JP2007517062A - Coating of drug granules giving adhesion resistance during mechanical compression - Google Patents

Abstract

  Disclosed is a drug formulation comprising a granule having a substrate and a coating, wherein the granule base comprises a solubilizing surfactant or a low solubility therapeutic agent or both, and the granule coating is hydrophilic. A functional polymer. Further disclosed is a drug composition comprising a tablet core formulated by mechanical compression, wherein the tablet core comprises a granule having a substrate and a coating, the base of the granule being a solubilized surfactant or low A solubility therapeutic agent or both, and the granule coating comprises a hydrophilic polymer. Further disclosed is a dosage form for oral administration of topiramate comprising a tablet core and an osmotic delivery system. Also disclosed is a method for controlling the release pattern of topiramate by altering the composition of the topiramate dosage form.

Description

Relationship with related applications

  This application is hereby incorporated by reference in its entirety, U.S. Provisional Application No. 60 / 533,112, filed on Dec. 29, 2003, and U.S. Provisional Application, filed on Dec. 29, 2003. Claims priority of 60 / 533,470.

  Disclosed is a drug formulation comprising a compressed tablet core comprising a solubilizing agent, preferably a surfactant and a low solubility therapeutic agent, in a granule coated with one or both of the therapeutic agent and the solubilizing agent. Is done. Further disclosed is a controlled release dosage form for oral administration of topiramate comprising a tablet core. Disclosed is a method of controlling the release pattern of topiramate by modifying the composition of the coated granules in the controlled release dosage form.

  Various dosage forms for the controlled release of pharmaceutical substances are known. Various dosage forms for delivering a particular drug may be known, but solubility, metabolic processes, absorption and other physical, chemical and physiological properties that may be unique to the drug Due to the parameters as well as the delivery method, not all drugs can be properly delivered from these dosage forms.

  Dosage forms that use surfactants are known in the art. US Pat. No. 6,057,017 describes a dosage form using a drug formulation consisting of coated granules, wherein the coating consists of a mixture of at least one surfactant and preferably a surfactant with a hydrophobic drug and a lipophilic additive. (See Patent Document 1). This base coating facilitates rapid dispersion of the drug in the absence of liquid components and provides rapid, sustained solubilization. Lipophilic additives further enhance drug solubilization or promote in vivo dispersion.

  In general, dosage forms that incorporate low solubility drugs, including high drug loads on dosage forms that tend to be too large for the patient to swallow them comfortably, are sensitive to controlled release delivery technology. ) Continue to be the goal.

  Dosage forms manufactured in the form of osmotic delivery systems are both known in the art of delivery in US Pat. Nos. 5,037,036 and 5,037,956 approved by patent holders Felix Theeuwes and Takeru Higuchi. ). The dosage forms disclosed and claimed in these patents comprise a semi-permeable wall surrounding a compartment containing a beneficial substance, usually a beneficial drug (eg, a pharmaceutical or therapeutic drug).

  The walls are permeable to the passage of external fluids and are substantially impermeable to the passage of beneficial drugs. There is at least one route through the wall to deliver the beneficial agent from the dosage form. The dosage form releases beneficial substances by the continuous absorption of liquid through the wall into the dosage form at a rate determined by the permeability of the semipermeable wall and the osmotic gradient through the wall. To do. This physico-chemical action produces a solution containing beneficial substances that are hydrodynamically dispersed from the dosage form through the passageway.

  Said patent is also useful for delivering beneficial substances that represent drugs with low solubility in the external fluid absorbed in the dosage form. The dosage form delivers such beneficial substances by mixing the drug with a solute that acts by osmotic pressure, also known as an osmagent. The osmagent in the dosage form exhibits an osmotic gradient through the wall of the dosage form and is a substantial driving force to absorb fluid into the dosage form. The osmagent is delivered osmotically from the dosage form, and together with it produces a solution containing the absorbed fluid that transports the undissolved or dissolved drug from the dosage form.

  The dosage forms of these patents significantly advance delivery technology and the delivery mechanics are ideal for many drugs. However, when a low solubility drug is mixed with an osmagent resulting in an equilibrium ratio, the solubility of the drug produced in the presence of the osmagent is often still too low, usually less than 100 mg / ml. In this case, the drug cannot be released at a controlled rate over a long period of time. If the beneficial drug produced has low solubility, it is difficult to deliver the beneficial drug at a meaningful therapeutic rate.

  Another improvement is described in Patent Document 4 (see Patent Document 4). This patent teaches an osmotic material encapsulated as a means to improve the delivery dynamics of the dosage form. However, the disadvantages of this approach are all too obvious in that it is based on the process of controlling the delivery rate by osmotic gradient alone through the outer wall of the dosage form.

  Various devices in which drug compositions are delivered as slurries, suspensions or solutions from a small outlet opening by the action of an expandable layer are described in US Pat. 12). A typical device includes a tablet comprising an inflatable push layer and a drug layer, surrounded by a semipermeable membrane having a delivery opening. In certain cases, tablets are provided with a subcoat to delay the release of the drug composition relative to the environment of use.

  Devices in which a drug composition is delivered in a dry state from a large outlet opening by the action of an expandable layer are described in US Pat. These references are distributed to deliver beneficial substances to the environment of use, including semipermeable walls containing a layer of expandable material that extrudes the composition of the dry drug layer from the compartment formed by the walls. The device is described. The outlet opening of the device has a diameter that is substantially the same as the inner diameter of the compartment formed by the wall. In such devices, a substantial area of the drug layer composition is exposed to the environment of use, resulting in a release performance that can be exposed to the swaying conditions in such an environment.

  Other similar devices have delivered drugs by expelling separate drug-containing tablets at a controlled rate over time (see Patent Documents 17-23).

  Other devices attempt to deliver low solubility drugs by incorporating liquid drug formulations that are released at a controlled rate over time. These devices are disclosed in Patent Documents 24-27 (see Patent Documents 24-27). However, such liquid osmotic delivery systems are limited in drug concentration in the liquid preparation, and thus available drug loading, which can be unacceptably large in size. Bring.

  Yet another delivery system utilizes a liquid carrier to deliver a small time pill suspended in a liquid carrier. Such devices are disclosed in Patent Documents 28 and 29 (see Patent Documents 28 and 29). These suspensions can be dispensed by a metering device, such as a graduated cylinder or measuring spoon, in a dispensing method that can easily contaminate and administer a therapeutic amount of a pharmaceutical substance to a patient. It needs to be distributed by volume.

  A dosage form that delivers a drug composition to a use environment in a dry state through a large delivery opening may provide adequate release of the drug over an extended period of time, but fluctuating turbulence such as the upper gastrointestinal tract Exposure of the drug layer to the fluid use environment may result in a drug-dependent release that is difficult to control in some environments. In addition, high solid content compositions tend to adhere to the dosage form at sites of large openings, so that in a semi-solid environment devoid of sufficient volume of bulk water, such as in the lower colon environment of the gastrointestinal tract Such dosage forms that are delivered in a dry state may have difficulty releasing a drug composition that is dry-distributed into the environment. Thus, as a fully hydrated slurry or suspension that can provide a means to control the rate of expansion of the push layer to minimize the effect of locally fluctuating conditions on delivery performance, and dosage forms It may be advantageous to release the drug in combination with a smaller sized outlet opening. Move this clause right before [00012]? ?

The dosage form delivers the therapeutic agent with a substantially zero dimensional release rate. Substantially dosage forms for delivering certain drugs at an ascending rate of release, such as Concerta ^(R) methylphenidate products ALZA Corporation have been disclosed in recent years. (Patent Documents 30, 31, and 32). Such disclosed dosage forms involve the use of multiple drug layers with sequentially increasing concentrations of drug in each drug layer to provide an increased rate of drug delivery over time. While such multi-layered tablet structures represent a significant advancement in the art, these devices also have a relatively large amount of such low-solubility pharmaceutical substances, particularly those that can be swallowed by the patient. It has a limited ability to deliver substances associated with various substances.

Thus, there remains a need for means to produce and deliver large amounts of low solubility drug compounds in a variety of delivery patterns that are convenient and applicable to patients in need of swallowing. The demand preferably extends the time between administration preferably twice a day, and most preferably the drug over time by increasing the solubility of the active substance to obtain a once-daily dosing regimen. Effective administration methods, dosage forms, and devices that would allow controlled release of the compound are included. Such dosage forms should preferably have the option of delivery in a hybrid delivery rate pattern suitable for increasing or delivered therapeutic agents at a substantially zero dimensional release rate.
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  The present invention comprises granules and coatings having a substrate, wherein the granule base comprises a solubilizing substance, preferably a surfactant, or a low solubility therapeutic agent or both, and the granule coating comprises The present invention relates to a drug composition comprising a hydrophilic polymer.

  One invention relates to granules and coatings in which the core of the tablet has a substrate, wherein the granule base comprises a solubilizing substance, preferably a surfactant or a low solubility therapeutic agent or both, and granules A drug formulation comprising a core of a tablet formulated by mechanical compression, wherein the coating comprises a hydrophilic polymer.

  Another invention relates to granules and coatings in which the capsule has a substrate, wherein the granule base comprises a solubilizing substance, preferably a surfactant, or a low-solubility therapeutic agent or both, and A drug formulation comprising a capsule comprising a coating comprising a hydrophilic polymer).

  One aspect of the present invention is a drug formulation wherein the granule base comprises a surfactant. Another embodiment is a drug formulation wherein the granule base further comprises a drug. Yet another embodiment is a drug formulation wherein the granule base comprises a drug. A related embodiment is a drug formulation wherein the amount of solubilizing material, preferably surfactant, in the base of the granule is between about 1% and about 90% by weight. A preferred embodiment is a drug formulation wherein the amount of solubilizing substance, preferably a surfactant, in the granule base is between 5% and about 50% by weight of the drug.

  Another aspect of the invention is that the solubilizing material, preferably the surfactant is polyoxyl 40 stearate, polyoxyl 50 stearate, ethylene oxide / propylene oxide / ethylene oxide triblock copolymer, sorbitan monopalmitate, sorbitan monostearate, Grecerol monostearate, polyoxyethylene stearate, polyoxyethylene 40 sorbitol lanolin derivative, polyoxyethylene 75 sorbitol lanolin derivative, polyoxyethylene 6 sorbitol beeswax derivative, polyoxyethylene 20 sorbitol beeswax derivative, polyoxyethylene 20 sorbitol lanolin Derivatives, polyoxyethylene 50 sorbitol lanolin derivatives, polyoxyethylene 23 lauryl ether, polyoxyethylene Len 23 lauryl ether, polyoxyethylene 2 cetyl ether, polyoxyethylene 10 cetyl ether, polyoxyethylene 20 cetyl ether, polyoxyethylene 2 stearyl ether, polyoxyethylene 10 stearyl ether, polyoxyethylene 20 stearyl ether, polyoxyethylene 21 stearyl ether, polyoxyethylene 20 oleyl ether, polyoxyethylene 40 stearate, polyoxyethylene 50 stearate, polyoxyethylene 100 stearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, polyoxyethylene A group consisting of 4 sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate and mixtures thereof A drug formulation selected. In a preferred embodiment, the surfactant comprises polyoxyl 40 stearate, polyoxyl 50 stearate, ethylene oxide: propylene oxide di-block copolymer, ethylene oxide: propylene oxide: ethylene oxide a: b: a triblock copolymer and mixtures thereof. A drug formulation selected from

  Another aspect of the invention is a drug formulation wherein the granule base further comprises a viscous material. A further aspect of the invention is a drug formulation wherein the granule base further comprises a binding substance. Another further embodiment is a drug formulation wherein the granule base further comprises an osmotic substance, and more preferably an osmotic substance selected from the group consisting of sodium chloride, sucrose, sorbitol and mannitol.

  Another aspect of the invention is a drug formulation having a water solubility in the absence of a solubilizing agent, preferably a surfactant, between about 1 μg / ml and about 100 mg / ml of the therapeutic agent. A preferred embodiment is a drug formulation having a water solubility where the therapeutic agent is between about 1 μg / ml and about 50 mg / ml in the absence of a solubilizing agent, preferably a surfactant.

  Another aspect of the present invention is a drug formulation in which the granule coating is continuous. An alternative embodiment is a drug formulation in which the granule coating is discontinuous.

  Another embodiment of the present invention is that the granule coating is water soluble, and more preferably the granule coating is polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, vinyl acetate-vinyl. Pyrrolidone copolymer, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinylacetate polyethylene glycol copolymer, starch, maltodextrin, sugar, sorbitol, mannitol, sucrose, gelatin, casein, natural Rubber, alginate and their A drug formulation comprising a compound selected from the group consisting of compounds.

  A related embodiment of the present invention is that the granule coating is water soluble, and more preferably the granule coating is selected from the group consisting of polyether, polyester, cellulose acetate, cellulose acetate butyrate, polyacrylate and mixtures thereof. A drug formulation comprising the compound. Another embodiment is a drug formulation wherein the granule coating further comprises a compound selected from the group consisting of polyethylene glycol, polyoxyethylene-polyoxypropylene copolymer, hydroxypropylcellulose, glycerin, citrate ester and dibutyl sebacate. . A preferred embodiment is a drug formulation wherein the polyether of the granule coating is ethyl cellulose. Another preferred embodiment is a coating of granules in which the polyester is polyvinyl acetate. Yet another preferred embodiment is a coating of granules wherein the polyacrylate is an ethyl acrylate-methyl methacrylate copolymer. Yet another preferred embodiment is a coating of granules wherein the citrate ester is triethyl citrate or acetyl triethyl citrate.

  Another aspect of the invention is a drug formulation wherein the granule coating is a monolayer. A preferred embodiment is a drug formulation wherein the monolayer coating consists of polyvinyl pyrrolidone or polyethylene oxide. Another embodiment is a drug formulation wherein the monolayer coating is between about 1% to about 3% of the granule weight, or at least about 24% of the granule weight.

  Another embodiment is a drug formulation in which the granule coating is a multiple layer. A preferred embodiment is a drug formulation wherein the coating comprises two layers. A more preferred embodiment is a drug formulation wherein the coating consists of an outer layer of methylcellulose and an inner layer of polyethylene oxide or polyvinylpyrrolidone.

  One embodiment is a dosage form for oral administration of topiramate comprising any of the aforementioned drug formulations wherein the drug is topiramate.

  Another invention relates to granules and coatings in which the core of the tablet has a substrate, the base of the granules comprising a solubilizing substance, preferably a surfactant or topiramate or both, and the granules A dosage form for oral administration of topiramate comprising a tablet core formulated by mechanical compression, wherein the coating comprises a hydrophilic polymer.

  One aspect of the present invention is a topiramate dosage form further comprising an osmotic delivery system and a tablet core, wherein the osmotic delivery system and tablet core are surrounded by a semipermeable membrane having a delivery port through the membrane. .

  Another aspect of the invention is a topiramate dosage form in which the tablet core is incorporated into a matrix delivery system. The matrix system can be either an erodible matrix delivery system or a non-erodible matrix delivery system.

  Another aspect of the invention is a topiramate dosage form, wherein the dosage form is a controlled release topiramate dosage form.

  Another aspect of the present invention is where the solubilizing material, preferably the surfactant is polyoxyl 40 stearate, polyoxyl 50 stearate, ethylene oxide / propylene oxide / ethylene oxide triblock copolymer, sorbitan monopalmitate, sorbitan monostearate Glycerol monostearate, polyoxyethylene stearate, polyoxyethylene 40 sorbitol lanolin derivative, polyoxyethylene 75 sorbitol lanolin derivative, polyoxyethylene 6 sorbitol beeswax derivative, polyoxyethylene 20 sorbitol beeswax derivative, polyoxyethylene 20 sorbitol Lanolin derivatives, polyoxyethylene 50 sorbitol lanolin derivatives, polyoxyethylene 23 lauryl ether, polyoxyethylene Len 23 lauryl ether, polyoxyethylene 2 cetyl ether, polyoxyethylene 10 cetyl ether, polyoxyethylene 20 cetyl ether, polyoxyethylene 2 stearyl ether, polyoxyethylene 10 stearyl ether, polyoxyethylene 20 stearyl ether, polyoxyethylene 21 stearyl ether, polyoxyethylene 20 oleyl ether, polyoxyethylene 40 stearate, polyoxyethylene 50 stearate, polyoxyethylene 100 stearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, polyoxyethylene A group consisting of 4 sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate and mixtures thereof A controlled release topiramate dosage form chosen. Preferred embodiments are solubilizing materials, preferably the surfactant is polyoxyl 40 stearate, polyoxyl 50 stearate, ethylene oxide: propylene oxide diblock copolymer, ethylene oxide: propylene oxide: ethylene oxide a: b: a triblock copolymer and the like A topiramate dosage form selected from the group consisting of: The most preferred embodiment is a topiramate dosage form in which the solubilizing material, preferably the surfactant, is a polyoxyethylene-polyoxypropylene copolymer. Another embodiment is a topiramate dosage form wherein the weight ratio of polyoxyethylene-polyoxypropylene copolymer to topiramate is up to about 3.0.

Another aspect of the invention is that the amount of solubilizing material, preferably a surfactant, is from about 5% of the core to
A controlled release topiramate dosage form that is between about 90% and preferably between about 5% and about 50% by weight of the core.

  Another embodiment is a controlled release topiramate dosage form in which the granule coating is continuous or alternatively the granule coating is discontinuous.

  Another embodiment is that the granule coating is water soluble and preferably polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, vinyl acetate-vinyl pyrrolidone copolymer, hydroxypropyl cellulose, From hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinyl acetate polyethylene glycol copolymer, starch, maltodextrin, sugar, sorbitol, mannitol, sucrose, gelatin, casein, natural gum, alginate and mixtures thereof Morphism selected from the group A controlled release topiramate dosage form comprising from the object.

  An alternative embodiment is that the granule coating is water-insoluble and preferably a polyether such as ethyl cellulose, a polyester such as polyvinyl acetate, a cellulose acetate, cellulose acetate butyrate, a polymer such as ethyl acrylate methyl methacrylate copolymer. A controlled release topiramate dosage form consisting of a compound selected from the group consisting of acrylates and mixtures thereof. In one embodiment, the granule coating may further include citrate esters such as polyethylene glycol, polyoxyethylene-polyoxypropylene copolymer, hydroxypropyl cellulose, glycerin, triethyl citrate and acetyl triethyl citrate in addition to the above components. And a topiramate dosage form comprising a compound selected from the group consisting of dibutyl sebacate.

  Another aspect of the present invention is a controlled release dosage form in which the granule coating consists of a single layer. Another embodiment is a topiramate dosage form in which the monolayer coating consists of polyvinylpyrrolidone or polyethylene oxide. Another embodiment is a topiramate dosage form in which the monolayer coating is up to about 3% of the granule weight or up to about 30% of the granule weight.

  Another embodiment is a controlled release topiramate dosage form in which the granule coating consists of multiple layers. A preferred embodiment is a topiramate dosage form in which the coating comprises two layers. A more preferred embodiment is a topiramate dosage form in which the coating consists of an outer layer of methylcellulose and an inner layer of polyethylene oxide or polyvinylpyrrolidone. Another aspect is a topiramate dosage form comprising an expandable layer, wherein a semipermeable wall is disposed on at least a portion of the expandable layer.

  One aspect of the present invention is a controlled release topiramate dosage form in which the granule base comprises both topiramate and a solubilizing substance, preferably a surfactant. Another embodiment is a controlled release topiramate dosage form in which the granule base further comprises a viscous material. Another embodiment is a controlled release topiramate dosage form wherein the granule base further comprises a binding agent.

  Another embodiment is a controlled release topiramate dosage form in which the release rate of topiramate is at its maximum for at least 2 hours in an in vitro release rate assay. A further embodiment is a controlled release topiramate wherein the release rate of topiramate is at its maximum in an in vitro release rate assay for at least about 3 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours and at least about 12 hours. Dosage form.

  A further aspect of the invention is that the maximum release rate of topiramate in an in vitro release rate assay is about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 4 hours, about 5 hours. Controlled release topiramate dosage forms reached after about 6.5 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours and about 16 hours.

  One aspect of the present invention is a drug composition comprising a granule having a substrate and a coating, wherein the granule base comprises a low-solubility therapeutic agent and optionally a solubilizing substance, and The granule coating comprises one or more layers, wherein each granule coating layer comprises an independently selected hydrophilic polymer, and the drug composition has a therapeutic agent dissolution rate, a therapeutic agent maximum It has a time to release and a period of therapeutic drug delivery (when the drug composition is tested in an in vitro assay or administered to a subject).

  Another embodiment of the present invention is a drug composition comprising a granule having a substrate and a coating, wherein the base of the granule comprises a low solubility therapeutic agent and optionally a solubilizing substance, and The granule coating comprises one or more layers, wherein each granule coating layer comprises an independently selected hydrophilic polymer, and the drug composition is treated with a therapeutic agent when subjected to solubility measurements. Dissolution rate, time to maximum release of therapeutic agent and duration of therapeutic agent delivery.

One aspect of the present invention is:
(A) a core comprising a drug composition, wherein the drug composition comprises a granule having a substrate and a coating, the base of the granule comprising a low-solubility therapeutic agent and optionally a solubilizing substance And wherein the granule coating comprises one or more layers, wherein each granule coating layer comprises an independently selected hydrophilic polymer),
(B) a semi-permeable wall surrounding the core, and (c) an outlet opening through the semi-permeable wall for releasing the drug composition from the dosage form over an extended period of time,
A dosage form comprising

  One aspect of the present invention is that the number of coating layers of the granule reduces the dissolution rate of the therapeutic agent, or extends the time to the maximum release rate of the therapeutic agent, or extends the period of therapeutic agent delivery, or the therapeutic agent The dosage form selected to reduce the maximum release rate number.

  Another aspect of the invention is that the granule coating comprises one layer and the hydrophilic polymer reduces the dissolution rate of the therapeutic agent or extends the time to the maximum release rate of the therapeutic agent or treatment Dosage forms selected to prolong the duration of drug delivery or to decrease the maximum release rate figure of the therapeutic agent.

  Another aspect of the invention is that the granule coating comprises one layer and the amount of coating reduces the dissolution rate of the therapeutic agent or extends the time to the maximum release rate of the therapeutic agent, or Dosage forms selected to extend the duration of therapeutic agent delivery or to reduce the number of maximum release rates of the therapeutic agent.

  Another aspect of the present invention is that the dissolution rate of the therapeutic agent or the time to maximum release rate of the therapeutic agent or the period of therapeutic agent delivery or the maximum release rate of the therapeutic agent is: Dosage forms controlled by varying one or more of (b) the amount of granule layer in each coating or (c) the hydrophilic polymer in the granule layer of each coating.

  One embodiment of the present invention is a dosage form wherein the therapeutic agent is topiramate, the granule coating comprises one layer, and the hydrophilic polymer is selected from the group consisting of methylcellulose and polyvinylpyrrolidone.

  One aspect of the present invention is a dosage form in which the amount of granule coating is in the range of between about 2.5% to about 23% by weight. Another aspect of the invention is a dosage form wherein the amount of granule coating is in the range of between about 2.5% to about 23% by weight.

  In one embodiment of the invention, the granule coating comprises one layer and the hydrophilic polymer is (a) methylcellulose in an amount in the range between about 2.5% to about 13% by weight, (b) A dosage form selected from the group consisting of polyvinylpyrrolidone in an amount in the range between about 3% and about 23% by weight and (c) an amount in the range between about 5% and about 15% by weight polyethylene oxide. It is a thing.

  Another embodiment of the invention is a dosage form wherein the granule coating comprises one layer and the hydrophilic polymer is methylcellulose present in an amount of about 3% by weight.

Another aspect of the present invention is
(A) preparing a granule base comprising topiramate and a solubilizing substance, preferably a surfactant;
(B) a step of coating a granule base;
(C) mechanically compressing the coated granules to form a tablet core;
(D) mechanically compressing the tablet core with the push layer, and (e) surrounding the tablet core and push delivery with a semipermeable membrane having a delivery port through the membrane;
A method of controlling the release pattern of a low solubility therapeutic agent, preferably topiramate, from a controlled release dosage form.

A preferred embodiment of the present invention is therefore where the step of preparing the coated granules further comprises (a) mixing topiramate with a solubilizing substance, preferably a surfactant and a solvent,
(B) forming a wet mass;
(C) drying the mass;
(D) sieving the dried mass to form a granule base;
(E) a step of transferring the granule base to a fluid bed granulator and (f) a step of spray-coating the granule base with a spray coat mixer to form a coated granule,
Is a method for controlling the release pattern of topiramate.

  Another aspect of the present invention controls the release pattern of topiramate that is selected to increase the amount of time that the content and amount of the granule coating reaches the maximum release rate of topiramate in an in vitro release rate assay. Is the method. An alternative embodiment is a method of selecting the content and amount of the granule coating to adjust the period of time that the release rate of topiramate is at its maximum in an in vitro release rate assay. Another embodiment is a method of selecting the content and amount of the granule coating to adjust the topiramate maximum release rate number in an in vitro release rate assay.

  Another aspect of the present invention is to adjust the amount of time that the weight ratio of solubilizing substance, preferably surfactant, to topiramate in the granule base is at its maximum in the in vitro release rate assay. A method of controlling the controlled release pattern of topiramate, which is selected to be. An alternative embodiment is to modify the weight ratio of solubilizing agent, preferably surfactant, to topiramate in the granule base so that the time period during which the release rate of topiramate is in its maximum release pattern of topiramate in an in vitro release rate assay. Or the number of topiramate maximum release rate.

  A further aspect of the present invention is a topiramate release pattern comprising the further step of spray coating the coated granules with a second spray coat mixture to form a coated granule having an outer coating layer and an inner coating layer. It is a method to control. A related aspect is a method of increasing the amount of time to reach the maximum release rate of topiramate in an in vitro release rate assay by selecting the content and amount of the coating layer outside the granule coating. An alternative embodiment is to modify the content and amount of the outer coating layer of the granule coating so that the time period in which the release rate of topiramate is at its maximum value in an in vitro release rate assay or the figure of the maximum release rate of topiramate. It is a method to adjust.

  The invention further provides that the pharmaceutical substance is selected from a low solubility pharmaceutical substance or a low dissolution rate pharmaceutical substance, wherein the pharmaceutical substance comprises 11% by weight or more of the drug composition, solubilized It relates to a pharmaceutical composition comprising a pharmaceutical substance and a solubilizing substance, wherein the substance is a surfactant and the surfactant comprises about 10% by weight or more of the drug composition.

  The invention further provides that the pharmaceutical substance is selected from a low solubility pharmaceutical substance or a low dissolution rate pharmaceutical substance, wherein the pharmaceutical substance comprises more than 11% by weight of the drug composition, and It relates to a pharmaceutical composition comprising a pharmaceutical substance and a solubilizing substance, wherein the solubilizing substance is a surfactant.

  In one embodiment of the invention, the pharmaceutical substance is selected from a low solubility pharmaceutical substance or a low dissolution rate pharmaceutical substance, and the pharmaceutical substance comprises 11% by weight or more of the drug composition. A pharmaceutical composition comprising a pharmaceutical substance, a solubilizing substance and a structural polymer.

  The invention further relates to a drug composition comprising topiramate and a solubilizing substance. In one embodiment of the invention, topiramate comprises 11% or more by weight of the drug composition. Another aspect of the present invention is a drug composition comprising topiramate, a solubilizing substance and a structural polymer. The solubilizing substance is preferably a surfactant. The solubilizing material preferably comprises about 10% or more by weight of the drug composition.

  In one embodiment of the invention, topiramate comprises 11% or more by weight of the drug composition, the solubilizing material is a surfactant, and the surfactant comprises about 10% or more by weight of the drug composition. A drug composition comprising topiramate and a solubilizing substance.

  One aspect of the present invention is a drug composition wherein the pharmaceutical substance, preferably topiramate, comprises about 20% or more by weight of the drug composition. The pharmaceutical agent, preferably topiramate, preferably comprises about 30% or more of the drug composition, more preferably the pharmaceutical agent, preferably topiramate, comprises about 40% or more of the drug composition. Become.

  Another aspect of the invention is a drug composition wherein the pharmaceutical agent, preferably topiramate, comprises between about 25% to about 55% by weight of the drug composition. The pharmaceutical substance, preferably topiramate, preferably comprises between about 30% and 50% by weight of the drug composition.

  One aspect of the present invention is a drug composition wherein the solubilizing substance is a surfactant. Another aspect of the invention is that the solubilizing material, preferably a surfactant, is about 10% by weight of the drug composition, preferably about 20% by weight of the drug composition, more preferably about 30% by weight of the drug composition. %, Most preferably a drug composition comprising about 40% by weight of the drug composition.

  Another aspect of the invention is a drug composition wherein the solubilizing material, preferably a surfactant, comprises between about 35% and about 55% by weight of the drug composition. The solubilizing material, preferably a surfactant, preferably comprises between about 40% to about 50% by weight of the drug composition.

  In one aspect of the invention, the solubilizing material is in an amount greater than about 5%, more preferably in an amount greater than about 10%, even more preferably in an amount greater than about 17.5%, even more preferably. In an amount greater than about 25%, even more preferably greater than about 30%, even more preferably greater than about 40%, and even more preferably greater than about 42.5%. Even more preferably, it is present in an amount greater than about 45%.

  Another aspect of the invention is a drug composition further comprising a structural polymer. The structural polymer preferably comprises between about 1% and about 90% by weight of the drug composition, and the structural polymer preferably comprises between about 5% and about 75% by weight of the drug composition. More preferably, the structural polymer comprises between about 10% to about 40% by weight of the drug composition.

  The present invention further relates to dosage forms comprising any drug composition or preparation described herein. One aspect of the present invention is a dosage form comprising a drug composition, wherein the drug composition comprises topiramate and a solubilizing substance.

  In one embodiment of the invention, the dosage form is in matrix form. In another aspect of the invention, the dosage form is an osmotic dosage form. In another embodiment of the invention, the dosage form is a controlled release dosage form. The dosage form is preferably an osmotic dosage form, preferably controlled release, for oral administration.

  One aspect of the present invention is a method wherein the pharmaceutical agent is present in an amount ranging from about 1 milligram to about 750 milligrams, preferably from about 5 milligrams to about 250 milligrams, more preferably from about 10 milligrams to about 250 milligrams. A dosage form comprising a drug composition as described in the specification. Another aspect of the present invention provides that the total amount of pharmaceutical agent present in the drug composition is from about 1 milligram to about 750 milligrams, preferably from about 5 milligrams to about 250 milligrams, more preferably about 10 milligrams. A dosage form comprising two drug compositions as described herein, in the range of to about 250 milligrams.

  Another embodiment of the present invention wherein the drug composition comprises topiramate and a solubilizing substance, and the topiramate is about 1 milligram to about 750 milligrams, preferably about 5 milligrams to about 250 milligrams, more preferably about 10 Drug composition present in an amount ranging from milligrams to about 250 milligrams, and even more preferably topiramate is present in an amount selected from 10 mg, 20 mg, 40 mg, 45 mg, 80 mg, 90 mg, 120 mg, 135 mg, 160 mg, 180 mg or 200 mg. A dosage form comprising a product.

  Another aspect of the invention is that each drug composition comprises topiramate and an independently selected solubilizing agent, preferably a surfactant, and the total amount of topiramate comprising the drug composition is from about 1 milligram to about 750 milligrams, preferably in the range of about 5 milligrams to about 250 milligrams, more preferably about 10 milligrams to about 250 milligrams, and even more preferably topiramate is 10 mg, 20 mg, 40 mg, 45 mg, 80 mg, 90 mg, 120 mg, 135 mg , 160 mg, 180 mg or 200 mg, a dosage form comprising two drug compositions present in an amount selected.

  One aspect of the invention comprises (a) a core comprising a push layer comprising a first drug composition and an osmopolymer, (b) a semipermeable wall surrounding the core, and (c) for a long period of time. A dosage form comprising an outlet opening through a semi-permeable wall for releasing the drug composition from the dosage form.

  Another aspect of the present invention is: (a) a core comprising a first drug composition, a second drug composition, and a push layer comprising an osmopolymer; (b) a semi-permeable surrounding the core A dosage form comprising a sex wall and (c) an exit opening through the semi-permeable wall for releasing the drug composition from the dosage form over an extended period of time.

  Another aspect of the present invention comprises (a) a first drug composition, a second drug composition, and a push layer, wherein the first and second drug compositions are topiramate and independently selected. A core comprising a solubilizing substance, (b) a semi-permeable wall surrounding the core, and (c) an outlet opening through the semi-permeable wall for releasing the drug composition from the dosage form over an extended period of time A dosage form comprising

  Another aspect of the present invention provides: (a) a first drug composition comprising a pharmaceutical agent and a solubilizing agent, wherein the pharmaceutical agent is a low solubility pharmaceutical agent or a low dissolution rate agent. A pharmaceutical substance, preferably selected from topiramate, the pharmaceutical substance comprises 11% by weight or more of the drug composition, the solubilizing substance is a surfactant, and the surfactant is about about 1% of the agent composition. A second drug composition comprising a pharmaceutical substance and a solubilizing substance (where the pharmaceutical substance is a low-solubility pharmaceutical substance or a pharmaceutical having a low dissolution rate) Selected from a pharmaceutical substance, the pharmaceutical substance comprises 11% by weight or more of the drug composition, the solubilizing substance is a surfactant, and the surfactant comprises about 10% by weight or more of the drug composition And a core comprising a push layer, (b) a core Outlet opening through the wall and (c) a semi-permeable wall for releasing the drug composition from the dosage form over a prolonged period of time of semipermeable surrounding a comprising a dosage form.

  In one embodiment of the invention, the pharmaceutical substance and the solubilizing substance in the first and second drug compositions are independently selected. Preferably, the pharmaceutical substance in the first and second drug compositions is the same, more preferably the pharmaceutical substance in the first and second drug compositions is topiramate.

  In one embodiment of the invention, the amount and / or concentration of the pharmaceutical substance, preferably topiramate, in the first drug composition is the amount of the pharmaceutical substance, preferably topiramate, in the second drug composition. / Or lower than concentration.

  Another aspect of the present invention is: (a) a core comprising a first drug composition, a second drug composition, and a push layer comprising an osmopolymer; (b) a semi-permeable surrounding the core A dosage form comprising: a sex wall; and (c) an exit opening through the semipermeable wall for releasing the first drug composition and the second drug composition from the dosage form over an extended period of time. Wherein the first drug composition comprises between about 25% to about 40% by weight topiramate and between about 35% to about 50% by weight surfactant and the second drug composition The product comprises between about 30% and about 40% by weight topiramate and between about 45% and about 55% by weight surfactant. In a preferred embodiment of the present invention, the first drug composition further comprises about 10% to about 20% by weight structural polymer, and the second drug composition further comprises between about 0% and about 10% by weight. A structural polymer of Preferably, the first drug composition comprises between about 30% to about 35% by weight topiramate, between about 40% to about 45% by weight surfactant and between about 15% to about 20% by weight structure. A second drug composition comprising between about 40% and about 45% by weight topiramate, between about 46% and about 54% by weight surfactant and between about 0% and about 5% by weight. A structural polymer in between. More preferably, the first drug composition comprises about 32% by weight topiramate, about 42% by weight surfactant and about 16% by weight structural polymer, and the second drug composition has about 43% by weight. % Topiramate, about 50% by weight surfactant and about 0% by weight structural polymer. Preferably, the surfactant in both the first and second drug compositions is LUTROL F127 and the structural polymer in both the first and second drug compositions is POLYOX N180.

  Another aspect of the present invention is: (a) a core comprising a first drug composition, a second drug composition, and a push layer comprising an osmopolymer; (b) a semi-permeable surrounding the core And (c) an exit opening through the semipermeable wall for releasing the first drug composition and the second drug composition from the dosage form over an extended period of time. Wherein the first drug composition comprises between about 1% to about 25% by weight topiramate and between about 1% to 35% by weight surfactant and the second drug composition comprises About 10% to about 25% by weight topiramate and about 10% to 35% by weight surfactant. In a preferred embodiment of the invention, the first drug composition further comprises between about 75% to about 95% by weight structural polymer, and the second drug composition further comprises about 65% to about 80% by weight. A structural polymer in between. Preferably, the first drug composition comprises between about 2% to about 8% by weight topiramate, between about 1% to about 5% by weight surfactant and between about 85% to about 90% by weight structure. A second drug composition comprising between about 10% and about 15% by weight topiramate, between about 10% and about 15% surfactant and between about 70% and about 75% by weight. A structural polymer in between. More preferably, the first drug composition comprises about 5% by weight topiramate, about 2% by weight surfactant and about 89% by weight structural polymer, and the second drug composition has about 12% by weight. % Of the topiramate, about 12% by weight of surfactant and about 72% by weight of the structural polymer. Preferably, the surfactant in both the first and second drug compositions is LUTROL F127 and the structural polymer in both the first and second drug compositions is POLYOX N80.

  In one embodiment of the invention, the push layer comprises an osmopolymer. In another embodiment of the invention, the push layer comprises an osmopolymer and an osmoagent.

  In one embodiment of the invention, the dosage form is over a long period of time, preferably more than 4 hours, more preferably more than about 8 hours, even more preferably more than about 10 hours, most preferably Release the drug over about 14 hours. In another embodiment of the invention, the dosage form releases the drug over a period of time greater than about 14 hours and up to about 24 hours.

  In one embodiment of the invention, the dosage form releases the drug at a substantially ascending release rate. In another embodiment of the invention, the dosage form releases the drug at a substantially ascending release rate. In yet another aspect of the invention, the dosage form releases the drug at a rate that results in a substantially elevated plasma concentration of the drug.

  One aspect of the present invention is a drug composition comprising topiramate, a surfactant, preferably LUTROL F127, and a structural polymer, preferably POLYOX N80, wherein topiramate comprises about 5% by weight of the drug composition. The surfactant comprises about 2% by weight of the drug composition and the structural polymer comprises about 88.7% by weight of the drug composition.

  One embodiment of the present invention is a drug composition comprising topiramate, a surfactant, preferably LUTROL F127, and a structural polymer, preferably POLYOX N80, wherein topiramate comprises about 12% by weight of the drug composition. Wherein the surfactant comprises about 12% by weight of the drug composition and the structural polymer comprises about 71.7% by weight of the drug composition.

  One aspect of the present invention is a drug composition comprising topiramate, a surfactant, preferably LUTROL F127, and a structural polymer, preferably POLYOX N80, wherein topiramate comprises about 32% by weight of the drug composition. The surfactant comprises about 42% by weight of the drug composition and the structural polymer comprises about 16.5% by weight of the drug composition.

  One aspect of the invention is a drug composition comprising topiramate and a surfactant, preferably LUTROL F127, wherein topiramate comprises about 43% by weight of the drug composition, wherein the surfactant is a drug About 49.9% by weight of the composition.

  One aspect of the present invention is a topiramate (wherein topiramate comprises about 5% by weight of the drug composition); a surfactant, preferably LUTROL F127, where the surfactant is about 2% by weight of the drug composition. Structural polymer, preferably POLYOX N80 (where the structural polymer comprises about 88.7% by weight of the drug composition); PVP, preferably PVP K29-32 (where PVP is the drug) Stearic acid (wherein stearic acid comprises about 1% by weight of the drug composition); magnesium stearate (wherein magnesium stearate is about about 1% by weight of the drug composition); And butyl hydroxytoluene (BHT) (where BHT comprises about 0.02% by weight of the drug composition) A drug composition comprising a.

  One aspect of the present invention is topiramate (wherein topiramate comprises about 12% by weight of the drug composition); a surfactant, preferably LUTROL F127, where the surfactant is about 12% by weight of the drug composition. Structural polymer, preferably POLYOX N80 (where the structural polymer comprises about 71.7% by weight of the drug composition); PVP, preferably PVP K29-32 (where PVP is the drug) Stearic acid (wherein stearic acid comprises about 1% by weight of the drug composition); magnesium stearate (wherein magnesium stearate is about about 1% by weight of the drug composition); Iron oxide (wherein iron oxide comprises about 0.02% by weight of the drug composition) and BHT (where BHT is the drug) Comprise from about 0.02% by weight of the composition comprising) a drug composition comprising a.

  One aspect of the present invention is a topiramate (wherein topiramate comprises about 32% by weight of the drug composition); a surfactant, preferably LUTROL F127 (wherein the surfactant is about 42% by weight of the drug composition). Structural polymer, preferably POLYOX N80 (where the structural polymer comprises about 16.5% by weight of the drug composition); PVP, preferably PVP K29-32 (where PVP is the drug) Stearic acid (wherein stearic acid comprises about 1% by weight of the drug composition); magnesium stearate (wherein magnesium stearate is about about 1% by weight of the drug composition); 0.5% by weight); BHT (where BHT comprises about 0.02% by weight of the drug composition) and methylcellulose (wherein Le Cellulose is a drug composition comprising comprising from about 2.5 wt% of the drug composition).

  One embodiment of the invention is topiramate (wherein topiramate comprises about 43% by weight of the drug composition); a surfactant, preferably LUTROL F127 (wherein the surfactant is about 49.% of the drug composition). PVP, preferably PVP K29-32 (where PVP comprises about 3% by weight of the drug composition); stearic acid (wherein stearic acid is about 1% of the drug composition); Magnesium stearate (wherein magnesium stearate comprises about 0.5% by weight of the drug composition); ferric oxide (wherein ferric oxide is of the drug composition) BHT (where BHT comprises about 0.02% by weight of the drug composition) and methylcellulose (wherein methylcellulose is about 2% of the drug composition). A drug composition comprising 5 wt%).

  One aspect of the invention is (a) topiramate, a surfactant, preferably LUTROL F127 and a structural polymer, preferably POLYOX N80, wherein topiramate comprises about 5% by weight of the drug composition, A first drug composition comprising about 2% by weight of the drug composition and the structural polymer comprises about 88.7% by weight of the drug composition; topiramate, surfactant, preferably LUTROL F127 and a structural polymer, preferably POLYOX N80 (wherein topiramate comprises about 12% by weight of the drug composition, the surfactant comprises about 12% by weight of the drug composition, and the structural polymer comprises A second drug composition comprising: about 71.7% by weight of the drug composition; and a push layer A is a dosage form comprising a.

  Another aspect of the invention is (a) topiramate, a surfactant, preferably LUTROL F127, and a structural polymer, preferably POLYOX N80, wherein topiramate comprises about 32% by weight of the drug composition, A first drug composition comprising: about 42% by weight of the drug composition, and the structural polymer comprising about 16.5% by weight of the drug composition; topiramate and a surfactant; A second drug composition comprising preferably LUTROL F127, wherein topiramate comprises about 43% by weight of the drug composition and surfactant comprises about 49.9% by weight of the drug composition A dosage form comprising a core comprising an article; and a push layer.

  Another aspect of the present invention is (a) topiramate (wherein topiramate comprises about 5% by weight of the drug composition), a surfactant, preferably LUTROL F127 (wherein the surfactant is the drug composition). A structural polymer, preferably POLYOX N80 (where the structural polymer comprises about 88.7% by weight of the drug composition), PVP, preferably PVP K29-32 (wherein PVP comprises about 3% by weight of the drug composition), stearic acid (wherein stearic acid comprises about 1% by weight of the drug composition), magnesium stearate (wherein magnesium stearate is the drug composition) A first drug comprising about 0.25% by weight of the product) and BHT (where BHT comprises about 0.02% by weight of the drug composition) Topiramate (wherein topiramate comprises about 12% by weight of the drug composition), a surfactant, preferably LUTROL F127 (wherein the surfactant comprises about 12% by weight of the drug composition) ), A structural polymer, preferably POLYOX N80 (where the structural polymer comprises about 71.7% by weight of the drug composition), PVP, preferably PVP K29-32 (where PVP is about 3% of the drug composition). Stearic acid (wherein stearic acid comprises about 1% by weight of the drug composition), magnesium stearate (wherein magnesium stearate is about 0.25% by weight of the drug composition) Iron oxide (wherein iron oxide comprises about 0.02% by weight of the drug composition) and BHT (where BHT is about 0% of the drug composition). A core comprising: a second drug composition comprising: 02% by weight; and a push layer comprising an osmopolymer; (b) a semipermeable wall surrounding the core; and (c) A) a dosage form comprising an exit opening through a semipermeable wall for releasing the first drug composition and the second drug composition from the dosage form over an extended period of time.

  Another aspect of the present invention is (a) topiramate (wherein topiramate comprises about 32% by weight of the drug composition), a surfactant, preferably LUTROL F127 (wherein the surfactant is the drug composition). A structural polymer, preferably POLYOX N80 (where the structural polymer comprises about 16.5% by weight of the drug composition), PVP, preferably PVP K29-32 (wherein PVP comprises about 3% by weight of the drug composition), stearic acid (wherein stearic acid comprises about 1% by weight of the drug composition), magnesium stearate (wherein magnesium stearate is the drug composition) About 0.5% by weight of the product), BHT (where BHT comprises about 0.02% by weight of the drug composition) and methylcellulose ( A first drug composition comprising: methylcellulose comprising about 2.5% by weight of the drug composition; topiramate, wherein topiramate comprises about 43% by weight of the drug composition; A surfactant, preferably LUTROL F127 (where the surfactant comprises about 49.9% by weight of the drug composition), PVP, preferably PVP K29-32 (where PVP is about 3% of the drug composition). Stearic acid (wherein stearic acid comprises about 1% by weight of the drug composition), magnesium stearate (wherein magnesium stearate is about 0.5% by weight of the drug composition) Iron oxide (wherein iron oxide comprises about 0.08% by weight of the drug composition), BHT (where BHT comprises about 0.02% by weight of the drug composition) And a second drug composition comprising methylcellulose, wherein methylcellulose comprises about 2.5% by weight of the drug composition; and a push layer comprising an osmopolymer, b) a semi-permeable wall surrounding the core and (c) an exit opening through the semi-permeable wall for releasing the first drug composition and the second drug composition from the dosage form over time. A dosage form comprising

  One aspect of the present invention includes epilepsy, migraine, glaucoma and other ophthalmology comprising administering any of the drug compositions or dosage forms described herein to a subject in need of treatment. Disorders (including diabetic retinopathy), essential tremor, restless limb syndrome, obesity, weight loss, type II diabetes, syndrome X, impaired oral glucose tolerance, diabetic skin damage, cluster headache , Neuralgia, neuropathic pain (including diabetic neuropathy), high blood sugar level, hypertension, high lipid, bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, OCD, PTSD, ADHD, Impulsive dysregulation (including bulimia, binge eating, substance dependence, etc.), ALS, asthma, autism, Treating a disorder selected from the group consisting of autoimmune disorders (including psoriasis, rheumatoid arthritis, etc.), chronic neurodegenerative disorders, acute neurodegeneration, sleep apnea and other sleep disorders and / or wound healing Is a way to promote.

  The disorder preferably consists of epilepsy, migraine, diabetic retinopathy, diabetic neuropathy, diabetic skin injury, obesity, weight loss, type II diabetes, syndrome X, impaired oral glucose tolerance, high blood sugar level and hypertension Selected from the group.

Detailed Description of the Invention
The terminology is best understood by reference to the following definitions, drawings and description provided herein.

  In order to provide a more accurate description, some quantitative displays given herein are not qualified with the term “about”. Whether or not the term “about” is used exclusively, it is meant that all amounts given herein actually represent the given value, which is further to such given value. It is understood that it is also meant to represent an approximate value for such a given value that would be reasonably inferred based on the art, including an approximate value from experimental and / or measurement conditions.

  The expressions “exit”, “exit opening” and “delivery outlet” shall mean an opening in the dosage form that allows the drug to drain the dosage form. Suitable examples include, but are not limited to, pathways, apertures, orifices and holes. The expression also includes openings formed or formable from materials or polymers that erode, dissolve or leach from the outer wall, thereby forming an outlet opening.

  By “dosage form” is meant a pharmaceutical composition or device capable of delivering a pharmaceutical substance. Suitable examples of dosage forms include, but are not limited to, tablets, capsules, gel-capsules, matrix forms, osmotic forms, immediate release forms, controlled release forms, sustained release forms, extended release forms, etc. Is included. Similarly, the term “tablet core” shall mean any drug composition or preparation comprising that portion of a dosage form comprising a therapeutic or pharmaceutical substance. The tablet core can be incorporated into any suitable dosage form including, but not limited to, tablets, capsules, gelcaps and the like. In addition, the tablet core can optionally be partially or wholly surrounded by an outer layer, such as a semipermeable membrane wall, a hard shell capsule, or the like. The tablet core can be further compressed or constructed by filling or the like.

  The terms “drug composition” and “drug formulation” as used herein shall mean a preparation comprising at least one pharmaceutical substance, unless otherwise specified. The drug composition preferably comprises a pharmaceutical substance and a solubilizing substance, preferably a surfactant, more preferably a solubilizing surfactant. The drug composition more preferably comprises a pharmaceutical substance, a solubilizing substance, preferably a surfactant and a structural polymer. The drug composition optionally further comprises one or more inert ingredients, such as disintegrants, binders, diluents, lubricants, stabilizers, antioxidants, penetrants, colorants, plasticizers, coatings, etc. Such pharmaceutically acceptable excipients can be included.

  As used herein, the term “push layer”, unless stated otherwise, shall mean a preparation that does not contain a pharmaceutical substance and comprises an osmopolymer. The push layer preferably comprises an osmopolymer and an osmoagent. The push layer further optionally contains one or more inert ingredients such as disintegrants, binders, diluents, lubricants, stabilizers, antioxidants, penetrants, colorants, plasticizers, coatings, etc. Can be contained. Similarly, the term “osmotic delivery system” refers to any means for delivering a therapeutic or pharmaceutical substance that utilizes an osmotic gradient to achieve such delivery, such as extrusion as described above. Let's mean layer.

  The terms “pharmaceutical substance”, “therapeutic agent”, “therapeutic substance”, “drug compound”, and “drug” as used herein, unless otherwise stated, are pharmaceutical substances, drugs, compounds, pharmaceuticals. It shall mean a pharmaceutically acceptable salt, prodrug or derivative thereof. The pharmaceutical substance or drug is preferably a pharmaceutical substance with low solubility and / or low dissolution rate. More preferably, the pharmaceutical substance is topiramate.

  The term “pharmaceutically acceptable salt” as used herein, unless stated otherwise, does not significantly contribute to the toxicity or pharmacological activity of the salt and therefore they are compounds. Any salt that is a pharmacological equivalent of the acid or base of Suitable pharmaceutically acceptable salts include suitable pharmaceutically acceptable salts such as, for example, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. An acid addition salt that can be formed by reacting an acceptable acid with a drug compound; and an alkali metal salt that can also be prepared by reacting the drug compound with a suitable pharmaceutically acceptable base; Base addition salts include, for example, sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts formed with suitable organic ligands such as quaternary ammonium salts.

  Thus, representative pharmaceutically acceptable salts include, but are not limited to: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, vital tartrate, borate, bromide, calcium edetate, camsylate , Carbonate, chloride, clavulanate, cytolate, dihydrochloride, edetate, edicylate, estrate, esylate, fumarate, glucoceptate, gluconate, glutamate, glycolylarsanilate, hexyl resorcinate, hydrabamine, hydrobromide, hydro Chloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl Romide, methyl nitrate, methyl sulfate, mucate, napsilate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalactronate, salicylate, stear Included are rate, sulfate, subacetate, succinate, tannate, tartrate, theocrate, tosylate, triethiodide and valerate.

  Representative acids and bases that can be used in the preparation of pharmaceutically acceptable salts are: acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-asparagine Acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S) -camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, Cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-glucone Acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrogen bromide , Hydrochloric acid, (+)-L-lactic acid, (±) -DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid, (±) -DL-mandelic acid, Methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid , L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid Acids; and ammonia, L-arginine, venesamine, benzathine, calcium hydroxide, choline, deanol, diethano Ruamine, diethylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4- (2-hydroxyethyl) -morpholine, piperazine, Bases including potassium hydroxide, 1- (2-hydroxyethyl) -pyrrolidine, secondary amines, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

  The term “low solubility” as used herein refers to about 100 mg of neat pharmaceutical substance (in the absence of a surfactant or other excipient) in deionized water at 37 ° C. It is meant to indicate a solubility of less than / ml. The low solubility is preferably less than about 50 mg / ml, more preferably less than about 25 mg / ml, even more preferably less than about 15 mg / ml, even more preferably less than about 10 mg / ml, even more preferably about It shall mean a solubility of less than 5 mg / ml, most preferably less than about 1 mg / ml. Thus, similarly, the term “low solubility” when used to characterize a drug shall mean a drug that exhibits low solubility as defined herein.

  The solubility of a pharmaceutical substance, as defined herein, is defined as a pharmaceutical product in agitated or stirred deionized water maintained in a constant temperature bath at a temperature of 37 ° C. until the pharmaceutical substance is no longer dissolved. It is determined by adding the target substance. The resulting solution saturated with the pharmaceutical substance is then filtered under pressure, typically through a 0.8-micron Millipore filter, and the concentration of the pharmaceutical substance in the solution is determined gravimetrically, ultraviolet light It is measured by any suitable analytical method, including spectroscopic analysis, chromatography, and the like. The solubility of the pharmaceutical substance is measured at equilibrium.

The term “low dissolution rate” as used herein means that the dissolution rate of a pharmaceutical substance under a constant surface area (ie the rate at which the pharmaceutical substance dissolves in deionized water at 37 ° C.) is 0 mg / min. / Cm ² to about 20 mg / min / cm ² , preferably about 0.1 mg / min / cm ² to about 10 mg / min / cm ² , more preferably about 0.1 mg / min / cm ² to about Between 5 mg / min / cm ² , even more preferably between about 0.1 mg / min / cm ² and about 2 mg / min / cm ² , even more preferably between about 0.1 mg / min / cm ² and about 1. It shall mean between 5 mg / min / cm ² , most preferably between about 0.1 mg / min / cm ² and about 1.25 mg / min / cm ² .

  The dissolution rate of the pharmaceutical substance as defined herein is USP 26, NF21, p. 2333.

  Suitable examples of low solubility pharmaceutical substances (ie those having a solubility in deionized water of 37 ° C. of less than about 100 mg / ml) include, but are not limited to, itraconazole, loratadine, thioridazine, thiethylperazine, ketoconazole, terfenadine , Tretinoin, methodirazine, buprenorphine, thiothixene, simvastatin, indomethacin, domperidone, erythromycin, vitamin B, levonorgestrel, lovastatin, nicardipine, diclofenac, chlorpromazine, estradiol, digitoxin, riosilonine, glyburide, droperidol , Lindan, Flurbiprofen, Oxaprozin, Progesterone, Pimozide, Methi Lothiazide, ethinyl estradiol, finasteride, clozapine, haloperidol, diflunisal, procloperazine, warfarin, imipramine, felodipine, mefenamic acid, methotrimeprazine, ibuprofen, spironolactone, nimodipine, biperidene, perphenazine, fluphenazine, pyridogine, pyridogazine, methyltestosterone Metoxalene, diazepam, penicillin, ketoprofen, nifedipine, etoposide, metolazone, digoxin, betamethasone, fluoxime esterone, nabumetone, reserpine, furosemide, sulfadiazine, nitrendipine, nitrofurantoin, rolazepam, triamcinolone, omeprazole, dexametron Ndroflumethiazide, chlorthalidone, methylprednisolone, pyrimethamine, flumazenil, tetracaine, fludrocortisone, quinidine, morphine, temazepam, oxazepam, epinephrine, fentanyl, cefazoline, prednisolone, tetracycline, chlorpropamide, chlorothiazidopreza, , Hydrocortisone, nystatin, phenazopyridine, trimethoprim, fenfluamine, isosorbide dinitrate, allopurinol, sulfamethoxazole, doxycycline, hydrochlorothiazide, amphotericin B, diphenoxylate, trichlormethiazide, zidovudine, famotidine, Etc.

  The low solubility pharmaceutical agent is preferably (but not) other than phenytoin. Pharmaceutical agents with low solubility are preferably other than phenytoin and carbamazepine. The low-solubility pharmaceutical substance is preferably phenytoin, mephenytoin, phenobarbital, primidone, carbamazepine, ethosuximide, methosuximide, fencesuximide, trimetadione, clonal adipam, chlorazepate, phenazemide, parameterdione, primoclon, clobazam, felbamate, Other than flunarizine, lamotrigine, progabide, vivabatim, eterobulb, gabapentin, oxycarbozepine, laritrin, thiagobin, sulthyme and thioridone.

  The low solubility and / or low dissolution rate pharmaceutical agent is in the range of about 1 milligram to about 750 milligrams, preferably in the range of about 5 mg to about 250 mg, more preferably in the range of about 10 mg to about 250 mg. The amount can be incorporated into the pharmaceutical composition and / or dosage form of the present invention.

  “Immediate release dosage form” refers to a dosage form that releases about 80% or more of the pharmaceutical substance within about one hour.

  By “sustained release” is meant a continuous release of a pharmaceutical substance over an extended period of time.

  By “controlled release” is meant a continuous release of a pharmaceutical substance over an extended period of time, where the pharmaceutical substance is released at a controlled rate over a controlled period of time.

  By “long term”, more than about 1 hour, preferably more than about 4 hours, more preferably more than about 8 hours, more preferably more than about 10 hours, even more preferably more than about 14 hours, Most preferably, it means a continuous period of more than about 14 hours and up to about 24 hours.

  As used herein, the “release rate” or “release rate” of a drug is the amount of drug released from the dosage form per unit time, eg, milligrams of drug released per hour (unless otherwise stated). mg / hr). The drug release rate for a dosage form is typically in vitro drug release rate, ie, the amount of drug released from the dosage form per unit time, measured under appropriate conditions and in a suitable fluid, As measured.

  The release rate referred to herein places the dosage form to be tested in deionized water in a metal coil or metal cage sample holder attached to a USP type VII bath indexer in a 37 ° C. constant temperature water bath. Is determined by Next, an aliquot of the release rate measurement solution collected at pre-set intervals is chromatographed with an ultraviolet or refractive index detector to quantify the amount of drug released during the test period. Inject into the system. Thus, the above method is an example of an in vitro release rate assay.

As used herein, the drug release rate obtained at a particular time represents the in vitro release rate obtained at a particular time after performing the release rate test. The point in time at which a certain percentage of the drug in the dosage form is released from the dosage form is expressed as a “T _x ” value, where “x” is the percentage of drug released. For example, a commonly used reference measurement for assessing drug release from a dosage form is the point at which 70% of the drug in the dosage form has been released. This measurement is referred to as the “T ₇₀ ” of the dosage form. _T70 is preferably about 8 hours or more, more preferably _T70 is about 12 hours or more, even more preferably _T70 is about 16 hours or more, and most preferably _T70 is about 20 hours or more. _T70 is preferably less than about 24 hours, more preferably _T70 is less than about 20 hours.

By “C” is meant the drug concentration in the subject's plasma or serum, generally expressed as mass per unit volume, typically nanograms per milliliter. Conveniently, this concentration is intended herein to encompass the drug concentration measured in any suitable body fluid or tissue, as used herein “drug plasma concentration”, “plasma drug concentration” or “plasma It can be called “concentration”. Plasma drug concentration at any time after drug administration is referred to as C _time , such as C _{9 hours} or C _{24 hours} , etc.

A “steady state” as used herein when used in representing drug plasma concentrations of a pharmaceutical substance is the [C _max -C _min ] / C _average (ie, 24 hours after administration) Assuming that the quotient formed by the variation in the plasma concentration of the drug is about 3 or less, preferably about 2 or less, more preferably about 1 or less, about 5 ng / ml to about 500 ng / ml, preferably about 25 ng / ml It shall mean a plasma drug concentration in the range of ml to about 250 ng / ml.

  Those skilled in the art will recognize that plasma drug concentrations obtained in individual subjects will vary due to patient-to-patient variability in a number of parameters that affect drug absorption, distribution, metabolism and excretion. Let's go. For this reason, unless otherwise stated, when listing drug plasma concentrations, the values listed are average values calculated based on values obtained from the group of subjects being tested.

  The term “zero timed release rate” as used herein means, unless otherwise stated, the rate of release at which the amount of drug released as a function of time is substantially constant. . More particularly, the release of drug as a function of time if the measurement is collected over a time period where the cumulative release is between about 25% and about 75%, preferably between about 25% and about 90%. The rate will vary by less than about 30%, preferably less than about 20%, more preferably less than about 10%, and most preferably less than about 5%.

  The term “ascending release rate” as used herein means that unless otherwise stated, the amount of drug released as a function of time increases over time, preferably continuously and gradually. It shall mean the rate of release. The amount of drug released as a function of time is preferably increased (not stepwise) in a uniform manner. More preferably, the increasing rate of release can have the following characteristics: The release rate as a function of time for the dosage form is measured and plotted as% drug release over time or as milligrams of released drug per hour over time. The ascending release rate is such that the rate within a given 2 hour span is about 2 hours to about 12 hours, preferably about 2 hours to about 18 hours, more preferably about 4 hours to about 12 hours, even more. Characterized by the average rate (expressed in mg / hour of drug), preferably over a period of about 4 hours to about 18 hours, compared to the previous 2 hour span. The increase in average rate is preferably gradual so that less than about 30% of the dose is delivered during any 2 hours, and more preferably less than about 25% of the dose is delivered during any 2 hours. The increasing release rate is preferably maintained until at least about 50%, more preferably at least about 75% of the drug in the dosage form is released.

  Those skilled in the art will inevitably reduce the total time that the drug is released from the dosage form as the increase in area under the curve increases (eg, from 1% to 10%), and thus the determination of the increased release rate is It will be appreciated that it will take a shorter total time.

  As used herein, the term “ascending drug plasma concentration” refers to an increase in the profile to a maximum concentration that is greater than about 6 hours after the first dose, preferably after the first dose. It shall mean a profile of drug plasma concentration over the first about 24 hours after the first dose, which occurs over about 8 hours, more preferably over about 12 hours after administration.

  “High dose” when referring to a drug composition means that the pharmaceutical substance, preferably topiramate, is greater than or equal to about 20% by weight of the total drug composition, preferably greater than or equal to about 30%, more preferably greater than or equal to about It shall mean a drug composition present in an amount of 40% by weight or more.

  “High dose” when referring to a dosage form means that the pharmaceutical substance, preferably topiramate, is about 20% or more, preferably about 30% or more, of the drug composition in the dosage form, More preferably, it means a dosage form present in an amount of about 40% by weight or more.

  The term “therapeutically effective amount” as used herein refers to a tissue system sought by a researcher, veterinarian, physician or other clinician that encompasses alleviation of symptoms of the disease or disorder being treated. Means the amount of a pharmaceutical substance that elicits a biological or pharmaceutical response in an animal or human.

  The term “subject” as used herein refers to an animal, preferably a mammal, most preferably a human, that has been the subject of treatment, observation or experiment.

The term “structural polymer” as used herein, unless otherwise stated, is water-absorbable, can increase the viscosity of the drug composition, and / or can impart osmotic activity to the drug composition and It shall mean any ingredient that can act as a suspending material for the drug composition, for example a polymer or a sugar. Suitable examples of the structural polymer, but are not limited to, polyethylene oxide ^{(POLYOX (R) N80; POLYOX} (R) N10; POLYOX N750, such as etc.) 100,000～750,000 encompassing the Between polyalkylene oxide polymers; polymethylene oxide, polybutylene oxide and polyhexylene oxide and poly (alkali carboxymethyl cellulose), poly (sodium carboxymethyl cellulose), poly (potassium carboxymethyl cellulose) poly (lithium carboxymethyl cellulose), etc. Representative are poly (carboxymethylcellulose) having a number average molecular weight of 40,000 to 400,000. Suitable examples are also sugars such as, but not limited to, maltodextrins (such as MALTRIN M040, MALTRIN M100, MALTRIN M150, MALTRIN M200, MALTRIN M250, etc.); lactose, glucose, raffinose, sucrose, mannitol And sugars comprising sorbitol and the like. Suitable examples also include, but are not limited to, polyvinylpyrrolidone (PVP) (PVP such as grade 12PF or K2932); hydroxypropylcellulose; hydroxypropylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylbutylcellulose, hydroxypropyl Included are 9200-125,000 average molecular weight hydroxypropylalkylcellulose represented by pentylcellulose, etc .; polyvinyl pyrrolidone vinyl acetate copolymer; and poly (vinyl pyrrolidone) having an average molecular weight up to 1,000,000. The structural polymer is preferably a polymer of polyethylene oxide with a molecular weight between 100,000 and 300,000. Structural polymer more preferably ^{POLYOX (R)} N80.

  The structural polymer is preferably selected from MALTRIN M100, POLYOX N10 and POLYOX N80, more preferably the structural polymer is POLYOX N80.

  As used herein, the term “solubilizing substance”, unless stated otherwise, shall mean any ingredient that increases the solubility and / or dissolution rate of a pharmaceutical substance. The solubilizing substance is preferably a surfactant. Suitable examples of solubilizing materials include, but are not limited to, polyethylene glycol (PEG) 3350, polyethylene glycol 8K and, but are not limited to, KOLLIDON K90, KOLLIDON 12PF, KOLLIDON 17PF, KOLLIDON 25/30; LUTROL Surfactants including F68, LUTROL F87, LUTROL F127, LUTROL F108; MYRJ52, MYRJ53; PVP K2939, etc. are included. Further preferred surfactants include, but are not limited to, sorbitan monopalmitate, sorbitan monostearate, glycerol monostearate, polyoxyethylene stearate, sucrose cocoate, polyoxyethylene 40 sorbitol lanolin derivative, poly Oxyethylene 75 sorbitol lanolin derivative, polyoxyethylene 6 sorbitol beeswax derivative, polyoxyethylene 20 sorbitol beeswax derivative, polyoxyethylene 20 sorbitol lanolin derivative, polyoxyethylene 50 sorbitol lanolin derivative, polyoxyethylene 23 lauryl ether, butyl as preservative Hydroxyanisole and citric acid added polyoxyethylene 23 lauryl ether, butylated hydroxyaniso as preservative And polyoxyethylene 2-cetyl ether, polyoxyethylene 2-stearyl ether, polyoxyethylene 21 stearyl ether, polyoxyethylene 100 stearyl ether, butylated hydroxyanisole and citric acid as preservatives Polyoxyethylene 10 cetyl ether, polyoxyethylene 20 cetyl ether with butylated hydroxyanisole and citric acid added as preservative, polyoxyethylene 2-stearyl ether with butylated hydroxyanisole and citric acid added as preservative, storage Polyoxyethylene 10 stearyl ether with butylated hydroxyanisole and citric acid added as preservatives, butylated hydroxyanisole and citric acid as preservatives Polyoxyethylene 20 stearyl ether, polyoxyethylene 21 stearyl ether with butylated hydroxyanisole and citric acid added as preservatives, polyoxyethylene 20 oleyl ether with butylated hydroxyanisole and citric acid added as preservatives, poly Oxyethylene 40 stearate, polyoxyethylene 50 stearate, polyoxyethylene 100 stearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, polyoxyethylene 4 sorbitan monostearate, polyoxyethylene 20 sorbitan tri Stearate.

The solubilizing material is more preferably a surface activity selected from the group of copolymers of ethylene oxide and propylene oxide according to the general formula OH (C ₂ H ₄ O) _a (C ₃ H ₆ O) _b (C ₂ H ₄ O) H It is an agent. Even more preferably, the surfactant is selected from the group consisting of LUTROL F68, LUTROL F87, LUTROL 108, LUTROL F127, MYRJ52, MYRJ53; most preferably the surfactant is LUTROL F127.

As used herein, the term “osmopolymer” refers to an expandable hydrophilic polymer that interacts with water and highly swells or expands, typically exhibiting a 2-50 fold increase in volume, unless otherwise noted. Means. Suitable examples include, but are not limited to, poly (alkylene oxide) having a number average molecular weight of 1 to 15 million, as represented by poly (ethylene oxide), the alkali of which is sodium, potassium or lithium 500 the number average molecular weight of the poly (alkali carboxymethylcellulose) of 000~3,500,000; CARBOPOL ^(R) acid carboxymethyl polymer, carboxymethyl polyallyl sucrose and crosslinked acrylic also known as polymethylene polymer and 250,000 polymers to form a hydrogel, such as carboxyvinyl polymers having a molecular weight of ~4,000,000; CYANAMER ^(R) polyacrylamide; crosslinked water-swellable indene maleic anhydride polymers; 80,000～200, GOOD-RITE having a molecular weight of 00 ^(R) polyacrylic acid; consisting condensation glucose units such as diester cross-linked Porigururan AQUA-KEEPS ^(R) acrylate polymers polysaccharides; and the like.

  As used herein, the terms “osmoagent”, “osmotic substance” and “osmotic active substance” shall mean a substance that exhibits an osmotic activity gradient through a semipermeable membrane unless otherwise stated. Suitable osmoagents include but are not limited to sodium chloride, potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium phosphate, mannitol, urea, inositol, succinic acid Magnesium, tartaric acid, raffinose, sucrose, glucose, lactose, sorbitol, inorganic salts, organic salts, carbohydrates, and the like are included.

  Throughout this specification, the chemical names and trade names / trademarks of preferred surfactants and structural polymers can be used interchangeably. For clarity, the following is a list of chemical names and corresponding trade names / trademarks of the surfactants and structural polymers.

  As used herein, the term “hydrophilic polymer” shall mean any polymer that has an affinity for water, unless otherwise specified. The affinity polymer may be water-soluble or water-insoluble.

  Suitable examples of water-soluble hydrophilic polymers include, but are not limited to, polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, vinyl acetate-vinyl pyrrolidone copolymer, hydroxypropyl. Includes cellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinyl acetate polyethylene glycol copolymer, starch, maltodextrin, sugar, sorbitol, mannitol, sucrose, gelatin, casein, natural rubber, alginate, etc. Is done. The water-soluble hydrophilic polymer is preferably methylcellulose.

  Suitable examples of water insoluble hydrophilic polymers include, but are not limited to, polyethers, polyesters, cellulose acetates, cellulose acetate butyrate and polyacrylates. In another embodiment, the coated granules therein are further selected from the group consisting of polyethylene glycol, polyoxyethylene-polyoxypropylene copolymer, hydroxypropyl cellulose, glycerin, citrate, dibutyl sebacate, and the like. It is a drug formulation comprising a compound.

  Preferred hydrophilic polymers include polyethers such as methyl cellulose or ethyl cellulose; polyesters such as polyvinyl acetate; polyacrylates such as ethyl acrylate-methyl methacrylate copolymers; citrate esters such as triethyl citrate or acetyl triethyl citrate Polyethylene oxide and polyvinylpyrrolidone (PVP) are included.

  In the present invention, when the granule coating is composed of a plurality of layers (ie, two or more layers), the composition of each layer is independently selected and may be the same or different.

  The granule coating is preferably a single layer. The granule coating is more preferably a monolayer of methylcellulose.

Drug formulation OROS ^(R) Push-Pull ^TM system, to promote dissolution of poorly soluble drugs in the system, provides a high concentration of surface active agent to provide the desired delivery pattern. When a drug tablet prepared with a high loading of a low solubility drug absorbs water, the membrane of the system ruptures when the push layer compresses the large drug layer mass. Incorporating a surfactant into the drug layer dissolves a sufficient percentage of the drug so that the drug layer can be smoothly extruded through a relatively small delivery outlet.

  Although delivery systems comprising high concentrations of solubilizing substances, preferably surfactants, function very effectively and can be easily processed by manual compression, these systems are capable of high-power compression (high- It is difficult to manufacture in a speed power compression. This is because the drug layer granules containing a high concentration of solubilizing material, preferably a surfactant, are pasty and tend to adhere to the tablet press. During high speed tableting, the adhered material may peel off, resulting in loss of control over the tablet layer weight and tablet layer composition. FIG. 1 illustrates the adhesion problem of a typical preparation comprising a drug and a solubilizing substance, preferably a surfactant, during power compression. The phenomenon observed during compression is essentially explained as the deposition of the granulated material on the turret of the tablet press. Frictional forces that occur during compression result in the continuous formation of deposits on the turret, which results in stopping operation in less than 15 minutes of travel time.

  Adhesion affects the relative weight of the tablet core composition and concomitantly loses the ability to control the composition and structure of the compressed product.

  The present invention addresses the problems associated with the compression of drug compositions comprising pharmaceutical substances, preferably topiramate and solubilizing substances, preferably surfactants. The specificity of the drug / surfactant combination used in drug granulation requires granule protection to avoid sticking during compression. The approach described in the present invention is based on the encapsulation of granules with a polymer film. The present invention provides a method for producing a drug / surfactant composition that can be formulated into tablets under power compression without adhesion.

  The surface of the tablet press during power compression of the topiramate / LUTROL F127 composition was clean with no deposits. This preparation was in the form of coated granules. The coated granules were fully compressed at high speed with minimal or no adhesion.

  Film properties important to the present invention are plasticity and strength. The present invention provides a method for producing a drug / solubilizing material, preferably a drug / surfactant composition, that can be prepared into a tablet under power compression without adhesion.

  One aspect of the present invention comprises a tablet core formed by mechanical compression, wherein a solubilizing material (preferably a surfactant) or a drug or both are in a coated granule) Preferably, it is a drug formulation comprising a surfactant and a low solubility therapeutic agent, preferably topiramate.

Dosage forms according to the present invention are formulated by standard techniques. For example, the dosage form is formulated by wet granulation. In the wet granulation method, the drug and solubilizing material, preferably a surfactant, are blended using an organic solvent such as denatured anhydrous ethanol as the granulation liquid. The remaining ingredients can be dissolved in a portion of the granulation liquid, such as the solvent described above, and this latter prepared solution is slowly added to the drug blend with continuous mixing in the blender. The granulation liquid is added until a wet blend is formed, and then the wet mass blend is forced through a predetermined screen on an oven tray. The blend is dried in a forced air oven at 24 ° C to 35 ° C for 18-24 hours. The dried granules are then sized. Next, magnesium stearate or another suitable lubricant is added to the drug granules and the granules are placed in a milling jar and mixed on a jar mill for up to 10 minutes. The composition e.g., compressed into a layer by Manesty ^(R) press or Korsch LCT during pressing. For a bilayer core, the drug-containing layer is pressed and compressed against the drug-containing layer if a similarly prepared wet blend of the push layer composition is included. Medium compression, typically with a force of about 50-100 Newtons. The final stage of compression is typically performed at a force of 3500 Newtons or more, often 3500-5000 Newtons. Monolayer or a compressed core of a two-layer dry coater press, supplied to, for example, Kilian ^(R) Dry Coater press, and then coated with the wall materials as described above. For cores formulated with a push layer and two or more drug layers, a similar method is typically used on a Korsch multilayer press.

  The present invention also comprises a solubilizing substance, preferably a surfactant and a low solubility therapeutic agent, in which the solubilizing substance (preferably surfactant) or drug or both are present in the coated granules. Includes a drug formulation comprising a core of a capsule consisting of a semipermeable membrane filled with a mixture.

  The coated granules can contain a solubilizing substance (preferably a surfactant) alone, a drug alone or a mixture of a drug and a solubilizing substance (preferably a surfactant). The coated granules can contain other ingredients. These can include viscous materials, binding materials or permeable materials.

  The granule coating may be continuous or discontinuous. The coating can be water soluble. For example, the coating of granules is polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, vinyl acetate-vinyl pyrrolidone copolymer, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose. , Calcium carboxymethyl cellulose, polyvinyl acetate polyethylene glycol copolymer, starch, maltodextrin, sugar, sorbitol, mannitol, sucrose, gelatin, casein, natural gum, alginate and mixtures thereof. . Alternatively, the granule coating can be water insoluble. For example, the granule coating is a group consisting of polyether (eg, ethyl cellulose), polyester (eg, polyvinyl acetate), cellulose acetate, cellulose acetate butyrate, polyacrylate (eg, ethyl acrylate-methyl methacrylate copolymer) and mixtures thereof. It can consist of a compound selected from Further, the granule coating consists of polyethylene glycol, polyoxyethylene-polyoxypropylene copolymer, hydroxypropylcellulose, glycerin, citrate (eg, triethyl citrate or acetyl triethyl citrate or dibutyl sebacate) or mixtures thereof. be able to.

  The granule coating may be a single layer or multiple layers.

  In the case of a single layer, the coating preferably consists of polyvinylpyrrolidone or polyethylene oxide. The monolayer coating can be between about 1% to about 3% of the granule weight or about 24% of the granule weight, depending on the specificity selected for the dosage form.

  If the coating is multilayer, the coating preferably consists of two layers. For example, the coating can preferably consist of an outer coating layer of methylcellulose and an inner coating layer of polyethylene oxide or polyvinylpyrrolidone.

  As described in the following section, the drug formulation is included as a component in a dosage form in which the granules coated therein contain a therapeutic agent, preferably topiramate, preferably as a dosage form of topiramate. Can do.

  If the drug is present at a high dosage, exceeding 20% by weight of the drug layer, the present invention may provide beneficial increased solubility of the low solubility drug resulting in the formation of a deliverable drug layer. it can. Furthermore, the present invention can provide possible beneficial increased bioavailability of low solubility drugs by increasing its solubility and moist surface for greater bioadhesion to the gastrointestinal mucosa. . The wetting properties of the solubilizing material, preferably a surfactant, also prevent the released drug and hydrogel carrier from aggregating, thereby increasing the rate and extent of the drug that its increased surface area is absorbed. And can have the effect of providing a more complete diffusion of the drug composition dispensed onto the resorbable surface of the gastrointestinal tract, providing a wider absorbent surface area to promote a therapeutic response. Further, the solubilizing material, preferably a surfactant, can provide adhesion to the dispersed drug / hydrogel, which extends the time for the drug / hydrogel to contact the absorbable mucosal tissue of the gastrointestinal tract. Thus, additional time can be given for the drug to be diffused thereon and absorbed once it has been delivered. In yet another possible effective effect, the solubilizing agent, preferably a surfactant, further increases the permeability of the mucosa to the drug molecule, and its enhanced permeability also increases the biological activity of the drug. Can provide availability and increased therapeutic response.

  When the drug of the present invention is present at a low dose of less than 20% of the drug layer, the present invention has increased wet and mucosal surfaces due to its solubility and stronger bioadhesion to the gastrointestinal mucosa Increasing permeability can provide beneficial increased bioavailability of low solubility drugs. Increased drug solubility, increased surface contact area on mucosal tissue, increased contact time to mucosal tissue, and increased permeability of mucosal tissue to drug molecules, individually or collectively, provide overall treatment of the drug according to the present invention It can contribute to promotion.

  The drug is exemplified herein by the use of topiramate, which is poorly soluble and needs to be delivered therapeutically in large quantities. Topiramate falls within the therapeutic category of anticonvulsants, although it may be therapeutic for other applications as well.

  The solubility of undoped topiramate was determined to be 13 mg / ml in deionized water at 37 degrees Celsius.

Topiramate dosage forms Another invention in which the core comprises a solubilizing substance, preferably a surfactant and topiramate, and the solubilizing substance (preferably a surfactant) or topiramate or both are coated. A dosage form for oral administration of topiramate, comprising a tablet core formulated by mechanical compression in a granule.

  One aspect of the present invention is an osmotic delivery system (e.g., a push layer) wherein the osmotic delivery system and tablet core are surrounded by a semipermeable membrane having a delivery port through the membrane and topiramate administration further comprising It is a form.

  Alternatively, the tablet core can be incorporated into a matrix delivery system. The matrix system can be either an erodible matrix delivery system or a non-erodible matrix delivery system.

  When the present invention is used in an erodible matrix application, the erodible matrix morphology further comprises a structural polymer in which the molecular weight of the structural polymer is selected to modify the erosion rate of the system. High molecular weight polymers are used to provide a slow erosion rate and slow delivery of the drug, while low molecular weight polymers provide a faster erosion rate and faster release of the drug. A blend of high and low molecular weight structural polymers provides an intermediate delivery rate.

  When the present invention is used in a non-erodible porous matrix, the non-erodible matrix form is further selected such that the molecular weight of the structural polymer provides a hydrogel having viscosity in the pores of the matrix. Comprising. This viscosity suspends the drug particles and facilitates partial or complete dissolution of the drug in the presence of a solubilizing substance, preferably a surfactant, prior to delivery from the pores of the dosage.

  The invention further relates to a topiramate dosage form that is a controlled release topiramate dosage form.

  In one embodiment, the controlled release topiramate dosage form comprises a push layer (one type of osmotic delivery system) and a semipermeable wall disposed over at least a portion of the push layer.

Sustained or controlled release dosage forms can be prepared as osmotic dosage forms. The osmotic dosage form has a driving force to absorb fluid into a compartment formed by a semipermeable wall that at least partially allows free diffusion of water but does not allow diffusion of drugs or other components. Utilizes osmotic pressure to form An important advantage over osmotic systems is that the operation is pH-dependent, so that even if the dosage form passes through the gastrointestinal tract and encounters different microenvironments with significantly different pH values, To continue at an osmotically determined rate. A discussion of such dosage forms can be found in Santus and Baker, “Osmotic drug delivery: a review of the patent literature (Osmotic drug delivery: review of patent literature),” Journal of Controlled 21 ( Release 35, Journal 19). Which is incorporated herein by reference in its entirety. In particular, the following U.S. Pat. Nos. 3,845,770, 3,916,899, 3,995,631, 4,008,719, owned by ALZA Corporation, the assignee of this application, No. 4,111,202, No. 4,160,020, No. 4,327,725, No. 4,519,801, No. 4,578,075, No. 4,681,583, No. 5 , 019,397 and 5,156,850 were directed to osmotic dosage forms. Such osmotic dosage forms generally comprise a drug layer, an optional push layer, a drug and push layer, and a semipermeable membrane including one or more outlet openings.

  Within the aqueous environment of the gastrointestinal (GI) tract, water is absorbed through the semipermeable membrane of the osmotic dosage form at a controlled rate. This swells the push layer and hydrates the drug composition or compositions to form a viscous but deformable material. The push layer expands against the drug composition or compositions and it is pushed through the openings. As water from the gastrointestinal tract is absorbed into the delivery system, one or more drug compositions drain from the system through the outlet opening in the membrane for an extended period of time. Upon completion of drug release, the biologically inert component of the dosage form is eliminated as a tablet shell.

  FIG. 2 is a perspective view of one embodiment of a standard biconvex round tablet sustained release osmotic dosage form. The dosage form 10 comprises a semi-permeable wall 20 that encloses and encloses an internal compartment (not shown in FIG. 2). The internal compartment comprises a drug composition comprising a pharmaceutical substance and a solubilizing substance. The semi-permeable wall 20 has at least one outlet opening 60 for communicating the external environment with the internal compartment. Thus, after oral ingestion of the dosage form 10, water is absorbed through the semipermeable wall 20 and the pharmaceutical substance / drug composition is released through the outlet 60.

  2 represents a standard biconvex round tablet, the dosage form of the present invention includes oral capsules, oval, triangular, and oral including buccal or sublingual dosage forms. Other geometric structures can be included, including other shapes for administration.

  FIG. 3 is a cross-sectional view of FIG. 2 showing an internal compartment 15 containing a single drug composition 30 comprising a pharmaceutical substance 31 in which the drug composition is mixed with selected excipients. is there. The excipient forms a drug composition that is deliverable upon absorption of fluid and / or increases the solubility of the drug composition 30 and / or from the external environment for other performance and / or manufacturing purposes. One can choose to provide an osmotic activity gradient for driving fluid through the semipermeable wall 20.

  In one embodiment, the present invention provides that the drug composition is at least one pharmaceutical substance 31, preferably 1-2 pharmaceutical substances, more preferably one pharmaceutical substance and solubilizing substance 33. To a pharmaceutical composition 30 comprising The pharmaceutical substance 31 is preferably topiramate. The solubilizing substance 33 is preferably a surfactant.

  The drug composition 30 preferably comprises a pharmaceutical substance 31 and a solubilizing substance 33, wherein the pharmaceutical substance 31 is a low solubility and / or low dissolution rate pharmaceutical substance. The drug composition of the present invention is preferably at least about 5% of the drug composition, more preferably at least about 11%, more preferably at least about 17.5%, more preferably at least about 25%, more preferably at least about about 30%, more preferably at least about 40%, more preferably at least about 42%, more preferably at least about 45% of solubilizing material 33.

  In another embodiment of the invention shown in FIG. 3, the drug composition comprises a pharmaceutical substance 31, a solubilizing substance 33 (represented by a vertical dashed line) and a structural polymer 32 (represented by a horizontal dashed line). It becomes.

  The excipients of the drug composition 30 may further optionally include a lubricant 34 (represented by a horizontal wavy line), an osmotic active substance (represented by the “X” symbol), also known as osmoagent 35, and / or Alternatively, a suitable binder 36 (represented by a large circle) can be included.

  During the action following oral ingestion of the dosage form 10, the osmotic activity gradient through the semipermeable wall 20 allows gastrointestinal water to be absorbed through the semipermeable wall 20 and thereby delivered into the internal compartment. Such as a solution or suspension or hydrogel. The deliverable drug composition is then released through the outlet opening 60 as the water continues to enter the internal compartment. As release of the drug composition occurs, water continues to be absorbed, thereby driving continuous release. In this way, the drug is released in a continuous and continuous manner over a long period of time.

  4 is a cross-sectional view of FIG. 2 with an alternative embodiment of the internal compartment 15 wherein the internal compartment comprises a two-layer structure. In this embodiment, the internal compartment 15 contains a two-layer compressed core having a first drug composition 30 and a push layer 40. As described above with reference to FIGS. 2 and 3, the drug composition 30 comprises further pharmaceutical and solubilizing materials mixed with optional excipients.

  As described in more detail below, the second component push layer 40 comprises one or more components of osmotic activity but no pharmaceutical agent. In one embodiment of the invention, push layer 40 comprises osmopolymer 41. The components in the push layer 40 preferably comprise an osmoagent 42 (represented by a very large circle) and one or more osmopolymers 41 (represented by the “V” symbol).

  Further optional excipients in the push layer 40 are binders 43 (represented by downward triangles), lubricants 44 (represented by upward semicircles), antioxidants 45 (represented by diagonal lines) and / or. Or a colorant 46 (represented by a vertical wavy line).

  As the water is absorbed through the semipermeable wall 20, the one or more osmopolymers in the push layer 40 expand and compress the drug composition 30, thereby causing the drug composition through the outlet opening 60. Facilitate the release of the pharmaceutical substance from the product and thus the dosage form.

  In one embodiment of the invention, as described with reference to FIGS. 3 and 4, the drug composition 30 is a pharmaceutical substance (eg, topiramate) mixed with additional optional excipients. And a solubilizing substance 33. The excipient can be one or more selected from the structural polymer 32, the lubricant 34, the osmoagent 35 and / or the binder 6.

  In another embodiment of the present invention, the push layer 40 comprises an osmotic active ingredient, more particularly an osmoagent 42 and an osmopolymer 41, as described with reference to FIG. Contains nothing.

  FIG. 5 shows another embodiment of the present invention, in FIG. 2, wherein the tablet includes a further optional immediate release coating 50 of a pharmaceutical substance, preferably topiramate, which includes the dosage form of FIG. FIG. 2 is a diagram of such a biconvex round standard tablet.

  More specifically, the dosage form 10 of FIG. 5 comprises a topcoat 50 on the outer surface of the semipermeable wall 20 of the dosage form 10. Topcoat 50 is a drug composition comprising from about 10 μg to about 500 mg of drug 31, preferably topcoat 50 comprises from about 10 μg to about 200 mg of drug 31, and more preferably, topcoat 50 is from about 5 mg to about 500 mg. About 100 mg of drug 31 and about 5 mg to about 200 mg of a pharmaceutically acceptable carrier selected from the group consisting of alkylcellulose, hydroxyalkylcellulose and hydroxypropylalkylcellulose. The topcoat pharmaceutically acceptable carriers are methylcellulose, hydroxyethylcellulose, hydroxybutylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose and hydroxypropylbutylcellulose, polyvinylpyrrolidone / vinyl acetate copolymer, polyvinyl alcohol-polyethylene Represented by a polymer or copolymer such as a graft copolymer. Topcoat 50 provides immediate release of the pharmaceutical substance because topcoat 50 dissolves in the presence of gastrointestinal fluid and at the same time delivers drug 31 into the gastrointestinal tract for immediate treatment. The drug 31 in the topcoat 50 may be the same as or different from the drug 31 in the drug composition 30. The drug 31 in the topcoat 50 is preferably the same as the drug 31 in the drug composition 30. Drug 31 is more preferably topiramate.

  FIG. 6 represents another preferred embodiment of the present invention which represents an open view of a three layer capsule osmotic dosage form. FIG. 6 represents an embodiment of a capsule tablet of the present invention comprising a first drug composition 30, a second drug composition 70 and a push layer 40. The capsule core (comprising the first and second drug compositions and the push layer) is surrounded by a semipermeable membrane 20. The dosage form further comprises at least one outlet opening 60 that exposes the first drug composition 30 to the environment of use. The dosage form of FIG. 6 further serves as a flow promoting layer and / or as a smoothing layer and / or a further optional internal that can contribute to control of the rate of water absorption into the dosage form. The film | membrane 80 of this is comprised.

  As shown in FIG. 6, in one embodiment of the present invention, the amount and / or concentration of drug in the first drug composition 30 is equal to the amount and / or concentration of drug in the second drug composition 70. Different. In another aspect of the invention, the amount and / or concentration of drug in the first drug composition 30 is lower than the amount and / or concentration of drug in the second drug composition 70. The amount and / or concentration of drug in the first drug composition 30 is preferably lower than the amount and / or concentration of drug in the second drug composition 70. The amount and / or concentration of drug in the first and second drug compositions is more preferably selected to provide a substantially increasing release rate of the pharmaceutical substance.

  The dosage form shown in FIG. 6 may further provide different release rates and / or patterns and / or different drug amounts and / or to achieve alternate drug plasma concentration profiles that may be preferred. Additional drug compositions having a concentration can be included.

  The pharmaceutical composition of the present invention comprises two components: (a) a pharmaceutical substance 31, preferably a low solubility and / or low dissolution rate pharmaceutical substance, more preferably topiramate and (b) a solubilizing substance 33, preferably A surfactant. In one embodiment of the invention, the drug composition comprises (a) pharmaceutical substance 31, preferably a low solubility and / or low dissolution rate pharmaceutical substance, more preferably topiramate, (b) solubilizing substance 33, Preferably, it comprises a surfactant and (c) the structural polymer 32. The drug composition may further optionally contain one or more excipients as described herein.

  In a preferred embodiment of the invention, the pharmaceutical substance in drug layer 30 is present in a therapeutically effective amount. In another aspect of the invention, the total amount of pharmaceutical agent present in one or more drug compositions of the dosage form of the invention is a therapeutically effective recommended or desired daily Equals or exceeds the dose.

  In one embodiment of the invention, the pharmaceutical substance in the drug composition 30 (or the pharmaceutical substance in the combined drug composition if the dosage form comprises two or more drug compositions) ) Is present in an amount greater than the recommended or desired daily dose of the pharmaceutical substance to be administered to a patient in need of treatment, thereby allowing administration less frequently than once a day.

  Where there are two drug compositions 30 and 70, for example as in FIG. 6, if the dosage form contains more than one drug composition, each drug composition is independently selected (a) Pharmaceutical It comprises a chemical substance 31, preferably a low solubility and / or low dissolution rate pharmaceutical substance, more preferably topiramate and (b) a solubilizing substance 33, preferably a surfactant. Each drug composition may further optionally contain an independently selected structural polymer 32 and / or one or more independently selected excipients as described below.

  When more than one drug composition is present in the dosage form of the present invention, the daily dose of the pharmaceutical substance is present in divided doses. For example, if the pharmaceutical substance dose is 400 mg and the dosage form comprises two drug compositions (eg, drug compositions 30 and 70 as illustrated in FIG. 6), the first The total amount of the pharmaceutical substance in the first drug composition plus the total amount of the pharmaceutical substance in the second drug composition will be 400 mg or more in total.

  When two drug compositions are present in the dosage form of the present invention, the drug concentration in the second drug composition 70 relative to the drug concentration in the first drug composition 30 as shown in FIG. Is preferably in the range of about 1.0 to about 2.5, preferably about 1.0 to about 2.0, more preferably about 1.25 to about 1.75.

  The pharmaceutical substance 31 is preferably a low solubility and / or low dissolution rate pharmaceutical substance, more preferably topiramate. Topiramate is within the therapeutic category of anticonvulsants. The solubility of unloaded topiramate is in the range of about 9.8 mg / ml to 13.0 mg / ml, where the solubility in deionized water is measured to be about 12 mg / ml.

  The pharmaceutical substance 31 can be provided in the drug composition in an amount in the range of about 1 mg to about 750 mg per dosage form. The pharmaceutical agent is preferably present in an amount in the range of about 1 mg to about 250 mg, and more preferably in the range of about 5 mg to about 250 mg per dosage form. The amount of pharmaceutical substance in the dosage form will depend on the required dosage level that must be maintained over the period of delivery, ie, the period between successive administrations of the dosage form. In one embodiment of the invention the pharmaceutical agent is present in an amount in the range of about 5 mg to about 250 mg, more preferably in the range of about 10 mg to about 250 mg per day.

  The pharmaceutical substance 31 is preferably present in the drug composition in micronized form. The micronized pharmaceutical material preferably has a nominal particle size of less than about 200 microns, more preferably less than about 100 microns, and most preferably less than about 50 microns.

  The solubilizing substance 33, preferably a pharmaceutically acceptable solubilizing substance, more preferably a surfactant, is one or more of the dosage forms of the invention as represented by the vertical dashes in FIGS. Included in multiple drug compositions.

  Solubilizing substances, and more particularly surfactants, are wetting substances, drug solubilizers, meltable carriers, oily liquid fillings in gel capsules for oral administration, parenteral solutions for injection, eye drops, topical solutions. It can be used in liquid drug delivery systems as ointments, salves, lotions and creams, suppositories, and in lung and nasal sprays. It is well known that surfactants have low cohesive properties due to their amphiphilic molecular structure comprising oppositely polar hydrophilic and nonpolar hydrophobic moieties with opposite physical and chemical properties . Thus, at room temperature, these surfactants are generally liquids, pastes whose physical form and properties are generally unacceptable for use as ingredients in compressed solid tablets that are sufficiently durable for manufacturing and practical use Or because of the physical form of a brittle solid, surfactants have been limited to such applications.

  As noted above, surfactants typically have low cohesion and are therefore not compressed as hard durable tablets. In addition, surfactants are in liquid, paste or waxy solid physical forms at standard temperatures and conditions and are unsuitable for tableted oral pharmaceutical dosage forms. However, it is unexpected that surfactants can be used in accordance with the drug compositions and dosage forms of the present invention to increase the solubility and possibly bioavailability of the pharmaceutical substance. It's been found.

  A group of solubilizing substances that can be used in the drug compositions and / or dosage forms of the present invention is, for example, the interface of POLYOXYL 40 stearate (also known as MYRJ52) and POLYOXYL50 stearate (also known as MYRJ53). Includes active agents. The solubilizing agent is preferably a drug solubilizing surfactant selected from the group of propylene glycol (PEG) 3350; PEG 8K; KOLLLIDON K90; LUTROL F68, F87, F127, F108; MYRJ 52S and PVP K2939. The solubilizing material is preferably the surfactant LUTROL F127.

Another group of surfactants that can be used in the drug compositions and / or dosage forms of the invention is the general formula OH (C ₂ H, also known as poloxamers or by their trade names PLURONIC and LUTROL. A group of copolymers of ethylene oxide and propylene oxide according to ₄ O) _a (C ₃ H ₆ O) _b (C ₂ H ₄ O) H. In this class of surfactant, the hydrophilic ethylene oxide end of the surfactant molecule and the hydrophobic intermediate block of propylene oxide of the surfactant molecule serve to dissolve and suspend the drug in a pumpable hydrogel. .

  Other surfactants that are solid at room temperature and can be used in the drug compositions and / or dosage forms of the present invention are essentially sorbitan monopalmitate, sorbitan monostearate, glycerol monostearate , Polyoxyethylene stearate (self-emulsifying), polyoxyethylene 40 sorbitol lanolin derivative, polyoxyethylene 75 sorbitol lanolin derivative, polyoxyethylene 6 sorbitol beeswax derivative, polyoxyethylene 20 sorbitol beeswax derivative, polyoxyethylene 20 sorbitol lanolin Derivatives, polyoxyethylene 50 sorbitol lanolin derivatives, polyoxyethylene 23 lauryl ether, polyoxyethylene 23 lauric to which butylated hydroxyanisole and citric acid are added as preservatives Ether, polyoxyethylene 2-cetyl ether with butylated hydroxyanisole and citric acid added as preservatives, polyoxyethylene 10 cetyl ether with butylated hydroxyanisole and citric acid added as preservatives, butylated hydroxy as preservatives Polyoxyethylene 20 cetyl ether with anisole and citric acid added, butylated hydroxyanisole and polyoxyethylene 2-stearyl ether with preservative added, butylated hydroxyanisole and citric acid as preservatives Polyoxyethylene 10 stearyl ether, butylated hydroxyanisole and polyoxyethylene 20 stearyl ether with citric acid added as preservative, butylated hydroxyaniss as preservative And polyoxyethylene 21 stearyl ether to which alcohol and citric acid are added, polyoxyethylene 20 oleyl ether to which butylated hydroxyanisole and citric acid are added as preservatives, polyoxyethylene 40 stearate, polyoxyethylene 50 stearate A substance selected from the group consisting of polyoxyethylene 100 stearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, polyoxyethylene 4-sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, etc. ["Handbook of Pharmaceutical Excipients", 2nd edition, editors Ainley Wade and Paul J. et al. See Weller, 1994].

A particularly preferred family of surfactants is a three-block copolymer of ethylene oxide: propylene oxide: ethylene oxide a: b: a. “A” and “b” represent the average number of monomer units for each block of the polymer chain. These surfactants are commercially available from BASF Corporation of Mount Olive, New Jersey at a variety of different molecular weights and with different values for the “a” and “b” blocks. For ^{example, LUTROL} (R) F127 has a molecular weight range of 9,840～14,600, where "a" is about 101, "b" is approximately 56, LUTROL F68 is "a" 64 Yes, it represents a molecular weight of 6,840-8,830, where “b” is 37, LUTROL F108 has an average molecular weight of 12,700-17,400, where “a” is 141, and “b” is 44 LUTOL F68 represents an average molecular weight of 7,680-9,510 with “a” having a value of about 80 and “b” having a value of about 27. Sources of surfactants, including solid surfactants and their properties, are available in McCutcheon's Detergents and Emusifiers , International Edition 1979 and McCutcheon's Detergents and Emulators , 19th Amerit . Other sources of information on the properties of solid surfactants include BASF Technical Bulletin PLUEONIC & TETRONIC Surfactants 1999 and General Characteristics of Surfactants from ICI Americas 80 Bulletin Bull .

One of the surfactant characteristics tabulated in these references is the HLB value or the hydrophilic / lipophilic equilibrium value. This value represents the relative hydrophilicity and relative hydrophobicity of the surfactant molecule. Generally, the higher the HLB value, the higher the hydrophilicity of the surfactant, while the lower the HLB value, the greater the hydrophobicity. For example, for a LUTROL molecule, the ethylene oxide moiety represents a hydrophilic moiety and the propylene oxide moiety represents a hydrophobic moiety. The HLB values of LUTROL F127, F87, F108 and F68 are 22.0, 24.0, 27.0 and 29.0, respectively.
It is.

Other particularly preferred surfactants include sugar ester surfactants which are sugar esters of fatty acids. Such sugar ester surfactants include sugar fatty acid monoesters, sugar fatty acid diesters, triesters, tetraesters or mixtures thereof, with mono- and di-esters being most preferred. The sugar fatty acid monoester preferably comprises a fatty acid having 6 to 24 carbon atoms, which can be a linear or branched or saturated or unsaturated C _{6 to} C ₂₄ fatty acid. C ₆ -C ₂₄ fatty acids are C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ , C ₁₆ , C in any subrange or combination. ₁₇ , C ₁₈ , C ₁₉ , C ₂₀ , C ₂₁ , C ₂₂ , C ₂₃ and C ₂₄ are included. These esters are preferably selected from stearates, behenates, cocoates, arachidonates, palmitates, myristates, laurates, caprates, oleates, laurates and mixtures thereof.

  The sugar fatty acid monoester preferably comprises at least one saccharide unit such as sucrose, maltose, glucose, fructose, mannose, galactose, arabinol, xylose, lactose, sorbitol, trehalose or methylglucose. Most preferred are disaccharide esters such as sucrose esters, and sucrose cocoate, sucrose monooctanoate, sucrose monodecanoate, sucrose mono- or dilaurate, sucrose monomyristate, sucrose mono- or dipalmitate, sucrose mono- and Such as sucrose polyesters such as distearate, sucrose mono-, di- or trioleate, sucrose mono- or dilinoleate, sucrose pentaoleate, hexaoleate, heptaoleate or octaoleate and sucrose palmitate / stearate Including mixed esters.

  Particularly preferred examples of such sugar ester surfactants are sucrose steares prepared using a method for adjusting the degree of esterification, as described in US Pat. No. 3,480,616. Included are those sold by the company Croda Inc. of Parsippany, NJ under the trade names CRODESTA F10, F50, F160 and F110 indicating various mono-, di- and mono / diester mixtures comprising rates. These preferred sugar ester surfactants provide the added advantage of tableting ease and non-stick granulation. Sugar ester surfactants can also provide increased compatibility with sugar-based therapeutics exemplified by topiramate.

  For example, the sugar sold by the company Mitsushishi under the trade name RYOTO SUGAR ESTERS as reference number B370 corresponding to sucrose behenate formed with 20% monoester and 80% di-, tri- and polyester. Surfactants can also be used. Sucrose mono- and dipalmitate / stearate sold by the company Goldschmidt under the trade name “TEGOSOFT PSE” can also be used. It is also possible to use mixtures of these various products. The sugar ester can also be present in a mixture with another compound that is not derived from sugar, a preferred example being that of sorbitan stearate and sucrose cocoate sold under the name “ARLATONE 2121” by the company ICI. Includes mixtures. Other sugar esters include, for example, glucose trioleate, galactose di-, tri-, tetra- or pentaoleate, arabinose di-, tri- or tetralinoleate or xylose di-, tri- or tetralinoleate or mixtures thereof To do. Other sugar esters of fatty acids include methyl glucose and polyglycerol-3 distearate sold by the company Goldschmidt under the trade name TEGOCARE450. Glucose or maltose monostearates such as methyl O-hexadecanoyl-6-D-glucoside and O-hexadecanoyl-6-D-maltose can also be included. Certain other sugar ester surfactants include oxyethylenated derivatives such as PEG-20 methylglucose sesquistearate sold by the company Amerchol under the trade name "GLUCAMATE SSE20".

  The solubilizing substance 33 can be a surfactant or a blend of surfactants. Surfactants are selected so that they have values that promote drug dissolution and solubility. If certain drugs require intermediate HLB values, high HLB surfactants can be blended with low HLB surfactants to achieve their intermediate net HLB values. Surfactant 33 is selected depending on the drug to be delivered so that the appropriate HLB grade is used.

  The solubilizing substances are preferably MYRJ 52, MYRJ 53, MYRJ 59FL, KOLLIDON 12PF, KOLLIDON 17PF, KOLLIDON 25/30, KOLLIDON K90, LUTROL F68, LUTROL F87, LUTROL F87, LUTROL F87, PEG 3350; PEG 8K; sorbitan monopalmitate, sorbitan monostearate, glycerol monostearate, polyoxyethylene stearate, sucrose cocoate, polyoxyethylene 40 sorbitol lanolin derivative, polyoxyethylene 75 sorbitol lanolin derivative, polyoxyethylene 6 Sorbitol beeswax derivative, polyoxyethylene 20 sorbitol Wax derivative, polyoxyethylene 20 sorbitol lanolin derivative, polyoxyethylene 50 sorbitol lanolin derivative, polyoxyethylene 23 lauryl ether, polyoxyethylene 23 lauryl ether added with butylated hydroxyanisole and citric acid as preservative, as preservative Polyoxyethylene 2-cetyl ether, polyoxyethylene 2-stearyl ether, polyoxyethylene 21 stearyl ether, polyoxyethylene 100 stearyl ether with butylated hydroxyanisole and citric acid added, butylated hydroxyanisole and citric acid as preservatives Polyoxyethylene 10 cetyl ether added, polyoxyethylene 2 with butylated hydroxyanisole and citric acid added as preservative 0 cetyl ether, polyoxyethylene 2-stearyl ether with butylated hydroxyanisole and citric acid added as preservative, polyoxyethylene 10 stearyl ether with butylated hydroxyanisole and citric acid added as preservative, butyl as preservative Polyoxyethylene 20 stearyl ether added with sulfonated hydroxyanisole and citric acid, polyoxyethylene 21 stearyl ether added with butylated hydroxyanisole and citric acid as preservatives, butylated hydroxyanisole and citric acid as preservatives Polyoxyethylene 20 oleyl ether, polyoxyethylene 40 stearate, polyoxyethylene 50 stearate, polyoxyethylene 100 stearate, sorbitan Palmitate, sorbitan monostearate, sorbitan tristearate, polyoxyethylene 4 sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, and is selected from the group consisting of mixtures thereof.

  The solubilizing substance is more preferably a surfactant selected from the group consisting of LUTROL F68, LUTROL F87, LUTROL 108, LUTROL F127, MYRJ 52, MYRJ 53; the solubilizing substance is most preferably of a surfactant LUTROL F127.

  In a preferred embodiment of the invention, the surfactant is not a sugar ester.

  In the pharmaceutical composition and / or dosage form of the invention, the pharmaceutical substance is preferably combined with a suitable said solubilizing substance, preferably a solid surfactant or a mixture of surfactants. .

  A suitable surfactant can be selected by preparing an aqueous solution of the selected surfactant over a range of HLB values and a range of concentrations. The pharmaceutical substance is then added in excess to the surfactant solution and the saturated solubility of the pharmaceutical substance (equilibrium) is measured by a suitable analytical method such as UV spectroscopy, chromatography or gravimetric analysis. The solubility values are then plotted as a function of HLB and as a function of surfactant concentration. A solubilizing substance (preferably a surfactant) can then be selected by evaluating the highest point of solubility formed in the plots at different concentrations.

  When the pharmaceutical substance is topiramate, the solubilizing substance is preferably a surfactant and the surfactant is preferably PLURONIC F127 or its corresponding pharmaceutically acceptable grade LUTROL F127.

  Solubilizing substances, preferably surfactants, are preferably present in the drug composition in micronized form. The micronized solubilizing material, preferably a surfactant, preferably has a nominal particle size of less than about 200 microns, more preferably less than about 100 microns, and most preferably less than about 50 microns.

  In order to achieve a substantially zero dimensional release rate profile, the ratio of solubilizing agent, preferably surfactant, to the pharmaceutical agent is preferably in the range of about 1.3 to about 2.7, and more. Preferably it is in the range of about 1.5 to about 2.5, and even more preferably in the range of about 1.8 to about 2.2.

  In order to achieve a substantially increasing release rate profile, the ratio of solubilizing agent, preferably surfactant, to the pharmaceutical agent is preferably within the range of about 0.1: 1 to about 3: 1. More preferably in the range of about 0.25: 1 to about 2.5: 1, more preferably in the range of about 0.5: 1 to about 2: 1, even more preferably from about 1: 1 to about 2. : 1 and even more preferably in the range of about 1.5: 1 to about 2: 1.

  The present invention provides a beneficial increased biological potential for low solubility and / or low dissolution rate drugs by increasing its solubility and wet surface for greater biological attachment to the gastrointestinal mucosa. Can provide availability. The wettability of a solubilizing substance (preferably a surfactant) can also have the effect of preventing the released drug from aggregating when released into the environment of use, thereby allowing absorption of the gastrointestinal tract More complete diffusion of the dispersed drug composition on a smooth surface. The increased surface area produced can provide a larger absorption surface area, increasing the rate and extent of drug absorbed and thus increasing the therapeutic response.

  The solubilizing substance (preferably a surfactant) can further impart adhesion to the dispensed drug composition, which is the contact between the drug composition and the absorbable mucosal tissue of the gastrointestinal tract. The time can be extended, thereby allowing more time for the drug to diffuse and be absorbed once delivered.

  In yet another possible effective effect, the solubilizing substance (preferably a surfactant) further increases mucosal permeability to the drug molecule, which facilitates increased permeability of the drug. And can lead to an enhanced therapeutic response.

  When the drug 31 is present at a low dose of less than about 20% of the drug composition 30, the present invention provides a moist surface and mucosal surface for its solubility and stronger bioadhesion to the gastrointestinal mucosa. Increasing the increased permeability of can provide effective increased bioavailability of low solubility and / or low solubility rate drugs. Increased drug solubility, added surface contact area on mucosal tissue, increased contact time to mucosal tissue, and increased permeability of mucosal tissue to drug molecules, individually or collectively, facilitates overall treatment of drugs according to the present invention Can contribute.

  Structural polymer 32 comprises optional ingredients, for example, a hydrophilic polymer that provides adhesion to the blend so that a durable tablet can be formulated. Structural polymers can also form hydrogels for viscosity control during operation of the delivery system. The structural polymer further suspends the drug particles to facilitate partial or complete solubilization of the drug within the dosage form prior to delivery from the dosage form.

  The molecular weight of the structural polymer 32 can be selected to impart desired properties to the dosage form, and more particularly to the drug composition within the dosage form. High molecular weight polymers are used to provide slow and slow rates of drug hydration, while low molecular weight polymers result in faster hydration and faster release of the drug. A blend of high and low molecular weight structural polymers provides an intermediate delivery rate.

  When the drug composition of the present invention is used in an erodible matrix dosage form, the molecular weight of the structural polymer is selected to modify the erosion rate of the system. High molecular weight polymers are used to provide a slow erosion rate and slow delivery of the drug, while low molecular weight polymers provide a faster erosion rate and faster release of the drug. A blend of high and low molecular weight structural polymers provides an intermediate delivery rate.

  When the drug composition of the present invention is used in non-erodible porous matrix dosage forms, the molecular weight of the structural polymer is selected to provide a viscous hydrogel in the pores of the matrix. The viscosity of the hydrogel serves to suspend the drug particles to promote partial or complete solubilization of the drug in the presence of a surfactant prior to delivery from the pores of the dosage form.

  Structural polymer 32 is a hydrophilic polymer particle in the drug composition that contributes to controlled delivery of the active agent. Representative examples of suitable structural polymers include, but are not limited to, 100,000 and 750 including poly (ethylene oxide), poly (methylene oxide), poly (butylene oxide), and poly (hexylene oxide). Poly (alkylene oxide) with a number average molecular weight of 1,000, and poly (alkali carboxymethyl cellulose), poly (sodium carboxymethyl cellulose), poly (potassium carboxymethyl cellulose), poly (calcium carboxymethyl cellulose) and poly (lithium carboxymethyl cellulose) Representative are poly (carboxymethylcellulose) having a number average molecular weight of 40,000 to 400,000. Alternatively, the drug composition may have a 9,200-125,000 number average, such as hydroxypropylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylbutylcellulose, hydroxypropylpentylcellulose, etc., to facilitate the delivery of the dosage form. Molecular weight hydroxypropylalkylcellulose and / or poly (vinyl pyrrolidone) with 7,000-75,000 number average molecular weight to promote fluidity of the dosage form can be included. Preferred structural polymers are polymers of poly (ethylene oxide) having 100,000 and 300,000 number average molecular weights. Particularly preferred are structural polymers that erode within the gastrointestinal environment, ie biologically erodible structural polymers.

  Other structural polymers that can be incorporated into drug composition 30 include carbohydrates that exhibit sufficient osmotic activity, used alone or in conjunction with other osmoagents. Such carbohydrates comprise monosaccharides, disaccharides and polysaccharides. Representative examples include, but are not limited to, maltodextrins (ie, glucose polymers produced by hydrolysis of cereal starches such as rice or corn starch) and lactose, glucose, raffinose, sucrose, mannitol, sorbitol, dilitol. Including saccharides comprising Preferred maltodextrins are those having a dextrose equivalent (DE) of about 20 or less, preferably maltodextrins having a DE in the range of about 4 to about 20, and more preferably about 9 to about 20. A maltodextrin having a DE of about 9-12 and a molecular weight of about 1,600-2500 is preferred.

  Said carbohydrate, preferably maltodextrin, is used in the drug composition 30 without the addition of an osmoagent and administered once a day for a long period of time and providing a therapeutic effect up to 24 hours. The desired release of the pharmaceutical substance from the form can be brought about.

  The structural polymer is preferably poly (ethylene oxide), poly (methylene oxide), poly (butylene oxide) and poly (hexylene oxide); poly (carboxymethylcellulose), poly (alkalicarboxymethylcellulose), poly (sodium carboxymethylcellulose), Poly (potassium carboxymethylcellulose), poly (calcium carboxymethylcellulose), poly (lithium carboxymethylcellulose), hydroxypropylcellulose, hydroxypropylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylbutylcellulose, hydroxypropylpentylcellulose, poly (vinylpyrrolidone), biological Erodible structural polymer (carrier), maltodextrin, polyvinylpyro Pyrrolidone, polyvinyl pyrrolidone-vinyl acetate copolymers, lactose, glucose, raffinose, sucrose, mannitol, sorbitol, are selected from the group consisting of Jiritoru and mixtures thereof.

  The structural polymer is more preferably selected from the group consisting of MALTRIN M100, POLYOX N10 and POLYOX N80, most preferably the structural polymer is POLYOX N80.

  It has further been found that the structural polymer and the solubilizing material (preferably a surfactant), when present, are preferably present in the drug composition in specific amounts. The structural polymer should preferably be present in an amount up to about 90% by weight of the drug composition and the surfactant should be present in an amount between 0 and about 50% by weight of the drug composition. . For high doses, the structural polymer should preferably be present in an amount of no more than about 30% by weight of the drug composition, more preferably less than about 20% by weight of the drug composition, and the interface The active agent is in an amount of about 15% by weight or more of the drug composition, more preferably in an amount of about 25% by weight or more of the drug composition, even more preferably in an amount of about 35% by weight or more of the drug composition, most preferably Must be present in an amount of at least about 40% by weight of the drug composition.

  For high doses, the preferred range of concentration of structural polymer within the drug composition of the osmotic delivery system is from about 5% to about 5%, with a particularly preferred range of 0 to about 20% by weight of the drug composition. 50% by weight of polyoxyethylene (POLYOX N80) with a molecular weight of 200,000.

  For low doses, the preferred range of concentration of the structural polymer within the drug composition of the osmotic delivery system is about 50% to about 90%, with a particularly preferred range of 75% to about 90% by weight of the drug composition. 90% by weight of 2,000,000 molecular weight polyoxyethylene (POLYOX N80).

  Lubricant 34 can optionally be included in the drug composition as represented by the horizontal wavy lines in FIGS. Lubricant 34 is used during the tableting process to prevent sticking to the die wall or punch face. Typical lubricants include, but are not limited to, magnesium stearate, sodium stearate, stearic acid, calcium stearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid, sodium stearyl fumarate and magnesium palmitate Or a blend of such lubricants. The amount of lubricant present in the drug composition is preferably in the range of about 0.01 to about 20 mg.

  A binder 36, preferably a therapeutically acceptable vinyl polymer binder, may also optionally be included in the drug composition, as represented by the small circles in FIGS. Exemplary binders include, but are not limited to, vinyl polymer binders, acacia, starch and gelatin. When the binder is a vinyl polymer, the vinyl polymer may be poly-n-vinylamide, poly-n-vinylacetamide, poly (vinylpyrrolidone), also known as poly-n-vinylpyrrolidone, poly-n-vinylcaprolactone, Poly-n-vinyl-5-methyl-2-pyrrolidone and poly with one member selected from the group consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl laurate and vinyl stearate -An average molecular weight of 5,000 to 350,000, represented by one member selected from the group consisting of n-vinylpyrrolidone copolymers. Other exemplary binders suitable for preparation in the drug composition include, but are not limited to, acacia, starch and gelatin. The binder present in the drug composition is preferably in an amount in the range of about 0.01 to about 25 mg.

  Disintegrants can also optionally be included in the drug composition. The disintegrant can be selected from starches, clays, celluloses, algins and gums and crosslinked starches, celluloses and polymers. Exemplary disintegrants include, but are not limited to, corn starch, potato starch, croscarmellose, crospovidone, sodium starch glycolate, VEEGUM HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum, low substitution Hydroxypropyl cellulose, microcrystalline cellulose and the like are included.

  In one embodiment of the invention, at least one drug composition in the dosage form comprises a pharmaceutical substance and a solubilizing substance. The pharmaceutical agent is preferably topiramate, the solubilizing agent is a surfactant, and the solubilizing agent is more preferably the surfactant PLURONIC F127 or its corresponding pharmaceutically acceptable grade LUTROL F127. It is.

  It has further been found that the surfactant can be operated as both a structural polymer as well as a surfactant, and thus it can be used as the sole excipient in the drug composition.

  If the drug composition comprises a pharmaceutical substance 31, a solubilizing substance 33, preferably a surfactant and a structural polymer 32, the structural polymer 32 and the surfactant 33 prepared in the drug composition The amount must be selected and adjusted appropriately.

  One skilled in the art will appreciate that the amount of solubilizing material and structural polymer is selected to optimize the characteristics of the drug layer composition. The amount allows the dosage form to maintain structural integrity before and during administration, the drug layer composition can be hydrated and extruded from the dosage form to provide the desired release pattern. Is selected to be able to.

  One aspect of the invention is a drug composition wherein the pharmaceutical agent is topiramate and the topiramate is present in an amount in the range of about 10 mg to about 200 mg. A further aspect of the invention is a drug composition wherein topiramate is present in an amount of 10 mg, 20 mg, 40 mg, 45 mg, 80 mg, 90 mg, 120 mg, 135 mg, 160 mg, 180 mg and 200 mg.

  One aspect of the present invention is one or more drug compositions wherein the total amount of topiramate present in the dosage form (ie the total amount present in the drug composition) is in an amount in the range of about 10 mg to about 200 mg. , Preferably a dosage form comprising one or two drug compositions. A further aspect of the invention comprises one or two drug compositions wherein the total amount of topiramate present is an amount of 10 mg, 20 mg, 40 mg, 45 mg, 80 mg, 90 mg, 120 mg, 135 mg, 160 mg, 180 mg or 200 mg. A dosage form consisting of

  One aspect of the present invention is a first drug comprising a pharmaceutical substance, preferably a solubilizing substance with low solubility and / or low dissolution rate, more preferably topiramate and a solubilizing substance, preferably a surfactant. Compositions and pharmaceutical substances, preferably comprising a second drug composition comprising a solubilizing substance, preferably a low solubility and / or low dissolution rate, more preferably topiramate and a solubilizing substance, preferably a surfactant. A dosage form.

  Another aspect of the invention comprises (a) a pharmaceutical substance, preferably a solubilizing substance, preferably a low solubility and / or low dissolution rate, more preferably topiramate and a solubilizing substance, preferably a surfactant. A core comprising a first drug composition and a push layer comprising an osmopolymer; (b) a semipermeable wall surrounding the core; and (c) releasing the pharmaceutical substance from the dosage form over time. A dosage form comprising an outlet opening through a semi-permeable wall for carrying out the treatment.

  Yet another aspect of the present invention comprises (a) a pharmaceutical substance, preferably a solubilizing substance with low solubility and / or low dissolution rate, more preferably topiramate and a solubilizing substance, preferably a surfactant. A first drug composition comprising: a pharmaceutical substance, preferably a low-solubility and / or low-dissolution rate solubilizing substance, more preferably topiramate and a solubilizing substance, preferably a second drug comprising a surfactant A core comprising a push layer comprising an osmopolymer; (b) a semipermeable wall surrounding the core; and (c) for releasing the pharmaceutical substance from the dosage form over time. A dosage form comprising an outlet opening through a semipermeable wall.

  One skilled in the art will include a first drug composition comprising a pharmaceutical substance and a solubilizing substance and a second drug composition comprising a pharmaceutical substance and a solubilizing substance. The pharmaceutical substances in the first and second drug compositions may be the same or different, and the solubilizing substances in the first and second drug compositions may be the same or different. I will admit that. Those skilled in the art further know when additional optional ingredients in the first and second drug compositions, such as structural polymers, binders, lubricants, etc., are present in both the first and second drug compositions. It will be appreciated that they may be the same or different as well.

  Preparations and methods for the manufacture of the push layer 40, the semipermeable wall 20 and the one or more outlet openings 60 are well known in the art. Components and methods for the manufacture of the push layer, semipermeable wall and one or more outlet openings are also briefly described below.

  Push layer 40 comprises a replacement composition in a layered arrangement in contact with drug composition 30 as shown in FIG. When more than one drug composition is present in the dosage form (as in FIG. 6), push layer 40 is preferably in a layered arrangement in contact with the only drug composition.

  In one embodiment of the invention, push layer 40 comprises an osmopolymer. In another embodiment of the present invention, push layer 40 comprises an osmopolymer and an osmoagent.

  The push layer 40 comprises an osmopolymer 41 that absorbs water and swells to push the drug composition of one or more drug layers through the outlet opening of the dosage form. Osmopolymers are swellable, hydrophilic polymers that interact with water and typically swell or expand with a volume increase of 2-50 times. The osmopolymer may be uncrosslinked or crosslinked. Push layer 40 preferably comprises from about 20 to about 375 mg of osmopolymer 41, represented by the “V” symbol in FIG.

  When the osmopolymer is present in both the drug composition and the push layer, the osmopolymer 41 in the push layer 40 has a higher molecular weight than the osmopolymer in the drug composition. For example, such a situation can be observed when the structural polymer in the drug composition is an osmopolymer.

Representative of osmopolymers (ie fluid-absorbing replacement polymers) are poly (alkylene oxides) with a number average molecular weight of 1 to 15 million, as represented by poly (ethylene oxide), where the alkali is sodium, potassium or lithium It comprises a substance selected from poly (alkali carboxymethyl cellulose) having a number average molecular weight of 500,000 to 3,500,000. Examples of alternative osmopolymers, ^{CARBOPOL (R)} acid carboxymethyl polymer, carboxymethyl also polyallyl sucrose and crosslinked acrylic polymer known as polymethylene (a polymer acrylic cross-linked with a) and 250,000～4 , the polymer to form a hydrogel, such as carboxyvinyl polymers having a molecular weight of 000,000; having a molecular weight of 80,000 to 200,000; Cyanamer ^(R) polyacrylamide; crosslinked water-swellable indene maleic anhydride polymers GOOD-RITE ^(R) polyacrylic acid; AQUA-KEEPS ^(R) acrylate polymer polysaccharide consisting of condensed glucose units such as diester cross-linked polygulrane; and the like. Representative polymers that form hydrogels are US Pat. No. 3,865,108 granted to Hartop, No. 4,002,173 granted to Manning, No. 4 approved to Michaels. , 207,893 and Handbook of Common Polymers , Scott and Roff. Chemical Rubber Co. , Cleveland, OH.

  The push layer 40 further optionally comprises an osmoagent 42, an osmotic pressure effective compound represented by a large circle in FIG. Osmoagent 42 preferably comprises up to about 40% by weight of the push layer, more preferably from about 5% to about 30% by weight of the push layer, and even more preferably from about 10% to about 30% by weight of the push layer. . Osmotically effective compounds are also known as osmoagents and / or as osmotically effective solutes. The push layer 40 preferably comprises an osmo agent.

  The osmoagent 42 that can be found in the drug composition and / or push layer in the dosage form of the present invention exhibits an osmotic activity gradient through the wall 20. Suitable osmoagents include but are not limited to sodium chloride, potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium phosphate, mannitol, urea, inositol, succinic acid Magnesium, tartaric acid, raffinose, sucrose, glucose, lactose, sorbitol, inorganic salts, organic salts, carbohydrates, and the like are included.

  The push layer 40 can optionally further comprise a pharmaceutically acceptable binder 43, such as a vinyl polymer represented by the triangle in FIG. Vinyl polymers include poly-n-vinyl amide, poly-n-vinyl acetamide, poly (vinyl pyrrolidone), also known as poly-n-vinyl pyrrolidone, poly-n-vinyl caprolactone, poly-n-vinyl-5-methyl- 2-pyrrolidone and a poly-n-vinylpyrrolidone copolymer with one member selected from the group consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl laurate and vinyl stearate It comprises a viscosity-average molecular weight of 5,000-350,000, represented by one member selected from the group. Push layer 40 preferably contains from about 0.01 to about 25 mg of vinyl polymer.

  The push layer 40 may further optionally comprise 0 to about 5 mg of a non-toxic colorant or dye 46 identified by the vertical wavy line in FIG. Suitable examples of colorants or dyes 46 are FD & C No. 1 Blue dye, FD & C No. 1 4 Food & Drug Administration colorants (FD & C) such as red dye, red ferric oxide, yellow ferric oxide, titanium dioxide, carbon black, indigo, etc.

  The push layer 40 may further optionally comprise a lubricant 44 identified by a semicircle in FIG. Suitable examples include, but are not limited to, sodium stearate, potassium stearate, magnesium stearate, stearic acid, calcium stearate, sodium oleate, calcium palmitate, sodium laurate, sodium ricinoleate and potassium linoleate and Includes one member selected from the group consisting of blends of such lubricants. The amount of lubricant included in the push layer 40 is preferably in the range of about 0.01 to about 10 mg.

  The push layer 40 may further optionally comprise an antioxidant 45, represented by a hatched dash in FIG. 4, where the antioxidant prevents oxidation of the components in the push layer. Push layer 40 comprises 0.0 to about 5 mg of antioxidant. Representative antioxidants include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and di-tert-butyl-4-hydroxyanisole, butylated hydroxytoluene, isoalcorbic acid Sodium, dihydroguaretic acid, potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E, 4-chloro-2,6-ditertiary butylphenol, alpha-tocopherol and propyl gallate Is included.

  Sometimes the semi-permeable wall 20, also called a membrane, is formed to be permeable to the passage of external water. The semipermeable wall 20 is also substantially impermeable to the passage of drug compositions and push layer components such as drugs, solubilizing materials, structural polymers, osmagents, osmopolymers, and the like. Thus, the wall 20 is semi-permeable. The selectively semipermeable composition used to form the semipermeable wall 20 is essentially non-erodible and is substantially free of biological fluid during the lifetime of the dosage form. Insoluble.

  Exemplary polymers suitable for forming the semipermeable wall 20 comprise semipermeable homopolymers, semipermeable copolymers, and the like. Such materials include, but are not limited to, cellulose esters, cellulose ethers, and cellulose ester-ethers. Cellulose polymers collectively have a degree of substitution (DS) of their anhydroglucose units from 0 to 3. Degree of substitution (DS) refers to the average number of hydroxyl groups initially present on an anhydroglucose unit that are substituted by a substituent or converted to another group. Anhydroglucose units are acyl, alkanoyl, alkenoyl, aroyl, alkyl, alkoxy, halogen, carboalkyl, alkyl carbamate, alkyl carbonate, alkyl sulfonate, alkyl sulfamate, organic moieties of 1-12 carbon atoms, and preferably Can be partially or wholly substituted with groups such as semi-permeable polymers forming groups containing from 1 to 8 carbon atoms.

The semipermeable wall 20 is further composed of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tri-cellulose alkanylates, mono-, di- And a semi-permeable polymer selected from the group consisting of tri-alkenylates, mono-, di- and tri-alloyates, and the like. Exemplary polymers include a cellulose acetate having a DS in the range of about 1.8 to about 2.3 and an acetyl content in the range of about 32 to about 39.9%; a DS in the range of about 1 to about 2 Cellulose diacetate having an acetyl content in the range of about 21 to about 35%; a cellulose triacetate having a DS in the range of about 2 to about 3 and an acetyl content in the range of about 34 to about 44.8%; Include. Preferred cellulose polymers are cellulose propionates having a DS of about 1.8 and a propionyl content in the range of about 38.5%; an acetyl content in the range of about 1.5 to about 7% and about 39% to about Cellulose acetate propionate having an acetyl content in the range of 42%; acetyl content in the range of about 2.5% to about 3%, average propionyl content in the range of about 39.2% to about 45%, and about Cellulose acetate propionate having a hydroxyl content in the range of 2.8% to about 5.4%; DS of about 1.8, acetyl content in the range of about 13% to about 15%, and about 34% to about Cellulose acetate butyrate having a butyryl content in the range of 39%; an acetyl content in the range of about 2% to about 29%, a butyryl content in the range of about 17% to about 53%, and about 0. Cellulose acetate butyrate having a hydroxyl content in the range of from about 4.7% to about 4.7%; about 2.6 such as cellulose trivalerate, cellulose trilamate, cellulose tripalmitate, cellulose trioctanoate and cellulose tripropionate. From about 2.2 to about 2.6, such as cellulose triacylate having a DS in the range of from about 3; cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate, and the like. Cellulose diesters having a DS within the range; and cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, cellulose acetate octanoate, cellulose valerate palmitate, cellulose acetate Including heptanoate, mixed cellulose esters, such as equal. Semipermeable polymers are known from U.S. Pat. No. 4,077,407, and are described in Encyclopedia of Polymer Science and Technology , Vol. 3, pp. 325-354 (1964), Interscience Publishers Inc. , New York, NY.

Additional semipermeable polymers that can be used to form the semipermeable wall 20 are: cellulose acetaldehyde dimethyl acetate; cellulose acetate ethyl carbamate; cellulose acetate methyl carbamate; cellulose dimethylamino acetate; semipermeable polyamide; Semipermeable sulfonated polystyrene; U.S. Pat. Nos. 3,173,876, 3,276,586, 3,541,005, 3,541,006 and 3,546, Cross-linked selectively semipermeable polymer formed by coprecipitation of anions and cations as disclosed in US Pat. No. 142; disclosed by Loeb et al. In US Pat. No. 3,133,132 Such as semipermeable polymers; semipermeable polystyrene derivatives; semipermeable poly (Natriu) Styrene sulfonate); semipermeable poly (vinylbenzyl trimethylammonium chloride); and 10 -5 ^{to 10} -2 ^(cc expressed as per atmosphere of the difference between the hydrostatic or osmotic through the semipermeable wall Semi-permeable polymer exhibiting fluid permeability of .mil / cm.hour.atm.). The polymers are described in U.S. Pat. Nos. 3,845,770, 3,916,899 and 4,160,020 and in Handbook of Common Polymers , Scott and Roff (1971) CRC Press, Cleveland, OH. Known in the technical field. The wall 20 can optionally be formed as two or more thin layers as described in US Pat. No. 6,210,712.

  Semipermeable wall 20 preferably comprises a polymer selected from the group consisting of cellulose acetate and cellulose acetate butyrate.

  The semipermeable wall 20 can further optionally comprise a flow regulating material. A flow regulating substance is a compound that is added to help regulate the permeability or flow of water through the semipermeable wall 20. The flow regulating substance may be a flow promoting substance or a flow reducing substance. Thus, the flow regulating substance can be preselected to increase or decrease the flow rate of external water through the semipermeable membrane. Flow control materials that cause a significant increase in permeability to fluids such as water are often inherently hydrophilic, while those that cause a significant decrease in permeability to fluids such as water are essentially hydrophobic. When the flow regulator in the semipermeable wall 20 is incorporated therein, the amount is preferably in the range of about 0.01% to about 25% by weight or more.

  Suitable flow control materials include, but are not limited to, polyhydric alcohols, polyalkylene glycols, polyalkylene diols, alkylene glycol polyesters, and the like.

Flow enhancers include, but are not limited to, polyethylene glycol 300, 400, 600, 1500, 4000, 6000, etc .; low molecular weight glycols such as polypropylene glycol, polybutylene glycol and polyamylene glycol; poly (1,3 -Propanediol), poly (1,4-butanediol), poly (1,6-hexanediol) and the like; 1,3-butylene glycol, 1,4-pentamethylene glycol, 1,4 An aliphatic diol such as hexamethylene glycol; an alkylene triol such as glycerin, 1,2,3-butanetriol, 1,2,4-hexanetriol, 1,3,6-hexanetriol; ethylene glycol Dipropionate, ethylene glycol Encompasses Chireto, butylene glycol dipropionate, glycerol acetate esters, esters such as like, the. Preferred flow accelerators, ^PLURONIC commonly known as ^(R) copolymer (sold by pharmaceutical grade under the trade name LUTROL) formula _{OH (C 2 H 4 O)} a (C 3 H 6 O) b (C 2 H 4 It includes a group of ethylene oxide and propylene oxide bifunctional block copolymers according to O) H.

  Flow reducing materials include, but are not limited to, phthalates substituted with alkyl or alkoxy, such as diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate and [di (2-ethylhexyl) phthalate] or with both alkyl and alkoxy groups Aryl phthalates such as triphenyl phthalate and butyl benzyl phthalate; polyvinyl acetate, triethyl citrate, Eutragit; insoluble salts such as calcium sulfate, barium sulfate, calcium phosphate, etc .; insoluble oxides such as titanium oxide; polystyrene, poly Polymers in the form of powders, granules, etc., such as methyl methacrylate, polycarbonate and polysulfone; esters such as citrate esters esterified with long chain alkyl groups; It encompasses cellulose main wall forming materials and compatible resin, etc.; substantially water impermeable fillers Te.

  Further, in some cases, to provide flexibility and / or extensibility, i.e. to reduce the fragility of the semi-permeable wall 20 and / or to give the semi-permeable wall 20 tear strength, Other materials can be included in the wall composition. Suitable materials include, but are not limited to, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, 6-11 carbon linear phthalate, di-isononyl phthalate, di-isodecyl phthalate, etc. Includes phthalate plasticizer. Plasticizers include non-phthalates such as triacetin, dioctyl azelate, epoxidized talate, tri-isooctyl trimellitate, tri-isononyl trimellitate, sucrose acetate isobutyrate, epoxidized soybean oil, etc. . The amount of plasticizer in the semipermeable wall 20 when incorporated therein is preferably in the range of about 0.01% to about 20% by weight or more.

  An outlet opening 60 is provided for each osmotic dosage form. The outlet 60 can include one or more outlet openings. The outlet 60 cooperates with one or more drug compositions within the dosage form for uniform release of the drug from the dosage form. The outlet can be provided during drug delivery by the dosage form in the formulation of the dosage form or in the fluid environment of use.

  The outlet 60 can include an opening formed or formable from a material or polymer that erodes, dissolves or leaches from the outer wall, thereby forming an outlet opening. Substances or polymers are, for example, erodible poly (glycol) acids or poly (milk) acids in semipermeable walls; gelatinous filaments; water-removable poly (vinyl alcohol); inorganic and organic salts, oxides, carbohydrates, Leachable compounds such as fluid removable pore formers selected from the group consisting of and the like can be included.

  Alternatively, outlet 60 or a plurality of outlets leach a member selected from the group consisting of sorbitol, lactose, fructose, glucose, mannose, galactose, talose, sodium chloride, potassium chloride, sodium citrate and mannitol. Can be formed by providing a hole-outlet opening with a uniform discharge dimension.

  The outlet 60 can have any shape, such as circular, triangular, square, oval, elliptical, etc., for the release of a uniform dose of drug from the dosage form.

  If more than one outlet opening is present in the dosage form, the outlet is assumed to be positioned to expose the drug composition to the external environment, assuming that the outlet is located in the dosage form. Can exist in spaced relation on two or more surfaces.

  The drug composition of the present invention can be prepared according to known methods, for example, as granules, as dry blends, as coprecipitates, roller compression blends, and the like. The drug composition is preferably prepared as a granule.

  Various processing methods can be used to promote uniformity of mixing between the pharmaceutical substance 31 and the solubilizing substance, preferably the surfactant 33, in the drug composition 30. In one method, the drug and surfactant are each micronized to a nominal particle size of less than about 200 microns, preferably to a nominal particle size of less than about 100 microns, more preferably to a nominal particle size of about 50 microns. Standard micronization methods such as jet milling, freeze grinding, bead milling, etc. can be used.

  Alternatively, the drug and solubilizing material can be dissolved in a common solvent to produce a mixture at the molecular level and co-dried to a uniform material. The resulting material can be crushed and sieved to a free flowing powder. The resulting free-flowing powder can be further granulated, optionally with optional structural polymer, by sieving a wet mass or by fluid bed granulation to form the drug composition of the present invention (in the form of granules).

  Alternatively or additionally, the pharmaceutical substance 31 and the solubilizing substance 33 can be melted together at an elevated temperature to mix the drug in the solubilizing substance, preferably a surfactant, and then set to room temperature. The resulting solid can be ground, sized and optionally further granulated with a structural polymer.

  In yet another process, the pharmaceutical substance 31 and the solubilizing substance 33 are dissolved in a common solvent or solvent blend and spray dried to form a coprecipitate, which is then further optionally flowed. Incorporated with the structural polymer by standard granulation by floor treatment or wet material sieving.

  In yet another process, pharmaceutical substance 31 and solubilizing substance 33 are dissolved in a common solvent or blend of solvents, and then the pharmaceutical substance / surfactant solution is optionally added directly in a fluid bed granulation process. Can be sprayed onto the structural polymer.

  The drug composition of the present invention can then be formulated into the dosage form of the present invention. The drug composition 30 in the dosage form is preferably formed by compression of the pharmaceutical substance 31, the solubilizing substance 33, preferably a surfactant and, if present, the structural polymer 32. For the preparation of an osmotic dosage form, one or more drug compositions are compressed into a stacking position where a push layer is prepared in the dosage form in contact with at least one of the drug compositions; Incorporated.

  Each drug composition is prepared by mixing the pharmaceutical substance 31 with the solubilizing substance 33 and further ingredients (eg structural polymer 33) in a homogeneous mixture.

Alternatively, the drug composition 30 is typically separated from the particles by grinding to provide the size of the pharmaceutical substance and any associated polymer used to process the drug composition as a core containing the compound. Can be formed. Methods for forming such particles include, but are not limited to, granulation, spray drying, sieving, freeze drying, grinding, milling, jet milling, pulverization and chopping to form the intended micron size. Is included. The method is a micro fine grinding mill, fluid energy grinding mill, grinding mill, roller mill, hammer mill, friction mill, chaser mill, ball mill, vibration ball mill, impact fine grinding mill, centrifugal fine grinding device, coarse grinding device, fine grinding device, It can be implemented by a size reduction device such as. The size of one or more particles can be ensured by sieving including a grizzly screen, flat screen, vibrating screen, rotating screen, shaking screen, oscillating screen, reciprocating screen and the like. Methods and apparatus for preparing drug and / or carrier particles are described in Remington's Pharmaceutical Sciences , 18th Ed. , Pp. 1615-1632 (1990); Chemical Engineers Handbook , Perry, 6th Ed. , Pp. 21-13-21-19 (1984); Journal of Pharmaceutical Sciences , Parrot, Vol. 61, no. 6, pp. 813-829 (1974); and Chemical Engineer, Hixon , pp. 94-103 (1990).

  Exemplary solvents suitable for preparing drug compositions and / or push layers for dosage forms comprise aqueous or inert organic solvents that do not adversely affect the materials used in the system. Such solvents include, but are not limited to, aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatic, heterocyclic solvents and mixtures thereof. Includes members selected from the group. Suitable examples of solvents include, but are not limited to, acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl Ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride nitroethane, nitropropane tetrachloride, ethyl ether, isopropyl ether, cyclohexane, Nothing like cyclooctane, benzene, toluene, naphtha, tetrahydrofuran, diglyme, water, sodium chloride, calcium chloride, etc. It encompasses aqueous solvent containing a salt, and acetone and water, acetone and methanol, acetone and ethyl alcohol, mixtures thereof, such as methylene dichloride and methanol, and ethylene dichloride and methanol.

  Similarly, the push layer 40 can be prepared according to a known method according to the above-mentioned method by mixing appropriate components (for example, osmoagent, osmopolymer, etc.) under appropriate conditions.

  The semipermeable wall 20 can likewise be prepared according to known methods, for example by pan coating and mixing the appropriate ingredients and applying the resulting mixture to the dosage form.

  In accordance with standard methods known in the art, the components of the dosage form (eg, one or more drug compositions, push layer, semipermeable wall, outlet opening, etc.) are combined to produce the present invention. The dosage form can be formed. More particularly, the core of the dosage form comprising one or more drug compositions and, if present, the push layer is first prepared, preferably by compression. A semi-permeable wall is then coated on the core and one or more outlet openings are provided through the semi-permeable wall to expose the one or more drug compositions to the external environment.

For example, the dosage form can be formulated by wet granulation. In the wet granulation method, the drug, optional structural polymer and solubilizing material, preferably a surfactant, are blended using an organic solvent such as denatured anhydrous ethanol as the granulation liquid. Any additional excipients can then be dissolved in a portion of the granulation liquid, such as the solvent described above, and the drug blend while continuously mixing this latter prepared solution in a blender Add slowly to. The granulation liquid is added until a wet blend is produced, and then the wet mass blend is forced through a predetermined screen on the oven tray. The blend is dried in a forced air oven at 24 ° C to 35 ° C for 18-24 hours. The dried granules are then sized. Next, magnesium stearate or another suitable lubricant is added to the drug granules and the granules are placed in a milling jar and mixed on a jar mill for up to 10 minutes. The composition e.g., compressed into a layer by Manesty ^(R) press or Korsch LCT during pressing.

  For a two-layer core (ie, a dosage form comprising a drug composition and a push layer), the drug composition is compressed, and a similarly prepared push layer granule is compressed against the drug composition . This intermediate compression is typically performed under a pressure of about 50-100 Newtons. Final stage compression is typically carried out under pressures of 3500 Newtons or more, often 3500-5000 Newtons.

  If the core comprises two or more drug compositions and a push layer, each drug composition prepared as described above is individually compressed. The push layer is then pressed against at least one drug composition in an intermediate compression step as described above. The final compression of the multilayer core is then applied as described above.

Then single-layer, two-layer or multi-layer of the compressed core dry coater press, ^e.g., fed to Kilian (R) Dry Coater press, and then coated with semipermeable wall material according to known methods.

  In another formulation method, the drug comprising the drug composition and other ingredients are blended and compressed into a solid layer. The layer has a dimension that corresponds to the internal dimension of the area that the layer can occupy in the dosage form, and further, if included, corresponds to the push layer to form an array in contact therewith Have dimensions to The drug and other ingredients are also blended with a solvent, mixed into a solid or semi-solid form by conventional methods such as ball milling, calendering, stirring or roll milling and then compressed to a preselected shape. . If a push layer is then included, the push layer component is placed in contact with the drug composition in a similar manner. One or more drug compositions and the layered product of the push layer can be processed by a conventional two-layer press method. The compressed core can then be coated with a semipermeable wall material according to known methods.

  Another process that can be used comprises blending the powdered ingredients for each layer in a fluid bed granulator. After the powdered component is dry blended in the granulator, a granulating liquid, such as poly (vinyl pyrrolidone) in water, is sprayed onto the powder. The coated powder is then dried in a granulator. This step granulates all the components present there while adding the granulating liquid. After the granules are dried, a lubricant such as stearic acid or magnesium stearate is mixed into the granules using a blender, such as a V-blender or tote blender. The granules are then compressed in the manner described above.

  Pan coating can be conveniently used to provide the semipermeable wall 20 of the finished osmotic dosage form. In a pan coat system, a wall-forming composition (comprising a semi-permeable polymer and optionally further substances) is applied to a compressed monolayer, bilayer or multi-layer core (one or more drug layers and present). If appropriate, it is deposited by continuous spraying of the appropriate wall composition onto the extruded layer and then mixing in a rotating pan. Often pan coaters are used because of their availability on a commercial scale.

Alternatively, other known coating methods can be used to coat the compressed core. For example, the semipermeable wall 20 of the dosage form can be formed in one way using air suspension. This method involves suspending and rotating a compressed single-layer, double-layer or multi-layer core in a stream of warm air and a semi-permeable wall-forming composition until the semi-permeable wall is applied to the core. Consists of. The air suspension method is well suited for independently forming the semipermeable walls of the dosage form. Air suspension method, US Pat. No. 2,799,241, J. Am. Phar. Assoc . , Vol. 8, pp. 451-459 (1959) and the above. , Vol. 49, pp. 82-84 (1960). Alternatively, the dosage form for example as a cosolvent for the wall forming material, using methylene dichloride methanol, can be coated with a Wurster ^(R) air suspension coater. Alternatively, using a suitable co-solvent, it can be used Aeromatic ^(R) air suspension coater.

  Once coated, the semipermeable wall 20 is dried in a forced air oven or a temperature and humidity control oven to remove any one or more solvents used during manufacture from the dosage form. To do. Drying conditions are usually selected based on available equipment, ambient conditions, solvent, coating, coating thickness, and the like.

  The drug composition, push layer and / or dosage form are preferably dried to remove volatile organic and inorganic solvents to a level that is pharmaceutically acceptable and / or optimal for manufacturing. The drug composition, push layer and / or dosage form is more preferably less than about 10% humidity, even more preferably less than about 5% humidity, and most preferably less than about 3% humidity.

  One or more outlet openings are provided at the end of the drug composition of the dosage form according to known methods, for example by perforation. Alternatively, one or more outlet openings can be provided at the end of the drug composition of the dosage form by erosion or leaching.

  Thus, the dosage form can be configured with one or more outlets in spaced relation on one or more surfaces of the dosage form.

  Through the semipermeable wall, the exit opening can be formed using perforations, including mechanical and laser perforations. Such outlets and devices for forming such outlets are described in US Pat. No. 3,916,899 by Theeuwes and Higuchi and in US Pat. No. 4,088,864 by Theeuwes et al. It is disclosed.

  The leaching or eroding outlet opening can or can be formed from a material or polymer that erodes, dissolves or leaches out of the outer semi-permeable (outer) wall, thereby forming the outlet opening. Can be. The material or polymer can be, for example, erodible poly (glycol) acid or poly (milk) acid in a semipermeable wall, gelatinous filaments, water-removable poly (vinyl) alcohol, fluid-removable pore formers, for example Leachable compounds such as inorganic or organic salts, oxides or carbohydrates can be included. The one or more outlets leach a member selected from the group consisting of sorbitol, lactose, fructose, glucose, mannose, galactose, talose, sodium chloride, potassium chloride, sodium citrate and mannitol, and are uniform Can be formed by providing a hole exit opening having a dimension that provides a smooth discharge. The outlet can have any shape such as a circle, triangle, square, ellipse, and the like.

  The dosage form can further be optionally coated with a further water-soluble topcoat that can be colored (eg, OPADRY colored coating) or transparent (eg, OPADRY Clear).

  The dosage form may further optionally comprise a smoothing coat whose smoothing coat is applied to the drug core compressed according to known methods prior to application of the semipermeable wall. Suitable examples of preparations and ingredients that can be used in the smoothing coat include, but are not limited to, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose, and the like. The coating may further optionally contain 400-6000 molecular weight polyethylene glycol, 2500-1,000,000 molecular weight polyvinylpyrrolidone, and the like.

  The dosage form of the present invention is for a long period of time, preferably greater than about 1 hour, more preferably at least 4 hours, even more preferably at least about 8 hours, more preferably at least about 10 hours, even more preferably at least about Provide controlled release of the pharmaceutical agent, preferably topiramate, for up to 14 hours, even more preferably at least 18 hours, even more preferably at least 20 hours, even more preferably at least 22 hours, even more preferably up to about 24 hours. . The dosage forms of the present invention preferably provide controlled release of the pharmaceutical agent over a period of about 2 to about 24 hours, more preferably about 4 to about 24 hours.

  In one aspect of the invention, the release of the drug from the dosage form of the invention provides an effective treatment over about 24 hours. In another embodiment of the invention, the dosage form releases the drug over about 16 to about 24 hours after administration.

  In one embodiment of the invention, the dosage form comprises an optional immediate release drug overcoat, which provides immediate drug delivery (ie within less than about 1 hour after administration) and the dosage form is preferably at least Continue for about 8 hours, more preferably about 12 hours, even more preferably about 16 hours, even more preferably about 18 hours, even more preferably about 22 hours, even more preferably about 24 hours, until drug release is terminated Provide controlled drug delivery.

Exemplary dosage forms of the present invention exhibit T ₇₀ values greater than about 8 hours, preferably greater than about 10 hours, more preferably greater than about 12 hours, even more preferably greater than about 16 hours, and about 12 hours. Release the drug, preferably topiramate, over a continuous period of time, more preferably greater than about 16 hours, and even more preferably about 24 hours.

  Within about 2 hours after administration, an exemplary dosage form of the present invention has a substantially zero dimensional release rate or a substantial increase, depending on the composition of the drug (s) and push layer. The drug, preferably topiramate, is released at a release rate. Drug release preferably continues over a long period of time. After prolonged delivery, the drug continues to be delivered for several more hours until the dosage form is exhausted or expelled from the GI tract.

In the two-layer embodiment of the once-daily dosage form according to the present invention, the dosage form has a T ₇₀ of about 15 hours to about 18 hours, preferably about 17 hours, and a continuous period, preferably at least 24. Provided time, release of drug, preferably topiramate. The dosage form preferably releases the drug at a substantially zero dimensional release rate.

In a three layer embodiment of the present invention, the dosage form of the present invention comprises two drug compositions and a push layer, wherein the amount and / or concentration of the drug in the first drug composition is the second Less than the amount and / or concentration of the drug in the drug composition. Exemplary three-layer dosage forms of the present invention exhibit T ₇₀ values greater than about 8 hours, preferably greater than about 12 hours, more preferably greater than about 14 hours, and greater than about 16 hours, preferably about 24 hours. The drug, preferably topiramate, is released over a continuous period of time. The dosage form preferably releases the drug at a substantially ascending release rate.

  In one embodiment of the invention, the dosage form of the invention releases the pharmaceutical substance (drug) at various release rates between about 1% / hour and about 12% / hour over a long period of time.

  In one embodiment of the invention, the dosage form releases the pharmaceutical substance with a substantially zero dimensional release rate. In another embodiment of the invention, the dosage form releases the pharmaceutical substance at a substantially ascending release rate. In yet another embodiment of the invention, the dosage form releases the pharmaceutical substance at a release rate that results in a substantially elevated drug plasma concentration.

  The present invention further relates to a method of treatment comprising the step of administering any drug composition or dosage form of the present invention to a patient in need of treatment. The drug composition and / or dosage form comprises a pharmaceutical agent, preferably topiramate, in the range of about 1 mg to about 750 mg.

  In one embodiment, the method treats a pharmaceutical agent, preferably topiramate, administered from a dosage form comprising a desired amount of the pharmaceutical agent and a solubilizing agent, preferably a surfactant. Orally administering to a patient in need.

  The present invention further provides a method for administering a pharmaceutical agent, preferably topiramate, to a patient and a method for producing a desired drug plasma concentration of topiramate. One aspect of the present invention is a method for orally administering to a patient in need of treatment a dosage form in which the drug for its intended treatment is administered at a controlled rate over a continuous period of up to about 24 hours. It is. In another embodiment of the present invention, the method comprises orally administering a therapeutic dose of a pharmaceutical agent, preferably topiramate, to a patient in need of treatment from a single dosage form in which topiramate is administered over a period of about 24 hours. Comprising.

  The present invention further provides an oral controlled release dosage form of a pharmaceutical substance, preferably topiramate, wherein the pharmaceutical substance is released from the dosage form at a substantially zero dimensional release rate. It relates to a treatment comprising the step of administering to

  The present invention further provides administration of an orally controlled release dosage form of a pharmaceutical substance, preferably topiramate, to a patient in need of treatment, wherein the pharmaceutical substance is released from the dosage form at a substantially ascending release rate. The present invention relates to a treatment method comprising the steps of:

  The present invention further provides an oral controlled release dosage form of a pharmaceutical substance, preferably topiramate, which is released from the dosage form at a rate that results in a drug plasma concentration at which the pharmaceutical substance substantially increases. It relates to a method of treatment comprising the step of administering to a patient in need.

  The present invention further includes epilepsy, migraine, glaucoma and other ophthalmic disorders (including diabetic retinopathy) comprising the step of administering any drug composition or dosage form of the present invention to a patient in need of treatment. ), Essential tremor, restless limb syndrome, obesity, weight loss, type II diabetes, syndrome X, oral glucose intolerance, diabetic skin damage, cluster headache, neuralgia, neuropathic pain (including diabetic neuropathy) High blood sugar level, high blood pressure, high lipid, bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, OCD, PTSD, ADHD, impulse control disorder (bulemia, bulimia ( Binge eating), substance dependence, etc.), ALS, asthma, autism, autoimmune disorders (including psoriasis, rheumatoid arthritis, etc.), chronic neurodegenerative disorders, acute neurodegeneration, Sleep time to a method for promoting the healing of treat or wounds a disorder selected from apnea and the group consisting of other sleep disorders.

  The disorder preferably consists of epilepsy, migraine, diabetic retinopathy, diabetic neuropathy, diabetic skin injury, obesity, weight loss, type II diabetes, syndrome X, impaired oral glucose tolerance, high blood sugar level and hypertension Selected from the group.

  In one embodiment, the push layer comprises a replacement composition in a layered arrangement that contacts the tablet core as shown in FIG. The push layer comprises an osmopolymer that absorbs water or biological fluid and swells to push the drug composition through an outlet opening through the semipermeable membrane. A polymer with suitable absorbency can be referred to herein as an osmopolymer. An osmopolymer is a swellable, hydrophilic polymer that interacts with water and aqueous biological fluids and typically swells or expands to a high degree with a volume increase of 2-50 times. The osmopolymer may be uncrosslinked or crosslinked.

  Push layer 40 preferably comprises from about 20 to about 375 mg of osmopolymer. The osmopolymer in the push layer preferably has a higher molecular weight than the osmopolymer in the drug layer.

Representative of fluid-absorbing displacement polymers are poly (alkylene oxide) having a number average molecular weight of 1 to 15 million, as represented by poly (ethylene oxide), and the alkali is sodium, potassium or lithium 500,000 Comprising a material selected from poly (alkali carboxymethylcellulose) having a number average molecular weight of ˜3,500,000. Extrusion - replacing Further examples of polymers for the preparation of the composition, Carbopol ^(R) acid carboxymethyl polymer, carboxymethyl also known polyallyl sucrose and crosslinked acrylic as polymethylene polymer and 250,000～4, to form a hydrogel, such as carboxyvinyl polymers having a molecular weight of 000,000 polymer; Cyanamer ^(R) polyacrylamide; crosslinked water-swellable indene maleic anhydride polymers; Good having a molecular weight of 80,000 to 200,000 An osmopolymer comprising: -rite ^(R) polyacrylic acid; Aqua-Keeps ^(R) acrylate polymer polysaccharide consisting of condensed glucose units such as diester cross-linked polygulrane; Representative polymers that form hydrogels are US Pat. No. 3,865,108 approved to Hartop, No. 4,002,173 granted to Manning, No. approved to Michaels. No. 4,207,893 and Handbook of Common Polymers , Scott and Roff. Chemical Rubber Co. , Cleveland, OH.

  In one embodiment, the push layer comprises from 0 to about 75 mg, and preferably from about 5 to about 75 mg of an osmotic pressure effective compound, osmoagent. Compounds effective by osmotic pressure are also known as osmoagents and as solutes effective by osmotic pressure. The osmoagents that can be found in the drug layer and push layer in the dosage form are substances that exhibit an osmotic activity gradient through the semipermeable membrane. Suitable osmoagents are sodium chloride, potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid, raffinose, sucrose, glucose A substance selected from the group consisting of lactose, sorbitol, inorganic salts, organic salts and carbohydrates.

  The push layer can further comprise a therapeutically acceptable vinyl polymer. Vinyl polymers include poly-n-vinyl amide, poly-n-vinyl acetamide, poly (vinyl pyrrolidone), also known as poly-n-vinyl pyrrolidone, poly-n-vinyl caprolactone, poly-n-vinyl-5-methyl- 2-pyrrolidone and a poly-n-vinylpyrrolidone copolymer with one member selected from the group consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl laurate and vinyl stearate It comprises a viscosity-average molecular weight of 5,000-350,000, represented by one member selected from the group. The push layer preferably comprises from about 0.01 to about 25 mg of vinyl polymer.

  The push layer can further comprise 0 to about 5 mg of a non-toxic colorant or dye. The colorant is FD & C No. 1 Blue dye, FD & C No. 1 4 Food and Drug Administration Colorants (FD & C) such as red dye, red ferric oxide, yellow ferric oxide, titanium dioxide, carbon black and indigo.

  The push layer can further comprise a lubricant. Typical lubricants are sodium stearate, potassium stearate, magnesium stearate, stearic acid, calcium stearate, sodium oleate, calcium palmitate, sodium laurate, sodium ricinoleate and potassium linoleate and such lubricants. Comprising a member selected from the group consisting of a blend of agents. In one embodiment, the amount of lubricant included in the push layer 40 is about 0.01 to about 10 mg.

  The push layer can further comprise an antioxidant that prevents oxidation of the component comprising the expandable preparation. In one embodiment, the push layer comprises 0.00 to about 5 mg of antioxidant. Representative antioxidants include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3 tert-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium isoalcorbate, dihydroguaretic acid , Potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E, 4-chloro-2,6-ditertiary butylphenol, alpha-tocopherol and propyl gallate One member.

  Controlled release topiramate dosage forms can consist of coated granules comprising both topiramate and a solubilizing material, preferably a surfactant. The coated granule can further comprise a viscous material or a binder or both.

  One advantage of the present invention is the ability to modify the content and amount of granule coating and granule composition to modify the release rate of topiramate from the dosage form.

  For example, the composition of the controlled release topiramate dosage form can be selected so that the release rate of topiramate is at its maximum for at least 2 hours in an in vitro release rate assay.

  Alternatively, a controlled release topiramate dosage form whereby the release rate of topiramate is at its maximum in an in vitro release rate assay over at least 3 hours, 4 hours, 6 hours, 8 hours, 10 hours or at least 12 hours. The composition can be selected.

  Additionally or alternatively, the release rate of topiramate is about 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours after in vitro release rate assay. The composition of the controlled release topiramate dosage form reached after 6.5 hours, 8 hours, 10 hours, 12 hours, 14 hours or 16 hours can be selected.

Illustrative description of the invention The following examples illustrate the invention, and these and other equivalents will be apparent to those skilled in the art in light of the specification, drawings and appended claims of the invention. As such, they should not be considered as limiting the scope of the invention in any way.
[Example 1]

  For comparative purposes, a regular topiramate drug formulation was prepared as follows.

  First, a binder solution was prepared. 3 kg of polyvinylpyrrolidone (K29-32; average molecular weight of 40,000) was dissolved in 17 kg of water. Next, fluidized bed granulation of 17.28 kg of topiramate, 5.75 kg of polyethylene oxide N-80 (about 2 million molecular weight) and 32.16 kg of poloxamer 407 and 1.5 kg of polyvinylpyrrolidone identified as K29-32. Added to the bowl of the apparatus. The dried raw material was fluidized and mixed while spraying 10 kg of binder solution from three nozzles onto the powder. The granules were dried in a fluidized bed chamber to an acceptable humidity level. The coated granules were sized using a Fluid Air mill with a 7-mesh screen. The granules were transferred to a tote tumbler, mixed with 12 g butylated hydroxytoluene and lubricated with 1.2 kg stearic acid and 600 g magnesium stearate.

FIG. 1 shows the adhesion observed with a conventional preparation without the use of coated granules.
[Example 2]

  One kilogram of coated granules was processed as follows. 304 grams of topiramate free acid, 566 grams of LUTROL F127 and 30 grams of polyvinylpyrrolidone 12PF (PVP) were passed through a # 40 mesh sieve and dry mixed. Prior to this sizing operation, the drug particle size was nominally about 100 microns, and LUTROL F127 was refined to a finely divided particle size. 100 grams of POLYOX N80 was blended into the mixture through a # 50 mesh screen. The mixed powder was introduced into a small bowl mixer. When the mixer was started and 100 ml of absolute ethanol was slowly and continuously added to the mixture while mixing the powder, a uniform wet mass was formed. The wet mass was removed from the mixer, spread on an open tray and air dried overnight in a fume hood. The dried material was then passed through a # 20 mesh sieving screen.

  The resulting bulk granules were transferred to a mini-Glatt fluid bed granulator (FBG) and fluidized in a stream of warm dry air. A solution of wall forming polymer was spray coated onto the granules. The solution consisted of 5 weight percent PVP 12PF dissolved in water. Spraying was continued until the granules accumulated a 24 percent PVP wall coating weight. During the spraying process, the granule bed was removed 4 times and passed through a # 16 mesh screen each time to break up the agglomerates. The granule bed was also sized through a 16-mesh sieve after 24 weight percent was coated.

  The PVP-coated granules were returned to the FBG unit and spray coated with the second wall forming composition. This solution consisted of 5 weight percent methylcellulose A15LV (MC) dissolved in water. This second solution was spray coated onto the granules and a small sample of the granules was removed during the process at weight gains representing 1%, 2% and 3% MC. Each fraction was sized through a # 16 screen. This produces coated granules having a particle size of about 1.2 millimeters (47 mils).

  These steps formed 4 batches of coated granules, 1 sample of granules coated with a single layer of PVP and 3 batches of granules coated with 2 layers of PVP / MC.

For comparative testing of their adhesion resistance, bare core granules (before any coating), granules containing 24% PVP, granules containing 24% PVP + 1% MC, granules containing 24% PVP + 2% MC and 24% PVP + 3 Samples of granules containing% MC were assembled. A small portion of each was placed on a hard flat surface at room temperature. To test for adhesion, each sample was manually pressed with a spatula and a shear force was applied. Resistance to adhesion was observed as follows: bare granules << 0% MC <1% MC <2% MC <3% MC. The relatively thick layer of PVP provided a thick subcoat for a more complete coating of the granule core. A thin cellulose topcoat provided improved resistance to crushing and adhesion.
[Example 3]

  A solubilized granule of granule core and coating composition approximately equal to the granules described in Example 2 was produced on a 30 kg scale using a pilot production scale device. The resulting coated granules were fed to a Korsch multilayer press to measure adhesion. After these granules were formulated into tablets for about 30 minutes, the surface of the press turret was clean and the adherent material was almost completely absent.

  The delivery system was then manually processed using this batch of coated granules and tested for drug release. The performance of these systems with 30 kg scale coated granules was compared to the performance of a 1 kg scale encapsulated system by measuring the release rate.

FIG. 8 shows the topiramate release pattern of controlled release topiramate dosage forms with coated granules prepared in 1 kg and 30 kg batch sizes. The results show that the release patterns of both production systems were comparable. That is, no difference was observed in the time to reach the maximum release rate, the number of maximum release rates and the period during which the maximum release rate was maintained.
[Example 4]

  The coated granules of Example 3 were manually compressed into tablets with a push layer. The drug layer weight was fixed at 182 mg and the push layer weight was fixed at 60 mg. The drug content was about 45 mg. The resulting tablets were coated with a rate control membrane (semi-permeable membrane), 40 mil holes were drilled and dried.

FIG. 9 shows how a two-layer granule coating can extend the period of zero-dimensional release kinetics. In all examples, the first layer of the granule coating was 23% PVP. An outer second layer containing MC was added. Comparison of the release patterns obtained with the 0% MC and 3% MC granule coating layers shows that a two-layer granule coating can extend the duration of zero-dimensional drug delivery. That is, a second layer of 3% MC extended the zero-dimensional release rate by at least 2 hours.
[Example 5]

  A polyethylene oxide encapsulated drug formulation of the present invention was prepared as follows.

  First, an encapsulation solution was prepared. 4.5 kg of polyethylene oxide N-10 (about 1 million molecular weight) was dissolved in 70.5 kg of water. The 26 kg drug granules described in Example 4 were then added to the fluid bed granulator bowl. The granules were fluidized and mixed while spraying 50 kg of coating solution onto the powder from a nozzle. The coated granules were dried in a fluidized bed chamber to an acceptable humidity level. The coated granules were sized using a fluidized air mill with a 7-mesh screen. The granules were transferred to a Gemco rotating tumbler, mixed with 5.6 g butylhydroxytoluene and lubricated with 565 g stearic acid.

Use tests were performed using a Korsch multilayer press. The feasibility of the method was clearly demonstrated: no adhesion of drug granules on the turret was observed during the 30 minute run time. The first (non-encapsulated) granule used as a control (Example 1) showed significant adhesion in the first 5 minutes of compression at comparable parameters (see FIG. 1).
[Example 6]

  Coated granules having a core comprising topiramate, LUTROL F127, POLYOX N80 and PVP, the composition and weight of the wall (semi-permeable wall) of the inner coating layer of 23% PVP and the outer coating layer of 3% MC Was encapsulated on a 1 kg scale according to the method described in Example 2. Four batches of coated granules were encapsulated with the two layers of walls. Each batch represented a different ratio of solubilized surfactant to drug. The delivery system was manually processed according to the method of Example 2 and tested for drug release.

FIG. 10 represents the release profile of the generated system. Drug release was 99% by 24 hours. The uniformity from system to system was excellent for the ratio of LUTROL F127 / drug in the range of 1.86 to 1.18. Variation was observed at the Lutrol F127 / drug ratio = 0.93. Accordingly, the optimal ratio of topiramate / LUTROL F127 within the granules is generally within the range of about 1.9 to 1.2. The smaller the ratio, the greater the zero-dimensional release period, the slower the time to reach the maximum release time, and the higher the maximum release rate number.
[Example 7]

Changes in the granule coating can change the drug delivery rate. FIG. 11 shows how changing the bilayer coating of topiramate granules can change the delivery rate. Two compositions were prepared. Granules containing 28.8 / 53.6 / 9.58 / 1 / 0.02 topiramate / LUTROL F127 / PVP K2932 / POLYOX N80 / stearic acid / Mg stearate / BHT were coated with 23% MC. The first was two layers consisting of 23% PVP inner coating layer with 3% MC outer coating layer. The second was a granule coated with a single layer of 10% POLYOX N10. The results showed differences in the maximum release rate figures, and the two layers significantly reduced the maximum release rate.
[Example 8]

Preparations were prepared from 35/52/10/3 topiramate / refined LUTROL F127 / POLYOX N80 / PVP 12PF to test the effect that the weight of a single layer coating could have on adhesion resistance. This mixture was coated to the target percentage weight with methylcellulose A15LV to form coated granules. 180 mg of these coated granules were compressed with 60 mg of push layer (60 mg of 73.7 / 20/5/1 / 0.25 POLYOX 303 / NaCl / PVPK2932 / Fe ₂ O ₃ / stearic acid / BHT). Adhesion resistance was measured by the force of ejecting the tablet from the die in manual compression mode.

The test results are shown in FIG. The adhesion resistance due to 3% MC was weak, the adhesion resistance due to 4% MC was moderate, and the adhesion resistance due to 7% or more MC was good. FIG. 12 shows that a dosage form comprising 13% MC-coated granules has a period of zero-dimensional release kinetics that is extended by 2 hours compared to (a) 3% MC; (b) 3 It shows a delay of more than 2 hours in reaching the maximum release rate compared to% MC.
[Example 9]

In order to test the effect that a two-layer coating could have on adhesion resistance, a preparation was prepared from 35/52/10/3 topiramate / refined LUTROL F127 / POLYOX N80 / PVP 12PF. This mixture was coated with PVP 12PF and then with methylcellulose A15LV to the target percentage weight to form coated granules. 180 mg of these coated granules were compressed with 60 mg of push layer (60 mg of 73.7 / 20/5/1 / 0.25 POLYOX 303 / NaCl / PVP K2932 / Fe ₂ O ₃ / stearic acid / BHT) . Tablets are 1/10 mil smooth coat of 90/10 HEC / LUTROL F127 and 2 membranes-6 / mil (1 mil = 1/1000 of an inch) consisting of 55/40/5 EC100 cps / HPCEFX / MYRJ 52S And a 6 mil membrane of 70/30 CA 398-10 / Poloxamer 188 with 1 × 40 mil openings. Adhesion resistance was measured by the force of ejecting the tablet from the die in manual compression mode. The release rate was measured using the USPII method.

The results are shown in FIG. The results show that the two layers of coating provide adhesion resistance compared to a single wall. The release pattern also indicates that adhesion resistance can be achieved in an in vitro assay without changing the release characteristics of the dosage form.
[Example 10]

Granules were prepared as in Example 8 and coated with two layers. The inner layer was 10% PVP and various weight percentages of MC: 3%, 7% and 10% were applied to the outer coating layer. FIG. 14 shows how changing the coating weight of a single layer changes the time to reach the maximum delivery rate of topiramate. Increasing the MC weight percentage in the outer coating layer increased the time to reach the maximum release rate and decreased the duration of the zero-dimensional release rate.
[Example 11]

Two-layer osmotic dosage form of topiramate The drug composition of the present invention was prepared as follows. An aqueous solution of five surfactants was prepared. The surfactants selected were 4 grades: ethylene oxide / propylene oxide / ethylene oxide (LUTROL grades F127, F87, F108 and F68) and PEG-40 stearate (MYRJ 52). Solutions were prepared at concentrations of 1, 5 and 15 weight percent. The aqueous surfactant blend solution was cooled as necessary to facilitate complete dissolution of the surfactant prior to drug solubility studies. Each surfactant had a different HLB value and ranged from 16.9 to 29 HLB units.

  The aqueous surfactant solution was equilibrated to a constant temperature in a 37 ° C. water bath. The additive-free topiramate drug was then slowly added to the surfactant solution with stirring in an increase of about 10 mg until the drug was no longer dissolved. A control sample of drug dissolved in deionized water without surfactant was included for comparison purposes. The resulting saturated solution of drug was filtered through a 0.8 micron filter and analyzed for drug concentration by refractive index chromatography. The resulting solubility values were plotted as a function of both surfactant concentration and the hydrophilic-lipophilic equilibrium value of each surfactant.

  This method disclosed three facts. The solubility of topiramate in water increased with each surfactant. The solubility of the drug was higher in the presence of each surfactant compared to the control where the solubility in deionized water without surfactant was 13.0 mg / ml. Secondly, higher concentrations of surfactant were more effective at solubilizing drugs than those at lower concentrations. Third, the most effective HLB value to increase the solubility of this drug was at the lower limit in the range of 16.9-22. Each of the three concentrations of surfactant formed the maximum solubility of topiramate with HLB encompassing this range of HLB values.

  According to this finding, the drug composition of the present invention was prepared. First, 55 grams of topiramate, 30 grams of granular LUTROL127, 11.5 grams of polyethylene oxide (PEO) N80 and 3 grams of polyvinylpyrrolidone (PVP) 2932 are passed through a # 40 mesh sieve and the composition is passed through PVP. Acted as a binder and PEO as a structural polymer (carrier) was dry mixed into a homogeneous blend. The molecular weight of polyethylene oxide was 200,000 grams / mole, and the molecular weight of polyvinyl pyrrolidone was about 10,000. Polyethylene oxide acts as a carrier and structural polymer 32. Polyvinylpyrrolidone acts as a drug layer binder 36. The dry mixture was then wetted with anhydrous ethyl alcohol SDA3A and stirred to form a uniform wetted material. The wetted material was then passed through a 20-mesh sieve to form a wetted noodle. The noodles were air dried overnight under ambient conditions and then re-passed through a # 20 mesh screen to form free-flowing granules. Finally, 0.5 grams of magnesium stearate of drug layer lubricant 34 over the granules was passed through a # 60 mesh sieve and swirled into the granules. This formed drug composition granules.

  The extruded layer granules were prepared in a similar manner. First, 89 grams of polyethylene oxide 303, 7 grams of sodium chloride and 3 grams of hydroxypropyl methylcellulose E5 were passed through a # 40 mesh screen and dry mixed. Polyethylene oxide had a molecular weight of about 7,000,000 and hydroxypropylmethylcellulose had a molecular weight of about 11,300. Polyethylene oxide served as push layer osmopolymer 41 and hydroxypropyl methylcellulose provided push layer binder 43. The dry mixture was then wetted with anhydrous ethyl alcohol SDA3A and mixed into a uniform wetted material. The material was passed through a # 20 mesh screen to form a noodle that was air dried overnight. The noodles were then passed again through a # 20 mesh sieve to form free flowing granules. Finally, 0.5 grams of minus # 60 mesh of magnesium stearate and push layer lubricant 44 were spun into the blend. This formed extruded layer granules.

  Part of granules of drug composition weighing 182 mg was filled into a 3/16 inch (4.8 mm) diameter die cavity and a 3/16 inch (4.8 mm) biconvex round tableting device. Packed lightly. 60 mg of push layer granules were then filled into a die, compressed, and applied to the drug layer using a Carver press using 0.5 ton pressure. Six of these bilayer tablets were compressed.

  The tablets were then coated with 3 layers. First, a solution was prepared by dissolving 57 grams of hydroxyethylcellulose 250L and 3 grams of polyethylene glycol in 940 grams of deionized water. Hydroxyethylcellulose had a molecular weight of about 90,000 and polyethylene glycol had a molecular weight of 3,350. This formed a smooth coating solution to provide a smooth coatable surface for subsequent coatings.

  Six active tablets were mixed into a tablet bed of placebo tablets weighing 0.5 kg. The tablet bed was coated with a smooth coating solution in an Aeromatic coater. The solution was applied in a stream of warm dry air until a coating weight of about 4 mg accumulated on each active tablet. The coating solution was continuously stirred during the coating process. The resulting smooth coat provided a smooth tablet base and rounded the corners of the tablets. The resulting smooth tablets were dried in a forced air oven at 40 ° C. overnight. (This smooth coat is optional and is useful for rounding the corners of tablets, especially when the tablet land has flash from the compression process).

  The following coating solution was prepared by stirring and dissolving 269.5 grams of ethyl cellulose 100 cps, 196.0 grams of hydroxypropylcellulose EFX and 24.5 grams of MYRJ 52 in 6510 grams of absolute ethanol SDA3A. . Ethylcellulose had a molecular weight of about 220,000 and hydroxypropylcellulose had a molecular weight of about 80,000. The solution was left at ambient temperature. This formed a membrane subcoat solution.

  Smooth tablets from above were mixed into a placebo tablet bed weighing 1.2 kg and the resulting mixed bed was filled into a Vector LCS pan coater with a 14 inch (35.6 cm) diameter coated pan. . The membrane subcoat solution was then sprayed onto the tablet bed in the coater in a warm air stream. The coating solution was continuously stirred during the process. The solution was applied in this manner until approximately 5.5 mil of coating had accumulated on each drug tablet.

  175 grams of cellulose acetate 398-10 and 75 grams of LUTROL F68 were then dissolved in 4,750 grams of acetone with warming and stirring. The cellulose acetate had an average acetyl content of about 39.8 weight percent and a molecular weight of about 40,000. This formed a film overcoat solution.

  The membrane topcoat solution was applied to the active core and placebo core floors in an LDCS pan coater until a 5 mil membrane topcoat accumulated on each drug tablet. Three coat layers formed the wall 20 of the present invention. The outlet opening 60 was mechanically drilled through three coating layers on the drug layer side of the tablet using a 40 mil diameter drill bit and drill press. The system was then dried in a forced air oven at 40 ° C. to remove residual process solvent.

  The six dosage forms produced (systems) were tested for drug release as a function of time in 37 ° C. deionized water by taking every 2 hours over a 24 hour period. Drug release was monitored by refractive index chromatography. Drug 31 was delivered in an ascending release pattern for 12-14 hours. The time to deliver 90% of the 100 mg dose was about 18 hours. Cumulative delivery at 24 hours was 97.5%. The membrane was normal throughout the delivery pattern.

  The dosage form was small enough to be easily swallowed by the patient, even with the 55% high drug load present in drug composition 30.

In an attempt to practice the prior art method, a similar dosage form with a push layer was prepared with 55% drug in the drug composition but without solubilizing surfactant. These dosage forms of the prior art were not operable. The drug compositions representing the prior art did not solubilize the drug and resulted in drug compositions that would not be able to be pumped out of the dosage form. The membranes of these dosage forms ruptured in situ during in vitro testing, releasing the drug bolus in an uncontrollable manner. The rupture of the dosage form was due to strain induced in the membrane by the expansion pressure formed by the push layer, pressing against the insoluble drug composition through a narrow 40 mil outlet.
[Example 12]

Two layer topiramate dosage form 9.0 grams of finely divided LUTROL F127 drug composition was dry mixed with 16.5 grams topiramate. Topiramate had a nominal particle size of 80 microns. 3.45 grams of POLYOX N80 and 0.9 grams of polyvinylpyrrolidone were then screened through a minus 40 mesh and blended into the mixture. Next, 5 grams of absolute ethanol was added slowly with stirring to form a wet mass. The wet material was passed through a # 16 mesh screen and air dried overnight at ambient temperature. The resulting dried noodles were again passed through a # 16 mesh screen. 150 mg of magnesium stearate was then passed over the # 60 mesh sieve over the dry granules and spun into the granules. The concentration of surfactant in the granules of this drug composition was 30 weight percent.

  The extruded layer granules were prepared by passing 63.67 grams of POLYOX 303, 30 grams of sodium chloride and 5 grams of hydroxypropylmethylcellulose through a # 40 mesh sieve and dry mixed to form a uniform blend. . Then 1.0 gram of ferric oxide red was passed through a # 60 mesh sieve through the mixture. The resulting mixture was slowly added with stirring of anhydrous ethyl alcohol and anhydrous SDA3A to form a uniformly moist material to make a wet material. The material was passed through a # 20 mesh screen to form a noodle, which was dried overnight in forced air at 40 ° C. The dried noodles were passed through a # 16 mesh sieve to form free flowing granules. Finally, 25 mg of magnesium stearate and 8 mg of butylated hydroxytoluene were sifted through the granules through # 80 mesh and swirled.

  A portion of the 182 mg weight drug composition granule was filled into a 3/16 inch (4.8 mm) diameter die and lightly packed with a 3 / 16-inch recessed punch. 60 mg of push layer granules were then added to the drug layer and the two layers were bonded together with a force of 800 pounds (363 kg). Six tablets were formulated.

  The tablets were coated as described in Example 11 with a 5 mg smooth coat, a 5.4 mil subcoat film and a 5.4 mil topcoat film. One outlet opening of 40 mil diameter was drilled through the three coating layers and the system was dried in forced air at 40 ° C. overnight.

The resulting dosage form was tested as described in Example 11. The system released 99% of the drug over a 24 hour period. The release rate was substantially increased during the first 14 hours when about 76% of the drug was released at that time. The system released about 90% of the drug in 19 hours. The last system, similar to that described in Example 11, was a convenient and possible size for patients in need of treatment to swallow.
[Example 13]

A two-layer topiramate dosage form system was prepared as described in Example 12 except that surfactant 33 comprised a blend of two solubilized surfactants. Drug composition granules according to the method in Example 2 except that the surfactant consisted of 15 weight percent refined LUTROL F127 and 15 weight percent MYRJ 52 substituted for 30 weight percent refined LUTROL F127 Was formulated. The weighed average HLB value of the two surfactants gave an HLB value of 19.5, the midpoint between the two HLB values of a single surfactant.

The dosage form was delivered at a substantially zero dimensional rate between time 2 and time 14. The dosage form released 89% of the dose in 24 hours.
[Example 14]

Two-layer topiramate dosage form The dosage form was formulated as described in Example 13, but using a higher weight push layer. The weight of the push layer was 90 mg substituted for the 60 mg weight of the system of Example 13.

The system delivered at a substantially ascending release rate over about 12 hours. After 12 hours, the speed went down. The amount of drug delivered during 24 hours was about 93%.
[Example 15]

Bilayer topiramate dosage form 30% by weight drug topiramate, 56% by weight surfactant LUTROL F127, 10% by weight carrier POLYOX N80 and 3% by weight PVP K2932 and 2% by weight stearic acid Product 30 was formed by wet granulation with absolute ethanol.

  63.37 wt% POLYOX 303 (7,000,000 molecular weight), 30 wt% NaCl, 5 wt% HPMC E5, 1 wt% ferric oxide, 0.5 wt% Mg stearate and The extruded layer consisting of 0.08 wt% BHT was granulated with absolute ethanol.

Tablets containing 333 mg drug composition (100 mg topiramate) and 133 mg push layer were compressed using a 9/32 "(7.1 mm) vertical compression tableting tool. Total tablet (capsule type) weight The system was coated, perforated and dried according to the method described in Example 11. The system was then tested for drug release, resulting in a substantially zero dimensional release pattern, about The drug was delivered at a constant rate of about 5.8 mg per hour for 16 hours.
[Example 16]

Topiramate capsule-type 3 layer 100 mg system first drug composition was prepared as follows. First, 3000 g of topiramate, 2520 g of polyethylene oxide with an average molecular weight of 200,000 and 3630 g of poloxamer 407 (LUTROL F127) with an average molecular weight of 12,000 were added to the fluid bed granulator bowl. Next, two separate binder solutions, a poloxamer binder solution and a polyvinylpyrrolidone binder solution identified as K29-32 having an average molecular weight of 40,000, were added to 540 g of the same poloxamer 407 (LUTROL) in 4860 g of water. F127) and 495 g of the same polyvinylpyrrolidone in 2805 g of water. The dried material was fluid bed granulated by first spraying with 2700 g poloxamer binder solution and then with 2000 g polyvinylpyrrolidone binder solution. The wet granules were then dried in a granulator to an acceptable humidity content of 0.3% and sized by passing through a 7-mesh screen. The granules were then transferred to a blender and mixed with 5 g butylated hydroxytoluene as an antioxidant and lubricated with 200 g stearic acid and 75 g magnesium stearate.

  A second drug composition was prepared as follows. First, fluidized bed granulation of 4000 g topiramate, 213 g polyethylene oxide with an average molecular weight of 200,000, 4840 g of poloxamer 407 (LUTROL F127) with an average molecular weight of 12,000 and 10 g of ferric oxide black. Added to the bowl of the apparatus. Then two separate binder solutions, a poloxamer binder solution and a polyvinylpyrrolidone binder solution identified as K29-32 with an average molecular weight of 40,000, 720 g of the same poloxamer 407 in 6480 g of water, and Prepared by dissolving 495 g each of the same polyvinylpyrrolidone in 2805 g of water. The dried material was fluid bed granulated by first spraying with 3600 g of poloxamer binder solution and then with 2000 g of polyvinylpyrrolidone binder solution. The wet granulation was then dried in a granulator to an acceptable humidity content and sized by passing through a 7-mesh screen. The granules were then transferred to a blender, mixed with 2 g butylated hydroxytoluene as an antioxidant and lubricated with 200 g stearic acid and 75 g magnesium stearate.

  Next, a push layer was prepared as follows. First, a binder solution was prepared. 7.5 kg of polyvinylpyrrolidone identified as K29-32 having an average molecular weight of 40,000 was dissolved in 50.2 kg of water. Next, 37.5 kg of sodium chloride and 0.5 kg of ferric oxide were sized using a Quadro Comil with a 21-mesh screen. The screened material and 80.4 kg of polyethylene oxide (molecular weight of about 7,000,000) were then added to the fluid bed granulator bowl. The dried material was fluidized and mixed onto the powder while spraying 48.1 kg of binder solution from 3 nozzles. The granules were dried in a fluidized bed chamber to 0.5% of acceptable humidity content. The coated granules were sized using a Fluid Air mill with a 7-mesh screen. The granules were transferred to a tote tumbler, mixed with 63 g butylated hydroxytoluene and lubricated with 310 g stearic acid.

  The first and second drug compositions and push layer were then compressed into three layer tablets on a multilayer Korsch press. First 120 mg of the first drug composition is added to the die cavity and pre-compressed, then 160 mg of the second drug composition is added to the die cavity, pre-pressed again, and finally the push layer is Upon addition, a total system weight of 480 mg was achieved, and the layers were compressed into a ¼ ″ (6.3 mm) diameter capsule-shaped deep recessed 3-layer array.

  The three-layer array was then coated with a two-layer polymer film laminate where the first coat layer was a hard but water-permeable laminate and the second coat layer was a semi-permeable membrane laminate. The first film laminate composition comprised 55% ethylcellulose, 45% hydroxypropylcellulose and 5% POLYOXYL 40 stearate (PEG 40 stearate or MYRJ 52S). The film-forming composition was dissolved in 100% ethyl alcohol to form a 7% solid solution. The film-forming composition was sprayed onto or around the three-layer array in a 10 kg scale pan coater until about 45 mg of film was applied to each tablet.

  The three layer array coated with the first membrane laminate was then coated with a semipermeable membrane. The film-forming composition comprised 80% cellulose acetate with an acetyl content of 39.8% and 20% poloxamer 188 (PLURONIC F68 or LUTROL F68). The film-forming composition was dissolved in 100% acetone solvent to form a 5% solid solution. The film-forming composition was sprayed onto and around the three-layer array in a pan coater until approximately 35 mg of film was applied to each tablet.

  Next, a 40 mil (1 mm) exit path is laser drilled through the two-layer membrane laminate to communicate the drug layer with the exterior of the dosing system. Residual solvent was removed by drying at 40 ° C. and ambient humidity for 72 hours.

  The holes were then drilled and the dried system was painted over. The colored topcoat was a 12% solid suspension of OPADRY in water. The colored topcoat suspension was sprayed onto the three layer system until an average wet coat weight of about 25 mg / system was achieved.

  The colored topcoat system was then transparently coated. The clear coat was OPADRY 5% solid solution in water. The clear coat solution was sprayed onto the colored coat core until an average wet coat weight of about 10 mg per system was achieved.

  The dosage form formed by this formulation is 30% topiramate, 25.2% polyethylene oxide with 200,000 molecular weight, 39% poloxamer 407 (LUTROL F127), 3% polyvinyl with 40,000 molecular weight. A first drug composition of pyrrolidone, 0.05% butylated hydroxytoluene, 2% stearic acid and 0.75% magnesium stearate and 40% topiramate, 2.13% having a 200,000 molecular weight Polyethylene oxide, 52% poloxamer 407 (LUTROL F127), 3% polyvinylpyrrolidone with 40,000 molecular weight, 0.1% black ferric oxide, 0.05% butylated hydroxytoluene, 2% Stearic acid and 0.75% magnesium stearate 100 mg of topiramate was delivered from the core containing the second drug composition at a release rate substantially increasing the release at a specific controlled delivery rate. The push layer comprises 64.3% polyethylene oxide comprising 7,000,000 molecular weight, 30% sodium chloride, 5% polyvinylpyrrolidone having an average molecular weight of 40,000, 0.4% oxidized second Consists of iron, 0.05% butylated hydroxytoluene (BHT) and 0.25% stearic acid. The two-layer membrane laminate consists of 55% ethylcellulose, 45% hydroxypropylcellulose and 5% POLYOXYL 40 stearate (PEG40 stearate or MYRJ 52S), and the second membrane laminate is 39 It was a semi-permeable wall composed of 80% cellulose acetate with an acetyl content of 8% and 20% poloxamer 188 (PLURONIC F68 or LUTROL F68). The dosage form comprised one route of 40 mil (1 mm) in the middle of the drug side. The final dosage form contained a colored topcoat and a clear topcoat.

The final dosage form released so that about 90% of the drug was released with a release rate that increased substantially over about 16 hours.
[Example 17]

A 3 layer 12.5 mg system dosage form in topiramate capsule form was formulated starting with the first drug composition as follows. First, 4 g of topiramate, 40 g of polyethylene oxide with an average molecular weight of 200,000, 4 g of poloxamer 407 (LUTROL F127) with an average molecular weight of 12,000 and K29-32 with an average molecular weight of 40,000 The identified 1.5 g of polyvinylpyrrolidone was added to a beaker or mixing bowl. The dry material was then mixed for 60 seconds. Then 16 mL of denatured anhydrous alcohol was slowly added to the blended material with continuous mixing for about 2 minutes. The freshly prepared wet granules were then dried at room temperature for about 16 hours and passed through a 16-mesh screen. The granules were then transferred to a suitable container, mixed and lubricated with 0.5 g stearic acid.

  A second drug composition was then prepared as follows: 6 g topiramate, 35.95 g polyethylene oxide with an average molecular weight of 200,000, 6 g poloxamer 407 with an average molecular weight of 12,000 (LUTROL F127). 1.5 g of polyvinylpyrrolidone identified as K29-32 having an average molecular weight of 40,000 and 0.05 g of ferric oxide are added to a beaker or mixing bowl. The dry material was then mixed for 60 seconds. Then 16 mL of denatured anhydrous alcohol was slowly added to the blended material with continuous mixing for about 2 minutes. The freshly prepared wet granules were then dried at room temperature for about 16 hours and passed through a 16-mesh screen. The granules were then transferred to a suitable container and mixed with 0.5 g stearic acid and lubricated.

  Next, a push layer was prepared as follows. First, a binder solution was prepared. 7.5 kg of polyvinylpyrrolidone identified as K29-32 having an average molecular weight of 40,000 was dissolved in 50.2 kg of water. Next, 37.5 kg of sodium chloride and 0.5 kg of ferric oxide were sized using a Quadro Comil with a 21-mesh screen. The screened material and 80.4 kg of polyethylene oxide (molecular weight of about 7,000,000) were then added to the fluid bed granulator bowl. The dry substance was fluidized and mixed while spraying 48.1 kg of binder solution from 3 nozzles onto the powder. The granules were dried in a fluidized bed chamber to an acceptable humidity level of 0.5%. The coated granules were sized using a Fluid Air mill with a 7-mesh screen. The granules were transferred to a tote tumbler, mixed with 63 g butylated hydroxytoluene and lubricated with 310 g stearic acid.

  The first and second drug compositions and push layer were then compressed into 3 layer tablets on a Carver tablet press. First, 56 mg of the first drug composition is added to the die cavity and pre-compressed, then 67 mg of the second drug composition is added to the die cavity, pre-compressed again, and finally the push layer is applied. It was added to achieve a total system weight of 211 mg and the layers were compressed into a 3/16 ″ (3.7 mm) diameter, capsule-shaped, deeply recessed 3-layer array.

  The three-layer array was coated with a laminate of two polymer films, where the first coat layer was a hard but water permeable laminate, and the second coat layer was a semipermeable laminate. The coating was performed on a 10 kg scale pan coater by spike loading a topiramate three layer system with placebo tablets. The first film laminate composition consisted of 55% ethylcellulose, 45% hydroxypropylcellulose and 5% POLYOXYL 40 stearate (PEG 40 stearate or MYRJ52S). The film-forming composition was dissolved in 100% ethyl alcohol to form a 7% solid solution. The film-forming composition was sprayed onto and around the three-layer array in a pan coater until about 30 mg of film was applied to each tablet.

  The three layer array coated with the first membrane laminate was then coated with a semipermeable membrane. The film-forming composition consisted of 80% cellulose acetate with an acetyl content of 39.8% and 20% poloxamer 188 (PLURONIC F68 or LUTROL F68). The film-forming composition was dissolved in 100% acetone solvent to form a 5% solid solution. The film-forming composition was sprayed onto and around the three-layer array in a pan coater until approximately 25 mg of film was applied to each tablet.

  A single 30 mil (0.76 mm) exit path was then laser drilled through the two-layer membrane laminate to communicate the drug layer with the exterior of the dosing system. Residual solvent was removed by drying at 40 ° C. and ambient humidity for 72 hours.

  The holes were then drilled and the dried system was painted over. The colored topcoat was a 12% solid suspension of OPADRY in water. The colored topcoat suspension was sprayed onto the three layer system until an average wet coat weight of about 15 mg / system was achieved.

  The dosage form formed by this formulation was 8% topiramate, 80% polyethylene oxide with 200,000 molecular weight, 8% poloxamer 407 (LUTROL F127), 3% polyvinylpyrrolidone with 40,000 molecular weight and First drug composition of 1% stearic acid as well as 12% topiramate, 71.9% polyethylene oxide with 200,000 molecular weight, 12% poloxamer 407 (LUTROL F127), 3% with 40,000 molecular weight At a specific controlled delivery rate from a core containing 10% polyvinylpyrrolidone, 0.1% ferric oxide and a second drug composition of 1% stearic acid at a rate of increased release of 12 Delivered 5 mg of topiramate. The push layer comprises 64.3% polyethylene oxide comprising 7,000,000 molecular weight, 30% sodium chloride, 5% polyvinylpyrrolidone having an average molecular weight of 40,000, 0.4% oxidized second Consists of iron, 0.05% butylated hydroxytoluene (BHT) and 0.25% stearic acid. The two-layer membrane laminate consists of 55% ethylcellulose, 45% hydroxypropylcellulose and 5% POLYOXYL 40 stearate (PEG40 stearate or MYRJ 52S), and the second membrane laminate is It was a semi-permeable wall composed of 39.8% acetyl content 80% cellulose acetate and 20% poloxamer 188 (PLURONIC F68 or LUTROL F68). The dosage form comprised one route of 30 mil (0.76 mm) in the middle of the drug side. The final dosage form contained a colored topcoat and a clear topcoat.

The final dosage form releases topiramate so that about 90% of the drug is released with a release rate that substantially increases over about 16 hours.
[Example 18]

A topiramate capsule bilayer 100 mg system dosage form was formulated as follows. First, 2880 g of topiramate, 958 g of polyethylene oxide having an average molecular weight of 200,000 and 4980 g of poloxamer 407 (LUTROL F127) having an average molecular weight of 12,000 were added to the bowl of the fluid bed granulator. Next, two separate binder solutions, a poloxamer binder solution and a polyvinylpyrrolidone binder solution identified as K29-32 having an average molecular weight of 40,000, were each added to 500 g of the same poloxamer (4500 g of water). LUTROL F127) and 750 g of the same polyvinylpyrrolidone was dissolved in 4250 g of water. The dried material was fluid bed granulated by first spraying with 3780 g poloxamer binder solution and then with 3333 g polyvinylpyrrolidone binder solution. The granules moistened to 0.5% of acceptable humidity content were then dried in a granulator and sized by passing through a 7-mesh screen. The granules were then transferred to a blender, mixed with 2 g butylated hydroxytoluene (BHT) as an antioxidant and lubricated with 200 g stearic acid and 100 g magnesium stearate.

  Next, a push layer was prepared as follows. First, a binder solution was prepared. 7.5 kg of polyvinylpyrrolidone identified as K29-32 having an average molecular weight of 40,000 was dissolved in 50.2 kg of water. Next, 37.5 kg of sodium chloride and 0.5 kg of ferric oxide were sized using a Quadro Comil with a 21-mesh screen. The screened material and 80.4 kg of polyethylene oxide (about 7,000,000 molecular weight) were then added to the fluid bed granulator bowl. The dry substance was fluidized and mixed while spraying 48.1 kg of binder solution from 3 nozzles onto the powder. The granules were dried in a fluidized bed chamber to an acceptable humidity level. The coated granules were sized using a Fluid Air mill with a 7-mesh screen. The granules were transferred to a tote tumbler, mixed with 63 g butylated hydroxytoluene and lubricated with 310 g stearic acid.

  The drug composition and extrusion composition were then compressed into two-layer tablets on a multilayer Korsch press. First 278 mg of the drug composition is added to the die cavity, pre-compressed, and then the extrusion composition is added to achieve a total system weight of 463 mg and the layer is 15/64 ″ (5.9 mm) diameter. Compressed into a deeply indented two-layered array of capsules.

  The two-layer array was coated with a two-layer polymer film laminate in which the first coat layer was a hard but water-permeable laminate and the second coat layer was a semi-permeable membrane laminate. The first film laminate composition consisted of 55% ethylcellulose, 45% hydroxypropylcellulose and 5% POLYOXYL 40 stearate (PEG 40 stearate or MYRJ 52S). The film-forming composition was dissolved in 100% ethyl alcohol to form a 7% solid solution. The film-forming composition was sprayed onto and around the array in a pan coater until about 38 mg of film was applied to each tablet.

  The two-layer array coated with the first membrane laminate was then coated with a semipermeable membrane. The film-forming composition comprised 80% cellulose acetate with an acetyl content of 39.8% and 20% poloxamer 188 (PLURONIC F68 or LUTROL F68). The film-forming composition was dissolved in 100% acetone solvent to form a 5% solid solution. The film-forming composition was sprayed onto and around the array in a pan coater until approximately 30 mg of film was applied to each tablet.

  A 45 mil (1.14 mm) exit path was then laser drilled through the two layers of membrane laminate to communicate the drug layer with the exterior of the dosing system. Residual solvent was removed by drying at 40 ° C. and ambient humidity for 72 hours.

  The perforated and dried dosage form was then coated with an immediate release drug overcoat. The drug overcoat was 780 g topiramate, 312 g coPOVIDONE (KOLLIDONE VA64) and 208 g 13% solids aqueous solution containing hydroxypropyl methylcellulose having an average molecular weight of 11,200. The drug overcoat solution was sprayed onto the dry coat core until an average wet coat weight of about 33 mg per system was achieved.

  The drug topcoat system was then overcoated. The colored topcoat was a 12% solid suspension of OPADRY in water. The colored topcoat suspension was sprayed onto the drug topcoat system until an average wet coat weight of about 25 mg / system was achieved.

  The colored topcoat system was then transparently coated. The clear coat was OPADRY 5% solid solution in water. The clear coat solution was sprayed onto the color coated core until an average wet coat weight of about 25 mg per system was achieved.

  The dosage form formed by this formulation was 20 mg topiramate as an immediate release from a topcoat consisting of 60% topiramate, 24% coPOVIDONE and 16% hydroxypropylmethylcellulose, then 28.8% topiramate. 9.58% polyethylene oxide having 200,000 molecular weight, 53.6% poloxamer 407 (LUTROL F127), 5% polyvinylpyrrolidone having 40,000 molecular weight, 0.02% butylated hydroxytoluene (BHT) ) To be delivered by controlled delivery of 80 mg topiramate from a drug composition containing 2% stearic acid and 1% magnesium stearate. The push layer comprises 64.3% polyethylene oxide comprising a molecular weight of 7,000,000, 30% sodium chloride, 5% polyvinylpyrrolidone having an average molecular weight of 40,000, 0.4% oxidized It consisted of 2 iron, 0.05% butylated hydroxytoluene and 0.25% stearic acid. The two-layer membrane laminate consists of 55% ethylcellulose, 45% hydroxypropylcellulose and 5% POLYOXYL 40 stearate (PEG40 stearate or MYRJ52S), and the second membrane laminate is 39. It was a semi-permeable wall consisting of 80% cellulose acetate with 8% acetyl content and 20% poloxamer 188 (PLURONIC F68 or LUTROL F68). The dosage form comprised one route of 45 mil (1.14 mm) in the middle of the drug side. The final dosage form contained a colored topcoat and a clear topcoat.

The final dosage form had an average release rate of 6 mg topiramate per hour, releasing topiramate with a substantially zero-dimensional release rate.
[Examples 19-24]

Topiramate Dosage Forms Tables 1-9 below list details of compositions according to further embodiments of the invention. More specifically, the following table provides details of the composition of a three-layer, controlled release, osmotic dosage form containing topiramate. The dosage form comprised two drug compositions differing in the amount and / or concentration of topiramate in the two drug compositions and a push layer.

  Each of the following dosage forms was prepared according to the method described in Example 25 by selecting and replacing the appropriate ingredients.

  Table 1 below lists the components of the dosage form as a function of the total topiramate dose. For each layer or coating (eg, for drug layer, push layer, semipermeable membrane, other coatings, etc.), the weight is given in milligrams. Table 1 further shows the size of each dosage form at the time of preparation.

  Table 2 below lists the ingredients and amounts used in preparing the first drug composition of the dosage form comprising a total amount of topiramate from 45 to 180 mg. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

  Table 3 below lists the ingredients and amounts used in the preparation of the second drug composition of the dosage form comprising a total amount of 45-180 mg of topiramate. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

  Table 4 below lists the ingredients and amounts used in the preparation of the first drug composition of the dosage form comprising a total amount of 10-20 mg topiramate. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

  Table 5 below lists the ingredients and amounts used in the preparation of the second drug composition of the dosage form comprising a total amount of 10-20 mg topiramate. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

  Table 6 below lists the ingredients and amounts used to prepare the topiramate push layer for all dosage forms. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

  Table 7 below lists the ingredients and amounts used in the preparation of topiramate subcoats (aqueous subcoats) for all dosage forms. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

  Tables 8 and 9 below list the ingredients and amounts used in the preparation of CAB (cellulose acetate butyrate) and CA (cellulose acetate) membrane coats, respectively, for all dosage forms of topiramate. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

［実施例２５］

[Example 25]

A large scale push layer granule of topiramate dosage form was formulated as follows. The composition of the extruded layer is as follows: 64.3% polyethylene oxide, 30% sodium chloride, 5% POVIDONE, 0.4% ferric oxide, 0.25% stearic acid, extruded 0.05% butyl Hydroxytoluene.

  The binder solution was prepared as follows: 7.5 kg of POVIDONE was added to 50.2 kg of purified water in a mixing vessel and mixed until POVIDONE was completely in solution. The net weight of the prepared binder solution was measured by weighing.

  Dry ingredient—80.4 kg of polyethylene oxide, 37.5 kg of sodium chloride and 0.5 kg of ferric oxide were charged into the tote. A gun required to spray the binder solution was attached to the fluid bed granulator. The granulator was then warmed to an incoming air temperature of 43-47 ° C. and 48 kg of binder solution was metered into the granulator. After spraying was complete, the granules were dried in a granulator until a humidity content of 1% or less was obtained. The dried granules were then ground through Granummill using a 7 mesh screen. The milled granules were weighed and collected in a tote. 0.05% by weight of the granules butylated hydroxytoluene was added to the tote and the granules were mixed for 5 minutes. 0.25% equivalent of stearic acid in the granules was weighed and added to the tote. The granules were then mixed for an additional 5 minutes.

  Granules of the first drug composition were formulated as follows. The composition of the first drug composition is: 32% topiramate, 16.32% polyethylene oxide, 42% poloxamer 407, 3% POVIDONE, 2.5% methylcellulose, 3% stearic acid, 1.25% magnesium stearate and 0.02% butylated hydroxytoluene.

  A binder solution was prepared as follows: 480 g of POVIDONE was added to 4.32 kg of purified water in a mixing vessel and mixed until POVIDONE was completely in solution. The net weight of the prepared binder solution was measured by weighing.

  A methylcellulose granule coating solution was prepared as follows: 2.6 kg of purified water was heated to a temperature above 50 ° C. 400 g of methylcellulose was gradually added to hot water while mixing. Mixing was continued until all solids were dispersed. Next, 5 kg of purified water was added to the mixing vessel and mixing was continued until all solids were dissolved. The net weight of the prepared granule coating solution was measured by weighing.

  Dry ingredients-3.2 kg topiramate, 1.623 kg polyethylene oxide and 4.2 kg poloxamer were charged into a tote. A gun required to spray the binder solution was attached to the fluid bed granulator. The granulator was then warmed to an exhaust temperature below 25 ° C. and 3 kg of binder solution was metered into the granulator. After spraying the binder solution, 5 kg of granule coating solution was sprayed onto the granules. After spraying was complete, the granules were dried in a granulator until a humidity content of 0.5% or less was obtained. The dried granules were then ground through Granummill using a 7 mesh screen. The milled granules were weighed and collected in a tote. 0.05% by weight of the granules butylated hydroxytoluene was added to the tote and the granules were mixed for 5 minutes. 3% equivalent of stearic acid in the granules was weighed and added to the tote. The granules were then mixed for an additional 5 minutes. 1.25% equivalent of magnesium stearate of the granules was weighed and added to the tote. The granules were then mixed for an additional 30 seconds.

  Granules of the second drug composition were formulated as follows. The composition of the second drug composition is: 43% topiramate, 49.9% poloxamer 407, 3% POVIDONE, 2.5% methylcellulose, 1% stearic acid, 0.5% magnesium stearate, 0.08% yellow Ferric oxide and 0.02% butylated hydroxytoluene.

  A binder solution was prepared as follows: 480 g of POVIDONE was added to 4.32 kg of purified water in a mixing vessel and mixed until POVIDONE was completely in solution. The net weight of the prepared binder solution was measured by weighing.

  A methylcellulose granule coating solution was prepared as follows: 2.6 kg of purified water was heated to a temperature above 50 ° C. 400 g of methylcellulose was gradually added to hot water while mixing. Mixing was continued until all solids were dispersed. Next, 5 kg of purified water was added to the mixing vessel and mixing was continued until all solids were dissolved. The net weight of the prepared granule coating solution was measured by weighing.

  Dry ingredient-4.3 kg topiramate, 4.9 kg poloxamer and 8 g ferric oxide were charged into the tote. A gun required to spray the binder solution was attached to the fluid bed granulator. The granulator was then warmed to an exhaust temperature below 25 ° C. and 3 kg of binder solution was metered into the granulator. After spraying the binder solution, 5 kg of granule coating solution was sprayed onto the granules. After spraying was complete, the granules were dried in a granulator until a humidity content of 0.5% or less was obtained. The dried granules were then ground through Granummill using a 7 mesh screen. The milled granules were weighed and collected in a tote. 0.05% by weight of the granules butylated hydroxytoluene was added to the tote and the granules were mixed for 5 minutes. 1% equivalent of stearic acid in the granules was weighed and added to the tote. The granules were then mixed for an additional 5 minutes. 0.5% equivalent of magnesium stearate of the granules was weighed and added to the tote. The granules were then mixed for an additional 30 seconds.

  The core compression was completed as follows. The granules were compressed into a three layer tablet core. Different weights were compressed into different sized cores for different doses.

  A three layer tablet core for delivering 90 mg of drug was compressed as follows: 28.6 wt% drug layer 1, 28.6 wt% drug layer 2 and 42.9 wt% on a Korsch tablet press. % Push layer was compressed to form a 3-layer tablet. For 90 mg tablets, 120 mg drug layer 1, 120 mg drug layer 2 and 180 mg push layer were compressed together using a 15/64 ″ (5.9 mm) diameter tool set.

  Application of the subcoat was completed as follows. The composition of the subcoat was: 95% hydroxyethyl cellulose and 5% polyethylene glycol 3350.

  A subcoat solution was prepared as follows: 14.1 kg of water was added to the mixing vessel. 45 g polyethylene glycol was added and mixed until all solids were dissolved. 855 g of hydroxyethyl cellulose was weighed and filled into the PEG solution with mixing. Mixing was continued until all solids were dissolved. The net weight of the prepared subcoat solution was measured by weighing.

  The coater was filled with 9 kg of compressed core and the core was stirred in the coater until a target exhaust temperature of 32 ° C. was achieved. The subcoat solution was applied to the core while rotating the coater at 12 rpm. The coating was continued until a target weight of 34 mg was achieved. The core was removed from the coater at the end of spraying.

  The speed control membrane was completed as follows. The composition of the rate control membrane was: 99% cellulose acetate and 1% poloxamer 188.

  A film coat solution was prepared as follows: 47 kg of acetone was charged to the mixing vessel. Acetone was heated to 28 ° C. while the mixer was running. 25 g of poloxamer was added to acetone and mixed until completely dissolved. 2.475 kg of cellulose acetate was added to the poloxamer solution, followed by 475 g of purified water. The solution was mixed until all solids were in solution. The net weight of the prepared film coating solution was measured by weighing.

  9 kg of the subcoated core was loaded into the coater and the core was stirred in the coater until the target exhaust temperature of 32 ° C. was achieved. The membrane coating solution was applied to the core while rotating the coater at 12 rpm. The coating was continued until a target weight of 36 mg was achieved. At the end of spraying, the core was removed from the coater.

The exit opening was perforated and the dosage form was then dried as follows. Using a laser drill, a hole was drilled on a core coated with a 1 mm opening. The drilled core was then spread on a drying tray and dried at 40 ° C. at ambient humidity for up to 10 days.
[Example 26]

Topiramate dosage form About 30 drug core compositions comprising 53.7 grams topiramate, 29.8 grams CRODESTAF160, 10 grams polyethylene oxide N-80 and 6 grams polyethylenepyrrolidone K90 in a particle size of less than 40 mesh. Dry blend for minutes. The dry blend was then wetted with 20 grams of anhydrous ethyl alcohol SDA 3A with stirring to form a uniform wet dough. The wet dough was passed through a # 20 stainless steel screen to form noodles and dried under hood under ambient conditions for about 12 hours (overnight). The dried noodles were passed through a # 20 stainless steel screen to form granules. These dried granules were then lubricated with 0.5 grams <60 mesh magnesium stearate by roller blending for 3 minutes.

  Using a similar process of dry blending 73.7 grams polyethylene oxide 303, 20 grams sodium chloride, 5 grams polyvinylpyrrolidone K2932, 1 gram ferric oxide and 0.05 grams BHT for 30 minutes, The push layer granules were formulated. The dry blend was then wetted with 80 grams of anhydrous ethyl alcohol SDA 3A with stirring to form a uniform wet dough. The wet dough was then passed through a # 20 mesh stainless steel screen to form noodles. These noodles were dried under hood for about 12 hours under ambient conditions. The dried noodles were then passed through a # 20 mesh stainless steel screen to form granules. These dry granules were then lubricated with 0.25 grams of stearic acid by roller blending for 3 minutes.

  A two-layer core was formed using a 3 / 16-inch (4.7 mm) diameter LCT tool using both drug and push layer. First, 182 mg weight drug layer granules were introduced into the die, then after slightly light compression, 60 mg weight push layer granules were introduced, and then compressed by Carr Press with 0.75 ton pressure. This process was repeated until the desired amount of test tablets was formed. For the first test, 10 tablets were produced.

  Three layers of coating were applied to these tablets. The first coating, the smoothing coating, provided a smooth surface for subsequent rate control membrane coating. For smoothing coating, 5 grams of poloxamer 407 was dissolved in 783 grams of deionized water with stirring. 45 grams of hydroxyethyl cellulose was then introduced into the solution and stirred until a clear solution was achieved. An Aeromatic Coater was utilized for this coat. Ten active tablets were mixed with placebo tablets (fillers) to provide a coater load of 500 grams. Approximately 3-4 mg of coating was coated on each active tablet according to the standard Aeromatic coating method. The coated active tablets were dried at 40 ° C. in an ambient humidity oven for 12 hours.

  A second coating was prepared by dissolving 77 grams of ethylcellulose (100 cps), 56 grams of hydroxypropylcellulose EFX and 7 grams of MYRJ 52S in 4,527 grams of warm ethanol SDA3A with stirring. Stirring was performed until a homogeneous solution was achieved. After stirring, the solution was sealed and stored under ambient conditions for about 2 days before application. An LDCS Vector Pan Coater was used for this coat. To achieve a coater load of 1.2 kg, 10 smooth coated active tablets were mixed with placebo filler tablets and coated with a second coating. A standard pan coat method was used for the coat method with a target coat of about 6 mils.

  For the third coating, 87.5 grams of cellulose acetate 398-10 and 37.5 grams LUTROL F68 were dissolved in 2,375 grams of acetone while stirring and warming. This coating was applied using the same coater and standard coating method as the second coat. After coating, the active tablet was manually pierced to form a 40 mil opening and then dried in an oven at 40 ° C. and ambient humidity for about 12 hours (overnight).

Residues were measured for drug release rate from 5 of these tablets every 2 hours as described in Example 11 for 24 hours. The results indicate that topiramate was delivered at a substantially increasing release rate for 12-14 hours. The time to deliver 90% of the 100 mg dose was about 16 hours. The cumulative delivery at 24 hours was 99%. The membrane was normal throughout the delivery pattern.
[Example 27]

Topiramate Dosage Form Using a granulation method similar to that described in Example 26 above, 50 grams topiramate, 33.5 grams CRODESTA F-160, 10 grams polyethylene oxide N-80 and 6 The following preparation consisting of grams of polyvinylpyrrolidone K90 was wet granulated and lubricated with 0.5 grams of magnesium stearate. This constituted a drug layer with a 33.5% surfactant loading. Tablets were formulated according to the following method and the materials described in Example 26.

Drug release rate was measured as described in Example 11. The results indicate that topiramate was delivered at a substantially increasing release rate over 12-14 hours. The time to deliver 90% of the 100 mg dose was about 16 hours. The cumulative delivery volume at 24 hours was 99.5%. The membrane was normal throughout the delivery pattern.
[Example 28]

Topiramate dosage form tablets were formulated as described in Examples 26 and 27 but using drug layer granules consisting of 38.5% surfactant (CRODESTA F160). A push layer composition in the amount of 60 mg was used. The applied membrane composition and amount were similar to the corresponding tablets in Examples 26 and 27.

The drug release rate was determined for these tablets according to a method similar to that described in Example 11. The results indicate that topiramate was delivered at a release rate that increased substantially between 14 and 16 hours. The time to deliver 90% of the 100 mg dose was about 17 hours. The cumulative delivery volume at 24 hours was 98.7%. The membrane was normal throughout the delivery pattern.
[Example 29]

Granulate 288 grams topiramate, 536 grams CRODESTA F-160, 95.8 grams polyethylene oxide N-80 and 5 grams polyvinylpyrrolidone using standard methods for topiramate dosage form fluid bed granulation. did. The granules were then lubricated with 2 grams of stearic acid and 1 gram of magnesium stearate. A Glatt Fluid Bed Granulator (1 kg) volume was used for the granules.

  In order to test whether the granules adhered or not under formulation conditions, a tableting process was performed using a multi-layer tablet press (Korsch Multi-Layer Tablet Press). Using the same tableting press and parameters, another tableting process was performed using the corresponding granules containing poloxamer 407 as a surfactant. It was found that there was no adhesion on the turret table and punch due to the granules containing CRODESTA F160. In contrast, adhesion was observed with the poloxamer 407-containing granules.

Accordingly, sugar ester surfactants provide advantages in preparing dosage forms for poloxamer surfactants, and sugar ester surfactants CRORESTA are another preferred interface for topiramate in the present invention. It is an activator.
[Examples 30-35]

Topiramate Dosage Forms Tables 10-17 below provide details of compositions according to further embodiments of the invention. More specifically, the following table provides details of the composition of a three layer controlled release, osmotic dosage form containing topiramate. The dosage form comprised two drug compositions differing in the amount and / or concentration of topiramate in the two drug compositions and a push layer.

  Each of the following dosage forms was prepared according to the method described in Example 25 by selecting and replacing the appropriate ingredients.

  Table 10 below shows the components of the dosage form as a function of the total topiramate dose. For each layer or coating, the weight is expressed in milligrams (eg, for drug layers, push layers, semipermeable membranes, other coatings, etc.). Table 10 further shows the size of each dosage form at the time of preparation and the size of the opening on the dosage form.

  Table 11 below shows the ingredients and amounts used in preparing the first drug composition of the dosage form comprising topiramate in a total amount of 40-160 mg. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

  Table 12 below shows the ingredients and amounts used in the preparation of the second drug composition of the dosage form comprising a total amount of 45-180 mg of topiramate. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

  Table 13 below shows the ingredients and amounts used in the preparation of the first drug composition of the dosage form comprising a total amount of 10-20 mg topiramate. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

  Table 14 below shows the ingredients and amounts used in the preparation of the second drug composition of the dosage form comprising a total amount of 10-20 mg topiramate. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

  Table 15 below shows the ingredients and amounts used in the preparation of the push layer for all dosage forms of topiramate. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

  Table 16 below shows the ingredients and amounts used to prepare the subcoat (aqueous subcoat) for all dosage forms of topiramate. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

  Table 17 below shows the ingredients and amounts used in the preparation of CA (cellulose acetate) membrane coats for all dosage forms of topiramate. The target% (weight / weight) in the granule is the weight percent of the ingredients as a function of the total weight of the drug layer.

  As long as the foregoing specification includes the disclosed aspects, it will be understood herein that what changes and modifications can be made in accordance with the disclosed principles without departing from the invention. it can.

Fig. 4 shows the adhesion of a compressed preparation in the absence of coated granules. It is drawn not based on actual measurements and is shown to represent various aspects of the present invention. 1 represents one embodiment of an osmotic dosage form of the present invention representing a dosage form prior to administration to a subject. FIG. 3 represents the dosage form of FIG. 2 in open section, representing the drug composition contained within a single interior. FIG. 3 represents the dosage form of FIG. 2 in an open cross-section, representing two layers comprising a drug composition and another and contacting push layer for extruding the drug composition from the dosage form. FIG. 3 represents the dosage form of FIG. 2 further comprising an immediate release outer topcoat of pharmaceutical agent on the dosage form. Dosage form of the present invention representing a three layer arrangement comprising two drug compositions in a parallel arrangement and another and adjacent push layer for extruding the drug layer from a capsule dosage form Fig. 4 represents an open view of another aspect of an object. FIG. 5 shows the release of drug from a controlled release dosage form consisting of an extruded stick system containing coated granules. Figure 3 shows the topiramate release pattern of controlled release topiramate dosage forms with coated granules in batch sizes of 1 kg (upper panel) and 30 kg (lower panel). FIG. 5 shows the release of topiramate from a controlled release topiramate dosage form. In all dosage forms, the granules were coated with 23% PVP. Upper panel: 0% methylcellulose granule coating; lower panel: 3% methylcellulose granule coating. Figure 3 shows the delivery pattern of topiramate dosage form as a function of the weight ratio of LUTROL F127 / topiramate (surfactant / drug) in the coated granules. From top to bottom panel: 1.86 surfactant / drug; 1.49 surfactant / drug; 1.18 surfactant / drug; 0.93 surfactant / drug. Figure 3 shows the delivery pattern of topiramate dosage form as a function of coating content. Upper panel: 2 layer coating of 23% PVP with 3% methylcellulose; Lower panel: 10% POLYOX N10 monolayer coating. Figure 6 shows the adhesion resistance and delivery pattern of topiramate dosage forms as a function of coating thickness. From top to bottom panel: 3% methylcellulose, 7% methylcellulose, 13% methylcellulose. Figure 6 shows the adhesion resistance and delivery pattern of topiramate dosage forms as a function of coating content. Upper panel: single layer, 3% methylcellulose, lower panel: 10% PVP granule coating with 2 layers, 3% methylcellulose. Figure 3 shows the delivery pattern of topiramate dosage form as a function of coating content. All dosage form coatings have 10% PVP. From top to bottom panel: 3% methylcellulose, 7% methylcellulose, 10% methylcellulose granule coating.

Claims (34)

Comprising a granule having a substrate and a coating, and wherein
A drug formulation wherein the granule base comprises a solubilizing agent or a low solubility therapeutic agent or both, and the granule coating comprises a hydrophilic polymer.   The drug formulation of claim 1, wherein the granule base comprises a solubilizing substance.   The drug formulation according to claim 2, wherein the solubilizing substance is a surfactant.   4. The drug formulation of claim 3, wherein the granule base comprises a low-solubility therapeutic agent.   5. The drug formulation of claim 4, wherein the low solubility therapeutic agent is topiramate.   The drug formulation of claim 4, wherein the amount of surfactant is between about 5% and about 50% by weight of the core.   Surfactant is polyoxyl 40 stearate, polyoxyl 50 stearate, ethylene oxide / propylene oxide / ethylene oxide triblock copolymer, sorbitan monopalmitate, sorbitan monostearate, glycerol monostearate, polyoxyethylene stearate, polyoxyethylene 40 sorbitol lanolin derivatives, polyoxyethylene 75 sorbitol lanolin derivatives, polyoxyethylene 6 sorbitol beeswax derivatives, polyoxyethylene 20 sorbitol beeswax derivatives, polyoxyethylene 20 sorbitol lanolin derivatives, polyoxyethylene 50 sorbitol lanolin derivatives, polyoxyethylene 23 lauryl Ether, polyoxyethylene 23 lauryl ether, polyoxyethylene 2 cetyl Ether, polyoxyethylene 10 cetyl ether, polyoxyethylene 20 cetyl ether, polyoxyethylene 2 stearyl ether, polyoxyethylene 10 stearyl ether, polyoxyethylene 20 stearyl ether, polyoxyethylene 21 stearyl ether, polyoxyethylene 20 oleyl ether , Polyoxyethylene 40 stearate, polyoxyethylene 50 stearate, polyoxyethylene 100 stearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, polyoxyethylene 4 sorbitan monostearate, polyoxyethylene 20 5. A drug formulation according to claim 4 selected from the group consisting of sorbitan tristearate and mixtures thereof.   8. The surfactant of claim 7 wherein the surfactant is selected from the group consisting of polyoxyl 40 stearate, polyoxyl 50 stearate, ethylene oxide: propylene oxide di-block copolymer and ethylene oxide: propylene oxide: ethylene oxide a: b: a triblock copolymer. Drug formulation.   5. The drug formulation of claim 4, wherein the low solubility therapeutic agent in the absence of a solubilizing substance has a water solubility of about 1 [mu] g / ml to about 50 mg / ml.   The drug formulation of claim 1, wherein the granule coating is continuous.   The drug formulation of claim 1, wherein the granule coating is water soluble.   The hydrophilic polymer is polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, vinyl acetate-vinyl pyrrolidone copolymer, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, calcium 12. The drug formulation of claim 11 selected from the group consisting of carboxymethyl cellulose, polyvinyl acetate polyethylene glycol copolymer, starch, maltodextrin, sugar, sorbitol, mannitol, sucrose, gelatin, casein, natural gum, alginate or mixtures thereof.   The drug formulation of claim 1, wherein the granule coating is insoluble in water.   14. The drug formulation of claim 13, wherein the hydrophilic polymer is selected from the group consisting of polyether, polyester, cellulose acetate, cellulose acetate butyrate, polyacrylate and mixtures thereof.   The drug formulation according to claim 1, wherein the granule coating comprises a single layer.   16. The drug formulation of claim 15, wherein the monolayer granule coating comprises a hydrophilic polymer selected from polyvinylpyrrolidone, polyethylene oxide or methylcellulose.   The drug formulation according to claim 16, wherein the hydrophilic polymer is methylcellulose.   The drug formulation of claim 1, wherein the granule coating comprises multiple layers.   The drug formulation of claim 18, wherein the granule coating comprises two layers.   20. The drug formulation of claim 19, wherein the granule coating comprises an outer coating layer of methylcellulose and an inner coating layer of polyethylene oxide or polyvinylpyrrolidone.   The dosage form comprising the drug formulation of claim 1 wherein the granules comprise a low solubility therapeutic agent and the low solubility therapeutic agent is topiramate. (A) a core comprising a first drug composition, a second drug composition, and a push layer comprising an osmopolymer, wherein each of the first and second drug compositions comprises a substrate The granule base comprises a solubilizing substance and a low-solubility therapeutic agent, and the granule coating comprises a hydrophilic polymer).
(B) a semi-permeable wall surrounding the core, and (c) an outlet opening through the semi-permeable wall for releasing the drug composition from the dosage form over an extended period of time,
A dosage form comprising   23. The dosage form of claim 22, wherein the low solubility therapeutic agent is topiramate.   24. The dosage form of claim 23, wherein the solubilizing substance is a surfactant.   The dosage form of claim 24, wherein the hydrophilic polymer is methylcellulose. (A) a core comprising a drug composition comprising a granule having a substrate and a coating, wherein the granule base comprises a low-solubility therapeutic agent and optionally a solubilizing substance; and A core (b) a semipermeable wall surrounding the core, wherein the coating comprises one or more layers, and the coating layer of each granule comprises an independently selected hydrophilic polymer; and (c ) An outlet opening through the semi-permeable wall for releasing the drug composition from the dosage form over an extended period of time;
A dosage form comprising   The number of coating layers of the granule (a) reduces the dissolution rate of the therapeutic agent, or (b) extends the time to the maximum release rate of the therapeutic agent, or (c) extends the period of delivery of the therapeutic agent, or ( 27. The dosage form of claim 26, wherein the dosage form is selected to reduce d) the maximum release rate figure of the therapeutic agent.   The granule coating comprises one layer and the hydrophilic polymer (a) reduces the dissolution rate of the therapeutic agent, or (b) extends the time to the maximum release rate of the therapeutic agent, or (c) 27. The dosage form of claim 26, wherein the dosage form is selected to increase the period of delivery of the therapeutic agent or (d) decrease the figure of the maximum release rate of the therapeutic agent.   The granule coating comprises one layer and the amount of coating (a) reduces the dissolution rate of the therapeutic agent, or (b) extends the time to the maximum release rate of the therapeutic agent, or (c) 27. The dosage form of claim 26, wherein the dosage form is selected to increase the period of delivery of the therapeutic agent or (d) decrease the figure of the maximum release rate of the therapeutic agent.   The dissolution rate of the therapeutic agent or the time to the maximum release rate of the therapeutic agent or the duration of delivery of the therapeutic agent or the magnitude of the maximum release rate of the therapeutic agent is (a) the number of granule layers of the coating, (b) the granules of each coating 27. The dosage form of claim 26, controlled by varying the amount of layer or (c) one or more of the hydrophilic polymers in the granular layer of each coating.   27. The dosage form of claim 26, wherein the low solubility therapeutic agent is topiramate, the granule coating comprises a single layer, and the hydrophilic polymer is selected from the group consisting of methylcellulose, polyvinylpyrrolidone and polyethylene oxide.   32. The dosage form of claim 31, wherein the amount of granule coating is in the range between about 2.5% to about 23% by weight.   The granule coating comprises one layer and the hydrophilic polymer is (a) methylcellulose in an amount in the range between about 2.5% to about 13% by weight, (b) about 3% to about 27. The dosage form of claim 26, selected from the group consisting of polyvinylpyrrolidone in an amount within the range of 23% by weight and (c) polyethylene oxide in an amount in the range of about 5% to about 15% by weight.   27. The dosage form of claim 26, wherein the granule coating comprises one layer and the hydrophilic polymer is methylcellulose in an amount of about 3% by weight.

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