JP2012162533A - Multi-layered permeation device - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a simple improved multi-layered permeation device (1) which can supply the first active agent in an outer layer (2) to one use environment and supply the second active agent in a core (5) to another use environment.SOLUTION: A permeation device is provided, in which the first and second active agents are identical to or different from each other. A leachable polymer coating (3), between an inner semi-permeable membrane (4) and an outer coating (2) containing the second active agent, contains poly(vinylpyrrolidone)-(vinyl acetate) copolymer. An improved multi-layered permeation device having an advantage exceeding related devices known in the field is obtained with the specific leachable polymer. An active agent in a core (5) is supplied through pores (6) including a leachable plug (7). The permeation device (1) can be coated with a final finishing coating (8).

Description

  The present invention relates to an osmotic device for the controlled supply of active agent to the environment of use. More specifically, allows for immediate delivery of the first active agent, followed by continuous control and / or delayed delivery under monitoring of a second active agent that is the same or different from the first active agent. It relates to a multi-layer osmotic device.

  Osmotic devices are useful in the supply of useful active agents such as pharmaceuticals, nutrients, foods, pesticides, herbicides, fungicides, algicides, chemical reagents, etc. to a controlled environment over a long period of time It is shown. Known devices include tablets, pastels, pills or capsules, etc., which typically contain one or more substances that are leached or that slowly release the active agent by slowly dissolving in the environment of use. It has a layer to do.

  U.S. Pat. No. 4,014,334 to Theeuwes et al. Includes: a) a core containing a drug and a penetrant; b) a semipermeable layer surrounding a core comprising an outer semipermeable thin layer and an inner semipermeable thin layer; and c) Disclosed is an osmotic device for controlled and sustained delivery of a drug that includes a passageway that communicates the core with the outer portion of the device. The two semipermeable thin layers maintain their chemical and physical integrity in the presence of the drug and the liquid from the environment. The passages of Theeuwes et al. Include openings, orifices or holes through the layers formed by mechanical manipulation or by leaching a leachable material such as a gelatin plug in the environment of use. Theeuwes et al. Does not disclose a polymer coating containing a poly (vinyl pyrrolidone)-(vinyl acetate) copolymer surrounding a third thin layer or semipermeable membrane containing the drug.

Guittard et al. US Pat. No. 4,576,604 (Guittard et al. '604) is an Argentine patent 234.493.
Several embodiments of an osmotic device are disclosed which have a drug in the core and at least one thin layer surrounding the core. In particular, one embodiment of the osmotic device includes: a) a core containing a formulation that can include a osmotic agent for controlled release of the drug; b) an inner semipermeable membrane lamina, an intermediate microporous lamina, and A semipermeable membrane wall consisting of an outer water-soluble thin layer containing the drug; and c) a passageway that communicates the core with the outer part of the device. The Guittard et al. '604 patent does not disclose the use of poly (vinyl pyrrolidone)-(vinyl acetate) copolymers as materials suitable for microporous thin layers or leachable elements.

  U.S. Pat. No. 4,673,405 to Guittard et al. (Guittard et al. '405 patent): a) a core or compartment containing a beneficial agent; b) an inert semipermeable wall containing a beneficial agent surrounding the core; and c) Disclosed is an osmotic device comprising at least one passage in the wall of the osmotic device that releases a beneficial agent in the wall by being formed when the osmotic device is in the liquid environment of use and in contact with liquid Where the formed passageway communicates with the compartment within the osmotic device and the outside of the device, thereby dispersing the beneficial agent from the compartment when the device is in the liquid environment of use. The Guittard et al. '405 patent discloses the use of leachable elements to form passages, but the use of poly (vinyl pyrrolidone)-(vinyl acetate) copolymers as materials suitable for leachable elements Is not disclosed.

US Pat. No. 5,558,879 to Chen et al. (Chen et al. '879 patent) discloses a controlled release tablet for a water-soluble drug that forms a passageway in the environment of use, i.e., the gastrointestinal tract of a human being administered the formulation. . In particular, the controlled release tablet essentially comprises a) a core containing 5-20% by weight of a drug, a water soluble penetrant, a water soluble polymer binder and a pharmaceutical carrier; and b) essentially (1) a plasticized water insoluble polymer. And an internal sustained release coating containing a water soluble polymer; and (2) a bilayer coating around the core consisting of an external immediate release coating containing a drug and a water soluble polymer. The Chen et al. '879 patent discloses the formation of a passageway in a controlled release tablet in a use environment to form an osmotic tablet, the passageway comprising a poly (vinyl pyrrolidone)-covering a preformed opening. It is not formed by the use of leachable elements containing a (vinyl acetate) copolymer.

  US Pat. No. 4,810,502 to Ayer et al. (Ayer et al. '502 patent) encloses a) a core containing pseudoephedrine (Ps) and brompheniramine (Br); b) a core containing cellulose acylate and hydroxypropyl cellulose C) a passage in the wall for drug delivery; and d) improving the mechanical integrity and pharmacokinetics of at least one of Ps, Br, hydroxypropylcellulose and hydroxypropylmethylcellulose, and the wall Disclosed is an osmotic dosage form for the supply of Ps and Br having a thin layer outside the wall with poly (ethylene oxide). The Ayer et al. '502 patent does not disclose a polymer coating between the wall and the drug-containing lamina as required by the present invention.

U.S. Pat. No. 4,801,461 to Hamel et al. (Hamel et al. '461 patent) is a pseudoephedrine (Ps
) Is disclosed. In particular, the osmotic dosage form comprises: a) a core containing various amounts of Ps; b) a semipermeable wall around the core containing various amounts of cellulose acetate or cellulose triacetate and various amounts of hydroxypropylcellulose; c) a passage in the wall for the supply of drug from the core; and optionally d) a thin layer outside the wall containing Ps. The core can also contain one or more of sodium chloride, microcrystalline cellulose, hydroxypropyl methylcellulose, magnesium stearate and poly (vinyl pyrrolidone). The passages of the device can extend through only the semipermeable wall, or can extend through both the semipermeable wall and the outer lamina. The passageway can also contain materials that leach or elute in the environment of use. Although various leachable materials have been described as suitable for use in the formation of passages, the specification discloses or suggests poly (vinyl pyrrolidone)-(vinyl acetate) copolymers for this use. Not. Also, the Hamel et al. '461 patent does not describe a polymer coating positioned between the drug-containing outer thin layer and the semipermeable wall.

US Pat. No. 5,681,584 to Savastano et al. (Savastano et al. '584 patent) includes: a) a core containing a drug, an optional penetrant and optional excipients; b) at least of a binder, penetrant and lubricant around the core A delayed release jacket containing one; c) a semipermeable membrane surrounding the delayed release jacket and optionally having a passage; d) containing a drug either outside the semipermeable membrane or between the semipermeable membrane and the delayed release jacket And e) either outside the drug-containing layer, between the drug-containing layer and the semipermeable membrane, or outside the semipermeable membrane if the drug-containing layer is between the delayed release jacket and the semipermeable membrane. A controlled release drug delivery device having an optional enteric coating. That is, the device of the Savastano et al. '584 patent requires a delayed release jacket and includes a polymer coating of a water soluble poly (vinyl pyrrolidone)-(vinyl acetate) copolymer between the semipermeable membrane and the drug containing layer. Not in.

Examples of osmotic devices for other active agent controlled delivery are described in U.S. Pat. No. 3,845,770 and Argentine 199,301, which are formed by walls surrounding a compartment containing a drug. Is disclosed. The wall has a passage or orifice that communicates between the compartment and the environment of use. The wall is made of a semi-permeable material that is semi-permeable to external liquids and impermeable to the active agent inside the device. None of these patents disclose a polymer coating of a water-soluble poly (vinyl pyrrolidone)-(vinyl acetate) copolymer between the semipermeable membrane and the drug-containing layer.

  Although the prior art discloses a wide variety of multi-layer osmotic devices, none of them have found general applicability, and in fact most known devices function within a relatively narrow range of conditions in the environment of use. It has been devised. The improved multilayer osmotic device described herein has been found to overcome many of the difficulties inherent in the related prior art devices. The osmotic device of the present invention can provide a wide range of independent release characteristics for one or more active agents, either simultaneously or sequentially, as a result of the particular improvements disclosed herein. Furthermore, the osmotic device of the present invention provides greater control over the release of the active agent from each layer compared to the device core.

  It is an object of the present invention to provide an improved supply of active substances present in the outer coating to the use environment and a delayed and controlled supply of the active substance contained in the core of the osmotic device to the same or different use environment. Is to provide a multi-layer osmotic device.

The present invention is an improved multi-layer osmotic device for controlled delivery of one or more active agents to one or more use environments, wherein the osmotic device comprises the following components: a) first active agent and agent A penetrant for controlled and sustained release of, and optionally a compressed core containing poly (vinyl pyrrolidone); b) the wall is permeable to liquids in the environment of use, but the first Substantially impervious to the active agent, surrounding the core and having preformed passages therein, preferably cellulose ester, more preferably cellulose acetate, and more essential than poly (ethylene glycol) C) an inert containing a poly (vinyl pyrrolidone)-(vinyl acetate) copolymer partially or substantially completely surrounding the semipermeable membrane and filled into a passage in the wall water And d) optionally poly (vinyl pyrrolidone) and poly for immediate release of the drug, wherein the first active agent is released from the core after the outer coating is partially or completely dissolved or leached. An external coating containing (ethylene glycol) and a second active agent is provided.

  The first and second active agents can be the same or different. In addition, active agents include biologically or pharmacologically active agents, pharmaceuticals, nutrition, foods, insecticides, agricultural chemicals, herbicides, fungicides, algicides, fungicides, chemical reagents, growth regulators, Parasiticides, fertility agents, breeding promoters, biocides, rodenticides, disinfectants, antioxidants, plant growth promoters, preservatives, fermentants, reproduction inhibitors, air fresheners, microbial inhibitors, catalysts , Foods, food additives, nutrients, cosmetics, vitamins and other agents beneficial to the environment of use. The present invention also contemplates the case where the first and second active agents can be delivered to one or more use environments at different rates at different times.

  A preferred embodiment of the present invention is that when the first and second active agents are pharmacologically or biologically active agents, or the first use environment is the stomach or intestinal region and the second use Includes the case where the environment is further below the mammalian gastrointestinal tract.

  Other preferred embodiments are: a) the compressed core contains the first active agent, penetrant and poly (vinyl pyrrolidone); b) the semipermeable membrane consists essentially of cellulose acetate and poly (ethylene glycol); Alternatively, c) includes the case where the outer coating contains poly (vinyl pyrrolidone), poly (ethylene glycol) and a second active agent. Yet another preferred embodiment includes when the first and second active agents are the same and when they are different.

  Various environments for the use of osmotic devices include the oral cavity, eyes, nose, vagina, glands, gastrointestinal tract, anus, cervix, internal uterus, artery, vein, ear, sublingual, skin, epidermis, subcutaneous, Biological environments such as implants, buccal, bioadhesives, mucous membranes and other similar environments are included. Similarly, it may be used in aquariums, industrial warehouses, research facilities, hospitals, chemical reactions and other facilities.

  Other features, advantages, and embodiments of the invention will be readily apparent to those skilled in the art from the following description, examples, and claims.

  The following drawings are part of the present specification and are presented to further illustrate certain features of the present invention. The present invention is more clearly understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments herein.

  Although not limited to a particular operating mechanism, it is believed that the osmotic device of the present invention supplies one or more active agents to the environment of use as follows. As shown in FIG. 2, an osmotic device (1) having a core (5) containing a first active agent surrounded by a semipermeable membrane (4) has a plug (7) partially or completely dissolved from the passageway. Alternatively, after leaching and after the core has inhaled or absorbed sufficient liquid from the use environment, the first active agent is supplied to the use environment in a controlled manner through passageway (6). At least a portion of the semipermeable membrane (4) is surrounded by a water soluble polymer coating (3) that forms a plug (7) that completely covers the passageway (6). At least one part or all of the polymer coating (3) is dissolved in the liquid present in the use environment after the outer coating (2) containing the second active agent is partially or completely dissolved in the use environment. Leach.

  In certain embodiments, the active agent or osmotic agent dissolves or swells in a liquid that enters the core (5) through the semipermeable membrane (4), thereby creating an osmotic gradient through the semipermeable membrane (4). This gradient provides the necessary force to push the first active agent through the passageway (6) from the core to the outer part of the osmotic device (1). The first active agent continues to be released from the core (5) until osmotic equilibrium is reached between the core and the environment of use. This equilibrium of osmotic force occurs gradually over a period of time and thus serves to control the release of the first active agent and also the release characteristics. It is known that the degree of controlled release of the first active ingredient depends on many other factors such as the permeability of the semipermeable membrane (4) and the magnitude of the osmotic pressure gradient.

  When used as a drug delivery device, the multilayer osmotic device of the present invention functions as follows as long as the various layers and cores of the osmotic device are prepared using the correct combination of materials. After administration to the mammal, the outer coating (2) containing a second active ingredient that is soluble, leachable and / or swellable in acid begins to dissolve, leach, swell and / or desorb from the osmotic device; This releases the second active agent into the stomach. As the osmotic device (1) moves through the gastrointestinal tract, a portion of the outer coating (2) partially or completely dissolves, leaches or desorbs, so that in a preferred embodiment, in acidic gastric fluid The insoluble polymer coating (3) is exposed. The polymer coating (3) then dissolves or leaches in one or more regions of the intestine depending on the particular material that makes up the polymer coating (3). For example, substances soluble in pH 4-6 fluids dissolve in the small intestine, whereas substances soluble in pH 7-8 fluid 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 into the core (5) of the osmotic device (1) without dissolving the polymer coating (3). . After the polymer coating (3) has dissolved or leached, or after at least the plug (7) of the polymer coating (3) has been dissolved or leached, the core (5) is first active via the passage (6). Begin to release the agent into the intestines.

  The osmotic device (1) supplies one or more active agents in a controlled manner, and the mechanism used for such controlled supply is pH dependent or pH independent; diffusion control or dissolution control; It can include quasi-zero order, zero-order, quasi-first order, first-order or second-order; or active agent release that is by rapid, slow, delayed, timed or sustained release or other control.

  FIG. 1 shows an example of an osmotic device (1) having a shape as an oval pill or tablet, but the osmotic device may be any shape or form of osmotic device currently known in the osmotic device field. There can also be. That is, the osmotic device may be any shape and / or size that is optimal for the intended use environment. In certain embodiments, the shape and size of the osmotic device is optimal for use in mammals such as animals or humans. The devices of the present invention can be pills, spheroids, tablets, sticks, plates, granules, agglomerates and the like. The osmotic device can also have surface marks, cuts, grooves, letters and / or numbers for decoration, identification and / or other purposes.

The outer coating (2) contains a second active agent which may be the same as or different from the first active agent of the core (5). The second active agent can be used for immediate, slow, delayed, sustained, pseudo first order, pseudo zero order, timed, controlled release, or combinations thereof. The second active agent can be applied to the surface of the device according to common preparation methods for similar osmotic devices well known to those skilled in the art, for example, solids in solution or suspension can be spread evenly across the core Apply to the surface using an atomizer, use nucleation compression, or use other suitable methods in the art. The outer coating can contain poly (vinyl pyrrolidone) (PVP) and poly (ethylene glycol) (PEC), for example, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (CMC) ), Dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, ethyl acrylate-methyl methacrylate copolymer (GA-MMA), C-5 or 60 SH-50 (Shin-Etsu Chemical Corp.) and combinations thereof it can. The active agent-containing outer coating (2) can also contain solubilizers, stability modifiers and bioabsorbability improvers.

  If the outer coating (2) contains a combination of materials, the relative amounts and ratios of these materials can be varied as desired. For example, if the outer coating (2) contains PVP and PEG, the PVP: PEG ratio is generally about 3-60 wt.% PVP: about 0.1-30 wt.% PEG, based on the weight of the outer coating. Range.

The outer coating (2) can also contain a second active agent generally present in an amount ranging from about 0.1 to 99% by weight of the coating. This wide range offers a wide range of possibilities in the design and application of osmotic devices. As the skilled person knows, the specific amount of the second active agent used is, inter alia, the second active agent itself and its physical properties, the intended use of the osmotic device, the second active agent is intended to have. The desired action to be taken and the physiological symptoms to be treated vary depending on the symptoms.

  The polymer coating (3) that covers the semipermeable wall (4) and blocks the passage (6) unblocks the passage via selective dissolution or leaching and initiates the permeation feeding process. Formed from synthetic or natural materials that can. This slow or rapidly dissolving polymer coating (3) is impermeable to the first external liquid, but is soluble to the second external liquid. This property facilitates the achievement of controlled and selective release of the active compound in the nucleus.

The polymer coating (3) generally contains inert and non-toxic substances that are soluble or leachable at least partially and preferably substantially completely in the environment of use. The polymer coating (3) can be soluble in one or more of the use environments. For example, the polymer coating (3) can be soluble in the same environment in which the outer coating (2) is soluble, or in the same environment as the environment in which the core (5) is soluble. It can also be soluble. The presence of a poly (vinyl pyrrolidone)-(vinyl acetate) copolymer in the polymer coating (3) is disclosed, although a microporous layer containing a material that can be included in the polymer coating (3) is disclosed. Have been found to provide unique and advantageous properties of polymer coatings. That is, the polymer coating (3) contains a poly (vinyl pyrrolidone)-(vinyl acetate) copolymer, which can also contain other materials useful for this type of coating. Examples thereof are described in the texts of US Pat. Nos. 4,576,604 and 4,673,405 and Pharmaceutical Dosage Forms: Tablets Vol. I, 2nd Ed., A. Lieberman ed. 1989, Marcel Dekker Inc. Incorporated herein by reference.

In a preferred embodiment, the polymer coating (3) is insoluble in the fluid of the first use environment, such as gastric juice, acidic fluid, or polar fluid, and the intestinal fluid, substantially pH neutral or basic It is soluble or leached in a liquid of a second use environment, such as a liquid or a nonpolar liquid. A wide variety of other polymeric materials have been found to have such various solubility characteristics and can be included in the polymer coating (3). Such other polymeric materials include, but are not limited to, cellulose acetate phthalate (CAP), cellulose acetate trimerate (CAT), poly (vinyl acetate) phthalate (PVAP), hydroxypropyl methylcellulose phthalate ( HP), poly (methacrylate ethyl acrylate) (1: 1) copolymer (MA-EA), poly (methacrylate methyl methacrylate) (1: 1) copolymer (MA-MMA), poly (methacrylate methyl methacrylate) ( 1: 2) Copolymer, Eudragit L-30-D ^™ (MA-EA, 1: 1), Eudragit L-100-55 ^™ (MA-EA, 1: 1), Hydroxypropyl methylcellulose acetate succinate (HPMCAS) ), Coateric ^™ (PVAP), Aquateric ^™ (CAP), AQOAT ^™ (HPMCAS), and combinations thereof. The polymer coating (3) can also contain solubilizers, stability modifiers and bioabsorbability improvers.

Hydroxypropylcellulose, microcrystalline cellulose (MCC, Avicel ^™ , manufactured by FMC Corp.), poly (ethylene-acetic acid) when the polymer coating (3) is intended to dissolve, leach or detach from the core in the colon. Vinyl) (60:40) copolymer (EVAC, manufactured by Aldrich Chemical Co.), 2-hydroxyethyl methacrylate (HEMA), MMA, N, N'-bis (methacryloyloxyethyloxycarbonylamino) -azobenzene Synthesized HEMA: MMA: MA trimer, azopolymer, enteric coating timed release system (Time Clock®, Pharmaceutical Profiles, Ltd., UK) and materials such as calcium pectate polymer coating It can be contained in (3).

Preferred polymeric materials for use in the polymer coating (3) include an enteric material that resists the action of gastric juice and prevents passage through the semipermeable wall, but the core (5) One or more of the substances therein dissolve in the intestinal tract, thereby initiating supply of the drug in the core (5) by the osmotic pump. A material that easily meets this criterion is a poly (vinyl pyrrolidone) -vinyl acetate copolymer such as the material sold by BASF under the trademark Kollidon VA64 mixed with magnesium stearate and other similar excipients. It is a coalescence. The polymer coating (3) can also contain povidone sold by BASF under the trademark Kollidon K30 and hydroxypropylmethylcellulose sold by Dow under the trademark Methocel E-15. Such materials can be prepared as solutions having various concentrations of polymer depending on the desired solution viscosity. For example, a 10% P / V aqueous solution of Kollidon K30 has a viscosity of about 5.5-8.5 cps at 20 ° C., and a 2% P / V aqueous solution of Methocel E-15 has a viscosity of about 13-18 cps at 20 ° C.

  The polymer coating (3) can also contain other suitable materials that are substantially resistant to gastric juice and promote release in the intestine or colon. For this purpose, the polymer coating (3) is one or more in the stomach that does not dissolve, disintegrate or change its structure for the time that the osmotic device (1) stays inside the stomach. The substance can be contained. Representative substances capable of maintaining their integrity within the stomach include (a) keratin, keratin sandalac-tolu, salol (phenyl salicylate), salol beta-naphthyl benzoate and acetotannin, salol + peru balsam, salol + Selected from the group consisting of true, salol + mastic, salol and stearic acid and salol and shellac; (b) from formalin-treated protein, formalin-treated gelatin, and formalin-treated cross-linked gelatin and exchange resin (C) selected from the group consisting of myristic acid hydrogenated castor oil-cholesterol, stearic acid-shallow, stearic acid trobalsam and stearic acid-castor oil; (d) shellac, Ammonia sum shera (E) abietic acid, methyl abi, selected from the group consisting of: aqua, ammoniac shellac-sarol, shellac-wool fat, shellac-acetyl alcohol, shellac-stearic acid-tolubalsum, and shellac n-butyl stearate; Selected from the group consisting of kutate, benzoin, trout balsam, sandalac, mastic + true, and mastic + true, and mastic + acetyl alcohol; (f) anionic system synthesized from methacrylate acid and methacrylic acid methyl ester Acrylic resin represented by polymer, copolymer acrylic resin of methacrylic and methacrylic acid and alkyl methacrylate ester, copolymer of alkacrylic acid and alkyl ester of alkacrylic acid, acrylic resin For example, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer with a molecular weight of 150,000, methacrylic acid-methyl methacrylate with a molecular weight of 135,000 50:50 copolymer, methacrylic acid-methyl methacrylate with a molecular weight of 135,000 30:70 copolymer, molecular weight 750,000 methacrylic acid-dimethylaminoethyl-methacrylate-ethyl acrylate, molecular weight 1,000,000 methacrylic acid-methyl methacrylate-ethyl acrylate, and molecular weight 550,000 ethyl acrylate-methyl methacrylate-ethyl acrylate, and (g) cellulose acetyl phthalate, cellulose diacetyl phthalate , Cellulose triacetyl phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, sodium cellulose Cellulose acetate phthalate, cellulose ester phthalate, cellulose ether phthalate, methyl cellulose phthalate, cellulose ester-ether phthalate, hydroxypropyl cellulose phthalate, alkali salt of cellulose acetate phthalate, alkaline earth salt of cellulose acetate phthalate, calcium salt of cellulose acetate phthalate, Ammonium salt of hydroxypropylmethylcellulose phthalate, cellulose acetate hexahydrophthalate, hydroxypropylmethylcellulose hexahydrophthalate, polyvinyl acetate phthalate diethyl phthalate, dibutyl phthalate, dialkyl phthalate where alkyl has 1 to 7 alkyl groups of linear and branched chain, Than aryl phthalate Enteric compositions containing those selected from the group, and others known to those of ordinary skill in the art are included.

  A preformed passageway (6) in the semipermeable wall (4) that communicates the core (5) of the osmotic device with the outer part of the device may be mechanically drilled, laser drilled or other similar known to those skilled in the art. It can be formed by a method. Although the osmotic device (1) is shown as having one passage (6), the device of the present invention has 2, 3, 4, 5, 6, 7, 8, 9, 10 or more passages. Including at least one passage.

The semipermeable membrane (4) is formed from a material that is substantially permeable to the passage of liquid from the environment of use to the core but substantially impermeable to the passage of active agent from the core. The Many common materials known to those skilled in the art are suitable for this purpose. Examples of materials include cellulose esters, cellulose ethers and cellulose ester-ethers. However, when used in combination with other materials required in the osmotic device of the present invention, essentially cellulose acetate (CA) and poly (ethylene glycol) (PEG),
In particular, it has been found that a semipermeable membrane made of PEG 400 is preferred. This specific combination of CA and PEG gives the osmotic device fully controlled release properties of the active agent in the core and can maintain its chemical and physical integrity in the environment of use Is obtained. The ratio of CA: PEG is generally in the range of about 50 to 99% by weight of CA: about 50 to 1% by weight of PEG, preferably about 95% by weight of CA: about 5% by weight of PEG. This ratio can be varied to change the permeability and ultimately the release characteristics of the osmotic device. Other preferred materials include some of the cellulose acylates such as cellulose acetate, cellulose diacetate, cellulose triacetate and combinations thereof. Many suitable polymers include those described in Argentine Patent 199,301 and other references cited herein, the contents of which are incorporated herein by reference.

  The core (5) of the osmotic device of the present invention contains a first active agent and an osmotic agent, and can further contain many other materials discussed herein. The amount of first active agent present can vary as described above for the outer coating (2). Generally, the first active agent is present in an amount ranging from 0.1 to 99.9% by weight of the uncoated core (5). The preferred range will vary depending on the use of the active agent and the intended use of the osmotic device.

  If the active agent to be administered has limited solubility in the environment of use, add an osmotically effective solute, penetrant or osmagent that can be completely or partially solubilized in the liquid . These osmagents promote either suspension or dissolution of the active agent in the core. 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, calcium bicarbonate, Sodium sulfate, calcium sulfate, calcium lactate, d-mannitol, urea, tartaric acid, raffinose, sucrose, α-d-lactose monohydrate, glucose, combinations thereof, and other similar or widely known in the art Equivalent substances are mentioned.

  Osmagent can also be incorporated into the core of the osmotic device to control the release of the active agent contained therein. If the active agent dissolves only partially or incompletely in the liquid in the environment of use, it is suspended only if sufficient liquid is inhaled or absorbed by the core to form a suspension. It can be released as a liquid.

  The osmotic device of the present invention also includes adsorbents, antioxidants, buffers, colorants, flavors, sweeteners, tablet anti-adhesive agents, tablet binders, tablet capsule diluents, tablet direct compression excipients, tablet disintegrants, Tablet lubricants, tablet lubricants, tablet or capsule opacifiers and / or tablet abrasives can be included.

As used herein, the term “adsorbent” is intended to indicate an agent capable of holding another molecule on its surface by means of physical or chemical (chemisorption). Such compounds include, for example, without limitation, powders and activated charcoal, and other materials known to those skilled in the art.

  As used herein, the term “antioxidant” is intended to indicate an agent that is used to inhibit oxidation and thus prevent degradation of the formulation due to the oxidation process. Examples of such compounds include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, heavy Sodium sulfite, sodium formaldehyde sulfoxylate and sodium metabisulfite and other materials known to those skilled in the art are included.

  As used herein, the term “buffering agent” is intended to indicate a compound used to resist changes in pH due to acid or alkali dilution or addition. Such compounds include, but are not limited to, for example, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other materials known to those skilled in the art. The

  As used herein, the term “sweetener” is intended to indicate a compound used to impart sweetness to a formulation. Such compounds include, but are not limited to, for example, aspartame, dextrose, glycerin, mannitol, sodium saccharin, sorbitol and sucrose and other materials known to those skilled in the art.

In the present specification, the term “tablet anti-adhesive agent” is intended to indicate an agent that prevents adhesion of tablet formulation components to a punch or die of a tablet manufacturing machine during manufacture. Such compounds include, but are not limited to, for example, magnesium stearate, talc, calcium stearate, glyceryl behenate, PEG, hydrogenated vegetable oil, mineral oil, stearic acid and other materials known to those skilled in the art. Is done.

  As used herein, the term “tablet binder” is intended to indicate a substance used to cause powder particle adhesion in tablet granulation. Examples of such compounds include, but are not limited to, acacia, alginic acid, sodium carboxymethylcellulose, poly (vinyl pyrrolidone), compressible sugars (eg NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and glue. Modified starch and other materials known to those skilled in the art are included.

  A binder may be contained in the osmotic device of the present invention as necessary. Examples of binders include acacia, tragacanth, gelatin, starch, cellulose materials such as methylcellulose and sodium carboxymethylcellulose, alginic acid and its salts, polyethylene glycol, guar gum, polysaccharides, bentonite, sugar, invert sugar, poloxamers (PLURONICF68, PLURONIC F127), collagen, albumin, gelatin, cellulose derivatives in non-aqueous solvents, combinations thereof and the like. Other binders include, for example, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, combinations thereof, and other materials known to those skilled in the art.

  As used herein, the term “tablet capsule diluent” or “filler” refers to an inert substance used as a filler in tablet and capsule preparations to obtain the desired bulk, flow and compression properties. The substance shall be indicated. Such compounds include, but are not limited to, dibasic calcium phosphate, kaolin, lactose, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol and starch, and others known to those skilled in the art. Substances are included.

As used herein, the term “tablet direct compression excipient” is intended to indicate a compound used in direct compression tablet formulations. Such compounds include, but are not limited to, dibasic calcium phosphate (eg, Ditab) and other materials known to those skilled in the art.

  As used herein, the term “tablet lubricant” is intended to indicate an agent used in tablet and capsule formulations to reduce friction during tablet compression. Such compounds include, but are not limited to, colloidal silica, corn starch, talc, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel, and other materials known to those skilled in the art. .

  As used herein, the term “tablet lubricant” is intended to indicate a material used in a tablet formulation to reduce friction during tablet compression. Such compounds include, for example, without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate, and other materials known to those skilled in the art.

  As used herein, the term “tablet / capsule opacifier” is intended to indicate a compound used to impart opacity to a capsule or tablet coating. It may be used alone or with a colorant. Such compounds include, but are not limited to, for example, titanium dioxide and other materials known to those skilled in the art.

  As used herein, the term “tablet abrasive” is intended to indicate a compound used to impart gloss to coated tablets. Such compounds include, for example, without limitation, carnauba wax and white wax, and other materials known to those skilled in the art.

  As used herein, the term “tablet disintegrant” is intended to indicate a compound used in a solid dosage form to facilitate disintegration of the solid mass into smaller particles that are more easily dispersed or dissolved. Such disintegrants include, but are not limited to, corn starch, potato starch, starches such as gelatinized and modified starches, sweeteners, clays such as bentonite, microcrystalline cellulose (e.g. Avicel), carboxymethylcellulose calcium, cellulose polyacrylic acid potassium (eg Amberlite), alginate, sodium starch glycolate, agar, guar, locust bean, gums such as Karaya, pectin, tragacanth, and other materials known to those skilled in the art Is included.

As used herein, the term “colorant” is intended to indicate a compound used to impart color to a solid (eg, tablet) pharmaceutical formulation. Examples of such compounds include, but are not limited to, 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 FD & C dyes and grape skin extract, beet red powder, beta carotene, anato, carmine, turmeric, paprika and other natural colorants, and Other materials known to the vendor are included. The amount of colorant used varies as desired.

  As used herein, the term “flavor” is intended to indicate a preferred flavor in pharmaceutical formulations and often a compound used to impart odor. Examples of flavors or flavors include synthetic flavor oils and flavor fragrances and / or natural oils, extracts such as plants, leaves, flowers, fruits, and combinations thereof. These also include cinnamon oil, winter green oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil and cassia oil. Other useful flavors include vanilla, citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences such as apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. . Flavors that have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavor depends on various factors including the desired sensory effect. The flavor is present in the amount desired by those skilled in the art. Particularly preferred flavors are grape and cherry flavors, and citrus flavors such as orange.

  The osmotic device of the present invention can also use one or more commonly known surfactants or cosolvents that improve the wettability or disintegration of the core or layer of the osmotic device.

Plasticizers can also be included in the osmotic devices of the present invention that alter the properties of the polymer used in the device coating or core. As used herein, the term “plasticizer” includes all compounds capable of plasticizing or softening the polymer or binder used in the present invention. The plasticizer must be able to lower the melting point or glass transition point (softening point) of the polymer or binder. Plasticizers such as low molecular weight PEG generally broaden the average molecular weight range of the polymers in which they are contained, thereby lowering the glass transition point or softening point. Plasticizers also generally reduce the viscosity of the polymer. Plasticizers provide certain advantageous physical properties that are present in the osmotic devices of the present invention.

  Plasticizers useful in the present invention include, but are not limited to, for example, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyl groups, ester type plasticizers, Examples include glycol ethers, poly (propylene glycol), multiblock polymers, single block polymers, low molecular weight poly (ethylene glycol), citrate ester type plasticizers, triacetin, propylene glycol, and glycerin. Such plasticizers 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 monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl Citrate, tributyl citrate and allyl glycolate are included. All such plasticizers are commercially available from sources such as Aldrich or Sigma Chemical Co. Furthermore, the present invention also contemplates the use of combinations of plasticizers in the formulations of the present invention. Commercially available PEG plasticizers can be used, or can be prepared by various methods such as those described in Poly (ethylene glycol) Chemistry: Biotechnical and Biomedical Applications (JM Harris, Ed; Plenum Press). The contents are incorporated herein for reference.

The osmotic devices of the present invention also comprise oils such as fixed oils such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil; fatty acids such as oleic acid, stearic acid and isostearic acid; and fatty acid esters such as ethyl oleate, It can contain isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. These are alcohols such as ethanol, isopropanol, hexadecyl alcohol, glycerol and propylene glycol; glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol; ethers such as poly (ethylene glycol) 450 Petroleum hydrocarbons such as mineral oils and petrolatum; can be mixed with water or mixtures thereof with or without pharmaceutically suitable surfactants, suspending agents or emulsifiers.

  Soaps and synthetic detergents may be used as detergents in detergent compositions and as vehicles. Suitable soaps include alkali metal, ammonium and triethanolamine salts of fatty acids. Suitable detergents include cationic detergents such as dimethyldialkylammonium halides, alkylpyridinium halides and alkylamine acetates; anionic detergents such as alkyl, aryl and olefin sulfonates, alkyls, olefins, ethers and monoglyceride sulfates, and sulfosuccinates. Nonionic detergents such as aliphatic amine oxides, fatty acid alkanolamides, and poly (oxyethylene) -block-poly (oxypropylene) copolymers; and amphoteric detergents such as alkyl β-aminopropionates and 2 -Alkyl imidazoline quaternary ammonium salts; and mixtures thereof.

Various other ingredients not mentioned above can also be added to the formulations of the present invention to optimize the desired active agent release characteristics, examples of such ingredients include, but are not limited to, glyceryl mono Stearate, nylon, cellulose acetate butyrate, d, l-poly (lactic acid), 1,6-hexanediamine, diethylenetriamine, starches, derived starches, acetylated monoglyceride, gelatin coacervate, poly (styrene-maleic acid) Polymer, glycowax, castor oil wax, stearyl alcohol, glycerol palmitostearate, poly (ethylene), poly (vinyl acetate), poly (vinyl chloride), 1,3-butylene glycol dimethacrylate, ethylene glycol-dimethacrylate And methacrylate hydrogels.

  Compounds used in the field of pharmaceutical compositions are generally considered to perform various functions or purposes. That is, when a compound shown herein is mentioned only once or is used to define more than one term in this specification, its purpose or function is only the stated purpose or function. It is not limited to.

  Active agents include physiological or pharmacologically active substances that have systemic or local effects on animals and humans. Active agents also include pesticides, herbicides, insecticides, antioxidants, plant growth promoters, fertility agents, catalysts, chemical reagents, foods, nutrients, cosmetics, vitamins, fertility inhibitors, reproduction promoters, Microbes, flavors, sweeteners, detergents, and other similar compounds for pharmaceutical, veterinary medicine, horticulture, household, food, culinary, agriculture, cosmetics, industrial, cleaning, confectionery and flavor applications Is included. An activator is neutral, ionic, salt, basic, acidic, natural, synthetic, cyanastereomer, isomer, enantiomerically pure, racemate, hydrate, chelate, derivative, analog, or other common Can exist in various forms.

  Still other therapeutic compounds that can be formulated into the osmotic device of the present invention include antibacterials, antihistamines and decongestants, anti-inflammatory agents, antiparasitic agents, antiviral agents, local anesthetics, antifungal agents, amoeba drugs or Trichomonas, analgesic, anti-arthritic, anti-asthmatic, anticoagulant, anticonvulsant, antidepressant, antidiabetic, anti-neoplastic, antipsychotic, neuroleptic, antihypertensive, muscle relaxant , Suppressor, hypnotic, sedative, psychostimulant, tranquilizer, anticonvulsant, antiparkinsonian, muscle contractor, antimicrobial, antimalarial, hormone, contraceptive, sympathomimetic, Includes diuretics, hypoglycemic agents, ophthalmic drugs, electrolytes, diagnostic agents and cardiovascular agents.

  Representative antibacterials are beta-lactam antibiotics, tetracycline, chloramphenicol, neomycin, gramicidin, bacitracin, sulfonamide, aminoglycoside antibiotics, tobramycin, nitrofurazone, nalidixic acid, penicillin, tetracycline, oxytetracycline, chlorotetracycline, erythromycin , Cephalosporins and analogs and fludaranin / pentididone antimicrobial complex. Other representative antibacterial agents include less water-soluble pyridone-carboxylic acid forms such as benofloxacin, nalidixic acid, enoxacin, ofloxacin, amifloxacin, flumequin, tosufloxacin, pyromido acid, pipemidic acid, miloxacin, oxophosphate, sinoxacin, Norfloxacin, ciprofloxacin, pefloxacin, lomefloxacin, enrofloxacin, danofloxacin, vinfloxacin, sarafloxacin, ivafloxacin, difloxacin and salts thereof are included.

Representative antiparasitic compounds are ivermectin, bephenium, hydroxynaphthoate, dichlorophen and dapsone. Representative antimalarial compounds are 4-aminoquinolines, 8-aminoquinolines and pyrimethamine.
Representative antiviral compounds are acyclovir and interferon.

  Representative anti-inflammatory agents include cortisone, hydrocortisone, betamethasone, dexamethasone, fluocortron, prednisolone, phenylbutazone, triamcinolone, sulindac and its salts and corresponding sulfides, indomethacin, salicylamide, naproxen, colchicine, fenoprofen , Diclofenac, isodoprofen, dexamethasone, allopurinol, oxyphenbutazone, probenecid and sodium salicylamide.

Typical analgesics are diflunisal, aspirin, ibuprofen, profen type compounds, morphine, codeine, meperidine, nalorphine or acetaminophen.
Representative antihistamines and decongestants are perillamine, chlorpheniramine, cimetidine, tetrahydrozoline, loratadine and antazoline.
Representative anti-asthma agents are theophylline, pseudoephedrine, ephedrine, beclomethasone dipropionate and epinephrine.

Typical anticoagulants are heparin, bishydroxycoumarin and warfarin.
Typical psychostimulants are isocoboxazide, niaramide, phenelzine, imipramine, tranicipromine and pargliene.
Representative anticonvulsants are diphenylhydantoin, primidone, enitabas, diphenylhydantoin, eslutione, phenethlide, ethoximide and diazepam.

Representative antidepressants are amitriptyline, chlordiazepoxide perphenazine, protriptyline, imipramine and doxepin.
Representative antidiabetic agents are insulin, somatostatin and its analogs, tolbutamide, tolazamide, chlorpropamide, isophan insulin, protamine zinc insulin suspension, globin zinc insulin, extended insulin zinc suspension and acetohexamide. .

Representative antineoplastic agents are adriamycin, fluorouracil, methotrexate, nechloretamine, uracil mustard, 5-fluorouracil, 6-6-thioguanine and procarbazine asparaginase.
Representative steroidal agents are prednisolone, cortisone, cortisol and triamcinolone; androgen steroids such as methyltesterone and fluoxymesterone; androgen steroids such as 17β-estradiol, α-estradiol, estriol, α-estradiol 3 benzoate And 17-ethynylestradiol-3-methyl ether; progesterone steroids such as progesterone, 19-nor-pregn-4-ene-3,20-dione, 17-hydroxy-19-nor-17-α-pregne-5 ( 10) -ene-20-in-3-one, 17α-ethynyl-17-hydroxy-5 (10) -estren-3-one, and 9β, 10α-pregna-4,6-diene-3,20-dione It is.

Representative antipsychotic agents are prochlorperazine, lithium carbonate, lithium citrate, thioridazine, morindon, fluphenazine, trifluoroperazine, perphenazine, amitriptyline and trifluoropromazine.
Typical hypnotics and sedatives are sodium pentobarbital, phenobarbital, secobarbital, thiopenital, heterocyclic hypnotics, dioxopiperidines, glutarimides, diethylisovaleramide, α-bromoisovaleryl urea, urethanes , Disulfane and mixtures thereof.

Representative antihypertensive agents are spironolactone, methyldopa, hydralazine, clonidine, chlorothiazide, deserpidine, timolol, propanolol, metoprolol, prazosin hydrochloride, methyldopa (L-β-3,4-dihydroxyphenylalanine), α-methyldopa hydrochloride Hydrate pivaloyloxyethyl ester and reserpine.
Exemplary tranquilizers are chloropromazine, promazine, fluphenazine, reserpine, deserpidine, meprobamate, and benzodiazepines such as chlordiazepoxide.

Representative anticonvulsants and muscle contractors are atropine, scopolamine, methoscopolamine, oxyphenonium, papaverine, and prostaglandins such as PGE ₁ , PGE ₂ , PGF _1α , PGF _2α and PGA.
Typical local anesthetics are benzocaine, procaine, lidocaine, maepine, piperocaine, tetracaine and dibucaine.
Exemplary muscle relaxants and anti-parkinsonian agents are succinylcholine chloride, danbrolen, cyclobenzaprine, metcarbamol, diazepam, mephenesin, methcarbomar, trihexylphenidyl and piperidene.

Representative sympathomimetic agents are epinephrine, amphetamine ephedrine and norepinephrine.
Representative cardiovascular agents are procainamide, procainamide hydrochloride, amyl nitrite, nitroglycerin, dipiredamol, sodium nitrate and mannitol nitrate.
Typical diuretics are chlorathiazide, acetazolamide, metasolamide and flumethiazide.

Exemplary beta blockers are pindolol, propranolol, practolol, metoprolol, oxyprenolol, timolol, atenolol, alprenolol and acebutolol.
Typical nutrients are ascorbic acid, niacin, nicotinamide, folic acid, choline biotin, pantothenic acid, and vitamin B ₁₂ , essential amino acids; essential fats.
Representative ophthalmic agents are pilocarpine, pilocarpine salts such as pilocarpine nitrate, pilocarpine hydrochloride, diclofenamide, atropine, atropine sulfate, scopolamine and eseryl salicylate.

Typical electrolytes are calcium gluconate, calcium lactate, potassium chloride, potassium sulfate, sodium chloride, potassium fluoride, iron lactate, iron gluconate, iron sulfate, iron fumerate and sodium lactate.
A typical agent that acts on α-adrenergic receptors is clonidine hydrochloride.

  The therapeutic compound contained in the osmotic device of the present invention can be formulated into its pharmaceutically acceptable salt. As used herein, “pharmaceutically acceptable salt” is intended to indicate a derivative of the disclosed compound wherein the therapeutic compound is modified by forming an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids, and the like. Can be mentioned. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, sulfamic acid, phosphoric acid, nitric acid; and amino acids, acetic acid, Propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2- Included are salts prepared from organic acids such as acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent therapeutic compound that contains a basic or acidic moiety by conventional chemical methods. Examples of suitable salts are described in Remington's Pharmaceutical Sciences, 17th ed, Mack Publishing Company, Easton, PA, 1985, p. 1418, the contents of which are hereby incorporated by reference.

  The expression “pharmaceutically acceptable” refers herein to humans and animals without undue toxicity, irritation, allergic response, or other problems or complications within the scope of sound medical judgment. Compounds, substances, compositions and / or dosage forms suitable for use in contact with other tissues and compatible with reasonable benefit / risk ratios.

As used in this disclosure, the term vitamin is intended to indicate trace amounts of organic substances required in the diet. For the purposes of the present invention, the term vitamin includes, for example, without limitation, thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B ₁₂ , lipoic acid, ascorbic acid, Vitamin A, vitamin D, vitamin E and vitamin K are included. Vitamins also include their coenzymes. Coenzymes are of the specific chemical structure of vitamins: thiamine pyrophosphate (TPP), flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NAD), nicotinamide adenine including retinal and 1,25-dihydroxycholecalciferol - dinucleotide phosphate (NADP), coenzyme a (CoA), pyridoxal phosphate, biocytin, tetrahydrofolic acid, coenzyme B _12, Ripoirishin, 11-cis. The term vitamin also includes choline, carnitine and alpha, beta and gamma carotene.

  In the present disclosure, the term “inorganic” is intended to indicate an inorganic substance, metal, or the like required for a human diet. That is, as used herein, the term “inorganic” includes, but is not limited to, calcium, iron, zinc, selenium, copper, iodine, magnesium, phosphorus, chromium, and the like and mixtures thereof.

  “Nutritional supplement” as used herein means a substance that provides favorable nutritional effects when administered in small amounts. Examples of “nutritional supplements” include, but are not limited to, bee pollen, bran, wheat germ, kelp, cod liver oil, ginseng, and fish oil, amino acids, proteins, plant extracts, plant powders, herbs, herbs Ingredients such as extracts and powders, vitamins, minerals, and combinations thereof. As long as desired, essentially any nutritional supplement may be incorporated into the osmotic device of the present invention.

  The amount of therapeutic compound formulated in each osmotic device is at least one dosage unit or more, and can be selected as known from pharmaceutical principles. Effective amounts of therapeutic compounds are set individually. “Effective amount” means, for example, a pharmaceutically effective amount for a medicine. A pharmaceutically effective amount is an amount of a drug or pharmaceutically active substance that is necessary or sufficient to exhibit a desired therapeutic response, in other words, to exhibit a favorable biological response when administered to a patient. The amount is sufficient. In the case of vitamins or minerals, an “effective amount” shall mean at least about 10% of the United States Recommended Daily Allowance (RDA) for that particular ingredient for the patient. For example, if the intended ingredient is vitamin C, an effective amount of vitamin C shall include an amount of vitamin C sufficient to provide 10% or more of RDA. Typically, if the tablet contains minerals or vitamins, it can be formulated in higher amounts, preferably in an amount of about 100% or more of the corresponding RDA.

  For nasal administration of therapeutic compounds, osmotic devices may be suitable solvents (eg, water, aqueous, non-aqueous, polar, non-polar, hydrophobic, hydrophilic, and / or combinations thereof) and possibly others. In a paste, cream or ointment containing a compound (stabilizer, fragrance, antimicrobial agent, antioxidant, pH regulator, surfactant and / or bioavailability regulator). Bioavailability enhancing agents such as alcohol or other compounds that enhance penetration of the therapeutic compound from the pharmaceutical formulation into the nasal mucosa may be necessary to prepare a formulation suitable for nasal administration.

  For oral, buccal and sublingual administration, the osmotic device may be in the form of a caplet, tablet, suspension, agglomerate, granule or powder. For anal administration, the osmotic device can be contained in a suppository, ointment, enema, tablet or cream for release of the therapeutic compound into the intestine, sigmoid colon and / or anus.

  “Unit dosage form” as used herein refers to an osmotic device containing an amount of a therapeutic compound, the amount being intended to indicate the case where one or more predetermined units are given as a single dose.

  The osmotic devices of the present invention can be manufactured according to the methods disclosed herein or methods well known to those skilled in the art. For example, according to one manufacturing method, an excipient with an active agent and a core is mixed into a solid, semi-solid or gelatinous form, wetted and sieved through a specific screen to obtain an uncoated core. The uncoated core is then dried in a dryer and compressed, for example by punching. The compressed uncoated core (5) is then coated with a solution of a suitable material containing a semipermeable membrane (4). Thereafter, the semipermeable membrane (4) surrounding each core is perforated by, for example, a laser device. The coated and perforated core is then coated with a polymer suspension as described above which blocks the passage and forms a polymer coating (3). Finally, an activator-containing outer coating (2) is applied.

  If desired, the osmotic device of the present invention may be coated with a finish coating (8) (schematic diagram) as is commonly done in the art to obtain the desired gloss, color, taste or other aesthetic properties. it can. Materials suitable for the production of finish coatings are those known in the art and are described in many disclosures of references, the contents of which are hereby incorporated by reference.

  The following examples are not exhaustive and only a few of the many embodiments contemplated by the present invention are described. The osmotic device of the present invention can be manufactured according to the methods described in the specification.

It is a side view of an example of the embodiment of the multilayer penetration device of the present invention. FIG. 2 is a cross-sectional view of the device of FIG.

Example 1
Theophylline monoethanolamine (2.0 kg), mannitol (0.173 kg), Kollidon 90 ^™ (0.075 kg), Povidone (0.150 kg) and colloidal silicon dioxide (0.005 kg) are mixed in a bowl. The mixture is sieved through a 40 mesh USP screen. A solution containing Kollidon 90 (0.025 kg), polyethylene glycol 1500 (0.1 kg) and deionized water (0.18 L) is then added with shaking until the desired consistency is obtained. The resulting wet mixture is sieved through a 10 mesh screen and the resulting granules are placed in a tray and heat dried in an oven at 45 ± 2 ° C. for 12 hours. The dried granules are then sieved through a 20 mesh screen and placed in a powder mixer or in a double polyethylene bag. A mixture of colloidal silicon dioxide (0.0075 kg) and magnesium stearate (0.015 kg) is prescreened through a 50 mesh screen and added to the dried granules. This mixture is then compressed with a set of 11 mm diameter punches to form the partial core of the example osmotic device.
The partial core was then coated with a suspension of 22% Kollidon VA64 ^™ and 88% talc in isopropyl alcohol to a 20 mg core weight to form the final core, which was then added to 80% methylene chloride and 20%. 95% cellulose acetate in 5% methanol, 5% polyethylene glycol 400
Coating with a solution containing about 62 mg of a semipermeable membrane coating core.
The coated core semipermeable membrane is then perforated using a conventional laser device to form a core having at least one passage through each semipermeable membrane.
Next, the perforated core was subjected to Kollidon VA64 (19.56%, poly (vinylpyrrolidone) copolymer-vinyl acetate), titanium dioxide (16.59%), talc (62.2%) in isopropyl alcohol.
And a suspension containing Punzo'4R Aluminum Lake (1.66%) to form a core coated with the polymer coating of the present invention.
The external drug-containing coating is a theophylline monoethanolamine (73.60%), colloidal silicon dioxide (3.70%) in a solution of 75% methylene chloride and 25% ethyl alcohol (96% in water) against the coating core immediately after formation. ), A suspension containing CL-M Kollidon (7.40%), polyethylene glycol 6000 (2.04%), hydroxypropylmethylcellulose (10.46%), polyethylene glycol 400 (1.40%) and Tween 20 (1.40%) To coat.
A finish coating surrounding the drug-containing outer coating is applied as follows. Immediately formed osmotic device containing hydroxypropyl methylcellulose 60 (11%), polyethylene glycol 6000 (17.3%) and titanium dioxide (22.59%) in a solution of 50% methylene chloride and 50% ethyl alcohol (96% in water) Coat with suspension.
The above solutions and suspensions are applied in a suitable powdering apparatus. After each coating is formed, the device is placed in a forced air circulating heater for 12 hours to dry the coating.

Example 2
D-pseudoephedrine hydrochloride (2,400 g), sodium chloride (810 g), microcrystalline cellulose (360.0 g) and poly (vinyl pyrrolidone) (500 g) are mixed in a laboratory mixer. The mixture is then sieved through a 40 mesh screen and kneaded while adding a solution containing poly (ethylene glycol) 400 (10.7%) in ethyl alcohol (96% in water). The wet product is sieved through an 8 mesh screen and dried in a heated oven at 45 ° C. for 12 hours. A mixture of colloidal silicon dioxide (25.0 g) and magnesium stearate (75.0 g) previously screened through a 50 mesh screen is added to the dry granules. The resulting granule mixture is compressed with a compressor having a 10 mm diameter punch to form an uncoated core.
The resulting uncoated core is then coated with a solution containing cellulose acetate (95%) and polyethylene glycol 400 (5%) in a mixture of methylene chloride (80%) and methanol (20%) to produce a semipermeable membrane Form a coating core.
The semipermeable membrane coating of each core is then drilled with a laser device to form at least one passage through the semipermeable coating.
Next, the perforated core was washed with Kollidon VA64 (19.56%, poly (vinylpyrrolidone) copolymer-vinyl acetate), titanium dioxide (16.59%), talc (62.2%) and Punzo'4R Aluminum Lake (1.66%) in isopropyl alcohol. Cover with the containing suspension to form a core coated with the polymer coating of the present invention.
A coating core having a sealed passage is subjected to a compression coating process using granules as follows. In a laboratory mixer kneader, loratidine (80 g), lactose monohydrate (1516.0 g), microcrystalline cellulose (1600 g), and corn starch (400 g) are mixed. This wet mixture is sieved through a 40 mesh screen and then kneaded with a solution containing Povidone (41.18%), polyethylene glycol 4000 (47.06%) and polyethylene glycol 400 (11.16%) in deionized water. The wet mixture is then sieved through a 10 mesh screen and dried in an oven at 45 ° C. for 12 hours. The dried granules are screened with a 20 mesh screen, then mixed with a preformed mixture of colloidal silicon dioxide (16.0 g) and magnesium stearate (48.0 g), and the final mixture is screened with a 50 mesh screen, Form granules. The granules thus obtained are applied onto the coating core by compression as described above. This particular device has an outer diameter of 14 mm and an osmotic core with an outer diameter of 10 mm.
Finally, apply a suspension containing hydroxypropyl methylcellulose (60.27%), polyethylene glycol (17.18%) and titanium dioxide (22.55%) in a mixture of 50% methylene chloride and 50% ethyl alcohol (96% in water). Apply the finish coating to the device.

Example 3
In a laboratory mixer kneader, ranitidine hydrochloride (2400 g), microcrystalline cellulose (811.0 g) and colloidal silicon dioxide (4.0 g) are mixed. The mixture is sieved through a stainless steel 40 mesh screen and kneaded with a 30% Povidone solution in ethyl alcohol. The wet mixture is then screened with an 8 mesh screen, heat dried in an oven at 40 ° C. for 12 hours, and the resulting granules are screened with a 20 mesh screen. The granules are mixed with a mixture of colloidal silicon dioxide (10.0 g) and magnesium stearate (90.0 g) previously screened through a 50 mesh screen. The final mixture is then compressed with a compressor having a 10 mm diameter punch to form an uncoated core.
The uncoated core is coated with a solution of 95% cellulose acetate and 5% polyethylene glycol 400 in a mixture of 80% methylene chloride and 20% methanol. The coated core is placed in a 45 ° C. heater for 12 hours and finally subjected to laser perforation of each semipermeable membrane as described above.
Next, the perforated core was washed with Kollidon VA64 (19.56%, poly (vinylpyrrolidone) copolymer-vinyl acetate), titanium dioxide (16.59%), talc (62.2%) and Punzo'4R Aluminum Lake (1.66%) in isopropyl alcohol. Cover with the containing suspension to form a core coated with the polymer coating of the present invention.
The coating core with the closed passage is subjected to a compression coating process using granules prepared in advance as follows. In a laboratory mixer, mix ranitidine hydrochloride (557.2 g) and microcrystalline cellulose (1993.3 g). The mixture is sieved through a 40 mesh screen and kneaded with a solution of 12.5% ammonium poly (methacrylate) in isopropyl alcohol. The wet mixture is sieved through an 8 mesh screen and dried in a heater at 40 ° C. for 12 hours. The dried granules are then sieved through a 20 mesh screen. In a separate laboratory mixer, mix cisapride monohydrate (207.7 g), Povidone (300 g) and microcrystalline cellulose (1373.3 g). The mixture is sieved through a stainless steel 40 mesh screen and kneaded with a solution of polyethylene glycol 6000 (34.73%) and polyethylene glycol 400 (6.95%) in deionized water. The wet mass is sieved through an 8 mesh screen and dried in a heater at 40 ° C. for 12 hours. After drying, this is sieved through a 20 mesh screen.
Both granules just formed are mixed and then mixed with sodium carboxymethylcellulose (105.4 g), colloidal silicon dioxide (33.7 g) and magnesium stearate (75.3 g) in a laboratory powder mixer. The granule mixture thus obtained is applied onto the coating core by compression as described above. The device thus obtained has an outer diameter of 14 mm and has a coated, perforated and closed core.
Finally, apply a suspension containing hydroxypropyl methylcellulose (60.27%), polyethylene glycol (17.18%) and titanium dioxide (22.55%) in a mixture of 50% methylene chloride and 50% ethyl alcohol (96% in water). Apply the finish coating to the device.

Example 4
D-pseudoephedrine (2,400.0 g), sodium chloride (810.02 g), microcrystalline cellulose (1335.0 g) and poly (vinyl pyrrolidone) (400.0 g) are mixed in a laboratory mixer. The mixture is then sieved through a 40 mesh screen and kneaded while adding a solution containing poly (vinylpyrrolidone) (30%) in ethyl alcohol (96% in water). The wet product is sieved through an 8 mesh screen and dried in a heated oven at 45 ° C. for 5 hours. A mixture of colloidal silicon dioxide (29.97 g) and magnesium stearate (75.0 g) previously screened through a 50 mesh screen is added to the dry granules. The resulting granule mixture is compressed with a compressor having a 10 mm diameter punch to form an uncoated core.
The resulting uncoated core is then coated with a solution containing cellulose acetate (95%) and polyethylene glycol 400 (5%) in a mixture of methylene chloride (80%) and methanol (20%) to produce a semipermeable membrane Form a coating core.
The semipermeable membrane coating of each core is then drilled with a laser device to form at least one passage through the semipermeable coating.
The perforated core is then suspended in isopropyl alcohol (25%) containing Copolyvidone (19.56%, poly (vinylpyrrolidone)), titanium dioxide (16.59%), talc (62.2%) and Punzo'4R Aluminum Lacquer (1.66%). Coating with a turbid liquid forms a coated core with passages sealed with the polymer coating of the present invention.
Coated cores with closed passages astemizole (52.00%) in isopropyl alcohol (4%); colloidal silicon dioxide (2.65%); Crospovidone (15.63%); PEG 6000 (1.63%); Copolyvidon (25.95%); polysorbate Coat with a suspension containing 20 (1.06%) and PEG 400 (1.06%).
Then the following suspensions: hydroxypropyl methylcellulose (60.27%), polyethylene glycol 6000 (17.18%) in a mixture of 50% methylene chloride and 50% ethyl alcohol (96% in water); titanium dioxide (21.50%) Applying the final coating by spraying aluminum lacquer dye (1.05%) onto the core, and then drying the final coating.

Example 5
In a laboratory mixer kneader, mix diltiazem maleate (364.9 g), anhydrous glucose (255.93 g) and colloidal silicon dioxide (6.0 g). The mixture is sieved through a 40 mesh screen and kneaded while adding a solution of Povidone (34.2%) in ethyl alcohol (96% in water) and PEG 400 (0.57%). The wet product is sieved through a 10 mesh screen and dried in a heating oven at 40 ° C. for 3 hours. A mixture of colloidal silicon dioxide (9.0 g) and magnesium stearate (6.84 g) previously screened through a 50 mesh screen is added to the dry granules. The resulting granule mixture is compressed with a compressor having a 9 mm diameter punch to form 336 mg of uncoated core.
The resulting uncoated core is then coated with a solution containing cellulose acetate (95%) and polyethylene glycol 400 (5%) in a mixture of methylene chloride (80%) and methanol (20%) to give a coating of 24.8 per core. A semipermeable membrane coating core having mg is formed.
Each core is then perforated with a semipermeable membrane coating with a laser device to form at least one passage through the semipermeable coating.
The perforated core is then 5.2% Copolyvidone (30.00%) in a mixture of methylene chloride (75%) and 96 ° ethyl alcohol (25%); hydroxypropyl methylcellulose (37.00%); PEG 6000 (10.50%); Cover with a colored suspension containing titanium (18.50%); yellow (4.00%) quinoline aluminum lacquer and seal the passage.

Example 6
This device is prepared in the same manner as in Example 5 until the drilling. The perforated core is then coated with a colored suspension, 4.6% of which is enalapril maleate (40.97%) in a mixture of methylene chloride (50%) and 96 ° ethyl alcohol (50%). (5.0 mg / tablet); contains colloidal silicon dioxide (2.10%); Crospovidone (12.29%); Copolividone (20.45%); polysorbate 20 (0.82%); PEG 6000 (17.20%); titanium dioxide (22.56%) It shall be.

Example 7
Oxybutynin chloride (154.5 g), mannitol (2660.5 g), anhydrous glucose (400.0 g) and Povidone (250.0 g) are mixed in a laboratory mixer. The mixture is kneaded with an alcoholic solution containing poly (ethylene glycol) 400 (3.04%) and PEG 6000 (13.04%). The wet product is sieved through a 10 mesh screen and dried in a heated oven at 45 ° C. for 5 hours. The dried granules are sieved through a 20 mesh screen. A mixture of colloidal silicon dioxide (80.0 g) and magnesium stearate (40.0 g) previously screened through a 50 mesh screen is added to the dry granules. The resulting granule mixture is compressed with a compressor having a 9.25 mm diameter punch to form 380 mg of an uncoated core.
The resulting uncoated core was then coated at a concentration of 5% with a solution containing cellulose acetate (95%) and PEG 400 (5%) in a mixture of methylene chloride (80%) and methanol (20%). To form a semipermeable membrane coated core with 30 mg coating per core. The semipermeable membrane of each core is then perforated to form at least one passage through the semipermeable coating. The perforated core is then coated with a colored suspension containing Copolividone (19.50%); titanium dioxide (17.50%); Ponceau 4R aluminum lake (0.50%) and talc 1 (62.50%) in isopropyl alcohol at a concentration of 6%. Cover and seal the passage.
Spray the coating core with a suspension containing hydroxypropylmethylcellulose (60.25%); PEG 6000 (17.2%); and titanium dioxide (22.55%) in a mixture of methylene chloride (75%) and 50% methanol (25%) Apply the final coating to obtain a solids concentration of 5.13%.

Example 8
In a laboratory mixer kneader, cisapride monohydrate (83.08 g), microcrystalline cellulose (100.12 g), sodium chloride (150.0 g), PEO (180.0 g), hydroxypropylmethylcellulose (12.40 g), Povidone (63.0 g) ). The mixture is sieved through a 40 mesh screen. The mixture is kneaded in an alcoholic solution of polysorbate 20 (3.40%). The wet mixture is sieved through a 10 mesh screen and dried in a heating oven at 40 ° C. for 3.5 hours. The dried granules are sieved through a 20 mesh screen. A mixture of colloidal silicon dioxide (3.0 g) and magnesium stearate (5.0 g) previously screened through a 50 mesh screen is added to the dry granules. The resulting granule mixture is compressed with a compressor having a 9.25 mm diameter punch to form 300 mg of uncoated core.
The resulting uncoated core is then coated at a 5% concentration with a solution containing cellulose acetate (95%) and polyethylene glycol 400 (5%) in a mixture of methylene chloride (80%) and methanol (20%). To form a semipermeable membrane coated core having a coating of 36 mg per core.
The semipermeable membrane coating of each core is then drilled with a laser device to form at least one passage through the semipermeable coating.
The perforated core is then 5.2% Copolyvidone (30.00%) in a mixture of methylene chloride (75%) and 96 ° ethyl alcohol (25%); hydroxypropyl methylcellulose (37.00%); polyethylene glycol 6000 (10.50%); Cover with a colored suspension containing titanium dioxide (18.50%); yellow (4.00%) of quinoline aluminum lacquer and seal the passage.
Hydroxypropyl methylcellulose (60.27%); PEG 6000 (17.20%); titanium dioxide (22.20%); aluminum in a mixture of methylene chloride (50%) and methyl alcohol (96% in water) (50%) at a concentration of 4.65% The final coating is applied by spraying the core with a suspension containing lacquer dye (0.37%).

  The foregoing description details specific embodiments of the invention. Modifications from the disclosed embodiments are possible within the scope of the invention, and obvious modifications will be apparent to those skilled in the art. The full scope of the invention is as set forth in the claims that follow. Accordingly, the claims and specification do not unduly narrow the full scope of protection afforded this invention.

  Many modifications may be made in the specific embodiments described herein by reference to the present disclosure, and similar results can be obtained without departing from the spirit and scope of the invention. All of the compositions and methods described and claimed herein can be made and executed without particular experimentation with reference to the present disclosure. It will be appreciated that certain compounds that are physiologically and chemically related can replace the therapeutic compounds described herein, with similar results.

Claims (22)

A multi-layer osmotic device for controlled delivery of one or more active agents to one or more use environments, the osmotic device comprising:
a) a compressed core containing a first active agent and a penetrant for controlled sustained release of the first active agent;
b) a semipermeable membrane surrounding the core and having a preformed passage inside;
c) a fully leachable or water-soluble inert polymer coating partially or completely surrounding the semipermeable membrane and filling a preformed passage in the wall; and d) release of the second active agent. The activator-containing outer coating for releasing the first active agent from the core after the polymer coating has partially or completely dissolved or leached, and the first and second active agents A device as described above, wherein the first active agent and the second active agent are the same.   The osmotic device of claim 1, wherein the outer coating provides immediate, rapid, slow, delayed, sustained, pseudo first order, pseudo zero order, timed, controlled, or combinations thereof of the second active agent.   The osmotic device of claim 1 or 2, wherein the compressed core further comprises poly (vinyl pyrrolidone).   The osmotic device according to claim 1 or 2, wherein the semipermeable membrane consists essentially of cellulose acetate and poly (ethylene glycol).   The osmotic device of claim 1 or 2, wherein the outer coating contains poly (vinyl pyrrolidone) and poly (ethylene glycol).   The osmotic device of claim 1 or 2, wherein the second active agent in the outer coating contains a therapeutic agent.   The osmotic device of claim 1 or 2, wherein the first active agent in the core contains a therapeutic agent.   The osmotic device of claim 1 or 2, wherein the second active agent in the outer coating contains a therapeutic agent and the first active agent in the core contains the therapeutic agent.   The osmotic device of claim 1, wherein the first and second active agents are theophylline.   The osmotic device of claim 1 or 2, wherein the first and second active agents are released into different use environments.   The osmotic device according to claim 1 or 2, wherein the first use environment is a gastrointestinal region of a mammal, and the second use environment is further below the gastrointestinal tract of the mammal.   The osmotic device of claim 1 or 2, wherein the first and second active agents are released into the same use environment.   Controlled delivery of one or more active agents is pH dependent, pH independent, diffusion controlled, dissolution controlled, pseudo zero order, zero order, pseudo first order, first order or second order, rapid, slow, delayed, timed and The osmotic device of claim 1 or 2, comprising one or more of sustained delivery.   The osmotic device of claim 1 or 2, wherein at least a portion of the polymer coating dissolves or leaches into a liquid present in the use environment after the outer coating is at least partially dissolved in the use environment.   The osmotic device of claim 1 or 2, wherein the polymer coating is soluble in the same use environment in which the outer coating is soluble and is soluble in the same use environment in which the core is soluble.   The osmotic device according to claim 1 or 2, wherein the semipermeable membrane comprises a material selected from cellulose ether, cellulose ester and cellulose-ester-ether.   The osmotic device of claim 1 or 2, wherein the outer coating further comprises poly (vinyl pyrrolidone).   The first and second active agents are antibacterial substances, antihistamines, decongestants, anti-inflammatory agents, antiparasitic agents, antiviral agents, local anesthetics, antifungal agents, amoeba drugs, trichomonas drugs, analgesics, Anti-arthritis, anti-asthma, anti-coagulant, anticonvulsant, antidepressant, antidiabetic, anti-neoplastic, antipsychotic, neuroleptic, antihypertensive, muscle relaxant, inhibitor, hypnotic, Sedative, psychostimulant, tranquilizer, antiparkinsonian, muscle contractor, antimicrobial, antimalarial, hormone, contraceptive, sympathomimetic, diuretic, hypoglycemic, ophthalmic drug, The osmotic device according to claim 1 or 2, each selected from the group consisting of an electrolyte, a diagnostic agent and a cardiovascular agent.   The first and second active agents are pesticides, herbicides, insecticides, antioxidants, plant growth promoters, sterilants, catalysts, chemical reagents, foods, nutrients, cosmetics, vitamins, fertility inhibitors, breeding The osmotic device according to claim 1 or 2, each selected from the group consisting of an accelerator, a microorganism, a flavor, a sweetener and a detergent.   The osmotic device of claim 1 or 2, wherein the fully leachable or water soluble inert polymer coating comprises a poly (vinyl pyrrolidone)-(vinyl acetate) copolymer.   The osmotic device of claim 1 or 2, wherein the coating and / or core polymer comprises a plasticizer.   The osmotic device of claim 1 or 2, wherein the delivery of the first active agent is delayed relative to the delivery of the second active agent.

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