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    • 专利摘要:
    Pharmaceutical composition of tramadol for ophthalmic use. The present invention relates to a pharmaceutical composition of tramadol for ophthalmic use. The composition is characterized in that it contains tramadol in a low concentration, in particular comprised between 0.02% and 0.09%, and is highly effective in the treatment of ocular pain, for example after injuries or eye surgery, or the associated ocular pain to dry eye syndrome. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2604816A1
    申请号:ES201500657
    申请日:2015-09-09
    公开日:2017-03-09
    发明作者:Nuria Sanz Menéndez；Raquel HORCAJADA CÓRDOBA；Fernando Martínez-Alzamora；Rocío HERRERO VANRELL；José Manuel BENÍTEZ DEL CASTILLO；Antonia Gómez Calvo
    申请人:Farmalider SA；
    IPC主号:
    专利说明:


    TRAMADOL PHARMACEUTICAL COMPOSITION FOR OPHTHALMIC USE Technical field
    The present invention relates to pharmaceutical compositions for topical ophthalmic administration for the treatment of eye pain, in particular, to compositions containing tramadol as an active ingredient. Prior art
    Eye pain can be described as a burning, throbbing, painful or lacerating sensation in or around the eye, or it can also be perceived as if he had a foreign body lodged in his eye.
    Eye pain can originate, for example, after traumatic injuries or surgery in the eye area, or as a result of infections, inflammation, dry eyes, neuropathy, contact lens problems
    or eye fatigue.
    One of the possible causes of eye pain is the postoperative states after ophthalmic surgery, for example, after cataract surgery or refractive surgery.
    Topical drug administration is the preferred route for the treatment of eye pain, since it provides a higher concentration of the drug locally in the affected area, while avoiding unwanted systemic effects associated with oral administration.
    Among the various drugs that are commonly used ophthalmically for the treatment of eye pain, non-steroidal anti-inflammatory agents (NSAIDs) and local anesthetics, mainly.
    NSAIDs have been widely used in ophthalmology for some years now, as described for example in the review article by Kim et al. Nonsteroidal Anti-inflammatory drugs in ophthalmology, Survey Ophthalmol., 2010, 55 (2), p108-133, which highlights the use of NSAIDs topically, for example, to reduce myosis and inflammation in eye surgery, for the treatment of scleritis, prevention and treatment of macular edema associated with cataract surgery, for
    alleviate postoperative pain and photophobia associated with refractive surgery and to reduce the itching associated with allergic conjunctivitis.
    Thus, various NSAID-based eye drops have been marketed as active ingredients, mainly with bromfenac, diclofenac, flurbiprofen, ketorolac and nepafenac.
    Other topical drugs described in the state of the art for the treatment of ophthalmic pain are local anesthetics, such as tetracaine, procaine, benoxinate or proparacaine.
    However, the use of these drugs is not entirely satisfactory, both in terms of their limited efficacy for the treatment of acute eye pain, and because of the risk of certain unwanted effects associated with their use.
    In general, the most frequent adverse reactions to eye drops based on NSAIDs are generally mild, burning eye type, conjunctival hyperemia or hypersensitivity reactions.
    In some cases, however, when patients are treated with high doses or for prolonged periods of time, the use of topical NSAIDs can cause more serious complications, mainly keratitis, corneal thinning, corneal erosions, corneal ulcerations and corneal perforations, as described, for example, in the article Guidera et al. Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs. Ophthalmology 2001, 108 (5), p936-44.
    For its part, repeated or prolonged use of local anesthetics is associated with harmful effects for the corneal epithelium and can sometimes present more serious toxic effects, such as corneal infiltration, ulceration or even corneal perforation, as described in the article McGee et to the. Toxicities or, topical ophthalmic anesthetics. Review Expert Opino Drug Safety, 2007, 6 (6), p637-640.
    Tramadol is a synthetic opioid that acts as an analgesic to
    central level according to a double mechanism: as a receptor agonist
    opiates and as a reuptake inhibitor of norepinephrine and serotonin,
    so that both modes of action, opioid and non-opoiode, seem to act synergistically. In addition, in general, tramadol is well tolerated, so it is often the drug of first choice for the treatment of post-operative pain, ahead of NSAIDs and other opioid drugs such as morphine, as described in the Lehmann KA article, Le tramadol dans les douleurs aigues, Drugs, 1997, 53 (2), Supplement, p25-33. The most common forms of administration of tramadol are oral, rectal and parenteral.
    Occasionally, tramadol has also been postulated for topical administration by ophthalmic route, as a possible alternative analgesic for the treatment of eye pain.
    Thus, in patent application WO-A-2012/136969 compositions for ophthalmic use containing tramadol in a concentration of at least 0.5% are described, together with lubricating polymers of the eye, these being essential since the effect Tramadol narcotic causes a decrease in blinking and a consequent dry eye.
    Thus, examples 6 to 9 of said patent application describe the administration of lubricating eye drops containing 0.5% or 1.0% of tramadol for the treatment of patients with ocular pain caused by infection, allergy, eye dry and blepharitis, respectively, and it is stressed that with the concentration of 1.0% more effective results are achieved.
    Despite the different alternatives described to date, there remains a need for a composition for ophthalmic topical use for the treatment of eye pain that is effective and that carries a lower risk of undesirable side effects.
    Object of the invention The object of the present invention is an ophthalmic pharmaceutical composition comprising tramadol. The use of said composition for the treatment of eye pain is also part of the object of the invention.
    Detailed description of the invention
    The object of the present invention is an aqueous ophthalmic pharmaceutical composition comprising tramadol or a pharmaceutically acceptable salt thereof, in which tramadol is in a concentration between 0.02% (plv) and 0.09% (w / v ), expressed as equivalent concentration of tramadol hydrochloride.
    The authors of the present invention have developed an aqueous composition of tramadol for ophthalmic use which, surprisingly, is highly effective for the treatment of eye pain even when said active ingredient is in a remarkably low concentration, specifically between 0.02 and 0 , 09% (w / v), therefore, said composition is especially safe and substantially devoid of side effects.
    Throughout this description, unless otherwise specified, the concentrations expressed as percentages always refer to the weight / volume (w / v) percentage, that is, grams of a given component per 100 ml of composition .
    Tramadol
    Tramadol is the International Common Designation (INN) by which the compound (±) -cis-2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol is commonly known.
    Tramadol is a drug belonging to the group of opioids, although its mechanism of action is usually described as an opioid "; atypicoquot;" since it is neither completely opioid nor completely non-opioid. Tramadol has a dual action mechanism because, on the one hand, it acts on the opioid IJ receptors to which it binds with low affinity and, on the other hand, inhibits the reuptake of norepinephrine and serotonin, thereby increasing the concentration of these neurotransmitters in localized areas of the brain lowering the pain threshold, as described, for example, in the article Raffa et al., Opioid and nonopioid components independently contribute to the mechanism of action of hatched /, an 'atypical' opioid analgesic, J Pharmacol Exp. Ther., 1992,260 (1), p275-85.
    Tramadol is commercially available and can also be prepared, for example, according to the procedure described in US Patent US3652589.
    In the context of the present invention, any of its solvates, polymorphs, stereoisomers, mixtures of stereoisomers and racemic forms is broadly included with the term tramadol.
    Pharmaceutically acceptable salts of tramadol refer to acid addition salts, which can be prepared according to conventional methods well known to those skilled in the art, using pharmaceutically acceptable organic or inorganic acids and substantially non-toxic. Such acids include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, maleic acid, malonic acid, succinic acid, citric acid, tartaric acid, malic acid, salicylic acid or phthalic acid, among others. Preferably, hydrochloric acid is used.
    In a preferred embodiment of the invention, tramad01 is in the form of its hydrochloride salt, or tramad hydrochloride 01. More preferably, it is in the form of tramadol hydrochloride, in racemic form.
    The concentration of tramadol in the ophthalmic pharmaceutical composition of the invention is between 0.02% and 0.09%, preferably between 0.03% and 0.08%, more preferably between 0.04% and 0.07 %, And even more preferably between 0.05% and 0.06%, expressed as equivalent concentration of tramadol hydrochloride.
    In a particularly preferred embodiment of the invention, the composition contains only frame 01 as an active ingredient.
    Throughout the present description, tramadol concentrations in the ophthalmic composition of the invention always refer to the equivalent concentration of tramadol hydrochloride, regardless of whether tramad01 is used as a free base or in the form of another Salt. Thus, for example, a concentration of tramadol of 0.05% expressed as equivalent concentration of hydrochloride of tramad01 corresponds approximately to a concentration of 0.044% of tramad01 as a free base, as the person skilled in the art already knows how to calculate, based on the weights molecules of said substances.
    Ophthalmic composition
    The pharmaceutical composition according to the present invention is an aqueous composition intended to be administered ophthalmic topically, that is, intended for local application in the eye or adjacent areas, in line with the definition of the European Pharmacopoeia where ophthalmic compositions are defined as sterile preparations (liquids, semi-solids or solids) intended to be administered in the eyeball or conjunctiva, or for insertion into the conjunctival sac.
    The general characteristics of ophthalmic compositions are well known to the person skilled in the art. For example, in the chapter "Ophthalmic Preparations", which corresponds to chapter 43 of the recognized manual of pharmaceutical technology "; Remington The Science and Practice of Pharmacy"; 20th edition, Lippincott, Williams & Wilkins, Philadelphia, 2000 [ ISBN: 0-683-306472], the characteristics, formulation, mode of use and form of preparation of said compositions are described in detail.
    The ophthalmic composition according to the present invention is administered topically on the eye surface, for example, typically in the form of drops or by spraying. Alternatively, it can also be administered by subconjunctival injection or retrobulbar injection, as described in chapter "Ophthalmic Preparationsquot; aforesaid.
    Preferably, the composition of the invention is administered topically on the ocular surface, including both direct administration on said surface and its deposition on the edges of the eyelids, as is known by the person skilled in the art and as described in the chapter mentioned above. For example, the composition can be applied by means of a dropper, instilling in the lower conjunctival sac, which is accessed by gently pulling the lower eyelid downwards forming a sac where the drop is deposited.
    The ophthalmic composition according to the present invention is an aqueous formulation, that is, the vehicle is water.
    The composition of the invention may be in the form of a solution.
    or suspension. In the ophthalmic solution all ingredients are completely dissolved in the aqueous medium, while the ophthalmic suspension is a dispersion in the aqueous vehicle of finely divided particles of the drug, relatively insoluble.
    Preferably the ophthalmic composition according to the present invention is in the form of a solution.
    The composition may optionally comprise a viscosifying agent, whereby it can have a typically liquid, or slightly gelled, appearance depending on its viscosity.
    The ophthalmic composition according to the present invention may additionally contain other optional components.
    Viscosifying agent
    The composition of the invention optionally contains a viscosifying agent.
    The viscosifying agent is a substance that increases the viscosity of the composition, which allows to increase the contact time of the active ingredient with the surface of the eye, which in turn can favor its absorption. The viscosifying agent may also eventually have a mucoadhesive and / or mucomimetic effect, that is, an interaction occurs between it and the mucins of the cornea and / or the conjunctiva, which also results in prolonging the residence time of the composition on the surface of the eye and favor the absorption of the active substance. Additionally, the viscosifying agent can also have a lubricating effect of the eye.
    In a preferred embodiment of the invention, the composition comprises a viscosifying agent.
    The composition of the invention has a viscosity generally between 1 and 100 cP, preferably between 2 and 50 cP, more preferably between 3 and 40 cP, even more preferably between 4 and 30 cP, and even more preferably between and 20 cP.
    Depending on its lower or higher viscosity, the ophthalmic composition according to the invention may have a completely liquid appearance.
    or slightly gelled.
    Among the suitable viscosifying agents to be incorporated into the ophthalmic composition are, for example, cellulosic derivatives as well as their possible associations such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, among others, polyvinyl alcohol, polymers, polymers, polymers, polymers, polymers polyoxyethylene, polyvinylpyrrolidone, hyaluronic acid, sodium hyaluronate, sodium salt of chondroitin sulfate, gellan gum, xanthan gum, carrageenan, sodium alginate, pectin, or mixtures thereof.
    The person skilled in the art will have no difficulty in formulating the ophthalmic composition, possibly using a viscosifying agent in a suitable proportion that gives the composition an optimum viscosity and / or mucoadherence.
    In a preferred embodiment, the viscosifying agent is chosen from those with better mucoadhesive properties, so that it is preferably chosen from methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium alginate, carrageenan, guar gum, carbomer, polyacrylamide, polyacrylamide hyaluronic, sodium hyaluronate and mixtures thereof.
    In a particularly preferred embodiment, the viscosifying agent is chosen from hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hyaluronic acid, sodium hyaluronate and mixtures thereof.
    The viscosifying agent is generally added in a proportion between 0.1% and 1.0%, preferably between 0.2% and 0.8% in the case of hydroxypropyl methylcellulose, between 0.1% and 1.0% in the case of sodium carboxymethylcellulose and between 0.1% and 0.5% in the case of hyaluronic acid or sodium hyaluronate.
    Isotonizing agent
    The composition optionally contains an agent for regulating osmolality, or isotonizing agent, which is chosen, for example, from sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, mannitol, glycerol, propylene glycol, sorbitol, glucose, dextrose, sucrose, and their mixtures Preferably, the isotonizing agent is sodium chloride.
    The function of the isotonizing agent is to modify the osmolality of the composition, bringing it closer to the tonicity of the eye to avoid discomfort in the application thereof, so that it is preferably isotonic with respect to the tear fluid of the eye, or slightly hypertonic or hypotonic.
    The composition according to the present invention has an osmolality generally comprised between 200 and 330 mOsm / Kg. Preferably, it has an osmolality between 280 mOsm / Kg and 330 mOsm / Kg, more preferably between 290 mOsm / Kg and 320 mOsm / Kg, even more preferably between 295 mOsm / Kg and 305 mOsm / Kg, and even more preferably It is approximately 300 mOsm / Kg, for all proposed indications except in the case of hyperosmolar dry eye syndrome where the present invention preferably has an osmolality between 200 mOsm / Kg and 320 mOsm / Kg, more preferably between 220 mOsm / Kg and 280 mOsm / Kg, even more preferably between 240 mOsm / Kg and 260 mOsm / Kg, and even more preferably is about 250 mOsm / Kg.
    If an isotonizing agent is added, it is in a suitable proportion to obtain osmolality values in the specified preferred ranges.
    In a preferred embodiment of the invention, the composition
    contains chloridesodiumhowagentisotonizinginaproportion
    preferably understoodbetween0.5%Y1.5%plus preferably
    between 0.75% and 1.25%.
    PH regulating agent
    Also, the composition according to the present invention optionally contains an ophthalmically acceptable pH regulating agent, whose function is to adjust the pH value of the composition to the preferred values, usually in the vicinity of the physiological pH of the tear fluid.
    The pH of the composition is generally between 6.0 and 8.0, preferably between 6.7 and 7.8, more preferably between 7.0 and 7.7, even more preferably between 7.3 and 7 , 5, And even more preferably it has a pH of 7.4.
    The ophthalmically acceptable pH regulating agents are well known to those skilled in the art and include, without limitation, acids such as hydrochloric acid, acetic acid, citric acid or boric acid; and bases such as sodium hydroxide, sodium phosphate or sodium citrate. A buffer system that is acceptable for ophthalmic application can also be used to regulate the pH at the required values, as are also well known to those skilled in the art, for example, acetate buffer, citrate buffer, phosphate buffer, borate buffer or bicarbonate buffer, or mixtures thereof.
    The person skilled in the art will have no difficulty in choosing a suitable pH regulating agent and incorporating it in the amount necessary to obtain a pH value within the preferred ranges indicated above.
    In a preferred embodiment of the invention, sodium hydroxide and / or hydrochloric acid is used to adjust the pH value.
    Preservatives
    Optionally, the composition of the invention contains an ophthalmologically acceptable preservative agent, especially when the composition is arranged in the usual multi-dose containers, to avoid microbial contamination of the composition once the container is opened.
    In general, the presence of a preservative is not necessary when single-dose or multi-dose containers that maintain its contents are sterile, or packages that include a 0.22 micron filter to dispense a sterile product.
    Among the preservatives suitable for use in the ophthalmic composition according to the present invention are, for example, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetrimony chloride, cetrimonium bromide or polymers of quaternary amines called polyquaterno-1 (commercially available under the name Polyquad®, Alcon); organomercurial compounds such as phenylmercury nitrate, phenylmercury acetate, phenylmercury borate or thimerosal; parabens, such as methylparaben or propylparaben; substituted alcohols or phenols, such as chlorobutanol, phenethyl alcohol, or benzyl alcohol; or others such as chlorhexidine, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, sodium perborate; as well as some commercial preservative compositions such as the so-called SofZia®, which contains borate, sorbitol, propylene glycol and zinc; or their mixtures.
    Preferably, the preservative is chosen from the quaternary amines polymers called polyquaterno-1 (commercially available under the name Polyquad®, Alcon) and some commercial preservative compositions such as the so-called SofZia®, which contains borate, sorbitol, propylene glycol and zinc.
    Other components
    Optionally, the composition of the invention comprises a chelating agent, for example, sodium citrate or edetate salts, such as disodium edetate, disodium calcium edetate, trisodium edetate, or dipotassium edetate, or mixtures thereof.
    Optionally, the composition of the invention comprises an antioxidant. Among the antioxidants suitable for use in the composition according to the present invention are, for example, sodium bisulfite, ascorbic acid or acetylcysteine, or mixtures thereof.
    Likewise, optionally, the composition of the invention comprises a surfactant whose function is typically to favor the contact of the active principle with the surface of the eye by decreasing the surface tension of the liquid and favoring its penetration.
    Among the surfactants suitable for use in the composition of the invention are, for example, fatty esters of polyoxyethylene sorbitan (polysorbates), ethoxylated alkylphenols, ethylene glycolpropylene glycol block copolymers, lecithins, or phospholipids.
    Reference is made here to the recognized manual on pharmaceutical excipients, elll Handbook of Pharmaceutical Excipientsquot; from Rowe Re,
    Sheskey PJ and Quinn ME, sixth edition, 2009, where you can find the definitions and characteristics for the different ingredients mentioned.
    In an embodiment of the invention, the pharmaceutical composition
    aqueous ophthalmic comprises: tramadol or a pharmaceutically acceptable salt thereof, preferably tramadol hydrochloride, in a concentration between 0.02% and 0.09%, preferably comprised between 0.03% and 0.08%, more preferably comprised between 0.04% and 0.07%, and even more preferably between 0.05% and 0.06%, expressed as equivalent concentration of tramadol hydrochloride;
    - an isotonizing agent chosen from sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, mannitol, glycerol, propylene glycol, sorbitol, glucose, dextrose, sucrose, and mixtures thereof, more preferably is sodium chloride;
    - a viscosifying agent chosen from methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, carbomer, polycarbophilic, polyacrylamide, polyoxyethylene, polyvinylpyrrolidone, hyaline gum, sodium gum, gialic acid carrageenan, sodium alginate, pectin, and mixtures thereof, preferably chosen from methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium alginate, carrageenan, guar gum, carbomer, polyacrylamide, polycarbophilic acid, hyalurphonic acid, hyalurphonic acid, mixtures; Y
    - optionally, a pH regulating agent chosen from such as hydrochloric acid, acetic acid, citric acid or boric acid, sodium hydroxide, sodium phosphate, sodium citrate, acetate buffer, citrate buffer, phosphate buffer, borate buffer, bicarbonate buffer and mixtures thereof, preferably chosen from hydrochloric acid, sodium hydroxide and mixtures thereof;
    where the composition has an osmolality between 200 mOsm / Kg and 330 mOsm / Kg:
    - preferably between 280 mOsm / Kg and 330 mOsm / Kg, more preferably between 290 mOsm / Kg and 320 mOsm / Kg, even more preferably between 295 mOsm / Kg and 305 mOsm / Kg, and even more preferably about 300 mOsm / Kg; O well
    - preferably between 200 mOsm / Kg and 320 mOsm / Kg, more preferably between 220 mOsm / Kg and 280 mOsm / Kg, even more preferably between 240 mOsm / Kg and 260 mOsm / Kg, and even more preferably it is about 250 mOsm / Kg;
    wherein the composition has a viscosity between 1 and 100 cP, preferably between 2 and 50 cP, more preferably between 3 and 40 cP, even more preferably between 4 and 30 cP, and even more preferably between 5 and 20 cP; wherein the composition has a pH between 6.0 and 8.0, preferably between 6.7 and 7.8, more preferably between 7.0 and 7.7, even more preferably between 7.3 and 7 , 5, And even more preferably has a pH of 7.4; and wherein preferably the composition contains tramadol as the only active ingredient.
    In a particularly preferred embodiment of the invention, the aqueous ophthalmic pharmaceutical composition comprises:
    - tramadol or a pharmaceutically acceptable salt thereof, preferably tramadol hydrochloride, in a concentration between 0.02% and 0.09%, preferably between 0.03% and 0.08%, more preferably between 0.04% and 0.07%, and even more preferably between 0.05% and 0.06%, expressed as equivalent concentration of tramadol hydrochloride;
    - sodium chloride in a proportion between 0.5% and 1.5%, preferably between 0.75% and 1.25%; -hydroxypropyl methylcellulose in a proportion between 0.2% and 0.8%, preferably between 0.3% and 0.5%
    - optionally, a pH regulating agent chosen from acid
    hydrochloric, sodium hydroxide and mixtures thereof; wherein the composition has a pH between 6.0 and 8.0, preferably between 6.7 and 7.8, more preferably between 7.0 and 7.7, even more preferably between 7.3 and 7 , 5, And even more preferably has a pH of 7.4; And where preferably the composition contains tramadol as the only active ingredient.
    In another particularly preferred embodiment of the invention, the aqueous ophthalmic pharmaceutical composition comprises:
    tramadol or a pharmaceutically acceptable salt thereof, preferably tramadol hydrochloride, in a concentration between 0.02% and 0.09%, preferably between 0.03% and 0.08%, more preferably between 0.04% and 0.07%, and even more preferably between 0.05% and 0.06%, expressed as equivalent concentration of tramadol hydrochloride;
    - sodium chloride in a proportion between 0.5% and 1.5%, preferably between 0.75% and 1.25%; -sodium carboxymethylcellulose in a proportion between 0.1% and 1.0%, preferably between 0.5% and 0.8% -optional, a pH regulator chosen from acid
    hydrochloric, sodium hydroxide and mixtures thereof; wherein the composition has a pH between 6.0 and 8.0, preferably between 6.7 and 7.8, more preferably between 7.0 and 7.7, even more preferably between 7.3 and 7 , 5, And even more preferably has a pH of 7.4; and wherein preferably the composition contains tramadol as the only active ingredient.
    In another particularly preferred embodiment of the invention, the aqueous ophthalmic pharmaceutical composition comprises:
    - tramadol or a pharmaceutically acceptable salt thereof, preferably tramadol hydrochloride, in a concentration between 0.02% and 0.09%, preferably between 0.03% and 0.08%, more preferably between 0.04% and 0.07%, Yaún more preferably comprised between 0.05% and 0.06%, expressed as equivalent concentration of tramadol hydrochloride;
    - sodium chloride in a proportion between 0.5% and 1.5%, preferably between 0.75% and 1.25%;
    - hyaluronic acid or sodium hyaluronate in a proportion between 0.1% and 0.5%, preferably between 0.2% and 0.4%; - optionally, a pH regulating agent chosen from acid
    hydrochloric, sodium hydroxide and mixtures thereof; wherein the composition has a pH between 6.0 and 8.0, preferably between 6.7 and 7.8, more preferably between 7.0 and 7.7, even more preferably between 7.3 and 7 , 5, Yaun more preferably has a pH of 7.4; And where preferably the composition contains tramadol as the only active ingredient.
    Use of tramadol ophthalmic composition
    The efficacy of the ophthalmic composition of the invention for the treatment of eye pain was evaluated in a trial in which the activity of the composition in the nerve endings of polymodal receptors and cold receptors in the cornea was determined, as described in the Acosta et al., Comparative effects of the nonsteroidal anti-inflammatory drug nepafenac on corneal sensory nerve fibers responding to chemical irritation,
    Invest Ophthalmol Vis Sci. 2007 Jan; 48 (1): 182-8.
    It was found that, surprisingly, the compositions of the invention, which contain a low concentration of the active substance tramadol, were highly effective in said model.
    Therefore, the use of the composition of the invention for the preparation of a medicament for topical ophthalmic administration for the treatment of eye pain is part of the object of the present invention.
    Alternatively, said object can be formulated as the composition of the invention for use in the treatment of ocular pain by ophthalmic topical administration.
    Within the framework of the present invention, the term "treatment" includes treatment for therapeutic purposes, that is, aimed at the elimination, reduction, improvement or relief of symptoms when they have already manifested, and also includes treatment for preventive purposes or prophylactic, that is, aimed at preventing or delaying the onset of eye pain, or reducing its incidence.
    The treatment according to the use of the present invention is indicated to be applied to any mammalian animal that requires such treatment, preferably humans.
    Likewise, the eye pain according to the object of the present invention is broadly understood, including both the conditions of the eye itself, including all its parts, including iris, crystalline, cornea, conjunctiva, sclera, choroid, retina, papilla. optics, or vitreous humor; as well as in the surrounding areas, for example the eyelids.
    On the other hand, the etiology of such pain can be diverse, for example, in response to trauma or eye surgery, or due to infectious processes, allergies, immunological reactions, or for other causes, all of which are included in the scope of present invention
    Thus, the use that is part of the present invention refers to the treatment of ocular pain associated with various diseases or pathological conditions, for example, not limited to the following: post-surgical states after ocular surgery; -inflammatory states of diverse origin and location, such as conjunctivitis
    allergic, viral conjunctivitis, bacterial conjunctivitis, blepharitis, uveitis, iridocyclitis, intermediate uveitis, chorioretinitis, scleritis, episcleritis, retinitis, or keratitis, among others;
    - dry eye syndrome; - eye injury due to trauma, burn, radiation, introduction of a foreign body, or by contact with chemical agents; or -use of contact lenses.
    Within the framework of the present invention, eye surgery includes any surgical technique performed on the eye, including, for example, cataract surgery, corneal transplantation, oculoplasty, or any technique of
    refractive surgery For its part, refractive surgery includes techniques such as radial keratotomy (QR), astigmatic keratotomy (QA), photorefractive keratectomy (QFR), or laser-assisted in situ keratomileusis (QISACL), all of which are included in the scope of the present invention. . Also included within the causes of pain caused by eye surgery, in particular, macular edema after cataract surgery and photophobia after eye surgery, especially photophobia after refractive surgery.
    In a particularly preferred embodiment, the use according to the present invention relates to the treatment of eye pain associated with post-surgical conditions after eye surgery.
    In an even more preferred embodiment, the use according to the present invention refers to the treatment of inflammation and / or eye pain associated with post-surgical conditions after cataract surgery, radial keratotomy (QR), photorefractive keratectomy (QFR), or laser-assisted in situ keratomileusis (QISACL), including macular edema after cataract surgery and photophobia after radial keratotomy (QR), and photophobia after photorefractive keratectomy (PKR).
    In another preferred embodiment, the use according to the present invention relates to the treatment of eye pain associated with an eye injury. In another preferred embodiment, the use according to the present invention relates to the treatment of ocular pain associated with dry eye syndrome.
    Composition Preparation
    The aqueous composition for ophthalmic use according to the present invention is prepared by usual procedures, which are well known to the person skilled in the art, as described, for example, in the tlOphthalmic Formulationstl chapter of the tlRemington The Science and Practice manual, or Pharmacyquot; , cited above.
    Thus, one of the requirements that ophthalmic compositions must meet is that they must be sterile. For the sterilization of the ophthalmic compositions of the invention, different techniques can be used, all of which are well known to those skilled in the art, such as
    for example, with high pressure steam at 121 0 C (in an autoclave), by sterilizing filtration, sterilization with ethylene oxide, or by radiation.
    Preferably, the ophthalmic composition of the invention is sterilized by sterilizing filtration and / or with high pressure steam at 121 0 C.
    The aqueous composition of the invention can be prepared with purified water, according to the characteristics specified in the Royal Spanish Pharmacopoeia, second edition, or with water for injection, which are commercially available.
    The purified water is usually obtained by distillation, ion exchange or any other suitable method from drinking water. Water for injection is usually obtained by sterilization of distilled, pyrogen-free water.
    Thus, the composition for ophthalmic use according to the present invention can be prepared, for example, according to a process comprising the dissolution or dispersion in purified water / for injection of tramadol, or a salt thereof, together with other possible optional ingredients, such as an isotonizing agent, a preservative agent, a viscosifying agent, among others, as described above, or a combination thereof.
    The pH of the composition can be adjusted to a value between 6.0 and 8.0, adding if necessary a suitable pH regulating agent.
    Finally, if necessary, purified water / for additional injection is added up to the required final volume, and it can also be verified that the osmolality value is between the preferred values, that is, between 200 and 330 mOsmlKg, more preferably between 280 mOsm / Kg and 330 mOsm / Kg for all proposed indications except in the case of hyperosmolar dry eye syndrome where the osmolality is more preferably between 200 mOsm / Kg and 320 mOsm / Kg.
    The solution obtained can be sterilized, for example, by sterilizing filtration. Finally, the resulting solution can be dosed in multi-dose or single-dose containers, suitable for ophthalmic administration, such as
    Well known to the expert in pharmaceutical technology. Optionally, said packages containing the composition of the invention are sterilized in an autoclave, for example, by treatment at 121 ° C for approximately 20 minutes.
    Eventually, the composition of the invention can be prepared under non-sterile conditions and packaged in a container that includes a 0.22 micron filter to provide a sterile product at the time of administration.
    In the following, several examples are provided by way of illustration but not limitation of the invention.
    Examples Example 1: 0.05% eye drops of tramadol hydrochloride An aqueous solution was prepared using the components detailed in the following table:
    Ingredient Amount% (p / v)
    Tramadol HCI 0.05
    I was born 0.90
    NaOH / HCI c.s.p. pH 7.4
    purified water c.s.p. 100 mi
    A portion of the purified water was placed in a reactor, in an amount of approximately 75% of the total. Then, under continuous stirring, tramadol hydrochloride and the
    sodium chloride until completely dissolved.
    The pH was then adjusted with NaOH / HCI to a value of 7.4, and the rest of purified water was added flushing to the final volume. The solution thus obtained was sterilized by filtration by a 0.22 filter.
    25 microns
    The solution had an osmolality of 300 mOsm.
    Example 2: 0.05% eye drops of tramadol hydrochloride An aqueous solution was prepared using the proportions detailed in the following table:
    Ingredient Amount% (p / v)
    Tramadol HCI 0.05
    I was born 0.990
    Hydroxypropyl methylcellulose 0.30
    NaOH / HCI c.s.p. pH 7.4
    purified water c.s.p. 100 mi
    A portion of the purified water was placed in a reactor, in an amount of approximately 75% of the total. Then, under continuous
    After stirring, tramadol hydrochloride, sodium chloride and the appropriate amount of a solution of hydroxypropylmethylcellulose previously dissolved in cold purified water were added consecutively until completely dissolved. The pH was then adjusted with NaOH / HCI to a value of
    15 7.4, And the rest of purified water was added flushing to the final volume. The solution thus obtained was sterilized by filtration by a 0.22 micron filter. The solution had an osmolality of 300 mOsm.
    权利要求:
    Claims (15)
    [1]
    1.-Aqueous ophthalmic pharmaceutical composition comprising tramadol or a pharmaceutically acceptable salt thereof, characterized in that tramadol is in a concentration between 0.02% (w / v) and 0.09% (w / v), expressed as equivalent concentration of tramadol hydrochloride.
    [2]
    2. Composition according to claim 1, characterized in that tramadol is in the form of its hydrochloride salt.
    [3]
    3. Composition according to any of claims 1 or 2, characterized in that it contains tramadol as the only active ingredient.
    [4]
    4. Composition according to any one of claims 1 to 3, characterized in that it comprises a viscosifying agent that is selected from the group consisting of methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, carbomer, polycarbophil, polyacrylamide polyoxyethylene, polyvinylpyrrolidone, hyaluronic acid, sodium hyaluronate, sodium salt of chondroitin sulfate, gellan gum, xanthan gum, carrageenan, sodium alginate, pectin, and mixtures thereof.
    [5]
    5. Composition according to claim 4, characterized in that the viscosifying agent is selected from the group consisting of methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium alginate, carrageenan, guar gum, carbomer, polyacrylamide, polycarbophilic acid, hyalurophonic acid, sodium hyaluronate and mixtures thereof.
    [6]
    6. Composition according to any of claims 1 to 5, characterized in that it comprises an isotonizing agent that is chosen from the group consisting of sodium chloride, potassium chloride, sodium sulfate, potassium nitrate,
    Mannitol, glycerol, propylene glycol, sorbitol, glucose, dextrose, sucrose, and mixtures thereof.
    [7]
    7. Composition according to claim 6, characterized in that the isotonizing agent is sodium chloride.
    [8]
    8. Composition according to any of claims 1 to 7, characterized in that it has a pH between 6.0 and 8.0.
    [9]
    9. Composition according to any of claims 1 to 8, characterized in that it comprises a preservative agent.
    [10]
    10. Composition according to any of claims 1 to 3, characterized
    because it comprises: tramadol or a pharmaceutically acceptable salt thereof, in a concentration between 0.02% (w / v) and 0.09% (w / v), expressed as equivalent concentration of tramadol hydrochloride; sodium chloride in a proportion between 0.5% (w / v) and 1.5% (w / v); Y
    hydroxypropyl methylcellulose in a proportion between 0.2% (w / v) and 0.8% (plv).
    [11]
    11. Composition according to any of claims 1 to 3, characterized
    because it comprises: tramadol or a pharmaceutically acceptable salt thereof, in a concentration between 0.02% (plv) and 0.09% (w / v), expressed as equivalent concentration of tramadol hydrochloride;
    - sodium chloride in a proportion between 0.5% (plv) and 1.5% (plv);
    Y
    - sodium carboxymethyl cellulose in a proportion between 0.1%
    (plv) and 1.0% (w / v).
    [12]
    12. Composition according to any of claims 1 to 3, characterized
    because it comprises: tramadol or a pharmaceutically acceptable salt thereof, in a concentration between 0.02% (w / v) and 0.09% (w / v), expressed as equivalent concentration of tramadol hydrochloride; sodium chloride in a proportion between 0.5% (w / v) and 1.5% (w / v); and hyaluronic acid or sodium hyaluronate in a proportion between 0.1% (w / v) and 0.5% (w / v).
    [13]
    13. Use of a composition according to any of claims 1 to 12 for the preparation of a medicament for ophthalmic topical administration for the treatment of eye pain.
    [14]
    14. Use according to claim 13, characterized in that the eye pain is
    associated with: post-surgical states after eye surgery; or allergic conjunctivitis, viral conjunctivitis, bacterial conjunctivitis, blepharitis, uveitis, iridocyclitis, intermediate uveitis, chorioretinitis, scleritis, episcleritis, retinitis, or keratitis; or dry eye syndrome; or eye injury due to trauma, burn, radiation, introduction of a foreign body, or contact with chemical agents; or wearing contact lenses.
    [15]
    15. Use according to claim 14, characterized in that the eye pain is associated with post-surgical conditions after eye surgery, dry eye syndrome or eye injury.
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    同族专利:
    公开号 | 公开日
    RU2018112239A|2019-10-09|
    HUE054930T2|2021-10-28|
    PL3348260T3|2021-12-06|
    HRP20211181T1|2021-10-15|
    ES2604816B1|2018-01-29|
    US20190224114A1|2019-07-25|
    EP3348260A1|2018-07-18|
    EP3348260A4|2019-04-17|
    RU2018112239A3|2020-01-30|
    WO2017042404A1|2017-03-16|
    ES2882116T3|2021-12-01|
    RU2744570C2|2021-03-11|
    EP3348260B1|2021-06-02|
    DK3348260T3|2021-07-05|
    PT3348260T|2021-08-06|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2012136969A2|2011-04-05|2012-10-11|Anant Sharma|Ophthalmic treatments|
    WO2013150277A1|2012-04-05|2013-10-10|Anant Sharma|Ophthalmic therapy|
    ES2540151A1|2013-10-11|2015-07-08|Farmalider S.A.|Pharmaceutical composition of ibuprofen and tramadol for ophthalmic use |
    US7893040B2|2005-07-22|2011-02-22|Oculis Ehf|Cyclodextrin nanotechnology for ophthalmic drug delivery|
    ITMI20052036A1|2005-10-26|2007-04-27|Professional Dietetics Srl|PHARMACEUTICAL COMPOSITIONS OPHTHALMIC BASED ON AMINO ACIDS AND SODIUM HYALURONATE|WO2021260622A1|2020-06-26|2021-12-30|Sifi S.P.A.|Ophthalmic composition and use thereof in the treatment of eye diseases|
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