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WO2010062034A2 - Composition pharmaceutique de type goutte ophtalmique ou gel contenant de l'extrait de graine de vitis vinifera - Google Patents

Composition pharmaceutique de type goutte ophtalmique ou gel contenant de l'extrait de graine de vitis vinifera Download PDF

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Publication number
WO2010062034A2
WO2010062034A2 PCT/KR2009/005750 KR2009005750W WO2010062034A2 WO 2010062034 A2 WO2010062034 A2 WO 2010062034A2 KR 2009005750 W KR2009005750 W KR 2009005750W WO 2010062034 A2 WO2010062034 A2 WO 2010062034A2
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Prior art keywords
extract
vitis vinifera
relative humidity
seed extract
acetone
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PCT/KR2009/005750
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English (en)
Korean (ko)
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WO2010062034A3 (fr
Inventor
박세완
이근혁
류종현
김재신
박진하
곽은영
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Hanlim Pharmaceutical Co Ltd
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Hanlim Pharmaceutical Co Ltd
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Publication of WO2010062034A2 publication Critical patent/WO2010062034A2/fr
Publication of WO2010062034A3 publication Critical patent/WO2010062034A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/87—Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to pharmaceutical compositions in the form of eye drops or gels containing a seed extract of the European species Vitis vinifera .
  • Vitis is a vine that belongs to Rhamnales and Vitaceae, and grows or grows all over the earth except near the equator and above 50 ° latitude. There are 700 genera of 11 genera, Vitis vinifera , Vitis labrusca , Vitis riparia , Vitis rupestris , Vitis rupestris , and Vitis berladieri , and Vitis. coignetiae ) and Vitis amurensis are mainly grown for fruit use.
  • extracts obtained from seeds of the European species Vitis vinifera include (-) epicatechin, proanthocyanidins B1 and B2, (+) catechins, and mixtures of polymerized derivatives thereof, which are procyano Known as stone or flavonol oligomers (GB-A-1541469 and FR-A-2092743).
  • the extract mainly acts on glycosaminoglycans such as connective tissue, blood vessels, lymph and joints selectively to promote synthesis and inhibit degradation of fibers related to the binding ability of collagen, elastin, fibronectin, etc. It has been reported to inhibit the capillary permeability and quickly restore the elasticity of veins. [Arteres et veines Vol. 5 (5), 397-401 (1986); Sem-dex Hopitaux 48/47, 2009-2013 (1981)]
  • grape seed extract has been reported to have a therapeutic effect on capillary vulnerability, hypertension-related retinopathy, and residual retinal edema after retinal detachment in diabetic patients [Gazette Mde France Vol. 88, No. 14, 2035-2038]. (1981), which protects the various structures of the retina, speeds up the regeneration of visual pigment, and has been reported to be effective in restoring the retina after exposure to scintillation in clinical trials [Bull. Soc. Opth. France Vol 88 (2), 173-4, 177-9 (1988).
  • oral tablets containing seed extracts of the European species Vitis vinifera are commercially available as adjuvants for disorders related to retina and choroid circulation.
  • the direct pharmacological effect can be expected when the seed extract of the European grape varieties ( Vitis vinifera ) is directly administered to the eye.
  • topical ophthalmic eye drops or gel-based external preparations have been reported. none. Particularly, since eye drops or gels are faster than tablets in solid form due to the characteristics of the formulation, securing stability, particularly long-term stability for about three years, is a very important factor in formulation design.
  • the present inventors have conducted various studies to develop an ophthalmic preparation comprising the seed extract of the European grape ( Vitis vinifera ) as an active ingredient, that is, a formulation having excellent physical and chemical stability as an eye drop or gel.
  • a formulation having excellent physical and chemical stability as an eye drop or gel.
  • the present invention provides pharmaceutical compositions in the form of eye drops or gels containing seed extracts of Vitis vinifera having excellent stability.
  • seed extract of the European species grape Vitis vinifera
  • an antioxidant selected from the group consisting of ascorbic acid or salts thereof, sodium bisulfite, potassium pyrosulfite, and L-threonine or salts thereof
  • a pharmaceutical composition in the form of eye drops or gels.
  • the content of the antioxidant may be 0.01 to 15% by weight based on the total weight of the composition
  • the content of the seed extract of the European species grape ( Vitis vinifera ) as an active ingredient may be 0.1 to 30% by weight relative to the total weight of the composition.
  • the seed extract of the grape varieties ( Vitis vinifera ) is a procyanidolic value (PCV) of 80 to 130; Content of (+) catechin and ( ⁇ ) epicatechin of up to 30%; And a proanthocididine content of 95 to 105%.
  • the seed extract of the grape varieties Vitis vinifera is (a) extract the seeds of the pulverized grape varieties ( Vitis vinifera ) at room temperature with a mixed solvent of acetone and water having a volume ratio of acetone and water of 1: 1 to 2, and filtered step; (b) distilling the filtrate obtained in step (a) to remove acetone, then saturating sodium chloride and filtering; (c) extracting the filtrate obtained in step (b) with ethyl acetate and concentrating; And (d) adding chloroform to the concentrate obtained in step (c) and filtering to obtain a precipitate.
  • the seed extract of the grape varieties Vitis vinifera may be (1) (i) a mixed solvent of acetone and water having a volume ratio of acetone and water of 3-5 to 1: 1 in the ground seed of the grape varieties Vitis vinifera .
  • Extracting with filtration and filtering (ii) concentrating the filtrate obtained in step (i) to remove acetone and filtering; (iii) extracting the filtrate obtained in step (ii) with ethyl acetate; (iv) drying the extract obtained in step (iii) to obtain a first extract; (2) (p) extracting the seeds of crushed Vitis vinifera with water and filtering; (q) extracting the filtrate obtained in step (p) with ethanol and filtering; (r) drying the filtrate obtained in step (q) to obtain a second extract; And (3) it can be obtained by a manufacturing method comprising the step of mixing the first extract and the second extract.
  • the pharmaceutical composition in the form of eye drops or gels according to the present invention comprises a seed extract of grape varieties Vitis vinifera as an active ingredient, ascorbic acid or salts thereof, sodium hydrogen sulfite, potassium pyrosulfite, and L-threonine or By including an antioxidant selected from the group consisting of salts thereof, physical and chemical stability can be maintained for a long time. Therefore, the pharmaceutical composition in the form of eye drops or gels according to the present invention can be usefully applied to the pharmaceutical field because it can be stored for a long time.
  • the present invention is a seed extract of European species grape ( Vitis vinifera ); And an antioxidant selected from the group consisting of ascorbic acid or a salt thereof, sodium bisulfite, potassium pyrosulfite, and L-threonine or a salt thereof.
  • compositions of the present invention enhance the physical and chemical stability of eye drops or gels obtained by the inclusion of certain antioxidants, namely ascorbic acid or salts thereof, sodium bisulfite, potassium pyrosulfite, and / or L-threonine or salts thereof. Let's do it.
  • the amount of the antioxidant is different depending on the type of antioxidant used, but may be 0.01 to 15% by weight, preferably 0.0125 to 1% by weight based on the total weight of the composition.
  • ascorbic acid or a salt thereof about 0.1% by weight of ascorbic acid or a salt thereof, about 0.3% by weight of sodium hydrogen sulfite, 0.0125 to 0.025% by weight of potassium pyrosulfite, 0.3% by weight of L-threonine or a salt thereof It may contain.
  • the content of the seed extract of the grape varieties Vitis vinifera contained as an active ingredient may be in a range sufficient to provide a therapeutically effective amount.
  • the content of the seed extract of the grape varieties Vitis vinifera may range from 0.1 to 30% by weight, preferably from 0.5 to 5.0% by weight and more preferably from about 1.0% by weight relative to the total weight of the composition. .
  • Seed extracts of the European grape varieties include a procyanidolic value (PCV) of 80-130; Content of (+) catechin and ( ⁇ ) epicatechin of up to 30%; And those having a proanthocididine content of 95 to 105% are particularly preferably used.
  • PCV procyanidolic value
  • PCV procyanidolic value
  • 100 mg of the sample is precisely weighed and operated in the same manner as the standard solution to prepare a sample solution.
  • test tubes 10 ml of the sample solution and 10 ml of standard solution are placed in 5 test tubes, and capped, and then heated in a 100 ° C. water bath for 45 minutes. After heating, the test tubes were cooled in cold water, 2 ml of each test tube was taken, and 20 ml of isopropanol was added thereto. Take the reacted test solution and the standard solution, and measure the absorbance at 550 nm using isopropanol as a reference solution.
  • the content of the (+) catechin and (-) epicatechin means a value quantified as follows.
  • sample solution 50 mg of the sample is precisely weighed, dissolved in an acetonitrile and dilute phosphoric acid mixed solution (5:95), and 10 ml is used as the sample solution.
  • proanthocididine content means a value calculated by the following method and formula.
  • BHT 2,6-di-tert-butyl-4-methylphenol
  • -Standard solution 2 Accurately weigh 10 mg of proanthocyanidin standard into a 10 ml volumetric flask and dissolve in 5 ml of internal standard solution.
  • Detector ultraviolet absorbance photometer (wavelength: 280 nm)
  • Lithium bromide aqueous solution 1.04 g of lithium bromide is precisely taken and placed in a 1000 ml volumetric flask.
  • Standard solutions 1, 2, 3 and sample solutions 1, 2 are analyzed twice with the following liquid chromatography method.
  • the calibration curve of the standard solution is prepared using the concentration of the standard solution and the corresponding main peak to IS peak area ratio (A proanthocyanidin / A BHT ) and calculated according to the following formula.
  • Ti% ⁇ [(A proanthocyanidin / A BHT ) test -a] / b ⁇ x (1 / C test ) x 100
  • a proanthocyanidin peak area of proanthocyanidins in the sample solution
  • a BHT peak area of BHT in the sample solution
  • Proanthocyanidin content Ti% x [(100-KF std ) / (100-KF test )]
  • the seed extract of the grape varieties Vitis vinifera may be preferably used by the improved manufacturing method developed by the present inventors (ie, WO2009 / 031826).
  • the seed extract of the grape varieties ( Vitis vinifera ) is (a) the seeds of the pulverized grape varieties ( Vitis vinifera ) are extracted at room temperature with a mixed solvent of acetone and water having a volume ratio of acetone and water of 1: 1 to 2, Filtration; (b) distilling the filtrate obtained in step (a) to remove acetone, then saturating sodium chloride and filtering; (c) extracting the filtrate obtained in step (b) with ethyl acetate and concentrating; And (d) adding chloroform to the concentrate obtained in step (c) and filtering to obtain a precipitate.
  • Seeds of crushed European grapes are washed with skin, seeds and branches obtained by pressing European grapes ( Vitis vinifera ) in water, dried using an oven, etc., and then the seeds are separated, and the conventional method is used. It can be obtained by grinding.
  • the manufacturing method is compared to the conventional extraction method (for example, GB-A-1541469)
  • a water-acetone mixed solvent having a low acetone content is used as the primary extraction solvent, and the primary extraction process is performed at room temperature (about 25 ° C.) without additional heating.
  • a water-acetone mixed solvent used in the preparation method a mixed solvent having a volume ratio of acetone and water of 1: 1 to 2, preferably about 1: 1.5 may be used.
  • the first extraction may be performed once or repeatedly, more preferably 2 to 3 times.
  • the filtration of step (a) may be carried out in a conventional manner, and the filtrate is recovered for carrying out the next step.
  • step (b) In the step of distilling the filtrate obtained in step (a) to remove acetone, and then saturating sodium chloride and filtering [step (b)], the acetone having a relatively low boiling point is removed by the distillation and is dissolved in acetone.
  • the impurities are precipitated.
  • the distillation may be performed according to a conventional distillation method, for example, may be carried out by distillation under reduced pressure. Preferably it is carried out under reduced pressure conditions of about 50 °C or less.
  • the extract obtained through the distillation process is subjected to saturation of sodium chloride and filtration immediately, without a separate organic solvent extraction process.
  • the extract that is, the extract obtained by distilling acetone
  • impurities such as a tannin component are precipitated, which is removed through a filtration process.
  • the impurity precipitation by saturation of sodium chloride and filtration is preferably filtered after saturating sodium chloride and then leaving it for 2 to 3 hours.
  • the filtration can be carried out in a conventional manner, and the filtrate is recovered for carrying out the next step.
  • step (c) the extraction with ethyl acetate (secondary extraction) may be performed once or repeatedly, preferably Preference is given to repeating 2-3 times.
  • concentration is preferably carried out to be concentrated to 0.4 to 0.7 times the total volume of the extract (ie filtrate) obtained in step (b).
  • step [c] of adding the chloroform to the concentrate obtained in step (c), and filtering to obtain a precipitate when the chloroform is added, active ingredients including oligomers which are not dissolved in chloroform are precipitated and formed.
  • the precipitates can be isolated by simply filtering the seed extract of Vitis vinifera .
  • the precipitate obtained by filtration can be obtained in the form of a dry powder by drying according to a conventional method, and the drying can be carried out by drying under reduced pressure, for example, a reduced pressure of 50 °C or less.
  • the seed extract of the grape varieties Vitis vinifera contained as an active ingredient in the pharmaceutical composition of the present invention (1) (i) the seed of the ground grape varieties ( Vitis vinifera ) is a volume ratio of acetone and water of 3 ⁇ 5: extraction with a mixed solvent of acetone and water of 1 and filtration; (ii) concentrating the filtrate obtained in step (i) to remove acetone and filtering; (iii) extracting the filtrate obtained in step (ii) with ethyl acetate; (iv) drying the extract obtained in step (iii) to obtain a first extract; (2) (p) extracting the seeds of crushed Vitis vinifera with water and filtering; (q) extracting the filtrate obtained in step (p) with ethanol and filtering; (r) drying the filtrate obtained in step (q) to obtain a second extract; And (3) it can be obtained by the method of producing a seed extract of the European species grape ( Vitis vinifera ) comprising the step of mixing the first extract and
  • the preparation method is performed by separately preparing the first extract and the second extract, and mixing them to obtain an extract. Therefore, the manufacturing method not only reduces the amount of acetone used as a whole, but also lacks a sodium chloride saturation process and a chloroform extraction process, thereby simplifying extraction and minimizing the problem of environmental pollution due to the use of an organic solvent. In addition, the yield of the resulting extract can be greatly increased by about 10 times.
  • step (i) extracts the seeds of pulverized European grapes ( Vitis vinifera ) with a mixed solvent of acetone and water having a volume ratio of acetone and water of 3-5 to 1, more preferably 4: 1, , By filtration.
  • the first extraction may be performed once or repeatedly, more preferably 2 to 3 times.
  • the filtration of step (i) can be carried out in a conventional manner, and the filtrate is recovered for the performance of the next step.
  • step (ii) is carried out by concentrating the filtrate obtained in step (i) to remove acetone and filtering.
  • the acetone having a relatively low boiling point is removed by the concentration, and impurities dissolved in acetone are precipitated.
  • the concentration may be carried out by conventional vacuum concentration (or distillation under reduced pressure), for example, may be carried out by distillation under reduced pressure conditions. After concentration, the precipitate is removed by filtration and the filtrate is recovered.
  • step (iii) is carried out by extracting the filtrate obtained in step (ii) with ethyl acetate. Extraction using the ethyl acetate (secondary extraction) may be performed once or repeatedly, preferably 2 to 3 times.
  • step (iii) may further include a dehydration process using anhydrous sodium sulfate after performing the extraction process using the ethyl acetate.
  • step (iv) is carried out by drying the extract obtained in step (iii).
  • the drying may be carried out by conventional methods, for example drying under reduced pressure of up to 50 ° C.
  • the extract obtained in step (iii) may be concentrated to remove ethyl acetate, and the resulting concentrate is dissolved in water and then spray dried.
  • step (p) can be carried out by extracting the seeds of pulverized European grape ( Vitis vinifera ) with water and filtering;
  • step (q) can be carried out by extracting the filtrate obtained in step (p) with ethanol and filtering.
  • the extraction of step (q) may be performed once or repeatedly, preferably two to three times.
  • step (r) may be carried out by drying the filtrate obtained in step (q).
  • the drying of step (r) is carried out by spray drying the filtrate obtained in step (q); It is preferably carried out by concentrating the filtrate obtained in step (q) and then spray drying the obtained concentrate.
  • the concentration may be concentrated to 0.4 to 0.7 times the total volume of the filtrate obtained in step (q), but is not limited thereto.
  • Mixing of the first extract and the second extract obtained as described above may be carried out by simply mixing the extract, the mixing ratio of the first extract and the second extract may be a weight ratio of 1: 0.5 to 1.5.
  • the pharmaceutical composition of the present invention may contain additives commonly used in the pharmaceutical field for the preparation of eye drops or gels, such as stabilizers, thickeners, buffers, isotonic agents, preservatives, pH adjusting agents and the like.
  • the stabilizer comprises D-sorbitol, glycerin, sodium edetate and the like;
  • the thickener includes sodium carboxymethyl cellulose;
  • the buffer includes phosphoric acid or a salt thereof, boric acid, borax, citric acid or a salt thereof, and the like;
  • the tonicity agent includes sodium chloride and the like;
  • the preservative includes benzalkonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol and the like;
  • the pH adjusting agent (pH 5-8) includes hydrochloric acid, sodium hydroxide and the like.
  • the amount of the additive may be in the range conventionally used in the pharmaceutical field, for example, 0.01-15 wt% of the buffer and 0.01-50 wt% of the stabilizer (specifically, 0.01 g of the concentrated glycerin) based on the total weight of the composition. ⁇ 15.0%, D-sorbitol solution (70%) is 0.01 to 50% by weight), the thickener may be in the range of 0.01 to 30.0% by weight, the content of the additive may be appropriately selected according to the purpose of use.
  • the filtrate obtained was extracted three times with 250 ml of ethyl acetate and then dehydrated with anhydrous sodium sulfate.
  • the resulting extract was concentrated under reduced pressure until the volume was reduced to about 125 ml.
  • About 600 ml of chloroform was added to the obtained concentrate, and a precipitate was produced and filtered.
  • the precipitate obtained by filtration was dried in a vacuum oven at 50 ° C. or lower to obtain about 3.5 g of the seed extract of Vitis vinifera as a brown powder.
  • the obtained extract was hydrolyzed by heating in a dilute acid solution, and then the procyanidolic value (PCV) was measured by quantifying the content of procyanidolic oligomer, and showed a high value of about 105.
  • the proanthocyanidin content was measured as described above and found to be 103%. Therefore, the extract contains a large amount of oligomers in which two or more monomers of (+) catechin and (-) epicatechin are polymerized.
  • the first extract and the second extract were mixed to obtain about 35 g of the seed extract of the grape varieties Vitis vinifera .
  • the obtained extract was hydrolyzed by heating in a dilute acid solution, and then the procyanidolic value (PCV) was measured by quantifying the content of procyanidolic oligomer, showing a high value of about 98.
  • the proanthocyanidin content was measured as described above and found to be 98.5%. Therefore, the extract contains a large amount of oligomers in which two or more monomers of (+) catechin and (-) epicatechin are polymerized.
  • Example 4 pH change Storage condition Early 3 months 6 months 9 months 12 months
  • Example 1 25 ⁇ 2 °C / Relative Humidity 60 ⁇ 5% 6.0 6.0 6.0 6.0 40 ⁇ 2 °C / relative humidity 75 ⁇ 5% 6.0 6.0 5.9 - -
  • Example 2 25 ⁇ 2 °C / Relative Humidity 60 ⁇ 5% 6.0 6.0 6.0 6.0 40 ⁇ 2 °C / relative humidity 75 ⁇ 5% 6.0 6.0 5.8 - -
  • Example 3 25 ⁇ 2 °C / Relative Humidity 60 ⁇ 5% 6.0 6.0 6.0 6.0 40 ⁇ 2 °C / relative humidity 75 ⁇ 5% 6.0 6.0 5.9 - -
  • Example 4 25 ⁇ 2 °C / Relative Humidity 60 ⁇ 5% 6.0 6.0 6.0 6.0 40 ⁇ 2 °C / relative humidity 75 ⁇ 5% 6.0 5.9 - - Comparative Example 1 25 ⁇ 2
  • the composition containing an antioxidant such as ascorbic acid, sodium hydrogen sulfite according to the present invention does not have a significant color change at room temperature and accelerated conditions as well as no precipitate was produced. And there is no pH change. Therefore, it can be seen that the eye drop solution and the gel composition of the present invention have excellent physical stability.
  • procyanidolic oligomer which is an indicator
  • the quantification was performed by calculating the amount (mg) of potential cyanidol chloride in 1 mL of eye drop solution (eye drop gel 1 g), and the amount (mg) of potential cyanidol chloride in 1 ml (or 1 g) of sample was calculated as follows. The results are shown in Table 5.
  • Example 1 25 ⁇ 2 °C / Relative Humidity 60 ⁇ 5% 0.86 0.86 0.85 40 ⁇ 2 °C / relative humidity 75 ⁇ 5% 0.86 0.83 -
  • Example 2 25 ⁇ 2 °C / Relative Humidity 60 ⁇ 5% 0.86 0.86 0.85 40 ⁇ 2 °C / relative humidity 75 ⁇ 5% 0.86 0.84 -
  • Example 3 25 ⁇ 2 °C / Relative Humidity 60 ⁇ 5% 0.86 0.86 0.86 40 ⁇ 2 °C / relative humidity 75 ⁇ 5% 0.86 0.85 -
  • Example 4 25 ⁇ 2 °C / Relative Humidity 60 ⁇ 5% 0.86 0.86 0.83 40 ⁇ 2 °C / relative humidity 75 ⁇ 5% 0.86 0.82 - Comparative Example 1 25 ⁇ 2 °C /
  • the composition containing the antioxidant according to the present invention is chemically stable at room temperature and accelerated conditions without significant change of the indicator material, especially a composition containing ascorbic acid (Example 3 and 7) showed the best chemical stability. Therefore, it can be seen that the eye drop solution and the gel composition of the present invention have excellent chemical stability.

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Abstract

La présente invention concerne une composition pharmaceutique de type goutte ophtalmique ou gel contenant de l'extrait de graine de vitis vinifera; et un antioxydant sélectionné dans le groupe comprenant acide ascorbique ou un sel de celui-ci, hydrogènosulfite de sodium, pyrosulfite de potassium, et L-thréonine ou un sel de celle-ci. La composition pharmaceutique selon la présente invention maintient une stabilité physique et chimique pendant une longue durée. La composition pharmaceutique de l'invention peut ainsi être stockée pendant une longue durée et être utilisée de manière avantageuse dans le domaine de la fabrication de médicaments.
PCT/KR2009/005750 2008-11-28 2009-10-08 Composition pharmaceutique de type goutte ophtalmique ou gel contenant de l'extrait de graine de vitis vinifera Ceased WO2010062034A2 (fr)

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KR1020080119366A KR101047356B1 (ko) 2008-11-28 2008-11-28 유럽종 포도의 씨 추출물을 함유하는 점안용 액제 또는 겔제 형태의 약학 조성물
KR10-2008-0119366 2008-11-28

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IT1255029B (it) * 1992-05-11 1995-10-13 Paolo Morazzoni Formulazioni farmaceutiche orali contenenti antocianosidi
US20030086986A1 (en) * 1998-08-06 2003-05-08 Bruijn Chris De Ophthalmic, pharmaceutical and other healthcare preparations with naturally occurring plant compounds, extracts and derivatives
TW200812575A (en) * 2006-04-28 2008-03-16 Alcon Inc Formulations containing amide derivatives of carboxylic acid NSAIDs for topical administration to the eye
EP2023945B1 (fr) * 2006-06-08 2019-08-07 IAMS Europe B.V. Compositions pour améliorer la santé oculaire

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