CN100389752C - controlled release composition - Google Patents

Abstract

A solid dosage formulation having a core with a pharmacological agent dispersed in a first controlled-release matrix from which release of the agent is relatively slow; and a coat formed over the core and having the agent dispersed in a second controlled-release matrix from which release of the agent is relatively fast. The first matrix can be a cross-linked high amylose starch and the second matrix can be a mixture of polyvinyl acetate and polyvinylpyrrolidone.

Description

controlled release composition

technical field

[0001] The present invention relates to solid dosage forms wherein the active ingredient is released over a sustained period of time.

Background technique

[0002] An important factor affecting the rate of absorption of active agents administered in tablet or other solid formulation form, and thus the efficacy and safety of the formulation, is the rate of dissolution of the dosage form in human or animal body fluids.

[0003] Thus, the ability of the formulation components to influence the release rate of the active agent constitutes the so-called controlled release, delayed release, slow release or engineered to produce a slow uniform release of the active agent over a period of hours, days, weeks or months. And the basis of long-acting pharmaceutical preparations for absorption. Advantages of controlled-release formulations compared to immediate-release dosage forms include reduced dosing frequency required, often improving patient compliance; maintenance of relatively stable drug concentrations in vivo, resulting in sustained efficacy over a set period of time; And reduce the incidence and intensity of unexpected side effects of the active agent caused by the reduction in high plasma concentration that often occurs after administration of the immediate release dosage form.

[0004] A number of substances have been proposed and developed as matrices for the controlled release of active agents, ie, drugs, precursors, and the like. These materials include polymers such as polyvinyl chloride, polyvinylamide, ethylcellulose, silicones, and poly(hydroxymethacrylate). See, for example, U.S. Patent U.S. 3,087,860 to Endicott et al; U.S. Patent U.S. 2,987,445 to Levesque et al; Pharm. Acta Helv., 55, 174-182 (1980) to Salomon et al; 37 Polymers for Controlled Drug Delivery, Ed Tarcha, CRC Press, Boca Raton, Fla. USA (1991); and Buri et al. Pharm. Acta Helv. 55, 189-197 (1980).

[0005] High amylose slurries have also been used for controlled release purposes, and especially recent developments use cross-linked high amylose slurries. For example, U.S. Patent No. 5,456,921 published on October 10, 1995 (Mateescu et al.), U.S. Patent No. 5,616,343 published on April 1, 1997 (Cartilier et al.), U.S. Patent No. 6,284,273 published on September 4, 2001 (Lenaerts et al), U.S. Patents U.S. 6,419,957 (Lenaerts et al.) published July 16, 2002 and U.S. Patent No. 6,607,748 (Lenaerts et al.) published August 19, 2003, describe oral pharmaceutical dosage units in the form of solid controlled-release tablets , the tablet comprises dry powder of medicine and dry powder of cross-linked high-amylose pulp, wherein the cross-linked high-amylose pulp comprises a mixture of 10-60% amylopectin and about 40-90% amylose by weight.

Other examples of controlled release materials include Kollidon ^™ SR sold by BASF Corporation (Germany), which is a physical mixture of polyvinyl acetate (PVA) and polyvinylpyrrolidone (povidone), reportedly composed of about 80 % PVA and 19% povidone, stabilized with about 0.8% sodium lauryl sulfate and about 0.2% silicon dioxide. BASF Technical Information (July 2001) discloses that Kollidon ^™ SR can be used in the preparation of sustained release matrix dosage forms, including tablets, pills and granules, and different techniques such as direct compression, roller compaction, wet granulation Method and extrusion can be used to produce pharmaceutical preparations. A number of patent publications also provide information on PVA-povidone mixtures: U.S. Patent US Publication No. 2001/0038852 (Kolter et al.), published Nov. 8, 2001; US Patent US Publication No. 2002/0012701 (Kolter et al.), and US Patent US Publication No. 2003/0021846 (Kolter et al.), published January 30, 2003.

[0007] Proposed delayed release and controlled release formulations related to tramadol, examples are described in: U.S. Patent Publication No. 2003/0143270 published on July 31, 2003, (Deboeck et al.); U.S. Patent No. 2001/0036477 published on November 1, 2001 (Miller et al.); U.S. Patent No. 6,326,027 published on December 4, 2001 (Miller et al.), WO03/080031 published Oct. 2, 2003 (CILAG AG et al.). Comparative data between "once-daily" and immediate-release tramadol formulations are presented in a published paper: Adler et al., "A Comparison of Once-Daily Tramadol with NormalRelease Tramadol in the Treatment of Pain in Osteoarthritis, "The Journal of Rheumatology (2002) 29(10): 2195-2199; and Bodalia et al., "A Comparison of the Pharmacokinetics, Clinical Efficacy, and Tolerability of Once-Daily suour Caplen Tablets with Tramadol Re of Pain and Symptom Management (2003) 25(2): 142-149.

[0008] In this specification, citation or identification of any reference is not to be construed as an admission that said reference is available as prior art to the present invention.

Contents of the invention

[0009] The present invention relates to solid formulations for controlled release of pharmaceutical agents. In one embodiment, the formulation comprises a core having a pharmaceutical agent dispersed within a first controlled release matrix, said first controlled release matrix comprising cross-linked high amylose starch, said agent being extracted from the first controlled release matrix. Release is relatively slow. A coating is formed on the core and the coating includes an agent dispersed within a second controlled release matrix from which the agent is released relatively quickly.

[0010] In the context of the present invention, "relatively fast" refers to at least twice the initial release rate of the reagent when it is measured separately for each matrix substance under the same conditions. To carry out the measurement, one prepares a preparation with core reagents and coating reagents labeled differently from one another. In the case of tramadol, for example, core tramadol can be labeled with ¹⁵ N and coated tramadol can be labeled with ¹³ C. There are a number of methods known to those skilled in the art for differentially labeling the compound so that its diffusion from the formulation can be minimal without significantly affecting its rate of diffusion. Assuming that the rates are significantly different from each other, one skilled in the art can evaluate the relative rates to a reasonable value based on the observed biphasic behavior of the release of the agents from a single formulation, for example, the rates at t=0 and t=12 hours in Figure 2. approximate value. Typically, the measurements are performed under the conditions related to FIG. 2 .

[0011] In another broader embodiment, the invention is a solid formulation comprising a core comprising a pharmaceutical agent within a first controlled release matrix. A coating is formed on the core, the coating including the pharmaceutical agent within a second controlled release matrix. The second controlled release matrix is a physical mixture of polyvinyl acetate and polyvinylpyrrolidone, and the release of the agent from the core matrix is relatively slow relative to the release of the agent from the coating matrix. Relatively slow means that when the initial release rate of the reagent is measured separately for each matrix substance under the same conditions, it does not exceed half of it, and the above-mentioned measurements are related to relatively fast measurements.

[0012] The reagents in the core and in the coating may, in either embodiment, be the same or different. In a preferred embodiment, the formulation includes a single agent, tramadol.

[0013] In a preferred aspect of the invention, the coating and core comprise relative amounts of the agent such that release of the agent from the formulation is biphasic.

[0014] Preferably, the reagent is water soluble and the first matrix is relatively hydrophilic relative to the second matrix.

[0015] Many reagents are capable of forming ionic salts, and this is often the preferred form of reagents into formulations of the invention. Preferred reagents contain at least one amino group, and these reagents conveniently come, for example, as the hydrochloride salt.

[0016] Preferably, the rate of release of the agent from the coating is at least twice the rate of release of the agent from the core. Other relative rates are possible: the rate of release of the agent from the coating can be at least 3 times the rate of release of the agent from the core; the rate of release of the agent from the coating can reach the rate of release of the agent from the core The release rate of the agent from the coating can reach 12 times the release rate of the agent from the core; the release rate of the agent from the coating can reach 10 times the release rate of the agent from the core the rate of release of the agent from the coating can be up to 8 times the rate of release of the agent from the core; the rate of release of the agent from the coating can be up to 6 times the rate of release of the agent from the core; or The release rate of the agent from the coating may be about 4 times the release rate of the agent from the core. In other embodiments a biphasic release behavior is observed and the release rate of the agent from the coating is 3-9 times the rate of release of the agent from the core, more preferably the release rate of the agent from the coating is The release rate of the reagent from the core is 4-8 times, more preferably the release rate of the reagent from the coating is 5-7 times the release rate of the reagent from the core.

In certain embodiment, when adopting USP Type I equipment in the phosphate of 50mM pH6.8 in the phosphate of 50mM and when testing under the situation of the rotating speed of 50-150rpm in vitro, within 0-2 hour Between 10% and 30% of the reagents are released.

In certain embodiments, 10%-40% of the reagent is released from the preparation when the measurement is carried out for about 0-2 hours, and about 30%-60% is released when the measurement is carried out for 2-7 hours. % of the agent is released from the formulation, about 50%-80% of the agent is released from the formulation when the measurement is performed for 7 to about 12 hours, and about 80%-100% is released when the measurement is performed for about 20 hours The agent is released from the formulation.

[0019] The preferred active agent of the core and the coating is an analgesic, in particular, the active substance may be tramadol.

The reagent of preparation of the present invention is preferably water-soluble, and solubility is at least 1g/L, or greater than 10g/L, or greater than 100g/L, or greater than 500g/L, or greater than 1000g/L, or greater than 2000g/L .

[0021] In certain embodiments, the formulations of the present invention are produced such that their core to coating ratio (weight/weight) is from about 1 to about 0.1, or from about 0.9 to about 0.2, or from about 0.8 to about 0.2, Or about 0.7 to about 0.2, or about 0.5 to about 0.2, or about 0.4 to about 0.2, or about 0.35. Herein, when determining the weight ratio, the total weight of the core and the total weight of the coating will be taken into account.

In certain embodiments, the ratio (weight/weight) of agent in core to agent in coating is about 0.1-about 10, or about 0.1-about 8, or about 0.2-about 7, or about 0.3- About 6, or about 0.4-about 5, or about 0.5-about 4, or about 0.6-about 3, or about 0.6-about 2, or about 0.6-about 1.5, or about 0.6-about 1.3, or about 0.7-about 1, or about 0.7 to about 0.9 or about 0.8.

[0023] In a particular embodiment of the invention, said formulation is one wherein said agent is from about 10% to about 90% by weight of said core, or from about 20% to about 80% by weight of said core, Or about 30% to about 70% of the weight of the core, or about 40% to about 60% of the weight of the core, or about 50% of the weight of the core.

[0024] In particular embodiments, the formulation of the present invention is one wherein said agent is about 5% to about 90% of said coating weight, or about 5% to about 80% of said coating weight, or about 10% to about 70% of the coating weight, or about 10% to about 60% of the coating weight, or about 15% to about 50% of the coating weight, or the coating From about 15% to about 45% by weight, or from about 15% to about 40% by weight of the coating, or from about 20% to about 35% by weight of the coating, or from about 20% by weight of the coating - about 30%.

[0025] According to a certain aspect of the present invention, the formulation is such that the ratio (weight/weight) of the coating substrate to the coating agent is about 0.1 to about 10, or about 0.2 to about 9, or about 0.2 to about 8, or about 0.3 to about 7, or about 0.4 to about 6, or about 0.5 to about 5, or about 0.6 to about 4, or about 0.7 to about 4 or about 1 to about 4, or about 1 to about 3 to about 1.5 - about 2.5.

[0026] According to certain aspects, the formulation is such that the ratio of nuclear matrix to nuclear agent (weight/weight) is about 0.1 to about 10, or about 0.2 to about 9, or about 0.3 to about 7, or about 0.4 to About 6, or about 0.5-about 5, or about 0.5-about 4, or about 0.5-about 3, or about 0.6-about 3, or about 0.7-about 2 or about 0.8-about 1.5, or about 0.9-about 1.5 , or about 0.9-about 1.3, or about 1, or about 0.55.

[0027] Preferably, the reagent is a water-soluble single reagent having a solubility of at least 0.5 gm/mL at room temperature (approximately 21° C.).

In certain aspect, each reagent of described preparation contains an acidic group, a basic group or an acidic group and a basic group, and each reagent is the salt of described group form exists. Preferably, the agent contains an ionizable group and said group is at least 90% ionized in gastric fluid (0.1 M HCI).

The reagent of preparation of the present invention can be following any one or more: the hydrochloride of isonicotinic acid hydrazine, sodium salicylate, pseudoephedrine, the sulfate of pseudoephedrine, acetaminophen or diclofenac sodium, Verapamil, Glipizide, Nifedipine, Felodipine, Betahistine, Albuterol, Avastin, Omeprazole, Misoprostol, Tramadol, Oxybutynin , trimethophan, ciprofloxacin, and their salts. Additionally, the pharmaceutical agent may be an antifungal agent such as ketoconazole, or an analgesic such as acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisal , naproxen, ketorolac, diclofenac, tolmetin, sulindac, phenacetin, piroxicam, mefenamic acid, dextromethorphan, other NSAIDs including salicylates, Its pharmaceutically acceptable salt or its mixture.

[0030] Preferably, the formulations of the invention are prepared by compression. Typically, the core is formed by pressing and the coating is subsequently prepared by pressing on said pre-formed core.

[0031] In a preferred aspect, the coating consists of a mixture of polyvinyl acetate and polyvinylpyrrolidone. The ratio (weight/weight) of polyvinyl acetate to polyvinylpyrrolidone in the coating is typically from about 6:4 to 9:1, or from 7:3 to 9:2, or it is about 8:2.

[0032] The coating often includes a binder, a preferred binder being xanthan gum.

Described preparation can be tablet, and preferred cross-linked high-amylose starch is chemically modified cross-linked high-amylose starch, which is prepared by the following method, the method comprising: (a) cross-linked high-amylose starch, followed by ( b) chemical modification of the cross-linked high-amylose starch, followed by (c) gelation, and (d) drying to obtain a powder of the controlled-release excipient; wherein the cross-linked high-amylose starch is characterized in Dissolving in 90% DMSO for about 3 days at 80° C. and carrying out gel permeation chromatography analysis, the corresponding peak height of the amylose in the cross-linked high-amylose starch is the same as that in the high-amylose starch before step (a). At least 90% of the peak height corresponding to amylose.

Another process for obtaining the cross-linked high-amylose pulp used in the formulation of the present invention comprises: (a) cross-linked high-amylose pulp to form a reaction medium containing a reaction medium consisting of cross-linked high-amylose pulp product; (b) chemically modifying said cross-linked high amylose pulp of step (a) at a temperature of about 10 to about 90° C. for about 1 to about 72 hours; (c) neutralizing step (b) with an acid said reaction medium obtained in , washing the formed slurry and optionally dewatering or forming a starch cake or dry powder; (d) diluting said slurry or reslurrying said starch cake or said dry powder of step (c) with water to Form a slurry with a concentration of about 2% to about 40% weight/weight, adjust the pH to a desired value of about 3 to about 12, and gelatinize the slurry at a temperature of about 80 to 180° C. for about 1 second to about 120° C. minutes; and (e) drying the heat-treated product obtained in step (d) to obtain the powdered controlled-release excipient, which mainly consists of chemically modified and cross-linked high amylose starch.

[0035] Another process for producing a controlled-release excipient consisting essentially of cross-linked high-amylose starch in an aqueous medium comprises (a) chemically modifying the high-amylose slurry at a temperature of from about 10 to about 90° C. for about 1 - about 72 hours, thereby forming a reaction medium containing a chemically modified high-amylose pulp; (b) crosslinking said chemically-modified high-amylose starch in said pulp obtained in step (a); (c) using an acid neutralizing the pulp obtained in step (b), washing the resulting pulp and optionally dewatering to form a starch cake or drying to form a dry powder; (d) diluting the pulp or repulping with water step (c ) of said starch cake or said dry powder to form a slurry with a concentration of about 2% to about 40% weight/weight, adjust the pH to a desired value of about 3 to about 12, and make the said starch cake at a temperature of about 80-180°C gelatinizing the slurry for about 1 second to about 120 minutes; and (e) drying the heat-treated product obtained in step (d) to obtain the powdered controlled-release excipient mainly composed of chemically modified and cross-linked high amylose starch composition.

Another process for obtaining the cross-linked high-amylose starch used in the present invention comprises: (a) cross-linked high-amylose starch, followed by (b) chemical modification of the cross-linked high-amylose starch, followed by (c) glue coagulation, and (d) drying to obtain a powder of the controlled-release excipient; wherein the cross-linked high-amylose starch is characterized by dissolving in 90% DMSO at 80°C for about 3 days and performing gel permeation chromatography analysis, The peak height corresponding to amylose in the cross-linked high-amylose slurry is at least 90% of the peak height corresponding to amylose in the high-amylose starch prior to step (a).

Another process for obtaining the cross-linked high-amylose starch used in the present invention comprises: (a) cross-linked high-amylose starch, followed by (b) chemical modification of the cross-linked high-amylose starch, followed by (c) glue coagulation, and (d) drying to obtain a powder of the controlled-release excipient; wherein the cross-linked high-amylose starch is characterized in that less than about 20 % of amylose chemically cross-linked to amylopectin.

Another process for obtaining the cross-linked high-amylose starch used in the present invention comprises: (a) cross-linked high-amylose starch, followed by (b) chemical modification of the cross-linked high-amylose starch, followed by (c) glue coagulation, and (d) drying to obtain a powder of the controlled-release excipient; wherein the cross-linked high-amylose starch is characterized in that it is dissolved in 90% DMSO at 80° C. for about 3 days and subjected to gel permeation chromatography Assayed, less than about 20% of the amylose present prior to step (a) is chemically cross-linked with amylopectin and eluted.

Another process for obtaining the cross-linked high-amylose pulp used in the present invention comprises: (a) cross-linked high-amylose pulp, followed by (b) chemical modification of the cross-linked high-amylose starch, followed by (c ) gelation, and (d) drying to obtain a powder of the controlled-release excipient; wherein the cross-linked high-amylose starch is characterized in that it is dissolved in 90% DMSO at 80° C. for about 3 days and gelled In permeation chromatography, the peak heights corresponding to amylose were higher than those corresponding to bulk-containing amylopectin.

Another process for obtaining the cross-linked high-amylose starch used in the present invention comprises: (a) cross-linked high-amylose starch, followed by (b) chemical modification of the cross-linked high-amylose starch, followed by (c) glue coagulation, and (d) drying to obtain a powder of said controlled-release excipient; wherein said cross-linked high-amylose starch is characterized by less than about 20% of said high-amylose starch present prior to step (a) The amylose is chemically crosslinked into amylopectin.

Another process for obtaining the cross-linked high-amylose starch used in the present invention comprises: (a) cross-linked high-amylose starch, followed by (b) chemical modification of the cross-linked high-amylose starch, followed by (c) glue coagulation, and (d) drying to obtain the powder of the controlled-release excipient; wherein the cross-linked high-amylose starch is characterized in that it is dissolved in 90% DMSO at 80°C for about 3 days and analyzed by gel permeation chromatography , less than about 20% of the amylose present prior to step (a) is chemically cross-linked with amylopectin and eluted.

Another process for obtaining the cross-linked high-amylose starch used in the present invention comprises: (a) cross-linked high-amylose starch, followed by (b) chemical modification of the cross-linked high-amylose starch, followed by (c) glue coagulation, and (d) drying to obtain a powder of the controlled-release excipient; wherein the cross-linked high-amylose starch is characterized in that it is dissolved in 90% DMSO at 80° C. for about 3 days and subjected to gel permeation chromatography Analysis, the peak heights corresponding to amylose were higher than those corresponding to amylopectin containing bulk.

[0043] Certainly, the product with a cross-linked high-amylose structure obtained by one of the above-mentioned processes, even if the production process is different from one of the above-mentioned processes, is also within the scope of the present invention.

[0044] The core of the formulations of the invention often includes a lubricant, which is optionally a hydrogenated vegetable oil.

[0045] In a preferred aspect, the formulation of the present invention is a tablet made orally.

[0046] In a specific embodiment, the present invention is a solid dosage form comprising: a core having a pharmaceutical agent dispersed in a first controlled release matrix, the release of said agent from the first controlled release matrix being relatively slower; and a coating formed on said core and comprising said agent dispersed within a second controlled release matrix comprising polyvinyl acetate and polyvinylpyrrolidone The physical mixture, and the release of the agent from the second controlled release matrix is relatively fast.

In another embodiment, the present invention provides a solid dosage form comprising: a core having a pharmaceutical agent dispersed within a first controlled release matrix, said first controlled release matrix comprising a cross-linked high amylose slurry, wherein release of the agent from the first controlled release matrix is relatively slow; and a coating formed on the core and comprising the agent dispersed within a second controlled release matrix, the second controlled release matrix The matrix comprises a physical mixture of polyvinyl acetate and polyvinylpyrrolidone, and wherein: release of the agent from the core matrix is relatively slow relative to release of the agent from the coating matrix.

[0047] Another aspect of the present invention is a solid dosage form comprising: a core having a pharmaceutical agent in a first controlled release matrix; and a pharmaceutical agent formed on said core and included in a second controlled release matrix coating, the second controlled release matrix comprises a physical mixture of polyvinyl acetate and polyvinylpyrrolidone, and wherein, relative to the release of the agent from the coating matrix, the release of the agent from the core matrix relatively slow.

[0048] In another aspect, the present invention includes a solid formulation comprising a pharmaceutical agent that is self-releasing over a sustained period of time, said formulation comprising: a core having the agent within a first release-controlling matrix , the first controlled-release matrix comprising cross-linked high-amylose starch; and a coating of the agent formed on the core and contained within a second controlled-release matrix comprising polyvinyl acetate and polyvinylpyrrolidone, and wherein the presence of the agent in the core is sufficient to obtain no more than 50% release of the agent from the formulation into an aqueous environment such as gastric juice within a quarter cycle.

[0049] In the formulation, the period may be from about 12 to about 24 hours, and from about 30% to about 70% of the agent is within the core. The agent in said first matrix and the agent in said second matrix are preferably water-soluble with a solubility of at least 1 g/L, or greater than 10 g/L, or greater than 100 g/L, or greater than 500 g/L, Or greater than 1000g/L, or greater than 2000g/L. The agent may be an analgesic.

A specific embodiment of the present invention includes a solid formulation for use in a cycle of every 4 hours, or every 6 hours, every 8 hours, every 12 hours, or every 24 hours, the formulation comprising: a flat core comprising an amino group-containing pharmaceutical agent in the form of a pharmaceutically acceptable salt dispersed in a first controlled release matrix comprising a cross-linked high amylose slurry; and a coating layer passed through The agent formed by compression on the core and included within a second controlled release matrix comprising a physical mixture of polyvinyl acetate and polyvinylpyrrolidone, and wherein, during the period, the agent The release from the formulation includes a first phase, with an average release rate in the first 5% of the cycle of 3-8 times the release rate of the agent in half a cycle.

[0051] In a particular aspect of this particular embodiment, the ratio (weight/weight) of reagents in the core to reagents in the coating is from 0.2 to about 7, said reagents being 20% to 80% by weight of said core, so The reagent is 15%-50% by weight of the coating, and the ratio of coating substrate to coating reagent (weight/weight) is 0.3-7. Also, the preferred agent is tramadol, and preferably, the coating comprises a cement.

[0052] In another aspect, the present invention is a controlled-release tablet comprising: a flat core comprising cross-linked high-amylose starch with tramadol or a salt thereof contained therein; and a coating, the The coating is formed by pressing over the core and comprises a physical mixture of polyvinyl acetate, polyvinylpyrrolidone, binder, tramadol; and, wherein the ratio of core to coating (weight/weight) is about 0.2-0.6; the ratio of tramadol in the core to tramadol in the coating is about 0.7 to about 1; the ratio of polyvinyl acetate/polyvinylpyrrolidone (weight/weight) is about 6:4-9:1; And the release rate of tramadol from the coated matrix was at least twice that of the release rate of tramadol from the core when measured using a USP Type I apparatus in 50 mM pH 6.8 phosphate at a rotational speed of 50-150 rpm.

The present invention comprises a kind of method for producing controlled-release medicine, and the method comprises: (i) mixes a kind of pharmaceutical agent and a kind of first matrix material that comprises cross-linked high amylose; (ii) in step (i) (iii) mix a kind of pharmaceutical agent and a kind of second matrix substance, and described second matrix substance comprises a kind of material that releases relatively quickly with respect to described first matrix substance; (iv) The mixed product of step (iii) is formed as a coating on the exterior of the core.

[0054] The method for producing a controlled-release drug of the present invention may comprise: (i) mixing a pharmaceutical agent and a first matrix substance; (ii) forming the mixed product of step (i) into a nucleus; (iii) mixing a A pharmaceutical agent and a second matrix substance comprising a physical mixture of polyvinyl acetate and polyvinylpyrrolidone and being a relatively quick release substance relative to said first matrix substance; (iv ) forming the mixed product of step (iii) as a coating on the exterior of the core.

[0055] Step (ii) preferably comprises compressing the mixed product of step (i). Step (iv) may comprise compressing the mixed product of step (iii) onto the core exterior. The core agent and coating are preferably tramadol, the total amount of tramadol in the medicament is an effective daily dose, and the medicament includes a formulation as properly defined in the specification.

[0056] The present invention includes an oral tramadol pharmaceutical composition, suitable for once-a-day administration, comprising an effective amount of tramadol or a pharmaceutically acceptable salt thereof, provided in vivo after a single administration The median time to peak plasma concentration of tramadol (T _max ) was 2-8 hours and the mean peak plasma concentration of tramadol (C _max ) was less than the mean obtained 24 hours after administration (C _24h ) of a single dose of the composition. 3 times the plasma concentration.

[0057] The composition is such that the mean peak plasma concentration (C _max ) of the tramadol is less than twice the mean plasma concentration obtained 24 hours after administration (C _24h ) of a single dose of the composition.

[0058] In another embodiment, the present invention is an oral tramadol pharmaceutical composition suitable for continuous administration once a day, which includes an effective amount of tramadol or a pharmaceutically acceptable salt thereof, in A steady state is provided in vivo in which the maximum mean plasma concentration of tramadol ( _Cmax ) is 2-3 times the minimum mean plasma concentration of tramadol ( _Cmin ) during a given 24 hour period. According to a particular aspect, the mean _Cmax is not greater than 350 ng/ml. The mean plasma concentration of tramadol is preferably less than 90% of _Cmax for at least 18 hours of said 24 hour period.

[0059] The present invention includes a solid formulation comprising: a core having a pharmaceutical agent dispersed within a first controlled-release matrix comprising a cross-linked high-amylose slurry; and a coating comprising Formed on the core and comprising the agent dispersed within a second controlled release matrix different from the first controlled release matrix such that release of the agent from the formulation is biphasic.

[0060] According to another aspect, the present invention is a solid dosage form comprising: a core having a pharmaceutical agent dispersed within a first release-controlling matrix; and a coating formed on said core and comprising a dispersed The agent is within a second controlled release matrix comprising a physical mixture of polyvinyl acetate and polyvinylpyrrolidone such that release of the agent from the formulation is biphasic.

[0061] According to another aspect, the present invention is a solid formulation comprising: a core having a pharmaceutical agent dispersed in a controlled release matrix, said controlled release matrix comprising cross-linked high amylose; and a coating, which Formed on the core and comprising a pharmaceutical agent within a second controlled release matrix comprising a physical mixture of polyvinyl acetate and polyvinylpyrrolidone.

In another embodiment, the present invention is a solid formulation comprising: a core comprising about 50 mg, or about 75 mg or about 100 mg or about 125 mg or about 150 mg or about 175 mg or about 200 mg or about 225 mg or about 250 mg or about 275 mg or about 300 mg or about 325 mg or about 350 mg or about 350 mg or about 375 mg or about 400 mg of tramadol dispersed in a controlled release matrix comprising cross-linked high amylose starch; and a coating, It is formed on the core and includes the pharmaceutical agent within a second controlled release matrix comprising a physical mixture of polyvinyl acetate and polyvinylpyrrolidone.

[0063] The term "comprising" is used herein in its broad sense unless the context dictates otherwise. That is, a formulation that includes first and second matrices and agents, for example, may thus also include other ingredients, such as lubricants.

[0064] Formulations of the formulations described above provide advantageous properties in vivo, as further described below. Accordingly, another aspect of the present invention is a once-daily oral pharmaceutical composition for the controlled release of tramadol or a salt thereof, wherein analgesia begins within 2 hours upon first administration of a dose of said composition Effect, the analgesic effect lasts for at least 24 hours after administration.

[0065] Another aspect of the present invention is a once-a-day oral pharmaceutical composition for controlled release of tramadol or a salt thereof, wherein, when a dose of the composition is administered for the first time, within 2 hours of administration Provides a mean plasma concentration of at least 100 ng/mL and continues to provide a mean plasma concentration of at least 100 ng/mL for at least 22 hours after dosing.

[0066] Another aspect of the present invention is a once-a-day oral pharmaceutical composition for controlled release of tramadol or a salt thereof, wherein, when a dose of the composition is administered for the first time, within 2 hours of administration Provides a mean plasma concentration of at least 100 ng/mL and continues to provide a mean plasma concentration of at least 100 ng/mL for at least 23 hours after dosing.

[0067] In another aspect, the present invention is a once-a-day oral pharmaceutical composition for controlled release of tramadol or a salt thereof, wherein, when a dose of said composition is administered for the first time, upon administration Provided a mean plasma concentration of at least 100 ng/mL within 2 hours and continued to provide a mean plasma concentration of at least 100 ng/mL for at least 24 hours after dosing.

[0068] In a preferred aspect, the once-daily oral pharmaceutical composition of the present invention comprises about 200 mg of tramadol or a salt thereof.

[0069] In another aspect, the present invention is a once-a-day oral pharmaceutical composition for controlled release of tramadol or a salt thereof, comprising 100 mg of tramadol or a salt thereof, wherein a dose of Provides a mean plasma concentration of at least 50 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 50 ng/mL for at least 22 hours after administration.

[0070] According to another aspect, the present invention provides an oral pharmaceutical composition once a day for controlled release of tramadol or a salt thereof, comprising 100 mg of tramadol or a salt thereof, wherein, in the first administration of a dose Provides a mean plasma concentration of at least 50 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 50 ng/mL for at least 23 hours after administration.

[0071] Another aspect of the present invention is an oral pharmaceutical composition once a day for controlled release of tramadol or a salt thereof, which includes 300 mg of tramadol or a salt thereof, wherein the first administration of a dose of The composition provides a mean plasma concentration of at least 150 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 150 ng/m for at least 22 hours after administration.

[0072] Another aspect of the present invention is an oral pharmaceutical composition once a day for controlled release of tramadol or a salt thereof, comprising 300 mg of tramadol or a salt thereof, wherein the first administration of a dose of the The composition provides a mean plasma concentration of at least 150 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 150 ng/mL for at least 23 hours after administration.

[0073] Another aspect of the present invention is an oral pharmaceutical composition once a day for controlled release of tramadol or a salt thereof, which includes 300 mg of tramadol or a salt thereof, wherein the first administration of a dose of the The composition provides a mean plasma concentration of at least 150 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 150 ng/mL for at least 24 hours after administration.

In another aspect, the once-a-day oral pharmaceutical composition for controlled release of tramadol or a salt thereof comprises 200 mg of tramadol or a salt thereof, wherein, at the first administration of 400 mg, the composition is Provide a mean plasma concentration of at least 200 ng/mL for at least 22 hours post-dose.

[0075] Another aspect of the present invention is an oral pharmaceutical composition once a day for controlled release of tramadol or a salt thereof, comprising 200 mg of tramadol or a salt thereof, wherein, when 400 mg is administered for the first time, the The composition provides a mean plasma concentration of at least 190 ng/mL for at least 23 hours after administration.

Another aspect of the present invention is an oral pharmaceutical composition once a day, for controlled-release tramadol or its salt, comprising 200mg of tramadol or its salt, wherein, when the first administration of 400mg, the The composition provides a mean plasma concentration of at least 180 ng/mL for at least 24 hours after administration.

[0077] The present invention also provides a once-daily oral pharmaceutical composition wherein the mean maximum plasma concentration ( _Cmax ) is less than 100 ng/mL.

[0078] Furthermore, the once-daily oral pharmaceutical composition of the present invention can provide a mean maximum plasma concentration ( _Cmax ) of less than 300 ng/mL, or a mean maximum plasma concentration ( _Cmax ) of less than 200 ng/mL.

[0079] The once-daily oral pharmaceutical composition of the present invention can result in a mean maximum plasma concentration ( _Cmax ) less than 2.2 times the mean plasma concentration obtained 24 hours after administration ( _C24h ).

[0080] The once-daily oral pharmaceutical composition can result in a mean maximum plasma concentration ( _Cmax ) of less than 300 ng/mL.

[0081] The mean maximum plasma concentration ( _Cmax ) may be less than twice the mean plasma concentration obtained 24 hours after administration ( _C24h ).

[0082] The mean maximum plasma concentration (C _max ) may be less than 2.3 times the mean plasma concentration obtained 24 hours after administration (C _24h ).

[0083] The once-a-day oral pharmaceutical composition of the present invention can provide a median time to maximum plasma concentration (t _max ) of 2-10 hours, or 3-6 hours, or 5-6 hours.

[0084] The present invention also provides a once-a-day oral pharmaceutical composition for controlled-release tramadol or a salt thereof, which includes 200 mg of tramadol or a salt thereof, wherein, after the first administration of a dose of The composition provides a mean plasma concentration of O-desmethyltramadol of at least 24 ng/mL within 2 hours of administration and continues to provide at least 25 ng/mL of O-desmethyltramadol for at least 24 hours after administration multiple mean plasma concentrations.

According to another embodiment, the present invention provides a once-a-day oral pharmaceutical composition for controlled-release tramadol or a salt thereof, comprising 100 mg of tramadol or a salt thereof, wherein, in the first administration of a A dose of the composition provides a mean plasma concentration of O-desmethyltramadol of at least 11 ng/mL within 2 hours of administration and continues to provide an O-nortramadol of at least 12 ng/mL for at least 24 hours after administration. Mean plasma concentrations of tramadol.

According to another embodiment, the present invention provides a once-a-day oral pharmaceutical composition for controlled-release tramadol or a salt thereof, comprising 300mg of tramadol or a salt thereof, wherein, in the first administration of a A dose of the composition that provides a mean plasma concentration of O-desmethyltramadol of at least 32 ng/mL within 2 hours of administration and continues to provide an O-nortramadol of at least 32 ng/mL for at least 24 hours after administration Mean plasma concentrations of tramadol.

In another embodiment, the present invention is a once-a-day oral pharmaceutical composition for controlled-release tramadol or a salt thereof, comprising 200 mg of tramadol or a salt thereof, wherein, at the first administration of 400 mg The composition provides a mean plasma concentration of O-desmethyltramadol of at least 50 ng/mL within 2 hours of administration and continues to provide at least 50 ng/mL of O-desmethyltramadol for at least 24 hours after administration multiple mean plasma concentrations.

[0088] It is an object of the present invention to provide flexible dosage options for patients with varying analgesic needs using a once-daily formulation.

[0089] One embodiment of the present invention provides a once-a-day formulation that will provide the expected early onset of action upon initial ingestion of a dose of 100 mg, but achieve an average of at least 45 ng/mL within 2-24 hours Tramadol plasma concentrations.

[0090] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose of 200 mg, will provide the expected early onset of action but achieve an average of at least 100 ng/mL within 2-24 hours Tramadol plasma concentrations.

[0091] Another embodiment of the present invention provides a once-a-day formulation that will provide the expected early onset of action upon initial ingestion of a dose of 300 mg, but achieve a concentration of at least 150 ng/mL within 2-24 hours. Mean tramadol plasma concentrations.

[0092] Another embodiment of the present invention provides a once-a-day formulation that will provide the expected early onset of action upon initial ingestion of a dose of 400 mg, but achieve a concentration of at least 180 ng/mL within 2-24 hours. Mean tramadol plasma concentrations.

[0093] Another embodiment of the invention provides a once-a-day formulation that will provide a _C'max /dose ratio of about 0.90 to about 1.0 upon initial ingestion of a dose.

[0094] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose, will provide a steady increase in plasma concentrations of tramadol until between about 4 hours and about 6 hours. Peak tramadol concentrations are reached at T _max . Preferably, said T _max occurs at about 5 hours to about 5.5 hours.

[0095] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose, will provide a slow, steady decline in plasma concentrations of tramadol after _Tmax , reflecting a clearance process Sustained absorption other than. Preferably, after _Tmax , the decrease in tramadol plasma concentration occurs in a linear-logarithmic manner with a mean apparent terminal elimination half-life of about 5.5 hours to about 6.5 hours.

[0096] Another embodiment of the present invention provides a once-a-day formulation that will provide a slow, steady decline in plasma concentrations of tramadol after _Tmax upon initial ingestion of a dose, reflecting the removal of Sustained absorption outside of course and continued for at least 20 hours after _Tmax .

[0097] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose, provides a linear-logarithmic decrease in tramadol plasma concentration after _Tmax , for said Tramadol For the plasma concentration of madol, the apparent terminal clearance constant (λz) is about 0.12h ^-1 .

[0098] Another embodiment of the present invention provides a once-a-day formulation that will provide a mean residence time (MRT) of tramadol of about 15 hours to about 18 hours upon initial ingestion of a dose.

[0099] Another embodiment of the present invention provides a once-a-day formulation that will provide a tramadol half value duration (HVD) of about 22.5 hours to about 25.4 hours upon initial ingestion of a dose.

[00100] Another embodiment of the present invention provides a once-a-day formulation that will provide a _C'max /AUC0 _-∞ ratio of about 0.04h ^-1 to about 0.06h upon initial ingestion of a dose ^-1 . Preferably, C' _max /AUC _0-∞ . The ratio is about 0.04h ⁻¹ to about 0.05h ⁻¹ . The C' _max /AUC _0-∞ ratio was used to assess the absorption rate of the drug.

[00101] Another embodiment of the present invention provides a once-a-day formulation which, upon initial ingestion of a dose, will provide a mean AUC _0-24 corresponding to a plasma concentration of tramadol, at the controlled-release The dose concentration range of the composition 100mg-300mg is proportional to the dose increase.

[00102] Another embodiment of the present invention provides a once-a-day formulation that will provide a mean AUC0 _-Tmax of about 610 ng.h/mL to about 630 ng.h/mL upon initial ingestion of a dose of 100 mg.

[00103] Another embodiment of the present invention provides a once-a-day formulation that will provide a mean AUC0 _-Tmax of about 910 ng.h/mL to about 920 ng.h/mL upon initial ingestion of a dose of 200 mg.

[00104] Another embodiment of the present invention provides a once-a-day formulation that will provide a mean AUC0 _-Tmax of about 1570 ng.h/mL to about 1590 ng.h/mL upon initial ingestion of a dose of 300 mg.

[00105] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose, provides an _AUC0-24 /AUC0 _-∞ mean ratio of tramadol plasma concentrations of about 70 % - about 85%. Preferably, said AUC _0-24 /AUC _0-∞ mean ratio of tramadol plasma concentrations is from about 74% to about 80%. Thus, depending on the dose administered, from about 15% to about 30% of the administered dose is still circulating in the plasma 24 hours after the dose.

[00106] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose, will provide a _C'max equal to that of the dose released into plasma within the first 24 hours. The ratio (ie, AUC _0-24 /AUC _0-∞ multiplied by dose) ranged from about 1.10 to about 1.35. Preferably the ratio is from about 1.15 to about 1.31.

[00107] Another embodiment of the invention provides a once-a-day formulation that, upon initial ingestion of a dose, will provide a ratio of _C'max / _Tmax to the administered dose of about 0.10 to about 0.20. Preferably, the ratio is from about 0.12 to about 0.19.

[00108] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose, will provide a slope of ng/ml-hr after peak plasma concentration levels not exceeding A factor of about 0.035 of the total dose of the drug. Preferably, the factor is about 0.03.

[00109] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose, will provide a calculated _C'max corresponding to the plasma concentration of O-desmethyltramadol and The ratio of tramadol doses is about 0.19 to about 0.22. Preferably, the ratio is about 0.20-0.21.

[00110] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose, will provide a steadily rising plasma concentration of O-desmethyltramadol until between about 8 hours to about The peak tramadol concentration _Tmax was reached at 16 hours.

[00111] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose, will provide a slow, steady decline in O-desmethyltramadol plasma concentration after _Tmax , reflecting Sustained tramadol absorption and subsequent metabolite formation in addition to clearance processes. Preferably, the decrease in plasma concentration of O-desmethyltramadol occurs in a linear-logarithmic fashion with a mean apparent terminal elimination half-life of about 6.7 hours to about 8.1 hours.

[00112] Another embodiment of the invention provides a once-a-day formulation that will provide for the formation of metabolites at least 18 hours after _Tmax upon initial ingestion of a dose.

[00113] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose, after _Tmax , will provide a linear logarithmic concentration of O-desmethyltramadol in plasma The apparent terminal clearance constant (λz) of O-desmethyltramadol concentration is about 0.1h ^-1 .

[00114] Another object of the present invention is to provide a once-a-day formulation that provides O-desmethyltramadol plasma concentration half-value duration (HVD) of 25.6- 28.1 hours.

[00115] Another embodiment of the present invention provides a once-a-day formulation which, upon initial ingestion of a dose, will provide a median value duration (HVD) of O-desmethyltrama to about 25.6 hours- About 28.1 hours.

[00116] Another embodiment of the present invention provides a once-a-day formulation which, upon initial ingestion of a dose, will provide a calculated _C'max /AUC ₀ corresponding to the plasma concentration of O-desmethyltramadol. _{The -∞} ratio is about 0.04h ^-1 . The C' _max /AUC _0-∞ ratio was used to assess the rate of metabolite formation.

[00117] Another embodiment of the present invention provides a once-a-day formulation which, upon initial ingestion of a dose, will provide a mean _AUC0-24 calculated corresponding to the plasma concentration of O-desmethyltramadol, It is proportional to the dose increase within the dose concentration range of 100mg-300mg of the controlled release composition.

[00118] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a 100 mg dose, will provide a mean AUC _0-Tmax corresponding to a plasma concentration of O-desmethyltramadol of about 175ng.h/mL-about 180ng.h/mL.

[00119] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose of 200 mg, will provide a mean AUC _0-Tmax corresponding to a plasma concentration of O-desmethyltramadol of about 530 ng .h/mL-approximately 550ng.h/mL.

[00120] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose of 300 mg, will provide a mean AUC _0-Tmax corresponding to a plasma concentration of O-desmethyltramadol of about 580 ng .h/mL-approximately 590ng.h/mL.

[00121] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose, provides a mean _AUC0-24 /AUC0 _-∞ of plasma concentrations of O-desmethyltramadol The ratio is from about 65% to about 80%. Preferably, said plasma concentration of O-desmethyltramadol has a mean AUC _0-24 /AUC _0-∞ ratio of about 68% to about 75%. Thus, about 25% to about 32% of the active metabolite is still circulating in plasma 24 hours after dose.

[00122] Another embodiment of the present invention provides a once-a-day formulation that, upon initial ingestion of a dose, will provide a calculated _C'max corresponding to the O-desmethyltramadol plasma concentration at A 24-hour ratio of plasma concentrations of O-desmethyltramadol (the dose of tramadol multiplied by AUC _0-24 /AUC _0-∞ ) ranged from about 0.0025 to about 0.0035. Preferably, the ratio is from about 0.0027 to about 0.0031.

[00123] The invention may be more fully understood by reference to the following detailed description and illustrative examples which illustrate non-limiting embodiments of the invention.

Description of drawings

[00124] Various features and advantages of the present invention will become apparent from the following more detailed description, with reference to the accompanying drawings, in which:

[00125] Figure 1 is a flowchart showing the tablet manufacturing process.

Fig. 2 is the dissolution profile (release %) of preparation A, B and C in 24 hours: the in vitro performance of preparation A, B and C: under USP Type 1 condition: sodium phosphate buffer, 50mM, pH 6.8 , 100 rpm, 6 tablets were tested at each time point.

LP BID ql2h(△)后48小时内的平均曲马多血浆浓度(ng/ml)。采用HPLC/UV分析法测定血浆浓度。[00127] Figure 3(a): After administration of the composition (formulation B) (▲) and 1x200mg of Topalgic

Mean tramadol plasma concentrations (ng/ml) over 48 hours after LP BID ql2h (△). Plasma concentrations were determined by HPLC/UV analysis.

LPBIDq12h(○)和1x200mg的

LP BID ql2h(△)后48小时内的平均O-去甲曲马多血浆浓度(ng/ml)。[00128] Fig. 3(b): The composition (formulation B) (●), the composition (▲) of the 2x200mg dose, the Topalgic

LPBIDq12h (○) and 1x200mg

Mean O-desmethyltramadol plasma concentration (ng/ml) over 48 hours after LP BID ql2h (△).

[00129] FIG. 4(a): 27 within 48 hours after a single dose of tramadol formulations (A, B and C, respectively) at one of the concentrations of 100 mg (♦), 200 mg (○) or 300 mg (Δ). Plasma tramadol concentration (ng/ml) of the subjects.

[00130] FIG. 4(b): 27 within 48 hours after a single administration of tramadol formulations (A, B and C, respectively) at one of concentrations of 100 mg (♦), 200 mg (○) and 300 mg (Δ). Plasma O-desmethyltramadol concentration (ng/ml) of the subjects.

Fig. 5: the mean steady-state plasma tramadol (●) and O-desmethyl tramadol (○) concentrations (ng/ml) of 26 routine test subjects taking 200mg tramadol, preparation B, and Steady plasma tramadol (▲) and O-desmethyltramadol (△) concentrations of 26 subjects taking Topalgic LP100mg BID.

Detailed ways

nuclear

[00132] The core of the tablet of the present invention comprises at least one active ingredient and a matrix which are combined in such a way that the release of the pharmaceutical ingredient from the matrix is controlled. In a specific embodiment, the core matrix is a cross-linked high-amylose starch known by the name Contramid , and more recently described in US Patent No. 6,607,748 (Lenaerts et al.), published August 19, 2003. A preferred formulation in the context of the present invention is provided in the specification of US Pat. No. 6,607,748.

[00133] Preferably, the core is formed by mixing the ingredients (granular or powdered) and then compressing the mixture, followed by forming the coating on the core. The weight of the core may be any percentage between 10% and 80% of the total weight of the composition. In other aspects, the preferred percentages depend on the total dosage of the pharmaceutical agent. In a specific example described further below, the tablet contains 100 mg tramadol hydrochloride and the core is about 26% of the total weight of the tablet. In another embodiment, the tablet contains 200 mg tramadol hydrochloride and the core constitutes about 33% of the total weight of the tablet. In another embodiment, the tablet contains 300 mg tramadol hydrochloride and the core comprises 33% of the total weight of the tablet.

nuclear active agent

[00134] An active pharmaceutical ingredient is present in the core of the composition of the present invention. A suitable pharmaceutical composition according to the invention is any composition which is desired to be delivered in a sustained release dosage form. A detailed list of suitable pharmaceutical agents can be found in the Merck Index (12th Edition). Preferably, the pharmaceutical ingredients are, but not limited to, isoniazid, sodium salicylate, pseudoephedrine hydrochloride, pseudoephedrine sulfate, acetaminophen or diclofenac sodium, verapamil , Glipizide, Nifedipine, Felodipine, Betahistine, Albuterol, Avastin, Omeprazole, Misoprostol, Tramadol, Oxybutynin, Trimethopridine , ciprofloxacin, and salts thereof. Furthermore, the pharmaceutical agent may be an antifungal agent such as ketoconazole, or an analgesic such as acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisal, Naproxen, ketorolac, diclofenac, tolmetin, sulindac, phenacetin, piroxicam, mefenamic acid, dextromethorphan, other NSAIDs including salicylates, their pharmaceutical Acceptable salts or mixtures thereof. Prodrugs are part of this invention.

[00135] The solubility of pharmaceutical agents in aqueous solutions can have a wide variety of values. The water solubility of pharmaceutical reagents can be less than 10 ^-3 g/L, greater than 10 ^-3 g/L, greater than 10 ^-2 g/L, greater than 10 ^-1 g/L, greater than 1g/L, greater than 10g/L, greater than 100g /L, greater than 500g/L, greater than 1000g/L, or greater than 2000g/L. Preferably, the solubility is greater than 100 g/L. More preferably, the solubility is greater than 500 g/L. Most preferably, the solubility is greater than 1000 g/L.

[00136] The pharmaceutical agent can meet various dosage requirements. For example, the dosage requirement of a pharmaceutical agent may be less than 1 mg/dosage unit, greater than 1 mg/dosage unit, greater than 10 mg/dosage unit, greater than 100 mg/dosage unit, greater than 200 mg/dosage unit, greater than 300 mg/dosage unit, greater than 400 mg/dosage unit, Greater than 500 mg/dosage unit, or greater than 1000 mg/dosage unit. Preferably, the pharmaceutical agent is greater than 50 mg per dosage unit. More preferably, the pharmaceutical agent is 100 mg/dosage unit, or more such as 150 mg/dosage unit, or 200 mg/dosage unit, or 250 mg/dosage unit, or 300 mg/dosage unit, or more.

[00137] Particular embodiments include cores comprising tramadol hydrochloride, wherein the cores contain from about 10% to 90% of the total tramadol present in the tablet, for example about 45 mg in a 100 mg strength tablet (the 45%), or approximately 90 mg (45% of the entire tablet) for a 200 mg strength tablet, or 151 mg (50% of the entire tablet) for a 300 mg strength tablet.

nuclear matrix

并且45mg为盐酸曲马多。在这种情况下，

因此组成了核重量百分比的约49％。[00138] The release of the active pharmaceutical ingredient located within the core from the formulation is slower than the release of the active pharmaceutical ingredient located within the coating matrix. A preferred matrix for the core is cross-linked high amylose starch, known by the name and described in US Patent No. 6,607,748. In particular embodiments, the matrix constitutes from about 10% to about 90% by weight of the core, i.e., the ratio of core matrix to core active ingredient (weight/weight) is from about 0.1 to about 10, or from about 0.2 to about 9, or About 0.2-about 8, or about 0.3-about 7, or about 0.4-about 6, or about 0.5-about 5, or about 0.6-about 4, or about 0.7-about 4 or about 1-about 4, or about 1 - about 3 - about 1.5 - about 2.5. In a specific embodiment, the total weight of the cores is about 90 mg, of which about 44 mg is

And 45mg is tramadol hydrochloride. in this case,

It thus constitutes about 49% by weight of the core.

preferred components

[00139] The core component of the present invention may optionally contain a pharmaceutically acceptable carrier or excipient. Such carriers or excipients are well known to those skilled in the art and can be found, for example, in Remingtons' Pharmaceutical Sciences (14th Edition) (1970). Examples of such carriers or excipients include lactose, starch, dicalcium phosphate, calcium sulfate, kaolin, mannitol and powdered sugar. In addition, when necessary, suitable binders, lubricants and disintegrants may be contained. Dyes and sweetening or flavoring agents may, if desired, be contained.

[00140] The core component of the present invention may optionally contain additional ingredients including, but not limited to, dispersants such as microcrystalline cellulose, starch, cross-linked starch, cross-linked polyvinylpyrrolidone and sodium carboxymethyl cellulose, flavor enhancers Agents, color enhancers, adhesives, preservatives, surfactants, etc.

[00141] The core may also optionally include one or more suitable binders known to those skilled in the art.

[00142] Suitable forms of microcrystalline cellulose are, for example, MCC-PH101, MCC-102, MCC-105, and the like.

[00143] A suitable lubricant may also be included, as known to those skilled in the art. For example, magnesium stearate, vegetable oil, talc, sodium stearyl fumarate, calcium stearate, stearic acid and the like.

[00144] Suitable glidants known in the art may also be included. Examples of such glidants include, but are not limited to, talc, colloidal silicon dioxide, and the like.

Proportion

[00145] The active agent is present from about 1 to about 90% by weight of the total core, preferably from about 10 to about 70% by weight of the entire composition core, more preferably from about 20 to about 60% by weight of the entire composition core, And probably most often from about 30 to about 50% by weight of the entire composition core.

[00146] Of course, the total amount of all components is 100% by weight, and one of ordinary skill in the art can vary the amounts within the stated ranges to obtain a useful composition.

coating

和其它的任选组分。在一种优选实施例中，涂层通过干压而形成。涂层的重量可以为整个组合物重量的介于约10％和约90％之间的任何百分比，但优选该范围的较高部分。因此，涂层通常组成本发明片剂的约20％-约90％(重量/重量)，或约25％-约90％，或约30％-约85％，或约35％-约85％，或约40％-约85％，或约45％-约85％，或约45％-约90％，或约50％-约90％或约50％-约85％，或约55％-约90％，或约55％-约85％，或约55％-约80％，或约60％-约90％，或约60％-约85％，或约60％-约80％，或约60％-约75％，或约65％-约90％，或约65％-约85％，或约65％-约80％，或约65％-约75％，或约65％或约70％或约75％。[00147] The coating of the dosage form comprises a physical mixture of polyvinyl acetate and polyvinylpyrrolidone and the active pharmaceutical ingredient of the coating. Coatings may also include crosslinked high amylose starches such as

and other optional components. In a preferred embodiment, the coating is formed by dry pressing. The weight of the coating can be any percentage between about 10% and about 90% by weight of the total composition, although the higher portion of the range is preferred. Thus, the coating generally constitutes from about 20% to about 90% (weight/weight), or from about 25% to about 90%, or from about 30% to about 85%, or from about 35% to about 85%, of the tablet of the present invention , or about 40% - about 85%, or about 45% - about 85%, or about 45% - about 90%, or about 50% - about 90% or about 50% - about 85%, or about 55% - about 90%, or about 55% to about 85%, or about 55% to about 80%, or about 60% to about 90%, or about 60% to about 85%, or about 60% to about 80%, or About 60% to about 75%, or about 65% to about 90%, or about 65% to about 85%, or about 65% to about 80%, or about 65% to about 75%, or about 65% or about 70% or about 75%.

Coatings often include an optional cement.

Coated polyvinyl acetate and polyvinylpyrrolidone

[00148] The weight percent of the polyvinyl acetate/polyvinylpyrrolidone mixture in the coating can be anywhere within a wide range of values. Depending on the solubility of the active ingredients in the coating in water, the amount of the polyvinyl acetate/polyvinylpyrrolidone mixture in the coating can be adjusted. US Patent Publication No. 2001/0038852 describes a method by which such adjustments can be made. For example, for active ingredients that are soluble to very water soluble, the polyvinyl acetate/polyvinylpyrrolidone mixture can be about 20-about 80% by weight of the coating, preferably about 30-about 65% by weight, or about 40- About 55% by weight. In the specific example described below, Kollidon ^(TM) SR constituted about 45% by weight of the coating, ie about 31% by weight tramadol HCl and about 23% xanthan gum. For active ingredients that are poorly to slightly soluble in water, the amount of polyvinyl acetate/polyvinylpyrrolidone mixture is often very low, as described in US Patent Publication No. 2001/0038852.

[00149] In the polyvinyl acetate/polyvinylpyrrolidone mixture, the weight ratio of polyvinyl acetate to polyvinylpyrrolidone can be within a wide range of values. Preferably, the ratio is about 6:4-9:1; more likely about 7:3-6:1, even more preferably about 8:2.

[00150] In polyvinyl acetate/polyvinylpyrrolidone mixtures, the molecular weight of the polyvinyl acetate component can be within a wide range of values. Preferably, the polyvinyl acetate has an average molecular weight of about 100 to about 10,000,000; or about 1,000 to about 1,000,000; or about 10,000 to about 1,000,000; or about 100,000 to about 1,000,000; or about 450,000.

[00151] In polyvinyl acetate/polyvinylpyrrolidone mixtures, the molecular weight of the polyvinylpyrrolidone component can be within a wide range of values. The polyvinylpyrrolidone has an average molecular weight of about 100 to about 10,000,000; or about 1,000 to about 1,000,000; or about 5,000 to about 500,000; or about 10,000 to about 100,000; or about 50,000.

[00152] Polyvinyl acetate and polyvinylpyrrolidone mixtures can be prepared by a variety of processes, including simply mixing powders of polyvinylpyrrolidone and polyvinylpyrrolidone. In a preferred embodiment, the mixture is a spray dry powder of a colloidal dispersion of polyvinyl acetate and polyvinylpyrrolidone solution. Optionally, sodium lauryl sulfate is used as a stabilizer to prevent agglomeration during the spray drying process and/or silica gel is used to improve the flow properties of the polyvinyl acetate/polyvinylpyrrolidone mixture. Optionally, polyvinyl acetate and polyvinylpyrrolidone can be formed as random or block copolymers.

optional components

[00153] Binders suitable for the present invention include, but are not limited to, plant extracts, gums, synthetic or natural polysaccharides, polypeptides, alginates, synthetic polymers, or mixtures thereof.

[00154] Plant extracts suitable for use as gelling agents include, but are not limited to, agar, psyllium ovata, psyllium, quince, cornea, or mixtures thereof.

[00155] Gums suitable for use as gelling agents include, but are not limited to, xanthan gum, guar gum, gum arabic, gum ghatti, karaya, tragacanth, or mixtures thereof.

[00156] Synthetic or natural hydrophilic polysaccharides suitable for use as gelling agents include, but are not limited to, hydroxyalkylcelluloses, cellulose ethers, cellulose esters, nitrocellulose, dextrins, agar, horn Carrageenan, pectin, furfuran gum, starch or starch derivatives, cross-linked high amylose pulp, or mixtures thereof.

[00157] Polypeptides suitable for use as gelling agents include, but are not limited to, gels, collagens, polygelines, or mixtures thereof.

[00158] Alginates suitable for use as gelling agents include, but are not limited to, alginic acid, propylene glycol alginate, sodium alginate, or mixtures thereof.

[00159] Synthetic polymers suitable for use as gelling agents include, but are not limited to, carboxyvinyl polymers, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, polyethylene glycol, cyclic Copolymers of ethylene oxide and propylene oxide and their copolymers or mixtures thereof.

[00160] In a preferred embodiment, the gelling agent is a gum, such as xanthan gum, guar gum, gum arabic, gum ghatti, karaya gum, gum tragacanth or a mixture thereof, PEO 7000000 and HPMC K100M.

[00161] In the most preferred embodiment, the gelling agent is xanthan gum.

coating active agent

[00162] A suitable active pharmaceutical ingredient of the present invention is any active agent that is desired to be delivered in a sustained release dosage form. A detailed list of suitable pharmaceutical agents can be found in the Merck Index (12th Edition). Preferably, the pharmaceutical agent is, but not limited to, isoniazid, sodium salicylate, pseudoephedrine hydrochloride, pseudoephedrine sulfate, acetaminophen or diclofenac sodium, verapamil , Glipizide, Nifedipine, Felodipine, Betahistine, Albuterol, Avastin, Omeprazole, Misoprostol, Tramadol, Oxybutynin, Trimethopridine , ciprofloxacin, and salts thereof. Furthermore, the pharmaceutical agent may be an antifungal agent such as ketoconazole, or an analgesic such as acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisal, Naproxen, ketorolac, diclofenac, tolmetin, sulindac, phenacetin, piroxicam, mefenamic acid, dextromethorphan, other NSAIDs including salicylates, their pharmaceutical Acceptable salts or mixtures thereof.

[00163] The solubility of pharmaceutical agents in aqueous solutions can have a wide variety of values. The water solubility of pharmaceutical reagents can be less than 10 ^-3 g/L, greater than 10 ^-3 g/L, greater than 10 ^-2 g/L, greater than 10 ^-1 g/L, greater than 1g/L, greater than 10g/L, greater than 100g /L, greater than 500g/L, greater than 1000g/L, or greater than 2000g/L. Preferably, the solubility is greater than 100 g/L. More preferably, the solubility is greater than 500 g/L or even 1000 g/L.

[00164] The pharmaceutical agent can meet various dosage requirements. For example, the dosage requirement of the pharmaceutical agent may be less than 1 mg/dosage unit, greater than 1 mg/dosage unit, greater than 10 mg/dosage unit, greater than 100 mg/dosage unit, greater than 200 mg/dosage unit, greater than 300 mg/dosage unit, greater than 400 mg/dosage unit Unit, greater than 500 mg/dosage unit, or greater than 1000 mg/dosage unit. Preferably, the pharmaceutical agent is greater than 50 mg per dosage unit. More preferably, the pharmaceutical agent is greater than 100 mg per dosage unit. Most preferably, the pharmaceutical agent is greater than 200 mg per dosage unit.

[00165] The active pharmaceutical ingredient may range from about 5% to about 90% by weight of the coating, or from about 5% to about 80% by weight, or from about 10% to about 70% by weight, or from about 10% to about 70% by weight. 60%, or about 15% to about 50% by weight, or about 15% to about 45% by weight, or about 15% to about 40% by weight, or about 20% to about 35% by weight, or about 20% to about 35% by weight, or About 20% - about 30%.

[00166] In a specific example described further below, for a 100 mg tablet of tramadol, the weight of tramadol is about 21% of the coating weight. For a 200 mg tablet, the weight of tramadol is about 31% of the coating weight. For a 300 mg tablet, the weight of tramadol is about 30% of the coating weight.

Route of administration

[00167] The tablet compositions of the present invention may be administered by, but not limited to, a number of routes such as oral, sublingual and rectal. A preferred route of administration of the compositions of the present invention is oral.

[00168] Compositions of the present invention suitable for oral administration may be presented as discrete units such as tablets or granules. Preferably, said composition of the invention is presented in tablet form. The tablets may be formed by compression or molding as conventional. Compressed tablets may be prepared by compressing in a suitable machine a mixture of one or more of the above ingredients. Molded tablets may be made by molding in a suitable machine the ingredients of the above, which may optionally be moistened with an inert liquid diluent. Tablets may optionally be coated and/or have other identifying markings visible to the consumer. Tablets may also be in various forms, for example, uncoated, dry-coated or film-coated, and the like. Tablets can also come in a variety of shapes (eg, oval, spherical, etc.) and sizes. A review of tablets can be found in references such as The Theory and Practice of Industrial Pharmacy (Third Edition) by Lachman et al. (Lea & Febiger, 1986).

Dissolution profile of sustained-release composition

[00169] The active agent of the composition exhibits the following dissolution profile in vitro when tested using USP Type I equipment in 50 mM pH 6.8 phosphate with agitation at 50-150 rpm.

[00170] In vitro when measured using USP Type I equipment in 50 mM pH 6.8 phosphate with stirring at 50-150 rpm, the average rate is 10%-30%/hour over a period of 0-2 hours The reagents are released: or

[00171] 10%-40% of the agent is released from the formulation within 0 to about 2 hours of measurement, about 30%-60% of the agent is released from the formulation within 2 to about 7 hours of measurement, about 50%- 80% of the agent is released from the formulation within 7 to about 12 hours of measurement, and about 80% to 100% of the agent is released from the formulation in about 20 hours after measurement: or more preferably

[00172] 15%-35% of the reagent was released from the formulation when measuring 2 hours, about 40%-60% of the reagent was released from the formulation when measuring 7 hours, and about 60%-80% of the reagent was released from the formulation when measuring Released from the formulation at 12 hours and about 85%-100% of the agent released from the formulation at about 20 hours after measurement, or

[00173] 20%-40% of the reagent was released from the formulation when measured at 2 hours, about 40%-60% of the reagent was released from the formulation when measured at 7 hours, and about 60%-80% of the reagent was released from the formulation when measured at 7 hours Released from the formulation at 12 hours, and about 85%-100% of the agent was released from the formulation at about 20 hours after measurement.

[00174] The present invention will be understood more readily by reference to the following examples, which are given to illustrate the invention and not to limit its scope.

Example

[00175] The cross-linked high-amylose pulp employed in these examples was prepared by a process involving cross-linking and chemical modification followed by gelatinization and drying steps. The process is described in more detail in US Patent No. 6,607,748 (Lenaerts et al.), published August 19, 2003, and is known on the market as and described in Examples 1 and 11.

Example I

A. Cross-linking

[00176] 30.0 kg of high amylose slurry containing approximately 70% w/w amylose (Cl AmyloGel 03003) was placed into the reactor. To the reactor was charged 55.0 L of water containing 30.0 g of sodium hydroxide and 2.40 kg of sodium sulfate. The resulting slurry was heated to 30°C. 22.5 g of phosphorus oxychloride was added to the reaction mixture and reacted for 1 hour.

B. Chemical modification, hydroxypropylation

[00177] The crude reaction mixture from Part A was transferred to the hydroxypropylation reactor. The reaction mixture was heated to 40 °C for 30 minutes and the reaction was flushed with nitrogen. After complete flushing, 1.80 kg of propylene oxide was added. The reaction mixture was maintained at 40°C for 20 hours. The reaction mixture was neutralized to pH 5.5 with _0.1NH2SO4 (1:2 v/v) _. The starch slurry was washed with a basket centrifuge at a speed of 1200 rpm. The starch cake obtained was reslurried in 35 L of water and subjected to a second centrifugation. The starch cake produced was dried in an airflow dryer with an inlet temperature of 160°C and an outlet temperature of 60°C.

C. Gelation

[00178] The modified granular starch cake was diluted in demineralized water to form a slurry having a consistency of about 8% calculated on dry matter. The resulting slurry had a relative density of 1.032 kg/l compared to water. The pH of the modified starch slurry was adjusted to 6.0. The slurry was then heated to 160°C by direct steam injection (SchlickModel 825). The temperature difference is not higher than ±1°C. The slurry was held in the holding column for 4 minutes at a temperature of 160°C and a pressure of about 5.5 bar. The pressure was then reduced to atmospheric by passing through a flash evaporator. Next, the slurry was stored at 95°C in a storage tank.

D. Spray-drying

[00179] The slurry from part C was dried using a Niro FSD 4 spray-drying tower fitted with a 0.8 mm nozzle and fed at a rate of 10 L/hour. The inlet temperature was fixed at 300°C. and the outlet temperature was 120°C. The obtained powder is a controlled release excipient with the following properties:

Example II

A. Cross-linking

[00180] 30.0 kg of high amylose starch containing approximately 70% w/w amylose (Cl AmyloGel 03003) was placed into the reactor. To the reactor was charged 55.0 L of water containing 30.0 g of sodium hydroxide and 2.40 kg of sodium sulfate. The resulting slurry was heated to 30°C. 45 g of trisodium metaphosphate was added into the reaction mixture and reacted for 1 hour.

B. Chemical modification, hydroxypropylation

[00181] The crude reaction mixture from Part A was transferred to the hydroxypropylation reactor. The reaction mixture was heated to 40°C for 30 minutes and the reaction was flushed with nitrogen. After complete flushing, 1.80 kg of propylene oxide was added. The reaction mixture was maintained at 40°C for 20 hours. _The reaction mixture was neutralized to pH 5.5 with 0.1N _H2SO4 (1:2 v/v). Wash the starch slurry with a basket centrifuge at a speed of 1200 rpm. The starch cake obtained was reslurried in 35 L of water and subjected to a second centrifugation. The starch cake produced was dried in an airflow dryer with an inlet temperature of 160°C and an outlet temperature of 60°C.

C. Gelation

[00182] The modified granular starch cake was diluted in demineralized water to form a slurry having a consistency of about 8% calculated on dry matter. The resulting slurry has a relative density of 1.032 kg/l compared to water. The pH of the modified starch slurry was adjusted to 6.0. The slurry was heated to 160°C by direct steam injection (Schlick Model 825). The temperature difference is not higher than 1°C. The slurry was held in the holding column for 4 minutes at a temperature of 160°C and a pressure of about 5.5 bar. Subsequently, the pressure was reduced to atmospheric pressure by passing through a flash evaporator. Next, the slurry was stored at 95°C in a storage tank.

D. Spray-drying

[00183] A Niro FSD 4 spray-drying tower equipped with a 0.8 mm nozzle was used and the slurry from part C was fed at a rate of 10 L/hour. The inlet temperature was fixed at 300°C and the outlet temperature was 120°C. The obtained powder is a controlled release excipient with the following properties:

为Penwest Pharmaceuticals Co.(CedarRapids，IA，USA)销售的产品。Kollidon^TM SR为BASF(Germany)生产的产品。Encompress^TM为磷酸二钙二水合物，其可购自Mendell(Patterson，NY)。盐酸曲马多可以从Chemagis Ltd.，3Hashlosha Street，P.O.Box 9091，61090，Tel Aviv，Israel获得。合成和净化曲马多的方法在，例如，美国专利U.S.No 3,652,589、5,414,129、5,672,755、5,874,620、5,877,351和6,169,205中进行了描述。[00184] Lubritab

Product sold by Penwest Pharmaceuticals Co. (Cedar Rapids, IA, USA). Kollidon ^™ SR is a product manufactured by BASF (Germany). Encompress ^™ is dicalcium phosphate dihydrate, which is commercially available from Mendell (Patterson, NY). Tramadol hydrochloride can be obtained from Chemagis Ltd., 3 Hashlosha Street, PO Box 9091, 61090, Tel Aviv, Israel. Methods of synthesizing and purifying tramadol are described, for example, in US Pat.

production process

[00185] Tablets of the present invention may generally be produced according to the process set forth in the flow diagram of Figure 1 and described in more detail below.

[00186] Weighing: Raw material is dispensed into clearly marked containers.

和二氧化硅胶体并通过30号网筛进入适当的容器内。[00187] Core Premix: Mix part Contramid

and colloidal silica through a No. 30 mesh screen into a suitable container.

放入混合器。将盐酸曲马多通过30号网筛并加入到混合器。冲洗具有部分Contramid

的容器并加入到混合器。通过30号网筛过滤氢化植物油Type I并加入到混合器。将所述预混的核加入到混合器中。将剩余的Contramid

加入到混合器，并混合所有成分。通过30号网筛过滤硬脂酸镁并与其它成分混合。在适当的容器内分配混合并鉴定为混合核。[00188] Nuclear mixing: part Contramid

Put in a mixer. Pass Tramadol HCl through a No. 30 mesh screen and add to the mixer. Flush with Part Contramid

container and add to the mixer. Strain the hydrogenated vegetable oil Type I through a No. 30 mesh screen and add to the mixer. Add the premixed nuclei to the mixer. The remaining Contramid

Add to mixer and combine all ingredients. The magnesium stearate was filtered through a No. 30 mesh screen and mixed with the other ingredients. Dispense mix in appropriate containers and identify as mix nuclei.

[00189] Premix for dry coating: Mix part of the xanthan gum and all of the colloidal silica and pass through a No. 30 mesh screen.

SR放入混合器中。将盐酸曲马多通过具有30号网筛的Kason分离器至容器并加入到混合器。用剩余的黄原胶冲洗容器并加入到混合器。通过30号网筛过滤氢化植物油Type1并加入到混合器。将干涂的预混物和Kollidon

SR的剩余物放入混合器，并与所有成分混合。通过30号网筛过滤硬脂酸镁并与其它成分混合。在适当的容器中分配颗粒并鉴定为干涂的混合。[00190] Mixing of dry coating: part Kollidon

SR into the mixer. Pass tramadol hydrochloride through a Kason separator with a No. 30 mesh screen into the vessel and add to the mixer. Rinse container with remaining xanthan gum and add to mixer. Filter the hydrogenated vegetable oil Type 1 through a No. 30 mesh screen and add to the mixer. Mix dry-coated premix with Kollidon

The remainder of the SR is placed in a mixer and mixed with all ingredients. The magnesium stearate was filtered through a No. 30 mesh screen and mixed with the other ingredients. Dispense the granules in an appropriate container and identify the mix as dry applied.

[00191] Compression: Manesty Dry-Cota presses were used to produce compression coated tablets.

Example 1

[00192] Formulations A, B and C as shown in Table 3 were produced according to the procedure set forth above.

Table 3: Formulations of controlled-release tramadol formulations A, B, and C

[00193] The dissolution profiles of Formulations A, B, and C are shown in FIG. 2 .

bioavailability

single dose

Example 2

制剂相对照，在单次口服200mg(制剂B)后，测定曲马多及其主要代谢物O-去甲曲马多的血浆药物动力学曲线，并与当前可用的一日2次给药的200mg Topalgic

制剂相对照，在双倍剂量给药200mg后进行测定(制剂B)。该研究为一种开放式的、单剂量的、随机地、3种方式交叉的设计，在每次给药之间有至少7天的洗净期。结果显示在图3(a)和3(b)中。with currently available 100mg Twice a day Topalgic

In contrast to the formulation, after a single oral administration of 200 mg (formulation B), the plasma pharmacokinetic profiles of tramadol and its major metabolite O-desmethyltramadol were determined and compared with the currently available twice-a-day dosing 200mg Topalgic

Formulation versus control, assayed after a double dose of 200 mg (Formulation B). The study was an open-label, single-dose, randomized, 3-way crossover design with a washout period of at least 7 days between each dose. The results are shown in Figures 3(a) and 3(b).

Example 3

[00194] The plasma pharmacokinetic profiles of tramadol and its major metabolite O-desmethyltramadol were determined after single oral administration of 100, 200 and 300 mg of Formulations A, B and C, respectively. The study was an open-label, single-dose, randomized, 3-way crossover design with a washout period of at least 7 days between each dose. The results are shown in Figures 4(a) and 4(b).

[00195] A median time to peak plasma concentration of tramadol (T _max ) and a mean peak plasma concentration of tramadol (C _max ) were obtained between 2-8 hours, which was less than that of a single dose administered. 3 times the mean plasma concentration obtained 24 hours after the composition (C _24h ). In a narrow sense, the peak plasma concentration (C _max ) of tramadol obtained in each case was less than twice the plasma concentration obtained 24 hours after administration of a single dose of the composition of the invention (C _24h ).

Example 4

steady state

[00196] The steady-state plasma pharmacokinetic profiles of tramadol and its major metabolite O-desmethyltramadol were determined following daily dosing of 200 mg of Formulation B. The curves were obtained in an open-label, two-phase crossover randomized study. The results obtained are shown in FIG. 5 .

[00197] The present invention provides an oral tramadol pharmaceutical composition suitable for continuous once-a-day administration comprising in vivo an effective amount of tramadol at a steady state wherein, within a specified 24 hour period , the maximum plasma concentration (C _max ) of tramadol obtained is 2-3 times the minimum plasma concentration (C _min ) of tramadol. More specifically, an average C _max of not more than 350 ng/ml can be obtained. Furthermore, plasma concentrations of tramadol averaging less than 90% of C _max can be achieved over at least 18 hours of a 24 hour period.

[00198] The term "λz" is the apparent terminal clearance constant, determined by the slope of the regression line on the linear-log scale.

[00199] The term ''AUC _0-Tmax '' is the average area of time _0-Tmax on the plasma concentration-time curve and is used as an indicator of drug absorption rate or metabolite formation. This was calculated as the arithmetic mean area of the time 0-T _max on the plasma concentration-time curve for each individual participating in the bioavailability study.

[00200] The term " _AUC0-∞ " is the average area extrapolated to infinity in the plasma concentration-time curve. It is calculated as the arithmetic mean area extrapolated from time 0 to infinity on the plasma concentration-time curve for each individual participating in the bioavailability study.

[00201] The term "_C'max" is the maximum observed plasma concentration calculated as the mean of the individual maximum plasma concentration.

[00202] The term "half-life" is the apparent terminal elimination half-life.

[00203] The term "HVD" is the half-value duration, ie, the time during which the concentration of tramadol exceeds half _{of C'max} . This parameter is an indicator of the shape of the plasma concentration-time curve, ie, the larger the HVD value, the better the controlled release.

[00204] The term "MRT" is mean residence time, which is an estimate of the average time a tramadol molecule remains in the body after oral administration.

[00205] The term " _tmax " is the time to reach _Cmax .

[00206] The term " _Tmax " is the time at which maximum plasma concentration is observed for each individual subject participating in a bioavailability study.

[00207] The term "Rstart" is the time at which the plasma concentration begins to decline in a linear-logarithmic manner, ie, the time at which drug absorption or metabolite formation is complete.

[00208] The tramadol pharmacokinetic parameters of the controlled-release composition are listed in Table 4, and the O-desmethyltramadol pharmacokinetic parameters of the controlled-release composition are listed in Table 5.

Table 4. Table of Pharmacokinetic Parameters of Tramadol

Preparation concentration (mg) Dose (mg) Descriptive Statistics C'max(ng/ml) AUC_0-∞(ng.h/ml) AUC_0-Tm_ax(ng.h/ml) C’max/AUC_0-_∞(h^-1) λz(h^-1) Rstart(h) Half-life (h) MRT(h) HVD(h) AUC_0-2₄(ng.h/ml) AUC_0-2₄/AUC0-∞(%)

100 100 Arithmetic mean SD 91.0326.83 2108731 625471 0.04420.0052 0.1180.024 21.24.3 6.111.31 16.032.13 22.53.4 1635465 78.96.60 200 200 arithmetic mean SD 196.5558.33 44161192 915567 0.04550.0108 0.1180.025 22.95.0 6.111.26 16.462.28 23.54.5 3374860 77.28.1 300 300 Arithmetic mean SD 290.08147.16 67412156 15781338 0.04320.0126 0.1150.023 24.84.4 6.301.52 17.603.03 25.46.6 49001544 73.910.1 200 400 Arithmetic mean SD 487.35210.43 93323767 NCNC 0.05440.0198 0.1200.027 21.16.5 6.111.53 15.332.83 NCNC 74712887 80.010.1

NC - not calculated

5. Pharmacokinetic parameter table of O-desmethyltramadol

Preparation concentration (mg) Dose (mg) Descriptive statistics C'max(ng/ml) AUC_0-_∞(ng.h/ml) AUC_0-_Tma_x(ng.h/ml) C′max/AUC_0-_∞(h^-1) λz(h^-1) Rstart(h) Half-life (h) HVD(h) AUC_0-₂₄(ng.h/ml) AUC_0-₂₄/AUC_0-_∞(%) 100 100 Arithmetic mean SD 20.386.67 520170 17992 0.03940.0054 0.1060.256 23.14.2 6.961.91 25.62.9 380123 72.57.69 200 200 Arithmetic even 43.1316. 1080 540 0.0395 0.111 25.1 6.69 26.3 782 71.3

Average SD 53 328 164 0.0079 0.029 4.0 1.84 5.0 259 8.8 300 300 Arithmetic mean SD 59.8819.19 1641538 587312 0.03740.0092 0.1020.029 25.836 7.362.21 28.16.6 1107346 67.911.0 200 400 Arithmetic mean SD 114.3446.39 2866773 NCNC 0.04570.0147 0.0940.028 18.75.5 8.142.98 NCNC 1909651 74.610.9

NC - not calculated

[00209] The present invention is not to be limited in scope by the particular embodiments disclosed in the foregoing examples, which are intended to illustrate the most preferred embodiments of the invention. Indeed, various modifications of the invention or other embodiments which are functionally equivalent to those shown and described herein will be apparent to those skilled in the art and are intended to be covered by the appended claims. Moreover, although various embodiments of the combination principles of the present invention have been described, it should be understood that these are inexhaustible and that features of one embodiment may be combined with features of other embodiments, and that other combinations are also within the scope of the present invention. within the expected range disclosed here.

[00210] A number of references are cited, the entire contents of which are incorporated herein by reference.

Claims (19)

1. A solid dosage formulation comprising: a core having a pharmaceutical agent dispersed within a first controlled release matrix; and a coating formed on said core and comprising a pharmaceutical agent dispersed within a second controlled release matrix, in said first controlled release matrix comprises cross-linked high amylose starch and/or said second controlled release matrix comprises a physical mixture of polyvinyl acetate and polyvinylpyrrolidone, and, When each matrix material was tested under the conditions of USP Type I, pH 6.8 sodium phosphate buffer at 50mM and a rotating speed of 100rpm, the initial release rate of the pharmaceutical agent of the second controlled release matrix was at least equal to that of the first controlled release matrix. twice as much reagent. 2. The solid dosage form of claim 1, wherein the release rate of the agent from the coating is at least 3 times the release rate of the agent from the core. 3. The solid formulation according to claim 2, wherein the release rate of the agent from the coating is 3 to 9 times that of the agent from the core. 4. The formulation according to any one of the preceding claims, when measured with USP Type I equipment in 50 mM pH 6.8 phosphate and stirred at a speed of 50-150 rpm, it has the following in vitro dissolution profile: time cost Reagent release weight percentage 0-2 10-40 2-7 30-60 7-12 50-80 20 80-100 5. A formulation according to any one of the preceding claims, wherein the weight ratio of agent in the core to agent in the coating is 0.6-2. 6. A formulation according to any one of the preceding claims, wherein the agent in the core is present in an amount of 30-70% by weight of the total composition of the core. 7. A formulation according to any one of the preceding claims, wherein the weight ratio of the second controlled release matrix of the coating to the agent of the coating is 0.7-4. 8. A formulation according to any one of the preceding claims, wherein the polyvinyl acetate of the coating has a molecular weight of 100,000 to 1,000,000. 9. A formulation according to any preceding claim, wherein the polyvinylpyrrolidone of the coating has a molecular weight of 10,000 to 100,000. 10. A formulation according to any preceding claim, wherein the coating further comprises xanthan gum. 11. A formulation according to any one of the preceding claims, wherein the weight ratio of the core to the coating is from 0.2 to 0.5. 12. The formulation according to any one of the preceding claims, wherein the first controlled release matrix comprises cross-linked high amylose starch and the second controlled release matrix comprises a physical mixture of polyvinyl acetate and polyvinylpyrrolidone. 13. A formulation according to any preceding claim, wherein the solubility of the agent in water is greater than 500 g/L. 14. A formulation according to any one of the preceding claims, wherein said agent contains an ionizable group and said group is at least 90% ionized in gastric juice, 0.1 M HCI. 15. A formulation according to any one of the preceding claims, wherein the pharmaceutical agent of the core and coating is also tramadol. 16. The preparation according to claim 15, which is a once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, wherein, when a dose of the composition is administered for the first time, at Provide a mean plasma concentration of at least 100 ng/mL within 2 hours of dosing and continue to provide a mean plasma concentration of at least 100 ng/mL for at least 22 hours after dosing. 17. The formulation according to claim 15, wherein the mean maximum plasma concentration C _max is less than 2.2 times the mean plasma concentration obtained 24 hours after administration C _24h . 18. A formulation according to any one of claims 15 to 17, which provides a plasma concentration of tramadol which, after the observed maximum plasma concentration _Cmax , decreases in a linear-logarithmic manner with an apparent terminal clearance constant λz of 0.12 per hour. 19. A tablet comprising a formulation as claimed in any one of the preceding claims.

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