Title of Invention

CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING MELATONIN

Abstract ABSTRACT CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION COMPRISIG MELATONIN A pharmaceutical composition which comprises melatonin and releases it in a controlled manner, has enhanced efficacy for amelioration or prevention of symptoms of hypertension developing in a patient who is resistant to the antihypertensive effect of an antihypertensive compound administered in absence of melatonin.
Full Text

FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to a method and pharmaceutical formulation for treating a patient who is resistant to the antihypertensive effect of an antihypertensive compound in absence of melatonin, a method for lowering nocturnal blood pressure in patients who have an abnormal rhythm in blood pressure in the absence or presence of an antihypertensive compound, a method for lowering Cortisol levels and protecting from cardiovascular events, and use of melatonin in the manufacture of medicaments for the stated purposes.
There is a daily variation in blood pressure (circadian blood pressure rhythm) which is characterized by a nocturnal fall and a diurnal rise. The normal pattern of circadian blood pressure rhythm is reversed in elderly people and in those with Cushing's syndrome, those undergoing glucocorticoid treatment, and those with hyperthyroidism, central and/or peripheral autonomic dysfunction (Shy-Drager syndrome, tetraplegia, diabetic or uremic neuropathy etc.), chronic renal failure, renal or cardiac transplantation, congestive heart failure, eclampsia, sleep apnea syndrome, malignant hypertension, systemic atherosclerosis, accelerated hypertensive organ damage (Imai, Abe et al. Journal of hypertension (supplement) 8:S125-132, 1990) and fatal familial insomnia (Portaluppi, Cortelli et al. Hypertension 23:569-576, 1994). A less-than-normal decline in nocturnal blood pressure is seen in some hypertensive patients despite treatment with antihypertensive drugs. A less-than-normal decline in nocturnal blood pressure has been associated with excessive cardiovascular complications in hypertensive patients. Patients with impaired nocturnal blood, pressure reduction (nondippers) are at increased risk of developing target organ damage (1-4) and nondipper women have been shown to develop more cardiovascular events (5) than their dipper counterparts. The mechanism of the normal fall of blood pressure during sleep and the pathophysiological

mechanisms responsible for lack of noctumal fall in blood pressure remain to be fully elucidated.
Glucocorticoid hormones play a critical role in a variety of bodily functions. In the basal state, glucocorticoids exert a permissive effect on diverse body functions such as maintenance of blood pressure, euglycemia, and electrolyte and water hemostasis. In humans, Cortisol is essential for life. Normally, Cortisol secretion from the adrenal gland is rhythmic, with maximal blood levels in the early morning hours, and a decline to half of the peak value in the afternoon. During stress, excretion of Cortisol is greatly increased to cope with serious whole body insult. However, sustained elevation of Cortisol in circulation has detrimental effects on the immune system and on the ability of the body to cope with stress and disease. Most importantly, corticosteroids can provoke a neurodegenerative process in the hippocampus leading to impaired memory and cognitive functions. Prolonged exposure of the brain to corticosteroids makes it more vulnerable to degeneration induced by ischemia and epilepsy (McEwen, Annals of the New York Academy of Science, 1994, 746: 145-154). With aging, the basal secretion of Cortisol increases by unknown mechanisms and its peak occurs earlier in the morning than in young adults (Moreley and Korenman. eds., Blackwell Scientific Publications, 1992, pp. 70-91). In addition, nocturnal Cortisol levels have been found to be higher in coronary patients than aged-matched healthy subjects (Brugger and Herold, Biological Rhythm Research, 1995, 26: 373). There is an assocation between hypertension and high urine Cortisol values (Lichtenfeld, Hunt et al. Hypertension, 31:569-74, 1998), oral Cortisol increases blood pressure in a dose dependent manner (Kelly. Mangos et al, Clin Exp Pharmacol Physiol SuppI 25:351-6, 1998). It has not been previously suggested that there is an association between the high Cortisol levels and the absence of noctumal dip in blood pressure.
Melatonin, the hormone secreted at night from the pineal gland, reaches its peak levels before the onset of the Cortisol peak in humans. The production of melatonin declines with age. Also, noctumal melatonin levels are lower in coronary patients than in healthy aged-matched individuals.

However, it has not been suggested that melatonin affects Cortisol secretion under normal conditions.
Cardiovascular effects of conventional release melatonin
Melatonin, the hormone of the pineal gland, is normally secreted at night and plays a role in the biologic regulation of circadian rhythms, including sleep (Brzezinski, N Engl J Med 1997; 336; 186-195. Penev and Zee. Ann Neurol 1997; 42; 5-45-553). Vasorelaxing action of melatonin (at high concentrations 10-1000 M) has been observed in rabbit aorta in vitro (Satake et aL. Gen. Pharmacol.. 1991, 22; 219-221. and 22; 1127-1133).
Rodent studies indicate the presence of melatonin receptors in some arterial vessels and it's ability to modulate rat vascular smooth muscle tone (Capsoni et al. Neuroreport 1995; 6; 1346-1348, Mahle et al, J Biol Rhythms 1997; 12; 690-696). This modulation may be manifested as vasodilatation or vasoconstriction depending on the animal species.
The effects of melatonin on blood pressure and on the human cardiovascular system is complex (Lusardi et al. Blood Press Monit 1997; 2; 99-103. Cagnacci et al.1998; 274; 335-338, Arangino et al. Am J Cardiol 1999; 83; 1417-1419; Terzolo at al. J. Pineal Research, 1990, 9; 113-124). Bedtime melatonin ingestion (5 mg) for 4 weeks to young normotensive subjects caused a decrease in systolic blood pressure throughout the 24 h period, a decrease in diastolic blood pressure limited to the second half of the night, a slight lowering of the heart rate during the diurnal hours, and an acceleration during the second half of the night (Lusardi et al, Blood Press Monit 1997; 2; 99-103). The daytime administration of melatonin (1 mg) to young women or men reduced the systolic and diastolic blood pressure within 90 min after administration Cagnacci et al,1998; 274; 335-338 ; Arangino et al. Am J Cardiol 1999; 83; 1417-1419)). The administration of melatonin at 08;00 to aged postmenopausal women surprisingly increases their Cortisol levels (Cagnacci, Soldani and Yen, L Pineal Res, 22:81-5, 1997).
The effects of long-term (2 months), low dose (2 mg/os daily), time specified (18:00 h) melatonin administration on endocrine and cardiovascular variables in adult men have also been studied by Terzolo at al. (J. Pineal

Research, 1990, 9: 113-124). After treatment, a marKeo serum melatonin levels were recorded, with a significant advance of its circadian rhythm. The 24 h patterns of Cortisol and testosterone displayed an anticipation of the morning acrophases at about 1.5 h (not significant) for Cortisol and 3 h (significant) for testosterone. Prolactin pattern was unchanged as well as serum levels of triiodothyronine and thyroxine. Likewise, the response of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, thyroid stimulation hormone (TSH) Cortisol, adrenocorticotrophin (ACTH) and aldosterone to a stimulation test with gonadotropin releasing hormone (GNRH) thyrotropin releasing hormone (TRH), adrenocorticotrophin (ACTH) and testosterone to human chorionic gonadotrophin (HCG) were also unaffected. The circadian organization of the cardiovascular variables, i.e. systolic and diastolic blood pressure, heart rate, did not show any changes after melatonin treatment.
It is an object of the present invention to the lower Cortisol level in humans and particularty to defer the peak of Cortisol in the human Cortisol profile. It is a further object of the invention to lower the blood pressure of a patient who is resistant to the antihypertensive effect of an antihypertensive compound in absence of melatonin, and especially to lower the nocturnal blood pressure in non-dippers. It is believed that these objects will potentially contribute to decrease in blood pressure, prevention of ischemic attacks and provide prophylactic protection against the detrimental effects of ischemia on the heart- Other objects of the invention will be apparent from the description which follows.
In US. Patent No. 5,700,828, there is described a method for treating or minimizing anoxic or ischemic brain injuries, by administering melatonin to a mammal suffering from an anoxic or ischemic insult, this being defined as a trauma that causes a lack of blood flow to the brain and/or a lack of oxygen to the brain. This patent does not suggest that melatonin might prevent or ameliorate the anoxic or ischemic insult, per se.
In U.S. Patent No. 5,849,338, filed August 26, 1997, there is described a unit dosage form for treating vasoconstriction and physiological conditions giving rise to it, comprising, in brief, Mg, vitamins C and E, folic acid Se and

melatonin. Melatonin is included only because of certain of its properties v/hich were knov»/n at the filing date and which are described in this patent.
The entire contents of these U.S. Patents are incorporated by reference
herein.
SUMMARY OF THE INVENTION The above objects may be achieved by the present invention, which in one aspect, provides a pharmaceutical formulation which compnses, in addition to at least one carrier, diluent or adjuvant:
melatonin in an amount effective to ameliorate or prevent symptoms of hypertension developing in a patient who is resistant to the antihypertensive effect of an antihypertensive compound administered in absence of melatonin; and at least one antihypertensive compound in an amount effective to exert an antihypertensive effect in presence of melatonin, in a patient requiring such
treatment.
The present invention also provides use of melatonin in the manufacture of a medicament for the prevention or treatment of symptoms of hypertension in a patient who is resistant to the antihypertensive effect of an antihypertensive compound administered in absence of melatonin, as well as a method for the prevention or treatment of symptoms of hypertension in a patient who is resistant to the antihypertensive effect of an antihypertensive compound administered in absence of melatonin, which comprises administering melatonin to such patient, in an amount effective to ameliorate or prevent symptoms of hypertension developing in the patient.
According to another aspect, the invention provides use of melatonin in the manufacture of a medicament for imparting in a patient at least one effect selected from improvement in mood and daytime vigilance, postponement of the peak level of Cortisol in the patient and potential prophylactic protection against the detrimental effects of ischemia on the heart, the medicament being a pharmaceutical formulation vich comprises melatonin in an amount effective to impart at least one of the above-stated effects.
According to still another aspect, the invention provides a method for imparting in a patient at least one effect selected from improvement in mood

and daytime vigilance, po.stponement of the peak level of Cortisol in the patient and potential prophylaclic protection against the detrimental effects of ischemia on the heart, which comprises administering to the patient melatonin in an amount and in a manner effective to achieve said at least one effect.
The expression "improvement in mood" in the present context is intended to connote avoidance of mood depression which may be assodated with administration of melatonin in conventional form, i.e. not in controlled release form.
Surprisingly, administration of melatonin to humans appears to lower excretions rates and diurnal variations. Also, there is a difference in this respect between controlled- and regular- release melatonin in that the controlled release form is able to change and delay the diurnal profile of Cortisol whereas the regular form just suppresses but does not shift significantly the time of the peak.
DETAILED DESCRIPTION OF THE INVENTION The medicament/pharmaceutical formulation may be administered in any convenient form, such as one adapted for oral, rectal, parenteral or transdermal administration- It may be e.g. in unit dosage form. In a particular embodiment, the melatonin is in the form of a controlled release formulation, wherein the melatonin is preferably released at a predetermined controlled
rate.
The at least one carrier, diluent or adjuvant may, for example, include at least one acrylic resin.
The amount of melatonin presently contemplated for use in preventing or treating hypertension wilt be the amount found to be effective for this purpose, presently believed to be, in the case of oral administration, more than 0.5 mg and no more than 100 mg daily, e.g. 0.5-50 mg, preferably 2.5-20 mg, and for parenteral or transdermal administration, between 0.1 and 50 mg. In accordance with the invention, an effective amount of melatonin may be formulated e.g. together with an effective dosage of a antihypertensive drug. The present medicament/pharmaceutical formulation

may comprise also at least one melatonin receptor modifier and/or melatonin profile modifier.
Once the concept of the present invention for treatment or prevention of hypertension using melatonin is known according to the present invention, no inventive skill would be required to ascertain the range of effective amounts of melatonin for the present purpose, for various routes of administration. Where the pharmaceutical formulation includes at least one antihypertensive agent, this may for example be selected from Diltiazem, Captopril, Atenolol, Benazepril, Enalapril, Valsartan. Metoprotol, Terazosin, Prazosin, Minoxidil, Clonidine, Ramipril and pharmaceutically acceptable salts thereof. The daily dosage rates for oral administration of the exemplified hypertensive compounds, is shown in the following table:


The invention will be illustrated by the following Examples.
Example 1
The following ingred.enls are mixed together and the mixture was
compressed in a 7 mm cylindncal punch, at 2.5 tons, in order to make
controlled release tablets: Captopril (12.5mg/tablet), melatonin (5 mg/tablet).
and Eudragit- RS 100 acrylic resin carrier (Rohm Pharma) and lactose in an
approximately 1:1 ratio by weight. While this formulation should be
administered in accordance with a physicians instructions, it ,s presently
contemplated that two such tablets taken two hours before bedtime would be
appropriate.
Example 2
The following ingredients are mixed together and the mixture was
compressed in a 7 mm cylindrical punch, at 2.5 tons, .n order to make
controlled release tablets: Diltiazem (180mg/tablet). melatonin (5 mg/.ablet),
and Eudragit- RSPO acrylic resin earner (Rohm Pharma), lactose and
calcium hydrogen phosphate in an apoxima.ely 21:2.5 ratio by weight.
while this formulauon should be administered in accordance with a phys,c,ans
instructions, ,t is presently contemplated that two such tablets taken two hours
before bedtime would be appropriate.
Fxperiment 1 The effect of melatonin on blood pressure was detem.,ned on a trial population of 52 hypertensive and 130 normotensive elderly patients. All patients who had been insomniacs, were diagnosed according to DSM IV. They consisted of 86 men and 96 women, age 72±9 years. In a randomized, double blind, subjects were given daily either 1, 2 or 5 mg melatonin in a controlled-release formulation (Circadin-. Neunm Pharmaceuticals. Israel), o hours before bedtime, or a placebo of identical appearance, for a penod of 3 weeks Dunng the last week of the treatment period, BP was assessed a. the morning and compansons were made beeen placebo or melatonin treatments, and baseline. The results are shown in tables 2 and 3.


Conclusions Exogenous melatonin administration in the evening decreased daytime systolic and diastolic in hypertensive elderly subjects. Surprisingly, the administration of the controlled release formulation (1-5 mg) had no significant effect in normotensive subjects. It may be noted that antihypertensive drugs cause a decrease in blood pressure when administered to normotensive subjects and that administration of a regular release formulation of melatonin (5 mg) in the evening has been shown to lower blood pressure in young normotensive subjects throughout the 24 h period. (Lusardi et al, Blood Press Monit 1997; 2: 99-103).

Experiment 2 Sixteen elderly patients with essential hypertension were studied. Twenty-four hour ambulatory blood pressures were measured in all patients. Patients were defined as dippers (n = 8) or nondippers (n = 8) according to nocturnal fall in mean arterial pressure. 24-hours urine was collected in two collections, one during daytime, and one during nighttime. Urinary excretion of the main melatonin metabolite 6-sulfatoxymelatonin (6SMT) was determined by ELISA assay in duplicates. Both groups were similar in regard to age and sex. Mean arterial pressure decreased by 10.2% during nighttime in the dippers and increased by 8% in the nondipper patients. Urinary 6SMT increased by 240% during sleep, from 3.28 ± 0.87 (units) during daytime to 8.19 ± 1.68 (units) during nighttime (p
Conclusions Nondipper hypertensive patients exhibit blunted nocturnal melatonin secretion. Thus, exogenous melatonin may play a role in the circadian rhythm of blood pressure.
Investigation of the effect of melatonin on Cortisol profile and mood
The following experiments were performed in a double-blind, placebo controiied crossover fashion. Each patient received all three kinds of tablets (placebo, regular release and controlled release) but in random order not known to him or the staff.

Experiment 3
Administration of melatonin (2 mg) in a controlled release formulation (SR-Mf), once daily at 10 PM. for one week, to eight healthy eiderly persons suffering from insomnia, resulted in a significant increase in their sleep efficiency but not sleep latency. (Sleep efficiency is the amount of time spent asleep from total time in bed; sleep latency is the time taken to fall asleep from first lights-off). On the other hand treatment of the same individuals with melatonin (2 mg) in a regular release formulation (RM) did not improve sleep efficiency but shortened sleep latency compared to placebo treatment of the same subjects. These results can be explained by the short half-life of melatonin in the blood. Namely, the controlled release formulation produces lower blood levels of the hormone for extended periods of time and thus its effects may start slowly but may be significant later on during the night.
The Cortisol level in these patients was assessed by the urinary excretion of the hormone at 2 hours intervals over a 24 hour period, (n the placebo treatment group, patients displayed a Cortisol rhythm which reached its peak at 8:36 AM and the Cortisol then declined as is known for subjects above 40 years of age (see Sherman et a!., Journal of Clinical Endocrinology and Metabolism 1985, 61: 439). The mean 24 hour excretion rate/hour (which approximated blood concentrations) of the Cortisol in urine in the control group was 3.2 microgram/hour. The amplitude of the rhythm (i.e. maximal deviation of the mean 24 h to maximum or minimum excretion rate) was 1.8 pig/hour.
After treatment for 1 week with the regular release melatonin the overall amount of Cortisol excreted was reduced. The mean 24 hour excretion rate decreased to 2.5 ug/hour and the amplitude decreased to 1.0 fag/hour. In addition there was a slight backwards shift in the time of the peak, which occurred at 8:27 AM. Anticipation of the Cortisol rhythm after administration of regular release melatonin is compatible with observations made by Terzoio at al., J. Pineal Research, 1990, 9: 113-124. However, decrease in mean 24 hour levels and amplitude of the Cortisol rhythm was not observed by Terzoio.
After one week's treatment with controlled release melatonin, it was found that like the regular melatonin, secretion of Cortisol was attenuated (mean 24 h rate was 2.5 pg /hour) and the amplitude 1.2 |jg/hour as with the

regular release), but the peak was delayed significantly to later in the day and occurred at 12:06 PM. Thus, the peak was delayed by administration of controlled release melatonin instead of being the same or slightly advanced. The same Cortisol profile was also found in these patients after 1 month's treatment with the controlled release formulation (mean 24 hour excretion 2.5 ng /hour, amplitude 1.0 jig /hour and peak time 12:08 hours).
Conclusions These results show that the response of the body to melatonin is not obvious: the body reads the melatonin profile and not just the fact that it is present at some time. Interestingly, in humans younger than 40 years, the Cortisol rhythm is also delayed compared to older individuals (Sherman et al., loc cit). Hence, the Cortisol profile generated in the elderly after the controlled release melatonin treatment is similar to that in younger individuals.
Discussion It has recently been found that in coronary patients, melatonin at night is low whereas Cortisol levels are high (Bnjgger and Herold, Biological Rhythm Research, 1995, 26: 373). It should be noted that Cortisol is a stress hormone, and its high levels in the morning may be linked to the increased prevalence of heart attacks in the morning hours. The present experiment shows that administration of regular release melatonin can lower Cortisol production but that administration of controlled release melatonin both lowers the Cortisol level and delays its peak and thus can potentially lower the risk for an ischemic attack during the morning hours.

Experiment 4
This experiment was performed on 10 young healthy males age 26-30. They received one controlled-release (SR-Mf) or regular release (RM) tablet containing melatonin (2 mg) or placebo per day with one day v/ashout between treatments. The tablets were taken at 11.00 AM and the subjects were asked to sleep between 12-15 hours. Mood was assessed by Lader-Bond visual analog scale questionnaires before and after the sleep The results indicated that regular melatonin (2 mg) significantly shortened nap sleep latency and increased sleep efficiency. The controlled release formulation also had similar effects. However, the regular release form produced feelings of hostility and sleepiness whereas the controlled release form had no negative effect on mood. These data also indicate that the effects of melatonin on mood depend on the profile generated. It should be noted that the lack of effect on mood cannot be explained by the lower concentrations of melatonin generated in he blood by the controlled release formulation since similar concentrations of melatonin (regular) have been shown by several studies to affect mood and sleepiness. Hence, both the timing and pattern of melatonin administration are important in affecting physiological parameters. The same dose given at different times or in different patterns may have different effects.
While particular embodiments of the invention have been particularly described hereinabove, it will be appreciated that the present invention is not limited thereto, since as will be readily apparent to skilled persons, many variations and modifications can be made. Such variations and modifications which have not been detailed herein are deemed to be obvious equivalents of the present invention. For example, structural analogs of melatonin which substantially imitate the function of melatonin in the human body are deemed to be obvious chemical equivalents of melatonin. The essential concept, spirit and scope of the present invention will be better understood in the light of the claims which follow.


WE CLAIM;
1. A controlled release pharmaceutical composition adapted for oral, parenteral or transdermal administration, which comprises melatonin and releases it in a controlled manner, and having enhanced efficacy for amelioration or prevention of symptoms of hypertension developing in a patient who is resistant to the antihypertensive effect of an antihypertensive compound administered in absence of melatonin, the melatonin being present in said composition in an amount effective for said amelioration or prevention, said amount further being such as to afford a daily dose of >0.5 mg and up to 100 mg for oral administration and between 0.1 and 50 mg for parenteral or transdermal administration, and wherein said composition comprises at least one carrier, diluent or adjuvant.
2. The pharmaceutical composition as claimed in claim 1, which comprises at least one antihypertensive compound in an amount known to be effective to exert an antihypertensive effect in presence of melatonin, in a patient requiring such treatment.
3. The pharmaceutical composition as claimed in claim 1 or claim 2, in which additionally at least one of the following features is present:
(i) it is in unit dosage form, each unit dosage comprising an amount of melatonin
which lies within the range of 2.5-20 mg;
(ii) said antihypertensive compound is selected from Diltiazem, Captopril,
Atenolol, Benazepril, Enalapril, Valsartan, Metoprolol, Terazosin, Prazosin,
Minoxidil, Clonidine, Ramipril and pharmaceutically acceptable salts thereof;
(iii) said carrier, diluent or adjuvant includes at least one acrylic resin.
4. The pharmaceutical composition as claimed in claim 1, which is in unit dosage
form, each unit dosage comprising an amount of melatonin which lies within the range
of 0.5-50 mg.

5. The pharmaceutical composition as claimed in claim 4, wherein said unit
dosage is in particulate form comprising coated particles and the desired controlled
release properties are achieved by at least one of the following features, namely:
(a) by variation in the particle size of the melatonin;
(b) by use of at least two different coating materials which dissolve at different rates in the human body; and
(c) by varying the thickness of coating material(s) whereby the particulate melatonin is coated with different thicknesses of coating material(s) which dissolve at different rates in the human body.
6. The pharmaceutical composition as claimed in claim 4 or claim 5, in which
additionally at least one of the following features is present:
(i) each unit dosage comprises an amount of melatonin which lies within the range
of 2.5-20 mg;
(ii) said carrier, diluent or adjuvant includes at least one acrylic resin.
7. The pharmaceutical composition as claimed in claim 1, which is adapted for oral administration, and possesses the additional property of imparting in a patient at least one effect selected from improvement in mood and daytime vigilance, modifying the 24-hour Cortisol profile by both reduction of the 24-hour average Cortisol level and delaying the 24-hour peak level of Cortisol in the patient, and prophylactic protection against cardiac ischemia.
8. The pharmaceutical composition as claimed in claim 7, which is adapted to release melatonin in a profile which simulates the nocturnal profile in plasma of a human having a normal endogenous melatonin nocturnal profile.
9. The pharmaceutical composition as claimed in claim 8, which is in particulate form comprising coated particles and the desired controlled release properties are achieved by at least one of the following features, namely:

(a) by variation in the particle size of the melatonin;
(b) by use of at least two different coating materials which dissolve at different
rates in the human body; and
(c) by varying the thickness of coating material(s) whereby the particulate
melatonin is coated with different thicknesses of coating material(s) which
dissolve at different rates in the human body.
10. The pharmaceutical composition as claimed in claim 9, which comprises particulate melatonin coated with at least one polymeric coating material.
11. The pharmaceutical composition as claimed in claim 1, wherein said patient is a non-dipper and/or exhibits a morning rise in blood pressure, despite use of antihypertensive drugs.


Documents:

in-pct-2002-1189-che abstract.pdf

in-pct-2002-1189-che claims duplicate.pdf

in-pct-2002-1189-che claims.pdf

in-pct-2002-1189-che correspondence-others.pdf

in-pct-2002-1189-che correspondence-po.pdf

in-pct-2002-1189-che description (complete) duplicate.pdf

in-pct-2002-1189-che description (complete).pdf

in-pct-2002-1189-che form-1.pdf

in-pct-2002-1189-che form-18.pdf

in-pct-2002-1189-che form-26.pdf

in-pct-2002-1189-che form-3.pdf

in-pct-2002-1189-che form-5.pdf

in-pct-2002-1189-che pct search report.pdf

in-pct-2002-1189-che pct.pdf

in-pct-2002-1189-che petition.pdf


Patent Number 223552
Indian Patent Application Number IN/PCT/2002/1189/CHE
PG Journal Number 47/2008
Publication Date 21-Nov-2008
Grant Date 12-Sep-2008
Date of Filing 02-Aug-2002
Name of Patentee NEURIM PHARMACEUTICALS (1991) LTD.
Applicant Address 8 HANECHOSHET STREET, TEL AVIV 69710,
Inventors:
# Inventor's Name Inventor's Address
1 ZISAPEL, NAVA KISSUFIM STREET 23, TEL AVIV 69355,
2 LAUDON, MOSHE HERZL STREET 30, KFAR SABA 44444,
PCT International Classification Number A61K9/24
PCT International Application Number PCT/IL00/00009
PCT International Filing date 2000-01-05
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA