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Methods and compositions

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Methods and compositions


The present invention relates generally to the field of pain management, and in particular, the management of neuropathic or inflammatory pain including a neuropathic or inflammatory component of nociceptive pain. More particularly, the present invention provides methods and compositions which treat, alleviate, prevent, diminish or otherwise ameliorate the symptoms of neuropathic or inflammatory pain. The present invention further contemplates combination therapy involved in the treatment of pain in association with the treatment of a particular disease condition or pathology. The present invention further also provides sustained and slow release formulations, tamper-proof deliver systems and stents, catheters and other mechanical devices coated with formulations which permit sustained or slow release of active ingredients involved in pain management.

Browse recent Relevare Aust. Pty Ltd patents - Abbotsford, AU
Inventors: Raymond NADESON, Adam Paul TUCKER, Colin GOODCHILD
USPTO Applicaton #: #20120277271 - Class: 514352 (USPTO) - 11/01/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai >Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms >Nitrogen Attached Directly To The Six-membered Hetero Ring By Nonionic Bonding



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The Patent Description & Claims data below is from USPTO Patent Application 20120277271, Methods and compositions.

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CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 12/958,210, filed on Dec. 01, 2010, which is a continuation of U.S. patent application Ser. No. 10/574,438, filed Jun. 25, 2007, which application is a U.S. national phase of International Application No. PCT/AU2004/001772, filed Dec. 16, 2004, which application claims priority to Australian Application No. 2003906981, filed Dec. 16, 2003, which applications are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to the field of pain management, and in particular, the management of neuropathic or inflammatory pain including a neuropathic or inflammatory component of nociceptive pain. More particularly, the present invention provides methods and compositions which treat, alleviate, prevent, diminish or otherwise ameliorate the symptoms of neuropathic or inflammatory pain. The present invention further contemplates combination therapy involved in the treatment of pain in association with the treatment of a particular disease condition or pathology. The present invention further also provides sustained and slow release formulations, tamper-proof deliver systems and stents, catheters and other mechanical devices coated with formulations which permit sustained or slow release of active ingredients involved in pain management.

2. Description of the Related Art

Bibliographical details of references provided in the subject specification are listed at the end of the specification.

Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in such terms. In considering approaches to treatment of pain, it is important to understand the distinction between acute and persistent or chronic pain. Acute pain occurs as a result of tissue injury, and is mediated by chemical, mechanical or thermal stimulation of pain receptors known as nociceptors. 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 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 edn. 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 the clinic 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 Clin J Pan 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 monoradiculopathies, trigeminal neuralgia, postherpetic neuralgia, phantom limb pain, complex regional pain syndromes, back pain and the various peripheral neuropathies. Neuropathic pain may also be associated with diabetes, radio- or chemo-therapy and infections such as HIV. Neuropathic pain may also result as a side effect of drug treatment or abuse.

For clinical purposes, 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 and toxic agents.

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 et al Ann NY Acad Sci, 933: 157-174, 2001): 1. There is the presence of an abnormal, unpleasant sensation (dysesthesia) that frequently has a burning or electrical quality with an occasional paroxysmal, brief, shooting, or stabbing quality. 2. Although the onset of most neuropathic pain is within days after the precipitating injury, there is no absolute temporal relationship to the originating neural trauma such that it can begin weeks, months, or even years later. 3. Pain may be felt in a region of sensory deficit. 4. Non-noxious stimuli may be painful (allodynia). 5. Noxious stimuli may produce greater than normal response (hyperalgesia). 6. There may be an increase in the intensity of pain with repeated stimuli and the pain may persist after the removal of stimuli.

There are no analgesic agents specific for one type of pain component over another and neuropathic and nociceptive pains often respond differently to various analgesics.

Accordingly, although there are numerous available therapies for acute pain caused by stimulation of the nociceptors, especially treatment with opioid and non-steroidal anti-inflammatory drugs (NSAIDs), neuropathic pain is an area of largely unmet therapeutic need. Due to the distinct pathophysiochemical 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. In particular, the effectiveness of opioids in the treatment of neuropathic pain is diminished relative to their use in the treatment of pain caused as a result of nociceptor stimulation or acute pain, and drug dose response curves for treatment of neuropathic pain are shifted to the right of those for treatment of pain caused as a result of nociceptor stimulation or acute pain (Teng and Mekhail, 2003 supra, De Andres and Garcia-Ribas, 2003 supra, Stute et al J. Pain Symptom Management 25:1123-1131, 2003).

Due to the diminished effects 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. These side effects include euphoric effects, emetic effects, spastic constipation and increased smooth muscle tone.

The conventional pharmacological mainstays of clinical management of neuropathic pain are the 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.

There is a pressing need for improved regimes for the treatment of neuropathic and inflammatory pain as well as improved regimes for treating disease conditions which have a neuropathic or inflammatory pain component.

SUMMARY

OF THE INVENTION

Throughout the specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The present invention provides methods and compositions which treat, alleviate, prevent, diminish or otherwise ameliorate the symptoms associated with neuropathic and/or inflammatory pain in a subject. Reference to “neuropathic pain” or “inflammatory pain” includes the neuropathic or inflammatory component of nociceptive pain. In particular, the present invention contemplates a method for inducing an analgesic response to neuropathic or inflammatory pain in a mammal comprising administering to the mammal an amount of flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof effective to reduce the level of or otherwise ameliorate the sensation of pain. In a related aspect, the compositions and methods of the present invention do not induce overt sedation and/or cause reduced side effects associated with agents used in the treatment of pain.

The present invention also provides a method of inducing an analgesic response in a mammal suffering neuropathic or inflammatory pain by administering to the mammal one of an analgesic agent or flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof concurrently, separately or sequentially with respect to the other of an analgesic agent or flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof, in an amount effective to reduce the level of or otherwise ameliorate the sensation of pain. Preferably, the flupirtine or a pharmaceutically acceptable salt derivate, homolog or analog thereof is administered in an amount effective to reduce at least one adverse side effect of the analgesic agent. Such an effective amount is considered a synergistic effective amount. Preferably, the method does not induce overt sedation such as caused by the analgesic agent. Preferably, the analgesic agent is an opioid, such as but not limited to fentanyl, oxycodone, codeine, dihydrocodeine, dihydrocodeinone enol acetate, morphine, desomorphine, apomorphine, diamorphine, pethidine, methadone, dextropropoxyphene, pentazocine, dextromoramide, oxymorphone, hydromorphone, dihydromorphine, noscapine, papverine, papveretum, alfentanil, buprenorphine and tramadol and pharmaceutically acceptable salts, derivatives, homologs or analogs thereof as well as opioid agonists.

Another embodiment the present invention relates to the use of flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof in the manufacture of a medicament for inducing an analgesic response in the treatment of neuropathic or inflammatory pain. Preferably, the analgesia is induced without overt sedation and preferably the pain is neuropathic pain.

In a further embodiment, the present invention relates to the use of an analgesic agent and flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof, in the manufacture of one or more separate or combined medicaments for inducing analgesia in response to inflammatory or neuropathic pain. Preferably, the analgesia is induced without overt sedation and preferably the pain is neuropathic pain. In a preferred embodiment the analgesic agent is an opioid and preferably the opioid is selected from one or more of the opioids listed above or a pharmaceutically acceptable salt, derivatives, homologs or analogs thereof.

In a further embodiment, the present invention contemplates combination therapy such as in the treatment of cancer, inflammation, a neurological condition or a chronic disease or condition or other pathology wherein the treatment of the disease, condition or pathology is conducted in association with pain management using flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof or optionally an opioid or another analgesic compound.

In a still further embodiment of the present invention, there is provided a delivery system for inducing analgesia in response to neuropathic or inflammatory pain in a mammal comprising an analgesic agent and flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof. In a preferred embodiment the analgesic agent is an opioid and preferred the opioid is selected from one or more of the opioids listed above or pharmaceutically acceptable salts, derivatives, homologs or analogs thereof. The delivery system may, for example, be in the form of a sustained release or slow release formulation, or a tamper proof formulation, or a pharmaceutical formulation or coated onto a stent, catheter or other mechanical device designed for use in a medical procedure.

The compounds according to the present invention may be administered, inter alia, orally, transmucosally, rectally including via suppository, subcutaneously, intravenously, intramuscularly, intraperitoneally, intragastrically, intranasally, intrathecally, transdermally or intestinally. In particularly preferred forms of the present invention, the compounds are orally or transdermally administered.

The present invention further provides a method of treatment of a condition such as cancer, back pain, inflammation or a neurological condition which has a neuropathic or inflammatory pain component, the treatment comprising the administration of flupirtine and optionally an opioid or a pharmaceutically acceptable salts, derivatives, homologs or analogs thereof.

Preferably, the flupirtine or pharmaceutically acceptable salt, derivative, homolog or analog thereof is administered at a dose of between about 0.5 mg/kg and about 20 mg/kg, at intervals of between about 1 hour and about 50 hours, when administered either alone or in combination with an analgesic agent. Preferably, the intervals are between about 12 hours and about 24 hours.

In a particularly preferred embodiment of the present invention the mammal is a human.

A further aspect of the subject invention provides a system for the controlled release of flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof and optionally an opioid, alone or together with another analgesic or active agent, wherein the system comprises: (a) a deposit-core comprising an effective amount of an active substance and having defined geometric form, and (b) a support-platform applied to the deposit-core, wherein the deposit-core contains at least one active substance, and at least one member selected from the group consisting of: (i) a polymeric material which swells on contact with water or aqueous liquids and a gellable polymeric material wherein the ratio of the swellable polymeric material to the gellable polymeric material is in the range 1:9 to 9:1, and (ii) a single polymeric material having both swelling and gelling properties, and wherein the support-platform is an elastic support applied to the deposit-core so that it partially covers the surface of the deposit-core and follows changes due to hydration of the deposit-core and is slowly soluble and/or slowly gellable in aqueous fluids.

The present invention further provides an agent for inducing an analgesic response in a mammal, the agent comprising flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof and optionally an analgesic compound such as an opioid and optionally an active compound for treating a condition, disease or pathology. In one particular example, the present invention contemplates a treatment protocol for cancer, the protocol comprising the administration of a anti-cancer agent and/or radiation therapy in combination with flupirtine and optionally an opioid or a pharmaceutically acceptable salt, derivative, homolog or analog thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graphical representation of time response curves for carrageenan-induced hyperalgesia in male Wistar rats, where paw flick latency (seconds) is plotted against time (minutes) for saline controls (diamonds), flupirtine at 5 mg/kg (squares), flupirtine at 10 mg/kg (stars), morphine at 0.8 mg/kg (vertical bars), morphine at 1.6 mg/kg (horizontal bars), the combination of flupirtine at 5 mg/kg with morphine at 0.4 mg/kg (squares) and the combination of flupirtine at 10 mg/kg with morphine at 0.4 mg/kg (circles).

FIG. 2 is a graphical representation of time response curves for antinociception assessed with the Electrical Current Threshold (ECT) test in male Wistar rats, where standardized ECT value as a ratio against the control is plotted against time for saline controls (triangles), flupirtine at 5 mg/kg (diamonds), morphine at 0.4 mg/kg (circles) and the combination of flupirtine at 5 mg/kg with morphine at 0.4 mg/kg (squares); and

FIG. 3 is a graphical representation of antinociceptive effects in streptozotocin-induced diabetic neuropathy in male Wistar rats, where paw withdrawal threshold (grams) is plotted against time (minutes), where zero time is time of test drug injection, for saline controls (diamonds), flupirtine at 5 mg/kg (squares), flupirtine at 10 mg/kg (triangles), morphine at 1.6 mg/kg (crosses), morphine at 3.2 mg/kg (stars), the combination of flupirtine at 5 mg/kg with morphine at 3.2 mg/kg (closed circles) and the combination of flupirtine at 10 mg/kg with morphine at 1.6 mg/kg (open squares), with results for weight matched non-diabetic controls shown with an open circle.

DETAILED DESCRIPTION

OF THE PREFERRED EMBODIMENTS

Before describing the present invention in detail, it is to be understood that unless otherwise indicated, the subject invention is not limited to specific formulations of components, manufacturing methods, dosage regimes, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

The singular forms “a”, “an” and “the” include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to “an opioid” includes a single opioid, as well as two or more opioids; reference to “an analgesic agent” includes a single agent, as well as two or more agents.

In describing and claiming the present invention, the following terminology is used in accordance with the definitions set forth below.

The terms “compound”, “agent”, “active agent”, “chemical agent”, “pharmacologically active agent”, “medicament”, “active” and “drug” are used interchangeably herein to refer to a chemical compound that induces a desired pharmacological and/or physiological effect. The terms also encompass pharmaceutically acceptable and pharmacologically active ingredients of those active agents specifically mentioned herein including but not limited to salts, esters, amides, prodrugs, active metabolites, analogs and the like. When the terms “compound”, “agent”, “active agent”, “chemical agent” “pharmacologically active agent”, “medicament”, “active” and “drug” are used, then it is to be understood that this includes the active agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, metabolites, analogs, etc.

Reference to a “compound”, “agent”, “active agent”, “chemical agent” “pharmacologically active agent”, “medicament”, “active” and “drug” includes combinations of two or more actives such as two or more opioids. A “combination” also includes multi-part compositions such as a two-part composition where the agents are provided separately and given or dispensed separately or admixed together prior to dispensation.

For example, a multi-part pharmaceutical pack may have two or more active agents maintained separately.

The terms “effective amount” and “therapeutically effective amount” of an agent as used herein mean a sufficient amount of the agent (e.g. flupirtine and/or an opioid) to provide the desired therapeutic or physiological effect or outcome. Undesirable effects, e.g. side effects, are sometimes manifested along with the desired therapeutic effect; hence, a practitioner balances the potential benefits against the potential risks in determining what is an appropriate “effective amount”. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, mode of administration and the like. Thus, it may not be possible to specify an exact “effective amount”. However, an appropriate “effective amount” in any individual case may be determined by one of ordinary skill in the art using only routine experimentation.

By “pharmaceutically acceptable” carrier, excipient or diluent is meant a pharmaceutical vehicle comprised of a material that is not biologically or otherwise undesirable, i.e. the material may be administered to a subject along with the selected active agent without causing any or a substantial adverse reaction. Carriers may include excipients and other additives such as diluents, detergents, coloring agents, wetting or emulsifying agents, pH buffering agents, preservatives, and the like.

Similarly, a “pharmacologically acceptable” salt, ester, emide, prodrug or derivative of a compound as provided herein is a salt, ester, amide, prodrug or derivative that this not biologically or otherwise undesirable.

The terms “treating” and “treatment” as used herein refer to reduction in severity and/or frequency of symptoms of the condition being treated, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms of the condition and/or their underlying cause and improvement or remediation or amelioration of damage following a condition.

“Treating” a subject may involve prevention of a condition or other adverse physiological event in a susceptible individual as well as treatment of a clinically symptomatic individual by ameliorating the symptoms of the condition.

A “subject” as used herein refers to an animal, preferably a mammal and more preferably human who can benefit from the pharmaceutical formulations and methods of the present invention. There is no limitation on the type of animal that could benefit from the presently described pharmaceutical formulations and methods. A subject regardless of whether a human or non-human animal may be referred to as an individual, patient, animal, host or recipient. The compounds and methods of the present invention have applications in human medicine, veterinary medicine as well as in general, domestic or wild animal husbandry. The compositions also have industrial applications.

As indicated above, the preferred animals are humans or other primates such as orangutangs, gorillas, marmosets, livestock animals, laboratory test animals, companion animals or captive wild animals, as well as avian species.

Examples of laboratory test animals include mice, rats, rabbits, simian animals, guinea pigs and hamsters. Rabbits, rodent and simian animals provide a convenient test system or animal model. Livestock animals include sheep, cows, pigs, goats, horses and donkeys.

The present invention provides a method of an inducing analgesic response to neuropathic or inflammatory pain in a mammal. In this context the term “mammal” is intended to encompass both humans and other mammals such as laboratory test animals.

Throughout this specification, the term “neuropathic pain” is to be understood to mean pain initiated or caused by a primary lesion or dysfunction within the nervous system. Examples of categories of neuropathic pain that may be treated by the methods of the present invention include monoradiculopathies, trigeminal neuralgia, postherpetic neuralgia, phantom limb pain, complex regional pain syndromes, back pain, neuropathic pain associated with AIDS and infection with the human immunodeficiency virus and the various peripheral neuropathies, including, but not limited to drug-induced and diabetic neuropathies.

The term “inflammatory pain” is intended to describe the subset of acute and chronic pain that results from inflammatory processes, such as may arise in the case of infections, arthritis and neoplasia or tumor related hypertrophy. Tumor or cancer associated pain is, therefore, considered to fall within the category of inflammatory pain.

Reference to “neuropathic pain” or inflammatory pain” includes reference to a neuropathic or inflammatory component of nociceptive pain.

The method according to the present invention to induces an analgesic response to neuropathic and/or inflammatory pain being suffered by a mammalian, preferably human, patient. A patient, in this context, is also referred to as a “subject”, “target” or “recipient”. In this context the terms “analgesia” and “analgesic response” are intended to describe a state of reduced sensibility to pain, which preferably occurs without overt sedation and preferably without an effect upon the sense of touch. Preferably, the sensibility to pain is reduced by at least 30%, preferably at least 50%, more preferably at least 70% and particularly preferably at least 85%. In a most preferred aspect of the present invention, the sensibility to the neuropathic pain is completely, or substantially completely, removed. To assess the level of reduction of sensibility to pain associated with the analgesia induced by the methods according to the present invention it is possible to conduct tests such as the short form McGill pain questionnaire and/or visual analogue scales for pain intensity and/or verbal rating scales for pain intensity and/or measurement of tactile allodynia using von Frey hairs or similar device. These tests are standard tests within the art and would be well known to the skilled person.

Accordingly, one aspect of the present invention contemplates a method for inducing an analgesic response to neuropathic or inflammatory pain in a mammal comprising administering to the subject an amount of flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof effective to reduce the level of or otherwise ameliorate the sensation of pain.

Another aspect of the present invention provides a method of inducing analgesia in a mammal suffering neuropathic or inflammatory pain by administering to the mammal one of an analgesic agent or flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof concurrently, separately or sequentially with respect to the other of an analgesic agent or flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof, in an amount effective to reduce the level of or otherwise ameliorate the sensation of pain.

Still another aspect of the present invention contemplates combination therapy such as in the treatment of cancer, inflammation, back pain a neurological condition or a chronic disease or condition or other pathology wherein the treatment of the disease, condition or pathology is conducted in association with pain management using flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof and optionally in addition to an analgesic agent.

In both cases, the analgesic effect is preferably without overt sedation or the other side effects of flupirtine or the analgesic agent.

By the term “overt sedation” it is intended to convey that the methods (and compositions) of the invention do not result in practically meaningful sedation of the patient or subject being treated, i.e. significant, visible or apparent drowsiness or unconsciousness of the patient being treated. Thus, the treatment methods of the invention do not result in sleepiness or drowsiness in the patient that interfere with, or inhibit, the activities associated with day to day living, such as driving a motor vehicle or operating machinery for human subjects, or feeding and grooming for animal subjects.

Collectively, the flupirtine or pharmaceutically acceptable salt, derivative, homolog or analog thereof and the other analgesic agent will be referred to as the “active agents”. A synergistically effective amount of flupirtine or a pharmaceutically acceptable salt, derivative, homolog or analog thereof, when administered concurrently, separately or sequentially with an analgesic agent such as an opioid may restore or improve opioid responsiveness to neuropathic or inflammatory pain. The active agents may be administered either as a combined form, i.e. a single composition containing the active agents, or as discrete dosages. The active agents will preferably be administered within a time frame allowing the desired additive or synergistic analgesic effect to be achieved. That is, the timing of administration should allow each of the active agents or their active metabolites to simultaneously be present within the patient within their respective therapeutic concentration ranges. The time between the delivery of the agents is between seconds, minutes, hours, days or weeks.

The term “analgesic agent” is intended to encompass known and as yet unknown compounds (including pharmaceutically acceptable salts, derivatives, homologs or analogs thereof) that are effective for treatment of pain in mammals, including opioids and compounds such as aspirin, indomethacin, naproxen, fenoprofen, sulindac, diclofenac, indoprofen, nitroglycerin, propanolol, valproate, timolol, atenolol, alprenolol, cimetidinze, clonidine, imipramine, levodopa, chloropromazine, reserpine, methyl-dopa, dihydroxyphenylalanine, provaloxyloxyethyl ester of alpha-methyldopa hydrochloride, theophylline, calcium gluconate, ferrous lactate, vincamine, diazepam, phenoxybenzamine, blocking agents, paracetamol; NSAIDs such as ibuprofen, indomethacin and phenylbutazone; the opioids; tricyclic antidepressants such as amitryptyline; anticonvulsants such as carbamazepine and sodium valproate; local anaesthetics such as lignocaine, mexiletine; NMDA antagonists such as dextromethorphan or ketamine; neurosteroid analgesics such as alphadolone; and GABA analogs such as GABApentin and pre-gabalin and pharmaceutically acceptable salts, derivatives, homologs or analogs thereof. One of the actions of the GABA analogs, such as GABApentin and pre-gabalin, act on the alpha(2)delta subunit of voltage-dependent calcium channels. The term is intended to particularly encompass analgesics in relation to which dose limiting side effects are associated, and especially those associated with induction of sedation. Particularly preferred other analgesic agents are the opioids.

GABAergic drugs can also be used in combination with flupirtine for the treatment of neuropathic and inflammatory pain. GABAergic drugs include compounds that enhance the action of gamma aminobutyric acid (GABA) in the central nervous system; these include drugs that act directly on receptors such as baclofen, muscimol, alcohols, neurosteroids and benzodiazepines, drugs such as vigabatrin that cause inhibition of extra neuronal enzymatic breakdown of GABA, drugs such as topiramate that modulate GABA-coupled ion channels and drugs such as tiagabine that inhibit the reuptake of synaptic GABA by neurons and glial cells.

As used herein, opioid compounds (opioids) include any compound that is physiologically acceptable in mammalian systems and is a full or at least partial agonist of an opioid receptor. Opioid compounds are well known and include naturally occurring compounds derived from opium such as codeine, morphine and papavarine as well as derivatives of such compounds that generally have structural similarity as well as other structurally unrelated compounds that agonise an opioid receptor present in a mammalian system. Specific examples of opioid compounds contemplated by the present invention include: fentanyl, oxycodone, codeine, dihydrocodeine, dihydrocodeinone enol acetate, morphine, desomorphine, apomorphine, diamorphine, pethidine, methadone, dextropropoxyphene, pentazocine, dextromoramide, oxymorphone, hydromorphone, dihydromorphine, noscapine, nalbuprhine papaverine, papaveretum, alfentanil, buprenorphine and tramadol and pharmaceutically acceptable salts, derivatives, homologs or analogs thereof.

The phrase “pharmaceutically acceptable salt, derivative, homologs or analogs” is intended to convey any pharmaceutically acceptable tautomer, salt, pro-drug, hydrate, solvate, metabolite or other compound which, upon administration to the subject, is capable of providing (directly or indirectly) the compound concerned or a physiologically (e.g. analgesically) active compound, metabolite or residue thereof. An example of a suitable derivative is an ester formed from reaction of an OH or SH group with a suitable carboxylic acid, for example C1-3alkyl-CO2H, and HO2C—(CH2)n—CO2H (where n is 1-10 such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, but preferably 1-4), and CO2H—CH2phenyl.

Thus, the active compounds may be in crystalline form, either as the free compounds or as solvates (e.g. hydrates). Methods of solvation are generally known within the art.



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stats Patent Info
Application #
US 20120277271 A1
Publish Date
11/01/2012
Document #
13536741
File Date
06/28/2012
USPTO Class
514352
Other USPTO Classes
International Class
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Drug, Bio-affecting And Body Treating Compositions   Designated Organic Active Ingredient Containing (doai)   Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai   Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms   Nitrogen Attached Directly To The Six-membered Hetero Ring By Nonionic Bonding