RABINOVICH-GUILATT LAURA (IL)
LALLEMAND FREDERIC (FR)
GARRIGUE JEAN-SEBASTIEN (FR)
PHILIPS BETTY (FR)
LAMBERT GREGORY (FR)
RABINOVICH-GUILATT LAURA (IL)
LALLEMAND FREDERIC (FR)
GARRIGUE JEAN-SEBASTIEN (FR)
PHILIPS BETTY (FR)
| WO2007042262A2 | 2007-04-19 |
| EP0696452A1 | 1996-02-14 | |||
| US5110493A | 1992-05-05 | |||
| EP1688144A1 | 2006-08-09 | |||
| EP0390071A1 | 1990-10-03 |
CLAIMS
1. An ophthalmic oil-in-water emulsion comprising a non-steroidal anti-inflammatory drug and a quaternary ammonium halide in which the nitrogen atom is substituted by one or more alkyl group having at least 16 carbon atoms.
2. An oil-in-water emulsion according to claim 1, wherein said non-steroidal anti-inflammatory drug is chosen among ketorolac, salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen, suprofen, piroxicam, COX2 inhibitors, diclofenac, nimesulide, nepafenac.
3. An oil-in-water emulsion according to claim 1, wherein said non-steroidal anti-inflammatory drug is flurbiprofen.
4. An oil-in-water emulsion according to anyone of claims 1 to 3, comprising 0.001% to 10% of a non- steroidal anti-inflammatory drug, preferably 0.01% to 1%, more preferably 0.02% to 0.05% w/w of the emulsion.
5. An oil-in-water emulsion according to anyone of claims 1 to 4, wherein the amount of quaternary ammonium halide in which the nitrogen atom is substituted by one or at least one alkyl group having at least 16 carbon atoms represents between 10 to 30% w/w measured in dry weight relatively to the total amount of all quaternary ammonium halides present in the emulsion.
6. An oil-in-water emulsion according to anyone of claims 1 to 4, wherein the amount of quaternary ammonium halide in which the nitrogen atom is substituted by one or at least one alkyl group having at least 16 carbon atoms represents between more than 30% w/w measured in dry weight relatively to the total amount of all quaternary ammonium halides present in the emulsion, preferably more than or equal to 50% w/w, preferably more than or equal to 70%, preferably more than or equal to 80% w/w, preferably more than or equal to 90% w/w.
7. An oil-in-water emulsion according to anyone of claims 1 to 6, wherein said quaternary ammonium halide is benzyl dimethyl ammonium chloride or bromide, in which the nitrogen atom is substituted by an alkyl group having at least 16 carbon atoms.
8. An oil-in-water emulsion according to claim 7, wherein said quaternary ammonium halide is Clβ-alkyl benzyl dimethyl ammonium chloride.
9. An oil-in-water emulsion according to anyone of claims 1 to 6, wherein said quaternary ammonium halide is a trimethyl ammonium chloride or bromide, wherein the nitrogen atom is further substituted by an alkyl group having at least 16 carbon atoms.
10. An oil-in-water emulsion according to anyone of claims 1 to 9, further comprising an oil phase comprising MCT, castor oil or mineral oil, surfactants preferably chosen among at least one of tyloxapol, poioxamer, tocopherol, polyethylene glycol succinate, sorbitan monolaurate and poiysorbate, and optionally antioxidants and/or isotonicity agents preferably chosen among at least one of glycerol and mannitol.
11. An oil-in-water emulsion according to anyone of claims 1 to 10, comprising 0.001 to 0.1% of ammonium haiide .
12. An oil-in-water emulsion according to anyone of claims 1 to 11, said emulsion having a positive zeta potential .
13. An oil-in-water emulsion according to anyone of claims 1 to 12, said emulsion having a droplet size of
100 to 500 nm.
14. An oil-in-water emulsion according to anyone of claims 1 to 13, said emulsion being preserved.
15. An oil-in-water emulsion according to anyone of claims 1 to 13, said emulsion being unpreserved.
16. An oil-in-water emulsion according to anyone of claims 1 to 15, further comprising an immunosuppressive agent, preferably cyclosporin.
17. Medicament comprising an oil-in-water emulsion according to anyone of claims 1 to 16.
18. Medicament according to claim 17, in a unitary dosage form.
19. Medicament according to claim 17 or 18, wherein the emulsion is sterile.
20. An oil-in-water emulsion according to anyone of claims 1 to 16 for the treatment of an eye disease caused by, associated with or accompanied by inflammatory processes .
21. An oil-in-water emulsion according to anyone of claims 1 to 16 for preventing inflammation or preventing the development of an inflammatory process through pre- surgicai or immediate post-traumatical application.
22. An oil-in-water emulsion according to anyone of claims 1 to 16 for the treatment of an inflammation or the limitation of an inflammatory process.
23. The oil-in-water emulsion according to any of claims 20 to 22, for administration less than 4 times a day, preferably twice a day and more preferably once a day.
24. Process for manufacturing a pre-concentrate of an oil in water emulsion according to anyone of claims 1 to 16, said ρre-concentrate having a content in oil of at least 3 % w/w, preferably of 10% w/w or more, more preferably of 20% w/w or more, even more preferably of 30% w/w or more, the process comprising the steps of emulsifying/mixing the oil phase with an aqueous phase, said oil phase containing a surface-active component (s) , one or more NSAID, preferably flurbiprofen or esters thereof, and a quaternary ammonium halide in which the nitrogen atom is substituted by one or more aikyl group having at least 16 carbon atoms;
25. Pre-concentrate of a therapeutic oil-in-water emulsion, which is itself an oil-in-water emulsion obtainable by the process of claim 24.
26. A process for manufacturing an ophthalmic oil in water emulsion according to anyone of claims 1 to 16, comprising
(1) manufacturing a pre-concentrate of an ophthalmic oil in water emulsion, said pre-concentrate having a content in oil of at least 3 % w/w, preferably of 10% w/w or more, more preferably of 20% w/w or more, even more preferably of 30% w/w or more comprising the steps of emulsifying/mixing an oil suitable for ophthalmic use selected in the group comprising mineral oil, castor oil and MCT, with an aqueous phase and with surface-active component (s) and
(2) diluting a volume of the resulting pre- concentrate with 2 to 50 volumes of water, optionally containing a quaternary ammonium chloride, preferably BAK cl6. |
OIL IN WATER EMOLSION COMPRISING NSAIDs AND QUATERNARY
AMMONIUM HALIDES.
This invention relates to pharmaceutical, including ophthalmic compositions comprising non-steroidal antiinflammatory drugs (NSAIDs), more preferably to ophthalmic emulsions being useful for the treatment of eye conditions. This invention also relates to oil-in-water emulsions comprising NSAIDs and further including at least one quaternary ammonium compound as cationic agent.
The topical use of NSAIDs in the treatment of ophthalmic diseases was first taught in US 4,454,151. This US patent disclosed efficacious formulations with NaH2PO4H2O, Na2PO4H2O, NaCl, benzalkonium chloride (BAK) and sterilized water. However, these formulations were found to not have the stability required for shelf life in formulations. Ocufen® Ophthalmic solution, a non-patented medicament launched in 1988, is the first NSAID (flurbiprofen) approved by the FDA for ophthalmic use, and incorporates thimerosal as its preservative system. Thimerosal is an irritating organomercury compound (approximately 49% mercury by weight), and is known for its teratogenic side effects. New generations of ophthalmic formulations deprived from thimerosal are therefore needed.
US patent 5,110,493 disclosed improved and stable ophthalmic solutions (but no emulsions) including NSAID and using BAK as preservative. This formulation comprises 0.001% to 10 % of NSAID, 0.001% to 1% of preservative such as BAK, 0.001% to 1% of surfactant such as octoxynol 40, excipients and water. This formulation was shown to be stable for at least the minimum reasonable shelf life of such products. However, bioavailability is poor: typical
dosage ranges for this formulation to treat an eye condition is disclosed to be about 2-10 drops of 0.1% solution of NSAID per day.
This raises the problem of bioavailability of topically instilled drugs such as NSAIDs. Most of these NSAIDs exhibit complex ocular formulations problem due to aqueous solubility limitations. Therefore, attempts have been made to improve ocular bioavailability of NSAIDs by designing new colloidal delivery systems based either on nanoparticles, and negatively or positively charged submicron emulsions. Examples of such emulsions are disclosed in Klang et al (Journal of Controlled Release, 1999, 57:19-27): NSAID 0.1%, MCT 8.5%, Lipoid E80 1.2%, stearylamine 0.3%, alpha-tocopherol 0.02%, poloxamer 188 1%, glycerol 2.25% and water.
Quaternary ammonium compounds are organic compounds usually used as an antiseptic or antimicrobial agent.
As an example of quaternary ammonium compound, benzalkonium chloride may be cited. Benzalkonium chloride, also known as n-alkyl dimethyl benzyl ammonium chloride, is a nitrogenous cationic surface-active agent having positively charged nitrogen, covalently bonded to a benzyl group, to two methyl groups and to one Cs-Ci 8 aikyl chain.
Benzalkonium chloride generally is available in the form of a mixture of compounds having various alkyl chain lengths, from C 8 to C 18 ,
When used in pharmaceutical composition, as a preservative, benzalKonium chloride always is a mixture of n-alkyl dimethyl benzyl ammonium chlorides having various aikyl
chain lengths, from C s to C 1 H : this is a requirement of both European and/or American Pharmacopeia.
According to the American Pharmacopeia, benzaikonium chloride is a mixture of alkylbenzyldimethylammonium chlorides of the general formula:
[C 6
H 5
CH 2
N (CH 3
J 2
R] Ci in which R represents a mixture of alkyis, from n-C 8
Hi 7
to longer alkyl chains. On the anhydrous basis, in the mixture, the content of the
For example, FeF Chemicals A/S (Denmark) supplies, under reference 8100301U (BAK USP/NF) , a mixture of three alkyl dimethyl benzyl ammonium chlorxdes including : (1) 60-70% of Ci2~alkyl dimethyl benzyl ammonium chloride (2) 30-40% of Ci 4 ~alkyl dimethyl benzyl ammonium chloride, and less than 5% of Ci 6 -alkyl dimethyl benzyl ammonium chloride.
Benzaikonium chloride, as a mixture of alkyl dimethyl benzyl ammonium having various alkyl chain lengths was used as a preservative agent in topical ophthalmic products.
Benzaikonium chloride also has cationic agent properties, and was used as cationic agent for emulsions, especially ophthalmic emulsions.
When mixtures of benzalkonium chlorides having various alkyl chain lengths are used in emulsions, they may act both as preservative agents and cationic agents.
The Applicant worked on different ophthalmic emulsions for NSAIDs in order to obtain an emulsion having a better stability, being less toxic and providing a better ocular bioavailability of NSAIDs.
Therefore, the Applicant worked on long chain quaternary ammonium compounds such as BAK, and noticed that the length of the alkyl chain was important with regards to the function performed by the quaternary ammonium compounds in an oil-in-water emulsion containing NSAIDs: acting on the length of the alkyl chain resulted in enhancing or reducing the cationic power of the quaternary ammonium compounds. Without wanting to be linked by any theory, the Applicant observed on working on oil-in-water emulsions containing NSAIDs, that long chain alkyl quaternary ammonium compounds were preferentially localized at the oil/water interface of the emulsions, resulting in (1) emulsions with higher zeta potential (2) more stable emulsions. As quaternary ammonium may be considered as undesirable or toxic, it is thus a goal of this invention to provide cationic composition having a reduced content of quaternary ammonium compound.
The Applicant also observed that, in emulsions, quaternary ammonium compounds having long alkyl chains, for example quaternary ammonium compounds having C16- or Clδ-alkyl chains, when compared to C12-alkyl chains, did not have a good bactericidal activity, whereas they conferred a greatest cationic power.
Moreover, the Applicant observed that long chain quaternary ammonium compounds were present preferentially at the oil/water interface of the emulsion droplets, and less in the aqueous phase. The fact that quaternary ammonium compounds may be present in the aqueous phase in a very small amount only, or not present, leads to a loss of preservative effect or poor preservative effect, as well as to less toxic emulsions.
In the emulsion according to the present invention, the quaternary ammonium halide having at least 16 carbon atoms is essentially present in the oily phase.
Thus, one of the goals of this invention is to provide stable cationic emulsions comprising a reduced amount of benzalkonium chlorides, and still using said benzalkonium chlorides as a source, or the only source, of cationic agents, said emulsions being preserved or not.
In addition, the Applicant observed that an emulsion comprising NSAID and a quaternary ammonium halide in which the nitrogen atom is substituted by one or more alkyl group having at least 12, preferably 14 or 16, more preferably 16 carbon atoms provides a better ocular bioavailability compared to others formulations, which is of importance and resulted in the design of therapeutic emulsions having a content in oil of less than 6%, preferably of 5% or less, thus less irritating than the prior art emulsion.
Therefore, the goal of this invention is to provide an oil- in-water emulsion comprising a non-steroidal antiinflammatory drug and a quaternary ammonium halide in which the nitrogen atom is substituted by one or more alkyl group
having at least 12 carbon atoms, preferably 14 or 16 carbon atoms .
According to the invention, said emulsion is useful for ophthalmic purposes.
In the meaning of this invention,
"Cationic emulsions" are emulsions having a positive zeta potential, preferably a zeta potential higher to 10 mV;
"long chain aikyl" are alkyl moieties having at least 12 carbon atoms, preferably at least 14 carbon atoms, more preferably at least 16 carbon atom;
"quaternary ammonium compounds" refer to ammonium halides in which the nitrogen atom is substituted by only one or at least one alkyl group having at least 12 carbon atoms ; quaternary ammonium compounds also, but not exclusively, include n-alkyl dimethyl benzyl ammonium chloride also called benzalkonium chloride (hereinafter also referred to as BAK or ADBAC) ;
"C12-alkyl quaternary ammonium haiide", "C14-alkyl quaternary ammonium haiide" and "Clδ-alkyl quaternary ammonium haiide" mean respectively quaternary ammonium haiide in which the nitrogen atom of the ammonium group is substituted by at least one alkyl group having at least 12 carbon atoms, 14 carbon atoms and 16 carbon atoms.
"BAK C12" refers to benzododecinium chloride (CAS 139-07- 1 ) ;
"BAK C14" refers to myristalkonium chloride (CAS 139-08-2); "BAK C16" or "CKC" refers to cetalkonium chloride (CAS 122- 18-9) ;
"MCT" means Medium chain triglycerides; for the experimentation, TCM™ (Societe des Oleagineux, France) was the MCT used.
"Flurbiprofen" means a compound selected from 2- ( (3-fluoro- 4-phenyl) phenyl) propanoic acid and salts thereof, preferably the sodium salt, and hydrates thereof and flurbiprofen anhydride ; the term " flurbiprofen" in the meaning of this invention also includes flurbiprofen derivatives, especially flurbiprofen acid derivatives wherein the acid function is protected by any suitable protecting group, for example esters of flurbiprofen or flurbiprofen amide derivatives. Esters of flurbiprofen are preferably chosen among flurbiprofen propionate, flurbiprofen butyrate, flurbiprofen valerate, flurbiprofen caproate, flurbiprofen caprylate, flurbiprofen caprate, flurbiprofen laurate, flurbiprofen myristate, flurbiprofen palmitate or flurbiprofen stearate.
The term " flurbiprofen" in the meaning of this invention may designate (1) racemic flurbiprofen, i.e. a mixture of
(S) -flurbiprofen and (R) -flurbiprofen, and includes not only a mixture of (S) -flurbiprofen and (R) -flurbiprofen at a molar ratio of 50:50, but also a mixture of (S)- flurbiprofen and (R) -flurbiprofen at a molar ratio from 20:80 to 80:20, preferably from 30:70 to 70:30, (2) or pure or enriched enantiomer forms, such as for example (R) -flurbiprofen or S-fiurbiprofen, preferably S- fiurbiprofen as well as pharmaceutical acceptable salts.
This invention thus relates to an ophtalmic oil-in-water emulsion comprising at least one NSAID and at least one quaternary ammonium halide, more preferably ammonium
chloride or bromide, in which the nitrogen atom of the ammonium group is substituted by at least one or only one aikyl group having at least 12 carbon atoms, more preferably by one alkyl group having at least 14 carbon atoms, more preferably by one alkyl group having at least 16 carbon atoms.
According to an embodiment, the non-steroidal antiinflammatory drug is chosen among ketorolac, salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen, suprofen, piroxicam, COX2 inhibitors, nimesulide, nepafenac, including any derivatives, prodrugs and salts thereof, in particular esters thereof, such as proprionyl, butyryl, valeryl, caproyl, caprylyl, capryl, lauryl, myristyl, palmityl, or stearyl esters.
According to another embodiment, the non-steroidal antiinflammatory drug is chosen among ketorolac, salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen, suprofen, piroxicam, nimesulide, nepafenac, tenoxicam, ketoprofen and pranoprofen, including any derivatives, prodrugs and salts thereof, in particular esters thereof, such as proprionyl, butyryl, valeryl, caproyl, caprylyl, capryl, lauryl, myristyl, palmityl, or stearyl esters.
According to another embodiment, the non-steroidal antiinflammatory drug is chosen among ketorolac, flurbiprofen, suprofen, nimesulide, nepafenac, tenoxicam, ketoprofen and pranoprofen, including any derivatives, prodrugs and salts thereof, in particular esters thereof, such as proprionyl, butyryl, valeryl, caproyl, caprylyi, capryl, lauryi, myristyl, palmityl, or stearyi esters.
Advantageously, said non-steroidal anti-inflammatory drug is flurbiprofen or esters of flurbiprofen, such as flurbiprofen propionate, flurbiprofen butyrate, flurbiprofen valerate, flurbiprofen caproate, flurbiprofen caprylate, flurbiprofen caprate, flurbiprofen laurate, flurbiprofen myristate, flurbiprofen palmitate or flurbiprofen stearate.
According to an embodiment, the therapeutic oil-in-water emulsion of the invention comprises 0.001% to 10% preferably 0.01% to 1%, more preferably 0.02% to 0.05% of a non-steroidal anti-inflammatory drug, preferably flurbiprofen or esters of flurbiprofen, in weight by total weight of the emulsion.
According to an embodiment of the invention, the oil-in- water emulsion comprises a mixture quaternary ammonium halides in which the nitrogen atom of the ammonium group is substituted by at least one or only one alkyl group having at least 12 carbon atoms, more preferably by one alkyl group having at least 14 carbon atoms, more preferably by one alkyl group having at least 16 carbon atoms.
In a first embodiment, the oil-in-water emulsion of the invention includes three ammonium halides, preferably a
C12-alkyl ammonium halide and a C14-alkyl ammonium halide and a C16-alkyl ammonium halide, more preferably BAK C12 and BAK C14 and BAK C16 ; in another embodiment, the ammonium halide includes two ammonium halides, preferably a C14-alkyi ammonium haiide and a C16-alkyl ammonium halide, preferably BAK C14 and BAK C16 ; in another embodiment of the invention, the oil-in-water emulsion of the invention
includes only one ammonium halide, preferably C16-alkyi ammonium haiide, more preferably BAK C16.
Advantageously, the oil-in-water emulsion of the invention contains a Ci6-alkyl quaternary ammonium halide, preferably a C16-alkyl benzyl dimethyl ammonium chloride, more preferably BAK C16 or a mixture of BAK C12, BAK C14 and BAK C16.
According to an embodiment, the only ammonium halide of the oil-in-water emulsion of the invention is BAK C14 or BAK C16 or a mixture thereof.
According to an embodiment, the amount of quaternary ammonium halides in which the nitrogen atom is substituted by one or at least one alkyl group having at least 16 carbon atoms, such as C16-alkyl quaternary ammonium halide, preferably C16-alkyl benzyl dimethyl ammonium chloride, more preferably BAK C16, represents between 10 to 30% w/w measured in dry weight relatively to the total amount of all quaternary ammonium halides present in the emulsion.
According to an embodiment, the amount of quaternary ammonium halides in which the nitrogen atom is substituted by one or at least one alkyl group having at least 16 carbon atoms, such as Clβ-alkyl quaternary ammonium halide, preferably Clβ-alkyl benzyl dimethyl ammonium chloride, more preferably BAK C16, represents more than 30% w/w measured in dry weight relatively to the total amount o ail quaternary ammonium halides present in the emulsion, preferably more than or equal to 50% w/w, preferably more than or equal to 70%, preferably more than or equal to 80% w/w, preferably more than or equal to 90% w/w.
According to an embodiment, the therapeutic oil-in-water emulsion of the invention is cationic. By cationic oil-in water emulsion is understood an oil-in-water emulsion having a positive seta potential. In this embodiment, the emulsion of the invention has a positive zeta potential. Advantageously, the emulsion of the invention keeps a positive zeta potential overtime.
According to an embodiment, the therapeutic oil-in-water emulsion of the invention comprises 0.001 to 0.1%, preferably 0.002 to 0.05%, more preferably 0.002 to 0.005% in weight of ammonium halide by total weight of the emulsion .
The therapeutic oil-in-water emulsion according to the invention further comprises an oil phase preferably comprising MCT, castor oil, soybean oil or any suitable vegetal or mineral oil, surfactants preferably chosen among at least one of tyloxapol, poloxamer, tocopherol, polyethylene glycol succinate and polysorbate, sorbitan monolaurate, and optionally antioxidants and/or isotonicity agents preferably chosen among at least one of glycerol, NaCl and mannitol. According to an embodiment, the therapeutic oil-in-water emulsion of the invention comprises 0.1 to 5 %, preferably 0.5 to 4 %, more preferably 1 to 3% in weight of oil, preferably MCT, by- total weight of the emulsion. According to an embodiment, the therapeutic oil-in-water emulsion of the invention comprises 0.01 to 2 %, preferably 0.05 to 1 %, more preferably 0.1 to 0.5% In weight of surfactants to the total weight of the emulsion. According to an embodiment, the emulsion of the invention includes at least one
surfactant In the oily phase, preferably in an amount of 0.1 to 0.5 %, preferably 0.3% in weight to the total weight of the emulsion and at least one surfactant in the aqueous phase preferably in an amount of 0.02 to 0.2 %, preferably 0.1% in weight to the total weight of the emulsion. Preferred surfactants are tyloxapol, poloxamer and sorbitan monolaurate .
According to a an embodiment, the emulsion of the invention includes buffering agents such as citrate, phosphate, tris, borate, acetate, carbonate, borate-polyol complexes, histidine, gluconate or lactate buffers.
According to an embodiment, the pH is of emulsion is chosen in order to optimize the incorporation and solubilisation of the NSAID into the oil phase.
According to an embodiment, the therapeutic oil-in-water emulsion of the invention has a droplet size of 100 to 500 run, preferably 150 to 400 nm, more preferably 110 to 250 nm.
According to an embodiment, the therapeutic oil-in-water emulsion of the invention is preserved.
According to another embodiment, the oil-in-water emulsion of the invention is unpreserved.
According to an embodiment, the therapeutic oil-in-water emulsion of the invention is presented In single use units.
According to another embodiment, the oil-in-water emulsion of the invention is marketed in multidose containers.
This invention also relates to a medicament comprising a therapeutic oil-in-water emulsion of the invention.
This invention also relates to an oil-in-water emulsion according to the invention for the treatment of an eye disease caused by, associated with or accompanied by inflammatory processes or to the use of an oil-in-water emulsion according to the invention for the manufacture of a medicament for the treatment of an eye disease caused by, associated with or accompanied by inflammatory processes. In the meaning of the invention, eye diseases caused by, associated with or accompanied by inflammatory processes means a wide variety of ocular conditions such as for example glaucoma, ocular inflammatory conditions such as keratitis, uveitis, intra-ocular inflammation, allergy and dry-eye syndrome ocular infections, ocular allergies, ocular infections, retinal oedema, macular oedema, diabetic retinopathy, or any trauma caused by eye surgery or eye injury, LASIK surgery, Peri-surgery (pre, per and/or post) for prevention and treatment of pain and inflammation.
In a particular embodiment, the invention relates to an oil-in-water emulsion according to the invention for preventing inflammation or preventing the development of an inflammatory process through pre-surgical or immediate post-traumatical application, or for the treatment of an inflammation or the limitation of an inflammatory process.
This invention also relates to the combination of an NSAID further comprising other active drugs for the treatment of eye diseases, where both compound are within an oil-in- water emulsion according to the invention. According to an
embodiment, said other active drug is an immunosuppressive agent, preferably cyclosporine, sirolimus or tacrolimus.
According to an embodiment, in the emulsion of the invention, NSAID is combined with cyclosporin A. In a preferred embodiment, this combination shows synergistic effects. By synergistic effects, it is understood that the combination has better efficacy than the separate administration of the two molecules, or that it allows reducing the dose or administration frequency compared to the two separate entities.
Advantageously, the medicament is administrated less than 4 times a day, preferably less than three times a day and more preferably once daily. According to an embodiment, the medicament may be both curative and preventive. Where applied, for example, pre-surgically or immediately post- traumatically, i.e. before inflammation develops, the emulsion of the invention prevents development of inflammation. When applied directly to the eye suffering from any of the named ophthalmic diseases, it suppresses or attenuates or limits already existing inflammatory processes. This invention thus relates to the use of the therapeutic oil-in-water emulsion or of a medicament containing such, for preventing inflammation, and/or for treating inflammation when applied to an eye.
This invention also relates to a therapeutic of ophthalmic oil-in-water emulsion or a medicament containing such, in a unitary dosage form, for a single use. Advantageously, in this embodiment, the emulsion is sterile.
Another object of this invention is a pre-concentrate of the therapeutic oil-in-water emulsion of the invention and a process for manufacturing said pre-concentrate.
According to this invention, a pre-concentrate is defined as an emulsion having an amount of oil higher than the amount of oil of the therapeutic emulsion administered to a patient. In a first embodiment, the amount of oil in the pre-concentrate is of at least 3% w/w, preferably at least 4% w/w. In a second embodiment, the amount of oil in the pre-concentrate is of at least 8% w/w. In a third embodiment, the amount of oil in the pre-concentrate is of at least 10% w/w, preferably of at least 20 % w/w, more preferably of at least 30% w/w.
The pre-concentrate may be in a liquid form or in a gel form, or in any form suitable in view of its further dilution with water.
According to an embodiment, the pre-concentrate of ophthalmic oil-in-water emulsion according to the present invention may be sterilized, for example, by heat, such as by autociaving, or by filtering or filtration, or by irradiation, or by gas sterilization. In another embodiment, the concentrate of the ophthalmic emulsion is prepared in an aseptic manner.
This invention also relates to a process for manufacturing a pre-concentrate of a therapeutic oil-in-water emulsion comprising the steps of emulsifying/mixing the oil phase with an aqueous phase and with surface-active component (s) , wherein the non-steroidal anti-inflammatory drug Is dissolved in the oil phase. The process for manufacturing
said pre-concentrate comprises emulsifying an amount of oil with an aqueous phase and with suitable surfactants, in order to obtain an emulsion having an amount in oil higher than the amount in oil of the corresponding emulsion to be administered for therapeutic purposes.
Before beginning the manufacturing process, the therapeutic oil-in-water emulsion is designed, with a wished concentration of oil, the type of oil (suitable for ophthalmic use, such as for example castor oil, MCT ...) , the type of elements needed for emulsification such as surfactants for example, and one or more NSAID. The concentration of the concentrate is then decided, depending on the industrial volumes needed.
This invention also relates to a process for manufacturing a therapeutic oil-in-water emulsion comprising: (1) manufacturing a pre-concentrate of an ophthalmic oil in water emulsion, said pre-concentrate having a content in oil of at least 3% w/w, preferably at least 4 % w/w, preferably of 10% w/w or more, more preferably of 20% w/w or more, even more preferably of 30% w/w or more by emulsifying/mixing an oil suitable for ophthalmic use selected in the group comprising mineral oil, castor oil and MCT, with an aqueous phase, said oil phase containing a surface-active component (s) , one or more NSAID, preferably flurbiprofen or esters thereof, and a quaternary ammonium hallde in which the nitrogen atom is substituted by one or more alkyl group having at least 16 carbon atoms; and then (2) diluting one volume of the resulting pre-concentrate with 2 to 50 volumes of water.
According to an embodiment, the emulsification is such that the droplet size or the distribution of the droplet size in the pre-concentrate Is about the same as the droplet size or the distribution of the droplet size of the therapeutic oil-in-water emulsion.
According to an embodiment, the diluting water may comprise additives selected from the group comprising tonicity agents, such as for example NaCl, glycerol or mannitol, viscosifying agents, buffering agents, preservatives, antioxidants or colorants.
According to an embodiment, the diluting water may also comprise a quaternary ammonium halide.
Then, according to the invention, a pre-concentrate of this desired emulsion is produced by mixing the oil suitable for ophthalmic use, with an aqueous phase and with surface- active component (s) ; the average hydrophilic-lipophilic balance (HLB) of the surface-active component (s) may advantageously be about equal to the HLB or average HLB emulsion requirement of the oil or oils used in the present compositions .
An advantage of this invention is to produce large volumes of emulsions without having to scale-up the emulsifying process .
This invention relates to a process for manufacturing a therapeutic oil-in-water emulsion according to the invention, comprising manufacturing a concentrate according to the above-mentioned process and then diluting said concentrate, by mixing 1 volume of concentrate with 2 to 50
volumes of water, to obtain a final therapeutic emulsion having an oil content of 5% w/w of less, preferably of 3% w/w or less, more preferably of 2% w/w or less, even more preferably of 1% w/w or less.
This invention also relates to a method for the treatment of ocular diseases or conditions consisting in the administration to a patient of an ophthalmic emulsion prepared from a pre-concentrate, according to the above described process.
The invention also relates to oil-in-water emulsions obtainable by the process of the invention, i.e. by manufacturing a concentrate including at least one NSAID such as for example flurbiprofen or esters thereof, and then diluting said concentrate with 2 to 50 volumes of water, said water optionally comprising additives, such as for example tonicity agents, viscosifying agents, buffering agents, preservatives, antioxidants or colorants.
One advantage of the invention is that the oil-in-water emulsions obtained by dilution of the concentrates are formed with reduced energy input.
The following examples and figures illustrate the invention and should not be interpreted in any way as reducing the scope of this invention.
Fig.l is a graph showing bioavailability of the emulsions of the invention. This graph shows the aqueous humour concentration of flurbiprofen overtime after administration .
1) Examples of formulations of an oil-in-water emulsion:
Emulsion 1 (Table 1) :
Emulsion 2 (Table 2) :
Emulsion 3 (Table 3)
Stability of the Emulsion 2 (Table 4
2) Bioavailability evaluated in an in vivo study:
Forty-five (45) pigmented rabbits were divided into three groups of fifteen animals corresponding to three treatments with five time-points each (0.5, I 1 2, 4 and 6 hours after administration! All animals were treated with iO ul single instillation in each eye of 50 μl of flurbiprofen at 0.03% (Emulsion according to the invention, cationic
micelles and solution marketed under the tradename Ocufen©) .
At the respective time-points aqueous humor was sampled from both eyes for flurbiprofen determination.
For this in vivo study, the emulsion and the micelle are as described in Table 5 and Table 6. Ocufen© is an ophthalmic solution containing excipients such as buffer citrate (pH 6.45); edetate disodium; polyvinyl alcohol (1.4%); potassium chloride; purified water and sodium chloride. It has a pH of 6.0 to 7.0 and an osmolality of 260 - 330 mθsm/kg. The multidose version contains 0.005% thimerosal as preservative.
Table 5: emulsion of the invention
Table 6: cationic micelles
Results shown in figure 1 evidence that cationic emulsions of the invention improves the ocular bioavailability compared to marketed solution and compared to cationic micelles .
3) Evaluation and comparison of the toxicological profiles of benzalkonium chloride (BAK) and cetalkonium chloride
(CKC) , in standard solution or cationic emulsion formulations in rabbit eyes using in vivo and ex vivo experimental approaches.
Methods: Seventy eyes of 35 adult male New Zealand albino rabbits were used in this study. They were randomly divided into five groups : 50μl of phosphate-buffered saline (PBS), PBS containing 0.02% of BAK and 0.002% CKC (BAK Sol and CKC Sol respectively), and emulsion containing 0.02% BAK or 0.002% CKC (BAK Em and CKC Em, respectively) were applied to rabbit eyes 15 times ate 5-min intervals. The ocular surface changes induced by these eye drops were in investigated using slit-lamp examination, flow cytometry
(FCM), impression cytology (IC) on conjunctiva, and corneal in vivo confocal microscopy (IVCM) . Standard immunohistology in cryosections was also examined for cluster of differentiation (CD) 45+ infiltrating and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labelling (TUNEL)+ apoptotic ceils.
Table 7: composition of the CKC emulsion
Table 8: composition of the BAK emulsion
BAK Em
Products Theoretical composition w/w)
Light
0.50 mineral oil
Oily Heavy phase 0.50 mineral oil
Tyloxapol 0.30
BAK 0.02
Poloxamer 0.10
Aqueous Mannitol 3.30 phase 5OmM buffered 10.00 solution
Water MiIiQ Qs 100
Table 9: composition of BAK solution and CKC solution
Results: Clinical observations and IVCM showed that the highest toxicity was induced by BAK Sol, characterized by damaged corneal epithelium and a high level of inflammatory infiltration. BAK Em and CKC Sol presented moderate effects, and CKC Em showed the lowest toxicity with results similar to those of PBS. Conjunctival imprints analyzed by FCM showed a higher expression of RLA-DR and TNFRl markers in BAK Sol-instilled eyes than in all other groups, especially at 4h. Immunohistology was correlated with an in vivo and ex vivo findings and confirmed this toxicity profile. A high level of infiltration of CD45+ inflammatory cells and TUNEL+ apoptotic cells was observed in limbus and conjunctiva, especially in QAC solution-receiving eyes compared to QAC emulsion-instilled eyes.
Conclusion: The highest toxicity is induced by the BAK solution, and the lowest level of toxicity is induced by the CKC emulsion. Furthermore, these results show that the CKC emulsion induces less toxicity than the BAK emulsion. Therefore, it can be expected that an oil-in-water emulsion comprising a non-steroidal anti-inflammatory drug, for example flurbiprofen, and a quaternary ammonium halide in which the nitrogen atom is substituted by one or more alkyl
group having at least 16 carbon atoms, for example CKC, may Induce less toxicity than if the emulsion comprises a pharmaceutical BAK in the meaning of the pharmacopeia.
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