RU2328275C2 - Composed tramadole of prolonged release with 24- hour action - Google Patents

Abstract

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to solid dosed composition for pain treatment, containing: nucleus including active pharmaceutical ingredient and matrix, an coating including physical compound of polyvinyl acetate, polyvinyl pyrrolidone and active pharmaceutical ingredient, where active pharmaceutical ingredient and matrix are interconnected in such a way that release of pharmaceutical ingredient placed within nucleus from matrix is controlled, and release of composed active ingredient placed within nucleus occurs more slowly than release of active pharmaceutical ingredient placed in coating matrix. Yet nucleus and coating active pharmaceutical ingredient is the same and considered to tramadole or its stereoisomer or pharmaceutically acceptable salt. Invention also refers to tablet containing specified composition. Composition under invention provides pain relief not later than 2 hour after primary introduction in one dosage; pain relief lasts within at least 24 hours after introduction.

EFFECT: agent is characterised by high efficiency.

14 cl, 7 dwg, 9 tbl, 6 ex

Description

Field of Invention

This invention relates to a new, single, daily administration of a pharmaceutical composition for the controlled release of tramadol or a salt thereof.

State of the art

Tramadol pharmaceutical compositions

Tramadol hydrochloride (HCl) was developed by Grunental GmbH, Germany. It has been sold in Germany since 1977 (eg, Tramal ™), in the United States as Ultram® since 1995. The efficacy and safety profile of tramadol HCl makes it very suitable for prolonged treatment of chronic pain.

Tramadol HCl is a synthetic central analgesic, the effectiveness of which has been shown in a variety of conditions of acute and chronic pain. It has been shown, in particular, that tramadol HCl in both immediate and slow release compositions in combination with non-steroidal anti-inflammatory drugs (NSAIDs) (Roth SH. "Efficacy and safety of tramadol HCl in breakthrough musculoskeletal pain attributed to osteoarthritis". J. Rheumatol 1998; 25: 1358-1363. Wilder-Smith CH et al. "Treatment of severe pain from osteoarthritis with slow-release tramadol or dihydrocodeine in combination with NSAID's: a randomized study comparing analgesia, antinociception and gastrointestinal effects". Pain 2001; 91: 23-31.), Reduces pain associated with osteoarthritis (OA). After oral administration, tramadol HCl is rapidly and almost completely absorbed and carefully metabolized. The main metabolic pathways are N- and O-demethylation and glucuronidation or sulfonation in the liver. Only one metabolite, mono-O-desmethyltramadol (M1), appears to be pharmacologically active with approximately 200 times higher affinity for the μ-opioid receptor than the racemic tramadol (DeJong R. "Comment on the hypoalgesic effect of tramadol in relation to CYP2D6 "(comment) Pain Dig 1997; 7: 245; Kogel B. et al" Involvement of metabolites in the analgesic action of tramadol "Proc. 9 ^th World Congress on Pain, Vienna, 1999). In healthy people, tramadol is demethylated by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6) to the M1 metabolite.

The mechanism of action of tramadol HCl is not fully understood. In animal models, it has been shown that the drug (and its active M1 metabolite) acts as an opioid agonist, probably by selective activity on the μ receptor. In addition to the activity of the opioid agonist, tramadol HCl inhibits the reuptake of certain monoamines (norepinephrine, serotonin), which, it turns out, contribute to the analgesic effect of the drug. The antinociceptive effect of tramadol HCl is only partially antagonized by naloxone in some tests in animals and humans. In addition, due to the opioid agonistic activity of this drug, it was suggested that tramadol HCl may be addictive; however, its abuse potential is low and tramadol HCl is not “controlled” under the United States Federal Substances Control Act 1970 as a listed drug.

Immediate release tramadol HCl compositions are well known in the art. Such compositions, however, require frequent dosing to provide effective pain relief. The lack of compliance with high dosing frequency regimes may result from inappropriate plasma concentrations of the drug and, therefore, less persistent analgesia. Compositions of daily two-time administration are more useful and desirable compared to compositions with immediate release, as they provide longer periods of pain relief after administration and require less frequent dosing. Daily single-use formulations are even more desirable for enhanced effectiveness, safety and convenience.

The decisive factor affecting the rate of absorption, and therefore the safety and effectiveness of the active drug ingredient after oral administration to the body in tablet or other solid dosage form, is the rate of release of the active drug ingredient from the dosage form after oral administration.

Thus, the ability of the ingredients of the dosage form to control the release rate, which forms the basis for the so-called controlled release, sustained release, sustained release, or sustained release drugs, which are designed to create a slow, uniform release and absorption of the active drug ingredients over a period of hours, days, weeks, or months. The benefits of such controlled release compositions include a reduction in the required frequency of administration of the drug compared to conventional immediate release dosage forms, often leading to improved patient compliance with the treatment regimen and regimen; maintaining a stable concentration of the drug in the body, and therefore, a continuous therapeutic effect for a specified time; and reducing the occurrence and severity of unwanted side effects of the active agent caused by high plasma concentrations that occur after administration of continuous release dosage forms.

Many substances have been proposed and developed as a matrix for the controlled release of active drug ingredients. Such substances include, for example, polymeric materials such as polyvinyl chloride, polyethylene amides, ethyl cellulose, silicone and poly (hydroxymethyl methacrylate). See for example. U.S. Patent No. 3087860 Endicott et al .; U.S. Patent No. 2,987,445 to Lavesque et al .; Salomon et al. Pharm. Acta Helv., 55, 174-182 (1980); Korsmeyer, Diffusion Controlled Systems: Hydrogeis, Chap. 2, pp. 15-37 in Polymers for Controlled Drug Delivery, Ed Tarcha, CRC Press, Boca Raton, Fla. USA (1991); and Buri et al., Pharm. Acta Helv. 55, 189-197 (1980).

High amylose starch is also used for controlled release purposes, in particular recent advances have been made using crosslinked high amylose starch. For example, US Patent No. 6,284,273 (Lenaerts et al.), Issued September 4, 2001, and No. 6419957 (Lenaerts et al., Issued July 16, 2002, describe a controlled-release solid oral dosage form in the form of tablets containing a dry pharmaceutical powder the product and a dry powder of crosslinked high amylose starch, wherein said crosslinked high amylose starch is a matrix containing a mixture of about 10-60 wt.% amylopectin and about 40-90% amylose. U.S. Patent №6607748 (Lenaerts et al.), Issued August 19, 2003, discloses a process for preparing crosslinked high amylose starch which is known under the name Contramid ^®.

Sustained Release Compositions Known in the Art

Sustained and controlled release compositions have been proposed related to tramadol HCl, and examples of such compositions are described in US Patent Application Publication No. 2003/0143270, (Deboeck et al.), Published July 31, 2003; U.S. Patent No. 6,254,887 (Miller et al.), Issued July 3, 2001; US Patent Application Publication No. 2001/0036477 (Miller et al.), published November 1, 2001; US patent No. 6326027 (Miller et al.), Issued December 4, 2001; and US Patent No. 5,591,452 (Miller et al.), issued January 7, 1997; and European Patent No. 1190712 (Vanderbist), published March 27, 2002.

Although there are several controlled release tramadol HCl formulations on the market that mean daily disposable formulations, none of them have successfully replaced daily tramadol HCl formulations.

Published articles presenting comparative data between the proposed daily disposable compositions of tramadol HCl and tramadol HCl with immediate release: Alder 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, Clinical Efficacy, and Tolerability of Once-Daily Tramadol Tablets with Normal Release Tramadol Capsules", Journal of Pain and Symptom Management (2003) 25 (2): 142-149.

Side effects from the introduction of tramadol HCl

The most commonly reported side effects of tramadol observed in clinical trials in the United States include constipation, nausea, dizziness / vertigo, headache, drowsiness, and vomiting. Such phenomena are typical side effects of narcotic drugs. Epileptic seizures and anaphylactic reactions have also been reported, although the estimated incidence of epileptic seizures in patients receiving tramadol HCl is less than 1% (Kazmierczak, R., and Coley, K .: Doctor letters on prescribing: evaluation of the use of tramadol HCl . "Formulary 32: 977-978, 1997).

Adler et al., Supra, report the results of a clinical study comparing a single daily composition of tramadol with tramadol with immediate release in the treatment of pain in osteoarthritis. The authors report similar profiles of adverse events in individuals in both treatment groups. Table 2 by Adler et al. indicates that a larger percentage of people who were in the single daily treatment group dropped out due to side effects compared to those who dropped out of the second treatment group.

In Bodalia et al., Comparative tolerance is reported above with a single daily dose of 150 mg, a daily single dose of 200 mg, and three doses of 50 mg of a normal-release tramadol composition. This article, however, does not contain any information on how to make compositions that are understood as “single daily,” does not disclose any pharmacokinetic data after a single dose.

The citation or reference to any link in this section should not be construed as an assumption that such a link is available as prior art in relation to the present invention.

SUMMARY OF THE INVENTION

An object of the present invention is to provide an improved sustained release tramadol composition with 24-hour effective analgesia.

In accordance with one aspect of the present invention, there is provided a single daily oral pharmaceutical composition for controlled release tramadol or a salt thereof, in which, upon initial administration, the analgesic effect begins within 2 hours, the analgesic effect of which continues for at least 24 hours after administration .

In accordance with another aspect of the present invention, there is provided a single daily oral pharmaceutical composition for controlled release tramadol or a salt thereof in which the composition, upon initial administration of a single dose, provides an average plasma concentration of at least 100 ng / ml no later than 2 hours after administration and continues to provide an average plasma concentration of at least 100 ng / ml for at least 22 hours after administration.

In one embodiment, the invention provides a single daily oral controlled-release tramadol pharmaceutical composition or salt thereof, when the composition, upon initial administration of a single dose, provides an average plasma concentration of at least 100 ng / ml no later than 2 hours of administration and continues provide an average plasma concentration of at least 100 ng / ml for at least 22 hours after administration, and where the average maximum plasma concentration (C _max ) less than 2.2 times taken the average plasma concentration obtained 24 hours after administration (C _24h ).

The designation "λ _z " corresponds to the probable constant of the final elimination rate, determined by the slope of the regression line during the logarithmic phase.

The designation "AUC _0-max " corresponds to the average area under the curve of the concentration versus time in plasma, from time 0 to T _max , and is used as an indicator of the absorption rate of the drug, or the formation of the metabolite. It is calculated as the arithmetic mean of the area under the curve of concentration versus time in plasma, from time 0 to T _max, calculated for each individual participating in bioavailability studies.

The designation "AUC _0-∞ " corresponds to the average area under the curve of the concentration versus time in the plasma extrapolated to infinity. It is calculated as the arithmetic average of the area under the curve of the concentration versus time in plasma versus time 0 extrapolated to infinity, calculated for each individual participating in bioavailability studies.

The term "analgesic effect" is defined for the purposes of the present invention as providing an average plasma concentration of at least about 100 ng / ml tramadol.

The designation "C ' _max " means the maximum of the observed plasma concentration, calculated as the average of the individual maximum plasma concentrations.

The term “controlled release” is defined for the purposes of the present invention as a method for delivering an oral drug, wherein the release rate of the active pharmaceutical ingredient from the composition depends not only on the concentration of the active pharmaceutical ingredient remaining in the composition and / or the solubility of the active pharmaceutical ingredient in the environment surrounding the composition , and where the period of time and / or localization of the release of the active ingredient from the pharmaceutical composition is iraetsya to achieve a therapeutic effect, or convenience objectives not offered by conventional dosage forms.

The term "half-life" means the apparent period of the final half-life.

The term "CPM" means the duration of maintaining the average, i.e. the time during which tramadol concentrations higher than half the C _'max. This indicator is an indicator of the shape of the curve of the dependence of concentration on time in plasma.

The term "immediate release" is defined for the purposes of the present invention as the release of the active ingredient from the pharmaceutical composition, when the rate of release of the active pharmaceutical ingredient from the pharmaceutical composition is not inhibited by a controlled release matrix and where the ingredients of the pharmaceutical composition are designed so that when ingested, the maximum exposure to the specified active pharmaceutical ingredient on the body occurs in a minimum period.

The term "initial administration" is defined for the purposes of the present invention as the first single dose of a composition containing the active ingredient administered to a patient or object, or the first dose administered to a patient or object after an appropriate withdrawal period.

The term "CBH" means the average time spent in the body, which corresponds to the average time spent by the tramadol molecule in the body after oral administration.

The term "average maximum plasma concentration" (C _max ) is defined for the purposes of the present invention as the maximum average plasma concentration.

The term "average plasma concentration" is defined for the purposes of the present invention as the arithmetic mean concentration in plasma.

The designation "t _max " corresponds to the period of time after which With _max .

The designation "t _max " corresponds to the period of time after which the maximum plasma concentration is reached in each of the individuals participating in bioavailability studies.

The term "R _start " means the time at which the concentration in the plasma begins to decrease according to the logarithmic law, i.e. the time at which either the absorption of the drug is completed, or the formation of its metabolite is completed.

The word "tramadol" as used here refers to tramadol, its stereoisomers and its pharmaceutically acceptable salts.

The term "stable state" is defined for the purposes of the present invention as the condition following the administration of a multiple dose, when the elimination rate of the drug corresponds to the rate of administration, and the plasma concentrations of the drugs at the moment within the dosage interval are approximately the same, from one dosing interval to another.

BRIEF DESCRIPTION OF THE DRAWINGS

Various features and advantages of the present invention will become apparent with a more detailed description below with reference to the accompanying drawings:

Figure 1: Schematic representation of a tablet manufacturing process.

Figure 2: Dissolution profiles of compositions A, B and C: In vitro implementation of compositions A, B and C: under USP Type 1 conditions; sodium phosphate buffer, 50 mM, pH 6.8, 100 rpm, 6 tablets per unit time were tested.

Figure 3: Average plasma concentrations of tramadol after administration of a single dose of (i) a dose of 100 mg of a controlled release composition according to the invention (●), (ii) a dose of 200 mg of a controlled release composition according to the invention (■), and (iii) mg dose controlled release compositions 300 according to the invention (▲).

), либо 200 мг (О), либо 300 мг (Δ) активного вещества композиции трамадола (А, В и С соответственно).Figure 4: Average plasma concentrations of O-desmethyltramadol after administration of a single dose containing either 100 mg (

), or 200 mg (O), or 300 mg (Δ) of the active substance of the tramadol composition (A, B and C, respectively).

Figure 5: Average plasma concentrations of tramadol after administration of a single dose of (i) 2 × 200 mg of a controlled release composition according to the invention (▲); and (ii) Topalgic® LP 200 mg BID q12h (Δ).

Figure 6: Average plasma concentrations of O-desmethyltramadol after administration of a single dose of (i) 2 × 200 mg of a controlled release composition according to the invention (▲); and (ii) Topalgic® LP 200 mg BID q12h (Δ).

Figure 7: Average stable plasma concentration of tramadol and O-desmethyltramadol after administration (i) of a 200 mg dose of a controlled release composition according to the invention (● &○); and (ii) Topalgic® LP 100 mg BID q12h (▲ & Δ).

DETAILED DESCRIPTION OF THE INVENTION

CORE

The tablet core according to the invention includes at least one active ingredient and a matrix, these ingredients are linked in such a way that the release of the pharmaceutical ingredient from the matrix is controlled. In a particular embodiment, the core matrix is a cross-linked high amylose starch, known as Contramid® and most recently described in US Pat. No. 6,607,748 (Lenaerts et al.), Issued August 19, 2003. A preferred composition in the context of this invention is described in US Pat. No. 6607748.

Preferably, the core is formed by mixing the ingredients (in the form of granules or powder) and then compressing the mixture to form a core over which a shell is sequentially formed. The weight of the core can be any percentage of the weight of the whole composition between 10% and 80%. The preferred percentage depends, inter alia, on the total dosage of the pharmaceutical. In a special embodiment described below, the tablet contains 100 mg of tramadol hydrochloride and a core, representing approximately 26% of the total weight of the tablet. In another embodiment, the tablet contains 200 mg of tramadol hydrochloride and the core comprises up to about 33% of the total weight of the tablet. In another embodiment, the tablet contains 300 mg of tramadol hydrochloride and the core comprises 33% of the total weight of the tablet.

Active agent in the core

An active pharmaceutical ingredient is present in the core of the composition of the invention. A suitable pharmaceutical ingredient according to the invention is any such ingredient that is desirably to be delivered in a sustained release dosage form. A detailed list of suitable pharmaceuticals can be found in The Merck Index, 12 ^th Ed. Preferably, the pharmaceutical ingredient is, but is not limited to, isonicotonic acid hydrazide, sodium salicylate, pseudoephedrine hydrochloride, pseudoephedrine sulfate, acetaminophen or diclofenac sodium, verapamil, glipizide, nifedipine, felodipinom, tribrominomolithromide, alburolithromide, tribrominomolithromide, tribrominomolithromide, tribromibominomolithromide, tribromibominomolithromide, tribromibominomolithromide and , ciprofloxacin and their salts. In addition, the pharmaceutical agent may be an antifungal agent, such as ketoconazole, or an anesthetic agent, such as acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisal, naproxen, ketorolac, diclofenacin, tolmet, , piroxicam, mefenamic acid, dextromethorphan, other non-steroidal anti-inflammatory drugs, including salicylates, their pharmaceutically acceptable salts or mixtures thereof. Prodrugs are part of the present invention.

The solubility of a drug in an aqueous solution can have a wide variety of meanings. The water solubility of the drug may be less than 10 ^-3 g / l, more than 10 ^-3 g / l, more than 10 ^-2 g / l, more than 10 ^-1 g / l, more than 1 g / l, more than 10 g / l, more than 100 g / l, more than 500 g / l, more than 1000 g / l or more than 2000 g / l. Preferably, the solubility is more than 100 g / L. More preferably, the solubility is greater than 500 g / L. Most preferably, the solubility is more than 1000 g / l.

A drug can satisfy a variety of dosage requirements. For example, the required dosage of a medicinal product may be less than 1 mg / dosage unit, more than 1 mg / dosage unit, more than 10 mg / dosage unit, more than 100 mg / dosage unit, more than 200 mg / dosage unit, more than 300 mg / dosage unit , more than 400 mg / dosage unit, more than 500 mg / dosage unit or more than 1000 mg / dosage unit. Preferably, if the drug is more than 50 mg / unit dosage. More preferably, when the drug is more than 100 mg / dosage unit or, for example, more than 150 mg / dosage unit or 200 mg / dosage unit, or 250 mg / dosage unit, or 300 mg / dosage unit or more.

In particular embodiments, the core contains tramadol hydrochloride, wherein the core contains between about 10% and 90% of the total tramadol present in the tablet, for example about 45 mg 100 mg of the active substance content of the tablet (45% of the total tablet) or about 90 of 200 mg of the active substance tablets (45% of the total tablet) or about 151 mg of 300 mg of the active substance content of the tablet (50% of the entire tablet).

Core matrix

The release of the active pharmaceutical ingredient in the core from the composition is slower than the release of the active pharmaceutical ingredient in the shell matrix. A preferred core matrix is cross-linked high amylose starch, known as Contramid® and described in US Pat. No. 6,607,748. In special embodiments, the matrix is 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 1 and about 4, or between about 1 and about 3, and about 1.5 and about 2.5. In one particular embodiment, the core is about 90 mg, of which 44 mg is Contramid® and 45 mg is tramadol hydrochloride. In this case, Contramid® thus represents about 49 weight percent of the core.

Optional components

The core of the composition according to the invention may optionally include a pharmaceutically acceptable carrier or solvent. Such carriers or solvents are known to those skilled in the art and can be found, for example, in Remington's Pharmaceutical Sciences, 14 ^th Ed. (1970). Examples of such carriers or solvents include lactose, starch, dicalcium phosphate, calcium sulfate, kaolin, mannitol and icing sugar. Additionally, if necessary, suitable binders, emollients and disintegrants may be included. Dyes may also be included, as well as sweeteners or flavorings, if desired.

The core of the composition according to the invention may optionally include additional ingredients, including, without limitation, dispersing agents such as microcrystalline cellulose, starch, crosslinked starch, crosslinked polyvinylpyrrolidone and sodium carboxymethyl cellulose; flavoring agents; coloring agents; binding agents; preservatives; surface-active agents, etc.

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

Suitable forms of microcrystalline cellulose, for example, MCC-F101; MCC-102; MCC-105, etc.

Suitable emollients, such as, for example, those known to those skilled in the art, may also be included. For example, magnesium stearate, vegetable oil, talc, sodium fumarate, calcium stearate, stearic acid and so on.

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

Quantitative ratio

The active agent is present in amounts ranging from about 1 to about 90 wt.% The total weight of the core, preferably from about 10 to about 70 wt.% Of the total composition of the core, more preferably from about 20 to about 60 wt.% Of the total composition nuclei and probably most often from about 30 to about 50 wt.% of the total composition of the nucleus.

Of course, the total amount of all ingredients is 100 wt.%, And ordinary specialists in this field, can change the number within the established ranges to achieve useful compositions.

Coating (sheath)

The coating of the dosage form includes a physical mixture of polyvinyl acetate and polyvinylpyrrolidone and the active pharmaceutical ingredient of the coating. The shell may also include cross-linked high amylose starch, such as Contramid® and other possible ingredients. In a preferred embodiment, the shell is formed by dry pressing. The weight of the shell can be any percentage of the weight of the total composition, between about 10% and 90%, but preferably in a higher part of this range. The shell thus typically comprises between about 20% and 90% (w / w) of the tablet according to the invention or about 25% and about 90% or about 30% and about 85%, or about 35% and about 85%, or about 40% and about 85%, or about 45% and about 85%, or about 25% and about 90%, or about 45% and about 90%, or about 50% and about 90%, or about 50%, and about 85%, or about 55% and about 90%, or about 55% and about 85%, or about 55% and about 80%, or about 60% and about 90%, or about 60% and about 85%, or about 60% and about 80%, or with about 60% and about 75%, or about 65% and about 90%, or about 65% and about 85%, or about 65% and about 80%, or about 65% and about 75%, or about 65% and about 70% or about 75%.

The shell often includes an optional binder.

Polyvinyl acetate and polyvinylpyrrolidone coatings (shells)

The percentage weight of the polyvinyl acetate / polyvinylpyrrolidone mixture in the shell can be enclosed in a wide range of values. Depending on the solubility in water of the active ingredient in the shell, the amount of the polyvinyl acetate / polyvinylpyrrolidone mixture in the shell may be selected. US Patent Publication No. 2001/0038852 describes selection methods. For example, for active ingredients that are highly soluble in water, a polyvinyl acetate / polyvinylpyrrolidone mixture may comprise from about 20% to about 80% by weight of the coating, preferably from about 30 to about 65% by weight or from about 40 to about 55% .%. In a particular embodiment described below, Kollidon ™ SR comprises about 45% by weight of the shell, which is about 31% by weight of tramadol hydrochloride and about 23% of xanthan gum. For active ingredients, from moderately soluble to slightly soluble in water, the amount of the polyvinyl acetate / polyvinylpyrrolidone mixture is often less, as described in US Patent Publication No. 2001/0038852.

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

The molecular weight of the polyvinyl acetate ingredient in the polyvinyl acetate / polyvinylpyrrolidone mixture can be a wide range of values. Preferably, the average molecular weight of the polyvinyl acetate is from about 100 to about 1,000,000; or from about 1000 to about 1,000,000; or from about 10,000 to about 1,000,000; or from about 100,000 to about 100,000, or about 450,000.

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

A mixture of polyvinyl acetate and polyvinylpyrrolidone can be prepared in a variety of ways, including simply mixing powders of polyvinylpyrrolidone and polyvinyl acetate. In a preferred embodiment, the mixture is a spray dried colloidal dispersion powder of a solution of polyvinyl acetate and polyvinylpyrrolidone. Optionally, sodium lauryl sulfate is used as a stabilizer to prevent agglomeration during the spray drying process and / or colloidal silicon is used to improve the flow properties of the polyvinyl acetate / polyvinylpyrrolidone mixture. Optionally, polyvinyl acetate and polyvinylpyrrolidone can be formed optionally or in a block copolymer.

Optional components

Suitable binders according to the invention include, without limitation, plant extracts, resins, synthetic or natural polysaccharides, polypeptides, alginates, synthetic polymers or a mixture thereof.

Suitable plant extracts to be used as gelling agents include, but are not limited to, agar, ispaghula, plantain, quince, heifer, or a mixture thereof.

Suitable resins to be used as gelling agents include, but are not limited to, xanthan gum, guar gum, gum arabic, ghatti gum, karaya gum, tragacanth gum, or a mixture thereof.

Suitable synthetic or natural hydrophilic polysaccharides used as gelling agents include, but are not limited to, hydroxyalkyl cellulose, cellulose ethers, cellulose ethers, nitrocellulose, dextrin, agar, carrageenan, pectin, furcellaran, starch or starch derivatives, starch, starch, starch, starch, starch, starch, starch, or a mixture thereof.

Suitable polypeptides useful as gelling agents include, but are not limited to, gelatin, collagen, polyheline, or a mixture thereof.

Suitable alginates used as gelling agents include, but are not limited to, alginic acid, propylene glycol alginate, sodium alginate, or a mixture thereof.

Suitable synthetic polymers used as gelling agents include, but are not limited to, a carboxyvinyl polymer, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, polyethylene glycols, ethylene oxide and propylene oxide copolymers and copolymers thereof or a mixture thereof.

In a preferred embodiment, the gelling agent is gum, such as xanthan gum, guar gum, gum arabic, ghatti gum, karaya gum, tragacanth gum or a mixture thereof, PEO 7000000 and HPMC K100 M.

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

Active agent in the coating

A suitable active pharmaceutical ingredient according to the invention is any active agent that is desirably provided in a sustained release dosage form. A detailed list of suitable pharmaceuticals can be found in The Merck Index, 12 ^th Ed. Preferably, the pharmaceutical ingredient is, without limitation, isonicotinic acid hydrazide, sodium salicylate, pseudoephedrine hydrochloride, pseudoephedrine sulfate, acetominophene or diclofenac sodium, verapamil, glipizide, nifedipine, felodipine, betahistine, albuterol, omapolistol®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolistin®, acrypolitin trimebutin, ciprofloxacin and their salts. 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, diclofenacin, pirmetin, tolmet , mefenamic acid, dextromethorphan, other non-steroidal anti-inflammatory drugs, including salicylates, their pharmaceutically acceptable salts or mixtures thereof.

The solubility of a drug in an aqueous solution can have a wide range of values. The water solubility of the pharmaceutical agent may be less than 10 ⁻³ g / l, more than 10 ⁻³ g / l, more than 10 ⁻² g / l, more than 10 ⁻¹ g / l, more than 1 g / l, more than 10 g / l, more than 100 g / l, more than 500 g / l, more than 1000 g / l or more than 2000 g / l. Preferably, the solubility is more than 100 g / L. More preferably, if the solubility is more than 500 g / l or even 1000 g / l.

A drug may satisfy different dosage requirements. For example, a desired dosage of a drug may be less than 1 mg / dosage unit, more than 1 mg / dosage unit, more than 10 mg / dosage unit, more than 100 mg / dosage unit, more than 200 mg / dosage unit, more than 300 mg / dosage unit, more than 400 mg / dosage unit, more than 500 mg / dosage unit, or more than 1000 mg / dosage unit. Preferably, the drug is more than 50 mg / dosage unit. More preferably, the drug is more than 100 mg / dosage unit. Most preferably, the drug is more than 200 mg / dosage unit.

The shell may comprise between about 5% and about 90% by weight of the pharmaceutically active ingredient, or between about 5% and about 80% by weight api, or between about 10% and about 70% by weight api, or between about 10% and about 60 wt.% api, or between about 15% and about 50 wt.% api, or between about 15% and about 45 wt.% api, or between about 15% and about 40 wt.% api, or between about 20% and about 35 wt.% api, or between about 20% and about 30 wt.% api.

In the specific embodiments described below, the weight of tramadol in a 100 mg tablet of tramadol is about 21% by weight of the coating. The weight of tramadol in a 200 mg tablet of tramadol is approximately 31 wt.% Shell. The weight of tramadol in a 300 mg tablet of tramadol is approximately 30% by weight of the coating.

WAYS OF INTRODUCTION

The tablet composition according to the invention can be administered, without limitation, through a number of routes, such as, for example, oral, sublingual and rectal. The preferred route of administration of the compositions of the invention is via the oral route.

Compositions of the invention that are suitable for oral administration may be presented as discrete units such as tablets and granules. Preferably, the compositions of the invention are presented in tablet form. Such tablets may be conventionally formed by compression or molding. Compressed tablets may be prepared by compressing a mixture of one or more of the components described above in a suitable device. Molded tablets may be prepared by compressing the above ingredients in an appropriate device, and the above ingredients may, if desired, be moistened with an inert liquid solvent. Tablets may, if required, be coated (coated) and / or have identification marks visible to the consumer. A tablet can also be obtained in various forms, for example, uncoated, dry-coated or film-coated, and so on. A tablet may also have a variety of shapes (for example, oval, spherical, etc.) and sizes. A detailed discussion of tablets can be found in the references, for example, in The Theory and Practice of Industrial Pharmacy by Lachman et al., 3 ^th Ed. (Lea & Fibiger, 1986).

Sustained Release Dissolution Profile

The active agent of the composition has the following in vitro dissolution profile, when measured using a USP Type I device in 50 mM phosphate, pH 6.8 and with stirring between 50 and 150 rpm:

an average rate of between 10% and 30% per hour of the drug is released between 0 and 2 hours, when tested in vitro using a USP Type I device in 50 mM phosphate, pH 6.8 and with stirring between 50 and 150 rpm .; or

between 10% and 40% of the agent is released from the composition between 0 and about 2 hours of measurement, between about 30% and 60% of the agent is released from the composition between 2 and about 7 hours of measurement, between about 50% and 80% of the agent is released from the composition between 7 and about 12 hours of measurement, and between about 80% and 100% of the agent is released from the composition after about 20 hours of measurement; or more preferably

between about 15% and 35% of the agent is released from the composition after 2 hours, between about 40% and 60% of the agent released from the composition after 7 hours, between about 60% and 80% of the agent is released from the composition in 12 hours and between about 85% and 100% of the product is released from the composition when measured after 20 hours, or

between 20% and 40% of the agent is released from the composition after 2 hours, between about 40% and 60% of the agent is released from the composition after 7 hours, between about 60% and 80% of the agent is released from the composition in 12 hours and between about 85% and 100 % of the drug is released from the composition after 20 hours of measurement.

The present invention will be more readily understood by reference to the following examples, which are given more to illustrate the invention than to limit its scope.

EXAMPLES

The crosslinked high amylose starch used in these examples was created by a process comprising the steps of crosslinking and chemical modification, followed by gelatinization and drying. This method is described in detail in detail in US Patent No. 6607748 (Lenaerts et al.), Issued August 19, 2003, and is known in the market under the name Contramid®; it is described in Examples 1 and 2.

Example 1

A. Cross-linking

High amylose starch (30.0 kg) containing about 70% w / w. amylose (Cl AmyloGel 03003) is placed in a reactor. Water (55.0 L) containing sodium hydroxide (30.0 g) and sodium sulfate (2.40 kg) is added to this reactor. The resulting suspension is heated to a temperature of 30 ° C. Phosphorus oxychloride (22.5 g) is added to the reaction mixture, which reacts within 1 hour.

B. Chemical modification, hydroxypropylation

The crude reaction mixture from Part A is transferred to a hydroxypropylation reactor. The reaction mixture is heated to 40 ° C for more than 30 minutes, and the reaction is purified by nitrogen. After complete purification, propylene oxide (1.80 kg) is added. The reaction mixture is stored at 40 ° C. for 20 hours. The reaction mixture is neutralized with 0.1 N. H ₂ SO ₄ (1: 2 v / v) to a pH of 5.5. The starch precipitate is washed with a basket centrifuge at a speed of 1200 rpm. The resulting starch precipitate is re-emulsified in 35 L of water and centrifuged a second time. The resulting starch precipitate is dried in an instantaneous dryer at an inlet temperature of 160 ° C. and an outlet temperature of 60 ° C.

C. Gelatinization

The modified granular starch precipitate is dissolved in demineralized water to form a precipitate at a concentration of about 8% based on dry matter. The resulting suspension has a relative density of 1.032 kg / l with respect to water. The pH of the modified starch suspension is adjusted to 6.0. Then the solution is heated to 160 ° C by direct introduction of steam (Schlick Model 825). Temperature fluctuations are not more than ± 1 ° C. The suspension is held in a storage column for 4 minutes at a temperature of 160 ° C and a pressure of about 5.5 bar. The pressure is then reduced to atmospheric by flash transmission. Then the solution is contained at 95 ° C in a storage tank.

D. Spray Drying

The suspension from Part C is dried by using a Niro FSD 4 tower spray dryer equipped with a 0.8 mm valve and 10 l / h flow. The inlet temperature is fixed at 300 ° C, and the outlet temperature is 120 ° C. The resulting powder is a controlled release adjuvant with the following properties:

The properties Moisture contents 4,5% Bulk density 150 g / l Apparent density 210 g / l pH 5,4 Peak particle size 50 microns (Laser Particle Meter - Sympatec)

Example 2

A. Cross-linking

High amylose starch (30.0 kg) containing about 70% w / w. amylose (Cl AmyloGel 03003) is placed in a reactor. Water (55.0 L) containing sodium hydroxide (30.0 g) and sodium sulfate (2.40 kg) is added to this reactor. The resulting suspension is heated to a temperature of 30 ° C. Sodium trimethophosphate (45 g) is added to the reaction mixture, which reacts within one hour.

B. Chemical modification, hydroxypropylation

The crude reaction mixture from Part A is transferred to a hydroxypropylation reactor. The reaction mixture is heated to 40 ° C for more than 30 minutes, and the reaction is purified by nitrogen. After complete purification, propylene oxide (1.80 kg) is added. The reaction mixture is stored at 40 ° C. for 20 hours. The reaction mixture is neutralized with 0.1 N. H ₂ SO ₄ (1:. 2 v / v.) To pH 5.5. The starch precipitate is washed with a basket centrifuge at a speed of 1200 rpm. The resulting starch precipitate is re-emulsified in 35 l of water and centrifuged a second time. The resulting starch precipitate is dried in an instantaneous dryer at an inlet temperature of 160 ° C. and an outlet temperature of 60 ° C.

C. Gelatinization

The modified granular starch precipitate is dissolved in demineralized water to form a precipitate, at a concentration of about 8%, based on dry matter. The resulting sediment has a relative density of 1.032 kg / l with respect to water. The pH of the modified starch precipitate is adjusted to 6.0. The solution is then heated to 160 ° C. by direct steam injection (Schlick Model 825). Temperature fluctuations are not more than ± 1 ° C. The suspension is held in a storage column for 4 minutes at a temperature of 160 ° C and a pressure of about 5.5 bar. Then the pressure is reduced to atmospheric by flash transmission. Then the solution is kept at 95 ° C in a storage tank.

D. Spray Drying

The suspension from Part C is dried by using a Niro FSD 4 tower spray dryer equipped with a 0.8 mm valve and 10 l / h flow. The inlet temperature is 300 ° C and the outlet temperature is 120 ° C. The resulting powder is a controlled release adjuvant with the following properties:

The properties Moisture contents 5.2% Bulk density 103 g / l Apparent density 155 g / l pH 5.3 Peak particle size 70 microns (Laser Particle Meter - Sympatec)

Lubritab® is a product sold by Penwest Pharmaceuticals Co. (Cedar Rapids, IA, USA). Kollidon ™ SR is a product manufactured by BASF (Germany). Encompress ™ is a dicalcium phosphate dihydrate that 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 for the synthesis and purification of tramadol are described, for example, in US Patent Nos. 3652589, 5414129, 5672755, 5874620, 5877351 and 6169205.

Preparation method

Tablets according to the invention can be manufactured according to the method generally set forth in the process diagram of the method of Figure 1 and described in detail below.

Dosing by mass: The starting materials are distributed in clearly labeled containers.

Core pre-mix: Mix a portion of Contramid® and colloidal silica and pass through a # 30 mesh sieve into an appropriate container.

Kernel mixture: Place a portion of Contramid® in the mixer. Pass tramadol hydrochloride through a # 30 mesh sieve and add to the mixer. Rinse container with a portion of Contramid® and add to mixer. Sieve Type I hydrogenated vegetable oil through a # 30 mesh sieve and add to the blender. Add a preliminary core mixture to the mixer. Add the remaining Contramid® to the mixer and mix all the ingredients. Sift the magnesium stearate through a # 30 mesh sieve and add the mixture with other ingredients. Distribute the mixture into an appropriate container and determine as a mixture of the core.

Dry coating pre-mix: Mix a portion of xanthan gum and all colloidal silicon dioxide and pass through a # 30 mesh sieve.

Dry Coating Mixture: Place a portion of Kollidon ™ SR in the mixer. Pass tramadol hydrochloride through a Kason c # 30-mesh screen separator into an appropriate container and add to the mixer. Rinse the container with the remaining xanthan gum and add to the mixer. Sieve Type I hydrogenated vegetable oil through a # 30 mesh sieve and add to the blender. Place the dry-coated pre-mix and Kollidon ™ SR residues in the mixer and mix with all ingredients. Sift the magnesium stearate through a # 30 mesh sieve and mix with other ingredients. Distribute the granulation into an appropriate container and determine as a dry coating mixture.

Pressing: Apply a Manesty Dry-Cota press to produce compressed coated tablets.

Example 3

Compositions A, B and C, as shown in Table 1, were made in accordance with the method described above.

Table 1 Formulations of compositions A, B, and C for controlled release tramadol. 1) INGREDIENT Composition A Composition B Composition C % mg / tablet % mg / tablet % mg / tablet Core Tramadol hydrochloride fifty 45 fifty 90 63.25 151.8 Contramid® 48.3 43,47 48.3 86.94 35.05 84.1 Hydrogenated vegetable oil 0.75 0.675 0.75 1.35 0.75 1.8 Silicon 0.2 0.18 0.2 0.36 0.20 0.5 Magnesium stearate 0.75 0.675 0.75 1.35 0.75 1.8 Total core weight one hundred 90 one hundred 180 one hundred 240 2) SHELL Tramadol hydrochloride 21.15 55 30.56 110 30.56 148.5 Silicon 0.20 0.52 0.20 0.72 0.20 1,0 Kollidon SR® 51,42 133.7 45.16 162.58 45.16 219 Xanthan gum 25.72 66.86 22.58 81.3 22.58 109.5 Hydrogenated vegetable oil 1.00 2.6 1.00 3.6 1.00 4.9 Magnesium stearate 0.50 1.3 0.50 1.8 0.50 2,4 Total shell weight one hundred 260 100.00 360 one hundred 485 3) SHELLED TABLET Tramadol hydrochloride 28.57 one hundred 37.04 200 41.38 300 Contramid® 12,42 43,47 16.10 86.94 11.60 84.1 Hydrogenated vegetable oil 0.94 3,275 0.92 4.95 0.92 6.7 Silicon 0.20 0.7 0.20 1,08 0.20 1,5 Magnesium stearate 0.56 1,975 0.58 3.15 0.58 4.2 Kollidon SR® 38,20 133.7 30.11 162.58 30.21 219 Xanthan gum 19.11 66.86 15.06 81.3 15.10 109.5 Total weight of the coated tablet: one hundred 350 one hundred 540 one hundred 725

Dissolution profiles of compositions A, B and C are shown in Figure 2.

The composition of tramadol daily single dose

The present invention relates to a controlled release tablet composition that provides an analgesic effect no later than 2 hours after oral administration, which lasts at least 24 hours after administration.

A 200 mg dose of the controlled release composition of the invention unexpectedly provides a rapid onset of analgesic effect no later than 2 hours after oral administration and an average plasma concentration of tramadol between 100 ng / ml and 200 ng / ml for at least 24 hours after single dose.

In addition, when stable, the average plasma concentration of tramadol remains between 100 ng / ml and 350 ng / ml. Surprisingly, it has been shown that the controlled release compositions of the invention provide a complete clinical effect for at least 24 hours after oral administration.

Bioavailability study

An object of the present invention enables flexible dosing choices for patients with different needs for pain relief using a single daily dosage composition.

One embodiment of the present invention relates to a composition for a single daily intake, which, with an initial oral dose of 200 mg, provides the desired early onset of action, but at which average plasma concentrations of tramadol of at least 45 ng / ml are reached between 2 and 24 hours .

An additional embodiment of the present invention provides a composition for a single daily intake, which, at an initial dose of 200 mg, provides the required early onset of action, but at which average plasma concentrations of tramadol of at least 100 ng / ml are reached between 2 and 24 hours.

An additional embodiment of the present invention provides a composition for a single daily intake, which, at an initial dose of 300 mg, provides the required early onset of action, but at which average plasma concentrations of tramadol of at least 150 ng / ml are reached between 2 and 24 hours.

An additional embodiment of the present invention provides a composition for a single daily intake, which, at an initial dose of 400 mg, provides the required early onset of action, but at which average plasma concentrations of tramadol of at least 180 ng / ml are reached between 2 and 24 hours.

An additional embodiment of the present invention provides a composition for a single daily intake, which at the initial dose, provides C ' _max for a dose ratio of from about 0.9 to about 1.0.

An additional embodiment of the present invention provides a composition for a single daily intake, which at the initial dose provides a concentration of tramadol in the plasma, which is steadily increasing until a peak concentration of tramadol is reached at T _{max of} about 4 hours to about 6 hours. Preferably, T _max is from about 5 hours to about 5.5 hours.

An additional embodiment of the present invention provides a composition for a single daily intake, which at the initial dose, provides a concentration of tramadol in the plasma, which after T _max decreases slowly and evenly, reflecting continuous absorption, in addition to elimination processes. Preferably, the decrease in the concentration of tramadol in plasma after T _max occurs according to a logarithmic law with an average apparent half-life of between about 5.5 hours and about 6.5 hours.

An additional embodiment of the present invention provides a composition for a single daily intake, which, at the initial dose, provides a concentration of tramadol in the plasma, which after T _max decreases slowly but evenly, reflecting continuous absorption, in addition to elimination processes, and the absorption of which continues at least within 20 hours from the start of absorption of the dose.

An additional embodiment of the present invention provides a composition for a single daily intake, which, at the initial dose, provides a plasma concentration of tramadol, which, after T _max, decreases according to a logarithmic law, with an apparent constant constant for elimination (λ _z ) of about 0.12 hours ^-1 .

An additional embodiment of the present invention provides a composition for a single daily intake, which, at the initial dose, provides an average residence time (STS) of tramadol ranging from about 15 hours to about 18 hours.

An additional embodiment according to the invention provides a composition for a single daily intake, which, at the initial dose, provides an average duration (UCS) of tramadol ranging from about 22.5 hours to about 25.4 hours.

An additional embodiment of the present invention provides a composition for a single daily intake, which, at the initial dose, provides a ratio of C ' _max to AUC _{0-∞ of} about 0.04 h ^{-1 to} about 0.06 h ^-1 . Preferably, the ratio of C ' _max to AUC _0-∞ is from about 0.04 h ^{-1 to} about 0.05 h ^-1 . The ratio C ' _max / AUC _0-∞ is used to estimate the absorption rate of the drug.

An additional embodiment of the present invention provides a composition for a single daily intake, which, upon initial dose administration, provides an average AUC of _0-24 plasma concentrations of tramadol, which increases in proportion to the dose, in a dose range of 100 mg to 300 mg of a controlled release composition.

An additional embodiment according to the invention provides a composition for a single daily intake, which, at an initial dose of 100 mg, provides an average AUC of _0-Tmax from about 610 ng · h / ml to about 630 ng · h / ml.

An additional embodiment of the present invention provides a composition for a single daily intake, which at an initial dose of 200 mg provides an average AUC of _0-Tmax from about 910 ng · h / ml to about 920 ng · h / ml.

An additional embodiment according to the invention provides a composition for a single daily intake, which, at an initial dose of 300 mg, provides an average AUC of _0-Tmax from about 1570 ng · h / ml to about 1590 ng · h / ml.

An additional embodiment of the present invention provides a composition for a single daily intake, which at the initial dose provides an average ratio of AUC _0-24 / AUC _0-∞ plasma concentration of tramadol, which ranges from about 70% to about 85%. Preferably, the average ratio of AUC _0-24 / AUC _0-∞ plasma tramadol concentration ranges from about 74% to about 80%. As a result, from about 15% to about 30% of the administered dose continues to circulate in plasma 24 hours after administration, depending on the administered dose.

An additional embodiment of the present invention provides a composition for a single daily intake, which at the initial dose, provides a ratio of C ' _max to the dose released into the blood plasma in the first 24 hours (AUC _0-24 / AUC _0-∞, multiplied by the dose) from about 1.10 to about 1.35. Preferably, the ratio is from about 1.15 to about 1.31.

An additional embodiment according to the invention provides a composition for a single daily intake, which at the initial dose provides a ratio of C ' _max / T _max for the administered dose from about 0.10 to about 0.20. Preferably, this ratio is from about 0.12 to about 0.19.

An additional embodiment of the present invention provides a composition for a single daily intake, which at the initial dose, provides a slope in ng / ml-hour, after a peak plasma concentration that does not exceed a coefficient of about 0.035 of the total dose administered in mg. Preferably, the coefficient is about 0.03.

The pharmacokinetics of tramadol controlled release formulations are presented in Table 2.

An additional embodiment of the present invention provides a composition for a single daily intake, which at the initial dose, provides a C ' _max ratio calculated relative to the plasma concentration of O-desmethyltramadol for a dose of tramadol from about 0.19 to about 0.22. Preferably, the ratio is from about 0.20 to 0.21.

An additional embodiment of the present invention provides a composition for a single daily intake, which, at the initial dose, provides a plasma concentration of O-desmethyltramadol that increases uniformly until it reaches a peak concentration of tramadol at T _max from about 8 hours to about 16 hours.

An additional embodiment of the present invention provides a composition for a single daily intake, which at the initial dose provides a concentration of O-desmethyltramadol in plasma, which after T _max decreases slowly but evenly, reflecting the continuous absorption of tramadol and the formation of sequential metabolites, in addition to elimination processes. Preferably, the decrease in the concentration of O-desmethyltramadol in plasma occurs according to a logarithmic law, with an apparent average half-life of about 6.7 hours and about 8.1 hours.

An additional embodiment of the present invention provides a composition for a single daily intake, which at the initial dose, provides the formation of a metabolite for at least 18 hours.

An additional embodiment of the present invention provides a composition for a single daily intake, which, at the initial dose, after T _max provides a decrease in the concentration of O-desmethyltramadol in plasma according to the logarithmic law with a constant constant apparent elimination rate (λ _z ) of about 0.1 hour ^-1 .

An additional embodiment of the present invention provides a composition for a single daily intake, which, at the initial dose, provides an average duration (UCS) of O-desmethyltramadol in the range of about 25.6 hours to about 28.1 hours.

An additional embodiment of the present invention provides a composition for a single daily intake, which at the initial dose provides a ratio of C ' _max to AUC _0-∞ , calculated relative to the concentration of O-desmethyltramadol in plasma, about 0.04 hour ^-1 . The ratio C ' _max / AUC _0-∞ is used to evaluate the rate of metabolite formation.

An additional embodiment of the present invention provides a composition for a single daily intake, which at initial dose, provides an average AUC of _0-24 calculated relative to the concentration of O-desmethyltramadol in plasma, which increases in proportion to the dose in the dosage range from 100 mg to 300 mg of the controlled release composition.

An additional embodiment of the present invention provides a composition for a single daily intake, which at an initial dose of 100 mg provides an average AUC of _0-Tmax relative to the concentration of O-desmethyltramadol in plasma from about 175 ng · h / ml to about 180 ng · h / ml.

An additional embodiment of the present invention provides a composition for a single daily intake, which at an initial dose of 200 mg provides an average AUC of _0-Tmax relative to the concentration of O-desmethyltramadol in plasma from about 530 ng · h / ml to about 550 ng · h / ml.

An additional embodiment of the present invention provides a composition for a single daily intake, which at an initial dose of 300 mg provides an average AUC of _0-Tmax relative to the concentration of O-desmethyltramadol in plasma from about 580 ng · h / ml to about 590 ng · h / ml.

An additional embodiment of the present invention provides a composition for a single daily intake, which, upon initial dose administration, provides an average plasma AUC ratio of _0-24 / AUC _0-∞ of O-desmethyltramadol concentration ranging from about 65% to about 80%. Preferably, the average AUC ratio of _0-24 / AUC _0-∞ in plasma concentration of O-desmethyltramadol ranges from about 68% to about 75%. As a result, from about 25% to about 32% of the active metabolite continues to circulate in plasma 24 hours after the dose is administered.

An additional embodiment of the present invention provides a composition for a single daily intake, which, at the initial dose, provides a ratio of C ' _max , calculated relative to the concentration of O-desmethyltramadol in plasma, to the concentration of O-desmethyltramadol in blood plasma in the first 24 hours (AUC _0-24 / AUC _0-∞ times 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 pharmacokinetics of O-desmethyltramadol controlled release formulations are presented in Table 3.

HB - uncalculated

Example 4

(i) Dose Proportionality - Single Dose.

A bioavailability study was conducted to evaluate dose proportionality between three dosages of the active substance (100 mg, 200 mg and 300 mg). This study was conducted with an appropriate washout period between each administration. Doses were taken from 27 healthy volunteers under fasting conditions.

The figure 3 shows the temporal dependence of the average plasma concentration of tramadol obtained from subjects after administration of the composition according to the invention with controlled release (doses of 100 mg, 200 mg and 300 mg of tramadol HCl). The data used to create Figure 3 is included in Table 4.

Table 4 Average (± SD) plasma tramadol concentration (ng / ml) Time 100 mg dose of a composition according to the invention for controlled release 200 mg dose of a composition according to the invention for controlled release 300 mg dose of a composition according to the invention for controlled release 0 0 0 0 one 41.8 ± 14.1 82.5 ± 24.1 110.2 ± 36.7 2 60.0 ± 14.6 129.2 ± 25.7 168.6 ± 52.1 3 69.2 ± 20.2 156.5 ± 37.0 218.1 ± 82.3 four 72.5 ± 21.8 164.0 ± 44.9 242.0 ± 96.2 5 81.7 ± 24.2 177.2 ± 61.8 277.1 ± 153.8 6 77.9 ± 24.7 169.2 ± 58.1 260.3 ± 134.8 8 83.0 ± 25.6 164.1 ± 52.7 243.6 ± 127.1 10 81.0 ± 24.7 157.8 ± 57.8 219.8 ± 101.6 12 84.4 ± 25.3 156.4 ± 55.9 223.4 ± 85.1 16 73.0 ± 24.1 152.8 ± 42.0 209.9 ± 70.2 twenty 56.4 ± 19.4 121.0 ± 34.4 185.7 ± 62.7 24 47.2 ± 20.9 101.6 ± 38.2 157.0 ± 60.4 thirty 26.8 ± 15.0 56.4 ± 28.3 99.9 ± 50.3 36 13.2 ± 9.4 29.1 ± 18.7 55.9 ± 37.9 48 3.7 ± 3.5 8.5 ± 6.7 15.7 ± 13.1

The results of this study showed that doses of 100 mg, 200 mg and 300 mg of a controlled release composition according to the invention are proportional to the rate and degree of absorption of tramadol and the rate and degree of formation of O-desmethyltramadol.

A bioavailability study was conducted to characterize the pharmacokinetic properties of the composition according to the invention with controlled release and to demonstrate a similar effect of the drug and / or its active metabolite compared to the control product.

Example 5

(ii) Comparison of a double daily composition with a single dose

2 x 200 dosages of the controlled-release composition of the invention were compared with a daily, two-dose composition, Topalgic® LP (200 mg) tablets manufactured by Laboratoires Hoechst Houde, in a comparative bioavailability study after fasting administration to 24 healthy volunteers.

The pharmacokinetic results of administering a controlled-release composition according to the invention were compared with the results of two-time administration (at 12-hour intervals) of the control composition in order to evaluate the bioequivalence between the test and control product. Based on the calculation of the 90% confidence interval of the test to control geometric mean values, the degree of exposure (determined by the AUC _0-t and AUC _0-∞ tramadol estimates after dose adjustment) was within the generally accepted bioequivalent interval of 80-125% for logarithmically transformed parameters. Thus, it was found that the controlled release composition according to the invention and the daily two-time composition are bioequivalent in terms of the total exposure to tramadol. The results for tramadol AUC _{0-∞ are} presented in Table 5.

Table 5 Comparison of AUC _0-∞ (Single dose versus daily two-time composition) Treatment Arithmetic mean ± SD (ng · h / ml) Geometric average ratio (90% confidence interval) 2 × 200 mg dose of a composition according to the invention with controlled release 9332 ± 3767 103 (98-109) 1 × 200 Topalgic® LP BID 8897 ± 3124

The figure 5 presents graphs of the time dependence of the arithmetic mean concentration of tramadol in plasma obtained after administration of a single daily composition according to the invention with controlled release and control product administered per day at 12 hour intervals in 24 healthy volunteers. The data used to obtain figure 5 are included in Table 6.

Table 6 The average concentration of tramadol in plasma (ng / ml) Test composition Control composition Time Conc. 2 × 200 mg dose of a composition according to the invention Time Conc. 200 mg BID 0 0 0 0 one 138.49 ± 58.62 one 101.93 ± 43.72 2 257.56 ± 81.20 2 226.89 ± 72.90 3 350.21 ± 166.42 3 296.35 ± 99.46 four 373.93 ± 124.33 four 318.22 ± 91.27 5 427.66 ± 166.90 5 330.88 ± 98.68 6 424.72 ± 176.20 6 281.67 ± 85.95 9 408.61 ± 196.28 9 236.39 ± 87.89 12 357.88 ± 162.48 12 167.41 ± 65.49 16 312.70 ± 153.34 13 181.96 ± 70.51 twenty 243.94 ± 117.93 fourteen 284.67 ± 126.76 24 184.96 ± 102.9 fifteen 378.82 ± 136.23 thirty 99.78 ± 61.60 16 396.87 ± 146.56 36 51.01 ± 43.33 17 388.83 ± 142.32 48 0 eighteen 396.38 ± 140.65 21 331.81 ± 121.52 24 275.00 ± 110.61 thirty 118.69 ± 64.92 36 54.04 ± 39.07 48 0

The figure 6 presents graphs of the time dependence of the arithmetic mean plasma concentration of O-desmethyltramadol obtained after a single daily administration of the controlled release composition of the invention and the control product for one day at 12-hour intervals to 24 healthy volunteers. The data used to obtain figure 6 are included in Table 7.

Table 7 Average (± SD) plasma concentrations of O-desmethyltramadol (ng / ml) Test composition Control composition Time Conc.
2 × 200 mg dose of a composition according to the invention Time Conc.
200 mg BID 0 0 0 0 one 29.82 ± 17.0 one 17.7 ± 14.6 2 57.8 ± 17.0 2 48.3 ± 17.5 3 76.3 ± 31.6 3 66.2 ± 25.9 four 84.9 ± 30.9 four 74.3 ± 26.2 5 98.0 ± 41.4 5 80.64 ± 29.2 6 100.6 ± 41.7 6 74.3 ± 26.1 9 99.9 ± 41.7 9 68.1 ± 24.6 12 96.52 ± 38.8 12 56.6 ± 22.1 16 83.9 ± 32.6 13 59.1 ± 23.8 twenty 68.2 ± 28.8 fourteen 75.1 ± 32.6 24 57.6 ± 28.0 fifteen 92.6 ± 38.0 thirty 33.2 ± 20.0 16 96.7 ± 37.0 36 0 17 97.0 ± 34.5 48 0 eighteen 100.4 ± 33.6 21 93.0 ± 32.4 24 83.3 ± 37.8 thirty 44.4 ± 21.6 36 18.1 ± 16.8 48 0

Example 6

(iii) Comparison of the Twice Daily Composition and the Continuous Release Composition

A dosage of 200 mg of a controlled-release composition according to the invention was compared with a twice daily composition, Topalgic® LP tablets (100 mg) manufactured by Laboratoires Hoechst Houdé, in a comparative study of bioavailability after repeated administration in fasting conditions in 26 healthy volunteers.

The results of this study showed that the controlled release composition of the invention is equivalent to a control product in terms of the rate and degree of absorption of tramadol and the rate and degree of formation of O-desmethyltramadol. The comparative bioavailability of the two products was evaluated on the basis of the confidence interval for the main variable AUC _ss for tramadol and O-desmethyltramadol relative to the generally accepted range of bioequivalence from 80% to 125%. The results for tramadol AUC _{ss are} presented in Table 8.

Table 8 Comparison of AUC _ss (Composition once a day versus daily two-time) Treatment Arithmetic mean ± SD (ng · h / ml) Geometric mean ratio
(90% confidence interval) 2 × 200 mg dose of a controlled release composition according to the invention 5185 ± 1460 92.4 (87.5-97.5) Topalgic® LP 100 mg BID 5538 ± 1214

7 is a graph of time curves of the arithmetic mean concentration of tramadol in plasma and O-desmethyltramadol after administration of a 200 mg dose of a single daily controlled release composition according to the invention and a control product (Topalgic® LP 100 mg BID) for one day at 12-hour intervals. The data used to obtain figure 7 are included in Table 9.

Table 9 Average (± SD) plasma concentrations of tramadol and O-desmethyltramadol (ng / ml) Test composition (200 mg dose of a controlled release composition according to the invention) Control composition (100 mg BID) Time Tramadol Metabolite Time Tramadol Metabolite 0 113.3 ± 48.8 37.6 ± 9.0 0 157.8 ± 48.8 49.1 ± 10.7 one 195.4 ± 58.4 49.9 ± 13.9 one 220.2 ± 61.1 58.1 ± 12.9 2 249.5 ± 61.0 58.9 ± 14.4 2 251.6 ± 60.9 63.1 ± 14.6 3 285.0 ± 66.0 65.4 ± 16.3 2,5 282.7 ± 65.3 68.0 ± 14.7 four 290.6 ± 65.5 66.2 ± 16.0 3 290.8 ± 59.7 69.4 ± 15.6 5 298.9 ± 81.1 67.3 ± 16.7 3,5 290.9 ± 70.6 69.6 ± 15.7 6 280.0 ± 70.7 67.7 ± 17.5 four 297.3 ± 71.3 71.3 ± 15.3 9 244.9 ± 58.4 63.9 ± 16.8 4,5 305.2 ± 75.2 72.8 ± 15.6 12 226.0 ± 70.2 59.8 ± 17.2 5 281.8 ± 65.5 69.1 ± 15.7 16 209.4 ± 73.4 57.3 ± 14.8 6 262.8 ± 55.5 67.4 ± 17.3 twenty 161.5 ± 68.9 47.9 ± 12.1 7 243.9 ± 60.2 64.9 ± 15.2 24 119.9 ± 59.1 37.1 ± 8.9 9 198.0 ± 54.4 57.0 ± 12.8 12 154.6 ± 47.8 46.2 ± 10.5 13 203.5 ± 55.4 53.2 ± 12.8 fourteen 260.7 ± 54.2 63.7 ± 15.0 14.5 307.2 ± 59.9 72.2 ± 16.5 fifteen 303.7 ± 60.5 73.2 ± 17.1 15,5 290.7 ± 54.3 71.3 ± 16.8 16 289.0 ± 54.6 72.1 ± 15.6 16.5 276.4 ± 53.2 72.1 ± 16.8 17 267.6 ± 55.2 71.6 ± 16.8 eighteen 244.6 ± 58.4 68.2 ± 15.0 19 237.1 ± 59.4 66.4 ± 14.8 21 201.5 ± 52.7 57.9 ± 12.0 24 156.9 ± 49.9 49.6 ± 10.1

The scope of the present invention is not limited to the specific embodiments disclosed in these examples, which are intended to illustrate the most preferred embodiments of the invention. Indeed, various modifications of the invention or other embodiments that are functionally equivalent to those shown and described herein become apparent to those skilled in the art and are intended to protect the appended claims.

Here, a number of references were used, which are fully included in this description.

Although various examples of combined elements according to the invention have been described, it is also clear that they are not exhaustive and the features of one embodiment may be combined with the features of another, and such other combinations are considered within the scope of the invention disclosed herein.

Claims (14)

1. A solid dosage composition for treating pain, comprising: a core comprising an active pharmaceutical ingredient and a matrix, and a coating comprising a physical mixture of polyvinyl acetate, polyvinylpyrrolidone and an active pharmaceutical ingredient, where the active pharmaceutical ingredient and the core matrix are connected in such a way that the release of the pharmaceutical ingredient from the core matrix is controlled, while the release of the active ingredient in the core from the composition is slower than the release of the active pharmaceutical ingredient in the shell matrix; moreover, the active pharmaceutical ingredient of the core and shell is the same and is a tramadol, or its stereoisomer, or a pharmaceutically acceptable salt. 2. The composition according to claim 1, which has the following in vitro dissolution rate when measured using a USP Type 1 device at 50-150 rpm in 50 mm phosphate buffer at pH 6.8: from 10 to 40 wt.% tramadol is released from the composition between 0 and 2 hours of measurement, from 30 to 60 wt.% of tramadol is released from the composition between 2 and 7 hours of measurement, from 50 and 80 wt.% of tramadol is released from the composition between 7 and 12 hours of measurement, and from 80 to 100 wt.% Tramadol is released from the composition after 20 hours of measurement 3. The composition according to claim 1 or 2, which, upon administration of a single dose, provides an average plasma concentration of tramadol of at least 100 ng / ml for 2 hours after administration and continues to provide an average plasma concentration of tramadol of at least 100 ng / ml for at least 22 hours after administration. 4. The composition according to any one of the preceding paragraphs, in which tramadol is present in the nucleus in an amount of from 30 to 50 wt.% The total mass of the nucleus. 5. The composition according to any one of the preceding paragraphs, in which tramadol is present in the shell in an amount of from 15 to 40 wt.%. 6. The composition according to any one of the preceding paragraphs, in which the polyvinyl acetate present in the shell has a molecular weight in the range from 100,000 to 1,000,000. 7. The composition according to any one of the preceding paragraphs, in which the polyvinylpyrrolidone present in the shell has a molecular weight in the range from 10,000 to 100,000. 8. The composition according to any one of the preceding paragraphs, in which the shell further comprises xanthan gum. 9. The composition according to any one of the preceding paragraphs, in which the core matrix is a crosslinked high amylose starch. 10. The composition according to any one of the preceding paragraphs, in which the tramadol present in the core has a solubility greater than 500 g / L. 11. The composition according to any one of the preceding paragraphs, in which the tramadol present in the shell has a solubility greater than 500 g / L. 12. The composition according to any one of the preceding paragraphs, which is an oral pharmaceutical composition for the controlled release of tramadol, or its stereoisomer, or its pharmaceutically acceptable salt, administered once a day, where, at the initial administration of a single dose, the composition provides an average plasma concentration of tramadol according to at least 100 ng / ml for 2 hours after administration and continues to provide an average plasma concentration of tramadol of at least 100 ng / ml for at least 22 hours after administration and I. 13. The composition of claim 12, wherein the average maximum plasma concentration (C _max ) is less than the average plasma concentration obtained 24 hours after administration (C _24h ) taken 2.2 times. 14. A tablet comprising a composition according to any one of the preceding paragraphs.

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