Device for delivery of a medicinal product in the form of a suspension with controlled its release

 

(57) Abstract:

The device has an extruded core containing at least two layers. At least one layer contains a mixture of pharmaceutically active agent and polymer. The polymer in the hydration process forms a microscopic gelatinase balls. The second layer contains a polymer that in the hydration process forms a microscopic gelatinase balls. The polymer is selected from sodium acrylate acrylate polymer, carboxypolymethylene, carbamine polymers and their pharmaceutically acceptable salts. At the core of applied not soluble in water and not water-permeable polymer coating. The coating surrounds the core and is connected with it. The floor has a hole that opens from 5 to 75% of the surface of the nucleus. Holes designed to hydrate and release microscopic gelatinousness balls. The invention allows the delivery of pharmaceutically active ingredient in a controlled way, with intensity close to zero. 2 C. and 20 C.p. f-crystals, 6 ill.

The background to the invention

The invention relates to the useful and the new device delivery of a medicinal product intended for the delivery of Lech is better pharmaceutically active ingredient in a controlled way, with intensity close to zero. Dosage form consists of a nucleus surrounded by an impermeable, insoluble coating, which features holes that expose certain areas of the core to the environment of use. The chemical composition of the coating is selected so that the hydration of ingredients kernel is found only on the exposed parts of the kernel. The core consists of at least two layers. One of them contains a pharmaceutically active compound. There is also at least one other layer containing pharmaceutically active ingredient. In each layer of the core include at least one polymer that swells and forms in the process of hydration of the gel beads.

In the environment use of biological fluid in contact with the open surface of the core, where the open hydration of the polymer. As the polymer particles on the outside surface absorb moisture, are formed microscopic gel beads. If the open area of the kernel and contains pharmaceutically active compound and the polymer, forming microscopic gel beads, while the swelling of the polymer and its movement in the environment of the application he shall, together with a pharmaceutically actioner.

Control over the intensity of hydration of the polymer and, consequently, the intensity of the delivery of the ingredients from the open kernel environment the application is done by creating impermeable, insoluble coverage holes. These holes or cracks open a separate predetermined areas of the surface of the nucleus. Since the open area of the surface of the nucleus is surrounded by a coating, the hydration of the polymer occurs only at pre-selected surface of the core. The resulting microscopic gel beads come in an environment of use.

The intensity of release of the pharmaceutically active ingredient is not dependent on the solubility of the useful tools in biological fluids. Most likely the intensity of the release depends on the intensity with which microscopic gelatinase balls are formed on the open surface and leave the device that carries a useful tool, and any other present in the core of the fillers. Therefore, the intensity of the release can be controlled by controlling the number and size of holes, the opening surface of the core to the environment.

The intensity of the delivery of pharmaceutically AK the STI. This means you can achieve delayed delivery or intermittent delivery using a layer of the kernel, which does not contain a pharmaceutically active ingredient, while ensuring full delivery of the pharmaceutically active ingredient.

The need for systems that can deliver both soluble and insoluble pharmaceutically active ingredients with constant speed within four to twenty-four hours, is well known. In addition, it is recognized the need for a single device, allowing programmed delayed start of delivery.

It was suggested several approaches to this problem. Existing technologies rely primarily on the system controlled by diffusion, which are efficient only in the case of extraction of soluble active agents. Another limitation of osmotic systems is that smagent must dissolve in the presence of swelling of the polymer and any inadvertent interaction between omogenia and the polymer can lead to unpredictable changes in the intensity of release of the pharmaceutically active ingredient.

Also described dosage forms, preduster the while moving in vivo, for example in the gastrointestinal tract. If part of the superstructure will be chipped off, greater than, preferably, the surface area will be open to the influence of the environment, which can lead to unpredictable release of active funds.

In U.S. patent 4814182 described the use of rods or plates pre-hydrated and swollen polietilenoksidnoy hydrogel. The polymer is impregnated with biologically active agent during the procedure hydration. The hydrated polymer is then dried and partially covered with impermeable, insoluble material. When placed in an aqueous medium, the polymer swells but does not dissolve and does not break up. Captured the active ingredient is released from the polymer by diffusion. The release mechanism is based on the ability of soluble medicinal substances to diffuse through the re-hydrated hydrogel and move in the aquatic environment.

In U.S. patent 4839177 described using compressed in a defined geometric form hydrogels, which mixed with biologically active ingredients, and some device attached to the "reference platform", made of insoluble polymer materialet superstructure, a release of the active tool or by diffusion, if the active agent is soluble, or by erosion, if the active agent is insoluble. The formation and preservation of the superstructure is vital for the successful use of the device.

In U.S. patent N 4971790 described osmotic dosage form that uses a semipermeable wall containing at least one "output means" passing through the wall, surrounding a core containing an osmotic agent, neutral and Ionithermie hydrogel and active ingredient. The floor in this device is permeable by the environment. Water is supplied to the engine through a semipermeable membrane. Once inside the device, the water dissolves the osmotic agent and Ionithermie hydrogel. Inside the device increases the pressure that is associated with the ionization of omogenia. Ultimately dissolved Ionithermie hydrogel containing a useful tool, a neutral hydrogel and other fillers kernel, are ejected from the nucleus via the output means in the environment of use.

In U.S. patent N 4915954 described device containing a two-layer core. One layer provides more intensively is wlosy. The bottom layer may also be formed of cellulose polymers, but has a different or more high molecular weight. This layer with less intense release may also contain a hydrogel, preferably polyethylene oxide. For such a device requires a semi-permeable wall. Control of the wall thickness is one of the main negative traits of devices shipping with osmotic control.

In the application for the European patent 0378404 A2 charged microporous hydrogel coating on the osmotic core. This device includes a cover, through which may pass the pharmaceutically active agent at a time when the device is opened to impact the aquatic environment. Like other considered devices functioning of this device must be caused by wetting, hydration or dissolution of material due to absorption of liquid through the floor.

In U.S. patent N 5366738 the described device, which consists essentially of a homogeneous compressed core made from a mixture containing a therapeutically effective amount of pharmaceutically active ingredient and the polymer forming the hydration process microscopic gelatinase ball is about, usher to him, and the floor has a lot of holes opening from about 5 to about 75% of the surface of the nucleus. While this dosage form allows you to control the release of insoluble pharmaceutically active ingredient, the delivery delay is not provided.

The usefulness of these devices could be increased if they were found device and method for improving the release of pharmaceutically active ingredients at a constant intensity, and if found it was also a means for delayed release of the pharmaceutically active ingredient. Another improvement would be realized if the proposals of the dosage form, allowing intermittent delivery of pharmaceutically active ingredient.

The invention

The described device for the delivery of a medicinal product intended for the controlled formation and release directly to the application site contains a useful means of suspension, which mainly contains:

(A) extruded core containing at least two layers, of which at least one layer comprises a mixture of a therapeutically effective for those,then forms a microscopic gelatinase balls; and at least one other layer containing the polymer, which in the hydration process forms a microscopic gelatinase balls; and

(B) not soluble in water and not water-permeable polymer coating on the core, which surrounds the core and sticks to it, and the coating contains a hole that opens from about 5 to about 75% of the surface of the kernel.

Description of drawings

In Fig. 1 schematically shows one embodiment of the present invention. Impermeable, insoluble coating (10) completely surrounds the device. Holes (11) are located in certain areas, which after placing the dosage form in the environment of use is hydrated the surface of the nucleus. The core consists of a Central layer (14) and two outer layers (13). The Central layer (14) contains as a pharmaceutically active ingredient (15) and the polymer (16), in which the hydration process swells and forms gelatinase wigs. The outer layers of the kernel (13) contain the polymer (16), but does not contain a pharmaceutically active ingredient.

In Fig. 2 and 3 schematically shows an additional embodiment of the engine according to the present invention, where the tablet (20) containing farmacia balls, pressed into the shell (21) of inert material containing the polymer (16).

In Fig. 4 schematically shows the preferred embodiment of the engine in accordance with worthless invention, in which there are two layers. In this embodiment, the implementation of one layer of the kernel and contains pharmaceutically active ingredient (15) and the polymer (16), while another layer core contains the polymer (16).

In Fig. 5 shows the graph of the release of the pharmaceutically active ingredient in the two embodiments of the present invention, in conjunction with the release of devices with a uniform kernel with the same number of holes in the floor.

Detailed description of drawings

In the process, an aqueous solution of the environment in contact with the surface of the core, open the holes (11) Available water starts hydration located on the surface of the core polymer (16), forming microscopic gel beads. In the presence of an open surface of the core agent modulation of hydration of the polymer (not shown) is its dissolution and education environment necessary for the controlled hydration of the polymer. As the hydration of the polymer (16) it is separated HHS (14), present on the surface of which particles useful means (15) are separated from the surrounding surface. These particles are useful means (15) are moved from the surface of the nucleus in the environment of use in a suspension of microscopic gelatincapsule balls hydrated polymer (16).

If the holes are drilled on both sides or surfaces of the device, hydration can occur on both sides at the same time. In another case, when the holes are drilled from only one side or surface of the device, hydration occurs first in the outer layer, closest to the hole, then in the Central layer (14) and, finally, in the outer layer most remote from the holes. When this hydration layer, gelatinase beads of polymer are allocated through the holes and make the rest of the content of the middle layer (14) from the nucleus to the environment of use. This effect removal prolongs the intensity of the zero order delivery and facilitates effective delivery of pharmaceutically active ingredient.

Fig. 2, 3 and 4 are considered in this document.

In Fig. 5 graphically shows the dependency of release of pharmaceutically active ingredient of the uniform kernel, having the same port configuration.

Detailed description of the invention

A new device for the delivery of the medicinal product in accordance with the present invention designed for the controlled formation and release directly to the application site contains a useful means of suspension contains:

(A) extruded core containing at least two layers, of which at least one layer comprises a mixture of a therapeutically effective for those who need it, the amount of pharmaceutically active ingredient and a polymer, in which the hydration process forms a microscopic gelatinase balls; and at least one other layer containing the polymer, which in the hydration process forms a microscopic gelatinase balls; and

(B) not soluble in water and not water-permeable polymer coating that surrounds the core and sticks to it, and the coating contains a hole that opens from about 5 to about 75% of the surface of the kernel.

Under "device for delivery of a medicinal product" means a pharmaceutical form, represents a convenient means of delivering pharmaceutically active ingredient Il is I am in such pharmaceutically active ingredient. The device is designed in such a way as to be useful for the delivery of pharmaceutically active ingredient in any pharmaceutically acceptable manner, such as ingestion, retention in the oral cavity until the liberation of useful tools, placing it in the buccal pocket, etc.

Under "controlled formation directly at the place of use" means that the intensity of release of the pharmaceutically active ingredient, i.e., the amount of pharmaceutically active ingredient released from the device in the environment of use, should the specified schema. So, within the prescribed period of time can be released relatively constant or varies in a predictable quantity of useful tools.

By "pharmaceutically active agent" refers to any connection, denoted by the General term "drug" and its equivalents that contain any physiologically or pharmacologically active substance that has a localized or systemic effect or effects in animals. The term "animal" includes mammals, humans and primates, such as home, indoor, sport and the animals such as mice, rats, Guinea pigs, fish, birds, reptiles, and animals zoos.

Pharmaceutically active ingredients that can be delivered to a new device, in accordance with the present invention include without limitation, inorganic and organic compounds, including drugs affecting the peripheral nervous system, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscles, the blood circulatory system, synaptic point, the point of articulation of neuroeffector, endocrine and hormonal system, immune system, reproduction system, the skeletal system, the self-destruct system, digestion and excretion, braking and histamine systems, as well as those materials, which affect the Central nervous system such as hypnotics and sedatives.

Examples of pharmaceutically active ingredients are listed in Remington''s Pharmaceutical Sciences, 16th Ed., 1980, published by Mack Publishing Co., Eaton, Pa. and The Phar-macological Basis of Therapeutics, by Goodman and Gilman. 6th Ed., 1980, published by MacMillan Company, London and in The Merck Index, 11th Edition, 1989, published by Merck & Co., Rahway, N. J. the Dissolved drug can the Lu acceptable salts include, not limited to, hydrochloride, hydrobromide, sulfate, laurate, palmitate, phosphates, nitrates, borates, acetates, maleate, malate, tromethamine, tartratami, oleates, salicylates, metal salts, and amines, or organic cations, for example, Quaternary ammonium.

Derivatives of pharmaceutically active ingredients, such as ethers and esters and amides can be used regardless of their ionization and indicators solubility or separately, or in a mixture with other compounds. In addition, the pharmaceutically active ingredient can be used in a form that is in the process of release from the device is converted by enzymes, hydrolyzed under the influence of the pH of the body or other metallicheskih processes in its original form or biologically active form, i.e., to the concept of biologically active ingredients specially assigned and prodrugs.

Specific examples of pharmaceutically active ingredients that can be adapted for use, can serve as barbiturates, such as pentobarbital sodium, phenobarbital, secobarbital, thiopental and mixtures thereof; heterocyclic hypnotics such as dioxopiperidin and glutarimide; ID and alpha-bromo-isovalerylglycine, hypnotic and sedative urethanes and disulfide; antidepressants such as isocarboxazid, nialamide, hydrochloride, hydrochloride amitriptyline, Margilan and hydrochloride of protriptyline; tranquilizers, such as chlorpromazine, promazine, Florentin, reserpine, deserpidine and meprobamate; benzodiazepines, such as diazepam and chlordiazepoxide; anticonvulsants such as primidone, phenytoin and ethosuximide; muscle relaxants and tools against Parkinson's disease, such as mephenesin, methocarbomal, hydrochloride of cyclobenzaprine, hydrochloride of trihexyphenidyl, levodopa/carbidopa and biperiden; antihypertensives, such as alpha-hydrochlorothiazide methyldopa and pivaloyloxymethyl ether alpha methyldopa; calcium channel blockers such as nifedipine, diltiazem hydrochloride, malate diltiazem and verapamil hydrochloride; analgesics, such as morphine sulphate, codeine sulfate, meperidine and nalorfin; antipyretics and anti-inflammatory drugs such as aspirin, indomethacin, ibuprofen, endomyocarditis sodium, salicylamide, naproxen, colchicine, fenoprofen, sulindac, diflunisal, diclofenac, indoprofen and salicylamide sodium; local anesthetics such as procaine, lidocaine, tetracaine and dibucaine; spasmin; prostaglandins such as PGE1, PGE2, PGE2a; antimicrobial and anti-parasitic agents such as penicillin, tetracycline, oxytetracycline, chlortetracycline, chloramphenicol, thiabendazole (benzimidazole), ivermectin, and sulfonamides; antimalarial agents such as 4-aminoquinoline, 8-aminoquinoline and pyrimethamine; hormonal and steroidal agents such as dexamethasone, prednisolone, cortisone, cortisol and triamcinolone; androgenic steroids such as methyltestosterone; estrogenic steroids such as 17-alpha-estradiol, alpha-estradiol, estriol, alpha-estradiol 3-benzoate, and 17-ethinyl estradiol-3-methylether; gestagenna steroids, such as progesterone; sympathomimetic agents such as epinephrine, hydrochloride phenylpropanolamine, amphetamine, ephedrine and norepinephrine; antihypertensives such as hydralazine; cardiovascular drugs, such as hydrochloride, procainamide, amyl nitrate, nitroglycerin, dipyridamole, sodium nitrate and nitrate mannitol; diuretics, such as chlorothiazide, acetazolamide, methazolamide, hydrochlorothiazide, amiloride hydrochloride and flumethiazide, ethacrynate sodium and furosemide; anti-parasitic agents such as befani, hydroxynaphthoate, dichlorophen, Gipson; FR is atory, such as pindolol, propranolol, metoprolol, oxprenolol, timolol maleate, atenolol; hypoglycemic agents such as insulin, isovanillin, suspension protaminensulin insulin, globinsky insulin, extended insurancesave suspension, tolbutamide, acetohexamide, tolazamide and hlorpropamid; anti-ulcer agents such as cimetidine, ranitidine, famotidine and omeprazole nutritional agents such as ascorbic acid, Niacin, nicotinamide, folic acid, choline, Biotin, pantotheria acid, basic amino acids; essential fats; ophthalmic tools such as the maleate of timolol, pilocarpine nitrate, pilocarpine hydrochloride, atropine sulfate, scopolamine; electrolytes such as calcium gluconate, calcium lactate, potassium chloride, potassium sulfate, sodium fluoride, iron lactate, iron gluconate, ferrous sulfate, fumarate iron and sodium lactate; and drugs acting on alpha-adrenergic receptors such as clonidine hydrochloride; analgesics, such as acetaminophen oxycodone, hydrocodone and propoksifen; antihypercholesterolemic tools, such as simvastatin, pravastatin, lovastatin and gemfibrozil; anti-infective agents such as cefoxitin, Cefazolin, nitrofurantoin, minocycline, doxycycline, cephalo-Smoking, miconazole, clotrimazole, phenazopyridine, clorsulon, flutolanil, pesticide, cilastin, phosphonomycin, imipenem; drugs for the gastrointestinal tract, such as bethanechol, clydine, dicyclomine, meclizine, prochlorperazine, trimethobenzamide, loperamide, Diphenoxylate and metoclopramide; anticoagulants, such as warfarin, finition and anisindione; and other drugs such as trientine, cambendazole, ronidazole, rafoxanide, dactinomycin, asparaginase, naropin, rifamycin, carbamazepin, bitartrate metaraminol, allopurinol, probenecid, diethylpropion, alkaloids digidrirovannoe of ergot, nystatin, pentazocine, phenylpropanolamine, phenylephrine, pseudoephedrine, trimethoprim and ivermectin.

The above list of drugs should not be considered exhaustive. In the present invention can be used to fully and many other medicines.

Under "extruded core consisting of at least two layers" refers to the mixture of ingredients containing useful tool, the polymer formed by hydration of microscopic gel beads and other ingredients that may be able to provide the (3) characteristics of confusion or pressing the mixture, mixed thereby to obtain a homogeneous product. Then this homogeneous product is pressed in a die to obtain the desired shape, usually in the form of tablets. This extruded product is at least one extruded layer of the kernel.

After this second mixture of ingredients containing polymer, formed by hydration of microscopic gel beads and other ingredients that can affect: (1) the intensity of the formation of the suspension, (2) the stability of the components of the dosage form, or (3) characteristics of confusion or pressing the mixture is stirred so as to obtain a homogeneous product. Then this homogeneous product is pressed in a die to obtain the desired shape, usually in the form of tablets. This extruded product is at least one additional layer of the extruded core.

"Extruded core consisting of at least two layers can be produced manually or described here using automated equipment.

In addition, the "extruded core consisting of at least two layers, can be produced using multilayer tablet press, vypuskaetsya of the present invention extruded core is made of three layers. The middle layer contains as a pharmaceutically active ingredient and the polymer, which in the hydration process forms a microscopic gelatinase balls, and other fillers that are useful in the manufacture, dissolution and delivery layer. In a preferred embodiment of the invention there are also upper and lower layer, which top and bottom adjacent to the middle layer, each of which contains a polymer, in which the hydration process forms a microscopic gelatinase balls, and other fillers that are useful in the manufacture, dissolution and delivery layer.

In this configuration, the top and bottom of the core, also known as the upper and lower surfaces of the cores are identical. As a result, in the case when, as in the preferred embodiment of the invention, holes are drilled on one side only of the kernel, there is no need to post the exact orientation of the nucleus. This means that since the top and bottom of the cores are identical, holes can be drilled in any surface, without taking into account the orientation of the tablet. This allows faster processing device in the drilling process and also gives the programmed delay time delivery of pharmaceutically active with the a and the polymer, which in the hydration process forms a microscopic gel beads. By "therapeutically effective amount" means the amount of pharmaceutically active ingredient, which turned out to be sufficient to cause the desired effect in the studies using the connection.

In the layers of the kernel may also be present other fillers, such as lactose, magnesium stearate, microcrystalline cellulose, starch, stearic acid, calcium phosphate, glycerol monostearate, sucrose; polyvinylpyrrolidone, gelatin, methylcellulose, carboxymethylcellulose sodium, sorbitol, mannitol, polyethylene glycol and other ingredients usually used as a stabilizer or to facilitate the manufacture of tablets.

Pharmaceutically active ingredient may be in the core layer in the form of a disperse system, particles, granules or powder. In addition, the pharmaceutically active ingredient may be mixed with a binder, dispersing agent, emulsifier or wetting agent and dye.

The share of the pharmaceutically active ingredient may be from about 0.01% to about 75% by weight of the core. Typically, the device dossa, for example, 25 ng, 1 mg, 5 mg, 250 mg, 500 mg, 1.5 g, etc.

The polymer, which in the hydration process forms a microscopic gel beads" used in the new device which is the subject of the present invention, in a broad sense encompasses any polymer that is in the process of hydration may form discrete microscopic gel beads, which supports the education of the suspension, including a useful tool. Used for gel formation, the polymer must be separated from the surface of the nucleus in such a way that a useful tool taken on Wednesday consumption. In the hydration process gelatinase the beads must be predisposed to to leave the surface, taking a drug. This provides a constant openness surface exposure of the solvent from the environment and allows you to maintain constant the intensity of the release.

"Microscopic gelatinase balls are composed of discrete particles of hydrated polymer. And the size and rate of hydration of these microscopic gel beads vary in different polymers. An illustration of this type of polymer can serve as "AQUAKEEP J-550", "AQUAKEEP J-400", which Awlaki Co., Hyogo, Japan. Generic description of polymers "AQUAKEEP is shown in U.S. patent 4340706. Another illustration of this type of polymers are carboxypolymethylene, made of acrylic acid, crosslinked with allilaire sucrose or pentaerythritol and supplied to the market under the name "CARBOPOL 934P and CARBOPOL 947P", which are trade names of the two polymers carbamino type, manufactured by B. F. Goodrich Chemical Company, Cleveland, DT. Ohio. Generic description carbamine polymers described in the patent CDA 2909462 and in the National Formulary XVII, R. 1911, registration number CAS 9003-01-4. All previous references are hereby incorporated here as reference.

In the dry state the size of the particles "CARBOPOL 934P and CARBOPOL 974P" is from 2 to 7 μm. When hydrating these particles are formed microscopic gel beads size up to 20 microns. When hydrating particles "AQUAKEEP J-550" and "AQUAKEEP J-400" diameter microscopic gel beads may be in the range from 100 to 1000 microns.

"Modulator hydrating polymer" used in the new device which is the subject of the present invention, in a broad sense covers any water-soluble compound that can slow down or speed up Hydratight, you can mark acids, bases and salts acids and bases, such as adipic acid, citric acid, fumaric acid, tartaric acid, succinic acid, sodium carbonate, sodium bicarbonate, hydrochloride betamin, sodium citrate, arginine, meglumine, sodium acetate, sodium phosphate, potassium phosphate, calcium phosphate, ammonium phosphate, magnesium oxide, magnesium hydroxide, sodium tartrate, and tromethamine. Other compounds that can be used as modifiers of hydration of the polymer, include sugars such as lactose, sucrose, mannitol, sorbitol, pentaerythritol, glucose and dextrose. To modulate the hydration of the polymer can also be used polymers such as microcrystalline cellulose and polyethylene glycol, as well as surfactants and other organic and inorganic salts.

Means to modulate the hydration dissolved water environment environment and form the environment such as pH, ionic strength or hydrophilic properties, which correspond to the intensity of hydration of this polymer, forming microscopic gel beads. For example, these funds modulation of hydration may increase or down the deposits.

Described here, the core containing the drug, a modulator of hydration and polymer forming microscopic gel beads, usually has the form of a solid conventional tablets. The core layer may contain tamping additives and diluents, such as lactose, which can contribute to CT. Layers of the core can consist of a mixture of agents that are combined to obtain a desired production and consumption characteristics. The number of agents that can be combined to obtain the kernel, practically are not limited to, but should not be less than two components: a gel-forming polymer and a useful tool.

Desirable characteristics containing pharmaceutically active element layer of the kernel can be summarized as follows:

1. The content of the drug in the core (size): from 0.01 to 75% by weight of the total mass of the nucleus or from 0.05 ng to 5 g or more (including dosage forms for humans and animals).

2. The modulator of hydration of the polymer, from 0 to 75% by weight of the total weight of the kernel.

3. Gel-forming polymer is from 5 to 75% by weight of the total weight of the kernel.

Desirable characteristics when forming polymer is from 5 to 75% by weight of the total weight of the kernel.

2. Modulator hydrating polymer; from 0 to 75% by weight of the total weight of the kernel.

In another preferred embodiment, the implementation of the core in accordance with the present invention is first pressed pill, which contains a pharmaceutically active ingredient and a gelling polymer, and then put her in a large outer inert pill that contains a gelling polymer, but does not contain a pharmaceutically active agent. This allows you to get the device contains an internal tablet, pressed in an inert shell of gel-forming polymer, opening one surface of the inner tablet. This embodiment is shown in Fig. 2 and 3.

In Fig. 2 shows a top view of the finished dosage form, consisting of internal tablets (20), containing pharmaceutically active ingredient, and a gelling polymer, and a larger inert outer tablet-shell (21). In Fig. 3 shows an image with the same options for the implementation side, and you can see that one surface (22) of the inner tablets (20) is open to the environment, while the edges (23) and the other surface (24) of the inner tablets (20) surrounded by a more inert outer tablet (21).

For the manufacture of these tablets, you can use automated equipment, such as Manesty Drycoater. This equipment supply company Thomas Engineering, Hoffman Estates, PCs Illinois or Manesty Machines Limited, Evans Road, Speke, Liverpool, L249LQ, England.

After fabrication of the core can be coated, in which drill the holes, as described below. Depending on the intensity and the required mode of delivery of the pharmaceutically active ingredient holes can be placed on both sides or on one side only. Similarly, it may be desirable to drill holes in such a way as to open the ante kernel of the present invention is applied to the core with two layers. In this embodiment, the implementation of which is shown in Fig. 4, one layer (30) contains a pharmaceutically active ingredient and a gelling polymer, while the inert layer (31) contains heliopause polymer and does not contain a pharmaceutically active ingredient. These nuclei can be prepared manually, by filling the stamp granules containing the active ingredient, and manually tamped this layer flat stamp or standard concave punch and the pressing force, preferably not exceeding 500 lb (227 kg), using the cut-out laboratory press Model or using press F Stokes Model 519-2. Then stamp on top containing a pharmaceutically active ingredient layer fill of inert granules and compressed to a degree sufficient to obtain a solid core, which is then coated using the procedure described below.

Two layer made thus, it is possible to apply the coating and drill holes in it any of the above methods. However, if you want to have holes only on one surface of the device, there is a need to use some sort of authentication mechanism, so that could be distinguished in the process of drilling the surface , solayman the detector to identify the required surface for the drilling operation. In such detectors for this purpose can be used photoacoustic spectroscopy, infrared and near infrared spectroscopy, ultraviolet spectroscopy and spectroscopy in the visible rays, fluorescence spectroscopy, magnetometry, and any other suitable technique known to the specialists in analytical chemistry.

In cases when the pharmaceutically active ingredient, heliopause the polymer and the agent to modulate the hydration of the polymer demonstrate the required intensity of release, stability and performance, there is no critical upper or lower limit on the amount of pharmaceutically active ingredient which may be included in the core layer. The content of the medicinal product to the filler is determined by the required time delay and order release, and pharmacological activity of the drug.

Usually containing a pharmaceutically active ingredient layer kernel will contain by weight from about 1% to about 50% by weight of the useful tools, mixed with other dissolved Wei can function as a dissolved substance, are not limited to, any of the described compounds.

The coating on the core, in accordance with the invention, is a material impervious to and insoluble in the environment of use, may form a film and have no negative impact on the pharmaceutically active ingredient, the body of the animal or the recipient. The coating is impervious to water and, in addition, is not permeable to a specific product, drugs, agents, modulation of hydration of the polymer or other compounds used in the device. This impermeable material is not soluble in biological fluids and is not destroyed or may become biorazlagaemykh after a certain period of bioerosion accompanying the end of the period of active release of the drug. In any case it is not permeable to the solvent and dissolved substances in the environment of use, and is suitable for manufacturing devices.

The polymer coating is applied and adheres to the entire surface of the nucleus. In order to open the core, the coating cut the holes using a mechanical or laser drill, the drilling device, or any other pharmaceutically acceptable vehicle. In one of wursti use the laser.

The holes allow the solution in use, come into contact only with the open areas of the kernel. The number, size and configuration of the openings are selected so as to achieve the desired intensity of the release matching pharmacologically recognized requirements, because the hydration of the polymer will occur only where the holes allow such contact.

The coating can be applied by immersing the cores in a suitable polymer solution or by spraying the core polymer solution. Among the polymers that can provide this type of protection, you can specify acetylbutyrate cellulose and polyvinyl chloride. In addition, the coating composition may include other materials such as plasticizers, in order to improve its stability, color, elasticity, ease of application or opacity, provided that these ingredients do not reduce the tightness or the insolubility of the coating. In a similar way to the floor, you can add such compounds as triethylcitrate.

The coating is applied with a thickness of from about 1 to about 1000 μm, but preferably from about 10 to about 500 μm, although the invention provides the possibility of applying both more subtle and more open surface of the core effects of the environment. The size and number of holes is chosen in such a way as to achieve the desired intensity of the release. When determining the size and number of holes you need to take into account the intensity of hydration of the gelling polymer type and concentration used in the kernel agent that modulates the hydration of the polymer and the ability of the useful tools to the formation of ions. Usually the holes are placed at the right scheme on both surfaces of the device, although they can be located anywhere on the engine, including the edges, or, as described above, on the same surface. The holes are generally circular in shape but can be of any form that provides the desired intensity of selection. When the hole is round, its diameter is from about 0.1 mm to about 5 mm, with typical diameters ranging from about 0.3 mm to about 3.5 mm

One embodiment of the impermeable wall includes a mixture of eight parts by weight of acetylbutyrate cellulose, two parts by weight of cellulose acetate and one part by weight of diethylphthalate. This mixture was diluted in a solution of methylene chloride and methanol (volume ratio 3:1) and sprayed on the cores up to obtain a coating thickness of about 250 μm. Another preferred coating is and acetone and methanol (volume ratio 3: 1). This mixture is sprayed on the core or immersed in the mixture so that the coating thickness of approximately 100 microns.

In a preferred embodiment, the implementation of an impenetrable wall using a mixture of ten parts by weight of acetylbutyrate cellulose and one part by weight of triethylcitrate. This mixture at 3% the ratio of mass to volume is diluted in a solution of acetone and ethanol (volume ratio 3:1) or methylene chloride and methanol (volume ratio 3:1) and sprayed on the core to obtain a coating thickness of about 100 μm.

Used to cover the described polymers known in this technical field and can be made according to the procedures described in Encyclopedia of Polumer Science and Technology, vol. 3, published by Interscience Publishers Inc. , New York, in Handbook of Conmon Polymers by Scott, J. R. and Roff, W. J., 1971, published by CRC press, Cleveland, Ohio.

The following examples illustrate the manufacture of the delivery device of the medicinal product according to the present invention and controlled release them one or more therapeutically active ingredients in the environment of use and should not be construed as limiting the invention set forth in the claims appended to the present description.

Considered two configurations of holes; 39 holes of 0.5 mm, drilled in the surface of the device (see Fig. 5, # 53) that allow you to open a core layer containing a pharmaceutically what the overarching pharmaceutically active ingredient.

The rate of release in both groups of devices in vivo was measured at a temperature of 37oin isotonic phosphate buffer solution with a pH of 7.4, containing 0.4 wt.% sodium dodecyl sulfate and the use of USP Apparatus 11 at 50 rpm./minutes Total quantity released lovastatin plotted on the graph depending on time and shown in Fig. 5 using as reference devices with a core of one composition with 39 holes of 0.5 nm (Fig. 5, # 52) and 22 holes of 0.5 mm (Fig. 5, # 51). As shown in Fig. 5, curves release for bilayer devices were significantly better than for the kernel of the same composition due to the fact that the last 20% of lovastatin were released with a more constant rate and more than 95% of the content lovastatina was released less than 20 hours. It is 10-15% more of the total shares allocated to the device with the core of one composition.

Example 2

Tablets for controlled release of nifedipine were prepared from the following composition:

Ingredients: active layer - mg/layer

Crushed nifedipine - 33

"CARBOPOL 974P" NF - 15

Dibasic sodium phosphate (anhydrous) USP - 37,5

Water lactose NF (spray dried) - 7,5

Povidone USPK-90 - 2 "CARBOPOL 974P" NF - 15

Citrate dihydrate sodium USP - 37,5

Water lactose NF (fine powder) - 7,5

Povidone USPK-90 - 2,5

Magnesium stearate NF - 0,5

All 96,0

Crushed nifedipine combined with dibasic sodium phosphate, CARBOPOL), lactose and polyvinylpyrrolidone, thoroughly mixed, and then subjected to granulation using a mixture of water-alcohol solvent (10% water by volume).

Solvated mass pass through sieve No. 20 and subjected to preliminary drying at 60oC for two to four hours and at a temperature of 40oC during the night. Over the dried granulated mass was sifted start magnesium and the whole mixture pass through sieve No. 40. The same procedure was used to prepare the inactive granules, in which nifedipine replaced AVICEL. First active granulate filled standard concave stamp with a diameter of 9/32 inch (7.1 mm) and subjected to pressing with a force of 200-800 pounds (91-364 kg), and then lightly pressed the active layer placed inactive granules and two layers compressed together when the pressing force 1500-2000 pounds (680-907 kg). The resulting thickness of the tablets was equal to 4.3 mm and a hardness of 18 kg per tablet was coated with a thickness of 100 μm with slidey of the coating film is Number

Acetylbutyrate cellulose (Eastman 381-20) - 140 g

Triethylcitrate NF - 14 grams

Methylene chloride - 3000 ml

Alcohol USP - 1000 ml

In the coating on the active surface tablets mechanically drilled 16 holes with a diameter of 0.45 mm

Test release in vitro was carried out at a temperature of 37oC using USP Apparatus 2 in phosphate buffer solution with a pH of 7.4, containing 2% sodium dodecyl sulfate at 100 rpm./min. Release of the drug was monitored by UV spectrometry at a wavelength of 340 nm. The results of the study shown in Fig. 6. Two or three tablets can be placed in a gelatin capsule to obtain doses of 60 or 90 mg

1. Device for delivery of pharmaceutically active agent for controlled directly at the place of use of education and releasing the suspension containing pharmaceutically active agent, which includes: (A) extruded core containing at least two layers, of which at least one layer comprises a mixture of a therapeutically effective amount of pharmaceutically active agent and a polymer, in which the hydration process forms a microscopic gelatinase above gelatinase balls, when this polymer is selected from sodium acrylate acrylate polymer, carboxypolymethylene derived from acrylic acid crosslinked with allilaire sucrose or pentaerythritol, carbamine polymers and their pharmaceutically acceptable salts, and (B) not soluble in water and not water-permeable polymer coating on the core, which surrounds the core and is connected with it, and the floor has a hole that opens from 5 to 75% of the surface of the kernel.

2. The device under item 1, in which the content of the pharmaceutically active agent in the core is from 1 to 75% by weight of the kernel.

3. The device under item 1, in which the pharmaceutically active agent is an inhibitor of HMG CoA reductase.

4. The device according to p. 3, in which the pharmaceutically active agent is selected from the group consisting of lovastatin, pravastatin and simvastatin.

5. The device under item 1, in which the pharmaceutically active agent is lovastatin.

6. The device under item 1, in which the pharmaceutically active agent is nifedipine.

7. The device under item 1, in which the content in the nucleus of the polymer forming the hydration process gelatinase microscopic beads ranges from 75 to 10% by weight of the poison and polymer, selected from the group consisting of acids, bases, salts, sugars, surfactants and water soluble polymer.

9. The device under item 8, in which the agent to modulate the hydration of a polymer selected from the group consisting of sodium citrate, hydrochloride betamin, sodium bicarbonate, sodium carbonate and arginine.

10. The device under item 1, which is not soluble in water, not water-permeable coating is selected from polyvinyl chloride, cellulose acetate, acetylbutyrate cellulose and ethyl cellulose.

11. The device under item 1, in which the diameter of the holes in the coating is from 0.1 to 5 mm

12. The device according to p. 11, in which the holes are placed on the surface randomly.

13. The device under item 1, in which the pharmaceutically active agent is a nifedipine in the form of a suspension, comprising: (A) extruded core containing the first layer and the second layer, the first layer contains a therapeutically effective amount of nifedipine and a polymer, in which the hydration process forms a microscopic gelatinase balls, and the second layer contains a polymer, in which the hydration process forms a microscopic gelatinase balls, when it is Oh acid, stitched with allilaire sucrose or pentaerythritol, carbamine polymers and their pharmaceutically acceptable salts, and (B) not soluble in water and not water-permeable polymer coating on the core, which surrounds the core and is connected with it, and the floor has a hole that opens from 5 to 75% of the surface of the kernel.

14. Device for delivery of nifedipine on p. 13, in which said polymer is CARBOPOL 974P.

15. Device for delivery of nifedipine on p. 13, in which insoluble, impermeable polymeric coating includes acetylbutyrate pulp and triethylcitrate.

16. Device for delivery of nifedipine on p. 13, shaped, biconvex tablets, with each convex side of the tablet is the outer surface and each outer surface has at least two holes drilled in the floor to open the portion of the surface of the core to the environment of use.

17. Device for delivery of nifedipine on p. 14, shaped, biconvex tablets, with each tablet is the outer surface and only one outer surface has holes drilled in the floor to open the part of the surface of the nucleus who is drilled from about 10 to 60 holes.

19. The method of manufacture of the delivery device under item 1 for controlled directly at the place of use of education and releasing the suspension containing pharmaceutically active agent, comprising: (A) the manufacture of layers of the core by dry mixing or wet granulation of one or more compounds, each consisting of a polymer, which is in the process of hydration forms gelatinase microscopic balls, and optional fillers, and a separate dry mixing or wet granulation of one or more compounds, each of which includes a pharmaceutically active agent, the polymer forming the hydration process gelatinase microscopic balls, and optional fillers, (B) pressing mixtures for the formation consists of layers of the core; (C) the application is not water soluble, not water-permeable polymeric coating or by dipping the whole kernel, or by spraying on all the core suspension of the coating material, and (D) drilling the holes in the floor in order to open the desired spot on the surface of the nucleus.

20. The method according to p. 19, in which the pharmaceutically active agent is nifedipine.

21. The method according to p. 19, in which formatnum agent is simvastatin.

 

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