JPH03190825A - Prescribed therapeutic preparation having prolonged releasing ability and comfortably applicable for treating glaucoma and method for controlling or reducing intraocular pressure - Google Patents

Abstract

PURPOSE: To obtain a composition for ophthalmology comprising a basic active substance, an anionic pseudo-mucous polymer and a cation exchange resin, excellent in perpetuity and comfortability and used for lowering or control of intraocular pressure. CONSTITUTION: This composition in the form of aqueous dispersion comprises (A) a basic active substance, e.g. β-blocker such as betaxolol or thymol, (B) an anionic pseudomucous polymer, preferably a polymer having a carboxylic acid group containing 2-7 carbon atoms per functional group and having 50,000 to 6,000,000 molecular weight and (C) a powdery cation exchange resin, preferably sodium poly(styrene-divinylbenzene)sulfonate having 1-20μm average particle diameter in ratios of 0.01-40wt.%, especially 0.01-1.0wt.% component A, the component B capable of imparting the composition with 1-20,000cps viscosity and 0.05-10.0wt.% component C.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention This invention relates to ophthalmic formulations useful for controlling and lowering intraocular pressure (IOP) in the treatment of glaucoma. The formulations of the present invention are characterized by long-lasting (sustained release) and are comfortable to the eye both initially and continuously. In particular, the invention relates inter alia to formulations with the above-mentioned characteristics, containing a basic active substance and a cation exchange resin (fine powder) dispersed in an aqueous solution or gel of an acidic mucomimetic polymer. The aqueous gel or pourable liquid formulation thus obtained is characterized by controlled cation-anion interactions,
This interaction is believed to be responsible for the resulting comfort and sustained release properties. The present invention also relates to a method of treatment comprising administering the disclosed compositions when indicated for the treatment of ocular hypertension and glaucoma.

The term "basic active agent" refers to a disclosed substance that has a desired effect on intraocular pressure and is or can be positively charged during or when formulated into a final product formulation. Refers to the active ingredient or ingredients in the formulation. Accordingly, the term basic or cationic active agent is descriptive for purposes of the detailed description and claims of the invention.

Such basic active substances include all currently known essential cationic charge and beta blockers that exhibit IOP effects. Typically, such beta blockers have the following general structure R'-0-CH-CH(OH
) -CH2-NR2R3---(I) [However, R1 in the formula is a substituted or unsubstituted cyclic or aliphatic component, and the cyclic component includes one or more of C, N, and 0 to Monocyclic and polycyclic structures optionally containing selected heteroatoms are included, where R2 and R3 are independently H and
selected from substituted and one unsubstituted alkyl group. ], which structure also represents the beta-blocker basic active agents herein.

Regarding structural formula (I) above, the following documents are cited herein:

Annual Report in Medicinal Chemistry
ts in MedicinalCbemis
try) 14,8]-87 (1979), J.
Med, C:hem, 1983, 26.15
70-1576, 肚 1 ゆう degree 84, 27, 503-50
9, 匡i ゆう 上degree多ゆう, 26.7-11゜ 1 ゆう 上degree 雈3, 26.1561-1569, 匪 1ゆう 上degree 多 3.1109-111.2゜匪11↓degree 13, 26
, 950-957, Ren (Yu upper degree lower 3, 26, 649-6
57, and [, 1983, 26, 352-357゜A representative example of such a basic active substance is befunolol (b
etaxolo), ), timolol
, befunolol, 2 labechlor (abetalol), propranolol (propranolol), bupranolol (bupranolol), mecbrolol (m
etaprolo, ), bunalol
) esmalol, pindolol, carteolol, hepunolol, methiplanolol
pranololj, celiprolol (celiprolol)
lol), azotinolol)
(S-596), diacetolo
l acebutolol, salbutamol, atenolol
nulol), inxaprolol (j-soxaprolol) and the like.

The definition of basic active substances also includes the following types of drugs, pilocarpine (
pi 1ocarpine), epinephrine (epin
ephrine) proepinephrine
prine), norepinephrine (norepine)
phrine), pronorepinephrine (pronor
epinephrine), clonidine (clonid)
ine), and clonidine derivatives 9 such as p-aminoclonidine and p-acetoamidoclonidine
idoclonidine) is also included.

Therefore, in summary, the basic active ingredients of the present invention are:
It is defined by its intraocular pressure-lowering effect or its static control and by its cationic nature in the pH range 3.0 to 8.5 in aqueous media.

The following patent publications further representatively explain the basic active substance of the present invention, and are therefore cited here.

U.S. Patent No. 4,252,984, U.S. Patent No. 3
, 309,406, U.S. Patent No. 3,619,3
No. 70, U.S. Patent No. 3,655,663, U.S. Patent No. 3,657,237, U.S. Patent No. 4.01.2,444, U.S. Patent No. 3,663
, 607, U.S. Pat. No. 3,836,671, U.S. Pat. No. 3,857,952, U.S. Pat. No. 3,202,660, and U.S. Pat.
, No. 774,789.

The ophthalmic formulations of the present invention are in the form of anhydrous salts, pourable aqueous dispersions, and aqueous gels. The formulation contains, for example, a critical polyanionic polymer, a cation exchange resin and a predominately basic active substance in addition to the usual ingredients which provide bacteriostatic and compounding residual effects. Such anhydrous salts are added to ointments or solid ophthalmic inserts that form a colloidal gel in situ when administered to the eye. Pouring liquid and gel embodiments are applied topically to the eye. It must be noted that such liquid and gel embodiments 5 can be obtained by blending anhydrides with water.

The formulations of the invention demonstrate sustained release of basic active substances and are comfortable when administered topically to the eye. In a general sense, it should be noted that when the basic active substances mentioned above are administered neat, a pinprick sensation occurs. Achieving both comfort and sustained release is therefore an unexpected result and allows for the administration of otherwise unimaginable types of mixtures.

Bo1-ion A The high molecular weight polyanionic polymer useful in the present invention is
It has a molecular weight of about 50,000 to about 6,000,000. The polymer is characterized as having carboxylic acid functional groups, preferably 2 per functional group.
Contains from 7 to 7 carbon atoms. The gel that forms during the manufacture of the ophthalmic polymer dispersion has a viscosity of about 1,000 to about 300,000 cps. In addition to the basic active agent-polymer (anionic-cationic) 6 interaction described above, the high molecular weight polymers used in the compositions of the present invention thicken the composition and form a gel. and provides a special type of rheology, ie, plastic viscosity, which may account for the sustained release properties and comfort of the final composition. Such compositions have a pH of 3.0 to 8.0.
It ranges up to 5.

Pourable liquid embodiments of the invention (administered to the eye as drops) have a flow rate of about 1 to 20,000 cps.
It has a viscosity of The pH requirements are the same as listed above for the final gel product, i.e. pH 3.0
to 8.5.

The third pharmaceutical form of the invention, the anhydrous salt form, is derived from a polycarboxylic acid polymer salt and a basic active substance.

(The presence of a cationic ion exchange resin also contributes to the formation of salts, and the nature of the ion exchange resin in all embodiments of the invention is defined below.) Such salts
As mentioned above, upon addition of water, they can be formulated or reconstituted into aqueous gels and pourable dispersions, or can be formulated as ophthalmic inserts according to known techniques and shapes. Alternatively, they can be combined with an oil vehicle to form an ophthalmic ointment. All such final ophthalmic dosage forms are fully described below.

The term "plastic viscosity" above is a measure of a material that does not flow appreciably until a certain force or stress value is exceeded, which is called the yield value.

Although not wishing to be bound by any theory, it is believed that the increased duration of activity of the compositions of the present invention is related, in part, to the yield value. The compositions of the present invention exhibit a unique response to shear stress. When the yield value is exceeded, the gel structure is temporarily altered, causing the gel to flow. In the eye, this mechanism is due in part to the blinking eyelid. When the stress is removed (the eyelid is at rest), the gel structure is partially re-established. Other factors that explain the duration of the formulations of the present invention are ionic interactions and dynamic interactions, including normal tear production and replacement of basic active cations by cations present in the tears. It involves a release mechanism explained by equilibrium. This mechanism is restated below.

Suitable polymers useful in this invention are carboxyvinyl polymers. Preferred polymers of this type include those manufactured by B.F. under the trade name Carbopol.
Gutdrich Company (B, F.

So-called Carbomers, available from Goodrich Company
), and the Monsanto Company under the trade name HMA.
There is an ethylene maleic anhydride polymeric material available from Pany. Carbopo is a well-known and easily available polymer.
l) 934 and Carbopol 940 are particularly preferred. These polymers may be used in aqueous gel compositions at levels up to about 8% by weight, and pourable liquid compositions may contain from 0.05% to 2.0% by weight of the polymers. include.

Preferred basic active substances of the present invention are those disclosed above. The most preferred basic active agents are betaxolol and timolol.
It's olj. The basic active material is present in gel and pourable liquid embodiments at a level of about 0.01 to 4.0% by weight, with the most preferred range being 0.01 to 1.0% by weight. It is.

The cationic resin component of the formulations of the present invention provides an additional means of sustained release of the basic active, yet is necessary for initial comfort and extended comfort. It seems to be. Such resins are characterized as either strongly acidic, such as those with sulfonic acid functionality, or weakly acidic cation exchangers, such as those with carboxylic acid functionality. The resin must be added as a fine powder. That is, the resulting spherical particles are 20
．． It must have a diameter less than 0 microns. The release of basic active substances retained by cation exchange resins and anionic polymers is due to the fact that naturally occurring ions in tear fluid, primarily sodium and potassium, are bound for sites on the polymer vehicle and ion exchange resin. This is done when competing with basic active substances. Once released, the basic active substance is presented to the ocular surface for transport to receptor sites.

Any pharmaceutical cationic ion exchange resin is suitable for this formulation as long as they can be used in either the hydrogen or sodium form. Such resin is
For example, Rohm & Haas
As) from "Amherlite"
J, and from the Dow Chemical Company (Dow Chemical Go) as "Dow J".
It is easily available under the trade name 1,7, (Dowex) J. ' can be done.

The ion exchange resin component is 0.05% to 10% by weight.
Present in the formulations of the invention at a level of 0%. The average particle size diameter of the resin is 1 to 20 microns.

The particle size of this resin is critical both with regard to mode of action and comfort. Typically, the average particle size of commercially available fine ion exchange materials is about 40 to 150 microns. Such particles are most conveniently reduced to a particle size range of about 1.0 to 25 microns by ball milling according to known techniques.

Ophthalmic products are typically multidose.
) packaged in shape. Preservatives are therefore required to prevent microbial contamination during use. Suitable preservatives include benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium.
, um), sorbic acid, Onamer M, or other agents known to those skilled in the art. Typically, such preservatives are used at levels of 0.001% to 1.0% by weight.

Strength of tonicity agent product (
tonicity), or osmolality (osm)
olaHty) can be adjusted to either hypotonic, isotonic or hypertonic pressures with respect to normal tears by the use of common substances known in the art. However, such tensioning agents are limited to non-ionic compounds and typically range from 0.0% to 10% by weight in the final product when used.

Typical non-ionic agents include mannitol, dextrose, glycerin and glycerin, however their presence in the final product is optional.

spoon phrase The composition of the present invention has three basic conditions: 1) gel, 2) a pourable liquid, and 3) Anhydrous salt It is prescribed in the following conditions.

1) Disperse the cation exchange resin component in water. Then add the basic active ingredient while stirring. The polyanionic polymer component is then added. The resulting product has between 1000 and 300,000 cps depending on the anionic polymer concentration.
It has a viscosity in the range of . The resulting pH is between 3.0 and 8.5, which can be HCβ or N
It can be adjusted with aOH.

2) Dispersing the cation exchange resin component in 10 to 50 volume percent of the total water incorporated into the formulation and then dispersing and/or dissolving the basic active agent with stirring. . The polyanionic polymer is added until the desired product pH as an aqueous dispersion is obtained. The pH of the product can be adjusted to the desired value by changing the basic active substance/polymer/resin ratio. If desired, the final I)H of the product can be modified with NaOH or H
It can be adjusted by adding either Cρ. The preferred pH range for ophthalmic formulations is between 3.0 and 8.
．． It is 5. The final product is a dispersion, which may require high-energy mixing to break up any agglomerations to achieve uniformity. Next, add the other ingredients while stirring. The resulting product is 1.0 to 20,000 eps depending on the anionic polymer concentration.
It has a viscosity in the range of .

3) Water blind μ The basic active substance, ion exchange resin, and polyanionic polymer are brought together in water, mixed and then lyophilized to a powder. Fillers such as mannitol and other substances are added to facilitate the freeze/dry process according to techniques well known to those skilled in the art. The anhydrous salts produced in this manner can then be formulated or reconstituted into aqueous gels and liquids, or formulated and shaped as ophthalmic inserts. The lyophilized powder can also be combined with a non-aqueous vehicle to form an ophthalmic ointment.

Such anhydrous salt embodiments of the invention also provide the desired salt by extracting the initial aqueous dispersion with an organic solvent such as ethanol, chloroform, benzene, or the like and evaporating the organic solvent. It can also be manufactured by forming a complex.

The ophthalmic formulations of the present invention are administered to the eye as gels, pourable liquids (eye drops), and in the form of ointments and ophthalmic inserts, although this latter category Prescribed. All such compositions are formulated to control the release of the basic active when administered to the eye, thereby providing sustained release. Typically such administration is required once or twice daily. Precise dose control is left to the routine discretion of the clinician.

EXAMPLES The following examples specifically illustrate, but do not limit, the therapeutic aspects or methods of the present invention.

Make the mixture basic. At this point, the pH of the mixture
is approximately 9.6. The white solid thus obtained is collected by filtration and washed with copious amounts of water.

After pressing/drying in the filter funnel, the semi-dry solids are resuspended in a large volume of water and stirred for 1 to 2 hours. The white solid is collected by filtration and washed with copious amounts of water to obtain salt-free betaxolol free base, which is dried under vacuum.

Betaxolol hydrochloride is described in US Pat. No. 4,252,984 and is commercially available.

Betaxolol hydrochloride (0.88 mol) is dissolved in water and the solution is cooled in a water bath. To this solution, while stirring vigorously, an aqueous solution of sodium hydroxide (0.97 mol) was added in several parts. JLj Hada-no (3) is mixed in 50% of the total water content to form a uniform dispersion. Carbopol -
934P is added slowly as an aqueous dispersion. Homogenize the mixture at high speed. Add other ingredients as an aqueous solution. Add water to final volume. Products A and B obtained
and C are white homogeneous suspensions.

Disaster - Blood - Yu (1) Finely powdered Amberlite
I RP-69 resin, sodium poly(styrene-divinylbenzene) sulfonate and betaxolol 12-JLJ-1 (2) 1-14-U (3) 1 liter of solutions A, B and C of Example 3. , prepared according to the procedure of Example 2. The resulting product is a white to off-white homogeneous suspension with p)(5.5 to 6.5).

Following the procedures of Examples 2 and 3 yields virtually identical results when the betaxolol component is replaced by an equivalent amount of timolol, respectively, or any of the beta blockers and other basic actives noted above. can get.

The invention has been disclosed herein with respect to certain preferred embodiments. However, obvious variations thereon will be apparent to those skilled in the art and the invention should not be considered limited thereto.

Claims (1)

[Claims] (1) Basic active substance, anionic pseudomucosal (muc)
1. An ophthalmic pharmaceutical composition for controlling and lowering intraocular pressure, comprising a cation exchange resin and a cation exchange resin. (2) The composition according to claim 1, wherein the composition is an aqueous dispersion. (3) basic active substance, anionic pseudomucosal polymer,
and a finely divided cation exchange resin, an ophthalmic pharmaceutical composition for controlling and lowering intraocular pressure as an aqueous dispersion. (4) The composition according to claim 3, wherein the basic active substance is betaxolol. (5) The composition according to claim 3, wherein the basic active substance is timolol. (6) The basic active substance is pilocarpine, epinephrine, proepinephrine (p
roepinephrine), norepinephrine (n
orepinephrine), pronorepinephrine, clonidine, p-aminoclonidine
ne), p-acetamidoclonidine (p-aceto
amido-clonidine), or betaxolol, timolol, acebutolol, alprenolol, atenolol (at
enolol), bevantolol, bucomolol, bupranolol, butidrine, bunitolol, bunolol, butocrol, butidrine Tamin (
butamine, carazolol, carteolol, exaprolol, indenolol, iprochlorol, labetolol, mepind olol), metipranolol, metaprolol, moprolol
lol), nadolol, nifenalol, oxprenolol, pamatolol, paragolol, penbutolol, pindolol, practorol (practolol), procinolol (procinolol) ), pronethalol, propranolol (
propranolol), sotalol (propranolol), sotalol (propranolol)
l), tazolol, tiprenolol, tolamolol, toliprolol, befunolol, esmalol, hepnolol, cel iprolol, azotinolol , diacetalol (di
acetalol, acebutol
lol), salbutanol,
and isoxaprolol
4. A composition according to claim 3, wherein the composition is selected from beta blockers selected from: (7) Therapeutically effective amount formula R^1-O-CH_2-CH(OH)-CH_2-NR
^2R^3 (wherein R^1 is a substituted or unsubstituted cyclic or aliphatic moiety, and R^2 and R^3 are independently H and substituted and (selected from unsubstituted alkyl groups) having carboxylic acid functional groups containing 2 to 7 carbon atoms per functional group and having a molecular weight of 50,000 to 6,000,000. anionic pseudomucosal polymer in an amount such that the composition in the form of an aqueous gel or pourable aqueous dispersion has a viscosity of about 1 to 20,000 cps, and about 0 cps by weight. Pourable aqueous gel for controlling and lowering intraocular pressure containing a particulate cation exchange resin at a concentration of .05% to 10.0%, and the pH of the composition is about 3.0 to 8.5. A composition according to claim 1, which is a colored ophthalmic pharmaceutical composition in the form of an aqueous dispersion or an anhydrous salt. (8) The composition of claim 7, wherein the particulate cation exchange resin is in the form of a fine powder, and the powder contains spherical particles. (9) The composition of claim 8, wherein the cation exchange resin is sodium poly(styrene divinylbenzene) sulfonic acid and the beta blocker is betaxolol. (10) the beta blocker is present at a concentration of about 0.25% by weight, the anionic pseudomucosal polymer is present at a concentration of about 0.20% by weight, and the cation exchange resin is present at a concentration of about 0.25% by weight; 8. A composition according to claim 7, wherein the composition is present in a concentration of % by weight. (11) A method of treatment for controlling and lowering intraocular pressure, comprising administering to a patient the composition of claim 1. (12) The composition is an aqueous dispersion, the cation exchange resin is micronized, and the basic active agent is pilocarpine, epinephrine, proepinephrine (p
roepinephrine), norepinephrine (n
orepinephrine), pronorepinephrine, clonidine, p-aminoclonidine
ne), p-acetamidoclonidine (p-aceto
amido-clonidine), or betaxolol, timolol, acebutolol, alprenolol, atenolol (at
enolol), bevantolol, bucomolol, bupranolol, butidrine, bunitolol, bunolol, butocrol, butidrine Tamin (
butamine, carazolol, carteolol, exaprolol, indenolol, iprochlorol, labetolol, mepind olol), metipranolol, metaprolol, moprolol
lol), nadolol, nifenalol, oxprenolol, pamatolol, paragolol, penbutolol, pindolol, practorol (practolol), procinolol (procinolol) ), pronethalol, propranolol (
propranolol), sotalol (propranolol), sotalol (propranolol)
l), tazolol, tiprenolol, tolamolol, toliprolol, befunolol, esmalol, hepnolol, cel iprolol, azotinolol , diacetalol (di
acetalol, acebutol
lol), salbutanol,
and isoxaprolol
Claim 11 selected from beta blockers selected from
The method described in.