EP2890369A1 - Compositions pharmaceutiques comprenant un principe actif - Google Patents

Compositions pharmaceutiques comprenant un principe actif

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Publication number
EP2890369A1
EP2890369A1 EP13756151.0A EP13756151A EP2890369A1 EP 2890369 A1 EP2890369 A1 EP 2890369A1 EP 13756151 A EP13756151 A EP 13756151A EP 2890369 A1 EP2890369 A1 EP 2890369A1
Authority
EP
European Patent Office
Prior art keywords
soft gelatin
gelatin capsule
component
fill
clause
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP13756151.0A
Other languages
German (de)
English (en)
Inventor
Joaquim DOMINGO GONZALEZ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Galenicum Health SL
Original Assignee
Galenicum Health SL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Galenicum Health SL filed Critical Galenicum Health SL
Priority to EP13756151.0A priority Critical patent/EP2890369A1/fr
Publication of EP2890369A1 publication Critical patent/EP2890369A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals

Definitions

  • 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-tetraenoic acid.
  • the invention further relates to a process for preparing such soft gelatin capsules.
  • 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.
  • compositions 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
  • 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.
  • 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.
  • 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.
  • the properties of the capsule filling may be changed, and, upon administration, the pharmacologically active substance may not be correctly or reproducibly absorbed.
  • the capsule shell is formed from wet gelatin bands and the resultant wet capsules are dried.
  • 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.
  • 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.
  • 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.
  • 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).
  • Soft gelatin capsules can be prepared, among other methods, by two methods.
  • 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.
  • the second method was invented by Robert P. Scherer in 1933 and is called the rotary-die 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.
  • 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.
  • soft gelatin capsules as herein disclosed 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.
  • the soft gelatin capsules as herein disclosed shows good characteristics to be marketed.
  • 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
  • the soft gelatin capsule comprises a capsule shell and a fill
  • 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
  • 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-te
  • 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.
  • 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.
  • the micronization of the active agent gives better soft gelatin capsules, for example, more stable.
  • 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
  • step (ii) filling a soft gelatin capsule with the fill as prepared in step (i) forming the soft gelatin capsule;
  • the soft gelatin capsule fill for the manufacture of immediate release soft gelatin capsules 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 first component is an oily substance or mixtures of
  • the process for the preparation of the fill of the third aspect 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
  • 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.
  • the skin lesion is eczema.
  • 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.
  • 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.
  • 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
  • the soft gelatin capsule comprises a capsule shell and a fill
  • 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
  • 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-te
  • 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.
  • Hydrogenated Coco-Glycerides + Ceteareth-25+ Glyceryl Ricinoleate 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.
  • 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.
  • substantially free of incompatible excipient(s) 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical compositions of the present invention does not comprise any hard fat.
  • 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).
  • 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.
  • 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.
  • 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.
  • the soft gelatin capsules as herein disclosed releases at least a 80 % in 15 min, and at least a 95 % in 60 min.
  • 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).
  • 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.
  • the antioxidant is preferably selected from DL-[alpha]-tocopherol, butylhydroxytoluene (BHT) and butylhydroxyanisole (BHA).
  • 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
  • the soft gelatin capsule consists essentially of a capsule shell and a fill
  • 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
  • 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
  • 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
  • the soft gelatin capsule comprises a capsule shell and a fill
  • 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
  • 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
  • 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
  • the soft gelatin capsule comprises a capsule shell and a fill
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the soft capsules are apt to stick to each other to form an aggregated mass.
  • 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.
  • 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.
  • a plastifying agent can be a mixture of different components.
  • the shell 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.
  • 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.
  • 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.
  • the shell comprises a plastifying agent selected from sorbitol, propylene glycol, glycerol and mixtures thereof.
  • the shell comprises a plastifying agent selected from sorbitol, glycerol and mixtures thereof.
  • the shell comprises a plastifying agent and the plastifying agent is a mixture of sorbitol and glycerol.
  • the antioxidant or antioxidants present in the fill are selected from DL-[alpha]-tocopherol, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA) and mixtures thereof.
  • the antioxidant or antioxidants present in the fill are selected from DL-[alpha]-tocopherol, butylhydroxytoluene (BHT) and mixtures thereof.
  • the antioxidant or the mixture of antioxidants present in the fill comprises DL-[alpha]-tocopherol.
  • the antioxidant or the mixture of antioxidants present in the fill consists of DL-[alpha]-tocopherol.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the capsules comprise glyceryl behenate or glyceryl distearate.
  • the glyceryl behenate or glyceryl distearate is in the fill.
  • 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.
  • 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.
  • the first component comprises at least one natural vegetable oil or mixtures of natural vegetable oils.
  • the first component is a natural vegetable oil or mixtures of natural vegetable oils.
  • the first component comprises olive oil, soybean oil, sesame oil, sunflower oil, safflower oil, rapeseed oil or mixtures thereof.
  • the first component is olive oil, soybean oil, sesame oil, sunflower oil, safflower oil, rapeseed oil or mixtures thereof.
  • the first component comprises soybean oil.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the second component comprises Miglyol 812.
  • the second component is Miglyol 812.
  • liquid lipid 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.
  • 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%.
  • 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.
  • 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.
  • 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.
  • 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.
  • the third component comprises partially hydrogenated soybean oil.
  • the third component is partially hydrogenated soybean oil.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the glyceryl behenate or glyceryl distearate is in the fill.
  • 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
  • (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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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
  • step (ii) filling a soft gelatin capsule with the fill as prepared in step (i) forming the soft gelatin capsule;
  • 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.
  • 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;
  • step (ii) filling a soft gelatin capsule with the fill as prepared in step (i) forming the soft gelatin capsule;
  • 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)non
  • step (ii) filling a soft gelatin capsule with the fill as prepared in step (i) forming the soft gelatin capsule;
  • 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.
  • 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.
  • the soft gelatin capsule fill for the manufacture of immediate release soft gelatin capsules 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 first component is an oily substance or mixtures of
  • 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
  • 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
  • the process for the preparation of the fill of the third aspect 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
  • 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.
  • the soft gelatin capsule is formed by using a rotary die and producing the soft gelatin capsule.
  • 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.
  • the skin lesion is eczema.
  • 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.
  • 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-tetra
  • 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.
  • 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.
  • 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.
  • 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.
  • the shell comprises a plastifying agent selected from sorbitol, propylene glycol, glycerol and mixtures thereof.
  • the shell comprises a plastifying agent selected from sorbitol, glycerol and mixtures thereof.
  • the shell comprises a plastifying agent and the plastifying agent is a mixture of sorbitol and glycerol.
  • the antioxidant or antioxidants present in the fill are selected from DL-[alpha]-tocopherol, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA) and mixtures thereof.
  • antioxidant or antioxidants present in the fill are selected from DL-[alpha]-tocopherol, butylhydroxytoluene (BHT) and mixtures thereof.
  • the antioxidant or the mixture of antioxidants present in the fill comprises, preferably consists of, DL-[alpha]-tocopherol.
  • 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 agent (2E,4E,6Z,8E)-3,7- dimethyl-9-(2,6,6-trimethyl-1 -cyclohexenyl)nona-2,4,6,8-tetraenoic acid is micronized.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the third component comprises partially hydrogenated soybean oil.
  • the third component is partially hydrogenated soybean oil.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the filling mixture comprises a mixture of the second component and of the third component.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • step (ii) optionally drying the soft gelatin capsules.
  • step (ii) comprises encapsulating the soft gelatin capsule fill as prepared in step (i) using a rotary die and producing the soft gelatin capsule.
  • step (ii) comprises encapsulating the soft gelatin capsule fill as prepared in step (i) using a rotary die and producing the soft gelatin capsule.
  • 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
  • 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
  • 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 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 hydrogen
  • 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.
  • Miglyol 812 75 65 soybean oil 120 120 partially hydrogenated soybean oil 65 55
  • 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).
  • 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.
  • 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.
  • 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.
  • gelatin melting 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.
  • 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.
  • a metered positive-displacement pump between the gelatin ribbons forcing them to expand and fill the die cavities.
  • 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.
  • 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).
  • 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.

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Abstract

La présente invention concerne des gélules de gélatine molle à libération immédiate comprenant un principe actif. L'invention concerne en outre un procédé de préparation de telles gélules de gélatine molle.
EP13756151.0A 2012-08-31 2013-09-02 Compositions pharmaceutiques comprenant un principe actif Withdrawn EP2890369A1 (fr)

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PCT/EP2013/068059 WO2014033291A1 (fr) 2012-08-31 2013-09-02 Compositions pharmaceutiques comprenant un principe actif
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US6326397B1 (en) * 1998-11-10 2001-12-04 Hoffman-La Roche Inc. Retinoid antagonists and use thereof
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