WO1999004797A1 - Use of 2,3-benzodiazepine derivatives for the preparation of pharmaceutical compositions to treat diseases connected with the endogenous opioid system - Google Patents

Use of 2,3-benzodiazepine derivatives for the preparation of pharmaceutical compositions to treat diseases connected with the endogenous opioid system Download PDF

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Publication number
WO1999004797A1
WO1999004797A1 PCT/HU1998/000069 HU9800069W WO9904797A1 WO 1999004797 A1 WO1999004797 A1 WO 1999004797A1 HU 9800069 W HU9800069 W HU 9800069W WO 9904797 A1 WO9904797 A1 WO 9904797A1
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methyl
benzodiazepine
pharmaceutical compositions
active ingredient
azep
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PCT/HU1998/000069
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French (fr)
Inventor
Márton Fekete
József Haller
József Székely
Katalin HORVÁTH
Pál FEKETE
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EGIS Gyógyszergyár Rt.
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Priority to AU85538/98A priority Critical patent/AU8553898A/en
Publication of WO1999004797A1 publication Critical patent/WO1999004797A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep

Definitions

  • This invention relates to the use of 2,3-benzod ⁇ azep ⁇ ne derivatives for the preparation of pharmaceutical compositions " useful for the treatment or prevention of diseases connected with disturbances of the opioid system Background of the invention
  • Hedonia the overstated demand of pleasure
  • ahedonia inability to feel pleasure
  • these symptoms are mentioned in the Diagnostic and Statistical Manual of Mental Disorders, IV ed (American Psychiatric Association, Washington D C , USA, 1994) among diagnostic criteria for schizophrenia and depression
  • the increased desire of pleasure is considered to play an important role by initiating the progress of disease state [Drug addiction and alcoholism and opioid signals, Koob, G F Ann N Y Acad Sci 654 1171-191 (1992)]
  • the state of pleasure is primarily the consequence of specific actions of the endogenous opioid peptides [(Ber ⁇ dge, K C Neurosci Biobehav Rev 20 1-25 (1996)]
  • the opioid peptide is released and acts only in areas of the brain performed to evoke the state of pleasure, on the other hand the appropriate receptor of the opioid peptides
  • the present invention is based on the recognition that the effect of 2 " 3-benzod ⁇ azep ⁇ ne derivatives on the behaviour of experimental animals is inhibited in states of opioid tolerance induced by morphine This means that the compounds are acting via the opioid signal transduction system Consequently, the 2,3-benzod ⁇ azep ⁇ nes may be employed in the therapy or prevention of disease states in which the endogenous opioid system is playing a role Disturbances of the hedonic state (increased or depressed ability of feeling pleasure) are the most characteristic examples of these symptoms of diseases
  • the experiments were carried out in Charles River Wistar rats The animals were treated subcutaneously with saline or morphine for 4 consecutive days Treatments were carried out twice a day between 8 and 9 o'clock a m and between 17 and 18 o'clock p m
  • the group treated with morphine received on the first day two times 5 mg/kg, on the second day two times 10 mg/kg, on the third day two times 15 mg/kg and on the fourth day two times 20 mg/kg of morphine
  • This treatment schedule decreases the analgesic potency of morphine to about one fifth 18 hours after the last treatment
  • the test compounds, that is the 2,3- benzodiazepine derivatives were administered on the fifth day On the fifth day of the experiment, 15-20 hours after the last treatment, open field tests were carried out as specified in the literature [(Van Ree, J M , G Wolternik "Motility and grooming as measures of anxiolysis with homophtalazines", Eur J Pharmacpl 72 107-
  • Control 109.9 10.8 10 4.60 1.03 10 80.6 36.8 10 nerisopam 129 3 34.0 5 3.33 1.52 5
  • Figure 1 shows the effect of tofisopam, nerisopam and girisopam on the motility and grooming behaviour of rats in open field test after treatment with saline or morpholine
  • Tables 1-3 are presented as percentages of the control values
  • the vertical bars indicate the standard errors of the mean, * P 0 05, ** P 0 01 (analysis of variance followed by Duncan test)
  • the 2,3-benzod ⁇ azep ⁇ nes induce their psychopharmacological effects (anxiolysis) due to an action on the endogenous opioid system evoking good feeling, pleasure
  • This effect envisages that the 2,3-benzod ⁇ azep ⁇ ne derivatives may be employed to treat or prevent hedonic disturbances These disturbances are present in cases of schizophrenia, depression, alcoholism or drug dependence In cases of schizophrenics with anhedonia the 2,3- benzodiazepine derivatives increasing the feeling of pleasure decrease the desire for drug or alcohol.
  • depression induced by stress or loss of weight of animals induced by stress may be counteracted by 2,3-benzodiazepines.
  • compositions of the present invention useful for the treatment or prevention of diseases connected with the opioid system can be prepared by methods known per se by admixing the active ingredient with suitable inert solid or liquid carriers and bringing the mixture to galenic form.
  • compositions of the present invention can be presented preferably in the form of orally administerable preparations (such as tablets, pills, coated pills, soft or hard gelatin capsules, solutions or suspensions etc.), or as compositions for parenteral (e.g. injection solutions), rectal (e.g. suppositories) or nasal (e.g. aerosols) administration.
  • the pharmaceutical compositions may release the active ingredient at once, in which case the duration of the effect depends only on the duration of effect of the applied ingredients When applying special pharmaceutical compositions, however, the release of the active ingredient may be prolonged, and in this case the duration of the therapeutic effect is influenced by the form of the pharmaceutical composition as well (sustained-release or controlled-release preparations)
  • compositions can be prepared by methods generally applied in the pharmaceutical industry
  • inorganic salts secondary calcium phosphate, calcium sulfate, calcium carbonate, etc
  • gelatin polyvinyl pyrrolidone, different cellulose ethers (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, etc ), hydrolyzed starches, various vegetal gums (gum arable, guar gum) may be applied in solutions formed with water, C ⁇ - aliphatic alcohols or the mixtures thereof
  • disintegrant various kinds of starches (potato, corn, wheat, etc ) as well as super-disintegrants (carboxymethyl cellulose [the commercial product known as Ac-di-sol], carboxymethyl starch Na [commercial products known as P ⁇ mojel, Ultraamilopectin, Explo-Tab], polyvinyl
  • the preparation of the active ingredients and auxiliaries for the tabletting procedure may be carried out by dry or damp " granulation, or - when applying directly compressable auxiliaries, such as microcrystalline cellulose, spray-homogenized lactose, Tablettose, Ceilactose, etc. - by a simple spray-homogenization.
  • auxiliaries such as microcrystalline cellulose, spray-homogenized lactose, Tablettose, Ceilactose, etc. - by a simple spray-homogenization.
  • the granules or the spray-homogenized ingredients instead of being tabletted, may also be filled into hard gelatin capsules. In this way hard gelatin capsule formulations can be prepared.
  • hydrophilic polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyacrylic acid derivatives, polysaccharoses, guar gum, xanthan gum, etc.
  • hydrophobic polymers such as ethyl cellulose, metacrylic acid esther copolymers, polyvinyl acetate, polyvinyl butyral, etc. and mixtures thereof
  • the matrix having a function of retarding the release of the active ingredient may, however, be produced by the application of mixtures of hydrophilic and hydrophobic polymers, as well as by the application of mixtures of polymer substances and fat-like substances
  • the matrix preparations may also be prepared in the form of multi-layer tablets by incorporating the ingredients in different layers each In this way the release profile of the ingredients can more readily be adjusted to their individual pharmacokinetic properties
  • the coTitrolled-release preparations containing the active ingredients according to the present invention may also be produced in the form of coated pellets
  • the preparation of pellets can be carried out either from the individual active ingredients or from mixtures thereof
  • the pellets may be prepared by extrusion spheronization, rotogranulation or placebo layering methods
  • the pellets may be coated in rotating or fluidization apparatus
  • As coating agent solutions of water-insoluble polymer substances in organic solvents usually in C 1 . 3 aliphatic alcohols and/or C ⁇ -2 chlorinated carbohydrates containing two or more chlorine atoms, acetone and/or ethyl acetate or the mixtures thereof), or aqueous dispersions of same may be applied
  • the active ingredients of the present invention may also be finished in the form of osmotic or diffusion-osmotic preparations
  • tablets containing hydrophilic polymers e g hydroxypropyl methyl cellulose
  • these tablets are then coated by methods known from the literature with a semipermeable (such as cellulose acetate) or permeable (such as aminomethacrylate copolymer) film layer, and a passageway is bored into the layer through which the active ingredient can be osmotically pressed into the aqueous medium
  • the setting free velocity of the active ingredient may be preferably adjusted to the rate that at least 80 % of the active ingredient should be released in vitro within 2 to 24 hours (measured as specified in the pharmacopoeias)
  • cosolvents may be e g the following substances ethyl alcohol propylene glycol, polyethylene glycol, sorbite, cyclodext ⁇ nes, surface active agents, polyethylene glycol/polypropylene glycol copolymers, etc
  • compositions When injectable compositions are produced, usually only preparations containing organic cosolvents may be formed because of the above considerations In these preparations, in addition to the above-mentioned cosolvents further substances (such as benzyl alcohol, dimethyl acetamide methylpyrrolidone, etc ) may also be applied If desired the injections may be produced in the form of emulsion preparations as well In this case the ingredients, in the form of bases, are dissolved in liquid, fat-like auxiliary substances (such as soya oil) and the emulsification of the oily solution in aqueous medium is carried out by the application of surface active agents (e g lecithins)
  • surface active agents e g lecithins
  • Suppository preparations may be prepared by methods known from the literature The ingredients are dissolved or suspended in the melted suppository matrix then the liquid "mixture is poured into suppository forms or into small suppository-shaped polymer blisters pre-fab ⁇ cated from a polymer film and solidified by cooling
  • binding material either natural (e g cocoa butter) or synthetic fat-like substances (e g commercial products of the trade name Witepsol) may be applied
  • the active ingredient gets to the respiratory system in the form of sprayed drops or powder/air suspension
  • the active ingredients according to the invention primarily formulations suitable for nasal administration may be applied
  • the solution or suspension of the active ingredients is filled into holders supplied with a proportioning valve either with or without the application of a power-gas
  • a nozzle supplemented with a proportioning pump is to be applied

Abstract

The invention relates to the use of 2,3-benzodiazepine derivatives for the preparation of pharmaceutical compositions useful for the treatment or prevention of diseases connected with the endogenous opioid system, particularly disturbances of the hedonic state. Particularly preferable 2,3-benzodiazepine derivatives for use according to the present invention are the following compounds: 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine (tofisopam), 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (girisopam), or 1-(4-aminophenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (nerisopam).

Description

USE OF 2 , 3-BENZODIAZEPINE DERIVATES FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS TO TREAT DISEASES CONNECTED WITH THE ENDOGENOUS OPTOID SYSTEM
Technical field of the invention
This invention relates to the use of 2,3-benzodιazepιne derivatives for the preparation of pharmaceutical compositions " useful for the treatment or prevention of diseases connected with disturbances of the opioid system Background of the invention
Hedonia (the overstated demand of pleasure), as well as ahedonia (inability to feel pleasure) are known characteristic symptoms of different mental diseases These symptoms are mentioned in the Diagnostic and Statistical Manual of Mental Disorders, IV ed (American Psychiatric Association, Washington D C , USA, 1994) among diagnostic criteria for schizophrenia and depression In the development of drug addiction and alcoholism the increased desire of pleasure is considered to play an important role by initiating the progress of disease state [Drug addiction and alcoholism and opioid signals, Koob, G F Ann N Y Acad Sci 654 1171-191 (1992)] Under psychological circumstances the state of pleasure is primarily the consequence of specific actions of the endogenous opioid peptides [(Berπdge, K C Neurosci Biobehav Rev 20 1-25 (1996)] There is a double specificity of action of the endogenous opioid peptides on the one hand the opioid peptide is released and acts only in areas of the brain performed to evoke the state of pleasure, on the other hand the appropriate receptor of the opioid peptides is activated on the effect of stimuli evoking pleasure The main opioid receptor types, namely μ, K and δ do not play equal roles in producing the feeling of pleasure Summary of the invention
The present invention is based on the recognition that the effect of 2"3-benzodιazepιne derivatives on the behaviour of experimental animals is inhibited in states of opioid tolerance induced by morphine This means that the compounds are acting via the opioid signal transduction system Consequently, the 2,3-benzodιazepιnes may be employed in the therapy or prevention of disease states in which the endogenous opioid system is playing a role Disturbances of the hedonic state (increased or depressed ability of feeling pleasure) are the most characteristic examples of these symptoms of diseases
The objects of the present invention are as follows
- to provide pharmaceutical compositions containing as active ingredient a 2,3-benzodιazepιne derivative useful for the treatment or prevention of diseases connected with the opioid system, particularly disturbances of the hedonic state,
- to provide a process for the preparation of pharmaceutical compositions suitable for the treatment or prevention of diseases connected with the disturbances of the endogenous opioid neural system, particularly disturbances of the hedonic behaviour, - to provide a method of use of 2,3-benzodιazepιne derivatives for the treatment or prevention of the above- mentioned diseases,
- to provide a process for the treatment or prevention of the above-mentioned diseases by applying 2,3- benzodiazepme derivatives
Detailed description of the invention
According to the present invention the following 2,3- benzodiazepine derivatives are preferably used
1 -(3 ,4-d ιmethoxyphenyl)-4-methyl-5-ethyl-7 , 8- dιmethoxy-5H-2,3-benzodιazepιne (tofisopam),
1 -(3-chlorophenyl)-4-methyl-7,8-dιmethoxy-5H-2,3- benzodiazepine (giπsopam), or
1 -(4-amιnophenyl)-4-methyl-7,8-dιmethoxy-5H-2,3- benzodiazepine (nensopam)
According to a preferred embodiment of the present invention the following 2,3-benzodιazepιne derivative is used
1 -(3 ,4-d ιmethoxyphenyl)-4-methyl-5-ethyl-7 , 8- dιmethoxy-5H-2,3-benzodιazepιne (tofisopam)
The efficacy of 2,3-benzodιazepιnes in the treatment of hedonic disturbances was proved by the following experiments Experiments
The experiments were carried out in Charles River Wistar rats The animals were treated subcutaneously with saline or morphine for 4 consecutive days Treatments were carried out twice a day between 8 and 9 o'clock a m and between 17 and 18 o'clock p m The group treated with morphine received on the first day two times 5 mg/kg, on the second day two times 10 mg/kg, on the third day two times 15 mg/kg and on the fourth day two times 20 mg/kg of morphine This treatment schedule decreases the analgesic potency of morphine to about one fifth 18 hours after the last treatment The test compounds, that is the 2,3- benzodiazepine derivatives were administered on the fifth day On the fifth day of the experiment, 15-20 hours after the last treatment, open field tests were carried out as specified in the literature [(Van Ree, J M , G Wolternik "Motility and grooming as measures of anxiolysis with homophtalazines", Eur J Pharmacpl 72 107-111 (1981)] The motility (the number of crossing one of the lines among the 16 squares on the surface of the open field) and the number and length of grooming periods were measured during an observation period of 10 minutes
The obtained results show that the tested 2,3- benzodiazepines decreased the motility (Tables 1-3 and Figure 1 ) of the test animals In parallel with the decrease of motility the frequency and length of the grooming period increased, too These effects indicate the anxiolytic property of the test compounds [(K Horvath, F Andrasi, P Botka, T Hamon Acta Physiol Hung 79 , 153-161 (1992)] In the state of morphine tolerance the above-described effects of the compounds disappeared or basically decreased Table 1
The effect of topisopam in open field test in rats S E standard error of the mean, n number of measurements
Figure imgf000007_0001
Table 2
The effect of nehsopam in open field test in rats S.E.: standard error of the mean, n:number of measurements
Motility/10 min Grooming Grooming time number of crossings number/10 min (sec)
Saline- Mean ±S.E n Mean ±S.E n Mean ±S.E n treated
Control 158 1 10 2 19 4 00 0 78 19 10 5 3 00 13 neπsopam 161 0 28.8 5 5.60 1 28 5
0.3 mg/kg nerisopam 121.9 22.1 10 6.00 1.28 10 22.0 6.85 5
0 6 mg/kg nerisopam 92.5 14.9 10 3.00 0.59 10 22 8 8.30 5
1 2 mg/kg
Morphine tolerant
Control 109.9 10.8 10 4.60 1.03 10 80.6 36.8 10 nerisopam 129 3 34.0 5 3.33 1.52 5
0 3 mg/kg nerisopam 92.8 9.52 10 5.80 1.35 10 61 8 20 9 10
0 6 mg/kg nerisopam 1 15 8 6.06 10 3 72 0.63 10 25 6 12 0 10
1.2 mg/kg Table 3
The effect of girisopam in open field test in rats S E standard error of the mean, n number of measurements
Figure imgf000009_0001
Further results are shown in Figure 1 Explanation
Figure 1 shows the effect of tofisopam, nerisopam and girisopam on the motility and grooming behaviour of rats in open field test after treatment with saline or morpholine The results of Tables 1-3 are presented as percentages of the control values The vertical bars indicate the standard errors of the mean, *P 0 05, **P 0 01 (analysis of variance followed by Duncan test)
The above results show that the state of morpholine tolerance inhibits the anxiolytic effect of 2,3-benzodιazepιnes The surprising results prove that the said compounds exert their action via the opioid receptoral mechanism The inhibition of an effect by morphine tolerance (in a state when the opioid neuronal system is relatively intensive towards compounds acting on specific receptors) is an accepted evidence to prove that an action is mediated by opioids In this latter case the effect of a given compound is inhibited by opioid tolerance [(Martin, W R C G Eades, J A Thompson R E Huppler, P E Gilbert J Pharmacol Exptl Ther , 197 517-532 1 (1976)]
Consequently, the 2,3-benzodιazepιnes induce their psychopharmacological effects (anxiolysis) due to an action on the endogenous opioid system evoking good feeling, pleasure This effect envisages that the 2,3-benzodιazepιne derivatives may be employed to treat or prevent hedonic disturbances These disturbances are present in cases of schizophrenia, depression, alcoholism or drug dependence In cases of schizophrenics with anhedonia the 2,3- benzodiazepine derivatives increasing the feeling of pleasure decrease the desire for drug or alcohol. Similarly, depression induced by stress or loss of weight of animals induced by stress may be counteracted by 2,3-benzodiazepines.
The doses of the 2,3-benzodiazepine derivatives are shown in the following Table:
Figure imgf000011_0001
The pharmaceutical compositions of the present invention useful for the treatment or prevention of diseases connected with the opioid system can be prepared by methods known per se by admixing the active ingredient with suitable inert solid or liquid carriers and bringing the mixture to galenic form.
The pharmaceutical compositions of the present invention can be presented preferably in the form of orally administerable preparations (such as tablets, pills, coated pills, soft or hard gelatin capsules, solutions or suspensions etc.), or as compositions for parenteral (e.g. injection solutions), rectal (e.g. suppositories) or nasal (e.g. aerosols) administration. The pharmaceutical compositions may release the active ingredient at once, in which case the duration of the effect depends only on the duration of effect of the applied ingredients When applying special pharmaceutical compositions, however, the release of the active ingredient may be prolonged, and in this case the duration of the therapeutic effect is influenced by the form of the pharmaceutical composition as well (sustained-release or controlled-release preparations)
The pharmaceutical compositions can be prepared by methods generally applied in the pharmaceutical industry
In the course of further processing the product to tablets different kinds of lactose (monohydrate, anhydrate, spray-dried substances, etc ), inorganic salts (secondary calcium phosphate, calcium sulfate, calcium carbonate, etc ) may be applied as fillers As binding agents gelatin, polyvinyl pyrrolidone, different cellulose ethers (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, etc ), hydrolyzed starches, various vegetal gums (gum arable, guar gum) may be applied in solutions formed with water, Cι- aliphatic alcohols or the mixtures thereof As disintegrant various kinds of starches (potato, corn, wheat, etc ) as well as super-disintegrants (carboxymethyl cellulose [the commercial product known as Ac-di-sol], carboxymethyl starch Na [commercial products known as Pπmojel, Ultraamilopectin, Explo-Tab], polyvinyl polypyrrolidone [the product of trade name Po plasdone], etc ) may be used As lubricant or fluidity improving auxiliary material alkali metal stearates (such as magnesium or calcium stearate), fatty acids (stearic acid), various glycerides (e.g. products of the trade name Precirol, Cutina H), paraffin oil or silicon oils, silicon oil emulsions, talc or silica may be used.
The preparation of the active ingredients and auxiliaries for the tabletting procedure may be carried out by dry or damp" granulation, or - when applying directly compressable auxiliaries, such as microcrystalline cellulose, spray-homogenized lactose, Tablettose, Ceilactose, etc. - by a simple spray-homogenization. If desired, the granules or the spray-homogenized ingredients, instead of being tabletted, may also be filled into hard gelatin capsules. In this way hard gelatin capsule formulations can be prepared.
For the preparation of controlled release (retard) solid pharmaceutical dosage forms all the technologies known from the literature may be applied. So various matrix preparations may be prepared, wherein hydrophilic polymers (such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyacrylic acid derivatives, polysaccharoses, guar gum, xanthan gum, etc.) and mixtures thereof or hydrophobic polymers (such as ethyl cellulose, metacrylic acid esther copolymers, polyvinyl acetate, polyvinyl butyral, etc. and mixtures thereof) may be applied as retarding matrix substance. The matrix having a function of retarding the release of the active ingredient may, however, be produced by the application of mixtures of hydrophilic and hydrophobic polymers, as well as by the application of mixtures of polymer substances and fat-like substances The matrix preparations may also be prepared in the form of multi-layer tablets by incorporating the ingredients in different layers each In this way the release profile of the ingredients can more readily be adjusted to their individual pharmacokinetic properties
The coTitrolled-release preparations containing the active ingredients according to the present invention may also be produced in the form of coated pellets The preparation of pellets can be carried out either from the individual active ingredients or from mixtures thereof The pellets may be prepared by extrusion spheronization, rotogranulation or placebo layering methods The pellets may be coated in rotating or fluidization apparatus As coating agent solutions of water-insoluble polymer substances in organic solvents (usually in C1.3 aliphatic alcohols and/or Cι-2 chlorinated carbohydrates containing two or more chlorine atoms, acetone and/or ethyl acetate or the mixtures thereof), or aqueous dispersions of same may be applied
If desired, the active ingredients of the present invention may also be finished in the form of osmotic or diffusion-osmotic preparations In this case tablets containing hydrophilic polymers (e g hydroxypropyl methyl cellulose) are prepared from the active ingredients, these tablets are then coated by methods known from the literature with a semipermeable (such as cellulose acetate) or permeable (such as aminomethacrylate copolymer) film layer, and a passageway is bored into the layer through which the active ingredient can be osmotically pressed into the aqueous medium
By suitable preparation of the sustained release compositions the setting free velocity of the active ingredient may be preferably adjusted to the rate that at least 80 % of the active ingredient should be released in vitro within 2 to 24 hours (measured as specified in the pharmacopoeias)
When preparing pharmaceutical preparations in liquid form, either the pH value of the preparations is adjusted so that it does not exceed 5 because of the poor solubility in aqueous medium of the 2,3-benzodιazepιne derivatives at pH values higher than 5, or substances improving the solubility (cosolvents) have to be applied Such cosolvents may be e g the following substances ethyl alcohol propylene glycol, polyethylene glycol, sorbite, cyclodextπnes, surface active agents, polyethylene glycol/polypropylene glycol copolymers, etc
When injectable compositions are produced, usually only preparations containing organic cosolvents may be formed because of the above considerations In these preparations, in addition to the above-mentioned cosolvents further substances (such as benzyl alcohol, dimethyl acetamide methylpyrrolidone, etc ) may also be applied If desired the injections may be produced in the form of emulsion preparations as well In this case the ingredients, in the form of bases, are dissolved in liquid, fat-like auxiliary substances (such as soya oil) and the emulsification of the oily solution in aqueous medium is carried out by the application of surface active agents (e g lecithins)
Suppository preparations may be prepared by methods known from the literature The ingredients are dissolved or suspended in the melted suppository matrix then the liquid "mixture is poured into suppository forms or into small suppository-shaped polymer blisters pre-fabπcated from a polymer film and solidified by cooling As binding material either natural (e g cocoa butter) or synthetic fat-like substances (e g commercial products of the trade name Witepsol) may be applied
When using aerosol-type preparations, the active ingredient gets to the respiratory system in the form of sprayed drops or powder/air suspension In case of the active ingredients according to the invention primarily formulations suitable for nasal administration may be applied When preparing such formulations the solution or suspension of the active ingredients is filled into holders supplied with a proportioning valve either with or without the application of a power-gas When no power-gas is used, a nozzle supplemented with a proportioning pump is to be applied
The invention is further illustrated by the following Examples of non-limiting character Example 1 Preparation of tablets
5 parts by weight of tofisopam and 9 parts by weight of lactose are admixed with 3 parts by weight of microcrystalline cellulose The powder mixture is granulated in a rotary fluid granulator with the solution of 0 5 parts by weight of polyvinyl pyrrolidone in "4 parts by weight of ion-exchanged water The granules are then dried, 1 3 parts by weight of carboxymethyl cellulose and 0 2 parts by weight of magnesium stearate are added to it and the mixture is passed through a 1 0 mm mesh sieve The thus obtained granules are made up into tablets on a rotary tabletting machine by using a tabletting tool 8 mm in diameter Thus tablets containing 50 mg of active ingredient are prepared (average weight 200 mg) Example 2 Preparation of hard gelatin capsules
The sieved granules prepared according to Example 1 are filled into hard gelatine capsules of size No 2 Example 3 Preparation of sustained release tablets
5 parts by weight of girisopam are mixed with 8 parts by weight of hydroxypropyl methyl cellulose (commercial name Metocel K 4 M, made by Colorcon Ltd ) and 10 parts by weight of lactose The powder mixture is granulated in a spiral air stream granulator with the solution of 0 4 parts by weight of polyvinyl pyrrolidone in isopropanol The granules are dried and 0 3 parts by weight of talc and 0 3 parts by weight of magnesium stearate are added to it The granules are then passed through a 1 0 mm mesh sieve, pressed into tablets with the aid of a rotary tabletting machine by using a 10 m diameter lenticular pressing tool Thus tablets containing 50 mg of active ingredient are prepared (average weight 300 mg) Example 4 Preparation of suppositories
5 parts by weight of tofisopam are dispersed in 55 parts by weight of suppository matrix (Witepsol S 58, commercial trade name) at a temperature of 50°C The suspension, while still liquid, is filled into suppository forms, the suppositories are solidified by cooling to a temperature of 25°C and removed from the forms Thus suppositories average weight of the thus obtained suppositories containing 50 mg of active ingredient are prepared (average weight 6 g)

Claims

What we claim is:
1. Use of 2,3-benzod╬╣azep╬╣ne derivatives for the preparation of pharmaceutical compositions useful for the treatment or prevention of diseases connected with the endogenous opioid system, particularly disturbances of the hedonic state "
2. A use as claimed in claim 1 , which comprises applying as 2,3-benzod╬╣azep╬╣ne
1 -(3 ,4-d ╬╣methoxyp henyl)-4-methyl-5-ethyl-7 , 8- d╬╣methoxy-5H-2,3-benzod╬╣azep╬╣ne (tofisopam),
1 -(3-chlorophenyl)-4-methyl-7,8-d╬╣methoxy-5H-2,3- benzodiazepine (girisopam), or
1 -(4-ammophenyl)-4-methyl-7,8-d╬╣methoxy-5H-2,3- benzodiazepine (nerisopam)
3. A use as claimed in claim 2, which comprises applying as 2,3-benzod╬╣azep╬╣ne 1-(3,4-d╬╣methoxyphenyl)-4- methyl-5-ethyl-7,8-d╬╣methoxy-5H-2,3-benzod╬╣azep╬╣ne (tofisopam)
4. Pharmaceutical compositions useful for the treatment or prevention of diseases connected with the endogenous opioid system, particularly disturbances of the hedonic state, comprising as active ingredient a 2,3- benzodiazepine derivative together with inert, solid or liquid pharmaceutical carriers and/or auxiliaries
5. Pharmaceutical compositions as claimed in claim 4 comprising as active ingredient a compound according to claim 2
6. A process for the preparation of pharmaceutical compositions comprising as active ingredient a 2,3- benzodiazepine derivative, which comprises admixing the active ingredient with carriers and/or auxiliaries generally used in the pharmaceutical industry and converting the mixture into pharmaceutical compositions suitable for the treatment or prevention of diseases connected with the endogenous opioid system, particularly disturbances of the hedonic state
7. A process as claimed in claim 6, which comprises using as active ingredient
1 -(3 ,4-d ╬╣methoxyp henyl)-4-methyl-5-ethyl-7 , 8- d╬╣methoxy-5H-2,3-benzod╬╣azep╬╣ne (tofisopam),
1 -(3-chlorophenyl)-4-methyl-7,8-d╬╣methoxy-5H-2,3- benzodiazepine (girisopam), or
1 -(4-am╬╣nophenyl)-4-methyl-7,8-d╬╣methoxy-5H-2,3- benzodiazepine (nerisopam)
8. A process as claimed in claim 7, which comprises using as active ingredient 1-(3,4-d╬╣methoxyphenyl)-4-methyl- 5-ethyl-7,8-d╬╣methoxy-5H-2,3-benzod╬╣azep╬╣ne (tofisopam)
9. A process as claimed in any of claims 6 to 8, which comprises preparing a pharmaceutical composition suitable for oral, rectal or parenteral administration
10. A process as claimed in claim 9, wherein the said pharmaceutical composition is in the form of tablets, capsules, dragees, solutions, suspensions, suppositories or injections
11. A process as claimed in any of claims 9 or 10 which comprises preparing pharmaceutical compositions in the form of tablets, capsules, dragees, solutions, suspensions, suppositories or injections containing 5 to 100 mg of active ingredient
12. A method for the treatment or prevention of diseases connected with the endogenous opioid system, particularly disturbances of the hedonic state, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a 2 3- benzodiazepine derivative
13. A method as claimed in claim 12, which comprises administering a 2,3-benzod╬╣azep╬╣ne derivative specified in claim 2
PCT/HU1998/000069 1997-07-24 1998-07-23 Use of 2,3-benzodiazepine derivatives for the preparation of pharmaceutical compositions to treat diseases connected with the endogenous opioid system WO1999004797A1 (en)

Priority Applications (1)

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AU85538/98A AU8553898A (en) 1997-07-24 1998-07-23 Use of 2,3-benzodiazepine derivatives for the preparation of pharmaceutical compositions to treat diseases connected with the endogenous opioid system

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HUP9701284 1997-07-24
HU9701284A HUP9701284A3 (en) 1997-07-24 1997-07-24 Use of 2,3-benzodiazepine derivatives for producing pharmaceutical compositions for treating and prophylacting illnesses and conditions connected with the endogene opioide system

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US10350157B2 (en) 2001-05-24 2019-07-16 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US8955512B2 (en) 2001-06-05 2015-02-17 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US9308208B2 (en) 2001-06-05 2016-04-12 Alexza Pharmaceuticals, Inc. Aerosol generating method and device
US9439907B2 (en) 2001-06-05 2016-09-13 Alexza Pharmaceutical, Inc. Method of forming an aerosol for inhalation delivery
US9687487B2 (en) 2001-06-05 2017-06-27 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
US11065400B2 (en) 2001-06-05 2021-07-20 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
AU2003263357B2 (en) * 2002-09-13 2009-02-26 Motac Neuroscience Limited Treatment of basal ganglia-related movement disorders with 2,3-benzodiazepines
US8991387B2 (en) 2003-05-21 2015-03-31 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
US9370629B2 (en) 2003-05-21 2016-06-21 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
US11642473B2 (en) 2007-03-09 2023-05-09 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device

Also Published As

Publication number Publication date
AU8553898A (en) 1999-02-16
HUP9701284A3 (en) 2005-11-28
HUP9701284A2 (en) 1999-03-29
HU9701284D0 (en) 1997-09-29

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