KR950013746B1 - Pharmacentical composition for ophtalmic use - Google Patents

Abstract

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Description

Ophthalmic Pharmaceutical Compositions

The present invention relates to ophthalmic pharmaceutical compositions useful for reducing intraocular pressure (IOP) when treating glaucoma.

The composition of the present invention is characterized by sustaining long-term efficacy (serving property) while continuously relaxing the eyes from the beginning. In particular, the present invention provides a preparation composition comprising basic active ingredients and cation exchange resins (finely divided) dispersed in an aqueous solution of acidic mucus, mucomimetic polymers or gels having the above characteristics. It is about.

The liquefied gel or fluidized liquid formulation composition is characterized by controlled cation-anion interactions that are believed to exhibit comfortable and lasting medicinal properties.

The present invention also relates to a method of treatment using the above-mentioned compositions when treating ocular hypertension and glaucoma.

Activity of the composition according to the invention which has a favorable effect on the mean intraocular pressure of the term "basic active" or which can be positively charged or seized during the manufacture of the final product or in the form of the final product. Means a component or components.

Thus, the terms "basic active ingredient" or "cationic active ingredient" are used for the purpose of clarifying the specification and claims of the present invention.

The basic active ingredients include all beta blockers known to date which exhibit essentially positive charge and IOP effects.

Typically the beta blockers are represented by the following structural formula (I), which also represents the basic active ingredient in the present invention.

In formula (I), R ¹ is a substituted or unsubstituted cyclic or aliphatic monomer, wherein the cyclic monomer is a mono- and polycyclic structure containing one or more heteroatoms selected from C, N and O. Means; R ² and R ³ are each selected from H and substituted or unsubstituted alkyl.

The following references are cited for the above structural formula (1): Annual Reports in Medicinal Chemistry 14, 81-87 (1979); J. Med. Chem. 1983, 26 1570-1576; ibid., 1984, 27, 503-309; 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.

Such basic active ingredients are typically betasolol (betaxolol), timolol (acelolol), acebutolol (acebutolol), alprenolol (alprenolol), atenolol (atenolol), bevantolol (buvantolol), bucomo Bucomolol, Buprenolol, Butidrine, Butitolol, Bunitolol, Bunolol, Butocrolol, Butamine, Carazolol, Carazolol Theolol, exaprolol, indenolol, inprocrolol, inprocrolol, labetolol, mipindolol, metipranolol, metaprolol Metaprolol, moprololol, nadolol, nifenalol, oxprenool, oxprenolol, pamatolol, paragolol, penbutolol ), Pindolol, practolol, pronolol, pronethalol, pronethalol, propranolol, sotalol, tazolol, and tip Renolol, tolamorol, toliprolol, toliprolol, befunolol, esmalol, hefuolol, helionolol, celiprolol, azotinol azotinolol, diacetalol, acebutolol, salbutanol, and isosaprolol.

The definition of basic active ingredients also includes the groups of drugs described below for use in the treatment of hypertension and glaucoma in the eye.

Ie, pilocarpine, epinephrine, proepinephrine, noroepinephrine, pronorepinephrine, clonidine and para-aminoclonidine and para-aminoclonidine And clonidine derivatives such as amidoclinidine (p-acetoamidoclonidine).

Therefore, in summary, the basic active ingredients in the present invention are defined as those that have an effect of lowering intraocular pressure, continuously regulate it, and exhibit positive charge in an aqueous medium having a pH of 3.0 to 8.5.

The following patents, which represent the basic active ingredients in the present invention, are cited in the present invention. These are U.S. Patent Nos. 4, 252, 984, 3, 309, 406, 3, 619, 370, 3, 655, 663, 3, 657, 237, 4, 012, 444. , 3, 663, 607, 3, 836, 671, 3, 857, 952, 3, 202, 660 and 2, 774, 789.

Ophthalmic pharmaceutical compositions in the present invention are in the form of anhydrous salts, flowable dispersions and liquefied gels. The pharmaceutical formulation composition of the present invention consists of polyvalent anionic polymers, cation exchange resins and basic active ingredients in addition to conventional components that provide bacterial growth inhibition and control of the formulation.

Such anhydrous forms form colloidal gels as they are when administered to the eye in the form of ointments or solid ocular implants. Flowable liquid and gel forms are applied topically to the eye.

It should be noted that such liquid and gel states can be obtained by preparing anhydrous salts with water.

The formulation composition according to the present invention can slowly release the active ingredient and feel comfortable when administered topically to the eye. Generally, when the above-mentioned active ingredient is administered to the eye, it feels tingling.

Thus, achieving a comfortable and long lasting effect is an unexpected result or the composition may not be used.

[Polyanionic Polymer Component]

High molecular weight polyvalent anionic polymers useful in the present invention have a molecular weight of about 50,000 to about 6 million. The polymers are characterized by having carboxylic acid functional groups, and preferably contain 2 to 7 carbon atoms for each functional group.

Gels formed during the preparation of polymer dispersions in the eye have a viscosity of about 1,000 to 300,000 cps.

As mentioned above, the high molecular weight polymers used in the compositions of the present invention, as well as the mutual attraction of the basic active ingredient-polymers (cation-anions), provide long lasting efficacy while imparting the composition to the gel and giving comfort to the final composition. Helps to impart special forms of fluidity such as plastic viscosity that can be sustained. The pH range of the composition is 3.0 ~ 8.5.

An anhydrous salt state, the third pharmaceutical form in the present invention, is prepared from salts of polycarboxylic acid polymers and active ingredients (the presence of cation exchange resins also contributes to salt formation and is used in all examples in the present invention. The properties of the resin are described below.)

The salts, as mentioned above, may not only be prepared or reconstituted into liquefied gels and flowable dispersions by the addition of water, but may also be prepared by administering to the eye according to known techniques and forms, or mixed with oily media for ophthalmic ointment It may be prepared as.

All of these ophthalmic pharmaceutical forms are described in more detail below.

The term " solid viscosity " means to indicate a state that is non-flowable so as not to be detected until a particular force or stress is exceeded, such force or stress being expressed as a yield value. Although no theoretical basis has been provided, it is believed that long lasting activity of the composition according to the invention is partly related to the yield.

The compositions in the present invention exhibit inherent values for shear stress. When the yield is exceeded, the gelled structure is temporarily changed to flow.

The mechanism in the eye is due in part to blinking of the eye. When the stress is removed (when the eyelids return to place), the gelled structure partially reshapes.

Another factor in which the formulation composition of the present invention can sustain its medicinal effects is related to the ionic interaction, and the mechanism is based on the dynamic equilibrium that occurs during normal tear formation and the cations present in the tear. It is demonstrated by what is substituted.

The mechanism is discussed again below.

Preferred polymers for use in the present invention are carboxy vinyl polymers. Preferred polymers included in this class are named Carbomer, which may be used under the trade name Carbopol from B.F.Goodrich.

As the anhydride polymer of ethylene male, Monsanto trade name EMA is used. Particular preference is given to the known Carbopol 934 and 940 which can be easily used.

The polymer used in the composition of the liquefied gel state may be used up to about 8 wt%, and the flowable liquid composition contains 0.05 wt to 2.0 wt% of the polymer.

[Base active ingredient]

Preferred basic active ingredients in the present invention have already been mentioned above.

The most preferred basic active ingredients are betaxolol and timolol. The basic active ingredient in the gel state and fluid liquid state may be contained at about 0.01 to 4.0 wt%, most preferably in the range of 0.10 to 1.0 wt%.

[Ion exchange resin]

The cationic resin component of the formulation composition according to the present invention is necessary not only to act as an additional means of long-lasting the active ingredient but also to provide comfort from the beginning. The resins can be characterized as weakly acidic cation exchange resins having strong acidic or carboxylic acid functionalities, such as those having sulfuric acid functionality.

The resin must be in the form of finely ground powder. That is, 95% of the final spherical particles should be less than 20.0 microns in diameter. The release of the base active ingredient retained by the cation exchange resin and the anionic polymer occurs when the ions inherently present in the tears, mainly sodium and potassium, compete with the base active ingredients to take place on the polymer medium and the ion exchange resin.

Thus, the released basic active ingredient is placed on the eye surface to be moved to an acceptable location.

Any pharmaceutical grade cation exchange resin can also be preferably used in the formulation compositions and they can be used in hydrogen or sodium form. As the resin, trade name " Amberlite " manufactured by Rohm & Haas Corporation and trade name " Dowex "

The ion exchange resin component present in the formulation composition according to the present invention may be 0.05 wt% to 10.0 wt%. The average diameter size of the resin is 1-20 microns.

The size of the resin particles is very important in terms of form of action and comfort. The average particle size of commercially available resins should typically be chosen between about 40 and 150 microns.

Particles of this size can be easily reduced to a particle size between about 1.0-25 microns by ball mill or the like according to known techniques.

[Other Ingredients]

Antimicrobial Preservatives

Ophthalmic products are typically packaged in multiple dosage forms.

Thus preservatives are needed to prevent bacterial contamination during use. Preferred preservatives include benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, onna Onamer M, or other reagents well known to those of ordinary skill in the art, can be used.

Typically the preservatives are used in 0.001wt ~ 1.0wt%.

[Tonicity agents]

Osmotic agents or osmolality of such products are hypotonicity, isotonicity or failure associated with those used in tears by those of ordinary skill in the art. It can be adjusted and used as a hypertonicity.

However, the osmotic agents are limited to nonionic compounds and are typically used at 0.0 wt% to 10 wt% in the final product.

Nonionic reagents are typically mannitol, dextrose, glycerin and propylene glycol, but these are optionally used in the final product.

[Production composition]

The composition of the present invention is prepared in three forms: 1) gel, 2) flowable liquid and 3) anhydrous salt.

[1] gels

The cation exchange resin component is dispersed in water. The basic active ingredient is then added with stirring. Then the polyvalent ionic polymer component is added. The viscosity of the final product is 1,000 to 300,000 cps, depending on the concentration of the anionic polymer. pH is 3.0-8.5 and if necessary, adjust with hydrochloric acid or sodium hydroxide.

[2) fluid liquids]

The cation exchange resin component is dispersed at 10-50% by volume relative to the total water in the formulation composition, and then dispersed and / or dissolved while stirring the basic active ingredient. As the dispersion, the polyanionic polymer is added until it is a product having the desired pH.

The pH of the product is adjusted to the desired value by varying the ratio of active ingredient / polymer / resin. If necessary, the final pH of the product may be adjusted by adding NaOH or HCI.

The preferred pH range of the ophthalmic composition is 3.0-8.5.

High energy mixing may be required to break up any mass to achieve uniformity of the final dispersion.

Other components of the formulation composition were then added to the mixture. The viscosity of the final product is 1.0 to 20,000pcs, depending on the concentration of the anionic polymer.

[3] anhydrous salts]

The basic active ingredient, the ion exchange resin and the polyvalent anionic polymer were mixed with water and then dried to prepare a powder. Fillers such as manirol and other materials have been added to facilitate the freeze / dry process in accordance with techniques well known to those of ordinary skill in the art. Anhydrous salts prepared in this manner can then be prepared or reconstituted in liquefied gel and liquid state or formulated in the form of an eye implant.

The frozen precursor powder may also be mixed with the non-aqueous medium to form ointment for the eyes.

The anhydrous salts in the present invention may also be prepared as desired salt complexes by extracting the initial dispersion with ethanol, chloroform, benzene or similar solvents or by evaporating the organic solvent. The final product is substantially the same product as the lyophilized product mentioned above.

[How to use]

The ophthalmic compositions in the present invention are used in the form of gels, flowable liquids (administered as drops to the eyes), and ointments and insertions into the eyes when administered to the eye. The ointment and the insert into the eye are anhydrous.

All of the above compositions are prepared to provide a long lasting effect by controlling the release of the basic active ingredient when administered to the eye.

Typically, the administration should be once or twice a day, but the correct prescription should be as directed by the doctor.

Specific details will be mentioned in the following examples.

However, the following examples do not limit the compositions and methods of treatment in the present invention.

Example 1

A method for preparing a betaso free base from betasohydrochloride.

Betaso hydrochloride is shown in US Pat. No. 4, 252, 984 and is also commercially available.

Betasolol hydrochloride (0.88 moles) is dissolved in water and the solution is cooled in an ice-bath. The solution is added to an aqueous NaOH (0.97 moles) solution to form a basic mixture while stirring vigorously. The pH of the mixture is then about 9.6.

The resulting white solid was filtered off and washed with plenty of water. After pressurization / drying in a filter funnel, the partially dried solid is resuspended in a large amount of water and stirred for 1-2 hours.

The white solid is filtered off, washed with a large amount of water, and dried in vacuo to prepare a betasolol glass base which is a free salt.

Example 2

[Manufacturing method]

Finely ground Amberlite IRP-69 resin, sodium poly (styrene-divinylbenzene) sulfonate and the betasolol were mixed at 50% by volume relative to the total water to form a uniform dispersion.

Carbopol-934P is slowly added to the dispersion. The mixture is homogenized at high speed. Other components are also added to the aqueous solution.

The final resulted product was a white homogeneous suspension marked A, B and C.

Example 3

[Manufacturing method]

Solutions A, B and C in Example 3 were prepared according to the method of Example 2. The resulting product was a white or slightly grayish white uniform suspension with a pH of 5.5-6.5.

According to the method of Examples 2 and 3, substantially the same result was obtained when the betasorol component was substituted in the same amount with the same amount of timolol or the above-mentioned beta blockers and other basic active ingredients.

The invention mentioned herein refers to certain preferred examples.

However, those of ordinary skill in the art will recognize that the present invention is not limited thereto.

Claims (8)

A therapeutically effective amount of a betablocker represented by the following structural formula (I), an anionic mucus polymer of molecular weight 50,000-6 million having a carboxylic acid functional group and 2-7 carbon atoms per functional group, and 0.05- A sustained-release ophthalmic pharmaceutical composition for regulating and lowering intraocular pressure, which is composed of a particulate cation exchange resin at a concentration of 10% by weight. R ¹ -O-CH ₂ -CH (OH) -CH ₂ -NR ² R ³ (I) R ¹ in the formula (I) is a substituted or unsubstituted cyclic or aliphatic monomer; R ² is R ³ are each selected from H and substituted and unsubstituted alkyl. 2. An ophthalmic pharmaceutical composition according to claim 1, wherein the ophthalmic pharmaceutical composition is in the form of a liquefied gel, a fluid dispersion or an anhydrous salt, which gives eye comfort continuously from the beginning upon administration. The ophthalmic pharmaceutical composition according to claim 1, wherein the particulate cation exchange resin is in the form of finely divided powder, and the powder is composed of spherical particles. 4. The ophthalmic pharmaceutical composition according to claim 3, wherein the cation exchange resin is sodium poly (styrene dibutylbenzene) sulphonic acid and the beta blocker is betasolol. The method of claim 1, wherein the beta blocker is present at a concentration of about 0.25 wt%, the aqueous polymer of the anionic mucus is present at a concentration of about 0.20 wt%, and the cation exchange resin is present at a concentration of about 0.25 wt%. Ophthalmic pharmaceutical composition, characterized in that. The ophthalmic pharmaceutical composition according to claim 2, wherein the ophthalmic composition in the form of a liquefied gel and a fluid dispersion has a viscosity of about 1,000-300,000 cps and about 1-20,000 cps, respectively, and a pH of 3.0-8.5. The method of claim 1, wherein the beta blocker is betasolol, timolol, acebutorol, alprenolol, atenolol, bevantolol, bucomolol, buprenolol, butidrin, bunitrol, bunolol, butokro Rolls, Butamines, Carrazorols, Caterols, Esaprolols, Indenolols, Iprocrolols, Lavetrols, Miffindorols, Metifranolols, Metaprolols, Morprools, Nidorols, Nifenarols , Oxprenolol, paratorol, paragolol, fenbutolol, pindorol, pratolol, procenolol, pronetanol, propranolol, sotarol, tazolol, tiprenolol, tolamorol, tol Ophthalmic medicament, characterized in that it is selected from the group consisting of reprolol, befunolol, esmarol, hefunolol, selifrol, azotinolol, diacetarol, acebutorol, salbutanol, and isosaprolol Composition. A therapeutically effective amount of a basic active ingredient selected from the group consisting of pilocarpine, epinephrine, proepinephrine, norepinephrine, pronorpinephrine, clonidine, para-aminoclinidine and para-acetoamido clonidine, having a carboxylic acid function Ophthalmology to control and lower intraocular pressure, comprising a mucominetic polymer of anionic mucus with a molecular weight of 50,000-6 million with 2-7 carbon atoms per functional group and a particulate cation exchange resin at a concentration of 0.05-100% by weight. Pharmaceutical composition.