WO2010119305A1

WO2010119305A1 - Using of quaternary ammonium compounds in dissolving of latanoprost

Info

Publication number: WO2010119305A1
Application number: PCT/IB2009/051543
Authority: WO
Inventors: Farhad Farshi; Recep Avci; Demet Yedigocmen; Serdar Soylemez; Fikret Koc
Original assignee: Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2009-04-14
Filing date: 2009-04-14
Publication date: 2010-10-21

Abstract

This invention relates to an opthalmic solution of latanoprost characterized in that latanoprost is dissolved in a presence of an opthalmologically acceptable quaternary ammonium compound, preferably benzalkonium chloride, or mixtures thereof with proviso that excipient or excipients other than opthalmologically acceptable quaternary ammonium compound or mixtures thereof do not exist in dissolving phase.

Description

Title of Invention: USING OF QUATERNARY AMMONIUM COMPOUNDS IN DISSOLVING OF LAT ANOPROST

[1] This invention relates to an opthalmic solution of latanoprost characterized in that Ia- tanoprost is dissolved in the presence of an opthalmologically acceptable quaternary ammonium compound, preferably benzalkonium chloride, or mixtures thereof with proviso that excipient or excipients other than opthalmologically acceptable quaternary ammonium compound or mixtures thereof do not exist in dissolving phase .

[2] Latanoprost is a therapeutic agent for glaucoma or ocular hypertension. WO

9002553, which describes latanoprost as a molecule, points out that benzalkonium chloride may be used as a preservative (page 8). There is no exposing with respect to using of benzalkonium chloride as a dissolving agent and dissolving of latanaprost in benzalkonium chloride without additional excipient or excipients .

[3] EP 1 532 981 patent focuses on the stability of latanoprost by using of aminocaproic acid and adjusting pH. EP 1 532 981 patent uses benzalkonium chloride as a preservative. But our invention is relevant to dissolving of latanoprost in benzalkonium chloride which means benzalkonium chloride is used as a single excipient to dissolve latanoprost. Additionally our method does not require warming. However EP 1 532 981 delineates using of multiexcipients and warming to dissolve latanoprost. Accordingly, crystalline sodium dihydrogenphosphate , sodium chloride and benzalkonium chloride were dissolved in purified water, a 1 N aqueous sodium hydroxide solution was added thereto to adjust pH to 6.0, and purified water was added to the mixture . The vehicle was added to latanoprost and the mixture was stirred and warmed to dissolve latanoprost (page 4, example 5, 033).

[4] EP 1 547 599 discloses to obstacle turbidity by using of benzalkonium chloride in a specific amount. Our invention is different from EP 1 547 599 because latanoprost is dissolved in benzalkonium chloride which means benzalkonium chloride is used as single excipient to dissolve latanoprost. Additionally our method does not require warming. According to example 1-1 of EP 1 547 599 (page 4, 0032), Crystalline sodium dihydrogenphosphate , sodium chloride , Polysorbate 80 and benzalkonium chloride were dissolved in purified water, pH was adjusted to 6.7, and purified water was added to the solution . Then latanoprost was added and the mixture was stirred and warmed to dissolve latanoprost.

[5] EP 1 759 702 claims an ophthalmic aqueous solution comprising latanoprost, hy- droxypropylbetacyclodextrines and sodium hyaluronate. EP 1 759 702 discloses a long process to dissolve latanoprost (0025-0026-0027, page 4). Our invention embraces different solution to dissolve latanoprost since we directly dissolve latanoprost in ben- zalkonium chloride .

[6] Latanoprost is an oily substance practically insoluble in water. To facilitate water solubility surfactants should be used with. Quaternary ammonium compounds especially benzalkonium chloride acts as cationic surfactant and antibacterial preservative as well, is a good choice for this purpose.

[7] Latanoprost is containing an ester group which is susceptable to cleavage especially in basic pH range.

[8] Benzalkonium chloride has pH range between 5-8 depending on the concentration.

[9] Prior art preparations were cautious about these facts. To avoid degradation , diluted and pH corrected solutions were prepared to dissolve Latanoprost. But dissolving procedure became more difficult. Excessive heating and stirring had to be applied which may lead to degradation. Despite these efforts not allways a complete dissolving of Latanoprost was achieved as can be seen by becoming turbid these preparations later.

[10] To avoid excessive stirring time and heating which are the potential source of risk to degradation, no satisfactory attemps were undertaken up to date.

[11] In our invention, despite the fact that benzalkonium chloride solutions are slightly basic, we are surprisingly and unexpectedly able to dissolve Latanoprost (in quaternary ammonium solutions, especially benzalkonium chloride) in a short period of time at ambient temperature without degradation. No heating is needed. The solutions are clear and remains so after completion of formulation and storage. We have invented an easy and shortcut way of preparing ophthalmic solutions without the risk of degradation and turbidity faced by prior art preparations.

[12] Dissolving latanoprost in an opthalmologically acceptable pharmaceutical excipient is problematic on the grounds of rationales mentioned above. In aspect of dissolving of latanoprost, problem solution methods in the prior art, offer using of multiple ex- cipients, multiple phases and warming. According to our invention, latanoprost is directly dissolved in opthalmologically acceptable quaternary ammonium compound,such as benzalkonium chloride, or mixtures thereof. To dissolve Ia- tanoprost,our method does not require complex mixtures and phases with additional excipients and it is an easy and simple way. Especially, in industrial scale, absence of warming process and dissolving of latanoprost in single excipient provides effective and shortcut way. In this invention, opthalmologically acceptable quaternary ammonium compound or mixtures thereof, preferably benzalkonium chloride, is used both as a preservative and a dissolving agent. We invent an easy, simple and economic way to dissolve latanoprost.

[13] According to our invention, latanoprost is dissolved in the presence of an opthalmo- logically acceptable quaternary ammonium compound or mixtures thereof with proviso that excipient or excipients other than opthalmologically acceptable quaternary ammonium compound or mixtures thereof do not exist in dissolving phase. Namely, so as to dissolve latanoprost it is treated with only opthalmologically acceptable quaternary ammonium compound or mixtures thereof . It does not need further excipient or excipients.

[14] Opthalmologically acceptable quaternary ammonium compounds are, but not limited to,benzalkonium chloride, benzethonium chloridejauralkonium chlorideor mixtures thereof.

[15] Opthalmologically acceptable quaternary ammonium compound or mixtures thereof, preferably benzalkonium chloride, may be in solution form. Solution form may comprise water and benzalkonium chloride. Dissolving of latanoprost can be performed in a 10-99 % mixture of quaternary ammonium compound, preferably benzalkonium chloride, in a suitable solution. Said mixture is preferably 50% benzalkonium chloride in water.

[16] Another aspect of this invention is a pharmaceutical composition of opthalmic solution. Accordingly, opthalmic solution comprises Latanoprost and sodium di- hydrogen phosphate monohydrate, sodium chloride, anhydrous disodium phosphate,benzalkonium chloride and water for injection.

[17] In yet another aspect, this invention provides a preparation method of opthalmic solution which comprises (i) sodium dihydrogen phosphate monohydrate, anhydrous disodium phosphate, sodium chloride and purified water are mixed until completely dissolved and, (ii)latanoprost and benzalkonium chloride are mixed until completely dissolved and, (iii) solutions prepared in phase (i) and phase (ii) are mixed and, (iv)mixed solution is filtered.

[18] Example 1 (Preparation Method of Opthalmic Solution)

[19] Solution A : In a stainless stell tank, by order of sodium dihydrogen phosphate monohydrate, anhydrous disodium phosphate, sodium chloride are added in 3/4 of total purified water and it is mixed for 5 minutes until completely dissolved. Solution B : In another stainless stell tank, Latanoprost and benzalkonium chloride are mixed by spatula for 5 minutes until completely dissolved. Preperation of an aqueous ophthalmic solution of Latanoprost : Add solution B to solution A and mixed them for 5 minutes. Top up the volume with purified water and continue to agitate approximately one hour in order to complete the solution . Filtering: The solution is filtered 0.2μ filter.

[20] Example 2 (Pharmaceutical Composition) [Table 1]

[Table ]

Table 1 : Pharmaceutical Composition of Latanoprost Solution

Claims

[Claim 1] An opthalmic solution of latanoprost characterized in that latanoprost is dissolved in the presence of an opthalmologically acceptable quaternary ammonium compound or mixtures thereof with proviso that excipient or excipients other than opthalmologically acceptable quaternary ammonium compound or mixtures thereof do not exist in dissolving phase .

[Claim 2] According to claim 1 quaternary ammonium compounds are ben- zalkonium chloride, benzethonium chloride and lauralkonium chloride.

[Claim 3] According to claim 2, quaternary ammonium compound is ben- zalkonium chloride .

[Claim 4] According to claim 1, quaternary ammonium compound is in the form of solution.

[Claim 5] According to claim 4, quaternary ammonium compound solution comprising water and quaternary ammonium compound in which quaternary ammonium compound is 10-99 % in water .

[Claim 6] According to claim 5, solution is 50% quaternary ammonium compound in water.

[Claim 7] According to claim 4, quaternary ammonium compound solution is benzalkonium chloride solution.

[Claim 8] According to claim 7, benzalkonium chloride solution comprising water and benzalkonium chloride in which benzalkonium chloride is

10-99 % in water .

[Claim 9] According to claim 8, solution is 50% benzalkonium chloride in water.

[Claim 10] According to claim 1, opthalmic solution comprises latanoprost, sodium dihydrogen phosphate monohydrate,sodium chloride, anhydrous disodium phosphate, benzalkonium chloride, water for injection.

[Claim 11] A preparation method of latanoprost opthalmic solution comprising steps of ;

(i) sodium dihydrogen phosphate monohydrate, anhydrous disodium phosphate, sodium chloride and purified water are mixed and dissolved and,

(ii) latanoprost and benzalkonium chloride are mixed and dissolved and,

(iii) solutions prepared in phase (i) and phase (ii) are mixed and,

(iv) obtained solution is filtered.