Title of Invention	ANALGESIC COMPOSITION OF TOPICALLY APPLIED NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND OPIOIDS
Abstract	The present invention relates to pharmaceutical formulations comprising at least two compounds, one effecting opioid analgesia and one effecting cyclooxygenase 1 and 2 activity, in amounts sufficient to potentiate an antinociceptive response when both compounds are topically administered in a physiologically acceptable topical excipient. The pharmaceutical formulations of the present invention are used to prevent or relieve acute pain and chronic peripheral neuropathy and/or neuropathic inflamma¬tion in a patient in need of such treatment.

Title of Invention

ANALGESIC COMPOSITION OF TOPICALLY APPLIED NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND OPIOIDS

Abstract

The present invention relates to pharmaceutical formulations comprising at least two compounds, one effecting opioid analgesia and one effecting cyclooxygenase 1 and 2 activity, in amounts sufficient to potentiate an antinociceptive response when both compounds are topically administered in a physiologically acceptable topical excipient. The pharmaceutical formulations of the present invention are used to prevent or relieve acute pain and chronic peripheral neuropathy and/or neuropathic inflamma¬tion in a patient in need of such treatment.

Full Text	FORM 2 THE PATENT ACT 1970 (39 of 1970) The Patents Rules, 2003 COMPLETE SPECIFICATION (See Section 10, and rule 13) TITLE OF INVENTION ANALGESIC COMPOSITION OF TOPICALLY ANTIINFLAMMATORY DRUGS AND OPIOIDS APPLIED NONSTEROIDAL APPLICANT(S) a) Name b) Nationality c) Address FLAMEK CORP. OUE ESTONIAN Company PADRIKU TEE 7/3 -EE11912 TALLINN, ESTONIA 9, PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed : - Field of invention The present invention relates to a topical pharmaceutical composition, formulated with at least one nonsteroidal antiinflammatory drug and at least one opioid anal¬gesic, and to methods of providing pain relief to a subject through topical admini¬stration of the composition in an amount and duration sufficient to synergistically potentiate an antinociceptive response. Background art The mechanism by which inflammatory prostaglandins enhance pain perception is incompletely understood. The enhancement of pain perception occurs as the result of prostaglandin-mediated sensitization of the peripheral and central nervous systems. Arachidonic acid is derived from normally sequestered membrane phospholipids. Trauma or inflammation exposes membrane-bound phospholipids to phospholipase A2, which converts them into arachidonic acid. COX-2 converts arachidonic acid into inflammatory prostoglandins (Svensson CI, Yaksh TL. The spinal phospholipase-cyclooxygenase-prostanoid cascade in nociceptive processing. Annu Rev Pharmacol Toxi-col.2002; 42:553 -583). Animal models have demonstrated that COX-2 is induced in the dorsal horn of the spinal cord following the peripheral injury (Hefferan MP, Carter P, Haley M, Loomis CW. Spinal nerve injury activates prostaglandin synthesis in the spinal cord that contributes to early maintenance of tactile allodynia. Pain.2003; 101(1-2):139 -147.) PGE2 is a potent vasodilator and hyperalgesic agent. Its vasoactive ef¬fects are enhanced by synergistic actions with other inflammatory mediators such as bradykinin and histamine . The hyperalgesia produced by PGE2 to mechanical stim¬uli and to other inflammatory mediators may explain the mechanism of postopera¬tive pain (Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, et ah Inter-kukin-lbeta-mediated induction ofCox-2 in the CNS contributes to inflammatory pain hy¬persensitivity. Nature.2001; 410:471 -475). Because prostaglandins act via a number of receptors coupled with second messengers, the prostonoid receptors for PGE2 are probably important for the effect on sensory neurons. This process is known as pe¬ripheral sensitization {Hefferan MP, Carter P, Haley M, Loomis CW. Spinal nerve injury activates prostaglandin synthesis in the spinal cord that contributes to early maintenance of tactile allodynia. Pain.2003; 101(1-2):139 -147 ). Neuropathic pain arising from lesions to peripheral nerves poses a serious clinical problem. Most analgesics used to treat this syndrome have either a relatively poor therapeutic action or marked side effects, including the tricyclic antidepressants (Fishbain DA. Analgesic effects of antidepressants. } Clin Psychiatry. 2003;64: 96-97), diverse anticonvulsant agents, sodium channel blockers, and opioids ( Hewitt D], The use of NMDA-receptor antagonists in the treat¬ment of chronic pain. Clin J Pain. 200Q;16(2 suppl):S73-S79). Although anecdotal evi¬dence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs), widely used for inflammatory pain, have no efficacy in neuropathic pain, no randomized double blind clinical trials have tested this. Typical examples of the nonsteroidal anti in¬flammatory propionic acid derivatives include ketoprofen, ibuprofen, diclofenac, flurbiprofen, naproxen, fenoprofen, benoxaprofen, indoprofen. pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen and fenbufen, ketorolac, celebrex, rofecoxib, etc. They have potent antiinflammatory and analgesic activities and are widely used for the treatment of rheumatic arthritis and its related condi¬tions. Conventionally, these drugs have been administered orally in the form of solid preparations such as tablets and capsules. However, they have accompanied sys¬temic side effects or gastrointestinal irritation following their oral administration. In order to reduce these side effects, these drugs have been formulated as transdermal preparations based on the fact that the skin permeability of these nonsteroidal antiin¬flammatory drugs are known to be relatively higher than other nonsteroidal antiin¬flammatory drugs. For examples, JP 58-39616, JP 58-83622, JP 58-103311, JP 61-238723 and U.S. Pat. Nos. 4,393,076 and 4,534,980 disclosed formulating nonsteroidal antiin¬flammatory drugs of propionic acid derivatives into transdermal preparations, gen¬erally an ointment or a cream. They claimed that the systemic side effects and gastro¬intestinal irritation of these drugs were significantly reduced while satisfied thera¬peutic effects were obtained. In these patents, they usually used carboxyvinyl poly¬mer or hydroxypropylmethylcellulose as a gel base in the formulation of transder¬mal preparations of the drugs. However, the skin permeations of the drugs from their preparations were not enough to achieve pharmacological effects comparable to the oral administration of the drugs due to the low percutaneous absorption of the drugs from the preparations and, thus, a large amount of the preparation needed to be applied to achieve a desired efficacy. Many other chemical and pharmaceutical compositions are known to produce antinociceptive effects. These include, for in¬stance, steroids; non-steroidal anti-inflammatory drugs; local anesthetics; and opioids. These antinociceptive drug classes are useful for modulating many different types of pain, including postoperative, acute, chronic and inflammatory pain. Pain can be alleviated systemically for instance by ingestion or parenteral administration of a suitable composition or, at the site of the pain for instance, by local or topical administration thereof. Opiates are drugs derived from opium and include mor¬phine, codeine and a wide variety of semisynthetic opioid congeners derived from these and from the baine, another component of opium. Opioids include the opiates and all agonists and antagonists with morphine-like activity and naturally occurring endogenous and synthetic opioid peptides (Miyoshi HR, Leckband SG. Systemic opioid analgesics. In: Loeser JD, ed. Bonica's Management of Pain, Philadelphia, PA: Lippincott Williams & Wilkins; 2001: 1682-1709). Although morphine and other morphine-like opioid agonists are commonly used to produce analgesia, the severity and high inci¬dence of side effects limits their use. The analgesic effects of morphine are trans¬duced through opioid receptors in the central nervous system (CNS), located at both spinal and multiple supraspinal sites (Pert CB, Snyder SH: Opiate receptor, demonstra¬tion in nervous tissue. Science 1973; 179:1101-1104). Morphine and its agonists induce profound analgesia when administered inrrathecally or instilled locally into the dor¬sal horn of the spinal cord (Lewis J, Mansour A, Khachaturian H, Watson SJ, Akil H. Opioids and pain regulation. Pain Headache. 1987;9:129-159). Several mechanisms of action are believed to mediate the inhibition of nociceptive reflexes from reaching higher centers of the brain, including the inhibition of neuro¬transmitter release by opioid receptors on the termini of primary afferent nerves and post-synaptic inhibitory actions on interneurons and on the out-put neurons of the spinothalamic tract. However, opiates can interfere with normal gastrointestinal functioning. Systemic morphine decreases both gastric motility and stomach secre¬tion of hydrochloric acid. Morphine can delay passage of gastric contents through the duodenum for as long as 12 hours. Morphine also decreases biliary, pancreatic, and intestinal secretions and delays the digestion of food in the small intestine. Pro¬pulsive peristaltic waves in the colon are diminished or abolished after administra¬tion of morphine and commonly, constipation occurs. For a detailed review of the physiologic effects of morphine, see Reisine and Pasternak ,1996 Goodman & Gilnanfs, The pharmacological basis of therapeutics, Ninth Edition (Hardman et al. eds.)McGraw-Hillpp.521-555. Systemic morphine also exerts effects on the immune system. The most firmly estab¬lished immunologic effect of morphine is its ability to inhibit the formation of hu¬man lymphocyte rosettes. The administration of morphine to animals causes sup¬pression of the cytotoxic activity of natural killer cells and enhances the growth of implanted tumors. These effects appear to be mediated by actions within the CNS (Sibinga et al. 1988 Annu. Rev. Immunol. 6:219.). Additionally, systemic morphine pro¬vokes the release of histamines, which can cause hypotension. Morphine depresses respiration, at least in part by direct effects on brainstem regulatory systems. In hu¬mans, death from morphine poisoning is nearly always due to respiratory arrest. Opioid antagonists can produce a dramatic reversal of severe respiratory depression; naloxone is currently the treatment of choice. High doses of morphine and related opioids can produce convulsions that are not always relieved by naloxone (see Reisine and Pasternak (1996) Goodman & Gilnan's, The pharmacological basis of therapeu¬tics, Ninth Edition (Hardman et al. eds.)McGraw-Hillpp.521-555). In addition to morphine, a variety of opioids are suitable for clinical use. These include, but are not limited to, Levorphanol, Meperidine, Fentanyl, Methadone, Co¬deine, Propoxyphene, Hydrocodone, Hydromorphone, Oxycodone, Oxymorphone, Loperamide, Tramadol and various opioid peptides. Certain opioids are mixed ago¬nists/antagonists and partial agonists. These include pentazocine, nalbuphine, bu-torphanol, and buprenorphine. Morphine produces analgesia primarily through the mu-opioid receptor. However, among the opioid receptors, there is substantial over¬lap of function as well as of cellular distribution. The mu-opioid receptor mediates the actions of morphine and morphine-like opioids, including most clinical analgesics. In addition to morphine, several highly selective agonists have been developed for mu-opioid receptors, including [D-Ala2, MePhe4 ,Gly5-ol] enkephalin (DAMGO), levorphanol, etorphine, fentanyl, sufentanil, bremazocine, tramadol and methadone. Mu-opioid receptor antagonists include naloxone, naltrexone, D-Phe-Cys-Try-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), diprenorphine, [beta]-finaltrexamine, naloxonazine, nalorphine, nalbuphine, and naloxone benzoylhydrazone. Differential sensitivity to antagonists, such as naloxonazine, indicates the pharmacologic distinctions between the mu-opioid re¬ceptor subtypes, mu, and mu2. Several of the opioid peptides also interact with mu-opioid receptors. Because of extensive investigations with attempts to improve the shortcomings of the existing patents and products, the present inventors have suc¬ceeded in establishing novel topical formulations containing a nonsteroidal antiin¬flammatory drug in conjunction with synergistic doses of opioids and transdermal delivery system. To improve skin penetration of opioids and NSAIDs combination of the propylene glycol and lauric acid has been used. The formulations have high skin permeation rate and, thus, excellent antiinflammatory and analgesic activities com¬parable to its oral administration. Disclosure of invention It is an object of the present invention to provide a pharmaceutical formulation comprising at least two compounds, one effecting opioid analgesia and one effecting cyclooxygenase 1 and 2 activity, in amounts sufficient to potentiate an antinocicep¬tive response when both compounds are topically administered in a physiologically acceptable topical excipient. According to the invention a topical pharmaceutical composition is preferred com¬prising at least one analgesic and wherein the analgesic is selected from the group consisting of an opiate, an opiate derivative, an opioid, enkephalins, endorphins and synthetic opioid peptides. According to the invention it is preferred, that the opioid is selected from the group consisting of ethylmorphine, hydromorphone, morphine, oxymorphone, codeine, levorphanol, oxycodone, hydrocodone, pentazocine, propoxyphene, fentanyl, sufen¬tanil, lofentanil, morphine-6-glucuronide, loperamide, meperidine, tramadol, naloxone, naltrexone, buprenorphine, methadone, etorphine, [D-Ala2, MePhe4, Gly5-ol]enkephalin (DAMGO), butorphanol, nalorphine, nalbuphine, naloxone ben-zoylhydrazone, bremazocine, ethylketocyclazocine, U-50488, U-69593, spiradoline, naltrindole, [D-Pen2,D-Pen5]enkephalin (DPDPE), [D-Ala2, Glu4]deltorphin, and [D-Ser2 ,Leu5 ]enkephalin-Thr6 (DSLET). According to the invention it is also preferred, that the cyclooxygenase 1 and 2 activ¬ity effecting compound is a non-steroidal anti-inflammatory drug (NSAID). According to the invention it is also preferred, that the NSAID is selected from the group consisting of ibuprofen, ketoprofen, flurbiprofen, naproxen, fenoprofen, be-noxaprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen, diclofenac, ketorolac, aspirin, acetaminophen, celebrex and rofecoxib. An especially preferred embodiment of the present invention is characterized in that the analgesic is morphine and the NSAID is ibuprofen. An especially preferred embodiment of the present invention is characterized in that the analgesic is morphine and the NSAID is diclofenac. An especially preferred embodiment of the present invention is characterized in that the analgesic is methadone and the NSAID is ibuprofen. An especially preferred embodiment of the present invention is characterized in that the analgesic is methadone and the NSAID is diclofenac. An especially preferred embodiment of the present invention is characterized in that the analgesic is hydrocodone and the NSAID is diclofenac. An especially preferred embodiment of the present invention is characterized in that the analgesic is hydrocodone and the NSAID is ibuprofen. According to the present invention it is preferred, that the opioid analgesic is present in a dose of about 0.001% to about 10%. According to the present invention it is preferred, that the NSAIDs is present in a dose of about 0.01% to about 20%. A preferred topical formulation according to the present invention is in the form of solution, suspension, gel, emugel, cream, ointment, lotion, spray or transdermal patch. It is also preferred according to the invention that the topical combination of the skin penetration enhancers is preferred, wherein combination of propylene glycol and lauric acid in ratio 10:1 work synergistically. A further object of the present invention is the use of at least two compounds, one effecting opioid analgesia and one effecting cyclooxygenase 1 and 2 activity, for the production of a topical pharmaceutical combination to prevent or relieve acute inci¬sional pain and chronic peripheral neuropathy in a patient in need of such treatment. A further object of the present invention is also the use of at least two compounds, one effecting opioid analgesia and one effecting cyclooxygenase 1 and 2 activity, for the production of a topical pharmaceutical combination to prevent or relieve neuro¬pathic inflammation in a patient in need of such treatment. s £7 SEP 2009 It is especially preferred to use the pharmaceutical composition, wherein the admini¬stration of the pharmaceutical composition is directed to cutaneous, mucosal, vagi¬nal, rectal, ocular, or nasal surfaces. In other words, the present invention encompasses pharmaceutical compositions comprising at least two compounds, at least one effecting opioid analgesia and at least one effecting on cyclooxygenase 1 and 2 activity, in amounts sufficient to po¬tentiate an antinociceptive response when both compounds are topically adminis¬tered in a physiologically acceptable topical excipient. The invention further encom¬passes a method of providing topical analgesia to a subject comprising topical ad¬ministration of a pharmaceutical composition comprising at least two compounds, at least one effecting opioid analgesia and at least one effecting cyclooxygenase 1 and 2 activity, wherein the pharmaceutical composition is administered in a physiologi¬cally acceptable topical excipient and in an amount and a duration sufficient to po¬tentiate an antinociceptive response. The topical gel formulation of the present invention can be prepared by dissolving a mixture comprising a nonsteroidal antiinflammatory drug of a propionic acid de¬rivative such as ketoprofen, flurbiprofen, ibuprofen, naproxen, fenoprofen, be-noxaprofen, indoprofen, pirprofen, carprofen, oxaproztn, pranoprofen, suprofen, alminoprofen, butibufen, diclofenac, ketorolac, aspirin, bextra, celebrex, vioxx and acetaminophen in conjunction with opioids such as morphine, methadone, meperidine, tramadol, buprenorphine, pentasozine, hydromorphone, hydrocodone, oxycodone, fentanyl, sufentanyl, loperamide, naloxone and naltrexone. To improve skin penetration of selected synergistic combination of the NSAIDs and opioids we have used poloxamer; and one or more agents selected from lower alcohol, glycerin, propylene glycol and polyethylene glycol; one or more agent enhancers selected from fatty acids, fatty alcohols and menthol. More specifically, the lower alcohol used in the present invention may be ethanol and isopropyl alcohol, and poloxamer derivatives may be poloxamer 407 and polox- amer 338, poloxamer 237 and others. The concentrated aqueous solution of polox-amer, used as a gel forming agent of this invention, is a low viscous transparent liq¬uid at refrigerator temperature or lower, but turns to a clear semisolid gel on heating to room or body temperature. The polymer also possesses several properties, which make it particularly suitable for use in the formulation of transdermal dosage forms. These include low toxicity and skin irritation, excellent compatibility with other chemicals, high solubilizing capacity for different drugs and good drug release char¬acteristics. Polyethylene glycol may be polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000 and others. Fatty acids may be lauric acid, oleic acid, captic acid, myristic acid and oth¬ers, and fatty alcohols may be lauryl alcohol, oleyl alcohol and others. In the present invention, the pH of the gel may be 4-8 which is usual for the con¬ventional gel forming agent, but it is desirable to use a buffer solution having a pH value around the pKa value of each active compound. The best mode for carrying out the invention Both opioids and NSAID provide peripheral analgesia. Synergistic potentiation of analgesia through topical administration of a topical NSAID/opioid combination offers a new approach to peripheral pain management. Topical administration of a topical NSAID/opioid synergistic drug formulation provides a superior method for the clinical treatment of peripheral pain. It has now been found that topical admini¬stration of a composition comprising certain relative amounts of opioids and NSAID results in the synergistic potentiation of peripheral antinociceptive responses. Use of topically administered compositions comprising the proportions of opioids and topical NSAID described and claimed herein provides an important new approach to management of the peripheral pain. The invention encompasses a pharmaceutical composition comprising at least one opioid and at least one NSAID, in amounts suf¬ficient to potentiate an antinociceptive response when the composition is adminis¬tered topically in a physiologically acceptable topical excipient. As used herein "po¬tentiated antinociceptive response" is a pain-reducing response elicited through the synergistic effect of at least one opioid and at least one NSAID, in which the com¬bined effect is greater than the sum of the effect produced by either agent alone. The preferred opioid is methadone and, preferably, the opioid in the composition of the present invention is methadone. Other opioids are suitable, including, but not limited to, compounds based on or derived from morphine-like compounds and analogs. The opioid can be, but is not limited to, morphine, heroin, ethylmorphine, hydromorphone, oxymorphone, codeine, hydrocodone, levorphanol, oxycodone, pentazocine, loperamide, propoxyphene, fentanyl, sufentanil, lofentanil, morphine-6-glucuronide, buprenorphine, etorphine, [D-Ala2, MePhe4, Gly5-ol] enkephalin (DAMGO), butorphanol, nalorphine, nalbuphine, naloxone benzoylhydrazone, naloxone, naltrexone, meperidine, bremazocine, ethylketocyclazocine, U-50488, U-69593, spiradoline, naltrindole, [D-Pen2, D-Pen5] enkephalin (DPDPE), [D-Ala2, Glu4]deltorphin, and [D-Ser2,Leu5]enkephalin-Thr6 (DSLET), [D-Ala2, MePhe4, Gly5-ol] enkephalin, and (3-endorphin, dynorphin A, dynorphin B and cc-neoendorphin and small molecule and combinatorial chemistry products thereof. Ibuprofen is the preferred NSAIDs in the composition of the present invention. The NSAIDs can be any known in the art, including, but not limited to ketoprofen, flur¬biprofen, naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, oxaproztn, pranoprofen, suprofen, alminoprofen, butibufen, diclofenac, ketorolac, acetaminophen, aspirin, celebrex and rofecoxib. The topical formulations used in the present invention are particularly suitable for formulations as topical preparations. Formulations suitable for topical administra¬tion include liquid or semi-liquid preparations suitable for penetration through the skin to the site of where treatment is required. Examples of liquid and semi-liquid preparations include, but are not limited to, topical solutions, liniments, lotions, creams, ointment or paste or gel. Other topical ingredients used in the topical formu¬lation are in general those commonly used and generally recognized by person skilled in the art of topical formulation. Topical solution of the present invention may contain aqueous or oily solution or suspensions. They may be prepared by dis- solving the pharmaceutical compound in a suitable aqueous solution, which may also contain a bactericidal agent, a fungicidal agent, or any other suitable preserva¬tive, and may preferably include a surface active agent. Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol, and propylene gly¬col. Optionally, L-menthol may be added to the topical solution. Lotions and lini¬ments include those suitable for application to the skin containing a sterile aqueous solution and optionally, a bactericide. They may also include an agent to hasten dry¬ing and cooling of the solution on the skin, such as alcohol or acetone. They may fur¬ther include a moisturizer, such as glycerol, or an oil, such as castor oil or arachis oil. Cream, ointments, or pastes, are semi-solid formulations made by mixing the phar¬maceutical with a greasy or non-greasy base. The topical formulation is in finely-divided or powdered form and may be alone or in a aqueous or non-aqueous solu¬tion or suspension. The topical formulation may be mixed with the greasy or non-greasy base with the aid of suitable machinery. The base may contain hydrocarbons. Examples of the hydrocarbons include, but are not limited to, hard, soft, or liquid paraffin, glycerol, beeswax, a metallic soap, a mucilage, an oil of natural origin (such as almond, corn, arachis, castor or olive oil), wool fat or its derivative, a fatty acid (such as stearic acid or oleic acid), or a combination thereof. The formulation may also contain a surface active agent, such as an anionic, cationic or non-ionic surfac¬tant. Examples of the surfactants include, but are not limited to, sorbitan esters or polyoxyethylene derivatives thereof (such as polyoxyethylene fatty acid esters) and carboxy poly methylene derivatives thereof (such as carbopol). Suspending agents such as natural gums, cellulose derivatives inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included. For ointment, polyethylene glycol 540, polyethylene glycol 3350, and propylene glycol may also be used to mixed with the topical formulation. A gel or emugel formulation includes any gel forming agent commonly used in the pharmaceutical gel formulations. Examples of gel forming agents are cellulose de¬rivatives such as methyl cellulose, hydroxyethyl cellulose, and carboxymethyl cellu- lose; vinyl polymers such as polyvinyl alcohols, polyvinyl pyrrolidones; carboxy-poly-methylene derivatives such as carbopol. Further gelling agents that can be used for the present invention are pectins and gums (such as gum arabic and tragacanth, alginates, carrageenates, agar and gelatin). The preferred gelling agent is carbopol. Furthermore, the gel or emugel formulation may contain auxiliary agents commonly used in the kind of formulations such as preservatives, antioxidants, stabilizers, col¬orants, and perfumes. The analgesic topical formulations of the present invention prepared as above exhibited excellent pharmacological activities as shown in the Experiments below. The following examples describe the present invention in more detail. The examples do not intend to limit the scope of the invention. All in vivo studies were carried out in accordance with the Declaration of Helsinki and with the Guide for Care and Use of Laboratory Animals, as adopted and prom¬ulgated by the Estonian Pollumajandusministeerium. Male Crl:CD-l® (ICR) BR mice (20-25 g) were purchased from Charles River Laboratories (Germany) and were housed in a 12:12-h light-dark cycle temperature-controlled room with food and wa¬ter freely available. Drugs were obtained from Sigma (St. Louis, MO, USA). Drugs were applied topically and analgesia assessed as previously described (Kolesnikov et al (2000) J of Pharmacol and Experimental Ther. 295(2): 546-551). Briefly, the distal por¬tion of the tail (2-3cm) was immersed in a propylene glycol/dH2O(10:l ratio) alone or propylene glycol and lauric acid combination (10:1) solution containing the indi¬cated drugs for the stated time, usually 2 min. ). Analgesia was defined quantita¬tively as tail-flick latency for an individual animal that was twice its baseline latency or greater using tail flick apparatus (Ugo Basile, Italy). Baseline latencies typically ranged from 2.5 to 3.5 s, with a maximum cut-off latency of 10 s to minimize tissue damage in analgesic animals. Since analgesia was assessed quantitatively, groups comparisons were performed with the Fishers exact test (Kolesnikov et al, (1993) Proc, Natl Acad. Sci. USA 90:5162). ED50 values were determined with GraphPad Software. Short description of the Figures Figl: Topical morphine and lidocaine effects in radiant heat tail-flick assay Groups of mice (n > 10) were exposed to the indicated concentration of the free base of lidocaine (1.1 - 8.6 mmol) or morphine (1.5-15 mmol) for 2 min and tested imme¬diately afterward. Fig 2: Addition lauric acid to propylene glycol shifts topical lidocain and morphine dose response curve to left A. Groups of mice (n > 10) were exposed to the indicated concentration of the free base of lidocaine dissolved in PG alone (1.1- 8.6 mmol) or in combination of PG/LA (0.2- 2.1 mmol) for 2 min and tested immediately afterward. B. Other groups of mice (n£ 10) were exposed to morphine sulphate dissolved in propylene glycol (1.5 -11.3 mmol) or in combination of propylene glycol and lauric acid (0.15 -1.5 mmol) for 2 min and tested immediately afterwards. K&3: Time dependence of topical lidocaine and morphine analgesia A. Groups of mice (n > 10) were exposed for 2 min to a fixed concentration of topical lidocaine (0.9 mmol) dissolved either in PG or PG/LA and then were tested in the tail-flick assay immediately after termination of drug exposure. B. Groups of mice (n > 10) were treated for 2 min with fixed dose of morphine (1.5 mmol) dissolved either in PG or PG/LA and then tested in tail-flick assay at the in¬ dicated time over 90 min. Fig 4: Addition lauric acid to propylene glycol shifts topical methadone dose response curve to left and increase the duration of analgesic effect A. Groups of mice (n > 10) were exposed to the indicated concentration of the methadone (0.7 -14 rrunol) dissolved either in PG alone or in PG/LA for 2 min and tested immediately afterward. B. Other groups of mice (n > 10 ) were treated with fixed dose of methadone ( 3.0 mmol) dissolved either in PG or PG/LA and then tested in tail-flick assay at indi¬ cated time over 60 min. Fig 5: Addition lauric acid to propylene glycol shifts topical S-ibuprofen and diclofenac dose response curve to left A. Groups of mice (n > 10) were exposed to the indicated concentration of diclofenac dissolved in PG alone (1.8 - 7.0 mmol) or in combination of PG/LA (0.9 - 3.5 mmol) for 2 min and tested immediately afterward. B. Other groups of mice (n £ 10) were exposed to S-ibuprofen dissolved in PG (4.8- 19.2 mmol) or in combination of PG and LA(1.2- 4.8 mmol) for 2 min and tested im¬ mediately afterwards. Fig 6: Time dependence of topical S-ibuprofen and diclofenac analgesia A. Groups of mice (n > 10) were exposed for 2 min to a fixed concentration of topical S-ibuprofen (4.8 mmol) dissolved either in PG or PG/LA and then were tested in the tail-flick assay at the indicated time over 90 min. B. Groups of mice (n > 10) were treated for 2 min with fixed dose of diclofenac (3.5 mmol) dissolved either in PG or PG/LA and then tested in tail-flick assay at the in¬ dicated time over 90 min. Topical diclofenac and morphine interactions A. Groups of mice received either topical morphine (0.15 mmol; n = 10) or diclofenac (0.9 mmol; n = 10) alone or both together (n = 10) for 2 min. The combination was significantly (P agents. B. Groups of mice (n=30) received either topical morphine (0.15 mmol) or diclofenac (0.9 mmol) or the combination of the two for 2 min and were tested in the tail-flick assay over 90 min. Topical S-ibuprofen and morphine interactions A. Groups of mice received either topical morphine (0.15 mmol; n = 10) or S-ibuprofen (1.2 mmol; n = 10) alone or both together (n = 10) for 2 min. B. Groups of mice (n=30) received either topical morphine (0.15 mmol) or S-ibuprofen (1.2 mmol) or the combination of the two for 2 min and were tested in the tail-flick assay over 90 min. Fig 9: Topical methadone and diclofenac interactions A. Groups of mice received either topical methadone (0.7 mmol; n = 10) or diclofenac (0.9 mmol; n = 10) alone or both together (n = 10) for 2 min. The combination was significantly (P agents. B. Groups of mice (n=30) received either topical methadone (0.7 mmol, n=10) or diclofenac (0.9 mmol, n=10) or the combination (n=10) of the two for 2 min and were tested in the tail-flick assay over 90 min. Fig 10: Topical methadone and S-ibuprofen interactions A, groups of mice received either topical methadone (0.7 mmol; n = 10) or S-ibuprofen (1.2 mmol; n = 10) alone or both together (n = 10) for 2 min. The combi¬nation was significantly (P B. Groups of mice (n=30) received either topical methadone (0.7 mmol, n=10) or S-ibuprofen (1.2 mmol, n=10) or the combination (n=10) of the two for 2 min and were tested in the tail-flick assay over 120 min. Fig 11: Topical NSAIDs and hydrocodone interactions A. Groups of mice (n= 20) received topical hydrocodone (0.6-4,4 mmol) dissolved either PG or PG/LA solution for 2 min and then tested immediately afterwards. B. Groups of mice (n=30) received either topical hydrocodone ( 0.6 mmol, n=10 ) or S-ibuprofen (1.2 mmol, n=10) alone or both together (n=10) for 2 min. C. Other groups on animals received topical either hydrocodone (0.6 mmol, n=10) or diclofenac (0.9 mmol, n=10) or together (n=10) and were tested in the tail-flick assay. Addition of lauric acid to propylene glycol improves drug penetration through skin and increase the potency of the lidocaine and opioids and NSAIDs Propylene glycol is a widely used trans-dermal vehicle for number of the drugs. In early studies, we demonstrated the topical lidocaine and morphine analgesia using DMSO as solvent and skin penetration enhancer . DMSO alone was ineffective in our pain model. In current studies, we also found that propylene glycol alone did not increase significantly base line latencies in mice in radiant heat tail-flick assay (data not shown). To ensure local action, in all studies, we examined a region of the tail that was immersed in vehicle and a more proximal segment that was not exposed. Tail-flick latencies from the unexposed portion of the tail were similar to baseline latencies. Testing regions of the tail that were exposed and not exposed to vehicle revealed no significant antinociceptive effect in either location. In comparative stud¬ies of potency topically applied drugs using different vehicles, we found no differ¬ences in ED50 of the morphine and lidocaine (Fig 1). However, addition of lauric acid to propylene glycol dramatically improves penetration of the morphine and lido¬caine, measured as drug^s ED50. We observed significant dose response shift to left for lidocainevs ED50 (5-fold shift, Fig 2A, Table 1) and for morphine^ ED50 (19-fold shift, Fig 2B, Table 1). In time course studies the distinctions in the potency of the drugs have been even more expressed (Fig 3). Low lidocaine dose in propylene gly¬col and lauric acid solution produced significant and long acting analgesic effects compared with propylene glycol alone (Fig 3A). Duration of the analgesic activity of the morphine in propylene glycol and lauric acid was far beyond compared with the same dose of the drug dissolved in propylene glycol only (Fig 3B). Methadone pro¬duced also analgesic activity in this experimental paradigm. As anticipated, metha¬done elicited dose dependent (Fig 4A) and naloxone sensitive (data not shown) an¬algesia after topical administration. Addition of lauric acid to propylene glycol modulated the methadone potency and its duration effect (Fig 4B, Table 1). We ob¬served significant dose response shift to the left (6.7 fold, Table 1). The hydrocodone demonstrated the most potent analgesic activity in this paradigm (Table 1). Table 1 Addition of the lauric acid to propylene glycol enhances the potency of topical drugs in radiant heat tail flick assay Analgesics ED 50 value (95 % CL) Propylene glycol alone Propylene glycol and lauric acid Shift P value Lidocaine Morphine Methadone Hydrocodone S-ibuprofen Diclofenac 2.2 (1.6-3.2) mmol 7.6 (4.2- 10.9)mmol 6.7 (4.8- 8.8) mmol 1.6 (1.1 - 2.2) mmol 9.3 (6.1-16.5) mmol 3.3 (1.7-5.3) mmol 0.35 (0.2-0.42)mmol 0.4 (0.33-0.54)mmol 1.0 (0.8-1.2) mmol 1.2 (0.8-1.8) mmol 2.1 (0.88- 3.3) mmol 1.1 (0.6-1.78) mmol 6.2 19 6.7 1.3 4.4 3 >0.05 Topical S - ibuprofen and diclofenac analgesia in radiant tail-flick assay Both' S-ibuprofen and diclofenac produced dose dependent analgesia in this para¬digm (Fig 5) with ED50 9.3 and 3.3 mmol, respectively. As anticipated, addition of lauric acid to propylene glycol resulted in to significant increase the potency of the drugs (Table 1). The maximal analgesic effect of S-ibuprofen and diclofenac observed on 2 min after topical application and duration of analgesia was 90 min. Topical opioid and S-ibuprofen and diclofenac synergistic interactions in radiant tail flick assay We next assessed potential interactions between opioids and ibuprofen and di¬clofenac using a fixed, low dose of each. Alone, morphine and diclofenac produced analgesia in 20% and 30% of mice, respectively. However, when the same doses were administered together, the combination produced analgesia in 80% of mice, significantly greater than anticipated from simple additive interactions (50% versus 80 %, p Topical hydrocodone potentates S-ibuprofen and diclofenac analgesia in radiant tail flick assay Alone, hydrocodone produced dose dependent response in this paradigm (Fig 11A). Then we assessed potential interactions between hydrocodone and ibuprofen and diclofenac. Alone, hydrocodone and S-ibuprofen produced 20% and 30% of analge¬sia in mice and combination of the drugs were effective in 50 % of mice, respectively (Fig 11 B), indicating additive interaction in this pain model (50% versus 50%). The combination of hydrocodone and diclofenac produced analgesia in 50% mice, how¬ever, it have not reach statistical significance compared with anticipated additive interactions (50% versus 40%, p CLAIM: 1. A pharmaceutical formulation comprising at least two compounds, one effect¬ing opioid analgesia and one effecting cyclooxygenase 1 and 2 activity, in amounts sufficient to potentiate an antinociceptive response when both com¬pounds are topically administered in a physiologically acceptable topical ex-cipient. 2. The topical pharmaceutical composition according to claim 1 comprising at least one analgesic and wherein the analgesic is selected from the group con¬sisting of an opiate, an opiate derivative, an opioid, enkephalins, endorphins and synthetic opioid peptides. 3. The topical pharmaceutical composition according to claim 2, wherein the opioid is selected from the group consisting of ethylmorphine, hydromor-phone, morphine, oxymorphone, codeine, levorphanol, oxycodone, hydro-codone, pentazocine, propoxyphene, fentanyl, sufentanil, lofentanil, mor-phine-6-glucuronide, loperamide, meperidine, tramadol, naloxone, naltrex¬one, buprenorphine, methadone, etorphine, [D-Ala2, MePhe4, Gly5-ol]enkephalin (DAMGO), butorphanol, nalorphine, nalbuphine, naloxone benzoylhydrazone, bremazocine, ethylketocyclazocine, U-50488, U-69593, spiradoline, naltrindole, [D-Pen2,D-Pen5]enkephalin (DPDPE), [D-Ala2, Glu4]deltorphin, and [D-Ser2, Leu^ ]enkephalin-Thr6 (DSLET). 4. The topical pharmaceutical composition according to claim 1, wherein the cyclooxygenase 1 and 2 activity effecting compound is a non-steroidal anti¬inflammatory drug (NSAID). 5. The topical pharmaceutical composition according to claim 4, wherein the NSAID is selected from the group consisting of ibuprofen, ketoprofen, flurbi¬profen, naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carpro- fen, oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen, diclofenac, ketorolac, aspirin, acetaminophen, celebrex and rofecoxib. The topical pharmaceutical composition according to claim 1, wherein the analgesic is morphine and the NSAID is ibuprofen. The topical pharmaceutical composition according to claim 1, wherein the analgesic is morphine and the NSAID is diclofenac. The topical pharmaceutical composition according to claim 1, wherein the analgesic is methadone and the NSAID is ibuprofen. The topical pharmaceutical composition according to claim 1, wherein the analgesic is methadone and the NSAID is diclofenac. The topical pharmaceutical composition according to claim 1, wherein the analgesic is hydrocodone and the NSAID is diclofenac. The topical pharmaceutical composition according to claim 1, wherein the analgesic is hydrocodone and the NSAID is ibuprofen. The topical pharmaceutical composition according to any of the preceding claims 1 to 11, wherein the opioid analgesic is present in a dose of about 0.001% to about 10%. The topical pharmaceutical composition according to any of the preceding claims 1 to 11, wherein the NSAIDs is present in a dose of about 0.01% to about 20%. 14. The topical formulation according to claim 1, wherein said topical formula¬tion is in the form of solution, suspension, gel, emugel, cream, ointment, lo¬tion, spray or transdermal patch. 15. The topical combination of the skin penetration enhancers according to any of the preceding claims 1 to 14, wherein combination of propylene glycol and lauric acid in ratio 10:1 work synergistically. 16. Use of at least two compounds, one effecting opioid analgesia and one effect¬ing cyclooxygenase 1 and 2 activity, for the production of a topical pharma¬ceutical combination to prevent or relieve acute incisional pain and chronic peripheral neuropathy in a patient in need of such treatment. 17. Use of at least two compounds, one effecting opioid analgesia and one effect¬ing cyclooxygenase 1 and 2 activity, for the production of a topical pharma¬ceutical combination to prevent or relieve neuropathic inflammation in a pa¬tient in need of such treatment. 18. Use according to claim 16 or 17, wherein the administration of the pharma¬ceutical composition is directed to cutaneous, mucosal, vaginal, rectal, ocular, or nasal surfaces.

Full Text

FORM 2
THE PATENT ACT 1970 (39 of 1970)
The Patents Rules, 2003 COMPLETE SPECIFICATION (See Section 10, and rule 13)

TITLE OF INVENTION
ANALGESIC COMPOSITION OF TOPICALLY
ANTIINFLAMMATORY DRUGS AND OPIOIDS

APPLIED NONSTEROIDAL

APPLICANT(S)
a) Name
b) Nationality
c) Address

FLAMEK CORP. OUE ESTONIAN Company PADRIKU TEE 7/3 -EE11912 TALLINN, ESTONIA

9,

PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed : -

Field of invention
The present invention relates to a topical pharmaceutical composition, formulated with at least one nonsteroidal antiinflammatory drug and at least one opioid anal¬gesic, and to methods of providing pain relief to a subject through topical admini¬stration of the composition in an amount and duration sufficient to synergistically potentiate an antinociceptive response.
Background art
The mechanism by which inflammatory prostaglandins enhance pain perception is incompletely understood. The enhancement of pain perception occurs as the result of prostaglandin-mediated sensitization of the peripheral and central nervous systems. Arachidonic acid is derived from normally sequestered membrane phospholipids. Trauma or inflammation exposes membrane-bound phospholipids to phospholipase A2, which converts them into arachidonic acid. COX-2 converts arachidonic acid into inflammatory prostoglandins (Svensson CI, Yaksh TL. The spinal phospholipase-cyclooxygenase-prostanoid cascade in nociceptive processing. Annu Rev Pharmacol Toxi-col.2002; 42:553 -583). Animal models have demonstrated that COX-2 is induced in the dorsal horn of the spinal cord following the peripheral injury (Hefferan MP, Carter P, Haley M, Loomis CW. Spinal nerve injury activates prostaglandin synthesis in the spinal cord that contributes to early maintenance of tactile allodynia. Pain.2003; 101(1-2):139 -147.) PGE2 is a potent vasodilator and hyperalgesic agent. Its vasoactive ef¬fects are enhanced by synergistic actions with other inflammatory mediators such as bradykinin and histamine . The hyperalgesia produced by PGE2 to mechanical stim¬uli and to other inflammatory mediators may explain the mechanism of postopera¬tive pain (Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, et ah Inter-kukin-lbeta-mediated induction ofCox-2 in the CNS contributes to inflammatory pain hy¬persensitivity. Nature.2001; 410:471 -475). Because prostaglandins act via a number of receptors coupled with second messengers, the prostonoid receptors for PGE2 are probably important for the effect on sensory neurons. This process is known as pe¬ripheral sensitization {Hefferan MP, Carter P, Haley M, Loomis CW. Spinal nerve injury activates prostaglandin synthesis in the spinal cord that contributes to early maintenance of

tactile allodynia. Pain.2003; 101(1-2):139 -147 ). Neuropathic pain arising from lesions to peripheral nerves poses a serious clinical problem. Most analgesics used to treat this syndrome have either a relatively poor therapeutic action or marked side effects, including the tricyclic antidepressants (Fishbain DA. Analgesic effects of antidepressants. } Clin Psychiatry. 2003;64: 96-97), diverse anticonvulsant agents, sodium channel blockers, and opioids ( Hewitt D], The use of NMDA-receptor antagonists in the treat¬ment of chronic pain. Clin J Pain. 200Q;16(2 suppl):S73-S79). Although anecdotal evi¬dence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs), widely used for inflammatory pain, have no efficacy in neuropathic pain, no randomized double blind clinical trials have tested this. Typical examples of the nonsteroidal anti in¬flammatory propionic acid derivatives include ketoprofen, ibuprofen, diclofenac, flurbiprofen, naproxen, fenoprofen, benoxaprofen, indoprofen. pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen and fenbufen, ketorolac, celebrex, rofecoxib, etc. They have potent antiinflammatory and analgesic activities and are widely used for the treatment of rheumatic arthritis and its related condi¬tions. Conventionally, these drugs have been administered orally in the form of solid preparations such as tablets and capsules. However, they have accompanied sys¬temic side effects or gastrointestinal irritation following their oral administration. In order to reduce these side effects, these drugs have been formulated as transdermal preparations based on the fact that the skin permeability of these nonsteroidal antiin¬flammatory drugs are known to be relatively higher than other nonsteroidal antiin¬flammatory drugs. For examples, JP 58-39616, JP 58-83622, JP 58-103311, JP 61-238723 and U.S. Pat. Nos. 4,393,076 and 4,534,980 disclosed formulating nonsteroidal antiin¬flammatory drugs of propionic acid derivatives into transdermal preparations, gen¬erally an ointment or a cream. They claimed that the systemic side effects and gastro¬intestinal irritation of these drugs were significantly reduced while satisfied thera¬peutic effects were obtained. In these patents, they usually used carboxyvinyl poly¬mer or hydroxypropylmethylcellulose as a gel base in the formulation of transder¬mal preparations of the drugs. However, the skin permeations of the drugs from their preparations were not enough to achieve pharmacological effects comparable to the oral administration of the drugs due to the low percutaneous absorption of the

drugs from the preparations and, thus, a large amount of the preparation needed to be applied to achieve a desired efficacy. Many other chemical and pharmaceutical compositions are known to produce antinociceptive effects. These include, for in¬stance, steroids; non-steroidal anti-inflammatory drugs; local anesthetics; and opioids. These antinociceptive drug classes are useful for modulating many different types of pain, including postoperative, acute, chronic and inflammatory pain. Pain can be alleviated systemically for instance by ingestion or parenteral administration of a suitable composition or, at the site of the pain for instance, by local or topical administration thereof. Opiates are drugs derived from opium and include mor¬phine, codeine and a wide variety of semisynthetic opioid congeners derived from these and from the baine, another component of opium. Opioids include the opiates and all agonists and antagonists with morphine-like activity and naturally occurring endogenous and synthetic opioid peptides (Miyoshi HR, Leckband SG. Systemic opioid analgesics. In: Loeser JD, ed. Bonica's Management of Pain, Philadelphia, PA: Lippincott Williams & Wilkins; 2001: 1682-1709). Although morphine and other morphine-like opioid agonists are commonly used to produce analgesia, the severity and high inci¬dence of side effects limits their use. The analgesic effects of morphine are trans¬duced through opioid receptors in the central nervous system (CNS), located at both spinal and multiple supraspinal sites (Pert CB, Snyder SH: Opiate receptor, demonstra¬tion in nervous tissue. Science 1973; 179:1101-1104). Morphine and its agonists induce profound analgesia when administered inrrathecally or instilled locally into the dor¬sal horn of the spinal cord (Lewis J, Mansour A, Khachaturian H, Watson SJ, Akil H. Opioids and pain regulation. Pain Headache. 1987;9:129-159).
Several mechanisms of action are believed to mediate the inhibition of nociceptive reflexes from reaching higher centers of the brain, including the inhibition of neuro¬transmitter release by opioid receptors on the termini of primary afferent nerves and post-synaptic inhibitory actions on interneurons and on the out-put neurons of the spinothalamic tract. However, opiates can interfere with normal gastrointestinal functioning. Systemic morphine decreases both gastric motility and stomach secre¬tion of hydrochloric acid. Morphine can delay passage of gastric contents through

the duodenum for as long as 12 hours. Morphine also decreases biliary, pancreatic, and intestinal secretions and delays the digestion of food in the small intestine. Pro¬pulsive peristaltic waves in the colon are diminished or abolished after administra¬tion of morphine and commonly, constipation occurs. For a detailed review of the physiologic effects of morphine, see Reisine and Pasternak ,1996 Goodman & Gilnanfs, The pharmacological basis of therapeutics, Ninth Edition (Hardman et al. eds.)McGraw-Hillpp.521-555.
Systemic morphine also exerts effects on the immune system. The most firmly estab¬lished immunologic effect of morphine is its ability to inhibit the formation of hu¬man lymphocyte rosettes. The administration of morphine to animals causes sup¬pression of the cytotoxic activity of natural killer cells and enhances the growth of implanted tumors. These effects appear to be mediated by actions within the CNS (Sibinga et al. 1988 Annu. Rev. Immunol. 6:219.). Additionally, systemic morphine pro¬vokes the release of histamines, which can cause hypotension. Morphine depresses respiration, at least in part by direct effects on brainstem regulatory systems. In hu¬mans, death from morphine poisoning is nearly always due to respiratory arrest. Opioid antagonists can produce a dramatic reversal of severe respiratory depression; naloxone is currently the treatment of choice. High doses of morphine and related opioids can produce convulsions that are not always relieved by naloxone (see Reisine and Pasternak (1996) Goodman & Gilnan's, The pharmacological basis of therapeu¬tics, Ninth Edition (Hardman et al. eds.)McGraw-Hillpp.521-555).
In addition to morphine, a variety of opioids are suitable for clinical use. These include, but are not limited to, Levorphanol, Meperidine, Fentanyl, Methadone, Co¬deine, Propoxyphene, Hydrocodone, Hydromorphone, Oxycodone, Oxymorphone, Loperamide, Tramadol and various opioid peptides. Certain opioids are mixed ago¬nists/antagonists and partial agonists. These include pentazocine, nalbuphine, bu-torphanol, and buprenorphine. Morphine produces analgesia primarily through the mu-opioid receptor. However, among the opioid receptors, there is substantial over¬lap of function as well as of cellular distribution.

The mu-opioid receptor mediates the actions of morphine and morphine-like opioids, including most clinical analgesics. In addition to morphine, several highly selective agonists have been developed for mu-opioid receptors, including [D-Ala2, MePhe4 ,Gly5-ol] enkephalin (DAMGO), levorphanol, etorphine, fentanyl, sufentanil, bremazocine, tramadol and methadone. Mu-opioid receptor antagonists include naloxone, naltrexone, D-Phe-Cys-Try-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), diprenorphine, [beta]-finaltrexamine, naloxonazine, nalorphine, nalbuphine, and naloxone benzoylhydrazone. Differential sensitivity to antagonists, such as naloxonazine, indicates the pharmacologic distinctions between the mu-opioid re¬ceptor subtypes, mu, and mu2. Several of the opioid peptides also interact with mu-opioid receptors. Because of extensive investigations with attempts to improve the shortcomings of the existing patents and products, the present inventors have suc¬ceeded in establishing novel topical formulations containing a nonsteroidal antiin¬flammatory drug in conjunction with synergistic doses of opioids and transdermal delivery system. To improve skin penetration of opioids and NSAIDs combination of the propylene glycol and lauric acid has been used. The formulations have high skin permeation rate and, thus, excellent antiinflammatory and analgesic activities com¬parable to its oral administration.
Disclosure of invention
It is an object of the present invention to provide a pharmaceutical formulation comprising at least two compounds, one effecting opioid analgesia and one effecting cyclooxygenase 1 and 2 activity, in amounts sufficient to potentiate an antinocicep¬tive response when both compounds are topically administered in a physiologically acceptable topical excipient.
According to the invention a topical pharmaceutical composition is preferred com¬prising at least one analgesic and wherein the analgesic is selected from the group consisting of an opiate, an opiate derivative, an opioid, enkephalins, endorphins and synthetic opioid peptides.

According to the invention it is preferred, that the opioid is selected from the group consisting of ethylmorphine, hydromorphone, morphine, oxymorphone, codeine, levorphanol, oxycodone, hydrocodone, pentazocine, propoxyphene, fentanyl, sufen¬tanil, lofentanil, morphine-6-glucuronide, loperamide, meperidine, tramadol, naloxone, naltrexone, buprenorphine, methadone, etorphine, [D-Ala2, MePhe4, Gly5-ol]enkephalin (DAMGO), butorphanol, nalorphine, nalbuphine, naloxone ben-zoylhydrazone, bremazocine, ethylketocyclazocine, U-50488, U-69593, spiradoline, naltrindole, [D-Pen2,D-Pen5]enkephalin (DPDPE), [D-Ala2, Glu4]deltorphin, and [D-Ser2 ,Leu5 ]enkephalin-Thr6 (DSLET).
According to the invention it is also preferred, that the cyclooxygenase 1 and 2 activ¬ity effecting compound is a non-steroidal anti-inflammatory drug (NSAID).
According to the invention it is also preferred, that the NSAID is selected from the group consisting of ibuprofen, ketoprofen, flurbiprofen, naproxen, fenoprofen, be-noxaprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen, diclofenac, ketorolac, aspirin, acetaminophen, celebrex and rofecoxib.
An especially preferred embodiment of the present invention is characterized in that the analgesic is morphine and the NSAID is ibuprofen.
An especially preferred embodiment of the present invention is characterized in that the analgesic is morphine and the NSAID is diclofenac.
An especially preferred embodiment of the present invention is characterized in that the analgesic is methadone and the NSAID is ibuprofen.
An especially preferred embodiment of the present invention is characterized in that the analgesic is methadone and the NSAID is diclofenac.

An especially preferred embodiment of the present invention is characterized in that the analgesic is hydrocodone and the NSAID is diclofenac.
An especially preferred embodiment of the present invention is characterized in that the analgesic is hydrocodone and the NSAID is ibuprofen.
According to the present invention it is preferred, that the opioid analgesic is present in a dose of about 0.001% to about 10%.
According to the present invention it is preferred, that the NSAIDs is present in a dose of about 0.01% to about 20%.
A preferred topical formulation according to the present invention is in the form of solution, suspension, gel, emugel, cream, ointment, lotion, spray or transdermal patch.
It is also preferred according to the invention that the topical combination of the skin penetration enhancers is preferred, wherein combination of propylene glycol and lauric acid in ratio 10:1 work synergistically.
A further object of the present invention is the use of at least two compounds, one effecting opioid analgesia and one effecting cyclooxygenase 1 and 2 activity, for the production of a topical pharmaceutical combination to prevent or relieve acute inci¬sional pain and chronic peripheral neuropathy in a patient in need of such treatment.
A further object of the present invention is also the use of at least two compounds, one effecting opioid analgesia and one effecting cyclooxygenase 1 and 2 activity, for the production of a topical pharmaceutical combination to prevent or relieve neuro¬pathic inflammation in a patient in need of such treatment.
s £7 SEP 2009

It is especially preferred to use the pharmaceutical composition, wherein the admini¬stration of the pharmaceutical composition is directed to cutaneous, mucosal, vagi¬nal, rectal, ocular, or nasal surfaces.
In other words, the present invention encompasses pharmaceutical compositions comprising at least two compounds, at least one effecting opioid analgesia and at least one effecting on cyclooxygenase 1 and 2 activity, in amounts sufficient to po¬tentiate an antinociceptive response when both compounds are topically adminis¬tered in a physiologically acceptable topical excipient. The invention further encom¬passes a method of providing topical analgesia to a subject comprising topical ad¬ministration of a pharmaceutical composition comprising at least two compounds, at least one effecting opioid analgesia and at least one effecting cyclooxygenase 1 and 2 activity, wherein the pharmaceutical composition is administered in a physiologi¬cally acceptable topical excipient and in an amount and a duration sufficient to po¬tentiate an antinociceptive response.
The topical gel formulation of the present invention can be prepared by dissolving a mixture comprising a nonsteroidal antiinflammatory drug of a propionic acid de¬rivative such as ketoprofen, flurbiprofen, ibuprofen, naproxen, fenoprofen, be-noxaprofen, indoprofen, pirprofen, carprofen, oxaproztn, pranoprofen, suprofen, alminoprofen, butibufen, diclofenac, ketorolac, aspirin, bextra, celebrex, vioxx and acetaminophen in conjunction with opioids such as morphine, methadone, meperidine, tramadol, buprenorphine, pentasozine, hydromorphone, hydrocodone, oxycodone, fentanyl, sufentanyl, loperamide, naloxone and naltrexone. To improve skin penetration of selected synergistic combination of the NSAIDs and opioids we have used poloxamer; and one or more agents selected from lower alcohol, glycerin, propylene glycol and polyethylene glycol; one or more agent enhancers selected from fatty acids, fatty alcohols and menthol.
More specifically, the lower alcohol used in the present invention may be ethanol and isopropyl alcohol, and poloxamer derivatives may be poloxamer 407 and polox-

amer 338, poloxamer 237 and others. The concentrated aqueous solution of polox-amer, used as a gel forming agent of this invention, is a low viscous transparent liq¬uid at refrigerator temperature or lower, but turns to a clear semisolid gel on heating to room or body temperature. The polymer also possesses several properties, which make it particularly suitable for use in the formulation of transdermal dosage forms. These include low toxicity and skin irritation, excellent compatibility with other chemicals, high solubilizing capacity for different drugs and good drug release char¬acteristics. Polyethylene glycol may be polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000 and others. Fatty acids may be lauric acid, oleic acid, captic acid, myristic acid and oth¬ers, and fatty alcohols may be lauryl alcohol, oleyl alcohol and others.
In the present invention, the pH of the gel may be 4-8 which is usual for the con¬ventional gel forming agent, but it is desirable to use a buffer solution having a pH value around the pKa value of each active compound.
The best mode for carrying out the invention
Both opioids and NSAID provide peripheral analgesia. Synergistic potentiation of analgesia through topical administration of a topical NSAID/opioid combination offers a new approach to peripheral pain management. Topical administration of a topical NSAID/opioid synergistic drug formulation provides a superior method for the clinical treatment of peripheral pain. It has now been found that topical admini¬stration of a composition comprising certain relative amounts of opioids and NSAID results in the synergistic potentiation of peripheral antinociceptive responses. Use of topically administered compositions comprising the proportions of opioids and topical NSAID described and claimed herein provides an important new approach to management of the peripheral pain. The invention encompasses a pharmaceutical composition comprising at least one opioid and at least one NSAID, in amounts suf¬ficient to potentiate an antinociceptive response when the composition is adminis¬tered topically in a physiologically acceptable topical excipient. As used herein "po¬tentiated antinociceptive response" is a pain-reducing response elicited through the

synergistic effect of at least one opioid and at least one NSAID, in which the com¬bined effect is greater than the sum of the effect produced by either agent alone.
The preferred opioid is methadone and, preferably, the opioid in the composition of the present invention is methadone. Other opioids are suitable, including, but not limited to, compounds based on or derived from morphine-like compounds and analogs. The opioid can be, but is not limited to, morphine, heroin, ethylmorphine, hydromorphone, oxymorphone, codeine, hydrocodone, levorphanol, oxycodone, pentazocine, loperamide, propoxyphene, fentanyl, sufentanil, lofentanil, morphine-6-glucuronide, buprenorphine, etorphine, [D-Ala2, MePhe4, Gly5-ol] enkephalin (DAMGO), butorphanol, nalorphine, nalbuphine, naloxone benzoylhydrazone, naloxone, naltrexone, meperidine, bremazocine, ethylketocyclazocine, U-50488, U-69593, spiradoline, naltrindole, [D-Pen2, D-Pen5] enkephalin (DPDPE), [D-Ala2, Glu4]deltorphin, and [D-Ser2,Leu5]enkephalin-Thr6 (DSLET), [D-Ala2, MePhe4, Gly5-ol] enkephalin, and (3-endorphin, dynorphin A, dynorphin B and cc-neoendorphin and small molecule and combinatorial chemistry products thereof. Ibuprofen is the preferred NSAIDs in the composition of the present invention. The NSAIDs can be any known in the art, including, but not limited to ketoprofen, flur¬biprofen, naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, oxaproztn, pranoprofen, suprofen, alminoprofen, butibufen, diclofenac, ketorolac, acetaminophen, aspirin, celebrex and rofecoxib.
The topical formulations used in the present invention are particularly suitable for formulations as topical preparations. Formulations suitable for topical administra¬tion include liquid or semi-liquid preparations suitable for penetration through the skin to the site of where treatment is required. Examples of liquid and semi-liquid preparations include, but are not limited to, topical solutions, liniments, lotions, creams, ointment or paste or gel. Other topical ingredients used in the topical formu¬lation are in general those commonly used and generally recognized by person skilled in the art of topical formulation. Topical solution of the present invention may contain aqueous or oily solution or suspensions. They may be prepared by dis-

solving the pharmaceutical compound in a suitable aqueous solution, which may also contain a bactericidal agent, a fungicidal agent, or any other suitable preserva¬tive, and may preferably include a surface active agent. Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol, and propylene gly¬col. Optionally, L-menthol may be added to the topical solution. Lotions and lini¬ments include those suitable for application to the skin containing a sterile aqueous solution and optionally, a bactericide. They may also include an agent to hasten dry¬ing and cooling of the solution on the skin, such as alcohol or acetone. They may fur¬ther include a moisturizer, such as glycerol, or an oil, such as castor oil or arachis oil.
Cream, ointments, or pastes, are semi-solid formulations made by mixing the phar¬maceutical with a greasy or non-greasy base. The topical formulation is in finely-divided or powdered form and may be alone or in a aqueous or non-aqueous solu¬tion or suspension. The topical formulation may be mixed with the greasy or non-greasy base with the aid of suitable machinery. The base may contain hydrocarbons. Examples of the hydrocarbons include, but are not limited to, hard, soft, or liquid paraffin, glycerol, beeswax, a metallic soap, a mucilage, an oil of natural origin (such as almond, corn, arachis, castor or olive oil), wool fat or its derivative, a fatty acid (such as stearic acid or oleic acid), or a combination thereof. The formulation may also contain a surface active agent, such as an anionic, cationic or non-ionic surfac¬tant. Examples of the surfactants include, but are not limited to, sorbitan esters or polyoxyethylene derivatives thereof (such as polyoxyethylene fatty acid esters) and carboxy poly methylene derivatives thereof (such as carbopol). Suspending agents such as natural gums, cellulose derivatives inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included. For ointment, polyethylene glycol 540, polyethylene glycol 3350, and propylene glycol may also be used to mixed with the topical formulation.
A gel or emugel formulation includes any gel forming agent commonly used in the pharmaceutical gel formulations. Examples of gel forming agents are cellulose de¬rivatives such as methyl cellulose, hydroxyethyl cellulose, and carboxymethyl cellu-

lose; vinyl polymers such as polyvinyl alcohols, polyvinyl pyrrolidones; carboxy-poly-methylene derivatives such as carbopol. Further gelling agents that can be used for the present invention are pectins and gums (such as gum arabic and tragacanth, alginates, carrageenates, agar and gelatin). The preferred gelling agent is carbopol. Furthermore, the gel or emugel formulation may contain auxiliary agents commonly used in the kind of formulations such as preservatives, antioxidants, stabilizers, col¬orants, and perfumes. The analgesic topical formulations of the present invention prepared as above exhibited excellent pharmacological activities as shown in the Experiments below.
The following examples describe the present invention in more detail. The examples do not intend to limit the scope of the invention.
All in vivo studies were carried out in accordance with the Declaration of Helsinki and with the Guide for Care and Use of Laboratory Animals, as adopted and prom¬ulgated by the Estonian Pollumajandusministeerium. Male Crl:CD-l® (ICR) BR mice (20-25 g) were purchased from Charles River Laboratories (Germany) and were housed in a 12:12-h light-dark cycle temperature-controlled room with food and wa¬ter freely available. Drugs were obtained from Sigma (St. Louis, MO, USA). Drugs were applied topically and analgesia assessed as previously described (Kolesnikov et al (2000) J of Pharmacol and Experimental Ther. 295(2): 546-551). Briefly, the distal por¬tion of the tail (2-3cm) was immersed in a propylene glycol/dH2O(10:l ratio) alone or propylene glycol and lauric acid combination (10:1) solution containing the indi¬cated drugs for the stated time, usually 2 min. ). Analgesia was defined quantita¬tively as tail-flick latency for an individual animal that was twice its baseline latency or greater using tail flick apparatus (Ugo Basile, Italy). Baseline latencies typically ranged from 2.5 to 3.5 s, with a maximum cut-off latency of 10 s to minimize tissue damage in analgesic animals. Since analgesia was assessed quantitatively, groups comparisons were performed with the Fishers exact test (Kolesnikov et al, (1993) Proc, Natl Acad. Sci. USA 90:5162). ED50 values were determined with GraphPad Software.

Short description of the Figures
Figl:
Topical morphine and lidocaine effects in radiant heat tail-flick assay
Groups of mice (n > 10) were exposed to the indicated concentration of the free base of lidocaine (1.1 - 8.6 mmol) or morphine (1.5-15 mmol) for 2 min and tested imme¬diately afterward.
Fig 2:
Addition lauric acid to propylene glycol shifts topical lidocain and morphine
dose response curve to left
A. Groups of mice (n > 10) were exposed to the indicated concentration of the free
base of lidocaine dissolved in PG alone (1.1- 8.6 mmol) or in combination of PG/LA
(0.2- 2.1 mmol) for 2 min and tested immediately afterward.
B. Other groups of mice (n£ 10) were exposed to morphine sulphate dissolved in
propylene glycol (1.5 -11.3 mmol) or in combination of propylene glycol and lauric
acid (0.15 -1.5 mmol) for 2 min and tested immediately afterwards.
K&3:
Time dependence of topical lidocaine and morphine analgesia
A. Groups of mice (n > 10) were exposed for 2 min to a fixed concentration of topical
lidocaine (0.9 mmol) dissolved either in PG or PG/LA and then were tested in the
tail-flick assay immediately after termination of drug exposure.
B. Groups of mice (n > 10) were treated for 2 min with fixed dose of morphine (1.5
mmol) dissolved either in PG or PG/LA and then tested in tail-flick assay at the in¬
dicated time over 90 min.
Fig 4:
Addition lauric acid to propylene glycol shifts topical methadone dose response
curve to left and increase the duration of analgesic effect

A. Groups of mice (n > 10) were exposed to the indicated concentration of the
methadone (0.7 -14 rrunol) dissolved either in PG alone or in PG/LA for 2 min and
tested immediately afterward.
B. Other groups of mice (n > 10 ) were treated with fixed dose of methadone ( 3.0
mmol) dissolved either in PG or PG/LA and then tested in tail-flick assay at indi¬
cated time over 60 min.
Fig 5:
Addition lauric acid to propylene glycol shifts topical S-ibuprofen and diclofenac
dose response curve to left
A. Groups of mice (n > 10) were exposed to the indicated concentration of diclofenac
dissolved in PG alone (1.8 - 7.0 mmol) or in combination of PG/LA (0.9 - 3.5 mmol)
for 2 min and tested immediately afterward.
B. Other groups of mice (n £ 10) were exposed to S-ibuprofen dissolved in PG (4.8-
19.2 mmol) or in combination of PG and LA(1.2- 4.8 mmol) for 2 min and tested im¬
mediately afterwards.
Fig 6:
Time dependence of topical S-ibuprofen and diclofenac analgesia
A. Groups of mice (n > 10) were exposed for 2 min to a fixed concentration of topical
S-ibuprofen (4.8 mmol) dissolved either in PG or PG/LA and then were tested in the
tail-flick assay at the indicated time over 90 min.
B. Groups of mice (n > 10) were treated for 2 min with fixed dose of diclofenac (3.5
mmol) dissolved either in PG or PG/LA and then tested in tail-flick assay at the in¬
dicated time over 90 min.
Topical diclofenac and morphine interactions
A. Groups of mice received either topical morphine (0.15 mmol; n = 10) or diclofenac (0.9 mmol; n = 10) alone or both together (n = 10) for 2 min. The combination was

significantly (P agents.
B. Groups of mice (n=30) received either topical morphine (0.15 mmol) or diclofenac
(0.9 mmol) or the combination of the two for 2 min and were tested in the tail-flick
assay over 90 min.
Topical S-ibuprofen and morphine interactions
A. Groups of mice received either topical morphine (0.15 mmol; n = 10) or
S-ibuprofen (1.2 mmol; n = 10) alone or both together (n = 10) for 2 min.
B. Groups of mice (n=30) received either topical morphine (0.15 mmol) or
S-ibuprofen (1.2 mmol) or the combination of the two for 2 min and were tested in
the tail-flick assay over 90 min.
Fig 9:
Topical methadone and diclofenac interactions
A. Groups of mice received either topical methadone (0.7 mmol; n = 10) or diclofenac
(0.9 mmol; n = 10) alone or both together (n = 10) for 2 min. The combination was
significantly (P agents.
B. Groups of mice (n=30) received either topical methadone (0.7 mmol, n=10) or
diclofenac (0.9 mmol, n=10) or the combination (n=10) of the two for 2 min and were
tested in the tail-flick assay over 90 min.
Fig 10:
Topical methadone and S-ibuprofen interactions
A, groups of mice received either topical methadone (0.7 mmol; n = 10) or S-ibuprofen (1.2 mmol; n = 10) alone or both together (n = 10) for 2 min. The combi¬nation was significantly (P
B. Groups of mice (n=30) received either topical methadone (0.7 mmol, n=10) or S-ibuprofen (1.2 mmol, n=10) or the combination (n=10) of the two for 2 min and were tested in the tail-flick assay over 120 min.
Fig 11:
Topical NSAIDs and hydrocodone interactions
A. Groups of mice (n= 20) received topical hydrocodone (0.6-4,4 mmol) dissolved
either PG or PG/LA solution for 2 min and then tested immediately afterwards.
B. Groups of mice (n=30) received either topical hydrocodone ( 0.6 mmol, n=10 ) or
S-ibuprofen (1.2 mmol, n=10) alone or both together (n=10) for 2 min.
C. Other groups on animals received topical either hydrocodone (0.6 mmol, n=10) or
diclofenac (0.9 mmol, n=10) or together (n=10) and were tested in the tail-flick assay.
Addition of lauric acid to propylene glycol improves drug penetration through skin and increase the potency of the lidocaine and opioids and NSAIDs
Propylene glycol is a widely used trans-dermal vehicle for number of the drugs. In early studies, we demonstrated the topical lidocaine and morphine analgesia using DMSO as solvent and skin penetration enhancer . DMSO alone was ineffective in our pain model. In current studies, we also found that propylene glycol alone did not increase significantly base line latencies in mice in radiant heat tail-flick assay (data not shown). To ensure local action, in all studies, we examined a region of the tail that was immersed in vehicle and a more proximal segment that was not exposed. Tail-flick latencies from the unexposed portion of the tail were similar to baseline latencies. Testing regions of the tail that were exposed and not exposed to vehicle revealed no significant antinociceptive effect in either location. In comparative stud¬ies of potency topically applied drugs using different vehicles, we found no differ¬ences in ED50 of the morphine and lidocaine (Fig 1). However, addition of lauric acid to propylene glycol dramatically improves penetration of the morphine and lido¬caine, measured as drug^s ED50. We observed significant dose response shift to left for lidocainevs ED50 (5-fold shift, Fig 2A, Table 1) and for morphine^ ED50 (19-fold shift, Fig 2B, Table 1). In time course studies the distinctions in the potency of the

drugs have been even more expressed (Fig 3). Low lidocaine dose in propylene gly¬col and lauric acid solution produced significant and long acting analgesic effects compared with propylene glycol alone (Fig 3A). Duration of the analgesic activity of the morphine in propylene glycol and lauric acid was far beyond compared with the same dose of the drug dissolved in propylene glycol only (Fig 3B). Methadone pro¬duced also analgesic activity in this experimental paradigm. As anticipated, metha¬done elicited dose dependent (Fig 4A) and naloxone sensitive (data not shown) an¬algesia after topical administration. Addition of lauric acid to propylene glycol modulated the methadone potency and its duration effect (Fig 4B, Table 1). We ob¬served significant dose response shift to the left (6.7 fold, Table 1). The hydrocodone demonstrated the most potent analgesic activity in this paradigm (Table 1).
Table 1
Addition of the lauric acid to propylene glycol enhances the potency of topical drugs
in radiant heat tail flick assay

Analgesics ED 50 value (95 % CL)

Propylene glycol alone Propylene glycol and lauric acid Shift P value
Lidocaine
Morphine
Methadone
Hydrocodone
S-ibuprofen
Diclofenac 2.2
(1.6-3.2) mmol
7.6
(4.2- 10.9)mmol
6.7
(4.8- 8.8) mmol
1.6
(1.1 - 2.2) mmol
9.3
(6.1-16.5) mmol
3.3
(1.7-5.3) mmol 0.35 (0.2-0.42)mmol
0.4 (0.33-0.54)mmol
1.0
(0.8-1.2) mmol
1.2
(0.8-1.8) mmol
2.1
(0.88- 3.3) mmol
1.1
(0.6-1.78) mmol 6.2
19
6.7
1.3
4.4
3 >0.05

Topical S - ibuprofen and diclofenac analgesia in radiant tail-flick assay
Both' S-ibuprofen and diclofenac produced dose dependent analgesia in this para¬digm (Fig 5) with ED50 9.3 and 3.3 mmol, respectively. As anticipated, addition of lauric acid to propylene glycol resulted in to significant increase the potency of the drugs (Table 1). The maximal analgesic effect of S-ibuprofen and diclofenac observed on 2 min after topical application and duration of analgesia was 90 min.
Topical opioid and S-ibuprofen and diclofenac synergistic interactions in radiant tail flick assay
We next assessed potential interactions between opioids and ibuprofen and di¬clofenac using a fixed, low dose of each. Alone, morphine and diclofenac produced analgesia in 20% and 30% of mice, respectively. However, when the same doses were administered together, the combination produced analgesia in 80% of mice, significantly greater than anticipated from simple additive interactions (50% versus 80 %, p Topical hydrocodone potentates S-ibuprofen and diclofenac analgesia in radiant tail flick assay
Alone, hydrocodone produced dose dependent response in this paradigm (Fig 11A). Then we assessed potential interactions between hydrocodone and ibuprofen and

diclofenac. Alone, hydrocodone and S-ibuprofen produced 20% and 30% of analge¬sia in mice and combination of the drugs were effective in 50 % of mice, respectively (Fig 11 B), indicating additive interaction in this pain model (50% versus 50%). The combination of hydrocodone and diclofenac produced analgesia in 50% mice, how¬ever, it have not reach statistical significance compared with anticipated additive interactions (50% versus 40%, p
CLAIM:
1. A pharmaceutical formulation comprising at least two compounds, one effect¬ing opioid analgesia and one effecting cyclooxygenase 1 and 2 activity, in amounts sufficient to potentiate an antinociceptive response when both com¬pounds are topically administered in a physiologically acceptable topical ex-cipient.
2. The topical pharmaceutical composition according to claim 1 comprising at least one analgesic and wherein the analgesic is selected from the group con¬sisting of an opiate, an opiate derivative, an opioid, enkephalins, endorphins and synthetic opioid peptides.
3. The topical pharmaceutical composition according to claim 2, wherein the opioid is selected from the group consisting of ethylmorphine, hydromor-phone, morphine, oxymorphone, codeine, levorphanol, oxycodone, hydro-codone, pentazocine, propoxyphene, fentanyl, sufentanil, lofentanil, mor-phine-6-glucuronide, loperamide, meperidine, tramadol, naloxone, naltrex¬one, buprenorphine, methadone, etorphine, [D-Ala2, MePhe4, Gly5-ol]enkephalin (DAMGO), butorphanol, nalorphine, nalbuphine, naloxone benzoylhydrazone, bremazocine, ethylketocyclazocine, U-50488, U-69593, spiradoline, naltrindole, [D-Pen2,D-Pen5]enkephalin (DPDPE), [D-Ala2, Glu4]deltorphin, and [D-Ser2, Leu^ ]enkephalin-Thr6 (DSLET).
4. The topical pharmaceutical composition according to claim 1, wherein the cyclooxygenase 1 and 2 activity effecting compound is a non-steroidal anti¬inflammatory drug (NSAID).
5. The topical pharmaceutical composition according to claim 4, wherein the NSAID is selected from the group consisting of ibuprofen, ketoprofen, flurbi¬profen, naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carpro-

fen, oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen, diclofenac, ketorolac, aspirin, acetaminophen, celebrex and rofecoxib.
The topical pharmaceutical composition according to claim 1, wherein the analgesic is morphine and the NSAID is ibuprofen.
The topical pharmaceutical composition according to claim 1, wherein the analgesic is morphine and the NSAID is diclofenac.
The topical pharmaceutical composition according to claim 1, wherein the analgesic is methadone and the NSAID is ibuprofen.
The topical pharmaceutical composition according to claim 1, wherein the analgesic is methadone and the NSAID is diclofenac.
The topical pharmaceutical composition according to claim 1, wherein the analgesic is hydrocodone and the NSAID is diclofenac.
The topical pharmaceutical composition according to claim 1, wherein the analgesic is hydrocodone and the NSAID is ibuprofen.
The topical pharmaceutical composition according to any of the preceding claims 1 to 11, wherein the opioid analgesic is present in a dose of about 0.001% to about 10%.
The topical pharmaceutical composition according to any of the preceding claims 1 to 11, wherein the NSAIDs is present in a dose of about 0.01% to about 20%.

14. The topical formulation according to claim 1, wherein said topical formula¬tion is in the form of solution, suspension, gel, emugel, cream, ointment, lo¬tion, spray or transdermal patch.
15. The topical combination of the skin penetration enhancers according to any of the preceding claims 1 to 14, wherein combination of propylene glycol and lauric acid in ratio 10:1 work synergistically.
16. Use of at least two compounds, one effecting opioid analgesia and one effect¬ing cyclooxygenase 1 and 2 activity, for the production of a topical pharma¬ceutical combination to prevent or relieve acute incisional pain and chronic peripheral neuropathy in a patient in need of such treatment.
17. Use of at least two compounds, one effecting opioid analgesia and one effect¬ing cyclooxygenase 1 and 2 activity, for the production of a topical pharma¬ceutical combination to prevent or relieve neuropathic inflammation in a pa¬tient in need of such treatment.
18. Use according to claim 16 or 17, wherein the administration of the pharma¬ceutical composition is directed to cutaneous, mucosal, vaginal, rectal, ocular, or nasal surfaces.

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Patent Number

268613

Indian Patent Application Number

1687/MUMNP/2009

PG Journal Number

37/2015

Publication Date

11-Sep-2015

Grant Date

08-Sep-2015

Date of Filing

07-Sep-2009

Name of Patentee

FLAMEK CORP. OUE

Applicant Address

PADRIKU TEE 7/3 - 9, EE TALLINN,

Inventors:

#	Inventor's Name	Inventor's Address
1	KOLESNIKOV YURI	PADRIKU TEE 7/3-9, EE11912 TALLINN,

PCT International Classification Number

A61K31/135

PCT International Application Number

PCT/EP2008/052530

PCT International Filing date

2008-02-29

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	07090036.0	2007-03-02	EPO