MXPA01003098A - Sustained release, and comfortable ophthalmic composition and method for ocular therapy - Google Patents
Sustained release, and comfortable ophthalmic composition and method for ocular therapyInfo
- Publication number
- MXPA01003098A MXPA01003098A MXPA/A/2001/003098A MXPA01003098A MXPA01003098A MX PA01003098 A MXPA01003098 A MX PA01003098A MX PA01003098 A MXPA01003098 A MX PA01003098A MX PA01003098 A MXPA01003098 A MX PA01003098A
- Authority
- MX
- Mexico
- Prior art keywords
- composition
- further characterized
- composition according
- active ingredient
- basic active
- Prior art date
Links
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- 229960003712 propranolol Drugs 0.000 description 1
- UNKALAXSDAZJJW-UHFFFAOYSA-N propyl 4-hydroxy-2-methylbenzoate Chemical compound CCCOC(=O)C1=CC=C(O)C=C1C UNKALAXSDAZJJW-UHFFFAOYSA-N 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 229940016590 sarkosyl Drugs 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 230000001954 sterilising Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
Disclosed are reduced stinging, sustained release ophthalmic formulations. Also disclosed are methods of treatment comprising administering such formulations topically to the eye when in need thereof.
Description
OPHTHALMIC COMPOSITION OF SUSTAINED RELEASE AND THAT DOES NOT CAUSE DISCOMFORT AND METHOD FOR OCULAR THERAPY
FIELD OF THE INVENTION The present invention relates to the improvement of sustained release and non-burning ophthalmic formulations ocular para-therapy and methods of treatment comprising the administration of said formulations topically to the eye when indicated.
BACKGROUND OF THE INVENTION
Many patients do not easily accept numerous drugs because they cause ocular discomfort, that is, "burning", in the instillation to the eyes. This side effect is problematic because it causes a poor compliance of the patient and because it restricts the amount of drug that can be included in topical formulations. In addition, to comply with the global microbiological standards and USP, one or more preservatives must be included in the eye formulations. These conservatives, particularly those needed to meet more stringent global requirements, tend to increase the level of "burning", thereby increasing the patient's discomfort. In this way, the combined needs of comfort and satisfactory compliance of the patient together with the provision of a composition that meets strict global conservation requirements represent a challenge that, to date, has not been satisfactorily achieved. A method for addressing problems related to topical administration is described in U.S. Patent No. 4,911,920. Glaucoma is a disease characterized by elevated intraocular pressure (IOP) that is associated with damage to the optic nerve and loss of visual field. Statistically, when the IOP is decreased, the prognosis is improved to preserve the visual field in an eye with elevated IOP. In this way, one goal of glaucoma therapy is to reduce the IOP to a level within a scale tolerated by the eye to lessen the progressive loss of the visual field. The current medical therapy of glaucoma is related to the reduction of IOP by several drugs, predominantly ophthalmic beta-adrenergic blocking drugs. Betaxolol is among the approved ophthalmic beta-blockers for use in the treatment of glaucoma in the United States. In the '920 patent, active ingredients such as betaxolol are administered to treat glaucoma in a composition that includes, among others, an ion exchange resin and a polyanionic polymer. These compositions have an excellent profile that does not cause discomfort, but still some patients experience "burning". Therefore, there is a need to provide an ophthalmic composition that achieves the combined needs of comfort and compliance of the patient, while at the same time meeting the strict requirements of global preservation.
BRIEF DESCRIPTION OF THE INVENTION
An advantage of this invention is that it achieves the combined needs of comfort and satisfactory compliance of the patient, while at the same time fulfilling the strict requirements of global preservation, by which it allows the topical administration of ophthalmic drugs at higher concentrations. The additional advantages and other features of the present invention will be explained in part in the description that follows, and in part will be apparent to those skilled in the art upon reviewing the following, or that can be learned from the practice of the invention. . The objects and advantages of the invention can be effected and obtained as indicated in particular in the appended claims. In accordance with the present invention, the above and other advantages can be achieved in part by an ophthalmic composition, comprising: a) at least one basic active ingredient; b) a polyanionic polymer; c) an ion exchange resin; and d) a pH adjusting agent, wherein said agent is present in an amount sufficient to adjust the pH of the composition between about 3.5 and 9.5. Another aspect of this invention is a method of treatment comprising the topical administration to an affected eye of an ophthalmic composition comprising: a) at least one basic active ingredient; b) a polyanionic polymer; an ion exchange resin; and d) a pH adjusting agent, wherein said agent is present in an amount sufficient to adjust the pH of the composition between about 3.5 and 9.5. Other objects and advantages of the present invention will be readily apparent to those skilled in the art from the following detailed description, wherein only the preferred embodiment of the invention is illustrated and described, simply by way of illustration of the best mode contemplated for perform the invention. It should be noted that the invention has the capacity for other and different modalities, and its various details have the ability to be modified in various obvious ways, all without departing from the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based, in part, on a surprising and unexpected discovery that the use of certain pH adjusting agents results in ophthalmic compositions that achieve the combined needs of comfort and satisfactory compliance of the patient, while at the same time meeting the requirements strict global conservation. The pH adjusting agents useful in the present invention can be any "basic amine", that is, any amine that has a basic character and does not substantially destroy the interaction between a basic active ingredient and an ion exchange resin. Preferred pH adjusting agents include ammonia, tromethamine (TRIS or Tris (hydroxymethyl) aminomethane), triethanolamine (TEA), N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), and mixtures thereof. Breaks between a basic active ingredient and an ion exchange resin normally occur when smaller ions, such as sodium ions, are used to adjust the pH of the compositions in question, because they adjust sterically better at the binding site of the resin, whereby the basic active ingredient of the resin is displaced and the concentration of "free" basic active ingredient in the solution increases. Since ocular discomfort with many basic active ingredients is proportional to the amount of this "free" or unambiguously "active" basic active ingredient in the composition, the level of discomfort experienced by patients increases when the concentration of unattached basic active ingredient increases. Without wishing to be bound by any particular theory, it is believed that the pH adjusting agents of this invention minimize the breakdown of the basic active ingredient / resin interaction when the pH is adjusted, which usually occurs with smaller ions. , such as sodium ions. It is believed that the larger ions provided by the present invention do not fit very well at the resin binding site, and therefore, do not displace as many basic active molecules.
The term "basic active ingredient", as used throughout the specification means the active ingredient or ingredients in the formulations of the invention that can cause eye discomfort in the instillation to the eye, and has the desired effect that they exhibit or have the ability to withstand a positive charge during the formulation of the final product or as formulated in the form of the final product. Thus, the term basic, or cationic, active ingredient is descriptive for the purposes of the description and the claims. Said basic active ingredients include all ophthalmic agents that may be of topical application. Such ophthalmic agents include, but are not limited to, glaucoma agents, such as beta-blockers, muscarinics, and carbonic anhydrase inhibitors; dopamine agonists and antagonists; a-2 agonists; anti-infective agents; anti-inflammatory drugs without steroids and steroids; prostaglandins; proteins; Growth factors and antiallergics. The compositions of this invention may also include combinations of ophthalmic agents. A preferred basic active ingredient is beta-blockers which, almost always, are represented by the following generic structure, which also represents the basic active ingredients of beta-blockers of the present invention: R1-0-CH2-CH (OH) -CH2-NR2R3 (I) wherein: R1 is a substituted or unsubstituted cyclic or aliphatic portion; the cyclic portions include mono- and polycyclic structures which may contain one or more of the heteroatoms selected from C, N, and O; R2 and R3 are independently selected from H and substituted and unsubstituted alkyl. With respect to Structure 1, above, the following is incorporated herein by way of reference: Annual Reports in Medical Chemistry 14, 81-87 (1979); J. Med. Chem. 1983, 26, 1570-1576; ibid .. 1984. 27, 503-509; ibid .. 1983. 26, 7-11; ibid .. 1983 26, 1561-1569; ibid .. 1983 1109-1112; ibid .. 1983, 26, 950-957; ibid .. 1983. 26, 649-657; and ibid., 1983, 26, 352-357. The elements that represent these basic active ingredients are: betaxolol, timolol, befunolol, labetalol, propranolol, bupranolol, metaprolol, bunalol, esmalol, pindolol, carteolol, hepunolol, metipranolol, celiprolol, aoztinolol (S-596), diacetolol, acebutolol, salbutamol, atenulol, isoxaprolol, and the like. The following patent publications which are incorporated herein by reference also representatively demonstrate the beta-blockers of the present invention: patents of E.U.A. us. 4,252,984; 4,311, 708 and 4,342,783. Preferred beta-blockers of the present invention include betaxolol and timolol. Another preferred basic active ingredient is the (S) -isomer of betaxolol, mainly levobetaxolol, the most active of the enantiomers. The formulations of the invention may propose more than one basic active ingredient, such as levobetaxolol or betaxolol and a carbonic anhydrase inhibitor or a prostaglandin. In the case where more than one basic active ingredient is employed in the formulation of the invention, the preferred basic active ingredients include betaxolol or levobetaxolol with prostaglandin, or a prostaglandin analog, such as, but not limited to, cloprostenol or fluprostenol. . More preferably, the prostaglandin includes isopropyl ester of the (+) isomer of fluprostenol (travoprost) having a formula as follows:
The basic active ingredient, in the gel and liquid modalities that can be poured, is present at a level of approximately 0.0001 a
. 0% by weight; the scale of greatest preference is 0.001 to 1.0% by weight. As used herein, prostaglandin includes prostaglandin and prostaglandin analogs thereof, such as, but not limited to, cloprostenol and fluprostenol, as described in U.S. Pat. No. 5,510,383, which is incorporated herein by reference in its entirety to the extent that describes the preparation and known pharmacological profiles of prostaglandin and prostaglandin analogs, especially cloprostenol, fluprostenol, latanoprost and travoprost. The high molecular weight, polyanionic polymers useful in the present invention have a molecular weight of about 50,000 to about 5,000 million, preferably about 700,000 to about 3,000 million. The polymers are characterized by having carboxylic acid functional groups, and preferably contain from 2 to 7 carbon atoms per functional group. The gels that are formed during the preparation of the ophthalmic polymer dispersion have a viscosity of about 3,000 to about 100,000 cps. In addition to the above-mentioned interactions of the basic active ingredient-polymer (anionic-cationic), the high molecular weight polymers that are employed in the compositions of this invention thicken the compositions to provide a gel, and provide a special type of rheology, that is, plastic viscosity, which can be transferred to sustained release and no longer cause discomfort to the final compositions. Said compositions vary in pH from 3.0 to 8.5. The modalities of liquid that can be poured (administration as drops in the eye) of the present invention have a viscosity of about 1 to 20,000 cps. The pH requirements are the same as indicated above for the final gel products, ie, pH 3.0-8.5. The third pharmaceutical form of the present invention, the anhydrous salt form, is derived from the free acid or the salt of the polycarboxylic acid polymer and the basic active ingredient. (The presence of the cationic ion exchange resin also contributes to the formation of salt, the nature of the ion exchange resin, in all embodiments of the present invention is defined below). Said salts can be formulated or reconstituted to aqueous gels and dispersions that can be poured, as already described, by adding water; or can be formulated as eye inserts in accordance with known technology and forms; or can be combined with an oil vehicle to form an ophthalmic ointment. All of those final ophthalmic dosage forms are fully described below. The term "plastic viscosity", above, is indicative of a material that does not flow perceptibly until a determined force or stress value is exceeded; This force or tension is referred to as the performance value. While not wishing to be bound by any theory, it is believed that the increase in the duration of activity of the compositions, as well as the relevant suspension properties of the present invention are related to the viscous / elastic response of the polymer for shear stress, is say to exhibit a definite performance value. The compositions of the present invention show a unique response to shear stress. When the performance value is exceeded, the gel structure is temporarily altered, thereby allowing the gel to flow. In the eye, this mechanism can be attributed in part to blinking. When the tension is removed (eyelid at rest), the structure of the gel is partially restored. Other factors that explain the duration of the formulations of this invention relate to ionic interactions, and a release mechanism that is explained by a dynamic equilibrium involving the normal production of tears and the displacement of basic active cations by cations present in tears . Suitable polyanionic polymers that are useful in this invention are carboxy-vinyl polymers. Preferred polymers of this class include the so-called carbomers, available under the trademark Carbopol from B.F. Goodrich Company; and ethylene-maleic anhydride polymer material, available under the trademark EMA from Monsanto Company. The polymers known and readily available Carbopol 974 P are specifically preferred. The polymers are employed in aqueous gel compositions at a level up to about 8% by weight, pourable liquid compositions comprising from 0.05% to 2.0% by weight of the polymer. The cationic resin component of the formulations of this invention provides an additional means of sustained release of the basic active ingredient, and appears to be necessary to alleviate discomfort in the beginning and in the long term. Said resins are characterized as highly acidic, such as those having sulfonic acid functionality or weakly acidic cation exchangers, such as those having carboxylic acid functionality. The resin should be incorporated as a finely divided powder, that is, 95% of the resulting spherical particles should have a diameter of less than 25 microns, preferably 10 or less. The release of the basic active ingredient found in the cation exchange resin and the anionic polymer is achieved when the ions that occur naturally in the fluid of tears, mainly sodium and potassium, compete with the basic active ingredient bound by the sites in the polymer vehicle and the ion exchange resin. The basic active ingredient released in this way is presented on the surface of the eye to be transported to the receptor sites. Any pharmaceutical grade cationic ion exchange resin is suitable for the formulation, and may be employed in the form of hydrogen or in the form of sodium. Such resins are readily available, for example, from Rohm & Haas under the trademark "Amberlite" of Dow Chemical Co. under the trademark "Dowex". A preferred ion exchange resin is Amberlite® IRP-69, an interlaced polystyrene sulfonic acid. The ion exchange resin component is present in the formulations of this invention at a level of 0.05% to 10.0% by weight. The average particle size diameter of the resin ranges from 1 to 25 microns preferably 1-10. The particle size of the resin is important with respect to the mode of action and comfort. Almost always the average particle size of the commercially available form of the ion exchange material of choice is about 40 to 150 microns. Said particles are reduced for convenience at a particle size scale of about 1.0 to 25, preferably 1-10 microns by a ball mill, in accordance with known techniques. The pH adjusting agents are present in an amount sufficient to adjust the pH of the composition between about 3.5 and about 9.5, preferably between about 5 and about 9, more preferably between about 6 and 8, and more preferably even a pH of approximately 6.5. HCl can optionally be used to adjust the pH together with the pH adjusting agents of this invention. Ophthalmic products are almost always packed in unit doses (a single dose) or in the form of multiple doses. The preservatives are required for multiple dose packaging to avoid contamination by microbes. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methylpropylparaben, phenylethyl alcohol, disodium edetate, boric acid, sorbic acid, M onomer, or other agents known to those skilled in the art. Certain modified sarcosinates having the following generic structure are also useful as conservation enhancers in this invention:
wherein: R1 = saturated or unsaturated hydrocarbon of C-C27: M = H or a pharmaceutically acceptable salt; and n = 1, 2 or 3. In general, an amount of one or more sarcosinates of this structure is used in the compositions of this invention in an amount between about 0.005 and about 0.5 weight percent, preferably between about 0.01 and 0.05. approximately 0.2% by weight. Even more preferred is the use between about 0.03 and about 0.12% by weight of one or more of these sarcosinates. Also preferred are certain lactylates having the following generic structure:
wherein: R2 = saturated or unsaturated C4-C2 hydrocarbon; M = H or a pharmaceutically acceptable salt; and n = 1, 2 or 3. In general, one or more lactylates of this structure can be employed in the compositions in an amount between about 0.1 and about 5.0% by weight. It is preferred to use an amount between about 0.1 and 2.0% by weight, and more preferably the use of about 0.5% by weight of the lactylate. Preferred surfactants are sold under the trademarks Hamposyl® (W.R. Grace), Sarkosyl® and Medialan® (Ciba-Geigy). Especially preferred: lauroyl sarcosine (Hamposyl® L), oleoilsarcosine (Hamposyl® O), mirstoilsarcosine (Hamposyl® M), cocoilsarcosine (Hamposyl® C), stearoyl sarcosine (Hamposyl® S), pelargodoilsarcosine (Hamposyl® P) and capryl Sodium lactylate (Pationic® 122A).
These surfactants can be used in any ophthalmic composition containing cationic antimicrobials that also contain polyelectrolytes, such as high molecular weight anionic mucomimetic polymers (eg, carboxyvinyl polymers, such as Carbopol®, polystyrene-sulfuric acid polymers, cation exchange resins). (for example, Amberlite® or Dowex®), or the like Examples of suitable polyelectrolytes are detailed below.Almost always, such preservatives are employed at a level of 0.001% to 1.0% by weight.The tonicity, or osmolality, of the The product can be adjusted to hypotonicity isotonicity or hypertonicity in relation to normal tears by the use of conventional materials known in the art, however, said tonicity agents are limited to non-ionic compounds and almost always, when used, vary from 0.0 % to 10% by weight in the final product.The non-ionic agents include yen representatively: mannitol, dextrose, glycerin and propylene glycol: however their presence in the final product form is optional. The ophthalmic formulations of this invention are in the form of: anhydrous salts; aqueous dispersions and that can vertese; and aqueous gels. The formulations comprise, in addition to the conventional ingredients that are provided, for example, bacteriostatic and formulation equilibrium considerations; a polyanionic vehicle, a cation exchange resin, and the basic active ingredient of choice. Said forms of anhydrous salt are incorporated in ointments or solid eye inserts that form colloidal gels in situ in the administration to the eye. The gel and liquid modalities can be poured and are topically applied to the eye. It should be noted that said liquid and gel modalities can be obtained from the anhydrous form in the formulation with water. The formulations of this invention demonstrate the sustained release of the basic active ingredient and do not cause discomfort in topical administration to the eye. It should be noted, in a general sense, that a burning sensation results when the active ingredients, previously identified, are administered in a net manner. Therefore, by achieving discomfort mitigation and sustained release, an unexpected result is obtained and allows the administration of a class of compounds that otherwise could not be considered. The compositions are formulated in three basic conditions: 1) gels; 2) liquids that can be poured and 3) anhydrous salts. 1) Gels: The cation exchange resin component is dispersed in water. The component of the basic active ingredient is then added with stirring. The polyanionic polymer component is added. The resulting product has a viscosity ranging from 1000 to 300, 000 cps depending on the concentration of the anionic polymer. The resulting pH is 3.0 to 8.5, which can be adjusted, if necessary, with one of the pH adjusting agents according to the invention, and optionally, HCl. 2) Liquids that can be poured: The component of the cation exchange resin is dispersed in 10 to 50% by volume of total water that is taken in the formulation, and then in basic active ingredient it is dispersed and / or dissolved with agitation. The polyanionic polymer, as an aqueous dispersion, is added until the desired pH of the product is obtained. The pH of the product can be adjusted to the desired value by varying the ratio of basic active ingredient / polymer / resin. The final pH of the product can be adjusted with the addition of the pH adjusting agents according to the invention, and optionally, HCl. The preferred pH scale for ophthalmic formulations is from 3.0 to 8.5. The final product is a dispersion, which may require a high energy mix to break up any agglomeration to achieve uniformity. Other ingredients of the formulation are added by mixing. The resulting product has a viscosity ranging from 1.0 to 20,000 cps, depending on the concentration of the anionic polymer. 3) Anhydrous salts: The basic active ingredient, the ion exchange resin and the polyanionic polymer are combined in water, and after mixing, they are lyophilized to a powder. Fillers such as mannitol and other materials can be added to facilitate freezing / drying processing in accordance with techniques already known to the experts. The anhydrous salts produced in this way can then be formulated or reconstituted to aqueous and liquid gels, or can be formulated and formed as ocular inserts. The lyophilized powder can also be combined with a non-aqueous vehicle to form an ophthalmic ointment. Said embodiments of anhydrous salts of the present invention can also be prepared by extracting the initial aqueous dispersion with an organic solvent, such as ethanol, chloroform, benzene or the like, and with evaporation of the organic solvent to produce the desired salt complex. The resulting product is substantially equivalent to the lyophilized product described above. The ophthalmic formulations of the present invention are administered to the eyes as gels, pouring liquids (eye drops), and in the form of ointments and eye inserts.; Subsequent classifications are formulated from anhydrous salts. All of those compositions are formulated to control the release of the basic active ingredient upon administration to the eye, and consequently provide a sustained release effect. Almost always, such administration is necessary one to four times, usually one to two per day. The precise dosing regimen is at the discretion of the medical specialist. The compositions according to the present invention are further described in the following manner:
Components Specific examples%
Active ingredient Betaxolol hydrochloride 0.1-5.0%
Viscosity agent Carbopol polymer, HPMC, HEC, CMC 0.1 -1.0%
Exchange resin Poly [styrene (divylbenzene) sulfonic acid 0.1-5.0% ionic preservative benzalkonium chloride, polyiquad 0.002-1.0%
Tonicity agent Mannitol 1.0-5.0%
Conservative auxiliary Boric acid 0.001-1.0%
Chelating agent Disodium edetate 0-1.0% N-lauroyl sarcosine preservative 0-1% pH adjusting agent Trometamine To adjust pH,
PH adjusting agent Hydrochloric acid To adjust pH
Solvent Water qs 100% While the present invention is generally described above, the additional embodiments are explained and illustrated in more detail with reference to the following examples. However, the examples
~ They are represented only to illustrate the invention and are not considered as limitations of it.
EXAMPLE 1
The compositions illustrated in Table 1 were prepared in the following manner: To a solution of levobetaxol hydrochloride, in purified water was added poly (styrene-divinylbenzene) sulfonic acid. The suspension was stirred by adding suspension of Carbomer 974P, mannitol, boric acid, disodium edatate solution and benzalkonium chloride with continuous stirring. The weight of the filler was adjusted with purified water, and the pH was adjusted to 6.5 ± 0.2 with tromethamine. The suspension was placed in an autoclave and then filtered with sterilization, N-lauroyl sarcosine was added aseptically. The weight of the formulation charge was then brought to 100 ml and the final pH adjusted, as necessary.
TABLE 1 Formulations of levobetaxolol hydrochloride
Concentration Ingredient 0.25% by volume 0.5% by volume 0.75% by volume
0.28a 0.56 0.84c hydrochloride levobetaxolol 0.375 0.75 0.125 poly (stirendiviniben cen) sulphonic Carbomer 974 P 0.35 0.35 0.35 Mannitol 4.5 4.0 3.67 Boric acid 0.3 0.3 0.3
Disodium edetate 0.01 0.01 0.01 Chloride 0.01 + 5% excess 0.01 + 5% excess 0.01 + 5% excess benzalkonium N-Lauroyl sarcosine 0.03 0.03 0.03 Trometamine pH adjustment at 6.5 'pH adjustment at 6.5+ 0.2
Hydrochloric acid 6.5 + 0.2 6.5 + 0.2 6.5 + 0.2
(if necessary) Purified water QS 100% QS 100% QS 100%
Equivalent to 0.25% of betaxolol-free base Equivalent to 0.5% of betaxolol-free base Equivalent to 0.75% of betaxolol-free base 5% of excess is added as an average of development. EXAMPLE 2
The results in Table 2 show that there is an increase in the binding fraction of betaxolol when TRIS or triethanolamine are used to adjust the pH of S betoptic, as measured by HPLC.
TABLE 2 Influence of several pH adjusting bases on the suspended betaxol link
EXAMPLE 3
The results in table 3 summarize the work done with TRIS vs. NaOH and confirm that the use of TRIS as a pH adjuster increases the binding fraction of betoxolol to the resin, which in turn increases discomfort relief.
TABLE 3
R.S. - Betaxolol Carbomer HCl 934P
EXAMPLE 4
The results in table 4 summarize the work done with TRIS vs. NaOH and confirm that the use of TRIS as a pH adjusting agent increases the binding fraction of betaxolol to the resin. These results also confirm that the TRIS inclusion does not modify the preservative properties of the formulations.
TABLE 4 PET and discomfort relief results of the first three 0.50% formulations of suspension formulations of (S) Betaxolol
In the above descriptions, numerous specific details are explained, such as specific materials, structures, chemistries, procedures, etc., to provide a thorough understanding of the present invention. However, this invention can be practiced without adhering to the details specifically explained. In other cases, the already known processing structures have not been described in detail so as not to obscure the present invention unnecessarily.
EXAMPLE 5
Tables 5, 6 and 7 summarize the preferred formulations of the invention.
TABLE 5 Ophthalmic suspension of brizozolamide / levobetaxolol
Equivalent to 0.5 of base of betaxolol TABLE 6
NJ
TABLE 7
or
Only the preferred embodiment of the invention and an example of its versatility are illustrated and described in the present description. It should be understood that the invention has the ability to be used in various combinations and environments and has the capacity for changes or modifications within the scope of the inventive concept as expressed herein.
Claims (2)
1- An ophthalmic composition comprising: at least one basic active ingredient; a polyanionic polymer; an ion exchange resin; and a pH adjusting agent, which is a basic amine that does not substantially break the interaction between the basic active ingredient and the ion exchange resin, and wherein the agent is present in an amount sufficient to adjust the pH of the composition between about 3.5 and around 9.5. 2. The composition according to claim 1, further characterized in that the basic active ingredient is selected from the group consisting of glaucoma agents, such as beta-blockers, muscarinics, carbonic anhydrase inhibitors, dopamine agonists and antagonists, and agonists - 2, anti-infective agents, anti-inflammatory and steroidal anti-inflammatory, prostaglandins, proteins, growth factors, anti-allergic and mixtures thereof. 3. The composition according to claim 2, further characterized in that the basic active ingredient is a beta-blocker. 4. The composition according to claim 2, further characterized in that the basic active ingredient is betaxolol. 5. - The composition according to claim 3, further characterized in that the beta-blocker is levobetaxolol. 6. The composition according to claim 3, further characterized in that the beta-blocker is present in a concentration between about 0.1% and about 5.0% > . 7. The composition according to claim 1, further characterized in that the pH adjusting agent is selected from the group consisting of ammonia, tromethamine (TRIS or Tris (hydroxymethyl) aminomethane), triethanolamine (TEA), N-
2-hydroxyethylpiperazine-N? -2-ethanesulfonic acid (HEPES), and mixtures thereof. 8. The composition according to claim 1, further characterized in that the pH adjusting agent comprises hydrochloric acid. 9. The composition according to claim 1, further characterized in that the pH adjusting agent is present in an amount sufficient to adjust the pH of the composition between about 5 and about 9. 10. The composition according to claim 9, further characterized in that said pH adjusting agent is present in an amount sufficient to adjust the pH of the composition between about 6 and about 8. 11. - The composition according to claim 10, further characterized in that the pH adjusting agent is present in an amount sufficient to adjust the pH of the composition to about 6.5. 12. The composition according to claim 1, further characterized in that the composition is in the form of an aqueous gel, an aqueous dispersion that can be poured or an anhydrous salt. 13. The composition according to claim 1, further characterized in that it comprises one or more preservatives. 14. The composition according to claim 1, further characterized in that it comprises one or more tonicity agents. 15. An ophthalmic composition comprising: levobetaxolol hydrochloride; poly (stirendivilbenzene) sulfonic acid; carbomer; mannitol; boric acid; disodium edetate; benzalkonium chloride; N-lauroyl sarcosine; and tromethamine, and hydrochloric acid optionally in an amount sufficient to adjust the pH of the composition to about 6.5. 16. The composition according to claim 4, further characterized in that it comprises a porstaglandin or prostaglandin analog. 17. The composition according to claim 16, further characterized in that the betaxolol is levobetaxolol, and the prostaglandin analogue is cloprostenol, fluprostenol, latanoprost or travoprost. 18. The composition according to claim 16, further characterized in that the prostaglandin analogue is travoprost. 19. - The use of a composition that basically comprises: at least one basic active ingredient; a polyanionic polymer; an ion exchange resin; and a pH adjusting agent which is a basic amine that does not substantially break the interaction between the basic active ingredient and the ion exchange resin for the preparation of a medicament for topical treatment of an eye, wherein said agent is present in an amount sufficient to adjust the pH of the composition between about 3.5 and about 9.5. 20. The use as claimed in claim 19, wherein the basic active ingredient is selected from the group consisting of glaucoma agents, such as beta-blockers, muscarinics, carbonic anhydrase inhibitors, dopamine agonists and antagonists, agonists a- 2, anti-infective agents, anti-inflammatory drugs without steroids and steroids, prostaglandins, proteins, growth factors, antiallergics and mixtures thereof. 21- The use as claimed in claim 20, wherein the basic active ingredient is a beta-blocker. 22. The use as claimed in claim 20, wherein the basic active ingredient is betaxolol. 23. The use as claimed in claim 21, wherein the beta-blocker is levobetaxolol. 24. - The use as claimed in claim 21, wherein the beta-blocker is present in a concentration between about 0.1% and about 5.0%. 25. The use as claimed in claim 19, wherein the pH adjusting agent is selected from the group consisting of ammonia, tromethamine (TRIS or Tris (hydroxymethyl) aminometan), triethanolamine (TEA), N-2 acid hydroxyethylpiperazine-N'-2-ethanesulfonic acid), (HEPES), and mixtures thereof. 26. The use as claimed in claim 19, wherein the pH adjusting agent further comprises hydrochloric acid. 27. The use as claimed in claim 19, wherein the pH of the composition is between about 5 and about 9. 28.- The use as claimed in claim 27, wherein the pH adjusting agent is present in an amount sufficient to adjust the pH of the composition between about 6 and about 8. The use as claimed in claim 28, wherein said pH adjusting agent is present in an amount sufficient to adjust the pH of the composition at about 6.5. 30. The use as claimed in claim 19, wherein the composition is in the form of an aqueous gel, an aqueous dispersion that can be poured or an anhydrous salt. 31. The use as claimed in claim 19, wherein the composition further comprises one or more preservatives. 32. - The use as claimed in claim 19, wherein the composition further comprises one or more tonicity agents. 33. The use as claimed in claim 22, wherein the composition further comprises prostaglandin or prostaglandin analogue. 34. The use as claimed in claim 33, wherein the betaxolol is levobetaxolol, and the prostaglandin analogue is cloprostenol, fluprostenol, latanoprost or travoprost. 35. The use as claimed in claim 33, wherein the prostaglandin analogue is travoprost.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/101,959 | 1998-09-25 |
Publications (1)
Publication Number | Publication Date |
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MXPA01003098A true MXPA01003098A (en) | 2001-12-13 |
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