KR20070017335A - Oral matrix formulations comprising licarbazepine - Google Patents

Abstract

The present invention provides a pharmaceutical composition comprising 10,11-dihydro-10-hydroxy-5H-dibenz [b, f] azepine-5-carboxamide (also referred to as "ricarbazepine") as a pharmaceutical component. It is about.

10,11-dihydro-10-hydroxy-5H-dibenz [b, f] azepine-5-carboxamide, ricarbazepine, sustained release formulation, affective disorder, bipolar depression

Description

ORAL MATRIX FORMULATIONS COMPRISING LICARBAZEPINE}

The present invention provides a pharmaceutical composition comprising 10,11-dihydro-10-hydroxy-5H-dibenz [b, f] azepine-5-carboxamide (also referred to as "ricarbazepine") as a pharmaceutical component. It is about.

As used herein, the term ricarbazepine refers to (S) -10,11-dihydro-10-hydroxy-5H-dibenz [b, f] azepine-5-carboxamide and (R) -10,11 Refers to the racemic mixture of -dihydro-10-hydroxy-5H-dibenz [b, f] azepine-5-carboxamide.

In the present invention, ricarbazepine, (S) -10,11-dihydro-10-hydroxy-5H-dibenz [b, f] azepine-5-carboxamide and (R) -10,11- A mixture comprising an excess of one of the two enantiomers of dihydro-10-hydroxy-5H-dibenz [b, f] azepine-5-carboxamide, or essentially pure of ricarbazepine or One of the pure enantiomers may be used as the pharmaceutical component, which is collectively referred to herein as the "compound of the present invention".

Ricarbazepine (also known as MHD) is well known in the literature (see, eg, Schutz H. et al., Xenobiotica (GB), 16 (8), 769-778 (1986)), It can be prepared synthetically, for example starting from oxcarbazepine, according to conventional methods such as described in US-3,637,661.

Pure enantiomers of ricarbazepine can be obtained starting from racemates by methods known per se. For example, racemates can be prepared by diastereoisomers as disclosed in WO 02/092572, alternatively by salt formation with enantiomer-pure chiral acid, or by chromatographic substrates with chiral ligands. The enantiomers can be separated by chromatography using, for example, HPLC. In one embodiment of the invention, the pure enantiomers of ricarbazepine are prepared by the enantioselective method described in the Examples.

Ricarbazepine is known to be suitable for the treatment of psychosomatic disorders, epilepsy, trigeminal neuralgia and cerebral stiffness. Both racemates of ricarbazepine and its pure enantiomers have both been shown to show equal efficacy against epilepsy. Although the mechanism by which the compounds of the present invention exhibit anticonvulsive effects is not fully known, their activity may be due in part to the effect on ion flow across neuronal membranes. However, the pharmacokinetics, absorption sites and mechanism of action of the compounds of the present invention are not known in detail.

Ricarbazepine is slightly soluble in water (3.2 mg / ml at 25 ° C). In view of these properties, parenteral preparations of ricarbazepine can be prepared, for example, as described in EP-1 033 988. Despite the advantages of known parenteral dosage forms, there is a need to establish advantageous oral dosage forms of the compounds of the invention. One of the problems that can occur with oral dosage forms is the ups and downs of blood levels of the compounds of the invention upon repeated administration, which may be associated with side effects.

After numerous trials, it has been found that advantageous oral sustained release pharmaceutical compositions can be administered once daily, are particularly well tolerated in various groups of patients, and exhibit good bioavailability.

Thus, one aspect of the present invention exhibits continuous symptom control by low fluctuation index and sufficient C _min (lowest plasma concentration) value compared to particularly good tolerance, and also high AUC (area under curve) and low C _max (highest plasma). It relates to an oral sustained release pharmaceutical composition (hereinafter referred to as "oral dosage form of the present invention") suitable for once-daily administration, comprising one or more compounds of the present invention, having the advantage of a concentration) value. .

The oral dosage form of the present invention may show significant advantages over other oral dosage forms in that the patient is more convenient and / or safer to use and increases the patient's adaptability to therapy. The patient will only take the oral dosage form of the present invention once a day.

As used herein, the term "once a day" means once every 20 to 28 hours, especially once every 24 hours.

Preferred oral dosage forms of the invention include compounds of the invention, in particular ricarbazepine and lipophilic or hydrophilic, preferably hydrophilic, swellable materials.

In such oral dosage forms, the compounds of the invention, in particular ricarbazepine, may be present in an amount of from 55 to 80%, preferably from 65 to 70%, for example about 68% by weight of the total composition.

Compounds of the invention, in particular ricarbazepine, have an intermediate particle size (x ₅₀ ) of about 20 to about 50 μm, preferably about 30 to about 50 μm, more preferably about 35 to about 45 μm, for example about It is preferable to use it as a granule which is 40 micrometers.

Swellable materials commonly used in tablet formulations can be used, and extensive literature on suitable swellable materials, in particular Fiedier's "Lexikon der Hilfsstoffe", 4th edition, ECV Aulendorf (1996) (hereafter referred to), is hereby incorporated by reference. Referred to as "LdH" and "Handbook of Pharmaceutical Excipients", Wade and Weller, 3rd ed. (2000)] (hereinafter referred to as “HoPE”).

In one embodiment of the invention, the oral dosage form is a group of compounds consisting of natural or partially or fully synthetic hydrophilic gums, cellulose derivatives and water soluble protein materials, preferably anionic or preferably nonionic, which is natural or partially or fully synthetic. A group of compounds consisting of hydrophilic gums, modified cellulose materials, and water soluble protein materials; For example, acacia gum, tragacanth gum, locust bean gum, guar gum, karaya gum, agar, peptin, carazine, soluble or insoluble alginate, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydrate Hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxypolymethylene and gelatin, preferably one or more hydrophilic swellable materials selected from the group of compounds consisting of cellulose materials such as methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose . Especially preferred is hydroxypropyl methyl cellulose.

Various viscous swellable materials used in accordance with the present invention can be prepared as disclosed in HoPE.

The swellable material may be present in an amount of about 5 to about 45%, preferably about 5 to about 35%, more preferably about 10 to about 15%, for example about 13% by weight of the total composition.

The weight ratio of the swellable substance to the pharmaceutical component, in particular ricarbazepine, is about 1: 3 to about 1:10, preferably about 1: 4 to about 1: 7, more preferably about 1: 5 to about 1: 6 days. Can be.

The swellable material may be a mixture of two or more swellable materials.

In a further aspect, the present invention provides the USP No. 2 device (rotary paddle) for a 500 mg dosage form, preferably at 37 ° C. in a phosphate buffered aqueous solution having a pH of about 6.8, for example at a stirring speed of 50 rpm. As a result of the standard in vitro dissolution test used (hereinafter referred to as “in vitro ricarbazepine dissolution test conditions” of the present invention), from about 70 to about 90%, preferably from about 80 to about 90% of ricarbazepine when used is 8 to A sustained release pharmaceutical composition for oral administration comprising ricarbazepine, characterized in that released within 12 hours.

In one embodiment of the invention, the oral dosage form comprises a pharmaceutical component, in particular a ricarbazepine, a tablet core comprising at least one hydrophilic swellable cellulose ether, preferably hydroxypropyl methyl cellulose and optionally a filler, and a coating. . The weight ratio of hydroxypropyl methyl cellulose to the pharmaceutical component, in particular ricarbazepine, in this oral dosage form is preferably from about 1: 3 to about 1:10, preferably from about 1: 4 to about 1: 7, more preferably May be between about 1: 5 and about 1: 6.

Clinical studies, such as bioavailability testing, can be conducted in conventional manner. For example, it can be practiced over 7 days using a 500 mg dosage form of a compound of the invention. Typically 6 or more, for example 10 subjects. In such studies, the controlled release properties, bioavailability, food effects, safety, acceptability, C _max , C _min and / or AUC of the oral dosage forms of the invention can be determined.

Bioavailability of a pharmaceutical component depends on physiochemical properties such as solubility and pharmacokinetic properties such as, for example, absorption site, rate and extent. It is also known that food alters the physiology of the gastrointestinal tract (GI). Such changes can cause, among other things, delays in gastric emptying, irritation of bile secretion and changes in pH. Food can also alter intestinal metabolism and interact physically or chemically with pharmaceutical ingredients. Thus, it is not surprising that food can affect the bioavailability of the pharmaceutical component. As used herein, the term "food effect" means that the bioavailability of a pharmaceutical component in a subject who is postprandial is different from the bioavailability of the pharmaceutical component in a fasting subject. The food effect is complex and difficult to predict and will depend, for example, on the nature of the food, for example its nutrient content, fluid volume, calorie content and temperature. The presence or absence of a food effect on a given pharmaceutical ingredient can be determined after numerous tests.

It is not desirable that the bioavailability of the pharmaceutical component depends on whether the patient is in a postprandial or fasting state. This will be inconvenient for patients who must adjust their dosing time relatively at least in accordance with food intake.

It is therefore surprising that it has been found that oral dosage forms of ricarbazepine can be administered to a patient regardless of the patient's condition, ie whether the patient is postprandial or fasting.

Thus, in a further aspect, the present invention relates to an oral dosage form of the present invention having no food effect when administered to a patient.

In a further aspect, the present invention relates to a package comprising instructions for use, e.g., as described, indicating that the oral dosage form of the invention and the oral dosage form can be administered equally to post-prandial or fasting patients. .

More specifically, the present invention relates to oral dosage forms of the present invention packaged with instructions, for example described, indicating that oral dosage forms can be administered equally with or without food.

The presence or absence of a food effect can be quantified by performing AUC measurements and / or C _max measurements according to methods well known in the art. Typically, such measurements can be made by taking a biological fluid sample over time and plotting the serum concentration of the pharmaceutical component, such as ricarbazepine, over time. The values obtained are the values obtained from the subjects in the patient group and are therefore represented as mean values for the entire patient group. By comparing the average AUC and / or C _max values, it is possible to determine whether a medicinal component, such as ricarbazepine, exhibits a food effect.

Subjects who are “postprandial” may conveniently be considered subjects who have been on an empty stomach for at least 10 hours and then have received an FDA approved standard high fat diet. A medicinal component, for example ricarbazepine, may be administered with water immediately after a meal, for example after 5 minutes. After administration of the medicinal component, for example ricarbazepine, preferably no food should be consumed, for example for 4 hours, but a small amount of water is allowed, for example after 2 hours.

Subjects who are “fasting” may conveniently take a pharmaceutical component, for example, ricarbazepine, with water after an empty stomach for at least 10 hours. After administration of the medicinal component, for example ricarbazepine, preferably no food should be consumed for, for example, 4 hours, but a small amount of water may be consumed, for example, after 2 hours.

As used herein, “FDA approved standard high fat meal” may include any meal that is expected to cause maximum perturbation due to the presence of food in the gastrointestinal tract. The high fat meal typically contains 50% of its calorie levels as fat. Representative examples may include two eggs fried in butter, two rows of bacon, two buttered breads, four ounces of fried potatoes and eight ounces of milk.

In order to study the effect of food on the bioavailability of the pharmaceutical component, any conventional study design known in the art, such as randomized, balanced single dose, two treatments, two periods, two steps, crossover design Can be used. The analysis can be performed using software from SAS Institute, Cary, North Carolina, for example SAS PROC GLM.

Suitable study designs for determining the bioavailability of the oral dosage form, including the food effect, of the present invention are randomized, open-label, single oral administration, crossover studies, and accordingly the compounds of the present invention The bioavailability of the oral dosage form of the present invention may be compared with the bioavailability of a solution of the same compound of the present invention, optionally including an oxcarbazepine film coated tablet, comprising a healthy male subject after meals or fasting Evaluate the effect of food on

In studies in which the pharmaceutical component is for example ricarbazepine, an oral dosage form of the invention comprising oxcarbazepine film coated tablets (600 mg), and for example 500 mg ricarbazepine, was administered to subjects with tap water 240 It can be administered with ml. Ricarbazepine clinical trial form (500 mg) delivered in powder should be dissolved in tap water prior to drug administration. During the period of treatment requiring fasting conditions, a single dose of test drug is administered after maintaining an empty stomach overnight for at least 10 hours. During treatment periods requiring postprandial conditions, each subject is required to consume an FDA approved standard high fat breakfast within 30 minutes prior to drug administration. During the treatment period requiring fasting conditions, breakfast is not provided prior to drug administration, and subjects must remain fasted for up to 4 hours after administration. Safety and tolerability monitoring includes continuous monitoring of side effects, physical examination, blood pressure and pulse measurements, ECG recordings, and routine basic tests (blood chemistry, urinalysis, and blood tests).

During the first seven days, subjects will be given the oral dosage form of the present invention under fasting conditions, and during the second period the subjects will be provided with the same treatment under postprandial conditions. Subjects will be fasting overnight for at least 10 hours in the evening prior to the first dose of a compound of the invention (stage 1). For example, after administration of breakfast time, appropriate time intervals, for example, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 32 after administration And pharmacokinetic blood samples can be taken at 48 hours and used for the assay.

Absorption profiles of the compounds of the present invention can be quantified by single AUC measurements or by steady state AUC measurements.

The constant plasma concentration of the compound of the present invention means that the plasma concentration of the compound of the present invention exhibits a low index of variation. The C _min and C _max values of the compounds of the present invention can be maintained within a narrow range. To determine the variation between C _min and C _max , the plasma concentration of the compound of the invention is measured at steady state, and the index of variation is (C _min -C _max ) / C _av (where C _max , C _min and C _av is calculated according to the highest concentration, the minimum concentration, and the average concentration observed at a specific time interval, for example, within 24 hours.

The low change between C _min and C _max avoids the highest plasma concentrations of the compounds of the present invention that can be harmful to the patient. Low index of variability can provide good tolerance and safety for patients treated with the compounds of the present invention.

Thus, in a further aspect, the present invention provides an oral dosage form of the present invention which comprises ricarbazepine as a pharmaceutical ingredient and which does not exhibit a food effect when administered to a patient at any time, for example after meals or on an empty stomach. A method for reducing the body's variability of lycarbazepine bioavailability levels in a patient during oral administration of lycarbazepine, comprising administering.

In a further aspect, the present invention relates to the use of ricarbazepine for the manufacture of a medicament for the treatment of a patient with an affective disorder.

As used herein, the term "depressive disorder" refers to unipolar and bipolar depression, bipolar disorder, premenstrual discomfort, postpartum depression, postmenopausal depression, neurodegeneration-associated depression, depression that occurs after discontinuation of psychostimulants, psychosis Conditions such as but not limited to manic schizophrenia and transient mood swings that require behavioral stabilization.

Use of the oral dosage form of the present invention in the treatment of affective disorders involves standard animal tests or standard clinical studies, eg, administering lycarbazepine at doses ranging from about 500 to about 3000 mg per day, for example bipolar disorders. It can be observed in clinical studies of patients.

Oral dosage forms of the present invention can be prepared by conventional methods by mixing the components. The resulting mixture may be in powder form, which may be compressed to form tablets in conventional tableting machines.

Typically, oral dosage forms of the present invention can be prepared using conventional tableting methods to compress the compounds of the present invention, for example with conventional tableting excipients, to form tablet cores and then to coat the cores. Tablet cores may be prepared by conventional granulation methods, for example by wet or dry granulation, followed by compression and coating. Granulation methods are described, for example, in R. Voigt, "Lehrbuch der Pharmazeutischen Technologie", Verlag Chemie, 6th edition, pages 156-169.

The granules can be prepared using methods known per se, for example wet granulation methods known for the production of "build-up" granules or "broken-down" granules.

The method for producing the granulated granules is sprayed and dried simultaneously, for example, by spray drying or spray solidification, for example in a drum granulator, a pan granulator, a disk granulator or a fluidized bed, to the material to granulate the granulation solution. For example, discontinuously in a fluidized bed, batch mixer or spray-drying drum.

Depending on the method used, the granulation material may be in premixed form or obtained, for example, by mixing the compound of the invention with one or more excipients. Wet granules are preferably dried, for example by tray drying or in a fluidized bed.

Oral dosage forms of the present invention may include conventional excipients, in addition to the compounds of the present invention, depending on the exact nature of the formulation. Suitable types of excipients include fillers, lubricants, film coatings, binders, glidants, glidants, surfactants and disintegrants.

Literature, for example, as disclosed in Fiedler's "Lexikon der Hilfstoffe", 4 ^th Edition, ECV Aulendorf and "Handbook of Pharmaceutical Excipients", Wade and Weller, Third Edition (2000) Excipients can be used in the pharmaceutical compositions according to the invention. Conveniently, excipients comprise less than 40% of the dosage weight.

We have found that certain excipients, such as the following cellulose ethers, exhibit particularly interesting properties in the oral dosage form of the present invention comprising ricarbazepine.

i) hydroxypropyl methylcellulose, for example

Methocel 60 HG 4000 CP, preferably at a weight ratio of about 1: 4 to about 1: 8;

Methocel HG having a viscosity of about 4000 mPa s, a methoxy content of 26 to 30%, and a hydroxypropyl content of 7 to 12% of a 2% aqueous solution;

2% aqueous solution with a viscosity of about 4000 mPa s, a number average molecular weight of about 90,000, a methoxy content of 28.0 to 30.0%, a hydroxypropyl content of 7.0 to 12.0% or equivalent, eg 10-20% per tablet Tocel E-4M; And

A 2% aqueous solution has a viscosity of about 50 mPa s, a number average molecular weight of about 20,000, a methoxy content of 28.0 to 30.0%, a hydroxypropyl content of 7.0 to 12.0% or equivalent (eg 10 to 20% per tablet). Tocel E-50 Premium.

The preferred weight ratio of total hydroxypropylmethyl cellulose to ricarbazepine is from about 1: 3 to about 1:10 in the granules and in the outer phase of the granules.

Hydroxypropyl methyl cellulose (HPMC) polymers, alone or in combination with other materials, can be used as matrix components to control drug release.

Oral dosage forms of the invention containing HPMC polymers, when exposed to the aqueous medium of the stomach, form a swellable matrix that prevents their rapid disintegration by preventing or delaying the penetration of the aqueous medium of the stomach into the dosage form to prevent drug release. Can be extended. The gel matrix is formed as a result of hydration of the HPMC polymer. Minor instability problems may arise during the storage of oral dosage forms of the invention comprising oxcarbazepine and excipients with HPMC.

Preferred excipients for use as the matrix component are cellulose ether products such as methylcellulose and hypromellose. Such hypromellose products can be prepared using methyl chloride and propylene oxide to obtain hydroxypropyl substitution on the anhydroglucose units in cellulose. This substituent, -OCH ₂ CH (OH) -CH ₃ , contains secondary hydroxyl groups on carbon 2 and is believed to form propylene glycol ethers of cellulose. These products have varying proportions of hydroxypropyl and methyl substitution, factors that affect organic solubility and thermal gelation temperature of aqueous solutions.

The viscosity is preferably 100 to 120.000 mPas at 20 ° C.

Such products include methocel products available from Dow Chemical Company, USA. Alternatives include ethyl cellulose, for example, to obtain a 30% ethylcellulose dispersion from FMC weight available AQUA Coat (Aquacoat) ^® or standing Released (Surelease) ^®.

For example Pharma Coat ^{(Pharmacoat) ® 603 (Fiedler,} loc. Cit., 1172 p.) Into available, viscosity (referred to above) of about 3 mPa s of cellulose HPM 603 levels of hydroxypropyl methyl cellulose is a preferred excipient . The molecular weight of cellulose derivatives such as hydroxypropylmethylcellulose is preferably 10,000 to 1,500,000 daltons.

ii) Ethocel Premium 7 cps with a viscosity of about 7 cps of ethylcellulose, for example a 2% aqueous solution, with an ethoxy content of 44.0 to 51.0% or equivalent, eg 7 to 10% per tablet.

iii) Klucel having a hydroxypropylcellulose, for example a 5% aqueous solution viscosity of about 100 cps and a hydroxypropoxyl content of about 54 to 77% or equivalent (eg 0.5 to 5% per tablet) ) LF or hydroxyethyl cellulose (HEC)

Hydroxypropyl cellulose can be, for example, hydroxypropyl cellulose having a hydroxypropyl content of 5 to 16% by weight and a molecular weight of 80,000 to 1,150,000, more particularly 140,000 to 850,000.

Examples of other binders include

Starches having a molecular weight of 30,000 to 120,000, for example potato starch, wheat starch, corn starch;

Polyvinyl pyrrolidone, for example Povidone having an average molecular weight of about 1000 and a degree of polymerization of about 500 to 2500, and polymethylacrylates having a molecular weight of 100,000 Daltons or more, such as Eudragit RL 30D. Handbook of Pharmaceutical Excipients loc. Cit., P. 402), copolymers of acrylic or methacrylic acid esters.

Preferably microcrystalline cellulose is present. It can be used as a filler. Examples include Avicel ^® systems (FMC Corporation), for example Avicel ^® PH101, 102, 105, RC581 or RC 591 (Fiedler loc. Cit., P. 216), Emcocel ^® systems (Mendell Corporation), Elcema ^® system (Degussa), Filtrak ^® system, Heweten ^® system And Pharmacel ^® . Preferably, the weight ratio of microcrystalline cellulose to the compound of the present invention is about 1: 3 to about 1: 6, more preferably about 1: 4 to about 1: 5.

Other preferred fillers are, for example, carbohydrates such as lactose, dextrose, saccharose, glucose, sorbitol, mannitol, xylitol, potato starch, corn starch, rice starch, wheat starch or sugars such as amylopectin, sugar alcohols, starches or starches Micropowder fillers, in particular optionally having fluidizing properties, comprising derivatives, calcium triphosphate or calcium hydrogen phosphate.

Preferably polyvinyl-polypyrrolidone is present. Conveniently, it acts as a disintegrant. Preferred examples include crosslinked polyvinylpyrrolidones such as crospovidone, such as Polyplasdone ^® XL (Fiedler loc. Cit., P. 1245) and Kollidon ^® CL disintegrants There is.

Examples of other disintegrants include: (i) natural starches such as corn starch, potato starch, etc., ready-to-compress starch such as Sta-rx ^® 1500, for example Primojel ^® , Explotab ^® and Explorer brush (Explosol) modified starch derivatives such as starch, amylose and the like, available carboxymethyl starch and sodium starch glycolate in ^®; (ii) eg with Ac-di-sol ^® , Primellose ^® , Pharmacel ^® XL, Explocel ^® and Nymcel ^® ZSX Available crosslinked sodium carboxymethylcellulose; (iii) alginic acid and sodium alginate; (iv) methacrylic acid-divinylbenzene copolymer salts, e.g., Amberlite (Amberlite) ^® IRP-88; And (v) magnesium aluminum silicate, bentonite, alginic acid and alginate.

It is preferred that colloidal silica, such as Aerosil 200, be present. They can act as glidants. Examples of other glidants include silica, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

Magnesium stearate is the preferred excipient. It can act as a lubricant. Examples of other lubricants include sodium stedecate, mineral oil and polyoxyethylene, also known as calcium stearate, zinc stearate, talc, polyethylene glycol, stearic acid, sodium benzoate, sulfuric acid monododecyl ester sodium salt Monostearate. Combinations of lubricants may also be used.

Ricarbazepine granules may be coated. Suitable coating materials include those conventionally used to coat tablets, granules and the like. In one group of embodiments, the coating layer is water soluble. In a group of other embodiments, the coating layer is gastric fluid soluble, but soluble in intestinal fluids.

Unless otherwise stated, all percentages are weight percentages.

Oral dosage forms of the invention can be combined with immediate release. The combination may be a bilayer tablet comprising a matrix system having immediate release and sustained release properties of a compound of the invention, for example ricarbazepine. Bilayer tablets may comprise a two-part administration portion of a compound of the invention, such as ricarbazepine, one layer suitable for providing sustained release administration and the other layer suitable for providing immediate release administration. . For tablets comprising ricarbazepine, immediate release means releasing a dosage of at least 90% in 0.5 hours and 100% in 1.5 hours under the in vitro ricarbazepine test dissolution conditions of the present invention. do.

In one embodiment of the present invention, a dosage of 500 mg ricarbazepine is preferably used.

In addition, the present invention,

Sustained release for oral administration suitable for once-daily administration, comprising 10,11-dihydro-10-hydroxy-5H-dibenz [b, f] azepine-5-carboxamide and a hydrophilic swellable material Sex pharmaceutical compositions;

Pharmaceutical compositions according to any of claims 1 to 11 requiring treatment of 10,11-dihydro-10-hydroxy-5H-dibenz [b, f] azepin-5-carboxamide Affective disorder by oral administration of 10,11-dihydro-10-hydroxy-5H-dibenz [b, f] azepin-5-carboxamide, comprising oral administration once daily to a patient How to treat

To provide.

In the following, the compositions and methods of the present invention are described for purposes of illustration only. In Example 1, 500 mg of the pharmaceutical component (particulate pharmaceutical component; x ₅₀ : 40 μm) was used. In a similar manner, tablets can be prepared comprising 750 mg, 250 mg or 125 mg of the pharmaceutical ingredient per tablet.

Abbreviation

Ac acetyl

aqu. Aqueous solution

Single thread 5- (dimethylamino) -1-naphthalenesulfonyl

Et ethyl

HPLC high pressure liquid chromatography

Me methyl

NMR nuclear magnetic resonance

RT room temperature

THF tetrahydrofuran

Ts chubby

Example 1 Sustained Release Composition of Ricarbazepine Based on HPMC Matrix

A premix containing ricarbazepine, microcrystalline cellulose and cellulose HPM 603 was prepared. Purified water was added to the premix and granulated using a high shear mixer (Collette 25). The resulting granules were filtered using a Quadraco mill and dried using a fluid bed dryer (Aeromatic Fielder MP1). Dry granules were filtered from polyvinyl polypyrrolidone XL, microcrystalline cellulose, methocell 60HG 4000 CP and aerosil 200 using a frit mill equipped with a 1 mm mesh, followed by a bin blender (ter Mix using Turbula). Magnesium stearate was filtered through a mesh (0.8 mm mesh) and added. The final blend was mixed with an empty blender (turbula).

The final blend was compressed with a Korsch PH250 tableting press. The tablets were oval, curved, 18 mm long, 7.1 mm wide and without a cutting bar. Tablet weight is 730.00 mg.

Formulation

Tablet Ingredients: (mg)

Ricarbazepine 500.00

Microcrystalline Cellulose 64.30

Cellulose HPM 603 14.00

Microcrystalline Cellulose 44.00

Methocel 60 HG 4000 CP 80.00

Polyvinyl-Polypyrrolidone XL 18.00

Aerosil 200 2.50

Magnesium Stearate 7.20

Tablet weight 730.00

<Example 2>

R (-)-10,11-dihydro-10-hydride by enantioselective selective hydrogenation of 10-oxo-10,11-dihydro-dibenzo [b, f] azepine-5-carboxylic acid amide Preparation with Roxy-5H-dibenz [b, f] azepine-5-carboxamide

10-oxo-10,11-dihydro-dibenzo [b, f] azepine-5-carboxylic acid amide (300 mg, 1.189 mmol) in CH ₂ Cl ₂ (15 ml) and Aldrich, Switzerland In a mixture of RuCl [(1R, 2R) -p-TsNCH (C ₆ H ₅ ) CH (C ₆ H ₅ ) NH ₂ ] (η ⁶ -p-cymene) (8.8 mg, 0.0138 mmol) A solution of mixed formic acid and NEt ₃ (5: 2, 328 mg: 289 mg) was added dropwise at 23 ° C. and stirred for 10 minutes. The clear solution was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, diluted with CH ₂ Cl ₂ (20 ml) and neutralized with aqueous NaHCO ₃ solution. After washing with brine, the solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a 6: 1 mixture of EtOAc-MeOH as eluent to afford R (-)-10,11-dihydro-10-hydroxy-5H-dibenzo [b, f]. Azepine-5-carboxamide was obtained (enantiomer purity (ee)> 99%, measured by HPLC on Chiracel OD, retention time 9.46 minutes). [α] D ^rt = -195.3 ° (ethanol).

¹ H-NMR (400 MHz, CDCl ₃ ): 7.70-7.20 (m, 8H), 5.30 (br s, 1H), 5.10-4.60 (br s, 2H), 3.75-3.40 (m, 1H), 3.20 -2.90 (m, 1 H), 2.50 (br s, 2 H). NMR data are reported in Benes, J. et al., J. Med. Chem. 1999, 42, 2582-2587. Molecular weight: 254.291.

<Example 3>

S (+)-10,11-dihydro-10-hydride by enantioselective selective hydrogenation of 10-oxo-10,11-dihydro-dibenzo [b, f] azepine-5-carboxylic acid amide Preparation of Roxy-5H-dibenz [b, f] azepine-5-carboxamide

10-oxo-10,11-dihydro-dibenzo [b, f] azepin-5-carboxylic acid amide (300 mg, 1.189 mmol) and RuCl [(1S, 2S) in CH ₂ Cl ₂ (15 ml) To a mixture of) -p-TsNCH (C ₆ H ₅ ) CH (C ₆ H ₅ ) NH ₂ ] (η ⁶ -p-cymene) (11 mg, 0.0173 mmol), premixed formic acid and NEt ₃ (5: 2, 656 mg: 578 mg) was added in two portions at 23 ° C. and stirred for 10 minutes. Formic acid was added (50 μl), and the clear solution was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, diluted with CH ₂ Cl ₂ (20 ml) and neutralized with aqueous NaHCO ₃ solution. After washing with brine, the solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a 6: 1 mixture of EtOAc-MeOH as eluent to afford S (+)-10,11-dihydro-10-hydroxy-5H-dibenzo [b, f]. Azepine-5-carboxamide was obtained (ee> 99%, determined by HPLC on Chiracel OD, retention time 12.00 min). [α] D ^rt = + 196.6 ° (ethanol).

¹ H-NMR (400 MHz, CDCl ₃ ): 7.70-7.20 (m, 8H), 5.30 (br s, 1H), 5.10-4.60 (br s, 2H), 3.75-3.40 (m, 1H), 3.20- 2.90 (m, 1 H), 2.50 (br s, 2 H). NMR data are reported in Benes, J. et al., J. Med. Chem. 1999, 42, 2582-2587. Molecular weight: 254.291.

Alternative preparation method: 10-oxo-10,11-dihydro-dibenzo [b, f] azepin-5-carboxylic acid amide (300 mg, 1.189 mmol) and RuCl in CH ₂ Cl ₂ (15 ml) Formic acid premixed to a mixture of [(1S, 2S) -p-monosilic NCH (C ₆ H ₅ ) CH (C ₆ H ₅ ) NH ₂ ] (η ⁶ -p-cymene) (8.5 mg, 0.012 mmol) And a solution of NEt ₃ (5: 2, 328 mg: 289 mg) was added dropwise at 23 ° C. and stirred for 10 minutes. The clear solution was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, diluted with CH ₂ Cl ₂ (20 ml) and neutralized with aqueous NaHCO ₃ solution. After washing with brine, the solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a 6: 1 mixture of EtOAc-MeOH as eluent to afford S (+)-10,11-dihydro-10-hydroxy-5H-dibenzo [b, f]. Azepine-5-carboxamide was obtained.

Example 4 Preparation of RuCl [(1S, 2S) -p-single NCH (C ₆ H ₅ ) CH (C ₆ H ₅ ) NH ₂ ] (η ⁶ -p-cymene)

a) Preparation of (S, S) -5-dimethylamino-naphthalene-1-sulfonic acid (2-amino-1,2-diphenyl-ethyl) -amide

To a solution of (S, S) -diphenylethylenediamine (250 mg, 1.2 mmol) and triethylamine (0.5 ml) in THF was added a solution of monoyl chloride (318 mg, 1.2 mmol) in THF (2 ml) at 0 ° C. Dropped at After stirring for 16 hours at room temperature, the solvent was removed in vacuo and the residue was redissolved in methylene chloride (20 ml). The organic solution was washed with NaHCO ₃ solution (5 ml), dried over Na ₂ SO ₄ and the solvent was removed after filtration. Flash chromatography was carried out to give (S, S) -5-dimethylamino-naphthalene-1-sulfonic acid (2-amino-1,2-diphenyl-ethyl) -amide as a yellow oil, which was dried under vacuum to crystallize. . M: 445.59.

¹ H-NMR (400 MHz, CDCl ₃ ): 8.36 (t, J = 7.5 Hz, 2H), 8.17 (dd, J = 7.2 Hz, 1.2 Hz, 1H), 7.47 (dd, J = 8.8 Hz, 1H) , 7.34 (dd, J = 8.5 Hz, 1H), 7.24-7.16 (m, 4H), 7.11 (d, J = 7.5 Hz, 1H), 6.99-6.74 (m, 6H), 4.61 (d, J = 8.5 Hz, 1H), 4.20 (d, J = 8.5 Hz, 1H), 2.80 (s, 6H).

b) Preparation of RuCl [(1S, 2S) -p-single NCH (C ₆ H ₅ ) CH (C ₆ H ₅ ) NH ₂ ] (η ⁶ -p-cymene)

(S, S) -5-dimethylamino-naphthalene-1-sulfonic acid (2-amino-1,2-diphenylethyl) -amide (80 mg, 0.18 mmol) in 2-propanol, NEt ₃ (36 mg, 0.36 mmol) and [RuCl ₂ (p-cymene)] ₂ (55 mg, 0.09 mmol) were heated at 80 ° C. for 1 hour. The solvent is then removed and the dark red residue is washed with water (2 ml). The solid was dried in vacuo and used without purification. M: 715.34.

Claims (14)

Sustained release pharmaceutical composition for oral administration comprising 10,11-dihydro-10-hydroxy-5H-dibenz [b, f] azepine-5-carboxamide (ricarbazepine). The pharmaceutical composition of claim 1, comprising ricarbazepine and a hydrophilic or lipophilic swellable material. The pharmaceutical composition of claim 2, wherein the hydrophilic swellable material is present at a ratio of 5 to 35% by weight of the total composition. The pharmaceutical composition according to any one of claims 1 to 3, comprising 55 to 80% by weight of the total composition weight of ricarbazepine. The pharmaceutical composition according to any one of claims 1 to 4, comprising ricarbazepine having a median particle size of 20 to 50 μm. The pharmaceutical composition according to any one of claims 1 to 5, comprising a tablet core comprising at least one hydrophilic swellable material which is ricarbazepine and optionally a filler and a cellulose ether. The pharmaceutical composition according to any one of claims 1 to 6, which uses hydroxypropyl methyl cellulose as the hydrophilic swellable material. 8. The pharmaceutical composition of claim 7, wherein the weight ratio of total hydroxypropyl methyl cellulose to ricarbazepine is from about 1: 3 to about 1:10. The pharmaceutical composition according to any one of claims 1 to 8 comprising microcrystalline cellulose. For a 500 mg dosage form, a standard in vitro dissolution test at 37 ° C., agitation rate of 50 rpm in a phosphate buffered aqueous solution with a pH of about 6.8 indicates that 70-90% of ricarbazepine, when used, is released within 8-12 hours. , Sustained release pharmaceutical composition for oral administration comprising ricarbazepine. The standard in vitro dissolution test results of standard in vitro dissolution at 37 ° C., agitation rate of 50 rpm in a phosphate buffered aqueous solution with a pH of about 6.8, for a 500 mg dosage form, between 80 and 90% of ricarbazepine in use of 8-12. Sustained release pharmaceutical composition for oral administration comprising ricarbazepine, which is released within time. A sustained release pharmaceutical composition for oral administration suitable for once-daily administration, comprising ricarbazepine and a hydrophilic swellable material. Use of lycarbazepine and excipients as defined in any one of claims 1 to 12 for the manufacture of a medicament for the treatment of patients with affective disorders. An affective disorder, for example by oral administration of ricarbazepine, comprising orally administering a pharmaceutical composition according to any one of claims 1 to 12 to a patient in need of treatment with ricarbazepine. Method of treatment.