Title of Invention


Abstract The invention concerns a pharmaceutical composition characterized in that it contains a combination of a parasym-patholytic agent, a sympathomimetic agent and a contact anesthetic. Such a composition can be injected into the anterior chamber of the eye prior to a cataract procedure or instilled on the eye prior to a laser treatment.
The present invention concerns the therapeutic field and more particularly the ophthalmologic field.
It more particularly deals with new pharmaceutical compositions for the treatment of pain and/or lesions of the eye during a surgical or physical operation.
Its subject is more precisely compositions based on a parasympatholytic agent, an adrenergic substance and a local anaesthetic, in solution or hi dispersion in a sterile aqueous solvent, in view of surgical or post surgical treatment of the eye for an operation on cataracts or laser treatment.
According to a particularity of the invention, the parasympatholytic agent is a mydriatic agent and preferably a derivative of tropic acid such as a tropic acid ester or a tropic acid amide or a cyclohexyl or cyclopentylacetic acid amide.
Among these parasympatholytic agents, we shall notably mention cyclopentolate, cyclodrine, eucatropine, homatropine as well as atropine (benzylic ester of tropic acid), N-methyl hyoscine and especially tropicamide (N-ethyl 2-phenyl N-4 pyridyl methyl hydracrylamide or pyridyl methyl benzene acetamide).
Among the local anaesthetics, we shall more particularly mention butocaine, prilocaine, procaine, novocaine, tetracaine, ambucaine, amylocaine, bupivacaine, carticaine, butoxycaine, formocaine, mevipacaine, etidocaine, prilocaine, orthocaine and mainly xylocaine or diethylamino 2,6 dimethyl acetanilide.
Among the adrenergic substances, we shall more particularly mention noradrenaline, neosynephrine, isopropylnorepinephrine or isoprenaline, dipivefrine, dimetrophine, norfenefrine, pholedrine or octedrine.
The compositions according to the invention are of major interest, notably for preparing the eye during a surgical operation, notably in the surgical treatment of cataracts or during a laser operation of the retina.
Compositions according to the invention are capable of providing very rapid anaesthesia and a nearly instantaneous dilation of the pupil for undertaking an examination and the surgical operation as quickly as possible. It also appears that such a combination has the advantage of
reinforcing the mydriatic effect of the parasympatholytic derivative, but without manifesting an overly long effect.
Actually, during surgical operations of the eye, the ophthalmologist needs to proceed with a paralysis of the sphincter of the iris causing a dilatation of the pupil in order to better access to the crystalline lens. Indeed, he has to use a mydriatic agent with a rapid effect.
In order to proceed, he has to instil, more often in the eye, a concentrated product for which the activity will be felt after 10 to 15 minutes, but having a longer effect (1 hour and a half to 2 hours) interfering the vision of the patient during many hours.
This interference of the vision caused by the intensity of the mydriase demand post-surgical precautions because it can induce equilibrium troubles, a general discomfort or atropinic effects such as dryness of the mouth or an increase of the intraocular pressure.
We already known preparations based on tropicamide having a mydriatic effect. However, such collyrium present the serious inconvenient to cause a mydriase too long and can lead to general effects of atropinic products.
We already known collyrium based on tropicamide and phenylephrine sold under the name "Mydriaticum". They ensure a mydriase for the observation of the fundus of the eye. We also already known ocular insert based on tropicamide and norepinephrine Mydriasert to be used on the eye or in the eye and to be dissolved slowly. The function of the norepinephrine is to reinforce mydriatic effect of tropicamide.
It also appeared necessary to better control the good effects of the mydriatic agent combining a rapid effect, nearly instantaneous, to a predefined period quasi unable to cause secondary . discomfortable effects and moreover to disturb the vision during an excessive period (4 to 6 hours).
The adrenergetic agent also has an important function reinforcing the local anaesthetic effect, apparently ensuring a local vasoconstriction providing or slowing down the diffusion or the metabolism of the anaesthetic agent. As a consequence, the area is quasi indolent and the ophthalmologist can proceed with the operation without causing any reaction of the patient or without having the obligation to proceed with a deeper or longer anaesthesia.
We know that the operation of the cataract is a delicate surgical operation demanding a lot of dexterity, but it can be done rapidly and without any secondary disturbing effect.
This mixture of mydriatic substances and local anaesthetic take all its importance during the surgical operation of the cataract. The advantages are:
- rapid dilatation of the pupil (instantaneous) and durable until the end of the operation,
- rapid and durable anaesthesia,
- respect of the epithelium and of the translucence of the cornea,
- exoneration of the dilatation of the pupil pre-surgical,
- compatible with all the process of extraction of the crystalline lens (current and less
current such as extra capsular extraction).
This mixture can also be indicated (following a particular protocol) in the dilatation of the pupil before the laser photocoagulation of the retina, which permits to weaken the pain.
This particular effect of the compositions of the invention is more particularly due to the specific mode of administration of the composition, by injecting the composition in an incision done during the surgical operation in the anterior chamber of the eye, which causes an immediate dilatation of the pupil and an entire suppression of the pain.
In order to do, the compositions according to the invention are in the form of solutions or aqueous suspension comprising three active principles simultaneously or separately. The compositions according to the invention may come in solid form or in liquid form, for example in the form of collyriums, in the form of single-dose recipients, in the form of installable preparations ready to use or on contrary in freeze-dried form to be reconstituted with an aqueous solvent when used.
The compositions according to the invention may also come in a mixed form, for example one of the active ingredients being freeze-dried to be reconstituted by adding an aqueous solution containing the other active ingredients. It is also possible to have a bottle containing one of the solid active ingredients, covered by a frangible membrane above which can be found the solution containing the other active ingredients.
The pharmaceutical compositions according to the invention contain between 0.1 to 0.6% of mydriatic agent, between 0.2 to 3% of local anaesthetic agent and between 0.1 to 0.5% of sympathomimetic agent.
A preferred composition contains between 0.20 to 0.5% of mydriatic agent, between 1 to 2% of local anaesthetic agent and between 0.2 to 0.4 % of sympathomimetic agent.
An highly preferred composition contains between 0.25 to 0.50% of mydriatic agent as the tropicamide, between 1.5 to 2% of xylocaine and between 0.25 to 0.4% of neosynephrine.
In the case of a laser operation, the concentrations of the pharmaceutical compositions will be different, particularly the concentrations of parasymatholytic agent will be lower and the concentrations of local anaesthetic agent will be slightly higher. Thus, the concentrations of sympathomimetic agent will be between 0.1 to 0.25% and the concentration of the local anaesthetic agent will be between 2 to 3%. The method of administration may also be different, proceeding with the instillation of the preparation on the treated eye in two to four times at ten minutes intervals. Thus, sedation of the pain is ensured more immediately and for a longer time.
The invention will be better defined using the examples below: EXAMPLE 1
Collyrium based on tropicamide
Tropicamide 0.05 g Norepinephrine 0.02 g Xylocaine (chlorhydrate) 0.02 g Sterile purified water 10 ml
Sinsle-use recipient containing a tropicamide solution
Tropicamide 0.002 g
Norepinephrine 0.002 g
Xylocaine (chlorhydrate) 0.004 g
Sterile purified water QSP for a single-use recipient of 1 ml
Collyrlum based on tropicamide
Tropicamide 0.0015 g Phenylephrine 0.030 g Bupivaca'ine (chlorhydrate) 0.050 g Sterile purified water 10 ml
This collyrium is particularly well suited to the treatment of pain during laser treatment.
The collyriums according to the invention are to be instilled on the eye, in three times one drop during the same day.

We claim:
1. An ophthalmologic pharmaceutical composition comprising:
a concentration of the parasympatholytic agent is between 0.015 and 0.025%; a concentration of the local anaesthetic is between 0.75 and 1.25%; and a concentration of the sympathomimetic agent is between 0.2 and 0.4%;
2. Ophthalmologic composition as claimed in claim 1 wherein the parasympatholytic agent is tropicamide.
3. Ophthalmologic composition as claimed in claim 1 or 2 wherein the local anaesthetic is selected from among butocaine, mepivacaine, tetracaine, carticaine, butoxycaine, orthocaine and lidocaine, or one of its salts.
4. Ophthalmologic composition as claimed in any of the previous claims wherein the sympathomimetic agent is selected from among phenylephrine, isoprenaline, dipivefrine, norfenefrine, pholedrine and octedrine.
5. Ophthalmologic composition as claimed in any of the previous claims wherein the parasympatholytic agent is tropicamide, the local anaesthetic is lidocaine and the sympathomimetic agent is phenylephrine.
6. Ophthalmologic composition as claimed in any of the previous claims, wherein a ratio of the sympathomimetic agent to the parasympatholytic is 15.8-16.1 to 1.
7. Ophthalmologic composition as claimed in any of the previous claims, wherein a ratio of the sympathomimetic agent to the parasympatholytic is 16 to 1.
8. Ophthalmologic composition as claimed in any of the previous claims, wherein the pharmaceutical composition is freeze dried.
9. Ophthalmologic composition as claimed in any of claims 1 to 6 as and when used for the preparation of a medicine to be injected into the anterior chamber of the

eye before a surgical operation on the lens or the retina, notably for a cataract operation.






6550-DELNP-2007-Correspondence Others-(02-02-2012).pdf




6550-delnp-2007-description (complete).pdf












Patent Number 256032
Indian Patent Application Number 6550/DELNP/2007
PG Journal Number 17/2013
Publication Date 26-Apr-2013
Grant Date 22-Apr-2013
Date of Filing 23-Aug-2007
# Inventor's Name Inventor's Address
PCT International Classification Number A61K 9/00
PCT International Application Number PCT/FR2006/000528
PCT International Filing date 2006-03-09
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0502357 2005-03-09 France