CA2039566A1

CA2039566A1 - Use of hexetidine or its derivatives or salts for the preparation of a pharmaceutical composition for ophthalmological use

Info

Publication number: CA2039566A1
Application number: CA002039566A
Authority: CA
Inventors: Andre Salkin
Original assignee: Individual
Current assignee: Individual
Priority date: 1990-04-18
Filing date: 1991-04-02
Publication date: 1991-10-19
Also published as: DK0453337T3; EP0453337A3; MC2217A1; AU7513291A; ES2109937T3; FR2661091B1; JPH04234818A; BR9101544A; HU911272D0; EP0453337A2; HUT57985A; ATE158719T1; EP0453337B1; FR2661091A1; DE69127767T2; AU643772B2; DE69127767D1

Abstract

PATENT APPLICATION
entitled: Use of hexetidine or its derivatives or salts for the preparation of a pharmaceutical com-position for ophthalmological use in the name of: André SALKIN

Assignee: André SALKIN

ABSTRACT OF THE DISCLOSURE

The invention relates to the use of hexetidine, or its derivatives or salts which are non-toxic in the use envisaged, for the preparation of a pharmaceutical composition with ophthalmic antiseptic activity, per-mitting especially therapeutic treatment of the connec-tive tissues in the absence or presence of ophthalmic prostheses and, in particular, contact lenses.
Application: ophthalmology.

Description

2 ~
~ 1 --Use of_hexetidine or its derivatives or salts for the preparation of a pharmaceutical composition for oph-thalmological use 05 The present invention relates essentially to the use of hexetidine for the preparation of therapeu-tic compositions for ophthalmological use.
Document EP~B-0 136 231 has disclosed a com-posi~ion having high bac~ericidal power which contains a biguanide and a pyrimidine, in particular hexetidine.
Hexetidine was used to boost the fungicidal power of the biguanides. The uses indicated concern ordinary disinfeckion of the skin.
It has now been discovered, totally unexpec-tedly, that hexetidine or its derivatives or salts canbe used as the active principle of a pharmaceutical composition for ophthalmological use, in particular for treating infections due to lesions, the eye tissues or abnormal contaminations of the eye, as well as for asepticizing ocular prostheses or contact lenses.
Thus the objPct of the present invention is to solve the novel technical problem which consists in providing a pharmaceutical composition for ophthalmo-logical use which is highly effective and simple to use and does not have harmful effects on the eye tissues or on ocular prostheses or contact lenses.
This technical problem is solved for the first time by the present invention in a manner which is par-ticularly simple and inexpensive and which can be used on the industrial scale.
Thus the present invention relates to the use of hexetidine, its derivatives or i~s salts as the active principle of a pharmaceutical composition for ophthalmological use.
According to one embodiment, the composition is in a concentrated form containing a hexetidine concen-tration of between 10-5% and 100%.
~ccording to another embodiment, the composi-tion is in a dilute form containing a hexetidine con-05 centration of between 5.10-l2% and 0.3~.
According to yet another embodiment, the thera-peutic composi~ion is ~ormulated as an eye lotion containing a concentration of hexetidine or its deriva-tives or salts of between 10-7% and 10-2%
According to yet another embodiment, the phar-maceutical composition is in the form of a hygiene treatment composition for asepticizing ocular pros-theses or contact lenses, containing a concentration of hexetidine or its derivatives or salts of between 10-7 and 0.0~%.
According to yet another embodiment, the compo-sition is formulated as a liquid or pasty compo~ition, as a powder or as a solid support impregnated with the composition, said support being selected in particular ~rom a conventional compress, a fabric, a gauze or a polyurethane compress.
According to yet another embodiment, the com-position is a liquid composition advantageously com-prising a buffer ~or adjusting the pH.
According to yet another embodiment, the com-po~ition is a liquid composition comprising a non~
ionic, amphoteric, cationic or anionic surfactant, preferably a surfactant of the non-ionic type.
According to yet another embodiment, the phar-maceutical composition comprises a sequestering agent, especially gluconolactone, in particular ~-glucono-lactone, or ethylenediaminetetraacetic acid (EDTA).
According to yet another embodiment, the phar-maceutical composition comprises at least one other antiseptic or at least one antibiotic.

3~

According to yet another embodiment, the afore-mentioned antiseptic is selected from a biguanide, in particular polyhexamethylenebi~uanide and its salts, or a quaternar~ ammonium compound, more particularly 05 didecyldim~thylammonium chloride.
According to yet another embodiment, the phar-maceutical composition comprises erythromycin or neo-mycin as the antibiotic.
The invention further relates to ophthalmic antiseptic pharmaceutical compositions in which hexe-tidine, its derivatives or its salts are present as the active principle. Particular embodiments of these com-positions follow ~rom the foregoing description rela-ting to the use~
15According to a third feature, the present invention also covers a process for the manufacture of ophthalmic antiseptic pharmaceutical compositions, which comprises incorporating hexetidine or its deri-vatives or salts, in an amount effective as an anti-septic, into an ophthalmologically acceptable carrier, vehicle or excipient.
Embodiments of this preparative process also follow from the foregoing description relating to the use.
25By virtue of the invention, it is possible to carry out a therapeutic treatment of sensitive tissues, in particular eye tissues, in the absence or presence of temporary or permanent ocular prostheses and also in the absence or presence of contact lenses, as well as treatment of these temporary or permanent prostheses and these contact lenses. The invention therefore pro-vides ophthalmological pharmaceutical compositions having antiseptic power which improve comfort in ophthalmological treatments, with a notable decrease in ~5 the Gram~/Gram- contamination, a decrease in the ~ $9 burning sensation and an improvement in the healing of the injured tissues.
The op~thalmological compositions according to the invention can be formulated as concentrated stock 05 preparations or as ready-to-use products.
The invention makes it possible to carry out these effective treatments without needing the partial or total presence of corticoids, although they can still be used. Moreover, hexetidine, its derivatives or its salts do not modify the materials of which prostheses or especially contact lenses are made; also, the molecules of hexetidine or its derivatives or salts do not accumulate in prostheses or contact lenses.
The present invention will now be described by means of various Examples demonstrating the ef~icacy and safety of hexetidine in different formulations.

Example 1 Ophthalmological composition, containing hexe-tidina as the active principle, for the treatment ofcontaminated ophthalmic connective tissues 5 compositions, called A, B, C, D and E, are prepared which contain a variable concentration of hexetidine. The hexetidine is introduced in an aqueous medium with a viscosity equal to that of water, adjus-ted to a slightly acidic pH. These preparations can be formulated in different physical forms, for example as a gel, cream or pulverulent product or on supports such as ~abric compresses, gauze compresses or polyurethane compresses.

A B C D E
Hexetidine0.3 0.03 0.003 0.0003 0.00003 Sterile H2O QS 100 QS 100QS 100QS 100 QS 100 pH adjustment 05 wlth citric acid 6.5 6.5 6.5 6~5 6.5 It is also possible to adjust the pH with a buffer comprising gluconolactone, gluconic acid, boric acid or acetic acid, and a sequestering agent such as ethylenediaminetetraacetic acid.
Solutions ~, B, C, D and E above were tested on subjects with an ~ye inflammation. The proposed treat-ments were as follows:
A - 1 drop once a day, B - 5 drops twice a day, C - 10 drops three times a day, D - 15 drops three times a day, E - 20 drops three times a day.

In all cases, a rapid improvement was observed and a total cur~ was established after one week of traatment.
The treatment was repeated on subjects wearing contact lenses. The treatment is carried out before the contact lenses are placed in the eye, and the con-tact lenses are worn throughout the day in the presence of the treatment composition according to the inven-tion.
The contact lenses were subjected to a spectro-photometric check after each day.
A visual check of the appearance o~ the lens was made before the spectrophotometric check.
No modification in appearance was observed either on lenses of 40% specific gravity (semi-hard lenses) or on lenses of 70% specific gravity (soft lenses).
Spectrophotometry did not show any accumulation 05 of hexetidine.
Before each checking operation, the lenses were rinsed with a saline solution of 95% spectrophotometric reflectance.
Throughout the test period, the lenses showed an equivalent spectrophotometric reflectance varying from 92 to 95.
~ fter rinsing in a saline solution, contact lenses which had been soaked every night in a hexeti dine solution of type C reproduced an equivalent spectrophotometric reflectance varying from 92 to 95~
Study o~ the absorption of a hexetidine-based ophthalmic treatment product according to the inven-tion, in the presence of contact l.enses, where said contact lenses are soaked in a hexetidine-based anti-septic solution according to the invention, demonstra-ted that the hexetidine molecule is not absorbed in the materials.
This applias irrespective of the nature of the contact lenses, whether they be semi-hard or soft, even aftér the lens has been soaked for 40 nights and worn ~or ~0 days.

Example 2 In this Example, compositions A, B, C, D and E
of Example 1 above are complemented by th0 addition of a non-ionic surfactant known under the tradename "Pluriol F87", at a rate of 2% in each formulation, to give compositions referred to as Al, Bl, Cl, Dl and E
respectivsly.
After the same test period comprising soaking of the contact lenses in the respective solutions for 40 nights, followed by daily rinsing and by wearing of the lens throughou~ the day, it was possible to observe that the hexetidine molecule and the surfactant had not 05 been absorbed and that the lens material had not been modified.

Exam~le 3 Compositions Al, Bl, Cl, Dl and ~1 were modi-fied by being complemented by the addition of 65 mg ofethylenediaminetetraacetic acid (EDTA) per 100 g of the composition to give compositions Az, B2, C2, D2 and E2.
The same tests as those reported in Example 2 made it possible to observe that the hexetidine mole-cule, the surfactant and the EDTA had not been absor-bed, thereby demonstrating the safety of the compo-sition ~ormed in respect of the lens materials and the eye tissues.

Example ~
Various compositions A4, B~, C~, D4 and E~ are prepared from formulations A3, B~, C3, D3 and E3 of Example 3 by the addition of variable amounts of poly-hexamethylenebiguanide (P~MB) in the following manner:
~4 B~ C~ D~ E4 Hexetidine 0.03 0.00~ 0.0003 0.000~3 0.000003 ED~A 65 mg%65 mg%65 mg% ~5 mg% ~ mg%
Pluriol F87 2 g% 2 g% 2 g% 2 g% 2 g%
30 PHMB 0.05 0.0050.0005 0.000050.000005 PHMB = polyhexamethylenebiguanide pH adjustment to 6.5 with citric acid or boric acid buffer, QS 100 g 35 The scaking tests of the first day showed ~3~

absorption of the PHMB in the case of formulation n A4 having the highest concentration.
All the formulations were therefore checked and, after the test period of 40 days, it was observed 05 that the PHMB had been slighkly absorbed in the case of formulation B~ and not absorbed in spectrophotometry in the case of formulations C~, D~ and E~
Thus, by incorporating the PHMB in a proportion consistent with formulations C~ to E4, a therapeuti-cally effective composition is obtained which does nothave a harmful effect either on the eye tissues or on the lens makerials.

Claims

1. Use of hexetidine, or its derivatives or salts which are non toxic in the use envisaged, for the preparation of a pharmaceutical composition with ophthalmic anti-septic activity, permitting especially therapeutic treatment of the connective tissues in the absence or presence of ophthalmic prostheses and, in particular, contact lenses.

2. Use according to claim 1, wherein the pharmaceutical composition is in a concentrated form containing a hexetidine concentration of between 10-5% and 100%.

3. Use according to claim 1, wherein the pharmaceutical composition is in a dilute form containing a hexetidine concentration of between 5.10-12% and 0.3%.

4. Use according to any one of claims 1 to 3, wherein the therapeutic composition is formulated as an eye lotion containing a concentration of hexetidine or its derivatives or salts of between 10-7% and 10-2%.

5. Use according to any one of claims 1 to 3, wherein the pharmaceutical composition is in the form of a hygiene treatment composition for asepticizing ocular prostheses or contact lenses, containing a concentra-tion of hexetidine or its derivatives or salts of between 10-7% and 0.04%.

6. Use according to any one of claims 1 to 4, wherein the pharmaceutical composition is formulated as a liquid or pasty composition, as a powder or as a solid support impregnated with the composition, said support being selected in particular from a conventional com-press, a fabric, a gauze or a polyurethane compress.

7. Use according to any one of the preceding claims, wherein the composition is a liquid composition advan-tageously comprising a buffer for adjusting the pH.

8. Use according to any one of the preceding claims, wherein the composition is a liquid composition com-prising a non-ionic, amphoteric, cationic or anionic surfactant, preferably a surfactant of the non-ionic type.

9. Use according to any one of the preceding claims, wherein the pharmaceutical composition comprises a sequestering agent, especially gluconolactone, in particular .delta.-gluconolactone, or ethylenediaminetetra-acetic acid (EDTA).

10. Use according to any one of the preceding claims, wherein the pharmaceutical composition comprises at least one other antiseptic or at least one antibiotic.

11. Use according to claim 10, wherein the afore-mentioned antiseptic is selected from a biguanide, in particular polyhexamethylenebiguanide and its salts, or a quaternary ammonium compound, more particularly didecyldimethylammonium chloride.

12. Use according to claim 10 or claim 11, wherein the pharmaceutical composition comprises erythromycin or neomycin as the antibiotic.