(a) providing a solution of said drug in a therapeutically effective amount, which therapeutically effective amount causes said side effect;
	(b) complexing a portion of said drug in said solution with a cyclodextrin or cyclodextrin derivative to lower the free active concentration such that the severity of said side effect is reduced; and
	(c) incorporating an effective amount of a viscosity increasing agent into said solution to increase the contact time of said solution at the point of administration to the eye of said patient such that the drug is delivered more effectively, whereby the complexed portion of the drug is released over time at a rate insufficient to cause said side effect.

Another aspect of this invention relates to a topical ophthalmic composition prepared by a process comprising
 

	(a) providing a solution of a stable and soluble drug in a therapeutically effective amount, which therapeutically effective amount causes a side effect;
	(b) complexing a portion of said drug in said solution with a cyclodextrin or cyclodextrin derivative to lower the free active concentration such that the severity of said side effect is reduced; and
	(c) incorporating an effective amount of a viscosity increasing agent into said solution to increase the contact time of said solution at the point of administration to the eye of said patient such that the drug is delivered more effectively.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a method of reducing an irritating or adverse side effect associated with the topical ophthalmic use of an active ophthalmic drug. The attenuation of the irritating side effect is accomplished by incorporating an effective amount of a cyclodextrin or cyclodextrin derivative into the formulation containing said drug to complex the active drug such that the concentration of the free active drug is reduced below a tolerable threshold. To compensate for the loss of bioavailability associated with the use of a cyclodextrin or cyclodextrin derivative, an effective amount of a viscosity-enhancing agent is used in the formulation with said drug, such that the bioavailability of said drug is high enough to be therapeutically effective. Unlike the related art, the cyclodextrin or cyclodextrin derivative is not required to solubilize or stabilize the active drug, meaning the drug is soluble and stable in the formulation in the absence of the cyclodextrin or cyclodextrin derivative.

The term "complex" related to an active drug has the meaning generally understood by those skilled in the art, and refers to noncovalent binding of the active drug to a cyclodextrin or cyclodextrin derivative such that significant changes in the physical, chemical, biological, pharmacokinetic, or spectroscopic properties of the active drug can be observed. The terms "complex" and "complexed active drug" should be interpreted broadly, and although the complexed active drug may be in the form of an inclusion compound, this does not necessarily have to be the case. The term "free active drug" refers to that portion of the active drug which is not complexed with the cyclodextrin or cyclodextrin derivative.

Another embodiment of this invention relates to a topical ophthalmic formulation comprising a therapeutically active amount of an ophthalmic drug, an effective amount of a cyclodextrin or cyclodextrin, and an effective amount of a viscosity-enhancing agent. Unlike the related art, the cyclodextrin or cyclodextrin derivative is not required to solubilize or stabilize the active drug. This means that the drug does not precipitate or chemically degrade in the formulation for two years when stored at about 15° C. to about 30° C., and three years when stored at 4° C. in the absence of a cyclodextrin or cyclodextrin derivative. The concentration of the cyclodextrin or cyclodextrin derivative is high enough to reduce the concentration of the free active drug so that the adverse irritating side effects are reduced to an acceptable level. An effective amount of a viscosity-enhancing agent is the quantity required to compensate for the reduced free drug concentration in the tears accompanying complexation of the active drug. By prolonging the precorneal residence time, this viscosity agent effectively restores the desired therapeutic effect of the active ingredient.

While not intending to be bound in any way by theory, the principles of this invention can be understood by considering the dynamic equilibrium between the complexed active drug and the free active drug. It is believed that the irritating side effects of an active drug are determined by the concentration of free active on the ocular surface. It is also believed that the cyclodextrin-drug complex itself cannot cross cell membranes and be transported into the ocular tissues. However, the bioavailability of the drug is affected by both the concentration of the free active drug in the formulation and the dissociation rate between the complexed and the free active drug. For the purpose of this discussion, we define the term "dissociation rate" as the rate at which the cyclodextrin complex releases free active drug on the ocular surface. This release rate is not expected to be the same as occurs upon simple dilution of the cyclodextrin-drug complex in saline because lipid and/or protein components of the tear film may compete with and displace active drug from the cyclodextrin complex.

We have unexpectedly found that cyclodextrin and cyclodextrin derivatives can be used to complex the active drug such that the concentration of an active drug is low enough to reduce or eliminate the irritating side effects, but the dissociation rate is high enough that adequate bioavailability of the drug is achieved. In other words, as the free drug is consumed by transport into the ocular tissues, more drug is released from the cyclodextrin complex. This release must occur at a high enough rate that said drug is therapeutically available while the topical composition is in contact with the ocular surface, before the composition is flushed from the surface by tears, or removed by blinking, etc. As mentioned previously, although the dissociation rate is great enough for some of the originally complexed drug to become therapeutically available when the free active drug is consumed, some loss of bioavailability is still observed due to the use of the cyclodextrin or cyclodextrin derivative. This loss of bioavailability is countered by optimizing the cyclodextrin-drug ratio and by the use of an appropriate viscosity-enhancing agent. While not desiring to be bound in any way by theory, it is believed that the viscosity-enhancing agent increases the amount of time that the topical ophthalmic formulation can adhere to the eye, thus allowing more of the complexed drug to be released for therapeutic use.

In a preferred embodiment of this invention the concentration of the cyclodextrin or cyclodextrin derivative is between about 0.01% and about 10%. In a more preferred embodiment of this invention the concentration of the cyclodextrin or cyclodextrin derivative is between about 0.05% and about 5%. In the most preferred embodiment of this invention the concentration of the cyclodextrin or cyclodextrin derivative is between about 0.05 and about 1.1%.

While not intending to narrow the scope of the invention in any way, in some situations it may be desirable to optimize the type of cyclodextrin or cyclodextrin derivative used in an effort to optimize the equilibrium between the complexed and free active drug as well as the dissociation rate of the free active drug from the cyclodextrin-drug complex. Doing this may be effective in making more of the active drug available for therapeutic uses while keeping the concentration of the free active drug low enough to avoid unacceptable levels of irritating side effects. This is done by varying the cyclodextrin or cyclodextrin derivative used in a formulation and testing the properties of the formulation prepared by the methods to be described herein. In preferred embodiments of this invention, the cyclodextrin or cyclodextrin derivative is 2-hydroxypropyl β-cyclodextrin, 2-hydroxypropyl γ-cyclodextrin, or native γ-cyclodextrin.

In a preferred embodiment of this invention, the amount or type of cyclodextrin or cyclodextrin derivative is adjusted so that free active drug comprises between about 8% and about 90% of the total active drug. More preferably, the free active drug comprises between about 8% and about 75% of the total active drug. Most preferably, the free active drug comprises between about 8% and about 25% of the total active drug.

This invention relates to active drugs used in topical ophthalmic formulations. While not intending to limit the scope of the invention in any way, typical examples of drugs used in topical ophthalmic formulations are prostaglandins, β-adrenoreceptor antagonists and α₂-adrenoreceptor agonists, antihistamines, anti-infective agents, and anti-inflammatory agents. In a preferred embodiment of this invention, the active drug is a prostaglandin. Prostaglandins can be described as derivatives of prostanoic acid which have the following structural formula: ##STR3##

Various types of prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side chain indicated by numerical subscripts after the generic type of prostaglandin [e.g. prostaglandin E₁(PGE₁), prostaglandin E₂ (PGE₂)], and on the configuration of the substituents on the alicyclic ring indicated by α or β [e.g. prostaglandin F_2α (PGF_2β)].

Prostaglandins were earlier regarded as potent ocular hypertensives, however, evidence accumulated in the last two decades shows that some prostaglandins are highly effective ocular hypotensive agents, and are ideally suited for the long-term medical management of glaucoma (see, for example, Bito, L. Z. Biological Protection with Prostaglandins, Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance , S. M. and Neufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505. Such prostaglandins include PGF_2α, PGF_1α, PGE₂, and certain lipid-soluble esters, such as C₁ to C₂ alkyl esters, e.g. 1-isopropyl ester, of such compounds.

In another preferred embodiment of this invention, the active drug is a prostamide. Prostamides are related to prostaglandins in that the carboxylic acid or ester at C₁ is substituted with an amide functional group. For the purposes of this invention, the term amide has the meaning generally understood by organic chemists. Prostamides are prepared by methods generally known in the art, and also by the methods described in U.S. Pat. No. 5,688,819, incorporated herein by reference. In the most preferred embodiment of this invention, the active drug is bimatoprost, which is marketed under the tradename Lumigan® by Allergan, Inc.

In the preferred embodiment of this invention the concentration of bimaprost in an ophthalmic formulation is between about 0.003% and about 0.1%, more preferably the concentration is between about 0.01% and about 0.05%, and most preferably the concentration is about 0.03%.

The term "irritating side effect" refers to any side effect or adverse event characterized by irritation on or near the surface of the eye and surrounding tissues. Such adverse events include, but are not limited to, stinging, ocular dryness, foreign body sensation, and ocular itchiness. In a preferred embodiment of this invention, the irritating side effect being reduced is ocular surface hyperemia. In embodiments of this invention where the hyperemia associated with the use of bimatoprost is reduced, it is preferable that the concentration of free (uncomplexed) bimatoprost is less than 0.02%.

As mentioned, a viscosity-enhancing agent is used in this invention to improve the bioavailability of the active drug. While not intending to limit the scope of the invention, we have found that it is preferable for the viscosity of the formulation to be between about 30 centipoise and about 100 centipoise. We have also found that the preferred concentration of the viscosity increasing agent is between about 0.1% and about 3%, more preferably the concentration of the viscosity agent is about 1%. The viscosity-enhancing agent may comprise a polymer containing hydrophilic groups such as monosaccharides, polysaccharides, ethylene oxide groups, hydroxyl groups, carboxylic acids or other charged functional groups. While not intending to limit the scope of the invention, some examples of viscosity-enhancing agents useful in this invention are sodium carboxymethylcellulose, hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, and polyethylene glycol. Preferably, the viscosity-enhancing agent is sodium carboxymethylcellulose or hydroxypropylmethylcellulose. Most preferably, the viscosity-enhancing agent is sodium carboxymethylcellulose. Particularly useful grades of sodium carboxymethylcellulose are sold under the trade name Aqualon® by Hercules, with low molecular weights of 100,000-900,000, and about 0.65-0.95 hydroxyl groups on each glucose unit substituted with carboxymethylether groups.

In another preferred embodiment, the topical ophthalmic formulation of this invention further comprises an effective amount of buffer necessary to maintain the pH at about 7.3, one or more tonicity agents, and a preservative.

Buffering agents used are those known to those skilled in the art, and, while not intending to be limiting, some examples are acetate, borate, carbonate, citrate, and phosphate buffers. In the most preferred embodiment of this invention, the buffer comprises borate.

The tonicity agents are used to adjust the composition of the formulation to the desired isotonic range. Tonicity agents are known to those skilled in the ophthalmic art, and, while not intending to be limiting, some examples include glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes. In the preferred embodiment of this invention, the tonicity agent is sodium chloride.

In another preferred embodiment of this invention, a preservative is used. Preservatives are used to prevent bacterial contamination in multiple-use ophthalmic preparations, and, while not intending to be limiting, examples include benzalkonium chloride, stabilized oxychloro complexes (otherwise known as Purite®™^?), phenylmercuric acetate, chlorobutanol, benzyl alcohol, parabens, and thimerosal. In a preferred embodiment of this invention, the preservative is Purite®, manufactured by Bio-Cide International, Inc, in Norman, Okla. Purite is an aqueous solution that has sufficient oxychloro complex to generate 2.1-2.3% chlorine dioxide. Purite (oxychloro complex) solution comprises of an equilibrium mixture of oxychloro species, predominantly chlorite (NaClO₂, at 99.5%), chlorate (NaClO₃, ˜0.5%) and traces of chlorine dioxide (ClO₂).

A person skilled in the art will recognize that there are many ways in which the preferences described above can be combined to form unique embodiments. Any combination of the preferences mentioned herein which would be obvious to those of ordinary skill in the art are considered to be separate embodiments which fall within the scope of this invention.

In addition to the considerations above, optimization of the formulation involves choosing both the type and concentration of the buffering system, the tonicity agent, and the preservative. In the current invention, optimization provides for more than just enhanced patient comfort. Any significant stinging, burning, or irritation upon instillation of the prescribed dose will elicit tear flow which in turn will tend to flush the cyclodextrin-drug complex from the ocular surface before adequate drug transport into the ocular tissues has occurred. Once the determinations of the concentration and type of cyclodextrin or cyclodextrin derivative and the viscosity-enhancing agent are made, optimization of the remaining ingredients of the formulation are well within the ability of a person of ordinary skill in the art.
 

Claim 1 of 14 Claims

1. A topical ophthalmic formulation comprising bimatoprost at a concentration of from 0.003% and 0.1%, an effective amount of a cyclodextrin derivative, and an effective amount of a viscosity increasing agent.

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