WO1999016424A1

WO1999016424A1 - Anti-inflammatory pharmaceutical formulation

Info

Publication number: WO1999016424A1
Application number: PCT/ES1997/000238
Authority: WO
Inventors: Ricardo Palacios Pelaez; Carlos Ruiz-Bravo Lopez
Original assignee: Industrial Farmaceutica Y De Especialidades, S.A.
Priority date: 1996-02-16
Filing date: 1997-09-30
Publication date: 1999-04-08
Also published as: ES2118033A1; ES2118033B1

Abstract

Pharmaceutical formulation comprising a eutomer of at least one anti-inflammatory, chiral and hydro-insoluble active principle having a physiologically acceptable pH in the form of a nano-emulsion. The nano-emulsion contains from 3 to 50 % by weight of a pharmaceutically acceptable organic solvent which is non miscible in water and has an apolar and non-ionic character and forms the internal phase of the nano-emulsion; from 5 to 45 % by weight of a pharmaceutically acceptable non-ionic surfactant; from 5 to 30 % by weight of a pharmaceutically acceptable non-ionic co-surfactant agent; from 5 to 87 % by weight of water or of a pharmaceutically acceptable buffer solution; as active ingredient, from 0.01 to 1.0 % by weight of a eutomer of at least one anti-inflammatory-chiral and hydro-insoluble principle; from 0 to 6.5 % of at least one pharmaceutically acceptable complementary excipient. The active ingredient is vehicled in molecular solution in the organic solvent.

Description

ANTI-INFLAMMATORY PHARMACEUTICAL FORMULATION OBJECT OF THE INVENTION

The present invention relates to an anti-inflammatory pharmaceutical formulation in the form of a nanoemulsion, in which the anti-inflammatory active ingredient is the eutomer of a chiral compound, racemic and substantially water-insoluble, and is transported in molecular solution in an organic solvent. The nanoemulsion contains, in addition to the organic solvent, a non-ionic surfactant, a non-ionic co-surfactant, water or a buffer solution and, optionally, at least one organic excipient.

BACKGROUND OF THE INVENTION Anti-inflammatory activity drugs can be classified according to the inflammatory phenomenon against which they are directed, in two clearly defined forms of pharmacological action, namely

- those applied against inflammations caused by internal pathologies, such as, for example, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, gout, renal colic, post-operative and post-traumatic inflammation, dysmenorrhea, etc; Y

- those applied against inflammations located in organs and tissues accessible from the outside, such as, for example, bronchial hyperreactivity, rhinitis, dermatitis, conjunctivitis, otitis, vaginitis, coloproctitis, stomatitis, laryngitis etc.

In the case of inflammations caused by internal pathology, the treatment must necessarily be applied at the systemic level, especially by means of glucocorticoid drugs ("GCCs") or non-steroidal anti-inflammatories ("NSAIDs"), administered either parenterally, either orally , or in the form of suppositories for absorption by hemorrhoidal veins. A serious problem of systemic treatments Anti-inflammatory is the difficulty in preventing the antiflogistic activity of the drugs administered not exerted outside the target organs. Therefore, conventional drugs do not have completely satisfactory therapeutic indices in all cases, since, although such drugs have high anti-inflammatory activity and potency, they also exert their effects at a general systemic level and, consequently, very frequently they are excessively toxic and with adverse side effects. Two of the conventional active ingredients used as anti-inflammatory drugs are for example Budesonide and Ibuprofen.

Budesonide, chemical name 16σ -17o - butylidene-dioxy-llj3, 21-dihydroxypropylene 1, 4-diene-3, 20 dione, has a molecular weight of 430.55, its molecular composition being C ₂₅ H ₃ O ₆ ; its main chiral center is located in the C nS 22 atom, so that, untreated, it comprises two isomers, the R and S epimers, said 50% epimers being present in the racemic mixture of Budesonide (ES-A-414673 ). Neither isomer is soluble in water.

The two epimers have very different biological characteristics. Thus, while the R epimer shows a greater affinity for binding to inflammation receptors, the S epimer shows a first step of metabolization through the longer and weaker liver as well as a lower volume of tissue distribution (BUDESONIDE, Clinical Experience in Asthma and Rhinitis; ADIS Press International Limited; Manchester, 1988; Clisold SP: Phar acology of Budesonide, p. 3-4; Anderson P. et al. "In vitro biotransformation of glucocorticoids in liver and skin homogenate fraction from man, rat and hairless mouse; J. Steroid Biochem., vol. 16, p. 787, 1982 Pergamon Press Ltd .; Dahlber et al.: Correlation bet een chemical structure, receptor binding and biological activity of some novel, highly active, 16, 17-acetal-substituted glucocorticoids; Molecular Pharmacology, 25: 70-78, 1984; EP-A-569369). This distribution of the characteristics assumes that the R epimer is 2 to 3 times more potent in anti-inflammatory activity than the S epimer. On the other hand, the fact that the R epimer is metabolized by the liver almost twice as quickly as the epimer S, represents a very significant reduction in the quantification of systemic adverse side effects. This makes the epimer R of Budesonide a pharmacological agent of extraordinary therapeutic possibilities against topical inflammatory processes.

On the other hand, Ibuprofen, whose chemical names are benzenoacetic acid, <i -methyl-4- (2- methylpropyl), (+); (+) - p-isobutylhydratropic acid; (+) - 2- (p-Isobutylphenyl) propionic acid, has a molecular weight of 206.28; being its molecular composition of C <| ₃ H <| ₈ P2- Its molecule has a chiral center, so that, untreated, the racemic comprises two isomers, the R and S epimers, 50%, both insoluble in water. Although the racemic mixture of Ibuprofen is one of the NSAIDs most used in pharmacology, the anti-inflammatory activity, determined by inhibition of cyclooxygenase, resides almost exclusively in the S enantiomer. Thus, the farmocytic studies conducted with the two enantiomers and the racemic mixture , have revealed that the epimeros administered orally and in isolation reach Cmax before the racemic. On the other hand, the production of a systematic bioinvestment of the epimer R in the epimer S is known, but not vice versa, at a certain rate. However, none of the conventional formulations based on anti-inflammatory principles, such as Budesonide or Ibuprofen, have reached the necessary conditions to, on the one hand, take advantage of the great anti-inflammatory potency of these active ingredients in their topical application exclusively local and another, to present a practically negligible systemic toxic capacity.

On the other hand, in recent decades microemulsions and nanoemulsions have been developed that contain pharmaceutically active compounds, such as antibiotics, NSAIDs, GCCs and / or combinations thereof.

Nanoemulsions are quaternary, Newtonian, macroscopically monophasic, isotropic and thermodynamically stable liquid systems. They have a low viscosity and are optically transparent, the diameter of their "nanogoticles" being less than 10 nm.

The nanoemulsions are generally prepared from two phases, namely an oil phase with a surfactant and an aqueous phase with a co-surfactant, which are spontaneously emulsified by simple stirring at room temperature, first obtaining a microemulsion with

"microgoticles • of diameters between 10 and 200 nm,

To form the nanoemulsions, there are basically three known pathways, namely: ultrasonic sonication of the emulsified mass under stirring, or based on the special nature of the hydrocarbon chains of the esters used in the oil phase and in the surfactant, as well as the relationship between the HLB values (= Hydrophile-Lipophile Balance) of the surfactant and the cosurfactant, whose optimal value to achieve nanoemulsions is that of HLB surfactant: HLB cosurfactant = 14:10.

Swarbrick (. Solubilized Systems in Pharmacy, J. Pharmaceutical Sciences, vol 54, n ^0-9, September 1965) makes a collection of information relating to various factors related to microemulsions.

EP-A-0171084 describes microemulsions of the oil-in-water type, comprising oily or fatty particles with an average particle size of 0.1 to 1 microns, which contain an anti-inflammatory agent, 4-biphenylacetic acid ester, and which allow you to take advantage the anti-inflammatory, analgesic and antipyretic activities of 4-biphenylacetic acid and avoid ulcerations or bleeding of the digestive organs that this compound caused when administered orally or parenterally. EP-A-0480690 describes microemulsions of the oil-in-water type for an anti-inflammatory, tepoxaline whose droplets have sizes between 0.0005 to 0.5 microns, for topical ophthalmic applications. WO-A-94/05298 describes microemulsions for ophthalmic administration of the oil-in-water type, whose droplets preferably have sizes between 0.1 and 3 microns containing, for example betaxolol, adrapolol or indomethacin. WO-A-91/18669 describes microemulsions of the oil-in-water type, with a particle size preferably from 30 to 70 nm, comprising for example Ibuprofen as an active ingredient.

Anti-inflammatory drugs basically exert their action by interfering with the molecular mechanisms of the inflammatory process. For this, they have to bind to specific receptors within the target cells, which implies the penetration of the anti-inflammatory molecule into the cell cytoplasm. Generally, said target cells are integrated by those cells belonging to the tissue or organ that has suffered the injury, or to the vascular endotheliums of the affected area (granulocytes, lymphocytes, monocytes / macrophages). The anti-inflammatory action of eutomeric drugs consists in the inhibition of the synthesis of prostanoids (prostaglandins, prostacyclines and thromboxanes) originated in the metabolization of arachidonic acid via the action of cyclooxygenase and also of leukotrienes (also metabolites of arachidonic acid by action of the phospholipase). These mechanisms develop inside the target cells. Another way of action Anti-inflammatory is to interfere with the production of cytokines (platelet activating factor, PAF; tumor necrosis factor, TNF; interleukins, IL) produced by endothelial inflammatory cells (neutrophils, monocytes and, later, lymphocytes).

The disadvantage of microemulsions that contain active ingredients of anti-inflammatory activity basically consists in the fact that the size of their droplets is excessively large so that they are absorbed by pinocytosis, in sufficient quantities, by the cells of the organs involved, which results, by a on the other hand, on an insufficient penetration of the active substance into the cells and, on the other, on the possibility that substantial amounts of the active substance are absorbed systemically intercellularly, resulting in unwanted side effects, in reduced activities of the active substance , and even at high levels of toxicity, resulting in the inability to fully exploit the potential activity of the active ingredients. With conventional anti-inflammatory formulations, the active anti-inflammatory principle has not been able to be dispensed or administered in a molecular solution, such liquid formulations consisting of cloudy, non-transparent, sedimentable emulsions, with high particle sizes (> 100nm), which results in substantial difficulties and even in the impossibility of the occurrence of pinocytosis in the target cells. OBJECT OF THE INVENTION The present invention solves the drawbacks of the state of the art by means of a nanoemulsion with a pH between 5 and 7, which contains 15 to 50% by weight of a pharmaceutically acceptable organic solvent that is non-miscible in water of a non-polar nature and not -ionic constituting the internal phase of the nanoemulsion; 10 to 45% by weight of a pharmaceutically non-ionic surfactant acceptable; 5 to 30% by weight of a pharmaceutically acceptable non-ionic co-surfing agent; 5 to 40% by weight of water or a pharmaceutically acceptable buffer solution; as active ingredient, 0.01 to 1.0% by weight of an eutomer of at least one chiral anti-inflammatory active substance, and substantially hydro-insoluble; 0 to 6.5% of at least one pharmaceutically acceptable complementary excipient, the active ingredient in molecular solution in the organic solvent being necessarily transported. Through the vehiculization of the active substance in a nanoemulsion, a pharmaceutical formulation is achieved that

- causes and facilitates the processes of pinocytosis in the target cells allowing quantitative and qualitatively effective availability of the active substance in the cytoplasm;

- prevents systemic absorption of the active substance;

- it has a high physical-chemical stability based on the absence of coalescence phenomena, breakage of the micellar balance, changes in the size of the nanogoticles, etc .;

- allows the possibility of including antioxidants and protective agents of the active substance; - it allows to provide an aqueous, isotonic, buffered solution with a physiologically compatible pH, not only due to the water supply of the inflamed tissues, but also to occupy the intercellular pathways and ionic mechanisms of systemic absorption; - It has a favorable partition coefficient of the active substance, between its oil phase and the phospholipid layer of the cell membrane.

The invention is based on the consideration that in the case of inflammations located in organs and tissues accessible from the outside, a possible vectorized treatment of the target organ, to eliminate unwanted systemic action and, therefore, reduce adverse effects to non-significant levels.

Since the mechanisms of the inflammation processes occur inside the cells, it is important that the drug is formulated and transported in such a way that it is directed to its destination point stimulating and allowing the entry by endo and pinocytosis into the cell Diana. The reduced size of the nanogoticulas containing Budesonide and / or Ibuprofen, smaller than 10 nm facilitates pinocytosis against icrogoticles, whose size ranges from 100 nm. Thus, considering that the average diameter of the set of endothelial cells is 10 microns, which implies that a neutrophil or a monocyte / macrophage (which has a diameter 100 times larger than that of a nanogoticle and 10 times larger than that of a microgoticle) present possibilities of pinocytosis substantially greater than in the first case. On the other hand, these possibilities increase not only because of their size, but also because of the greater statistical probability of contact due to the higher dispersion.

The interaction of the eutomer of the anti-inflammatory, chiral and substantially hydro-insoluble active ingredient, and its presentation in the oily droplets of the nanoemulsion, according to the invention produces a substantial and surprisingly lower therapeutic index than would be expected from the effects on the therapeutic indices which are conventionally produced by microemulsifying racemic forms, eutomers or dystomers of the same anti-inflammatory active ingredients.

Thus, in the nanoemulsions of the present invention, the ratio between Toxic Dose 50 (= LD 50) and Effective Dose 50, or Therapeutic index of the eutomer of the anti-inflammatory active substance, chiral and substantially Hydro-insoluble, it is substantially and surprisingly lower than the corresponding therapeutic ratios or indices of racemic, eutomeric and / or of the same anti-inflammatory active substances in the form of microemulsion.

From this, it is doubted that there is an interaction between the advantages of certain eutomers and their incorporation into nanogoticles.

Another advantage of nanoemulsions according to the present invention is that they remain stable even in adverse storage conditions, without losing their therapeutic efficacy.

DESCRIPTION OF THE INVENTION The present invention relates to an anti-inflammatory pharmaceutical formulation containing as an active ingredient the eutomeric form of an anti-inflammatory racemic, which has a Toxic Dose 50 of the eutomer equal to or less than 1.2 times the Toxic Dose of the distomer and a Effective Dose equal to or greater than 1.8 times the Effective Dose of the dystomer, whose formulation has a physiologically compatible pH, preferably between 5 and 7, in the form of a nanoemulsion containing

3 to 50% by weight of a pharmaceutically acceptable organic solvent not miscible with non-ionic and non-ionic water that constitutes the internal phase of the nanoemulsion;

5 to 45% by weight of a pharmaceutically acceptable nonionic surfactant;

5 to 30% by weight of a pharmaceutically acceptable non-ionic co-surfactant agent;

5 to 45% by weight of water or a pharmaceutically acceptable buffer solution;

0.01 to 1.0% by weight of an eutomer of at least one anti-inflammatory, chiral and substantially hydro-insoluble active ingredient; 0 to 6.5% of at least one complementary excipient; in which the active ingredient is transported in molecular solution in the organic solvent. The active substance present in the formulation is, therefore, the eutomeric form of an anti-inflammatory racemic that meets the following condition:

Therapeutic index of eutomer 1 <Therapeutic index of distomer 2.16

Toxic Dose 50 defining the Therapeutic Index as Effective Dose 50

The organic solvent is preferably at least one ester of a saturated fatty acid of eight or ten carbon atoms, and glycerol, or mixtures thereof, which is preferably selected from esters of caprylic or octanoic acid, esters of capric or decanoic acid , or mixtures of said esters, glyceryl tri-capryl caprate.

The surfactant is preferably constituted by mixtures of at least one ester of a saturated fatty acid of eight or ten carbon atoms and of at least one alcohol and is preferably a mixture of an ester of caprylic acid and ester of capric acid with polyethylene glycol and glycerol, or by capryl-glyceryl and polyethylene glycol 8 captures. The co-surfactant is preferably constituted by at least one ester of an unsaturated fatty acid of 16 to 20 carbon atoms, and an alcohol, preferably at least one glyceryl dioleate , or at least one nonoxynol. The complementary excipient is preferably an antioxidant, preferably vitamin E, a mucoadhesive, lactic acid or mixtures thereof.

The mucoadhesive is for example Polycarbophil acid. The complementary excipient preferably comprises 0.3 to 2.5% of Polycarbophil acid and Vitamin E, and 2 to 4% of lactic acid, based on the total weight of the nanoemulsion.

Based on the general and preferred formulations described above, the possibility of vehicular eutomers of active ingredients is achieved, such as, for example, the R epimer of Budesonide and the S epimer of Ibuprofen, hydro-soluble and chiral, as well as eutomers of other active ingredients chiral and substantially hydro-insoluble anti-inflammatories, in an oily phase of droplets smaller than 10 nm, present in a nanoemulsion, which due to its lipophilic character, its viscosity greater than that of plasma, the size and dispersion of its nanogoticles, and the non-polar character -ionic, has a special affinity to the phospholipid covering of the membranes of the target cells to excite the mechanisms of pinocytosis, while the aqueous phase of said nanoemulsion, being compatible in density, viscosity, tonicity and pH with the blood plasma, It covers the pathways and possibilities of systemic absorption that the inflamed tissue allows.

The nanoemulsions according to the invention are transparent liquids of Newtonian behavior, have a biologically compatible pH, preferably between 5 and 7, and constitute quaternary isotropic systems composed of an oil phase, an aqueous phase, a hydrophilic surfactant and a lipophilic cosurfactant. Its transparency is due to its nanostructure, consisting essentially of nanogoticles less than 10 nm suspended between the molecular mass of the surfactant and the cosurfactant that are intimately mixed. The active substances, such as the epimer R of Budesonide and the epimer S of Ibuprofen, are found inside the nanogoticles of the oil phase. Preferably, the nanoemulsions according to the invention have a viscosity between 50 and 80 cPs and a density of 1,030 to 1,038.

For the oil phase, for example, mixtures of tricaprilates and glyceryl tricaprates, marketed by the firm GATTEFOSSÉ S.A. can be used. (Saint-Priest, France) under the name LABRAFAC LIPOFILO.

As non-ionic surfactants, for example caprylates and captates of PEG-8 and glyceryl, marketed by the firm GATTEFOSSÉ S.A. can be used. (Saint-Priest, France) under the name LABRASOL that have a hydrophilic tendency and an HLB of 14. Other surfactants are those of the TWEEN ™ line such as TWEEN 80.

Commercially accessible products such as OLEPAL ™ and Lauroglycol can be used as co-surfactants. The nanoemulsions can be sterilized by conventional methods, such as by filtration through a 0.22 micron membrane.

For nasal administration, the formulations according to the invention comprise, for example, about 0.2% of epidermal budesonide R;

23-27% organic solvent;

22-33% surfactant;

12-25% co-surfactant agent;

0.05% Vitamin E; buffer solution up to 100%.

For otic administration, the formulations according to the invention comprise, for example, approximately 0.2% Budesonide epimer R; or 0.5% of Ibuprofen epimero S; 38-45% organic solvent; 20% surfactant; 20% co-surfactant agent; 0.05% Vitamin E; buffer solution up to 100%.

For topical administration to the skin, the formulations of the invention comprise, for example, about 0.02-0.6% Budesonide epimer R; or

0.5% of Ibuprofen epimer S;

3.0-32% organic solvent;

26-42% surfactant;

14-16% co-surfactant agent; 0.05% Vitamin E;

2.0% lactic acid; buffer solution up to 100%.

For administration as eye drops, the formulations according to the invention comprise, for example, approximately

0.075% Budesonide epimer R;

18-27% organic solvent;

20-30% surfactant; 19-26% co-surfactant agent;

1% polycarbophil acid;

0.05% Vitamin E; buffer solution up to 100%;

For administration as an enema, the formulations of the invention comprise, for example, approximately

0.002% Budesonide epimer R; 4-26% organic solvent; 30-40% surfactant; 14-21% co-surfactant agent;

0.3% polycarbophil acid;

0.05% Vitamin E; buffer solution up to 100%. The percentages of the various components of the formulations described above can logically vary depending on the specific application to be performed.

DETAILED DESCRIPTION OF THE INVENTION Next, the invention will be described based on several examples.

EXAMPLE 1: Various nanoemulsions are prepared in an equipment of stainless material, itself conventional, composed of a first and a second reactor, connected to each other and provided respectively with

- a slow anchor agitator (50-80 rpm) a heating-cooling coil

- a protection of the agitator shaft by means of an outer concentric tube to prevent the formation of a drag cone by agitation

- a system for loading and unloading liquids by pumping in a closed circuit. the first reactor being provided in addition to a vacuum intake and vacuum control to degas liquids.

In the preparation of the nanoemulsions, the following conventional process was followed:

1.- 80% of the surfactant is introduced into the first reactor and heated to 30 ° C. 2.- A solution of the antioxidant in the remaining 20% of the cosurfactant is introduced into the first reactor.

3.- The oil phase is added to the first reactor and the resulting mixture is kept under slow stirring and at a temperature of 30 ° C until total solution, avoiding, in case necessary, foaming using vacuum. 4.- The same operation is repeated with the cosurfactant.

5.- In the second reactor, the buffered aqueous phase is prepared and contoured with the incorporated water-soluble excipients.

6.- Maintaining the stirring and thermostating the solution contained in the first reactor at 30 ° C, a high power ultrasonic sonicator rod is introduced, up to a depth of 20 cm.

7.- The sonication is connected and refrigerated to maintain the temperature of 30 ° C in the first reactor. 8.- The buffer solution on the submerged sonic rod is added by pumping and directed tube, while stirring is maintained.

9.- When the liquid in the reactor is completely transparent, the preparation of the nanoemulsion is considered finished and vacuum is applied to degas and remove foam. 10.- For sampling for quality control, the nanoemulsion is allowed to stand for 18-20 hours.

EXAMPLE 2: Following the process of Example 1, a nanoemulsion was prepared for application as a dermal lotion of the following characteristics:

Budesonide Epimer R 0.025%

Tricapril-glyceryl caprate

(Labrafac Lipophilus) 5,000% alpha-Tocopherol 0,050%

Capryl-glyceryl caprate and PEG-8

(Labrasol) 39,210%

PEG-300 oleate

(Olepal) 16,710% Phosphate buffer pH 5, 3 39,925% pH 5.2 (+ 0.2)

Viscosity 60.3 cPs (+ 1%)

EXAMPLE 3: Following the process of Example 1, a nanoemulsion was prepared for application as a dermal lotion of the following characteristics:

Ibuprofen Epimer S 0.500% Tricapril-glyceryl caprate

(Labrafac Lipophilic) 5,000% alpha-Tocopherol 0.050% Capryl-glyceryl caprate and PEG-8

(Labrasol) 39,290% PEG-300 Oleate

(Olepal) 15.710% Phosphate buffer pH 5.3 39.450% pH 5.2 (± 0.2)

Viscosity 60.3 cPs (+ 1%)

EXAMPLE 4: Following the process of Example 1, a nanoemulsion was prepared for application for nasal nebulization of the following characteristics:

Budesonide Epimer R 0.20% Tricapril-glyceryl caprate

(Labrafac Lipophilus) 25.00% alpha-Tocopherol 0.05%

Capryl-glyceryl caprate and PEG-8

(Labrasol) 25.00% PEG-300 Oleate

(Olepal) 22.00% Phosphate buffer pH 5.3 27.75%

PH 5.2 (+ 0.2)

EXAMPLE 5: Following the process of Example 1, a nanoemulsion was prepared for application as ear drops of the following characteristics: Budesonide Epimero R 0.20% Tricapril-glyceryl caprate

(Labrafac Lipophilic) 40.00% alpha-Tocopherol 0.05% Capryl-glyceryl caprate and PEG-8

(Labrasol) 20.00% PEG-300 Oleate

(Olepal) 20.00%

Phosphate buffer pH 5.3 19.75% pH 5.2 (± 0.2)

EXAMPLE 6: Following the process of Example 1, a nanoemulsion was prepared for application as ear drops of the following characteristics: Ibuprofen Epimer S 0.50%

Tricapril-glyceryl caprate

(Labrafac Lipophilus) 42.00% alpha-Tocopherol 0.05%

Capryl-glyceryl caprate and PEG-8 (Labrasol) 20.00%

PEG-300 oleate

(Olepal) 20.00%

Phosphate buffer pH 5.3 17.45% pH 5.2 (± 0.2)

EXAMPLE 7: Following the process of example 1, a nanoemulsion was prepared for application as eye drops of the following characteristics:

Budesonide Epimero R 0.075% Tricapril-glyceryl caprate

(Labrafac Lipophilus) 26.00% alpha-Tocopherol 0.050%

Capryl-glyceryl caprate and PEG-8

(Labrasol) 22,000% PEG-300 Oleate (Olepal) 20,000%

1,000% acidic polycarbophil

Phosphate buffer pH 5.3 31.875% pH 7.4 (+ 0.4)

EXAMPLE 8: Following the process of example 1, a nanoemulsion was prepared for application as an enema of the following characteristics:

Budesonide Epimer R 0.002% Tricapril-glyceryl caprate

(Labrasol) 39,290% PEG-300 Oleate

(Olepal) 15,710%

0.300% acid polycarbophil

Phosphate buffer pH 5.3 39.648% pH 5.2 (± 0.2) Viscosity 60.3 cPs (± 1%)

EXAMPLE 9: Following the process of Example 1, a nanoemulsion was prepared for application as a dermal lotion of the following characteristics: Budesonide Epimer R 0.025% Tricapril-glyceryl caprate

(Labrafac Lipophilus) 10,000% alpha-Tocopherol 0.050%

Tween 80 20,000% PEG-300 Oleate

(Olepal) 40,000%

Lauroglycol 20,000%

Phosphate buffer pH 5.3 9.925% pH 5.2 (+ 0.2) Viscosity 60.3 cPs (+ 1%) EXAMPLE 10: Following the process of Example 1, a nanoemulsion was prepared for application as an enema of the following characteristics: Budesonide Epimer R 0.002% Tricapril-glyceryl caprate

(Labrafac Lipophilus) 10,000% alpha-Tocopherol 0.050%

T een 80 20,000% PEG-300 Oleate

(Olepal) 40,000%

Lauroglycol 20,000%

Phosphate buffer pH 5.3 9.948% pH 5.2 (+ 0.2) Viscosity 60.2 cPs (+ 1%)

EXAMPLE 11: The average droplet size of the internal oil phases was analyzed, as well as the frequency distribution of the sizes of the nanoemulsions of Examples 2-10, producing the results reflected in the following table:

Table I% of droplets size 100% <5.4 nm 99.8% <4.9 nm

96.3% <4.5 nm

75.7 <4.1 nm

52.8 <3.8 nm 22.6 <3.5 nm 12.0 <3.0 nm

EXAMPLE 12: Samples of the nanoemulsions of Examples 2-10 were subjected to the following stress tests:

- heating at 120 ° C for 0.5 hours; - maintenance at 45 ° C for 45 days; - maintenance for 45 days at room temperature in direct exposure to air and light;

- centrifugation at 16,000 g for 5 hours;

- thirty freeze / thaw cycles. After analyzing the samples submitted to the tests described above, it could be observed that none of them suffered degradation or alterations in their physical-chemical or galenic characteristics. Nor did the active ingredients dissolved in the oil phase suffer qualitative or quantitative variations.

Claims

1. Anti-inflammatory pharmaceutical formulation containing an active anti-inflammatory substance and presenting a physiologically compatible pH characterized in that it is a nanoemulsion containing

3 to 50% by weight of a pharmaceutically acceptable organic solvent not miscible with non-ionic and non-ionic water that constitutes the internal phase of the nanoemulsion; 5 to 45% by weight of a pharmaceutically acceptable nonionic surfactant;

5 to 45% by weight of water or a pharmaceutically acceptable buffer solution;

0.01 to 1.0% by weight of an eutomer of at least one active principle, chiral and substantially hydro-insoluble, having a therapeutic index equal to or less than 1 / 2.16 of the therapeutic index of its corresponding dystomer; 0 to 6.5% of at least one complementary excipient; in which the active ingredient is transported in molecular solution in the organic solvent.

2. Formulation according to claim 1, characterized in that the organic solvent is at least one ester of a saturated fatty acid of eight to ten carbon atoms, and glycerol, or mixtures thereof.

3. Formulation according to claim 2, characterized in that the organic solvent is an ester of caprylic acid, an ester of capric acid, or mixtures of said esters.

4. Formulation according to claim 2, characterized in that the organic solvent is glyceryl tri-capryl caprate.

5. Formulation according to claim 1, characterized in that the surfactant consists of mixtures of at least one ester of a saturated fatty acid of eight or ten carbon atoms and of at least one alcohol.

6. Formulation according to claim 5, characterized in that the surfactant is a mixture of an ester of caprylic acid and ester of capric acid with polyethylene glycol and glycerol.

7. Formulation according to claim 6, characterized in that the surfactant is composed of capryl-glyceryl and polyethylene glycol 8 capsules.

8. Formulation according to claim 1, characterized in that the co-surfactant is constituted by at least one ester of an unsaturated fatty acid of 16 to 20 carbon atoms, and an alcohol.

9. Formulation according to claim 8, characterized in that the co-surfactant is at least one glyceryl dioleate.

10. Formulation according to claim 8, characterized in that the co-surfactant is at least one nonoxynol.

11. Formulation according to claim 1, characterized in that the complementary excipient is an antioxidant, a mucoadhesive, lactic acid or mixtures thereof.

12. Formulation according to claim 11, characterized in that the antioxidant is vitamin E.

13. Formulation according to claim 11, characterized in that the mucoadhesive is Polycarbophil acid.

14. Formulation according to claim 11, characterized in that the complementary excipient comprises 0.3 to 2.5% Polycarbophil acid and Vitamin E, and 2 to 4% lactic acid, all referring to the total weight of the nanoemulsion

15. Formulation according to any of the preceding claims, characterized in that the active ingredient is selected from the R epimer of Budesonide or the S epimer of Ibuprofen.

16. Formulation according to claim 1 for nasal administration, characterized in that it comprises 0.2% of epimeric budesonide R;

23-37% organic solvent;

22-33% surfactant;

12-25% co-surfactant agent;

0.05% Vitamin E; buffer solution up to 100%

17. Formulation according to claim 1 for otic administration, characterized in that it comprises

0.2% Budesonide epimer R; or 0.5% of Ibuprofen epimer S;

38-45% organic solvent;

20% surfactant;

20% co-surfactant agent;

0.05% Vitamin E; buffer solution up to 100%.

18. Formulation according to claim 1 for topical administration, characterized in that it comprises

0.02-0.6% Budesonide epimer R; or 0.5% of Ibuprofen epimer S;

3-32% organic solvent; 26-42% surfactant; 14-65% co-surfactant agent; 0.05% Vitamin E; 2.0% lactic acid; buffer solution up to 100%.

19. Formulation according to claim 1 for administration as eye drops, characterized in that it comprises 0.075% Budesonide epimer R;

18-27% organic solvent;

20-30% surfactant;

19-26% co-surfactant agent;

1% polycarbophil acid; 0.05% Vitamin E; buffer solution up to 100%;

20. Formulation according to claim 1 for administration as an enema, characterized in that it comprises 0.002% Budesonide epimer R;

5-26% organic solvent;

30-40% surfactant;

14-65% co-surfactant agent;

0.3% polycarbophil acid; 0.05% Vitamin E; buffer solution up to 100%.