MXPA97001946A - Transfer oftalmica solution - Google Patents
Transfer oftalmica solutionInfo
- Publication number
- MXPA97001946A MXPA97001946A MXPA/A/1997/001946A MX9701946A MXPA97001946A MX PA97001946 A MXPA97001946 A MX PA97001946A MX 9701946 A MX9701946 A MX 9701946A MX PA97001946 A MXPA97001946 A MX PA97001946A
- Authority
- MX
- Mexico
- Prior art keywords
- time
- temperature
- stirring
- conductivity
- agitation
- Prior art date
Links
- 239000000203 mixture Substances 0.000 claims abstract description 31
- 229960001193 Diclofenac Sodium Drugs 0.000 claims abstract description 24
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 claims abstract description 24
- 239000004480 active ingredient Substances 0.000 claims abstract description 22
- 230000000699 topical Effects 0.000 claims abstract description 11
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims abstract description 4
- 229960000707 Tobramycin Drugs 0.000 claims abstract description 4
- NLVFBUXFDBBNBW-PBSUHMDJSA-N Tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 claims abstract description 4
- 230000003115 biocidal Effects 0.000 claims abstract description 4
- 229960002518 gentamicin Drugs 0.000 claims abstract description 4
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 claims abstract description 3
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract description 3
- 239000004094 surface-active agent Substances 0.000 claims abstract description 3
- 229960004605 timolol Drugs 0.000 claims abstract description 3
- 239000003795 chemical substances by application Substances 0.000 claims abstract 3
- 230000000111 anti-oxidant Effects 0.000 claims abstract 2
- 239000003995 emulsifying agent Substances 0.000 claims abstract 2
- 238000003756 stirring Methods 0.000 claims description 56
- 239000012153 distilled water Substances 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 claims description 11
- 229910001220 stainless steel Inorganic materials 0.000 claims description 9
- 239000010935 stainless steel Substances 0.000 claims description 9
- KGBXLFKZBHKPEV-UHFFFAOYSA-N Boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 8
- 229940075582 Sorbic Acid Drugs 0.000 claims description 8
- 239000004327 boric acid Substances 0.000 claims description 8
- 235000010338 boric acid Nutrition 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 claims description 8
- 235000010199 sorbic acid Nutrition 0.000 claims description 8
- 239000004334 sorbic acid Substances 0.000 claims description 8
- 229920002675 Polyoxyl Polymers 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 7
- 229940001607 sodium bisulfite Drugs 0.000 claims description 7
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 7
- 239000004615 ingredient Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 claims description 4
- -1 antibactericides Substances 0.000 claims description 4
- ZGTMUACCHSMWAC-UHFFFAOYSA-L disodium;2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 3
- 229940064005 Antibiotic throat preparations Drugs 0.000 claims description 2
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 claims description 2
- 229940042052 Antibiotics for systemic use Drugs 0.000 claims description 2
- 229940042786 Antitubercular Antibiotics Drugs 0.000 claims description 2
- 229940093922 Gynecological Antibiotics Drugs 0.000 claims description 2
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 229940079866 intestinal antibiotics Drugs 0.000 claims description 2
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 claims description 2
- 229960002645 boric acid Drugs 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 229960002668 sodium chloride Drugs 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 239000000969 carrier Substances 0.000 abstract description 9
- 230000000844 anti-bacterial Effects 0.000 abstract 1
- 239000003899 bactericide agent Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 34
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 5
- 229940099429 Polyoxyl 40 Stearate Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drugs Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 3
- 229910000619 316 stainless steel Inorganic materials 0.000 description 2
- 210000001138 Tears Anatomy 0.000 description 2
- 210000003484 anatomy Anatomy 0.000 description 2
- 230000003110 anti-inflammatory Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SJSYJHLLBBSLIH-SDNWHVSQSA-N (E)-3-(2-methoxyphenyl)-2-phenylprop-2-enoic acid Chemical compound COC1=CC=CC=C1\C=C(\C(O)=O)C1=CC=CC=C1 SJSYJHLLBBSLIH-SDNWHVSQSA-N 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L 7681-57-4 Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- 210000000795 Conjunctiva Anatomy 0.000 description 1
- 210000004087 Cornea Anatomy 0.000 description 1
- 210000003792 Cranial Nerves Anatomy 0.000 description 1
- 206010013082 Discomfort Diseases 0.000 description 1
- 229940012356 Eye Drops Drugs 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N Phenylacetic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 230000003078 antioxidant Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 230000030214 innervation Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 230000001052 transient Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
Abstract
The present invention relates to a composition of matter of the type that is used in the treatment of ophthalmic conditions and particularly refers to an ophthalmic carrier solution based on surfactants, emulsifiers, bactericides, antioxidants, etc., which form a carrier that wraps or masks an active ingredient such as diclofenac sodium or other antibiotic agents such as tobramycin, gentamicin or timolol sulfate, in order to avoid discomfort caused by the topical application of the mentioned active ingredients, such as pain, burning , irritation and other discomfort for the user
Description
TRANSFORMER OFTALMIC SOLUTION
TECHNICAL FIELD OF THE INVENTION The present invention belongs to the field of the compositions of matter used for ophthalmic treatments, particularly it is an aqueous solution with characteristics similar to the human precorneal tear film, which prevents a user from feeling the pain or burning due to the application of an ophthalmic medicament in topical form, and which also increases the ocular penetration of the ophthalmic composition and its bioavailability. BACKGROUND OF THE INVENTION There are in the international ophthalmological pharmaceutical market, medicines that when applied topically cause burning and irritation to the organ of vision. Based on this situation, it was thought to use some type of compound with anti-inflammatory characteristics that could be used in the form of eye drops to treat discomfort in the eyes. It was found that a compound derived from phenyl acetic acid, called diclofenac sodium, that is, sodium acetate of o- (2,6-dichlorophenyl) -amino-phenyl, whose method of preparation was
described in U.S. Pat. 3,558,690 from Geigy, covered the expectations for an adequate ophthalmic application. However, the main disadvantage of this composite is the intense burning and irritation it produces in the user's eyes, which makes it unsuitable for use. Despite the above disadvantage, taking into account the anti-inflammatory properties of diclofenac sodium, it was thought to prepare a suitable transporter that would allow the application of said compound but without presenting the associated discomforts of burning and irritation and with that in mind, arrived at the final formulation of the transporter or ophthalmic transporter solution that is the subject of the present invention. Therefore, it is an object of the present invention to provide an ophthalmic transporter solution suitable for the topical application of ophthalmic compounds of various types, among them diclofenac sodium or antibiotics such as tobramycin, gentamicin and timolol sulfate. Another object of the present invention is to provide the human eye with a compound based on Diclofenac sodium, which normally causes pain, burning, discomfort, transient irritation and lacrimation as undesirable effects of its topical application, but without the inherent discomfort of pain, burning and irritation.
Another additional objective of the present invention is to prepare a formulation containing the active ingredient but which is effective to avoid the undesirable effects mentioned.
DESCRIPTION OF THE DRAWINGS Figure 1 is a diagram of the reaction that takes place between the components of the formula of the present invention and the active principle. Figure 2 is an illustration of a polyoxyte stearate micelle
40 interlacing the active principle (diclofenac sodium) of the present invention. DETAILED DESCRIPTION OF THE INVENTION Considering the anatomy and histology of the ocular globe of the conjunctiva and of the cornea and of its abundant innervation by 6 of the 12 cranial nerves, it was thought to try to avoid and / or decrease the threshold of the
painful and burning stimuli mainly due to the presence of solutions containing drugs and / or active ingredients for ocular topical application. Based on the above, ophthalmologists were consulted with the objective of seeing the structure of the eyeball in terms of its anatomy, physiology and biochemistry in order to understand the interaction of what was developed
demonstrating the balance that is achieved with the interaction, transport, penetration and action of the drug without the classic and present side effects of this in other drugs of the above is based on which desired results have been achieved in the objective since the clinical tests performed they show that they do not have the classic undesirable effects. With the desired objectives in mind, we proceeded to carry out a literature review of ingredients, excipients, support molecules that contain an active ingredient (in this case diclofenac sodium). It was found that in particular all the compounds are in aqueous base and some in oil phase. For our case, the following was considered based on this literature review and experience: Starting from a surfactant molecule that has a molecular weight that varies between 1900 and 2100 and that has the characteristic of having two molecular fractions: a non-polar fraction and a polar b fraction. The first fraction with a molecular weight between 200 and 250 and the polarized fraction b with a molecular weight between 1750 to 1850, the previous is based on the need to have a molecule of these characteristics to maintain its polarized structure, highly excited , also considering that it should be maintained at a pH close to neutrality or neutral (6.8 - 7.2).
The molecule that combines these characteristics is polyoxyl 40 stearate whose formula and stoichiometric position allows the active ingredient, in this case diclofenac sodium, to be isolated and wrapped in the polarized portion of this molecule, serving as a carrier bearing ("carrier" ) inert, in such a way that at the moment of its application, the active ingredient is not reacting or "contaminated" with other radicals. The ratio of the molecular weight of the active ingredient (diclofenac sodium) to the molecular weight of the polarized fraction should be 5.68 times the fraction polarized with respect to the molecular weight of the active ingredient (diclofenac sodium). In order to achieve the above, a number of combinations of other components were carried out, and a composition and sequelae of preparation were found for different tests, which allowed the values of polarization, conductivity, pH, (REDOX potential) and isotonicity they resulted in a complex that is not described in the literature and that demonstrates that their balance was achieved as to consider this as a complex transporter of the active ingredient for topical ophthalmic formulations exclusively. In figure 2, it can be seen how the polar part (2) of the polyoxyl stearate 40, corresponding to the polyoxyethylene chain (CH2OCH2) 40, intertwines the molecules of the active ingredient (3) (diclofenac sodium). While
that in figure 1, the scheme of the reaction that takes place between
the components of the ophthalmic transporter composition and the active principle.
The composition of the ophthalmic carrier solution of the present
invention is made up of the following ingredients
INGREDIENT AMOUNT% IN WEIGHT Polyoxyl 40 stearate 7.0 g 10.20 Disodium edetate dihydrate 0.1 g 0.15 Sodium Chloride 0.7 g 1.03 Boric Acid 0.095 g 0.14 Sorbic Acid 0.22 g 0.32 Sodium Bisulfite 0.040 g 0.06 Distilled Water c.b. 100 ml 88.00
The typical composition using the composition of the solution
ophthalmic transporter of the previous formulation, also containing the
active ingredient, in this case diclofenac sodium, is as follows:
OPHTHALMIC COMPOSITION
Diclofenac sodium 0.1 g Polyoxyl stearate 40 7.0 o Disodium edetate dihydrate 0.1 g Sodium Chloride 0.7 g Boric Acid 0.095 g Sorbic Acid 0.22 g Sodium Bisulfite 0.40 g Distilled Water c.b. 100 ml
As described above, polyoxyl stearate 40 has a formula and a stoichiometric position that allows the active ingredient to be isolated and enveloped in the polarized portion of this molecule, serving as an inert carrier, thereby that at the time of its application, the active ingredient is not reacting or "contaminated" with other radicals. Edetate disodium dihydrate as a classic sequestrant is added to capture free ions that at any given time could interfere with the polarizing effect of stearate. NaCl is added to increase the isotonicity but mainly the conductivity of the solution, obtaining values described in table I. Boric acid is a pH-regulating substance that is added in order to keep the pH value close to neutrality , given the characteristics of the human precorneal tear film having a pH of 7.0 to 7.4 Sorbic acid is a preservative used in the preparation of ophthalmic solutions in order to protect said solutions from any contamination by microorganisms. It is characterized for being a non-irritating substance to the eyeball and having a broad spectrum.
Sodium hydroxide is used here to adjust pH to neutrality by protecting the oxide reduction potential of the already formed complex allowing the polarization of the stearate to be ready for when it is added to the active principle. Sodium metabisulfite has the distinction of being highly antioxidant, allowing that all the dissolved oxygen does not interact with the active principle and the polarization of the polyoxyl 40 stearate is not altered. Before adding the solution of the active principle, to the whole complex of the previously formed carrier composition which allows the orientation of the polar groups of polyoxyl 40 stearate, ready to "entangle" diclofenac sodium, should have a pH of 6.98 and a conductivity of 16.97. The volume of the solution of the active ingredient (0.3% solution) should be 30% with respect to the volume of the stearate complex, constantly obtaining a 30% reduction in conductivity (dilution factor) and a final pH of 6.84. EQUIPMENT USED IN THE PROCESS To carry out the preparation of the composition of the present invention, the following equipment is used: - Type 316 stainless steel tank, sanitary finish.
- Sanitary type agitator with stainless steel propellers type 316, propeller type.
- Type 316 stainless steel tank, sanitary finish with internal coil for heating distilled water. MANUFACTURING PROCESS As an example of preparation of the composition object of the present invention, the following sequence of steps and operating conditions is established: 1.- Heat 60% of the distilled water of the total volume of the preparation at a temperature of approximately 69 to 71 ° C, taking care to adjust the pH to 6.25 (with a limit of ± 0.25) and to maintain a conductivity not higher than 0.002 mS / cm. 2.- Empty the amount of distilled water described above in the stainless steel tank. 3.- Place the agitator with its stainless steel blade in the preparation tank. 4.- Turn on the agitator and select it at 800 rpm, (± 50 rpm). 5.- Add the polyoxyl stearate 40 slowly, maintaining the agitation of 800 rpm (with a limit of ± 50 rpm), for a time between 27 and 33 minutes; the pH at the end of the stirring time
it should be approximately 6.0 to 6.2 and the conductivity after the stirring time should be 0.12 mS / cm (with a limit of ± 0.05 mS / cm); likewise, the temperature after the stirring time should be between 63 and 67 ° C. 6.- Add the disodium edetate 2 H20 slowly, maintaining the agitation for a time comprised between 13 and 17 minutes, at 750-850 rpm; the pH at the end of the agitation time should be within the range of 5.54 to 5.58 and the conductivity after the agitation time should be between 0.679 to 0.681 mS / cm; the temperature after the stirring time should be between 59 and 61 ° C. 7.- Add the sodium chloride slowly, maintaining the agitation between the range of 750 to 850 rpm for an approximate time of 13 to 17 minutes; the pH at the end of the agitation time should be between 5.20 to 5.22. The conductivity after the stirring time should be between 15.32 mS / cm and 17.32 mS / cm; and the temperature after the stirring time should be 55 to 57 ° C. 8.- Add the boric acid slowly, maintaining the agitation between 750 and 850 for approximately 13 to 17 minutes. The pH at the end of the agitation time should be between 5.20 and 5.24; the conductivity
after the stirring time it should be between approximately 1.64 and 13.64 mS / cm; The temperature after the stirring time should be about 55-57 ° C. Wait until the temperature of the preparation drops to approximately 49-51 ° C. - Add the sorbic acid slowly, keeping the agitation between
750 and 850 rpm for a time of approximately 13 to 17 minutes.
The pH at the end of the agitation time should be between 3.84 to 3.88; and the conductivity after the stirring time should be in the range of 15.82 mS / cm to 15.92 mS / cm, likewise, the temperature after the stirring time should be about 46 to 48 ° C. - Adjust the pH with sodium hydroxide as soon as possible to a value of
7. 15 ± 0.1, maintaining the agitation at 750-850 rpm for a time omprendido between 9 and 1 1 minutes; The conductivity after the stirring time should be within the range of 16.06 to 18.06 mS / cm. The temperature after the stir time should be between 44.5 and
45. 5 ° C. - Wait until the temperature of the preparation drops to approximately
29 ° C-31 ° C.
13. - Add the sodium bisulfite slowly, keeping stirring
750 to 850 rpm for 13 to 17 minutes. The pH at the end of the stirring time should be 7.0 ± 0.1. The conductivity after the stirring time will be 16.97 mS / cm (with a limit of + 1.0 mS / cm); and the temperature after the stirring time should be about 25 to 29 °. PREPARATION OF THE ACTIVE INGREDIENT SOLUTION 14.-Transfer to a stainless steel container, 30% of distilled water of the total volume of the preparation at a temperature of approximately 21 to 25 ° C, place the agitator and select a speed of approximately 580 to 620 rpm; add diclofenac sodium slowly, maintaining the agitation for approximately 13 to 17 minutes; the pH at the end of the agitation time should be 7.25 ± 0.1. The conductivity after the stirring time should be 0.734 mS / cm (± 0.1 mS / cm). The temperature after the stirring time should be between approximately 21 to 25 ° C. 15. Transfer the preparation of Diclofenac sodium obtained in the previous step, to the tank containing the rest of the ingredients, maintaining an agitation of 800 ± 50 rpm for approximately 13 to 17 minutes.
16. - Emphasize the total volume with distilled water at a temperature of 21 to
° C and having a pH of about 6.00 to 6.50 The conductivity of this distilled water should be no greater than 0.002 mS / cm. 17.- Stir the resulting solution for a time of 2 hours ± 5 minutes.
18. - Adjust the pH at the end of the stirring time to a value between 6.83 and 6.85. The conductivity after the stirring time should be 11.77 mS / cm ± 0.5 mS / cm and the temperature after the stirring time should be approximately 21-25 ° C TABLE I
EXAMPLES OF REALIZATION
Example 1. Preparation of the ophthalmic transporter composition. As an industrial example of the present invention, the following procedure was carried out by which 200 lts of an ophthalmic transporter composition according to the present invention were prepared: 120 liters of distilled water were heated to a temperature of 70 ° C, the pH was adjusted to 6.25, maintaining a conductivity not higher than 0.002 mS / cm; the hot distilled water was then emptied into a stainless steel tank and stirred at a speed of approximately 800 rpm; while stirring was maintained, 14.0 kg of polyoxyl 40 stearate was added, slowly and stirring was continued for about 30 minutes, after which the solution had a pH of 6.1, a conductivity of 0.12 mS / cm at a temperature 65 ° C; then 0.2 kg of sodium edetate was added maintaining stirring for about 15 minutes at 800 rpm; at the end of this stage it was observed that the pH of the solution was 5.56 and the conductivity was 0.68 mS / cm at a temperature of 60 ° C; then, it
they added 1.4 kg of sodium chloride slowly, maintaining the stirring at 800 rpm for 15 minutes, after which it was observed that the pH of the solution was 5.21, the conductivity was 16.32 at a solution temperature of 56. ° C. Then, 0.19 kg of boric acid was slowly added, maintaining the stirring at 800 rpm for 15 minutes, after which the solution had a pH of 5.22, a conductivity of 12.64, while the temperature of the solution was 54 ° C; then, the solution was allowed to cool to a temperature of 50 ° C and 0.44 kg of sorbic acid was added slowly stirring at 800 rpm for 15 minutes, at the end of which, the solution showed a pH value of 3.86, a conductivity of 15.87, while the temperature of the solution was 47 ° C. Immediately the pH was adjusted to 7.21 by the addition of sodium hydroxide, maintaining the stirring at 800 rpm for 10 minutes; here the conductivity was 17.06 mS / cm and the temperature of the solution was 45 ° C. The solution was allowed to cool to a temperature of 30 ° C and then 0.080 kg of sodium bisulfite was added, slowly, maintaining stirring at 800 rpm for 15 minutes; a pH of 6.98 was observed, a conductivity of 16.97 and a solution temperature of 30 ° C.
Example 2. Preparation of a composition for ophthalmic use containing the carrier composition and diclofenac sodium as the active ingredient. a) Preparation of the solution of the active ingredient: 60 liters of distilled water were discharged into a steel vessel, at a temperature of 23 ° C and maintaining a stir at a speed of 600 rpm, 0.2 kg of diclofenac sodium was added slowly, maintaining the agitation for 15 minutes. The pH of the solution at the end of the stirring was 7.25 and the conductivity was 0.734 mS / cm while the temperature of the solution was 23 ° C.
b) Preparation of the ophthalmic composition containing the active ingredient: The solution of diclofenac sodium was then transferred to a stainless steel tank with a capacity of 200 liters, containing 120 liters of the solution of the carrier composition prepared by example 1, maintaining an agitation of 800 rpm for 15 minutes. Then, the total volume of 200 liters was adjusted with distilled water at a temperature of 23 ° C and whose conductivity should not be higher than 0.002 mS / cm. The solution has a
pH of 6.25. The solution was then stirred for about 2 hours and the pH was then adjusted to a value of about 6.84; the conductivity of the final solution is 11.77 and the final temperature of the solution was approximately 23 ° C. It is noted that the best method known to the applicant for carrying out the invention is that which is mentioned in the description and the examples, which are presented only in an illustrative manner and are in no way intended to be restrictive for the invention. claimed Having described the invention as above, property is claimed as contained in the following
Claims (5)
1. An ophthalmic transporter solution for use in the topical application of ophthalmic compounds, characterized in that it comprises the following ingredients: 10.20% by weight of polyoxyl stearate 40; 0.15% by weight of disodium edetate dihydrate 1.03% by weight of sodium chloride; 0.14% by weight of boric acid; 0.32% by weight of sorbic acid and 0.06% by weight of sodium bisulfite 88.00% by weight of distilled water.
2. A process for the preparation of an ophthalmic transporter solution, characterized in that it consists in forming a composition consisting of polyoxyl stearate 40, disodium edetate dihydrate, sodium chloride, boric acid, sorbic acid, sodium bisulfite and distilled water by the steps of: a) Heating a predetermined volume of distilled water to a temperature of about 69 to 71 ° C; adjust the pH to 6.25 (± 0.25) and maintain a conductivity not higher than 0.002 mS / cm; b) empty the hot distilled water in a stainless steel tank; c) adding the polyoxyl stearate 40 slowly to hot distilled water, maintaining the stirring for a time comprised between 27 and 33 minutes; the pH at the end of the stirring time should be approximately 6.0 to 6.2 and the conductivity after the stirring time should be 0.12 mS / cm (± 0.05 mS / cm); likewise, the temperature after the agitation time should be between 63 and 67 ° C; d) add the disodium edetate 2 H20 slowly, maintaining the agitation for a time comprised between 13 and 17 minutes, at 750-850 rpm; the pH at the end of the agitation time should be within the range of 5.54 to 5.58 and the conductivity after the agitation time should be between 0.679 to 0.681 mS / cm; the temperature after the stirring time should be between 59 and 61 ° C; e) add the sodium chloride slowly, maintaining the agitation in the range of 750 to 850 rpm for an approximate time of 13 to 17 minutes; The pH at the end of the stirring time should be between 5.20 to 5.22; the conductivity after the stirring time should be between 15.32 mS / cm and 17.32 mS / cm; and the temperature after the stirring time should be 55 to 57 ° C; f) adding the boric acid slowly, maintaining the stirring between 750 and 850 for approximately 13 to 17 minutes; the pH at the end of the agitation time should be between 5.20 and 5.24; the conductivity after the stirring time should be between approximately 1.64 and 13.64 mS / cm; the temperature after the stirring time in this step should be about 55-57 ° C; g) allowing the preparation to cool to a temperature of about 49 to 51 ° C; h) adding the sorbic acid slowly, maintaining the stirring between 750 and 850 rpm for a time of approximately 13 to 17 minutes; the pH at the end of the agitation time should be between 3.84 to 3.88; and the conductivity after the stirring time should be in the range of 15.82 mS / cm to 15.92 mS / cm, likewise, the temperature after the stirring time should be about 46 to 48 ° C; i) adjust the pH with sodium hydroxide as soon as possible to a value of 7. 15 ± 0.1, maintaining the agitation at 750-850 rpm for a time comprised between 9 and 11 minutes; the conductivity after the stirring time should be within the range of 16.06 to 18.06 mS / cm; the temperature after the agitation time should be between 44.5 and 45.5 ° C; j) allowing the preparation to cool to a temperature between about 29-31 ° C. k) adding the sodium bisulfite slowly, maintaining the stirring at a speed of 750 to 850 rpm for about 13 to 17 minutes; the pH at the end of the agitation time should be 7.0 ± 0.1; the conductivity after the stirring time should be 16.97 mS / cm (with a limit of ± 1.0 mS / cm); and the temperature after the stirring time should be about 25 to 29 °.
3. An ophthalmic composition for topical use, characterized in that it contains: 68.16% by weight of the composition of claim 1; 0.10% by weight of an active agent selected from diclofenac sodium, and antibiotics such as tobramycin or gentamicin; and distilled water with enough to complete 100% by weight of the solution.
4. An ophthalmic composition for topical use according to claim 3, characterized in that it contains: 68.16% by weight of the composition of claim 1; 0.10% by weight of diclofenac sodium and distilled water with enough to complete 100% by weight of the solution.
5. Process for the preparation of an ophthalmic composition for topical use consisting of an ophthalmic transporter solution according to claim 1 and an active ingredient such as diclofenac sodium, characterized in that it consists of the steps of: i) emptying a predetermined amount of water distilled in a stainless steel container; stir at a speed between about 580 to 620 rpm; add the sodium diclease slowly, maintaining the agitation for approximately 13 to 17 minutes; the pH at the end of the agitation time should be 7.25 ± 0.1. The conductivity after the stirring time should be 0.734 mS / cm (± 0.1 mS / cm); the temperature after the stirring time should be between approximately 21 to 25 ° C; ii) transfer the preparation of diclofenac sodium obtained in the stage above, to a stainless steel tank containing a predetermined volume of the composition prepared according to the process of claim 2, maintaining an agitation of 800 ± 50 rpm for an approximate time of 13 to 17 minutes; iii) gauging the total volume with distilled water at a temperature of 2 i at 25 ° C and having a pH of about 6.00 to 6.50; the conductivity of this distilled water should be no greater than 0.002 mS / cm; iv) stirring the resulting solution for a period of 2 hours ± 5 minutes, v) adjusting the pH at the end of the stirring time to a value between 6.83 and 6.85; the conductivity after the stirring time should be 11.77 mS / cm ± 0.5 mS / cm and the temperature after the stirring time should be approximately 21-25 ° C. EXTRACT OF THE INVENTION The present invention relates to a composition of matter of the type that is used in the treatment of ophthalmic conditions and particularly refers to an ophthalmic transporter solution based on surfactants, emulsifiers, antibactericides, antioxidants, etc. forming a transporter that envelops or masks an active ingredient such as diclofenac sodium or other antibiotic agents such as tobramycin, gentamicin or timolol sulfate, in order to avoid the discomfort caused by the topical application of the mentioned active ingredients, such as pain, burning, irritation and other discomfort for the user.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MX9701946A MX9701946A (en) | 1997-03-14 | 1997-03-14 | Transporting ophthalmic solution. |
| US08/958,681 US6071958A (en) | 1997-03-14 | 1997-10-27 | Ophthalmic carrier solution |
| CA002219065A CA2219065C (en) | 1997-03-14 | 1997-10-27 | Ophthalmic carrier solution |
| EP98104601A EP0868909B1 (en) | 1997-03-14 | 1998-03-13 | Ophthalmic carrier solution |
| DE69809489T DE69809489T2 (en) | 1997-03-14 | 1998-03-13 | Solutions as carriers for ophthalmic drugs |
| PT98104601T PT868909E (en) | 1997-03-14 | 1998-03-13 | VEHICLE SOLUTION OF OFALMIC |
| ES98104601T ES2187845T3 (en) | 1997-03-14 | 1998-03-13 | Ophthalmic vehicle solution. |
| DK98104601T DK0868909T3 (en) | 1997-03-14 | 1998-03-13 | Ophthalmic carrier solution |
| AT98104601T ATE227976T1 (en) | 1997-03-14 | 1998-03-13 | SOLUTIONS AS CARRIERS FOR EYE DRUGS |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MX9701946A MX9701946A (en) | 1997-03-14 | 1997-03-14 | Transporting ophthalmic solution. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MXPA97001946A true MXPA97001946A (en) | 1998-04-01 |
| MX9701946A MX9701946A (en) | 1998-04-30 |
Family
ID=19744965
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX9701946A MX9701946A (en) | 1997-03-14 | 1997-03-14 | Transporting ophthalmic solution. |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US6071958A (en) |
| EP (1) | EP0868909B1 (en) |
| AT (1) | ATE227976T1 (en) |
| CA (1) | CA2219065C (en) |
| DE (1) | DE69809489T2 (en) |
| DK (1) | DK0868909T3 (en) |
| ES (1) | ES2187845T3 (en) |
| MX (1) | MX9701946A (en) |
| PT (1) | PT868909E (en) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXJL02000046A (en) * | 2002-12-13 | 2004-06-24 | Jimenez Bayardo Arturo | Intravitreous injectable solution for the treatment of vitreous hemorrhages. |
| CA2511217A1 (en) * | 2002-12-20 | 2004-07-15 | Chakshu Research, Inc. | Ophthalmic formulation for the prevention and treatment of ocular conditions |
| US20060166879A1 (en) * | 2002-12-20 | 2006-07-27 | Chakshu Research Inc | Treatment of conditions associated with the presence of macromolecular aggregates, particularly ophthalmic disorders |
| US20060172972A1 (en) * | 2002-12-20 | 2006-08-03 | Chakshu Research Inc | Formulation and method for administration of ophthalmologically active agents |
| US20060177430A1 (en) * | 2002-12-20 | 2006-08-10 | Chakshu Research Inc | Treatment of ocular disorders with ophthalmic formulations containing methylsulfonylmethane as a transport enhancer |
| WO2004096261A1 (en) * | 2003-05-02 | 2004-11-11 | Arturo Jimenez Bayardo | Method of preparing an aqueous solution of cyclosporin-a and resulting aqueous solution |
| EP1972340A3 (en) | 2003-07-10 | 2008-11-26 | Arturo Jimenez Bayardo | Method of preparing an aqueous meloxicam solution and the resulting aqueous solution |
| EA200800338A1 (en) * | 2005-07-15 | 2008-08-29 | Чакшу Рисерч Инк. | PREVENTION AND TREATMENT OF OPHTHALMOLOGICAL COMPLICATIONS OF DIABETES |
| TW200812575A (en) * | 2006-04-28 | 2008-03-16 | Alcon Inc | Formulations containing amide derivatives of carboxylic acid NSAIDs for topical administration to the eye |
| KR20090015103A (en) * | 2006-06-01 | 2009-02-11 | 쉐링 코포레이션 | Phenylephrine pulsed release formulations and pharmaceutical compositions |
| BRPI0711871A2 (en) * | 2006-06-01 | 2011-12-06 | Schering Corp | pharmaceutical compositions for sustained release of phenylephrine |
| NZ573174A (en) * | 2006-06-01 | 2012-01-12 | Msd Consumer Care Inc | Sustained release pharmaceutical dosage form containing phenylephrine |
| MX2008015360A (en) * | 2006-06-01 | 2009-03-06 | Schering Plough Healthcare | Phenylephrine pharmaceutical formulations and compositions for colonic absorption. |
| EP3181580A1 (en) | 2006-11-02 | 2017-06-21 | Acceleron Pharma Inc. | Alk1 receptor and ligand antagonists and uses thereof |
| BRPI0812784A2 (en) * | 2007-06-01 | 2014-12-02 | Schering Plough Healthcare | Pharmaceutical composition comprising a substrate and a coating containing an active ingredient and polyvinyl alcohol |
| AU2008310956B2 (en) * | 2007-10-08 | 2014-08-07 | Aurinia Pharmaceuticals Inc. | Ophthalmic compositions comprising calcineurin inhibitors or mTOR inhibitors |
| CA2710843A1 (en) * | 2008-01-04 | 2009-07-16 | Alcon Pharmaceuticals Ltd. | Stable aqueous cyclosporin compositions |
| EP3398966A1 (en) | 2008-05-02 | 2018-11-07 | Acceleron Pharma, Inc. | Methods and compositions for modulating angiogenesis and pericyte composition |
| US9017725B2 (en) * | 2009-06-09 | 2015-04-28 | Aurinia Pharmaceuticals Inc. | Topical drug delivery systems for ophthalmic use |
| US20100323978A1 (en) * | 2009-06-22 | 2010-12-23 | Calvin Hanna | Non-aqueous oil delivery system for ophthalmic drugs |
| CN108341863A (en) | 2011-04-20 | 2018-07-31 | 阿塞勒隆制药公司 | Endoglin polypeptide and application thereof |
| EP2887923B1 (en) | 2012-08-24 | 2023-04-05 | Sun Pharmaceutical Industries Limited | Ophthalmic formulation of polyoxyl lipid or polyoxyl fatty acid and treatment of ocular conditions |
| KR20220013459A (en) | 2013-10-25 | 2022-02-04 | 악셀레론 파마 인코포레이티드 | Endoglin peptides to treat fibrotic diseases |
| PT3373976T (en) | 2015-11-10 | 2024-04-02 | Sun Pharmaceutical Ind Ltd | Topical formulations and uses thereof |
| WO2017151657A1 (en) | 2016-02-29 | 2017-09-08 | Ocular Technologies Sarl | Topical cyclosporine-containing formulations and uses thereof |
| US20190224275A1 (en) | 2017-05-12 | 2019-07-25 | Aurinia Pharmaceuticals Inc. | Protocol for treatment of lupus nephritis |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ226100A (en) * | 1987-09-11 | 1990-12-21 | Syntex Inc | Stabilised ophthalmic formulation containing non-steroidal anti-inflammatory drug |
| ES2098739T3 (en) * | 1992-05-13 | 1997-05-01 | Sandoz Ltd | OPHTHALMIC COMPOSITIONS CONTAINING A CYCLOSPORIN. |
| JPH06298649A (en) * | 1993-04-19 | 1994-10-25 | Teika Seiyaku Kk | Azelastine eye drop composition |
| JP3155689B2 (en) * | 1995-08-10 | 2001-04-16 | 昭和薬品化工株式会社 | Anti-inflammatory eye drops |
-
1997
- 1997-03-14 MX MX9701946A patent/MX9701946A/en unknown
- 1997-10-27 CA CA002219065A patent/CA2219065C/en not_active Expired - Fee Related
- 1997-10-27 US US08/958,681 patent/US6071958A/en not_active Expired - Lifetime
-
1998
- 1998-03-13 PT PT98104601T patent/PT868909E/en unknown
- 1998-03-13 EP EP98104601A patent/EP0868909B1/en not_active Expired - Lifetime
- 1998-03-13 DE DE69809489T patent/DE69809489T2/en not_active Expired - Fee Related
- 1998-03-13 AT AT98104601T patent/ATE227976T1/en not_active IP Right Cessation
- 1998-03-13 ES ES98104601T patent/ES2187845T3/en not_active Expired - Lifetime
- 1998-03-13 DK DK98104601T patent/DK0868909T3/en active
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