GB2207049A

GB2207049A - Heparin formulation for use in eye surgery

Info

Publication number: GB2207049A
Application number: GB08716690A
Authority: GB
Inventors: Steven B Siepser
Original assignee: Individual
Current assignee: Individual
Priority date: 1987-07-15
Filing date: 1987-07-15
Publication date: 1989-01-25
Also published as: GB8716690D0; DE3724158A1; FR2618074A1

Description

t 1 HEPARIN.FORMULATION FOR USE IN EYE SURGERY 2207049 This invention

relates to a composition for preventing fibrin formation during eye surgery.

It has been noted that as soon as the eye is opened in surgery, fibrin begins to form in the interior of the eye. Certain particular individuals have extremely profuse fibrin exudates in the anterior chamber. These exudates cause multiple adhesions and, thus, difficulty in intraocular lens surgery. Children are among those patients who more actively produce fibrin complicating their surgery. These individuals who tend to form more fibrin than normally encountered are at a significant disadvantage during eye surgery.

One material which has been proposed as an anti-coagulant is the substance known as heparin. A discovery in 1916 of a phospholipid anti- coagulant led to the development of a water soluble mucopolysaccharide, which has been given the name heparin because of its abundance in the liver. Nevertheless, it was not until the late 1960's and early 1970's that heparin became significant in its use in anticoagulant therapy.

The primary use for heparin has been to control the formation of clots in individuals prone to thrombophlebitis. Treatment of pulmonary embolism is one example of medical usage of the material. Heparin itself is normally introduced parenterally.

Intermittent intravenous therapy is best performed by using a heparin lock in which an initial dose of 10,000 units is given followed by dosages of 5,000-10,000 units every four to six hours.

fke- chieú complication of therapy with heparin S Uncordro 1 led- (Zareful c dasage, selection of patients and avoidance of i aspirin-containing medications generally reduces this risk significantly. The drug is normally ineffective if the dosage becomes too low.

The use of heparin in any form in eye surgery formulations has not been reported. Riviere discloses in U.S. Patent No 3, 232,833 certain pharmaceutical compositions having local action on inflammation. The primary.use of these compositions is in ophthalmology. Heparin is disclosed in Col. 1, lines 33-41, as being widely used as a surgical therapeutic agent. The reference states, however, that the pharmacological experiments and clinical experience of the inventor have proved that in ocular pathology, practically no appreciable curative action can be observed with the use of heparin or of compounds liberating it. Riviere purports to provide a useful treatment for ophthalmology from a mixture of a compound capable of liberating heparin and phenylephrine, along with an ophthalmological carrier. Riviere, in effect, teaches that heparin is k!:

1 not useful in eye surgery.

Two patents to the same inventor Furd-hashi, U.S. Patent Nos 3,371,012 and 3,547,904, disclose an invention which concerns the use of a solution comprising galactose, N-acety1glucosamine and a sulfate for the purpose of acting as a preservative for cornea grafts. The.function of the solution is to provide a preservative solution for either the eyeball or the cornea which has been removed from the eyeball, whereby the osomotic pressure on the inside and the outside of the cornea is controlled. In this manner, the water content within the cornea is retained at a constant level. Neither patent describes the use of heparin in eye surgery treatments.

U.S. Patent No 4,486,440 to Emanuel et al discloses a new medicinal drug for treating intraocular hemorrhage and other related areas. The patent describes a variety of conventional treatments. Neparin is mentioned for its specifically thrombolytic effect. The Emanuel et al Patent states that none of these agents, including heparin is capable of stabilizing membrane structures of the vascular wall, effecting the anti-coagulant and fibrinolytic properties of the blood and interfering with the destructive processes arising from increasing oxidation, particularly with light stimulation such as laser coagulation. The drug described in Emanuel et al is presented as being faster than a combination treatment of heparin and dexasone. This latter combination has virtually no effect on fundal hemorrhage involvement. Heparin is not tested alone. There is no teaching of any kind that would suggest that heparin would have any effect in the work done by Emanuel et al. 20 Nevertheless. it would be of great advantage to the field of eye surgery if a compound could be found which would assist in the prevention of fibrin during eye surgery. It has now been discovered that fibrin formation during eye surgery can be substantially prevented or controlled through the use of the solution of this invention. Fibrin formation is significantly prevented or controlled without subjecting the eye to unreasonable or significant risks of hemorrhage due to an over-abundance of anti-clotting factors.

The present invention provides a solution comprising heparin in a solution compatible with the anterior chamber of the human or animal eye.

The inventive solution may be txsed by irrigating the anterior chamber with the mixture to f j k maintain sufficient heparin in contact with the eye to limit fibrin reaction during the surgery.

The amount of heparin admixed in the solution may range from 0.1 to 10 USP units per cc of solution and preferably from about 0.5 to 2 USP units of heparin.

Heparin is available as a drug even though it is not possible to have a suitable chemical assay for standardization. Standardization of a sample of heparin is based upon a comparison in vitro with a known standard in a non-specific essay of anti-coagulant activity. A USP unit of heparin is that quantity that will prevent 1.0 ml of-citrated sheep plasma from clotting for one hour after the addition of 0.2 ml of a 1:100 calcium chloride solution. Heparin which is derived from the lungs contains at least 120 USP unitsImg and at least 140 USP units/mg when derived from other tissues. Because the potency of different preparations may vary over a wide range, heparin is required to be prescribed on a unit'basis.

Heparin when administered into the blood is administered in large dosages of 10,000 units or more followed by dosages of 5,000-10,000 units every four to six hours. The total daily dose for patients would range up to 500 units/kg of body weight or 20.000 units per square meter of body surface area.

The amount of heparin admixed in the solution for the present invention is substantially less than that required for blood treatment. Specifically. from 0.1 to 10 units USP is generally added to each cc of solution. More preferably, this admixture ranges from 0.5 to 2.0 units per cc of solution.

The irrigating solution which is to be employed bad which ib coulpa-tiblu with the anterior chamber of the eye is a synthetic approximation of the aqueous i i i f W j fluid contained in the eye. This aqueous solution in the eye is similar to plasma and commercial solutions are available which are formulated to approach the aqueous solution of this eye. There are several commercially available solutions most suitable. There are other formulations commercially available and any of these which effectively mimic the anterior chamber solution are effective.

The mixture is then formed by adding the heparin to the irrigating solution. It has been found that heparin is compatible with these solutions, and does not adversely affect pH or tonicity. Significant changes in either of these properties would damage the endothelium but, at least in the proportions used, heparin has surprisingly been found to be compatible without adversely affecting the properties of the irrigating solution.

A preferred technique for employing the solution of this invention is to prepare a fresh solution prior to surgery and store it in a bottle such as those used for intravenous treatment. A quantity of the solution then is supplied to the eye during surgery. The supply of liquid may either be a continuous stream or in the form of continuous drops or droplets. Treatment may be continued at the end of surgery with the remaining quantity of solution being left in the eye as a replacement for the lost fluids in the anterior portion of the eye.

The solution of heparin in an irrigating solution which is compatible with the anterior chamber of the eye is to be added during surgery and an example of the irrigation of the eye is given below, by way of illustration only. As is apprecit.ted, the eye itself is a soft flexible tissue which u-1a-J.i.,,--ai-!ts -JL'L-.-, shape, due. to the pressure of the fluid inside the eye as it is balanced by the f pressure outside. During surgery, it is necessary to add into the interior of the eye as much fluid as is taken out. The bottle which contains the irrigating solution and heparin is hung on an appropriate hanger, much like that used for intravenous feeding. The bottle is connected via tubing to a small dispensing needle which is inserted into the eye at the time the insertion-is made during surgery. The infusion rate is controlled by the height of the bottle with respect to the patient. The rate is adjusted so as to maintain the shape of the eye by adding as much fluid as is taken out of the eye during the operation. The needle may be attached to the side of the cutting device, or it may be inserted separately at the time the incision is made.

The apparatus used may be quite simple, comprising a container filled with the solution, an adjustible valve which may be gravity sensitive for dispensing the fluid through a tube and an insertion needle sized to fit into the eye either at the time the incision is made or as part of the cutting device itself.

In order to demonstrate the efficacy of the present invention, a number of experiments were performed with implantation of intraocular lenses in rabbits. The addition of heparin in the.dose of approximately 1.0 unit USPIcc had a remarkable effect -limiting the fibrin reaction in the anterior chamber of the rabbit. Other tests at lower dosages and higher dosages are also very effective.

When eye surgery is performed on humans. certain individuals have an extremely active fibrin exudation in the anterior chamber and this exudation causes multiple adhesions. This causes difficulty in ---5 on o:' ritra-corneal treatment such as the iiaplantat-L an intraocular lens. Use of the composition of this 1 i i j j invention limits the amount of fibrin formed so that adhesions would be limited.

Included in the invention is a system for use in preventing or controlling fibrium formation in the anterior chamber of the eye, comprising solution according to the invention and means for irrigating the anterior chamber of the eye therewith during eye surgery.

is 17 r..# j t k

Claims

CLAIMS:

1. A solution comprising heparin in a solution compatible with the anterior chamber of the human or animal eye.

2. A solution as claimed in claim 1 wherein the amount of heparin in the solution ranges from 0.1 10 to 10 USP units/cc of solution.

3. A solution as claimed in claim 2 wherein the amount of heparin is from 0.5 to 2 USP units/cc of solution.

4. A solution as claimed in any one of the preceding claims, wherein the irrigating solution is a balanced salt solution formulated to mimic the normal aqueous fluid of the anterior chamber of the 20 eye.

1 1

5. A solution as claimed in claim 4, wherein the amount of heparin is less than that amount which would affect the pH of the solution.

6. A solution as claimed in claim 4 or claim 5 wherein-the amount of heparin is less than that amount which would affect the tonicity of the solution.

7. A solution as claimed in any one of the Preceding claims for use in eye surgery.

8. The use of a solution as claimed in any one j'--or a human or 0 1 a -im-s 1 to 6 L 13. L, L veterinary pharmaceutical for use in preventing or 11 1 i i i i 1 i i i i 4 controlling fibrin formation during eye surgery.

9. The use of heparin for the manufacture of a medicament comprising heparin in a solution compatible with the anterior chamber of the human or animal eye and for use in preventing or controlling fibrin formation in eye surgery.

10. A method of making a solution as defined in any one of claims 1 to 7, comprising mixing heparin in a solution compatible with the anterior chamber of the eye.

11. A system for use in preventing or controlling fibrin formation in the anterior chamber of the eye, comprising a solution as claimed in any one of claims 1 to 7 and means for irrigating the anterior chamber of the eye with the solution during eye surgery.

12. A system as claimed in claim 11, wherein the irrigating means comprises a container containing the solution and connected to tube means which is in turn connected to a needle for insertion in the eye and which comprises an adjustable valve.

13. A system as claimed in claim 11 and substantially as hereinbefore described.

14. A solution as claimed in any one of claims 1 to 7 in a container for use with a system as defined in any one of claims 11 to 13.

15. Haparin for use in preventing or J'ormation in eye surgery- using a solution as claimed in any one of claims 1 to 7 or 14 - 10 or a system as c aimed in any one of claims 11 to 13.

is i i 1 1 i i i 1 j 1 1 i i i i i i Published 1988 at The Patent Office. SLaw flouse. 6671 High Holborn, London WC1R 4TP. Airther copies MaY be obtained from The Patent Office, Wes Branch, St Mary Cray. Orpington, Kent BRS 3RD. Printed by Multiplex techniques ltd, St Mary Cray, Kent. Con. 118-, -