HK1207963B - Oral pharmaceutical formulation of bcs class iii molecules - Google Patents

Description

The invention relates to an oral galenic formulation of the BCS class III molecule baclofen with improved bioavailability and permeability.

The oral route is the first route considered when forming a new pharmaceutical entity due to adherence to the treatment it induces. However, this route is abandoned for many developing molecules due to their low oral bioavailability. This may be due to various factors from the properties of the molecule itself or the physiology of the gastrointestinal tract (Fasinu, et al., 2011).

The Biopharmaceuticals Classification System (BCS) is a significant tool used for the development of oral forms in the pharmaceutical industry and is notably adopted by the FDA, EMEA, and WHO (Dahan, et al., 2009). It is divided into four categories of molecules and is based on the fundamental elements that control oral absorption, namely intestinal membrane permeability as well as the solubility of a molecule in the gastrointestinal environment. A molecule is considered soluble if the maximum dose of an oral form is soluble in 250 ml or less of an aqueous medium with a potential pH between 1.2 and 6.8 and is considered if its absorption through the intestinal membrane is between 90% or more. A particular BCS molecule with a high solubility and a high therapeutic potential for the development of the final therapeutically viable oral formulation is considered to be a persistent and highly soluble molecule.

Baclofen (Figure 1) is a BCS molecule belonging to class III. Its physicochemical characteristics are summarised in Table 1.

Masse molaire	213.66 g/mol
Point de fusion	180-191°C
pH d'une solution saturée	6,5
pKa
Solubilités
Log P	-1

Baclofen is known to have good oral bioavailability at usual therapeutic doses, but its low log P indicates some hydrophilia and thus low permeability. This is due to the presence of specific transporters in the small intestine that allow the molecule to pass through. This is all the more important at the jejunum level. Also, a low passage to the colon requires another passage mechanism through the intestinal barrier (Merino, et al., 1989). This area of the digestive system contains no transporters but the molecule is hydrophilic and small in size, so a low passive passage through the intestinal transporters is not possible.

Increased baclofen lipophilia and thus transcellular permeability has been observed through the production of baclofen ester prodrugs (Leisen, et al., 2003). These properties result in a higher concentration of prodrug in the target tissue, the brain, through easier passage of the blood-brain barrier. However, there is a greater affinity for the P-gp efflux pump as well as partial hydrolysis of the prodrug into baclofen which ultimately leads to a lower single-site rate of action in baclofen after administration of the prodrug compared to baclofen.

A window of absorption of baclofen is shown at the small intestinal level due to the presence of transporters (Merino, et al., 1989). To increase bioavailability, this window of absorption could be exploited by galenic techniques that allow the retention of the oral form at the window or upstream (Davis, 2005). Indeed, a longer residence time at the site of absorption should theoretically allow a greater passage of molecules through the intestinal barrier if they are not likely to undergo interstitial degradation prior to absorption. Thus, forms of bioadhesion to the intestinal mucosa through the use of polymeric forms such as chorionic acid or gastrostatic gonadotropin have been developed in recent years and their pharmacological effectiveness and efficacy is highly dependent on the individual but has been highly variable.

Under normal physiological conditions, the paracellular passage occupies less than 0.1% of the total surface area of the intestinal epithelium and is therefore not a major passageway (Anilkumar, et al., 2001). This is due to the presence of tight junctions between cells that limit the absorption of molecules larger than 0.1 nm. Thus, action on these molecules could allow a significant increase in absorption.This integrity is altered in response to various physiological and pathological agents, including secondary messengers from signalling pathways. Two factors appear to be involved in the action of the absorption promoters: the contraction of an actin-myosin ring and phosphorylation by protein kinases and phosphatases. Anilkumar et al. have listed the absorption promoters investigated in this indication. These include surfactants, bile acids and derivatives, fatty acids and derivatives, chelating agents, chitosan and its derivatives, and polycarbyl-cysteine conjugate.

Thus, since the tight junctions have a barrier and therefore a defensive role for the organism, it is important that the promoters acting on their opening have a reversible action and do not induce toxicity.

US patent application US2010/029771 describes a liquid pharmaceutical formulation that can be incorporated into a capsule for the treatment of gastroparesis and non-ulcer dyspepsia with gamma-aminobutyric acid-B (GABAB) receptor agonists, such as baclofen.

International application WO2005/025559 describes a liquid pharmaceutical formulation of the emulsion type containing an active substance such as baclofen in the aqueous phase and emulsifying agents in the oily phase.Surprisingly, the inventors found that the bioavailability, and in particular the intestinal membrane permeability, of Class III BCS molecules can be significantly improved by formulation as an oil-in-water microemulsion, the Class III BCS molecule being aqueous and the oily phase being a self-emulsifying heme excipient in contact with water.

In particular, they observed an increase in the Caco-2 cell permeability of baclofen in an oil-in-water microemulsion formulation between a 6 mg/ml baclofen aqueous solution in 0.01 M fumaric acid and Labrasol®.

Therefore, the subject matter of the invention concerns an oral pharmaceutical formulation based on a microemulsion between an aqueous phase containing at least one class III BCS (Biopharmaceuticals Classification System) active substance, the active substance being baclofen, and an oily phase containing an oil excipient which is self-emulsifying in contact with water.

The formulation according to the invention has the advantages of improved intestinal membrane permeability and non-toxicity.

Microemulsion means an emulsion with a droplet size of less than 200 μm.

an oily excipient which emulsifies on contact with water an excipient which will spontaneously form an oil-in-water emulsion with an aqueous phase, i.e. droplets of the aqueous phase surrounded by a lipid layer containing the excipient.

In order to assess the potential for increased permeability of an absorption promoter, in vivo techniques in rats or ex vivo (on infused rat gut) can be performed (Koga, et al., 2002) (Lin, et al., 2007) (Constantinides, et al., 1996).

Caco-2 cells are derived from a culture of human cancer cells capable of differentiation in the presence of a suitable culture medium (Pontier, 1997-1998). Their properties are dependent on the number of grafts they undergo. The cell clone obtained at step 198 has characteristics similar to enterocytes. Caco-2 cells are slightly smaller in size than enterocytes but have a monolayer comparable to that of the epithelium of the small intestine. The brush border is highly differentiated and developed and narrow junctions of 10 to 50 Åx are present (more than those in the small intestine).

The MTT test is an indicator of mitochondrial integrity and activity and is similar to a measure of cell viability (Sigentec). This test is based on the activity of a mitochondrial enzyme, succinate dehydrogenase. In the presence of the MTT substrate (3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide), the tetrazolium salts in the substrate are transformed into insoluble formazane crystals with the activity of the succinate dehydrogenase. After solubilization, the amount of formazane is dosed by spectrophotometry and then compared with a negative control with a cell viability of 100% (Buyzturk, et al., 2010).

The measurement of transepithelial electrical resistance (TEER) (in ohms/cm)^{2 and}The test is performed before and after the test and the loss of resistance must not exceed 30% to conclude that the product is not toxic (Oroxcell, 2011).

Lucifer yellow (LY) is a marker of paracellular passage (Buyukozturk, et al., 2010). Its dosage in the receiving compartment during the permeability test allows for the observation of an opening of tight junctions. The test can also be done after the test to assess cellular integrity (Nollevaux, et al., 2006).⁷The following table shows the data for the period from 1 January 2014 to 31 December 2015:

Preferably the ratio of Class III BCS active substance to oil-based excipient self-emulsifying in contact with water by weight is between 1/10 and 1/100, particularly preferably between 1/40 and 1/80

The oily phase is preferably 1 to 50% of the micro-emulsion, preferably 2 to 30%, particularly preferably 5 to 25%, or 15 to 20%.

Preferably, the aqueous phase of the micro-emulsion of the invention is a solution in which the class III BCS active substance is solubilized.

Preferably, the microemulsion of the invention is an oil-in-water microemulsion consisting of an aqueous phase containing at least one class III BCS (Biopharmaceuticals Classification System) active substance, baclofen, and an oil excipient which is self-emulsifying in contact with water.

The active substance of the invention is baclofen.

In a preferred method of manufacture, it is soluble in the aqueous phase, preferably in 0,01 M fumaric acid.

Preferably, an appropriate oil excipient which is self-emulsifiable in contact with water has a HLB (Hydrophilic-Lypophilic Balance) index greater than 12, particularly preferably 13 or 14, e.g. Labrasol® (Gattefossé) composed of caprylocaproylmacrogolglycerides or Gelucire® 50/13 semi-solid composed of Lauroylmacrogolglycerides (Gattefossé).

In particular, an appropriate oil excipient which emulsifies on contact with water is selected from the group consisting of: C8 to C10 fatty acids, whether or not pegylated, such as sodium caprate or one of its derivatives,C8-C10 triglycerides, such as capric (C10) and caprylic (C8) triglycerides, e.g. Miglyol and Captex® (Sasol Germany GmbH, 2012);mixtures of mono-, bi- and triglycerides, e.g. Capmul® (Abitec, 2012);mixtures of mono-, bi- and triglycerides of esterified propylene glycol fatty acids, e.g. capric and caprylic acids, such as caprylocaprocolylmacrolglycerides or a mixture of mono-, bi- and triglycerides of caprylic acids, e.g. PEG-8®;80 to 80% to 20% of caprylic acid, e.g. caprylic acid and 20 to 50% of caprylic acid, e.g. caprasol.

Miglyol® (Sasol) and Captex® (Abitec) are capric acid (C10) and caprylic acid (C8) triglycerides. Capmul®MCM (Abitec) is composed of capric and caprylic acid mono- and di-glycerides (Table 2).

Labrasol® (Gattefossé) is composed of caprylocaproylmacrogolglycerides, which are a mixture of mono-, bi- and triglycerides and esterified fatty acids of propylene glycol (Gattefossé).

Gelucyr® 50/13 (Table 2) is a semi-solid excipient, with a high HLB of 13 compounds of Lauroylmacrogolglycerides (Gattefossé).

In particular, the self-emulsifying oil excipient of the micro-emulsion of the invention is Labrasol®, a mixture of caprylocaproylmacrogolglycerides consisting of a mixture of mono-, bi- and triglycerides of esterified fatty acids of propylene glycol-8 with a proportion of 50 to 80% caprylic acid and 20 to 50% capric acid.

Another subject matter of the invention concerns the use of a microemulsion between an aqueous phase containing at least one class III BCS (Biopharmaceuticals Classification System) active substance baclofen and an oily phase containing an oil excipient which is self-emulsifying in contact with water for the manufacture of a drug for the treatment of alcohol dependence or for the maintenance of withdrawal from alcohol. (ABITEC, 2012)(GATTEFOSSE)(SASOL GERMANY GMBH, 2012)

	Miglyol® 810	Miglyol® 812	Miglyol® 829	Captex® 300 EP/NF	Captex® 355 EP/NF	Captex® 200P	Capmul® MCM, EP	Labrasol®	Gelucire® 50/13
Composition	Triglycérides de : 65-80% Ac caprylique (C8:0) / 20-35% Ac caprique (C10:0)	Triglycérides de : 50-65% Ac caprylique/ 30-45% Ac caprique	Triglycérides de : 45-65% Ac caprylique/ 30-45% Ac caprique/ 15-20% Ac succinique	Triglycérides de : 50-80% Ac caprylique/ 20-50% Ac caprique	Triglycérides de : 50-80% Ac caprylique/ 20-50% Ac caprique	Propylène glycol de : 50-80% Ac caprylique/ 20-50% Ac caprique	50-90% Ac caprylique/ 10-50% Ac caprique/ 45-75% mono;20-50% di;10% triacylglycerols	Triglycérides et mono/di PEG-8 esters de : 50-80% Ac caprylique/ 20-50% Ac caprique	40-50% Ac palmitique (C16)/ 48-58% Acstearique (C18)
Etat physique à Tamb	Liquide	Liquide	Liquide	Liquide	Liquide	Liquide	Semi-solide	Liquide
Solubilités	Hexane, toluenediethylet her, ethylacetate, acetone, isopropanol, ethanol 96%	Hexane, toluenediethylether, ethylacetate, acetone, isopropanol, ethanol 96%	Hexane, toluenediethyleth er, ethylacetate, acetone, isopropanol, ethanol 96%	Solvants organiques dont ethanol 95%	Solvants organiques dont ethanol 95%	N/C	N/C
Indice de réfraction	1,448-1,451	1,449-1,451	1,456-1,459	1,440-1,452	1,440-1,452	N/C	N/C	1,450-1,470	N/C
	0,94-0,95	0,94-0,95	1,00-1,02	0,93-0,96	0,93-0,96	N/C	N/C	1,060-1,070	N/C
Viscosité à 20°C (mPa.s)	27-33	27-33	230-270	25-33	25-33	N/C	N/C	80-110	N/C
Statut réglementaire	EP, USP, BP, GRAS	EP, USP, BP, GRAS	DMF, GRAS	EP/NF, DMF	EP/NF, DMF	EP/NF, USP, DMF	EP, DMF, GRAS	EP, USP/NF	EP, USP/NF

The pharmaceutical formulation of the invention may be any oral galenic pharmaceutical formulation known to the trade, whether liquid or solid.

Appropriate liquid formulations are any liquid galenic formulation in which the microemulsion between an aqueous phase containing at least one Class III BCS (Biopharmaceuticals Classification System) active substance and an oily phase containing an oil excipient which self-emulsifies in contact with water will remain stable.

Once formed, microemulsions can be directly introduced into capsules for oral administration, either flexible or rigid, e.g. in gelatine.

Many techniques exist to formulate a solid form from a liquid formula (Jannin, et al., 2008).For example, cold-chamber spraying allows droplets to be frozen which recrystallize into solid spherical particles.

The aqueous phase of an emulsion may also be dried by spraying in a fluidised air bed to form a dry emulsion .

It can also be sprayed on neutral spheres, possibly with adsorption capabilities, such as microcrystalline cellulose spheres, which after drying can be used to form tablets with compression excipients.

The use of solid excipients at room temperature but liquid at hot temperatures allows the use of thermogranulation or extrusion-sferonisation techniques.

Finally, adsorption on solid media, such as microcrystalline cellulose or silica, in a granulator mixer allows the adsorption of a large amount of liquid excipient while maintaining good flow properties.

The formulation of the invention may include any additional excipient of the conventional formulation.

The formulation according to the invention contains 10 to 80 mg of active substance per unit dose, preferably 20 to 60.

Examples Example 1: MATERIALS and METHODS a. Raw materials i. Active substance

Baclofen is from PCAS.

The following are the main components of the adsorption factor:

Labrasol® and Gelucir® 50/13 are sourced from Gattefossé®, Miglyol® 810 from Sasol® Germany GmBH and Capmul® MCM and Captex® 355 from Abitec®.

(iii) Other excipients

The excipients used in the various tests are the following: Fumaric acid (Merck), Avicel® PH102 (microcrystalline cellulose, FMC Biopolymer), Neusilin® (magnesium aluminometa-silicate, FugiChemicalIndustry), HPMC 603 (hydroxypropylmethylcellulose, Shin Etsu), Tween® 80 (polysorbate 80, Sigma).

The test chemical is a solvent.

Solubility is determined by a visual method by introducing exactly weighted amounts of baclofen into the selected excipient after agitation for 24 h. First, the room temperature solubility of baclofen in Labrasol®, Miglyol® 810 and Captex® 355 is assessed. The solubility of baclofen in Geclocir® 50/13 is determined after the excipient has melted at a temperature above 50°C in a thin, thermostatic plaster. In a second step, the solubility of baclofen in a non-acidic medium is assessed at a temperature of 60°C. In order to increase the solubility of baclofen in a non-smokeless medium, the solubility of baclofen in a non-acidic medium is measured at a temperature of 0.01°C.

c. Lipid formulations a. Other, including mixtures of metals

Miglyol® 810, Capmul® MCM and Captex® 355 are water-insoluble excipients. Baclofen is a hydrophilic molecule, so it is chosen to form microemulsions from these excipients using pseudo-terranean diagrams. i.e. having a fixed surfactant-cosurfactant ratio but varying the ratio of this mixture with the oily and aqueous phases.

Six tests are performed to obtain an H/E microemulsion using a 2:1 Tween®80-Labrasol® surfactant-cosurfactant mixture and Miglyol®810 for the oily phase (Figure 4).

Four tests are performed to obtain an E/H microemulsion using a surfactant-cosurfactant mixture Tween®80-Capmul®MCM in a 1:2 ratio and Captex®355 for the oily phase (Figure 5).

The aqueous phase, composed of purified water, is added last under agitation, and the microemulsions are formed instantly.

(ii) Binary mixtures

Labrasol® and Gelucir® 50/13 are excipients that self-emulsify in the presence of water. Various water/Labrasol® or water/Gelucir® 50/13 ratios are tested.

The following are the main features of the new system: 1. viscosities

The viscosity of the emulsions is determined by means of a rotary viscosimeter Brookfield DV-II+ and the mobile SC4-18 using a cylindrical Duvet geometry.

The results of the tests are presented in Table 2.

The granulometry of the emulsions is measured by quasi-elastic diffusion of light on a Coulter® N4 plus granulometer. The measurements are made at an angle of 90° directly on the emulsions taking into account the characteristics of the dispersive medium (viscosity, refractive index) and then after dilution in water.⁴and 1.10⁶The measurement shall be performed in three copies.

Stability

The stability of the emulsions is determined visually over two months by observation of the occurrence or absence of a phase shift and by granulometric measurement.

d. Selection of formulas: Permeability tests on Caco-2 cells i. Cell culture

The Caco-2 cells were cultured and differentiated for 21 to 30 days, and underwent a graft count of less than 110. The culture medium is a DMEM (Dulbecco's ModifiedEagle Medium) medium supplemented with 10% inactivated calf foetal serum, 1% non-essential amino acids and antibiotics.

The test shall be carried out on the test vessel.

The Caco-2 cells allowed the potential of eight formulae, presented in Tables 5a, 5b, 5c and 5d, to be evaluated in improving the apparent permeability of baclofen. The dilutions performed are at the choice of the subcontractor based on the baclofen concentration measurable by the dosing technique and the lowest non-toxic concentration given by preliminary toxicity studies. - What?

HBSS	HBSS
10 mM HEPES	10 mM HEPES
0,1% BSA	0,1% BSA
200 µM Lucifer Yellow	-
pH 6,8	pH 7,4

Samples are taken after introduction of the sample into the apical medium: at T5 minutes and T125 minutes in the donor compartment and at T65 minutes and T125 minutes in the receiving compartment. Baclofen is measured by an LC/MS/MS method of analysis. The apparent permeability of baclofen and the co-recovering ratio are then calculated as follows: - What? ΔQ = difference in the amount of baclofen measured between the two samples Δt = time interval between the two samplesA = exposure area (cm)^{2 and}) C_{0 Other}= the initial concentration deposited in the donor compartment.

The result is interpreted as follows: - What?

	Faible	Intermédiaire	Haute
< 0,5	0,5 à 5	> 5

Tableau 5a : Composition centésimale microémulsion huile-dans-eau

Captex 355	60
Capmul MCM	20
Tween 80	10
Solution aqueuse de Baclofène	10

Tableau 5b : Composition centésimale de l'émulsion huile-dans-eau

Miglyol 810	20
Labrasol	20
Tween 80	40
Solution aqueuse de Baclofène	20

Tableau 5c : Composition centésimale de l'émulsion de la solution eau-labrasol

Labrasol	25	10	5	1
Solution aqueuse de Baclofène	75	90	95	99

Tableau 5d : l'émulsion de la solution eau-gélucire

Gélucire 50/13	5	1
Solution aqueuse de Baclofène	95	99

The result should be between 75 and 125 per cent.

For the validity of the test, the permeability of a reference compound is also measured as a positive control, 20 μM metoprolol, a molecule with active transcellular transport, and baclofen alone is also used as a negative control.

The following are the main features of the new system: 1. Measurement of transepithelial resistance

Before each test, a transepithelial resistance measurement is performed, which must be above 1500Ω. A second measurement is performed after the test. If the loss of resistance is above 30%, it is concluded that the monolayer is altered.

2. Trial to the Lucifer Yellow

During the tests, the apical-to-basolateral passage of Lucifer Yellow, a marker of paracellular passage, is also evaluated. 200 μM of Lucifer Yellow is co-incubated with the test compound and its permeability is evaluated in the same way as for the test compound. Concentrations are measured by fluorescence in both compartments at the beginning and end of the test. The MTS-PMS test is a derivative of the MTT test, which is used to test the viability of cells. Living cells convert MTS into formasan soluble in culture medium. The amount of formasan produced is assessed by measuring the absorbance at 490 nm. This amount is directly related to the proportion of living cells in the medium.

e. Formation into solid form: adsorption/granulation technique

Following the results of the cell tests, Labrasol® was selected as the excipient for the formulation of a solid formulation. The adsorption/granulation tests were carried out in a Diosna PVAC 10 blender/granulator. A 2L tank and a 0.8 mm spray nozzle were used.

The test shall be carried out on the test vessel.

Granulation tests are carried out on microcrystalline cellulose (Avicel® PH102) according to Table 6. The rotation rate of the bottom blade is 200 rpm and that of the emulator is 1500 rpm. The spray flow rate is 30 g/min. A drying time of one hour at 50 °C under vacuum is required to obtain a grain with a residual moisture content of less than 5% (Mettler thermobalance). The grain is then sifted into 0.5 mm meshes. - What?

Avicel® pH 102	Adsorbant	95	285
HPMC 603	Liant	5	15
	-
Eau purifiée	Agent de granulation	50	150
Labrasol®	Promoteur d'absorption	50	150

The grain size is measured by Malvern® laser particle size measurement and the data are processed using Mastersizer 2000 software. The grain's compressibility and flow capabilities are assessed by measuring the apparent volume under settling (STAV 2003 volumetric) and calculating the Carr index as well as by measuring the flow time per 100 g of powder through a standardised funnel. These tests are carried out according to the current European Pharmacopoeia (European Pharmacopoeia 7th edition, 2012).

The test chemical is used to determine the concentration of the test chemical in the test medium.

Single adsorption tests are also performed in a blender by introducing Labrasol® into Avicel® PH102 or Neusilin® (Magnesiumaluminometasilicate) by stirring the pale at 150 and 300 rpm respectively. The flow rate is 20 g/min and the tests are done at 40°C under vacuum to fluidise the oily excipient Labrasol. The following adsorbents are also tested: Fujicalin®, Hubersorb®, 600 and Syloid®244FP.

Example 2: RESULTS a. Solubilities of baclofen

The solubilities shown in Table 7 below are determined from the visual observation of particles in the media. - What?

Miglyol®810	Ambiante	< 0,1 mg/ml
Captex® 355	Ambiante	< 0,1 mg/ml
Labrasol®	Ambiante	0,2-0,4 mg/ml
Gélucire® 50/13	60°C	0,5-1 mg/ml
Milieu aqueux Acide fumarique 0,01M	Ambiante	6-7 mg/ml

Baclofen appears to be soluble in aqueous media and practically insoluble in oily excipients.

b. Lipid formulas a. Other, including mixtures of metals

Depending on the compositions, different observations can be made. For the microemulsions based on Miglyol® 810 and Labrasol® (Figures 4 and 5), compositions 1, 2 and 3 produce clear media and composition 10 produces a milky medium. Compositions 8 and 9 are opaque and a phase shift is obtained after 24 h.

The four formulations based on Captex® 355 and Capmul® MCM provide clear microemulsions.

Microemulsions made with the active substance do not show any visual difference compared to those without the active substance.

(ii) Binary mixtures

Labrasol® is miscible in all proportions in water, but a clear and homogeneous mixture is obtained at concentrations of Labrasol greater than 1% in water, and at concentrations below 1% the medium becomes cloudy and the particles visible to the naked eye become sedimentary.

Gelucire® is also water-miscible but only water/Gelucire® mixtures at concentrations below 5% remain in liquid form at room temperature.

The following are the main features of the new system:

On the basis of the criteria discussed below, certain compositions are selected for cell permeability tests and are characterised here.

1. viscosities

The viscosities of microemulsions are given in Table 8 below. - What?

Microémulsion Miglyol®/Labrasol®	6	85	423
Microémulsion Capmul®/Captex®	30	60	59

The viscosities of binary mixtures are close to those of water.

The results of the tests are presented in Table 2.

The granulometry is measured 14 days after the systems are prepared, before and after dilution for microemulsions and for the binary mixtures Water/Labrasol®.

For microemulsions, dilution causes destabilization and the appearance of an opaque medium whose intensity at 90° is too high for measuring particle sizes. A dilution is therefore necessary to achieve an intensity within the range recommended by the granulometer manufacturer.

For the Water/Labrasol® mixtures, the dilution obtained is the same as for the Caco-2 cell tests.

Stability of microemulsions at T = 45 days

Granulometer measurements, as shown in Table 9, are also taken and compared with those obtained at 14 days.

The test chemical is a chemical that is capable of producing a specific chemical.

The measurement of transepithelial resistance (Figure 6) before and after the permeability test informs us of the toxic potential of the eight formulae and the different controls. Only microemulsions induce a resistance variation of more than 30% between the initial and final measurements indicating a loss of membrane integrity. The other 6 formulae and controls cause a variation of less than 30% indicating a recovery of cell resistance after the test.

For the action of the formulas on the tight junctions of the cell mat, the apparent permeability of Lucifer Yellow is monitored for each test (Figure 7).^-6However, for microemulsions this may be related to membrane destabilisation. Labrasol® 1 and 5% formulations and Gelucire® 5% formulations also cause a Lucifer Yellow pass of greater than 3.10^-7But this is still low, because it is less than 0.5.10^-6The controls, on the other hand, do not open tight junctions.

The MTS-PMS test shows that our formulas do not generate cellular toxicity. =

		Dilution	Milieu dispersant	Proportion (%)	Taille (nm)
	Emulsion Miglyol®/Labrasol®	N/A	Viscosité =423 cP, Indice de réfraction = 1,45	Absence de résultats
	Emulsion Captex®/Capmul®	N/A	Viscosité=59 cP, Indice de réfraction= 1,45	100	21,3
	Emulsion Miglyol®/Labrasol®	N/A	Viscosité =423 cP, Indice de réfraction = 1,45	Absence de résultats
	Emulsion Captex®/Capmul®	N/A	Viscosité=59 cP, Indice de réfraction= 1,45	100	24,2
	Emulsion Miglyol®/Labrasol®	1/5000	Eau	12-17	1
				10-20	50-70
				25-80	130-195
				50-60	218-285
	Emulsion Captex®/Capmul®	1/10000	Eau	1-2	1-3
				98-99	230-500
	Emulsion Captex®/Capmul®	1/10000	Eau	5	17
				11-12	75-77
				88	1000
	Emulsion Miglyol®/Labrasol®	1/5000	Eau	100	180-390

=

	Emulsion Miglyol®/Labrasol®	N/A	Viscosité =423 cP, Indice de réfraction = 1,45	Absence de résultats
	Emulsion Captex®/Capmul®	N/A	Viscosité=59 cP, Indice de réfraction= 1,45	100	27,2
	Emulsion Miglyol®/Labrasol®	1/5000	Eau	12-13	1
				14-20	70-74
				65-87	190-200
	Emulsion Captex®/Capmul®	1/10000	Eau	1	4-5
				99	530-630

/=

Labrasol® 25 %	Labrasol® 10 %	Labrasol® 5 %		Labrasol® à 1 %
50% à 1 nm	50% à 1 nm	30% à 1 nm	20% à 1 nm	> 2 µm
50% à 15 nm	50% à 12 nm	40-50% à 10 nm	80% à 13,5 nm
		20-30% à 400 nm
	Labrasol® 10% - 1/200	Labrasol® 5% - 1/100
	525,7 nm +/- 105,6; IP= 0,044	657,5 nm +/- 170; IP=-0,091

The results of the apparent permeability of baclofen according to the various formulae are given in Figure 8.

Cell tests confirm the low permeability of baclofen with an apparent permeability of less than 3.10^-7This permeability is increased to 3.10^-6The concentration of the active substance in the mixture is very high for Captex®/Capmul® and Labrasol® formulations at 25% and 10% respectively, ranging from 5 to 7.10^-6However, as with the results for Lucifer Yellow, the permeabilities associated with microemulsions are certainly due to the observed loss of membrane integrity. Labrasol® 1 and 5% formulations and Gelucir®-containing formulations do not allow an increase in the apparent permeability of baclofen.^-6The most promising formulas for increasing the membrane passage of baclofen are Labrasol® formulas, particularly those at 10% and 25% which allow increases of 20 and 28 times the apparent permeability of unformulated baclofen respectively. Furthermore, the recoveries calculated during the tests are around 100% confirming the absence of degradation of the product during the test. No loss is observed.

d. Passage in solid form The following shall be added:

A grain containing 33% Labrasol® is obtained, which is yellow and oily to the touch.

The results of the particle size measurements are shown in Figure 9.

The data obtained by the volumetric and flow time are given in Table 11 below. - What?

	Pesée (g)	V0 (ml)	V10 (ml)	V500 (ml)	V1250 (ml)	ρ0 (g/ml)	ρ tassée (g/ml)	V10-V500 (ml)	Indice de Carr (100x (V10-V1250)/V10)	Temps d'écoulement (s)
Grain 33% Labrasol®	100,14	184	172	158	158	0,54	0,63	14	8,14

The following are the main components of the test:

Adsorption tests on microcrystalline cellulose at the same concentration as granulation yield a yellow, greasy powder with a wet sand appearance and a clump-like appearance.

Adsorption tests on Neusilin® produced a powder containing 60% Labrasol®, a white, dry-looking mixture which is highly volatile.

The purpose of this step is to select an excipient for future compression tests, the loaded excipients being characterised in flow by the flow rate and Carr index (Ic) measurements (Table 12). - What?

Avicel® PH102	0	0,34	15,1	Bon
Avicel® PH102 + Labrasol®	0	0,34	16,4	Assez bon
Fujicalin®	20,2	0,47	6,9	Excellent
Fujicalin® + Labrasol®	19,3	0,65	9,5	Excellent
Neusilin® US2	2,9	0,15	8,9	Excellent
Neusilin® US2 + Labrasol®	23	0,48	6,0	Excellent
Neusilin® UFL2	0	0,11	25,0	Passable
Neusilin® UFL2 + Labrasol®	0	0,21	29,5	Mauvais
Hubersorb® 600	0	0,08	25,0	Passable
Hubersorb® 600 + Labrasol®	0	0,17	32,9	Très mauvais
Syloïd® 244FP	0	0,07	14,8	Bon
Syloïd® 244FP + Labrasol®	0	0,30	12,5	Bon

Thus, adsorbed powders without flow (Hubersorb® 600, Avicel® PH102, Neusilin® US2, Syloïd® 244FP) are not retained, while adsorbed Neusilin® US2 and Fujicalin® have a very good flow rate and can therefore be used.

I. Discussion Selection of formulae for permeability and stability tests

As expected, the solubility of the active substance in liquid uptake promoters was very low, below 1 mg/ml. Baclofen is a hydrophilic PA, as indicated by its log P of - 0.96 (Benet, et al., 2011), whereas the uptake promoters are oils.

However, products such as Labrasol® and Gelucir® 50/13 have the peculiarity of having a high HLB of 13-14 (Gattefossé) which allows them to mix with water. Thus, it was decided to make binary mixtures of Labrasol® or Gelucir® with an aqueous solution containing baclofen previously solubilised. The Labrasol®/water ratios are chosen to assess a possible impact of the concentration in Labrasol® on cells. For Gelucir®, the mixture is intended to remain in liquid form at room temperature, which limits the range of concentrations to less than 5%. Low concentrations (less than 5% for Labrasol® and less than 1% for Gelucir®) are observed to disrupt the presentation of Gelucir® and Gelucir®.The granulometric measurement indicates that the particles in the Labrasol® mixture are much larger than those observed at higher concentrations (2 μm versus 13 nm). The sizes obtained for the more concentrated solutions may explain the sedimentation observed. Four formulations of Labrasol® at 1, 5, 10 and 25% and two formulations of Gelucir® at 1 and 5% were prepared and sent to the subcontractor.

For microemulsions composed of Miglyol®/Labrasol®, three visually stable and clear compositions are provided (Table 13). - What? /

1	10 %	27 %	53 %	10 %
2	10 %	23 %	47 %	20 %
3	20 %	20 %	40 %	20 %

For cell testing, composition 3 is chosen for various reasons: firstly, Tween® 80 used as a surfactant is known for its toxicity problems, so the formula containing the least amount of it seems safer; secondly, the proportion of water is higher and therefore more active ingredient can be introduced; and thirdly, the amount of Miglyol® which is important from the point of view of promoting absorption is also higher.

The four microemulsions prepared from Captex®/Capmul® produce clear and stable formulae (Table 14). - What? /

1	60 %	20 %	10 %	10 %
2	64 %	22 %	11 %	3 %
3	55 %	28 %	14 %	3 %
4	56 %	26 %	13 %	5 %

Due to the same criteria as before, Composition 1 is selected for cell testing.

Thus, the permeability of baclofen incorporated in two microemulsions of different compositions is measured.

The mechanism of baclofen passage (Merino et al., 1989) consists of an active passage through transporters but these are saturated at high dose. Not knowing the composition of Caco-2 cells as transporters, a high concentration of baclofen in formulas is sought so that the transporters present are saturated. Thus, only the increase in paracellular passage will be evaluated. The saturation concentration of baclofen in water is 3 mg/ml (internal preformulation ratio). However, its solubility is highly pH dependent as the amino and carboxylic functions on the molecule indicate. Thus the addition of fumaric acid to 0.01 M, as demonstrated to be compatible with baclofen by internal preformulation, allows the solubility of baclofen to be doubled from 3.8 mg/ml to 6.8 mg/ml.

According to Constantinides et al (1996), the pH of a microemulsion does not affect its stability or particle size if the surfactants used are not ionized or ionizable. Thus, replacing the aqueous phase of microemulsions with 0.01 M fumaric acid at 6 mg/ml baclofen does not cause visual destabilization of microemulsions.

The stability of the systems is also monitored by granulometric measurements 14 and 45 days after microemulsions have been made.

For the Captex®/Capmul® emulsion, a measurement of 21.3 nm is obtained at 14 days for the placebo formula, confirming the presence of a microemulsion. A measurement of 24.2 nm is obtained for the formula with active ingredient indicating that the active ingredient does not influence the particle size as suggested by the study (Prajapati, et al., 2012). However, studies by Buyukozturk et al. (2010) and Gundogdu et al. (2011) show an influence of the active ingredient on the size of blood cells. After 45 days, the measurement is 27.2 nm, confirming the stability of the system.

The granulometry measurement of Miglyol®/Labrasol® emulsion could not be performed because of the high viscosity of the medium measured at 423 cP. To assess the stability of Miglyol®/Labrasol® emulsion, the system is diluted with the assumption that dilution does not affect the particle size of the emulsion, which is supported by Prajapati et al. For Miglyol®/Labrasol® emulsion, the 14 day active measurements appear to be higher than those obtained on placebo. However, the 45 day active measurements are of the same order of magnitude as those of the placebo emulsion. It therefore seems difficult to draw conclusions here about the granulometric stability of the emulsion/Captex® emulsion. We can visually observe the stability of the systems over the course of two months, which allows us to conclude that the same macroscopic stability of the systems is observed.

Interpretation of the results of permeability in relation to the characterisation of the formulae

The observation of a very low permeability of unformulated baclofen, less than 0,5.10^-6The concentration of the test chemical in the test medium is approximately 30 μg/ml, which is assumed to be close to the saturation of the transporters. This value can be compared with Labrasol® 25%, 10% and Gelucire® 1% tests diluted in the same way 200 times. Gelucire® at 1% does not increase the apparent permeability, while Labrasol® tests allow a large increase in permeability by 20 and 28 times.

For 100 times diluted formulations (Labrasol® 5%, Labrasol® 1% and Gelucir® 5%), the permeability values are very low, sometimes even lower than for unformulated baclofen. However, the baclofen concentrations deposited on cells for these tests are twice as high as for the negative control. It can therefore be assumed that the concentration of the control is not quite at full saturation of the transporters. Thus, the permeabilities cannot be fully compared with each other since they depend entirely on the active concentration which is different from the formula to the other. The principles of Baclofen® Gelucir® illustrate this effect.

Despite the effect of the baclofen concentration, a large difference in permeability can still be observed between Labrasol® 10 and 25% formulations and Labrasol® 1 and 5% formulations. At first, the search for differences in the structure of the mixtures is sought, in particular by the granulometric measurement of the particles. Indeed, Koga et al. have shown the importance of the concentration in Labrasol® on the size of the particles that would increase with the concentration.The first measurements were made on undiluted formulas. For formulas 1 to 5, 10 and 25%, the measurements obtained are of the same order of magnitude as those measured by Koga et al. but no relationship between the concentration in Labrasol® and particle size is clearly identified. A population is even observed at 400 nm for the 5% formula which disappears in the placebo formula and suggests an influence of the active substance on particle size. However, the measurements on formulas after dilution cancel the hypothesis of an influence of particle diameter since the observed differences disappear.In addition, a significant increase in particle size is noted with dilution.

It is noted that, taking into account the dilutions carried out on cells, two identical concentrations in Labrasol® were tested (Table 15) and did not give the same permeability results. This point is an argument for the importance of the initial active substance concentration in increasing membrane passage. The active substance/Labrasol® ratio is therefore important in the results observed. - What? /

Ratio PA/Labrasol®	facteur d'augmentation de Papp	concentration Labrasol®
1/1,7	0	0,01 %
1/8,8	0	0,05 %
1/13,4	7	0,03 %
1/18,5		0,05 %
1/55,5		0,125 %

Thus, it appears that the increase in the apparent permeability of baclofen occurs only from a certain threshold of Labrasol® relative to the baclofen concentration.

An increase in apparent permeability is also obtained for microemulsions, but despite this observation, these are not retained due to the toxicity shown on the cell mat by loss of membrane integrity.

Finally, in view of the significant increase in permeability obtained with Labrasol®, the main focus of the study will be on this excipient, particularly for galenic tests.

The test chemical is a chemical that is used to determine the concentration of a substance in a solution.

The granulation solid-state tests with microcrystalline cellulose do not allow the introduction of more than 33% of Labrasol®. By visual comparison with the adsorption test, the Labrasol® grain appears to have better properties due to a less wet effect, and theoretically allowing a better flow rate for future compression tests. The assumed Carr index of 8.14 allows good flow properties but low compressibility properties to be calculated.

Further adsorption tests are then carried out on Neusilin®, a silicate with an adsorption capacity three times greater than that of microcrystalline cellulose (Neusilin application data, www.Neusilin.com). The adsorption technique is preferred because it allows for the introduction of larger amounts of liquid than granulation. This latter technique also requires the adsorption of a certain amount of water which reduces the volume available for the oil. A dry mixture containing 60% Labrasol® is obtained which is encouraging and can allow the introduction of this powder into an oral pharmaceutical form.

Ac	Acide
ATP	Adénosine triphosphate
BCS	Biopharmaceutical Classification System
BP	British Pharmacopoeia
BSA	Bovine sérum albumine
C10, C8	Acide gras composé de 10 ou 8 atomes de carbone
cP	centiPoise
	Déciles 10,50 et 90%
DAG	Diacylglycérol
DMEM	Dulbecco'sModifiedEagle Médium
DMF	Drug master File
DSC	Differential scanning calorimetry
E/H	Eau dans huile
EMEA	European Agency for the Evaluation of Medicinal Products
EP	Pharmacopée Européenne
FDA	Food and Drug Administration
GRAS	Generally recognized as safe
H/E	Huile dans eau
HBSS	Hank'sBalanced Salt Solution
HEPES	acide 4-(2-hydroxyéthyl)-1-pipérazine éthane sulfonique
HLB	Balance hydrophile/lipophile
IP	Indice de polydispersité
IP3	Inositol triphosphate
JS	Jonctions serrées
LC/MS/MS	Chromatographie liquide couplé à la spectophotométrie de masse en tandem
LY	Lucifer yellow
ME	Microémulsion
MTT	bromure de 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
N/C	Non connu
NF	Norme française
OMS	Organisation mondiale de la Santé
PA	Principe actif
	Perméabilité apparente
P-gp	P-glycoprotéine
PIP2	phosphatidylinositol 4,5-bisphosphate
PLC	Phospholipase C
rpm	Rotor per minute (= tours par minute)
t ou T	Temps
T5, T65, T125	Temps à 5, 65 ou 125 minutes
	Température ambiante
TEER	Résistance transépithéliale
	Température de fusion
USP	United States Pharmacopoeia
V0	Volume vrac
V10, V500, V1250	Volume apparent après 10, 500 ou 1250 tassements
ZO	Zonulaoccludens
ρ	Masse volumique

The Bible is a book of inspiration.

Abitec Fiches techniques // Capmul MCM EP ; Captex 355 EP/NF ; Captex 300 EP/NF ; Captex 200P. - 2012.Anilkumar P [et al.] A rationalized description on study of intestinal barrier, drug permeability and permeation enhancers [Revue] // Journal of Global Trends in Pharmaceutical Sciences vol 2, no. 4. - 2001. - pp. 431-449.Boonme P [et al.] Characterization of microemulsion structures in the pseudoternary phase diagram of isopropyl palmitate/water/brij 97:1-brijol [Article] // AAPS PharmTech, vol 6, no. 2, 45. - 2006.Buyukozturk F, Benneya J, C and Carrier R, L Impact of emulsion-based drug delivery systems on intestinal permeability and drug release kinetics [Article] // Journal of Controlled Release, vol. 142. - 2010. - pp. 22-30.Cho S-W, Lee J, S and Choi S-H Enhanced oral bioavailability of poorly absorbed drug. I. Screening absorption carrier for the ceftriaxone complex [Revue] // Journal of Pharmaceutical Sciences, vol. 96, no. 3. - 2004. - pp. 612-620.Choi S-H, Lee J-S and Keith D Compositions and methods to imply the oral absorption of antimicrobial agents [Brevet] : EP 1 294 361 B1 - 2001/09785 WO1. - International, 2011.The following is a list of the most commonly used chemical compounds in the food industry: [A] (Pharmaceutical Research, vol. 13, n°2. - 1996. - pp. 210-215.Constantinides P, P and Scalart J-P Formulation and physical characterization of water-in-oil microemulsions containing long- versus medium-chain glycerides, [Rev.] // International Journal of Pharmaceutics, vol. 158. - 1997. - pp. 57-68.Constantinides P, P Lipid microemulsions for improving drug dissolution and oral absorption : Physical and pharmaceutical biopharmaceutical aspects [Revue] // Pharmaceutical Research, vol. 12, n°11. - 1995. - pp. 1561-1572.The results of the study were published in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of the American Academy of Pediatrics in the journal of Pediatrics in the journal of the American Academy of Pediatrics in the journal of Pediatrics in the journal of the American Academy of Pediatrics in the journal of Pediatrics in the journal of the journal of the American Academy of Pediatrics in the journal of Pediatrics in the journal of the journal of the American Academy of Pediatrics in the journal of the journal of the American Academy of Pediatrics in the journal of the journal of the year of the American Academy of Pediatrics in the year of the year of the year of the year of the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year the year theThe following is a list of the active substances in the active substance, including the active substances that may be used in the active substance, including the active substances that may be used in the active substance, including the active substances that may be used in the active substance, including the active substances that may be used in the active substance, including the active substances that may be used in the active substance, including the active substances that may be used in the active substance, including the active substances that may be used in the active substance, including the active substances that may be used in the active substance, including the active substances that may be used in the active substance, including the active substances that may be used in the active substance, including the active substances that may be used in the active substance, including the active substances that may be used in the active substance, including the active substances that may be used in the active substance, including the active substances that may be used in the active substance, and the active substances that may be used in the active substance.In vitro and in situ evidence for the contribution of labrasol and Gelucire 44/14 on transport of cephalexine and cefoperazone by rat intestine [Review] // European Journal of Pharmaceutics and biopharmaceutics, vol. 54. - 2002. - pp. 311-318.Leisen C, C [et al.] Lipophilicities of baclofen ester prodrugs correlate with affinities to the ATP-dependent efflux pump P-glycoprotein: relevance for their permeation across the blood-brain barrier? [Review] // Pharmaceutical Research, vol. 20, n°5. - 2003. - pp. 772-778.a P-Glycoprotein substrate, in rats [Revue] // Biological and Pharmaceutical Bulletin, vol 30, no. 7 . - 2007. - pp. 1301-1307.Maher S [et al.] Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic [Revue] // Advanced Drug Delivery Reviews, vol 31. - 2009. - pp. 1427-1449.Merino M [et al.] Evidence of a specialized transport mechanism for the intestinal absorption of baclofen [Revue] // Biopharmaceutics and Dreug, vol 10. - 1989. - pp. 279-297.Motlekar N [et al.] Oral delivery of low-molecular-weight heparin using sodium caprate as a drug to enhance therapeutic levels of absorption // Reaching targeted levels of drugThe results of the study were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and the results were published in the journal Physiology and Biology, and Biology, and Biology, and the results in the journal Physiology and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, and Biology, Biology, and Biology, and Biology, and Biology, and Biology, and Biology, Biology, and Biology, and Biology, Biology, and Biology, and Biology, and Biology, and Biology, Biology, and Biology, and Biology, and Biology, Biology,A comparative evaluation of Mono- Di- and Triglyceride of medium chaon fatty acids by lipid/surfactant/water phase diagram, solubility determination and dispersion testing for application in oharmaceutical dosage form development [Article] // Pharmaceutical research, vol. 29. - 2012. - pp. 285-305.pubchem Sodium Caprate [En] // pubchem. - 10 April 2012. - http://pubchem.ncbi.nnih.ni.gov.R Molecular Z Z Z Biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences within [Article] // Caucids and fluids of the CNS, vol. 8, n° 1233. - Solution of Sodium Sodium and Phletocoproteins [Scoproteins and Phletocoproteins] - Journal of Pharmaceutical Sciences [Revision of Rhodoproteins and Phletocoproteins] - 44/14 pages.The following table shows the results of the analysis of the results of the studies carried out by the European Chemicals Agency (ECHA) in the field of biotechnology and the results of the studies carried out by the European Chemicals Agency (ECHA) in the field of biotechnology and the results of the studies carried out by the European Chemicals Agency (ECHA) in the field of biotechnology and biotechnology:-1985. - Vol. 38: pp 251-257.KMerino M [et al.] Evidence of a specialized transport mechanism for the intestinal absorption of baclofen [Revue] // Biopharmaceutics and Dreug disposition, vol. 10. - 1989. - pp 279-297.Neusilin Application data [Online] // Neusilin.com. - http://www.neusilin.com/library/application_data. - 05 06 2012.Pharmacopoeia Europe 7th edition // Chapters 2.09.34-Bulk mass and bulk mass after settling and 2.09.36-Aptitude to flow of powders - 2012. - Vol. 7.4.

Claims (10)

1. An oral pharmaceutical formulation based on a microemulsion between an aqueous solution comprising at least one BCS (Biopharmaceutics Classification System) class III active ingredient, said active ingredient being baclofen, and an oil phase comprising an oil excipient self-emulsifiable in contact with water, said oil excipient self-emulsifiable in contact with water being a mixture of mono-, bi- and triglycerides and of PEG-8 esterified fatty acids in the proportion of 50 to 80 % caprylic acid and 20 to 50 % capric acid.
2. The formulation according to claim 1, said oil excipient self-emulsifiable in contact with water having an HLB value higher than 12.
3. The formulation according to any one of the preceding claims, wherein said oil phase represents 1 to 50 % of the microemulsion, preferably 2 to 30 %, more preferably 5 to 25 %.
4. The formulation according to any one of the preceding claims, wherein said microemulsion is an oil-in-water microemulsion formed of said aqueous phase and of said oil excipient self-emulsifiable in contact with water.
5. The formulation according to any one of the preceding claims, said oil excipient self-emulsifiable in contact with water being contained in a ratio of 1:10 to 1:100 by weight relative to the active ingredient.
6. The formulation according to any one of the preceding claims, in liquid form comprising said microemulsion.
7. The formulation according to any one of claims 1 to 5, in solid form.
8. The formulation according to claim 7, in soft or hard capsule form comprising said microemulsion inside the capsule.
9. The formulation according to claim 7, in tablet form comprising a neutral carrier coated or impregnated with said microemulsion, dried and compressed with compression excipients.
10. The formulation according to any one of the preceding claims, for use thereof in the treatment of alcohol dependence or for the maintaining of alcohol abstinence.