NZ231614A - Ophthalmic composition for controlling intraocular pressure - Google Patents
Ophthalmic composition for controlling intraocular pressureInfo
- Publication number
- NZ231614A NZ231614A NZ23161489A NZ23161489A NZ231614A NZ 231614 A NZ231614 A NZ 231614A NZ 23161489 A NZ23161489 A NZ 23161489A NZ 23161489 A NZ23161489 A NZ 23161489A NZ 231614 A NZ231614 A NZ 231614A
- Authority
- NZ
- New Zealand
- Prior art keywords
- composition
- exchange resin
- betaxolol
- basic
- intraocular pressure
- Prior art date
Links
Description
<div class="application article clearfix" id="description">
<p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number £31 614 <br><br>
231614 <br><br>
Priority Dato(s): <br><br>
Complete Specification Filed: <br><br>
Class: . ft !?.!. .* <br><br>
Publication Date: .. <br><br>
P.O. Journal, No: ... <br><br>
No.: Dale: <br><br>
NEW ZEALAND <br><br>
PATENTS ACT, 1953 <br><br>
i; <br><br>
COMPLETE SPECIFICATION <br><br>
SUSTAINED RELEASE, COMFORT FORMULATION FOR GLAUCOMA THERAPY <br><br>
» We, ALCON LABORATORIES, INC. a corporation of the state of Delaware, T"" nr\i United States of America, of 6201 South Freeway, Fort Worth, Texas 'J010T, <br><br>
I ^ <br><br>
United States of America hereby declare the invention for which we pray that a patent may be granted to Jart€"/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - <br><br>
- 1 - <br><br>
(followed by page 1A) <br><br>
23161 <br><br>
509-020B <br><br>
SUSTAINED RELEASE, COMFORT FORMULATION FOR GLAUCOMA THERAPY <br><br>
Background of the Invention <br><br>
This invention relates to ophthalmic formulations useful in controlling and lowering intraocular pressure (IOP) in the treatment of glaucoma. The formulations of the present invention are characterized as long lasting (sustained release) and are initially and continually comfortable to the eye. Specifically, the invention relates to formulations of the above characteristics which comprise, inter alia, a basic active and cationic exchange resin (finely divided) dispersed in an aqueous solution or gel of an acidic, mucomimetic polymer. Such resulting aqueous gel or pourable liquid formulations are characterized by controlled cationic-anionic interactions, which appear to be responsible for the resulting comfort and sustained release properties. This invention also relates to methods of treatment which comprise administering the described compositions when indicated for treating ocular hypertension and glaucoma. <br><br>
The term "basic active" means the active ingredient or ingredients in the disclosed formulations which have the desired effect on intraocular pressure and which bear, or are capable of bearing, a positive charge during formulation of the final product or as formulated in the final product form. Thus, the term <br><br>
2 <br><br>
231614' <br><br>
basic, or cationic, active is descriptive for purposes of the disclosure and claims. <br><br>
Such basic actives include all presently known beta blockers which demonstrate the requisite cationic 5 charge and IOP effect. Typically, such beta blockers are represented by the following generic structure, which structure also represents the beta blocker basic actives of the present disclosure: <br><br>
R1-0-CH2-CH(OH)-CH2-NR2R3 (I) <br><br>
10 wherein: R^ is a substituted or unsubstituted cyclic or aliphatic moiety; cyclic moieties include mono- and polycyclic structures which may contain one or more <br><br>
2 3 <br><br>
heteroatoms selected from C, N, and 0; R and R are independently selected from H and substituted and 15 unsubstituted alkyl. With regard to Structure (I), above, the following references are incorporated herein by reference: Annual Reports in Medicinal Chemistry 14, 81-87 (1979); J. Med. Chem. 1983, 2 6,1570-1576; ibid.. 1984, 27, 503-509; ibid.. 1983. 26, 7-11; ibid. . 1983. 20 26, 1561-1569 ; ibid.. 1983 1109-1112; ibid., 1983. 26 , 950-957; ibid.. 1983■ 26, 649-657; and ibid.. 1983. 26, 352-357. Representative of such basic actives are: betaxolol, timolol, befunolol, labetalol, propranolol, bupranolol, metaprolol, bunalol, esmalol, pindolol, 25 carteolol, hepunolol, metipranolol, celiprolol, azotinolol (S-596), diacetolol, acebutolol, salbutamol, atenulol, isoxaprolol, and the like. <br><br>
The definition of basic active also includes the following classes of drugs which are used in treatment 30 of ocular hypertension and glaucoma: pilocarpine; epinephrine; proepinephrine; norepinephrine; pronorepinephrine; clonidine; and clonidine <br><br>
3 <br><br>
2316 1 4 <br><br>
derivatives, for example, p-aminoclonidine and p-acetoamidoclonidine. <br><br>
Thus, in summary, the basic active component of the present invention is defined by its intraocular pressure lowering effect or static control thereof, and by its cationic nature in an aqueous medium in the pH range of from 3.0 to 8.5. The following patent publications, which are incorporated herein by reference, further representatively demonstrate the basic actives of the present invention: U.S. Patents Nos. 4,252,984; 3,309,406; 3,619,370; 3,655,663; 3, 65 7,237; 4,012,444; 3 , 663 , 607 ; 3,836 , 671; 3,857,952; 3,202,660; and 2,774,789. <br><br>
Detailed Description of the Invention <br><br>
The ophthalmic formulations of the present invention are in the form of: anhydrous salts; pourable, aqueous dispersions; and aqueous gels. The formulations comprise, in addition to conventional ingredients which provide, for example, bacteriostatic and formulatory balance functions, a critical polyanionic polymer, a cation exchange resin and the basic active of choice. Such anhydrous salt forms are incorporated into ointments or solid ocular inserts which form colloidal gels in, situ on administration to the eye. The pourable liquid and gel embodiments are applied topically to the eye. It should be noted that such liquid and gel embodiments can be obtained from the anhydrous form on formulation with water. <br><br>
The formulations of the present invention demonstrate sustained release of the basic active and are comfortable on topical administration to the eye. It should be noted, in a general sense, that a stinging sensation results when the basic actives, identified <br><br>
4 <br><br>
231614 <br><br>
above, are administered neat. Thus, achieving both comfort and sustained release is an unexpected result and permits administration of a class of compounds that otherwise might not be considered. <br><br>
5 Polyanionic Polymer Component <br><br>
The high molecular weight, polyanionic polymers useful in the present invention have a molecular weight of from about 50,000 to about 6 million. The polymers are characterized as having carboxylic acid functional 10 groups, and preferably contain from 2 to 7 carbon atoms per functional group. The gels which form during the preparation of the ophthalmic polymer dispersion have a viscosity of from about 1,000 to about 300,000 cps. In addition to the basic active-polymer (anionic-catonic) 15 interactions, mentioned above, the high molecular weight polymers used in the compositions of the present invention thicken the compositions to provide a gel, and provide a special type of rheology, i.e., plastic viscosity, which is translatable to the sustained 20 release and comfort of the final compositions. Such compositions range in pH from 3.0 to 8.5. <br><br>
The pourable liquid embodiments (administered as drops to the eye) of the present invention have a viscosity of from about 1 to 20,000 cps. The pH 25 requirements are the same as recited above for the gel final products, i.e., pH 3.0-8.5. <br><br>
The third pharmaceutical form of the present invention, the anhydrous salt form, is derived from a salt of the polycarboxylic acid polymer and the basic 30 active. (The presence of the cationic ion exchange resin also contributes to salt formation; the nature of the ion exchange resin, in all embodiments of the present invention, is defined below.) Such salts can <br><br>
5 <br><br>
231614 <br><br>
be formulated, or reconstituted, to aqueous gels and pourable dispersions, as described above, on addition of water; or can be formulated as ocular inserts according to known technology and shapes; or they can 5 be combined with an oleaginous vehicle to form an ophthalmic ointment. All such final ophthalmic pharmaceutical forms are fully described below. <br><br>
The term "plastic viscosity", above, is indicative of a material that does not perceptibly flow until a 10 certain force or stress value is exceeded; this force or stress is referred to as the yield value. While 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 15 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 altered temporarily, allowing the gel to flow. In the eye, this mechanism is partially attributable to the 20 blinking eyelid. When the stress is removed (eyelid at rest), the structure of the gel is partially reestablished. Other factors which explain the duration of the formulations of the present invention are related to ionic interactions, and a release mechanism 25 which is explained by a dynamic equilibrium involving normal tear production and the displacement of basic active cations by cations present in tears. This mechanism is mentioned again, below. <br><br>
Suitable polymers useful in the present invention 30 are carboxyl vinyl polymers. Preferred polymers of this class include the so called Carbomers, available under the trade name Carbopol from the B.F. Goodrich Company; and ethylene raaleic anhydride polymeric material, available under the trade name EMA from the <br><br>
2316 <br><br>
6 <br><br>
Monsanto Company. The known and readily available polymers Carbopol 9 34 and 940 are specifically preferred. The polymers are used in the aqueous gel compositions at a level up to about 8% by weight; <br><br>
5 pourable liquid compositions comprise 0.05% to 2.0% by weight polymer. <br><br>
Basic Active <br><br>
The preferred basic actives of the present invention are those disclosed above The most preferred 10 basic actives are betaxolol and timolol. The basic active, in the gel and pourable liquid embodiments, is present at a level of from about 0.01 to 4,0 wt. %; the most preferred range is from 0.10 to 1.0 wt. %. <br><br>
Ion Exchange Resin 15 The cationic resin component of the formulations of the present invention provides an additional means of sustained release of the basic active, and appears to be necessary for initial and prolonged comfort. Such resins are characterized as either strongly acidic 20 such as those having sulfonic acid functionality, or weakly acidic cation exchangers such as those having carboxylic acid functionality. The resin must be incorporated as a finely divided powder, that is, 95% of the resulting spheroidal particles must have a 25 diameter less than 20.0 microns. The release of the basic active held by the cation exchange resin and the anionic polymer is achieved when ions naturally present in the tear fluid, principally sodium and potassium, compete with the bound basic active for sites on the 30 polymer vehicle and the ion exchange resin. Thus released, the basic active is presented to the eye surface for transport to the receptor sites. <br><br>
7 <br><br>
2316 14 <br><br>
Any pharmaceutical grade cationic ion exchange resin is suitable for the formulation, an they can be used either in the hydrogen form or in the sodium form. Such resins are readily available, for example, from 5 Rohm & Haas under the "Amberlite" tradename and from Dow Chemical Co. under the "Dowex" tradename. <br><br>
The ion exchange resin component is present in the formulations of the present invention at a level of from 0.05% to 10.0% by weight. The average particle 10 size diameter of the resin ranges from 1 to 20 microns. <br><br>
The particle size of the resin is critical, both with respect to mode of action and comfort. Typically the average particle size of the commercially available from of the ion exchange material of choice is about 40 15 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. <br><br>
Other Ingredients <br><br>
Antimicrobial Preservative; <br><br>
20 Ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl 25 paraben, phenylethyl alcohol, edetate disodium, sorbic acid, Onamer M, or other agents known to those skilled in the art. Typically such preservatives are employed at a level of from 0.001% to 1.0% by weight. <br><br>
Tonicity Agents: <br><br>
30 The tonicity, or osmolality, of the product can be adjusted to either hypotonicity, isotonicity or <br><br>
8 <br><br>
2316 1 4 <br><br>
hypertonici ty relative to normal tears by use of conventional materials known to the art. Such tonicity agents, however, are limited to nonionic compounds and typically, when employed, range from 0.0% to 10% weight 5 percent in the final product. Nonionic agents representatively include: mannitol, dextrose, glycerine and propyleneglycol; their presence in the final product form, however, is optional. <br><br>
Formulation <br><br>
10 The compositions are formulated in three basic states: 1.) gels; 2.)pourable liquids; and 3.) anhydrous salts: <br><br>
1.) Gels <br><br>
The cationic exchange resin component is 15 dispersed in water. The basic active component is then added with stirring. The polyanionic polymer component is then added. The resulting product has a viscosity ranging from 1000 to 300,000 cps depending 20 on the anionic polymer concentration. The resulting pH is 3.0 to 8.5, which may be adjusted, if necessary, with HC1 or NaOH. <br><br>
2.) Pourable Liquids <br><br>
The cationic exchange resin component is 25 dispersed in 10 to 50 vol. percent of total water taken in formulation, and then basic active is dispersed and/or dissolved with stirring. The polyanionic polymer, as an aqueous dispersion, is added until the 30 desired pH of the product is obtained. The pH of the product can be adjusted to the desired value by varying basic active/polymer/resin ratio. If desired, <br><br>
23161 <br><br>
9 <br><br>
final pH of product can be adjusted with addition of either NaOH or HC1. The preferred pH range for ophthalmic formulations if from 3.0 to 8.5. The final product is a dispersion, which may require high energy mixing to break any agglomeration to achieve uniformity. Other formulation ingredients are then added with mixing. The resulting product has a viscosity ranging from 1.0 to 20,000 cps depending on the anionic polymer concentration. <br><br>
Anhydrous Salts <br><br>
The basic active, the ion exchange resin, and the polyanionic polymer are combined in water, and following mixing, are lyophilized to a powder. Fillers like mannitol and other materials may be added to facilitate the freeze/drying processing according to techniques well known to those skilled in the art. The anhydrous salts produced in this manner can then be formulated or reconstituted to aqueous gels and liquids, or can be formulated and shaped as ocular insets. The lyophilized powder can also be combined with a nonaqueous vehicle to form an ophthalmic ointment. <br><br>
Such anhydrous salt embodiments 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 evaporating the organic solvent to produce <br><br>
10 <br><br>
231614 <br><br>
the desired salt complex. The resulting product is substantially equivalent to the above-described lyophilized product. <br><br>
Utility <br><br>
5 The Ophthalmic formulations of the present invention are administered to the eyes as gels, pourable liquids (eye drops), and in the form of ointments and ocular inserts; the latter classifications are formulated form anhydrous salts. 10 All such compositions are formulated to control the release of the basic active upon administration to the eye and thereby provide a sustained release effect. Typically such administration is necessary once or twice per day. The precise dosage regimen is left to 15 the routine discretion of the clinician. <br><br>
The following examples illustrate, but do not limit the compositional or method of treatment aspects of the present invention. <br><br>
Example 1 <br><br>
20 Preparation of Betaxolol Free Base from Betaxolol Hydrochloride: <br><br>
Betaxolol Hydrochloride is disclosed in U.S. Patent 4,252,984, and is commercially available. 25 Betaxolol Hydrochloride (0.88 moles) is dissolved in water and the solution is chilled in an ice-bath. To this solution is added a solution of sodium hydroxide (0.97 moles) in water portionwise to make the mixture basic while it is stirred vigorously. At this 30 point the pH of the mixture is approximately 9.6. The resulting white solid is collected by filtration and washed with a large volume of water. <br><br>
11 <br><br>
2316 14 <br><br>
After press/drying in the filter funnel, the semi-dry solid is resuspended in a large volume of water and stirred for 1-2 hours. The white solid is collected by filtration and washed with a large volume of water to afford salt-free Betaxolol free base, which is dried in vacuo. <br><br>
Example 2 <br><br>
Product Composition <br><br>
A (wt % ) B (wt % ^ C (wt % 1 <br><br>
10 Betaxolol 0.50 0.25 1.0 <br><br>
CARBOPOL-934 P (Carbomer) 0.25 0.15 0.35 <br><br>
Sodium Poly(Styrene-Divinyl <br><br>
Benzene) Sulfonate 0.25 0.125 0.50 <br><br>
Benzalkonium Chloride 0.01 0.01 0.01 <br><br>
15 Mannitol 5.0 5.0 5.0 <br><br>
Water To Make 100% <br><br>
Procedure <br><br>
Finely divided Amberlite IRP-69 resin, a sodium poly(styrene-divinyl benzene) sulfonate, and the 20 betaxolol are mixed in 50% of the total water volume component to form a uniform dispersion. The Carbopol-934P is added slowly as an aqueous dispersion. The mixture is homogenized at high speed. The other ingredients are added as aqueous solutions. The final 25 volume is made on addition of water. The resultant products, A, B and C, are white uniform suspensions. <br><br></p>
</div>
Claims (14)
1. An ophthalmic pharmaceutical composition for 5 controlling and lowering intraocular pressure comprising a basic active, an anionic mucomimetic polymer, and a cation exchange resin.
2. The compositions according to claim 1 wherein the composition is an aqueous dispersion. 10
3. An ophthalmic pharmaceutical composition for controlling and lowering intraocular pressure as an aqueous dispersion comprising a basic active, an anionic mucuomimetic polymer, and a finely divided cation exchange resin. 15
4. The composition according to claim 3 wherein the basic active is betaxolol.
5. The composition according to claim 3 wherein the basic active is timolol.
6. The composition of claim 3 wherein the basic 20 active is selected from pilocarpine, epinephrine, proepinephrine, norepinephrine, pronorepinephrine, clonidine, p-aminoclonidine, p-acetoamidoclonidine, or a beta-blocker selected from betaxolol, timolol, acebutolol, alprenolol, atenolol, bevantolol, 25 bucomolol, bupranolol, butidrine, bunitolol, bunolol, butocrolol, butamine, carazolol, carteolol, exaprolol, indenolol, iprocrolol, labetolol, mepindolol, 14 231614 metiprariolol, metaprolol, moprolol, nadolol, nifenalol, oxprenolol, pamatolol, paragolol, penbutolol, pindolol, practolol, procinolol, pronethalol, propranolol, sotalol, tazolol, tiprenolol, tolamolol, toliprolol, 5 befunolol, esmalol, hepunolol, celiprolol, azotinolol, diacetalol, acebutolol, salbutamol , and isoxaprolol.
7. A composition according to claim 1 which is a sustained release ophthalmic pharmaceutical composition in the form of an aqueous gel, a pourable aqueous 10 dispersion, or anhydrous salt, for controlling and lowering intraocular pressure comprising: a therapeutically effective amount of a beta blocker of the formula: R1-0-CH2-CH(OH)-CH2-NR2R3 15 wherein R* is a substituted or unsubstituted cyclic or;2 3;aliphatic moiety, and R and R are independently selected for H and substituted and unsubstituted alkyl;;an amount of an anionic mucomimetic polymer having carboxylic acid functional groups which comprise 20 from 2 to 7 carbon atoms per function group and a molecular weight from 50,000 to 6 million such that the composition in the form of an aqueous gel or pourable aqueous dispersion has a viscosity of l to 20,000 cps. ; and a particulate cation exchange resin at a 25 concentration of from 0.05% to 10.0% by weight, the composition having a pH of from 3.0 to 8.5.;
8. The compositions of claim 7 wherein the particulate cation exchange resin is in the form of a.^;231614;15;finely divided powder, said powder consisting of spherical particles.;
9. The composition of claim 8 wherein the cation exchange resin is sodium poly(styrene divinylbenzene);5 sulfonic acid and the beta blocker is betaxolol.;
10. A composition according to claim 7 wherein the beta blocker is present at a concentration of about 0.25 wt.%, the anionic mucomimetic polymer is present at a concentration of about 0.20 wt.%, and the cation;10 exchange resin is present at a concentration of about 0 . 25 wt.%.;
11. A method of treatment for controlling and lowering intraocular pressure comprising administering to a non-human patient the composition of claim 1.;15
12. The method according to claim 11 wherein the composition is an aqueous dispersion, and the cation exchange resin is finely divided, and the basic active is selected from pilocarpine, epinephrine, proepinephrine, norepinephrine, pronorepinephrine, 20 clonidine, p-aminoclonidine, p-acetoamidoclonidine, or a beta-blocker selected from betaxolol, timolol, acebutolol, alprenolol, atenolol, bevantolol, bucomolol, bupranolol, butidrine, bunitolol, bunolol, butocrolol, butoamine, carazolol, carteolol, exaprolol, 25 indenolol, iprocrolol, labetolol, mepindolol, metipranolol, metaprolol, moprolol, nadolol, nifenalol, oxprenolol, pamatolol, paragolol, penbutolol, pindolol, practolol, procinolol, pronethalol, propranolol, sotalol, tazolol, tiprenolol, tolamQlol, toliprolol,;ZlMf* 231614 16 befunolol, esmalol, hepunolol, celiprolol, azotinolol, diacetalol, acebutolol, salbutamol and isoxaprolol.
13. An ophthalmic pharmaceutical composition as claimed in any one of claims 1 to 10 substantially as herein described with reference to any example thereof.
14. A method of treatment for controlling and lowering intraocular pressure as claimed in claim 11 or claim 12 substantially as herein described with reference to any example thereof. AfeCQA/ _lA gofiATo ei es. ,/jcl. By ,Wfs?T!icir authorised Agent A. J. PA/IK & SON,
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ23161489A NZ231614A (en) | 1989-12-01 | 1989-12-01 | Ophthalmic composition for controlling intraocular pressure |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ23161489A NZ231614A (en) | 1989-12-01 | 1989-12-01 | Ophthalmic composition for controlling intraocular pressure |
Publications (1)
Publication Number | Publication Date |
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NZ231614A true NZ231614A (en) | 1991-03-26 |
Family
ID=19923049
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NZ23161489A NZ231614A (en) | 1989-12-01 | 1989-12-01 | Ophthalmic composition for controlling intraocular pressure |
Country Status (1)
Country | Link |
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NZ (1) | NZ231614A (en) |
-
1989
- 1989-12-01 NZ NZ23161489A patent/NZ231614A/en unknown
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