MXPA98004242A - A compressed dispenser for the controlled supply of agents acti - Google Patents

Abstract

The present invention relates to: providing a simple and improved multilayer osmotic device that is capable of delivering a first active agent to an environment of use and a second active agent to another environment of use. A particular embodiment of the invention provides osmotic devices wherein the first and second active agents are similar or different. An erodible polymer coating between an internal semi-permeable membrane and an outer coating containing a second active agent comprises a poly (vinylpyrrolidone) - (vinyl acetate) copolymer. This particular erodible polymer results in an improved multilayer osmotic device which has advantages over related devices known in the art.

Description

A COMPRESSED DISPENSER FOR THE CONTROLLED SUPPLY D? ACTIVE AGENTS FIELD OF THE INVENTION 5 The present invention relates to a dispensing device for the controlled delivery of active agents to an environment of use. More particularly, it relates to a multi-layer osmotic device that allows the immediate delivery of a first active agent followed by the delivery of a second active agent by a continuous, monitored, controlled and / or delayed initiation regimen, said agent being active the same or different from the first active agent.

BACKGROUND OF THE INVENTION Osmotic devices have proven useful in providing a means of using useful active agents such as drugs, nutrients, foods, pesticides, herbicides, germicides, algicides, chemical reagents, and the like, in a controlled manner for extended periods of time. Known devices include tablets, pills, pills or capsules and others and generally include layers comprising one or more materials, which are subject to erosion or dissolving slowly in the medium of use, gradually releasing the active agent. US Pat. No. 4,014,334 to Theeuwes et al. Describes an osmotic device for the controlled and continuous release of a drug wherein the device comprises : a) a core containing a drug and an osmotic agent, b) a semipermeable laminate, surrounding the core, which includes a semipermeable outer sheet and a semipermeable inner sheet; and c) a passage that communicates the nucleus with the exterior of the device. The two semi-permeable sheets maintain their chemical and physical integrity in the presence of the drug and fluid from the environment. The passage of the Theeuwes et al patent includes an opening, orifice or perforation through the laminate formed by mechanical methods, or by erosion of an erodible element, such as a gelatin plug, in the environment of use. The Theeuwes et al. Patent does not disclose a third sheet containing a drug or a polymer coating comprising a copolymer of poly (vinylpyrrolidone) - (vinyl acetate) surrounding the semipermeable membrane.

The patent of the United States of America No. 4,576,604 to Guittard et al. Corresponding to Argentine patent No. 234,493 discloses several different embodiments of an osmotic device having a drug in the core and at least one sheet surrounding the core. Specifically, an embodiment of the osmotic device comprises: a) a core containing a drug formulation that can include an osmotic agent for controlled release of the drug; b) a semipermeable wall comprising a medium microporous sheet, an internal semipermeable sheet, and an external water soluble sheet containing drug; and c) a passage that communicates the nucleus with the exterior of the device. The Guittard et al. Patent does not disclose the use of poly (vinylpyrrolidone) - (vinyl acetate) copolymer as a suitable material for the microporous sheet of the erodible element.

The patent of the United States of America No. 4,673,405 to Guittard et al. Describes an osmotic device comprising: a) a core, or compartment, containing a beneficial agent; b) an inert semipermeable wall containing a beneficial agent surrounding the core; and e) at least one passage in the wall of the osmotic device, which is formed when the osmotic device is in the fluid of the medium of use and the fluid contacts and thus releases the beneficial agent from the wall, where the passage formed communicates the compartment of the osmotic device with the outside, to disperse the active agent from the compartment when the device is in the fluid of the environment of use. The '405 patent describes the use of an erodible element to form the passage; however, it does not disclose the use of poly (vinylpyrrolidone) - (vinyl acetate) copolymer as a suitable material for the erodible element.

U.S. Patent No. 5,558,879 to Chen et al. Describes a controlled release tablet for water soluble drugs where a passage is formed in the environment of use, e.g. in the Gl tract of a person who receives the formulation. Specifically, the controlled release tablet consists essentially of: a) a core containing a drug, 5-20% by weight of a water-soluble osmotic agent, a water-soluble binding polymer and a pharmaceutical carrier; and b) a double membrane coating around the core consisting essentially of: (1) an internal sustained release coating containing a water insoluble plasticizer polymer and a water soluble polymer; Y (2) an immediate release outer coating containing a drug and a water soluble polymer. Although the '879 patent to Chen discloses the formation of a passage in a controlled release tablet in an environment of use to form an osmotic tablet, the passage is not formed by the use of an erodible element comprising a poly (vinylpyrrolidone) copolymer ) - (vinyl acetate) covering a pre-formed opening.

The patent of the United States of America No. 4,810,502 to Ayer et al. Describes an osmotic dosage form for the release of pseudoephedrine (Ps) and brompheniramine (Br) which comprises: a) a core containing Ps and Br; b) a wall surrounding the core comprising cellulose acylate and hydroxypropylcellulose; c) a passage in the wall to supply the drug; and d) a sheet on the outside of the wall comprising Ps, Br, at least one of hydroxypropylcellulose and hydroxypropyl methylcellulose, and poly (ethylene oxide) to reinforce the mechanical integrity and pharmacokinetics of the wall. The '502 patent of Ayer does not disclose a polymeric coating between the wall and the drug containing sheet as required by the present invention.

The patent of the United States of America No. 4,801,461 to Hamel et al. Describes an osmotic dosage form for supplying pseudoephedrine (Ps). Specifically, the osmotic dosage form comprises: a) a core containing variable amounts of Ps; b) a semipermeable wall surrounding the core comprising varying amounts of cellulose acetate or cellulose triacetate and varying amounts of hydroxypropylcellulose; c) a passage in the wall to supply the drug from the nucleus; and optionally d) a sheet on the outside of the wall comprising Ps. The core may also contain one or more of sodium chloride, microcrystalline cellulose, hydroxypropyl methylcellulose, magnesium stearate, and poly (vinylpyrrolidone). The passage of this device can extend through the semipermeable wall only or through both, semipermeable wall and outer sheet. The passage also includes materials that are eroded or leached in the environment of use. Although a variety of erodible materials are listed as being suitable for use in the formation of the passage, the specification does not disclose or suggest the copolymer of poly (vinylpyrrolidone) - (vinyl acetate) for this use. In addition, the '461 patent of Hamel does not contemplate a polymeric coating positioned between the outer sheet containing the drug and the semipermeable wall.

U.S. Patent No. 5,681,584 to Svastano et al. Describes a device for controlled release drug delivery comprising: a) a core containing a drug, an optional osmotic agent and optional excipients, b) a cover delayed release comprising at least one of a binder, an osmotic agent and a lubricant surrounding the core; c) a semipermeable membrane surrounding the delayed release cover and optionally having a passage; d) a drug-containing layer either on the outside of the semipermeable membrane or between the semipermeable membrane and the delay cover; and e) an optional enteric coating either on the outside of the drug-containing layer, between the drug-containing layer and the semi-permeable membrane or on the outside of the semi-permeable membrane when the drug-containing layer is between the delayed-release coating and the semipermeable membrane. Then, the device of the '584 patent of Svastano et al. Requires a delayed release coating and does not include a water-soluble coating of poly (vinylpyrrolidone) - (vinyl acetate) copolymer between the semipermeable membrane and the drug-containing layer. .

Other devices for the controlled dispensing of active agents are described in US Pat. No. 3,845,770 and its equivalent Argentine patent No. 199,301 which describe an osmotic device constituted by a wall surrounding a reservoir containing the active agent. The wall has a passage or orifice that communicates the compartment containing the active agent with the exterior of the administering device. The wall of the device is constituted by a semipermeable material, permeable to an external fluid and impermeable to the active agent inside the device. None of these patents discloses a polymer coating of poly (vinylpyrrolidone) - (vinyl acetate) copolymer between the semipermeable membrane and the drug-containing layer.

While the prior art discloses a wide variety of multi-layer osmotic devices, no single device has been found that is generally applicable, and in fact, most known devices are designed to operate within a relatively narrow range of conditions in the environment of use. It has now been discovered that the improved multi-layer osmotic device described herein overcomes many of the disadvantages inherent in prior related art devices. The present osmotic device is capable of providing a wider range of independent release profiles for one or more active agents, both simultaneously and sequentially due to the particular improvements described. Furthermore, the present osmotic device provides greater control over the release of active agent from the layers versus the core of the device.

SYNTHESIS OF THE INVENTION It is an object of the present invention to provide an improved multilayer osmotic device that allows to provide the release to a medium of use of an active substance present in an outer coating as well as the delayed and controlled release of an active substance contained in the core of the device, in the same or in different means of use. The present invention provides an improved multi-layer osmotic device for the controlled release of one or more active agents to one or more means of use, wherein the osmotic device comprises: a) a compressed core containing a first active agent, an osmotic agent, and optionally poly (vinylpyrrolidone) for controlled and continuous release of the drug; b) a semipermeable membrane, which preferably consists essentially of cellulose esters, preferably cellulose acetate and poly (ethylene glycol), surrounding the core and having a passage preformed therein, said wall being permeable to a fluid belonging to the environment of use and substantially impermeable to the first active agent; c) an inert coating of water-soluble polymer comprising copolymer of poly (vinylpyrrolidone) - (vinyl acetate) which partially or substantially completely surrounds the semipermeable membrane and seals the passage in the wall, and d) an external coating comprising, optionally poly (vinylpyrrolidone) and poly (ethylene glycol), and a second active agent for immediate release of the drug, wherein the first active agent is released from the core after the outer coating has been partially or completely dissolved or eroded.

It has been contemplated that the first and second active agents may be the same or different. It has also been contemplated that the active agents may include compounds such as biologically or pharmacologically active agents, medicines, nutrients, foods, insecticides, pesticides, herbicides, germicides, algaecides, fungicides, chemical reagents, growth regulators, parasiticides, sterilants, promoters of fertility, biocides, rodenticides, disinfectants, anti-oxidants, plant growth promoters, preservatives, fermentation agents, fertility inhibitors, air purifiers, microorganism attenuators, catalysts, foods, food supplements, nutrients, cosmetics, vitamins, and other agents that benefit the medium of use. The present invention also contemplates that the first and second active agents can be delivered to one or more environments of use at different times and proportions.

Preferred embodiments of the invention include those wherein the first and second active agents are pharmacologically or biologically active agents or where the first environment of use is the stomach or gastric region and the second environment of use is the far end of the Gl tract of a mammal .

Other preferred embodiments include those where: a) the compressed core comprises a first active agent, an osmotic agent and poly (vinylpyrrolidone); b) the semipermeable membrane consists essentially of cellulose acetate and poly (ethylene glycol); or c) the outer coating comprises poly (vinylpyrrolidone), poly (ethylene glycol) and a second active agent. Still other preferred embodiments include those where the first and second active agents are the same and those where they are different.

Different means of using the osmotic device include biological environments such as oral, ocular, nasal, vaginal, glands, gastrointestinal tract, rectum, cervical, intrauterine, arterial, venous, otic, sublingual, dermal, epidermal, subdermal, implant, buccal, bioadhesive, mucosal and other similar environments. Similarly, it can be used in aquariums, industrial deposits, laboratory facilities, hospitals, chemical reactions and other facilities.

Other features, advantages and embodiments of the invention will become more apparent to those skilled in the art by the following description, accompanying examples and appended claims.

BRIEF DESCRIPTION D? THE DRAWINGS The following drawings are part of the present description and are included to further demonstrate certain aspects of the invention. The invention can be better understood with reference to one or more of these drawings in combination with the detailed description of the specific embodiments presented herein.

Figure 1 is a side elevational view of an embodiment of a multi-layer osmotic device according to the invention.

Figure 2 is a sectional elevation view of the device of Figure 1.

DETAILED DESCRIPTION OF THE INVENTION Without adhering to a particular mechanism of operation, it is believed that the osmotic device of the invention releases one or more active agents to an environment of use as follows. With reference to Figure 2, the osmotic device (1) comprising a core containing a first active agent (5) surrounded by a semipermeable membrane (4) delivers the first active agent to an environment of use in a controlled manner through the passage (6) after the plug (7) has partially or completely dissolved or eroded from the passage and after the core has absorbed or absorbed sufficient fluid from the environment of use. At least a portion of the semipermeable membrane (4) is surrounded by a coating of water-soluble polymer (3) which also forms the plug (7) that completely covers the passage (6). At least a portion or all of the polymer coating (3) dissolves or erodes in the fluid present in the environment of use after the second active agent containing coating (2) has partially or completely dissolved in the environment of use.

In a particular embodiment, the active agent or an osmotic agent will dissolve or swell in the fluid entering the core (5) through the semipermeable membrane (4) then creating an osmotic pressure gradient across the semipermeable membrane ( 4), whose gradient provides the force required to force the first active agent through the passage [6] from the core to the exterior of the osmotic device (1). The first active agent will continue to be dispensed from the core (5) until osmotic equilibrium is reached between the core and the environment of use. This balance of osmotic forces occurs gradually over a period of time thus serving to control the release and thus the release profile of the first active agent. It is known that the extension in time in which the release of the first active agent is controlled depends on a number of other variables such as the permeability of the semipermeable membrane (4) and the magnitude of the osmotic pressure gradient.

When used as a drug dispensing device, the multilayer osmotic device of the invention can operate as follows provided that the correct combination of materials is used to formulate the various layers and core of the osmotic device. After its administration to a mammal, the external soluble erodible and / or swelling outer coating containing the second active agent (2) begins to dissolve, erode, swell and / or peel off from the osmotic device thereby releasing the second active agent within the stomach. While the osmotic device (1) moves through the Gl tract, portions of the outer coating (2) will have partially or completely dissolved, eroded or detached, thus exposing the polymer coating (3), which in preferred embodiments is not soluble in acidic gastric juices. The polymer coating (3) then dissolves or erodes in one or more regions of the intestines according to the particular materials comprising the polymer coating (3). For example, materials soluble in fluids having a pH of 4-6 will dissolve in the small intestine, while materials that dissolve in fluids having a pH of 7-8 will dissolve in the large intestine or colon. Combinations of these materials can be used. The polymer coating (3) can also be microporous to allow absorption of water within the core (5) of the osmotic device (1) without dissolution of the polymeric coating (3). Once the polymer coating (3) has dissolved or eroded or once at least the plug (7) of the polymer coating (3) has been dissolved or eroded, the nucleus will begin to release the first active agent through the passage (6) within the intestines.

The osmotic device (1) will dispense one or more active agents in a controlled manner, and the mechanisms employed for such controlled release may include a pH dependent or independent pH releasing agent; controlled diffusion or dissolution; zero-order, first order or second order; fast, slow, or sustained or otherwise controlled release.

Although Fig. 1 describes an example of an osmotic device (1) configured as an oval pill or tablet, it should be understood that the osmotic device can assume any configuration or shape currently known in the art of osmotic devices. That is, the osmotic device can assume any different configuration and / or size according to what is optimal for the intended use environment. In particular embodiments, the shape and size of the osmotic device will be optimal for use in mammals such as animals or humans. The device of the invention can be a pill, sphere, tablet, bar, plate, granule, agglomerate or the like. The osmotic device may also include marks, slits, slots, letters and / or numbers for decoration, identification and / or other purposes.

The outer coating (2) contains a second active agent which may or may not be the same as the first active agent in the core (5). The second active agent is available for immediate, slow, delayed, sustained or controlled release or combinations thereof and can be applied to the surface of the device according to common methods of preparation of similar osmotic devices that are known to the artisan or common expert in the art, such as applying to its surface solids in solution or suspension by using a vaporizer that distributes it uniformly over the core or using nucleated compression or other suitable methods known in the art. The outer coating may comprise poly (vinylpyrrolidone) (PVP) and poly (ethylene glycol) (PEG and may further comprise materials such as, by way of example and without limitation, hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (CMC), dimethylaminoethyl methacrylate-methacrylic acid copolymer, ethylacrylate-methylmethacrylate copolymer (GA-MMA), C-5 or 60 SH-50 (Shin-Etsu Chemical Corp.) and combinations thereof. The external coating containing active agent (2) may also comprise dissolution additives, stability modifiers, and bioabsorption extenders.

When the external coating (2) comprises a combination of materials, the relative amounts and proportions of those materials can be varied as desired. For example, when the outer coating (2) comprises PVP and PEG, the PVP: PEG ratio will generally vary from 3% -60% by weight of PVP to 0.1-30% of PEG, based on the weight of the outer coating .

The outer coating (2) may also comprise a second active agent generally present in an amount between 0.1 and 99% by weight of the coating. This wide range provides great flexibility in the design and application of the osmotic device. The artisan or average expert will appreciate that the particular amount of a second active agent employed will vary according to, among other things, the identity and physical properties and characteristics of the second active agent, the desired application of the osmotic device, the effect that is desired. have the second active agent, and the physiological condition, if any, to be treated.

The polymeric coating that covers the semipermeable wall (4) and blocks the passage (6) is made of synthetic or natural material which, through selective dissolution or erosion, will allow the passage to be unblocked allowing the delivery process to begin osmotic. This polymer layer of slow or rapid dissolution can be impermeable to a first external fluid, being soluble in a second external fluid. This property can help achieve a controlled and selective release of the active compound in the nucleus. The polymeric coating (3) will generally comprise an inert and non-toxic material which is at least partially, and preferably substantially completely, soluble or erodible in the environment of use. The polymer coating (3) can be soluble in one or more environments of use. For example, the polymeric coating (3) can be soluble in the same medium of use in which the outer coating (2) is soluble or can be soluble in the same medium of use in which the core (5) is soluble. Although the art discloses microporous layers comprising materials that can be included in the polymer coating (3), it has been found that the presence of (vinylpyrrolidone) - (vinyl acetate) copolymer in the polymer coating (3) provides properties and unique and advantageous characteristics to the polymer coating. Then, the polymer coating (3) will comprise poly (vinyl pyrrolidone) - (vinyl acetate) copolymer and may also include other materials useful for this type of coating. Examples of other materials are described in U.S. Patent Nos. 4,576,604 and 4,673,405, and the text "Pharmaceutical Dosage Fomrts: Tablets Volume I," Second Edition. A. Lieberman. from. 1989, Marcel Dekker, Inc. whose descriptions are incorporated here as a reference.

In preferred embodiments, the polymer coating (3) will be insoluble in the fluid of a first environment of use, such as gastric juices, acidic fluids, or polar liquids, and soluble or erodible in the fluid of a second environment of use, such as intestinal juices, substantially fluids of neutral or basic pH, or apolar fluids. A wide variety of other polymeric materials are known which possess these different solubility properties and can be included in the polymer coating (3). Such other polymeric materials include, by way of example and without limitation, cellulose acetate phthalate (CAP), cellulose acetate trimelate (CAT), poly (vinyl acetate) phthalate (PVAP), hydroxypropylmethylcellulose phthalate (HP), poly (methacrylate ethylacrylate) copolymer (1: 1) (MA-EA), poly copolymer. { methacrylate methylmethacrylate) (1: 1) (MA-MMA), poly (methacrylate methylmethacrylate) copolymer (1: 2), Eudragit L-30-DMarca (MA-EA, 1: 1),? udragit L- 100 - 55Brand ( MA-EA, 1: 1), hydroxypropylmethylcellulose acetate succinate (HPMCAS), Coateric Brand (PVAP), Aquateric Brand, (CAP), AQOAT Brand (HPMCAS) and combinations thereof. The polymer coating (3) may also comprise dissolution additives, solubility modifiers, and bioabsorption extenders.

When the polymeric coating (3) is intended to dissolve, erode or detach from the nucleus in the colon, materials such as hydroxypropylcellulose, cellocrystalline cellulose (MCC, AvicelMark of FMC Corp.), polyethylene-vinyl acetate copolymer) (60:40) (EVAC from Aldrich Chemical Co.), 2-hydroxyethylmethylmethacrylate (HEMA), MMA, terpolymers of H? A: MMA: MA synthesized in the presence of N, N'-bis (methacryloyloxyethyloxycarbonylamino) -azobenzene, azopolymers, enteric coating temporary release system (Time Clock® from Pharmaceutical Profiles, Ltd., UK) and calcium pectinate, they can be included in the polymer coating (3).

A preferred polymeric material for use in the polymeric coating (3) comprises enteric materials that resist the action of gastric fluid by preventing permeation through the semipermeable wall while one or more of the core materials (5) are solubilized in the intestinal tract allowing the beginning of the process of releasing the drug in the nucleus (5) through osmotic pumping. A material that readily adapts to this type of requirement is a copolymer poly (vinylpyrrolidone) and vinyl acetate such as that provided by BASF by its Kollidon brand VA64, mixed with magnesium stearate and other excipients of similar characteristics. The polymeric coating (3) may also comprise povidone, which is provided by BASF by its Kollidon K 30 brand, and hydroxypropyl methylcellulose, which is supplied by Dow by its Methocel E-15 brand. The materials can be prepared in solutions with different concentrations of polymer according to the desired viscosity for the solution. For example, a 10% P / V aqueous solution of Kollidon K 30 has a viscosity of about 5.5-8.5 cps. at 20 ° C, and a 2% aqueous solution P / V of Methocel E-15 has a viscosity of about 13-18 cps. at 20 ° C.

The polymeric coating (3) may also comprise other suitable materials which are substantially resistant to gastric juices and which promote both enteric and colonic release. For this purpose, the polymeric coating (3) may comprise one or more materials that do not dissolve, disintegrate or change their structure in the stomach and during the period of time in which the osmotic device (1) resides in the stomach. Representative materials that preserve their integrity in the stomach can comprise a select member of the group consisting of (a) keratin, tolua sandrara keratin, salol (phenyl salicylate), salol beta-naphthylbenzoate and acetotanin, salol with balsam from Peru, salol with tolú, salol with chewing gum, salol and stearic acid, and salol and shellac; (b) a member selected from the group consisting of formalized proteins, formalized gelatins, formalized cross-linked gelatins and exchange resins; (c) a member selected from the group consisting of myristic acid-hydrogenated castor oil-cholesterol, sheep stearic acid tallow, stearic acid-tolu balsam, and stearic acid-castor oil; (d) a member selected from the group consisting of shellac, ammonia shellac, ammonia-saloon shellac, wool shellac, acetylated shellac, shellac-stearic acid-tolu-balsam, and shellac n-butyl stearate; (e) a member selected from the group consisting of abietinic acid, methyl abietate, benzoin, tolu balsam, sandrara, gum chews with tolu and gum chews with acetylated alcohol, (f) acrylic resins represented by anionic polymers synthesized from methacrylic acid and methacrylic acid methyl ester, copolymeric methacrylic acid acrylic resins and methacrylic acid alkyl esters, alkyd acrylic acid copolymers and alkyl esters of acrylic acid, acrylic resins such as dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer PM 150,000, 50:50 methacrylic acid copolymer -methylmethacrylate of MW 135,000, copolymer 30:70 of methacrylic acid-methylmethacrylate of MW 135,000, methacrylamic acid-dimethylaminoethyl-methacrylate-ethylacrylate of MW 750,000, ethacrylic acid-methyl methacrylate-ethylacrylate of MW 1,000,000 and ethylacrylate-methyl-methacrylate-ethylacrylate MW 550,000; and (g) an enteric composition comprising a member selected from the group consisting of acetyl cellulose phthalate, diacetyl cellulose phthalate, triacetyl cellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, sodium acetyl cellulose phthalate, ester of cellulose phthalate, cellulose phthalate ether, methyl cellulose phthalate, cellulose phthalate ether ester, hydroxypropyl cellulose phthalate, alkali salts of cellulose acetate phthalate, alkaline earth salts of cellulose acetate phthalate, salts of cellulose acetate phthalate calcium, hydroxypropyl methylcellulose ammonium phthalate salts, cellulose acetate hexahydroflate, hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, diethyl phthalate, dibutyl phthalate, dialkyl phthalate where the alkyl comprises 1 to 7 linear or branched alkyl groups, aryl phthalates, and other materials known to the average expert or in art.

The preformed passage (6) in the semipermeable wall (4) which communicates the core (5) of the osmotic device with the exterior of the device can be generated by mechanical perforation, laser drilling or any other similar method known to the artisan or ordinary artisan.

Although the osmotic device (1) is described with a simple passage (6), it is contemplated that a device according to the present invention may comprise at least one or more passages including two, three, four, five, six, seven, eight, nine, ten or more passages.

The semipermeable membrane (4) is formed of a material that is substantially permeable to the passage of fluid from the environment of use to the core and substantially impermeable to the passage of active agent from the core. Many common materials known to the artisan or the ordinary expert in the art are suitable for this purpose. Examples of materials are cellulose esters, cellulose ethers and cellulose ester-ethers, however, it has been found that a semipermeable membrane consisting essentially of cellulose acetate (CA) and poly (ethylene glycol) (PEG), in particular PEG 400, are preferred when used in combination with the other materials required in the present osmotic device. This particular combination of CA and PEG provides a semipermeable membrane which gives the osmotic device a good controlled release profile for the active agent in the core and which retains its chemical and physical integrity in the environment of use. The CA: PEG ratio generally ranges from about 50: 99% by weight of CA to about 50: 1% by weight of PEG and preferably ranges from about 95% by weight of CA to 5% by weight of PEG. The ratio can vary to alter the permeability and finally the release profile of the osmotic device. Other preferred materials may include a member selected from the group of cellulose acylates such as cellulose acetate, cellulose diacetate, cellulose triacetate and combinations thereof. Many suitable polymers include those described in Argentine Patent No. 199,301 and other references cited herein, the descriptions of which are incorporated herein by reference, which are known to the skilled artisan or artisan.

The core (5) of the osmotic device of the present invention will comprise a first active agent and an osmotic agent and may also comprise many other materials as discussed herein. The amount of active agent first present may vary as described above for the external coating (2). Generally, the first active agent can be present in an amount ranging from 0.10 to 99.9% by weight of the uncoated core (5). Preferred ranges will vary according to the active agent and the intended use of the osmotic device.

When the active agent to be administered is of limited solubility in the environment of use, osmotically effective solutes, osmotic agents or osmagents are added, capable of total or partial solubilization in the fluid. These osmagents will assist both in the suspension or dissolution of the active agent in the nucleus. Examples of osmagents include organic and inorganic compounds, such as salts, acids, bases, chelating agents, sodium chloride, lithium chloride, magnesium chloride, magnesium sulfate, lithium sulfate, potassium chloride, sodium sulfite, sodium bicarbonate, calcium, sodium sulfate, calcium sulfate, calcium lactate, d-mannitol, urea, tartaric acid, raffinose, sucrose, alpha-d-lactose monohydrate, glucose and combinations thereof and other similar or equivalent materials that are widely known in art.

These osmagents can also be incorporated into the core of the osmotic device to control the release of an active agent therein. When the agent is only partially or incompletely soluble in the fluid of an environment of use, it can be released as a suspension as long as sufficient fluid has been absorbed or absorbed in the core to form a suspension.

The osmotic device of the invention may also comprise adsorbents, antioxidants, buffering agents, colorants, flavorings, sweetening agents, tablet anti-sticks, tablet binders, tablet and capsule diluents, direct tablet compression excipients, tablet disintegrants, glidants tablets, opaque tablets or capsules and / or tablet polishing agents.

As used herein, the term "adsorbent" means an agent capable of maintaining other molecules on its surface by physical or chemical means (quemisorción). Such compounds include, by way of example and without limitation, activated and powdered carbon and other materials known to the ordinarian in the art.

As used herein, the term "antioxidant" means an agent that inhibits oxidation and thus is used to prevent deterioration of preparations by the oxidation process. Such compounds include, by way of example and without limitation, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxy toluene, hydrophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, and ratetabisulfite. of sodium and other materials known to the average artisan.

As used herein, the term "buffering agent" means a compound used to resist pH changes by dilution or addition of acid or alkali. Such compounds include, for example and without limitation, potassium metaphosphate, potassium phosphate, sodium monobasic acetate and anhydrous citrate and sodium dihydrate and other materials known to those skilled in the art.

As used herein, the term "sweetening agent" means a compound used to impart sweet taste to a preparation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, sodium saccharin, sorbitol and sucrose and other materials known to those skilled in the art.

As used herein, the term "tablet antiadhesives" means agents which prevent the sticking of the ingredients of the tablet formulation to the punches and molds in a tabletting machine during production. Such components include, by way of example and without limitation, magnesium stearate, calcium stearate, talc, glyceryl behenate, polyethylene glycol, hydrogenated vegetable oils, mineral oils, stearic acid, and other materials known to those skilled in the art.

As used herein, the term "tablet binders" means substances that are used to cause adhesion of the powder particles in tablet formulation granulates. These compounds include, by way of example and without limitation, acacia, alginic acid, sodium carboxymethylcellulose, poly (vinylpyrrolidone), compressible sugar (eg NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch and others. materials known to the artisan in the art.

When necessary, binders may also be included in the present osmotic device. Examples of binders include acacia, tragacanth, gelatin, starch, cellulose materials such as methylcellulose and sodium carboxymethyl cellulose, alginic acids and salts thereof, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, inverted sugars, poloxamers (PLURONIC F68 , PLURONIC F127) collagen, albumin, gelatin, cellulose in non-aqueous solvents, combinations of them and the like. Other binders include, for example, polypropylene glycol, polyoxyethylene polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, polyvinyl pyrrolidone, combinations thereof and other materials known to those skilled in the art.

As used herein, the term "tablet and capsule diluent" or "fillers" means inert substances used as fillers to create the desired mass, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, and starch and other materials known to the ordinarily skilled artisan. .

As used herein, the term "excipients for direct tablet compression" means a compound used in tablet formulations by direct compression. Such compositions include, by way of example and without limitation, calcium dibasic phosphate (eg, Ditab) and other materials known to those skilled in the art.

As used herein, the term "tablet glidants" means agents used in formulations of tablets and capsules to reduce friction during tablet compression. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, hydrogel silica, corn starch, talc and other materials known to the ordinarily skilled artisan.

As used herein, the term "tablet lubricant" means substances used in formulations for tablets to reduce friction during compression of the tablet. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate and other materials known to those skilled in the art.

As used herein, the term "tablet / capsule opaque" means a compound that produces an opaque capsule or tablet coating. It can be used alone or in combination with a dye. Such compounds include, by way of example and without limitation, titanium dioxide and other materials known to those skilled in the art.

As used herein, the term "tablet polishing agent" means a compound used to impart an attractive view to the coated tablets. Such compounds include, by way of example and without limitation, carnauba wax, and white wax and other materials known to the ordinarily skilled artisan.

As used herein, the term "tablet disintegrant" means a compound used in solid dosage forms to promote disruption of the solid mass into smaller particles that are more rapidly dispersed or dissolved. Examples of disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pre-gelatinized and modified starches thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (eg Avicel), calcium carboxymethylcellulose, potassium polyacrylline cellulose (eg Amberlite), alginates, sodium starch glycolate, gums such as agar, guar, locust bean gum, karaya, pectin, tragacanth, and other materials known in the art of pharmaceutical sciences .

As used herein, the term "colorant" means a compound used to impart color to solid pharmaceutical preparations (eg, tablets). Such compounds include, by way of example and without limitation, FD &C Red No. 3, FD &C Red No. 20, FD &C Yellow No. 6, FD &C Blue No. 2 / D &C Green No. 5, D &C Orange No. 5, D &C Red No. 8, caramel, and ferric oxide, red, other dyes FD & C. and natural coloring agents such as grape skin extract, red carotene powder, beta-carotene, annato, carmine, turmeric, paprika, other materials known to the average artisan. The amount of coloring agent used can vary as much as desired.

As used herein, the term "flavoring" means a compound used to impart a pleasant taste and often odor to a pharmaceutical preparation. Examples of flavoring agents include synthetic oils and aromatic flavors and / or natural oils, extracts of plants, leaves, flowers, fruits and combinations thereof. These may include cinnamon oil, wintergreen essence, peppermint oil, clove oil, laurel oil, anise, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil , bitter almond oil. Other useful flavorings include vanilla, citrus oil, including lemon, grapefruit orange, grape, lime and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, damask and others. Flavors that have been found particularly useful include commercially available flavors of orange, grape, cherry and chewing gum and mixtures thereof. The amount of flavoring may depend on a number of factors, including the desired organoleptic effects. Flavors may be present in any quantity as desired by the man of the trade. Particularly preferred flavors are grape, cherry and citrus orange.

The present osmotic device can also employ one or more agents known as surface activation or cosolvents that improve the wetting or disintegration of the core or layers of the osmotic device.

The plasticizers can also be included in the present osmotic device to modify the properties and characteristics of the polymers used in the coatings or the core of the device. As used herein, the term "plasticizer" includes all compounds capable of plasticizing or softening a polymer or binder used in the invention. The plasticizer should be able to lower the melting temperature or the glass transition temperature (softening point temperature) of the polymer or binder. Plasticizers, such as low molecular weight PEG, generally extend the average molecular weight of a polymer in which they are included thus lowering their glass transition temperature or softening point. Plasticizers also generally reduce the viscosity of a polymer. It is possible for the plasticizer to impart some particularly advantageous properties to the osmotic device of the invention.

Plasticizers useful in the invention may include, by way of example and without limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester type plasticizers, glycol ethers , poly (propylene glycol), multi-block polymers, simple block polymers, low molecular weight poly (ethylene glycol), citrate ester, triacetin, propylene glycol and glycerin plasticizers. Such plasticizers may also include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly (ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol, Tponoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycollate, dibutyl sebacate, acetylbutyl citrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. All these plasticizers are commercially available from sources such as Aldrich or Sigma Chemical Co. It is considered within the scope of the invention that a combination of plasticizers can be used in the present formulation. PEG-based plasticizers are commercially available or can be made by a variety of methods, as described in Poly (ethylene glycol) Chemistry: Biotechnical and Biomedical Applications (JM Harris, De .; Plenum Press, NY) whose description is incorporated here as a reference It is understood that the osmotic device of the invention may also include oils, for example, non-volatile oils, such as peanut oil, sesame oil, corn oil and olive oil; fatty acids, such as oleic acid, stearic acid, and isostearic, and fatty acid esters, such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. It can also be mixed with alcohols, such as ethanol, isopropanol, hexadecyl alcohol, glycerol and propylene glycol; with glycerol ketals, such as 2,2-dimethyl-l, 3-dioxolane-4-methanol, with ethers, such as poly (ethylene glycol) 450, with petroleum hydrocarbons, such as mineral oil and petrolatum, with water, or with mixtures of them; with or without the addition of a pharmaceutically suitable surfactant, a suspending agent or emulsifier.

Soaps and synthetic detergents can be used as surfactants and as vehicles for detergent compositions. Suitable soaps include fatty acids of an alkali metal, ammonium salts and triethanolamine. Suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, pyridin alkyl halides, and alkylamine acetates, anionic detergents, for example alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, amino-fatty oxides, fatty acid alkanolamides, and copolymers -poly (oxyethylene) -block-poly (oxypropylene); amphoteric detergents, for example, alkyl / 3-aminopropionates and quaternary ammonium salts 2-alkylimidazoline; and mixtures of them.

Several other components, although not listed above, may be added to the present formulation for optimization of the desired release profile of the active agent including, by way of example and without limitation, glyceryl monostearate, nylon, cellulose acetate butyrate, d, l -poly (lactic acid), 1,6-hexanediamine, starches, derived starches, acetylated monoglycerides, gelatin coacervates, poly (styrene-maleic acid) copolymer, glycerol, castor wax, stearyl alcohol, glycerol palmito-stearate, poly ( ethylene), poly (vinyl acetate), poly (vinyl chloride), 1,3-butylene-glycol dimethacrylate, ethylene glycol dimethacrylate and methacrylate hydrogels.

It should be understood that the compounds used in the art of pharmaceutical formulation generally serve a variety of functions or purposes. So, if a compound named here is mentioned only once or is used to define more than one term, its purpose or function should not be considered as limited only to that purpose or function.

Active agents include physiological substances or active pharmacological substances that produce a systemic or localized effect or effects on animals and humans. Active agents also include pesticides, herbicides, insecticides, antioxidants, instigators for plant growth, sterilization agents, catalysts, chemical reagents, food products, nutrients, cosmetics, vitamins, sterility inhibitors, fertility instigators, microorganisms, flavoring agents , sweeteners, cleaning agents or other compounds for pharmaceutical, veterinary, horticultural, home maintenance, food, culinary, agricultural, cosmetic, industrial, cleaning, confectionery and flavoring applications. The active agent can be present in its neutral, ionic, salt, basic, acidic, natural, synthetic, diastereomeric, isomeric, enantiomerically pure, racemic, hydrate, chelate, derivative, analog or other common form.

Other therapeutic compounds that may be formulated within the present osmotic devices also include antibacterial, antihistaminic and decongestant, antiinflammatory, antiparasitic, antiviral, local anesthetic, antifungal, amoebicidal, or trichomonocidal, analgesic, antiarthritic, anti-asthmatic, anticoagulant, anti-convulsant, antidepressants, antidiabetics, antineoplastics, antipsychotics, neuroleptics, antihypertensives, depressants, hypnotics, sedatives, psychic energizers, tranquilizers, anticonvulsants, anti parkinsonian agents, contracturers and muscle relaxants, antimicrobials, anti-malaria agents, hormonal agents, contraceptives, sympathomimetics, diuretics, hypoglycaemic agents, ophthalmic agents, electrolytes, diagnostic agents and cardiovascular drugs.

Representative antibacterial substances are beta-lactam antibiotics, tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin, sulfonamides, aminoglycoside antibiotics, tobramycin, nitrofurazone, nalidixic acid, penicillin, tetracycline, oxytetracycline, chlorotetracycline, erythromycin, cephalosporin and the like and the antimicrobial combination of fludalanin / pentizidone. Other antibacterial agents include those of the carboxylic acids type -pyrridone of low water solubility such as benofloxacin, nalidixic acid, enoxacin, ofloxacin, amifloxacin, flumequine, tosfloxacin, pyromidic acid, piperamidic acid, miloxacin, oxolinic acid, cinoxacin, norfloxacin, ciprofloxacin, pefloxacin , lomefloxacin, enrofloxacin, danofloxacin, binfloxacin, sarafloxacin, ibafloxacin, difloxacin and its salts.

Representative antiparasiticide compounds are ivermectin, befenium, hydroxynaphthoate, dichlorophen and dapsone. Representative anti-malaria compounds are 4-aminoquinolines, 8 aminoquinolines and pyrimethamine.

Representative antiviral compounds are acyclovir and interferon.

Representative anti-inflammatory drugs are cortisone, hydrocortisone, betamethasone, dexamethasone, fluocortolone, prednisolone, phenylbutasone, triamcinolone, sulindac and its salts and corresponding sulphides, indomethacin, salicylamide, naproxen, colchicine, fenoprofen, diclofenac, indoprofen, dexamethasone, allopurinol, oxyphenbutazone, probenecid and sodium salicylamide.

Representative analgesic drugs are diflunisal, aspirin, ibuprofen, profen-type compounds, morphine, codeine, meperidine, nalorphine or acetaminophen.

Representative antihistamines and decongestants are perylamine, loratadine, chlorpheniramine, cimetidine, tetrahydrozoline and antazoline.

Representative anti-asthma drugs are theophylline, pseudoephedrine, ephedrine, beclomethasone dipropionate and epinephrine.

Representative anticoagulants are heparin, hishidrox ± coumarin, and warfarin.

Representative psychic energizers are isocoboxazid, nialamin, phenelzine, imipramine, trandivromine and pargilen.

Ant representative icons are diphenylhydantoin, primidone, enitabas, difenilhidantion, etiltion, pheneturide, ethosuximide and diazepam.

Representative antidepressants are amitriptyline, chlordiazepoxida perphenazine, protriptyline, imipramine and doxepin.

Representative antidiabetics are insulin, somatostatin and its analogs, tolbutamide, tolazamide, chlorpropamide, isophane insulin, insulin protamine zinc suspension, zinc globin insulin, extended zinc insulin suspension and acetohexamide.

Representative antineoplastic drugs are adriamycin, fluoracil, methotrexate, nechloretamine, uracil mustard, 5-fluorouracil, 6-6-thioguanine and procarbazine asparginase.

Representative steroids are prednisolone, cortisone, cortisol and triamcinolone; androgenic steroids such as ethylesterone and fluoxesterone; estrogenic estrogens such as 17β3-estradiol, α-estradiol, estriol, α-estradiol 3-benzoate and 17-ethinylestradiol 3-methyl ether; progestational steroids such as progesterone, 19-norpregn-4-ena-3,20 dione, 17-hydroxy-19-nor-17-a-pregn-5 (10) -em-20-in-3-one, 17-a -etinyl-17-hydroxy-5 (10) -star-3-one, and 9β, 10 a-pregna-4,6-diene-3,20 dione.

Representative antipsychotics are prochlorperazine, lithium carbonate, lithium citrate, thioridazine, molindone, fluphenazine, trifluoperazine, perphenazine, amitriptyline and trifluopromazine.

Representative hypnotics and sedatives are sodium pentobarbitai, phenobarbital, secobarbital, thiopental, heterocyclic hypnotics, dioxopiperidines, glutarimides, diethylovaleramide, a-bromoisovaleryl urea, urethanes, disulfanes and their mixtures.

Representative antihypertensives are spiroñolactone, methyldopa, hydralazine, clonidine, chlorothiazide, deserpidine, timolol, propranolol, metoprolol, prazosin hydrochloride, methyl dopa (L-jS-3,4-dihydroxyphenylalanine), pivaloyloxyethyl ester of a-methyldopa hydrochloride dihydrate and reserpine .

Representative tranquillizers are chloropromazine, promazine, fluphenazine, reserpine, deserpidine, meprobamate and benzodiazepines such as chlordiazepoxide.

Representative antispasmodics and muscle contracturers are atropine, scopolamine, methoscopolamine, oxifenonium, papaverine, and prostaglandins such as PGElf PGE2, PGF - ^ PGF 3a and PGA.

Representative local anesthetics are benzocaine, procaine, lidocaine, maepain, piperocaine, tetracaine, and dibucaine.

Muscle relaxants and anti-parkinson's agents are succinylcholine chloride, danbrolene, cyclobenzaprine, ethocarbamol, diazepam, mefenasin, methocarbomal, trihexylphenidyl and periden.

Representative sympathomimetic drugs are epinephrine, amphetamine ephedrine and norepinephrine.

Representative cardiovascular drugs are procainamide, procainamide hydrochloride, amilnitrite, nitroglycerin, dipyridamole, sodium nitrate and p-anitol nitrate.

Representative diuretics are cloratiazide, methazolamide, flumetazide and acetazolamide.

Representative beta-blockers are pindolol, propanolol, practolol, metoprolol, oxprenolol, timolol, atenolol, alprenolol and acebutolol.

Representative nutritional agents are ascorbic acid, niacin, nicotiamide, folic acid, biotinoline, pantothenic acid, vitamin B12, essential amino acids, essential fats.

Representative ophthalmic agents are picocarpine, pilocarpine salts such as pilocarpine nitrate, pilocarpine hydrochloride, diclofenamide, atropine, atropine sulfate, scopolamine and eserine salicylate.

Representative electrolytes are calcium gluconates, calcium lactate, potassium chloride, potassium sulfate, sodium chloride, sodium fluoride, iron lactate, iron gluconate, ferrous sulfate, iron fumarate, and sodium lactate.

Drugs acting on adrenergic receptors such as clonidine hydrochloride.

The therapeutic content compound (s) within the present osmotic device can be formulated as its pharmaceutically acceptable salts. As "pharmaceutically acceptable salts" are used they refer to derivatives of the described compounds wherein the therapeutic compound is modified by means of acidic or basic salts thereof. Examples of pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the family compounds formed, for example, from non-toxic inorganic or organic acids. For example, such non-toxic conventional salts include those derived from inorganic acids such as, hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and the like; and salts prepared from organic acids such as amino acids, acetic, propidnic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymelic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, -acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the therapeutic compound of the family containing a basic or acidic group by conventional chemical methods. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th., Mack Publishing Company, Easton, PA, 1985, p. 1418, the description of which is incorporated herein by reference.

The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are within good medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, according to a reasonable risk / benefit ratio.

As used in this description, the term "vitamin" refers to trace organic substances that are required in the diet. For the purposes of the present invention, the term "vitamin (s)" includes, without limitation, thiamine, riboflavin, acid nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E and vitamin K. Also included in the term vitamin are the coenzymes of them. Coenzymes are specific chemical forms of vitamins and may include thiamin pyrophosphates (TPP), flavin mononucleotide (FMM), flavin adenine dinucleotide (FAD), Nicotinamide adenine dinucleotide (DNA), Nicotinamide adenine dinuclide phosphate (NADP), Coenzyme A (CoA) , pyridoxal phosphate, biocytin, tetrahydrofolic acid, coenzyme B12, lipoillysin, 11-cis-retinal, and 1,25-dihydroxycholecalciferol. The term vitamin (s) also includes choline, carnitine, and alpha, beta and gammacarotene.

As used in this description, the term "mineral" refers to inorganic substances, metals, and the like required in the human diet. Then, the term "mineral" as used herein includes, without limitation, calcium, iron, zinc, selenium, copper, iodine, magnesium, phosphorus, chromium and the like, and mixtures thereof.

The term "dietary supplement" as used herein means a substance that has an appreciable nutritional effect when administered in small amounts. Dietary supplements include, without limitation, ingredients such as pollen, fiber, wheat germ, seaweed, cod liver oil, ginseng and fish oils, amino acids, proteins, plant extracts, plant dust, herbs, extracts and powders of plants, vitamins, minerals, combinations of them and the like. As will be appreciated, essentially any dietary supplement can be incorporated within the present osmotic device.

The amount of therapeutic compound incorporated in each osmotic device will be at least one or more dose unit and can be selected according to known pharmacy principles. An effective amount of therapeutic compound is specifically provided. By the term "effective amount", it is understood that, with respect to, for example, pharmaceutical products, a pharmaceutically effective amount is provided. A pharmaceutically effective amount is the amount of a drug or pharmaceutically active substance that is sufficient to elicit the required or desired therapeutic response, or in other words, the amount that is sufficient to elicit an appreciable biological response when delivered to a patient. As used with reference to a vitamin or mineral, the term "effective amount" means an amount of at least about 10% of the United Recommended Daily Allowance ("RDA") of that particular ingredient for a patient. For example, if an ingredient is vitamin C, then an effective amount of vitamin C should include a sufficient amount of vitamin C to provide 10% or more of the RDA. Typically, where the tablet includes a mineral or vitamin, it will incorporate higher amounts, preferably about 100% or more of the applicable RDA.

For nasal administration of therapeutic compounds, the osmotic devices may be included in a paste, cream or ointment containing the appropriate solvents (such as water, aqueous, non-aqueous, polar, apolar, hydrophobic, hydrophilic and / or combinations thereof) and optionally other compounds (stabilizers, perfumes, antimicrobial agents, antioxidants, pH modifiers, surfactants and / or bioavailability modifiers) . It is considered that bioavailability extenders such as alcohols or other compounds that enhance the penetration of the therapeutic compound from the pharmaceutical formulation to the nasal mucosa may be necessary to prepare formulations suitable for nasal administration.

For oral, buccal, and sublingual administration, the osmotic device can be in the form of a tablet, tablet, suspension, agglomerate, granulate or powder. For rectal administration, the osmotic device can be included in a suppository, ung_ento, enema, tablet or cream for release of the therapeutic compound within the intestines, sigmoid and / or rectus muscle.

The term "dosage unit form" is used herein to mean an osmotic device containing an amount of therapeutic compound, said amount being such that one or more predetermined units may be provided as a single therapeutic administration.

The osmotic device of the invention can be prepared according to the methods described herein or those well described in the art. For example, according to a manufacturing technique, the active agent and the excipients comprising the core can be mixed in solid, semisolid or gelatinous form, then moistened and sieved through a specified mesh to obtain uncoated cores. The uncoated cores are then dried in a dryer and tablets, for example, by punching. The compressed and uncoated cores (5) are then covered with a solution of suitable materials comprising the semipermeable membrane (4). Subsequently, the semipermeable membrane (4) surrounding each core is perforated with, for example, laser equipment. The coated and perforated cores are then coated with a polymer suspension such as that previously described which blocks the passage and forms the polymer coating (3). Finally, the coating containing the external active agent (2) is applied.

If desired, the active agents of the invention can be coated with a finishing layer (8) (shown in phantom) as is commonly done in the art to provide the desired gloss, color, taste or other aesthetic characteristics. Suitable materials for preparing the finishing coating are well known in the art and are found in the description of many of the references cited and incorporated herein by reference.

The following examples should not be considered exhaustive, but merely illustrative of only some of the many embodiments provided by the present invention. The methods described herein can be followed to prepare the osmotic devices according to the invention.

EXAMPLE 1 Theophylline monoethanolamine (2.0 kg) mannitol (0.173 kg) is mixed in a mixing bowl; Kollidon 90 Brand (0.075 kg); Povidone (0.150 kg) and silicic anhydride (0.005 kg).

The mixture is passed through a 40 mesh screen U.S.P .. Then a solution of: Kollidon 90 is added to the mixture, (0.025 kg), polyethylene glycol 1500 (0.100 kg) and demineralized water (0.180 L); stirring to proper consistency.

The wet mixture is then passed through a 10 mesh screen. The granules are distributed in trays and dried in a drying oven at 45 ° C ± 2 ° C for 12 hours. The dried granulate is passed through a No. 20 mesh screen and placed in a powder mixer or double polyethylene bag. To the dry granulate is added a mixture of silicic anhydride (0.0075 kg) and magnesium stearate (0.015 kg), previously sieved by No. 50 sieve.

This mixture is compressed with a set of 11 mm diameter punches to form partial nuclei of the osmotic device of the example.

The cores are coated with a suspension composed of 22% Kollidon VA64Marc and 88% talc in isopropyl alcohol to form complete cores which are subsequently coated with a solution containing 95% cellulose acetate, and 5% polyethylene glycol 400, in methylene chloride, 80% and 20% methanol to form cores coated with a semipermeable membrane of about 62 mg.

The semipermeable membrane of the coated cores is then perforated using conventional laser equipment to form cores each having at least one passage through their respective semipermeable membrane.

The cores are then coated with a suspension comprising Kollidon VA64, (19.56%, copolymer of polyvinylpyrrolidone-vinyl acetate), titanium dioxide, (16.59%), talc (62.2%), and Aluminum Lacquer Punctured 4R, (1.66%) in isopropyl alcohol to form the cores coated with the polymer coating of the invention.

The drug-containing outer coating is applied onto the newly formed coated core by the application of a suspension comprising Theophylline monoethanolamine (73.60%); silicic anhydride (3.70%); Kollidon CL-M (7.40%), polyethylene glycol 6000 (2.04%); hydroxypropylmethylcellulose (10.46%); polyethylene glycol 400, (1.40%) and Tween 20 (1.40%) in a solution of 75% methylene chloride and 25% ethyl alcohol (96% in water).

A finishing layer that surrounds the outer layer containing the drug is plicated as detailed below.

The newly formed devices are coated with a suspension composed of: hydroxypropylmethylcellulose 60 (11%), polyethylene glycol 6000 (17.30%) and titanium dioxide (22.59%) in a 50% solution of methylene chloride and 50% ethyl alcohol (96% in water).

The solutions and suspensions indicated above are applied in an appropriate spray equipment. After finishing each coating, the tablets are placed in an oven with forced air circulation, for 12 hours to dry the coatings.

EXAMPLE 2 D-pseudoephedrine (2,400 g) is mixed in a laboratory mixer; sodium chloride (810.0 g); microcrystalline cellulose (360.0 g) and polyvinylpyrrolidone (500 g). The mixture is then screened by sieve No. 40. This mixture is kneaded with the addition of a 10.7% solution of polyethylene glycol 400 in ethyl alcohol (96% in water). The wet product is screened through a No. 8 mesh and dried in an oven with air circulation at 45 ° C for 12 hours. To the dried granulate, a mixture of silicic anhydride (25.0 g) and magnesium stearate (75.0 g), previously sieved by 50 mesh, is added.

The obtained mixture is compressed in a compressor with 10 mm diameter punches to form uncoated cores.

The cores obtained are coated with a solution containing cellulose acetate (95%) and polyethylene glycol 400 (5%), in a mixture of methylene chloride (80%) and methanol (20%) to form cores coated by a semipermeable membrane.

The coating of the semipermeable membrane of each core is pierced by a laser-equipped equipment to form at least one passage through the semipermeable coating.

The perforated cores are then coated with a suspension comprising Kollidon VA64 (19.56%, polyvinylpyrrolidone-vinyl acetate copolymer), titanium dioxide (16.59%), talc (62.2%); Punctured 4R aluminum lacquer (1.65%), in 25% isopropyl alcohol to form cores coated with the coating polymer of the invention.

The cores thus coated with the sealed perforation are subjected to a compression coating process with a granulate which is processed in the following manner: in a laboratory mixer-mixer, 80.0 g of Loratadine are mixed; lactose monohydrate, (1516.0 g); microcrystalline cellulose (1600.0 g); corn starch (400.0 g). This wet mixture is screened by No. 40 mesh and then kneaded with a solution containing: Povidone (41.18%), polyethylene glycol 4000 (47.06%), polyethylene glycol 400 (11.16%) in demineralized water.

The wet mixture is screened by No. 10 mesh and dried in an oven at 45 ° C for 12 hours. The dried granulate is screened by mesh No. 20. This granulate is mixed with a mixture previously made with silicic anhydride (16.0 g) and magnesium stearate, (48.0 g) and sieved by No. 50 mesh.

The resulting granulate is applied to the coated cores as mentioned above, by compression.

The processed tablets have a diameter of 14 mm in diameter and contain an osmotic core 10 mm in diameter.

Finally, a topcoat composed of a suspension of hydroxypropylmethylcellulose (60.27%) is applied to the tablets; polyethylene glycol, (17.18%); titanium dioxide (22.55%); in a solvent mixture of methylene chloride (50%) and ethyl alcohol (96% in water).

EXAMPLE 3 In a laboratory mixer-mixer, 2900.0 g of Ranitidine hydrochloride, microcrystalline cellulose (811.0 g), silicic anhydride (4.0 g) are mixed. The mixture is sieved by No. 40 stainless steel sieve. This mixture is kneaded with a solution of 30% Povidone in ethyl alcohol. The wet mass is screened by No. 8 mesh and dried in an oven at 40 ° C for 12 hours. The dried granulate is sieved by No. 20 sieve. This granulate is mixed with a mixture of silicic anhydride (10.0 g) and magnesium stearate (90.0 g) previously sieved by No. 50 mesh. The final mixture is compressed in a compressor with 10 mm diameter punches to form uncoated cores.

The core is coated with a solution of cellulose acetate (95%) and polyethylene glycol 400 (5%), in a mixture of methylene chloride (80%) and methanol (20%). The coated cores are placed in an oven at 45 ° C for? 2 hours and then subjected to the perforation of their respective semipermeable coating membranes, by means of an equipment provided with laser beam.

The perforated cores are then coated by a suspension comprising Kollidon VA64 (19.56%, polyvinylpyrrolidone-vinyl acetate copolymer), titanium dioxide (16.59%); talc (62.2%); Punctured 4R aluminum lacquer (1.65%), in isopropyl alcohol to form cores coated with the polymer coating of the invention.

The cores thus covered with the sealed hole are subjected to a compression coating process with a granulate which is previously prepared in the following way: In a laboratory mixer, 557.2 g of ranitidine hydrochloride and microcrystalline cellulose are mixed (1993.3 g). This mixture is screened by No. 40 mesh. This mixture is kneaded with a solution of 12.5% ammonium polymethacrylate in isopropyl alcohol. The wet mixture is passed through sieve No. 8. It is dried in an oven at 40 ° C for 12 hours. The dried granules are sieved by No. 20 sieve.

Independently of the previous preparation, 207.7 g of Cisapride monohydrate, Povidone (300 g) and microcrystalline cellulose are mixed in a laboratory mixer. (1373.3 g). This mixture is screened through stainless mesh No. 40 and kneaded with a solution of polyethylene glycol 6000 (34.73%) and polyethylene glycol 400 (6.95%) in demineralized water. The wet mass is passed through sieve No. 8. It is dried in an oven at 40 ° C for 12 hours. Once dry, it is sifted by No. 20 mesh.

Both granules thus formed are mixed in a laboratory powder mixer and with a mixture of sodium carboxymethylcellulose (105.4 g), silicic anhydride, (33.7 g) and magnesium stearate (75.3 g).

The resulting granulate is applied to the coated cores, as described above, by compression.

The elaborated tablets are 14 mm in diameter and include inside the core coated, perforated and sealed.

Finally, a finishing coating composed of a suspension of b-hydroxypropylmethylcellulose (60.27%), polyethylene glycol (17.18%), titanium dioxide (22.55%) is applied to the tablets; in a solvent mixture of methylene chloride (50%) and ethyl alcohol (96% in water).

EXAMPLE 4 D-pseudoephedrine (2400 g) is mixed in a laboratory mixer; Sodium chloride (810.02 g); microcrystalline cellulose (1335.0 g) and polyvinylpyrrolidone (400.0 g). The mixture is then sieved by No. 40 sieve. This mixture is kneaded with the addition of a 30% solution of polyvinylpyrrolidone in ethyl alcohol (96% in water). The wet product is sifted through a No. 10 mesh and dried in an oven with air circulation at 45 ° C for 5 hours. A mixture of silicic anhydride is added to the dry granulate . { 29.97 g) and magnesium stearate (75.0 g), previously sieved by 50 mesh.

The obtained mixture is compressed in a compressor with 10 mm diameter biconcave punches to form uncoated cores.

The cores obtained are coated with a solution containing cellulose acetate (95%) and polyethylene glycol 400 (5%), in a mixture of methylene chloride (80%) and methanol (20%) to form cores coated with a membrane semipermeable.

The coating of the semipermeable membrane of each core is pierced by a laser-equipped equipment to form at least one passage through the semipermeable coating.

The perforated cores are then coated with a suspension comprising Copolyvidone (19.56%), titanium dioxide (16.59%), talc (62.20%), Punzo 4R aluicic lacquer (1.65%), 25% isopropyl alcohol to form coated cores having the perforations sealed with the polymeric coating of the invention.

The coated cores, with the sealed perforation are subjected to a pan coating process, spraying by means of suitable equipment, a suspension containing: Astemizole (52.00%), silicic anhydride (2.65%), crospovidone (15, 63%), polyethylene glycol 6000 (1.63%), copolyvidone (25.95%), polysorbate 20 (1.06%) and polyethylene glycol 400 (1.06%), in 4% isopropyl alcohol.

Finally, a final coating is applied in a pan, spraying a suspension composed of hydroxypropylmethylmethylcellulose (60.27%), polyethylene glycol 6000 (17,18%), titanium dioxide (21.50%), aluminum lacquer dye (1.05%), in a solvent mixture of (50%) methylene chloride and (50%) ethyl alcohol (96% in water) followed by drying of the final coating.

EXAMPLE 5 In a laboratory mixer-mixer, 364.9 g of diltiazem-malate, anhydrous glucose (255.93 g), silicic anhydride (6.0 g) are mixed. The mixture is then sieved by No. 40 sieve. This mixture is kneaded with the addition of a 34.2% solution of povidone and polyethylene glycol 400 (0.57%) in ethyl alcohol (96% in water). The wet product is screened through a No. 10 mesh and dried in an oven with air circulation at 40 ° C for 3 hours. To the dry granulate is added a mixture of silicic anhydride (9.0 g) and magnesium stearate (6.84 g), previously sieved by 50 mesh.

The obtained mixture is compressed in a compressor with biconcave punches of 9 mm diameter to form uncoated cores of 336 mg in weight.

These cores are coated with a solution of cellulose acetate (95%) and polyethylene glycol 400 (5%) in a mixture of methylene chloride (80%) and methanol (20%), in a pan to form a semi-permeable membrane coated core. of 24.8 mg of weight per nucleus.

The coating of the semipermeable membrane of each core is perforated by means of a laser beam equipment to form at least one passage through the semipermeable coating.

The perforated cores are then coated with a colored suspension comprising Copolyvidone (30.00%), hydroxypropylmethylcellulose (37. 00%), polyethylene glycol 6000 (10.50%) titanium dioxide (18.50%), Quinoline yellow aluminum lacquer ( 4.00%), in a mixture of 75% methylene chloride and 25% ethyl alcohol (96% in water), at 5.2%, thus sealing the passage.

EXAMPLE 6 The procedure is the same as in Example 5, until the perforation stage of the cellulose coating. The perforated cores are then subjected to a coating process with a suspension comprising Copolyvidone (19.50%), titanium dioxide (17.50%), Punzo 4 R aluminum lacquer (0.50%) and talc (62%). , 50%), in 25% isopropyl alcohol to form cores coated with sealed perforation.

The cores covered with the sealed perforation are subjected to a pan coating process, spraying by means of suitable equipment, a suspension containing enalapril maleate (40.97%) silicic anhydride (2.1%), crospovidone (12.29). %), copolyvidone (20.45%), polysorbate 20 (0.82%); PEG 6000 (21.31%), in a 5.15% isopropyl alcohol mixture.

Finally, a final coating is applied in a paila spraying a suspension composed of hydroxypropylmethylcellulose (60.24%), polyethylene glycol 6000 (17.20%), titanium dioxide (22.56%), in a mixture of (50%) methylene chloride and (50%) ethyl alcohol (96% in water), 4, 6%.

EXAMPLE 7 In a laboratory mixer-kneader, 154.5 g of oxybutynin hydrochloride, mannitol (2660.5 g), anhydrous glucose (400.0 g) and povidone (250.0 g) are mixed. This mixture is kneaded with the addition of a solution at 3.04% polyethylene glycol 400 and polyethylene glycol 6000 (13.04%) in ethyl alcohol (96% in water). The wet product is sifted through a No. 10 mesh and dried in an oven with air circulation at 45 ° C for 5 hours. The dried granulate is screened by 20 mesh. Silicic anhydride (30.0 g) and magnesium stearate (40.0 g), previously sieved by 50 mesh, are added and added to the previous dry granulate.

The obtained mixture is compressed in a compressor with biconcave punches of 9.25 mm in diameter, to form uncoated cores of 380 mg in weight.

These cores are covered in paila, spraying with a suitable equipment, a solution constituted by cellulose acetate (95%) and polyethylene glycol 400 (5%) in a mixture of methylene chloride (80%) and methanol (20%), in a concentration of 5% to form a semipermeable membrane of 30 mg of weight per core.

The coating of the semipermeable membrane of each core is perforated to form at least one passage through the semipermeable coating.

Finally the perforated cores are covered with a colored solution, which seals the passage, and which comprises copolyvidone (19.50%), polyethylene glycol 6000 (10.50%), titanium dioxide (17.50%), aluminum lacquer Punzo 4R (0.50%) and talc (62.50%) in 6% isopropyl alcohol to form cores coated with the polymer coating of the invention.

A coating is then applied by spraying the cores coated with the following suspension: hydroxypropyl methylcellulose (60.25%), polyethylene glycol 6000 (17.25%); and titanium dioxide (22.55%) in a mixture of methylene chloride (75%) and 50% methanol (25%) resulting in a solids concentration of 5.13%.

EXAMPLE 8 In a mixer-mixer, 83.08 g of cisapride monohydrate, microcrystalline cellulose (100.12 g), sodium chloride (150.0 g), polyethylene oxide (180.0 g), hydroxypropylmethylcellulose (12.40 g) are mixed. g), povidone (63.0 g). This mixture is screened by 40 mesh screen. This mixture is kneaded with the addition of an alcoholic solution of polysorbate 20, at 3.40%. The wet mass is sieved by 10 mesh and dried in an oven at 40 °. for 3.5 hours. The dried granulate is screened by 20 mesh and a mixture of silicic anhydride (3.0 g) and magnesium stearate (5.0 g), previously sieved by 50 mesh, is added.

The above mixture is compressed in a compressor with biconcave punches of 9.25 mm in diameter to form uncoated cores of 300 mg in weight.

The coating of the semipermeable membrane of each core is pierced by a laser-equipped equipment to form at least one passage through the semipermeable coating.

The perforated cores are covered with a colored suspension sealing the passage comprising: Copolyvidone (30%), hydroxypropylmethylcellulose (37%), polyethylene glycol 6000 (10.50%), titanium dioxide (18.50%), yellow quinoline lacquer aluminum (4%) in a mixture of methylene chloride (75%) and 96% ethanol (25%), at 5.2%.

The perforated cores are also coated in paila, spraying a suspension composed of hydroxypropylmethylcellulose (60.27%), polyethylene glycol 6000 (17.20%), titanium dioxide (22.20%), aluminum lacquer dye (0.37%) in a mixture of methylene chloride (50%) and ethanol (50%), at a concentration of 4.65%.

The above is a detailed description of a particular embodiment of the invention. It is understood that changes can be made with respect to the described embodiment within the scope of the invention and that obvious modifications may be made by a person skilled in the art. The full scope of the invention is set forth in the claims that follow and their equivalents. Accordingly, the claims and the specification should not be considered as excessively diminishing the full scope of the protection to which the invention is directed.

Those skilled in the art should, in light of the present disclosure, appreciate that many changes can be made to the specific embodiments described herein and still obtain the same or similar results without departing from the spirit and scope of the invention. All compositions and methods described and claimed herein can be made and executed without undue experimentation in the light of the present disclosure. It will be apparent that certain compounds that are both physiologically and chemically related can be substituted in place of the therapeutic compound described herein so long as the same or similar results are achieved.

Claims (15)

R E I V I N D I C A C I O N S

1. An improved multilayer osmotic device for the controlled delivery of one or more active agents to one or more environments of use where the osmotic device comprises: a) a compressed core containing a first active agent and an osmotic agent for controlled and continuous release of the drug; b) a semipermeable membrane surrounding said core, and having a passage preformed therein, said membrane being permeable to a fluid in the environment of use and substantially impermeable to the first active agent; c) a coating of an inert water-soluble polymer comprising a copolymer of poly (vinylpyrrolidone) - (vinyl acetate) partially or substantially completely surrounding the semipermeable membrane and sealing the passageway in the wall; Y d) an outer coating comprising a second active agent for release of the drug, wherein the first active agent is released from the core after the outer shell has partially or completely been dissolved or eroded.

2. An osmotic device as claimed in clause 1, characterized in that the compressed core further comprises poly (vinylpyrrolidone).

3. An osmotic device as claimed in clause 1, characterized in that the semipermeable membrane consists essentially of cellulose acetate and poly (ethylene glycol).

4. An osmotic device as claimed in clause 1, characterized in that the outer coating comprises poly (vinylpyrrolidone) and poly (ethylene glycol).

5. An osmotic device as claimed in clause 1, characterized in that the second active agent in the external coating comprises a therapeutic agent.

6. An osmotic device as claimed in clause 1, characterized in that the first active agent in the core comprises a therapeutic agent.

7. An osmotic device as claimed in clause 1, characterized in that the second active agent in the external coating comprises a therapeutic agent and the first active agent in the core comprises a therapeutic agent.

8. An osmotic device as claimed in clause 7, characterized in that the first and second active agents are the same.

9. An osmotic device as claimed in clause 8, characterized in that the first and second active agents are theophylline.

10. An osmotic device as claimed in clause 1, characterized in that the second active agent in the external coating comprises a therapeutic agent and the first active agent in the core comprises a different therapeutic agent.

11. An osmotic device as claimed in clause 1, characterized in that the first active agent is pseudoephedrine and the second active agent is loratadine.

12. An osmotic device as claimed in clause 8, characterized in that the first and second active agents are theophylline.

13. An osmotic device as claimed in clause 10, characterized in that the first active agent is ranitidine and the second active agent is a combination of ranitidine and cisapride.

14. An osmotic device as claimed in clause 10, characterized in that the first active agent is pseudoephedrine and the second active agent is astemizole.

15. An osmotic device as claimed in clause 10, characterized in that the first agent is diltiazem and the second active agent is enalapril. E S U E N The present invention provides a simple and improved multilayer osmotic device that is capable of delivering a first active agent to an environment of use and a second active agent to another environment of use. A particular embodiment of the invention provides osmotic devices wherein the first and second active agents are similar or different. An erodable polymer coating between an inner semipermeable membrane and an outer coating containing a second active agent comprises a poly copolymer. { vinylpyrrolidone) - (vinyl acetate). This particular erodible polymer results in an improved multilayer osmotic device which has advantages over related devices known in the art.