DD297559A5 - Solid dosage form for pharmaceutical active ingredients - Google Patents

Abstract

The invention relates to a solid pharmaceutical dosage form from which the active substance or the drug mixture is approximately pH-independent, i. irrespective of the hydrogen ion and hydroxyl ion concentrations and / or other ions and also independent of enzymes of the surrounding liquid, specifically after a certain time, i. quantitatively after release of a certain time interval quantitatively after release can go into solution, characterized in that the one active ingredient or in active ingredient mixture, a water-swellable non-colloidal excipient (disintegrant) and at least one water-soluble traegerstoff (osmosis-inducing substances) and optionally containing other auxiliary forms of administration is coated with a semipermeable membrane, which upon penetration of aqueous fluid by the swelling pressure (blasting) of the swellable non-colloidal adjuvant and by the simultaneously occurring osmotic pressure and optionally internally generated gas pressure after a certain time lid-like jumps up and the Wirkstoffbzw , quantitatively releases the active ingredient mixture. Further a process for the preparation and the use of the solid pharmaceutical dosage form {solid pharmaceutical dosage form; pharmaceutical agents; Method; manufacture; Use}

Description

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Solid dosage form for pharmaceutical active ingredients

The invention relates to a solid dosage form which is suitable, the pharmaceutical active substance mixture or approximately pH-independent, i. regardless of the hydrogen ion, hydroxyl ion concentrations and / or other ions, e.g. Phosphate ions and also enzymes of the surrounding body fluid, specifically after a certain time, i. after a certain period of time can submit quantitatively in this.

The oldest and best-known mode of administering a drug, oral administration, is still considered to be extremely useful today in delivering the pharmaceutical agent into the systemic blood circulation of the body by immediate release, for example immediate dissolution via the gastrointestinal tract , However, in order to guarantee the therapeutic efficacy, however, these pharmaceutical Darreichüngsformen would have to be repeatedly taken several times at certain time intervals during the day .. As a result, other oral pharmaceutical dosage forms with delayed or repeated drug release, so-called sustained release forms (slow, release and sustained release forms) and also multiple forms (Repeatformen) developed that allow the most constant, continuous and long-lasting drug concentration or long-lasting variable drug concentration in the bloodstream, the achieved drug concentration, however, was directly dependent on the physiological nature of the gastrointestinal fluids.

The developed sustained-release or repeat forms allow a continuous release of the active ingredient in a constant or changeable (alternating) concentration, but so far the need

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a targeted, sudden, quantitative release after a certain time, i. after a time interval has elapsed, in the simple or repeated case, the release to be achieved is also independent of the pH, i. should be independent of the hydrogenation of the hydrogen ions and hydroxyl ions and / or other ions and enzymes.

It is described by Lachman et al. in "Theory and Practice of Industrial Pharmacy", pages 430-465 Cher edited by Lea and Febinger, Philadelphia, Pennsylvania, 1976), found that the release of the described dosage forms (sustained release and repeat forms) and also of other conventional administration forms from the Solubility of the drug and this in turn depends on the pH of the surrounding body fluid.

It is known that the solubility of many pharmaceutical active ingredients from the previously known administration forms, including sustained-release and repeated forms, are very different in these pH ranges. Depending on their solubility, the active ingredients can be divided into different classes, for example the class of active ingredients which are characterized by poor solubility or insolubility in the lower pH range of the stomach and greater solubility in the higher pH range of the intestinal tract. Another class Active ingredients are characterized by solubility in the low pH range and insolubility or poorer solubility in the higher pH range.

However, there are also agents whose solubility is strongly influenced by foreign ions, such as hydrogen and phosphate ions. Foreign ions can cause salting-out effects or else the precipitation of salts which are difficult to dissolve, so that complete release of the active ingredient in the dosage form can not take place.

It is known from DOS 1617724 a coated with a film dosage form, which after a predetermined time by the resulting crack or burst of the membrane, the active ingredient, or the active ingredient mixture in time

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controlled release. The bursting of the membrane is caused by the pressure of the colloidal swelling agent after the ingress of body fluid, either relatively good or relatively poorly in the physiological fluids soluble active ingredients can be used. Optionally, plasticizers, e.g. Glycerol added to facilitate the swelling of the colloidal swelling agents, such as gelatin. However, the dosage form described in the above-mentioned DOS 1617724 has the disadvantage that the entire amount of active ingredient is not immediately available due to the tear of the membrane, because after the crack has occurred, the membrane still envelops the majority of the active ingredient and does not immediately release it. Surprisingly, this disadvantage can be eliminated, however, in which according to the invention, in addition to the swelling pressure, a pressure produced by osmosis can simultaneously act on the membrane, which opens lidily, comparatively like a shell, and the active ingredient is quantitatively available for release immediately in which he can go into solution immediately or, if present in a retarded form, continuously. Optionally, the osmotic pressure used according to the invention can be increased by an internally generated gas pressure from released carbon dioxide, if one induces as osmosis. Carriers salts of carbonic acid, e.g. Alkaline or alkaline earth metal carbonates or bicarbonates in the presence of a water-soluble organic acid, such. Citric acid or tartaric acid, both used as osmotic inducing carriers. Upon penetration of water of the existing aqueous body fluid into the active substance-containing core, carbon dioxide is released by the reaction of the abovementioned auxiliaries and, in addition to the osmotic pressure and swelling pressure, an additional mechanical pressure is generated by the internal gas pressure which acts on the membrane.

The solid dosage form according to the invention, from which the active substance or the active ingredient mixture is approximately pH-independent, i. regardless of the hydrogen ion and hydroxyl ion concentrations and / or other ions and also independent of enzymes of the surrounding liquid, specifically after a certain time, i. after expiration of a certain

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Time interval quantitatively can go immediately or continuously into solution is characterized in that the one active ingredient or a mixture of active ingredients, a non-colloidal water-swellable auxiliary (disintegrant) and at least one water-soluble carrier (osmotic inducer) and optionally other Excipients containing dosage form is coated with a semipermeable membrane, the water-like upon entry of water of the existing body fluid by the swelling pressure of the swellable non-colloidal excipient and by the simultaneously occurring osmotic pressure and optionally internally generated gas pressure after a certain predetermined time jumps up and the Active substance or the active substance mixture quantitatively releases.

Depending on the dissolving power, the active ingredient or the active ingredient mixture can be dissolved immediately or, if given in sustained release form, continuously in solution.

The dosage form according to the invention consists essentially of a film Tahlette (pellet) or a pellet with an osmotically active core, which in addition to the drug or drug mixture and the non-colloidal swellable excipient and at least one water-soluble carrier (osmotic inducer) and other adjuvants such. May contain lubricants and retardants and a semipermeable membrane as a film coating. As already stated above, the water-soluble carriers may contain salts of carbonic acid, e.g. Alkaline or alkaline earth metal carbonates or bicarbonates and also organic water-soluble acids, such. include the citric acid. However, for example, the dosage form can also be made from a capsule, such as a capsule. consist of a gelatin capsule containing the active substance or mixture of active substances, the swellable auxiliary, at least one water-soluble carrier and other auxiliaries, such as. Contains lubricant and retardant in powder form and coated with a semipermeable membrane as a film.

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The semipermeable membrane attracts water at a certain rate, which can be controlled by the composition and thickness of the membrane. The penetrated into the core water of the existing body fluid dissolves the osmotic inducing carrier and optionally the active ingredient. This results in an osmotic pressure, which is the greater, the more molecules or ions go into solution, whereby in the normal case almost a saturated solution is formed.

In the simplest case, when the water enters the osmotic pressure, which also causes swelling of the swelling excipient as a follow-up reaction, can be generated in part by the active substance or by the active ingredient mixture itself, which, taken alone, is not large enough to burst cause the membrane in a desired manner, so that an addition of at least one osmosis-producing soluble carrier is essential. However, should the active ingredient be difficult or even insoluble in water, a greater proportion of a water-soluble carrier must be added to produce the necessary osmotic pressure. Hereby, the osmotic pressure necessary for the induction of the working principle of the dosage form can be achieved, so that the water entering to balance the osmotic gradient causes the desired swelling of the swellable non-colloidal excipient (disintegrant) and after a certain time, i. after a certain time interval, the lid-like opening (blasting) of the membrane, caused by the swelling and osmotic pressure and optionally internally generated gas pressure for the release of the active ingredient takes place. Due to the appropriate semipermeability of the membrane and by the addition of a water-soluble carrier in the core of the tablet, the dosage form according to the invention can be approximately as independent of pH, i. from the hydrogen ion and hydroxyl ion concentration and / or other ions, e.g. Phosphationen and enzymes, for example in the digestive tract, are produced. In an extreme case, the solid, for example perorally administered dosage form according to the invention can also be used for active substances or mixtures of active substances which are difficult or even insoluble in a certain pH range of the gastrointestinal tract.

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The time of release of the drug can

a) by the water permeability of the membrane film,

b) through the film thickness,

c) by the mechanical strength, i. Elasticity and tear strength of the membrane and

d) by the swelling properties of the swellable excipient in the core and by the ability of the carrier to induce an osmotic pressure by dissolution and

e) be determined by the total surface area of the dosage form. By varying the various degrees of freedom a), b), c), d) and e), the time of release (time bomb) can be precisely manipulated.

In principle, all known in the literature semipermeable membranes having water-permeable properties, for the production of the film of the dosage form according to the invention are suitable.

Suitable semipermeable membranes for the film layer are the semipermeable membranes described in the literature, for example in US Pat. Nos. 3,916,889 and 3,977,404, which are for the passage of water from the body fluid present and not the dissolved active substance and herewith for the formation of the osmosis are suitable. For example, artificially produced membranes of cellulose acetate, cellulose triacetate, Agarazetat, Amyloseazetat, Celluloseazetatäthylcarbamat, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate-dimethylaminoazetat, cellulose acetate-ethyl carbonate, cellulose acetate-chloroacetate, Celluloseazetat- äthyloxalat, cellulose acetate methylsulfonate, Celluloseazetat- butylsulfonate, cellulose ether, cellulose acetate propionate, cellulose acetate diethylaminoacetate, cellulose acetate octate, cellulose acetate laurate, methyl cellulose, cellulose acetate p-toluenesulfonate, hydroxylated ethylene vinyl acetate, cellulose acetate butyrate and other cellulose acetate derivatives. Also suitable as semi-permeable membranes are hydroxypropylmethylcellulose and polymeric epoxides, copolymers of alkylene oxide and alkylglycidyl ether, polyglycols or polylactic acid

derivatives and other derivatives thereof. Furthermore, mixtures such as e.g. water-insoluble acrylates (e.g., copolymer of acrylic acid ethyl ester and methyl methacrylate).

The film-forming coating material may be applied by any method as far as this results in a continuous film of substantially uniform thickness.

The coating of, for example, the tablet (pellet) and also of the pellet with a thick film of a semipermeable membrane as required can be carried out in fluidized beds, in coating pans or else with the aid of the coacervation method.

As swellable non-colloidal excipients (swelling or disintegrating agents) are indifferent, in contact with aqueous liquids rapidly swelling substances, such as. Alginic acid and derivatives, ultraamidopectins, cellulose, e.g. microcrystalline or microfine cellulose, carboxymethylcellulose-crosslinked, carboxymethyl starch, modified starch, polyvinylpolypyrrolidones, crosslinked, bentonites, veegum, montmorillonites, dried citrus pulp, xylans and also cationic and anionic exchangers, e.g. Cholestyramine.

As water-soluble osmotic inducing carriers, for example, the gastric or intestinal mucous membranes may be nonirritating substances, such as e.g. inorganic or organic salts, e.g. Common salt, sodium hydrogen phosphate, sodium nitrate and sodium acetate, or alkali metal or alkaline earth metal salts of carbonic acid, e.g. Sodium or calcium carbonate or bicarbonates or water-soluble organic acids, such. the tartaric, citric or succinic acid alone or in combination with the abovementioned carbonates and also sugars, in particular e.g. Mannitol, glucose, fructose, lactose and dextran compounds of different molecular weight to generate the osmotic pressure bzv. be used to induce the necessary for the swelling process osmosis. The amount of the carrier can vary from a fraction to several times the amount of the solid active substance or active substance mixture used.

As further adjuvants, lubricating agents, e.g. Magnesiurastearat, silicon airgel and in particular also talc can be used.

As optional additives in the film coating, e.g. including pigments, e.g. colored iron oxides or titanium dioxide and / or flavoring agents, e.g. Sweeteners (e.g., saccharin, Na-cyclamate, or sugar).

Suitable shaped articles (core) of active substance or mixtures of active substances and auxiliary substances are the compressed tablets (compacts), capsules and pellets customary in galenicals, as can be prepared by known processes. By way of example, the preparation of the tablet composition can be effected by mixing the solid particles _T ie the active ingredient or active ingredient mixture, swelling agent, the excipients and optionally other excipients, such as lubricants and if required also retarding agents. The production of the pellets and pellets can be done with the known for the production of, for example, round and rod-shaped pellets pellets and filling the capsules with the known Kapselabfullmaschinett.

As retarding adjuvants may be substantially water-insoluble excipients or mixtures thereof, such as lipids, u.a. Fatty alcohols, e.g. Cetyl alcohol, stearyl alcohol and cetostearyl alcohol; Glycerides, e.g. Glycerol monostearate or mixtures of mono-, di- and triglycerides of vegetable oils; hydrogenated oils, such as hydrogenated castor oil or hydrogenated cottonseed oil; Waxes, e.g. Beeswax or carnauba wax; solid hydrocarbons ,. e.g. Paraffin or earth wax; Fatty acids, e.g. stearic acid; certain cellulose derivatives, B-ethyl acetate or acetyl cellulose; Polymers or copolymers such as polyalkylenes, e.g. Polyethylene, polyvinyl compounds, e.g. Polyvinyl chloride or polyvinyl acetate, as well as vinyl chloride-vinyl acetate copolymers and copolymers

with crotonic acid or polymers and copolymers of acrylates and methacrylates, e.g. Copolymers of acrylic acid ethyl ester and methyl methacrylate, can be used.

In particular, the invention relates to a solid dosage form which is to be administered orally and which is suitable for selectively administering the active substance or the active substance mixture in a pH-independent manner after a certain time. independently of hydrogen and hydroxyl ions and also other ions, e.g. Quantitatively release phosphate ions and enzymes in the gastrointestinal tract.

The dosage form according to the invention can be used in particular if a release of the active substance or active substance mixture should take place several times after several desired successive time intervals, for example after several hours have elapsed. In particular, the solid pharmaceutical dosage form can be used if the release of active ingredient in each case after expiration of several equal time intervals, i. should be periodic. For example, pellets made according to the method of the dosage form of the present invention, but having a different and thus delayed release, may be administered in a single dosage form, such as e.g. Gelatin capsule. The release to be carried out at different time intervals can, as already mentioned, by the layer thickness of the membrane, mechanical strength and elasticity and optionally by the amount and source property of the Quell bz «- explosive and osmotic inducing property of the carrier or corresponding carbon dioxide-producing carriers according to enclosed drawing (A) are precisely controlled. From the drawing it can be seen that the release of the active ingredient (diclofenac sodium) in accordance with the information in Table I of Example 1 is carried out at different time intervals.

As used herein, "pharmaceutically active agent" includes all therapeutically useful agents, e.g. those in the human resp. Veterinary medicine useful therapeutically active substances.

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The dosage form 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 according to their indication as analgesics, antipyretics, antirheumatics, sedatives, hypnotics, antiepileptics, neuraltherapeutics, narcotics, antipsychotics, antihistarainics _T antihypertensives, Anticoagulants, antitrombolics, psychotropic drugs, psychoanaleptics, chemotherapeutics such as antibiotics, sulfonamides, antituberculosis, CTuberkulostatika) or chemotherapeutic agents against tropical infections, diuretics, spasmolytics, circulatory agents such as sympathomimetics, antihypertensive agents, cardiac drugs such as cardiac glycosides and digitaloids, parenteral sugar therapeutics, centrally acting Analeptics, Geriatrika, Tonolytika (the cross-striated muscles), Antiparkinson Hittel, cytostatics, immunosuppressants, tonic, hormones and vitamins according to B-Helwig (Modern Arzn Eimittel), 1980, are to be used.

For example, as antibiotics penicillin, tetracycline, chlorotetracycline, bacitracin, nystatin, streptomycin, neomycin, polymicine, gramicidin, oxytetracycline, chloramphenicol, erythromycin, rifampicin, cefazolin, cefoxitin, cefsulodin, cefotiam and mefoxin and as chemotherapeutic agents suflamethazine, sulfamerazine, sulfamethizole and Sulfisoxazole be used as solid active ingredients for the dosage form according to the invention. Furthermore, e.g. as sedatives and hypnotics chloral hydrate, midazolam, pentabarbital, phenobarbital, Secobarbital, Codeine and Carbromal and as cardiac glycosides and digitaloids digitoxin and digoxin and as sympathomimetics epinephrine as a solid drug substance in water-soluble form or water-insoluble form.

In particular, antipyretics, analgesics and antirheumatics in suitable water-soluble form or water-insoluble form may be exemplified by propyphenazone, aminophenazone, aspirin (ASA), antipyrine, ethylnifenazine, melamine sulfone, sulfenazone, phenacetin, pentazocine, lactophenine, paracetamol, quinine, flufenamic acid, yeastenamic acid, tolfen aminic acid, meclofenamic acid, niflumic acid, clonixin or clonixidine, flunixin, ibuprofen, suprofen, ketoprofen, fenoprofen, pirprofen, diclofenac, ibufenac, proctic acid, naproxen, cicloprofen, tolmetin,

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Clopirac, tiaprofenic acid, oxaprozin, Fenclozinsäure, Fentiazac, Clidanac, Fenclonac, Fenoprofen, Flurbiprofen, Carprofen, Sulindac, Cinnietacin, Fenbuten, Etodolac, Butifufen, be used as a solid active ingredient in the dosage form according to the invention.

Advantageously, psychotropic drugs, e.g. Neuroleptics, antidepressants, thymoleptics, thymmeretics and tranquilizers in water-soluble or water-insoluble form, e.g. Thioridazine, imipramine, desimipramine, clomipramine, ketimipramine, opipramol, amitriptyline, nortriptyline, reserpine, aromazine, chlorpromazine, fluopromazine, methopromazine, trimeprazine, diethazine, promethazine, Aminoρromaζin, mepazine, pipamazine and haprotiline be used as a solid active ingredient in the dosage form of the invention.

In particular, analgesics and antirheumatics such as e.g. Ibuprofen, pirprofen, ibufenac, naproxen and diclofenac be used in the inventive dosage form. Diclofenac in the dosage form according to the invention can be used particularly advantageously as analgesics and antirheumatics *

Furthermore, antihypertensives, such as e.g. Oxprenolol and Metoprolol or Hypnotica, such. Midazolam be used as a solid in the dosage form.

In the following non-limiting examples, the invention is explained in more detail. By parts, unless otherwise indicated, always parts by weight are understood. Temperatures are given in degrees centigrade.

Example 1: An oral dosage form (film-coated tablet) containing 50 mg of diclofenac sodium as an active ingredient in the compressed core and coated with a semipermeable membrane which releases the active ingredient in each case after a predetermined time is prepared as follows:

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a) Preparation of the core:

The cores of the following compilation are compressed using a 8 mm concave punch (R 12 mm) in a single-stamped tablet press.

Each compressed core contains:

Diclofenac sodium 50 mg

Polyvinylpolypyrrolidone (crosslinked) 100 mg

Sodium chloride 50 mg

O Silica aerogel (Aerosil 200) 7 mg

Magnesium stearate 3 mg

The powder for 2000 tablet cores is homogeneously mixed in a tumbler mixer (turbulamixer) for 20 minutes and compressed to cores a 210 mg total weight as indicated above.

b) Preparation of the film layer:

1500 compacted cores are airlaid using the fluidized bed process with a semipermeable film of the following composition.

Cellulose acetate containing 32% acetyl 46.5 g

Cellulose acetate containing 39.8% acetyl 48.5 g

Hydroxypropyl ethyl cellulose 5.0 g

The coating is carried out with a solution containing organic paint containing 5 % solid paint component in a substantially consisting of 1800 ml of methylene chloride and 200 mg of methanol solution mixture. The cores are coated with varnish layers of different thickness (ie different weights), for example with approximately 12 mg, 22 mg, 33 mg, 47 mg and 62 mg of varnish and dried in a stream of air in a fluidized bed dryer at 40 ° for 48 hours.

c) Determination of the release of the active substance:

10 film-coated tablets each with 5 different film thicknesses (coated with a film of different weight) are placed in a beaker containing 200 ml of deionized (desalted) water at 37 ° C. and the time of the lid-like opening (blasting) of the 5 systems is determined. The values are given in Table I.

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Table I

System weight of the time of lid-like opening (blasting) varnish

1 12 mg 57, 62, 64, 65, 75 (x = 65, S ^ ₁ = 9.1)

2 22 mg 103, 110, 127, 128, 130 (x = 120, S ^ ₁ = 9.2)

3 33 mg 159, 175, 178, 180, 188 (x = 176; S ^ ₁ = 5.A)

4 47 mg 201, 201, 203, 217, 222 (x = 209, S = 4.3)

5 62 mg 387, 390, 393, 395, 430 (x = 399, S ^ ₁ = 3.9)

Example 2: Approx. Five thousand nuclei containing 10 mg oxprenolol succinate as the active ingredient are compressed and contain the following composition.

Oxprenolol succinate 10 mg

Sodium chloride 25 mg

Choe s ty ramin USP 50 mg

Silica aerogels 4.5 mg

Magnesium stearate 0.5 mg

The cores of the above composition weighing about 90 mg are compressed using a 6 mm concave punch in a single-punch tablet press.

Approximately 1000 compressed cores are sprayed using the fluidized bed process in the air stream with a film consisting of 20 mg, 25 mg and 30 mg of varnish. The film membrane is composed of 40 % (by weight) of a cellulose acetate having an acetyl content of 32% and 55% (by weight) of a cellulose acetate having an acetyl content of 39.8% and 5% (by weight) of hydroxypropylmethylcellulose.

The coating is carried out with a solution containing organic paint containing 5% solid paint component in a mixed solution of methylene chloride: methanol in the ratio 9: 1.

The cores are coated with varnish layers of various thicknesses (various weights), for example approximately 20, 25 and 30 mg and then dried in a stream of air in a fluidized bed dryer at 40 ° C for 24 hours.

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Determination of the release of the active substance

10 film-coated tablets each with 3 "different film thicknesses (coated with a film of different weights) are placed in a beaker containing 200 ml of deionized (demineralized) water at 37 ° C. and the time of the lid-like opening (blasting) of the 3 systems is determined.

Table II

System weight of the time of the lid-like opening (blowing up)

j varnish

J 1 20 mg 118, 120, 125, 125, 130, 131, 132, 136, 140,

, 142 (x = 130, S = 6.1)

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2 25 mg 147, 158, 159, 160, 160, 166, 179, 180, 180,

184 (x = 167, S = 7.2) rel

3 30 mg 205, 209, 212, 212, 214, 215, 219, 219, 220,

222, (x = 215, S '= 2.4) rel

Example 3: Approx. 1000 nuclei containing 7 mg midazolam (Donnicum®) as an active ingredient are compressed and contain the following composition.

Midazolam 7 mg

Sodium chloride 50 mg

Polyvinylpolypyrrolidone cross-linked 100 mg

Silica aerogel 7.0 mg

Magnesium stearate 2.0 mg

The cores of the above composition weighing approximately 165 mg are compressed using a 8 mm concave punch in a single-punch tablet press.

Pressed cores are sprayed using the fluidized bed process in the air stream with a film consisting of about 38 mg of paint. The film membrane is composed of 46.5% (by weight) of a cellulose acetate having an acetyl content of 32% and 48.5% (by weight) of a cellulose acetate having an acetyl content of 39.8% and 5% (by weight) of hydroxypropylmethylcellulose.

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The coating is carried out with a solution containing organic lacquer containing 5% solid paint component in a mixed solution of methylene chloride: methanol in the ratio 8: 2.

The cores are coated with a lacquer layer of 38 mg and then dried in a stream of air in a fluidized bed dryer at 40 ⁰ C for 24 hours.

Determination of the release of the active substance

Ten film-coated tablets are placed in a beaker containing 200 ml of deionized (desalted) water at 37 ° C and the time of the lid-like opening (blasting) of the systems determined.

Table III

System weight of the time of the lid-like opening (blasting) in min. Of lacquer

1 38 mg 250, 250, 252, 260, 260, 264, 270, 272, 275,

280 (x = 263, S = 6.8) rel

Claims (23)

A-137559 claims 1. Solid pharmaceutical dosage form from which the active ingredient or the drug mixture approximately pH-independent, i. regardless of the hydrogen ion and hydroxyl ion concentrations and / or other ions and also independent of enzymes of the surrounding body fluid, specifically after a certain time, i. after a certain time interval can go quantitatively immediately or continuously into solution, characterized in that the one active ingredient or a drug mixture, a non-colloidal water-swellable excipients (disintegrants) and at least one water-soluble carrier (osmotic inducer) and optionally other excipients containing dosage form is coated with a semipermeable membrane, the lid-like jumps upon penetration of aqueous liquid by the swelling pressure of the swellable non-colloidal excipient and by the simultaneously occurring osmotic pressure and optionally internally generated gas pressure after a certain predetermined time and the active ingredient or ., The quantitative release of active ingredient mixture. 2. Solid pharmaceutical dosage form according to claim 1, characterized in that the solid dosage form consists of a film tablet (pellet) or a pellet with an osmotic active core, in addition to the active ingredient or active ingredient mixture and the swellable non-colloidal adjuvant and at least one water-soluble carrier ( Osmotic inducer) and other excipients, such as May contain lubricants and retardants and a semipermeable membrane as a film coating. 3. Solid pharmaceutical dosage form according to claim 1, characterized in that the solid dosage form consists of a capsule containing the active ingredient or the drug mixture ·, the swellable non-colloidal excipient, at least one water-soluble carrier and other excipients in powder form and having a semipermeable membrane as Film is covered. 4. Solid dosage form according to claims 1 and 3, characterized in that the solid dosage form consists of a gelatin capsule containing the active ingredient or the active ingredient mixture, the swellable non-colloidal excipient, at least one carrier, lubricant and retardant in powder form and with a semipermeable Membrane is coated as a film. 5. Solid dosage form according to claims 1-4, characterized in that one uses as swellable non-colloidal excipient in the solid dosage form an indifferent, rapidly swelling on contact with aqueous liquids substance. A solid dosage form according to claims 1-5, characterized in that, as a swellable non-colloidal excipient in the solid dosage form, one selected from the group consisting of e.g. Alginic acid and derivatives, ultraamidopectins, cellulose, e.g. microcrystalline or microfine cellulosis, carboxymethylcellulose-crosslinked, carboxymethyl starch, modified starch, polyvinylpolypyrrolidone crosslinked, bentonite, veegum, montmorillonite, dried citrus pulp, xylans, and also cationic and anionic exchangers. 7. Solid dosage form according to claims 1-6, characterized in that used as a swellable non-colloidal excipient in the solid dosage form Polyvinylpolypyrrolidone-crosslinked or cholestyramine. Solid dosage form according to claims 1-4, characterized in that as excipients (osmosis inducing substances) one from the group of water-soluble inorganic or organic salts, such. Common salt, sodium hydrogen phosphate, sodium nitrate and sodium acetate, or alkali metal or alkaline earth metal salts of carbonic acid, e.g. Alkali metal or alkaline earth metal carbonates or bicarbonates or else water-soluble organic acids, such as e.g. the tartaric, citric or succinic acid alone or in combination with the abovementioned carbonates and also sugars, in particular e.g. Hannit, glucose, fructose, lactose and dextran compounds of different molecular weight. ZS] SSS 9. Solid dosage form according to claims 1-4, characterized in that one uses as a semipermeable membrane as a film coating in the solid dosage form a membrane which is suitable for the passage of water from existing body fluid and not the dissolved active ingredient. 10. Solid dosage form according to claims 1-4 and 9, characterized in that as semipermeable membrane as a film coating an artificially prepared membrane of cellulose acetate, cellulose triacetate, agar acetate, amylose acetate, cellulose acetate ethyl acetate, cellulose acetate phthalate, cellulose acetate methylcarbamate, cellulose acetate succinate, cellulose acetate -diraethylaminoazetät, cellulose acetate-ethyl carbonate, cellulose acetate-chloroacetate, cellulose acetate-äthyloxalat, cellulose acetate methylsulfonate, cellulose acetate-butylsulfonate, cellulose ether, cellulose acetate propionate, cellulose acetate-diäthylaminoazetat, cellulose acetate-octoate, cellulose acetate laurate, methyl cellulose, cellulose acetate p-toluenesulfonate, hydroxylated Ethylene vinyl acetate, cellulose acetate butyrate, hydroxypropylmethyl cellulose from polymeric epoxides, copolymers of alkylene oxide and alkyl glycidyl ethers, polyglycols or polylactic acid derivatives and of acrylates (eg copolymer of acrylic acid ethyl ester he and methacrylic acid methyl ester) used. 11. Solid dosage form according to claims 1-9, characterized in that as active ingredients or mixtures of active substances, solid pharmaceutical active substances which may be inorganic or in particular organic active substances and according to their indication as analgesics, antipyretics, antirheumatics, sedatives, hypnotics, antiepileptics, Neural therapeutics, narcotics, neuroleptics, antihistamines, antihypertensives, anticoagulants, antithromboalics, psychotropic drugs, psychoanaleptics, chemotherapeutic agents, such as Antibiotics, sulfonamides, antituberculosis, (tuberculostatics) or chemotherapeutic agents against tropical infections, diuretics, spasmolytics, circulatory agents, such as. Sympathomimetics, antihypertensives, cardiac agents, e.g. Cardiac glycosides and digitaloids, parenteral sugar therapeutics, centrally acting analeptics, geriatrics, tonolytics (the striated muscle), 19J559 Antiparkinson agents, cytostatics, immunosuppressants, tonics, hormones and vitamins according to B-Helwig (Modern Medicines), 1980, are used 12. Solid pharmaceutical dosage form according to claims 1-9, characterized in that the active ingredient antibiotics, such as. Penicillin, tetracycline, chlortetracycline, bacitrazine, nystatin, streptomycin, neomycin, polymizine, gramicidin, oxytetracycline, chloramphenicol, erythromycin, rifampicin, cefazolin, cefoxitin, cefsulodin, cefotiam and mefoxin used- 13. Solid pharmaceutical dosage form according to claims 1-9, characterized in that as active ingredients chemotherapeutic agents, such as. Sulfamethazine, sulfamerazine, sulfamethizole and sulfisoxazole used. 14. Solid pharmaceutical dosage form according to claims 1-9, characterized in that as active substances sedatives and hypnotics, such as. Chloral Hydrate, Midazolam, Pentabarb j.tal, Phenobarbital, Secobarbital, Codeine and Carbromal are used. Solid pharmaceutical dosage form according to claims 1-9, characterized in that the active substances used are cardiac glycosides and digitaloids, e.g. Digitoxin and digoxin used. 16. Solid pharmaceutical dosage form according to claims 1-9, characterized in that as active substances sympathomimetics, such as. Used epinephrine. 17. Solid pharmaceutical dosage form according to claims 1-9, characterized in that as active ingredients antipyretics, analgesics and antirheumatics, such as. Propyphenazone, arainophenazone, aspirin (ASA), antipytin, kethylnifenazine, melamine sulfone, sulfenitazone, phenacetin, pentazocine, lactophenine, paracetamol, quinine, flufenamic acid, mefenamic acid, tolfenamic acid, meclofenamic acid, niflumic acid, clonixin or clonixidine, flunixin, ibuprofen, suprofen, ketoprofen , Fenoprofen, Pirprofen, Diclofenac, Ibufenac, Proctic Acid, Naproxen, Cicloprofen, Tolmetin, clopirac, tiaprofenic acid, oxaprozin, fenclozic acid, fentiazac, clidanac, fenclonac, fenoprofen, flurbiprofen, carprofen, sulindac, cinmetacin, fenbuten, etodolac, butifufen. 18. Solid pharmaceutical dosage form according to claims 1-9, characterized in that are used as active ingredients analgesics and anti-inflammatory drugs ibuprofen, pirprofen, ibufenac, naproxen and diclofenac. 19. Solid pharmaceutical dosage form according to claims 1-9, characterized in that one uses active ingredient diclofenac. 20. A solid pharmaceutical dosage form according to claims 1-9, characterized in that as active ingredients neuroleptics, antidepressants, thymoleptics, thymemes and tranquilizers, such. Thioridazine, imipramine, desimipramine, clomipramine, ketimipramine, opipramol, amitriptyline, nortriptyline, reserpine, aromazine, chlorpromazine, fluopromazine, hethopromazine, trimeprazine, diethazine, proraethazine, aminopromazine, mepazine, pipamazine, and maprotiline. 21. A solid pharmaceutical dosage form according to claims 1-9, characterized in that as active ingredients antihypertensives, such as. Oxprenolol or metoprolol used. 22. Solid pharmaceutical dosage form geraäss claims 1-9, characterized in that one uses as active ingredient midazolam. 23. A process for the preparation of a solid pharmaceutical dosage form from which the active drug or drug mixture is approximately pH independent, i. regardless of the hydrogen ion and hydroxyl ion concentrations and / or other ions and also independently Enzymen the surrounding liquid, specifically after a certain time, ι i.e. after a certain time interval quantitatively can go immediately or continuously into solution, characterized in that, one the active ingredient, or the drug mixture in the presence of a swellable non-colloidal excipient and at least one water-soluble carrier (inducing osmosis) and optionally other auxiliary -to " 1S / SS9 substances, such as Lubricants and retarding agents into a pharmaceutical dosage form, e.g. Pressed tablet or pellet, or powdered in a capsule and the pharmaceutical dosage form coated with a semipermeable membrane as a film which is suitable for the penetration of water from existing body fluid by the swelling pressure of the swellable non-colloidal excipient and by the concomitant osmotic pressure and optionally internally generated gas pressure after a certain predetermined time to crack open lid-like and release the active ingredient or the active ingredient mixture quantitatively. FO 7.4 / HFO / bg *