Pharmaceutical compositions comprising an active agent

The present invention relates to immediate release soft gelatin capsules comprising (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)nona-2,4,6,8-tetr aenoic acid. The invention further relates to a process for preparing such soft gelatin capsules.

BACKGROUND OF THE INVENTION

Some pharmacologically active substances may have biopharmaceutical and/or physicochemical properties which make them difficult to formulate into commercially acceptable formulations. Such substances may however be conveniently administered in liquid form, e.g in a complex carrier medium made up of several components. Liquid ingredients are difficult to include in any other solid dosage form such as a tablet.

Pharmaceutical dosage forms including liquids can be delivered in a variety of forms, for example in a capsule. Capsules are solid dosage forms in which therapeutic agents are enclosed in a soluble gelatin wall. The wall can be made of either soft or hard gelatin.

Liquid filled hard gelatin capsules have also been used. See, for example, D. Cade et. al., Liquid Filled and

Sealed Hard Gelatin Capsules, Drug Development and Industrial Pharmacy, 12(11 -13): 2289-2300, (1986).

Soft gelatin capsules ("SGC" or soft gels) comprise a soft, globular, gelatin wall. Soft gelatin capsules offer a convenient dosage form for the administration of drugs, nutrients, vitamins, foodstuff and cosmetics. Soft gelatin capsules are one-piece and hermetically sealed to enclose normally a liquid or semi-liquid fill. Upon ingestion by the consumer (or on contact with water), moisture causes the capsule to come apart at the seams where the two halves are joined thereby releasing the fill or contents of the capsule.

Encapsulation of such liquid formulations in soft gelatin capsules potentially offers a very convenient way of administering such pharmacologically active substances. However, the manufacture of commercially acceptable liquid filled soft gelatin capsules is fraught with difficulties, which restrict the availability of this approach. The carrier medium may be designed to form an emulsion/solution in the stomach thereby facilitating absorption of the pharmacologically active substance. The carrier medium may have to be accurately prepared in order not to destroy the beneficial properties of the pharmacologically active substance or of the soft gelatin capsule. For example, the solubilizing properties of the capsule filling may be changed in such a way that the active substance may precipitate out. This precipitation process may be irreversible, and, as a consequence, the patient may be under-dosed. Also, the properties of the capsule filling may be changed, and, upon administration, the pharmacologically active substance may not be correctly or reproducibly absorbed. Moreover, during manufacture, the capsule shell is formed from wet gelatin bands and the resultant wet capsules are dried. During this stage or even afterwards, components in the capsule filling may migrate into the capsule shell, and viceversa, thereby changing the composition of the capsule filling at least in the boundary region near the interface of the capsule filling and the capsule shell, with the result that the beneficial properties of the capsule filling are lost. Furthermore, such softened capsules will undergo deformation, because due to the migration of part of the solvent into the capsule shell from the capsule filling there will be a decrease in volume and a reduction in pressure in the interior of the capsule. These solubility challenges can affect bioavailability possibly resulting in reduced or unpredictable bioavailability.

The lack of stability of a soft gelatin capsule can affect the dissolution profile of such capsule. In most of the cases, it is important that the active ingredient is delivered as soon as possible in order to have a rapid onset of action. This kind of compositions is known as immediate release dosage forms. An immediate release dosage form should have the following characteristics to be marketed: It should dissolve and/or disintegrate in the stomach within a short period; It should be compatible with taste masking; It should be portable without fragility concern; It should have a pleasing mouth feel; It should leave minimal or no residue in the mouth after oral administration; It should exhibit low sensitivity to environmental condition as humidity and temperature; It should be manufactured using conventional processing and packaging equipment at low cost; It should show rapid dissolution and absorption profiles of the active ingredient, which may produce rapid onset of action.

The choice of excipients is important in order to ensure good solubility and good bioavailability of the pharmaceutically active compound when using soft gelatin capsules. See For example, K. Hutchison, Encapsulation in Softgels for Pharmaceutical Advantage, Spec. Pub. R. Soc. Chem, Vol. 138, pp 86-97, (1993). The EP 1680096 teaches that in case that the soft gelatin capsule comprises a retinoid as an active ingredient, the soft gelatin capsule has to comprise also a natural vegetable oil, a partially hydrogenated natural vegetable oil, medium chain triglycerides and a natural wax. In addition retinoids are normally hydrophobic substances, and particular issues with respect to formulation of hydrophobic pharmaceutical active compounds have been described, for example in K. Hutchison, Formulation of Softgels For Improved Oral Delivery of Hydrophobic Drugs, Spc. Pub. - R. Soc. Chem., Vol. 161 , pp 133-147 (1995).

Methods for preparation of soft gelatin capsules are known. See, for example, J. P. Stanley, Soft Gelatin Capsules, Ch. 13 - Part Two in: The Theory and Practice of Industrial Pharmacy, eds. L. Lachman et. al., 3 rd Ed., pp. 398-412, 1986, and W.R. Ebert, Soft Elastic Gelatin Capsules: A Unique Dosage Form, Pharmaceutical Technology, Vol. 1 , No. 5. Soft gelatin capsules can be prepared, among other methods, by two methods. In short, the first method is known as the plate process, where a set of molds is used. A warm sheet of gelatin is laid over a lower plate and the liquid fill is poured on it. A second sheet of gelatin is then placed on top followed by the top plate. The set is placed under pressure to form the desired capsule. In sum, the second method was invented by Robert P. Scherer in 1933 and is called the rotary-die process. In this process, soft gelatin capsules are made by continuously casting two separate ribbons of molten or flowable gelatin into two separate rotating dies of an encapsulation machine to produce soft, elastic gelatin capsules.

SUMMARY OF THE INVENTION The compositions as herein disclosed are directed to soft gelatin capsules comprising (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid which exhibit an immediate release profile, possess advantageous stability profiles and additionally disintegrate rapidly in aqueous solutions. The invention is particularly suitable for oral pharmaceutical dosage forms of (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid in which a therapeutically effective amount of the active ingredient has to be available in the use environment shortly after administration.

Another advantage of the soft gelatin capsules as herein disclosed is that they are homogeneously filled and safe to handle. The active ingredient (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid is a potent drug and therefore its quantity has to be precisely controlled and its handling must be safe. The soft gelatin capsules as herein disclosed can be manufactured by highly reproducible filling process, which helps ensure each soft gelatin capsule has the same drug content. Moreover, the operators are not exposed to any drug dust during the manufacturing process.

Moreover, the soft gelatin capsules as herein disclosed shows good characteristics to be marketed.

In a first aspect, the hard fat free stable immediate release soft gelatin capsule as herein disclosed comprises the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid, wherein the soft gelatin capsule comprises a capsule shell and a fill, wherein the shell of the soft gelatin capsule comprises preferably a plastifying agent in an amount sufficient to plastify the shell without incurring in incompatibilities with the fill or in an amount less than 45% w/w in respect of the total amount of the shell, preferably the plastifying agent is sorbitol, propylene glycol, glycerol or mixtures thereof, and wherein the fill of the soft gelatin capsule comprises: the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated natural oils; wherein the total amount of the filling mixture of at a least two of the three following components, a first component, a second component and a third component or the total amount of the filling mixture of the first component present in the fill is more than 60 % w/w in respect to the total content of the fill or an amount sufficient to obtain a hard fat free stable immediate release soft gelatin capsule comprising the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid; with the proviso that if the fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the fill does not comprise a natural wax. Preferably, the active agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid is micronized and the soft gelatin capsule comprises glyceryl behenate.

The compositions as herein disclosed are directed to soft gelatin capsules comprising (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid which exhibit an immediate release profile, and wherein the active agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid is micronized. Surprisingly, the micronization of the active agent gives better soft gelatin capsules, for example, more stable.

In a second aspect, the process for the preparation of hard fat free stable immediate release soft gelatin capsules containing the same agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid as defined in the first aspect, as herein disclosed, comprises at least the following steps: i) preparing a soft gelatin capsule fill comprising mixing the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6- trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; and a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax;

ii) filling a soft gelatin capsule with the fill as prepared in step (i) forming the soft gelatin capsule;

iii) optionally drying the soft gelatin capsules.

In a third aspect, the soft gelatin capsule fill for the manufacture of immediate release soft gelatin capsules, as herein disclosed, comprises the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax.

In a fourth aspect, the process for the preparation of the fill of the third aspect, as herein disclosed, is by mixing the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9- (2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; and a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax.

Another aspect is a hard fat free soft gelatin capsule as obtained by any one of the processes for the preparation of a hard fat free stable immediate release soft gelatin capsule containing the agent (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid, as herein disclosed.

Another aspect is the use of the hard fat soft gelatin capsule as herein disclosed in the first aspect and other aspects, or the soft gelatin capsule fill as herein disclosed in the third aspect, for skin lesions in a human being. In a preferred embodiment, the skin lesion is eczema. In a preferred embodiment, the hard fat soft gelatin capsule as herein disclosed in the first aspect and other aspects, or the soft gelatin capsule fill as herein disclosed in the third aspect, is used in adults who have severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids.

DESCRIPTION OF THE FIGURES

Figure 1 depicts the immediate release dissolution profile of a soft gelatin capsule which would be within some embodiments of the present invention.

Figure 2 depicts the dissolution profile of a soft gelatin capsule not having an immediate release effect.

Figure 3 depicts the particle size distribution of the active agent of the present invention. Horizontal axis: particle size in micrometers. Vertical axis: volume (%), indicating the percentage of particles with the corresponding particle size.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the hard fat free stable immediate release soft gelatin capsule as herein disclosed comprises the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid, wherein the soft gelatin capsule comprises a capsule shell and a fill, wherein the shell of the soft gelatin capsule comprises preferably a plastifying agent in an amount sufficient to plastify the shell without incurring in incompatibilities with the fill or in an amount less than 45% w/w in respect of the total amount of the shell, preferably the plastifying agent is sorbitol, propylene glycol, glycerol or mixtures thereof, and wherein the fill of the soft gelatin capsule comprises: the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated natural oils; wherein the total amount of the filling mixture of at a least two of the three following components, a first component, a second component and a third component or the total amount of the filling mixture of the first component present in the fill is more than 60 % w/w in respect to the total content of the fill or an amount sufficient to obtain a hard fat free stable immediate release soft gelatin capsule comprising the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid; with the proviso that if the fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the fill does not comprise a natural wax.

The filling mixture is the main part of the fill of the hard fat free stable immediate release soft gelatin capsule. Hard fats, also known as solid triglycerides, are the fats obtained through direct esterification of glycerol with defined fatty acid blends and have therefore precise properties regarding melting point, polarity (Hydroxyl Value) and consistency. Example of hard fats are the followings compounds: WITEPSOL H 5 ®. Hydrogenated Coco-Glycerides. Melting point ² C 34.0 to 36.0 max. Hydroxyl value (mg KOH/g) 5; WITEPSOL H 12 ®. Hydrogenated Coco- Glycerides. Melting point ² C 32.0 to 33.5. Hydroxyl value (mg KOH/g) 5 to 15; WITEPSOL H 15 ®. Hydrogenated Coco-Glycerides . Melting point ² C 33.5 to 35.5. Hydroxyl value (mg KOH/g) 5 to 15; WITEPSOL H 19 ®. Hydrogenated Coco-Glycerides+ Glyceryl Ricinoleate. Melting point ² C 33.5 to 35.5. Hydroxyl value (mg KOH/g) 20 to 30; WITEPSOL H 185 ®. Hydrogenated Coco-Glycerides. Melting point ² C 38.0 to 39.0. Hydroxyl value (mg KOH/g) 5 to 15; WITEPSOL H 32 ®. Hydrogenated Coco-Glycerides . Melting point ² C 31.0 to 33.0. Hydroxyl value (mg KOH/g) max. 3; WITEPSOL H 35 ®. Hydrogenated Coco-Glycerides . Melting point ² C 33.5 to 35.5. Hydroxyl value (mg KOH/g) max. 3; WITEPSOL H 37 ®. Hydrogenated Coco-Glycerides. Melting point ² C 36.0 to 38.0. Hydroxyl value (mg KOH/g) max. 3; WITEPSOL W 25 ®. Hydrogenated Coco-Glycerides. Melting point ² C 33.5 to 35.5. Hydroxyl value (mg KOH/g) 20 to 30; WITEPSOL W 31 ®. Hydrogenated Coco-Glycerides . Melting point ² C 35.5 to 37.0. Hydroxyl value (mg KOH/g) 25 to 35; WITEPSOL W 32 ®. Hydrogenated Coco-Glycerides. Melting point ² C 32.0 to 33.5. Hydroxyl value (mg KOH/g) 40 to 50; WITEPSOL W 35 ®. Hydrogenated Coco-Glycerides. Melting point ² C 33.5 to 35.5. Hydroxyl value (mg KOH/g) 40 to 50; WITEPSOL W 45 ®. Hydrogenated Coco- Glycerides. Melting point ² C 33.5 to 35.5 . Hydroxyl value (mg KOH/g) 40 to 50; WITEPSOL S 51 ®. Hydrogenated Coco-Glycerides + Ceteareth-25+ Glyceryl Ricinoleate" . Melting point ² C 30.0 to 32.0. Hydroxyl value (mg KOH/g) 55 to 70; WITEPSOL S 58 ®. Hydrogenated Coco-Glycerides + Ceteareth-25 + Glyceryl Ricinoleate. Melting point ² C 31.5 to 33.0. Hydroxyl value (mg KOH/g) 60 to 70; WITEPSOL E 75 ^* ®. Hydrogenated Coco-Glycerides + Bees Wax. ca. 38. Hydroxyl value (mg KOH/g) max. 15; WITEPSOL E 76 ®. Hydrogenated Coco-Glycerides. Melting point ² C 37.0 to 39.0. Hydroxyl value (mg KOH/g) 30 to 40; WITEPSOL E 85 ®. Hydrogenated Coco-Glycerides. Melting point ² C 42.0 to 44.0. Hydroxyl value (mg KOH/g) 5 to 15; MASSA ESTARINUM 299®. Hydrogenated Coco-Glycerides. Melting point 33.5 to 35.5 ² C. Hydroxyl value (mg KOH/g) 33.5 to 35.5 max. 2; MASSA ESTARINUM B®. Hydrogenated Coco-Glycerides. Melting point ² C 33.5 to 35.5. Hydroxyl value (mg KOH/g) 20 to 30; MASSA ESTARINUM BC ^* ®. Hydrogenated Coco-Glycerides + Glyceryl Ricinoleate. Melting point ² C 33.5 to 35.5. Hydroxyl value (mg KOH/g) 30 to 40; MASSA ESTARINUM C®. Hydrogenated Coco-Glycerides. Melting point ² C 36.0 to 38.0. Hydroxyl value (mg KOH/g) 20 to 30; SOFTISAN 378 ®. Hydrogenated Coco-Glycerides. Melting point ² C ~ 30. Hydroxyl value (mg KOH/g) 7 to 17; DYNACERIN CP ®. Cetyl Palmitate. Melting point ² C ~ 50. Hydroxyl value (mg KOH/g) max. 6; DYNASAN 114 ® Trimyristin. Melting point ² C 55 to 58; DYNASAN 118 ® Tristearin 21. Melting point ² C 70 to 74; DYNASAN P 60 ®. Hydrogenated Palm Oil USP-NF 58 to 62. Hydroxyl value (mg KOH/g) max. 10; SOFTISAN 154 ®. Hydrogenated Palm Oil. Melting point ² C 53 to 58. Hydroxyl value (mg KOH/g) max. 10; WITOCAN 42/44®. Hydrogenated Coco-Glycerides Melting point ² C 42 to 44. Hydroxyl value (mg KOH/g) max. 15.

The terms "substantially free of incompatible excipient(s)", "substantially free of hard fat" and "hard fat free" as used herein are intended to mean that the amount of incompatible excipient(s) Softisan® 378 (i.e. caprilic/capric/stearic triglycerides), present, if any, in the dosage form or pharmaceutical composition of the agent (2E,4E,6Z,8E)-3,7-dimethyl-9- (2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid is insufficient to cause the incompatibility discovered by the present inventors to detrimentally affect the stability of the dissolution profile of the pharmaceutical composition due to the presence of the particular excipient(s) Softisan ® 378 (i.e. caprilic/capric/stearic triglycerides), and when the composition is stored for 1 month at 40 ² C/75%RH the dissolution profile of the pharmaceutical composition still corresponds to an immediate release composition. Typically, the amount of any incompatible excipients that may be present in compositions of the present invention that are substantially free of incompatible excipients should be less than about 19% w/w in respect to of the total amount of the fill, preferably less than about 10% w/w, even more preferably, less than about 1% w/w and yet even more preferably the fill of the soft gelatin capsules as herein disclosed does not comprise Softisan ® 378. In a preferred embodiment, the total amount hard fats present in the pharmaceutical, if any, in the dosage form or pharmaceutical composition of the agent is insufficient to cause the incompatibility and the particular fat or fats discovered by the present inventors to detrimentally affect the stability of the dissolution profile of the pharmaceutical composition and when the composition is stored for 1 month at 40 ² C/75%RH the dissolution profile of the pharmaceutical composition still corresponds to an immediate release composition. Typically, the amount of any reactive excipients that may be present in compositions of the present invention that are substantially free of reactive substituents should be less than about 19% w/w in respect to of the total amount of the fill, preferably less than about 10% w/w, and even more preferably, less than about 1% w/w. Most preferably the pharmaceutical compositions of the present invention does not comprise any hard fat. In a preferred embodiment, the soft gelatin capsules as defined in the below clauses do not comprise any type of hard fat.

The capsule could comprise additional excipients as stabilizers (e.g. EDTA).

The soft gelatin capsules as herein disclosed are immediate release dosage forms. An immediate release dosage form as herein disclosed has to be understood as a dosage form having a dissolution performance such as 60 % or more of (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid contained in said pharmaceutical composition dissolves within 60 minutes. In a preferred embodiment, the immediate release composition as herein disclosed releases at least 80 % of (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid in 60 minutes. In another embodiment, the soft gelatin capsules as herein disclosed releases at least a 80 % in 45 min, preferably in 35 min and more preferably in 30 min. In another embodiment, the soft gelatin capsules as herein disclosed releases at least a 80 % in 15 min, and at least a 95 % in 60 min. In another embodiment, the soft gelatin capsules as herein disclosed releases at least a 80 % in 30 min and at least a 95 % in 60 min. The Figure 1 depicts the immediate release dissolution profile of a soft gelatin capsule which would be within some embodiments of the present invention. Figure 2 depicts the dissolution profile of a soft gelatin capsule not having an immediate release effect. The dissolution test for an immediate release soft gelatin capsule comprising (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid as herein disclosed is performed in the following conditions: USP Apparatus: I (Basket, with 20 mesh). Speed (RPMs): 100. Medium: 0.05 M potassium phosphate buffer, dibasic, pH 7.8, containing 0.5% solid LDAO (Lauryldimethylamine-oxide). The immediate release soft gelatin capsules as herein disclosed are stable immediate release soft gelatin capsules, what it means that the dissolution profile of the soft gelatin capsules as herein disclosed when the soft gelatin capsules as herein disclosed is stored for 1 month at 40 ² C/75%RH the dissolution profile of the soft gelatin capsules as herein disclosed still corresponds to an immediate release composition.

(2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid is also known as (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethylcyclohexen-1 -yl)nona-2,4,6,8-tetraenoic acid, 9-cis-retinoic acid or alitretinoin. Methods for the synthesis of (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid, i.e. 9-cis-retinoic acid, and similar compounds can be found in W09532946, WO9424082, E.J. Corey et al, J. Am. Chem. Soc. 90:5616 (1968); C.D.B. Bridges, R.A. Alvares (Meth. Enzymol. 81 :463 (1982)).

The antioxidant is preferably selected from DL-[alpha]-tocopherol, butylhydroxytoluene (BHT) and butylhydroxyanisole (BHA).

In another embodiment of the first aspect, the hard fat free stable immediate release soft gelatin capsule as herein disclosed comprises the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid, wherein the soft gelatin capsule consists essentially of a capsule shell and a fill, wherein the shell of the soft gelatin capsule comprises preferably a plastifying agent in an amount sufficient to plastify the shell without incurring in incompatibilities with the fill or in an amount less than 45% w/w in respect of the total amount of the shell, preferably the plastifying agent is sorbitol, propylene glycol, glycerol or mixtures thereof, and wherein the fill of the soft gelatin capsule comprises: the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9- (2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated natural oils; wherein the total amount of the filling mixture of at a least two of the three following components, a first component, a second component and a third component or the total amount of the filling mixture of the first component present in the fill is more than 60 % w/w in respect to the total content of the fill or an amount sufficient to obtain a hard fat free stable immediate release soft gelatin capsule comprising the agent (2E,4E,6Z,8E)-3,7-dimethyl- 9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; with the proviso that if the fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the fill does not comprise a natural wax.

In another embodiment of the first aspect, the hard fat free stable immediate release soft gelatin capsule as herein disclosed comprises the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid, wherein the soft gelatin capsule comprises a capsule shell and a fill, wherein the shell of the soft gelatin capsule comprises preferably a plastifying agent in an amount sufficient to plastify the shell without incurring in incompatibilities with the fill or in an amount less than 45% w/w in respect of the total amount of the shell, preferably the plastifying agent is sorbitol, propylene glycol, glycerol or mixtures thereof, and wherein the fill of the soft gelatin capsule comprises: the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; a filling mixture of at a least two of the three following components, a first component, a second component and a third component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated natural oils; wherein the total amount of the filling mixture of at a least two of the three following components, a first component, a second component and a third component or the total amount of the filling mixture of the first component present in the fill is more than 60 % w/w in respect to the total content of the fill or an amount sufficient to obtain a hard fat free stable immediate release soft gelatin capsule comprising the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid; with the proviso that if the fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the fill does not comprise a natural wax.

In another embodiment of the first aspect, the hard fat free stable immediate release soft gelatin capsule as herein disclosed comprises the agent (2E,4E,6Z,8E)-3,7-dimethyl-9- (2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid, wherein the soft gelatin capsule comprises a capsule shell and a fill, wherein the shell of the soft gelatin capsule comprises preferably a plastifying agent in an amount sufficient to plastify the shell without incurring in incompatibilities with the fill or in an amount less than 45% w/w in respect of the total amount of the shell, preferably the plastifying agent is sorbitol, propylene glycol, glycerol or mixtures thereof, and wherein the fill of the soft gelatin capsule comprises: the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the total amount of the filling mixture of the first component present in the fill is more than 60 % w/w in respect to the total content of the fill or an amount sufficient to obtain a hard fat free stable immediate release soft gelatin capsule comprising the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid; with the proviso that if the fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the fill does not comprise a natural wax.

In a preferred embodiment of the soft gelatin capsule as herein disclosed, the filling mixture consists of the first component, preferably soybean oil, and the fill of the capsule does not comprise neither a second component nor a third component.

In another embodiment of the soft gelatin capsules as herein disclosed, the fill of the soft gelatin capsule does not comprise any natural wax or, wherein the fill of the soft gelatin capsule comprises natural wax and the total amount of natural wax or natural waxes is less than 3 % w/w in respect of the total amount of the fill. In another embodiment of the soft gelatin capsules as herein disclosed, the fill of the soft gelatin capsule does not comprise any natural wax or, wherein the fill of the soft gelatin capsule comprises natural wax and the total amount of natural wax or natural waxes is less than 1 % w/w in respect of the total amount of the fill. In another embodiment of the soft gelatin capsules as herein disclosed, the fill of the soft gelatin capsule does not comprise any natural wax or, wherein the fill of the soft gelatin capsule comprises natural wax and the total amount of natural wax or natural waxes is less than 0.5 % w/w in respect of the total amount of the fill. In another embodiment of the soft gelatin capsules as herein disclosed, the fill of the soft gelatin capsule does not comprise any natural wax.

The soft gelatin capsule as herein disclosed are preferably natural wax-free. That means that the soft gelatin capsules as herein disclosed preferably do not comprise a natural wax, or if they do, it is in an amount which do not affect the behaviour of the pharmaceutical composition. In a preferred embodiment, the content of natural wax or natural waxes present in the soft gelatin capsules is less than 3 % w/w in respect of the total amount of the fill. In another preferred embodiment, the content of natural wax or natural waxes present in the soft gelatin capsules is less than 1 % w/w in respect of the total amount of the fill. In another preferred embodiment, the content of natural wax or natural waxes present in the soft gelatin capsules is less than 0.5 % w/w in respect of the total amount of the fill. In a preferred embodiment, the composition does not comprise a natural wax. Natural waxes are natural occurring waxes. Natural occurring waxes include beeswax (i.e. yellow wax). Natural waxes can be understood opposite to synthetic waxes.

In another embodiment of the soft gelatin capsules as herein disclosed, the shell is between about 15 and about 55 % w/w of the total amount of the immediate release soft gelatin capsule and the fill is between about 40 to about 85 % w/w of the total amount of the immediate release soft gelatin capsule. In another embodiment of the soft gelatin capsules as herein disclosed, the shell is between about 20 and about 45 % w/w of the total amount of the immediate release soft gelatin capsule and the fill is between about 50 to about 80 % w/w of the total amount of the immediate release soft gelatin capsule. In another embodiment of the soft gelatin capsules as herein disclosed, the shell is between about 25 and about 35 % w/w of the total amount of the immediate release soft gelatin capsule and the fill is between about 60 to about 75 % w/w of the total amount of the immediate release soft gelatin capsule.

The shell of the soft gelatin capsule generally comprises gelatin, a plastifying agent and water therein as the main components. Accordingly, the soft gelatin capsule can be normally kept in satisfactory conditions, so far as the water content of the shell is maintained within a certain range. The water content is preferably maintained in the range from about 5 to about 15 % for shell of a soft capsule. However, the water content of the soft capsule is apt to vary depending upon the circumferential conditions to deviate from the above-mentioned preferred range in the- course of lapse of time. If the water content reaches to so high level as to exceed the upper limit of the preferred range, the shell becomes wet to soften. Moreover, the soft capsules are apt to stick to each other to form an aggregated mass. On the other hand, if the water content reaches to a low level below the above-mentioned lower limit, the shell hardens to produce cracks therein. The soft capsule under these conditions shows poor lubricity and glidability so that the operations for packing the capsules cannot be carried out smoothly.

Soft Gelatin Capsules are manufactured using a gelatin solution that is plasticized, preferably with propylene glycol, sorbitol, glycerin or various approved mixtures thereof. Soft gelatin capsules as herein disclosed can be manufacture-formed, filled and sealed in one continuous operation.

In another embodiment of the soft gelatin capsules as herein disclosed, the shell of the soft gelatin capsule comprises no more than 42% w/w in respect of the total amount of the shell of a at least one plastifying agent. As used herein, a plastifying agent can be a mixture of different components. In another embodiment of the soft gelatin capsules as herein disclosed, preferably the shell of the soft gelatin capsule comprises between 20 % and 40% w/w in respect of the total amount of the shell of a at least one plastifying agent. In another embodiment of the soft gelatin capsules as herein disclosed, the shell of the soft gelatin capsule comprises between 25 % and 35% w/w in respect of the total amount of the shell of a at least one plastifying agent. In another embodiment of the soft gelatin capsules as herein disclosed, the shell of the soft gelatin capsule comprises about 30 % in respect of the total amount of the shell of a at least one plastifying agent. In another embodiment of the soft gelatin capsules as herein disclosed, the shell comprises a plastifying agent selected from sorbitol, propylene glycol, glycerol and mixtures thereof. In another embodiment of the soft gelatin capsules as herein disclosed, the shell comprises a plastifying agent selected from sorbitol, glycerol and mixtures thereof. In another embodiment of the soft gelatin capsules as herein disclosed, the shell comprises a plastifying agent and the plastifying agent is a mixture of sorbitol and glycerol.

In another embodiment of the soft gelatin capsules as herein disclosed, the antioxidant or antioxidants present in the fill are selected from DL-[alpha]-tocopherol, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA) and mixtures thereof. In another embodiment of the soft gelatin capsules as herein disclosed, the antioxidant or antioxidants present in the fill are selected from DL-[alpha]-tocopherol, butylhydroxytoluene (BHT) and mixtures thereof. In another embodiment of the soft gelatin capsules as herein disclosed, the antioxidant or the mixture of antioxidants present in the fill comprises DL-[alpha]-tocopherol. In another embodiment of the soft gelatin capsules as herein disclosed, the antioxidant or the mixture of antioxidants present in the fill consists of DL-[alpha]-tocopherol.

In another embodiment of the soft gelatin capsules as herein disclosed, the total amount of antioxidant or mixture of antioxidants present in the soft gelatin capsule is less than 0.5 % w/w in respect of the total amount of the fill. In another embodiment of the soft gelatin capsules as herein disclosed, the total amount of antioxidant or mixture of antioxidants present in the soft gelatin capsule is less than 0.05 % w/w in respect of the total amount of the fill. In another embodiment of the soft gelatin capsules as herein disclosed, the total amount of antioxidant or mixture of antioxidants present in the soft gelatin capsule is about 0.01 % w/w in respect of the total amount of the fill.

In another embodiment of the soft gelatin capsules as herein disclosed, the total amount of the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid present in the soft gelatin capsule is less than 20 % w/w in respect of the total amount of the fill.

In another embodiment of the soft gelatin capsules as herein disclosed, the total amount of the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid present in the soft gelatin capsule is between 0.2 % and 18 % w/w in respect of the total amount of the fill. In another embodiment of the soft gelatin capsules as herein disclosed, the total amount of the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid present in the soft gelatin capsule is between 1 % and 14 % w/w in respect of the total amount of the fill. In another embodiment of the soft gelatin capsules as herein disclosed, the total amount of the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid present in the soft gelatin capsule is between about 3 % and about 11 % w/w in respect of the total amount of the fill. In another embodiment of the soft gelatin capsules as herein disclosed, the total amount of the agent (2E,4E,6Z,8E)- 3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid present in the soft gelatin capsule is 10 mg. In another embodiment of the soft gelatin capsules as herein disclosed, the total amount of the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid present in the soft gelatin capsule is 30 mg.

In another embodiment of the soft gelatin capsules as herein disclosed, the agent (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid is micronized. As used herein, the term "micronization" refers to a decrease in particle size through application of force to a particle, resulting in the break-up of the particle. Such force may be applied by collision of particles at high speeds. In another embodiment of the soft gelatin capsules as herein disclosed, the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1- cyclohexenyl)nona- 2,4,6, 8-tetraenoic acid has a D50 of 8 microns and/or a D90 of 20 microns measured by laser diffraction spectroscopy. D50 and D90 represent the 50 percentile and the 90 percentile of the particle size volume distribution. That is, D50 (D90) is a value on the distribution such that 50 % (90 %) of the particles has a particle size of this value or less. In another embodiment of the soft gelatin capsules as herein disclosed, the agent (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid has a D50 of 4 microns and/or a D90 of 10 microns measured by laser diffraction spectroscopy. In another embodiment of the soft gelatin capsules as herein disclosed, the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid has a D50 of 2 microns and/or a D90 of 5 microns measured by laser diffraction spectroscopy. The active agent having a particle size distribution with a D50 of 8 microns or less, and/or a D90 of 20 microns or less, gives a better fill mass. The use of the micronized active agent allows the filling process into the capsules to be improved.

In another embodiment of the soft gelatin capsules as herein disclosed, the capsules comprise glyceryl behenate or glyceryl distearate. Preferably the glyceryl behenate or glyceryl distearate is in the fill. In another embodiment of the soft gelatin capsules as herein disclosed, the capsules comprise less than 3.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate or glyceryl distearate. In another embodiment of the soft gelatin capsules as herein disclosed, the capsules comprise less than 1.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate or glyceryl distearate. In another embodiment of the soft gelatin capsules as herein disclosed, the capsules comprise glyceryl behenate. In another embodiment of the soft gelatin capsules as herein disclosed, the capsules comprise less than 3.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate. In another embodiment of the soft gelatin capsules as herein disclosed, the capsules comprise less than 1.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate.

In another embodiment of the soft gelatin capsules as herein disclosed, the first component comprises at least one natural vegetable oil or mixtures of natural vegetable oils. In another embodiment of the soft gelatin capsules as herein disclosed, the first component is a natural vegetable oil or mixtures of natural vegetable oils. In another embodiment of the soft gelatin capsules as herein disclosed, the first component comprises olive oil, soybean oil, sesame oil, sunflower oil, safflower oil, rapeseed oil or mixtures thereof. In another embodiment of the soft gelatin capsules as herein disclosed, the first component is olive oil, soybean oil, sesame oil, sunflower oil, safflower oil, rapeseed oil or mixtures thereof. In another embodiment of the soft gelatin capsules as herein disclosed, the first component comprises soybean oil. In another embodiment of the soft gelatin capsules as herein disclosed, the first component is soybean oil.

Example of oily substances to be used in the present invention may be substances such as natural vegetable oils. Natural vegetable oils are lipid materials derived from plants. Physically, oils are liquid at room temperature. The melting temperature distinction between oils is normally imprecise, since definitions of room temperature vary, and typically natural oils have a melting range instead of a single melting point since natural oils are not normally chemically homogeneous. Preferred examples of oily substances are olive oil, soybean oil, sesame oil, sunflower oil, safflower oil and rapeseed oil. Most preferred, oily substance is soybean oil.

The melting points of the component present in the pharmaceutical compositions as herein disclosed can be measured according to The International Pharmacopoeia Fourth Edition - Second Supplement. Method of analysis. 1. Physicochemical Methods. 1.2. Determination of melting temperature and melting range. 1.2.1 Melting temperature and melting range (B). In another embodiment of the soft gelatin capsules as herein disclosed, the second component comprises at least one liquid lipid with a viscosity mPa-s 20° C between 5 and 40 or mixtures of liquid lipids with viscosities mPa -s 20° C between 5 and 40. The viscosity can be measured according to the European Pharmacopeia 5.0 2.2.9 capillary viscometer method.

In another embodiment of the soft gelatin capsules as herein disclosed, the second component is at least one liquid lipid with a viscosity mPa -s 20° C between 5 and 40 or mixtures of liquid lipids with viscosities mPa -s 20° C between 5 and 40. In another embodiment of the soft gelatin capsules as herein disclosed, the second component comprises at least liquid lipid with a viscosity mPa -s 20° C between 15 and 35 or mixtures of liquid lipids with viscosities mPa -s 20° C between 15 and 35. In another embodiment of the soft gelatin capsules as herein disclosed, the second component is at least one liquid lipid with a viscosity mPa -s 20° C between 15 and 35 or mixtures of liquid lipids with viscosities mPa -s 20° C between 15 and 35. In another embodiment of the soft gelatin capsules as herein disclosed, the second component comprises at least one liquid lipid with a viscosity mPa -s 20° C between 20 and 30 or mixtures of liquid lipids with viscosities mPa -s 20° C between 20 and 30. In another embodiment of the soft gelatin capsules as herein disclosed, the second component is at least one liquid lipid with a viscosity mPa -s 20° C between 20 and 30 or mixtures of liquid lipids with viscosities mPa -s 20° C between 20 and 30. In another embodiment of the soft gelatin capsules as herein disclosed, the second component comprises a liquid lipid wherein said liquid lipid is a mixture of triglycerides of the fractionated vegetable fatty acids C8 and C10. In another embodiment of the soft gelatin capsules as herein disclosed, the second component is a liquid lipid wherein said liquid lipid is a mixture of triglycerides of the fractionated vegetable fatty acid C8 and C10. In another embodiment of the soft gelatin capsules as herein disclosed, the second component comprises Miglyol 812. In another embodiment of the soft gelatin capsules as herein disclosed, the second component is Miglyol 812.

The term "liquid lipid" as herein used refers to liquid lipids are fatty acid esters or alcohols (2- Octyldodecanol). They are neutral carriers for various pharmaceutical applications. Because of their high polarity, they have superior solvent characteristics for active drugs (compared to hydrocarbons). Example of liquid lipids are C8/C10 esters as : MIGLYOL 808 ® Tricaprylin oily liquid. Viscosity mPa -s 20° C ~ 23; MIGLYOL 810 ® Caprylic / Capric Triglyceride, oily liquid. Viscosity mPa -s 20° C ~ 26; MIGLYOL 812 ® Caprylic / Capric Triglyceride, oily liquid. Viscosity mPa -s 20° C ~ 28; MIGLYOL 818 ® Caprylic / Capric/Linoleic Triglyceride. Oily liquid. Viscosity mPa -s 20° C ~ 33; MIGLYOL 829 ® Caprylic / Capric/Succinic Triglyceride. Oily liquid. Viscosity mPa -s 20° C ~ 300; MIGLYOL 8108 ® Caprylic / Capric Triglyceride. Oily liquid. Viscosity mPa -s 20° C ~ 25; MIGLYOL 840 ® Propylene Glycol Dicaprylate / Dicaprate. Oily liquid. Viscosity mPa -s 20° C ~ 10; MIGLYOL 8810 ® Butylene Glycol Dicaprylate / Dicaprate. Oily liquid Viscosity mPa -s 20° C ~ 11 ; DYNACET 285 ® Diacetylated Monoglycerides. Oily liquid. Viscosity mPa -s 20° C ~ 30. Other esters: DYNACERIN 660 ® Oleyl Erucate. Oily liquid. Viscosity mPa -s 20° C ~ 30; DYNACERIN CAP ® Cetearyl Ethylhexanoate (and) Isopropylmyristate. Oily liquid. Viscosity mPa -s 20° C ~ 13; DYNACERIN DO ® Decyloleate. Oily liquid Viscosity mPa -s 20° C ~ 18; MIGLYOL 612 © Glyceryl Trihexanoate. Oily liquid. Viscosity mPa -s 20° C ~ 15; Spezialol 107 ® Triheptanoin. Oily liquid. Viscosity mPa -s 20° C ~ 20. Preferred oily liquid are those with a Viscosity mPa -s 20° C between 5 and 40, more preferably between 15 and 35, and even more preferably between 20 and 30. The one of the most preferred liquid lipid is Miglyol 812. The composition of the Miglyol 812 is the following: Caproic max. 2.0; caprylic acid 50.0-60 %; capric acid 30.0-45.0%. In another embodiment of the soft gelatin capsules as herein disclosed, the third component comprises at least one partially hydrogenated oil selected from the list consisting of partially hydrogenated fish oil, partially hydrogenated animal oil, partially hydrogenated palm oil, partially hydrogenated high erucic acid rapeseed oil, partially hydrogenated sunflower oil, partially hydrogenated corn oil, partially hydrogenated peanut oil, partially hydrogenated safflower oil, partially hydrogenated olive oil, partially hydrogenated palm stearin, partially hydrogenated cotton seed oil, partially hydrogenated soybean oil, and mixtures thereof. In another embodiment of the soft gelatin capsules as herein disclosed, the third component is a partially hydrogenated oil selected from the list consisting of partially hydrogenated fish oil, partially hydrogenated animal oil, partially hydrogenated palm oil, partially hydrogenated high erucic acid rapeseed oil, partially hydrogenated sunflower oil, partially hydrogenated corn oil, partially hydrogenated peanut oil, partially hydrogenated safflower oil, partially hydrogenated olive oil, partially hydrogenated palm stearin, partially hydrogenated cotton seed oil, partially hydrogenated soybean oil, or mixtures thereof. In another embodiment of the soft gelatin capsules as herein disclosed, the third component comprises at least one partially hydrogenated oil selected from the list consisting of partially hydrogenated palm oil, partially hydrogenated sunflower oil, partially hydrogenated corn oil, partially hydrogenated peanut oil, partially hydrogenated safflower oil, partially hydrogenated olive oil, partially hydrogenated cotton seed oil, partially hydrogenated soybean oil, and mixtures thereof. In another embodiment of the soft gelatin capsules as herein disclosed, the third component is one partially hydrogenated oil selected from the list consisting of partially hydrogenated palm oil, partially hydrogenated sunflower oil, partially hydrogenated corn oil, partially hydrogenated peanut oil, partially hydrogenated safflower oil, partially hydrogenated olive oil, partially hydrogenated cotton seed oil, partially hydrogenated soybean oil, or mixtures thereof. In another embodiment of the soft gelatin capsules as herein disclosed, the third component comprises partially hydrogenated soybean oil. In another embodiment of the soft gelatin capsules as herein disclosed, the third component is partially hydrogenated soybean oil.

In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises a mixture of the first component and of the second component. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture is a mixture of the first component and of the second component. In a preferred embodiment of the soft gelatin capsule as herein disclosed, the filling mixture is a mixture of the first component and the second component and the fill of the capsule does not comprise the third component.

In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises between 50 to 98 % w/w of the first component and between 2 to 50 % w/w of the second component. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises between 60 to 95 % w/w of the first component and between 5 to 40 % w/w of the second component. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises between 70 to 90 % w/w of the first component and between 10 to 30 % w/w of the second component.

In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises a mixture of the first component and of the third component. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture is a mixture of the first component and of the third component. In a preferred embodiment of the soft gelatin capsule as herein disclosed, the filling mixture is a mixture of the first component and the third component and the fill of the capsule does not comprise the second component. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises between 40 to 95 % w/w of the first component and between 5 to 60 % w/w of the third component. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises between 50 to 90 % w/w of the first component and between 10 to 50 % w/w of the third component. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises between 60 to 80 % w/w of the first component and between 20 to 40 % w/w of the third component.

In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises a mixture of the second component and of the third component. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture is a mixture of the second component and of the third component. In a preferred embodiment of the soft gelatin capsule as herein disclosed, the filling mixture is a mixture of the second component and the third component and the fill of the capsule does not comprises first component.

In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises between 40 to 95 % w/w of the second component and between 5 to 60 % w/w of the third component. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises between 50 to 90 % w/w of the second component and between 10 to 50 % w/w of the third component. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises between 60 to 80 % w/w of the second component and between 20 to 40 % w/w of the third component.

In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises a mixture of the first component, the second component and the third component. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises between 30 to 94 % w/w of the first component, between 0.1 to 40 % w/w of the second component, and between 5 to 60 % w/w of the third component. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises between 45 to 85 % w/w of the first component, between 2 to 25 % w/w of the second component, and between 10 to 45 % w/w of the third component. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture comprises between 60 to 70 % w/w of the first component, between 5 to 15 % w/w of the second component, and between 20 to 30 % w/w of the third component.

In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture present in the fill is more than 75 % w/w in respect to the total content of the fill. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture present in the fill is more than 83 % w/w in respect to the total content of the fill. In another embodiment of the soft gelatin capsules as herein disclosed, the filling mixture present in the fill is more than 88 % w/w in respect to the total content of the fill.

In another embodiment of the soft gelatin capsules as herein disclosed, the fill of the soft gelatin capsule comprises hydrogenated castor oil. In another embodiment of the soft gelatin capsules as herein disclosed, the fill of the soft gelatin capsule comprises between a 0.5 % and a 8 % w/w of hydrogenated castor oil.

In another aspect, the stable immediate release soft gelatin capsule as herein disclosed comprises the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid, wherein the soft gelatin capsule comprises a capsule shell and a fill, and wherein the fill of the soft gelatin capsule comprises micronized (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid. In a preferred embodiment, the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid has a D50 of 8 microns and/or a D90 of 20 microns measured by laser diffraction spectroscopy. In another embodiment, the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid has a D50 of 4 microns and/or a D90 of 10 microns measured by laser diffraction spectroscopy. In another embodiment, the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid has a D50 of 2 microns and/or a D90 of 5 microns measured by laser diffraction spectroscopy. The micronized active agent improves the soft gelatin capsules, for example, their stability, especially when the soft gelatin capsules comprise glyceryl behenate, preferably less than 1 % w/w glyceryl behenate in respect of the total amount of the fill.

In another embodiment of the soft gelatin capsules as herein disclosed, the soft gelatin capsule comprises glyceryl behenate or glyceryl distearate. In another embodiment, the soft gelatin capsule comprises less than 3.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate or glyceryl distearate. In another embodiment, the soft gelatin capsule comprises less than 1.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate or glyceryl distearate. In another embodiment, the soft gelatin capsule comprises glyceryl behenate. In another embodiment, the soft gelatin capsule comprises less than 3.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate. In another embodiment, the soft gelatin capsule comprises less than 1.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate. Preferably the glyceryl behenate or glyceryl distearate is in the fill.

In another aspect, a process for the preparation of a stable immediate release soft gelatin capsule comprising micronized (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid as herein disclosed, comprising the steps of (i) preparing a soft gelatin capsule fill comprising micronized (2E,4E,6Z,8E)- 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)nona-2,4,6,8- tetraenoic acid and preferably comprising glyceryl behenate, more preferably comprising less than 1.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate; (ii) filling a soft gelatin capsule with the fill as prepared in step (i) forming the soft gelatin capsule; and (iii) optionally drying the soft gelatin capsules.

In another aspect, (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid wherein said (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid is micronized. In one embodiment, the micronized (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona- 2,4,6,8-tetraenoic acid has a D50 of 8 microns and/or a D90 of 20 microns measured by laser diffraction spectroscopy. Preferably, it has a D50 of 4 microns and/or a D90 of 10 microns measured by laser diffraction spectroscopy. More preferably, it has a D50 of 2 microns and/or a D90 of 5 microns measured by laser diffraction spectroscopy.

In another aspect, the micronized (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona- 2,4,6,8-tetraenoic acid as herein disclosed is used for the preparation of a soft gelatin capsule fill or of a soft gelatin capsule. Better results are obtained when micronized active agent is used, especially when the soft gelatin capsules also comprise glyceryl behenate, preferably in a proportion of less than 1.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule. In a second aspect, the process for the preparation of hard fat free stable immediate release soft gelatin capsules containing the same agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid as defined in the first aspect, as herein disclosed, comprises at least the following steps:

i) preparing a soft gelatin capsule fill comprising mixing the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6- trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; and a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax;

ii) filling a soft gelatin capsule with the fill as prepared in step (i) forming the soft gelatin capsule;

iii) optionally drying the soft gelatin capsules.

Normally, step (i) comprises mixing the components of the filling mixture until dissolved or until an homogeneous mixture is formed, followed by mixing the antioxidant or antioxidants and the agent (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid.

The antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time, are those which can decrease the decomposition rate of the (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona- 2,4,6,8-tetraenoic acid over time once the fill is encapsulated.

In a preferred embodiment, the process for the preparation of hard fat free stable immediate release soft gelatin capsules containing the same agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona- 2,4,6,8-tetraenoic acid as defined in the first aspect, as herein disclosed, comprises at least the following steps: i) preparing a soft gelatin capsule fill comprising mixing the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6- trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; and a filling mixture of at a least two of the three following components, a first component, a second component and a third component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax;

ii) filling a soft gelatin capsule with the fill as prepared in step (i) forming the soft gelatin capsule;

iii) optionally drying the soft gelatin capsules. In a preferred embodiment, the process for the preparation of hard fat free stable immediate release soft gelatin capsules containing the same agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona- 2,4,6, 8-tetraenoic acid as defined in the first aspect, as herein disclosed, comprises at least the following steps: i) preparing a soft gelatin capsule fill comprising mixing the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6- trimethyl-1 -cyclohexenyl)nona-2 , 4,6, 8-tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2, 4,6, 8-tetraenoic acid over time; and a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax;

ii) filling a soft gelatin capsule with the fill as prepared in step (i) forming the soft gelatin capsule;

iii) optionally drying the soft gelatin capsules.

In another embodiment of the process for the preparation of hard fat free stable immediate release soft gelatin capsules as herein disclosed, the step (ii) comprises encapsulating the soft gelatin capsule fill as prepared in step (i) using a rotary die and producing the soft gelatin capsule.

In another embodiment of the process for the preparation of hard fat free stable immediate release soft gelatin capsules as herein disclosed, to form the soft gelatin capsule according to the first aspect.

The soft gelatin capsules as herein disclosed can be manufactured by the following process: the soft gelatin encapsulation process starts with the preparation of two sheets called ribbons of gelatin from a molten gelatin mass. Then, each of the gelatin ribbons is passed over a die of the desired capsule shape and size and the capsule is formed at the point where the two rotating dies meet. When the capsule is formed, it is filled with a liquid that contains the active ingredient in a vehicle and it is washed to remove the lubricants used in the process and dried.

A more detailed description of how to manufacture soft gelatin capsules may be found in Ebert, "Soft Elastic Gelatin Capsules: A Unique Dosage Form" Pharmaceutical Technology, October 1977 and in "The Theory and Practice of Industrial Pharmacy", Chapter 13, Lachman et al., published by Lea and Febiger, 1970.

In a third aspect, the soft gelatin capsule fill for the manufacture of immediate release soft gelatin capsules, as herein disclosed, comprises the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4, 6, 8-tetraenoic acid over time; a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax.

In another embodiment of the soft gelatin capsule fill as herein disclosed, the soft gelatin capsule fill consists essentially of the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1- cyclohexenyl)nona-2,4,6,8- tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; a filling mixture of at a least two of the three following components or a filling mixture of the following first component, a first component, a second component and a third component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax.

In another embodiment of the soft gelatin capsule fill as herein disclosed, the soft gelatin capsule fill consists of the agent (2E,4E,6Z,8E)-3,7-dimethyl-9- (2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax.

In a fourth aspect, the process for the preparation of the fill of the third aspect, as herein disclosed, is by mixing the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9- (2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; and a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax.

In another aspect, the process for the preparation of a hard fat free stable immediate release soft gelatin capsule containing the agent (2E,4E,6Z,8E)-3,7-dimethyl-9- (2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid, as herein disclosed, is by encapsulating the soft gelatin capsule fill produced according to the second aspect or the soft gelatin capsule fill of the third aspect and forming the soft gelatin capsule. In a preferred embodiment, the soft gelatin capsule is formed by using a rotary die and producing the soft gelatin capsule. In a preferred embodiment, the soft gelatin capsules of the first aspect are formed.

Another aspect is a hard fat free soft gelatin capsule as obtained by any one of the processes for the preparation of a hard fat free stable immediate release soft gelatin capsule containing the agent (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid, as herein disclosed.

Another aspect is the use of the hard fat free soft gelatin capsule as herein disclosed in the first aspect and other aspects, or the soft gelatin capsule fill as herein disclosed in the third aspect, for skin lesions in a human being. Another aspect is the use of the soft gelatin capsule fill comprising micronized (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6- trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid as herein disclosed, or of the soft gelatin capsule comprising micronized (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid as herein disclosed, for skin lesions in a human being. In a preferred embodiment, the skin lesion is eczema. In a preferred embodiment, the hard fat soft gelatin capsule as herein disclosed in the first aspect and other aspects, or the soft gelatin capsule fill as herein disclosed in the third aspect, is used in adults who have severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids.

Further aspects and embodiments of the present invention can be found in the following numbered clauses: 1. A hard fat free stable immediate release soft gelatin capsule comprising the agent (2E,4E,6Z,8E)-3,7-dimethyl-9- (2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid, wherein the soft gelatin capsule comprises a capsule shell and a fill, and wherein the fill of the soft gelatin capsule comprises: the agent (2E,4E,6Z,8E)-3,7-dimethyl-9- (2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated natural oils; wherein the total amount of the filling mixture of at a least two of the three following components, a first component, a second component and a third component or the total amount of the filling mixture of the first component present in the fill is more than 60 % w/w in respect to the total content of the fill or an amount sufficient to obtain a hard fat free stable immediate release soft gelatin capsule comprising the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; with the proviso that if the fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the fill does not comprise a natural wax.

2. The soft gelatin capsule according to the preceding clause, wherein the fill of the soft gelatin capsule does not comprise any natural wax or, wherein the fill of the soft gelatin capsule comprises natural wax and the total amount of natural wax or natural waxes is less than 3 % w/w in respect of the total amount of the fill.

3. The soft gelatin capsule according to any one of the preceding clauses, wherein the fill of the soft gelatin capsule does not comprise any natural wax or, wherein the fill of the soft gelatin capsule comprises natural wax and the total amount of natural wax or natural waxes is less than 1 % w/w in respect of the total amount of the fill. 4. The soft gelatin capsule according to any one of the preceding clauses, wherein the fill of the soft gelatin capsule does not comprise any natural wax or, wherein the fill of the soft gelatin capsule comprises natural wax and the total amount of natural wax or natural waxes is less than 0.5 % w/w in respect of the total amount of the fill. 5. The soft gelatin capsule according to any one of the preceding clauses, wherein the fill of the soft gelatin capsule does not comprise any natural wax.

6. The soft gelatin capsule according to any one of the preceding clauses, wherein the shell is between about 15 and about 55 % w/w of the total amount of the immediate release soft gelatin capsule and the fill is between about 40 to about 85 % w/w of the total amount of the immediate release soft gelatin capsule.

7. The soft gelatin capsule according to any one of the preceding clauses, wherein the shell is between about 20 and about 45 % w/w of the total amount of the immediate release soft gelatin capsule and the fill is between about 50 to about 80 % w/w of the total amount of the immediate release soft gelatin capsule.

8. The soft gelatin capsule according to any one of the preceding clauses, wherein the shell is between about 25 and about 35 % w/w of the total amount of the immediate release soft gelatin capsule and the fill is between about 60 to about 75 % w/w of the total amount of the immediate release soft gelatin capsule.

9. The soft gelatin capsule according to any one of the preceding clauses, wherein the shell of the soft gelatin capsule comprises no more than 42% w/w in respect of the total amount of the shell of a at least one plastifying agent. 10. The soft gelatin capsule according to any one of the preceding clauses, wherein preferably the shell of the soft gelatin capsule comprises between 20 % and 40% w/w in respect of the total amount of the shell of a at least one plastifying agent.

11. The soft gelatin capsule according to any one of the preceding clauses, wherein the shell of the soft gelatin capsule comprises between 25 % and 35% w/w in respect of the total amount of the shell of a at least one plastifying agent.

12. The soft gelatin capsule according to any one of the preceding clauses, wherein the shell of the soft gelatin capsule comprises about 30 % in respect of the total amount of the shell of a at least one plastifying agent.

13. The soft gelatin capsule according to any one of the preceding clauses, wherein the shell comprises a plastifying agent selected from sorbitol, propylene glycol, glycerol and mixtures thereof.

14. The soft gelatin capsule according to any one of the preceding clauses, wherein the shell comprises a plastifying agent selected from sorbitol, glycerol and mixtures thereof.

15. The soft gelatin capsule according to any one of the preceding clauses, wherein the shell comprises a plastifying agent and the plastifying agent is a mixture of sorbitol and glycerol. 16. The soft gelatin capsule according to any one of the preceding clauses, wherein the antioxidant or antioxidants present in the fill are selected from DL-[alpha]-tocopherol, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA) and mixtures thereof.

17. The soft gelatin capsule according to any one of the preceding clauses, wherein the antioxidant or antioxidants present in the fill are selected from DL-[alpha]-tocopherol, butylhydroxytoluene (BHT) and mixtures thereof.

18. The soft gelatin capsule according to any one of the preceding clauses, wherein the antioxidant or the mixture of antioxidants present in the fill comprises, preferably consists of, DL-[alpha]-tocopherol.

19. The soft gelatin capsule according to any one of the preceding clauses, wherein the total amount of antioxidant or mixture of antioxidants present in the soft gelatin capsule is less than 0.5 % w/w in respect of the total amount of the fill.

20. The soft gelatin capsule according to any one of the preceding clauses, wherein the total amount of antioxidant or mixture of antioxidants present in the soft gelatin capsule is less than 0.05 % w/w in respect of the total amount of the fill. 21. The soft gelatin capsule according to any one of the preceding clauses, wherein the total amount of antioxidant or mixture of antioxidants present in the soft gelatin capsule is about 0.01 % w/w in respect of the total amount of the fill.

22. The soft gelatin capsule according to any one of the preceding clauses, wherein the total amount of the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid present in the soft gelatin capsule is less than 20 % w/w in respect of the total amount of the fill.

23. The soft gelatin capsule according to any one of the preceding clauses, wherein the total amount of the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid present in the soft gelatin capsule is between 0.2 % and 18 % w/w in respect of the total amount of the fill.

24. The soft gelatin capsule according to any one of the preceding clauses, wherein the total amount of the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid present in the soft gelatin capsule is between 1 % and 14 % w/w in respect of the total amount of the fill. 25. The soft gelatin capsule according to any one of the preceding clauses, wherein the total amount of the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid present in the soft gelatin capsule is between about 3 % and about 11 % w/w in respect of the total amount of the fill. 26. The soft gelatin capsule according to any one of the preceding clauses, wherein the agent (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid is micronized.

27. The soft gelatin capsule according to any of the preceding clauses, wherein the agent (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid has a D50 of 8 microns and/or a D90 of 20 microns measured by laser diffraction spectroscopy.

28. The soft gelatin capsule according to any of the preceding clauses, wherein the agent (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid has a D50 of 4 microns and/or a D90 of 10 microns measured by laser diffraction spectroscopy.

29. The soft gelatin capsule according to any of the preceding clauses, wherein the agent (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid has a D50 of 2 microns and/or a D90 of 5 microns measured by laser diffraction spectroscopy.

30. The soft gelatin capsule according to any of the preceding clauses, comprising glyceryl behenate or glyceryl distearate.

31. The soft gelatin capsule according to the preceding clause, comprising less than 3.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate or glyceryl distearate.

32. The soft gelatin capsule according to any of the preceding clauses, comprising less than 1.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate or glyceryl distearate. 33. The soft gelatin capsule according to any of the preceding clauses, comprising glyceryl behenate.

34. The soft gelatin capsule according to the preceding clause, comprising less than 3.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate. 35. The soft gelatin capsule according to any of the preceding clauses, comprising less than 1.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate.

36. The soft gelatin capsule according to any one of the preceding clauses, wherein the first component comprises at least one natural vegetable oil or mixtures of natural vegetable oils.

37. The soft gelatin capsule according to any one of the preceding clauses, wherein the first component is a natural vegetable oil or mixtures of natural vegetable oils. 38. The soft gelatin capsule according to any one of the preceding clauses, wherein the first component comprises olive oil, soybean oil, sesame oil, sunflower oil, safflower oil, rapeseed oil or mixtures thereof.

39. The soft gelatin capsule according to any one of the preceding clauses, wherein the first component is olive oil, soybean oil, sesame oil, sunflower oil, safflower oil, rapeseed oil or mixtures thereof.

40. The soft gelatin capsule according to any one of the preceding clauses, wherein the first component comprises soybean oil. 41. The soft gelatin capsule according to any one of the preceding clauses, wherein the first component is soybean oil.

42. The soft gelatin capsule according to any one of the preceding clauses, wherein the second component comprises at least one liquid lipid with a viscosity mPa -s 20° C between 5 and 40 or mixtures of liquid lipids with viscosities mPa -s 20° C between 5 and 40.

43. The soft gelatin capsule according to any one of the preceding clauses, wherein the second component is at least one liquid lipid with a viscosity mPa -s 20° C between 5 and 40 or mixtures of liquid lipids with viscosities mPa -s 20° C between 5 and 40.

44. The soft gelatin capsule according to any one of the preceding clauses, wherein the second component comprises at least liquid lipid with a viscosity mPa -s 20° C between 15 and 35 or mixtures of liquid lipids with viscosities mPa -s 20° C between 15 and 35. 45. The soft gelatin capsule according to any one of the preceding clauses, wherein the second component is at least one liquid lipid with a viscosity mPa -s 20° C between 15 and 35 or mixtures of liquid lipids with viscosities mPa -s 20° C between 15 and 35.

46. The soft gelatin capsule according to any one of the preceding clauses, wherein the second component comprises at least one liquid lipid with a viscosity mPa -s 20° C between 20 and 30 or mixtures of liquid lipids with viscosities mPa -s 20° C between 20 and 30.

47. The soft gelatin capsule according to any one of the preceding clauses, wherein the second component is at least one liquid lipid with a viscosity mPa -s 20° C between 20 and 30 or mixtures of liquid lipids with viscosities mPa -s 20° C between 20 and 30. 48. The soft gelatin capsule according to any one of the preceding clauses, wherein the second component comprises a liquid lipid wherein said liquid lipid is a mixture of triglycerides of the fractionated vegetable fatty acids C8 and CI O. 49. The soft gelatin capsule according to any one of the preceding clauses, wherein the second component is a liquid lipid wherein said liquid lipid is a mixture of triglycerides of the fractionated vegetable fatty acid C8 and C10.

50. The soft gelatin capsule according to any one of the preceding clauses, wherein the second component comprises Miglyol 812.

51. The soft gelatin capsule according to any one of the preceding clauses, wherein the second component is Miglyol 812.

52. The soft gelatin capsule according to any one of the preceding clauses, wherein the third component comprises at least one partially hydrogenated oil selected from the list consisting of partially hydrogenated fish oil, partially hydrogenated animal oil, partially hydrogenated palm oil, partially hydrogenated high erucic acid rapeseed oil, partially hydrogenated sunflower oil, partially hydrogenated corn oil, partially hydrogenated peanut oil, partially hydrogenated safflower oil, partially hydrogenated olive oil, partially hydrogenated palm stearin, partially hydrogenated cotton seed oil, partially hydrogenated soybean oil, and mixtures thereof.

53. The soft gelatin capsule according to any one of the preceding clauses, wherein the third component is a partially hydrogenated oil selected from the list consisting of partially hydrogenated fish oil, partially hydrogenated animal oil, partially hydrogenated palm oil, partially hydrogenated high erucic acid rapeseed oil, partially hydrogenated sunflower oil, partially hydrogenated corn oil, partially hydrogenated peanut oil, partially hydrogenated safflower oil, partially hydrogenated olive oil, partially hydrogenated palm stearin, partially hydrogenated cotton seed oil, partially hydrogenated soybean oil, or mixtures thereof.

54. The soft gelatin capsule according to any one of the preceding clauses, wherein the third component comprises at least one partially hydrogenated oil selected from the list consisting of partially hydrogenated palm oil, partially hydrogenated sunflower oil, partially hydrogenated corn oil, partially hydrogenated peanut oil, partially hydrogenated safflower oil, partially hydrogenated olive oil, partially hydrogenated cotton seed oil, partially hydrogenated soybean oil, and mixtures thereof.

55. The soft gelatin capsule according to any one of the preceding clauses, wherein the third component is one partially hydrogenated oil selected from the list consisting of partially hydrogenated palm oil, partially hydrogenated sunflower oil, partially hydrogenated corn oil, partially hydrogenated peanut oil, partially hydrogenated safflower oil, partially hydrogenated olive oil, partially hydrogenated cotton seed oil, partially hydrogenated soybean oil, or mixtures thereof. 56. The soft gelatin capsule according to any one of the preceding clauses, wherein the third component comprises partially hydrogenated soybean oil. 57. The soft gelatin capsule according to any one of the preceding clauses, wherein the third component is partially hydrogenated soybean oil.

58. The soft gelatin capsule according to any one of the preceding clauses, wherein the filling mixture comprises a mixture of the first component and of the second component.

59. The soft gelatin capsule according to any one of the preceding clauses, wherein the filling mixture is a mixture of the first component and of the second component.

60. The soft gelatin capsule according to any one of the two preceding clauses, wherein the filling mixture comprises between 50 to 98 % w/w of the first component and between 2 to 50 % w/w of the second component.

61. The soft gelatin capsule according to any one of the three preceding clauses, wherein the filling mixture comprises between 60 to 95 % w/w of the first component and between 5 to 40 % w/w of the second component. 62. The soft gelatin capsule according to any one of the four preceding clauses, wherein the filling mixture comprises between 70 to 90 % w/w of the first component and between 10 to 30 % w/w of the second component.

63. The soft gelatin capsule according to any one of the clauses 1 to 57, wherein the filling mixture comprises a mixture of the first component and of the third component.

64. The soft gelatin capsule according to the preceding clause, wherein the filling mixture is a mixture of the first component and of the third component.

65. The soft gelatin capsule according to any one of the two preceding clauses, wherein the filling mixture comprises between 40 to 95 % w/w of the first component and between 5 to 60 % w/w of the third component.

66. The soft gelatin capsule according to any one of the three preceding clauses, wherein the filling mixture comprises between 50 to 90 % w/w of the first component and between 10 to 50 % w/w of the third component. 67. The soft gelatin capsule according to any one of the four preceding clauses, wherein the filling mixture comprises between 60 to 80 % w/w of the first component and between 20 to 40 % w/w of the third component. 68. The soft gelatin capsule according to any one of the clauses 1 to 57, wherein the filling mixture comprises a mixture of the second component and of the third component.

69. The soft gelatin capsule according to the preceding clause, wherein the filling mixture is a mixture of the second component and of the third component.

70. The soft gelatin capsule according to any one of the two preceding clauses, wherein the filling mixture comprises between 40 to 95 % w/w of the second component and between 5 to 60 % w/w of the third component. 71. The soft gelatin capsule according to any one of the three preceding clauses, wherein the filling mixture comprises between 50 to 90 % w/w of the second component and between 10 to 50 % w/w of the third component.

72. The soft gelatin capsule according to any one of the four preceding clauses, wherein the filling mixture comprises between 60 to 80 % w/w of the second component and between 20 to 40 % w/w of the third component.

73. The soft gelatin capsule accordingjo any one of the clauses 1 to 57, wherein the filling mixture comprises a mixture of the first component, the second component and the third component.

74. The soft gelatin capsule according to the preceding clause, wherein the filling mixture comprises between 30 to 94 % w/w of the first component, between 0.1 to 40 % w/w of the second component, and between 5 to 60 % w/w of the third component.

75. The soft gelatin capsule according to any one of the two preceding clauses, wherein the filling mixture comprises between 45 to 85 % w/w of the first component, between 2 to 25 % w/w of the second component, and between 10 to 45 % w/w of the third component.

76. The soft gelatin capsule according to any one of the three preceding clauses, wherein the filling mixture comprises between 60 to 70 % w/w of the first component, between 5 to 15 % w/w of the second component, and between 20 to 30 % w/w of the third component.

77. The soft gelatin capsule according to any one of the preceding clauses, wherein the filling mixture present in the fill is more than 75 % w/w in respect to the total content of the fill.

78. The soft gelatin capsule according to any one of the preceding clauses, wherein the filling mixture present in the fill is more than 83 % w/w in respect to the total content of the fill.

79. The soft gelatin capsule according to any one of the preceding clauses, wherein the filling mixture present in the fill is more than 88 % w/w in respect to the total content of the fill. 80. The soft gelatin capsule according to any one of the preceding clauses, wherein the fill of the soft gelatin capsule comprises hydrogenated castor oil. 81. The soft gelatin capsule according to any one of the preceding clauses, wherein the fill of the soft gelatin capsule comprises between a 0.5 % and a 8 % w/w of hydrogenated castor oil.

82. A stable immediate release soft gelatin capsule comprising the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6- trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid, wherein the soft gelatin capsule comprises a capsule shell and a fill, and wherein the fill of the soft gelatin capsule comprises micronized (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6- trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid.

83. The soft gelatin capsule according to the preceding clause, wherein the agent (2E,4E,6Z,8E)-3,7-dimethyl-9- (2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid has a D50 of 8 microns and/or a D90 of 20 microns measured by laser diffraction spectroscopy.

84. The soft gelatin capsule according to any of the preceding clauses, wherein the agent (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid has a D50 of 4 microns and/or a D90 of 10 microns measured by laser diffraction spectroscopy.

85. The soft gelatin capsule according to any of the preceding clauses, wherein the agent (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid has a D50 of 2 microns and/or a D90 of 5 microns measured by laser diffraction spectroscopy. 86. The soft gelatin capsule according to any of the preceding clauses, comprising glyceryl behenate or glyceryl distearate.

87. The soft gelatin capsule according to the preceding clause, comprising less than 3.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate or glyceryl distearate.

88. The soft gelatin capsule according to any of the preceding clauses, comprising less than 1.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate or glyceryl distearate.

89. The soft gelatin capsule according to any of the preceding clauses, comprising glyceryl behenate.

90. The soft gelatin capsule according to the preceding clause, comprising less than 3.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate. 91. The soft gelatin capsule according to any of the preceding clauses, comprising less than 1.0 % w/w in respect of the total amount of the fill of the soft gelatin capsule of glyceryl behenate.

92. (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid, wherein said (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid is micronized.

93. (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid according to the preceding clause, wherein the particle size has a D50 of 8 microns and/or a D90 of 20 microns measured by laser diffraction spectroscopy.

94. (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid according to the preceding clause, wherein the particle size has a D50 of 4 microns and/or a D90 of 10 microns measured by laser diffraction spectroscopy. 95. (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid according to the preceding clause, wherein the particle size has a D50 of 2 microns and/or a D90 of 5 microns measured by laser diffraction spectroscopy.

96. A process for the preparation of hard fat free stable immediate release soft gelatin capsule containing the same agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid as defined in any one of the clauses 1 to 81 , wherein said process comprises at least the following steps:

i) preparing a soft gelatin capsule fill comprising mixing the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6- trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9- (2,6,6- trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; and a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax; ii) filling a soft gelatin capsule with the fill as prepared in step (i) forming the soft gelatin capsule;

iii) optionally drying the soft gelatin capsules. 97. The process according to the preceding clause, wherein the step (ii) comprises encapsulating the soft gelatin capsule fill as prepared in step (i) using a rotary die and producing the soft gelatin capsule. 98. The process according to any one of the two preceding clauses to form the soft gelatin capsule according to any one of the clauses 1 to 81.

99. A soft gelatin capsule fill for the manufacture of immediate release soft gelatin capsules, wherein the soft gelatin capsule fill comprises the agent (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax. 100. The soft gelatin capsule fill for the manufacture of immediate release soft gelatin capsules according to the preceding clause, wherein the soft gelatin capsule fill consists essentially of the agent (2E,4E,6Z,8E)-3,7-dimethyl-9- (2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; a filling mixture of at a least two of the three following components or a filling mixture of the following first component, a first component, a second component and a third component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax.

101. The soft gelatin capsule fill for the manufacture of immediate release soft gelatin capsules according to any one of the two the preceding clauses, wherein the soft gelatin capsule fill consists of the agent (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6- trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax. 102. A process for the preparation of the fill according to any of the three preceding clauses, by mixing the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid; optionally an antioxidant or mixtures of antioxidants in an amount sufficient to decrease the decomposition rate of the (2E,4E,6Z,8E)-3,7- dimethyl-9- (2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid over time; and a filling mixture of at a least two of the three following components, a first component, a second component and a third component or a filling mixture of the following first component; wherein the first component is an oily substance or mixtures of oily substances; wherein the second component is a liquid lipid or a mixture of liquid lipids; wherein the third component is a partially hydrogenated natural oil or a mixture of partially hydrogenated oils; with the proviso that if the soft gelatin capsule fill comprises a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides the soft gelatin capsule fill does not comprise a natural wax.

103. A process for the preparation of a hard fat free stable immediate release soft gelatin capsule containing the agent (2E,4E,6Z,8E)-3J-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid, by encapsulating the soft gelatin capsule fill produced according to clause 97 or the soft gelatin capsule fill according to any one of the clauses 99 to 101 and forming the soft gelatin capsule.

104. The process according to the preceding clause, wherein the soft gelatin capsule is formed by using a rotary die and producing the soft gelatin capsule. 105. The process according to any one of the two preceding clauses to form the soft gelatin capsule according to any one of the clauses 1 to 81.

106. A hard fat free soft gelatin capsule as obtained by any one of the clauses 96, 97, 103, 104 and 105. 107. Use of the hard fat soft gelatin capsule according to any one of clauses 1 to 91 or 106 or the soft gelatin capsule fill according to any of clauses 99 to 101 for skin lesions in a human being.

108. Use according to the preceding clause wherein the skin lesion is eczema. 109. Use according to the preceding clause for use in adults who have severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids.

Preferred combinations of the above clauses are as follows:

Clause 110.- 1 ,5 Clause 322.- 1 , 38, 70 Clause 534.- 1 , 68, 43

Clause 111.- 1 ,5,6 Clause 323.- 1 , 38, 71 Clause 535.- 1 , 68, 48

Clause 112.- 1 ,5,7 Clause 324.- 1 , 38, 72 Clause 536.- 1 , 68, 50 Clause 113.- 1,5,9 Clause 325.- 1 38,73 Clause 537.- ^' ,68 56

Clause 114.- 1,5,10 Clause 326.- 1 38,74 Clause 538.- ^' ,68 60

Clause 115.- 1,5,14 Clause 327.- 1 38,75 Clause 539.- ^' ,68 62

Clause 116,- 1,5,16 Clause 328.- 1 38,76 Clause 540.- ^' ,68 64

Clause 117.- 1,5,20 Clause 329.- 1 38,77 Clause 541.- 1 ,68 65

Clause 118.- 1,5,21 Clause 330.- 1 38,78 Clause 542.- 1 ,68 67

Clause 119.- 1,5,23 Clause 331.- 1 38,79 Clause 543.- 1 ,68 70

Clause 120.- 1,5,24 Clause 332.- 1 38,80 Clause 544.- 1 ,68 71

Clause 121.- 1,5,38 Clause 333.- 1 38,81 Clause 545.- 1 ,68 72

Clause 122.- 1,5,40 Clause 334.- 1 46 Clause 546.- 1 ,68 73

Clause 123.- 1,5,43 Clause 335.- 1 46, 14 Clause 547.- 1 ,68 74

Clause 124.- 1,5,46 Clause 336.- 1 46, 16 Clause 548.- 1 ,68 75

Clause 125.- 1,5,48 Clause 337.- 1 46,20 Clause 549.- 1 ,68 76

Clause 126.- 1,5,50 Clause 338.- 1 46,21 Clause 550.- 1 ,68 77

Clause 127.- 1,5,54 Clause 339.- 1 46,23 Clause 551.- 1 ,68 78

Clause 128.- 1,5,56 Clause 340.- 1 46,24 Clause 552.- 1 ,68 79

Clause 129.- 1,5,58 Clause 341.- 1 46,40 Clause 553.- 1 ,68 80

Clause 130.- 1,5,60 Clause 342.- 1 46,48 Clause 554.- 1 ,68 81

Clause 131.- 1,5,61 Clause 343.- 1 46,50 Clause 555.- 1 ,71

Clause 132.- 1,5,62 Clause 344.- 1 46,54 Clause 556.- 1 ,71, 14

Clause 133.- 1,5,63 Clause 345.- 1 46,56 Clause 557.- 1 ,71, 16

Clause 134.- 1,5,64 Clause 346.- 1 46,58 Clause 558.- 1 ,71, 20

Clause 135.- 1,5,65 Clause 347.- 1 46,60 Clause 559.- 1 ,71, 21

Clause 136.- 1,5,66 Clause 348.- 1 46,61 Clause 560.- 1 ,71, 23

Clause 137.- 1,5,67 Clause 349.- 1 46,62 Clause 561.- 1 ,71, 24

Clause 138.- 1,5,68 Clause 350.- 1 46,63 Clause 562.- 1 ,71, 40

Clause 139.- 1,5,70 Clause 351.- 1 46,64 Clause 563.- 1 ,71, 43

Clause 140.- 1,5,71 Clause 352.- 1 46,65 Clause 564.- 1 ,71, 48

Clause 141.- 1,5,72 Clause 353.- 1 46,66 Clause 565.- 1 ,71, 50

Clause 142.- 1,5,73 Clause 354.- 1 46, 67 Clause 566.- 1 ,71, 56

Clause 143.- 1,5,74 Clause 355.- 1 46,68 Clause 567.- 1 ,71, 60

Clause 144.- 1,5,75 Clause 356.- 1 46,70 Clause 568.- 1 ,71, 62

Clause 145.- 1,5,76 Clause 357.- 1 46,71 Clause 569.- 1 ,71, 64

Clause 146.- 1,5,77 Clause 358.- 1 46,72 Clause 570.- 1 ,71, 65

Clause 147.- 1,5,78 Clause 359.- 1, 46, 73 Clause 571.- 1 ,71, 67

Clause 148.- 1,5,79 Clause 360.- 1, 46,74 Clause 572.- 1 ,71, 72

Clause 149.- 1,5,80 Clause 361.- 1, 46,75 Clause 573.- 1 ,71, 73 Clause 150.- 1,5,81 Clause 362.- 1 ,46 76 Clause 574.- 1 ,71 74

Clause 151.- 119 121 Clause 363.- 1 ,46 77 Clause 575.- 1 ,71 75

Clause 152.- 119 123 Clause 364.- 1 ,46 78 Clause 576.- 1 ,71 76

Clause 153.- 119 127 Clause 365.- 1 ,46 79 Clause 577.- 1 ,71 77

Clause 154.- 119 129 Clause 366.- 1 ,46 80 Clause 578.- 1 ,71 78

Clause 155.- 119 129, 130 Clause 367.- 1 ,46 81 Clause 579.- 1 ,71 79

Clause 156.- 119 134 Clause 368.- 1 ,54 Clause 580.- 1 ,71 80

Clause 157.- 119 134, 135 Clause 369.- 1 ,54 16 Clause 581.- 1 ,71 81

Clause 158.- 119 138 Clause 370.- 1 ,54 20 Clause 582.- 1 ,73

Clause 159.- 119 138, 139 Clause 371.- 1 ,54 21 Clause 583.- 1 ,73 14

Clause 160.- 119 142 Clause 372.- 1 ,54 23 Clause 584.- 1 ,73 16

Clause 161.- 119 142, 143 Clause 373.- 1 ,54 24 Clause 585.- 1 ,73 20

Clause 162.- 119 146 Clause 374.- 1 ,54 40 Clause 586.- 1 ,73 21

Clause 163.- 119 149 Clause 375.- 1 ,54 43 Clause 587.- 1 ,73 23

Clause 164.- 151 154 Clause 376.- 1 ,54 48 Clause 588.- 1 ,73 24

Clause 165.- 151 155 Clause 377.- 1 ,54 50 Clause 589.- 1 ,73 40

Clause 166.- 151 156 Clause 378.- 1 ,54, 56 Clause 590.- 1 ,73 43

Clause 167.- 151 157 Clause 379.- 1 ,54, 58 Clause 591.- 1 ,73 48

Clause 168.- 151 158 Clause 380.- 1 ,54, 60 Clause 592.- 1 ,73 50

Clause 169.- 151 159 Clause 381.- 1 ,54, 61 Clause 593.- 1 ,73 56

Clause 170.- 151 160 Clause 382.- 1 ,54, 62 Clause 594.- 1 ,73 60

Clause 171.- 151 161 Clause 383.- 1 ,54, 63 Clause 595.- 1 ,73 62

Clause 172.- 151 162 Clause 384.- 1 ,54, 64 Clause 596.- 1 ,73, 64

Clause 173.- 152 154 Clause 385.- 1 ,54, 65 Clause 597.- 1 ,73, 65

Clause 174.- 152 155 Clause 386.- 1 ,54, 66 Clause 598.- 1 ,73, 67

Clause 175.- 152 158 Clause 387.- 1 ,54, 67 Clause 599.- 1 ,73, 70

Clause 176.- 152 159 Clause 388.- 1 ,54, 68 Clause 600.- 1 ,73, 72

Clause 177.- 152 160 Clause 389.- 1 ,54, 70 Clause 601.- 1 ,73, 74

Clause 178.- 152 161 Clause 390.- 1 ,54, 71 Clause 602.- 1 ,73, 75

Clause 179.- 152 162 Clause 391.- 1 ,54, 72 Clause 603.- 1 ,73, 76

Clause 180.- 153 156 Clause 392.- 1 ,54, 73 Clause 604.- 1 ,73, 77

Clause 181.- 153 157 Clause 393.- 1 ,54, 74 Clause 605.- 1 ,73, 78

Clause 182.- 153 158 Clause 394.- 1 ,54, 75 Clause 606.- 1 ,73, 79

Clause 183.- 153, 160 Clause 395.- 1 ,54, 76 Clause 607.- 1 ,73, 80

Clause 184.- 153, 161 Clause 396.- 1 ,54, 77 Clause 608.- 1 ,73, 81

Clause 185.- 153, 162 Clause 397.- 1 ,54, 78 Clause 609.- 1 ,75

Clause 186.- 1,7 Clause 398.- 1 ,54, 79 Clause 610.- 1 ,75, 14 Clause 187.- 1 7 9 Clause 399.- 1 54,80 Clause 611.- ^' ,75, 16

Clause 188.- 1 7 10 Clause 400.- 1 54,81 Clause 612.- ^' , 75, 20

Clause 189.- 1 7 14 Clause 401.- 1 58 Clause 613.- ^' ,75,21

Clause 190.- 1 7 16 Clause 402.- 1 58, 14 Clause 614.- ^' , 75, 23

Clause 191.- 1 7 20 Clause 403.- 1 58, 16 Clause 615.- ^' , 75, 24

Clause 192.- 1 7 21 Clause 404.- 1 58,20 Clause 616.- 1 , 75, 40

Clause 193.- 1 7 23 Clause 405.- 1 58,21 Clause 617.- 1 , 75, 43

Clause 194.- 1 7 24 Clause 406.- 1 58,23 Clause 618.- 1 , 75, 48

Clause 195.- 1 7 38 Clause 407.- 1 58,24 Clause 619.- 1 , 75, 50

Clause 196.- 1 7 40 Clause 408.- 1 58,40 Clause 620.- 1 , 75, 56

Clause 197.- 1 7 43 Clause 409.- 1 58,43 Clause 621.- 1 , 75, 60

Clause 198.- 1 7 46 Clause 410.- 1 58,48 Clause 622.- 1 , 75, 62

Clause 199.- 1 7 48 Clause 411.- 1 58,50 Clause 623.- 1 , 75, 64

Clause200.- 1 7 50 Clause 412.- 1 58,54 Clause 624.- 1 , 75, 65

Clause 201.- 1 7 54 Clause413.- 82, 85, 91 Clause 625.- 1 , 75, 67

Clause202.- 1 7 56 Clause 414.- 1 58,60 Clause 626.- 1 , 75, 70

Clause 203.- 1 7 58 Clause 415.- 1 58,61 Clause 627.- 1 , 75, 72

Clause 204.- 1 7 60 Clause 416.- 1 58,62 Clause 628.- 1 , 75, 76

Clause 205.- 1 7 61 Clause 417.- 1 58,63 Clause 629.- 1 , 75, 77

Clause 206.- 1 7, 62 Clause418.- 1 58,64 Clause 630.- 1 , 75, 78

Clause 207.- 1 7, 63 Clause 419.- 1 58,65 Clause 631.- 1 , 75, 79

Clause208.- 1 7, 64 Clause 420.- 1 58,66 Clause 632.- 1 , 75, 80

Clause209.- 1 7, 65 Clause 421.- 1 58,67 Clause 633.- 1 , 75, 81

Clause 210.- 1 7, 66 Clause 422.- 1 58,68 Clause 634.- 1 ,78

Clause 211.- 1 7, 67 Clause 423.- 1 58,70 Clause 635.- 1 ,78, 14

Clause 212.- 1 7, 68 Clause 424.- 1 58,71 Clause 636.- 1 ,78, 16

Clause 213.- 1 7, 70 Clause 425.- 1 58,72 Clause 637.- 1 , 78, 20

Clause 214.- 1 7, 71 Clause 426.- 1 58,73 Clause 638.- 1 ,78,21

Clause 215.- 1 7, 72 Clause 427.- 1 58,74 Clause 639.- 1 , 78, 23

Clause 216.- 1 7, 73 Clause 428.- 1 58,75 Clause 640.- 1 , 78, 24

Clause 217.- 1 7, 74 Clause 429.- 1 58,76 Clause 641.- 1 , 78, 40

Clause 218.- 1 7, 75 Clause 430.- 1 58,77 Clause 642.- 1 , 78, 43

Clause 219.- 1 7, 76 Clause 431.- 1 58,78 Clause 643.- 1 , 78, 48

Clause 220.- 1 7, 77 Clause 432.- 1 58,79 Clause 644.- 1 , 78, 50

Clause 221.- 1, 7, 78 Clause 433.- 1, 58,80 Clause 645.- 1 , 78, 56

Clause 222.- 1, 7, 79 Clause 434.- 1, 58,81 Clause 646.- 1 , 78, 60

Clause 223.- 1, 7, 80 Clause 435.- 1, 61 Clause 647.- 1 , 78, 62 Clause 224.- 1 7,81 Clause 436.- 1 ,61 14 Clause 648 1,78,64

Clause 225.- 1 10 Clause 437.- 1 ,61 16 Clause 649 1,78,65

Clause 226.- 1 10, 11 Clause 438.- 1 ,61 20 Clause 650 1,78, 67

Clause 227.- 1 10, 14 Clause 439.- 1 61 21 Clause 651 1,78,70

Clause 228.- 1 10, 16 Clause 440.- 1 61 23 Clause 652 1,78,72

Clause 229.- 1 10,20 Clause 441.- 1 61 24 Clause 653 1,78,74

Clause 230.- 1 10,21 Clause 442.- 1 61 40 Clause 654 1,78,75

Clause 231.- 1 10,23 Clause 443.- 1 61 43 Clause 655 1,78,76

Clause 232.- 1 10,24 Clause 444.- 1 61 48 Clause 656 1,78,79

Clause 233.- 1 10, 38 Clause 445.- 1 61 50 Clause 657 1,78,80

Clause 234.- 1 10,40 Clause 446.- 1 61 56 Clause 658 1,78,81

Clause 235.- 1 10,43 Clause 447.- 1 61 62 Clause 659 1,80

Clause 236.- 1 10, 46 Clause 448.- 1 61 63 Clause 660 1,80, 14

Clause 237.- 1 10,48 Clause 449.- 1 61 64 Clause 661 1,80, 16

Clause 238.- 1 10,50 Clause 450.- 1 61 65 Clause 662 1,80,20

Clause 239.- 1 10,54 Clause 451.- 1 61 66 Clause 663 1,80,21

Clause 240.- 1 10,56 Clause 452.- 1 61 67 Clause 664 1,80,23

Clause 241.- 1 10,58 Clause 453.- 1 61 68 Clause 665 1,80,24

Clause 242.- 1 10,60 Clause 454.- 1 61 70 Clause 666 1,80,40

Clause 243.- 1 10,61 Clause 455.- 1 61 71 Clause 667. 1,80,43

Clause 244.- 1 10,62 Clause 456.- 1 61 72 Clause 668. 1,80,48

Clause 245.- 1 10,63 Clause 457.- 1 61 73 Clause 669. 1,80,50

Clause 246.- 1, 10, 64 Clause 458.- 1 61 74 Clause 670. 1,80, 56

Clause 247.- 1, 10,65 Clause 459.- 1 61 75 Clause 671. 1,80,60

Clause 248.- 1, 10,66 Clause 460.- 1 61 76 Clause 672. 1,80,62

Clause 249.- 1, 10,67 Clause 461.- 1 61 77 Clause 673. 1,80,64

Clause 250.- 1, 10,68 Clause 462.- 1 61, 78 Clause 674. 1,80,65

Clause 251.- 1, 10,70 Clause 463.- 1 61, 79 Clause 675. 1,80,67

Clause 252.- 1, 10,71 Clause 464.- 1 61, 80 Clause 676. 1,80,70

Clause 253.- 1, 10,72 Clause 465.- 1, 61, 81 Clause 677. 1,80,72

Clause 254.- 1, 10,73 Clause 466.- 1, 63 Clause 678. 1,80,74

Clause 255.- 1, 10,74 Clause 467.- 1, 63, 14 Clause 679. 1,80,75

Clause 256.- 1, 10, 75 Clause 468.- 1, 63, 16 Clause 680. 1,80, 76

Clause 257.- 1, 10,76 Clause 469.- 1, 63, 20 Clause 681. 1,80,77

Clause 258.- 1, 10,77 Clause 470.- 1, 63, 21 Clause 682. 1,80,79

Clause 259.- 1, 10,78 Clause 471.- 1, 63, 23 Clause 683. 1,38,43,58,62

Clause 260.- 1, 10,79 Clause 472.- 1, 63, 24 Clause 684. 1,38,43,58,62,78 Clause 261.- 1 10 80 Clause 473.- , 63, 40 Clause 685.- 1 38, 54, 63, 66

Clause 262.- 1 10 81 Clause 474.- , 63, 43 Clause 686.- 1 38, 54, 63, 66, 78

Clause 263.- 1 22 Clause 475.- , 63, 48 Clause 687.- 1 43, 54, 68, 71

Clause 264.- 1 22 10 Clause 476.- ^' , 63, 50 Clause 688.- 1 43,54,68,71,78

Clause 265.- 1 22 14 Clause 477.- ^' , 63, 56 Clause 689.- 1 38, 43, 54, 73, 75

Clause 266.- 1 22 16 Clause 478.- ^' , 63, 60 Clause 690.- 1 38, 43, 54, 73, 75, 78

Clause 267.- 1 22 24 Clause 479.- ^' , 63, 62 Clause 691.- 1 5,28

Clause 268.- 1 22 38 Clause 480.- 1 , 63, 64 Clause 692.- 1 5,31

Clause 269.- 1 22 40 Clause 481.- 1 , 63, 65 Clause 693.- 1 5,33

Clause 270.- 1 22 43 Clause 482.- 1 , 63, 66 Clause 694.- 1 7,28

Clause 271.- 1 22 46 Clause 483.- 1 , 63, 67 Clause 695.- 1 7,31

Clause 272.- 1 22 48 Clause 484.- 1 , 63, 68 Clause 696.- 1 7,33

Clause 273.- 1 22 50 Clause 485.- 1 , 63, 70 Clause 697.- 1 10,28

Clause 274.- 1 22 54 Clause 486.- 1 , 63, 71 Clause 698.- 1 10,31

Clause 275.- 1 22 56 Clause 487.- 1 , 63, 72 Clause 699.- 1 10,33

Clause 276.- 1 22 58 Clause 488.- 1 , 63, 73 Clause 700.- 1 22,28

Clause 277.- 1 22 60 Clause 489.- 1 , 63, 74 Clause 701.- 1 22,31

Clause 278.- 1 22 61 Clause 490.- 1 , 63, 75 Clause 702.- 1 22,33

Clause 279.- 1 22 62 Clause 491.- 1 , 63, 76 Clause 703.- 1 38,28

Clause 280.- 1 22,63 Clause 492.- 1 , 63, 77 Clause 704.- 1 38,31

Clause 281.- 1 22, 64 Clause 493.- 1 , 63, 78 Clause 705.- 1 38,33

Clause 282.- 1 22, 65 Clause 494.- 1 , 63, 79 Clause 706.- 1 46,28

Clause 283.- 1 22, 66 Clause 495.- 1 , 63, 80 Clause 707.- 1 46,31

Clause 284.- 1 22, 67 Clause 496.- 1 , 63, 81 Clause 708.- 1 46, 33

Clause 285.- 1 22, 68 Clause 497.- 1 ,66 Clause 709.- 1 54,28

Clause 286.- 1 22, 70 Clause 498.- 1 ,66, 14 Clause 710.- 1 54,31

Clause 287.- 1 22, 71 Clause 499.- 1 ,66, 16 Clause 711.- 1 54,33

Clause288.- 1 22, 72 Clause 500.- 1 , 66, 20 Clause 712.- 1 58,28

Clause289.- 1 22, 73 Clause 501.- 1 ,66,21 Clause 713.- 1 58,31

Clause290.- 1 22, 74 Clause 502.- 1 , 66, 23 Clause 714.- 1 58,33

Clause 291.- 1 22, 75 Clause 503.- 1 , 66, 24 Clause 715.- 1 61,28

Clause 292.- 1 22, 76 Clause 504.- 1 , 66, 40 Clause 716.- 1 61,31

Clause 293.- 1, 22, 77 Clause 505.- 1 , 66, 43 Clause 717.- 1, 61,33

Clause 294.- 1, 22, 78 Clause 506.- 1 , 66, 48 Clause 718.- 1, 63,28

Clause 295.- 1, 22, 79 Clause 507.- 1 , 66, 50 Clause 719.- 1, 63,31

Clause 296.- 1, 22, 80 Clause 508.- 1 , 66, 56 Clause 720.- 1, 63,33

Clause 297.- 1, 22, 81 Clause 509.- 1 , 66, 60 Clause 721.- 1, 66,28 Clause 298.- 1 38 Clause 510.- 1 66, 62 Clause 722.- 1,66,31

Clause299.- 1 38, 14 Clause 511.- 1 66, 64 Clause 723.- 1 , 66, 33

Clause 300.- 1 38, 16 Clause 512.- 1 66, 67 Clause 724.- 1,68,28

Clause 301.- 1 38, 20 Clause 513.- 1 66, 68 Clause 725.- 1,68,31

Clause 302.- 1 38, 21 Clause 514.- 1 66, 70 Clause 726.- 1,68,33

Clause 303.- 1 38, 23 Clause 515.- 1 66, 71 Clause 727.- 1,71,28

Clause 304.- 1 38, 24 Clause 516.- 1 66, 72 Clause 728.- 1,71,31

Clause 305.- 1 38, 40 Clause 517.- 1 66, 73 Clause 729.- 1,71,33

Clause 306.- 1 38, 43 Clause 518.- 1 66, 74 Clause 730.- 1,75,28

Clause 307.- 1 38, 46 Clause 519.- 1 66, 75 Clause 731.- 1,75,31

Clause 308.- 1 38, 48 Clause 520.- 1 66, 76 Clause 732.- 1 , 75, 33

Clause 309.- 1 38, 50 Clause 521.- 1 66, 77 Clause 733.- 1,78,28

Clause 310.- 1 38, 54 Clause 522.- 1 66, 78 Clause 734.- 1,78,31

Clause 311.- 1 38, 56 Clause 523.- 1 66, 79 Clause 735.- 1,78,33

Clause 312.- 1 38, 58 Clause 524.- 1 66, 80 Clause 736.- 1,80,28

Clause 313.- 1 38, 60 Clause 525.- 1 66, 81 Clause 737.- 1,80,31

Clause 314.- 1 38, 61 Clause 526.- 1 68 Clause 738.- 1,80,33

Clause 315.- 1 38, 62 Clause 527.- 1 68, 14 Clause 739.- 1,28

Clause 316.- 1 38, 63 Clause 528.- 1 68, 16 Clause 740.- 1,5,28,31

Clause 317.- 1 38, 64 Clause 529.- 1 68, 20 Clause 741.- 1,5,28,31,33

Clause 318.- 1 38, 65 Clause 530.- 1 68, 21 Clause 742.- 82,84

Clause 319.- 1 38, 66 Clause 531.- 1 68, 23 Clause 743.- 82,87

Clause 320.- 1 38, 67 Clause 532.- 1 68, 24 Clause 744.- 82, 84, 87

Clause 321.- 1 38, 68 Clause 533.- 1 68, 40 Clause 745.- 82, 84, 87, 89

In the summary of the invention and this description, each numerical value should be read once as modified by the term "about" (unless already expressly so modified), and then read again as not so modified unless otherwise indicated in context. All percentages, parts, and ratios herein are by weight unless specifically noted otherwise. As used herein, the term "about" refers preferably to a range that is +-10%, preferably +-5%, or more preferably +-1% of a value with which the term is associated.

EXAMPLES

The following numbered examples correspond to fills to be used in the manufactured of soft gelatin capsules. The fills are encapsulated to form soft gelatin capsules with shell compositions having gelatin, plastifier agent or agents and water as described above.

Examples 1 and 2 Ex. 1 Ex. 2

Active agent 10 30

DL-alfa-tocopherol 0.028 0.028 hydrogenated castor oil 10 10

Miglyol 812 30 20 soybean oil 165 160 partially hydrogenated soybean oil 65 60

Total fill content (mg/capsule) 280.028 280.028

Examples 3 and 4

Total fill content (mg/capsule) 280.028 280.028

Examples 5 and 6

Total fill content (mg/capsule) 280.028 280.028

Examples 7 and 8

Ex. 7 Ex. 8 Active agent 10 30

DL-alfa-tocopherol 0.028 0.028 hydrogenated castor oil 10 10

Miglyol 812 75 65 soybean oil 120 120 partially hydrogenated soybean oil 65 55

Total fill content (mg/capsule) 280.028 280.028

Examples 9 and 10

Total fill content (mg/capsule) 280.028 280.028

Examples 11 and 12

Total fill content (mg/capsule) 280.028 280.028

Examples 13 and 14

yellow wax 10 10 soybean oil 185 175 partially hydrogenated soybean oil 75 65

Total fill content (mg/capsule) 280.028 280.028

Examples 15 and 16

Total fill content (mg/capsule) 280.028 280.028

Examples 17 and 18

Total fill content (mg/capsule) 280.028 280.028

Examples 19 and 20

soybean oil 1 85 175 partially hydrogenated soybean oil 70 60

Total fill content (mg/capsule) 280.028 280.028

Examples 21 and 22

Total fill content (mg/capsule) 280.028 280.028

Examples 23 and 24

Total fill content (mg/capsule) 280.028 280.028

Examples 25 and 26

Total fill content (mg/capsule) 280.028 280.028

Examples 27 and 28 Ex. 27 Ex. 28

Active agent 1 0 30

DL-alfa-tocopherol 0.028 0.028

Miglyol 812 30 20 yellow wax 15 15 soybean oil 225 215

Total fill content (mg/capsule) 280.028 280.028

Examples 29 and 30

Total fill content (mg/capsule) 280.028 275,028

Examples 31 and 32

Total fill content (mg/capsule) 280.028 280.028

Examples 33 and 34 Ex. 33 Ex. 34

Active agent 10 30

DL-alfa-tocopherol 0.028 0.028

Miglyol 812 50 40 yellow wax 5 5 soybean oil 215 205

Total fill content (mg/capsule) 280.028 280.028

Examples 35 and 36

Examples 37 and 38

Examples 39, 40 and 41

Examples 42, 43 and 44

Examples 45, 46 and 47

Examples 48, 49 and 50

Examples 51 , 52 and 53 Total fill content (mg/capsule) 280.028 280.028 280.028

Examples 54, 55, 56 and 57

Examples 58, 59, 60 and 61

Examples 62, 63, 64 and 65

The active agent is (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid in all the above soft gelatin capsules and the amounts are in mg. The active agent is micronized and its particle size distribution measured by laser diffraction spectroscopy shows a D50 of less than 8 microns and a D90 of less than 20 microns. Each one of the above fill examples is encapsulated with the two following types of shells: Pig gelatin (80 mg/capsule), glycerol (20 mg/capsule), sorbitol (20 mg/capsule) and water (15 mg/capsule calculated as dry matter in shell after drying); Bovine gelatin (80 mg/capsule), glycerol (20 mg/capsule), sorbitol (20 mg/capsule) and water (15 mg/capsule calculated as dry matter in shell after drying).

General process for the manufacture of the soft gelatin capsules:

All the fill ingredients are mixed and the temperature of the mixture is maintained and monitored to ensure that it does not exceed 40 ² C, until dissolved or homogeneously mixed. The solution is deaerated prior to encapsulation. Each manufacturing step (as appropriate) is be performed under yellow light/darkness and inert atmosphere (nitrogen) / vacuum.

In case that the fill ingredients are hard to mix, and no dissolution/homogeneous mixture is obtained, it may be convenient to use higher temperatures, not exceeding 70 ² C. In that case, the most sensitive ingredients, as for example the antioxidant and the (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8- tetraenoic acid, can be added after obtaining the dissolution/homogeneous mixture at a temperature not exceeding 40 ² C.

The gelatin solution needed in the production of soft capsules is called gelatin melting. The gelatin is prepared by blending gelatin NF, glycerin USP, sorbitol special and purified water USP. The raw material preparation proportion is the following: gelatin: about 42%, water: about 38%, plastifying agent: about 20%. The resulting mixture is heated in a pressurized reactor to melt the gelatin. The melting temperature of the gelatin is about 60 ² C to about 70 ² C. The gelatin melting time is about 1 hour to about 1.5 hours. The gelatin is then maintained in the molten state until used for encapsulation. The viscosity of qualified gelatin solution is normally about 18 Pa -s.

For encapsulation it is used a rotary die process. Two gelatin ribbons are formed when the heated gelatin is fed to an encapsulation machine, where it enters two spreader boxes which cast the gelatin on a cooling drum. The gelatin ribbons are also lubricated with a mixture of medium chain triglycerides, optionally comprising 0.1 % w/w of lecithin, on the external side to prevent the capsules from sticking together after manufacture, prior to drying. The ribbons are then conveyed to the encapsulation roller. Die cavities to form the capsules are located on the circumference of the two adjacent rollers, which rotate and pull the gelatin ribbons between them. The fill solution is injected by a metered positive-displacement pump, between the gelatin ribbons forcing them to expand and fill the die cavities. As the capsules are filled, they are simultaneously shaped, sealed and cut from the gelatin ribbon by the encapsulation rollers. The capsules are then conveyed to the rotating basket dryer.

It is recommended that the whole manufacturing process is carried out under yellow light and/or inert atmosphere (e.g. Nitrogen).

The capsules are dried by tumbling in a rotating basket dryer to remove sufficient moisture to allow handling. They are then transferred onto trays and allowed to dry until the moisture level of the fill solution is in an adequate level, normally not more than 2% (w/w).

Particle size volume distribution

The particle size distribution of the active agent was analysed by laser diffraction spectroscopy using a Malvern Mastersizer 2000 particle size analyzer. The particle size distribution was D10 of 0.75 microns, D50 of 1.61 microns and D90 of 4.09 microns (Fig. 3). Dissolution profiles

Sample preparation: Weigh and take 1 capsule in dissolution tester under the following conditions: apparatus: I (basket). Medium volume: 900 ml. Dissolution medium: pH 7.0 50 mM phosphate buffer + lauryl dimethyl amine oxide 4.5%. Sampling times: 15, 30, 45, 60, 90 and 120 minutes (Centrifuge 4000 rpm 6 minutes). Temperature: 37 ² C.

Dissolution medium preparation (1 liter): Weigh 27.22 g KH2P04 in 930 ml of purified water. Adjust pH to 7.0 if it is necessary. Dilute to 1000 ml with purified water. Dilute 250 ml to 1000 ml and add 45 g of lauryl dimethyl amine oxide.

The active agent was detected chromatographically.

Chromatographic System: column: ACE C8 150 x 4.0 5 μηι. Flow: 0.8 ml/min. Mobile phase: acetonitrile (85%), trifluoroacetic acid 0.01% (15%). Temperature: 40 ² C. Volume of injection: 35 μΙ for 30 mg capsules o 75μΙ for 10 mg capsules. Stop time: 6 minutes.