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    • 专利摘要:
    Topical hydroalcoholic pharmaceutical composition for treatment of otitis externa and corresponding method and use. Hydroalcoholic pharmaceutical composition, for topical use, with a water concentration comprised between 20% and 40% by weight with respect to the total weight of the composition, and with a concentration of a surfactant comprised between 0.5% and 4% by weight with respect to the total weight of the composition. It is suitable for the prevention and/or treatment of otitis externa. The alcoholic fraction is preferably between 60% and 80% by weight with respect to the final composition. The method for preparing the composition comprises mixing the alcohol, the surfactant and the water at a temperature comprised between 20ºC and 35ºC and an agitation between 2,500 rpm and 3,500 rpm. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2674130A1
    申请号:ES201631692
    申请日:2016-12-27
    公开日:2018-06-27
    发明作者:Antonio BUXADÉ VIÑAS；Montserrat Albreda Plaza；Miguel CÁNOVAS UBERA；Antonio Conchillo Teruel
    申请人:Laboratorios Vinas SA；
    IPC主号:
    专利说明:

    Field of the Invention
    The invention relates to a stable yantimicrobial antiseptic hydroalcoholic formulation, topically applied, with a high concentration in water and a low concentration of a surfactant, useful as a pharmaceutical composition for the prevention or treatment of otitis externa.
    The invention also relates to a method of preparing a composition according to the invention and a use thereof.
    State of the art
    20 External otitis (infections of the external ear), also called swimmer's or pool's otitis, is characterized by inflammation of the external auditory canal. It is a common problem that occurs mainly during climatic and humid conditions or by frequent contact of the ear with water. Statistical studies
    25 consider that it is up to five times more frequent in swimmers than in non-swimmers. The main symptom is otalgia, being able to become very intense, feeling pain when traction of the auricular pavilion or swallowing in more advanced phases, even reaching suppuration in the ear canal and reducing hearing. It is estimated that more than 80% of cases of otitis externa are due to bacterial and fungal infections, being
    30 the most frequent germs pseudolllona aeruginosa and staphylococcus aureus.
    In cases such as swimmer's otitis, the accumulation of water in the external canal leads to an alkalization of the environment, thereby favoring bacterial growth, with the consequent development of infection, so typical actions involve the
    5 water extraction by physical or chemical means to dry the excess and subsequent treatment with bacteriostatic agents, bactericides or pH modifiers.
    Thus, various substances such as hydrogen peroxide, isopropyl alcohol, aluminum acetate buffers, boric acid, etc. have been used, but which, however, usually also show an irritating effect on the outer ear canal tissue.
    Related to the above, in eN 103860558 iodine is described in povidone with a steroid for the treatment of internal or external otitis.
    15 In MX PA05002719, a solution in separate containers, containing one 50% ethyl alcohol and 5% glycerol to expose the skin to dehydrate and dry out, and in another 45% container, is exposed as a preventive of otitis externa. of 4% acetic acid. The discomfort is evident that, before use, the corresponding mixture must be made, in order to guarantee the stability of the solution.
    20 Direct treatment is common with topical agents, including drops, creams, gels, aerosols, etc. antibacterial and / or fungal, as well as systemic treatment.
    However, these treatments are not without problems. For example, it has been
    The usual use of aminoglycoside antibiotics that over time have led to the development of resistance, or compositions based on quinolone antibiotics combined with corticosteroids and anti-inflammatories, which have presented side effects with repeated use, both systemically and by topical route
    Other developments and treatments have sought different approaches in the compositions, for example:
    Patent ES 2,245.61 1 describes a pharmaceutical composition in the form of a microemulsion that does not exhibit ototoxicity, for topical use of the external otis based on diclofenac and ciprofloxacin.
    In US 4,073,937 a method for preventing otitis externa is described which consists in directly applying, and before having contact with water, a surface tension reducing agent containing ether, ester or amide bonds and more specifically oleate oleate. so polyoxyethylene rbitol.
    US patent 2015/297588 describes a mixture of antibiotics, antifungals and anti-inflammatories in a thick base so that the composition can be maintained for 15 to seven days in the external ear canal.
    US 2002/0076383 discloses a method for the treatment of otitis externa by increasing the permeability of the external auditory canal medi, before a mixture of aerosolized lipid crystals based on liquid lipid surfactants, of the type
    20 phospholipids or neutral lipids and "spraying" and propellant agents, in order to provide a film as a protective barrier against water and which can contain an active agent of antibiotic, antiviral, anti-inflammatory, antihistamine, decongestant, etc. .
    25 The problem of ototopic administration of active suture compositions to combat external otitis is not satisfactorily resolved and with sufficient safety to minimize the risk of irritation or ototoxicity, including comfort in its application. In addition, it is desirable to provide an effective way for administration.
    30 Accordingly, interest in the pharmaceutical field is evident in simple, effective formulations, of easy administration and without the aforementioned risks.
    Exhibition of the invention
    The present invention relates to a stable antiseptic and antimicrobial hydroalcoholic formulation, topically applied, with a high concentration in water and a low concentration of a surfactant, useful as a pharmaceutical composition for the prevention or treatment of otitis externa.
    In particular, the object of the invention is a pharmaceutical composition, for topical use, characterized in that it is a hydroalcoholic solution with a concentration in water between 20% and 40% by weight with respect to the total weight of the composition, and with a concentration of a surfactant between 0.5% Y
    15 4% by weight with respect to the total weight of the composition. Preferably the composition according to the invention is for use in the prevention and / or treatment of otitis externa. Also, the object of the invention is the use of a pharmaceutical composition according to the invention for the preparation of a medicament for the prevention or treatment of otitis externa.
    In relation to the issues and problems raised, the inventors of this patent application have discovered that it is possible to obtain stable hydroalcoholic pharmaceutical formulations with a high alcoholic and water content in which the antiseptic and microbial activity is enhanced by the presence of an agent
    25 surfactant in low concentration. The final solution formulation has good galenic-tarmaceutical qualities: stable and non-irritating, and therapeutic.
    Formulations with very high alcohol content usually present irritability problems, as well as a lower antiseptic capacity due to excessive dehydration of bacterial membranes. On the contrary, formulations with a low alcohol content have a low antiseptic capacity.
    On the other hand, if ester type components are present in the formulations, the possibility of transesterification with alcohol or hydrolysis of the ester groups should be considered.
    Faced with these problems, a balance in the hydroalcoholic composition in the concentration of both components is of interest: alcohol and water, in order to maintain a high antiseptic capacity without causing irritability and adequate stability, both in its preventive use and in the treatment for find damaged tissue.
    In addition, it is important to enhance or increase microbial activity. In this case, the presence of surfactants with antimicrobial action could also reduce
    15 the surface tension of the bacterial membranes, decrease the surface tension of the water present in the canal and increase the permeability of the tissue affected by the microorganisms.
    Surprisingly, the presence of water in amounts greater than 20%, and lower
    20 to 40%, and a surfactant composition greater than 0.5% and less than 4%, allows for a composition with desirable galenic-pharmaceutical, preventive and therapeutic properties: a single liquid solution easily administrable, stable, non-irritating, easily evaporable in the external auditory canal, with dehydrating capacity - which also allows the sequestration of water present in the tissue of the
    25 external auditory canal-, reduce water activity and enhance antimicrobial activity.
    An additional advantage of the composition of the present invention is produced after evaporation of the hydroalcoholic component, the deposition in the tissue 30 of a layer containing the non-volatile fraction acting as a protective film.
    The use of a pharmaceutical composition according to the invention for the prevention or treatment of otitis externa is also an object of the invention.
    Another object of the invention relates to the process of obtaining the patent composition, the combination and proportion of water, as well as the type and concentration of the surfactants, and the final incorporation of an acid allow a solution formulation Clean with the mentioned properties.
    Detailed description of embodiments of the invention
    The invention describes a pharmaceutical composition in the form of a clear solution, for topical use, based on a hydroalcoholic mixture containing water at a high concentration, a surfactant at a low concentration and an acid to maintain the acid solution.
    The composition is suitable for the prevention or treatment of otitis externa.
    The alcohol used for the hydroalcoholic formulation is preferably an aliphatic, linear or branched, low molecular weight alcohol: from 2 to 5 carbon atoms, preferably 2 or 3 carbon atoms more preferably ethyl alcohol, isopropyl alcohol or isobutyl alcohol, and most preferably ethyl alcohol or isopropyl alcohol, in any case I regret alone as mixtures thereof.
    The concentration of aliphatic alcohol may preferably vary between e160% and SO% by weight, based on the total weight of the composition.
    The concentration of water to maintain the hydroalcoholic balance and, in addition, 30 allows a high antiseptic or antimicrobial capacity, dcshidratante, and a low
    irritability, can 35%. to varybetween 20% and 40%, preferably between 25% and
    5 The surfactant is preferably a fatty acid ester with antimicrobial activity in which the carboxylic acid, in order to also enhance the interaction with the tissue of the ear canal, has a high polarity and, therefore, favors the hydrophilic interaction . Therefore, hydroxy acid esters of the formula are preferred as surfactants:
    ID orFormula (1) Formula (2)R, COO-CH (R¡) -COO-R, R, -COO- [CH (R¡) -COO] n -R
    fifteen in which R 1 is selected from H, Na or K; Rz represents H or a methyl (eH3) or ethyl (CHzCH3) group; R3 represents an alkyl chain or a fatty acid alkenyl chain of 6 to 14 carbon atoms; and n represents an integer with a value between 1 or 2.
    twenty Among the above surfactants, those that respond to formula (2) and more preferred are those that respond to formula (2) in which R2 is H or methyl (CH3).
    25 The above surfactants can be used alone, as pure substances, or as binary or ternary mixtures thereof. Being able to select for use among individual pure substances, mix in the desired proportion as binary or ternary mixtures, or use commercial mixtures that contain the desired proportion or can be supplemented with the pure substance.
    30 When binary or ternary mixtures are used, the proportions of the individual components may be in a ratio of 10% to 90% of the components.
    The concentration of surfactant may preferably vary from 0.5% to 4%, preferably from 1.0% to 3.0%.
    The pH of the final solution is advantageously between 4.0 and 5.5, preferably between 4.5 and 5.2, in order to regulate and maintain an acidic pH, more natural in the external ear canal, which does not favor bacterial growth.
    The acidifying agent may be a low molecular weight aliphatic acid of between two and five carbon atoms, preferably 2 or 3 carbon atoms.
    The subject of the invention is also a manufacturing process of the pharmaceutical composition.
    The manufacturing process is characterized by the mixture of aliphatic alcohol with the
    The surfactant and water are preferably carried out by maintaining a nitrogen atmosphere in the reactor and preferably at a temperature between 20 ° C and 35 ° C and with stirring between 2,500 rpm and 3,500 rpm.
    Preferably the final manufacturing phase is characterized by the addition of aliphatic acid 20 to achieve a pH between 4.5 to 5.2.
    The formulation obtained under the conditions described and with the selected components cs an acidic hydroalcoholic composition.
    Other minor components, such as perfumes, pigments, etc., commonly used in this type of formulations may also be present in the composition.
    Examples
    Table I shows three examples of connections made according to the components, the concentration of the components and the procedure described. Table 1:
    Formulation I Formulation 2Formulation 3
    Ethyl alcohol 96 45.00 g70.00 g
    Isopropyl Alcohol 99 65.00 g27.00 g
    Sodium Capriloyl Lactylate 1.50 g
    Sodium Caproyl-2-Lactylate 0.70 g1.00 g
    Sodium Lauroyl-2-Lactylate 1.00 g1.00 g
    Acetic acid 0.85 g0.90 g
    Propionic acid 0.90 g
    Water 32.65 g25.4 g27.10 g
    Total weight 100g100g100g
    Efficacy study
    Assay Evaluation of the antimicrobial activity of the test product by the formation of inhibition halos.
    Antimicrobial activity has been assessed by means of inhibition halos, which allows qualitatively determining when a substance or mixture of substances inhibits the growth of microorganisms. The product to be tested is contacted with the
    5 microorganisms that have been inoculated in a solid culture medium. After the incubation for the growth of the microorganisms, the presence of an inhibition halo around the test product is evaluated.
    Process
    Preparation of the suspensions of the microorganisms: The test strains are seeded in nutritive medium and incubated in the appropriate conditions for the growth of the strain. Stock cultures are prepared from the bank of strains and work cultures from the stock culture that are used for the test. From the
    15 work cultures are prepared test suspensions at high concentrations to inoculate the solid culture medium.
    Inoculation of the culture medium and addition of the test product: The liquefied solid culture medium is inoculated with the test microorganism and placed in plates of
    20 Petri. After the addition of the test product, the plates are incubated to favor the growth of the inoculated microorganism.
    Controls: In parallel with each test the following controls are carried out:
    25 -Negative control of the test conditions. -Product control; in the absence of the test strain and in the presence of the product, to verify the absence of microbial contamination of the product. - Growth control of the strain; in the presence of the strain and in the absence of the test product to verify the effective growth of the microorganism.
    - Positive control; in the presence of the strain and with a substance that has antimicrobial activity.
    Reading and internretation of results
    5 After the incubation period the plates are evaluated to determine the presence of inhibition halos around the point of application of the test product. The presence of a transparent zone around the point of application of the test product indicates inhibition of growth and therefore antimicrobial activity of the
    10 test product. The absence of a transparent area around the point of application of the test product indicates that there is no growth inhibition and therefore the product does not exhibit antimicrobial activity. A noticeable reduction in microbial growth is considered a positive result of growth inhibition.
    Culture media:
    -Ringer 1/4 salt solution-Tryptone Soy Agar (TSA)20 -S.bour.ud Dextrose Ag.r (SDA)
    Strains of microorganisms
    Microorganism Buffer solutionCulture mediumIncubation temperature
    Staphylococcus aureus ATCC6538 Ringer 1/4TSA37 ° C ± 1 oC
    Pseudo monas aeruginosa ATCC 9027 Ringer 1/4TSA37 ° C ± 1 oC
    Test 1: Product LV-AA attic drops
    S 10 Composition: Ethanol 96 oC / Glacial acetic acid The test is performed with each strain in sextuplicate. Petri dishes: 90 mm in diameter. Sterile cylinders (Oxford turrets): 6 mm internal diameter (di) and 8 mm external diameter (de) Concentration of the strain in the test suspension: Ixl 09 to Sx l 09 cfo / ml Concentration of inoculation of the test suspension in the culture medium: O, l%. Incubation time: 18-24 hours.
    fifteen Measurement: inhibition halos are measured with calibrated king's foot with an accuracy of 0.1 mm. Results Table 1: Inhibition of microbial growth (halos of inhibition, in mm)
    Staphy / ococcus aureus ATCC6538 Pseudo monas aeruginosa ATCC 9027
    Halo 1 13.010.3
    Halo 2 13.310.7
    Halo 3 12.811.2
    Halo 4 13.610.7
    Halo 5 14.210.9
    Halo 6 13.610.7
    Average (mm) 13.410.8
    SO (standard deviation) 0.50.3
    Inhibition TotalTotal
    Well diameter 8mm8mm
    At caseof Staphy / ococcus aureus ATCC6538 and Pseudo monas aeruginosa ATCC
    9027 bedetectinhibitiontotalof theincrease.Heproductfromtesttoa
    13
    IDO% concentration shows growth inhibition of the StaphyJococcus aureus A TCC6538 and Pseudomonas aeruginosa A TCC 9027 test microorganisms.
    Test 2: Product LV-AAW attic drops5
    Composition: Ethanol 96 o / Glacial acetic acid Purified water (33%)The test is performed with each strain in triplicate.Petri dishes: 90 mm in diameter.Sterile cylinders (Oxford turrets): 6 mm ID. and 8 mm d. and.
    10 Concentration of the strain in the test suspension: Ixl09 at 5xlO9 cfu / ml Inoculation concentration of the test suspension in the culture medium: 0.1% Incubation time: 18-24 hours. Measurement: inhibition halos are measured with calibrated king's foot with an accuracy of 0.1 mm.
    15 Results Table 2: Inhibition of microbial growth (halos of inhibition, in mm)
    Product tested StaphyJococcus aureus ATCC6538Pseudomonas aeruginosa ATCC 9027
    Halo I 12.914.4
    Halo 2 13.214.9
    Halo 3 13.914.3
    Average (mm) 13.314.5
    SD 0.50.3
    Inhibition TotalTotal
    Well diameter 8 mm8 mm
    In the case of StaphyJococcus aureus A TCC6538 and Pseudo monas aeruginosa ATCC 9027, total growth inhibition is detected. The test product at a concentration of 100% exhibits inhibition of the growth of the test microorganisms StaphyJococcus aureus A TCC6538 and Pseudomonas aeruginosa A TCC 9027.
    Test 3: Product Attic drops LV-AAWT Composition: Ethanol 96 oC / Glacial acetic acid Purified water (33%) / Sodium caproyl lactylate + Sodium lauroillactylate (2.2% between the two).
    5 The test is performed with each strain in triplicate. Petri dishes: 90 mm in diameter. Sterile cylinders (Oxford turrets): 6 mm ID. and 8 mm d. and. Concentration of the strain in the test suspension: 1 x 1 09 at 5x 109 cfu / ml Inoculation concentration of the test suspension in the culture medium: 0.1%
    10 Incubation time: 18-24 hours.
    Measurement: inhibition halos are measured with calibrated king's foot with an accuracy of 0.1 mm.
    15 Results Table 3: Inhibition of microbial growth (inhibition halos, in mm)
    Staphylococcus aureus ATCC6538 Pseudomonas aeruginosa ATCC 9027
    Halo I 19.213.4
    Halo 2 19.314.7
    Halo 3 19.115.7
    Average (mm) 19.214.6
    SD 0.11.2
    Inhibition TotalTotal
    Well diameter 8 mm8 mm
    In the case of StaphyJococcus aureus A TCC6538 and Pseudomonas aeruginosa A TCC 9027, total growth inhibition is detected. The test product at a concentration of 100% exhibits inhibition of the growth of the test microorganisms StaphyJococcus aureus A TCC6538 and Pseudomonas aeruginosa A TCC 9027.
    Product Staphylococcus aureus ATCC6538Pseudomonas aeruginosa ATCC 9027
    AA 13.410.8
    AAW 13.314.5
    AAWT 19.214.6
    The results show how the composition containing water, but without the presence of surfactant (composition AA W vs. composition AA) clearly enhances the
    5 antiseptic capacity of the composition AA, which contains only alcohol and acid, against Pseudomonas aeruginosa AlCe 9027. While the composition AAWl, (containing water and surfactant) unequivocally enhances the antiseptic and microbial activity against Staphylococcus aureus ATCC6538 and maintains the potency of the composition AA W versus Pseudomonas aeruginosa AleC 9027.
    权利要求:
    Claims (1)
    [1]
    1-Pharmaceutical composition, for topical use, characterized in that it is a hydroalcoholic solution with a concentration in water between 20% and 40% in
    5 weight with respect to the total weight of the composition, and with a concentration of a surfactant comprised between 0.5% and 4% by weight with respect to the total weight of the composition.
    2 - Composition according to claim 1, characterized in that the solution
    Hydroalcoholic comprises an aliphatic alcohol, linear or branched, with 2 to 5 carbon atoms or a mixture thereof, preferably ethyl alcohol, isopropyl alcohol, n-propyl alcohol and / or iso-butyl alcohol or a mixture thereof and more preferably ethyl alcohol and / or iso-propyl alcohol or a mixture thereof.
    Composition according to claim 2, characterized in that the concentration of said alcohol or mixture of alcohols is between 60% and 80%, preferably between 65% and 75% by weight with respect to the fine composition l.
    4 -Composition according to any of claims 1 to 3, characterized in that the
    The hydroalcoholic solution has a water content between 25% and 35% by weight with respect to the total weight of the composition.
    5. Composition according to any one of claims 1 to 4, characterized in that the surfactant is a hydroxy acid ester of the formula: Formula (1) R, COO-CH (R2) -COO-R, or Formula (2) R, -COO- [CH (R,) - COO] n -R
    30 in which:
    Rl is selected from H, Na or K;R2 represents H or a methyl or ethyl group;R3 represents an alkyl chain or a fatty acid alkenyl chain from 6 to 14carbon atoms; Y
    5 n represents an integer with a value between I or 2.
    6 - Composition according to claim 5 characterized in that the surfactants respond to the formula (2) and, preferably, the surfactants respond to the formula
    (2) where Rz is H or methyl.
    7. Composition according to one of claims 5 or 6, characterized in that it comprises a mixture of said surfactants.
    8 -Composition according to any of claims 5 to 7, characterized in that said surfactant is a surfactant of the group conjugated by sodium capriloyl lactylate, sodium caproyl-2-lactylate, sodium lauroyl-2-lactylate and mixtures of the foregoing.
    Composition according to any one of claims 5 to 8, characterized in that the concentration of said surfactant or mixture of surfactants is comprised between 20 1.0% to 3.0% by weight with respect to the total weight of the composition.
    Composition according to any one of claims 1 to 9, characterized in that the hydrocolic solution comprises an acidifying agent with between 2 and 5 carbon atoms, preferably with 2 or 3 carbon atoms and most preferably said
    Acidifying agent is acetic acid, propionic acid or a mixture of the foregoing.
    11. Composition according to claim 10, characterized in that the concentration of the acidifying agent is less than I% by weight, based on the total weight of the composition.
    12. Composition according to any of claims 1 to 11, characterized in that it has a pH between 4.0 and 5.5, preferably between 4.5 and 5.2.
    13-Pharmaceutical composition according to any of claims 1 to 12, 5 characterized in that it is for use in the prevention of otitis externa.
    14-Pharmaceutical composition according to any of claims 1 to 12, characterized in that it is for use in the treatment of otitis externa.
    Method for the preparation of a pharmaceutical composition according to any of claims 1 to 14, characterized in that it comprises the mixture of said alcohol, said surfactant and said water at a temperature between 20 ° C and 35 ° C and with stirring between 2,500 rpm and 3,500 rpm.
    Method according to claim 15, characterized in that the manufacturing process is carried out under a nitrogen atmosphere.
    17-Use of a pharmaceutical composition according to any of claims 1 to 14 for the preparation of a medicament for the prevention or treatment of otitis externa.
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    同族专利:
    公开号 | 公开日
    ES2674130B1|2019-04-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    ES2064288A1|1993-07-06|1995-01-16|Ornosa Enrique Viayna|Composition for the treatment of skin disorders, preparation thereof and use thereof|
    US20020160029A1|1995-06-22|2002-10-31|3M Innovative Properties Company|Stable hydroalcoholic compositions|
    WO2011063531A1|2009-11-27|2011-06-03|Nuvo Research Inc.|Topical ibuprofen formulations|
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    ES201631692A|ES2674130B1|2016-12-27|2016-12-27|Topical hydroalcoholic pharmaceutical composition for treatment of otitis externa and corresponding method and use|ES201631692A| ES2674130B1|2016-12-27|2016-12-27|Topical hydroalcoholic pharmaceutical composition for treatment of otitis externa and corresponding method and use|
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