Softgel Capsule Preparation

Abstract

The present invention relates to a pharmaceutical or food composition in the form of a softgel capsule comprising a liquid or semi-solid fill and a shell, the fill comprising at least one active ingredient or dietary supplement dissolved, suspended or solubilized in a solution comprising water and alcohol, and a solubilizer and a thickener.The present invention further relates to a method for reducing the brittleness and fragility of such softgel capsules.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical or food composition in the form of a softgel capsule comprising a liquid or semi-solid fill and a shell, the fill comprising at least one active ingredient or dietary supplement dissolved, suspended or solubilized in a solution comprising water and alcohol, and a solubilizer and a thickener.The present invention further relates to a method for reducing the brittleness and fragility of such softgel capsules. [Background technology]

[0002] The use of softgel capsules is increasing across a wide range of applications including prescription drugs, consumer health, vitamin and mineral supplements.

[0003] The process for producing softgel products involves five stages: preparation of the shell mass, production of the fill material, the encapsulation process, drying, and finishing (see, for example, Hutchison KG, Ferdinando J. "Soft capsules". In: Aulton ME, Taylor KMG. Aulton's pharmaceutics: the design and manufacture of medicine. Elsevier Health Sciences 2013, pp. 597-610).

[0004] Conventionally, the outer shell ("shell") is prepared from gelatin, one or more plasticizers, and water. Optional materials such as opacifiers, colorants, flavorings, sweeteners, and preservatives can be included in the shell formulation. This material forms the outermost layer of the capsule and is shaped into the shell that retains the fill material ("fill"), which usually contains one or more active ingredients or one or more nutrients and one or more excipients used to fill the shell itself.

[0005] One of the common challenges associated with softgel capsule performance is the tendency of the capsules to become brittle, especially for softgel capsules containing hygroscopic fills. Capsule manufacturers often link the poor performance of such capsules to the manufacturing process or storage conditions. However, the composition of the shell and / or fill formulation also plays an important role in this phenomenon.

[0006] Preventing brittleness may on the one hand be related to maintaining optimal malleability of the capsule shell, but other factors such as filling pressure and shocks during the packaging, storage and / or transportation processes also play a role.

[0007] The elasticity and malleability of the shell material are also related to the moisture content of the capsule shell. In this sense, in a certain way, the water of the shell formulation migrates from the shell material to the environment. The softgels freshly formed in the encapsulation machine exhibit a moisture content between about 35-40% (weight / weight; w / w). During the drying process, air penetrates the shell and migrates the water outwards to the softgel surface, reducing the initial moisture content to about 20-25% (w / w) in the first or dynamic drying process and to about 10-15% (w / w) in the second or static drying process (see, for example, Gullapalli RP. Soft gelatin capsules (soft gels). J Pharm Sci. 2010; 99(10): 4107-48), and if the capsules lose an excessive amount of moisture (become over-dried), they tend to become brittle. This phenomenon also occurs during storage. To minimize moisture migration, factors such as gelatin shelf life, gelatin ribbon thickness and lubricants used during the encapsulation process can be optimized, and drying and storage conditions (temperature, humidity and airflow conditions) can be further controlled.

[0008] Additionally, free water and glycerol in the shell formulation may migrate into the fill. The presence of hygroscopic compounds in the fill that attract water from the surroundings, either by absorption or adsorption, may promote brittle capsules by reducing the elasticity of the shell material or by increasing the internal pressure.

[0009] Furthermore, reverse migration from the fill to the shell also occurs, but this is a particular problem encountered when the fill contains a large amount of water and / or alcohol, as in the case of plant extracts, which usually contain a significant amount of alcohol and water to keep the extracted compounds soluble in the fill.As described for moisture migration from shell to fill, migration from fill to shell can also lead to capsule brittleness and fragility as well as misshapenness.

[0010] Thus, proper design of a particular softgel capsule formulation requires appropriate selection of shell and fill compositions, and specifically optimization of the fill composition, to enable efficient production of a chemically and physically stable product with the desired biopharmaceutical properties.

[0011] As a result, it is important to recognize that the formulation composition itself is critical to the overall performance of the capsule, including its tendency to become brittle. Therefore, extensive experience in the field of softgel capsule manufacturing is required to develop capsules suitable for encapsulating specific active ingredients and dietary supplements.

[0012] The present invention is therefore faced with the technical problem of providing a fill and shell combination for softgel capsules which is suitable for encapsulating active ingredients or dietary supplements having hygroscopic and / or hydrophilic fill compositions and which is able to overcome the above-mentioned problems of brittleness and fragility of such softgel capsules. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Hutchison KG, Ferdinando J. "Soft capsules" In:Aulton ME, Taylor KMG.Aulton's pharmaceutics: the design and manufacture of medicine.Elsevier Health Sciences 2013, pp. 597-610 [Non-Patent Document 2] Gullapalli RP.Soft gelatin capsules(soft gels).J Pharm Sci.2010;99(10):4107-48 Summary of the Invention [Means for solving the problem]

[0014] Accordingly, the present invention provides a pharmaceutical or dietary supplement composition in the form of a softgel capsule comprising a liquid or semi-solid fill and a shell, the fill being: a) at least one active ingredient or dietary supplement dissolved, suspended or solubilized in a solution comprising between 2% and 50% (w / w) water and between 5% and 0.2% (w / w) alcohol, preferably ethanol; b) at least one solubilizer selected from low molecular weight polyethylene glycols (PEGs), preferably PEGs with a molecular weight between 300 and 600, such as macrogol 400 or macrogol 600, vegetable oils, such as soybean oil, sunflower oil, olive oil or corn oil, and medium chain triglycerides, preferably selected from macrogol 600, sunflower oil, olive oil, corn oil, or combinations thereof; c) at least one thickening agent selected from high molecular weight polyethylene glycols, preferably macrogol 4000, beeswax, glycerol monostearate 40-55 (type I), colloidal silicon dioxide, hard fat, lauroyl polyoxylglycerides, such as lauroyl macrogol-32 glyceride (sold under the trade name Gelucire® 44 / 14), or stearoyl macrogol glycerides, such as stearoyl macrogol-32 glyceride (sold under the trade name Gelucire® 50 / 13), or combinations thereof; Includes; the shell comprises an edible polymer and / or a plasticizer, and optionally an opacifier and / or a colorant; It relates to a pharmaceutical or dietary supplement composition.

[0015] In a further embodiment of the invention, the solution comprising water and alcohol is i. less than 5% (w / w), less than 4% (w / w), less than 3% (w / w), less than 2%, less than 1% (w / w), less than 0.5% (w / w), or less than 0.25% (w / w) alcohol, preferably ethanol, and ii. Less than 50% (w / w), less than 45% (w / w), less than 40% (w / w), less than 35% (w / w), less than 30% (w / w), less than 25% (w / w), less than 20% (w / w), or less than 15% (w / w) water; Includes.

[0016] In one embodiment of the present invention, the solution comprising water and alcohol is i. between 4% and 0.5% (w / w), between 3% and 1% (w / w), between 2% and 1% (w / w), between 2% and 0.5% (w / w), or between 1% and 0.2% (w / w) of alcohol, preferably ethanol; and ii. Between 3% and 50% (w / w), between 4% and 50% (w / w), between 5% and 50% (w / w), between 6% and 50% (w / w), between 7% and 50% (w / w), between 8% and 50% (w / w), between 9% and 50% (w / w), between 10% and 50% (w / w), between 11% and 50% (w / w), between 12% and 50% (w / w), between 13% and 50% (w / w), between 14% and 50% (w / w) ), between 15% and 50% (w / w), between 20% and 50% (w / w), between 30% and 50% (w / w), between 35% and 50% (w / w), between 40% and 50% (w / w), between 45% and 50% (w / w), between 15% and 49% (w / w), between 20% and 48% (w / w), between 25% and 47% (w / w), between 30% and 46% (w / w), or between 35% and 45% (w / w) of water Includes.

[0017] In one embodiment of the pharmaceutical or nutraceutical composition of the present invention, a) the active ingredient is dissolved, suspended or solubilized in a solution containing between 5% and 0.2% (w / w) ethanol and between 2% and 50% (w / w) water; b) the at least one solubilizing agent is selected from macrogol 600, sunflower oil, olive oil and corn oil, or a combination thereof; c) at least one thickening agent is selected from macrogol 4000, glycerol monostearate 40-55 (type I), colloidal silicon dioxide and beeswax, or a combination thereof; The shell comprises an edible polymer and / or a plasticizer, and optionally an opacifier and / or a colorant.

[0018] In a further embodiment of the pharmaceutical or nutraceutical composition, the active ingredient is a hydrophilic active ingredient, preferably a hydrophilic plant extract, more preferably a highly concentrated hydrophilic plant extract.

[0019] In one embodiment, the active ingredient is a plant extract comprising at least one of chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candytuft fresh plant liquid extract, melissa leaf liquid extract, chamomile flower liquid extract, lemon balm leaf liquid extract, angelica root liquid extract, celandine herb liquid extract, milk thistle fruit liquid extract, or a combination thereof.

[0020] In one embodiment, the active ingredient is a plant extract comprising chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candy tuft fresh plant liquid extract and melissa leaf liquid extract. In a preferred embodiment, the active ingredient is Iberogast N concentrate, as further detailed in the following description.

[0021] In one embodiment, the active ingredient is a plant extract including chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candytuft fresh plant liquid extract, lemon balm leaf liquid extract, angelica root liquid extract, celandine herb liquid extract and milk thistle fruit liquid extract.

[0022] In one embodiment, the active ingredient is a plant extract comprising at least one of American aspen or aspen stem bark and leaf liquid extract, Common ash stem bark liquid extract, European goldenrod herb liquid extract, or a combination thereof.

[0023] In one embodiment of the invention, the edible polymer is selected from gelatin, gelatin RXL, gelatin GELITA® RXL R2 and non-animal derived compounds such as Seagel® CAP 203, carrageenan, vegetable starch such as corn or pea starch, or combinations thereof, preferably gelatin GELITA® RXL R2 or Seagel® CAP 203.

[0024] In a preferred embodiment of the pharmaceutical or nutraceutical composition of the present invention, a) the active ingredient is Iberogast N concentrate; b) the at least one solubilizing agent is selected from macrogol 600, sunflower oil, olive oil and corn oil, or a combination thereof; c) at least one thickening agent is selected from macrogol 4000, glycerol monostearate 40-55 (type I), colloidal silicon dioxide and beeswax, or a combination thereof; The shell comprises an edible polymer selected from gelatin, gelatin RXL, gelatin GELITA® RXL R2 and a non-animal derived compound such as Seagel® CAP 203, carrageenan, vegetable starch such as corn or pea starch, or combinations thereof, preferably gelatin GELITA® RXL R2 or Seagel® CAP 203.

[0025] In yet a further embodiment of the invention, the plasticizer is selected from glycerin, propylene glycol, mannitol, sorbitan, sorbitol, or similar low molecular weight polyols, or combinations thereof.

[0026] In one embodiment, the opacifying agent is selected from starch, titanium dioxide, calcium carbonate, zinc oxide, tricalcium phosphate, iron oxide, or a combination thereof.

[0027] In one embodiment, the colorant is selected from synthetic or natural colorants.

[0028] In a further embodiment of the pharmaceutical or dietary supplement composition of the invention, the water activity value of the fill material is between 0.30 and 0.60, preferably between 0.35 and 0.50, more preferably between 0.37 and 0.47, and most preferably between 0.38 and 0.45.

[0029] In a further embodiment of the pharmaceutical or dietary supplement composition of the invention, the water activity value of the fill material is between 0.70 and 0.90, preferably between 0.73 and 0.85, more preferably between 0.74 and 0.84, and most preferably between 0.75 and 0.83.

[0030] The present invention further relates to a method of reducing the brittleness of the softgel capsules described herein, wherein a solubilizer is added to the fill prior to encapsulation with the shell, and the solubilizer is selected from Macrogol 400, Macrogol 600, vegetable oils such as soybean oil, sunflower oil, olive oil and corn oil, preferably the solubilizer is Macrogol 600, sunflower oil, olive oil or corn oil, or a combination thereof.

[0031] The present invention also relates to a method for reducing the brittleness of the softgel capsules described herein, comprising the step of adding a solubilizer to the fill prior to encapsulation with the shell, wherein the solubilizer is selected from macrogol 400, macrogol 600, vegetable oils such as soybean oil, sunflower oil, olive oil and corn oil, preferably the solubilizer is macrogol 600, sunflower oil, olive oil or corn oil, or a combination thereof.

[0032] The present invention further relates to a pharmaceutical or nutraceutical composition as described herein for use in the treatment of functional disorders of the gastrointestinal (GI) tract, such as functional dyspepsia (FD) and irritable bowel syndrome (IBS), mild gastrointestinal complaints, such as abdominal bloating, mild cramping or burning sensation, pain, inflammation, swelling and functional disorders associated with diseases of the locomotor apparatus of rheumatic origin, such as rheumatoid arthritis, arthrosis, spinal syndromes, epicondylitis, periarthritis, Bechterew's disease and / or lower back pain. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] The present invention may be understood more readily by reference to the following detailed description of the preferred embodiments of the invention and the examples included therein.

[0034] Proper design of a particular softgel capsule formulation requires appropriate selection of the shell and fill compositions, as well as optimization of the two, to enable efficient production of a chemically and physically stable product with the desired biopharmaceutical properties.

[0035] The present invention is faced with the technical problem of providing a fill and shell composition for softgel capsules which is suitable for encapsulating active ingredients or dietary supplements having hygroscopic and / or hydrophilic fill compositions and which is able to overcome the above-mentioned problems of brittleness and fragility of such softgel capsules.

[0036] Accordingly, the present invention provides a pharmaceutical or dietary supplement composition in the form of a softgel capsule comprising a liquid or semi-solid fill and a shell, the fill being: a) at least one active ingredient or dietary supplement dissolved, suspended or solubilized in a solution comprising between 2% and 50% (w / w) water and between 5% and 0.2% (w / w) alcohol, preferably ethanol; b) at least one solubilizer selected from low molecular weight polyethylene glycols (PEGs), preferably PEGs with a molecular weight between 300 and 600, such as macrogol 400 or macrogol 600, vegetable oils, such as soybean oil, sunflower oil, olive oil and corn oil, and medium chain triglycerides, preferably selected from macrogol 600, sunflower oil, olive oil or corn oil, or combinations thereof; c) at least one thickening agent selected from high molecular weight polyethylene glycols, preferably macrogol 4000, beeswax, glycerol monostearate 40-55 (type I), colloidal silicon dioxide, hard fat, lauroyl polyoxylglycerides, such as lauroyl macrogol-32 glyceride (sold under the trade name Gelucire® 44 / 14), or stearoyl macrogol glycerides, such as stearoyl macrogol-32 glyceride (sold under the trade name Gelucire® 50 / 13), or combinations thereof; Includes; The shell comprises an edible polymer and / or a plasticizer, and optionally an opacifier and / or a colorant; It relates to a pharmaceutical or dietary supplement composition.

[0037] As used herein, the term "pharmaceutical composition" refers to a composition suitable for prescription and over-the-counter drugs and available only from a doctor at a pharmacy or drug store.

[0038] As used herein, the term "nutraceutical composition" means a composition intended to supplement regular food intake with additional nutritional elements to enhance the quality of life and which is freely available without a prescription in drug stores as well as grocery stores or supermarkets.

[0039] The active ingredient or dietary supplement of the present invention is solubilized, suspended or dissolved in a solution that includes water and alcohol, preferably ethanol.It should be understood that the active ingredient and dietary supplement of the present invention require a hydrophilic environment, which increases the challenge when it is desired to encapsulate in softgel capsule.The active ingredient according to the present invention can be any ingredient that provides pharmacological activity or other direct effect in the treatment or prevention of disease, or that affects the structure or any function of the body.

[0040] In a further embodiment of the invention, the solution comprising water and alcohol is i. less than 5% (w / w), less than 4.5% (w / w), less than 4% (w / w), less than 3.5% (w / w), less than 3% (w / w), less than 2.5% (w / w), less than 2%, less than 1.5% (w / w), less than 1% (w / w), less than 0.9% (w / w), less than 0.8% (w / w), less than 0.7% (w / w), less than 0.6% (w / w), less than 0.5% (w / w), less than 0.4% (w / w), less than 0.3% (w / w), or less than 0.25% (w / w) of alcohol, preferably ethanol, and ii. Less than 50% (w / w), Less than 49% (w / w), Less than 48% (w / w), Less than 47% (w / w), Less than 46% (w / w), Less than 45% (w / w), Less than 44% (w / w), Less than 43% (w / w), Less than 42% (w / w), Less than 41% (w / w), Less than 40% (w / w), Less than 39% (w / w), Less than 38% (w / w), Less than 37% (w / w), Less than 36%, Less than 35% (w / w), Less than 34% (w / w), Less than 33% (w / w), Less than 32% (w / w), Less than 31% (w / w), Less than 30% (w / w), Less than 29% (w / w), Less than 28% (w / w), Less than 27% (w / w) , less than 26%(w / w), less than 25%(w / w), less than 24%(w / w), less than 23%(w / w), less than 22%(w / w), less than 21%(w / w), less than 20%(w / w), less than 19%(w / w), less than 18%(w / w), less than 17%(w / w), less than 16%(w / w), less than 15%(w / w), less than 14%(w / w), less than 13%(w / w), less than 12%(w / w), less than 11%(w / w), less than 10%(w / w), less than 9%(w / w), less than 8%(w / w), less than 7%(w / w), less than 6%(w / w), less than 5%(w / w), less than 4%(w / w), or less than 3%(w / w) of water Includes.

[0041] In one embodiment of the present invention, the solution comprising water and alcohol is i. between 4% and 0.5% (w / w), between 3% and 1% (w / w), between 2% and 1% (w / w), between 2% and 0.5% (w / w), or between 1% and 0.2% (w / w) of alcohol, preferably ethanol; and ii. Between 3% and 50% (w / w), between 4% and 50% (w / w), between 5% and 50% (w / w), between 6% and 50% (w / w), between 7% and 50% (w / w), between 8% and 50% (w / w), between 9% and 50% (w / w), between 10% and 50% (w / w), between 11% and 50% (w / w), between 12% and 50% (w / w), between 13% and 50% (w / w), between 14% and 50% (w / w), between 15% and 16% (w / w), between 17% and 18% (w / w), between 19% and 20% (w / w), between 21% and 22% (w / w), between 23% and 24% (w / w), between 25% and 26% (w / w), between 26% and 27% (w / w), between 28% and 29% (w / w), between 30% and 31% (w / w), between 32% and 33% (w / w), between 33% and 34% (w / w), between 34% and 35% (w / w), between 35% and 36% (w / w), between 36% and 37% (w / w), between 37% and 38% (w / w), between 38% and 39% (w / w), between 39% and 40% (w / w), between 40% and 41 ... Between % and 50% (w / w), Between 14% and 50% (w / w), Between 15% and 50% (w / w), Between 20% and 50% (w / w), Between 30% and 50% (w / w), Between 35% and 50% (w / w), Between 40% and 50% (w / w), Between 45% and 50% (w / w), Between 3% and 49% (w / w), Between 4% and 49% (w / w), Between 5% between 6% and 49% (w / w), between 7% and 49% (w / w), between 8% and 49% (w / w), between 9% and 49% (w / w), between 10% and 49% (w / w), between 11% and 49% (w / w), between 12% and 49% (w / w), between 13% and 49% (w / w), between 14% and 49% (w / w), between 15% and 49% (w / w), between 9% (w / w), between 20% and 49% (w / w), between 30% and 49% (w / w), between 35% and 49% (w / w), between 40% and 49% (w / w), between 45% and 49% (w / w), between 20% and 48% (w / w), between 25% and 47% (w / w), between 30% and 46% (w / w), or between 35% and 45% (w / w) of water Includes.

[0042] In one embodiment, the solution comprising water and alcohol is less than 49% (w / w), less than 48% (w / w), less than 47% (w / w), less than 46% (w / w), less than 45% (w / w), less than 44% (w / w), less than 43% (w / w), less than 42% (w / w), less than 41% (w / w), less than 40% (w / w), less than 39% (w / w), less than 38% (w / w), less than 37% (w / w), less than 36% (w / w), less than 35% (w / w), less than 34% (w / w), less than 33% (w / w), less than 32% (w / w), less than 31% (w / w), less than 30% (w / w), less than 29% (w / w), less than 28% (w / w), less than 27% (w / w),

[0033] In one embodiment, the composition contains less than 26% (w / w), less than 25% (w / w), less than 24% (w / w), less than 23% (w / w), less than 22% (w / w), less than 21% (w / w), less than 20% (w / w), less than 19% (w / w), less than 18% (w / w), less than 17% (w / w), less than 16% (w / w), less than 15% (w / w), less than 14% (w / w), less than 13% (w / w), less than 12% (w / w), less than 11% (w / w), less than 10% (w / w), less than 9% (w / w), less than 8% (w / w), less than 7% (w / w), less than 6% (w / w), less than 5% (w / w), less than 4% (w / w), or less than 3% (w / w) of water.

[0043] In one embodiment, the solution comprising water and alcohol is at least 2% (w / w), at least 3% (w / w), at least 4% (w / w), at least 5% (w / w), at least 6% (w / w), at least 7% (w / w), at least 8% (w / w), at least 9% (w / w), at least 10% (w / w), at least 11% (w / w), at least 12% (w / w), at least 13% (w / w), at least 14% (w / w), at least 15% (w / w), at least 16% (w / w), at least 17% (w / w), at least 18% (w / w), at least 19% (w / w), at least 20% (w / w), at least 21% (w / w), at least 22% (w / w), at least 23% (w / w), at least 24% (w / w), at least 25% (w / w), at least 26% (w / w), at least 27% (w / w), at least 28% (w / w), at least 29% (w / w), at least 30% (w / w), at least 31% (w / w), at least 32% (w / w), at least 33% (w / w), at least 34% (w / w), at least 35% (w / w), at least 36% (w / w), at least 37% (w / w), at least 38% (w / w), at least 39% (w / w), at least 40% (w / w), at least 41% (w / w), at least 42% (w / w), at least 43% (w / w), at least 44% (w / w), at least 45% (w / w), at least 46% (w / w), at least 47% (w / w), at least / w), at least 26% (w / w), at least 27% (w / w), at least 28% (w / w), at least 29% (w / w), at least 30% (w / w), at least 31% (w / w), at least 32% (w / w), at least 33% (w / w), at least 34% (w / w), at least 35% (w / w), at least 36% (w / w), at least 37% (w / w), at least at least 38% (w / w), at least 39% (w / w), at least 40% (w / w), at least 41% (w / w), at least 42% (w / w), at least 43% (w / w), at least 44% (w / w), at least 45% (w / w), at least 46% (w / w), at least 47% (w / w), at least 48% (w / w), or at least 49% (w / w) water.

[0044] In one embodiment of the pharmaceutical or nutraceutical composition of the present invention, a) the active ingredient is dissolved, suspended or solubilized in a solution containing between 5% and 0.2% (w / w) ethanol and between 2% and 50% (w / w) water; b) the at least one solubilizing agent is selected from macrogol 600, sunflower oil, olive oil and corn oil, or a combination thereof; c) at least one thickening agent is selected from macrogol 4000, glycerol monostearate 40-55 (type I), colloidal silicon dioxide and beeswax, or a combination thereof; The shell comprises an edible polymer and / or a plasticizer, and optionally an opacifier and / or a colorant.

[0045] In one embodiment of the invention, the capsule fill is less than 14.0% (w / w), less than 13.5% (w / w), less than 13.0% (w / w), less than 12.5% ​​(w / w), less than 12.0% (w / w), less than 11.5% (w / w), less than 11.0% (w / w), less than 10.5% (w / w), less than 10.0% (w / w), less than 9.5% (w / w), less than 9.0% (w / w), less than 8.5% (w / w). The total moisture content of the fill may be less than 8.0% (w / w), less than 7.5% (w / w), less than 7.0% (w / w), less than 6.5% (w / w), less than 6.0% (w / w), less than 5.5% (w / w), less than 5.0% (w / w), less than 4.5% (w / w), less than 4.0% (w / w), less than 3.5% (w / w), less than 3.0% (w / w), less than 2.5% (w / w), or less than 2.0% (w / w). It should be understood that the total moisture content of the fill refers to the amount measured after the capsule is manufactured. The moisture content may change during and after storage.

[0046] In one embodiment of the invention, the capsule filling comprises water with a total moisture content of between 2.0-14.0% (w / w), between 2.5-13.5% (w / w), between 3.0-13.0% (w / w), between 3.5-12.5% ​​(w / w), between 4.0-12.0% (w / w), between 4.5-11.5% (w / w), between 5.0-11.0% (w / w), between 5.5-10.5% (w / w), between 6.0-10.0% (w / w), between 6.5-9.5% (w / w), between 7.0-9.0% (w / w), or between 7.5-8.5% (w / w).

[0047] In a preferred embodiment, the capsule fill contains a total moisture content of between 2.0-3.0% (w / w).

[0048] In a preferred embodiment, the capsule fill contains a total moisture content of between 3.0-4.0% (w / w).

[0049] In a preferred embodiment, the capsule fill contains a total moisture content of between 3.5 and 4.0% (w / w).

[0050] In a preferred embodiment, the capsule fill contains a total moisture content of between 4.0 and 4.5% (w / w).

[0051] In a preferred embodiment, the capsule fill contains a total moisture content of between 4.0-5.0% (w / w).

[0052] In a preferred embodiment, the capsule fill contains a total moisture content of between 5.0 and 5.5% (w / w).

[0053] In a preferred embodiment, the capsule fill contains a total moisture content of between 5.5 and 6.0% (w / w).

[0054] In a preferred embodiment, the capsule fill contains a total moisture content of between 6.0 and 6.5% (w / w).

[0055] In a preferred embodiment, the capsule fill contains a total moisture content of between 6.5 and 7.0% (w / w).

[0056] In a preferred embodiment, the capsule fill contains a total moisture content of between 7.0 and 8.0% (w / w).

[0057] In a preferred embodiment, the capsule fill contains a total moisture content of between 8.0 and 8.5% (w / w).

[0058] In a preferred embodiment, the capsule fill contains a total moisture content of between 8.5 and 9.0% (w / w).

[0059] In a preferred embodiment, the capsule fill contains a total moisture content of between 9.0 and 10.0% (w / w).

[0060] In a preferred embodiment, the capsule fill contains a total moisture content between 10.0 and 10.5% (w / w).

[0061] In a preferred embodiment, the capsule fill contains a total moisture content of between 10.5 and 11.0% (w / w).

[0062] In a preferred embodiment, the capsule fill contains a total moisture content of between 11.0 and 12.0% (w / w).

[0063] In a preferred embodiment, the capsule fill contains a total moisture content between 12.0 and 12.5% ​​(w / w).

[0064] In a further embodiment of the pharmaceutical or nutraceutical composition, the active ingredient is a hydrophilic active ingredient, preferably a hydrophilic plant extract, more preferably a highly concentrated hydrophilic plant extract.

[0065] In one embodiment, the active ingredient is a plant extract comprising at least one of chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candytuft fresh plant liquid extract, melissa leaf liquid extract, chamomile flower liquid extract, lemon balm leaf liquid extract, angelica root liquid extract, celandine herb liquid extract, milk thistle fruit liquid extract, or a combination thereof.

[0066] It should be understood that the plant extracts listed above can be mixed in any combination using 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or all 12 extracts to prepare a plant extract according to the present invention.

[0067] In one embodiment, the active ingredient is a plant extract comprising at least one of chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candy tuft fresh plant liquid extract, lemon balm leaf liquid extract, angelica root liquid extract, celandine herb liquid extract, milk thistle fruit liquid extract, or combinations thereof.It should be understood that the listed plant extracts can be mixed in any combination using 2, 3, 4, 5, 6, 7, 8, 9 or 10 of these extracts to prepare the plant extract according to the present invention.The combination comprising all 10 extracts is preferred.

[0068] In one embodiment, the active ingredient is a plant extract including chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candytuft fresh plant liquid extract, lemon balm leaf liquid extract, angelica root liquid extract, celandine herb liquid extract and milk thistle fruit liquid extract.

[0069] In a further embodiment, the active ingredient is a plant extract comprising at least one of American aspen or aspen stem bark and leaf liquid extract, Common ash stem bark liquid extract, European goldenrod herb liquid extract, or combinations thereof.It should be understood that the plant extract can be mixed in any combination, using two or three of these extracts to prepare the plant extract according to the present invention.The combination of all three extracts is preferred.

[0070] In a preferred embodiment, the active ingredient is a plant extract including chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candytuft fresh plant liquid extract and melissa leaf liquid extract.

[0071] In a preferred embodiment, the active ingredient is Iberogast N concentrate.

[0072] As described in Example 2, Iberogast N concentrate is the product of a distillation process of Iberogast N to remove ethanol and reduce water content to obtain a viable material to be encapsulated into softgel capsules. During the manufacturing process, the active ingredient, Iberogast N, is concentrated by distillation with 1 ml of Iberogast N dosage being converted to approximately 78-82 μl of Iberogast N concentrate, a concentrated form of Iberogast N. As shown in Table 7, Iberogast N concentrate refers to a concentrate of Iberogast N that contains 40-50% (w / w) water and up to 2% (w / w) ethanol.

[0073] As used herein, Iberogast N refers to a plant extract comprising a combination of chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candytuft fresh plant liquid extract, and melissa leaf liquid extract as disclosed in Table 6 of Example 2.

[0074] As mentioned above, one of the main challenges associated with the encapsulation of hydrophilic and / or hygroscopic fill formulations is the tendency of water and alcohol migration from the fill to the shell. This can be seen in Example 1, where several attempts were made to encapsulate Iberogast®, a plant extract containing a water content of about 68% (w / w) and an ethanol content of at least 29.5% (w / w), in softgel capsules. As a result of this, Iberogast N concentrate was prepared as described above in order to reduce the water and ethanol content of the plant extract filled into the softgel capsules. Thus, a preferred embodiment of the present invention is a pharmaceutical or nutraceutical composition in which the fill contains Iberogast N concentrate as at least one active ingredient. As shown in Example 2, although the reduction in water and ethanol content gave better results, the softgel capsules exhibited brittleness and fragility, compromising the stability of the product during handling and storage. The use of soybean oil as a solubilizer and beeswax as a thickener in the fill resulted in more storage stable softgel capsules that showed no signs of brittleness after 12 months of storage. However, these capsules also showed less flexibility after longer storage, as well as stickiness. Therefore, alternative formulations were developed to overcome these minor shortcomings, as shown in Examples 3-8.

[0075] Therefore, to further reduce the brittleness of the softgel capsules containing Iberogast N concentrate, at least one solubilizer selected from Macrogol 600, sunflower oil, olive oil and corn oil, or combinations thereof, was added to the fill in combination with at least one thickener selected from Macrogol 4000, Geleol™ mono- and diglycerides NF, colloidal silicon dioxide and beeswax, or combinations thereof.

[0076] Another challenge observed during the development of such softgel capsules was capsule misshapenness depending on the selected fill composition. As described herein, the term "misshapen" refers to capsule deformation. These capsules are more sticky to the packaging material, difficult to swallow, and detrimental to consumer quality perception. Therefore, such misshapenness should be avoided.

[0077] The solubilizer according to the present invention is selected from low molecular weight polyethylene glycols (PEG), preferably PEG with a molecular weight between 300 and 600, such as macrogol 400 or macrogol 600, vegetable oils such as soybean oil, sunflower oil, olive oil and corn oil, and medium chain triglycerides, preferably the solubilizer is selected from macrogol 600, sunflower oil, olive oil or corn oil, or combinations thereof.

[0078] Polyethylene glycol, due to its ability to be miscible with aqueous fluids in all proportions, can dissolve many pharmaceutical compounds while being an ideal vehicle for delivery. Polyethylene glycols with molecular weights ranging from 300 to 600 can be used as hydrophilic vehicles for fill formulations for softgel capsules. The solubilizing ability of polyethylene glycol increases at lower molecular weights. However, its use is limited due to its ability to diffuse into the shell and thereby act as a plasticizer for gelatin or other shell materials. The degree of diffusion of polyethylene glycol from the fill to the shell decreases with increasing its molecular weight. Thus, in one embodiment, macrogol 600 was selected as the most preferred solubilizing agent due to its low hygroscopicity compared to other low molecular weight PEGs, such as macrogol 400.

[0079] Further preferred solubilizers of the present invention are vegetable oils that can be added to the fill composition to reduce undesirable fill-shell migration.Preferred vegetable oils are soybean oil, sunflower oil, olive oil and corn oil.

[0080] Soybean oil is a fatty oil extracted from the seeds of soybeans (Glycine max). Sunflower oil is a fatty oil obtained by mechanical expression or extraction from the seeds of sunflowers (Helianthus annuus) and then refined. Olive oil is a fatty oil obtained by refining crude olive oil, which is obtained from the ripe stone of olives (Olea europaea) by cold expression or other suitable mechanical means. Corn oil is a fatty oil obtained by expression or extraction from the seeds of corn (Zea mays) and then refined.

[0081] The thickener of the present invention is added as an emulsifier and viscosity-increasing agent in the fill composition. The thickener of the present invention is selected from high molecular weight polyethylene glycols, preferably macrogol 4000, Geleol mono- and diglycerides NF, also called glycerol monostearate 40-55 (type I), colloidal silicon dioxide, beeswax, hard fat, lauroyl polyoxyl glycerides, such as lauroyl macrogol-32 glyceride (sold under the trade name Gelucire 44 / 14), or stearoyl macrogol glycerides, such as stearoyl macrogol-32 glyceride (sold under the trade name Gelucire 50 / 13), or combinations thereof.

[0082] Glycerol monostearate 40-55 (Type I), sold by Gattefosse as Geleol™ Mono- and Diglycerides NF, is an intermediate melting glyceride used as a lipid vehicle and modified release agent. In capsules, it can be used as a modified release matrix former and a coating agent for taste masking, or as a thickening agent.

[0083] Suitable thickening agents and solubilizing agents are further described in the Examples section.

[0084] In one embodiment of the invention, the edible polymer is selected from gelatin, gelatin RXL, gelatin GELITA® RXL R2 and non-animal derived compounds such as Seagel® CAP 203, carrageenan, vegetable starch such as corn or pea starch, or combinations thereof, preferably gelatin GELITA® RXL R2 or Seagel® CAP 203.

[0085] As is common for liquid-based capsule formulations, the encapsulating material can be a soft shell. Thus, the present disclosure provides a softgel capsule that includes a shell that encapsulates the inner filling. Shells, as well as compositions and / or mixtures used in preparing the shells, are also provided. As understood in the art, a typical shell for a softgel capsule can contain gelatin or non-animal-derived ingredients as the main encapsulating material, water, and a plasticizer, such as glycerin and / or sorbitol-sorbitan solution, to allow the gelatin or non-animal-derived ingredients to form and retain the desired capsule shape. However, in addition to gelatin and non-animal-derived ingredients, water, glycerin and / or sorbitol-sorbitan solution, the shell of the present invention can contain one or more additional colorants, such as pearlescent pigments or other opaque materials, that make the softgel capsule visually appealing to consumers.

[0086] In a preferred embodiment of the present invention, the softgel capsule comprises gelatin as the primary matrix of the shell, since the physical properties of gelatin can be easily modified with plasticizers or colorants as needed. For example, certain grades of gelatin characterized by bloom strength can be utilized for the shell.

[0087] In one embodiment, the capsule shell comprises about 20% to about 60% (w / w) gelatin, more preferably about 25% to about 52% (w / w) gelatin, and most preferably about 40% to about 52% (w / w) gelatin. The gelatin can be type A or type B, or a mixture thereof, having a bloom number in the range of about 60 to about 300, more preferably about 100 to 180 bloom.

[0088] In some embodiments, the gelatin shell comprises at least about 35%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53% gelatin by weight of the total weight of the shell.

[0089] In some embodiments, the shell comprises a non-animal derived component, such as Seagel® CAP 203, carrageenan, vegetable starch, such as corn or pea starch, or a combination thereof, as the primary matrix of the outer shell, the physical properties of which can be easily modified with plasticizers and / or colorants, as required.

[0090] In some embodiments, the shell comprising non-animal derived components comprises at least about 20% by weight, at least about 21% by weight, at least about 22% by weight, at least about 23% by weight, at least about 24% by weight, at least about 25% by weight, at least about 26% by weight, at least about 27% by weight, at least about 28% by weight, at least about 29% by weight, at least about 30% by weight, at least about 31% by weight, at least about 32% by weight, at least about 33% by weight, at least about 34% by weight, at least about 35% by weight of the total weight of the shell, e.g., Seagel® CAP 203.

[0091] Water is added to the gelatin and / or non-animal derived ingredients to provide a liquid shell mixture that is easily manipulated and shaped during the manufacturing process. In some embodiments, the shell comprises water. In certain embodiments, the shell has a water content of at least about 20%, at least about 25%, at least about 28%, at least about 30%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, or at least about 39.5% by weight of the total weight of the shell.

[0092] The shells of the present invention, when first prepared, generally contain from about 10% to about 35% (w / w) plasticizer, preferably from about 15% to about 30% (w / w) plasticizer, and most preferably from about 20% to about 30% (w / w) plasticizer. A preferred plasticizer according to the present invention is glycerin. Another preferred plasticizer is sorbitol, sorbitan, and / or a combination of sorbitol and sorbitan.

[0093] In another preferred embodiment, the plasticizer may be a mixture of glycerin, sorbitol and sorbitan.

[0094] In some embodiments, the shell comprises at least about 13.0%, at least about 14.0%, at least about 15.0%, at least about 16.0%, at least about 17.0%, at least about 18.0%, at least about 19.0%, or at least about 20.0% glycerin by weight of the total weight of the shell.

[0095] Plasticizers, including but not limited to glycerin and sorbitol sorbitan solutions, can be added to the shell to impart the desired material properties of the final shell for handling, storage and use. The soft shell thus obtained has the necessary flexibility properties for use as an encapsulant. Useful plasticizers of the present invention include glycerin, propylene glycol, sorbitan, sorbitol, or similar low molecular weight polyols, and mixtures thereof.

[0096] For example, glycerin and / or sorbitol-sorbitan can be added to increase the plasticity and flexibility of the shell. In some embodiments, the shell comprises one or more plasticizers. In certain embodiments, the one or more plasticizers comprise glycerin. In other embodiments, the one or more plasticizers comprise sorbitol-sorbitan.

[0097] Currently, there is an increasing interest in using materials that avoid animal-derived products or compounds in capsule shell formulations to address cultural, religious, and dietary requirements.For example, hydroxypropyl methylcellulose, which is used in V-caps, Quali-VC, and Vegicaps, as well as pullulan shell (NPCaps) and starch are envisioned alternatives for shell materials that do not contain animal-derived products.Therefore, in a preferred embodiment of the present invention, the shell does not contain animal-derived products.In one embodiment of the present invention, the shell comprises starch, carrageenan, Seagel® CAP 203, or a combination thereof.

[0098] In some embodiments, the shell comprises at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, or at least about 24% glycerin by weight of the total weight of the shell, with glycerin in an amount of at least about 25% being most preferred.

[0099] In some embodiments, the shell comprises a colorant, such as a dye or pigment. It should be recognized that any food grade dye known in the art is suitable for use in the shells of the present disclosure.

[0100] In addition to dyes, other colorants can be included to increase the opacity of the shell to provide a more attractive appearance to the softgel capsule. In other embodiments, the shell comprises titanium dioxide, starch, calcium carbonate, zinc oxide, tricalcium phosphate, iron oxide, or combinations thereof. In one embodiment, the shell comprises a pearlescent pigment. In certain embodiments, the pearlescent pigment comprises natural silicate or silica in combination with titanium oxide particles and / or iron oxide particles, the particles having a particle size between about 5 microns and about 150 microns. In certain embodiments, the shell comprises Candurin® pigment. In certain other embodiments, the shell comprises silver or gold pearlescent pigment.

[0101] In further embodiments, the present invention also provides a softgel capsule comprising an inner fill, an outer shell, and a coating, the outer shell encapsulating the inner fill and the coating being applied to the outer shell. The coating may be applied to the outer shell of the softgel capsule described herein for purposes including, but not limited to, further improving aesthetic appearance, flavor modification, ease of ingestion, capsule identification, and the like. In some embodiments, the coating is a film coating. In other embodiments, the coating is a pharmaceutical glaze. In other embodiments, the coating comprises food grade shellac.

[0102] If it is desired to improve the taste of the softgel capsule, flavoring and / or sweetening agents can be added to the capsule as a coating. In other embodiments, the coating comprises one or more flavoring agents. In certain embodiments, the coating comprises sugar or artificial sweeteners.

[0103] The coating may further comprise ink for labeling and / or identification. In some embodiments, the coating comprises ink. In certain embodiments, the ink comprises polypropylene glycol.

[0104] The present invention also specifically relates to softgel capsules containing dietary supplements.

[0105] A dietary supplement may be any composition containing one or more vitamins, herbs, enzymes, amino acids, or other ingredients taken orally to supplement the diet, such as by providing missing nutrients. The composition according to the present invention may contain at least two, three, four, five, or at least six nutrients selected from the group consisting of or including iron (i.e., iron carbonyl, ferrous fumarate, or ferrous sulfate), iodide (i.e., potassium iodide or iodate), magnesium (i.e., magnesium oxide), calcium (i.e., calcium carbonate), zinc (i.e., zinc oxide or zinc sulfate), copper selenite (i.e., copper sulfate or copper oxide), DHA, and EPA. Furthermore, the composition according to the invention may preferably contain at least two, three, four, five or at least six vitamins selected from the group consisting of or including vitamin A (i.e. retinol palmitate or β-carotene), vitamin B1 (i.e. thiamine or thiamine mononitrate), vitamin B2 (i.e. riboflavin), vitamin B3 (i.e. nicotinamide), vitamin B5 (as pantothenic acid or calcium pantothenate), vitamin B6 (i.e. pyridoxine or pyridoxine hydrochloride), vitamin B9 (i.e. folic acid or metafolin), vitamin B12 (i.e. cyanocobalamin), vitamin H (i.e. biotin), vitamin D (i.e. vitamin D3), vitamin E (i.e. DL-α-tocopheryl acetate, DL-α-tocopherol or D-α-tocopherol), choline (i.e. choline bitartrate) and vitamin K.

[0106] In one embodiment of the present invention, the dietary supplement can be combined with at least one active ingredient dissolved, suspended or solubilized in a solution that comprises less than 50% (w / w) water and less than 5% (w / w) alcohol, preferably ethanol, as further described herein above.In a preferred aspect of said embodiment, the dietary supplement is combined with at least one plant extract comprising chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candy tuft fresh plant liquid extract, melissa leaf liquid extract, chamomile flower liquid extract, licorice root liquid extract, lemon balm leaf liquid extract, angelica root liquid extract, celandine herb liquid extract, milk thistle fruit liquid extract, or combinations thereof.

[0107] In one embodiment of the present invention, the opacifying agent is selected from starch, titanium dioxide, starch, calcium carbonate, zinc oxide, tricalcium phosphate, iron oxide, or combinations thereof.

[0108] In one embodiment, the coloring agent is selected from synthetic or natural coloring agents. Exemplary synthetic coloring agents or lakes include, but are not limited to, FD&C Blue#1, D&C Red#33, D&C Red 40, FD&C Yellow#6, D&C Yellow#10. Exemplary natural coloring agents include, but are not limited to, copper complexes of chlorophyll, carmine, caramel, carotenoids, safflower, carrot, xanthophyll, beetroot red, paprika extract, sorghum extract, vegetable carbon, and annatto.

[0109] The moisture content of the softgel capsule may be described by its water activity value, which may be determined as further described in Example 3.

[0110] Water activity (a w ) is the partial pressure of water vapor in a solution divided by the partial pressure of water vapor at standard temperature. wis a measure of how much of that water is free, i.e. unbound, and therefore available to migrate to the shell. Standard moisture determination methods can be used to determine the total water content. However, water activity measurements were used by the inventors to give insight into the effect of water on important product quality attributes including capsule stability, dissolution rate, and physical properties. Water migrates from regions of high aw to regions of low aw. Thus, the inventors determined that a w was utilized as a parameter for selecting the packing contents of the present invention.

[0111] To minimize moisture migration, the water activity of the filling is ideally close to that of the shell.

[0112] In one embodiment of the pharmaceutical or food composition of the present invention, the water activity value of the filling is between 0.30 and 0.60, between 0.31 and 0.55, between 0.32 and 0.52, between 0.33 and 0.51, preferably between 0.35 and 0.50, more preferably between 0.37 and 0.47, and most preferably between 0.38 and 0.45. In a preferred embodiment, the water activity value of the filling is 0.39. In another preferred embodiment, the water activity value of the filling is 0.45.

[0113] In further embodiments of the pharmaceutical or dietary supplement composition of the invention, the fill has a water activity value between 0.70 and 0.90, preferably between 0.73 and 0.85, more preferably between 0.74 and 0.84, and most preferably between 0.75 and 0.83. In a preferred embodiment, the fill has a water activity value of 0.76. In another preferred embodiment, the fill has a water activity value of 0.82 or 0.81.

[0114] In a preferred embodiment of the pharmaceutical or dietary supplement composition of the present invention, the filler comprises: a) Iberogast N concentrate; b) at least one solubilizer selected from macrogol 600, sunflower oil, olive oil and corn oil, or a combination thereof; c) Macrogol 4000 and at least one thickening agent selected from Geleol™ mono- and diglycerides NF, colloidal silicon dioxide, beeswax or a combination thereof; Includes; The shell comprises an edible polymer and / or a plasticizer, and optionally an opacifier and / or a colorant.

[0115] In another preferred embodiment of the pharmaceutical or dietary supplement composition of the present invention, the filler comprises: a) Iberogast N concentrate; b) at least one solubilizer selected from macrogol 600, sunflower oil, olive oil and corn oil, or a combination thereof; c) macrogol 4000 and at least one thickening agent selected from Geleol™ mono- and diglycerides NF, colloidal silicon dioxide, beeswax, or a combination thereof; Includes; The shell comprises an edible polymer selected from gelatin, gelatin RXL, gelatin GELITA® RXL R2 and a non-animal derived compound such as Seagel® CAP 203, carrageenan, vegetable starch such as corn or pea starch, or combinations thereof, preferably gelatin GELITA® RXL R2 or Seagel® CAP 203.

[0116] In a preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) macrogol 600 and; c) colloidal silicon dioxide; Includes.

[0117] In a further preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) soybean oil; c) beeswax Includes.

[0118] In a further preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) olive oil; c) beeswax Includes.

[0119] In a further preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) with sunflower oil; c) beeswax Includes.

[0120] In a further preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) corn oil; c) beeswax Includes.

[0121] In a further preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) macrogol 600 and; c) Macrogol 4000 and Includes.

[0122] In a further preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) olive oil; c) Glycerol monostearate 40-55 (Type I) Includes.

[0123] In a further preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) with sunflower oil; c) Glycerol monostearate 40-55 (Type I) Includes.

[0124] In a further preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) corn oil; c) Glycerol monostearate 40-55 (Type I) Includes.

[0125] In a further preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) soybean oil; c) Glycerol monostearate 40-55 (Type I) Includes.

[0126] In a preferred embodiment, the shell is free of animal-derived products, with the use of Seagel® CAP 203 being most preferred.

[0127] In a preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) olive oil; c) beeswax Including, The shell comprises Seagel® CAP 203.

[0128] In a further preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) macrogol 600 and; c) colloidal silicone and Including, The shell comprises gelatin GELITA® RXL R2 and optionally sorbitol sorbitan.

[0129] In a further preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) macrogol 600 and; c) colloidal silicone and Including, The shell comprises gelatin RXL and optionally sorbitol sorbitan.

[0130] In a preferred embodiment of the pharmaceutical or food composition of the present invention, the filling comprises: a) Iberogast N concentrate; b) soybean oil; c) beeswax Including, The shell comprises gelatin GELITA® RXL R2 and optionally sorbitol sorbitan.

[0131] The present invention further relates to a method of reducing the brittleness of the softgel capsule disclosed herein, wherein a solubilizer is added to the fill prior to encapsulation with the shell, and the solubilizer is selected from Macrogol 400, Macrogol 600, vegetable oils such as soybean oil, sunflower oil, olive oil and corn oil, preferably the solubilizer is Macrogol 600, sunflower oil, olive oil or corn oil.

[0132] The inventors have shown that the use of certain solubilizing agents in the fill compositions of the present invention, i.e., hydrophilic fill compositions, can reduce the brittleness of softgel capsules caused by undesirable fill-shell interactions.

[0133] The above migration between the fill and the shell also results in a fragile softgel capsule that does not comply with industry standards. Therefore, the addition of a specific solubilizer to the fill composition of the present invention also reduced the fragility of the softgel capsule.

[0134] Therefore, the present invention also relates to a method for reducing the brittleness of a pharmaceutical or dietary supplement composition in the form of a softgel gelatine capsule comprising a liquid or semi-solid fill and a shell, comprising the step of adding a solubilizer to the fill prior to encapsulation with the shell, the solubilizer being selected from macrogol 400, polyethylene glycol 600, vegetable oils such as soybean oil, sunflower oil, olive oil and corn oil, preferably the solubilizer is polyethylene glycol 600, sunflower oil, olive oil or corn oil, or a combination thereof.

[0135] The present invention further relates to a pharmaceutical composition as described herein for use in the treatment of functional disorders of the gastrointestinal (GI) tract, such as functional dyspepsia (FD) and irritable bowel syndrome (IBS), mild gastrointestinal complaints, such as abdominal bloating, mild cramping and / or burning sensations, pain, inflammation, swelling and functional disorders associated with diseases of the locomotor apparatus of rheumatic origin, such as rheumatoid arthritis, arthrosis, spinal syndromes, epicondylitis, periarthritis, Bechterew's disease and / or lower back pain.

[0136] In a preferred embodiment, the present invention relates to a pharmaceutical composition as disclosed herein, wherein the active ingredient is a plant extract comprising chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candytuft fresh plant liquid extract and melissa leaf liquid extract, preferably, the active ingredient is Iberogast N concentrate, for use in the treatment of functional dyspepsia, mild gastrointestinal complaints such as abdominal bloating, mild cramping and / or burning sensation.

[0137] In another preferred embodiment, the present invention relates to a pharmaceutical composition as disclosed herein, wherein the active ingredient is a plant extract comprising a mixture of chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candytuft fresh plant liquid extract, lemon balm leaf liquid extract, angelica root liquid extract, celandine herb liquid extract and milk thistle fruit liquid extract, for use in the treatment of functional disorders of the gastrointestinal (GI) tract, such as functional dyspepsia (FD) and irritable bowel syndrome (IBS).

[0138] In another preferred embodiment, the present invention relates to a pharmaceutical composition as disclosed herein, wherein the active ingredient is a plant extract comprising a mixture of American aspen or aspen stem bark and leaf liquid extract, Common ash stem bark liquid extract and European goldenrod herb liquid extract, for use in the treatment of pain, inflammation, swelling and functional disorders associated with diseases of the locomotor system of rheumatic origin, such as rheumatoid arthritis, arthrosis, spinal syndrome, epicondylitis, periarthritis, Bechterew's disease and / or low back pain.

[0139] The soft shells of the present invention comprising gelatin can be prepared by combining the appropriate amounts of gelatin, water, plasticizer, and any optional ingredients in a suitable container and stirring and / or agitating while heating to about 65°C until a homogenous solution is obtained. This soft gelatin shell preparation can then be used to encapsulate a desired amount of the fill composition using standard encapsulation methods to produce a one-piece sealed soft gelatin capsule. The gelatin capsule is formed into the desired shape and size so that it can be easily swallowed. The soft gelatin capsules of the present invention are of a suitable size for easy swallowing and typically contain about 100 mg to about 2000 mg of the active composition.Soft gelatin capsules and encapsulation methods are reviewed in P. K. Wilkinson et al., "Soft gels: Manufacturing Considerations," Drugs and the Pharmaceutical Sciences, 41 (Specialized Drug Delivery Systems), edited by P. Tyle (Marcel Dekker, Inc., New York, 1990) pp. 409-449; F. S. Shorn et al., "Capsules, Soft," Encyclopedia of Pharmaceutical Technology, Vol. 2, edited by J. Swarbrick and J. C. Boylan (Marcel Dekker, Inc., New York, 1990) pp. 269-284; M. S. Patel et al., "Advances in Soft gel Formulation Technology," Manufacturing Chemist, Vol. 60, No. 7, pp. 26-28 (July 1989); M. S. Patel et al., "Soft gel Technology," Manufacturing Chemist, Vol. 60, No. 8, pp. 47-49 (August 1989); R. F. Jimerson, "Soft gels: Manufacturing Considerations," Drugs and the Pharmaceutical Sciences, 41 (Specialized Drug Delivery Systems), edited by P. Tyle (Marcel Dekker, Inc., New York, 1990) pp. 269-284; and W.R. Ebert, "Soft Elastic Gelatin Capsules: A Unique Dosage Form," Pharmaceutical Technology, Vol. 1, No. 5, pp. 44-50 (1977); these references are incorporated herein by reference in their entireties. The resulting soft gelatin capsules are soluble in water and gastrointestinal fluids. When the capsule is swallowed, the gelatin shell rapidly dissolves or ruptures in the gastrointestinal tract, thereby introducing the pharma- ceutical active from the liquid core into the physiological system.

[0140] The vegetarian or vegan soft shells of the present invention, which do not contain gelatin derived from animal sources, can be prepared as described above and have a melting temperature of about 95°C.

[0141] Preferably, the capsule has a rectangular or oval shape to facilitate swallowing. For a capsule containing 300-700 mg of the combined active ingredients, the rectangular capsule may have a length of about 10.0-20.0 mm, preferably 12.0-18.0 mm, in particular about 15.0-15.5 mm, and a diameter of about 5.0-11.0 mm, preferably 6.0-10.0 mm, in particular 8.0-9.0 mm, most preferably 8.8-9.0 mm.

[0142] In one embodiment of the present invention, the softgel capsule may be characterized by standard shape and size categories known in the art to describe the form and fill value of the softgel capsule. In some embodiments, the softgel capsule may have an oval, oblong, or circular shape. In certain embodiments, the softgel capsule may have a size between 12 and 18 mini. In some embodiments, the softgel capsule has an oval, oblong, or circular size of 12 mini or less of a gel capsule. In certain embodiments, the softgel capsule has a 12 mini oval or 12 mini rectangular size and shape. In some embodiments, the softgel capsule has a 12 mini rectangular size and shape. In other embodiments, the softgel capsule has an oval, oblong, or circular size of 18 mini or less of a capsule. In certain embodiments, the softgel capsule has an 18 mini oval or 18 mini rectangular size and shape. In yet other embodiments, the softgel capsule has an 18 mini rectangular size and shape.

[0143] It is finally contemplated that any feature described herein can be optionally combined with any of the method, medical use, kit and kit use embodiments of the present invention; any embodiment discussed herein can be implemented with respect to any of these. It will be understood that the specific embodiments described herein are shown by way of example and not as limitations of the present invention.

[0144] All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0145] The use of the word "a" or "an" can mean "one," but is also consistent with the meanings "one or more," "at least one," and "one or more than one." The use of the term "another" can also refer to one or more. Use of the term "or" in the claims is used to mean "and / or" unless expressly stated to refer to alternatives only or unless the alternatives are mutually exclusive.

[0146] As used in this specification and the claims, the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include") or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. The term "comprises" also encompasses and expressly discloses the terms "consists of" and "consists essentially of." As used herein, the phrase "consisting essentially of" limits a claim to the specified materials or steps, and those that do not materially affect one or more of the basic and novel characteristics of the claimed invention. As used herein, the phrase "consisting of" excludes any element, step, or ingredient not specified in the claim, except for, for example, impurities ordinarily associated with that element or limitation.

[0147] As used herein, the term "or combinations thereof" refers to all permutations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB, where order is important in a particular situation. Continuing with this example, combinations containing repeats of one or more items or terms, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, etc., are expressly included. One of ordinary skill in the art will understand that there is typically no limit to the number of items or terms in any combination, unless otherwise clear from the context.

[0148] As used herein, approximation words such as, but not limited to, "about", "around", "approximately", when so modified, are understood to be not necessarily absolute or complete, but refer to conditions that would be considered close enough by a person skilled in the art to warrant specifying that the condition exists. The extent to which the description may vary depends on how large a change can be made, yet still be recognized by a person skilled in the art that the modified feature still has the necessary properties and capabilities of the unmodified feature. In general, given the above explanation, numerical values ​​herein modified by approximation words such as "about" may vary from the stated value by ±1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%. Thus, the term "about" may mean the stated value ±5%, preferably the stated value ±2%, and most preferably, the term "about" means exactly the stated value (±0%).

[0149] Working Example Example 1: Formulation development for encapsulation of Iberogast® in soft gelatin capsules The objective was to develop a feasible formulation for encapsulation of Iberogast® in soft gelatin capsules. Iberogast® is a polypharmaceutical combination containing herbal extracts and is used to treat functional dyspepsia in the form of indigestion, stomach pain, abdominal bloating and gas. The target product must have the following main characteristics: -Fill and shell formulations must minimize water and alcohol loss. -Try to maintain a maximum of 2 capsules per dose.

[0150] The main challenge presented by Iberogast® for development in a soft gelatin capsule is the high ethanol and water content, 31% (v / v) ethanol-240 mg and approximately 66% water per dose. However, the amount of ethanol that can be loaded into a soft gelatin capsule is limited to less than 15% because ethanol can diffuse out of the capsule due to its volatility.

[0151] Previous compatibility and solubility testing has been performed which showed: - Iberogast® formulation "as is" dissolves the shell in 48 hours. Above 30°C, no shell was observed -Iberogast® is not soluble in soybean oil and medium chain triglycerides (50:50 w / w) -Iberogast® is soluble in macrogol (50:50). However, a turbid phase was observed after 24 hours. - The compatibility test of the solution Iberogast® / Macrogol (50:50 w / w) was successful, the shell maintains its integrity for 48 hours at room temperature and at 30°C.

[0152] Based on the analytical results, physicochemical parameters, compatibility tests, and taking into account the customer requirements for color, two formulations were selected as prototypes as shown in the table below:

[0153] [Table 1]

[0154] [Table 2]

[0155] Due to loss of ethanol and water during the drying process, capsules from batches G1 and G2 showed misshapenness after production.

[0156] Two additional batches with reduced capsule size were produced to evaluate whether the reduction in size would improve the capsule appearance. Batch V-G3 was encapsulated in 12 oval molds and batch V-G4 was encapsulated in 12 rectangular molds. Table 3 shows the fill and shell formulations for batches V-G3 and V-G4.

[0157] [Table 3]

[0158] During the production of batches V-G3 and V-G4, no improvement was achieved by chaining the molds or changing the dynamic drying time between 1 and 2 hours. After the drying process, the capsules show significant weight loss, leading to capsule deformation and shrinkage due to moisture loss.

[0159] Further attempts were made consisting of modifying the shell formulation and drying process. Two additional batches, V-G6 and V-G7, were produced. Tables 4 and 5 show their fill and shell formulations.

[0160] [Table 4]

[0161] [Table 5]

[0162] Cornstarch was included in pilot batch V-G7 to improve shell elasticity and minimize capsule bulkiness during drying.

[0163] The following drying tests were carried out to modify the drying conditions: -Standard (dynamic + static dry 20℃ / 20%RH) -Dynamic drying - Dynamic drying + slow drying in a climate chamber at 25°C / 60%RH - Dynamic drying + slow drying in a climate chamber at 30°C / 65% RH

[0164] However, none of these attempts were successful as all capsules were still misshapen after the drying step was performed.

[0165] Example 2: Iberogast N concentrate in soft gelatin capsules

[0166] [Table 6]

[0167] Iberogast N concentrate is the product of a distillation process of Iberogast N to remove ethanol and reduce the water content to obtain a feasible material to be encapsulated in soft gelatin capsules. During the manufacturing process, the active ingredient Iberogast N is concentrated by distillation, where 1 ml of Iberogast N dose is converted into approximately 78-82 μl of Iberogast N concentrate. The conversion in mg takes into account the density of the Iberogast N concentrate (1.20-1.30 g / ml) set in the raw material specifications. A description of the distillation process used can be found in Gaedcke&Steinhoff: "Herbal Medicinal Products" (2003), medpharm GmbH Scientific publishers.

[0168] [Table 7]

[0169] Specific examples of Iberogast N concentrates used in the formulation of the fill of exemplary capsule batches are detailed below:

[0170] [Table 8]

[0171] Despite the reduction in ethanol and water content, the amount of water makes it unfeasible to directly encapsulate Iberogast N concentrate into softgels. The amount of water is much higher than recommended. To avoid capsule clumsiness, development studies were performed to minimize the interaction of Iberogast N concentrate with the shell and obtain a feasible fill formulation. Focusing on the miscibility of Iberogast N concentrate in hydrophilic excipients, the formulations selected for prototyping are shown in Table 8.

[0172] [Table 9]

[0173] Physical stability studies were conducted with prototype E-G2 for 12 months; capsule fragility was observed from capsule release.

[0174] Vulnerability Testing The fragility test is an internal test developed to evaluate capsule brittleness. The method consists of placing the capsule on a metal platform so that the seam is always parallel to the plate. The placement of the capsule is critical to the test because of its influence on the results. The capsule is placed in the center of a methacrylate tube with an internal diameter of 30 mm and a height of 100 mm. A calibrated weight of 100 g is placed on the platform at the top of the tube. The platform is then opened and the weight is allowed to fall freely onto the capsule. After the fall, the capsule is checked for integrity. A representative sample of 25 capsules is subjected to the test and the results are expressed as the percentage of capsules destroyed.

[0175] Flexibility Test The flexibility of the capsules is measured by the resistance of the capsule when a compressive force is applied to produce a deformation of 2 mm, the resistance value is expressed in Newtons (N) and represents the hardness of the capsule. The flexibility is measured on 10 capsules using the hardness test Bareiss Digi Test Gelomat.

[0176] Disintegration test The disintegration test is carried out according to the procedure described in Ph Eur monograph 2.9.1. The disintegration test determines whether the capsule disintegrates within a specified time when placed in a liquid medium under the experimental conditions specified below. Use device A. Liquid temperature: 35-39°C. Liquid test water. If the test fails using water as the disintegration medium, a synthetic gastric fluid medium may be used. Disintegration is considered to be achieved when only shell fragments remain on the screen; if disks are used, shell fragments can be attached to the underside of the disk. Specifications: To pass the test, all six capsules must have disintegrated in 30 minutes.

[0177] Adhesion Test: The cohesiveness of the capsules is ranked using the following scores:

[0178] [Table 10]

[0179] [Table 11]

[0180] [Table 12]

[0181] Capsule fragility is detected during stability tests. The fragility is due to the interaction between the fill and the shell. From the encapsulation, water and plasticizers tend to migrate inside the fill, the hygroscopicity of the fill being the driving force of the process. Furthermore, Iberogast N concentrate migrates into the shell. Then, during storage, atmospheric conditions play an important role in the dynamics of moisture migration. In light of the results, the issue of capsule fragility can be considered as related to migration phenomena between the fill and the shell.

[0182] Example 3: Oil-based and hygroscopic fillings The objective was to develop a fill and shell formulation to improve capsule behavior with respect to brittleness observed in batch E-G2. The development tests established a test to reduce capsule brittleness.

[0183] Materials tested Vehicle / Solubilizer Macrogol 600 (Polyethylene glycol 600 (a-hydro-o-hydroxypoly(oxy-1,2-ethanediyl). A clear, viscous, colorless or nearly colorless, hygroscopic liquid. It is miscible with water, very soluble in acetone, alcohol and methylene chloride, and practically insoluble in fatty and mineral oils.

[0184] Poloxamer 124 is a non-ionic surfactant that contains hydrophilic and lipophilic groups. Therefore, it is miscible with water, alcohol and many oils. Poloxamer 124 is physiologically safe and stable to alkali salts and acids. It is a colorless or nearly colorless liquid.

[0185] Soybean oil is a clear, light yellow, odorless or nearly odorless liquid with a bland taste, solidifies between -10 and -16°C, and has a viscosity value of 50.09 (mPa.s) at 25°C. Emulsions or suspensions containing soybean oil have been used as a vehicle for the oral administration of drugs. Soybean oil is a stable material that is considered to be essentially non-toxic and non-irritating.

[0186] Emulsifiers & thickeners Colloidal silicon dioxide: a light, fine, white or nearly white amorphous powder having a particle size of about 15 nm and practically insoluble in water and mineral acids except hydrofluoric acid. It dissolves in hot solutions of alkali hydroxides. Colloidal silicon dioxide is also used to stabilize emulsions and as a thixotropic thickening and suspending agent in gel and semisolid preparations.

[0187] Macrogolglycerol Hydroxystearate is a non-ionic solubilizer and emulsifier. It is soluble in water and alcohol and miscible with many fat-soluble substances. It appears as a white or yellowish semi-liquid or pasty mass.

[0188] Povidone: Povidone (1-ethenyl-2-pyrrolidinone homopolymer) is a synthetic polymer, used to increase the solubility of active ingredients in hydrophilic vehicles. Different degrees of polymerization result in polymers of various molecular weights ranging from 2,500 to 3,000,000. It is characterized by its viscosity in aqueous solution relative to the viscosity of water, expressed as a K value ranging from 10 to 120. The ability of povidone to form water-soluble complexes with active substances can be used in pharmaceuticals to improve the release rate, solubility of drugs, and as an inhibitor of crystallization of drug substances. The viscosity of the fill formulation can be controlled by the selection of the appropriate molecular weight and concentration of the polymer.

[0189] Beeswax is made up of 70-75% C esters esterified with linear acids. 24 ~C 36 It consists of a mixture of various esters of linear monohydric alcohols having an even carbon chain length of 100-150 carbon atoms.

[0190] Beeswax is used as a thickening agent to prevent settling of particulate matter. Beeswax is considered an essentially non-toxic and non-irritating material. It is included in the FDA Inactive Ingredients Database.

[0191] Filling formulations tested The fill formulations were tested by combining solvents with emulsifiers and / or viscosity enhancing agents to produce approximately 200 g of fill formulation. The suitability of the fill formulations was evaluated by testing the physicochemical parameters described below.

[0192] [Table 13]

[0193] Physicochemical parameters The following parameters of the above formulations were evaluated:

[0194] a) Appearance The macroscopic appearance of the filling was photographically recorded. The target appearance was a brown homogenous suspension or solution.

[0195] b) Flow Test Viscosity was measured using a Ford cup No. 4 at 30°C ± 2°C by measuring the time flow rate of a known volume of liquid passing through an orifice located at the bottom. Specifications: The fill flows uninterrupted.

[0196] c)Kinematic viscosity Kinematic viscosity was measured using a digital rotational viscometer Brookfield DV II at 30°C ± 2°C. The recommended range was NMT 4000cPs.

[0197] d) Density at 30°C This test was performed as an informative parameter to estimate the final volume of the capsules. The test was performed in 10 mL volumetric flasks at 30° C.±2° C.

[0198] e) pH The pH of the fill formulation was measured directly in the hygroscopic fills, whereas in the oil-based fills it was measured in a 10% w / w aqueous dispersion.

[0199] f) Water activity A representative sample of each filling was taken to obtain the required amount of sample for the water activity assay. Test samples were homogenized and tested promptly after sampling to avoid uptake of water from the environment. Water activity was determined using an AquaLab TDL instrument according to the instructions provided.

[0200] g) Phase separation Approximately 2-3 gr of each fill formulation was kept in test tubes at 30°C and 40°C for 24 or 72 hours and observed to see if phase separation occurred.

[0201] If the formulation has good flow properties with no phase separation and viscosity value NMT 4000 cPs, the fill candidate for the pilot batch is confirmed.

[0202] result Table 11 (below) shows the physicochemical parameters of the tested fill formulations. Based on the criteria established for selecting fill formulations for prototyping, the fill formulations corresponding to Test 2 and Test 5 were considered feasible to proceed to the manufacture of pilot batches.

[0203] [Table 14]

[0204] The resulting fill and shell formulations selected for prototyping are reported in Tables 12 to 14. A colorant is included in the shell composition of batch G5 to avoid seeing internal phase separation.

[0205] [Table 15]

[0206] The capsules contained 2.7% (w / w) water in the fill.

[0207] [Table 16]

[0208] The capsules contained 3.21% (w / w) water in the fill.

[0209] [Table 17]

[0210] The capsules contained 8.46% (w / w) water in the fill.

[0211] As can be seen in the table below, the capsules did not exhibit brittleness under any of the storage conditions evaluated, and physical stability testing is still ongoing.

[0212] [Table 18]

[0213] [Table 19]

[0214] [Table 20]

[0215] [Table 21]

[0216] [Table 22]

[0217] [Table 23]

[0218] The tests carried out with batches E-G3 and E-G5 containing oil-based fill formulations can be summarized as follows: -Disintegration test met specifications -Capsules do not exhibit brittleness - Capsule flexibility decreases during storage, with values ​​(approximately 2N) lower than expected (approximately 7N) -Capsules are sticky -Capsule appearance of batch G3 shows phase separation

[0219] The tests performed with batch E-G6 containing the hygroscopic filler formulation can be summarized as follows: - Disintegration test does not meet specifications -Capsules do not exhibit brittleness -Capsule flexibility increased during storage

[0220] Based on these results, further formulations were prepared (see Example 4).

[0221] Example 4: Further formulations containing oily and hygroscopic fillers The objective was to develop further formulations to improve capsule behavior with regard to brittleness observed in batch E-G2 and stickiness and phase separation in batches E-G3 and E-G5. Development testing established the following new tests: -Reducing capsule brittleness of hygroscopic fills by increasing the molecular weight of polyethylene glycol and replacing colloidal silicon dioxide (considered a nanomaterial) with semi-solid polyethylene glycol (polyethylene glycol 4000). -Reduces adhesion by increasing capsule flexibility, avoiding or minimizing phase separation of oil-based fills.Replaces soybean oil, which can be considered an allergen, with alternative oils (sunflower, olive and corn oil).Replaces beeswax (animal origin) with other thickeners not of animal origin (Geleol Mono- and Diglycerides NF, Gelucire 50 / 13, Gelucire 44 / 14 and Hard Fat).

[0222] Materials tested Vehicle / Solubilizer Macrogol 600 (according to Example 3)

[0223] Sunflower oil - a fatty oil obtained from the seeds of the sunflower (Helianthus annuus) by mechanical expression or extraction. It is then refined. Appropriate antioxidants may be added. A clear, pale yellow liquid, miscible with light oils (bp: 40-60°C), practically insoluble in water and ethanol (96 percent).

[0224] Olive Oil - A fatty oil obtained by refining crude olive oil, obtained by cold expression or other suitable mechanical means from the ripe stone of olives (Olea europaea). Suitable antioxidants may be added. A clear, colorless or greenish-yellow transparent liquid, miscible with light oils (bp: 50-70°C) and practically insoluble in ethanol (96 percent). On cooling, it begins to become cloudy at 10°C and forms a buttery mass at about 0°C.

[0225] Corn oil - a fatty oil obtained by expression or extraction from the seeds of corn (Zea mays), which is then refined. A clear, pale yellow or yellow oil that is practically insoluble in water and ethanol (96 percent), miscible with light oil (bp: 40-60°C) and methylene chloride.

[0226] Emulsifiers & thickeners Geleol™ Mono- and Diglycerides NF- (Glycerol Monostearate 40-55 (Type I)), sold by Gattefosse, is a modified release matrix former for capsules. It can be used as a coating agent for taste masking or as a thickening agent. Safety of use is inferred by its GRAS status and priority of use in approved medicinal products.

[0227] Hard Fat - a mixture of triglycerides, diglycerides and monoglycerides, which can be obtained either by esterification of hydrogenated fatty acids of vegetable origin with glycerol or by transesterification of hydrogenated vegetable oils. Each type of hard fat is characterized by its melting point, its hydroxyl number and its saponification number. It does not contain additives. A white or almost white waxy brittle mass that is practically insoluble in water and slightly soluble in absolute ethanol and methylene chloride.

[0228] Gelucire® 44 / 14-(Lauroyl polyoxyl-32 glyceride) is considered an emulsifier; modified release agent; non-ionic water-dispersible surfactant for lipid-based formulations to solubilize poorly water-soluble APIs and increase their oral bioavailability. It self-emulsifies in aqueous media to form fine dispersions, i.e. microemulsions (SMEDDS).

[0229] Lauroyl polyoxylglycerides - USFA excipient, US Food Additives per 172.736 Food Additives Allowed for Direct Addition to Foods for Human Ingestion: Glycerides and polyglycides of hydrogenated vegetable oils. Consists of small amounts of mono-, di-, and triglycerides, and primarily PEG-32 (MW 1500) mono- and diesters of lauric acid (C12). It is considered a solubilizer and bioavailability enhancer for poorly soluble APIs. The single excipient formulation system self-emulsifies into a microemulsion-LFCS type III (SMEDDS) in aqueous fluids.

[0230] Gelucire® 50 / 13-(Stearoyl Macrogol-32 Glycerides) Solubilizer and bioavailability enhancer for poorly soluble APIs. Single excipient formulation system self-emulsifies to coarse emulsion-LFCS type III (SMEDDS) in aqueous fluids. Modulation of drug release. Lipid binder in melt processes. Safety of use is presumed by toxicity data and priority of use in approved drug products. Stearoyl Macrogol-32 Glycerides is a US Food Additive: Glycerides and Polyglycides according to USFA Excipient, 172.736 Food Additives Allowed for Direct Addition to Foods for Human Ingestion.

[0231] Macrogol 4000 - (Polyethylene glycol 4000 (a-hydro-o-hydroxypoly(oxy-1,2-ethanediyl)) is a white or almost white solid with a waxy or paraffinic appearance. It is miscible with water, very soluble in acetone, alcohol and methylene chloride, and practically insoluble in fatty and mineral oils.

[0232] Filling formulations tested Fill formulations were tested by combining solvents with emulsifiers and / or viscosity enhancers to produce approximately 200 g of fill formulation. The suitability of the fill formulations was evaluated by testing the physicochemical parameters described below. Tables 17-22 summarize the fill formulations tested.

[0233] [Table 24]

[0234] [Table 25]

[0235] [Table 26]

[0236] [Table 27]

[0237] [Table 28]

[0238] [Table 29]

[0239] Methods for testing physicochemical parameters have been previously described.

[0240] result

[0241] [Table 30]

[0242] Based on the criteria established for selecting fill formulations for prototyping, the fill formulation corresponding to I&D-0107-21 is deemed feasible to proceed to pilot batch manufacturing.

[0243] Tables 25 and 26 show the physicochemical parameters of the fill formulations containing Geleol™ mono- and diglycerides NF that were tested. Based on the criteria established for selecting fill formulations for prototyping, fill formulations corresponding to I&D-0108-21, I&D-0109-21 and I&D-0110-21 were deemed feasible to proceed to pilot batch manufacturing.

[0244] [Table 31]

[0245] [Table 32]

[0246] Although suitable in principle, based on the criteria established for selecting the most preferred filler formulations for prototyping, filler formulations corresponding to I&D-0095-21, I&D-0096-21, I&D-0097-21, I&D-0098-21, I&D-0099-21, I&D-0100-21, I&D-0101-21, I&D-0102-21 and I&D-0103-21 were considered less preferred and therefore were not selected for proceeding to the manufacture of pilot batches.

[0247] conclusion Based on insights gained from formulation testing, the following was concluded: The fill compositions corresponding to formulations I&D-0107-21, I&D-0108-21, I&D-0109-21 and I&D-0110-21 are generally the formulations most suitable for encapsulation in soft gelatin capsules.

[0248] The fill composition corresponding to formulation I&D-0107-21 exhibits a higher water activity value (0.45) than the fill corresponding to G2 (0.36), which exhibited brittleness. A higher water activity value of the fill means less migration phenomena during encapsulation and capsule storage.

[0249] The fill compositions of formulations I&D-0108-21, I&D-0109-21 and I&D-0110-21 showed the highest water activity values ​​of 0.81-0.82, which are close to the wet shell water activity values ​​(0.83-0.87), implying less migration phenomena during encapsulation. Furthermore, the hydrophobic properties of the fill may reduce the water uptake from the shell during the capsule shelf life.

[0250] The proposed fill formulation for the pilot batch is outlined in Table 27:

[0251] [Table 33]

[0252] Two new prototypes were manufactured: pilot batch G9 corresponding to fill formulation I&D-0107-21 and pilot batch G11 corresponding to fill formulation I&D-108-21.

[0253] Pilot batch G9 contained 8.81% (w / w) water in the charge.

[0254] Pilot batch G11 contained 3.82% (w / w) water in the charge.

[0255] So far, the capsules have not demonstrated brittleness under any of the selected storage conditions, and physical stability testing is currently underway.

[0256] [Table 34]

[0257] [Table 35]

[0258] [Table 36]

[0259] Example 5: Vegetable Shell Capsules To provide a vegan solution, gelatin-free softgel capsules were developed for the Iberogast N concentrate fill and the shell formulation is disclosed in Table 30:

[0260] [Table 37]

[0261] Pilot batch G14 contained 4.1% (w / w) water in the charge.

[0262] So far, the capsules have not demonstrated brittleness under any of the storage conditions and physical stability testing is currently underway.

[0263] [Table 38]

[0264] [Table 39]

[0265] Example 6: Softgel Capsules Containing Gelatin RXLR2 To improve the disintegration time of fill formulations containing PEG, a new pilot batch was produced, a composition containing a PEG-based fill (G16). Gelita® RXL® was specifically designed to avoid failure in disintegration tests. 2 Including.

[0266] [Table 40]

[0267] Pilot batch G16 contained 10.81% (w / w) water in the charge.

[0268] The capsules did not exhibit any brittleness upon release and physical stability testing is currently underway.

[0269] [Table 41]

[0270] [Table 42]

[0271] Example 7: Alternative formulations to improve capsule behavior regarding stickiness of oil-based formulations For oil-based formulations, the shell is optimized to avoid capsule stickiness and the gelatin level is increased to 46% as follows:

[0272] [Table 43]

[0273] [Table 44]

[0274] To improve capsule behavior with respect to stickiness, the following additional oil-based formulations were developed and tested:

[0275] [Table 45]

[0276] Pilot batch G24 contained 5.19% (w / w) water in the charge.

[0277] [Table 46]

[0278] [Table 47]

[0279] [Table 48]

[0280] Pilot batch G25 contained 5.56% (w / w) water in the charge.

[0281] [Table 49]

[0282] [Table 50]

[0283] [Table 51]

[0284] Pilot batch G26 contained 5.97% (w / w) water in the charge.

[0285] [Table 52]

[0286] [Table 53]

[0287] [Table 54]

[0288] Pilot batch G27 contained 5.75% (w / w) water in the charge.

[0289] [Table 55]

[0290] [Table 56]

[0291] [Table 57]

[0292] Pilot batch G28 contained 4.74% (w / w) water in the charge.

[0293] [Table 58]

[0294] [Table 59]

[0295] [Table 60]

[0296] Pilot batch G29 contained 6.79-6.88% (w / w) water in the charge.

[0297] [Table 61]

[0298] Pilot batch G30 contained 6.38-6.66% (w / w) water in the charge.

[0299] Example 8: Alternative formulations to improve disintegration Additionally, the shell formulation is further optimized to avoid cross-linking, which is the root cause of failure during disintegration testing of fill formulations containing PEG (hydrophilic fill).Tables 54 and 57 show the fill and shell formulations including sorbitol sorbitan solution in the shell formulation of the hydrophilic fill.

[0300] [Table 62]

[0301] Pilot batch G22 contained 12.05% (w / w) water in the charge.

[0302] [Table 63]

[0303] [Table 64]

[0304] [Table 65]

[0305] Pilot batch G23 contained 12.27% (w / w) water in the charge.

[0306] [Table 66]

[0307] [Table 67]

Claims

1. 1. A pharmaceutical or nutraceutical composition in the form of a softgel capsule comprising a liquid or semisolid fill and a shell, The filling material is a) at least one active ingredient or dietary supplement dissolved, suspended or solubilized in a solution comprising between 2% and 50% (w / w) water and between 5% and 0.2% (w / w) alcohol, preferably ethanol; b) at least one solubilizer selected from low molecular weight polyethylene glycols (PEGs), preferably PEGs with a molecular weight between 300 and 600, such as macrogol 400 or macrogol 600, vegetable oils, such as soybean oil, sunflower oil, olive oil and corn oil, and medium chain triglycerides, preferably selected from macrogol 600, sunflower oil, olive oil or corn oil; c) at least one thickening agent selected from high molecular weight polyethylene glycols, preferably macrogol 4000, beeswax, glycerol monostearate 40-55 (type I), colloidal silicon dioxide, hard fat, lauroyl polyoxylglycerides, such as lauroyl macrogol-32 glyceride, or stearoyl macrogol glycerides, such as stearoyl macrogol-32 glyceride, or combinations thereof; Including; the shell comprises an edible polymer and / or a plasticizer, and optionally an opacifier and / or a colorant; A pharmaceutical or nutraceutical composition.

2. The solution comprising water and alcohol (i) less than 5% (w / w), or less than 4% (w / w), or less than 3% (w / w), or less than 2%, or less than 1% (w / w), or less than 0.5% (w / w), or less than 0.25% (w / w) alcohol, preferably ethanol; and (ii) Less than 50% (w / w), or less than 45% (w / w), or less than 40% (w / w), or less than 35% (w / w), or less than 30% (w / w), or less than 25% (w / w), or less than 20% (w / w), or less than 15% (w / w) of water; 2. The pharmaceutical or nutraceutical composition of claim 1, comprising:

3. The solution comprising water and alcohol (i) an alcohol, preferably ethanol, between 4% and 0.5% (w / w), or between 3% and 1% (w / w), or between 2% and 1% (w / w), or between 2% and 0.5% (w / w), or between 1% and 0.2% (w / w); and (ii) between 3% and 50% (w / w), between 4% and 50% (w / w), between 5% and 50% (w / w), between 6% and 50% (w / w), between 7% and 50% (w / w), between 8% and 50% (w / w), between 9% and 50% (w / w), between 10% and 50% (w / w), between 11% and 50% (w / w), between 12% and 50% (w / w), between 13% and 50% (w / w), between 14% and 50% (w / w) between 15% and 50% (w / w), between 20% and 50% (w / w), between 30% and 50% (w / w), between 35% and 50% (w / w), between 40% and 50% (w / w), between 45% and 50% (w / w), between 15% and 49% (w / w), between 20% and 48% (w / w), between 25% and 47% (w / w), between 30% and 46% (w / w), between 35% and 45% (w / w) 3. The pharmaceutical or nutraceutical composition of claim 1 or 2, comprising:

4. a) the active ingredient is dissolved, suspended or solubilized in a solution containing between 5% and 0.2% (w / w) ethanol and between 2% and 50% (w / w) water; b) the at least one solubilizing agent is selected from macrogol 600, sunflower oil, olive oil and corn oil, or a combination thereof; c) the at least one thickening agent is selected from macrogol 4000, glycerol monostearate 40-55 (type I), colloidal silicon dioxide and beeswax, or a combination thereof; the shell comprises an edible polymer and / or a plasticizer, and optionally an opacifier and / or a colorant; 4. A pharmaceutical or nutraceutical composition according to any one of claims 1 to 3.

5. 5. A pharmaceutical or nutraceutical composition according to any one of claims 1 to 4, wherein the active ingredient is a hydrophilic active ingredient, preferably a hydrophilic plant extract, more preferably a highly concentrated hydrophilic plant extract.

6. 6. The pharmaceutical or nutraceutical composition of any one of claims 1 to 5, wherein the active ingredient is a plant extract comprising at least one of chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candytuft fresh plant liquid extract, melissa leaf liquid extract, chamomile flower liquid extract, lemon balm leaf liquid extract, angelica root liquid extract, celandine herb liquid extract, milk thistle fruit liquid extract, or combinations thereof.

7. 7. A pharmaceutical or nutraceutical composition according to any one of claims 1 to 6, wherein the active ingredient is a plant extract comprising chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candytuft fresh plant liquid extract and melissa leaf liquid extract, preferably the active ingredient is Iberogast N concentrate.

8. 7. The pharmaceutical or dietary supplement composition of any one of claims 1 to 6, wherein the active ingredient is a plant extract comprising chamomile flower liquid extract, peppermint leaf liquid extract, licorice root liquid extract, caraway fruit liquid extract, bitter candytuft fresh plant liquid extract, lemon balm leaf liquid extract, angelica root liquid extract, celandine herb liquid extract and milk thistle fruit liquid extract.

9. 7. The pharmaceutical or nutraceutical composition of any one of claims 1 to 6, wherein the active ingredient is a plant extract comprising at least one of American aspen or aspen stem bark and leaf liquid extract, Common ash stem bark liquid extract, European goldenrod herb liquid extract, or a combination thereof.

10. 10. The pharmaceutical or nutraceutical composition according to any one of claims 1 to 9, wherein the edible polymer is selected from gelatin, gelatin RXL, gelatin GELITA® RXL R2 and non-animal origin compounds such as Seagel® CAP 203, carrageenan, vegetable starch such as corn or pea starch, or combinations thereof, preferably gelatin GELITA® RXL R2 or Seagel® CAP 203.

11. a) the active ingredient is Iberogast N concentrate; b) the at least one solubilizing agent is selected from macrogol 600, sunflower oil, olive oil and corn oil, or a combination thereof; c) the at least one thickening agent is selected from macrogol 4000, glycerol monostearate 40-55 (type I), colloidal silicon dioxide and beeswax, or a combination thereof; the shell comprises an edible polymer selected from gelatin, gelatin RXL, gelatin GELITA® RXL R2 and a non-animal derived compound, e.g. Seagel® CAP 203, carrageenan, vegetable starch, e.g. corn or pea starch, or a combination thereof, preferably gelatin GELITA® RXL R2 or Seagel® CAP 203, 11. A pharmaceutical or nutraceutical composition according to any one of claims 1 to 10.

12. 12. The pharmaceutical or nutraceutical composition of any one of claims 1 to 11, wherein the plasticizer is selected from glycerin, propylene glycol, mannitol, sorbitan, sorbitol, or similar low molecular weight polyols, or combinations thereof.

13. 13. The pharmaceutical or nutraceutical composition of any one of claims 1 to 12, wherein the opacifying agent is selected from starch, titanium dioxide, calcium carbonate, zinc oxide, tricalcium phosphate, iron oxide, or combinations thereof.

14. (i) the water activity value of the filling is between 0.30 and 0.60, preferably between 0.35 and 0.50, more preferably between 0.37 and 0.47, and most preferably between 0.38 and 0.45; or (ii) the water activity value of the filling is between 0.70 and 0.90, preferably between 0.73 and 0.85, more preferably between 0.74 and 0.84, and most preferably between 0.75 and 0.83; 14. A pharmaceutical or nutraceutical composition according to any one of claims 1 to 13.

15. 15. A method for reducing the brittleness of a softgel capsule according to any one of claims 1 to 14, wherein a solubilizer is added to the fill before encapsulation with the shell, the solubilizer being selected from macrogol 400, macrogol 600, vegetable oils such as soybean oil, sunflower oil, olive oil and corn oil, preferably the solubilizer is macrogol 600, sunflower oil, olive oil or corn oil, or a combination thereof.

16. 15. A method for reducing the brittleness of a pharmaceutical or nutraceutical composition in the form of a softgel capsule according to any one of claims 1 to 14, comprising the step of adding a solubilizer to the fill before encapsulation with the shell, said solubilizer being selected from macrogol 400, macrogol 600, vegetable oils such as soybean oil, sunflower oil, olive oil and corn oil, preferably said solubilizer is macrogol 600, sunflower oil, olive oil or corn oil, or a combination thereof.

17. 15. A pharmaceutical or nutraceutical composition according to any one of claims 1 to 14 for use in the treatment of functional disorders of the gastrointestinal (GI) tract, such as functional dyspepsia (FD) and irritable bowel syndrome (IBS), mild gastrointestinal complaints, such as abdominal bloating, mild cramps and / or burning sensations, pain, inflammation, swelling and functional disorders associated with diseases of the locomotor apparatus of rheumatic origin, such as rheumatoid arthritis, arthrosis, spinal syndromes, epicondylitis, periarthritis, Bechterew's disease and / or low back pain.

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