Ophthalmic solutions

Details Ophthalmic solutions Ophthalmic solutions

2000-07-14

2003-03-04

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Solid synthetic organic polymer as designated organic active...

Aftertreated polymer

C424S078040, C514S912000, C514S642000

Reexamination Certificate

active

06528048

ABSTRACT:

TECHNICAL FIELD
The present invention relates to ophthalmic solutions formulated with a polymer comprising quaternary ammonium salts and alkylene groups having hydroxyl groups on the main chain, which are highly safe for the eyes, and have a negligible adsorption onto contact lenses.
BACKGROUND ART
Anti-microbial agents often formulated as preservatives in eye drops or eyewash solutions are, for example, p-hydroxybenzoate, benzalkonium chloride, benzethonium chloride, and chlorhexidine glucuronate. However, these drugs can cause refractory corneal epithelium disorders, and accordingly there is a strong need to develop anti-microbial agents with higher levels of safety.
The development of disposable unit-dose eye drops formulated without preservatives is underway, because preservatives, when used in eye drops for the treatment of corneal disorders, may be associated with a risk of worsening the condition of the diseases. However, disposable unit-dose eye drops have several problems such as, the expense, the problem of carrying the eye drops, the waste-disposal problem of the eye drop container, etc. Thus it is desirable to develop multi-dose eye drops containing much safer preservatives.
Contact lenses are divided into two main categories, hard contact lenses and soft contact lenses. Hard contact lenses are made of polymers of acrylic esters such as poly(methyl methacrylate) and soft contact lenses are made of polymers of water-absorbing acrylic esters with hydroxyl groups such as hydroxyethyl methacrylate.
Soft contact lenses are classified into hydrophilic lenses and hydrophobic (non-hydrophilic) lenses according to the materials thereof, the hydrophilic lenses being widely popular. However, hydrophilic contact lenses not only easily absorb water but also tend to adsorb, absorb, and concentrate anti-microbial agents. Based on clinical data and basic research with animal experiments, it has been frequently pointed out that, during the use of hydrophilic contact lenses, the anti-microbial agents accumulated and concentrated in the contact lenses are released over eyes, and the release results in corneal disorders including mild disorders such as, congestion-entailing diffuse superficial keratitis, and serious disorders like corneal erosion and corneal ulcer.
Therefore, it is necessary to make various efforts when formulating eye drops that are used together with contact lenses. For example, anti-microbial agents, which are not desirable for lenses, may have to be omitted, or the formulations may have to be modified so that they are not absorbed/adsorbed onto the lenses. However, such preparations carry some defects; they are inferior in preservative effectiveness or in safety for the eyes. Preservatives formulated into the solutions for disinfecting, storing, or cleaning contact lenses also have similar problems. Although anti-microbial agents have been improved not to adversely affect the lenses, they do not satisfy both safety and preservative effectiveness.
In particular, low-molecular-weight quaternary ammonium compounds such as benzalkonium chloride and benzethonium chloride are known to have a tendency of getting absorbed/adsorbed onto contact lenses. The compounds are concentrated 400 times or more within the lenses. As compared with benzalkonium chloride, biguanides such as chlorhexidine poorly bind on the surface of contact lenses. However, it is also known that biguanides are more easily adsorbed onto lenses when protein-like materials are deposited thereon and the adsorbed compounds tend to cause ophthalmopathy such as ophthalmia.
Since these anti-microbial agents are relatively large cation molecules, they are known to interact with proteins or acidic compounds to form insoluble complexes, which cause clouding or precipitation. Therefore, these types of anti-microbial agents should not be used in ophthalmic solutions comprising acidic compounds as active ingredients or as additives. Furthermore, benzalkonium chloride affects biomembranes and causes the instability of the lacrimal oil layer. This results in the enhancement of drug permeability even at low concentrations. Because of this problem, it should be carefully used in combination with drugs. Moreover, by interacting with a surfactant, p-hydroxybenzoate forms a complex and gets trapped in the micelles, causing a reduction of the anti-microbial efficacy. Accordingly, the concentration of the surfactant used as a solubilizer should be taken into consideration. Thus, the anti-microbial agents used as preservatives in eye drops and eyewash solutions have problems to be solved in the pharmaceutical aspects as well as in safety and preservative effectiveness.
Anti-microbial agents, often formulated into disinfectants for contact lens care, are hydrogen peroxide or other microbicidal agents. In the case of hydrogen peroxide, intense congestion can be caused by the negligence of the neutralization treatment following the use of hydrogen peroxide-containing disinfectants, and therefore, can be unsafe sometimes. An example of microbicidal agents other than hydrogen peroxide is polyquad, which is a polymer of a quaternary ammonium salt and has no hydroxyl group at the cross-liking positions thereof. The uses of this polymer for disinfecting contact lenses and for preserving ophthalmic solutions have been disclosed in the Examined Published Japanese Patent Application (JP-B) No. Hei 2-54804. Another example is polyhexamethylene biguanide, and the use of the polymer for disinfecting contact lenses has been disclosed in JP-B No. Hei 6-49642. The products including these polymers are commercialized under the names of OPTI-FREE (Alcon) and ReNu (Bausch&Lomb), respectively, as new types of chemical disinfectants.
However, polyquad has an insufficient anti-microbial efficacy, while polyhexamethylene biguanide is known to be irritating to the eye. Therefore, both compounds are not satisfactory in anti-microbial efficacy or safety as microbicidal agents in ophthalmic solutions.
DISCLOSURE OF THE INVENTION
An objective of the present invention is to provide ophthalmic solutions formulated with a water-soluble compound that has an anti-microbial efficacy in a concentration range where the compound is not toxic to human cells; does not irritate the eye; is highly stable in aqueous solutions; and is hard to get absorbed, adsorbed, and accumulated on hydrophilic contact lenses.
As a result of extensive studies done by the present inventors, it was revealed that a polymer comprising quaternary ammonium salts and alkylene groups having hydroxyl groups on the main chain is highly useful for the formulation of anti-microbial agents for ophthalmic apparatuses, eye drops, eyewash solutions, as well as cleaning solutions, disinfectants, or storing solutions for contact lenses, because the polymer compound has bactericidal and fungicidal effects within a concentration range where the compound causes no damage to human cells and is not irritating to the eyes as well as being hard to get absorbed, adsorbed, and accumulated on hydrophilic contact lenses. In addition, the present inventors have found that the polymer has a structure containing many hydroxyl groups and is highly hydrophilic, and thereby, when the polymer is used for contact lens care, the lenses become favorably lubricated to be worn comfortably and furthermore, the compound itself is very gentle to eyes.
The present invention relates to ophthalmic solutions that are formulated with a polymer comprising quaternary ammonium salts and alkylene groups having hydroxyl groups on the main chain, and more specifically to:
(1) an ophthalmic solution comprising a polymer comprising quaternary ammonium salts and alkylene groups having hydroxyl groups on the main chain;
(2) the ophthalmic solution as described in (1), wherein the polymer, comprising quaternary ammonium salts and alkylene groups having hydroxyl groups on the main chain, comprises a repetitive unit represented by the following formula:
 wherein R1, R2, R3, and R4 represent alkyl groups having 1 to 3 carbon atoms; A, B,

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