WO1995034299A1 - Inhibition du myosis/de la production de mydriase peroperatoire par des agents bloquant les canaux calciques - Google Patents

Inhibition du myosis/de la production de mydriase peroperatoire par des agents bloquant les canaux calciques Download PDF

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Publication number
WO1995034299A1
WO1995034299A1 PCT/US1995/007526 US9507526W WO9534299A1 WO 1995034299 A1 WO1995034299 A1 WO 1995034299A1 US 9507526 W US9507526 W US 9507526W WO 9534299 A1 WO9534299 A1 WO 9534299A1
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Prior art keywords
intraocular
calcium channel
channel blocker
type calcium
solution
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PCT/US1995/007526
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English (en)
Inventor
Carlos Belmonte-Martinez
Arthur H. Neufeld
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Telor Ophthalmic Pharmaceuticals, Inc.
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Application filed by Telor Ophthalmic Pharmaceuticals, Inc. filed Critical Telor Ophthalmic Pharmaceuticals, Inc.
Publication of WO1995034299A1 publication Critical patent/WO1995034299A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • This invention relates to a method for inhibiting intraoperative miosis or producing intraoperative mydriasis, wherein a calcium channel blocker is introduced into an intraocular chamber of a subject undergoing intraocular surgery.
  • Kits are provided for supplying the surgeon with an ophthalmologically-acceptable solution containing an effective amount of the calcium channel blocker.
  • SUBSTUUTE SHEET (RULE 26) of cholinergic M3 receptor antagonists to inhibit miosis.
  • Nagy U.S. patent no. 4,960,799 teaches topical administration of beta-blockers to treat inflammation of the eye and discloses that the beta-blockers also inhibit miosis during eye surgery.
  • Bock et al. U.S. patent no. 5,218,114 disclose that cholecystokinin antagonists may be used during intraocular surgery to prevent miosis.
  • Calcium channel blocking agents have been applied topically to the eye to reduce intraocular pressure and treat glaucoma. See, e.g., Abelson, U.S. patent no. 4,981,871.
  • the use of an N-type and an L-type calcium channel blocker as an inhibitor of miosis also has been explored, but the results were not successful. (European Journal of Pharmacology, 209 (1991) 175-183). This study involved the use of ⁇ -conotoxin, an N-type blocker, to block ruthenium red induced miosis.
  • L-type calcium channel blockers inhibit miosis associated with intraocular surgery. This discovery is surprising in that an L-type calcium channel blocker was unable to block miosis associated with ruthenium red. As discussed in greater detail below, it is believed that ruthenium red acts through different pathways in causing miosis than the pathways responsible for miosis associated with intraocular surgery. The invention is believed to take advantage of this difference.
  • a method for inhibiting intraoperative miosis or producing intraoperative mydriasis is provided.
  • An effective amount of an L-type calcium channel blocker is introduced into an intraocular chamber of a subject, substantially simultaneously with performing intraocular surgery on the subject.
  • L-type calcium channel blockers for use in the present invention are amlodipine, benedipine, bepridil, cinnarizine, cyclandelate, darodipine, diltiazem, etafenone, felodipine, fendiline, flunarizine, gallopamil, isradipine, lacidipine, lidoflazine, manidipine, mepirodipine, nicardipine, nifedipine,
  • SUBSTTTUTE SHEET (RULE 26) niludipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, perhexiline, piperazine, prenylamine, tiamdipine, tiapamil, verapamil, analogs thereof and pharmacologically acceptable salts thereof.
  • the preferred blocker is diltiazem.
  • the L-type calcium channel blocker is introduced into the intraocular chamber by instillation of a pharmacologically acceptable carrier containing said calcium channel blocker into the chamber.
  • the L-type calcium channel blocker is introduced into the intraocular chamber by perfusing the chamber with an intraocular irrigating solution containing the blocker.
  • the intraocular irrigation solution may contain the calcium channel blocker at a concentration of about 1 micromolar to 100 millimolar, but preferably at 0. lmM to lO.OmM.
  • the intraocular irrigating solution contains diltiazem at a concentration of O.lmM to lOmM.
  • kits for intraocular surgery comprise a package including a first container containing a first amount of an ophthalmologically acceptable carrier, the first amount being between 10ml and 1000 ml.
  • the package also includes a second container containing an L-type calcium channel blocker in a concentrated amount.
  • the calcium channel blocker is present in the solution at a concentration effective for inhibiting surgical miosis or producing intraoperative mydriasis when introduced into an intraocular chamber.
  • the kit comprises a package including a first container containing a first amount of an intraocular irrigation solution, wherein the solution is incomplete with respect to one or more irrigant components.
  • the first amount is between 100ml and 1000ml.
  • the package also includes a housing containing an L-type calcium channel blocker in a concentrated amount and containing said one or more irrigant components in a supplement amount.
  • the calcium channel blocker is present in the solution at a concentration effective for inhibiting surgical miosis or producing intraoperative mydriasis when introduced into an intraocular chamber and said solution is pH and osmotically compatible with intraocular tissues.
  • the housing may be a second container containing both the L-type calcium channel blocker and the one or more irrigant components.
  • the housing also can be a second and a third container, the second container containing the calcium channel blocker and the third container containing the one or more irrigant components.
  • kits of the invention may include, in addition, instructions for preparation of the therapeutic solution and for use of the solution in connection with intraocular surgery, and in particular to inhibit miosis or produce intraoperative mydriasis during intraocular surgery.
  • the intraocular solutions used in the invention are water solutions containing irrigant components preferably selected from members of the group consisting of sodium ions, potassium ions, calcium ions, magnesium ions, chloride ions, acetate ions, dibasic phosphate ions, bicarbonate ions, citrate ions, dextrose and glutathione disulfide.
  • the present invention also sets forth a device comprising a bottle containing an intraocular solution and an L-type calcium channel blocker present in an amount effective for inhibiting miosis when perfused or instilled into an intraocular chamber of an eye during intraocular surgery.
  • the bottle contains between 10ml and lOOOml of the intraocular solution and the calcium channel blocker, preferably at a concentration between O.lmM and lOmM.
  • the intraocular solution is ophthalmologically acceptable, including being pH compatible and iso-osmotic with the eye.
  • Figure 1 is a graph illustrating the effect on pupil size of intraocular perfusion with an irrigant containing lOO ⁇ M of the calcium channel blocker diltiazem.
  • Figure 2 is a graph illustrating the effect on pupil size of intraocular perfusion with an irrigant containing lmM of the calcium channel blocker diltiazem.
  • Figure 3 is a graph illustrating the effect on post-operative intraocular pressure following intraocular perfusion with an irrigant containing 100 ⁇ M diltiazem.
  • Figure 4 is a graph illustrating the effect on post-operative pupil size following intraocular perfusion with an irrigant containing 100 ⁇ M diltiazem.
  • Figure 5 is a graph illustrating the effect on post-operative intraocular pressure following intraocular perfusion with an irrigant containing 1 mM diltiazem.
  • Figure 6 is a graph illustrating the effect on post-operative pupil size following intraocular perfusion with an irrigant containing 1 mM diltiazem.
  • This invention encompasses methods for inhibiting intraocular surgical miosis or producing intraoperative mydriasis by delivering L-type calcium channel blockers to an intraocular chamber of an eye undergoing surgery.
  • Intraoperative miosis and surgical miosis are used interchangeably herein.
  • Miosis means the constriction of the pupil. Miosis occurs during standard intraocular operative procedures which involve mechanical contact with ocular tissue and manipulation of ocular components. The resultant small pupil size hinders the view of the surgeon, minimizes access to the intraocular cavity and may force modification of the surgical technique.
  • Inhibition of miosis is achieved by preventing, inhibiting or reversing the iris muscle contraction which causes a small pupil during intraocular surgery.
  • Mydriasis is an abnormal dilation of the pupil. Mydriasis can be useful intraoperatively by maximizing access to the intraocular cavity.
  • L-type calcium channel blockers are capable of inhibiting intraocular surgical miosis or producing intraoperative mydriasis when applied to an intraocular chamber substantially simultaneously with surgery. While not limiting the treatment of this invention to the validity of one proposed mechanism of action, it is believed that the L-type calcium channel blockers, when introduced into an intraocular chamber, decrease the ability of the iris to contract by blocking the neuronal conduction of electrical impulses by nerves within the eye, presumably in communication with the iris. It was known that ruthenium red can cause miosis and that this miosis was blocked by ⁇ -conotoxin but np_£ nifedipine.
  • ⁇ -conotoxin is an N-type calcium channel blocker while nifedipine is an L-type.
  • Ruthenium red is a noxious unnatural substance which is added exogenously to the eye to induce these changes. Its mechanism of action in causing miosis is unknown, and ruthenium induced miosis very well may result from effects unrelated to nerve transmission. We believe that surgically induced miosis and ruthenium red induced miosis involve different pathways. Calcium channels are of several types, L, N, P and T. These types have varying degrees of specificity for various drugs, with different drugs acting on different channels. They are believed to be involved in different neuronal functions.
  • the present invention involves the discovery that blockers of one such type of calcium channel, the L-type, can prevent, inhibit and even reverse the miosis induced by mechanical trauma to the eye during the course of eye surgery, even though one such blocker was shown in the prior art to be ineffective in stopping miosis induced using ruthenium red.
  • Intraocular chamber means a space within the eyeball which is bordered by characteristic tissues forming an identifiably separate region.
  • the eye is comprised of three chambers: the anterior chamber, the posterior chamber and the vitreous chamber.
  • the nerves activating iris contraction reside mainly in the tissue surfaces of the anterior and posterior chamber, they may travel as well to more remote intraocular surfaces such as those defining the vitreous chamber.
  • the L-type calcium channel blockers preferably are brought into contact with tissues forming the anterior and posterior chamber surfaces.
  • the method of the invention is for treatment of surgical miosis or for producing intraoperative mydriasis in eyes of mammalian subjects (e.g., humans, nonhuman primates, dogs, cats, horses, sheep, goats, cows, pigs and rodents).
  • Surgical procedures for which this invention is useful include, but are not limited to, the manipulation or the removal of the cataractous lens, phacoemulsification, the manipulation, insertion and/or removal of a prosthetic intraocular lens, pars plana vitrectomy, vitreal surgery, retinal surgery, extracapsular or intracapsular cataract extraction/lens aspiration and anterior segment reconstruction.
  • L-type calcium channel blockers The compounds useful in practicing this invention are L-type calcium channel blockers.
  • L-type "calcium channel blockers” defines a class of molecules well known to those of ordinary skill in the art. They include compounds which have been shown to prevent or delay the cardiac contracture which is caused by an accumulation of intracellular calcium. They also include compounds which have been shown to block the inward movement of extracellular Ca “ " " into a responsive cell. The term is equivalent to the terms "compound having L-type calcium channel blocking activity" or "calcium channel antagonist of the L-type".
  • L-type calcium channel blockers useful in this invention: amlodipine; benedipine; bepridil; cinnarizine; cyclandelate; darodipine; diltiazem; etafenone; felodipine; fendiline; flunarizine; gallopamil; isradipine; lacidipine; lidoflazine; manidipine; mepirodipine; nicardipine; nifedipine; niludipine; nilvadipine; nimodipine; nisoldipine; nitrendipine; perhexiline; piperazine; prenylamine; tiamdipine; tiapamil; verapamil; analogs thereof and pharmacologically acceptable salts thereof.
  • the preferred calcium channel blocker is diltiazem
  • Verapamil and the like are disclosed in U.S. patents 3,261,859, 4,593,042 and 4,681,970.
  • Nifedipine is disclosed in U.S. patent 3,485,847 and is a 1,4-dihydropyridine in which the 2 and 6 positions are substituted by methyl groups, the 4- position by 2-nitrophenyl and the 3 and 5 positions by carboxylic acid methyl ester groups.
  • Similar compounds are disclosed in U.S. patent nos. 3,455,945, 3,325,505 and 3,441,468 to Leow and 3,470,297 and 3,511,837 to Bossert, which introduced variations in the 4-substituent.
  • U.S. Patent No. 4,448,964 to Muto et al. discloses compounds in which the 3-position ester group contains certain substituted piperidinyl alkylene groups.
  • Analogs of the foregoing compounds that function as L-type calcium channel blockers also are specifically intended to be embraced by this invention.
  • An analog is a molecule that is structurally similar to the parent molecule and is capable of achieving the same or substantially the same function or activity in terms of miosis or mydriasis. The ability of such analogs to prevent, inhibit or reverse surgical miosis or produce intraoperative mydriasis according to the invention can be tested easily using no more than routine experimentation.
  • compositions of L-type calcium channel blockers include the conventional non-toxic salts formed from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, proprionic, succinic, glycolic, stearic, lactic, maleic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,
  • SUBSTTTUTE SHEET (RULE 26) salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, formic, malonic, naphthalene-2-sulfonic, benzenesulfonic and the like.
  • the structure of the preferred calcium channel blocker utilized in the method and compositions of this invention is as follows:
  • diltiazem The chemical name of diltiazem (d-diltiazem) is (2S,3S)-3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(4-(methoxyphenyl)-l,5-benzothi azepin-4(5H)-one hydrochloride.
  • the chemical name of the 1-enantiomer of diltiazem is (2R,3R)-3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(4(methoxyphenyl)- l,5-benzo-thiazepin-4(5H)-one hydrochloride.
  • Analogs of diltiazem include: l,3,4,5-tetrahydro-3-(methoxycarbonyl)-4- (4-methoxyphenyl)-2H-l-benzazepin-2-one; l,3,4,5-tetrahydro-3-hydroxy- 3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-l-benzazepin-2-one;l,3,4,5-tetrahydro-hydroxy- 4-(4-methoxycarbonyl)-2H-l-benzazepin-2-one: trans-1.3.4.5-tetrahydro- 3 -hydroxy-4-(4-methoxyphenyl)-2H- 1 -benzazepin-2-one; cis-3 -hydroxy- 1 -
  • the L-type calcium channel blockers are introduced into an intraocular chamber in ophthalmologically acceptable amounts and in ophthalmologically acceptable solutions. Such amounts and solutions are those that cause no medically unacceptable side-effects when administered to an intraocular chamber of the eye according to the methods described herein.
  • Preferred ophthalmologically acceptable solutions are sterile solutions which are approximately iso-osmotic with respect to the fluid in intraocular chambers. Such solutions are non-irritating to the eye and maintain the osmotic stability of the tissues defining the chamber.
  • the osmolality preferably is between about 250 and about 350 mOsm and most preferably about 280-320 mOsm.
  • the solutions also are pH compatible with the environment of the selected intraocular chamber.
  • the pH of the solution preferably is between about 6.5 and about 8.0 and more preferably between about 7.2-7.8. Most preferably the pH is 7.4.
  • the solutions optionally contain particular buffering agents and other factors to support metabolism of the eye tissue.
  • the solution may contain bicarbonate at a concentration of between about 10 and 50 rnM/1.
  • the solution also may contain, for example, dextrose (D-glucose) and glutathione.
  • the buffer preferably is a phosphate buffer whereby the final phosphate concentration is between about 1 and 5 mM/1.
  • Other additives include sodium and potassium salts such as sodium and potassium chlorides, sulfates, acetates, citrates, lactates, and
  • the L-type calcium channel blocker is introduced into the intraocular chamber in an ophthalmologically acceptable carrier solution containing the calcium channel blocker at an effective concentration for inhibiting surgical miosis or producing intraoperative mydriasis. Introduced into the chamber means instilling it in the chamber or perfusing it in the chamber.
  • the solution containing the calcium channel blocker can be instilled in an intraocular chamber using a syringe at a time prior to the start of surgery or very early in the procedure. This instillation may be a single application of a small amount of carrier solution containing the calcium channel blocker.
  • the L-type calcium channel blocker is intended to exert its effect for the total time anticipated for the surgical procedure.
  • the solution thus contains amounts of an L-type calcium channel blocker sufficient to assure persistent inhibition of miosis or continuous mydriasis during the surgery.
  • the solution also may be instilled into the chamber as a "wash", once or several times during the surgery.
  • the eye also may be perfused during the course of the surgery with an ophthalmologically acceptable irrigation solution containing the L-type calcium channel blocker. Perfusion is accomplished by means of a perfusing needle, cannula or probe which delivers in a sterile manner perfusing solution from a container.
  • the cannula (as generally used in intraocular surgery) is capable of both providing the irrigation solution to the eye and also aspirating fluid thereby maintaining a clear field of operation for the surgeon.
  • the duration of action of the L-type calcium channel blocker can influence the time at which the blocker is introduced into a chamber of the eye undergoing surgery. It is intended that the L-type calcium channel blocker be applied substantially simultaneously with the surgical procedure. “Substantially simultaneously” means that the blocker is introduced such that its effect coincides with the time during which the surgical procedure is being performed. The duration of action of the blocker will affect the choice of the blocker and the method by which the blocker is introduced into the intraocular chamber.
  • an L-type calcium channel blocker which is capable of exhibiting an effect for about a half hour or more (i.e., the entire time which may be needed to perform the eye surgery) may be introduced into an intraocular chamber in a single dose prior to or at the beginning of surgery.
  • Those L-type calcium channel blockers that have a somewhat shorter duration of action may need re-instillation, such as by a wash. In a preferred embodiment, however, the blockers have a
  • SUBSTTTUTE SHEET (RULE 26) short duration of action and are introduced into the intraocular chamber by constant perfusion of an intraocular chamber during the course of surgery.
  • the L-type calcium channel blockers of the invention are applied in effective amounts.
  • An effective amount is that amount which prevents, inhibits or reverses miosis or produces mydriasis to a medically useful extent during intraocular surgery, (e.g. the operative field is improved for the surgeon or it is easier for the surgeon to manipulate surgical instruments and intraocular tissues).
  • An effective amount is one controlled by a number of factors, including: the subject; the inherent anti-miotic or mydriatic activity of the L-type calcium channel blocker; the amount of the L-type calcium channel blocker used; its duration of action; and the method by which it is introduced into the intraocular chamber, i.e., whether by a single application or by continuous perfusion.
  • a perfusion solution having between 1 micromolar to lOOmM of L-type calcium channel blocker is believed to deliver an effective amount during intraocular surgery.
  • Preferably perfusion solutions contain between 0.1 mM to lOmM blocker. It is important that the L-type calcium channel blockers do not produce, at effective concentrations, long-term deleterious changes in the eye nor cause inflammation, discomfort or irritation. The determination of an effective dose for any selected compound is well within the level of ordinary skill in the art.
  • kits providing an L-type calcium channel blocker and a carrier for introducing the blocker into an intraocular chamber during surgery.
  • a carrier is an ophthalmologically acceptable solution in which the blocker is dissolved prior to application to an intraocular chamber. It is important that any solution applied to an intraocular cavity be free of any factors that would injure intraocular tissue. Thus it preferably is sterile, approximately iso-osmotic, at the correct pH and contains factors to support metabolism in the tissue, as described above.
  • the long-term effects of storage on the stability of L-type calcium channel blockers that contain, for example, an ester function within the structure are believed to be problematic, particularly when the blockers are in aqueous solutions at neutral or alkaline pH.
  • kits be provided for preparation of therapeutic solutions containing an L-type calcium channel blocker within hours of surgery.
  • the blockers can be in a stable powdered form or in a stable concentrated form such as concentrated in an acidic solution.
  • SUBSTTTUTE SHEET (RULE 26) blocker then can be dissolved or diluted in the ophthalmologically acceptable carrier solution immediately in advance of surgery.
  • kits comprise a package, such as a box, blister pack or similar packing vehicle used conventionally to hold containers of liquid.
  • the package may be coated with an impervious cover to assist in protecting the sterility of the contents during transport and storage.
  • a container containing an amount of a carrier solution (or components thereof) and one or more containers containing an L-type calcium channel blocker and any components missing from the carrier solution.
  • the containers preferably are glass bottles, but may be formed of any inert material such as a rigid or flexible plastic in the form of bottles or bags that allow transport and storage of liquid without loss of fluid or contamination of the contents.
  • the containers may be chambers in a single housing.
  • the container may comprise in addition a structure to permit communication of the contents of the chambers without opening the container.
  • the blocker and the ophthalmologically acceptable carrier solution can be supplied in separate chambers of a two-chamber vial. Communication between the chambers can be provided by a frangible membrane. In use, the membrane is pierced or ruptured, with the carrier solution flowing into the chamber containing the blocker (or vise versa). The blocker, in powdered form or in a concentrated form, then is dissolved or diluted into the solution.
  • the upper and lower chambers are constructed and arranged within a syringe.
  • the kit may be used to provide a carrier solution for instilling a single amount or wash amounts of an L-type calcium channel blocker into an intraocular chamber.
  • the containers for the carrier solution preferably includes about 10ml to about 50ml of carrier solution.
  • the container may be a bottle or vial with piercable septum.
  • the blocker may be supplied for example in a stable, concentrated solution (also in a bottle or vial with a piercable septum). In use, the septum of the bottle or vial containing the calcium channel blocker is pierced by the needle of a syringe and transferred to the bottle or vial containing the carrier solution.
  • An ophthalmologically acceptable solution of predetermined blocker concentration effective for inhibiting surgical miosis or producing intraoperative mydriasis when introduced into an intraocular chamber is thereby formed.
  • the solution then may be removed by syringe from the vial and instilled into the intraocular chamber.
  • the kit may be used to provide a carrier for perfusing an L-type calcium channel blocker into an intraocular chamber during eye surgery.
  • the first container contains an intraocular irrigation solution (or components thereof) in an amount from about 100ml to lOOOml, preferably about 500ml.
  • the first container is a bottle having a rubber septum which can be punctured by a needle attached to a tube for delivering the contents of the container to a perfusing needle and hence to the eye.
  • Another container(s) includes a predetermined amount of an L-type calcium channel blocker, and, in certain embodiments, components of the intraocular irrigation solution.
  • the contents of the containers are mixed in a manner that maintains sterility to form an ophthalmologically acceptable solution containing the blocker at a concentration effective for inhibiting surgical miosis when perfused into an intraocular chamber during surgery.
  • the solution contained in the first container may be only components of an intraocular irrigation solution.
  • the intraocular irrigation solution may be "incomplete".
  • One or more components of the intraocular irrigation solution may be provided in a second container with the blocker or separately in a different container.
  • Such arrangements can serve dual purposes. Firstly, certain components of the intraocular irrigation solution, such as organic components, may be more stable at pHs other than physiological intraocular pH.
  • the separation of such one or more components from the irrigation solution (and the calcium blocker solution) until the time of mixing just prior to surgery permits long term storage.
  • a package may be constructed and arranged whereby an ophthalmologically acceptable irrigation solution is created only when all of the various contents of the different containers are mixed together. In this manner, the surgeon or medical staff supporting the surgeon will be inclined to use the materials as directed as opposed to substituting other materials which may not be as clinically desirable.
  • the package includes a first container containing between 100ml and lOOOml of an intraocular solution, wherein the solution is incomplete with respect to one or more solution components.
  • the package also includes a second container containing an L-type calcium channel blocker and a third container containing said one or more solution components.
  • the contents of the first, second, and third containers are mixed together to form a solution which is pH and osmotically compatible with the intraocular environment of an eye and in which the blocker is
  • SUBST1TUTE SHEET present at a concentration effective for inhibiting surgical miosis when introduced into an intraocular chamber.
  • Suitable intraocular irrigation solutions are RINGERS solution, balanced salt solution and glutathione-bicarbonate-RINGERS solution.
  • the preferred compositions and methods of preparation of suitable irrigation solutions have been disclosed in U.S. patent numbers 4,550,022 and 4,443,432 to Garabedian which are hereby incorporated by reference.
  • kits may include instructions for preparation of a carrier or irrigation solution.
  • the instructions may detail the use of the L-type calcium channel blocker or solution in an intraocular chamber in connection with inhibiting surgical miosis. They also may include useful additional implements for mixing the contents of the containers in the kits or for delivery of the final therapeutic solution to an intraocular chamber.
  • the present invention also sets forth a device comprising a bottle, such as a wash bottle or an irrigation bottle, containing an intraocular irrigation solution including an L-type calcium channel blocker present in an amount effective for inhibiting miosis or producing mydriasis when instilled into an intraocular chamber of an eye during intraocular surgery.
  • the bottle preferably is formed from glass, but may also be rigid or flexible plastic and may be a bag.
  • the device is useful for instilling or perfusing a solution in an intraocular chamber during surgery.
  • a bottle suitable for wash or injection preferably contains 10ml to 50ml of the ocular irrigating solution and preferably contains the blocker at a concentration between about O.lmM and lOmM.
  • a bottle suitable for use in perfusion of an intraocular cavity contains at least 100 ml of the intraocular irrigation solution and preferably contains the blocker at a concentration between about 1 micromolarto lOmM.
  • Example 1 Lens removal surgery in dogs. All dogs underwent a presurgical work up including a complete physical exam, a complete ocular exam, an intraocular pressure measurement and a pupil measurement using a hand-held caliper (measured to the nearest millimeter).
  • the dogs were treated with the following anti-inflammatory regimen: on the morning before surgery, the dogs were given .5 mg lb prednisone PO, one drop of .1% dexamethazone with neomycin and polymixin B (AK-TrolTM) and .25 mg/lb flunixin meglumine IV. Beginning one hour before surgery, and every 15 minutes thereafter up until surgery, one drop of
  • AK-Trol was applied topically. Post-operatively, QID one drop .1% AK-Trol Sx day. This was repeated at 1, 2 and 3 days post-operatively.
  • SUBSTTTUTE SHEET (RULE 26) Surgical removal of the lens was performed using the techniques of phacoemulsification in mongrel dogs of either sex. General anesthesia was induced by intravenous Pentothal (25mg/ml, at a dose of 8mg/lb) and maintained by inhalation with isoflurane. The surgical site was prepared, draped and washed with BETADINE. Surgery was performed on one eye, then the other. Lactated RINGERS solution was administered IV during the procedure, 4ml/lb/hr.
  • the surgical procedure was performed by observation through a surgical microscope.
  • the anterior chamber was entered at the limbus and an anterior capsulotomy was performed.
  • the irrigation solution was a balanced salt solution containing either the drug substance or a vehicle control. Over 15-20 minutes of surgical time, 100-400 mis of irrigation solution were delivered. Pupil size was monitored under the surgical microscope with the hand-held caliper.
  • Example 2 The protocol of Example 1 was followed, except that three dogs were treated in one eye with a vehicle and in the other eye with a perfusion solution containing 1 millimolar diltiazem. As demonstrated in Fig. 2 and TABLE 2, the eye receiving the diltiazem had a pupil size substantially greater than the eye receiving the placebo. The results were as follows:
  • Example 4 The effect of lOO ⁇ M diltiazem on post-operative pupil size also was measured. No statistical differences were observed in eyes treated with lOO ⁇ M diltiazem versus eyes treated with placebo through 72 hours post-operatively. The results are shown in Fig. 4.
  • Example 5 The effect of lmM diltiazem on post-operative intraocular pressure (IOP) was measured. No statistical differences were apparent between the eyes treated with lmM diltiazem and the eyes treated with the placebo. The results are shown in Fig. 5.
  • Example 6 The effect of lmM diltiazem on post-operative pupil size also was measured. No statistical differences were observed in eyes treated with lmM diltiazem versus eyes treated with placebo through 72 hours post-operatively. The results are shown in Fig. 6.

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Abstract

Cette invention concerne un procédé d'inhibition du myosis peropératoire ou de production de mydriase peropératoire consistant à introduire un agent bloquant les canaux calciques dans une chambre intraoculaire d'un sujet subissant une chirurgie intraoculaire. On a prévu des matériels destinés à fournir au chirurgien une solution ophtalmologique contenant une dose efficace de l'agent bloquant les canaux calciques.
PCT/US1995/007526 1994-06-10 1995-06-09 Inhibition du myosis/de la production de mydriase peroperatoire par des agents bloquant les canaux calciques WO1995034299A1 (fr)

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US25908094A 1994-06-10 1994-06-10
US08/259,080 1994-06-10

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WO1995034299A1 true WO1995034299A1 (fr) 1995-12-21

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PCT/US1995/007526 WO1995034299A1 (fr) 1994-06-10 1995-06-09 Inhibition du myosis/de la production de mydriase peroperatoire par des agents bloquant les canaux calciques

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO1997038693A1 (fr) * 1996-04-18 1997-10-23 Alcon Laboratories, Inc. Antagonistes du calcium utilises comme inhibiteurs de la degranulation du mastocyte conjonctival chez l'homme pour le traitement d'allergies oculaires
WO2002053134A1 (fr) * 2000-12-29 2002-07-11 Pfizer Limited Compositions pharmaceutiques contenant du maleate d'amlodipine

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FR2593395A1 (fr) * 1986-01-28 1987-07-31 Corbiere Jerome Nouvelles compositions pharmaceutiques antiglaucomateuses a base de 3-acetoxy-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepine-4-one ou d'un de ses sels et leur procede d'obtention
WO1992004008A1 (fr) * 1990-09-07 1992-03-19 Universidad De Alicante Composition pour le traitement des douleurs oculaires
WO1995015958A1 (fr) * 1993-12-08 1995-06-15 Alcon Laboratories, Inc. Composes presentant une puissante activite d'antagonistes du calcium et d'antioxydants et leur utilisation en tant qu'agents cytoprotecteurs

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FR2593395A1 (fr) * 1986-01-28 1987-07-31 Corbiere Jerome Nouvelles compositions pharmaceutiques antiglaucomateuses a base de 3-acetoxy-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepine-4-one ou d'un de ses sels et leur procede d'obtention
WO1992004008A1 (fr) * 1990-09-07 1992-03-19 Universidad De Alicante Composition pour le traitement des douleurs oculaires
WO1995015958A1 (fr) * 1993-12-08 1995-06-15 Alcon Laboratories, Inc. Composes presentant une puissante activite d'antagonistes du calcium et d'antioxydants et leur utilisation en tant qu'agents cytoprotecteurs

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ANDERSSON S.E. ET AL: "Ruthenium Red and Capsicain Induce a Neurogenic Inflammatory Response in the Rabbit Eye: Effects of Conotoxin GVIA and Tetrodotoxin", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 209, no. 3, pages 175 - 183 *
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997038693A1 (fr) * 1996-04-18 1997-10-23 Alcon Laboratories, Inc. Antagonistes du calcium utilises comme inhibiteurs de la degranulation du mastocyte conjonctival chez l'homme pour le traitement d'allergies oculaires
US6225327B1 (en) 1996-04-18 2001-05-01 Alcon Laboratories, Inc. Compounds which inhibit human conjunctival mast cell degranulation for treating ocular allergic-type complications
WO2002053134A1 (fr) * 2000-12-29 2002-07-11 Pfizer Limited Compositions pharmaceutiques contenant du maleate d'amlodipine
US6919087B2 (en) 2000-12-29 2005-07-19 Synthon Bv Pharmaceutical compositions comprising amlodipine maleate
EA008101B1 (ru) * 2000-12-29 2007-04-27 Пфайзер Лимитед Фармацевтические композиции, включающие амлодипина малеат

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