BRPI0315657B1 - solid dosage formulation, and tablet - Google Patents

Abstract

"solid dosage formulation, controlled release tablet, method of manufacturing controlled release medication, pharmaceutical composition and use of a composition." solid dosage formulation having a core with a pharmacological agent dispersed in a first controlled release matrix from which the agent release is relatively slow; and a coating formed on the core and having the agent dispersed in a second controlled release matrix from which release of the agent is relatively rapid. the first matrix may be a cross-linked high amylose starch and the second matrix may be a mixture of polyvinyl acetate and polyvinyl pyrrolidone.

Description

(54) Title: SOLID DOSE FORMULATION, AND TABLET (51) Int.CI .: A61K 9/20; A61K 9/22; A61K 9/24; A61K 9/28 (30) Unionist Priority: 10/10/2003 US 60 / 510,000, 10/25/2002 US 60 / 509,062 (73) Holder (s): PALADIN LABS INC .. PALADIN LABS EUROPE LIMITED. PALADIN LABS (BARBADOS) INC.

(72) Inventor (s): VINCENT LENAERTS; JONATHAN BACON; RACHID OUZÉROUROU; SONIA GERVAIS; MILOUD RAHMOUNI; DAMON SMITH; LAURE PATRÍCIA QUADJI-NJIKI (85) Date of the Beginning of the National Phase: 25/04/2005 “FORMULATION OF SOLID DOSE, AND, COMPRESSED” FIELD OF THE INVENTION

This invention relates to a solid dosage formulation, in which an active ingredient is released over a sustained period. BACKGROUND OF THE INVENTION

An important factor, which influences the absorption rate of an active ingredient administered as a tablet or other solid dosage formulation, and thus the effectiveness and safety of the formulation, is the rate of dissolution of the dosage form in a person's body fluids. human or animal.

The ability of the components of the formulation to influence the release rate of the active agent (s) thus forms the basis for so-called controlled release, extended release, sustained release or prolonged action pharmaceutical preparations, which they are designed to produce a slow, uniform release and absorption of the active agent over a period of hours, days, weeks or months. The advantages of controlled-release formulations include a reduction in the frequency of required drug administration when compared to immediate-release dosage forms, which often result in improved patient compliance; maintaining a relatively stable concentration of the drug in the body, leading to a sustained therapeutic effect over a period of time; and the decreased incidence and intensity of undesirable side effects of the active agent, resulting from a reduction in high plasma concentrations, which often occur after administration of immediate release dosage forms.

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Many materials have been proposed and developed as matrices for the controlled release of active agents, that is, drugs, prodrugs, etc. These include polymeric materials, such as polyvinyl chloride, polyethylene amides, ethyl cellulose, silicone and poly (hydroxymethyl methacrylate). See, for example, U.S. Patent No. 3,087,860 to Endicott et al .; U.S. Patent No. 2,987,445 to Levesque et al .; Salomon et al., Pharm. Acta Helv., 55, 174-182 (1980); Korsmeyer, Diffusion Controlled Systems: Hydrogels, Chap. 2, p. 15-37 in Polymers for Controlled Drug Delivery, Ed. Tarcha, CRC Press, Boca Raton, Fia. USA (1991); and Buri et al., Pharm. Acta Helv. 55, 189-197 (1980).

Starch with a high amylose content has also been used for controlled release purposes and, in particular, recent advances have been made with the use of starch with a high content of cross-linked amylose. For example, U.S. Patent No. 5,456. 921 (Mateescu et al.), Which was issued on October 10, 1995, US Patent No. 5,616,343 (Cartilier et al.), Which was issued on April 1, 1997, US Patent No. 6. 284,273 (Lenaerts et al.) Which was issued on September 4, 2001, US Patent No. 6,419,957 (Lenaerts et al.), Which was issued on July 16, 2002, and US Patent No. 6,607. 748 (Lenaerts et al.), Which was issued on August 19, 2003, describes pharmaceutical units of controlled oral release in the form of tablets, which comprise a dry powder of a pharmaceutical product and a dry starch powder with high content of cross-linked amylose, in which starch with a high content of cross-linked amylose includes a mixture of about 10-60% by weight of amylopectin and about 40-90% of amylose.

Other examples of controlled release materials include Kollidon ™ SR marketed by BASF (Germany), this material being a physical mixture of polyvinyl acetate (PVA) and polyvinylpyrrolidone (povidone) consisting of approximately 80% PVA and 19% povidone respectively , and approximately 0.8% sodium dodecyl sulfate and approximately

0.2% silica as a stabilizer. BASF Technical Information (July 2001) reports that kollidon ™ SR can be used in the preparation of sustained release matrix dosage forms, which include tablets, pellets and granules, and that different technologies, such as direct compression, roller compaction, granulation wet and extrusion can be used in the manufacture of pharmaceutical formulations. A number of patent publications provide additional information on PVA-povidone mixtures: U.S. Patent Publication No. 2002/0038852 (Kolter et al.) Published on November 8, 2001; Patent Publication No. 2002/0012701 (Kolter et al.) Published on January 31, 2002, and U.S. Patent Publication No. 2003/0021846 (Kolter et al.) Published on January 30, 2003.

Extended and controlled release formulations have been suggested, referring to tramadol and examples are described in: U.S. Patent Publication No. 2003/0143270, (Deboeck et al.) Published on July 31, 2003; U.S. Patent No. 6,254,887 (Miller et al.) Issued July 3, 2001; U.S. Patent Publication No. 2001/0036477 (Miller et al.) Published November 1, 2002; U.S. Patent No. 6,326. 027 (Miller et al.) Issued on December 4, 2001, WO 03/080031 (CILAG AG et al.) Published on October 2, 2003. Articles were published, in which comparative data on tramadol formulations for administration “ once a day ”and immediate release tramadol formulations are presented: Adler et al. “A Comparison of Once-Daily Tramadol with Normal Release 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, Clinicai Efficacy, and Tolerability of Once-Daily Tramadol Tablets with Normal Release Tramadol Capsules, Journal of Pain and Symptom Mangement (2003) 25) (2): 142- 149.

The citation or identification of any reference in this specification is not intended to be construed as an admission that such

reference is available as prior art to the present invention. SUMMARY OF THE INVENTION

The present invention relates to a solid dosage formulation, which provides for the controlled release of a pharmacological agent. In one embodiment, the formulation includes a core having a pharmacological agent dispersed in a first controlled release matrix, comprising starch with a high cross-linked amylose content, from which the release of the agent matrix is relatively slow. There is a coating formed on the core and the coating includes the agent dispersed in a second controlled release matrix, from which the release of the agent is relatively rapid.

In the context of this invention, "relatively fast" means at least twice as fast when the initial rate of release of an agent is measured under the same conditions, separately for each matrix material. In order to perform such a measurement, a formulation is produced having the core agent and the coating agent differently labeled from each other. In the case of tramadol, for example, the core tramadol could be labeled with 15N and the coating tramadol could be labeled with ¹³ C. There are several ways known to those skilled in the art to differentially label such a compound in such a way so that its diffusion from the formulation can be traced without significantly affecting its diffusion rate. A person skilled in the art would estimate such relative rates in a reasonable approximation, as long as the rates are sufficiently differentiated from each other, from the biphasic behavior observed for the release of the agent from a single formulation, for example, from the rates in t = 0, t = 12 in Figure 2. Typically, the measurement could be performed under the conditions exposed in connection with Figure 2.

In another broad modality, the invention consists of a

Λ

solid dosage formulation, having a core with a pharmacological agent in a first controlled release matrix. There is a coating formed on the core with the pharmacological agent in a second controlled release matrix. The second controlled release matrix is a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone, and the release of the agent from the core matrix is relatively slow with respect to the release of the agent from the coating matrix. Relatively slow means no more than half as fast when the initial release rate of an agent is measured under the same conditions separately for each matrix material, the measurement being determined as described above, in connection with the determination of relatively fast.

The agent in the core and the coating can, in any embodiment, be the same or different. In a preferred embodiment, the formulation includes a single agent, which is tramadol.

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

Preferably, the agent is soluble in water, and the first matrix is relatively hydrophilic with respect to the second matrix.

Many agents are capable of forming ionic salts, and this is the often preferred form of the agent for incorporation into a formulation of the invention. Preferred agents contain at least one amino group, and these are conveniently incorporated in the form of, for example, a hydrochloride salt.

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 nucleus can be at least three times the rate of release of the agent from the nucleus; the rate of release of the agent from the coating can be up to fifteen 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 twelve times the rate of release of the agent from the core; the rate of release of the agent from the nucleus can be up to ten times the rate of release of the agent from the nucleus; the rate of release of the agent from the coating can be up to eight 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 six times the rate of release of the agent from the core; or the rate of release of the agent from the coating can be up to four times the rate of release of the agent from the core. In other embodiments, the biphasic release behavior is observed, and the release rate of the agent from the coating is between three and nine times the release rate of the agent from the core, more preferably the release rate of the agent from the coating is between four and eight times the rate of λ release of the agent from the core, more preferably, the rate of release of the agent from the coating is between five and seven times the release rate of the agent a from the core.

In certain embodiments, between 10% and 30% per hour of the agent are released between 0 and 2 hours, when tested in vitro using a USP Type I apparatus, in 50 mM phosphate, pH 6, 8, and agitation between 50 to 150 rpm .

In certain embodiments, between 10% and 40% of the agent are released from the formulation between 0 and 2 hours of measurement, between about 30% and 60% of the agent are released from the formulation between 2 and 7 hours of measurement, between about 50% and 80% of the agent is released from the formulation between 7 and 12 hours of measurement, and between 80% and 100% of the agent is released from the formulation after about 20 hours of measurement.

A preferred active agent for both the core and the coating is an analgesic, specifically the active substance can be tramadol.

It is preferred that an agent of the formulation of the invention is soluble in water, at least to an extent of 1 g / 1, or more than .10 g / 1, or more than 100 g / 1, or more than 500 g / 1, or more than 1000 g / 1, or more than 2000 g / 1.

In certain embodiments, the formulation of the invention is generated so as to have a core to coating ratio (w / w) of between about 1 and about 0.1, or between about 0.9 and 0.2 , or from about 0.8 to about 0.2, or from about 0.7 to about 0.2, or from about 0.5 to about 0.2, or from about 0.4 and about 0.2, or about 0.35. In this context, it is the total weight of the core and the total weight of the coating, which would be considered when determining the weight ratio.

In certain embodiments, the ratio of agent in the core to agent in the coating (w / w) is between about 0.1 and about 10, or between about 0.1 and about 8, or between about 0, 2 and about 7, or between about 0.3 and about 6, or between about 0.4 and about 5, or between about 0.5 and about 4, or between about 0.6 and about 3, or between about 0.6 and about 2, or between about 0.6 and about 1.5, or between about 0.6 and about 1.3, or between about 0, 7 and about 1, or between about 0.7 and about 0.9 or about 0.8.

In particular embodiments of the invention, a formulation is one, wherein the core is between about 10% and about 90%, by weight, of the agent, or between about 20% and about 80%, by weight, of the agent , or between about 30% and about 70% by weight of the agent, or between about 40% and about 60% by weight of the agent or about 50% by weight of the agent.

In particular embodiments, a formulation of the invention is one, wherein the coating is between about 5% and about 90%, by weight, of agent, or between about 5% and about 80%, by weight, agent , or between about 10% and about 70%, by weight, of agent, or between about 10% and about 60%, by weight, agent, or between about 15% and about 50%, in weight, agent, or between about 15% and about 45%, by weight, agent, or between about 15% and about 40%, by weight, agent, or between about 20% and about 35% by weight of agent, or between about 20% and about 30% by weight of agent.

According to certain aspects of the invention, the formulation is such that the coating matrix coating agent ratio (w / w) is between about 0.1 and about 10, or between about 0.2 and about 9, or between about 0.2 and about 8, or between about 0.3 and about 7, or between about 0.4 and about 6, or between about 0.5 and 5, or between about 0.6 and about 4, or between about 0.7 and about 4 or between about 1 and about 4, or between about 1 and about 3 and about 1.5 to about 2 , 5.

According to certain aspects, the formulation is such that the ratio of the core matrix to the core agent (w / w) is between about 0.1 and about 10, or between about 0.2 and about 9, or between about 0.3 and about 7, or between about 0.4 and about 6, or between about 0.5 and about 5, or between about 0.5 and about 4, or between about 0.5 and about 3, or between about 0.6 and about 3, or between about 0.7 and about 2, or between about 0.8 and about 1.5, or between about 0.9 and about 1.5, or between about 0.9 and about 1.3, or about 1, or is about 0.55.

Preferably, the agent is a single water-soluble agent at room temperature (about 21 ° C) to an extent of at least 0.5 g per ml.

In certain aspects, each agent of the formulation contains an acid group, a basic group or both an acid group and a basic group, and each agent is present in the form of a salt of such a group. Preferably, the agent contains an ionizable group and said is at least 90% ionized in gastric juices (0.1 M HCI).

Agents of a formulation of the invention can be one or more of the following: nicotinic acid hydrazide, sodium salicylate, pseudoephedrine hydrochloride, pseudoephedrine sulfate, acetaminophen or sodium diclofenac, verapamil, glicpizida, nifedipine, felodipine, acritastine, betahistine, albumin, albumin omeprazole, misoprostol, tramadol, oxybutynin, trimebutin, ciprofloxacin, and salts thereof. In addition, the pharmaceutical agent may be an antifungal agent, such as paracetamol, obuprofen, ketoprofen, indomethacin, diflunisal, naproxen, ketorolac, diclofenac, tolmetin, sulindac, phenacetin, piroxicam, mefamanic acid, dextromethorphan, other anti-malarial drugs, other anti-malarial drugs including salicylates, pharmaceutically acceptable salts thereof or mixtures thereof.

Preferably, a formulation of the invention is prepared by compression. Typically, the core is formed by compression, and then the coating is prepared by pressing on the previously formed core.

In a preferred aspect, the coating is produced from a mixture of polyvinyl acetate, polyvinyl pyrrolidone. The ratio of polyvinyl acetate to polyvinyl pyrrolidone in the coating (w / w) is usually between about 6: 4 and 9: 1, or 7: 3 and 9: 2, or about 8: 2.

The coating often includes a bonding agent, a preferred bonding agent being xanthan gum.

The formulation can be a tablet, and a preferred starch with a high cross-linked amylose content is a starch with a high cross-linked amylose content prepared by a method, which comprises:

(a) cross-linking of starch with high amylose content, followed by (b) chemical modification of starch with high cross-linked amylose content, followed by (c) gelatinization, and (d) drying to obtain a powder of said excipient of controlled release;

wherein said starch with a high content of cross-linked amylose is characterized by the fact that upon solubilization in 90% DMSO at 80 ° C for three days and gel permeation chromatography, the peak height corresponding to amylose in said starch with high crosslinked amylose content is at least 90% of that of the peak that corresponds to amylose in said high amylose starch before (a).

Another process for obtaining a cross-linked high amylose starch for the formulations of this invention includes:

(a) cross-linking starch with a high amylose content, thereby forming a reaction medium containing a reaction product consisting of a suspension of starch with a high cross-linked amylose content;

(b) subjecting said starch suspension with a high content of cross-linked amylose from stage (a) to chemical modification at a temperature of about 10 to about 90 ° C, for about 1 to about 72 hours;

(c) neutralizing said reaction medium obtained in stage (b) with an acid, washing the formed suspension and optionally dehydrating or to form a starch cake or dry powder;

(d) diluting said suspension or new suspension of said starch cake or said dry powder from stage (c) with water, so as to form a suspension in a concentration of about 2% to about 40% p / p, adjust the pH to a desired value between about 3 and about 12, and gelatinize said suspension at a temperature of about 80 to 180 ° C for about 1 second to about 120 minutes; and (e) drying said thermally treated product, obtained in stage (d), so that said controlled release excipient is obtained, which consists mainly of starch with a high content of cross-linked and chemically modified amylose in the form of a powder.

Another process for the manufacture, in an aqueous medium, of a controlled release excipient, which consists primarily of starch with a high content of cross-linked amylose, is one that includes:

(a) subjecting said high amylose starch to chemical modification at a temperature of about 10 to about 90 ° C, for about 1 to about 72 hours, thereby forming a reaction medium, which contains a suspension with high content of chemically modified amylose;

(b) cross-linking said starch with a high content of chemically modified amylose in said suspension obtained in stage (a);

(c) neutralizing said suspension obtained in stage (b) with an acid, washing the formed suspension, and optionally dehydrating it to form a starch cake or drying it to form a dry powder;

(d) dilute said suspension, or resuspend said starch cake or said dry powder from stage (c) with water, so as to form a suspension in a concentration of about 2% to about 40% w / w, adjust the pH to a desired value of between 3 and about 12, and gelatinize said suspension at a temperature of about 80 to 180 ° C, for about 1 second to about 120 minutes; and (e) drying the thermally treated product, obtained in stage (d), in order to obtain said controlled release excipient, which consists mainly of starch with a high content of cross-linked and chemically modified amylose, in the form of a powder.

Another process for obtaining a cross-linked high amylose starch for this invention includes:

(a) cross-linked starch with high amylose content, followed by (b) chemically modifying starch with high cross-linked amylose content, followed by (c) gelatinization, and (d) drying to obtain a powder of said release excipient controlled;

in which said starch with a high content of cross-linked amylose is characterized by the fact that, through solubilization in 90% DMSO at 80 ° C, for about three days, and gel permeation chromatography, the peak height corresponding to amylose in said starch with high content of cross-linked amylose it is at least 90% of that of the peak corresponding to amylose in said starch with high content of amylose before (a).

Another process for obtaining a starch with a high content of rectified amylose for this invention includes:

(a) cross-link starch with high amylose content, followed by (b) chemically modify starch with high cross-linked amylose content, followed by (c) gelatinization, and (d) drying to obtain a powder of said excipient of controlled release;

wherein said high amylose starch is characterized by the fact that about 20% of the amylose present in said high amylose starch before (a) is chemically cross-linked to amylopectin.

Another process for obtaining a high amylose starch for this invention includes:

(a) crosslink starch with a high amylose content, followed by (b) chemically modify the starch with a high amylose content, followed by (c) gelatinization, and (d) drying to obtain a powder of said controlled-release excipient ;

wherein said starch with a high content of cross-linked amylose is characterized by the fact that the solubilization in 90% DMSO at 80 ° C, for about three days and gel permeation chromatography, less than about 20% of the amylose present before (a) it is chemically cross-linked and eluted with amylopectin.

Another process for obtaining a cross-linked high amylose starch for the invention includes:

(a) cross-linked starch with high amylose content, followed by (b) chemically modifying starch with high cross-linked amylose content, followed by (c) gelatinization, and (d) drying to obtain a powder of said release excipient controlled;

where said starch with a high content of cross-linked amylose is characterized by the fact that, by solubilizing in 90% DMSO at S0 ° C, for about three days and permeation chromatography on gel, the peak height corresponding to amylose is higher than that of the peak corresponding to entities containing amylopectin.

Another process for obtaining a cross-linked high amylose starch for the invention includes:

(a) cross-link starch with high amylose content, followed by (b) chemically modify starch with high cross-linked amylose content, followed by (c) gelatinization, and (d) drying to obtain a powder of said excipient of controlled release;

wherein said high amylose starch is characterized by the fact that less than about 20% of the amylose present in said high amylose starch prior to (a) is chemically cross-linked to amylopectin.

Another process for obtaining a high starch content

cross-linked amylose for this invention includes:

(a) cross-link starch with high amylose content, followed by (b) chemically modify starch with high cross-linked amylose content, followed by (c) gelatinization, and (d) drying to obtain a powder of said excipient of controlled release;

wherein said starch with a high content of cross-linked amylose is characterized by the fact that upon solubilization in 90% DMSO at 80 ° C for about three days and gel permeation chromatography, less than about 20% of the amylose present before (a) is chemically cross-linked and eluted with amylopectin.

Another process for obtaining a cross-linked high amylose starch for this invention includes:

(a) cross-link starch with high amylose content, followed by (b) chemically modify starch with high cross-linked amylose content, followed by (c) gelatinization, and (d) drying to obtain a powder of said excipient of controlled release;

in which the said starch with a high content of cross-linked amylose is characterized by the fact that upon solubilization in 90% DMSO at 80 ° C for approximately three days and gel permeation chromatography, the peak height corresponding to amylose is higher that of the peak corresponding to entities containing amylopectin.

Naturally, a product having the structure of a starch with a high content of cross-linked amylose, obtained by one of these processes, although the manufacturing process is not identical to one of these, is also within the scope of this invention.

The core of a formulation according to this invention often includes a lubricant that is optionally a hydrogenated vegetable oil.

In a preferred aspect, a formulation according to the invention consists of a tablet formulated for oral administration.

In a particular embodiment, the invention consists of a solid dosage formulation, which includes:

a core having a pharmacological agent dispersed in a first controlled release matrix, from which release of the agent is relatively slow; and a coating formed on the core and comprising said agent dispersed in a second controlled release matrix, the second controlled release matrix comprising a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone and from which the release of the agent is relatively rapid. .

In another embodiment, the invention provides a solid dosage formulation, which includes:

a core, which comprises a pharmacological agent dispersed in a first controlled release matrix, which comprises starch with a high content of cross-linked amylose, from whose matrix the release of the agent is relatively slow; and a coating formed on the core and comprising a pharmacological agent in a second controlled release matrix, the second controlled release matrix comprising a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone, and in which:

the release of the agent from the core matrix is relatively slow with respect to the release of the agent from the coating matrix.

Another aspect of the invention consists of a (4 solid dosage formulation, which includes;

a core, which comprises a pharmacological agent in a first controlled release matrix; and a coating formed on the core and comprising a pharmacological agent in a second controlled release matrix, the second controlled release matrix comprising a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone, and in which:

the release of the agent from the core matrix is relatively slow with respect to the release of the agent from the coating matrix.

In another aspect, the invention includes a solid dosage formulation, which comprises a pharmacological agent for releasing it over an extended period of time, the formulation comprising:

a core, which comprises an agent in a first controlled release matrix, the controlled release matrix comprising starch with a high cross-linked amylose content; and a coating formed on the core and comprising the agent in a second controlled release matrix, the second controlled release matrix comprising a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone, and in which:

the agent is present in the nucleus in sufficient quantity to obtain the release to an aqueous environment, for example, gastric juices, of no more than 50% of the agent from the formulation within a quarter of the period.

In such a formulation, the period can be between about 12 and about 24 hours, and between about 30% and about 70% of the agent is in the core. The agent in the first matrix and the agent in the second matrix are preferably soluble in water, at least to an extent of 1 g / 1, or more than 10 g / 1, or more than 100 g / 1, or more than 500 g / 1, or more than 1000 g / 1, or more than 2000 g / 1.

A particular embodiment of the invention includes a solid dosage formulation for use over a period of every four hours, or every six hours, or every eight hours, or every twelve hours, or every twenty-four hours, the formulation comprising:

a compressed core comprising a pharmacological agent, which includes an amino group, the agent being present as a pharmacologically acceptable salt and being dispersed in a first controlled release matrix, which comprises starch with a high cross-linked amylose content; and a coating formed by compression on the core and comprising the agent in a second controlled release matrix, the second controlled release matrix comprising a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone, and in which:

the release of the agent from the formulation during the period includes a first phase with the average release rate during the first 5% of the period being between three and eight times the release rate of the agent in the middle of the period.

In a particular aspect of this particular embodiment, the ratio of agent in the core to the agent in the coating (w / w) is between 0.2 and about 7, the core has between 20% and 80% agent, by weight, the The coating has between 15% and 50% by weight of agent, and the ratio of the coating matrix to the coating agent (w / w) is between 0.3 and 7. In addition, the preferred agent is tramadol, and preferably the coating includes a bonding agent.

In another aspect, the invention consists of a controlled-release tablet, which comprises:

a compressed core comprising starch with a high cross-linked amylose content having tramadol, or a salt thereof, embedded in it; and a coating formed on the core by compression, and comprising a physical mixture of polyvinyl acetate, polyvinyl pyrrolidone, a binder, tramadol, and in which:

the core / coating ratio (w / w) is between about 0.2 and

0.6;

the ratio of tramadol in the core to tramadol in the coating is between about 0.7 and about 1;

the polyvinyl acetate / polyvinyl pyrrolidone (w / w) ratio is between about 6: 4 and 9: 1; and the rate of release of tramadol from the coating matrix is at least twice the rate of release of tramadol from the core when measured by a USP Type I apparatus in 50 mM phosphate, Ph of 6.8, and between 50 and 150 rpm.

The invention includes a method of manufacturing a controlled release measurement, the method comprising:

(i) mixing a pharmacological agent and a first matrix material, which comprises a starch with a high content of cross-linked amylose;

(ii) shaping the resulting mixture from stage (i) as a core;

(iii) mixing a pharmacological agent and a second matrix material, which comprises a relatively quick release material with respect to the first matrix material;

(iv) shaping the resulting mixture from stage (iii) as a coating on the outside of the core.

A method of manufacturing a controlled-release medication of the invention may include:

(i) mixing a pharmacological agent and a first matrix material;

(ii) shaping the mixture resulting from stage (i) as a core;

(iii) mixing a pharmacological agent and a second matrix material; the second matrix material comprising a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone and being a relatively quick release material with respect to the first matrix material;

(iv) shaping the resulting mixture from stage (iii) as a coating on the outside of the core.

Stage (ii) preferably comprises compressing the mixture resulting from stage (i). Stage (iii) may comprise compressing the mixture resulting from stage (iii) on the outside of the core. The agent in the core and the coating is preferably tramadol, the total amount of tramadol in the measurement being effective as a daily dosage, and the medication comprising a formulation, as appropriate as defined in this specification.

The invention includes a pharmaceutical composition of tramadol, suitable for administration once a day, which comprises an effective amount of tramadol or a pharmaceutically acceptable salt thereof, which provides, after a single in vivo administration, a median time to concentration in the peak tramadol plasma (T _max ) between 2 and 8 hours and peak plasma tramadol concentrations (C _max ), which are less than three times the average plasma concentration, obtained 24 hours after administration (C ₂ 4h ) of a single dose of such a composition.

Such a composition can be such that said peak plasma concentrations of tramadol (C _max ) are less than twice the average plasma concentration obtained 24 hours after administration (C _24h ) of a single dose of such a composition.

In another embodiment, the invention consists of a

λ) pharmaceutical composition of tramadol, suitable for successive administration, once a day, comprising an effective amount of tramadol or a pharmaceutically acceptable salt thereof, providing a continuous state in vivo, in which, for a given period of 24 hours , a mean maximum plasma concentration of tramadol (Cmax) is obtained from 2 to 3 times a mean minimum plasma concentration of tramadol (C _m j _n ). According to a particular aspect, the average C _max is not more than 350 ng / ml. The average plasma concentration of tramadol is preferably less than 90 percent Cmax for at least 18 hours of said 24 hour period.

The invention includes a solid dosage formulation, which comprises:

a core, which comprises a pharmacological agent dispersed in a first controlled release matrix, which comprises starch with a high content of cross-linked amylose; and a coating formed on the core and comprising said agent dispersed in a second controlled release matrix, different from the first, such that the release of the agent from the sejabiphasic formulation.

According to another aspect, the invention consists of a solid dosage formulation, which comprises:

a core comprising a pharmacological agent dispersed in a first controlled release matrix; and a coating formed on the core and comprising said agent dispersed in a second controlled release matrix, which comprises a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone, such that the release of the agent from the formulation is biphasic.

According to another aspect, the invention consists of a

Α 'solid dosage formulation, comprising:

a core comprising a pharmacological agent dispersed in a controlled release matrix, which comprises a starch with a high cross-linked amylose content; and a coating formed on the core and comprising a pharmacological agent in a second controlled release matrix comprising a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone.

In another embodiment, the invention consists of a solid dosage formulation, which comprises:

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 375 mg or about 400 mg of tramadol dispersed in a controlled release matrix, which comprises a starch with a high cross-linked amylose content; and a coating formed on the core and comprising a pharmacological agent in a second controlled release matrix, which comprises a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone.

The term "comprising", as used here, is used in an unlimited sense, unless the context indicates otherwise. That is, a formulation, which comprises a first and a second matrix and an agent, for example, could also include other ingredients, such as a lubricant.

Formulations of the formulations described above provide advantageous characteristics in vivo, as further exposed below.

Another aspect of the invention thus consists of an oral pharmaceutical composition for administration once a day, for the release

controlled use of tramadol or a salt thereof, where the composition, upon initial administration of a dose, provides a start of an analgesic effect within 2 hours, the analgesic effect of which continues for at least 24 hours after administration.

Another aspect of the invention consists of an oral composition for administration once a day, for the controlled release of tramadol or a salt thereof, in which the composition, upon initial administration of a dose, provides a mean plasma concentration of at least minus 100 ng / ml within 2 hours of administration and continues to provide an average plasma concentration of at least 100 ng / ml for at least 22 hours after administration.

Another aspect of the invention consists of an oral pharmaceutical composition for administration once a day, for the controlled release of tramadol or a salt thereof, in which the composition, upon initial administration of a dose, provides a mean plasma concentration of at least 100 ng / ml within 2 hours of administration and continues to provide an average plasma concentration of at least 100 ng / ml for at least 23 hours after administration.

In another aspect, the invention consists of an oral pharmaceutical composition for once-dial administration, for the controlled release of tramadol or a salt thereof, in which the composition, upon initial administration of a dose, provides a plasma concentration average of at least 100 ng / ml within 2 hours of administration and continues to provide an average plasma concentration of at least 100 ng / ml for at least 24 hours after administration.

An oral pharmaceutical composition for administration once a day, according to the invention, in a preferred aspect, includes about 200 mg of tramadol or a salt thereof.

In yet another aspect, the invention consists of a

oral pharmaceutical composition for administration once a day, for the controlled release of tramadol or a salt thereof, comprising 100 mg of tramadol or a salt thereof, in which the composition, upon initial administration of a dose, provides an average plasma concentration of at least 50 ng / ml within 2 hours of administration and continues to provide an average plasma concentration of at least 50 ng / ml for at least 22 hours after administration.

According to another aspect, the invention provides an oral pharmaceutical composition for administration once a day, for the controlled release of tramadol or a salt thereof, comprising 100 mg of tramadol or a salt thereof, wherein the composition, upon initial dose administration, provides an average plasma concentration of at least 50 ng / ml within 2 hours of administration and continues to provide a plasma concentration of at least 50 ng / ml for at least 23 hours after administration.

Another aspect of the invention consists of an oral pharmaceutical composition for administration once a day, for the controlled release of tramadol or a salt thereof, which comprises 300 mg of tramadol or a salt thereof, in which the composition, by means of initial dose administration, provides an average plasma concentration of at least 150 ng / ml within 2 hours of administration and continues to provide a plasma concentration of at least 150 ng / ml for at least 22 hours after administration.

Another aspect of the invention consists of an oral pharmaceutical composition for administration once a day, for the controlled release of tramadol or a salt thereof, which comprises 300 mg of tramadol or a salt thereof, in which the composition, by means of initial dose administration, provides an average plasma concentration of at least 150 ng / ml within 2 hours of administration and continues to provide a plasma concentration of at least 150 ng / ml for at least 23 hours after administration.

Another aspect of the invention consists of an oral pharmaceutical composition for administration once a day, for the controlled release of tramadol or a salt thereof, which comprises 300 mg of tramadol or a salt thereof, in which the composition, by means of initial dose administration, provides an average plasma concentration of at least 150 ng / ml within 2 hours of administration and continues to provide a plasma concentration of at least 150 ng / ml for at least 24 hours after administration.

In another aspect of A, an oral pharmaceutical composition for administration once a day, for the controlled release of tramadol or a salt thereof, comprises 200 mg of tramadol or a salt thereof, in which upon initial administration of 400 mg, the composition provides an average plasma concentration of at least 200 ng / ml for at least 22 hours after administration.

In another aspect of A, the oral pharmaceutical composition for administration once a day for the controlled release of tramadol or a salt thereof, which comprises 200 mg of tramadol or a salt thereof, where upon initial administration of 400 mg, the composition provides an average plasma concentration of at least 190 ng / ml for at least 23 hours after administration.

Another aspect of the invention consists of an oral pharmaceutical composition for administration once a day, for the controlled release of tramadol or a salt thereof, which comprises 200 mg of tramadol or a salt thereof, where upon initial administration of 400 mg, the composition provides an average plasma concentration of at least 180 ng / ml for at least 24 hours after administration.

The invention also provides an oral pharmaceutical composition

for administration once a day, where the average maximum plasma concentration (C _max ) is less than 100 ng / ml.

In addition, a pharmaceutical composition for administration once daily of the invention can provide a mean maximum plasma concentration (C _max ) of less than 300 ng / ml, or a mean maximum plasma concentration (C _max ) of less than 200 ng / ml. ml.

An oral pharmaceutical composition for administration once a day, according to the invention, can be such that the maximum average plasma concentration (C _max ) is less than 2.2 times the average plasma concentration obtained 24 hours after administration (C ^ h).

The oral pharmaceutical composition for administration once daily may be such that the maximum mean plasma concentration (C _max ) is less than 300 ng / ml.

The average maximum plasma concentration (C _max ) can be less than twice the average plasma concentration obtained 24 hours after administration (C ₂ 4h).

The average maximum plasma concentration (C _max ) can be less than 2.3 times the average plasma concentration obtained 24 hours after administration (C24h).

The oral pharmaceutical composition for administration once a day, according to the invention, can provide an average time for the average maximum plasma concentration (t _max ) of between 2 and 10 hours, or between 3 and 6 hours, or between 5 and 6 hours.

The invention also provides an oral pharmaceutical composition for administration once a day, for the controlled release of tramadol or a salt thereof, comprising 200 mg of tramadol or a salt thereof, in which the composition, upon administration initial dose, provides an average plasma concentration of O-desmethyltramadol of at least 24 ng / ml within 2 hours of administration and continues to provide an average plasma concentration of O-desmethyltramadol of at least 25 ng / ml for at least least 24 hours after administration.

According to another embodiment, the invention provides an oral pharmaceutical composition for administration once a day, for the controlled release of tramadol or a salt thereof, comprising 100 mg of tramadol or a salt thereof, wherein the composition, upon initial dose administration, provides an average plasma concentration of O-desmethyltramadol of at least 11 ng / ml within 2 hours of administration and continues to provide an average plasma concentration of O * desmethyltramadol of at least 12 ng / ml for at least 24 hours after administration.

According to another embodiment, the invention provides an oral pharmaceutical composition for administration once a day, for the controlled release of tramadol or a salt thereof, which comprises

300 mg of tramadol or a salt thereof, where the composition, upon initial administration of a dose, provides an average plasma concentration of O-desmethyltramadol of at least 32 ng / ml within 2 hours of administration and continues to provide an average plasma concentration of Odesmethyltramadol of at least 32 ng / ml for at least 24 hours after administration.

In another embodiment, the invention consists of an oral pharmaceutical composition for administration once a day, for the controlled release of tramadol or a salt thereof, comprising 200 mng of tramadol or a salt thereof, in which upon initial administration of 400 mg, the composition provides an average plasma concentration of O-desmethyltramadol of 50ng / ml within 2 hours of administration and continues to provide an average plasma concentration of Odesmethyltramadol of at least 50 ng / ml for at least 24 hours after administration.

An object of the present invention is to provide flexible dosing options for patients with different analgesic requirements with a formulation for administration once a day.

One embodiment of the present invention is to provide a formulation for administration once a day that, upon initial intake of a dose of 100 mg, could provide the desired early onset of action, but achieve mean plasma concentrations of tramadol of at least 45 ng / ml between 2 and 24 hours.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a 200 mg dose could provide the desired early onset, but achieve average plasma concentrations of tramadol at least minus 100 ng / ml between 2 and 24 hours.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial ingestion of a 300 mg dose could provide the desired early onset, but achieve average plasma concentrations of tramadol of at least 150 ng / ml between 2 and 24 hours.

Another embodiment of the present invention is to provide a formulation for administration once daily, which upon initial intake of a 400 mg dose could provide the desired early onset of action, but achieve average plasma concentrations of tramadol at minus 180 ng / ml between 2 and 24 hours.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose could provide a C ' _max to dose ratio of about 0.90 to about 1.0 .

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose could provide a plasma concentration of tramadol, which constantly increases until peak tramadol concentrations are reached in a T _max of about 4 hours to about 6 hours. Preferably, T _max occurs in about 5 hours to about 5.5 hours.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide a plasma concentration of tramadol, which after T _max , declines in a slow but steady manner , reflecting continuous absorption, in addition to elimination processes. Preferably *

the decline in plasma concentration of tramadol after T _max occurs in a log-linear mode with an apparent terminal elimination half-life of between about 5.5 hours and about 6.5 hours.

Another embodiment of the present invention is to provide a formulation for administration once a day, which, upon the initial ingestion of a dose, could provide a concentration in the weft plasma which, after T _max , declines in a slow but constant manner, reflecting continuous absorption in addition to elimination processes, and whose continuous absorption for at least 20 hours after T _max .

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, provides a plasma concentration of tramadol which, after T _max , declines in a log-linear mode with an apparent terminal elimination rate constant (λ _ζ ) of about 0.12 h-1 for the plasma concentration of tramadol.

Another modality of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide an average residence time (MRT) of tramadol in the range of about 15 hours and about 18 hours.

Another embodiment of the present invention is to provide a

Powder formulation for administration once a day, which upon initial intake of a dose, could provide a semi-value duration (HVD) of tramadol, which is in the range of about 22.5 hours to about 25.4 hours .

Another embodiment of the present invention is to provide a formulation for administration once a day which, upon the initial intake of a dose, could provide a ratio of C ' _ma x to AUCo-οο from about 0, 04 h-1 to about 0.06 h-1. Preferably, the C'tnax ratio for AUCo. _x is about 0.04 h-1 to about 0.05 h-1. The reason for

C ' _max / AUCo-οο is used to assess the rate of absorption of the drug.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose could provide an average AUC0-24, with respect to the plasma concentration of tramadol, which increases proportionally with the dose. in a range of dosage concentrations from 100 mg to 300 mg of the controlled release composition.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose of 100 mg, could provide an AUCo-max of about 610 ng. h / ml at about 630 ng. h / ml.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a 200 mg dose, could provide an AUCo-Tmax of about 910 ng. h / ml at about 920 ng. h / ml.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a 300 mg dose, could provide an AUCo-Tmax of about 1570 ng. h / ml at about 1590 ng.h / ml.

Another embodiment of the present invention is to provide a formulation for daily administration, which upon initial intake of

one dose provides an average AUCo-24 / AUCo-oo ratio of the plasma concentration of tramadol, which is in the range of about 70% to about 85%. Preferably, the average AUCo-24 / AUCo-oo ratio of the plasma concentration of tramadol is in the range of about 74% to about 80%.

As a result, about 15% to about 30% of the administered dose is still circulating in the plasma 24 hours after the dose, depending on the administered dose.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide a ratio of C ' _max to the dose released to the blood plasma in the first 24 hours (ie , AUC0-24 / AUCo-00) multiplied by the dose, from about 1.10 to about 1.35. Preferably, the ratio is from about 1.15 to about 1.31.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide a ratio of C ^ / Tmax for the dose administered from about 0.10 to about 0.20. Preferably, the ratio is about 0.12 to about 0.19.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide a decline in ng / ml - h following the concentration level in the peak blood plasma , which does not exceed a factor of about 0.035 in the total dose administered in mg. Preferably, the fact is about 0.03.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide a C '^ ratio, calculated with respect to the plasma concentration of O-desmethyltramadol, for the dose of tramadol, from about 0.19 to about 0.22. Preferably, the ratio is about 0.20 to 0.21.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide a plasma concentration of Odesmethyltramadol, which increases constantly until peak tramadol concentrations have reached a T _max of about 8 hours to about 16 hours is achieved.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide a plasma concentration of Odesmethyltramadol which, after T _max , declines slowly but steadily, reflecting the continuous absorption of tramadol and the subsequent metabolite formation, in addition to elimination processes. Preferably, the decline in plasma concentration of O-desmethyltramadol occurs in a log-linear mode with an average apparent terminal elimination half-life of between about 6.7 hours and about 8.1 hours.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide, after T T, the metabolite formation for at least 18 hours.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon ingestion of a dose, could provide, after T _max , a decline in the plasma concentration of O-desmethyltramadol in a log-linear mode , with an apparent terminal elimination rate constant (λ _ζ ) for the O-desmethyltramadol concentration of about 0.1 h-1.

Another object of the invention is to provide a formulation for administration once a day, which upon initial intake of concentrations of 100 mg, 200 mg and 300 mg provides a duration of

semi-value (HVD) of plasma concentration of O-desmethyltramadol, which is in the range of 25.6 to 28.1 hours.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide a half-life (HVD) of O-desmethyltramadol, which is in the range of about 25, 6 hours to 28.1 hours.

another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide a ratio of C ' _ma x to AUCo-', calculated with respect to the plasma concentration of O-desmethyltramadol, of about 0.04 h-1. The C ' _max / AUCo-oo ratio is used to assess the rate of metabolite formation.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide an average AUC0-24, calculated with respect to the plasma concentration of O-desmethyltramadol, which increases proportionally with the dose in a concentration range of 100 mg to 300 mg of the controlled release composition.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose of 100 mg, could provide an AUC ₀ -Tmax with respect to the plasma concentration of O-desmethyltramadol of approximately 175 ng. h / ml to about 180 ng.h / ml.

Another embodiment of the present invention is to provide a formulation for administration once a day, which by ingesting a dose of 200 mg, could provide an AUCo-max, with respect to the plasma concentration of O-desmethyltramadol from of about 530 ng. h / ml at about 550 ng. h / ml.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide an average ratio of AUCo-Tmax, with respect to the plasma concentration of O-desmethyltramadol from to from about 580 ng.h / ml to about 590 ng.h / ml.

Another embodiment of the present invention is to provide a formulation for administration once a day, which, upon initial intake of a dose, could provide an average ratio of AUC0-24 / AUC0-00 of plasma concentration of O-desmethyltramadol, which is in the range of about 65% to about 80%. Preferably, the average ratio of AUC0-24 / AUCo-00 to the plasma concentration of O-desmethyltramadol is in the range of about 68% to about 75%. As a result, about 25% to about 32% of the active metabolite is still circulating in the plasma 24 hours after the dose.

Another embodiment of the present invention is to provide a formulation for administration once a day, which upon initial intake of a dose, could provide a ratio of C ' _max , calculated with respect to the plasma concentration of O-desmethyltramadol, for the blood plasma concentration of O-desmethyltramadol in the first 24 hours (AUC0-24 / AUC0-00 multiplied by the dose of tramadol) from about 0.0025 to about 0.0035. Preferably, the ratio is from about 0.0027 to about 0.0031.

The present invention can be understood more fully with reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.

DESCRIPTION OF THE DRAWINGS

Various features and advantages of the present invention will be evident from the more detailed description provided below with reference to the accompanying drawings, in which:

Figure 1: Flow diagram showing the manufacturing process for the tablets.

Figure 2: Dissolution profiles (% released) of formulations A, B and C for 24 hours: Performance in vitro of formulations A, B and C: under USP Type 1 conditions; sodium phosphate buffer, 50 mM, pH 6.8, 100 rpm. 6 tablets were tested per time point.

Figure 3 (a): Average plasma concentrations of tramadol (ng / ml) over 48 hours, following the administration of doses of 2 x 200 mg of the composition (formulation B) (□), and 1 x 200 mg of Topalgic ® LP BID q 12h (Δ). Plasma concentrations were determined using an HPLC / UV assay.

Figure 3 (b): Average plasma concentrations of O-desmethyltramadol (ng / ml) over 48 hours, following a single administration of a dose of 1 x 200 mg of the composition (formulation B) (·), dose of 2 x 200 mg of the composition (À), 1 x 100 mg of Topalgic® LP BID ql2h (O), and 1 x 200 mg of Topalgic® LP BID q 12h (p).

Figure 4 (a): Plasma tramadol concentrations (ng / ml) of 27 patients over 48 hours, following a single administration of concentrations or tramadol formulations of 100 mg (♦), 200 mg (O), or 300 mg (p) (A, B and C, respectively).

Figure 4 (b): O-desmethyl tramadol concentrations (ng / ml) in the plasma of 27 patients over 48 hours, following a single administration of tramadol formulations with concentrations of 100 mg (♦), 200 mg (O ), or 300 mg (p) (A, B and C, respectively).

Figure 5: Concentrations (ng / ml) of tramadol (·) and O-desmethyl tramadol (O) in steady-state plasma averages of 26 patients, who were given 200 mg of tramadol, formulation B, and concentrations of tramadol (Á ) and O-desmethyl tramadol (p) from 26 patients who were given 100 mg of Topalgic LP BID.

DETAILED DESCRIPTION OF THE INVENTION

CORE

The tablet core of the invention includes at least one active ingredient and a matrix, these components being 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 starch with a high content of cross-linked amylose, known under the brand name Contramid®, and more recently described in US Patent No. 6,607,748 (Lenaerts et al.) Which was issued in August 19, 2003. A preferred formulation in the context of this invention is provided in the patent specification

No. 6,607,748.

Preferably, the core is formed by mixing the ingredients (in granular or powdered form) and then compressing the mixture to form the core, on which the coating is subsequently formed. The weight of the core can be any percentage of the weight of the total composition between 10% and 80%. The preferred percentage depends, among other things, on the total dosage of the pharmaceutical agent. In a particular embodiment described below, a tablet contains 100 mg of tramadol hydrochloride and the core represents about 26% of the total weight of the tablet. In another embodiment, a tablet contains 200 mg of tramadol hydrochloride and the core represents up to 33% of the total weight of the tablet. In yet another embodiment, a tablet contains 300 mg of tramadol hydrochloride, and the core contributes 33% of the total weight of the tablet.

Active Agent in the Nucleus

An active pharmaceutical ingredient is present in the core of the composition of the present invention. A suitable pharmaceutical ingredient of the present invention is one such that it is desired that it be supplied in a sustained release dosage form. A comprehensive list of suitable pharmaceutical agents can be found in The Merck Index, 12th ^to Ed. Preferably, the pharmaceutical ingredient is, but is not limited to, isonicotinic acid hydrazide, sodium salicylate, pseudoephedrine hydrochloride, acetaminophen or sodium diclofenac, verapamil, glipizide, nifedipine, felodipine, betahistine, albuterol, acrivastine, omeprazole, misoprostol, tramadol®, oxybutynin, trimebutine, ciprofloxacin, and salts thereof. In addition, the pharmaceutical agent may be an antifungal agent, such as ketoconazole, or an analgesic agent, such as acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisal, naproxen, ketorolac, diclofenac, tolmetin, tolmetin, sulmetin, tolmetin, sulmetin, tolindin, tolindin, sulmetin, tolindin, sulmetin, piroxicam, mefamanic acid, dextromethorphan, other non-steroidal anti-inflammatory drugs, including salicylates, pharmaceutically acceptable salts thereof or mixtures thereof. Prodrugs are part of the invention.

The solubility of the pharmaceutical agent in aqueous solution can constitute a wide range of values. The aqueous solubility of the pharmaceutical agent may be less than 10-3 g / 1, greater than 10-3 g / 1, greater than 10-2 g / 1, greater than 10-1 g / 1, greater than 1 g / 1 , greater than 10g / l, greater than 100 g / 1, greater than 500 g / 1, greater than 1000 g / 1, or greater than 2000 g / 1. Preferably, the solubility is greater than 100 g / 1. More preferably, the solubility is greater than 500 g / 1. Even more preferably, the solubility is greater than 1000 g / 1.

The pharmaceutical agent can satisfy a variety of dosage requirements. For example, the dosage requirement of the pharmaceutical agent may be less than 1mg / unit dose, greater than 10 mg / unit dose, greater than 100 mg / unit dose, greater than 200 mg / unit dose, 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 / unit dose. More preferably, the pharmaceutical agent is 100 mg / unit dose, or more, for example, 150 mg / unit dose, or 200 mg / unit dose, or 250 mg / unit dose, or 300 mg / unit. dosage unit, or more.

Preferred embodiments include a core containing tramadol hydrochloride, in which the core contains between 10% and 90% of the total tramadol present in the tablet, for example about 45 mg of a 100 mg tablet (45% of the total tablet), or about 90 of a 200 mg tablet (45% of the total tablet), or about 151 mg of a 300 mg concentration tablet (50% of the total tablet). Core Matrix

The release from the formulation of an active ingredient located in the core is slower than the release of an active ingredient located in the coating matrix. A preferred core matrix is cross-linked with starch with a high content of cross-linked amylose, known under the brand name Contramid® and described in U.S. Patent No. 6,607,748. In particular embodiments, the matrix constitutes between about 10% and about 90%, by weight, of the core, that is, the ratio of the core matrix to the active ingredient of the core (w / w) is between about 0, 1 and about 10, or between about 0.2 and about 9, or between about 0.2 and about 8, or between about 0.3 and about 7, or between about 0.4 and about 6, or between about 0.5 and about 5, or between about 0.6 and about 4, or between about 0.7 and about 4 or between about 1 and about 4, or between about 1 and about 3 and about 1.5 to about 2.5. In a particular embodiment, the core totals about 90 mg, of which about 44 mg is Contramid®, and 45 mg is tramadol hydrochloride. In this case, Contramid® makes up up to about 49 weight percent of the core. Optional Components

The core composition of the present invention may optionally include a pharmaceutically acceptable carrier or vehicle. Such carriers or vehicles are known to those skilled in the art and are found, for example, in Remington's Pharmaceutical Siences, 14th Ed. (1970). Examples of such carriers or vehicles include lactose, starch, dicalcium phosphate, calcium sulfate, kaolin, mannitol and powdered sugar. In addition, when required, suitable binders, lubricants, and disintegrating agents can be included. If desired, dyes, such as sweetening or flavoring agents, can be included.

The core composition of the present invention may optionally include accessory ingredients, including, but not limited to, dispersing agents, such as microcrystalline cellulose, starch, cross-linked starch, cross-linked poly (vinyl pyrrolidone), and sodium carboxymethyl cellulose ; flavoring agents; coloring agents; binders; preservatives; surfactants, and the like.

The core may optionally also include one or more suitable binders, known to those of ordinary skill in the art.

Suitable forms of microcrystalline cellulose, for example, MCC-PH101, MCC-102, MCC-105, etc.

Suitable lubricants, such as those known to the person skilled in the art, may also be included. For example, magnesium stearate, vegetable oil, talc, sodium stearyl fumarate, calcium stearate, stearic acid, etc.

Suitable glidants, known in the art, can also be included. Examples of such slip agents include, but are not limited to, colloidal silicon dioxide, etc.

Proportion

The active agent is present in levels in the range of about 1 to about 90%, by weight, of the total weight of the core, preferably of about

about 70% by weight of the total core composition, more preferably from about 20 to about 60% by weight of the total core composition, and probably more frequently between about 30 to about 50% of the core. total core composition.

Naturally, the total amount of all components is 100%, by weight, and those of ordinary skill in the art can decay the amounts within the ranges mentioned so that useful compositions are achieved.

COATING

The dosage form coating includes a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone and the active ingredient (s) of the coating. The coating may also include a starch with a high cross-linked amylose content, for example, Contramid®, and other optional components. In a preferred embodiment, the coating is formed by dry compression. The weight of the coating can be any percentage of the weight of the total composition between about 10% and about 90%, but is preferably at the top of this range. The coating thus constitutes between about 20% to about 90% (w / w) of a tablet of the invention, or about 25% to about 90%, or about 30% to about 85%, or about 35% to about 85%, or about 40% to about 85%, or about 45% to about 85%, or about 45% to about 90%, or about 50% to about 90%, or about 50% to about 85%, or about 55% to about 90%, or about 55% to about 85%, or about 55% to about 80%, or about 60% and 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%.

The coating often includes a binding agent.

Polyvinyl acetate and polyvinyl pyrrolidone coating

The weight percentage of the polyvinyl acetate / polyvinyl pyrrolidone mixture in the coating can be anywhere within a wide range of values. Depending on the water solubility of the active ingredient in the coating, the amount of the polyvinyl acetate / polyvinyl pyrrolidone mixture in the coating can be adjusted. U. S. Patent Publication No. 2001/0038852 describes ways in which such adjustments can be made. For example, for active ingredients that are soluble to extremely soluble in water, the polyvinyl acetate / polyvinyl pyrrolidone mixture can be about 20 to about 80%, by weight, of the coating, preferably about 30 to about 65% by weight, or about 40 to about 55% by weight. In a particular embodiment described below, Kollidon ™ SR constitutes about 45% by weight of a coating, which is about 31% by weight of tramadol hydrochloride and about 23% xanthan gum. For active ingredients, which are poorly soluble in water, the amount of the polyvinyl acetate / polyvinyl pyrrolidone mixture is often lower, as described in U.S. Patent Publication No. 2001/003852.

The weight ratio of polyvinyl acetate to polyvinyl pyrrolidone in the polyvinyl acetate / polyvinyl pyrrolidone mixture can be within a wide range of values. Preferably, such a ratio is between about 6: 4 and 9: 1, most likely between about 7: 3 and 6: 1, even more preferably about 8: 2.

The molecular weight of the polyvinyl acetate component in the polyvinyl acetate / polyvinyl pyrrolidone mixture can be within a wide range of values. Preferably, the molecular weight of polyvinyl acetate is about 100 to about 10,000,000; or from about 1,000 to about 1,000,000; or from about 10,000 to about 1,000,000; or from about 100,000 to about 1,000,000; or about 450,000.

♦

The molecular weight of the polyvinyl pyrrolidone component in the polyvinyl acetate / polyvinyl pyrrolidone mixture can be within a wide range of values. The average molecular weight of polyvinyl pyrrolidone can be from about 100 to about 10,000.00; or from about 1,000 to about 1,000,000; or from about 5,000 to about 500,000; or from about 10,000 to about 100,000; or about 50,000.

The mixture of polyvinyl acetate and polyvinyl pyrrolidone can be prepared through a variety of processes including simply mixing polyvinyl pyrrolidone and polyvinyl acetate.

In a preferred embodiment, such a mixture is a spray-dried powder of a colloidal dispersion of polyvinyl acetate and polyvinyl pyrrolidone. Optionally, sodium lauryl sulfate is used as a stabilizer, so as to avoid agglomeration during the spray drying process and / or colloidal silica is used to improve the flow properties of the polyvinyl acetate / vinyl pyrrolidone mixture. Optionally, polyvinyl acetate and polyvinyl pyrrolidone can be formed in a random or block copolymer.

Optional Components

Binding agents suitable for the present invention include, but are not limited to, plant extracts, gums, synthetic or natural polysaccharides, polypeptides, alginates, synthetic polymers, or a mixture thereof.

Plant extracts suitable for use as gelling agents include, but are not limited to, agar, ispagula, psyllium, cidonia, keratonia, or a mixture thereof.

Plant extracts suitable for use as gelling agents include, but are not limited to, xanthan gum, guar gum, acacia gum, gati gum, caraia gum, tragacanth gum or a mixture thereof.

Natural or synthetic hydrophilic polysaccharides for use as gelling agents include, but are not limited to, hydroxyalkylcelluloses, cellulose ethers, cellulose esters, nitrocelluloses, dextrin, agar, carrageenan, pectin, furcelaran, starch or meow derivatives, starch with starch high content of cross-linked amylose, or a mixture thereof.

Suitable polypeptides to be used as gelling agents include, but are not limited to, gelatin, collagen, polygeline or a mixture thereof.

Alginates suitable for use as gelling agents include, but are not limited to, alginic acid, propylene glycol alginate, sodium alginate, or a mixture thereof.

Synthetic polymers suitable for use as gelling agents include, but are not limited to, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycols, ethylene oxide copolymers and propylene oxide and their copolymers or a mixture of the themselves.

In a preferred embodiment, the gelling agent is a gum, such that xanthan gum, guar gum, acacia gum, gum gum, caraia gum, tragacanth gum or a mixture thereof, PEO 7,000,000 and HPMC K 100 M.

In a more preferred embodiment, the gelling agent is xanthan gum.

Coating active agent

An active pharmaceutical ingredient of the present invention is any active agent, which is desired to be delivered in a sustained release form. A comprehensive list of suitable pharmaceutical agents can be found in The Merck Index, 12th ^to Ed. Preferably, the pharmaceutical agent is, but is not limited to, isonicotinic acid bidrazide, sodium salicylate, pseudoephedrine hydrochloride, acetaminophen or diclofenac sodium, verapamil, glipizide, nifedipine, felodipine, betahistine, albuterol, acrivastine, omeprazole, misoprostol, tramadol®, oxybutyn, trimebutine, ciproflaxin, and salts thereof. In addition, the pharmaceutical agent may be an antifungal agent, such as ketoconazole, or an analgesic agent, such as acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisal, naproxen, ketorolac, diclofenac, tolmetin, sulmetin, tolmetin, sulindin, sulindin piroxicam, mefamânico acid, _r dextromethorphan, other non-steroidal anti-inflammatory drugs including salicylates 10, pharmaceutically acceptable salts thereof, or mixtures thereof.

The solubility of the pharmaceutical agent in aqueous solution can be in a wide range of values. The aqueous solubility of the pharmaceutical agent may be less than 10-3 g / 1, greater than 10-3 g / 1, greater than 10-2 g / 1, greater than 10-1 g / 1, greater than 1 g / 1 , greater than 10 g / 1, greater than 100 g / l, greater than 500 g / l, greater than 1000 g / l, or greater than 2000 g / 1. Preferably, the solubility is greater than 100 g / 1. More preferably, the solubility is greater than 500 g / 1 or even 1000 g / 1.

The pharmaceutical agent can satisfy a variety of 20 dosage requirements. For example, the dosage requirement for the pharmaceutical agent may be less than 1 mg / unit dose, greater than 1 mg / unit dose, greater than 10 mg / unit dose, greater than 100 mg / unit dose, 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 / unit dose. More preferably, the pharmaceutical agent is greater than 100 mg / unit dose. More preferably, the pharmaceutical agent is greater than 200 mg / unit dose.

r

The coating can be between about 5% and about 90%, by weight, of active pharmaceutical ingredient, or between about 5% and about 80%, by weight i. f. a., or between about 10% and about 70% by weight i. f. a., or between about 10% and about 60% i. f. a., or between about 15% and about 50% by weight i. f. a., or between about 15% and about 45% by weight i. f. a., or between about 15% and about 40% by weight i. f. a., or between about 20% and about 35% by weight i. f. a., or between about 20% and about 30% by weight i. f. The.

In particular embodiments, further described below, the weight of tramadol in a 100 mg tramadol tablet is about 21%, by weight, of the coating. The weight of tramadol in a 200 mg tablet is about 31% by weight of the coating. The weight of tramadol in a 300 mg tablet is about 30% by weight of the coating. ROUTES OF ADMINISTRATION

The tablet composition of the present invention can be administered via, but not limited to, a number of routes, such as oral, sublingual, and rectal. The preferred route of administration of the compositions of the present invention is oral.

The compositions of the present invention, which are suitable for oral administration, can be presented as separate units, such as tablets or granules. Preferably, the compositions of the present invention are presented in the form of a tablet. Such tablets can be conventionally formed by compression or molding. Pressed tablets can be prepared by compressing in a suitable machine the mixture of one or more components described above. Molded tablets can be produced by molding in a suitable machine the above components, which can optionally be moistened with an inert liquid diluent. The tablets can be optionally coated and / or have other

>

Pb identification signs, visible to the consumer. A tablet can also be presented in a variety of forms, for example, uncoated, dry coated, film coated, etc. A tablet can also be presented in a variety of configurations (for example, oval, spherical, etc.) and sizes. A comprehensive discussion of pills can be found in references, such as The Theory and Practice of Industrial Pharmacy by Lachman et al., 3rd ^to Ed. (Lea & Febiger, 1986).

Dissolution Profile of the Sustained Release Composition

The active agent in the composition exhibits the following in vitro dissolution profile when measured with a USP Type 1 apparatus in 50 mM phosphate, pH 6.8, and agitation between 50 and 150 rpm:

an average rate of between 10% and 30% per hour of the agent is released between 0 and 2 hours when tested in vitro using a USP Type I apparatus, in 50 mM phosphate, pH 6.8, and agitation between 50 to 150 rpm ; or between 10% and 40% of the agent are released from the formulation between 0 and 2 hours of measurement, between about 30% and 60% of the agent • are released from the formulation between 2 and 7 hours of measurement, between about 50% and 80% of the agent are released from the formulation between 7 and 12 hours of measurement, and between 80% and 100% of the agent are released from the formulation after about 20 hours of measurement, or more preferably between 15 % and 35% of the agent are released from the formulation in 2 hours of measurement, between about 40% and 60% of the agent are released from the formulation in 7 hours of measurement, between 60% and 80% of the agent are released from the formulation in 12 hours of measurement, and between about 85% and 100% of the agent are released from the formulation after about 20 hours of measurement, or between 20% and 40% of the agent are released from the formulation in 2 hours of measurement, between about 40% and 60% of the agent are released from the formulation in 7 hours of measurement, between about 60% and

80% of the agent is released from the formulation in 12 hours of measurement, and between about 85% and 100% of the agent is released from the formulation after about 20 hours of measurement.

The present invention will be more readily understood with reference to the following examples, which are provided in order to illustrate the invention, and not in order to limit its scope.

EXAMPLES

The high amylose starch used in these examples is produced through a process, which comprises the stages of cross-linking and chemical modification, followed by gelatinization and drying. Such a process is described in more detail in U.S. Patent No. 6,607. 748 (Lenaerts et al.), Which was issued on August 19, 2003 and is known on the market under the brand name Contramid®, and is described in Examples 1 and 2.

Example I:

A. Crosslinking

Starch with high amylose content (30.0 kg) containing about 70% w / w and amylose (Cl AmyloGel 03003) is placed in a reactor. To this reactor is added water (55.0 1) containing sodium hydroxide (30.0 g) and sodium sulfate (2.40 kg). The resulting suspension is heated to a temperature of 30 ° C. Phosphorus oxychloride (22.5 g) is added to the reaction mixture, which is reacted for one hour.

B. Chemical modification, hydroxypropylation

The Part A crude reaction mixture is transferred into a hydroxypropylation reactor. The reaction mixture is heated to 40 ° C for 30 minutes and the reaction is purged with nitrogen. After a total purge, propylene oxide (1.80 kg) is added. The reaction mixture is maintained at 40 ° C for 20 hours. The reaction mixture is neutralized with H ₂ SO ₄ (1: 2 v / v) 0.1 N at a pH of 5.5. The starch suspension is washed with a basket centrifuge at a speed of 1200 rpm. The starch pie

obtained is resuspended in 35 l of water and centrifuged a second time. The resulting starch cake is dried in a scintillation dryer at an inlet temperature of 160 ° C and an outlet temperature of 60 ° C.

C. Gelatinization

The modified granular starch cake is diluted in demineralized water to form a suspension in a concentration of about 8%, calculated as a dry substance. The resulting suspension has a relative density of 1.032 kg / 1 compared to water. The pH of the modified starch suspension is adjusted to 6.0. The suspension is then heated to 160 ° C by direct steam injection (Model Schlick 825). The temperature variation does not exceed ± 1 ° C. The suspension is maintained in a retention column for a period of 4 minutes at a temperature of 160 ° C, and a pressure of about 5.5 bar. The pressure is then reduced to atmospheric by passing through a scintillation apparatus. The suspension is then contained at 95 ° C in a holding tank.

D. Spray drying

The drying of the Part C suspension is carried out using a Niro FSD 4 spray tower, equipped with a 0.8 mm nozzle and fed at 10 l / hour. The inlet temperature is set at 300 ° C and the outlet temperature is 120 ° C. The powder obtained is a controlled release excipient with the following properties:

properties

Moisture Content 4.5%

Bulk Density 150 g / 1

Compacted density 210 g / 1

PH 5.4

Particle Size Peak Value 50 pm (Laser Particle Classifier -Sympatec)

Example II

A. Crosslinking

Starch with a high amylose content (30.0 kg) containing about

70% w / w amylose (Cl AmyloGel 03003) is placed in a reactor. To this reactor is added water (55.01) containing sodium hydroxide (30.0 g) and sodium sulfate (2.40 kg). The resulting suspension is heated to a temperature of 30 ° C. Sodium trimetaphosphate (45g) is added to the reaction mixture, which is reacted for one hour.

B. Chemical modification, hydroxypropylation

The Part A crude reaction mixture is transferred into a hydroxypropylation reactor. The reaction mixture is heated to 40 ° C for 30 minutes and the reaction is purged with nitrogen. After a total purge, propylene oxide (1.80 kg) is added. The reaction mixture is maintained at 40 ° C for 20 hours. The reaction mixture is neutralized with 0.1 N H2SO4 (1: 2 v / v) at a pH of 5.5. The starch suspension is washed with a basket centrifuge at a speed of 1200 rpm. The obtained starch cake is resuspended in 35 l of water and centrifuged a second time. The resulting starch cake is dried in a scintillation dryer at an inlet temperature of 160 ° C and an outlet temperature of 60 ° C.

C. Gelatinization

The modified granular starch cake is diluted in demineralized water to form a suspension in a concentration of about 8%, calculated as a dry substance. The resulting suspension has a relative density of 1.032 kg / 1 compared to water. The pH of the modified starch suspension is adjusted to 6.0. The suspension is then heated to 160 ° C by direct steam injection (Model Schlick 825). The temperature variation does not exceed ± 1 ° C. The suspension is maintained in a retention column for a period of 4 minutes at a temperature of 160 ° C, and a pressure of about 5.5 bar. The pressure is then reduced to atmospheric by passing through a scintillation apparatus. The suspension is then contained at 95 ° C in a holding tank.

D. Spray drying

The drying of the Part C suspension is carried out using a Niro FSD 4 spray tower, equipped with a 0.8 mm nozzle and fed at 10 l / hour. The inlet temperature is set at 300 ° C and the outlet temperature is 120 ° C. The powder obtained is a controlled release excipient with the following properties:

properties

Humidity Content 5.2%

Mass Density 103 g / 1

Compacted density 155 g / 1

PH 5.3

Particle Size Peak Value 70 pm (Laser Particle Classifier -Sympatec)

Lutritab® is a product sold by Penwest Pharmaceuticals

Co. (Cedar Rapids, IA, USA), Kollidon ™ SR is a product produced by BASF (Germany). Encompress ™ is a dicalcium phosphate dihydrate, which can be purchased from Mendell (Patterson, NY). Tramadol hydrochloride can be obtained from Chemagis Ltd., 3 Hashlosha Street, P.O., Box 9091, 61090, Tel Aviv, Israel. Methods of synthesis and purification of tramadol are described in, for example, U.S. Patent Nos. 3,652,589, 5,414,129, 5,672,755, 5,874,620, 5,877,351, and 6,129,205.

Manufacturing Procedure

The tablets according to the invention can be manufactured according to the process shown, in a generic way, in the flow diagram of Figure 1, and described in greater detail below.

Weighing: Raw materials are dispensed inside clearly labeled containers.

Core Pre-mixing: Mixing a portion of

Contramid® and Colloidal Silicon Dioxide and passed through a # 30 mesh sieve into a suitable container.

Mixing the Core: Place a portion of Contramid® inside a mixer. Pass tramadol hydrochloride through a

# 30 mesh sieve and add to the mixer. Rinse the container with a portion of Contramid® and add to the mixer. Sieve the Type I Hydrogenated Vegetable Oil through a # 30 mesh screen and add to the mixer. Add the Core Pre-Mix to the interior of the mixer.

Add Contramid® to the inside of the mixer, and mix all ingredients. Add the Magnesium Stearate through a # 30 mesh sieve and mix with the other ingredients. Dispense the mixture in a

- suitable container and identify it as Core Mix.

Dry Coated Premix: Mix a portion of xanthan gum and all colloidal silicon dioxide and pass through the # 30 mesh sieve.

Dry Coated Mixing: Place a portion of Kollidon®

SR inside the mixer. Pass tramadol hydrochloride through the Kason separator with a # 30 mesh sieve into a suitable container and add to the mixer. Rinse the container with the remaining xanthan gum and add to the mixer. Sieve Hydrogenated Vegetable Oil Type 1 through a # 30 mesh sieve and add to the mixer. Place the dry coated premix and the rest of the Kollidon® SR inside the mixer and mix all the ingredients. Sieve magnesium stearate through a # 30 mesh sieve and mix with the other ingredients. Dispense the granulation in a suitable container and identify it as Dry Coated Mixture.

Compression: Use a Manesty Dry-Cota press to produce compression-coated tablets.

Example 1:

Formulations A, B and C, as shown in Table 3, were manufactured according to the above process.

Table 3: Prescriptions for Tramadol Controlled Release Formulations A, B and C.

Formulation C ing / compriinido | OO T— < tn t — 1 84.1 QO 1- ^ © ^ θ ' 00 _Λ Τ-4 240 1 © ^ οο Tf r — I <ο 7— ^ 219 © _λ ο 7—1 Ύ cm © 00 1 300 | 1- ^ 3 r- © un CM ^ Ύ 1 ²¹⁹ 1 © ^ © < © 725 £ © <L cc © 35.05 0.75 1 ο cm θ ' © Γ ~ ^ θ ' ο ο ι — 1 | 30.56 1 1 0.20 1 45.16 ΟΟ ι / γ cm CM O © r — 1 © © © © © © 1- ^ OO cc vr 1 11.60 1 0.92 © © 00 © _Λ © T— < CM ^ © CC 1 15.10 © © O th Hey mg / tablet | 06 © OO © cc t— < 1 0.36 1 © fC Ο 00 7— < ο 1-) 7— < 1 0.72 | 00 © ^ cm © 1— < cy τ— ' 00 xo *s cc 00 d, | 360 1,200 The Cs © 00 © OO © © ι — H cc 1 162.58 oc 540 'd I 50 | 48.3 © ç- © CM θ ' θ, 75 | Ο ο 7—1 © © _λ © cc 1 0.20 | 45.16 ί οο ι / γ cm CM © © ^ ι — M | 0.50H © © © © 7 ^ | 37.04 1 16.10 1 0.92 8 © 00 © © 7—1 T — H © © | 15.06 © © í — l © «I th Hey rag / pill | 45 1 © © © οο θ ' 0.675 | 90 | © © 0.52 | ι> © m 66.86 | © Ç CM CC Ass 260 | yoo | ç- Cs CC ct © r- CM ^ cc r- ~ © 1,975 | j 133.7 © OO © © 350 Formul £ 50 1 48.3 © O CM Cs ο 0.75 | ο ο 1- ^ 21.15 I ο CM ο CM © CM © CM 1 ι, οο I 0.50 | © © © CS 00 CM I 12.42 I 1 0.94 1 1 0.20 1 © © © | 38.20 I 1 19.11 1 © © ι — H i O Core Tramadol hydrochloride Contramid® Hydrogenated vegetable oil 1 Silica Magnesium stearate Total Core Weight | 2) COATING I Tramadol hydrochloride Silica, ~ Ί Kollidon SR® Xanthan gum Hydrogenated Vegetable Oil Magnesium stearate Total Coating Weight 3) PILL COATED | Tramadol hydrochloride I Contramid® Hydrogenated Vegetable Oil «J cZ Magnesium stearate Kollidon SR® Xanthan gum Total Coated Tablet Weight:

ν

Dissolution profiles of formulations A, B and C as shown in Figure 2.

BIOAVAILABILITY

SINGLE ADMINISTRATION

Example 2

The plasma pharmacokinetic profile of tramadol and its main metabolite, O-desmethyltramadol, after a single oral administration of 200 mg (formulation B) was determined in comparison to a currently available 100 mg formulation, Topalgic®, administered twice daily , and after a double dose of 200 mg (formulation B) was determined in comparison to a currently available 200 mg formulation, Topalgic®, administered twice daily. The study was a three-way, randomized, single-dose, open design, with a 7-day cleaning period after each administration. The results are shown in Figures 3 (a) and 3 (b).

Example 3:

The pharmacokinetic profile in the plasma of tramadol and its main metabolite, O-desmethyltramadol, after a single oral administration of 100, 200 and 300 mg, of formulations A, B and C, respectively, was determined. The study was a three-way, randomized, single-dose, open design, with a 7-day cleaning period between each administration. The results are shown in Figures 4 (a) and 4 (b).

A median peak plasma concentration of tramadol (T _max ) between 2 and 8 hours and a mean peak plasma concentration of tramadol (Cm _ax ), which is less than three times the average plasma concentration obtained 24 hours after administration (C _24h ) a single dose of tramadol was obtained. In a more restricted sense, the peak plasma concentration of tramadol (C _max ), obtained in each case, is less than twice the plasma concentration obtained 24 hours after administration (C ₂₄ h) of a single dose of one composition of the invention.

Example 4 Constant State

The pharmacokinetic profile in plasma in a constant state of 5 tramadol and its main metabolite, O-desmethyltramadol, following daily administration of 200 mg, formulation B, was determined. The profile was obtained in a randomized, two-period, open label crossover study. The results obtained are shown in Figure 5.

- The invention provides a pharmaceutical composition of oral tramadol, suitable for successive administration, once a day, which comprises an effective amount of tramadol in vivo in a constant state, in which, during a determined period of 24 hours, a concentration in the maximum tramadol plasma (C _max ) of between 2 and 3 times a minimum plasma concentration of tramadol (Cmi _n ) is obtained. More particularly, an average C _max of no more than 350 ng / ml can be achieved. In addition, a plasma concentration of less than 90 percent C _max for at least 18 hours of the 24 hour period can be achieved, on average.

The term “λ _ζ ” is the apparent terminal elimination rate constant, determined by the decline of the regression during the log-linear phase.

The term "AUCo-Tmax" is the average area under the plasma concentration-time curve from time 0 to T _max and is used as an indicator of the rate of drug absorption, or metabolite formation. It is calculated as the arithmetic mean of the area under the concentration curve25 time in plasma from time 0 to T _max , calculated for each individual participating in the bioavailability study.

The term “AUCo-οο” is the average area under the concentration-time curve extrapolated to infinity. It is calculated as the arithmetic mean of the area under the plasma concentration-time curve from time 0 extrapolated to infinity, for each individual participating in the bioavailability study.

The term "C ' _m ax" is the maximum observed plasma concentration, calculated as the average of the maximum individual blood plasma concentrations.

The term “half-life” refers to the apparent terminal elimination half-life.

The term “HVD” is the duration of the semi-value, that is, the time during which the concentrations of tramadol are above half of the C '^. This parameter is an indicator of the plasma concentration time curve configuration, that is, the higher the HVD value, the better the controlled release.

The term “MRT” is the average residence time, which is an estimate of the average time that a tramadol molecule remains in the body, following oral administration.

The term “t _max ” is the time that C _max is reached.

The term “T _max ” is the time that the maximum blood plasma concentration is observed for each individual who participates in the bioavailability study.

The term "Rstart" is the time at which plasma concentrations begin to decline in a log-linear mode, that is, the time at which either drug absorption or metabolite formation is completed.

Pharmacokinetic parameters of tramadol from the controlled release composition are shown in Table 4, and pharmacokinetic parameters of O-desmethyltramadol from the controlled release composition are shown in Table 5.

Table 4. Summary of Pharmacokinetic Parameters of Tramadol

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Table 5. Summary of Pharmacokinetic Parameters for O-desmethyltramadol

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The present invention is not limited in scope by the specific modalities set out in these examples, which are intended to illustrate the most preferred embodiments of the invention. In fact, various modifications of the invention or other modalities, which are functionally equivalent to those presented and described herein, will become evident to those skilled in the art and are intended to be covered by the appended claims. Furthermore, although several examples of combined elements of the invention have been described, it will also be understood that they are not intended to be exhaustive and the characteristics of one modality can be combined with those of another, and such combinations are contemplated to be within the scope of scope of the invention in this exhibit. Several references were cited, whose totality of the exhibitions are incorporated to this one by reference.

Claims (14)

1. Solid dosage formulation, characterized by the fact that it comprises: - a core comprising tramadol dispersed in a first controlled release matrix and a coating formed on the core comprising tramadol dispersed in a second controlled release matrix, wherein the first controlled release matrix comprises starch with a high cross-linked amylose content and the second controlled release matrix comprises a physical mixture of polyvinyl acetate and polyvinylpyrrolidone, the weight ratio of tramadol in the core to tramadol in the coating is in the range between 0.6 and 2, polyvinyl acetate and polyvinylpyrrolidone in the second matrix are in a weight ratio of 6: 4 to 9: 1, and the initial release rate of tramadol for the second controlled release matrix is at least twice as fast as the release rate of tramadol from the first controlled release matrix when measured separately for each matrix material under USP Type I conditions with 50 mM sodium phosphate buffer, pH 6.8, and stirring between 50 and 150 rpm. 2. Formulation according to claim 1, characterized by the fact that the rate of release of tramadol from the coating is at least 3 times the rate of release of tramadol from the core. Formulation according to claim 2, characterized by the fact that the rate of release of tramadol from the coating is between 3 to 9 times the rate of release of tramadol from the core. 4. Formulation according to any of the claims 1 to 3, characterized by the fact that it has an in vitro dissolution profile when measured with a USP Type I apparatus in 50 mM phosphate at pH 6.8 and agitation between 50 and 150 rpm as follows: Time remaining in hours Percentage release in tramadol weight 0-2 10-40 2-7 30-60 7-12 50-80 20 80-100 Formulation according to any one of claims 1 to 4, characterized in that tramadol is present in the core in an amount between 30 and 70 percent, by weight, of the total core composition. 10 6. Formulation according to any of the claims 1 to 5, characterized by the fact that the weight ratio of the coating matrix to the tramadol of the coating is in the range between 0.7 and 4. Formulation according to any one of claims 1 to 6, characterized in that the coating's polyvinyl acetate 15 has a molecular weight in the range between 100,000 and 1,000,000. Formulation according to any one of claims 1 to 7, characterized in that the coating polyvinylpyrrolidone has a molecular weight in the range between 10,000 and 100,000. 9. Formulation according to any of the claims 20 1 to 8, characterized by the fact that the coating also comprises xanthan gum. Formulation according to any one of claims 1 to 9, characterized by the fact that the weight ratio of the core to the coating is in the range between 0.2 and 0.5. Formulation according to any one of claims 1 to 10, characterized in that the formulation is an oral composition for administration once daily, for the controlled release of tramadol or a salt thereof, in which the composition , upon initial dose administration, provides an average plasma concentration of at least 100 ng / ml within 2 hours of administration and continues to provide an average plasma concentration of at least 100 ng / ml for at least 22 hours after administration. 12. Formulation according to claim 11, characterized by the fact that the mean maximum plasma concentration (Cmax) is less than 2.2 times the mean plasma concentration obtained 24 hours after administration (C24h). Formulation according to either of claims 11 or 12, characterized in that it provides a plasma concentration of tramadol which, after the time when the maximum blood plasma concentration is observed (Cmax), declines in a log mode - linear with an apparent terminal elimination rate (λ) constant of 0.12 per hour. 14. Tablet, characterized by the fact that it comprises a formulation as defined in any one of claims 1 to 13. 1/6 Coating Mix Dry Core Mixture