JP2006507277A - 24 hour sustained release tramadol formulation - Google Patents

Abstract

A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, said composition providing an onset of analgesia within 2 hours upon administration of the first dose, Compositions are provided in which analgesic activity lasts at least 24 hours after administration.

Description

  The present invention relates to a novel once-daily oral pharmaceutical composition intended to control the release of tramadol and its salts.

(Tramadol pharmaceutical formulation)
Hydrochloric acid (HCl) tramadol was developed by Grunenthal, Germany. It has been sold as Altram® in Germany since 1977 (e.g. Tramalil) and since 1995 in the United States. Due to the efficacy and safety profile of tramadol hydrochloride, it is suitable for long-term administration for chronic pain.

Tramadol hydrochloride is a synthetic central nervous system analgesic that has been shown to be effective in a variety of acute and chronic pain conditions. In particular, both fast-release and delayed-release dosage forms of tramadol hydrochloride, together with non-steroidal anti-inflammatory (NSAID) (Roth SH. "Efficacy and safety of tramadol HCI
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.), Proven to reduce pain caused by osteoarthritis. Tramadol hydrochloride is almost completely absorbed after oral administration, and most is metabolized. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfonation in the liver. The only pharmaceutically active metabolite is mono-O-desmethyltramadol (M1), which has a 200-fold 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
Proc. gth World Congress on Pain, Vienna, 1999). In healthy humans, tramadol is a polymorphic enzyme cytochrome P450.
It is demethylated by 2D6 (CYP2D6) and converted to the M1 metabolite.

  The mechanism of action of tramadol hydrochloride has not been fully elucidated. Animal models indicate that the drug (and its M1 metabolite) acts as an opioid agonist, which appears to be due to selective activity at the μ-receptor. In addition to opioid agonist activity, tramadol hydrochloride also shows reuptake inhibition of certain monoamines (norepinephrine, serotonin) that appear to contribute to the analgesic action of drugs. In several studies involving animals and humans, the analgesic effect of tramadol hydrochloride is only partially antagonized by naloxene. Furthermore, although the opioid agonist activity of the drug has suggested that tramadol hydrochloride is addictive, its abuse potential appears to be low, and tramadol hydrochloride is subject to the Federally Regulated Drug Act of 1970. It is not a “regulatory object” as a designated drug.

  Rapid release formulations of tramadol hydrochloride are known in the art. Such formulations, however, require frequent administration to obtain effective analgesia. Lack of compliance when performing high-dose therapy may result in inconsistent plasma drug concentrations and thus inconsistent analgesia. Twice daily formulations are available and are preferred over immediate release formulations because they provide longer analgesic duration after administration and require less frequent administration. A once-daily formulation is more preferred for improving efficacy, safety and convenience.

  A decisive factor affecting the absorption rate of the active pharmaceutical ingredient by the body after oral administration in the form of a tablet or other solid dosage form, and thereby affecting safety and efficacy, is its dosage form after ingestion. The release rate of the active pharmaceutical ingredient from

  Therefore, it forms the basis of so-called controlled release, long release, sustained release or long acting pharmaceutical formulations designed to provide slow and uniform release and absorption of active pharmaceutical ingredients over hours, weeks or months The ability of the dosage form component to control the release rate. The advantages of such controlled-release formulations are that patient compliance is often reduced because the required number of doses of the drug is reduced compared to conventional immediate release dosage forms, and stable drug concentrations are maintained. Thus, the therapeutic effect is maintained over a set time, and the incidence and intensity of undesirable side effects of the active ingredient caused by the high plasma concentration occurring after administration of the immediate release dosage form.

Many materials have been proposed and developed as a base for the purpose of controlling the release of active pharmaceutical ingredients. These include polymeric materials such as, for example, polyvinyl chloride, polyethylene amides, ethyl cellulose, silicon and poly (hydroxymethyl methacrylate). For example, US Pat. No. 3,087,860 to Endicott et al., US Pat. No. 2,987,445 to Levesque et al., Pharm.
Acta Helv. 55,174-182 (1980), Korsmeyer's
Diffusion Controlled Systems: Hydrogels, Polymers for Controlled Drug Delivery, Tarcha CRC
Press, Boca Raton, Fla. USA (1991) Chapter 2 pages 15-37, and Buri et al., Pharm.
See Acta Helv. 55, 189-197 (1980).

  High amylose starch is also used for the purpose of controlled release, and cross-linked high amylase starch has been put to practical use particularly with recent progress. For example, U.S. Pat. No. 6,284,273 (Lenaerts et al.) Published on Sep. 4, 2001 and 6,419,957 (Lenaerts et al.) Published on Jul. 16, 2002 are: A solid controlled release oral pharmaceutical dosage unit in the form of a tablet comprising a dry powder of a drug and a powder of cross-linked high amylose starch, wherein the cross-linked high amylose starch comprises about 10-60% amylopectin and about 40-90% by weight A dosage unit is taught which is a base comprising a mixture of amyloses. US Pat. No. 6,607,748 (Lenaerts et al.), Published August 19, 2003, describes a process for producing a cross-linked high amylose starch known by the name of Contramid. Sustained release formulations are well known in the art.

  Prolonged release and controlled release formulations for tramadol hydrochloride have been proposed, US Patent Publication No. 2003/0143270 (Deboeck et al.) Published July 31, 2003, US Pat. No. 6,254 published July 3, 2001. , 887 (Miller et al.), US Patent Publication No. 2001/0036477 (Miller et al.) Published on November 1, 2001, US Pat. No. 6,326,027 (Miller et al.) Published on December 4, 2001. Examples are described in US Pat. No. 5,591,452 (Miller et al.) Published Jan. 7, 1997 and European Patent No. 1 190 712 (Vanderbist) published Mar. 27, 2002. .

  Although there are several controlled release tramadol hydrochloride formulations called once-daily formulations on the market, none of these have been successfully replaced with twice-daily tramadol hydrochloride formulations.

A paper that presents comparative data between the tramadol hydrochloride formulation presumed to be "once a day" and the immediate-release tramadol hydrochloride formulation: 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, 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 has been published.

(Adverse events caused by administration of tramadol hydrochloride)
The most frequently reported side effects of tramadol in clinical trials in the United States are constipation, nausea, dizziness / vertigo, headache, somnolence and vomiting. These are the adverse effects of typical opioid drugs. Seizures and anaphylactoid reactions have also been reported, but the incidence of seizures in patients receiving tramadol hydrochloride is estimated to be less than 1% (Kazmierczak, R. and Coley, K .: "Doctor
letters on prescribing: evaluation of the use of tramadol HCI. "Formulary
32: 977-978, 1997).

  Adler et al., Described above, report the results of a clinical trial comparing a once-daily tramadol formulation and an immediate-release tramadol in the treatment of osteoarthritis pain. The authors report similar adverse event profiles for patients in both treatment groups. Table 2 of Adler et al. Shows that the percentage of patients discontinued due to adverse events in the once daily group is higher than in the other groups.

  In the above-mentioned Bodalia et al., The authors report that the tolerability of 150 mg once daily, 200 mg once daily and 3 times 50 mg normal release tramadol formulation is about the same. However, this paper does not contain any information on how to produce a “once daily” formulation and the article does not disclose any pharmacokinetic data after a single dose.

  Citation or identification of any reference in this section shall not be construed as an admission that such reference is available as prior art to the present invention.

  It is an object of the present invention to provide an improved sustained release tramadol formulation that is effective for 24 hour analgesia.

  According to one aspect of the present invention, the composition provides onset of analgesia within 2 hours upon administration of the first dose, and this analgesia lasts at least 24 hours after administration or tramadol or a salt thereof A once-daily oral pharmaceutical composition for controlled release of is provided.

  In accordance with another aspect of the present invention, a once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, wherein the composition is administered within the first 2 doses within 2 hours of administration. Provides a mean plasma concentration of at least 100 ng / ml and continues to result in a mean plasma concentration of at least 100 ng / ml for at least 22 hours after administration.

In an embodiment of the present invention, a once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, wherein the composition is administered within the first two doses within 2 hours of administration. Provides an average plasma concentration of at least 100 ng / mL and continues to provide an average plasma concentration of at least 100 ng / mL for at least 22 hours after administration, and an average maximum plasma concentration (C _max ) obtained 24 hours after administration Compositions are provided that are less than 2.2 times the average concentration (C _24h ).

  The term “λz” is an apparent final disappearance rate constant calculated from the slope of the regression in the log-linear phase.

The term “AUC _0-Tmax ” is the average of the area under the plasma concentration-time curve from time 0 to Tmax and is used as an indicator of drug absorption or metabolite formation rate. Calculated as the arithmetic mean of the area under the plasma concentration-time curve from time 0 to _Tmax calculated for each participant in the bioavailability study.

The term “AUC _0-∞ ” is the average of the area under the plasma concentration-time curve extrapolated to infinite time. Calculated as the arithmetic mean of the area under the plasma concentration-time curve extrapolated from time 0 to infinite time, calculated for each participant in the bioavailability study.

  For the purposes of the present invention, the term “analgesic effect” is defined as providing an average tramadol plasma concentration of at least about 100 ng / mL.

  For the purposes of the present invention, the term “C′max” is the highest measured plasma concentration, calculated as the average of each highest plasma concentration.

  For the purposes of the present invention, the term “controlled release” means that the release rate of the active pharmaceutical ingredient from the formulation does not depend solely on the concentration of the active pharmaceutical ingredient remaining in the formulation and / or the solubility of the active pharmaceutical ingredient in the medium surrounding the formulation, And the time course and / or location of the release of the main component from the pharmaceutical formulation is defined as an oral drug delivery method selected to achieve a therapeutic or convenience objective not provided by conventional dosage forms.

  The term “half-life” is the apparent final elimination half-life.

  The term “HVD” is the half-time, ie the time over which the tramadol concentration exceeds half C′max. This parameter is an indicator of the shape of the plasma concentration time curve.

  For the purposes of the present invention, the term “first dose” refers to the first dose of the formulation containing the active ingredient administered to the patient or subject or the first dose administered to the patient or subject after an appropriate washout period. Is defined.

  The term “MRT” is the mean residence time, which is an approximation of the mean time that a tramadol molecule will stay in the body after oral administration.

For the purposes of the present invention, the term “mean maximum plasma concentration” (C _max ) is defined as the highest mean plasma concentration.

  For the purposes of the present invention, the term “mean plasma concentration” is defined as the arithmetic mean of plasma concentrations.

The term “t _max ” is the time at which C _max is achieved.

The term “T _max ” is the time at which the highest blood concentration was observed for each participant in the bioavailability study.

  The term “Rstart” is the time at which the plasma concentration begins to drop in a log-linear form, ie the time at which drug absorption or metabolite formation is complete.

  The word “tramadol” as used herein refers to tramadol, its stereoisomers, and pharmaceutically acceptable salts thereof.

  For the purposes of this specification, the term “steady state” means that the drug disappearance rate and the drug input rate are consistent after multiple doses and the plasma drug concentration is approximately between each dose at a given time between doses. Defined as the same state.

(Central lock)
The central tablet of the tablet of the present invention comprises at least one main component and a base, which are related to regulate the release of the pharmaceutical ingredient from the base. In a specific embodiment, the center tablet base is known by the name of Contramid and is a cross-linking described recently in US Pat. No. 6,607,748 (Lenaerts et al.) Published on August 19, 2003. High amylose starch. A preferred formulation in the context of the present invention is provided in the specification of US Pat. No. 6,607,748.

  Preferably, the central tablet is mixed with the ingredients (in the form of granules or powder) and then the mixture is compressed to form the central tablet, after which a coating is formed on top of it. The weight of the central tablet may be any percentage from 10% to 80% of the total weight of the composition. The preferred percentage depends inter alia on the total dose of the drug. In a specific embodiment further described below, the tablet comprises 100 mg of tramadol hydrochloride and the central tablet is about 26% of the tablet by total weight. In another embodiment, the tablet comprises 200 mg tramadol hydrochloride and the central tablet comprises about 33% of the total tablet weight. In another embodiment, the tablet comprises 300 mg tramadol hydrochloride and the central tablet contributes about 33% of the total tablet weight.

(Main ingredient in the center lock)
The active pharmaceutical ingredient is present in the central tablet of the composition of the present invention. Suitable pharmaceutical ingredients of the present invention are any ingredients that are desired to be delivered in the form of a sustained release formulation. The comprehensive list of suitable drugs is The
It can be confirmed in the Merck Index 12th edition. Preferably, the pharmaceutical ingredient is isonicotinic acid hydrazide, sodium salicylate, pseudoephedrine hydrochloride, pseudoephedrine sulfate, acetaminophen or diclofenac sodium, verapamil, glipizide, nifedipine, felodipine, betahistine, albuterol, acribastine, omeprazole, misoprostol, tramadol Trademark), oxybutynin, trimebutine, ciprofloxacin and salts thereof, but is not limited thereto. In addition, drugs include antifungal agents such as ketoconazole, acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisal, naproxen, ketorolac, diclofenac, tolmetine, sulindac, phenacetin, piroxicam, mefenamic acid, dextromethorphan, etc. Other analgesics, other non-steroidal anti-inflammatory drugs such as salicylic acids, pharmaceutically acceptable salts thereof or mixtures thereof. Prodrugs are part of the present invention.

The solubility of the drug in the aqueous solution can vary widely. The solubility of the drug in water is less than 10 ⁻³ g / L, 10 ⁻³ g / L or more, 10 ⁻² g / L or more, 10 ⁻¹ g / L or more, 1 g / L or more, 10 g / L or more, 100 g / L L or more, 500 g / L or more, 1000 g / L or more, or 2000 g / L or more may be sufficient. Preferably, the solubility is 100 g / L or more. More preferably, the solubility is 500 g / L or more. Most preferably, the solubility is 1000 g / L or more.

  The drug can meet a variety of dosing conditions. For example, the drug administration condition is less than 1 mg / dosage unit, 1 mg / dosage unit or more, 10 mg / dosage unit or more, 100 mg / dosage unit or more, 200 mg / dosage unit or more, 300 mg / dosage unit or more, 400 mg / dosage unit or more, 500 mg / Dose unit or more, or 1000 mg / dose unit or more. Preferably, the drug is 50 mg / dosage unit or more. More preferably, the drug is 100 mg / dosage unit, or more, such as 150 mg / dosage unit, alternatively 200 mg / dosage unit, alternatively 250 mg / dosage unit, alternatively 300 mg / dosage unit, or more.

  A specific embodiment is a central tablet containing tramadol hydrochloride, wherein the central tablet is about 10% to 90% of the total tramadol present in the tablet, for example about 45 mg of a 100 mg titer tablet (total 45% in tablet). %), Or a central tablet containing 90 mg of a 200 mg titer tablet (45% of the total amount in the tablet), or about 151 mg of a 300 mg titer tablet (50% of the total amount in the tablet).

(Base lock base)
The release of the active pharmaceutical ingredient located in the central tablet from the formulation is slower than the release of the active pharmaceutical ingredient located in the base of the coating. A preferred base for the center tablet is a cross-linked high amylose starch known by the name of Contramid and described in US Pat. No. 6,607,748. In a specific embodiment, the base comprises from about 10% to about 90% of the weight of the central tablet, i.e. the ratio (w / w) of the central tablet base to the main component of the central tablet is about 0.1. To about 10, alternatively about 0.2 to about 9, alternatively about 0.2 to about 8, alternatively about 0.3 to about 7, alternatively about 0.4 to about 6, alternatively about 0.5 to about 5, or From about 0.6 to about 4, alternatively from about 0.7 to about 4, alternatively from about 1 to about 4, alternatively from about 1 to about 3, and from about 1.5 to 2.5. In one specific embodiment, the central tablet is about 90 mg total, of which about 44 mg is contramid and about 45 mg is tramadol hydrochloride. Thus, in these examples, Contramid comprises about 49% by weight of the central tablet.

(Optional ingredients)
The central tablet composition of the present invention can optionally contain a pharmaceutically acceptable carrier or medium. Such carriers or media are well known to those skilled in the art and are identified, for example, in Remingtons's Pharmaceutical Sciences, 14th Edition (1970). Examples of such carriers or media include lactose, starch, dicalcium phosphate, calcium sulfate, kaolin, mannitol and powdered sugar. Furthermore, if necessary, suitable binders, lubricants, and disintegrants can be included. If desired, sweeteners or flavors as well as pigments can be included.

  The components of the core tablet of the present invention are dispersants such as microcrystalline cellulose, starch, crosslinked starch, crosslinked poly (vinyl pyrrolidone), and sodium carboxymethylcellulose, flavoring agents, coloring agents, binders, preservatives, surfactants. A subcomponent including, but not limited to can be optionally contained.

  The center lock can also optionally include one or more suitable binders well known to those skilled in the art.

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

Appropriate lubricants such as those well known to those skilled in the art may be included.
For example, magnesium stearate, vegetable oil, talc, sodium stearyl fumarate, calcium stearate, stearic acid and the like.

  Suitable fluidizing agents well known in the art can also be included. Examples of such fluidizers include, but are not limited to, talc and colloidal silicon dioxide.

(Percentage)
The active ingredient is about 1 to about 90% by weight of the total weight of the central tablet, preferably about 10 to about 70% by weight of the total composition of the central tablet, more preferably about 20 to about 60% by weight of the total composition of the central tablet. And perhaps most often at levels ranging from about 30 to about 50% by weight of the total composition of the central tablet.

  Of course, the total amount of all ingredients is 100% by weight, and one skilled in the art can vary the amounts within the stated ranges to obtain a useful composition.

(coating)
The dosage form coating comprises a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone, and the active pharmaceutical ingredient of the coating. The coating can include cross-linked high amylose starch such as, for example, contramid and other optional ingredients. In a preferred embodiment, the coating is formed by a dry compression method. The weight of the coating can be any percentage from about 10% to about 90% of the total weight of the composition, but it is preferably a larger portion within this range. Thus, the coating is typically from about 20% to about 90% (w / w) of the tablet of the present invention, alternatively from about 25% to about 90%, alternatively from about 30% to about 85%, alternatively from about 35% to about 85%, or About 40% to about 85%, alternatively about 45% to about 85%, alternatively about 45% to about 90%, alternatively about 50% to about 90%, about 50% to about 85%, alternatively about 55% to about 90% %, Or about 55% to about 85%, alternatively about 55% to about 80%, alternatively about 60% to about 90%, alternatively about 60% to about 85%, alternatively about 60% to about 80%, alternatively about 60% % To about 75%, alternatively about 65% to about 90%, alternatively about 65% to about 85%, alternatively about 65% to about 80%, alternatively about 65% to about 75%, alternatively about 65% to about 70% Rui make up about 75 percent. The coating often includes an optional binder.

(Coating polyvinyl acetate and polyvinylpyrrolidone)
The weight percent of the polyvinyl acetate / polyvinylpyrrolidone mixture in the coating can be any of a wide range of values. Depending on the solubility of the major component in the coating in water, the amount of the polyvinyl acetate / polyvinylpyrrolidone mixture in the coating can be adjusted. US Patent Publication No. 2001/0038852 describes how such an adjustment can be made. For example, for a water soluble to very soluble main component, the polyvinyl acetate / polyvinyl pyrrolidone mixture is about 20 to about 80%, preferably about 30 to about 65%, or about 40 to about 50% by weight of the coating. It can be. In the specific embodiment shown below, Kollidon ^™ SR comprises about 45% of the weight of the coating, where tramadol hydrochloride is about 31% by weight and xanthan gum is about 23%. As described in US Patent Publication No. 2001/0038852, the amount of polyvinyl acetate / polyvinyl pyrrolidone mixture is often less for those components that are slightly less soluble in water to less soluble.

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

  The molecular weight of the polyvinyl acetate component in the polyvinyl acetate / polyvinylpyrrolidone mixture can take a wide numerical range. Preferably, the average molecular weight of the polyvinyl acetate is from about 100 to about 10,000,000, alternatively from about 1,000 to about 1,000,000, alternatively from about 10,000 to about 1,000,000, alternatively about 100, 000 to about 1,000,000, alternatively about 450,000.

  The molecular weight of the polyvinylpyrrolidone component in the polyvinyl acetate / polyvinylpyrrolidone mixture can take a wide numerical range. The average molecular weight of polyvinylpyrrolidone is from about 100 to about 10,000,000, alternatively from about 1,000 to about 1,000,000, alternatively from about 5,000 to about 500,000, alternatively from about 10,000 to about 100,000. Alternatively, it can be about 50,000.

  The polyvinyl acetate and polyvinyl pyrrolidone mixture can be prepared by various methods such as simply mixing polyvinyl pyrrolidone and polyvinyl acetate powder. In a preferred embodiment, such a mixture is a powder obtained by spray drying colloidally dispersed polyvinyl acetate and polyvinylpyrrolidone. Optionally, sodium lauryl sulfate is used as a stabilizer to prevent agglomeration during spray drying and / or colloidal silica is used to improve the flowability of the polyvinyl acetate / polyvinylpyrrolidone mixture. Polyvinyl acetate and polyvinylpyrrolidone can arbitrarily form a random or block copolymer.

(Optional ingredients)
Binders suitable for the present invention include, but are not limited to, plant extracts, gums, synthetic or natural polysaccharides, polypeptides, alginic acids, synthetic polymers or mixtures thereof.

  Suitable plant extracts used as a gelling agent include, but are not limited to, agar, ispacula, psyllium, quince, carob, or mixtures thereof.

  Suitable gums used as gelling agents include, but are not limited to, xanthan gum, guar gum, gum arabic, Indian gum, karaya gum, tragacanth gum or mixtures thereof.

  Suitable synthetic or natural hydrophilic polysaccharides used as gelling agents are hydroxyalkyl cellulose, cellulose ether, cellulose ester, nitrocellulose, dextrin, agar, carrageenan, pectin, flucellaran, starch or starch derivatives, cross-linked high amylose starch, or Including but not limited to the mixture.

  Suitable polypeptides used as gelling agents include, but are not limited to gelatin, collagen, polyserine or mixtures thereof.

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

  Suitable synthetic polymers for use as gelling agents include, but are not limited to, carboxyvinyl polymers, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, copolymers of ethylene oxide and propylene oxide, and copolymers or mixtures thereof. It is not limited to.

In a preferred embodiment, the gelling agent is a gum such as xanthan gum, guar gum, gum arabic, Indian gum, karaya gum, tragacanth gum or mixtures thereof, PEO 7,000,000 and HPMC.
K100M.

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

(Main drug in coating)
Suitable active pharmaceutical ingredients of the present invention are any active ingredients that are desired to be delivered in a sustained release dosage form. The comprehensive list of suitable drugs is The
It can be confirmed in the Merck Index 12th edition. Preferably, the drug is isonicotinic acid hydrazide, sodium salicylate, pseudoephedrine hydrochloride, pseudoephedrine sulfate, acetaminophen or diclofenac sodium, verapamil, glipizide, nifedipine, felodipine, betahistine, albuterol, acribastine, omeprazole, misoprostol, tramadol ), Oxybutynin, trimebutine, ciprofloxacin and salts thereof, but not limited thereto. In addition, drugs include antifungal agents such as ketoconazole, acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisal, naproxen, ketorolac, diclofenac, tolmetine, sulindac, phenacetin, piroxicam, mefenamic acid, dextromethorphan, etc. Other analgesics, other non-steroidal anti-inflammatory drugs such as salicylic acids, pharmaceutically acceptable salts thereof or mixtures thereof.

The solubility of the drug in the aqueous solution can vary widely. The solubility of the drug in water is less than 10 ⁻³ g / L, 10 ⁻³ g / L or more, 10 ⁻² g / L or more, 10 ⁻¹ g / L or more, 1 g / L or more, 10 g / L or more, 100 g / L L or more, 500 g / L or more, 1000 g / L or more, or 2000 g / L or more. Preferably, the solubility is 100 g / L or more. More preferably, the solubility is 500 g / L or even 1000 g / L or more.

  The drug can meet a variety of dosing conditions. For example, the drug administration condition is less than 1 mg / dosage unit, 1 mg / dosage unit or more, 10 mg / dosage unit or more, 100 mg / dosage unit or more, 200 mg / dosage unit or more, 300 mg / dosage unit or more, 400 mg / dosage unit or more, 500 mg / More than the dosage unit, or 1000 mg / dose unit or more. Preferably, the drug is 50 mg / dosage unit or more. More preferably, the drug is 100 mg / dosage unit or more. Most preferably, the drug is 200 mg / dosage unit or more.

  The coating is from about 5% to about 90% by weight of the active pharmaceutical ingredient (api), or from about 5% to about 80% by weight, or from about 10% to about 70% by weight, or api weight From about 10% to about 60%, or from about 15% to about 50% by weight, or from about 15% to about 45% by weight, from about 15% to about 40% by weight, or from about 20% by weight. % To about 35%, or about 20% to about 30% by api weight.

  In the specific embodiment shown below, the weight of tramadol derived from 100 mg tramadol tablets is about 21% of the weight of the coating. The weight of tramadol from the 200 mg tablet is about 31% of the weight of the coating. The weight of tramadol from the 300 mg tablet is about 30% of the weight of the coating.

(Administration route)
The tablet composition of the present invention can be administered by many routes including, but not limited to, oral, sublingual and rectal. The preferred route of administration of the composition of the present invention is oral.

Compositions of the invention suitable for oral administration may be provided as discrete units such as tablets or granules. Preferably, the composition of the present invention is provided in the form of a tablet. Such tablets may be formed by compression or molding as is conventional. Compressed tablets may be prepared by compressing a mixture of one or more of the above-described components in a suitable machine. Molded tablets may be made by punching out the above ingredients in a suitable machine and can be appropriately moistened with an inert liquid diluent. The tablets may be coated as appropriate and / or with other identifying markings visible to the consumer. Further, the tablet can be in various forms such as a naked tablet, a dry coat tablet and a film coat tablet. Tablets can also have a variety of shapes (eg, oval, spherical, etc.) and sizes. A comprehensive discussion of tablets is given by The
Theory and Practice of Industrial Pharmacy, 3rd edition (Lea &
Febiger, 1986).

(Dissolution profile of sustained release composition)
The active ingredient of the composition is the following in when measured with a USP Type I apparatus in 50 mM phosphoric acid pH 6.8 and with stirring at 50 to 150 rpm:
In vitro dissolution profile is shown: when tested in vitro in 50 mM phosphoric acid pH 6.8 using a USP Type I apparatus and stirring at 50 to 150 rpm, the drug is 10% to 30% per hour between 0 and 2 hours. 10% to 40% of the drug is released from the formulation when measured from 0 to about 2 hours, and about 30 to 60% of the drug is released from the formulation when measured from 2 to about 7 hours. About 50% to 80% of the drug is released from the preparation at the measurement after about 12 hours, and about 80% to 100% of the drug is released from the preparation at the measurement of about 20 hours, or more preferably measurement for 2 hours 15% to 35% of the drug is released from the preparation during this period, and about 40% to 60% of the drug is released from the preparation during the measurement time of 7 hours. About 60% to 80% of the drug is released and about 85% to 100% of the drug is released from the formulation at the measurement after about 20 hours, or 20% to 40% from the formulation during the 2 hour measurement. The drug is released, about 40% to 60% of the drug is released from the formulation during the 7 hour measurement, about 60% to 80% of the drug is released from the formulation during the 12 hour measurement, and after about 20 hours About 85% to 100% of the drug is released from the preparation at the time of measurement.

  The present invention may be understood more readily by reference to the following examples, which are given to illustrate but not to limit the scope of the invention.

  The cross-linked high amylose starch used in these examples is formed by a method that includes a procedure of cross-linking and chemically modifying, followed by gelatinization and drying. Such a method is described in more detail in US Pat. No. 6,607,748 (Lenaerts et al.) Published on August 19, 2003, known on the market under the name Contramid®, and Examples 1 and 2 are described.

Example 1
(A. Cross-linking)
High amylose starch (Cl AmyloGel 03003) (3.0 kg) containing about 70% w / w amylose is charged to the reactor. To this reactor is added water (55.0 L) containing sodium hydroxide (33.0 g) and sodium sulfate (2.40 kg). The resulting slurry is heated to a temperature of 30 ° C. Phosphorous oxychloride (22.5 g) is added to the reaction mixture and allowed to react for 1 hour.

(B. Chemical modification, hydroxypropylation)
Transfer the crude reaction mixture from Section A to a hydroxypropylation reactor. The reaction mixture is heated at 40 ° C. for 30 minutes and the reaction is further purged with nitrogen. After complete purging, propylene oxide (1.80 kg) is added. The reaction mixture is held at 40 ° C. for 20 hours. The reaction mixture is neutralized to pH 5.5 with 0.1N H2S04 (1: 2 v / v). The starch slurry is washed in a basket centrifuge with a centrifugal speed of 1200 rpm. The resulting starch cake is reslurried with 35 L of water and centrifuged a second time. The resulting starch cake is dried in a flash dryer at an inlet temperature of 160 ° C and an outlet temperature of 60 ° C.

(C. Gelatinization)
The modified granular starch cake is diluted with deionized water to form a slurry with a concentration of about 8% calculated on dry matter. The specific gravity of the produced slurry with respect to water is 1.032 kg / L. Adjust the pH of the modified starch slurry to 6.0. Next, the slurry is directly vapor injected (Schlick
Heat to 160 ° C according to Model 825). Temperature variation does not exceed 1 ° C. The slurry is held for 4 minutes in a holding column at a temperature of 160 ° C. and a pressure of 5.5 bar. The pressure is then reduced to atmospheric pressure by passing a flash. The slurry is then held in a holding tank at 95 ° C.

(D. Spray drying)
Drying the slurry from Section C using a NiroFSD4 spray drying tower equipped with a 0.8 mm nozzle and fed at 10 L / hr. The inlet temperature is fixed at 300 ° C. and the outlet temperature is fixed at 120 ° C. The resulting powder is a controlled release excipient having the following characteristics:

(Example 2)
(A. Cross-linking)
High amylose starch (Cl AmyloGel 03003) (3.0 kg) containing about 70% w / w amylose is charged to the reactor. To this reactor is added water (55.0 L) containing sodium hydroxide (33.0 g) and sodium sulfate (2.40 kg). The resulting slurry is heated to a temperature of 30 ° C. Sodium trimetaphosphate (45 g) is added to the reaction mixture and allowed to react for 1 hour.

(B. Chemical modification, hydroxypropylation)
Transfer the crude reaction mixture from Section A to a hydroxypropylation reactor. The reaction mixture is heated at 40 ° C. for 30 minutes and the reaction is further purged with nitrogen. After complete purging, propylene oxide (1.80 kg) is added. The reaction mixture is held at 40 ° C. for 20 hours. Neutralize the reaction mixture to pH 5.5 with 0.1 NH ₂ SO ₄ (1: 2 v / v). The starch slurry is washed in a basket centrifuge with a centrifugal speed of 1200 rpm. The resulting starch cake is reslurried with 35 L of water and centrifuged a second time. The resulting starch cake is dried in a flash dryer at an inlet temperature of 160 ° C and an outlet temperature of 60 ° C.

(C. Gelatinization)
The modified granular starch cake is diluted with deionized water to form a slurry with a concentration of about 8% calculated on dry matter. The specific gravity of the produced slurry with respect to water is 1.032 kg / L. Adjust the pH of the modified starch slurry to 6.0. Next, the slurry is directly vapor injected (Schlick
Heat to 160 ° C according to Model 825). Temperature variation does not exceed + 1 ° C. The slurry is held for 4 minutes in a holding column at a temperature of 160 ° C. and a pressure of 5.5 bar. The pressure is then reduced to atmospheric pressure by passing a flash. The slurry is then held in a holding tank at 95 ° C.

(D. Spray drying)
The slurry from section C is carried out using a NiroFSD4 spray drying tower equipped with a 0.8 mm nozzle and fed at 10 L / hr. The inlet temperature is fixed at 300 ° C. and the outlet temperature is fixed at 120 ° C. The resulting powder is a controlled release excipient having the following characteristics:

Love TAB O is a product sold by Penwest Pharmaceutical Co., Ltd. (Cedar Rapids, Iowa, USA). Kollidon ^TM SR is a product manufactured by BASF (Germany). Encompress ^™ is dicalcium phosphate dihydrate which can be purchased from Mandale (Patterson, NY). Tramadol hydrochloride is from Kemajis (3
Hashlosha Street, PO Box 9091, 61090, Tel Aviv, Israel). Methods for the synthesis and purification of tramadol are described, for example, in US Pat. Nos. 3,652,589, 5,414,129, 5,672,755, 5,874,620, and 5,877,351. And 6,169,205.

(Production method)
The tablets of the present invention can be manufactured according to the method generally described in the flowchart of FIG. 1 and described in more detail below.

  Weighing: Place the ingredients in a clearly labeled container.

  Premixing of central tablet: Sift a portion of contramid and colloidal silicon dioxide through a # 30 mesh sieve into a suitable container.

  Mixing the center tablet: Take a portion of Contramid (registered trademark) and put it in the mixer. Sieve the 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. Sift the hydrogenated vegetable oil type I through a # 30 mesh sieve and add to the mixer. Add the center lock premix to the blender. Place the remaining Contramid® into the blender and mix all ingredients. Sieve the magnesium stearate through a # 30 mesh sieve and add the mixture with the other ingredients. Place the mixture in a suitable container and identify as the center tablet mixture.

  Dry coating premix: Mix a portion of xanthan gum and the entire amount of colloidal silicon dioxide and sift through a # 30 mesh screen.

Dry coating mixing: Take a portion of Kollidon® SR into a blender.
Sieve the tramadol hydrochloride through a Kason separator fitted with a # 30 mesh screen 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 with a # 30 mesh sieve and add to the mixer. The dry coating premix and the rest of Kollidon® SR are placed in a blender and all ingredients are mixed. Sieve the magnesium stearate through a # 30 mesh sieve and mix with the other ingredients. Place the granules in a suitable container and identify as a dry coating mixture.

  Compression: Compressed coated tablets are produced using a Manesty Dry-Cota compressor.

(Example 3)
As shown in Table 3, formulations A, B and C were prepared according to the method described above.

The dissolution profiles of formulations A, B and C are shown in FIG.

(Tramadol once-daily formulation)
The present invention relates to a controlled release tablet composition that provides an analgesic effect within 2 hours of oral administration and lasts at least 24 hours after administration.

  Surprisingly, the 200 mg dose of the controlled release composition of the present invention provides a rapid onset of analgesia within 2 hours after oral administration, and an average tramadol plasma concentration of 100 ng / mL for at least 24 hours after a single dose. To 200 ng / mL.

  Furthermore, the average plasma tramadol concentration is maintained from 100 ng / mL to 350 ng / mL at steady state. Surprisingly, it has been shown that the controlled release composition of the present invention provides full clinical effect for at least 24 hours after oral administration.

(Bioavailability test)
One of the objectives of the present invention is to provide flexible dosing options for patients with diverse analgesic requirements with once-daily formulations.

  One embodiment of the present invention provides the desired early onset of action when taking 100 mg for the first time, but once a day it is expected to achieve an average tramadol plasma concentration of at least 45 ng / mL by 2 to 24 hours. To provide a mold formulation.

  One of the other embodiments of the present invention provides the desired early onset of action when taking 200 mg for the first time, but is expected to achieve an average tramadol plasma concentration of at least 100 ng / mL by 2 to 24 hours. To provide a one-time formulation.

  One further embodiment of the present invention provides the desired early onset of action when taking 300 mg for the first time, but is expected to achieve an average tramadol plasma concentration of at least 150 ng / mL by 2 to 24 hours per day. It is to provide a batch formulation.

  One further embodiment of the present invention provides the desired early onset of action when taking 400 mg for the first time, but once a day, which is expected to achieve an average tramadol plasma concentration of at least 180 ng / mL after 2 to 24 hours. To provide a mold formulation.

Another embodiment of the present invention is to provide a once-type daily formulation the ratio of C _'max is believed to about 0.90 is about 1.0 for the dose when ingested 1 dose initial is there.

Other embodiments of the invention would result in a tramadol plasma concentration that rises steadily to achieve a maximum tramadol concentration with a T _max of about 4 to about 6 hours when taking the first dose 1 It is to provide a once-daily formulation. Preferably, T _max occurs from about 5 hours to about 5.5 hours.

Other embodiments of the present invention are believed to result in a tramadol plasma concentration that declines slowly but consistently after _Tmax when taking the first dose, reflecting sustained absorption in addition to the disappearance process. Providing a once-daily formulation. Preferably, the decrease in tramadol plasma concentration after T _max occurs in a log-linear fashion, with an average apparent final elimination half-life of about 5.5 hours to about 6.5 hours.

Another embodiment of the present invention is the absorption of the dose taken, reflecting a slow but steady decline after T _max when taking the first dose, and sustained absorption in addition to the disappearance process. It is to provide a once-daily formulation that would result in a tramadol plasma concentration that lasts at least 20 hours longer than when it was initiated.

In another embodiment of the present invention, when taking the first dose, tramadol plasma that falls to a log-linear form after T _max and has an apparent final elimination rate constant (λz) of about 0.12 h ^−1. It is to provide a once-daily formulation that provides a concentration.

  Another embodiment of the present invention is to provide a once-daily formulation that would result in a tramadol mean residence time (MRT) of about 15 hours to about 18 hours upon taking the first dose. .

  Another embodiment of the invention provides a once-daily formulation that would result in a tramadol half-life (HVD) of about 22.5 hours to about 25.4 hours upon taking the first dose. That is.

Another embodiment of the invention is that once the first dose is taken, the ratio of C ′ _max to AUC _0-∞ will be from about 0.04 h ⁻¹ to about 0.06 h ⁻¹ once daily. To provide a mold formulation. Preferably, the ratio of C′max to AUC _0-∞ is from about 0.04 h ⁻¹ to about 0.05 h−1. The C′max / AUC _0-∞ ratio is used to evaluate drug absorption rate.

Another embodiment of the present invention is that the mean AUC _0-24 for tramadol plasma concentration increases proportionally with dose over the range of dose titers of the controlled release composition from 100 mg to 300 mg upon taking the first dose. This is to provide a once-daily formulation that seems to be.

Another embodiment of the invention provides a once-daily formulation that would result in an average AUC _0-Tmax of about 610 ng · h / mL to 630 ng · h / mL when taking the initial 100 mg It is.

Another embodiment of the present invention is to provide a once-daily formulation that would result in an AUC _0-Tmax of about 910 ng · h / mL to 920 ng · h / mL when taking the initial 200 mg. is there.

Another embodiment of the invention provides a once-daily formulation that would result in an average AUC _0-Tmax of about 1570 ng · h / mL to 1590 ng · h / mL when taking the initial 300 mg It is.

Another embodiment of the present invention is that once the first dose is taken, the average ratio of AUC _0-24 / AUC _0-∞ of tramadol plasma concentration will be about 70% to about 85% once a day. To provide a mold formulation. Preferably, the tramadol plasma concentration AUC _0-24 / AUC _0-∞ is 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 administration, depending on the administered dose.

Another embodiment of the present invention is that the dose released into the plasma during the first 24 hours when taking the first dose (ie, AUC _0-24 / AUC _{0-∞ dosed} ) To provide a once-daily formulation that would have a ratio of C′max to about 1.10 to about 1.35. Preferably, the ratio is from about 1.15 to about 0.31.

Another embodiment of the present invention provides a once-daily formulation where the ratio of C ′ _max / T _max to dose is expected to be about 0.10 to about 0.20 when the first dose is taken It is to be. Preferably, the ratio is about 0.12 to 0.19.

  Other embodiments of the invention do not appear to have a slope of ng / mL · hr units after peak plasma levels greater than about 0.035 times the total dose in mg when taking the first dose. Providing a once-daily formulation. Preferably, the coefficient is about 0.03.

  The tramadol pharmacokinetic parameters of the controlled release composition are shown in Table 4.

Another embodiment of the invention is that when the first dose is taken, the ratio of C ′ _{max to} the tramadol dose calculated for plasma O-desmethyltramadol plasma concentration is from about 0.19 to about 0.22. Probable once-daily formulation. Preferably, the ratio is about 0.20 to 0.21.

Other embodiments of the invention result in O-desmethyltramadol plasma concentrations that rise steadily to achieve the maximum tramadol concentration at a T _max of about 8 to about 16 hours when taking the first dose. Is to provide a once-daily formulation that seems to be.

Another embodiment of the present invention is the slow but constant decline after T _max when taking the first dose, which continues the tramadol absorption and subsequent metabolite formation in addition to the disappearance process. To provide a once-daily formulation that would result in a reflecting O-desmethyltramadol plasma concentration. Preferably, the decrease in O-desmethyltramadol plasma concentration occurs in a log-linear fashion with an average apparent final elimination half-life of about 6.7 hours to about 8.1 hours.

  Another embodiment of the present invention is to provide a once-daily formulation that would result in the formation of metabolites for at least 18 hours upon taking the first dose.

Another embodiment of the present invention provides a log-linear form of O-desmethyltramadol plasma concentration with an apparent final elimination rate constant (λz) of about 0.1 h ⁻¹ after T _max when taking the first dose. Is to provide a once-daily formulation that is expected to decrease.

  Another embodiment of the invention is a once-daily form that would result in an O-desmethyltramadol half-life (HVD) of about 25.6 hours to about 28.1 hours upon taking the first dose. It is to provide a formulation.

Other embodiments of the invention would have a ratio of C′max to AUC _0-∞ calculated for O-desmethyltramadol plasma concentration of about 0.04 h ⁻¹ when taking the first dose. To provide a once-daily formulation. The C ′ _max / AUC _0-∞ ratio is used to assess the rate of metabolite formation.

Another embodiment of the present invention is calculated for O-desmethyltramadol plasma concentration upon taking the first dose and is proportional to the dose over a range of dose titers of 100 mg to 300 mg of the controlled release composition. It is to provide a once-daily formulation that would result in an increasing average AUC _0-24 .

Other embodiments of the invention would provide an average AUC _0-Tmax of about 175 ng · h / mL to 180 ng · h / mL for the plasma concentration of O-desmethyltramadol upon the initial dose of 100 mg. To provide a once-daily formulation.

Other embodiments of the invention would provide an average AUC _0-Tmax of about 530 ng · h / mL to 550 ng · h / mL for the plasma concentration of O-desmethyltramadol upon the initial dose of 200 mg. To provide a once-daily formulation.

Other embodiments of the invention would provide an average AUC _0-Tmax of about 580 ng · h / mL to about 590 ng · h / mL for the plasma concentration of O-desmethyltramadol upon the initial dose of 300 mg. Providing a once-daily formulation.

Another embodiment of the invention is that the AUC _0-24 / AUC _0-∞ average ratio of O-desmethyltramadol plasma concentration will be from about 65% to about 80% when taking the first dose 1 It is to provide a once-daily formulation. Preferably, the average of AUC _0-24 / AUC _0-∞ of O-desmethyltramadol plasma concentration is about 68% to about 75%. As a result, about 25% to about 32% of active metabolites are still circulating in the plasma 24 hours after administration.

Another embodiment of the invention is the ratio of C′max calculated for the plasma concentration of O-desmethyltramadol to the plasma concentration of O-desmethyltramadol 24 hours after administration when taking the first dose (AUC). _0-24 / AUC _{0-Tmax multiplied} by the tramadol dose) is to provide a once-daily formulation that would be about 0.0025 to about 0.0035. Preferably, the ratio is from about 0.0027 to about 0.0031.

  The tramadol pharmacokinetic parameters of the controlled release composition are shown in Table 5.

Example 4
((I) dose proportionality-single dose)
A bioavailability study was performed to assess dose proportionality between the three dose titers (100 mg, 200 mg and 300 mg). This study was conducted with an appropriate washout period between each dose. 27 healthy human volunteers were administered in a fasted state.

  FIG. 3 depicts the tramadol mean plasma concentration time profile obtained from subjects after administration of the controlled release composition of the present invention (100 mg, 200 mg and 300 mg doses of tramadol hydrochloride). Data used for creating FIG. 3 is included in Table 6.

  The results from this study show that the 100 mg, 200 mg and 300 mg formulations of the controlled release composition of the present invention are dose proportional with respect to the rate and degree of absorption of tramadol and the rate and degree of formation of O-desmethyltramadol. It was.

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

(Example 5)
(Ii) Comparison with twice a day preparation-single administration)
In a comparative bioavailability study after administration in the fasted state of 24 healthy human volunteers, a 2 × 200 mg dose of the controlled release composition of the present invention was produced twice daily by Laboratories Hoechst Hode. Compared to the type formulation Topargic® LP (200 mg) tablets.

In order to assess the bioequivalence of the test product and the reference product, pharmacokinetic results from the controlled release composition of the present invention were obtained after twice daily administration of the reference formulation (12 hour intervals). Compared with the ones. Based on the calculation of the 90% confidence interval of the geometric mean ratio of the test product to the reference product, the degree of exposure (calculated from the tramadol AUC _0-t and AUC _0-∞ assessment after dose standardization) is calculated for the logarithmic transformation parameters for conventional organism It was in the range of 80 to 125%, which is the equivalence interval. Thus, it was confirmed that the controlled release composition of the present invention and the twice-daily formulation are bioequivalent for overall tramadol exposure. The results for tramadol AUC _0-∞ are shown in Table 7.

  FIG. 5 shows the results of tramadol obtained after 24 daily healthy volunteers administered the controlled release composition (Test formation) of the present invention once a day and the reference product every 12 hours. Depicts the arithmetic mean plasma concentration time course profile of. Data used for creating FIG. 5 is included in Table 8.

  FIG. 6 shows the results obtained after administering the controlled release composition (Test formation) of the present invention once a day and the reference product (Reference formation) every 12 hours for 24 healthy volunteers. -Delineate the arithmetic mean plasma concentration time course profile of desmethyltramadol. Data used for creating FIG. 6 is included in Table 9.

(Example 6)
((Iii) Comparison with twice-daily formulation-steady state)

  In a comparative bioavailability study after multiple doses in a fasted state of 26 healthy human volunteers, a 200 mg dose of the controlled release composition of the present invention produced twice daily by Laboratories Hoechst Hohde The formulation was compared to Topargic® LP (100 mg) tablets.

  The results from this test showed that the controlled release composition of the present invention was comparable to the reference 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 based on the confidence interval of the main variable AUCss for tramadol and O-desmethyltramadol for the conventional bioequivalence range of 80% to 125%. The results for tramadol AUCss are shown in Table 10.

  FIG. 7 shows tramadol and O-desmethyltramadol (Metabolite) after a 200 mg dose of the controlled release composition of the present invention once a day and a reference product (Reference formulation: topargic (r) LP100 mBID) once every 12 hours. Depicts the arithmetic mean plasma concentration time course profile of. Data used for creating FIG. 7 is included in Table 11.

  The present invention is not limited to the scope by the specific embodiments disclosed in these examples, which are intended to illustrate the most preferred embodiments of the present invention. Indeed, various modifications and other embodiments of the invention which are functionally equivalent to those shown and described herein will be apparent to those skilled in the art and are set forth in the appended claims. Intended to be a target.

  Numerous references have been cited, the entire disclosures of which are incorporated herein by reference.

  While various examples of combined elements of the present invention have been described, it is not intended to be exhaustive and it is understood that the features of one embodiment may be combined with another It is contemplated that such other combinations are intended to be within the scope of the invention as disclosed herein.

Various features and advantages of the present invention will become apparent from the more detailed description presented below with reference to the accompanying drawings.
The flowchart which shows the manufacturing method of a tablet. Formulations A, B and C dissolution profiles: in vitro performance of formulations A, B and C at 50 rpm phosphate buffer pH 6.8, 100 rpm under USP type 1 conditions. Six tablets were tested for each measurement. (I) 100 mg dose controlled release composition of the present invention (●), (ii) 200 mg dose controlled release composition of the present invention (■), and (iii) 300 mg dose controlled release composition of the present invention (▲ ) Average Tramadol plasma concentration after a single dose. Plasma O-desmethyltramadol concentration after a single dose of 100 mg (♦), 200 mg (◯), or 300 mg (Δ) titer of a tramadol formulation (A, B and C, respectively). (I) Average plasma tramadol concentration after administration of a dose of 2 × 200 mg (▲) and (ii) Tolupagic® LP 200 mg twice a day every 12 hours (Δ) of the controlled release composition of the present invention. Mean plasma O-desmethyl tramadol after a single dose of 2 × 200 mg (▲) and (ii) Tolupagic® LP 200 mg every 12 hours, twice daily (Δ) of the controlled release composition of the present invention (O-Desmethyltramadol) concentration. Mean steady state plasma tramadol and O after administration of 200 mg (● and ○) and (ii) Tolupagic® LP 100 mg every 12 hours twice daily (▲ and Δ) of the controlled release composition of the present invention -Desmethyl tramadol concentration.

Claims (32)

A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, said composition providing an onset of analgesia within 2 hours upon administration of the first dose, A composition whose analgesic effect lasts at least 24 hours after administration. A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, said composition being an average of at least 100 ng / mL within 2 hours of administration when administering the first dose A composition that provides a plasma concentration and continues to provide an average plasma concentration of at least 100 ng / mL for at least 22 hours after administration. A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, said composition being an average of at least 100 ng / mL within 2 hours of administration when administering the first dose A composition that provides a plasma concentration and continues to provide an average plasma concentration of at least 100 ng / mL for at least 23 hours after administration. A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, said composition being an average of at least 100 ng / mL within 2 hours of administration when administering the first dose A composition that provides a plasma concentration and continues to provide an average plasma concentration of at least 100 ng / mL for at least 24 hours after administration. The once-daily oral pharmaceutical composition according to claim 1, 2, 3 or 4, wherein the pharmaceutical composition comprises about 200 mg tramadol or a salt thereof. A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof comprising 100 mg of tramadol or a salt thereof, wherein the composition is administered within 2 hours of administration when the first dose is administered A composition that provides an average plasma concentration of at least 50 ng / mL and continues to provide an average plasma concentration of at least 50 ng / mL for at least 22 hours after administration. A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof comprising 100 mg of tramadol or a salt thereof, wherein the composition is administered within 2 hours of administration when the first dose is administered A composition that provides an average plasma concentration of at least 50 ng / mL and continues to provide an average plasma concentration of at least 50 ng / mL for at least 23 hours after administration. A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof comprising 300 mg of tramadol or a salt thereof, wherein the composition is administered for 2 hours from the first administration of the first dose A composition that results in an average plasma concentration of at least 150 ng / mL within and continues to result in an average plasma concentration of at least 150 ng / mL for at least 22 hours after administration. A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof comprising 300 mg of tramadol or a salt thereof, wherein the composition is administered for 2 hours from the first administration of the first dose A composition that results in an average plasma concentration of at least 150 ng / mL within and continues to result in an average plasma concentration of at least 150 ng / mL for at least 23 hours after administration. A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof comprising 300 mg of tramadol or a salt thereof, wherein the composition is administered for 2 hours from the first administration of the first dose A composition that results in an average plasma concentration of at least 150 ng / mL within and continues to result in an average plasma concentration of at least 150 ng / mL for at least 24 hours after administration. A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof comprising 200 mg of tramadol or a salt thereof, wherein when the first dose of 400 mg is administered, the composition is at least for at least 22 hours after administration A composition that provides an average plasma concentration of 200 ng / mL. A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof comprising 190 mg of tramadol or a salt thereof, wherein when the first dose of 400 mg is administered, the composition is at least for at least 23 hours after administration A composition that provides an average plasma concentration of 190 ng / mL. A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof comprising 180 mg of tramadol or a salt thereof, wherein when the initial dose is 400 mg, the composition is at least for at least 24 hours after administration A composition that provides an average plasma concentration of 180 ng / mL. The once-daily oral pharmaceutical composition according to claim 6 or 7, wherein the mean maximum plasma concentration ( _Cmax ) is less than 100 ng / mL. 6. A once-daily oral pharmaceutical composition according to claim 1, 2, 3, 4 or 5, wherein said mean maximum plasma concentration ( _Cmax ) is less than 300 ng / mL. 6. A once-daily oral pharmaceutical composition according to claim 1, 2, 3, 4 or 5, wherein the mean maximum plasma concentration ( _Cmax ) is less than 200 ng / mL. The once-daily pharmaceutical composition according to claim 1, 2, 3, 4 or 5, wherein the average maximum plasma concentration (Cmax) is an average plasma concentration (C24h) obtained 24 hours after administration. A composition that is less than 2.2 times. 11. A once-daily oral pharmaceutical composition according to claim 8, 9 or 10, wherein the mean maximum plasma concentration ( _Cmax ) is less than 300 ng / mL. The once-daily pharmaceutical composition according to claim 8, 9 or 10, wherein the mean maximum plasma concentration (C _max ) is twice the mean plasma concentration (C _24h ) obtained 24 hours after administration. A composition that is less than. 14. The once-daily pharmaceutical composition according to claim 11, 12 or 13, wherein the average maximum plasma concentration ( _Cmax ) is an average plasma concentration ( _C24h ) obtained at 24 hours after administration. A composition that is less than 3 times. Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 once a day type A pharmaceutical composition, wherein the median mean time to reach maximum plasma concentration (t _max ) is 2 to 10 hours. Claims 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20 or 21 once a day type pharmaceutical composition A composition wherein the t _max is 3 to 6 hours. Claim 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21 or 22 once a day pharmaceutical composition A composition wherein the t _max is 5 to 6 hours. A once-daily oral pharmaceutical composition for controlling the release of tramadol or a salt thereof containing 200 mg of tramadol or a salt thereof, wherein the composition is administered within the first two doses within 2 hours of administration A composition that provides an average O-desmethyltramadol plasma concentration of at least 24 ng / mL and at least 24 ng / mL O-desmethyltramadol average plasma concentration for at least 24 hours after administration. A once-daily oral pharmaceutical composition for controlling the release of tramadol or a salt thereof containing 200 mg of tramadol or a salt thereof, wherein the composition is administered within the first two doses within 2 hours of administration A composition that provides an average O-desmethyltramadol plasma concentration of at least 11 ng / mL and continues to provide an average O-desmethyltramadol plasma concentration of at least 12 ng / mL for at least 24 hours after administration. A once-daily oral pharmaceutical composition for controlling the release of tramadol or a salt thereof containing 200 mg of tramadol or a salt thereof, wherein the composition is administered within the first two doses within 2 hours of administration At a concentration of at least 32 ng / mL O-desmethyltramadol mean plasma concentration and continues to produce at least 32 ng / mL O-desmethyltramadol mean plasma concentration for at least 24 hours after administration. A once-daily oral pharmaceutical composition for controlling the release of tramadol or a salt thereof containing 200 mg of tramadol or a salt thereof, wherein when the first dose of 400 mg is administered, the composition is at least within 2 hours from the administration. A composition that provides an average O-desmethyltramadol plasma concentration of 50 ng / mL and continues to provide an average O-desmethyltramadol average plasma concentration of at least 50 ng / mL for at least 24 hours after administration. A once-daily oral pharmaceutical composition according to any of the preceding claims, wherein the composition is a tablet. A formulation according to any of the preceding claims, wherein 10% to 40% of the drug is released from the formulation when measured from 0 to about 2 hours and from the formulation when measured from 2 to about 7 hours. About 30 to 60% of the drug is released, about 50% to 80% of the drug is released from the formulation at a measurement of 7 to about 12 hours, and about 20% of the drug from the formulation after about 20 hours of measurement. Formulations that release 80% to 100%. A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, said composition providing an onset of analgesia within 2 hours upon administration of the first dose, When the analgesic action lasts at least 24 hours after administration and is measured with a HPLC-USP1 instrument at 100 rpm in 50 mM phosphate buffer pH 6.8, in
Vitro dissolution rate from about 5% to about 30% after 1 hour; from about 15% to about 40% after 2 hours; from about 20% to about 50% after 4 hours; from about 30% to about 70% after 8 hours; A composition that is about 40% to about 90% later; about 50% to about 100% after 16 hours; about 60% to about 100% after 24 hours. A once-daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, said composition providing an onset of analgesia within 2 hours upon administration of the first dose, When the analgesic action lasts at least 24 hours after administration and is measured with a HPLC-USP1 instrument at 100 rpm in 50 mM phosphate buffer pH 6.8, in
Vitro dissolution rate from about 10% to about 25% after 1 hour; from about 15% to about 30% after 2 hours; from about 25% to about 40% after 4 hours; from about 40% to about 55% after 8 hours; A composition that is about 60% to about 75% later; about 70% to about 90% after 16 hours; about 90% to about 100% after 24 hours. 32. A once-daily oral pharmaceutical composition according to claims 30 and 31, wherein the composition comprises about 200 mg tramadol or a salt thereof.

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