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WO2008038160A2 - Substance à effet sédatif - Google Patents

Substance à effet sédatif Download PDF

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Publication number
WO2008038160A2
WO2008038160A2 PCT/IB2007/004218 IB2007004218W WO2008038160A2 WO 2008038160 A2 WO2008038160 A2 WO 2008038160A2 IB 2007004218 W IB2007004218 W IB 2007004218W WO 2008038160 A2 WO2008038160 A2 WO 2008038160A2
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substance
gamma
pyrone
administration
pain
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PCT/IB2007/004218
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WO2008038160A3 (fr
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Technology Commercialization Corp.
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Priority claimed from US11/459,659 external-priority patent/US20060252824A1/en
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Publication of WO2008038160A2 publication Critical patent/WO2008038160A2/fr
Publication of WO2008038160A3 publication Critical patent/WO2008038160A3/fr

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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 generally to pharmaceutical compounds and methods for the treatment of disorders relating to the nervous system in animals and humans. More specifically, the invention relates to the use of a subset of gamma-pyrones in pharmaceutically acceptable forms for the treatment of various disorders relating to the peripheral and central nervous system.
  • disorders relating to the nervous system or “neurotic disorders” include among others such conditions as pain, depression, anxiety, insomnia, neurosis, etc., as well as pain and other symptoms associated with the abstinence syndrome experienced by chemical and drug abuse patients. All of these conditions involve the neurons of the nervous system.
  • Sedative compounds known in the art are a chemically varied group of compositions of natural and synthetic origin that predominantly have a tranquilizing effect on the central nervous system. Different sedatives produce different physiological effects. Understanding of these effects is helpful in selectively treating various disorders. This mechanism of action is not always entirely clear but it is believed that sedative drugs in general are intended to cause selective suppression of subcortical (limbus) and cortical brain structures, which regulate emotions.
  • the mildest examples of sedative drugs include extracts of motherwort, passiflora, valerian root (Tinctura Valeriana), bromides of caustic metals (Kalium bromatum, Natrium bromatum). These drugs typically cause only a light tranquilizing effect on the subject. Stronger tranquilizers are used to lower a patient's anxiety.
  • synthetic medicinal preparations examples of which include derivatives of benzodiazepin (diazepam), diphenyl methane (benactyzine), propanediol (mepropan) and trioxazin.
  • Hypnotic compounds in small doses are also used as sedative drugs along with various neuroleptic agents (aminazine, tisercin) and some other compounds.
  • additional compounds include Bekhterev's mixture (sodium bromide, lychnis infusion, codeine phosphate), Corvalolum (ethyl ether of ⁇ -bromine isovaleric acid, monosodium salt of Phenobarbital, mint oil, ethyl alcohol, water), and Validol (menthol solution in menthyl valerate).
  • Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage.
  • Acute pain occurs as a result of tissue injury, and is mediated by chemical, mechanical or thermal stimulation of pain receptors known as nociceptors.
  • Acute pain serves a protective function, conditioning avoidance behavior of situations and events leading to such potential tissue damage.
  • Chronic pain In contrast to acute pain, chronic or persistent pain in itself constitutes a disease which serves no protective biological function. Chronic pain is unrelenting and can persist for years and frequently cannot be associated with a single or specific injury. Chronic pain predominantly constitutes chronic inflammatory pain (e.g. arthritis) or "neuropathic pain", which can be defined as pain initiated or caused by a primary lesion or dysfunction within the nervous system (Mersky and Bogduk, Classifications of Chronic Pain, 2nd edition. Seattle IASP Press: 394, 1994, De Andres and Garcia-Ribas, Pain Practice 3: 1-7, 2003). Neuropathic pain is associated with a variety of disease states and present in clinical settings for patients with a wide range of symptoms. (Woolf and Mannion Lancet 353: 1959-64, 1999). It does not require specific pain receptor stimulation although such stimulation can add to the intensity of the pain sensation (Baron Clinical J. Pain 16 (suppl2):S12-S20, 2003).
  • Neuropathic pain is often reported as having a lancinating or continuous burning character and is frequently associated with the appearance of abnormal sensory signs such as allodynia and hyperalgesia. Alloydnia is defined as pain resulting from a stimulus that does not normally elicit a painful response, and hyperalgesia is characterized by an increased pain response to normally non-painful stimuli. Some disorders characterized by neuropathic pain include mono-radiculopathies, trigeminal neuralgia, post-herpetic neuralgia, phantom limb pain, complex regional pain syndromes, back pain and the various peripheral neuropathies. Neuropathic pain may also be associated with diabetes, multiple sclerosis, radio-or chemotherapy and infections such as HIV and tuberculosis. Neuropathic pain may also result as a side effect of drug treatment or abuse.
  • nociceptive pain can be classified as somatic or visceral. Somatic pain results from prolonged activation of nociceptive receptors in somatic tissues such as a bone, joint, muscle or skin. Visceral pain, on the other hand, manifests from activation of nociceptive receptors by pathological mechanisms such as mechanical injury, x- ray irradiation, toxic agents, etc.
  • Neuropathic pain can be characterized by the following clinical features (Teng and Mekhail, Pain Practice, 3: 8-12,2003, Rajbhandari et al, Pain, 83: 627-629,1999, Melzack etal, Ann NY Acad Sci, 933 : 157-174,2001):
  • Pain may be felt in a region of sensory deficit
  • Non-noxious stimuli may be painful (allodynia);
  • Noxious stimuli may produce greater than normal response (hyperalgesia);
  • neuropathic pain is an area of largely unmet therapeutic need. Due to the distinct patho-physiochemical mechanisms and clinical manifestations associated with neuropathic pain relative to pain caused as a result of nociceptor stimulation or acute pain, agents useful in the treatment of pain caused as a result of nociceptor stimulation or acute pain have reduced effectiveness in neuropathic pain treatment.
  • analgesics non-narcotics and narcotics.
  • references include aspirin and other non-steroidal anti-inflammatory drugs (NSAIDS) in the class of analgesics, because they have some analgesic properties.
  • Aspirin and NSAIDS primarily have an anti-inflammatory effect, as opposed to being solely analgesic.
  • Acetaminophen (a NSAIDS) is the most commonly used over-the-counter, nonnarcotic analgesic. Acetaminophen is a popular pain-reliever because it is both effective for mild to moderate pain relief and relatively inexpensive. It must be emphasized though that the safety of acetaminophen is tied to proper use of the drug (use according to specific prescribing instructions). If acetaminophen is not used according to the directions on the label, serious side effects and possible fatal consequences can occur. For example, taking more than 4000 mg/day, or using it long-term, can increase the risk of liver damage. The risk of liver damage with acetaminophen use is also increased by ingesting alcohol.
  • acetaminophen is found in more than 600 over-the-counter drugs. It can be found in combination with other active ingredients in many cold, sinus, and cough medications. The cumulative effect of acetaminophen must be considered if one is taking multiple drugs which contain acetaminophen. In the body, acetaminophen changes into metabolites which are eliminated from the body, and by taking more than the recommended maximum daily dose of acetaminophen, more toxic metabolites are produced than can be eliminated, resulting in liver damage.
  • opiates There are two types of narcotic analgesics: opiates and opioids (derivatives of opiates). Opiates are the alkaloids found in opium (a white liquid extract of unripe seeds of the poppy plant). Opioids are any medications which bind to opioid receptors in the central nervous system or gastrointestinal tract. There are four broad classes of opiates/opioids:
  • Endogenous opioid peptides produced in the body: endorphins, dynorphins, enkephalins); 2. Opium alkaloids (such as morphine, codeine, thebaine);
  • Fully synthetic opioids such as pethidine or Demerol, methadone, fentanyl, propoxyphene, pentazocine, buprenorphine, butorphanol, tramadol, and more).
  • Opiates and opioids are used in medicine as strong analgesics, for relief of severe or chronic pain.
  • eMedicine "Some people with intense pain get such high doses that the same dose would be fatal if taken by someone who was not suffering from pain.”
  • opiates and opioids have been debates over the addictive potential of opiates and opioids vs. the benefit of their analgesic properties for treating non-malignant chronic pain, such as chronic arthritis. Some experts believe opiates and opioids can be taken safely for years with minimal risk of addiction or toxic side effects. The enhanced quality of life which opiates and opioids may provide the patient must be considered. Common side effects of opiates and opioids are nausea, vomiting, drowsiness, dry mouth, miosis (contraction of the pupil), orthostatic hypotension (blood pressure lowers upon sudden standing), urinary retention and constipation.
  • opioids Due to the diminishing effects over time (tolerance) of opioids in subjects suffering from neuropathic pain, the use of opioids is often frequent and sustained. This over use is often associated with addiction, the development of tolerance and an increase in the number and severity of side effects associated with opioid use.
  • a pharmacological mainstay of the conventional clinical management of neuropathic pain are tricyclic anti-depressants and certain anti-convulsants, but even these achieve a reduction in pain of less than 50% in greater than 50% of patients treated. These agents are also associated with significant side effect profiles.
  • Addiction as has been defined by the Drug Addiction Committee of the National Research Council, is a state of periodic or chronic intoxication detrimental to the individual and produced by the repeated administration of a drug.
  • an "addictive drug” as used herein is one that is initially used for any one of a number of purposes, e.g., for the relief of physical or psychic pain, and which if used consistently leads to dependency on the part of the individual taking the drug.
  • the addicted individual develops a continuing craving (physical and psychological) for the drug and experiences "withdrawal symptoms” if an attempt is made to discontinue drug use.
  • the terms "withdrawal syndrome” and “abstinence syndrome” are used to mean the same condition of the patient for the purposes of this description.
  • 4,696,818 by Kim relates to a method for alleviating symptoms associated with a variety of drugs, the method comprising administering an herbal composition to the drug dependent individual.
  • US Patent No. 3,706,831 by Plotnikoff also describes a method for treating addiction to any one of a number of different types of drugs, which method involves administering to the addict a composition containing 2-imino-5- phenyl-4-oxazolidinone.
  • US Patent Nos. 4,117,161 and 4,124,715 by Pozuelo disclose methods and compositions for treating withdrawal from narcotics and amphetamines which involve administration of alphamethyl-para-tyrosine or fusaric acid to the affected individual.
  • Treatment of nicotine withdrawal is described in the US Patent No. 4,325,952 by Baiocchi et al. and involves the use of a piperazine compound to treat the symptoms associated with withdrawal from nicotine.
  • US Patent No. 4,788,189 by Glazer involves treatment of nicotine withdrawal by administration of clonidine in conjunction with a tricyclic antidepressant drug.
  • US Patent No. 4,276,890 by Fichera describes a composition for alleviating symptoms of nicotine withdrawal by administering to the affected individual a composition containing a gamma-pyrone such as maltol or ethyl maltol.
  • Antagonists of opioid receptors such as naltrexone, naloxone, nalmephine, and antaxone;
  • Agonists/antagonists such as pentazocine, butorphanol, nalbuphine, and buprenorphine aimed to activate receptors of a particular subtype such as kappa, while blocking receptors of another subtype such as mu; and
  • substitution therapy Agonists such as methadone and others that are better controlled and have a lower affinity to receptors, this method is called substitution therapy.
  • compositions and methods of the invention are based on a better understanding of the physiological role of a recently discovered cell membrane signaling mechanism, including receptors located in the opioid receptor area (opioid or "opioid-like" receptors) and the tetrodotoxin-resistant slow sodium channel known as Na v 1.8.
  • opioid receptor area opioid or "opioid-like” receptors
  • tetrodotoxin-resistant slow sodium channel known as Na v 1.8.
  • gamma-pyrones Several compounds chosen from the group of gamma-pyrones have been used to activate this cell membrane signaling mechanism, the necessary molecular configuration for producing such effect has been established and the novel subset of such active gamma-pyrones compounds has been determined. These substances have their effect because the active centers of the gamma- pyrone molecule-agonist (in salt form) are located at a similar distance from each other as the active atoms of morphine.
  • One of the preferred compounds of the invention is comenic acid, also known as 5- hydroxy-4-oxo-4H-pyran-2-carbon acid, as well as 5-hydroxy-gamma-pyrone-2-carboxylic acid. It has been discovered that administration of this acid to animals at a specified dosage produces a desired sedative effect without causing drug dependency after a 50-day period of continued daily use. The effect is long lasting, up to 24 hours after administration.
  • the effective dosage range was found to be from about 0.005 to about 200 milligrams of comenic acid per 1 kilogram of body weight of the subject.
  • the acid can be administered in a number of pharmaceutically acceptable ways by mixing it with known and biologically acceptable carriers.
  • Administration methods include all parenteral modes, including injection (intravenously, subcutaneously, intramuscularly or intraperitoneal), transdermally, transmucosally, etc. It was discovered that over a relatively short period of time, administration of comenic acid in a pharmacologically effective dose as described herein provides an effective treatment for the cure of narcotic dependency in animals, and that the effective duration of administration ranges from about 5 to about 30 days with a preferred duration from about 13 to about 20 days. This duration compares quite favorably to a typical drug abuse treatment cycle of 3 to 6 months using substitution methods such as methadone.
  • Another preferred compound of the invention is 5-methoxy-gamma-pyrone-2- carboxylic acid. Based on patch clamp experiments on dorsal root ganglion neurons, it has been found that 5-methoxy-gamma-pyrone-2-carboxylic acid has similar effect as comenic acid on the Na ⁇ l.8 slow sodium channel, though less strongly exhibited. 5-methoxy-gamma- pyrone-2-carboxylic acid exists in the form of white or yellowish crystals, has a melting point of 282 0 C, and has a molecular mass equal to 170.122 (C7H ⁇ 5).
  • 5-methoxy-gamma-pyrone- 2-carboxylic acid is moderately water- and alcohol- soluble (though somewhat less so than comenic acid) and practically insoluble in non-polar organic solvents.
  • 5-methoxy-gamma- pyrone-2-carboxylic acid can be produced using kojic acid with good yield.
  • Figure 1 is the spatial structures of gamma-pyrone derivatives in free acid form: (I) comenic acid (5-hydroxy- ⁇ -pyrone-2-carboxylic acid), (II) meconic acid (3-hydroxy- ⁇ -pyrone- 2,6-dicarboxylic acid), (III) 5-methoxy- ⁇ -pyrone-2-carboxylic acid, (IV)kojic acid (2- hydroxymethyl-5-hydroxy- ⁇ -pyrone, and (V) chelidonic acid ( ⁇ -pyrone-2,6-dicarboxylic acid), and [0042]
  • Figure 2 is the spatial structures of gamma-pyrone derivatives in forms including the maximal number of bound cations: (I) comenic acid (5-hydroxy- ⁇ -pyrone-2-carboxylic acid), (II) meconic acid (3-hydroxy- ⁇ -pyrone-2,6-dicarboxylic acid), (III) 5-methoxy- ⁇ -pyrone-2- carboxylic acid, (IV) kojic acid (2-hydroxymethyl-5-
  • Morphine is one of the approximately 20 alkaloids present in natural opium. It is the best known agonist of opioid receptors and triggers a sequence of intracellular signaling processes. The first step in this sequence is ligand-receptor binding, in which the target of morphine is a well- studied class of cell membrane receptors (opioid receptors). Activation by morphine of opioid receptors, which are linked to ion channels, can produce analgesic and sedative effects. Opioids decrease pain sensitivity by reducing the calcium-dependent release of neuromediators from presynaptic terminals, thus inhibiting signal transmission between neurons.
  • the principle behind the present invention is to substitute morphine with a more friendly and benign compound, which is still capable of activating this newly-discovered signaling pathway, thereby reducing pain and pain and other negative effects of the abstinence syndrome, but does not create the physical dependency or euphoria associated with morphine and other opiate alkaloids and their derivatives.
  • Gamma-pyrones are generally known to be used for medicinal purposes. They have been predominately used as food additives, viral agents (as described for example in the PCT publication No. WO 92/13850); for treatment of iron-deficiency anemia (see for example the US Patent No. 4,575,502); high blood sugar and diabetes (see for example US Patent No. 5,888,993), allergic conditions (see for example US Patent No. 4,198,426), and other ailments. They have never been suggested to be used for sedation, pain relief or drug abuse related pain relief since there was no rationale known for doing so.
  • Comenic acid was found to be an excellent representative of the gamma-pyrone group in use for the purposes of the present invention.
  • 5-hydroxy-4-oxo-4H-pyran-2-carbon acid, or comenic acid exists in the form of yellowish crystals, has a melting point of about 270° C, and has a molecular mass equal to 156.095 (C ⁇ H4 ⁇ 5).
  • Comenic acid is moderately water- and alcohol- soluble and practically insoluble in nonpolar organic solvents.
  • Comenic acid is produced from kojic acid with good yield.
  • Comenic acid is one of the ingredients of a widely used antibacterial medicinal preparation sold in Russia, Baliz-2.
  • Group 1 - Control Male rats were subjected to the enteral introduction of 0.5 ml of saline solution. Then, the animals were divided into two groups. The rats in the first group were tested in "the open field” 60 minutes after the solution's introduction. The rats in the second group were tested 90 minutes after the introduction. The test consisted of the rat being placed in the center of "the open field", and then the number of squares of "the open field” that the rat crosses within 5 minutes is counted (an estimation of motor activity). [0049] Groups 2 - 5 - Valerian extract. Valerian extract was steamed until it became dry.
  • Groups 6 - 9 - Comenic acid were dissolved in saline in the desired dosages (see table 1 below). The solution's pH was adjusted to equal 6.5 - 6.8 using concentrated NaOH solution. Comenic acid was introduced into the rats in the same way as in control. The testing of rats in "the open field" was carried out as described for control group as well.
  • results above indicate that the administration of comenic acid to Wistar male rats with a body weight of 200 - 230 g in dosage of 50 and 100 mg/kg of body weight has lowered their motor activity by 68% and 78%, respectively, as compared with the control group (saline), and 52 and 53%, respectively, as compared with the valerian extract. Therefore, the sedative effect of comenic acid was twice that of valerian extract in these experiments with rats.
  • AnoceptinTM in medicinal form, referred to as "AnoceptinTM” was also tested on rats with transplanted tumors (Pliss limphosarcoma) to determine if it stimulated tumor growth (Effect of medicine Anoceptin on the growth of transplantable tumor in rats, State Oncology Institute, 2006, Saint-Petersburg, Russia). Pliss limphosarcoma was transplanted subcutaneously into 20 rats. Forty-eight hours after transplantation, the rats were randomly assigned into groups (10 rats in experimental group, and 10 in control group) and the injections were started. Both groups were injected i.p. (intraperitoneal) once per day, 5 times per week and given a total of 10 injections each.
  • the experimental group was administered 50 mg/kg of comenic acid in each injection, while the control group was injected with 1.5ml of physiological solution.
  • Comenic acid was utilized in its medicinal form ("AnoceptinTM”), a 1% solution with ions of proper moiety.
  • AdoceptinTM a 1% solution with ions of proper moiety.
  • the size of the tumor was measured on day 6, 9, 13 and 16 of the experiment, and the volumes were calculated. Based on the comparison between the two groups of 1) such tumor volumes and 2) rat mortality, it was determined that under the described conditions, comenic acid had no effect (no stimulation and no inhibition) on the growth of transplantable tumors of Pliss limphosarcoma. The data was determined to be statistically significant, with p ⁇ 0.05.
  • AnoceptinTM in medicinal form, referred to as "AnoceptinTM” was also tested on rats with transplanted tumors (Ehrlich carcinoma) to determine if it stimulated tumor growth (Effect of medicine Anoceptin on the growth of transplantable tumor, State Oncology Institute, 2006, Saint-Petersburg, Russia).
  • Ehrlich carcinoma was transplanted subcutaneously into 20 rats. Forty-eight hours after transplantation, the rats were randomly assigned into groups (10 rats in experimental group, and 10 in control group) and the injections were started. Both groups were injected i.p. (intraperitoneal) once per day, 5 times per week and given a total of 10 injections each.
  • the experimental group was administered 50 mg/kg of comenic acid in each injection, while each in the control group was injected with 0.125ml of physiological solution.
  • Comenic acid was utilized in its medicinal form ("AnoceptinTM"), a 1% solution with ions of proper moiety.
  • AdoceptinTM a 1% solution with ions of proper moiety.
  • the size of the tumor was measured on day 13, 16, 20, 23, 27, 30, 37 and 44 of the experiment, and the volumes were calculated. Based on the comparison between the two groups of 1) such tumor volumes and 2) rat mortality, it was determined that under the described conditions, comenic acid had no effect (no stimulation and no inhibition) on the growth of transplantable tumors of Ehrlich carcinoma. The data was determined to be statistically significant, with p ⁇ 0.05.
  • Ligands of opioid receptors normally have at least one positively charged moiety, which is generally thought to bind to an acidic residue of the receptor [Strader CD., Fong T.M., Tota M.R. et al. Structure and function of G-protein-coupled receptors. Annual Review Biochemistry. 1994. V. 63, N 7. P. 101].
  • Modeling of various opioid receptors ( ⁇ , ⁇ , K) [Baldwin J.M., Schertler G.F.X., Unger V. M. An alpha-carbon template for the transmembrane helices in the rhodopsin family of G-protein-coupled receptors. J. Molecular Biology 1997. V. 272, N 1. P.
  • Carboxy groups in the ⁇ -position to the pyranone ring oxygen can form salts with inorganic cations, whereas the hydroxy and the carbonyl groups in adjacent positions of the pyranone ring are known to chelate divalent cations in water and 50% aqueous dioxane [e.g., Bryant B.E., Fernelius W.C. Some metal complexes ofkojic acid. J. American Chemistry Soc. 1954. V. 76. N 21. P. 5351; Petrola R. Spectrophotometry study on the equilibrium of substituted 3-hydroxy-4H-pyran-4-ones with Zn(II) ions in aqueous solution. Finn. Chemistry Letters 1985. Vol. 12. N 5. P.
  • Mg + is known to act as a nonspecific blocker of synaptic transduction, and this highly negative physiological effect is exhibited at quite low Mg 2+ concentrations, such as 3 rnM [Andrianov G. N., Puyal J., Raymond J., Venteo S., Dememes D., Ryzhova LV.
  • the prerequisites for gamma-pyrones receptor activity are 1) a carboxy group in position 2 of the pyranone ring, 2) a carbonyl group in position 4 of the pyranone ring, and 3) a substituent in position 5 which can participate in Ca + chelation.
  • Patch-clamp results demonstrated that the affinity of the test molecule to the receptor decreased in the following manner: II > I > HI [Rogachevsky LV. , Plakhova V. B., Domnin LN. , Podzorova S. A., Krylov B.V. Physiological role of gamma-pyrones.
  • the present invention is useful as a sedative, pain reliever and for treating withdrawal symptoms from a wide range of drugs possessing addictive properties.
  • the compositions of the invention are most useful in treating an individual withdrawing from narcotics, and more specifically from the use of opium alkaloids such as morphine, heroin and codeine, or from various synthetic variations thereof.
  • the present invention also provides treatment for the depression, fear and anxiety experienced during withdrawal symptoms, and it is likely to provide improvements in such psychological pathologies commonly associated with patients experiencing chronic pain (neuropathic pain).
  • the selected gamma-pyrones as described in the proceeding section be administered as a substitute for the abused drug. Typically, this will involve administration of a therapeutically effective amount of a composition containing the compounds of the invention at least once every twenty- four hours.
  • therapeutically effective amount is intended a dosage quantity effective to significantly alleviate physical craving for the drug of abuse as well as reducing the intensity of or eliminating other withdrawal symptoms associated with its discontinuance. Anxiety, depression, fear and other psychological pathologies associated with the withdrawal syndrome were reduced significantly in animal experiments.
  • the effective daily dosage range was found to be from about 0.005 to about 200 milligrams of the compound per kilogram of body weight of the subject, providing a therapeutically effective blood level of the compound.
  • the preferred dosage range is from about 0.05 to about 0.5 mg per kilogram of body weight per day. Such daily dosage can be achieved in a single application, multiple applications or using a continuous release application.
  • the daily dosage entering the bloodstream is estimated to be from about 3 mg to about 100 mg per patient per day. It should of course be adjusted individually based on the decision of a treating physician and depending on the actual body weight of the patient, and depending on the mode of administration given that different modes result in varying losses in the amount of active ingredient actually transmitted into the blood stream.
  • the active ingredient unit dosage range entering the bloodstream is estimated to be from about 1 mg to about 100 mg per application.
  • the unit dosage contains about 5 mg to about 20 mg of the active ingredient (daily dosage) mixed with a pharmaceutically acceptable carrier. Examples of such carriers were described in the parent patent application.
  • effective duration of treatment ranges from about 5 days to about 30 days.
  • the most preferred duration is from about 13 to about 20 days.
  • an optimal regimen for the parenteral (non-oral) administration will involve daily injection of an aqueous composition containing 5-20 mg of a gamma-pyrone compound as described above.
  • Administration of the compounds described herein can be via any of the accepted modes of systemic parenteral administration for therapeutic agents, including by injection, transdermal, transmucosal, subcutaneous implant, rectal, and other systemic modes.
  • the preferred methods of administration are by injection, transdermal, transmucosal, and using a subcutaneous continuous release implant or with injected sorbents.
  • Parenteral administration is generally defined as non-oral administration, including by injection (intravenously, subcutaneously or intramuscularly), transdermally, transmucosally, etc.
  • the gamma pyrone substance is combined with disassociated ions (preferably Na + and/or Ca + ) of proper moiety, using for example sodium carbonate.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol, ethanol or the like.
  • compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, or the like.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, or the like.
  • the preferred method is to dissolve the gamma pyron substance in a biocompatible liquid along with disassociated ions (preferably Na + and/or Ca +2 ) of proper moiety, using for example sodium carbonate.
  • a more recent approach for parenteral administration employs the implantation or injection of a slow-release or sustained-release system, such that an approximately constant level of dosage is maintained. See for example US Patent No. 3,710,795, the disclosure of which is incorporated by reference herein in its entirety.
  • This application is especially beneficial in a subcutaneous continuous release form for drug addicts.
  • a single visit to a physician can result in a subcutaneous implant of a slow release substrate (similar to nicotine withdrawal implant strips such as "Norplant") or an injected slow release sorbent impregnated with the active ingredient providing a constant therapeutically effective level of a compound of the invention over the entire treatment period as described above.
  • unauthorized removal of an implant to stop the therapy is much more difficult to do for a drug addict than to discontinue the medication delivered by other means.
  • the compounds of the invention may also be delivered through the body surface, i.e., transdermally or transmucosally.
  • transdermal as used herein is meant passage into and through the skin to achieve effective therapeutic blood levels.
  • Transmucosal is intended to mean passage through a mucosal membrane of a living organism and thus includes delivery of drugs through nasal, lungs, sublingual, oral patch or buccal tissue.
  • Transdermal or transmucosal delivery will involve topical application of the compounds of the invention in the form of an ointment, gel, cream, powder, spray, or the like, or may involve use of a drug delivery device as taught, for example, in US Patent Nos. 3,742,951, 3,797,494, or 4,568,343.
  • Such compositions may optionally contain a permeation enhancer as known in the art, to increase the rate at which the compounds of the invention permeate through the skin or mucosal tissue.
  • Transmucosal administration of the present compositions is preferably effected transnasally, and more preferably by way of a nasal spray.
  • Preferred vehicles for use in such a nasal spray are sterile saline solutions having a pH compatible with that of the nasal mucosa, and a particularly preferred vehicle for use herein is the nasal lubricant manufactured and sold under the trademark "Pretz” by Parnell Pharmaceuticals (San Rafael, CA), or a similar carrier.
  • Solid nasal powders or insufflations can also be used in a similar manner for transmucosal delivery.
  • the compounds are administered in finely divided solid form together with a pharmaceutically accepted solid carrier.
  • a pharmaceutically accepted solid carrier is a finely divided polyethylene glycol (“Carbowax 1540") or finely divided lactose.
  • Such compositions may also include other finely divided excipients.
  • the active ingredient compound is dissolved in a biocompatible liquid such as water, saline, or ethanol and mixed with a volatile propellant, for example dichlorotetrafluoroethane and dichlorodifluoromethane, and placed in a pressurized container preferably having a metering valve to release a predetermined amount of material based on the guidelines described above.
  • a biocompatible liquid such as water, saline, or ethanol
  • a volatile propellant for example dichlorotetrafluoroethane and dichlorodifluoromethane
  • compositions e.g., for oral administration, the compounds will be formulated with pharmaceutical grades of acceptable carrier such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, sodium carbonate, or the like.
  • acceptable carrier such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, sodium carbonate, or the like.
  • the compositions may also be formulated as suppositories using, for example, polyalkylene glycols (e.g., propylene glycol) as the carrier.
  • Liquid pharmaceutically administerable compositions can be prepared by dissolving, suspending, dispersing, etc., the gamma-pyrones as described above and optional pharmaceutical carriers in an acceptable solution such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, or the like, to thereby form a sterile and pyrogen-free solution or suspension.
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents or the like, e.g., sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sodium carbonate, triethanolamine oleate, etc.
  • wetting or emulsifying agents e.g., sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sodium carbonate, triethanolamine oleate, etc.
  • Actual methods of preparing such dosage forms are known in the art, or will be
  • a pharmaceutically acceptable non-toxic composition is generally formed by the incorporation of any of the normally employed compounds described above.
  • Such compositions can take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
  • Such compositions can contain between about 1 wt.% to about 95 wt.% of the active ingredients, preferably between about 1 wt.% to about 70 wt.%.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Anesthesiology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une substance à effet sédatif, qui comprend une dose thérapeutiquement efficace d'un gamma-pyrone, tel que l'acide coménique, l'acide méconique, l'acide 5-méthoxy-gamma-pyrone-2-carboxylique et analogues, dans un support pharmaceutiquement acceptable. Administrée selon une posologie quotidienne de 0,05 mg à environ 10 000 mg du principe actif par dose unitaire d'un patient, la substance de l'invention peut servir à traiter divers troubles du système nerveux, par exemple la douleur, l'insomnie, l'anxiété, la névrose, la dépression, ainsi que des symptômes de sevrage chez des patients toxicomanes, en particulier des patients dépendants des opiacés. La substance de l'invention peut être administrée selon plusieurs voies d'administration systémique d'un agent pharmaceutique, notamment l'administration par voie orale, parentérale, transdermique ou transmuqueuse. Pour les patients toxicomanes, le procédé d'administration préféré implique un implant sous-cutané assurant une libération continue d'un principe actif, selon une dose quotidienne efficace, pendant toute la durée du traitement s'étalant entre 5 et 30 jours, de préférence, entre 13 et 20 jours.
PCT/IB2007/004218 2006-07-25 2007-06-21 Substance à effet sédatif WO2008038160A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11/459,659 2006-07-25
US11/459,659 US20060252824A1 (en) 2002-03-19 2006-07-25 Substance with sedative effect

Publications (2)

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WO2008038160A2 true WO2008038160A2 (fr) 2008-04-03
WO2008038160A3 WO2008038160A3 (fr) 2008-07-24

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2209062C1 (ru) * 2002-03-19 2003-07-27 Институт физиологии им. И.П.Павлова РАН Вещество, обладающее седативным действием

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