Classifications

• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives

Definitions

• the present invention relates to use of melatonin in the manufacture of medicaments for short-term potentiation of certain hypnotics, and to pharmaceutical formulations comprising melatonin and such hypnotics.
• GABA Gamma-aminobutyric acid acting via GABA-A receptors is the brain's major inhibitory neurotransmitter system and exerts a crucial role in regulating brain excitability.
• GABA-A receptors comprise five subunits.
• the different protein subunits that make up the receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) have been identified, and make up the alpha, beta, gamma and delta families, for each of which exist several subtypes.
• a number of drugs interact with binding sites on different subunits of the GABA-A receptors, and these include modern hypnotic drugs (i.e. benzodiazepines, and the newer non-barbiturate and non-benzodiazepine agents, e.g. imidazopyridines and cyclopyrrolones), as well as anticonvulsants, anaesthetics and neurosteroids (e.g. the progesterone metabolite pregnalone).
• hypnotic drugs i.e. benzodiazepines, and the newer non-barbiturate and non-benzodiazepine agents, e.g. imidazopyridines and cyclopyrrolones
• anticonvulsants e.g. the anaesthetics
• neurosteroids e.g. the progesterone metabolite pregnalone
• receptors that include an alphal subunit have a type (I) pharmacology and bind the non-barbiturate and non-benzodiazepine agents zolpidem and zaleplon with high affinity, whilst receptors with alpha2, alpha3 or alpha ⁇ subunits have a type (II) pharmacology and bind these drugs with low affinity. Both type (I) and (II) bind diazepam and other benzodiazepines. In contrast, receptors that contain alpha4 and alpha ⁇ subunits, are diazepam-insensitive.
• the ligand selectivity of receptor subunits assists in their characterization.
• Site-directed mutagenesis has indicated that benzodiazepines bind to a cleft on the GABA-A receptor surface at the interface between the alpha and gamma subunits.
• Other drugs flumazenil, zopiclone, zolpidem
• the subunit composition of GABA-A receptors has been shown to exhibit a degree of brain regional specificity.
• the predominant GABA-A receptor composition found in the brain is alph.a1beta2gamnr.a2, which are all encoded on human chromosome 5. Targeted gene disruption has provided clues to the physiological functions served by GABA-A receptors containing different subunits. Receptors containing gamma2 appear to have a vital role in maintaining appropriate central inhibition, beta3- containing receptors may also be important determinants of excitability in certain brain regions, whereas a clear role for alpha ⁇ -, alpha ⁇ - and gamma3-containing receptors has not yet been established by these techniques.
• GABA-A receptors are of great clinical significance in several disorders, including insomnia, epilepsy, anxiety and alcoholism; benzodiazepines are used commonly to treat anxiety, and studies suggest that benzodiazepine antagonists and inverse agonists (which induce the opposite effect to agonists at receptors) may be useful in alcohol rehabilitation.
• insomnia defined as problems initiating and/or maintaining sleep, at least three nights/week accompanied by daytime distress or impairment.
• Persistent insomnia is associated with an array of individual and societal consequences, including greater medical and psychiatric morbidity, life-threatening accidents, reduced quality of life, impaired job performance, and absenteeism.
• Insomnia is associated with negative consequences for health-related quality of life, daytime well-being, and also has economic implications. The cost of insomnia in terms of lost productivity and accidents has been estimated at $77-$92 billion annually.
• Benzodiazepines are very potent in sleep induction (shortening sleep latency) and maintenance (increasing total sleep time). These drugs have however detrimental effects on awakening from sleep (hangover effects) and daytime vigilance (psychomotor functioning), the next morning.
• the newer non-barbiturate and non- benzodiazepine hypnotic agents e.g. imidazopyridines and cyclopyrrolones
• the possible adverse effects of these sleep aids include residual sedation and psychomotor impairment, daytime anxiety, anterograde amnesia and cognitive impairment, rebound insomnia, and drug tolerance and dependence.
• benzodiazepines adversely affect cognition by disrupting both short and long term memory. Episodic, semantic and iconic memory are impaired.
• Former use of benzodiazepines is associated with a significantly increased risk of dementia in elderly persons (6 ⁇ years of age and older). The degree of memory loss is a function of the specific agent and dose. Therefore, lowering the dose of these agents, while maintaining their hypnotic effects, may be beneficial to circumvent these impairments.
• zolpidem hypnotic efficacy of zolpidem is generally comparable to that of the benzodiazepines flunitrazepam, flurazepam, nitrazepam, temazepam and triazolam as well as non-barbiturate and non-benzodiazepine hypnotic agents such as zopiclone and trazodone in the treatment of elderly and adult patients with insomnia.
• Zaleplon is N-[3-(3-cyanopyrazolo[1 , ⁇ -a]pyrimidin-7-yl)phenyl]-N- ethylacetamide; zolpidem is N,N,6-trimethyl-2-p-toyl-imidazo[1 ,2, ⁇ a]pyridine-3- acetamide L-(+)-tartrate (2:1); zopiclone is 6-( ⁇ -chloropyrid-2-yl)-5-(4- methylpiperazin-1-yl)carbonyloxy-7-oxo-6,7-dihydro- ⁇ H-pyrrolo[3,4-b]pyrazine; trazodone is 2-[3- ⁇ 4 -(m- chlorophenyl)-1-piperazinyl] propyl]s-triazolo[4,3-a]-pyridine- 3(2/-/)-one monohydrochloride.
• Zolpidem for example, is gaining favour worldwide because of its efficacy and its side effect profile, which is milder and less problematic than that of the benzodiazepines and barbiturates used to treat insomnia. There is little evidence of rebound insomnia or withdrawal symptoms after discontinuation of the drug when it is given as recommended (10 mg/day for ⁇ 1 month) or over longer periods. Initially, there were no reports of tolerance developing to the hypnotic effects of zolpidem in a number of studies of up to 6 months duration. Still, side effects (delirium, hallucinations) are not uncommon with zolpidem use and it may have a marked dependence potential. Yet, in a recent report of a WHO Expert Committee responsible for reviewing information on dependence-producing drugs to assess the need for their international control, zolpidem was recommended for international control. Lowering the risk of developing dependence is thus a public health issue.
• SCN suprachiasmatic nucleus
• the individual period of the endogenous clock is either slower or faster than the solar 24-h day/night cycle (in humans it is usually >24 h) and is normally entrained by the 24-h light dark cycle to match the environmental rhythm.
• Light is the ubiquitous signal for resetting the timing of the clock.
• An important output signal generated by the SCN is the induction of synthesis of the pineal hormone melatonin (N-acetyl- ⁇ - methoxytryptamine) at night.
• Melatonin is directly regulated by the SCN and thus serves as a marker of the circadian clock phase; but it can also relay time-of-day information (signal of darkness) to various organs, including the SCN itself.
• the phase shifting effects of melatonin are essentially opposite to those of light.
• melatonin given several hours before its endogenous peak at night, effectively advanced sleep time in delayed sleep phase syndrome patients and adjusted the sleep wake cycle to 24 h in the blind, where light therapy is inapplicable.
• Melatonin and light when properly timed (namely light in the subjective night and melatonin in the subjective day of the internal clock) may also alleviate jet lag and sleep in night- shift workers trying to sleep during daytime.
• Melatonin plays a major role in the induction and regulation of sleep.
• the sleep promoting activity of melatonin in humans is best demonstrated in daytime, when the hormone is not produced endogenously, or in subjects who suffer from abnormal melatonin production due to aging disease or use of certain drugs (e.g. beta adrenoceptor blockers).
• beta adrenoceptor blockers e.g. beta adrenoceptor blockers
• Benzodiazepine therapy has been found to suppress the nocturnal rise in plasma melatonin and shift its day-night rhythmicity; this suppression may interfere with normal sleep-wake rhythmicity and add-on melatonin replacement may help maintain the efficacy of benzodiazepine hypnotics.
• administration of sustained release melatonin (2 mg) to 23 chronic benzodiazepine-using elderly insomniacs resulted in a significant improvement in sleep maintenance and total sleep time compared to placebo.
• melatonin was also reported to allow reduction of the therapeutic dose of the benzodiazepine triazolam by ⁇ 0% while maintaining its hypnotic activity. These results could be ascribed to additive effects of melatonin and benzodiazepines of sleep induction. Most importantly, the sleep inducing, anxiolytic and anticonvulsant properties of melatonin are not mediated by the benzodiazepine receptor, since flumazenil, a benzodiazepine-antagonist, administered concomitantly was unable to block melatonin's effects.
• Melatonin is also an effective aid in withdrawal for addictive drugs, including benzodiazepines.
• a strong proof of melatonin's efficacy in withdrawal from an addictive drug has been found when applied in nicotine withdrawal, which is usually accompanied by negative mood and performance.
• administration of melatonin enabled rapid discontinuation of benzodiazepine therapy in a 43-year-old woman who was benzodiazepine addicted.
• melatonin potentiates the effects of the non-barbiturate and non- benzodiazepine hypnotics such as zolpidem, on sedation as well as on psychomotor skills.
• the interaction was not additive, and it was not due to a pharmacokinetic change in blood concentrations of either zolpidem or melatonin.
• the pharmacodynamic interaction was transient and disappeared within 2 hours, while the concentrations of both drugs in blood were still high.
• the present invention thus provides in one aspect, use of melatonin in the manufacture of a medicament effective for the short-term potentiation of the hypnotic effect of at least one compound selected from the group consisting of non-barbiturate and non-benzodiazepine hypnotics.
• the invention provides a pharmaceutical formulation which comprises, in addition to at least one carrier, diluent, coating or adjuvant: at least one compound selected from non-barbiturate and non-benzodiazepine hypnotics, and melatonin in an amount and form effective for short term potentiation of the hypnotic effect of the at least one compound.
• the hypnotics are GABA-A receptor modulators
• the hypnotics are compounds which include a fused-ring system containing ring nitrogen;
• the medicament or pharmaceutical formulation comprises at least one carrier, diluent, coating or adjuvant;
• the medicament or pharmaceutical formulation is in unit dosage form;
• the medicament or pharmaceutical formulation includes at least one compound selected from the group consisting of non-barbiturate and non- benzodiazepine hypnotics;
• the at least one compound is present in the medicament or pharmaceutical formulation, in an amount which, if administered in absence of melatonin, would be a sub-therapeutic amount;
• the medicament or pharmaceutical formulation is adapted for sustained release of melatonin.
• potentiation means potentiation for a period of not more than about 4 hours, preferably not more than about 2 hours, and particularly for a period of about one hour, +2 ⁇ %.
• the present invention focuses on the concept of combined use of melatonin and a therapeutic or sub-therapeutic dose of a non-barbiturate and non- benzodiazepine hypnotic so as to effectively promote sleep initiation for patients who have difficulty falling asleep, while reducing the risk of memory impairments, psychomotor performance accidents, and subsequent tolerance and dependence.
• the medicament or pharmaceutical formulation preferably includes at least one acrylic resin and is adapted for sustained release of melatonin; desirably, it is further adapted for regular release of said at least one compound.
• sustained release properties may be achieved, e.g., by at least one of the following features, namely:
• the at least one compound selected from non-barbiturate and non- benzodiazepine hypnotics preferably comprises a bicyclic fused ring system, e.g. one including at least two ring nitrogen atoms.
• exemplary such ring systems are: the pyrazolo[1 , ⁇ -a]pyrimidine skeleton, e.g. the hypnotic zaleplon; the imidazo[1 ,2,-a]pyridine skeleton, e.g. the hypnotic zolpidem; the pyrrolo[3,4-b]pyrazine skeleton, e.g. the hypnotic zopiclone; and the triazolo[4,3-a]-pyridine skeleton, e.g. the hypnotic trazodone.
• Blood samples were withdrawn from the subjects at pre-selected intervals after the administration of the tablets.
• Table 1 Pharmacokinetic parameters of melatonin (sustained release 2 mg) and zolpidem (10 mg) when given alone and in combination
• ARCI49 a decrease of euphoria (MBG scale) was observed 1 hour post-dosing with all groups. Four hours after administration, this effect was more pronounced with the three treatment groups as compared to placebo. An increase of dullness or slow- wittedness (LSD scale) was observed during the 4 hours post-dosing, for the three treatment groups compared to placebo.
• Zolpidem treatment resulted in a significant worsening in driving skills and memory tasks in the first hours of its administration, whereas the effect of melatonin was not different from those of placebo treatment.
• a sustained release melatonin formulation is of special interest in this respect, as it has been proven to improve sleep quality in patients with insomnia aged 5 ⁇ and older, with a subsequent improvement in daytime vigilance. Melatonin is however not perceived by patients as improving sleep initiation and that aspect is well provided by zolpidem. These facts will be important for designing a new hypnotic treatment with a better safety/efficacy profile.
• the present invention contemplates co-administration of melatonin and the defined hypnotic, such as zolpidem.
• co-administration in this context the purpose of which is to achieve an improved clinical outcome, may be practised by administering separate dosage forms of melatonin and hypnotic, or a combined dosage form.
• An illustrative Example of the preparation of a combined dosage form follows. It will be appreciated, however, that other known methods may be used for preparing a combined dosage form, such as, for example, the methods described in US 6,174,873 B1 , the entire contents of which are incorporated by reference herein.
• a two-layer tablet is prepared, which is sustained release in respect of melatonin (inner core), but regular release in respect of the exemplary hypnotic, zolpidem (outer layer). Because the outer layer undergoes immediate dissolution in the enteric system, the profile of zolpidem generated will resemble that given in Example 1 , whereas because the core tablet will dissolve gradually, the profile of melatonin generated in the blood will be similar to that of Example 1 also. Method.
• a sustained release core melatonin tablet was first prepared by mixing together the following ingredients and compressing the mixture in a 7 mm cylindrical punch, at 2.5 tons, namely, melatonin (2 mg/tablet), and Eudragit RSPO acrylic resin carrier (Rohm Pharma), lactose and calcium hydrogen phosphate, in an approximately 2:1 :2.5 ratio by weight.
• An aqueous coating spray suspension is then prepared by suspending an acrylic resin (Eudragit RD 100), polysorbate 80 and talc in an approximately 10:2:5 ratio by weight, and zolpidem tartrate (5 mg/tablet) in 6 ml water per 1 g solid.
• the core tablet is then sprayed with the suspension to a 2 mm dried coating thickness, thus forming a coated tablet.
• Sustained release melatonin has an effect of its own on sleep. This is demonstrated by an improvement in restorative sleep (improvement of subjective quality of sleep and subsequent improvement in daytime vigilance) as we have recently described in the patent on the use of melatonin to improve quality, and is given here as Examples 4, 5 and the delay in the cortisol peak towards the morning hours that is seen with the sustained release but not with the regular release formulation (Example 6). This effect may be responsible for the enhancement of restorative sleep.
• the left endpoint labeled “more restless than usual” and the right endpoint is labeled “more restful than usual”.
• the waking state question was "How do you feel now?"
• the patients marked the level of their perceived waking state on a 100 mm, non-hatched horizontal line with two endpoints.
• the left endpoint labeled "tired” and the right endpoint is labeled “alert”.
• the distance of the patient mark from the right endpoint in mm was measured, (a reduction in value therefore indicates a better sleep or less tired state).
• the mean distance across the three nights was calculated. Results. It was found that both quality of sleep and daytime alertness significantly improved with sustained release melatonin compared to placebo (Table 2) showing a link between improved restful sleep and less fatigue in the morning.
• Table 2 Effects of sustained release melatonin and placebo on subjectively assessed quality of sleep and daytime alertness in primary insomnia patients.
• cortisol level in these patients was assessed by urinary excretion of the hormone at 2 hour intervals over a 24 hour period.
• 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.
• 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 mg/hour.
• hypnotic drugs as defined for the purpose of the present invention, such as zolpidem, it is crucial that elimination will be rapid and that no drug will remain in the morning. Because the drug only affects the initiation of sleep, it is useful to augment its effects in the first hour so as to get maximal efficacy with a lower dose and avoid its detrimental effects later on in the night.
• the intrinsic effects of melatonin when co-administered with e.g. zolpidem, are maintained.
• the combination of melatonin and zolpidem will thus allow improvement of subjective sleep latency (that is not perceived with melatonin alone) while avoiding the bad effects of zolpidem later on in the night (on memory and coordination).
• the left endpoint is labeled "more restless than usual” and the right endpoint is labeled "more restful than usual”.
• the distance of the patient mark from the right endpoint in mm was measured, (a reduction in value therefore indicates a better sleep or less tired state).
• the mean distance across the three nights was calculated. Response was defined as a mean improvement in the 3 nights of 10 mm on the 100 mm visual analog scales.

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