MX2008006610A - Pharmaceutical compositions - Google Patents

Abstract

A method of providing systemic analgesia to cats, dogs and other small mammals by the otic or transdermal administration of opioids is disclosed. Compositions for use in such a method are also disclosed.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING BUPRENORPHINE FIELD OF THE INVENTION The present invention relates to compositions and methods for providing systemic analgesia, and more particularly to the otic and transdermal administration of opioid analgesics to cats, dogs and other mammals.

BACKGROUND OF THE INVENTION All patents, applications, publications, test methods, and other materials cited herein are incorporated by reference. Pain activates the hormonal systems of the body's stress and contributes to morbidity and mortality. Pain relief (analgesia) in animals can be safely provided by titrated opioids to cause effect. Opioids can provide deep analgesia with minimal cardiovascular side effects, are safe alone and in combination with anesthetics, and are reversed if an adverse event occurs. Historically, pharmacological agents, including opioids, have been administered through systemic injection (subcutaneous, intramuscular or intravenous), epidurally, intrathecally (in the subarachnoid space), sublingually, orally, rectally and transdermally to provide analgesia. With the exception of epidural and intrathecal supply, administration of these agents provides systemic drug delivery to produce analgesic effects. Epidural and intrathecal administration involves the direct administration of an analgesic agent to receptors in the spinal cord involved in the spinal transmission of pain (for example opioid receptors), avoiding the need for systemic exposure to the pharmacological agent in question. Opioids produce analgesia by binding with opioid receptors within the nervous system to block the transmission of the pain impulse to the higher brain centers, thus decreasing or blocking the perception of pain. There are three types of well-characterized opioid receptors: mu, kappa and delta. Most clinically useful opioid medications are mu agonists. TORBUGESIC-SA (butorphanol tartrate) is a veterinary product approved in the United States for perioperative analgesia. Butorphanol is an opioid agonist / antagonist. Complete opioid agonists such as oxymorphone, morphine, meperidine and fentanyl can provide deep analgesia to animals and are safe to use in combination with anesthetics. For example, hydromorphone is used in veterinary practice as a perioperative analgesic via the injectable route of administration. Without However, parenteral administration is not practical for use by owners of animals that do not have veterinary training. Oral formulations of many opioids are also available, but opioid agonists have low systemic availability when administered orally due to extensive hepatic first pass metabolism. Fentanyl has been administered transdermally by means of drug-loaded adhesive patches, but such patches are expensive and inconvenient to use in fur-coated animals. Furthermore, transdermal patches require up to six hours to achieve a therapeutic effect, and in the meantime analgesia must be provided through other means. In addition to the deficiencies of the present methods for the administration of opioids to animals that were raised above, the possibility of overdose and the potential for abuse by humans has limited its use in animals. U.S. Patent No. 5,589,480 relates to a method for inducing analgesia in inflamed skin by topically administering to the skin an opioid analgesic agent in an amount that is not effective for the induction of systemic analgesia. According to this patent, effective analgesia must be induced in "substantial absence of transdermal delivery of the opioid analgesic agent to the systemic circulation." U.S. Patent No. 6,01 1, 022 refers to a method for inducing analgesia in the mucosal or cutaneous tissue, comprising administering via the eyes an analgesic agent that affects the peripheral muscarinic receptors, said amount is systemically ineffective for the induction of analgesia, and therefore the analgesia of the mucosal or cutaneous tissue it is induced in the substantial absence of transdermal or transmucosal delivery of the analgesic agent to the central nervous system. While oxymorphone and morphine are mentioned as analgesic agents that can be used in conjunction with an analgesic muscarinic receptor agonist, they are not themselves muscarinic receptor agonists. "Mucous tissue" is defined specifically in the descriptive report excluding the conjunctiva of the eye. The administration of certain veterinary drugs through the otic route is also known, but not for the provision of systemic analgesia. For example, methymazole is administered to the ear pavilion of cats to control hyperthyroidism. U.S. Patent No. 5,543,434 relates to the nasal or ocular administration of ketamine to control chronic pain. US Patent No. 6,191, 126 B1 is directed to the administration of kappa opioid agonists to the eye to treat ocular pain. This patent emphasizes that kappa opioids act on receptors in peripheral tissue, while mu opioids relieve pain by activating receptors in the brain. It is said that the local action of the kappa opioids constitutes an advantage with respect to the systemic action. Accordingly, this invention is only suitable for the treatment of pain in the Ophthalmic tissues, not systemic analgesia. In view of the foregoing limitations and deficiencies of prior art formulations and methods, as well as other disadvantages not specifically mentioned above, it is clear that there is still a need in the art for improved means to induce analgesia systemically.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, pharmaceutically acceptable compositions for otic and transdermal administration to an animal and methods for the use thereof are disclosed. Said compositions comprise buprenorphine, a pharmaceutically acceptable carrier system comprising a solvent consisting of an aqueous phase and an organic phase, at least one penetration enhancing agent and, optionally, a stabilizing agent, a preservative, an antioxidant, an agent which increases the viscosity and / or a tonicity regulating agent. The present composition may also optionally include a non-opioid analgesic, such as a non-spheroid anti-inflammatory drug (NSAID), an N-methyl-d-aspartate (NMDA) receptor antagonist, an alpha-2 adrenergic receptor agonist, a Sodium channel blocker, or ligand of the transient receptor potential ion channel (TRP).

With the foregoing objects, advantages and features of the invention and others which will become apparent hereinafter, the nature of the invention can be understood more clearly by reference to the following detailed description of the invention and the appended claims.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph showing the mean buprenorphine concentration (+ 1 DS) in plasma versus time in five healthy cats after the otic administration of a buprenorphine formulation at a dose of 0.25-0.50 mg / kg. Figure 2 is a graph showing the average pain assessed by Visual Analogue Scale (VAS) for cats after the debulking procedure and treatment either with subcutaneous meloxicam, a post-operative analgesic for cats approved by the FDA, or with otic buprenorphine. The cats with meloxicam are represented by the dotted line and have +1 DS that is shown for each time point. Cats with buprenorphine are represented by the continuous line and have -1 SD shown for each time point. Figure 3 is a graph showing the mean plasma buprenorphine concentration versus time in six healthy cats after transdermal administration of a buprenorphine formulation to a dose either 0.17 - 0.35 mg / kg or 0.35 - 0.70 mg / kg. Data for cats with doses of 0.17 - 0.35 mg / kg are represented by the dotted line and have -1 SD displayed for each time point; The data for cats with doses of 0.35 - 0.70 mg / kg are represented by the continuous line and have +1 DS that is shown for each time point.

DETAILED DESCRIPTION OF THE INVENTION It has been found that effective opioid concentrations in the systemic circulation for the purpose of providing systemic analgesia can be achieved by otic or transdermal routes of administration. When using the otic or transdermal route of administration, intestinal / hepatic wall metabolism ("first step") of the opioid is avoided, which may improve bioavailability in relation to oral dosing. The present invention relates to an opioid analgesic product for providing systemic analgesia, for example, preventive and perioperative analgesia, for mammals such as cats and dogs. The present invention comprises at least one opioid analgesic in a pharmaceutically acceptable vehicle. The compositions of the present invention can be used to simultaneously prevent or reduce the pain associated with surgery or injuries. Also contemplated is the use for the treatment of chronic pain associated with, for example, neoplasia, osteoarthritis, pruritis, etc.

The terms "otic" and "through the ear" are used interchangeably in the present to denote that they refer to the ear. As used herein, "opiate" means any preparation or derivative of opium. The term "opioid" refers to both opiates and synthetic or semi-synthetic narcotics that resemble opiates. As used herein, the term "aqueous phase" means a solvent system composed of water, isotonic solution, a pH regulator system and / or any solvent miscible with water. As used herein, the term "organic phase" means a solvent system composed of any solvent system or organic solvent miscible or immiscible with water. Active ingredients include opioid analgesics, in particular those which possess mu-opioid receptor agonist activity, such as buprenorphine, morphine, diamorphine, meperidine, methadone, etorphine, levorphanol, fentanyl, alfentanil, sufentanil, oxycodone, hydrocodone, codeine, and oxymorphone. . Buprenorphine is particularly preferred because of a wider safety margin and a longer duration of activity. In the preferred embodiment, the formulation is long-acting, for example it is administered up to three times a day as needed. Because this is a long-acting formulation, as opposed to a quick-acting formulation, a particular advantage of the present invention consists of the reduced dosage frequency, which offers convenience for the person administering the product. It will also be appreciated that the present invention comprises, in one aspect, methods for alleviating pain by administering, for example, a pharmaceutically acceptable composition comprising, for example, buprenorphine, to an animal by otic or transdermal administration. Administration of the dosage can also be achieved, for example, by applying multiple or individual drops to the ear or skin of the animal. For example, concentrations of buprenorphine in plasma, after single-dose otic administration at a dose of about 0.05 to about 0.1 mg / kg achieved a Cmax approximately greater than 5 ng / ml at a Tmax of about 60 minutes, and at a At a dose of about 0.1 to about 0.2 mg / kg, a Cmax of approximately greater than 7 ng / ml was achieved at a Tmax of about 30 minutes. In another example, concentrations of buprenorphine in plasma, after single-dose otic administration at a dose of from about 0.3 to about 0.6 mg / kg achieved a Cmax of about 28 ng / ml at a Tmax of about 90 minutes, and a Dosage of about 0.25 to about 0.5 mg / kg, an initial peak approximately greater than 10 ng / mL was achieved at about 30 minutes, followed by a Cmax approximately greater than 12 ng / mL at a Tmax of about 2 hours.

In yet another embodiment, plasma buprenorphine concentrations, following a single dose transdermal administration at a dose of about 0.35 to about 0.70 mg / kg achieved a Cmax of about 10 ng / ml at a Tmax of about 30 minutes. When a dose of from about 0.17 to about 0.35 mg / kg was used, a Cmax of approximately greater than 3 ng / mL was achieved at a Tmax of about 4 hours. Opioid analgesic metabolites that have analgesic activity can also be used. Such metabolites include, for example, analgesically active forms of sulfate and glucuronide of opioids such as morphine-6-glucuronide. Due to possible problems created by the unpleasant smell of the drug, the low bioavailability, or the potential for the local analgesic effect, it may be desirable to use a prodrug form of said opioid. Particularly preferred prodrug forms are those in which the 3-hydroxy phenolic group is esterified. Examples of prodrug derivatives suitable for use in the present invention include those disclosed in U.S. Patent Nos. 4,668,685 and 4,673,679, both assigned to DuPont. In another embodiment, the present invention contemplates the inclusion of a non-opioid analgesic, such as an NSAID. Preferred NSAIDs include acemetacin, acetylsalicylic acid (aspirin), alminoprofen, benoxaprofen, bucilloxic acid, carprofen, celecoxib, clidanac, deracoxib, diclofenac, diflunisal, dipirona, etodolac, fenoprofen, fentiazac, firocoxib, flobufen, flufenamic acid, flufenisal, flunixin, fluprofen, flurbiprofen, ibuprofen, indomethacin, indoprofen, isoxicam, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, miroprofen, nabumetone , naproxen, niflumic acid, oxaprozin, oxepinac, phenylbutazone, piroxicam, pirprofen, pramoprofen, sudoxicam, sulindac, suprofen, tepoxaline, thiaprofenic acid, tiopinac, tolfenamic acid, tolmetin, trioxaprofen, zidometacin, or zomepirac, the pharmaceutically acceptable salts thereof and the mixtures thereof. Particularly preferred NSAIDS include carprofen, deracoxib, etodolac, firocoxib, flunixin, ketoprofen, meloxicam and tepoxaline. Preferred NMDA receptor antagonists include memantine, ketamine, tiletamine, and pharmaceutically acceptable salts thereof and mixtures thereof. A particularly preferred NMDA receptor antagonist is ketamine. Preferred alpha-2 adrenergic receptor agonists include clonidine, detomidine, dexmedetomidine, fadolmidine, medetomidine, moxonidine, romifidine, xylazine, and the pharmaceutically acceptable salts thereof and mixtures thereof. Particularly preferred alpha-2 adrenergic receptor agonists include detomidine and xylazine. Preferred sodium channel blockers include benzocaine, bupivacaine, lamotrigine, levobupivicaine, lidocaine, lignocaine, oxybuprocaine, prilocaine, proxymetacaine, ropivicaine, and the pharmaceutically acceptable salts of the same and the mixtures thereof. Particularly preferred sodium channel blockers include bupivacaine and lidocaine. In general, the formulations of the present invention will contain from about 0.1 to about 10% of the opioid (s) in an otic or transdermally acceptable vehicle. The amount of the opioid (s) can be varied to alter the volume of the dose and / or the dosage schedule. The amount of a second analgesic, such as an NSAID, will depend on synergy with the opioid and bioavailability and will be titled to take effect. The compositions of the present invention can take various forms. For example, they can be a gel, liquid, or ointment. The solvent used in the composition consists of an aqueous and organic phase. Suitable solvents for the formulation include, but are not limited to, glyceryl formaldehyde, dimethylformamide, N-methyl-pyrrolidone, 2-pyrrolidone, glycol, propylene glycol, polyethylene glycol, diethylosorbide, water, ethanol, isopropanol, 1,2-propanediol, glycerin, triethyl citrate, benzyl alcohol , dimethylisosorbide, C2-C9 alkylene diols, for example, butylene diol, pentylene glycol, neopentyl diol, propylene glycol diethylene glycol, monoethyl ether or similar compounds such as dialkylene diol C2-C5, monoethers of C-C4 alkyl, for example, dipropylene glycol, mono propyl ether, mono propyl ether, and mono ethyl ether. Preferred solvents include 2-pyrrolidone, glyceryl formal, dimethylformamide, N-methyl-pyrrolidone, propylene glycol, polyethylene glycol, diethylosorbide, ethanol, isopropanol, 1,2-propanediol, glycerin, citrate triethyl, benzyl alcohol, dimethyl isosorbide and water. A particularly preferred solvent is propylene glycol. Preferably, said solvent is present in an amount of up to about 80% by weight of the formulation. Preferably, said solvent is present at about 10% to about 75% of the formulation. Suitable penetration enhancers can include lipophilic and / or hydrophilic components. Suitable penetration enhancers can be, for example, an alcohol, an emulsifier or a non-ionic solubilizer. Suitable penetration enhancers include, but are not limited to, ethylene glycol, propylene glycol, dimethyl sulfoxide (DMSO), dimethyl polysiloxane (DMPX), oleic acid, caprylic acid, isopropyl alcohol, 1-octanol, ethanol (denatured or anhydrous), benzyl alcohol and other absolute or pharmaceutical grade alcohols with the exception of methanol. Other penetration enhancers include, water, sulfoxides and similar chemicals, such as DMSO, dimethylacetamide (DMA), dimethylformamide (DMF), etc., azone and related compounds, pyrrolidones, such as N-methyl-pyrrolidone (NMP), 2 -pyrrolidone (2-pyrrole), etc., fatty alcohols, fatty acids and related structures, such as oleyl alcohol, oleic acid, linoleic acid, isopropyl myristate, etc., alcohols and glycols, such as ethanol, propylene glycol, esters of lauryl alcohol, lauryl alcohol, etc., the propylene glycol esters, such as propylene glycol monolaurate, surfactants, such as sodium lauryl sulfate (SLS), etc., urea, essential oils, terpenes and terpenoids, such as menthol, eucalyptus oil, 8-cineole, etc., phospholipids and solvents and related compounds, such as transcutol (ethoxydiglycol), etc. Preferred penetration enhancers are menthol, alcohols, benzyl alcohol, ethanol, water, glycols, propylene glycol esters, propylene glycol monolaurate, lauryl alcohol esters or lauryl alcohol. The viscosity of the vehicle can be increased or decreased as necessary by the use of several additional agents. The viscosity improving agent may be a polysaccharide gum, a water dispersible acid polymer, and / or a mixture thereof. Viscosity improving agents suitable for use in the compositions of the present invention include, but are not limited to, polyvinyl alcohol, polyvinyl pyrrolidone magnesium sulfate, propylene glycol, lanolin, glycerin, hydroxypropyl cellulose and other agents known to those skilled in the art. for being suitable for use in the ear. A preferred viscosity improving agent is hydroxypropylcellulose. Emulsifiers suitable for use in the compositions of the present invention include, for example, polyethylene glycol dipolyhydroxystearate (PEG) 30 (for example ARLICEL P135, available from ICI Surfactants, Wilmington, DE), sorbitan stearate oleate PEG-40 (e.g. CRILL 4, available from Croda, Inc., Parsippany, NJ), polysorbate 80 (for example TWEEN 80, available from ICI Surfactants.) A component of the organic solution consists of a solvent consisting of compounds, such as suitable surfactants for the organic solution, which include, but are not limited to, monoglycerides or similar compounds such as glyceryl mono-oleate, -laurate, -behenate, -eicosadioate, -stearate, or other mono-substituted glycerides with fatty acids. Suitable film formers for the organic solution include, but are not limited to, polyacrylamide or other similar compounds, which act as thickening agents such as other acrylamide copolymers, polyacrylate copolymers, copolymers and cellulosic polymers, and copolymers and polymers of polyvinyl pyrrolidone. Other optional inert ingredients may be added to the present composition, as desired. These ingredients include, but are not limited to, preservatives, chelating agents, antioxidants and stabilizers. Exemplary preservatives include, but are not limited to, BHT, methyl p-hydroxybenzoate (methylparaben) and propyl p-hydroxybenzoate (propylparaben). It will also be estimated that the formulations of the present invention in another embodiment are self-preserving. Exemplary chelating agents include, but are not limited to, sodium edetate. Exemplary antioxidants include, but are not limited to, butylated hydroxyanisole (BHA), BHT and monothioglycerol sodium. Preferred stabilizers for preventing degradation of any of the active ingredients in the formulations of the present invention include, but are not limited to, BHT, BHA, monothioglycerol sodium, methyl p-hydroxybenzoate (methylparaben) and propyl p-hydroxybenzoate ( propylparaben). Other preferred stabilizers include, but are not limited to, triethyl citrate, USP, NF, acetic acid, glacial acetic acid, fumaric acid, hydrochloric acid, dilute hydrochloric acid, malic acid, nitric acid, phosphoric acid, dilute phosphoric acid, sulfuric acid and tartaric acid . Particularly preferred stabilizers for use in the present invention include, but are not limited to, BHT, BHA, monothioglycerol sodium or citric acid in a concentration of about 5% or less and monothioglycerol in a concentration of about 0.1% to 2% p / v. Preferably the pH of the compositions of the present invention is regulated to maintain buprenorphine or buprenorphine HCl in solution. Preferably, the pH of the compositions of the present invention is between about 3 and about 10, preferably about 3.5 to about 6. An appropriate pH regulating agent can be added to maintain the pH. Suitable pH regulators include, but are not limited to, potassium chloride, sodium or potassium phosphates (monobasic and dibasic), sodium or potassium acetates, sodium or potassium borates (eg, sodium tetraborate decahydrate) , sodium or potassium citrates, sodium or potassium hydroxides and equivalents or mixtures thereof, and weak acids, such as acetic, boric, and phosphoric acids. For the purpose of preparing the composition of the present invention, the vehicle (s) or a portion of the vehicle (s) is (are) added to the compounding vessel, followed by the active and the remaining excipients. The mixture is mixed until all the solids are dissolved or in suspension. Additional solvent (s) can be added to bring the composition to a final volume if necessary. The additives, such as those listed above, may also be included in the container and mixed within the formulation (the order of addition is not decisive). After the application of the formulation, the opioid present in the composition is absorbed systemically. It is an advantage of the method of the present invention that it can provide rapid initial absorption with some delayed release for continuous absorption of the active drug, thereby providing a better pharmacokinetic profile than intravenous or other parenteral routes for dosing. The onset of the analgesic action after the administration of the compositions of the present invention is initiated after 30 minutes of application, and the duration of the analgesic action generally lasts up to at least 8 hours. Another advantage of the present invention is that some of the formulations appear to have a rapid absorptive phase and a prolonged plateau phase (slow absorptive phase). In this way, the preceding desirable characteristics can be achieved with a formulation. Other advantages of the present invention consist in the fact that animals with pain and / or animals with an opiate can be aggressive. Accordingly, the administration of the present invention has the advantage that a person that manages animals never have to go near the mouth / teeth of the animal, that is, an increased security for those who handle animals. The method of the present invention, and the formulations for carrying out the method, possess other advantages with respect to the existing products, such as the ease of administration for both the veterinary personnel and the owner of the animal, the reduction of the effects secondary, etc. In the case of an adverse event, the activity of the opioid is reversed by the administration of opioid antagonists, for example naloxone. It is believed that the route of administration can improve the bioavailability of many analgesic agents such as opioids that undergo gastrointestinal degradation and hepatic first pass metabolism when administered orally. It is possible that the metabolism of said compounds may be favorably affected by the route of administration. The appropriate dosage can be determined according to the weight of the animal. As one skilled in the art will estimateIf renal or hepatic function is compromised, it may be necessary to decrease the dosage of the drug to account for the decreased elimination. The compositions of the present invention can be packaged in many forms. Preferably the formulation is packaged as single-dose, single-use units. Said single-dose pack overcomes problems of bacterial contamination of the preparations with multiple doses and minimizes the possibility of accidental acute overdose. The following examples are provided for the purpose of illustrating the present invention and should not be construed as limiting the scope or spirit of the invention.

Otica This Example can be prepared according to customary procedures known to the person skilled in the art. In a specific embodiment, the formulation can be prepared and stored in two different solvent systems consisting of an organic phase system and an aqueous phase system to be combined to obtain the final formulation.

EXAMPLE 2 Five healthy cats were administered the formulation of Example 1 at a dosage of 0.25-0.50 mg / kg. Serial blood samples were drawn at hour 0 before dosing, then at 0.25, 0.5, 1, 1.5. 2, 4, 6, 8, and 24 hours after dosing. The concentrations of buprenorphine in plasma (ng / mL) versus time were reported and presented graphically. The results are shown in figure 1. Two plasma peaks are evident - the first approximately 4 ng / mL occurs at 90 minutes, while the second approximately 5 ng / mL occurs at 8 hours. These data show that the formulation described in Example 1 has a benefit, in the sense that buprenorphine is detected in the plasma shortly after dosing, which suggests that the analgesia will take place soon. Second, the plasma peak occurs at approximately 8 hours after dosing, suggesting that the analgesia will be long lasting.

EXAMPLE 3 Fourteen healthy cats were used in a study described below to evaluate the analgesic properties of the formulation described in the Example. The cats underwent general anesthesia and underwent bilateral oniquectomy (debulking) of the front legs by a licensed veterinarian. Prior to the induction of anesthesia, six of the cats received a subcutaneous injection (0.3 mg / kg) of meloxicam, which is approved in the United States for postoperative analgesia in cats. Eight cats were given a dose of 0.6 mg / kg of the buprenorphine formulation described in Example 1. After surgery, all cats were evaluated for signs of pain using an Analog Visual Scale (VAS) at 0.5, 1, 2, 3, 4, 6, 8, and 24 hours. The mean VAS versus post-surgery time for cats treated with meloxicam or with buprenorphine was reported and plotted. The results are shown in Figure 2. These data suggest that the post-surgical analgesic profile of the formulation described in Example 1 is similar to that of a post-operative analgesic for cats approved by the FDA.

EXAMPLE 4 Otic This Example can be prepared according to customary procedures known to the person skilled in the art. In a specific embodiment, the formulation can be prepared and stored in two different solvent systems consisting of an organic phase system and an aqueous phase system to be combined to obtain the final formulation.

EXAMPLE 5 Topical / transdermal This Example can be prepared according to customary procedures known to the person skilled in the art. In a specific embodiment the formulation can be prepared and stored in two different solvent systems consisting of an organic phase system and an aqueous phase system to be combined to obtain the final formulation.

EXAMPLE 6 Six healthy cats were administered the formulation of Example 5 once using a dosage of 0.17-0.35 mg / kg, and then again using a dosage of 0.35-0.70 mg / kg. After each dosage, serial blood samples were taken at hour 0 before dosing, then at 0.25, 0.5, 1, 1 .5, 2, 3, 4, 6, 10, 24, and 32 hours after the dosage. The concentrations of buprenorphine in plasma (ng / mL) versus time were reported and presented graphically. The results are shown in figure 3.

These data show that the formulation described in Example 5 has a benefit, in the sense that buprenorphine is detected in the plasma shortly after transdermal dosing, which suggests that the analgesia will take place soon. Secondly, plasma levels are detected for as long as 32 hours after dosing, which suggests that the analgesia will be long lasting. Although certain currently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to those concerned by the invention that variations and modifications of the described embodiment can be made without departing from the spirit and scope of the invention. . Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1 . A pharmaceutically acceptable composition, useful for the otic administration to an animal, comprising buprenorphine, a pharmaceutically acceptable carrier system comprising a solvent consisting of an aqueous phase and an organic phase, and at least one penetration enhancing agent. 2. - The pharmaceutically acceptable composition according to claim 1, further characterized in that the penetration enhancing agent includes lipophilic and / or hydrophilic components. 3. The pharmaceutically acceptable composition according to claim 2, further characterized in that the penetration enhancing agent is selected from the group consisting of esters of propylene glycol, menthol, alcohol, glycols, or water in an amount sufficient to improve the penetration of buprenorphine. 4. - The pharmaceutically acceptable composition according to claim 3, further characterized in that the glycol is propylene glycol monolaurate. 5. The pharmaceutically acceptable composition according to claim 3, further characterized by the alcohol is selected from the group consisting of ethanol, lauryl alcohol and lauryl alcohol esters. 6. - The pharmaceutically acceptable composition according to claim 5, further characterized in that the alcohol is an ester of lauryl alcohol. 7. - The pharmaceutically acceptable composition according to claim 1, further characterized in that the solvent is selected from the group consisting of 2-pyrrolidone, glyceryl formal, dimethylformamide, N-methyl-pyrrolidone, propylene glycol, polyethylene glycol, diethylisorbide, ethanol, isopropanol , 1,2-propanediol, glycerin, triethyl citrate, benzyl alcohol, dimethyl isosorbide and water. 8. - The pharmaceutically acceptable composition according to claim 7, further characterized in that the solvent is propylene glycol. 9. - The pharmaceutically acceptable composition according to claim 1, further characterized in that the composition has a pH range of about 3 to about 10. 10. The pharmaceutically acceptable composition according to claim 1, further characterized by additionally comprising a stabilizing agent. eleven . - The pharmaceutically acceptable composition according to claim 10, further characterized in that the agent The stabilizer is selected from the group consisting of BHT, BHA and monothioglycerol sodium. 12. - The pharmaceutically acceptable composition according to claim 1, further characterized in that it additionally comprises a preservative agent. 13. - The pharmaceutically acceptable composition according to claim 12, further characterized in that the preservative is selected from the group consisting of BHT, methyl p-hydroxybenzoate (methylparaben) and propyl p-hydroxybenzoate (propylparaben). 14. - The pharmaceutically acceptable composition according to claim 1, further characterized in that it additionally comprises a viscosity improving agent and / or an antioxidant agent. 15. - The pharmaceutically acceptable composition according to claim 14, further characterized in that the viscosity improving agent is selected from the group consisting of a polysaccharide gum, a water dispersible acid polymer, and / or a mixture thereof . 16. - The pharmaceutically acceptable composition according to claim 15, further characterized in that the viscosity improving agent is hydroxypropylcellulose. 17. - The pharmaceutically acceptable composition according to claim 14, further characterized in that the antioxidant agent is selected from the group consisting of BHT, BHA and monothioglycerol sodium. 18. - The pharmaceutically acceptable composition according to claim 1, further characterized in that it additionally comprises a non-opioid analgesic. 19. - The pharmaceutically acceptable composition according to claim 18, further characterized in that the non-opioid analgesic is selected from the group consisting of acemetacin, acetylsalicylic acid (aspirin), alminoprofen, benoxaprofen, bucilloxic acid, cofen, celecoxib, clidanac, deracoxib , diclofenac, diflunisal, dipirone, etodolac, fenoprofen, fentiazac, firocoxib, flobufen, flufenamic acid, flufenisal, flunixin, fluprofen, flurbiprofen, indoprofen, isoxicam, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, miroprofen, nabumetone, naproxen, niflumic acid, oxaprozin, oxepinac, phenylbutazone, piroxicam, pirprofen, pramoprofen, sudoxicam, sulindac, suprofen, tepoxaline, thiaprofenic acid, tiopinac, tolfenamic acid, tolmetin, trioxaprofen, zidometacin, zomepirac, and pharmaceutically acceptable salts thereof and mixtures thereof. 20. The use of a pharmaceutically acceptable composition as claimed in claim 1 in the manufacture of a drug useful for inducing analgesia in an animal, wherein the medicament is adapted to be administrable by otic route. twenty-one . The use of a pharmaceutically acceptable composition as claimed in claim 1 in the manufacture of a medicament useful for inducing a systemic analgesic effect in an animal, wherein the medicament is adapted to be administrable by otic route. 22. The use as claimed in claim 21, wherein the analgesic effect is at least about 8 hours. 23. - The use as claimed in claim 21, wherein at a dosage range of from about 0.05 to about 0.6 mg / kg a level of buprenorphine in the animal of one Cmax is achieved in a range of about 5 ng / ml to about 28 ng / ml and a Tmax in the range of about 0.5 hours to about 2 hours. 24. A pharmaceutically acceptable composition for transdermal administration to an animal comprising buprenorphine, a pharmaceutically acceptable carrier system comprising a solvent consisting of an aqueous phase and an organic phase, and at least one penetration enhancing agent. 25. - The pharmaceutically acceptable composition according to claim 24, further characterized in that the penetration enhancing agent includes lipophilic and / or hydrophilic components. 26. The pharmaceutically acceptable composition according to claim 25, further characterized in that the penetration enhancing agent is selected from the group consisting of esters of propylene glycol, menthol, alcohol, glycols and water in an amount sufficient to improve the penetration of buprenorphine . 27. The pharmaceutically acceptable composition according to claim 26, further characterized in that the glycol is propylene glycol monolaurate. 28. - The pharmaceutically acceptable composition according to claim 26, further characterized in that the alcohol is selected from the group consisting of ethanol, lauryl alcohol and lauryl alcohol esters. 29. - The pharmaceutically acceptable composition according to claim 26, further characterized in that the penetration enhancing agent is menthol. 30. - The pharmaceutically acceptable composition according to claim 24, further characterized in that the solvent is selected from the group consisting of 2-pyrrolidone, glyceryl formal, dimethylformamide, N-methyl-pyrrolidone, propylene glycol, polyethylene glycol, diethylosorbide, ethanol, isopropanol , 1,2-propanediol, glycerin, triethyl citrate, benzyl alcohol, dimethyl isosorbide and water. 31 - The pharmaceutically acceptable composition according to claim 30, further characterized in that the solvent is propylene glycol. 32. - The pharmaceutically acceptable composition according to claim 24, further characterized in that the composition has a pH in the range of about 3 to about 10. 33. The pharmaceutically acceptable composition according to claim 24, further characterized in that it comprises additionally a viscosity improving agent, a preservative and / or antioxidant agent. 34. - The pharmaceutically acceptable composition according to claim 33, further characterized in that the viscosity improving agent is selected from the group consisting of a polysaccharide gum, a water dispersible acid polymer, and / or a mixture thereof . 35. The pharmaceutically acceptable composition according to claim 34, further characterized in that the viscosity improving agent is hydroxypropylcellulose. 36. - The pharmaceutically acceptable composition according to claim 33, further characterized in that the preservative agent is selected from the group consisting of BHT, p- methyl hydroxybenzoate (methylparaben) and propyl p-hydroxybenzoate (propylparaben). 37. - The pharmaceutically acceptable composition according to claim 33, further characterized in that the antioxidant agent is selected from the group consisting of BHT, BHA and monothioglycerol sodium. 38. - The pharmaceutically acceptable composition according to claim 24, further characterized in that it additionally comprises a non-opioid analgesic. 39. - The pharmaceutically acceptable composition according to claim 38, further characterized in that the non-opioid analgesic is selected from the group consisting of acemetacin, acetylsalicylic acid (aspirin), alminoprofen, benoxaprofen, bucilloxic acid, carprofen, celecoxib, clidanac, deracoxib , diclofenac, diflunisal, dipirone, etodolac, fenoprofen, fentiazac, firocoxib, flobufen, flufenamic acid, flufenisal, flunixin, fluprofen, flurbiprofen, indoprofen, isoxicam, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, miroprofen, nabumetone, naproxen, niflumic acid, oxaprozin, oxepinac, phenylbutazone, piroxicam, pirprofen, pramoprofen, sudoxicam, sulindac, suprofen, tepoxaline, thiaprofenic acid, tiopinac, tolfenamic acid, tolmetin, trioxaprofen, zidometacin, zomepirac, and pharmaceutically acceptable salts thereof and mixtures thereof. 40. The use of a pharmaceutically acceptable composition as claimed in claim 24 in the manufacture of a medicament useful for inducing analgesia in an animal, wherein the medicament is adapted to be administrable transdermally. 41 The use of a pharmaceutically acceptable composition as claimed in claim 24 in the manufacture of a medicament useful for inducing a systemic analgesic effect in an animal, wherein the medicament is adapted to be administrable transdermally. 42. - The use as claimed in claim 41, wherein the analgesic effect is at least about 8 hours. 43. The use as claimed in claim 41, wherein at a dosage range of from about 0.17 to about 0.70 mg / kg a level of buprenorphine in the animal of a Cmax of about 3 to about 10 ng / ml is achieved. and a Tmax of about 30 minutes to about 4 hours.