may be permeable or semi-permeable to water or common water body, such as the membrane for sustained release, described in the literature. This is the second film coating may be applied in the same way as the first film.

Preferred second film coating for the second component consists of ethyl cellulose, such as ethyl cellulose brand name Aqualon® N10 (marketed by the company Dow Chemicals Company). It can be applied, for example, by spraying a solution containing ethylcellulose and HPMC having a viscosity of 5 CPS, in mass ratio, 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.

Ethylcellulose preferably has a molecular weight of from 10,000 to 15000000, for example from 50000 to 1000000, for example from 75000 to 80000 Yes. Preferably, the cellulose is substituted by an approximately 2-3 ethoxypropane per unit of the saccharide. Preferably it has a content of taksigrup constituting 44-51%.

The hypromellose preferably has a viscosity of from 1 to 10 SP, for example from 2 to 8 JV, preferably 3 JV or 5 SP. Preferably it has a molecular weight of from 10,000 to 1,500,000 Da, such as from 100,000 to 1,000,000 Da, such as from 300,000 to 800000 Yes. Cellulose is preferably substituted ethyl and hydroxypropionate groups.

In p edocfile embodiment, the mass ratio of the first and second films, deposited on the second component is from 20:1 to 1:5, for example from 15:1 to 1:1, e.g. from 10:1 to 2:1.

In a preferred embodiment of the invention, the film thickness for the second component may be in the range from 50 to 800 micrometers (μm), for example from 100 to 600 μm. For the second component having a coating of one film, the preferred thickness is in the range from 300 to 500 μm, for example from 350 to 400 μm. For the second component having the coating of the two films, the preferred thickness is in the range from 100 to 300 μm, for example from 150 to 200 microns.

The nature and amount of excipients and active ingredient of the second component (except for the film(s) coatings(s) (s) is subject to(at) the gap) can be the same as for the first component, or may be different from them.

Suitable swelling excipients or baking powder for the second component can serve as an inert substance, which quickly swell upon contact with aqueous liquids, such as alginic acid and its derivatives, agar-agar, cellulose, such as microcrystalline or talismanically cellulose, methyl cellulose, crosslinked carboxymethylcellulose, carboxymethoxy starch, modified starch, cross-linked polyvinylpolypyrrolidone, colloidal silicon dioxide, polymers with large molecule the Noah mass, including ethylenoxide links, bentonite, veegum, montmorillonite, dried pulp citrus, Kilani, as well as cation and anion exchange resins, such as cholestyramine.

Other excipients that can be used for creating or inducing osmosis in the process of swelling of the second component are water-soluble media (inducing osmosis substances, for example substances that are not irritating the mucous membrane of the stomach or intestines, such as inorganic or organic salts such as sodium chloride, secondary, acidic sodium phosphate, sodium nitrate and sodium acetate, or acids, such as tartaric, citric or succinic acid, and sugar, especially, for example, mannitol, glucose, fructose, lactose, and derivatives of dextran with different molecular weights. The number of media can vary from some portion of the number of rivastigmine to over it many times.

The oil, which may not necessarily serve as an additional excipient for the second component may be, for example, magnesium stearate, silica aerogel, talc, stearic acid, hydrogenated castor oil, polyethylene glycol (PEG).

Optional additives for the second component can represent, for example, the antioxidant is, for example α-tocopherol or bottled hydroxytoluene (OSH).

Optional additives for film coating for the second component can represent, for example, pigments such as colored iron oxides or titanium dioxide, and/or corrigentov, such as sweeteners, for example saccharin, cyclamate sodium or sugar.

Preferably the second component contains (in wt.%), for example:

Core
rivastigmine BT0,5-25%
sodium chloride10-35%
avicel HY 1025-25%
PVPP-XL20-70%
α-tocopherol0.01 to 5%
Aerosil 2001-15%
magnesium stearate0.1 to 5%
First floor
the cellulose acetate1-20%
GPMC0,1-1%
Second floor
ethylcellulose0.5 to 10%
GPMC0,1-2%

In addition, the invention relates to pharmaceutical compositions comprising a core, covered in two films, the first inner film, which is polyphonica is my water or public water body, applied directly to the specified kernel and consists of a cellulose acetate such as cellulose acetate E320 or 398-10, and the second outer film, which is permeable to water or public water body, consists of ethyl cellulose, such as ethyl cellulose N10.

Consider the core containing the active substance, such as rivastigmine, and excipients may be, for example, compressed tablets, capsules and pellets, usually used in the preparation of galenic forms, and they can be prepared with known methods. For example, tableting mass can be obtained by mixing active ingredients, baking powder, and optionally other excipients, such as carriers, oil, and optionally also of excipients required for prolonged release. Manufacture of compressed tablets and pellets may be made, for example, using tabletiruemyh machines, which are known to be used for the manufacture of, for example, round, oblong pressed pellets and wood pellets and filling capsules can be carried out using known machines for filling capsules.

Used excipients for sustained release can be a practically water-insoluble excipients or mixtures thereof, e.g. the lipids, among other things, fatty alcohols such as cetyl alcohol, stearyl alcohol and cetosteatil alcohol; glycerides such as glycerol monostearate or mixtures of mono-, di - and triglycerides of vegetable oils, hydrogenated oils such as hydrogenated castor oil or hydrogenated cottonseed oil; waxes, such as beeswax or Carnauba wax; solid hydrocarbons, for example paraffin or mineral waxes; fatty acids, such as stearic acid; certain derivatives of cellulose, such as ethylcellulose or cellulose acetate; polymers or copolymers, such as polyalkylene, such as polyethylene, polyvinyl derivatives such as polyvinyl chloride or polyvinyl acetate, and also copolymers of vinyl chloride and vinyl acetate and copolymers with crotonic acid, or polymers and copolymers of acrylates and methacrylates, for example copolymers of acrylate and methacrylate.

To get the desired result, the person skilled in the art can use excipients other than the above excipients.

The necessary information can be gleaned from the extensive literature devoted to fit the excipients, see, in particular, references Fiedler "Lexicon der Hilfstoffe", 4th ed., ECV, Aulendorf, 1996, and "Handbook of Pharmaceutical Excipients" Wade and Weller (ed) (1994), the contents of which are incorporated in the present description as the e links.

As already noted, the process of liberation, which you want to perform through various time intervals can be precisely controlled using the composition and thickness of the coating layer (film)used for the second component, the mechanical strength and elasticity and is not necessarily due to the number and characteristics of swelling swelling or loosening agent.

The second component, for example, with one film coating according to the invention may, for example, have one or more, for example, all of the following characteristics release in water:

Time (min)Number (%)
00-1
1200-1
1800-1
2400-85
3000-97
360>99,5

The second component, for example, with two film coatings according to the invention may, for example, have one or more, for example, all of the following characteristics release in water:

Time (min)Number (%)
00-1
1200-1
1800-1
2400-85
3000-97
3600-99,5
4200-100
48070-100
54075-100
60085-100
66090-100
720>50

After a break for 30 minutes may occur the release of 85% or more, for example 90%, of the active substance contained in the second component.

The pharmaceutical composition according to the invention preferably contains from 0.5 to 25%, for example from 1 to 10%, for example from 2 to 5% of rivastigmine in terms of the weight of the entire composition.

The pharmaceutical compositions of the present invention can be used in accordance with known indications for specific included in each of the active substance.

The exact magnitude of the doses of the active substance and composition, subject to the introduction, depend on numerous factors, such as the condition to be treated, the desired duration of treatment and on the speed of release of the active substance.

Required amount of the active substance and its rate of release can be determined, for example, on the basis of known methods in vitro or in vivo, allowing us to determine how long the concentration of the particular active substance is stored in plasma at a level sufficient to provide a therapeutic action level.

For example, rivastigmine can be applied dose in the range from 1 mg to 12 mg of active ingredient per day for a mammal weighing 70 or 75 kg for the person and for the standard animal models. Unexpectedly increased tolerability of rivastigmine provided compositions may be demonstrated in standard animal experiments and in clinical trials.

The pharmaceutical compositions according to the invention is administered, for example orally once a day, if there are two doses of the active substance, and twice a day if there is a second dose of the active substance.

Another object of the present invention is the use of the active substance, such as rivastigmine, and the above mentioned excipients for the preparation of medicines intended for the treatment of patients, for example, dementia type Alzheimer's disease mild to moderate by oral administration once a day.

The invention is explained in more detail using the following examples, without limiting its scope. Unless otherwise stated, all percentages are wt.%. Temperatures are given in degrees Celsius.

The first component

The first component may be prepared in the usual manner by mixing the ingredients. Below are examples what s a specific form of the first component, allowing to obtain different release profiles contained in the active substance.

Example 1: the First component in the form of matrix tablets

The resulting mixture may be in the form of a powder, which can be compressed to obtain tablets at the usual tabletiruemyh machines at pressures, for example, from 2000 to 16000 psi.

A. Preparation of the granulate

Ingredients

- rivastigmine, for example, BTA,

- microcrystalline cellulose, for example, in the form of fine powder,

- purified water for dissolving the drug.

Rivastigmine BTA dissolved in purified water constituting from 10%to 20%, for example 16.3% in recalculation on weight of the entire granulate, and the solution is stirred until then, until it becomes transparent. Can be used mixer with overlapping blades, for example, when the rotation speed of 150-200 rpm, for example, 180 rpm, for 10 to 20 minutes, for example 15 minutes

Finely powdered microcristalline cellulose material, for example, via the hand-held vibrating sieve or a sieve with a grid with cell size, for example, 1600 μm and the diameter of the wire, for example, 500 μm, in a container, for example, a mixer with large shear effort type demand include Collette Gral® 10.

The powder is subjected to wet granulation in the mixer with large with the village of the Whigs efforts at the position of the knob of the mixer I and the position of the knife I with an aqueous solution of a medicinal substance (fluid granulation), which is added at a rate of 0.5-1 l/min, for example, 0.75 l/min

Vessel for dissolution (used to prepare the fluid for granulation) was washed with purified water and washing liquid is added to the mixer at the position of the knob of the mixer I and the position of the knife I at a rate of 0.5-1 l/min, for example, 0.75 l/min

Then the regulator knife is switched to position II and carry out stirring for approximately 1 min. Stop the granulation process and purify the vessel wall mixer in demand include Collette Gral®. The wet granulate is stirred for another minutes at the position of the knob of the mixer I and the position of the knife II.

Then the wet granulate is dried, for example, by transfer from the mixer with large shear forces in the drying Chan fluidized bed, and the supply air temperature at the inlet 40 to 60°S, 50°With, until the value of PP (loss density)equal to a 2.5-5.0% (corresponding to the temperature of the product is approximately 31°).

Then the dried granulate is milled, for example, passing it through a vibrator equipped with a sieve (for example, with a cell size of 800 μm and a wire diameter of 320 μm), in container mixer with free mixing (for example, type the turbula®T10A).

B. preparation of a mixture for tablets

Ingredients

- hydroxy who mobilecellular CM,

- microcrystalline cellulose, for example granulated powder,

- highly dispersed silicon dioxide.

Microcrystalline cellulose (MCC) in the form of a granulated powder, hypromellose and highly dispersed silicon dioxide can be mixed manually in a plastic container or in a mixer with a free stirring for approximately 2 minutes silica can be dispersed in HPMC and MCC to reduce any dust on the next stage of screening.

Preliminary mixture can sift by passing it through a sieve (or vibrating sieve). Used the size of the cells can be, for example, 800 μm and a wire diameter of 320 μm.

Dry pre-mix can be transferred into the vessel mixer with free mixing (for example, type the turbula®CA) and mixed with the granules within 100 rpm, for example, at a speed of 20 rpm for 5 minutes

Magnesium stearate may be pre-mixed by hand with about 10 parts of the dry pre-mix in a plastic bag or in a mixer with a free stirring for approximately 2 minutes magnesium Stearate may be dispersed in order to avoid any re-agglomeration after subsequent stage sifting.

Pre-mix may be the issue is Jan, for example, by passing her hand through a sieve (or vibrating sieve). Used the size of the cells can be, for example, 800 μm and a wire diameter of 320 μm.

The dry pre-blend containing magnesium stearate, transferred, for example, in a vessel mixer with free mixing (for example, type the turbula®T10A), containing the remainder of the pre-mixture and the entire mixture for tablets mixed with granules within 100 rpm, for example, at a speed of 20 rpm for 5 minutes

Century Tableting

Tablets are formed by pressing, for example, using teletrauma machine with one eccentric plug (for example, type Comprex®or rotary tablet press press (for example, type Betapress®, Korsch®PH250) using, for example, punches with a diameter of 6 mm (round, convex, beveled corners).

Examples of the first component, does not limit the invention, which can be prepared according to the above method, shown in the following table:

Composition No.123
rivastigmine BTA (mg)7,27,27,2
microcrystalline cellulose in the form of fine powder (mg) 25,9525,9525,95
the hypromellose KM (mg)of 18.7522,5030,05
microcrystalline cellulose in the form of a granulated powder (mg)to 22.3518,6011,05
magnesium stearate (mg)0,3750,3750,375
highly dispersed silicon dioxide (mg)0,3750,3750,375
The total mass75 mg75 mg75 mg

Composition No. 1, 2 and 3, when dissolved in water are characterized by the following release profile:

Composition 1:

Time (min)3060120180240300360420480
The drug release (%)29,342,6of 60.573,382,689,493,596,4of 97.8

Composition 2:

360
Time (min)3060120180240300420480
The drug release (%)3351,972,684,592,396,8the 98.999,9100

Composition 3:

Time (min)3060120180240300360420480
The drug release (%)32,14664,377,685,591,795,197,2of 97.8

Example 2: the First component in the form of particles coated

The Protocol solution for deposition of a film below. Not limiting the scope of invention example compositions prepared according to this Protocol, serves to explain the invention.

A. Ingredients:

The ingredients necessary for the preparation of solutions for the deposition of films shown in the following table:

IngredientCommentProvider
rivastigmine BTAbitartrate of rivastigmineNovartis
nonpareil and sugar beads with a diameter of 0.85-1.0 mm (USP)H.G. Werner
GPM-cellulose 3the viscosity hypromellose 3 SPShin-Etsu Chemical Co. Ltd.
ethylcellulose N10ethylcellulose N10Dow Chemicals Company
GPM-cellulose 5the hypromellose with a viscosity of 5 CPSDow Chemicals Company
Aerosil 200highly dispersed silicon dioxideDegussa AG
magnesium stearate-FACI SRL
gelatin capsules with solid floorsize 3, cover + body: bright yellow, opaque, type CONISNAP 6 with the notchCapsugel N.V.

B. Obtaining a solution for drawing film

Percentages (%) are given in terms of the mass of the obtained solution (the amount of purified water for 1, 2 and 3).

1. The preparation of an aqueous solution HPMC (5%)

HPMC with a viscosity of 3 JV was dispersed in purified water under stirring for approximately 2 minutes in a vessel stainless steel faucet with cross blades at 500 Rev/min the Solution was stirred at 250 rpm until then, until it becomes translucent (30 min). The resulting solution was allowed to stand for 12 h in a vessel of stainless steel.

2. prigotovleniya aqueous solution rivastigmine/GPMC for applying film

Rivastigmine BTA (15-25%) is dissolved with stirring in a solution GPMC (3-5%) (solution rivastigmine/GPMC). The resulting solution was stirred (approximately 15 min) in a vessel of stainless steel until then, until it becomes transparent (the rotation speed of the mixer with overlapping blades: 250 rpm). Then dispersed silicon dioxide (1-3%) in solution rivastigmine/GPMC located in a vessel of stainless steel (the rotation speed of the mixer with overlapping blades: 250 rpm). The resulting solution is stirred for approximately 10 minutes, If necessary, silicon dioxide can be dispersed in 2 parts of a solution rivastigmine/GPMC using a mortar and pestle before adding the rest of the solution.

3. The preparation of an aqueous solution GPMC for applying film

In solution rivastigmine/HPMC with a viscosity of 3 CPs (3-7%)in the vessel of stainless steel (the rotation speed of the mixer with overlapping blades: 250 rpm), is dispersed silicon dioxide (1,5-3%). The solution is stirred for approximately 10 minutes, If necessary, silicon dioxide can be dispersed in 2 parts of a solution rivastigmine/GPMC using a mortar and pestle before adding the rest of the solution.

4. Preparation of organic solvent

In a vessel of stainless steel (speed in the stop mixer with overlapping blades: 250 rpm) is mixed for approximately 2 min 94 wt.%-hydrated ethanol and acetone (see the proportions in section 5).

5. Preparation of an organic solution of the polymer film

Ethylcellulose N10 (5-10%) and HPMC with a viscosity of 5 CPS (0,5-2%) is dispersed in the vessel of stainless steel with stirring for approximately 1 min in an organic solvent (acetone (45-65% and 94%ethanol (35-45%)in mixer with cross blades with a speed of 500 rpm, and then stirred in a vessel of stainless steel to obtain a clear solution for approximately 30 min (250 rpm). The solution is allowed to stand for 12 hours

C. coating

1. Aqueous coating

The dryer fluidized bed type Glatt WST 5 (download: approximately 1.5 kg) set at the desired temperature of the incoming air (60° (C) and the rate of spraying of 15 g/min (pressure: 2.5 bar), by variation of the peristaltic pressure using a silicone tube (inner diameter : 4.0 mm). Use column type Wuster (6 inches) with a double nozzle (diameter 1.0-1.2 mm) in the center of the main plate, which carries the spray by means of a jet of air, preheated to 45°C. Add nonparallel and the flow of air is adjusted to make careful fluidization of nonparallel the admission of air at a rate of about 325 m3/H. Then the solution rivastigmine/GPMC obtained at the stage And, with the ABC spray for to minimize the abrasion nonparallel vessel, made of stainless steel. The temperature of the product is equal to approximately 45°C.

The vessel is then made of stainless steel and silicone tubing wash solution HPMC with a viscosity of 3 CPs (approximately 25 g). For applying a protective coating spray aqueous solution GPMC (first washing liquid, and then the rest of the solution GPMC). After that, wash vessel made of stainless steel and silicone tubing purified water (approximately 25 g) and spray the wash water.

2. Organic coating

The dryer fluidized bed type Glatt WST 5 (download: approximately 1.5 kg) set at the desired temperature of the incoming air (50° (C) and the rate of spraying of 25 g/min (pressure: 2.5 bar), by variation of the peristaltic pressure using a silicone tube (inner diameter : 4.0 mm). Use column type Wuster (6 inches) with a double nozzle (diameter 1.0-1.2 mm) in the center of the main plate, which carries the spray by means of a jet of air. Organic solvent spray to remove residue purified water from the pipeline system and nozzles (to prevent crystallization of ethyl cellulose (organic solution of the polymer film) in the tubes). The product temperature is about 40°C.

Then sbryzgivayut solution to obtain a polymer film. Vessel made of stainless steel and silicone tubing is washed with approximately 50 g of an organic solvent ethanol/acetone and spray washing fluid. Nonparallel with the coating is dried at a temperature of inlet air 50°up until the product temperature does not increase by 2°C.

Nonparallel coated dried manually in a shelf dryer type Waldner (air temperature at the inlet 30°C) for 6 h to remove the residue of the organic solvent from the coating and pass through a sieve (mesh size 1250 mm, wire diameter 400 mm) to remove agglomerates.

3. Preparation of a mixture for filling capsules

Magnesium stearate manually passed through a sieve with mesh size of 800 μm and a wire diameter of 320 μm. Then sifted magnesium stearate are mixed in a mixer with a free mix (Tubula 101) with pellets coated for 5 min at 20 rpm, i.e. within 100 turns.

4. Filling capsules

Mixture for filling capsules filled capsules hard gelatin coating (type CONI-SNAP 6 with the notch, size 3) using an automatic machine for filling capsules (Zanasi LZ 5). Nominal weight of the filler described above.

The parameters of the process are the following:

speed: 3000 MK/h

the spout/piston:

- size # 4

- height: 12-14 mm

negative pressure (vacuum): ,7 bar

raw bunker: no

G. preparation of a composition based on EXELON MR BID 4.5 mg NKR

The composition prepared according to the above process. The ingredients listed in the following table.

PhaseIngredientsMass (mg)Total weight (mg)
an aqueous solution of a medicinal substance/polymer1,3(drug loading)rivastigmine BTA7,207,20
the viscosity hypromellose 3 SP1,501,50
highly dispersed silicon dioxide0,750,75
purified water28,5028,50
an aqueous solution of polymer1,3(protective coating)the viscosity hypromellose 3 SP1,51,5
highly dispersed silicon dioxide0,750,75
purified water28,5028,50
the organic polymer solution2,3(diffusion coating)ethylcellulose N104,057,35
the hypromellose with Vascos the d 5 SP 0,453,15
94 wt.%-hydrated ethanol16,2037,80
acetone24,3056,70
15%solution GPMC

210%solution of the polymer/organic solvent (60% acetone, 40% ethanol (94 wt.%-nogo))

35%excess (taking into account losses during spraying)

Get the following release profiles

Time (min)3060120180240300360420480
ReleaseI)32,555,176,484,188,090,692.493,894,9
drugs (%II)15,536,361.272,979,7of 83.486,5of 89.190,6
in HCl 0.1 N.)

D. Magnitude of doses:

For all values of doses using the same nonparallel coated (with the same drug loading). Different size doses (1.5 mg - 9 mg) obtained by variation of the mass of filler capsule, as indicated in the table below.

The dose sizeWeight of filler capsules (approx.)Capsule size
1.5 mg50 mg4
3.0 mg100 mg3
4.5 mg150 mg3
6.0 mg200 mg2
9.0 mg300 mg2

For values doses of 6.0 mg, 3.0 mg and 1.5 mg, if necessary, may be added nonpareille as a placebo, in order to optimize the degree of filling of the capsules.

Example 3: the First component in the form of pellets coated

A. Ingredients:

- bitartrate of rivastigmine;

- microcrystalline cellulose Avicel®PH-101, FMC Corporation, Philadelphia, USA);

- lactose 200 mesh (firm DMV, Vehgel, the Netherlands);

- ethylcellulose N10 (Dow Chemicals Company, USA);

- hypromellose with a viscosity of 5 CPS (Dow Chemicals Company, USA);

- stearate;

gelatin capsules with solid pokr is a tie: size 3, cover + body: bright yellow opaque, CONISNAP®6 with the notch (firm Capsugel N.V.).

The required quantity of ingredients listed in the description of the Protocol or below in section J.

B. Preparation of solutions of drugs for film coating

Specified in sections 1, 2 and 3 percentages are wt.% in terms of the mass of the obtained solution.

1. The preparation of an aqueous solution of rivastigmine

Rivastigmine is dissolved with stirring in water, for example, in a vessel of stainless steel, and the solution is stirred, for example, in the mixer with overlapping blades for about 15 min at 250 rpm until then, until it becomes transparent. The amount of water is approximately 39%, calculated on the dry weight of the kernel, which is prepared according to the method described below.

2. Preparation of organic solvent

Ethanol (94 wt.%-tion) and acetone mix (acetone (60%)/94%ethanol (40%)for about 2 min in a vessel of stainless steel (the rotation speed of the mixer with overlapping blades: 250 rpm).

3. Preparation of an organic solution for deposition of the polymer film

Ethylcellulose N10 (8%) and HPMC with a viscosity of 5 CPS (2%) was dispersed in an organic solvent (90%) by stirring for about 1 min in a vessel of stainless steel is blowing steel mixer with overlapping blades (at a speed of 500 rpm). The solution is stirred until then, until it is translucent, for about 30 minutes (with a speed of 250 rpm), for example, in a vessel of stainless steel. The solution is allowed to stand for 12 hours

C. Preparation of pellets

Lactose and Avicel®loaded into the mixer of the type of demand include Collette Gral®(10 or 25 l) and stirred for 2 min (slow speed, slow speed of rotation of the knife). To a mixture of Avicel®and lactose, are in the mixer of the type of demand include Collette Gral®add a solution of rivastigmine at low speed (knife off). After making the solution of the drug in the mixer in demand include Collette Gral®in the same vessel, pour an additional amount of water for flushing. The amount of additional water is 18.5%, calculated on the dry weight of the kernel. This additional amount of water is brought into the above mixture while rotating at low speed (knife set).

Prepared as described above, the mixture granularit in the mixer in demand include Collette Gral®within 15 min (low speed rotation, the knife is disabled). The car stopped in 5-minute intervals and cleaned by scraping the walls of the vessel. In the last two or three minutes include the knife at a low speed of rotation. Thus obtained wet mass ekstragiruyut in the form of thin threads (settings: extras the der with dual augers type Gabler ®the mesh size of the sieve of 1 mm, the speed of screw rotation: 50 rpm, adjusting the position of the dispenser machine: 1,8, the pressure of the extruding mass: 10 bar).

Extruded mass is subjected to spheroidizing, i.e. converted into pellets portions 3 kg (parameters: spheroidization type Wyss Pharmex®loading spheroidization: 3 kg, speed: 870 rpm, time of spheroidizing: 6 minutes).

The wet pellets are dried (parameters: dryer fluidized bed type Aeromatic®temperature of air at inlet: 60°C, outlet temperature: 47-49°, drying to achieve LOD (loss on drying) of 2.5-3.0%.

The dried pellets are screened manually to remove agglomerates. All product passed through a sieve, collecting the coating (mesh size sieve: 1600 microns).

G. Floor

1. Organic coating

The dryer fluidized bed type Glatt®WST 5 (value zakuski: 1:5 kg) to regulate the temperature of the air inlet 50°with a volumetric flow of 235 m /h and the speed of zabryzgivaya 25 g/min (pressure: 2.5 bar) by variation peristaltic pump with silicone tubing (inner diameter : 4.0 mm). Use column Wurster (Wurster) (6 inches), fitted with a dual spray nozzle (diameter 1.0-1.2 mm), located in the center of the base plate, which carries the spray using supplied is Otok air. Sprinkle organic solvent to remove residue purified water from the system piping and nozzles (nasdaw) (to prevent crystallization of ethyl cellulose (organic solution for deposition of the polymer film)in the tubes. The product temperature is about 40°C.

Then sprinkle the organic solution for the deposition of the polymer film. Vessel made of stainless steel and silicone tubing is washed with approximately 50 g of an organic solvent ethanol/acetone and spray washing fluid. Then the pellets coated is dried at a temperature of inlet air 50°up until the product temperature will rise by 2°C.

Pellets coated dried manually in a shelf dryer type Waldner®HW 15/2N (air temperature input: 30°C) for 6 h to remove all residual organic solvent from the coating and then pass through a sieve (mesh size sieves 1600 μm and a wire diameter of 400 μm) to remove agglomerates.

D. preparation of a mixture for filling capsules:

Magnesium stearate is passed through a sieve with mesh size of 800 μm and a wire diameter of 320 μm. Then sifted magnesium stearate is mixed with pellets coated in a mixer with the free mixing of the turbula type®101) the ri speed 20 rpm for 5 min, i.e. within 100 turns.

E. Filling capsules

Mixture for filling capsules fill empty shell gelatin capsules with a solid floor (CONI-SNAP®6 with the notch, size 3) using a machine for filling capsules (type Zanasi®LZ 5). Nominal weight of the filler described above (process parameters: speed: 3000 NK/h, the spout/piston size number 4 height: 12-14 mm vacuum: 0.7 bar hopper: not used).

J. Composition Exelon MR BID 4.5 mg NKR

The composition prepared according to the above method.

The total number of film coating (in % of theoretical content of the capsules (150 mg)) - 3,0

Diffusion coating (ethylcellulose : hypromellose) 80:20

PhaseIngredientMass (mg)
Corerivastigmine BTA7,20
lactose 200 mesh60,30
microcrystalline cellulose (Avicel®)67,5
Diffusion coatingethylcellulose N103,24
the hypromellose with a viscosity of 5 CPS0,81
Sizing magnesium stearate0,15
The total mass of filler139,20
Weight capsulesCONISNAP®size 349,00
Only188,20

Get the following release profile:

Time (min)3060120180240300360420
Release4,2of 21.957,884,894,597,999,499,9
drugs (% 0,1N. HCl)

H. the dose Size

For all values of doses using the same pellets (with the same drug loading). Different size doses (1.5 mg - 9 mg) obtained by changing the mass of filler capsule, as indicated in the table below.

td align="center"> 4
The dose sizeWeight of filler capsules (approx.)Capsule size
1.5 mg46.4 mg
3.0 mg92,8 mg3
4.5 mg139,2 mg3
6.0 mg185,6 mg2
9.0 mg278,4 mg2

For values doses of 6.0 mg, 3.0 mg and 1.5 mg, if necessary, may be added placebo for pellets, in order to optimize the degree of filling of the capsules.

Preparation of the second component

The second component may be prepared in the usual manner by mixing the ingredients, for example, to obtain particles or pellets coated as described for the first component, and then by applying one or more thin film coatings, as described above.

Example 4: the Second component in the form of matrix tablets with a coating consisting of a single film

The second component containing 4.8 mg of rivastigmine BTA as of rivastigmine in the compressed core, for example in the pressed tablet, put the corresponding film coating. This system, which releases rivastigmine after a certain time after placing in the aquatic environment, can be prepared as follows:

A. Preparation kernel:

Product for 5000 cores is prepared as follows. 24 g of rivastigmine BTA dissolved in 1000 g of purified water. In a mixer, connected to the gra is Ostrom, for example, type Diosana®download 400 g polyplasdone (stitched polyvinylpolypyrrolidone) and 221 g of sodium chloride. The mixture is stirred for 5 minutes and add a solution of rivastigmine BTA to this mixture, podvergaemym wet granulation. Then the wet mass is passed through a sieve with a pore size of 2 mm and dried in the dryer fluidized bed at 60°C. After drying, the granules pass through a sieve with a pore size of 1 mm Pellets are weighed and mixed with an appropriate amount of silica, for example Aerosil 200®and microcrystalline cellulose for 20 minutes in a drum mixer (mixer type the turbula®and pressed, receiving, as mentioned above, the kernel of the total mass of 178 mg each. For this purpose, can be used tablet press press with only one punch, concave punch of 8 mm diameter (R=12), for example, type Kilian EKO®.

B. Preparation of a varnish film:

4000 compressed cores are coated with semi-permeable film (or membrane)having the following composition, using the method of fluidized bed in a stream of air, for example, in the device type Glatt-wurster:

the cellulose acetate containing 32% acetyl139,5 g
the cellulose acetate containing of 39.8% acetyl145,5 g
the hypromellose (HPMC)15.0 g
methylene chloride6750 g
methanol750 g

Film coating (semi-permeable membrane coating) is applied using the above organic varnish containing 4% of the components of the solid film in a solvent mixture consisting of methylene chloride and methanol. It should be noted that instead of methylene chloride/methanol can be used a different mixture of solvents, such as acetone/alcohol/water.

The kernel is applied film layers of different thickness, i.e. different weight, for example about 55 mg/kernel 70 mg/kernel 80 mg/core or more, providing a delay time, for example, 3-4, 5-6 or 7-8 hours, and dried in the air flow in the dryer fluidized bed within 48 h at 40°C.

Century Composition

1. IngredientsQuantity/tablet (mg)
polyplasdone-XL or crospovidone80,0
colloidal silicon dioxide5,0
sodium chloride44,2
rivastigmine BTA4,8
polyplasdone-XL or crospovidone20,0
avicel PH 10223,0
magnesium stearate 1,0
mass of nucleus178,0
the cellulose acetate E32025,52
the cellulose acetate 398-1026,74
HPMC 6032,74
The total mass233,0
2. IngredientsQuantity/tablet (mg)
polyplasdone-XL or crospovidone80,0
colloidal silicon dioxide5,0
sodium chloride44,2
rivastigmine BTA4,8
polyplasdone-XL or crospovidone20,0
avicel PH 10223,0
magnesium stearate1,0
mass of nucleus178,0
the cellulose acetate E32032,48
the cellulose acetate 398-1034,03
HPMC 6033,49
The total mass248,0

, The Definition of the profile of the release of rivastigmine:

The above tablets are film-coated with two different film thickness (film-coated with different weight), placed in a chemical beaker containing 200 ml of deionized (demineralized) water at 37°and determine the time, heart and soul is presented to rupture (semipermeable membrane) for two types of tablets. The results are shown in tables 1 and 2.

86,8
Table 1
The drug release (VL) (%) in water, 50 rpm, film thickness: 55 mg
Time (min)Cell 1Cell 2Cell 3Cell 4Cell 5Cell 6
00,00,00,00,00,00,0
1200,80,70,90,90,70,7
1500,70,80,70,70,60,7
1800,70,80,70,70,60,7
21053,41,40,90,746,90,6
24064,064,467,00,7of 57.50,7
30076,681,7to 89.569,869,782,1
36083,192,294,577,778,4
Table 2
The drug release (VL) (%) in water, 50 rpm, film thickness: 70 mg
Time (min)Cell 1Cell 2Eccica 3Cell 4Cell 5Cell 6
00,00,00,00,00,00,0
2400,60,40,30,30,30,2
2700,51,01,30,80,50,6
30045,60,342,946,80,52,2
33063,759,161,861,033,045,1
36072,771,269.870,151,256,0
42084,784,081,681,865,769,5

Example 5: the Second component in the form of matrix tablets with a coating consisting of two films

And: Cooking kernel:

Product for 70000 cores prepared with edusim way. 336 g of rivastigmine BTA dissolved in approximately 6400 g of purified water and 12 g of alpha-tocopherol are dissolved in approximately 388 g of ethanol (in the case of OSH also prepare a similar solution). 6938 g polyplasdone-XL, 1660 microcrystalline cellulose, 3094 g of sodium chloride (pre-ground) and 350 g of colloidal silicon dioxide (Aerosil 200) sieved through a sieve with a pore size of 1600 μm and contribute to the mixer with large shear effort type Collette Gral volume 75 liter mixer Collette Gral dry powders are mixed for one minute at low speed and when the knife. Then slowly add a solution of alpha-tocopherol and solutions rivastigmine, and the mixer and knife work with low speed. For the formation of granules add a further quantity of purified water. After that, the mixer Collette Gral include 2 min while rotating at a slow speed and the rotation of the knife with great speed. Then the granules are dried in the dryer fluidized bed at a temperature of inlet air to about 70°to achieve losses during drying, less than 4%. Thereafter, the granules are screened through a sieve with a pore size of 800 μm and mixed with magnesium stearate (pre-sifted) for 5 minutes in a mixer with free mixing. This mixture is then pressed into tablets of 178 mg, using protagonisten size 10× 5.2 mm and is suitable tablet press press.

B. coating:

First, prepare two solutions for the two films. 499 g of cellulose acetate 398-10, 499 g of cellulose acetate 320S and 53 g HPMC with a viscosity of 3 JV is dissolved in a solvent mixture containing 70% acetone, 20% ethanol and 10% purified water, obtaining a solution containing 7.5 wt.% solid ingredients. 441 g of ethyl cellulose N10 and 49 g HPMC with a viscosity of 5 CPS dissolved in a solvent mixture containing 60% acetone and 40% ethanol, obtaining a solution containing 5 wt.% solid ingredients. Should prigotovit 5% solution in order to compensate for the loss occurring during the drying of the sprayed substance in the coating process. The tablets obtained according to the method described above, are coated in a suitable perforated Chan for coating by spraying the first solution of cellulose acetate, and then ethyl cellulose solution to obtain the required mass films. You can also use other solvents, such as methylene chloride/methanol.

Century Composition

IngredientsQuantity/tablet (mg)
rivastigmine BTA4,84,8
sodium chloride44,244,2
avicel PH 10223,71223,712
PVPP-XL99,1199,11
α-tocopherol0,1780,178
Aerosil 2005,05,0
magnesium stearate1,01,0
mass of nucleus178,0178,0
the cellulose acetate 398-107,1257,125
the cellulose acetate E3207,1257,125
HPMC 6030,7500,750
ethylcellulose N104,56,3
HPMC with a viscosity of 5 CPS0,50,5
the total mass198200

The following composition metokoferol can be replaced by OSH (bottled hydroxytoluene):

td align="center"> magnesium stearate
IngredientsQuantity/tablet (mg)
rivastigmine BTA4,8
sodium chloride44,2
avicel PH 10223,0
PVPP-XL99,11
OSH0,890
Aerosil 2005,0
1,0
mass of nucleus178,0
the cellulose acetate 398-109,5
the cellulose acetate E3209,5
HPMC 6031,0
ethylcellulose N102,7
HPMC with a viscosity of 5 CPS0,3
the total mass201

G: Definition of profile release of rivastigmine:

Table 1
The drug release VL (%) in water at 50 rpm, oblong tablets (approximate size 10.25 mm × 5.5 mm × 4.80-4.85 mm)
Time (min)Cell 1Cell 2Cell 3Cell 4Cell 5Cell 6
2400,00,00,00,00,00,0
3000,00,00,00,00,00,0
360to 58.10,00,059,80,00,0
42089,662,4of 58.9of 83.4 0,060,6
48092,096,085,497,2to 97.185,5
54099,097,9for 95.2100,995,897,6
60099,4100,2102,7101,0100,299,9
660to 100.4100,9103,0to 102.3102,1102,5
720102,1101,8103,299,4104,2101,6
Table 2
The drug release VL (%) in water at 50 rpm, round tablets (approximate size 8.57 mm × 5.58 mm)
Time (min)Cell 1Cell 2Cell 3Cell 4Cell 5Cell 6
2400,00,00,00,00,00,0
3000,00,00,00,096,50,0
36092,50,00,00,099,4 0,0
420100,90,00,00,099,80,0
480101,6to 89.50,00,0100,30,0
540of 101.598,00,00,0100,288,7
600100,9100,194,40,099,497,0
660101,7101,7100,10,098,8101,0
720102,1100,7101,876,299,2102,1

Example 5: Filling capsules

Mixture for filling capsules containing first and second components together (or, if necessary, separately), fill with automatic machine for filling capsules (type Zanasi®LZ 5) empty shell gelatin capsules with hard coating (type CONISNAP®6 with the notch, size 3). Nominal weight of filler above. The parameters of the process are the following:

speed: 3000 MK/h

the spout/piston:

- size: No. 4

- height: 12-14 mm

vacuum: 0.7 bar

raw material hopper: none.

1. Solid the dosage form for oral administration, used for the treatment of dementia type Alzheimer's disease from mild to moderate, made of a pharmaceutical composition comprising rivastigmine or its pharmaceutically acceptable salts, characterized in that it is a gelatin capsule with a solid floor, filled with a mixture of pellets with magnesium stearate, and the pellets prepared from rivastigmine or its pharmaceutically acceptable salt, lactose and microcrystalline cellulose, and put on them a diffusion coating containing ethylcellulose and hypromellose.

2. Solid dosage form for oral administration used for the treatment of dementia type Alzheimer's disease from mild to moderate, made of a pharmaceutical composition comprising rivastigmine or its pharmaceutically acceptable salts, characterized in that it is a gelatin capsule with a solid floor, filled with a mixture of stearate with nonparallel with three coatings, the first coating contains rivastigmine or its pharmaceutically acceptable salt, hypromellose and silicon dioxide, the second protective coating is formed of hypromellose and silicon dioxide, the third diffusion coating includes ethylcellulose and hypromellose.

3. The dosage is the tool, used for the treatment of dementia type Alzheimer's disease mild to moderate severity, including rivastigmine or its pharmaceutically acceptable salts, and this tool is made in the form of matrix tablets, coated two films, and the specified first film comprises cellulose acetate and hypromellose, and the second film includes ethylcellulose and hypromellose.



 

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