WO2006120696A2

WO2006120696A2 - An improved pharmaceutical composition

Info

Publication number: WO2006120696A2
Application number: PCT/IN2006/000054
Authority: WO
Inventors: Rajeev Raut
Original assignee: Rajeev Raut
Priority date: 2005-02-21
Filing date: 2006-02-20
Publication date: 2006-11-16
Also published as: JP4239036B2; JP2008530202A; WO2006120696A3

Abstract

The present invention relates to a pharmaceutical composition containing 4-aminoquinoline compounds and Magnesium chloride for treatment of ocular inflammation of varied etiology such as immune disease factors, surgery, chemical or mechanical injury or prevention of injury due to exposure to radiation, infra-red or ultra-violet rays, degenerative changes, allergic or infective etiology using the novel pharmaceutical composition of the present invention.

Description

AN IMPROVED PHARMACEUTICAL COMPOSITION

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition containing 4- aminoquinoline compounds and Magnesium chloride.

The present invention also relates to a treatment of ocular inflammation of varied etiology such as immune disease factors, surgery, chemical or mechanical injury or prevention of injury due to exposure to radiation, infra-red or ultra-violet rays, degenerative changes, allergic or infective etiology using the novel pharmaceutical composition of the present invention.

The present invention also relates to the composition resulting from the said process and treatment of ocular inflammation with the said composition. The said ocular inflammation may also present as dry eye or ocular surface disorder.

BACKGROUND OF THE INVENTION

Inflammation of the eye may be localized to the eye, the eyes, or may be part of more generalized inflammatory process. Its etiology may be infection, allergy, immunological reactions, or as a response to surgery, injury, or due to any other causes. The ocular inflammation causes pain, irritation, watering, threatens visual function of the eye and may also change optical properties of the eye. Inflammation may be seen as Uveitis or keratoconjunctivitis. Inflammation may also be seen as "dry eye" or as ocular surface disorder.

Accordingly, a need exists for novel ophthalmic pharmaceutical compositions, which safely and effectively treat or prevent ocular inflammation conditions. The anti-inflammatory properties of the anti-malarial 4-aminoquinolone pharmaceuticals are well known. They have not been used to treat inflammation of the eye because their systemic use in high closes has been associated with a rare, but serious, incidence of ocular toxicity including corneal deposits known as verticillata, loss of foveal reflex, impairment of accommodation, maculopathy and retinopathy. These effects may be reversible or irreversible.

The present invention specifically avoids these dreaded side effects of 4 aminoquinolines by using a predetermined concentration in the composition, and by combining it with another predetermined and low concentration of magnesium chloride to achieve beneficial effects and at the same time avoid side effects.

The 4-aminoquinoline compounds used in prior art in ophthalmic pharmaceutical compositions have been previously reported to be useful as therapeutics in the treatment of malaria and rheumatoid arthritis.

In yet another prior art it was disclosed that 4-aminoquinolines have strong antiinflammatory action and are very effective for inflammatory diseases. Rynes, Rl, 36 BR J RHEUMATOL 799-805 (1997).

Magnesium chloride is a well-known electrolyte solution. It is used to wash eyes during eye surgery, along with other electrolytes.

It has now been found that certain 4-aminoquinolone compounds along with magnesium chloride are useful for preventing and treating ocular inflammation by application of the compositions to the eye prior to, during and after an inflammatory disorder, especially inflammation of the outer and middle coats of the eye, such as dry eye, etc. PRIORART

4-aminoquinolines and their derivatives to be used in present invention and processes for preparing these compositions are disclosed in: U.S. Patent No.4,421,920 to Baudouin, U.S. Patent No. 5,596,002, to Hofheinz, and U.S. Patent No. 5,948,791 , to Hofheinz, References:

EP Patent No. 1,374,867.

WO Patent No. 0007601

US Patent No. 6,086,597.

U.S. Patent No. 4,421,920. U.S. Patent No. 5,596,002.

U.S. Patent No. 5,948,791.

EP No.: 1, 374,867

Use of at least one 4 amino-quinolinic derivative to obtain a drug for the anti- retroviral therapy, especially in the therapy of the HIV disease-infection caused by retroviral strains, which are sensitive and/or resistant to known therapies. This 4 amino-quinolinic derivative is chloroquine and/or hydroxychloroquine and the drug can be orally administered once or several times a day.

WO patent application No.: 0007601

Ophthalmic compositions and methods of using the same to simultaneously treat eye surface inflammation and dry eye are disclosed. The ophthalmic preparation contains a tetracycline compound in aqueous solution. The preparation preferably further includes a balance of electrolytes sufficient to maintain or restore essentially normal levels of conjunctival mucus-containing goblet cells and corneal glycogen. These electrolytes can include potassium, chloride, bicarbonate, sodium, calcium, magnesium and phosphate.

US Patent No,: 6086597

Ophthalmic composition for use in ocular surgery includes an aqueous solution of sodium hyaluronate with a concentration within the range of 18-40 mg sodium hyaluronate/ml solution and the molecular mass of sodium hyaluronate being in the range of 1x106-10x106r,M. In a method for conducting ocular surgery, the composition is introduced into the eye as a surgical aid. The composition may be used in a method for conducting cataract surgery.

U.S. Patent No.: 4,421,920

4-Amino-chloroquinolines of the formula: ##STR1## in which R.sub.1 represents a hydrogen atom or an alkyl radical (1 to 5 carbon atoms), and R.sub.2 represents an alkyl radical (1 to 5 carbon atoms) optionally substituted by a dialkylamino group, or a phenyl radical optionally substituted by one or more carboxy and hydroxy radicals and alkyi radicals (1 to 4 carbon atoms) optionally substituted by a dialkylamino group, are prepared by the condensation of an amine of the formula: ##STR2## with a chloro-1 ,2,3,4-tetrahydroquinolin-4-one of the formula: ##STR3## with aromatization of the tetrahydroquinoline, the reaction being carried out in the presence of a ruthenium based catalyst on a support. The 4-amino-ch!oroquinoline products are useful as pharmaceuticals.

U.S. Patent No.: 5,596,002

Novel aminoquinoline derivatives of the general formula ##STR1## are described. Also described are methods for the treatment of malaria paihcger.c, particularly chlorαquine-resistance malaria pathogens with compounds of formula I or the pharmaceutically acceptable salts and hydrα!yzab!e ectere therccf. To the extent these applications and patents disclose 4-aminσquiπoline compounds and their derivatives, which are useful in the practice of the present invention, they are incorporated herein by reference.

In the preferred embodiment, the 4-aminoquinoline compounds in the ophthalmic pharmaceutical composition are mefloquine, quinacrine, and cletoquine.

A novel pharmaceutical composition for external application in inflammatory disorder of eye as eye drops, eye ointments or directly subconjunctivally or directly intra vitrea Hy is described. This new composition results in a prolonged and sustained intraocular levels of the active drug in mammals using formulations that not necessarily increase drug plasma levels, and therefore avoid hazards associated with raised plasma levels and implications thereof, like drug toxicity.

Another object of the present invention is to provide prolonged stable intraocular levels of 4- aminoquinolines.

It is also an object of the present invention to provide sustained intraocular levels of 4-aminoquinolines without having to increase their plasma levels.

The objects of the present invention are met and the problems and shortcomings associated with the prior art are overcome by the incorporation of the 4- aminoquinlines and magnesium chloride into a composition to be administered topically, directly to the eye, as eye drops, eye ointments, gels, a spray via an adsorbent contact lens, via a sustained release container placed in the eye, or subconjunctivally or intravitreally by direct injection.

Compounds suitable for the composition of the present invention herein include chloroquine, amodiaquine, an isomer, or a salt thereof, and structurally εirr.ϋsr compounds and magnesium chloride, or a salt thereof, and structurally similar compounds.

As used above, the term "salt thereof is meant to include any nontoxic pharmaceutically suitable salt of a compound described hereinabove with the desired pharmacological properties in mammals. Preparation of such a salt is well known to those skilled in pharmaceutical science.

4-aminoquinoline and magnesium chloride compounds are non-toxic to the eye when administered directly to the eye. Ocular administration permits the compound to be administered in adequate ocular doses and to maintain intraocular levels of the compound for prolonged periods. The 4-aminoquinolone compounds and magnesium chloride when used in ophthalmic pharmaceutical composition, are effective in preventing and treating ocular inflammation of varied etiology such as immune disease factors, surgery, chemical or mechanical injury, injury due to exposure to radiation, infrared or ultraviolet rays, degenerative changes, allergic conjunctivitis, allergic responses in the eye.

Therefore, the present invention, i.e. the pharmaceutical substance obtained by the process as herein described is a totally different and novel pharmaceutical composition, having synergetic properties.

The ophthalmic pharmaceutical compositions of this invention contain one or more 4«aminoquinoline and magnesium chloride compounds as the active component(s). Prior to describing this invention in further detail, the following terms will first be defined.

"Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts which are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetra-alkyl-ammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, tartrate, and the like. Among the conventional salts which can be utilized there are the base salts, for example, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or alkyl ammonium salts.

EXPERIMENTS CONDUCTED TO DEMONSTRATE SYNERGISTIC ACTION OF CHLOROQUINE AND MAGNESIUM CHLORIDE.

Four solutions were prepared.

Solution one (1) contained chloroquine phosphate aqueous solution 0.03 gm% Solution two (2) contained aqueous solution magnesium chloride 0.0003 gm% Solution three (3) contained aqueous solution chloroquine phosphate 0.03gm% and magnesium chloride 0.003gm%

Solution four (4) contained plain sodium chloride 0.9gms% as control.

Fresh ocular ectodermal cells attached to the basement membrane were taken on four glass slides.

The cells on slide number 1 were treated with solution 1.

Similarly, cells on slides number 2, 3 and 4 were treated with solutions 2, 3 and 4.

The slides were exposed to UV light, which peaked at wavelength of 390 nanometers, by placing them equidistantly from the source so that all the cells on the slides got equal exposure. The exposure time was 10 seconds.

The slides were stained with Leishmann stain and examined under microscope.

The cells were observed for signs of damage due to the Ultraviolet light.

The criteria that were used were Uniformity of shape. Uniform round shape 5 points

Irregular shape in more than 50% cells - 4 points Irregular shape in 80% cells - 3 points

Creation, truncation of cell wall - 1 point.

Rupture of cell wall zero points.

Intercellular distance Uniform closely packed cells 5 points

Increase in cell distance so that half the cells were covered by a standard high power microscope field 4 points

One third cells were covered by the field 3 points

No cells- zero points. Vacuolation of nucleus

No vacuoles - 5 points

Vacuoles in 50% of cells in a field - 4 points

Vacuoles in 80% of cells in a field - 3 points

Vacuoles in ail cells - 0 points.

The scores were tabulated and analyzed.

The scores were as follows :

Solution 1 : 8 points

Solution 2: 3 points Solution s: 15 points

Solution 4: 1 point.

CONCLUSION

Therefore, the photo protective action of Chloroquine phosphate combined with magnesium chloride in the above solution is not a simple additive effect of each, but the effect is produced by a synergistic action of both. STATEMENT OF THE INVENTION!

Therefore, according to the present invention, a novel pharmaceutical composition for external application in inflammatory disorders of eye comprising reacting 4-aminoquinolines and magnesium chloride with water, and ophthalmically acceptable acids and bases to adjust the pH, tonicity imparting agents, antimicrobial preservatives, suitable absorption enhancers, and stabilizing agents, bases for ointments for treatment of inflammatory disorders. Said 4 aminoquinolines is with concentrations between 0.001 nanograms per ml. and 1.00 mg per ml and magnesium chloride between 0.0001 grams percent to

0.3 grams percent along with water.

The said composition, which forms a novel Pharmaceutical compound when 4 aminoquinoline is mixed with magnesium chloride along with water.

The 4 aminoquinoline is chloroquine or its derivatives, isomers, salts. The said 4 aminoquinoline is hydroxychloroquine sulphate, chloroquine phosphate, chloroquine phosphate is amodiaquine or its derivatives, isomers, salts.

The said 4 aminoquinoline compound is selected from the group comprising of Chloroquine phosphate,

Hydroxychloroquine,

Chloroquine hydrochloride,

N₁N Dideethyl chloroquine,

Mefloquine, Cletoquine.

In the said composition Tonicity-imparting agents such as sorbitol, glycerin and dextrose are added.

In the said composition antimicrobial preservatives such as parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, benzalkonium chloride are added. In the said composition suitable absorption enhancers such as surfactants, bile acids are added. In the said composition stabilizing agents such as antioxidants like bisulfites and ascorbates are added. In the said composition viscosity- imparting agents such as sodium carboxymethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, and polyvinyl alcohol are added. In the said composition said wetting agent is carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, or hydroxyethylcellulose, or artificial tears.

In the present invention ophthalmically acceptable acids and bases are employed to adjust the pH, tonicity imparting agents, antimicrobial preservatives, suitable absorption enhancers, and stabilizing agents, bases for ointments prevents protein unfolding that results due to a heat shock.

The said compound is formulated as a suspension, solution, salve, ointment, spray, liposomal composition, nonoemulsion particle composition, or chitosan particle composition, slow release inserts, via contact lens.

Detailed descriptions of the preferred embodiment are provided herein; however, it is to be understood that the present invention may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in virtually any appropriately detailed system, structure or manner.

Claims

i Claim:

1. An improved pharmaceutical composition comprising reacting 4- aminoquinoiines and magnesium chloride with water, ophthalmically acceptable acids and bases to adjust the pH, tonicity imparting agents, antimicrobial preservatives, suitable absorption enhancers, stabilizing agents, wetting agents and bases for treatment of inflammatory disorders.

2. An improved pharmaceutical composition as claimed in claim 1 , wherein the concentration of 4 aminoquinoiines is between 0.001 nano-grams per ml. to 1.00 mg per ml of water.

3. An improved pharmaceutical composition as claimed in claim 1 , wherein the concentration of magnesium chloride is between 0.0001 grams percent to 0.3 grams percent with water.

4. An improved pharmaceutical composition as claimed in claim 1 and 2 wherein the said 4 aminoquinoline is chloroquine or its derivatives or isomers or salts.

5. An improved pharmaceutical composition as claimed in claim 4, wherein 4 aminoquinoline is hydroxychloroquine sulphate.

6. An improved pharmaceutical composition as claimed in claim 4, wherein 4 aminoquinoline is chloroquine phosphate.

7. An improved pharmaceutical composition as claimed in claim 6, wherein 4 aminoquinoline is chloroquine phosphate or amodiaquine or its derivatives, isomers, salts.

8. An improved pharmaceutical composition as claimed in claim 1 and 4, wherein 4 aminoquinoline compound is selected from the group of Chloroquine phosphate, Hydroxychloroquine, Chloroquine hydrochloride,

N₁N Dideethyl chloroquine, Mefloquine.or Cletoquine.

9. An improved pharmaceutical composition as claimed in claim 1 , wherein tonicity-imparting agents are sorbitol, glycerin, and dextrose.

10.An improved pharmaceutical composition as claimed in claim 1 , wherein antimicrobial preservatives are parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, benzalkonium chloride.

11.An improved pharmaceutical composition as claimed in claim 1, wherein absorption enhancers are surfactants, bile acids.

12. An improved pharmaceutical composition as claimed in claim 1 , wherein stabilizing agents are antioxidants like bisulfites and ascorbates.

13. An improved pharmaceutical composition as claimed in claim 1 , wherein viscosity-imparting agents are sodium carboxymethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, and polyvinyl alcohol.

14. An improved pharmaceutical composition as claimed in claim 1 , wherein said wetting agent is carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, or hydroxyethylcellulose, or artificial tears.

15. An improved pharmaceutical composition as claim in claim 1 , wherein the said composition is formulated as a suspension, solution, salve, ointment, spray, liposomal composition, non-emulsion particle composition, or chitosan particle composition, slow release inserts, via contact lens.

16. A novel pharmaceutical composition as claimed in claims 1 to 15 hereinabove substantially as herein described with reference to the accompanying specification.