(19)
(11)EP 2 614 821 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
09.11.2016 Bulletin 2016/45

(21)Application number: 10857022.7

(22)Date of filing:  06.09.2010
(51)International Patent Classification (IPC): 
A61K 38/05(2006.01)
A61K 38/17(2006.01)
A61K 38/21(2006.01)
A61K 31/18(2006.01)
A61K 31/198(2006.01)
A61K 31/355(2006.01)
A61K 31/525(2006.01)
A61K 31/5513(2006.01)
A61K 33/00(2006.01)
A61P 25/22(2006.01)
A61K 38/18(2006.01)
A61K 45/06(2006.01)
A61K 31/195(2006.01)
A61K 31/216(2006.01)
A61K 31/51(2006.01)
A61K 31/55(2006.01)
A61K 31/702(2006.01)
(86)International application number:
PCT/KR2010/006035
(87)International publication number:
WO 2012/033235 (15.03.2012 Gazette  2012/11)

(54)

PHARMACEUTICAL COMPOSITION FOR TREATING ANXIETY DISORDER, CONTAINING N-ACETYL-L-CYSTEINE OR DERIVATIVE THEREOF

PHARMAZEUTISCHE ZUSAMMENSETZUNG ZUR BEHANDLUNG VON ANGSTSTÖRUNGEN MIT N-ACETYL-L-CYSTEIN ODER EINEM DERIVAT DAVON

COMPOSITION PHARMACEUTIQUE POUR LE TRAITEMENT D'UN TROUBLE DE L'ANXIÉTÉ, CONTENANT DE LA N-ACÉTYL-L-CYSTÉINE OU UN DÉRIVÉ DE CELLE-CI


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

(43)Date of publication of application:
17.07.2013 Bulletin 2013/29

(73)Proprietor: SNU R&DB Foundation
Seoul 151-742 (KR)

(72)Inventors:
  • CHOI, Suk Woo
    Seoul 151-821 (KR)
  • LEE, Suk Won
    Seoul 151-821 (KR)
  • KIM, Jeong Yeon
    Seoul 151-782 (KR)
  • SONG, Beom Jong
    Seoul 137-796 (KR)
  • HONG, In Gie
    Seoul 151-050 (KR)
  • PARK, Sung Mo
    Bucheon-Si Gyeonggi-Do 422-715 (KR)
  • KIM, Ji Hye
    Seoul 137-062 (KR)
  • LEE, Jun Uk
    Seoul 151-050 (KR)
  • AN, Bo Bae
    Seongnam-Si Gyeonggi-Do 463-739 (KR)

(74)Representative: Bühler, Dirk 
Maiwald Patentanwalts GmbH Elisenhof Elisenstraße 3
80335 München
80335 München (DE)


(56)References cited: : 
WO-A1-2006/108055
KR-A- 20080 028 357
US-A1- 2007 286 909
DE-U1-202006 013 518
US-A1- 2006 257 502
US-A1- 2010 184 806
  
  • ZIEKER J ET AL: "Differential gene expression in peripheral blood of patients suffering from post-traumatic stress disorder", MOLECULAR PSYCHIATRY, BASINGSTOKE, GB, vol. 12, no. 2, 1 February 2007 (2007-02-01), pages 116-118, XP002507713, ISSN: 1359-4184, DOI: 10.1038/SJ.MP.4001905
  • SANJAY J.M. ET AL.: 'Recent Advances in the Neurobiology of Anxiety Disorders: Implications for Novel Therapeutics' AM.J.MED.GENET. PART C vol. 148C, 2008, pages 89 - 98, XP055082259
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

BACKGROUND OF INVENTION


Field of the Invention



[0001] The present disclosure relates to a composition comprising N-acetyl-L-cysteine or its derivatives before the background of treating anxiety disorder. Particularly, the composition as claimed in independent claim 1 is useful in preventing the return of fear memories in a patient suffering from post-traumatic stress disorder or phobia as claimed in independent claim 1.

Description of the Related Art



[0002] According to the Epidemiological Survey of Mental Disorders in Korea recently performed on 6,114 people between ages 18 to 64 by Seoul National University and National Mental Hospital, the lifetime prevalence of mental disorder was found to be about 34%. This indicates that one out of every three adults suffers from the illness at least once during their lifetime. Particularly, the survey shows that the lifetime prevalence of anxiety disorder including obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), phobia and the like counts for 6.4% of the total illness.

[0003] It has been shown that through a widely used fear conditioning method in animal model, the limbic system such as amygdaloid body and nucleus accumbens are involved in the development of PTSD. Recently it has also been suggested that prefrontal lobe was involved in the return of fear memories (Moussawi et al., Nat.Neurosci. 2009 (2):182-9). In addition, it has been shown that the changes in the expression of receptors and the secretion of glutamate in the amygdaloid body and prefrontal lobe play an important role in the maintenance of fear memories. The treatment of PTSD and phobia has been hampered by the return fear memories. The available treatments for PTSD and phobia include cognitive restructuring, group therapy, exposure therapy, selective serotonin reuptake inhibitors (SSRI) and the like. However, they are symptomatic therapy and only temporary. Therefore there are demands for the new therapy.

[0004] Among them exposure therapy is a behavior therapy, which involves reliving a traumatic situation or confrontation with a feared object, situation, thought or memory in a controlled and therapeutic environment. It is considered to be one of the most effective treatments for the condition due to its effectiveness in reducing the symptoms of PTSD. However, it has some clinical limitations. Exposure therapy is not permanent and the symptoms return in an unexpected time, place and/or situation. Many researches have been done to prevent the return of fear memories after exposure therapy (Schiller et al., 2010, Nature 463(7277):49-53; Kindt et al., 2009, Nat. Neurosci. 12(3):256-8). Further the combined use of a drug together with exposure therapy has been done to improve the efficacy of the therapy and to overcome the limitations (Ressler et al., 2004, Arch. Gen. Psychiatry: 1138-42).

[0005] Currently there are only limited drugs available to treat anxiety disorder such as PTSD and phobia, the efficacy of which is only marginal and temporary (US 2007/286909, DE 20 2006 013518, WO 2006/108055).

SUMMARY OF THE INVENTION



[0006] The present disclosure is to provide a pharmaceutical composition comprising N-acetyl-L-cysteine or its derivatives for use in preventing the return of fear memories in a patient suffering from post-traumatic stress disorder or phobia, wherein said patient is treated with exposure therapy and wherein said pharmaceutical composition is combined with said exposure therapy, wherein said
derivative thereof is N-acetyl-L-cysteine amide or its sila derivative.

[0007] In an embodiment, the composition as claimed may further comprises at least one of supplementary components selected from the group consisting of vitamin, mineral and blood circulation enhancing agents.

BRIEF DESCRIPTION OF THE DRAWINGS



[0008] These and/or other aspects and advantages of the invention will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:

FIG. 1 is an exemplary schematic representation of the experimental design to administer N-Acetyl-L-cysteine during the fear memory extinction process.

FIG. 2 is a graph showing the effect of N-Acetyl-L-cysteine administered during the fear memory extinction process. The result indicates that the return of fear-memories was prevented and the effect was long- lasted.

FIG. 3 is an exemplary schematic representation of the experimental design to determine the effect of N-Acetyl-L-cysteine administered after the fear memory extinction process, in which the fear memories were renewed one day after the administration of N-Acetyl-L-cysteine.

FIG. 4 is a graph showing the effect of N-Acetyl-L-cysteine administered after the fear memory extinction process and before the renewal of fear memories. The result indicates that the return of fear-memories was prevented in the rats tested.

FIG. 5 is an exemplary schematic representation of the experimental design to determine the extent to which the return is prevented by the administration of N-Acetyl-L-cysteine that was administered immediately before the renewal of fear memories.

FIG. 6 is a graph showing that the N-Acetyl-L-cysteine administered immediately before the renewal of fear memories prevented the return of fear-memories in the rats tested.


DETAILED DESCRIPTION OF THE EMBODIMENTS



[0009] The present disclosure relates to a pharmaceutical composition comprising N-acetyl-L-cysteine (NAC) or its derivatives as claimed in claim 1 for the use as claimed in claim 1.

[0010] The present composition comprising NAC prevents the return of fear memories, which is a serious side effect of exposure therapy, when combined with exposure therapy to treat post-traumatic stress disorder or phobia. NAC is known to regulate the concentration of glutamate outside of the nerve cells and receptors on the nerve cells in normal ranges and those effects are suspected to prevent the relapse of fear memory. Therefore, NAC and its derivatives may be useful for treating various anxiety disorder including post-traumatic stress disorder and phobia and the like.

[0011] The term "anxiety disorder" as used herein refers to a psychiatric disorder or condition or symptoms where excessive apprehension, uneasiness or fear causes psychological distress or dissociative reaction and includes generalized anxiety disorder, phobia (including specific phobias such as social phobia and agoraphobia , panic disorder, Obsessive-Compulsive Disorder, Post traumatic stress disorder (PTSD) and the like.

[0012] The effective component of the present composition is N-acetyl-L-cysteine or its derivatives which areN-acetyl-L-cysteine amide (Leonid Grinberg et al., Free Radical Biology & Medicine. 2005, 38, 136-145) or its sila derivatives (Uzma I. Zakai et al., Appl. Organometal. Chem. 2010, 24, 189-192). In one exemplary embodiment of the present disclosure, the preferred component is N-acetyl-L-cysteine.

[0013] N-acetyl-L-cysteine (NAC) is a precursor of an amino acid L-cysteine. Also, NAC is a precursor of glutathione which is an antioxidant that removes toxins from the liver. Further NAC has been shown to slow down the replication of Human Immunodeficiency virus, and to protect cells from the damage caused by chemotherapy, radio therapy and others drugs. NAC has been commercialized as medicine or health supplements due to its therapeutic effects on bronchitis, asthma, pneumonia and cystic fibrosis where NAC has been shown to clear the mucus. NAC is a weak acid having pKa of 3.24 and usually formulated as a tablet with calcium stearate.

[0014] Also, the present composition may further comprise at least one of supplemental components such as vitamins, minerals and blood circulation enhancing agents.

[0015] The example of vitamins which may be included in the present composition includes, but is not limited to, vitamins B1, B2, B6, B12, and C, pantothenate calcium, nicotinamide, folic acid and biotin and the like.

[0016] The example of minerals which may be included in the present composition includes, but is not limited to, zinc, iron, calcium, and magnesium.

[0017] The combined use of vitamins and minerals together with the present composition is beneficial because it complements the bioactivity. The vitamins and minerals may be included in the composition at the concentration of about 0.1 to 10% by weight of the total. Particularly, vitamins B1, B2, or C are included in the composition at the final concentration of about 0.01 to 3% by weight, about 0.01 to 3% by weight and 0.01 to 4 % by weight of the total, respectively.

[0018] The exemplary blood circulation enhancing agents that may be used for the present composition include, but are not limited to, gamma linoleic acid, EPA, and tocopherol and the like.

[0019] The blood circulation enhancing agents used with the present composition stimulates the blood circulation and complements the bioactivity. The preferred blood circulation agent is tocopherol, which may be included in the composition at the final concentration of about 5 to 30% by weight.

[0020] The present pharmaceutical composition can be administered by conventional methods known in the related art. The preferred routes of administration include intravenous, peritoneal, subcutaneous, intradermal, intranodal, muscular, transdermal, inhalation, intranasal, oral, intraocular, intraarticular, intraspinal, and intracephalic delivery.

[0021] The present pharmaceutical composition can be formulated into granules, tablets, capsules, suspension, emulsion, syrup, or aerosol for oral administration, sterilized injection fluid, suppository or can be formulated for transdermal delivery. The examples of carriers, excipients or diluents which can be used for the present composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, ethyl alcohol, methylhydroxy benzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

[0022] In one embodiment, the present pharmaceutical composition may be formulated into solid preparations for oral use. The solid preparations for oral delivery include tablets, granules, capsules, pills and powder. The solid preparations can be formulated with at least one excipient such as starch, calcium carbonate, sucrose, lactose or gelatin with the present effective ingredient. Or lubricants such as magnesium stearate, talc may also be used.

[0023] In other aspect, the present composition may be formulated into liquid preparations for oral use. The liquid preparations for oral delivery include suspension, liquid for internal use, emulsion, and syrups and the like. Also conventionally included in the preparations are inactive diluents (for example purified water, ethanol, liquid paraffin) and variety of excipients, for example, wetting agents, sweetening agents, odorants, and preservatives.

[0024] In other aspects, the present composition may be formulated into parenteral preparations particularly for peritoneal administration. The parenteral preparations include sterilized aqueous solution, non-aqueous solvent, suspension, emulsion, freeze dried preparations and suppository. The sterilized aqueous solution includes Hank's solution, Ringer's solutions or suitable buffer solutions such as buffered salt solutions. The non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable ester such as ethyl oleate. Preservatives, stabilizing agents, wetting agents, emulsifying agents, salts for regulating osmotic pressure and/or buffering agents may also be used if desired. The suppository preparation may include conventional bases such as Witepsol®, macrogol (polyethylene glycol), Tween® 61, cacao butter, Sevum Laurinum, or glycerogelatin.

[0025] The present composition formulated as described above may be administered in an effective amount via various routes including parenteral or non-parenteral methods. The term "effective amount" as used herein refers to the amount of a compound sufficient to result in the prevention or treatment of disorders or symptoms of interest.

[0026] The dosage may vary, and the optimal amount may be selected in consideration of administration routes used, age, sex, body weight, medical condition and/or other personal differences of the subject. Various amounts of the effective ingredient may be used depending on the severity of the disease, and may be administered as 1∼1000 mg/kg of body weight/day, particularly 10∼500 mg/kg of body weight/day, more particularly 100∼200 mg/kg of body weight /day.

[0027] The present composition is combined with exposure therapy for the use as claimed in independent claim 1 to treat patients suffering from PTSD or phobia, wherein it may be administered during, before and/or after the exposure therapy.

[0028] In accordance of the present disclosure, N-acetyl-L-cysteine was able to prevent the return of fear memories which is the severe side effects of exposure therapy to treat PTSD and phobia, particularly when NAC was administered during or after the exposure therapy.

[0029] Without being bound by the theory, it is presumed that NAC exerts its effects by regulating the concentration of glutamate at the normal level outside nerve cells and various receptors of nerve cells which are involved in the return of fear memories. Therefore, NAC or its derivatives can be used beneficially to treat anxiety disorders such as PTSD and phobia.

[0030] NAC, which has been approved by FDA, can be orally administered and penetrate a blood-brain barrier. Thus immediate clinical use is possible upon the demonstration of therapeutic effects of NAC on treating anxiety disorders such as PTSD and phobia

[0031] The present disclosure is further explained in more detail with reference to the following examples.

EXAMPLES


Example 1 Prevention of renewal of memory during an exposure therapy by the administration of NAC



[0032] The following experiments were performed to test the effect NAC on blocking the return of fear memories in exposure therapy to reduce the fear memories.

Example 1-1 Fear conditioning and extinction training.



[0033] All procedures were approved by the Institute of Laboratory Animal Resources of Seoul National University. Sprague-Dawley Rats (8-9 weeks old, from Samtaco, Korea) were maintained with free access to water and food with 12 hour dark/light cycles (lights off at 09:00 hrs). Group of three to six animals were used for each experiment. (26 in total)

[0034] For fear conditioning, the rats were presented with a tone (2.8 kHz, 85 dB) co-terminating with an electrical shock (1.0 mA, 1 s) three times at an interval of 100 sec.

[0035] The rats were returned to the cage 1 minute after the last shock has been applied. Three days after the conditioning, the exposure therapy was done in a chamber distinct from the conditioning chamber for both extinction training and tone tests. 10 tones were presented at an interval of 100 sec without shocks, during which the freezing responses were measured to determine the reduction of fear memories. Unpaired, two-tailed T-test was used to analyze the results.

Example 1-2 Administration of NAC



[0036] In the Example 1-1, from 3 to 5 days after the conditioning, NAC in physiological saline was peritoneally administered once a day at the concentration of 200 mg/kg, 2.5 hours before the exposure therapy was applied. The negative control was only received physiological saline. The scheme is shown in Fig. 1.

Example 1-3 Fear memory renewal test



[0037] The renewal test was done on day 12 after the conditioning was completed. The same chamber and place as it was used for the fear conditioning were used for the renewal. The rats with the extinction training were placed in the conditioning chamber and were left undisturbed for 10 minutes. Then the fear memory was recalled by presenting the rats with a tone for 30 sec. The fear memory recalled was determined by measuring the freezing response as described before (Kim et al., PNAS 104:20955-960, 2007). The freezing was defined as immobility except for respiratory movements and was quantified by trained observers who were blind to the experimental groups.

[0038] To test the sustained effects of the drug used, additional renewal test was performed on day 21 after the fear conditioning test was completed. As shown in Fig. 2, the renewal of the fear memory was blocked in the experimental groups that received NAC in contrast to the control group.

Example 2 The blockade of fear memories by the administration of NAC one day before a renewal test.



[0039] The same procedures as described in Example 1-1 were used for the conditioning and extinction training. The extinction training was performed for 4 days starting from day 3 after the conditioning was applied. On the 7th day, 200mg/kg of NAC was injected peritoneally. On the 8 and 9th day after the completion of the conditioning, the renewal test was performed to measure the response to fear as described in Example 1-3 (See Fig. 3). As shown in Fig. 4, on the 9 th day after the fear conditioning, the renewal of the fear memory was blocked in the experimental groups that received NAC in contrast to the control group.

Example 3 The prevention of fear memories by the administration of NAC immediately before a renewal test.



[0040] The same procedures as described in Example 1-1 were used for the conditioning and extinction training. The extinction training was performed for 4 days starting from the day 3 after the conditioning was applied. On the7th and 8th day after the completion of the conditioning, at 2.5 hours before the renewal test was started, 200mg/kg of NAC was injected peritoneally. The renewal test was performed as described in Example 1-3 (See Fig. 5). As shown in Fig. 6, on the 8th day after the fear conditioning, the renewal of the fear memory was blocked in the experimental groups received NAC in contrast to the control group.

[0041] In accordance with the present disclosure, NAC or its derivatives as claimed in independent claim 1 is utilized as pharmaceutical composition for the use as claimed in independent claim 1.


Claims

1. A pharmaceutical composition comprising N-acetyl-L-cysteine or a derivative thereof for use in preventing the return of fear memories in a patient suffering from post-traumatic stress disorder or phobia, wherein said patient is treated with exposure therapy and wherein said pharmaceutical composition is combined with said exposure therapy, wherein said derivative thereof is N-acetyl-L-cysteine amide or its sila derivative.
 
2. The composition for use according to claim 1, wherein the composition further comprises at least one of the supplemental components selected from the group consisting of a vitamin, a mineral and a blood circulation enhancing agent.
 
3. The composition for use according to claim 1, wherein the composition is administered during or before and/or after the exposure therapy to treat post-traumatic stress disorder or phobia.
 
4. N-acetyl-L-cysteine or a derivative thereof for use in preventing the return of fear memories in a patient suffering from post-traumatic stress disorder or phobia, wherein the patient is treated with exposure therapy and wherein said N-acetyl-L-cysteine or derivative thereof is combined with said exposure therapy, wherein said derivative thereof is N-acetyl-L-cysteine amide or its sila derivative.
 
5. The N-acetyl-L-cysteine or derivative thereof for use according to claim 4, wherein the N-acetyl-L-cysteine or derivative thereof is administered during or before and/or after the exposure therapy to treat post-traumatic stress disorder or phobia.
 


Ansprüche

1. Eine pharmazeutische Zusammensetzung umfassend N-Acetyl-L-Cystein oder ein Derivat davon zur Verwendung bei der Vermeidung der Rückkehr von Angsterinnerungen in einem Patienten, der unter posttraumatischer Belastungsstörung oder Phobie leidet, wobei besagter Patient mit Expositionstherapie behandelt wird und wobei besagte pharmazeutische Zusammensetzung mit besagter Expositionstherapie kombiniert wird, wobei besagtes Derivat davon N-Acetyl-L-Cystein Amid oder dessen Sila-Derivat ist.
 
2. Die Zusammensetzung zur Verwendung gemäß Anspruch 1, wobei die Zusammensetzung ferner mindestens eine der zusätzlichen Komponenten ausgewählt aus der Gruppe bestehend aus einem Vitamin, einem Mineral und einem durchblutungsfördernden Wirkstoff umfasst.
 
3. Die Zusammensetzung zur Verwendung gemäß Anspruch 1, wobei die Zusammensetzung während oder vor und/oder nach der Expositionstherapie verabreicht wird, um posttraumatische Belastungsstörung oder Phobie zu behandeln.
 
4. N-Acetyl-L-Cystein oder ein Derivat davon zur Verwendung bei der Vermeidung der Rückkehr von Angsterinnerungen in einem Patienten, der unter posttraumatischer Belastungsstörung oder Phobie leidet, wobei besagter Patient mit Expositionstherapie behandelt wird und wobei besagtes N-Acetyl-L-Cystein oder Derivat davon mit besagter Expositionstherapie kombiniert wird, wobei besagtes Derivat davon N-Acetyl-L-Cystein Amid oder dessen Sila-Derivat ist.
 
5. Das N-Acetyl-L-Cystein oder Derivat davon zur Verwendung gemäß Anspruch 4, wobei das N-Acetyl-L-Cystein oder Derivat davon während oder vor und/oder nach der Expositionstherapie verabreicht wird, um posttraumatische Belastungsstörung oder Phobie zu behandeln.
 


Revendications

1. Composition pharmaceutique comprenant la N-acétyl-L-cystéine ou un de ses dérivés pour une utilisation dans la prévention du retour de mémoires de peur chez un patient souffrant d'un trouble de stress post-traumatique ou d'une phobie, dans laquelle ledit patient est traité avec une thérapie d'exposition et dans laquelle ladite composition pharmaceutique est combinée avec ladite thérapie d'exposition, dans laquelle un de ses dérivés est le N-acétyl-L-cystéine amide ou son dérivé sila.
 
2. Composition pour une utilisation selon la revendication 1, dans laquelle la composition comprend en outre au moins un des composés supplémentaires choisi dans le groupe constitué par une vitamine, un minéral et un agent augmentant la circulation du sang.
 
3. Composition pour une utilisation selon la revendication 1, dans laquelle la composition est administrée durant ou avant et/ou après la thérapie d'exposition pour traiter un trouble de stress post-traumatique ou une phobie.
 
4. N-acétyl-L-cystéine ou un de se dérivés pour une utilisation dans la prévention du retour de mémoires de peur chez un patient souffrant d'un trouble de stress post-traumatique ou d'une phobie, dans lequel ledit patient est traité avec une thérapie d'exposition et dans lequel ladite N-actétyl-L-cystéine ou un de ses dérivés est combinée avec ladite thérapie d'exposition, dans lequel un de ses dérivés est le N-acétyl-L-cystéine amide ou son dérivé sila.
 
5. N-acétyl-L-cystéine ou un de ses dérivés pour une utilisation selon la revendication 4, dans lequel la N-acétyl-L-cystéine ou un de ses dérivés est administré durant ou avant et/ou après la thérapie d'exposition pour traiter un trouble de stress post-traumatique ou une phobie.
 




Drawing























Cited references

REFERENCES CITED IN THE DESCRIPTION



This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description




Non-patent literature cited in the description