Stable soft capsule preparations with liquid fill for moisture sensitive active ingredients

Abstract

Stable soft capsule preparations with liquid fill for moisture sensitive active ingredients The invention relates to a pharmaceutical or dietary supplement composition in the form of a soft gel capsule comprising a liquid fill and a shell, wherein the liquid fill comprises at least one moisture sensitive active ingredient and at least about 55% (w / w) of one excipient formed by an amphiphilic block copolymer of poly(ethylene oxide) and poly(propylene oxide). The invention furthermore relates to methods of stabilizing said moisture sensitive active ingredient.

Description

[0001] Stable soft capsule preparations with liquid fill for moisture sensitive active ingredients

[0002] Technical field

[0003] The invention relates to a pharmaceutical or dietary supplement composition in the form of a soft gel capsule comprising a liquid fill and a shell, wherein the liquid fill comprises at least one moisture sensitive active ingredient and at least about 55% (w / w) of at least one excipient formed by amphiphilic block copolymers of polyethylene oxide) and polypropylene oxide) groups. The invention furthermore relates to methods of stabilizing said moisture sensitive active ingredient.

[0004] Background of the invention

[0005] Capsules are solid dosage forms comprising one or more active components, active pharmaceutical ingredients (APIs) or nutrients, that can be formulated alone or with other excipients, inside of a hard or soft shell.

[0006] The traditional soft capsules consist of one piece (with or without seal) of flexible or elastic polymeric shell filled with a liquid form, which usually contains the active ingredients formulated in dissolution, emulsion, or suspension, offering the possibility to be delivered as a solid dosage form. Soft capsules are commonly used for oral, vaginal and rectal administration, among others, of a wide variety of pharmaceuticals or dietary products. However, the use of soft gel capsules is limited for active ingredients that are sensitive to the presence of water / moisture, because the commercial production of the shell involves water that cannot be fully removed after its production process and the moisture from the atmosphere may also diffuse through the capsule shell into the fill compromising any moisture sensitive actives located therein.

[0007] The production of traditional soft capsules consists of five steps: shell manufacturing, fill manufacturing, encapsulation process, drying and finishing. The shell cover is prepared from polymer, plasticizer(s), in particular water and at least one non-volatile plasticizer, and other optional ingredients such as colorants, opacifiers, flavors, sweeteners, preservatives, and also sugars or gastro-resistant substances. Based on the polymer used to form the cover shell, capsules may be classified as gelatin capsules or non-gelatin capsules, the latter based on plant-derived and / or synthetic non-gelatin alternatives. Despite its volatility, the 30-40% w / w water present in the shell formulation is reduced throughout the manufacturing process to 4-10% w / w in the final soft capsule product, the addition of such a high content of water is necessary for the formation of the polymeric structure and for obtaining a shell mass with a suitable viscosity for its dosing. Among other factors, the elasticity and malleability of the shell material is influenced by its water content but also by the moisture of the environment, which do not stay constant during production / storage.

[0008] During the encapsulation process, the shell material covers the fill formulation forming the proper soft capsule. From the moment that both materials come into contact, the water of the shell materials tends to diffuse at least partially into the fill, where the active ingredients are commonly located. In addition, as previous mentioned, the moisture from the atmosphere may also diffuse through the capsule shell into the fill. In general terms, too much humidity can compromise potency and effectiveness, leading to degradation or even toxicity in some products, reducing the shelf-life of the final product. But, for moisture sensitive actives, these negative effects may even appear under standard conditions. Thus, both migration phenomena can then compromise any moisture sensitive active ingredients located therein.

[0009] Acetylsalicylic acid (ASA), or Aspirin, is an example of such a moisture sensitive active ingredient. ASA has been commercially available in other dosage forms, such as coated or uncoated tablets, but instability of ASA to hydrolysis limits preparation of a dosage form in a soft capsule that is stable for prolonged storage period. Upon contact with water ASA hydrolyzes to salicylic acid (SA), which is considered a degradation product and thus, its amount must be controlled in the final product and must be maintained below a certain limit. Acceptance limits are closely linked to the dosage forms used, i.e., 3% for extended- release tablets and delayed-release tablets and 8% for effervescent tablets. Currently, no specific limits for the SA content are defined for soft gel capsules as ASA soft gel capsules are not marketed due to the high degradation rate. As a reference, a content of at least 35% and even up to 100% of SA can be observed after 1 month of storage when standard formulations for soft gel capsules are used. Given the many advantages of soft gel capsules for the consumer, there is therefore a high need to provide novel fill formulations for ASA that can be used to produce stable soft gel capsules.

[0010] To mitigate the stability problem of moisture sensitive pharmaceuticals in soft gel capsules, especially ASA, several formulations have been proposed in the prior art. Modifications in the shell and fill formulations are proposed. For example, regarding the shell material, US 5,814,338 presents a modified formulation in which, underneath the traditional gelatine shell, there is a hydrophobic silicon polymer- based layer and in which the lipophilic internal phase is supplemented with silicon resins. However, the approach to modify the shell formulation requires considerable modifications to the processes and equipment normally employed. Thus, the majority of the proposals are focused on improving the liquid or semisolid fill material.

[0011] For example, in WO 98 / 17673 the inventors attempted to overcome the known instability of Aspirin in its various administration forms including capsules with a liquid oil-based fill by modifying Aspirin itself using it in the form of esters with various alcohols. Salts and buffered forms of ASA have been developed to try to overcome these problems; however, these forms can act more slowly after ingestion than ASA itself and are not as effective.

[0012] In W02008 / 068276 the liquid or pasty fill of the disclosed soft gel capsules comprises Aspirin and solid polyhydroxylated organic compounds, such as maltose, trehalose, chondroitin sulphate, hyaluronic acid, guar gum, carrageenan, chitosan, alginate, agar, starch, erythritol, sorbitol, inositol, or polyvinyl alcohol, and water-soluble hygroscopic salts, such as calcium sulphate hemihydrate or anhydrous calcium chloride, that stabilize the Aspirin in the fill against hydrolysis caused by the presence of moisture.

[0013] US2012 / 045507 discloses a soft gelatin capsule formulation for Aspirin suspended in a monoglyceride matrix that comprises at least about 50% glyceryl monooleate. The soft gelatin capsule is substantially free of a base. The Aspirin in this non-solid formulation is resistant to hydrolysis and stable for prolonged storage periods under typical home storage conditions.

[0014] WO2017 / 095736 discloses a soft gelatin capsule for moisture sensitive pharmaceuticals and dietary supplements comprising at least one oil to stabilize the moisture sensitive pharmaceuticals and at least one surfactant to enhance the solubility of the moisture sensitive pharmaceuticals and dietary supplements. In that sense, the use of Poloxamers is mentioned as one class of possible surfactants that could be added into these capsules in an amount of 0.01 to 10% (w / w), however, they are neither disclosed as preferred surfactants, nor is a stabilizing effect on the active ingredient suggested for these specific surfactants.

[0015] Poloxamers, available also under the trademark Pluronics® (BASF), are a class of water-soluble nonionic A-B-A and B-A-B triblock copolymers, where A is polyethylene oxide) (PEO) and B is polypropylene oxide) (PPO). It is necessary to emphasize that each PEO unit is composed by ethylene oxide (EO) groups while PPO unit is based on propylene oxide (PO) groups. Poloxamers are available in a broad range of molecular weights and PPO / PEO ratios (Bodratti and Alexandridis 2017). BASF utilizes a specific notation for Pluronics®, where the first letter indicates the physical state (P: Paste, F: Flake, L: Liquid), the first one or two numbers relate to the molecular weight and the last number indicates the weight percent of the PEO block.

[0016] Poloxamer molecules form an array of thermodynamically stable self-assembled structures in solution, driven by differences in the solubility of their constituent PEO and PPO blocks.

[0017] Whilst the prior art describes various uses for poloxamers, to date the use of poloxamers in the formulation of soft gels or soft gel capsules is less common. Furthermore, the prior disclosure is not related to the stabilizing properties of the Pluronics, but in the prior art the Pluronics are rather described as micellization agents or surfactants that are added in the formulations in a low percentage along with other main excipients in much higher percentage. EP 0407 815 Al, for example, describes improved soft gel capsules where the Pluronics in an amount of less than 20% are used to increase absorbability of the pharmacological ingredient, specifically of indomethacin famesyl. If added in a higher percentage into the formulation, as is described in for example in EP 0 178 436 Al or WO 01 / 66087 Al, the Pluronics aid in the solubilization of poorly soluble active ingredients, such as Ibuprofen or NO-releasing Naproxen.

[0018] Given the consequent absence on the market of moisture sensitive active ingredients and especially Aspirin formulations in soft gel capsules, the problem remains of developing alternative soft gel capsules to those described in the prior art, i.e., soft gel capsules that are obtainable without modifying traditional processes or equipment, or without modifying the active principle used, hence allowing this advantageous pharmaceutical form to be also extended to moisture sensitive active ingredients such as for example ASA.

[0019] The proper design for a specific soft gelatin capsule formulation with moisture sensitive active ingredients requires the appropriate selection of the shell and fill compositions and specifically the optimization of the fill composition to allow for the efficient production of a chemically and physically stable product with the desired biopharmaceutical properties. It is specifically desirable to provide for a fill composition that can be formulated in a fast and simple process that limits as much as possible the degradation of the active ingredient during the production process and very importantly also over the shelf-life of the final product.

[0020] The present invention therefore confronts and solves the technical problem of providing fills for soft gel capsules that are suitable for encapsulating moisture sensitive active ingredients or dietary supplements in soft gelatin capsules, that can overcome the above-mentioned problems.

[0021] SUMMARY

[0022] The present invention therefore relates in one aspect to a pharmaceutical or dietary supplement composition in the form of a soft gel capsule comprising a liquid fill and a shell, wherein the liquid fill comprises a) at least one moisture sensitive active ingredient; and b) at least about 55% (w / w) of at least one excipient comprising or consisting of amphiphilic block copolymers of PEO and PPO groups; wherein the shell comprises an edible polymer and / or plasticizer, and optionally an opacifier and / or colorants.

[0023] In one embodiment of present invention the pharmaceutical or dietary supplement composition of present invention the at least one moisture sensitive active ingredient is selected from a non-steroidal antiinflammatory drug (NSAID), Itraconazole, Ketoconazole, Erythromycin, Acyclovir or Omeprazole.

[0024] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the NSAID is selected from the group consisting of Acetyl salicylic acid (Aspirin), Fenoprofen calcium, Flurbiprofen, Suprofen, Benoxaprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin, Diclofenac sodium, Diclofenac potassium, Etodolac, Indomethacin, Ketorolac tromethamine, Ketorolac, Nabumetone, Sulindac, Tolmetin, Meclofenamate sodium, Mefenamic acid, Piroxicam, Diflunisal, Oxyphenbutazone, Phenylbutazone, Acetaminophen, COX-2 inhibitors, or mixtures or combinations thereof. In one embodiment of the pharmaceutical or dietary supplement composition of present invention the NSAID is selected from the group consisting of Acetyl salicylic acid (Aspirin), Acetaminophen, Naproxen and Naproxen sodium.

[0025] In a further embodiment of the pharmaceutical or dietary supplement composition of present invention the at least one excipient comprises or consists of atri-block copolymer of PEO and PPO groups.

[0026] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the fdl comprises at least about 60% (w / w), preferably at least about 70% (w / w), more preferably at least about 80% (w / w), most preferably at least about 90% (w / w) of the at least one excipient based on the total weight of the fdl.

[0027] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the fdl comprises at least about 56% (w / w), at least about 57% (w / w), at least about 58% (w / w), at least about 59% (w / w), preferably at least about 60% (w / w), at least about 61% (w / w), at least about 62% (w / w), at least about 63% (w / w), at least about 64% (w / w), at least about 65% (w / w), at least about 66% (w / w), at least about 67% (w / w), at least about 68% (w / w), at least about 69% (w / w), more preferably at least about 70% (w / w), at least about 71% (w / w), at least about 72% (w / w), at least about 73% (w / w), at least about 74% (w / w), at least about 75% (w / w), at least about 76% (w / w), at least about 77% (w / w), at least about 78% (w / w), at least about 79% (w / w), most preferred at least about 80% (w / w), at least about 81% (w / w), at least about 82% (w / w), at least about 83% (w / w), at least about 84% (w / w) or at least about 85% (w / w) of the at least one excipient based on the total weight of the fdl.

[0028] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the fdl comprises at least about 86% (w / w), at least about 87% (w / w), at least about 88% (w / w), at least about 89% (w / w), preferably at least about 90% (w / w), at least about 91% (w / w), at least about 92% (w / w), at least about 93% (w / w), at least about 94% (w / w), at least about 95% (w / w), at least about 96% (w / w), at least about 97% (w / w), at least about 98% (w / w), at least about 99% (w / w) of the at least one excipient based on the total weight of the fdl.

[0029] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the fdl comprises only one excipient.

[0030] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the weight percent of the ethylene oxide (EO) chain in the copolymer is between 10-85% (w / w).

[0031] In a further embodiment of the pharmaceutical or dietary supplement composition of present invention the copolymer has a Molecular weight (Mw) of between about 1.100 to 14.600 g / mol. In one embodiment of the pharmaceutical or dietary supplement composition of present invention the at least one excipient is a poloxamer.

[0032] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the at least one excipient is selected from the group consisting of Pluronic L31, Pluronic L35, Pluronic L61, Pluronic L62, Pluronic L64, Pluronic L92, Pluronic L101, Pluronic L121, Pluronic P123, Pluronic F68, Pluronic F108, Pluronic F127, Pluronic RPE1720, Pluronic RPE1740 and Pluronic RPE3110.

[0033] In one preferred embodiment the at least one excipient is selected from the group consisting of Pluronic L31, Pluronic L35, Pluronic L61, Pluronic L62, Pluronic L92, Pluronic RPE1720, Pluronic RPE1740 and Pluronic RPE3110.

[0034] In one preferred embodiment the at least one excipient is Pluronic L35, Pluronic L61, Pluronic L62 and Pluronic L92.

[0035] In one embodiment the fill comprises a combination of the above excipients.

[0036] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the edible polymer is selected from gelatine, gelatine RXL, gelatine GELITA® RXL R2 and non-animal derived compounds, such as Seagel® CAP 203, carrageenan, vegetable starch, such as for example maize or pea starch, or combinations thereof, preferably gelatine GELITA® RXL R2 or Seagel® CAP 203.

[0037] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the plasticizer is selected from glycerine, propylene glycol, mannitol, sorbitan, sorbitol, or similar low molecular weight polyols, or combinations thereof.

[0038] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the opacifier is selected from starch, titanium dioxide, calcium carbonate, zinc oxide, tricalcium phosphate, iron oxides, or combinations thereof.

[0039] In one embodiment the colorants are selected from synthetic colorants or natural colorants.

[0040] In another aspect the present invention relates to a method of stabilizing a moisture sensitive active ingredient in the liquid fill of a soft gel capsule, wherein at least one excipient comprising or consisting of an amphiphilic block copolymer of PEG and PPG groups is added to the liquid fill at an amount of at least 55% (w / w), preferably at an amount of at least 60% (w / w) based on the weight of the total amount of excipient in the liquid fill or the weight of the liquid fill.

[0041] In one embodiment of the method the fill comprises the moisture sensitive ingredient and the at least one excipient as described herein. BRIEF DESCRIPTION OF THE FIGURES

[0042] FIG.l: Stability results of tested formulations during storage time. Degradation of ASA to AS was measured over 30 days in the different formulations prepared as described in Example 1.

[0043] FIG.2: Stability results of the different formulations as described in Example 2. Degradation of ASA to AS was measured over 30 days in the different formulations prepared as described in Example 2 and Example 3.

[0044] FIG.3: Stability study continued over 3 months with Pluronic L35 and Pluronic L62.

[0045] DESCRIPTION OF THE INVENTION

[0046] The present invention may be understood more readily by reference to the following detailed description of the preferred embodiments of the invention, and to the examples included therein.

[0047] The proper design for a specific soft gel capsule formulation requires the appropriate selection of fill composition(s) and its optimization to allow for the efficient production of a chemically and physically stable product with the desired biopharmaceutical properties.

[0048] The present invention therefore confronts and solves the technical problem of providing fills for soft gel capsules that are suitable for encapsulating moisture sensitive active ingredients or dietary supplements pharmaceuticals in soft gel capsules, that can overcome the problems encountered in the prior art as described above in the background.

[0049] The present invention therefore relates in one aspect to a pharmaceutical or dietary supplement composition in the form of a soft gel capsule comprising a liquid fill and a shell, wherein the liquid fill comprises a) at least one moisture sensitive active ingredient; and b) at least about 55% (w / w) of at least one excipient comprising or consisting of an amphiphilic block copolymer of PEG and PPG groups; wherein the shell comprises an edible polymer and / or plasticizer, and optionally an opacifier and / or colorants.

[0050] As used herein the term “soft gel capsule” or “soft gel cap” or “soft gelatin capsule” is a capsule formed predominantly of gelatin, glycerine, and water, that retains its solubility on prolonged storage. Soft gel caps can also be gelatine free as disclosed herein below, in which gelatine, which is predominantly from animal origin, is substituted to non-animal origin excipients. The term “stable soft gel capsule” as used herein refers to a capsule adapted for self-administration of an active ingredient, such as for example ASA, wherein the ASA does not significantly undergo hydrolysis upon storage for a period of some months, and wherein the soft gel capsule does not undergo significant degradation, such as can occur due to the release of SA from hydrolysis of the ASA in the soft gel capsule. In various embodiments, the ASA-containing soft gel capsule does not undergo significant “tanning” or degradation when stored at about 25 °C and about 60% relative humidity (RH) for a period of at least one month in final product.

[0051] As used herein, the term "pharmaceutical composition" means a composition, which is suitable for prescription and OTC medicaments, and which are available from doctors in chemist's shop or in drugstores, only.

[0052] As used herein, the term "dietary supplement composition" means a composition, which is for supplementing the regular food intake with additional nutritional elements to enhance quality of life, and which are freely available without prescription in groceries or supermarket, but not only in drugstores.

[0053] As used herein the terms “moisture sensitive actives”, “moisture sensitive active ingredients”, or “moisture sensitive pharmaceuticals” refers to pharmaceutical active ingredients or dietary supplement pharmaceuticals that may undergo hydrolysis or other degradation reactions when they are in contact with water or moisture resulting in the formation of unwanted impurities and a reduced level of the active molecule.

[0054] Excipients

[0055] To solve the stability problem of the moisture sensitive active ingredients in soft gel capsules the inventors have set out to find excipients that can provide for the required stability, are suitable and approved for use in pharmaceutical and dietary compositions and at the same time easy to handle during the elaborate production process of soft gel capsules.

[0056] It has been found that excipients comprising or consisting of an amphiphilic block copolymer of PEO and PPO groups and especially tri -block copolymers of PEO and PPO groups are specifically suitable.

[0057] Therefore, in one embodiment of present invention of the pharmaceutical or dietary supplement composition the at least one excipient comprises or consist of a tri-block copolymer of PEO and PPO groups.

[0058] As mentioned above, whilst the prior art focuses on various uses for poloxamers, their use in the formulation of soft gels or soft gel capsules for improving the stability of moisture sensitive active ingredients has not been described thus far. Instead, Pluronics are described as micellization agents or surfactants that are added in formulations in a low percentage along with other main excipients that are used in a higher percentage, or when added in higher percentages Pluronics are used as aids in the solubilization of poorly soluble active ingredients.

[0059] The inventors have now surprisingly found that poloxamers (Pluronics) can be used in the fdl of the soft gel capsules as the main excipient. This is possibly due to the fact that the characteristic formation of micelles is not necessary for increasing the stability of the active ingredient. It is thus possible to use Pluronics in a higher percentage in the fill and even as the main and / or only excipient without the need of adding another stabilizer. One benefit of using Pluronics as the main and / or only excipient is that the manufacturing process of the soft gel capsules can be performed under low temperature obviating additional process steps that can be required for other excipients.

[0060] In yet a further embodiment of the pharmaceutical or dietary supplement composition of present invention the copolymer has a Molecular weight (Mw) of between about 1. 100 to 14.600 g / mol.

[0061] The copolymer can have a Mw of between about 1.100 to 12.500 g / mol, between about 1.100 to 8.400 g / mol, between about 1.100 to 5.800 g / mol, between about 1.100 to 4.400 g / mol, between about 1.100 to 3.800 g / mol, between about 1.100 to 3.650 g / mol, about 1.900 to 12.500 g / mol, between about 1.900 to 8.400 g / mol, between about 1.900 to 5.800 g / mol, between about 1.900 to 4.400 g / mol, between about 1.900 to 3.800 g / mol, between about 1.900 to 3.650 g / mol, between about 1.900 to 3.500 g / mol, between about 1.900 to 2.650 g / mol, between about 1.900 to 2.150 g / mol, between about 1.900 to 2.000 g / mol.

[0062] In a preferred embodiment the copolymer has a Mw of between about 1.900 to 3.650 g / mol.

[0063] In a preferred embodiment the copolymer has a Mw of between about 1. 100 to 3.650 g / mol. Specifically preferred are tri-block copolymers with the Mw of about 1.100, 1.900, 2.000, 2.150, 2.650, 3.500 and 3.650 g / mol.

[0064] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the weight percent of the EO chain in the copolymer is between about 10 - 85% (w / w).

[0065] The weight percent of the ethylene oxide (EO) chain in the copolymer can be between about 10 - 75% (w / w), between about 10 - 73% (w / w), between about 10 - 47% (w / w), between about 10 - 40% (w / w), between about 10 - 36% (w / w), between about 10 - 26% (w / w), between about 10 - 24% (w / w), between about 10 - 17% (w / w), between about 10 - 14% (w / w), between about 20 - 75% (w / w), between about 20 - 73% (w / w), between about 20 - 47% (w / w), between about 20 - 40% (w / w), between about 20 - 36% (w / w), between about 20 - 26% (w / w), between about 20 - 24% (w / w).

[0066] In one embodiment the weight percent of the ethylene oxide (EO) chain in the copolymer is more than 20% and less than 75% (w / w). In a preferred embodiment the weight percent of the ethylene oxide (EO) chain in the copolymer can be between about 10 - 73% (w / w), the preferred embodiments being copolymers with a weight percent of the ethylene oxide (EO) chain of about 10 % (w / w), 20 % (w / w), 24 % (w / w), 26 % (w / w), 40 % (w / w) and 73 % (w / w).

[0067] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the at least one excipient is selected from the group consisting of Pluronic L31, Pluronic L35, Pluronic L61, Pluronic L62, Pluronic L64, Pluronic L92, Pluronic L101, Pluronic L121, Pluronic P123, Pluronic F68, Pluronic F108, Pluronic F127, Pluronic RPE1720, Pluronic RPE1740 and Pluronic RPE3110.

[0068] In one preferred embodiment the at least one excipient is selected from the group consisting of Pluronic L31, Pluronic L35, Pluronic L61, Pluronic L62, Pluronic L92, Pluronic RPE1720, Pluronic RPE1740 and Pluronic RPE3110.

[0069] In one preferred embodiment the at least one excipient is Pluronic L35, Pluronic L61, Pluronic L62 and Pluronic L92.

[0070] The inventors have furthermore found that the amount of excipient in the liquid fdl formulation is an essential factor for the advantageous properties of the fdl formulations of present invention. The minimum amount of the at least one excipient to ensure the required stability of the active ingredient is at least 55% (w / w) of this excipient in the fdl. If the fdl comprises further excipients, then the at least one excipient needs to be present in at least 55% (w / w) of the total amount of excipients in the fdl.

[0071] The excipient in the fdl formulation may, however, be present in varying lower amounts depending on the excipient used or the combination of other excipients added. The excipient may therefore alternatively also be present in an amount of at least about 20% (w / w), at least about 25% (w / w), at least about 30%

[0072] (w / w), at least about 35% (w / w), at least about 40% (w / w), at least about 41% (w / w), at least about 42%

[0073] (w / w), at least about 43% (w / w), at least about 44% (w / w), at least about 45% (w / w), at least about 46%

[0074] (w / w), at least about 47% (w / w), at least about 48% (w / w), at least about 49% (w / w), at least about 50%

[0075] (w / w), at least about 51% (w / w), at least about 52% (w / w), at least about 53% (w / w), or at least about 54% (w / w) based on the total weight of the fdl.

[0076] In a preferred embodiment of present invention the fdl comprises at least about 55% (w / w), at least about 56% (w / w), at least about 57% (w / w), at least about 58% (w / w), at least about 59% (w / w), at least about

[0077] 60% (w / w), at least about 61% (w / w), at least about 62% (w / w), at least about 63% (w / w), at least about

[0078] 64% (w / w), at least about 65% (w / w), at least about 66% (w / w), at least about 67% (w / w), at least about

[0079] 68% (w / w), at least about 69% (w / w), at least about 70% (w / w), at least about 71% (w / w), at least about

[0080] 72% (w / w), at least about 73% (w / w), at least about 74% (w / w), at least about 75% (w / w), at least about

[0081] 76% (w / w), at least about 77% (w / w), at least about 78% (w / w), at least about 79% (w / w), at least about 80% (w / w), at least about 81% (w / w), at least about 82% (w / w), at least about 83% (w / w), at least about 84% (w / w), at least about 85% (w / w), at least about 86% (w / w), at least about 87% (w / w), at least about 88% (w / w), at least about 89% (w / w), at least about 90% (w / w), at least about 91% (w / w), at least about 92% (w / w), at least about 93% (w / w), at least about 94% (w / w), at least about 95% (w / w), at least about 96% (w / w), at least about 97% (w / w), at least 98% (w / w), at least about 99% (w / w) based on the total weight of the fill. If the fill comprises further excipients, then the at least one excipient needs to be present in these amounts based on the total weight of excipients in the fill.

[0082] In one embodiment the fill comprises more than one excipient as described herein. In this embodiment the above percentages given for the at least one excipient is therefore based on the total weight of excipient in the fill and not on the total weight of the fill itself.

[0083] In one embodiment of present invention the fill comprises a further excipient selected from the group consisting of oils, glycerine, polyglycols (PGs), polyethylene glycols (PEGs), propylene carbonate, methoxy PEGs, Gelucires, Lauroglycol, Peceol, Transcutol, Capryol, Labrafil, Beeswax, Lecithin, Tween.

[0084] The inventors could show that the excipients as described above provide for a suitable storage stability of ASA (see Example 2 and Figure 1). Whilst in the control formulations at least 35% and even up to 100% of the ASA present in the soft gel capsule were degraded after 30 days of storage, formulations comprising these excipients could maintain more than 85% of ASA stable for 30 days. Some of the excipients could even provide for less than 8% degradation over 30 days, which is the current specification for SA component of effervescent tablets comprising ASA.

[0085] In some embodiments of present invention, the excipient in the liquid fill may also facilitate dissolution of the moisture sensitive pharmaceutical and / or dietary supplement in the digestive tract of a patient, which is an aqueous environment. The surfactant is capable of helping diffuse or solubilize the moisture sensitive pharmaceutical and / or dietary supplement from the oil-based fill into the aqueous environment of the digestive tract. The solubilized moisture sensitive pharmaceutical and / or dietary supplement can then be absorbed by the digestive tract.

[0086] In one aspect of the pharmaceutical or dietary supplement composition of present invention, the liquid fill comprises a) at least one moisture sensitive active ingredient; and b) at least about 20% (w / w) of at least one excipient comprising or consisting of amphiphilic block copolymers of PEG and PPG groups; wherein the shell comprises an edible polymer and / or plasticizer, and optionally an opacifier and / or colorants. This aspect can be combined with any of the embodiment as described above.

[0087] In a preferred embodiment of this aspect the active ingredient is selected from ASA or Acetaminophen, preferably ASA.

[0088] In a further embodiment of this aspect the at least one excipient is selected from the group consisting of Pluronic L31, Pluronic L61, Pluronic L62, Pluronic L64, Pluronic L92, Pluronic L101, Pluronic L121, Pluronic P123, Pluronic F68, Pluronic F108, Pluronic F127, Pluronic RPE1720, Pluronic RPE1740 and Pluronic RPE3110.

[0089] In a further embodiment of this aspect the at least one excipient is selected from the group consisting of Pluronic L31, Pluronic L35, Pluronic L61, Pluronic L62, Pluronic L64, Pluronic L92, Pluronic, Pluronic P123, Pluronic F68, Pluronic F108, Pluronic RPE1720, Pluronic RPE1740 and Pluronic RPE3110.

[0090] Active ingredients

[0091] In one embodiment of present invention the pharmaceutical or dietary supplement composition present invention the at least one moisture sensitive active ingredient is selected from a non-steroidal antiinflammatory drug (NSAID), Itraconazole, Ketoconazole, Erythromycin, Acyclovir or Omeprazole.

[0092] One preferred NSAID of present invention is acetyl salicylic acid (ASA). The ASA content of a soft capsule dosage form of the invention can contain any typically used dose of ASA. For example, doses of about 60 mg and of about 80 mg of ASA are commonly used prophylactically for prevention of heart disease and stroke. In various embodiments, each capsule contains about 60 mg, or about 80 mg, or about 100 mg, of ASA, or any amount in between. A dosage form capsule of the invention can further include larger ASA dosages. In various embodiments, an amount of ASA present in a capsule can range from about 50 mg to about 500 mg.

[0093] The preferred NSAID is ASA as it is a highly moisture sensitive active ingredients that is difficult to formulate into soft gel capsules and specifically into soft gel capsules with a liquid fill.

[0094] Other suitable NSAIDs include, without limitation Propionic acid drugs such as Fenoprofen calcium (Nalfon®), Flurbiprofen (Ansaid®), Suprofen; Benoxaprofen, Ibuprofen (prescription Motrin®), Ibuprofen (200 mg over the counter Nuprin, Motrin IB®), Ketoprofen (Orduis, Oruvall®), Naproxen (Naprosyn®), Naproxen sodium (Aleve, Anaprox, Aflaxen®), Oxaprozin (Daypro®), or the like; Acetic acid drugs such as Diclofenac sodium (Voltaren®), Diclofenac potassium (Cataflam®), Etodolac (Lodine®), Indomethacin (Indocin®), Ketorolac tromethamine (Acular, Toradol® intramuscular), Ketorolac (oral Toradol®), or the like; Ketone drugs such as Nabumetone (Relafen®), Sulindac (Clinoril®), Tolmetin sodium (Tolectin®) or the like; Fenamate drugs such as Meclofenamate sodium (Meclomen®), Mefenamic acid (Ponstel®), or the like; Oxicam drugs such as Piroxicam (Dolibid®), or the like; Salicylic acid drugs such as Diflunisal (Feldene®), or the like; Pyrazolin acid drugs such as Oxyphenbutazone (Tandearil®), Phenylbutazone (Butazolidin®), or the like; acetaminophen (Tylenol®), or the like; COX-2 inhibitors such as Celebrex, Vioxx, or the like, or mixtures or combinations thereof.

[0095] Shell formulation

[0096] In one embodiment of present invention the edible polymer is selected from gelatine, gelatine RXL, gelatine GELITA® RXL R2 and non-animal derived compounds, such as Seagel® CAP 203, carrageenan, vegetable starch, such as for example maize or pea starch, or combinations thereof, preferably gelatine GELITA® RXL R2 or Seagel® CAP 203.

[0097] As is common with liquid-based capsule formulations, the encapsulating material may be a soft outer shell. As such, the present disclosure provides for a soft gel capsule comprising an outer shell encapsulating the inner fill. Also provided are an outer shell and compositions and / or mixtures to be used in the preparation of the outer shell. As understood in the art, a typical outer shell for a soft gel capsule may contain gelatine or non-animal derived components as the principal encapsulating material, water, and plasticizers such as glycerine and / or sorbitol-sorbitan solution to allow the gelatine or the non-animal derived components to be formed to and retain the desired capsule shape. However, in addition to the gelatine and non-animal derived components, water, glycerine and / or sorbitol-sorbitan solution, the outer shells of present invention may contain one or more further colorants, such as pearlescent pigments or other opaque materials, making the soft gel capsule visually appealing to the consumer.

[0098] In one preferred embodiment of present invention the soft gel capsules comprise gelatine as the primary matrix for the outer shell, as the physical properties of the gelatine may be readily modified with plasticizers or colorants as needed. Certain grades of gelatine, as characterized by, for example, bloom strength, may be utilized in the outer shell.

[0099] In one embodiment, the shell of the capsules comprises from about 20% to about 60% (w / w) gelatine, more preferably from about 25% to about 52% (w / w) gelatine, and most preferably from about 40% to about 52% (w / w) gelatine. The gelatine can be of Type A or Type B, or a mixture thereof with bloom numbers ranging from about 60 to about 300, more preferred from about 100 to 180 bloom.

[0100] In some embodiments, the gelatine outer shell comprises at least about 35 wt%, at least about 40 wt%, at least about 41 wt%, at least about 42 wt%, at least about 43 wt%, at least about 44 wt%, at least about 45 wt%, at least about 46 wt%, at least about 47 wt%, at least about 48 wt%, at least about 49 wt%, at least about 50 wt%, at least about 51 wt%, at least about 52 wt%, at least about 53 wt% gelatine of the total weight of the shell.

[0101] In some embodiments, the shell comprises non-animal derived components, such as Seagel® CAP 203, carrageenan, vegetable starch, such as for example maize or pea starch, or combinations thereof, as the primary matrix for the outer shell. Its physical properties can be readily modified with plasticizers and / or colorants as needed.

[0102] In some embodiments, the outer shell comprising non-animal derived components comprises at least about 20 wt%, at least about 21 wt%, at least about 22 wt%, at least about 23 wt%, at least about 24 wt%, at least about 25 wt%, at least about 26 wt%, at least about 27 wt%, at least about 28 wt%, at least about 29 wt%, at least about 30 wt%, at least about 31 wt%, at least about 32 wt%, at least about 33 wt%, at least about 34 wt%, at least about 35 wt% of the non-animal derived components, such as for example Seagel® CAP 203, of the total weight of the shell.

[0103] Water is added to the gelatine and / or to the non-animal derived components to provide a liquid outer shell mixture that is easily manipulated and molded during the manufacturing process. In some embodiments, the outer shell comprises water. In certain embodiments, the outer shell has a water content of at least about 20 wt%, at least about 25 wt%, at least about 28 wt%, at least about 30 wt%, at least about 34 wt%, at least about 35 wt%, at least about 36 wt%, at least about 37 wt%, at least about 38 wt%, at least about 39 wt%, or at least about 39.5 wt% of the total weight of the outer shell.

[0104] The shell of the present invention, as initially prepared, generally comprises 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 glycerine. Another preferred plasticizer is sorbitol, sorbitan and / or a combination of sorbitol and sorbitan.

[0105] In another preferred embodiment the plasticizer can be a mixture of glycerine, sorbitol and sorbitan.

[0106] In some embodiments, the outer shell comprises at least about 13.0 wt%, at least about 14.0 wt%, at least about 15.0 wt%, at least about 16.0 wt%, at least about 17.0 wt%, at least about 18.0 wt%, at least about 19.0 wt%, or at least about 20.0 wt% glycerin of the total weight of the outer shell.

[0107] Plasticizers including, but not limited to, glycerine and sorbitol-sorbitan solution can be added to the outer shell to confer the desired material properties of the final outer shell for handling, storage, and use. The soft shell thus obtained has the required flexibility characteristics for use as an encapsulation agent. Useful plasticizers of the present invention include glycerine, propylene glycol, sorbitan, sorbitol, or similar low molecular weight polyols, and mixtures thereof.

[0108] For example, glycerine and / or sorbitol-sorbitan may be added to increase the plasticity and pliability of the outer shell. In some embodiments, the outer shell comprises one or more plasticizers. In certain embodiments, the one or more plasticizers comprise glycerine. In other embodiments, the one or more plasticizers comprise sorbitol-sorbitan. Currently there is a growing interest in using materials that avoid animal -derived products or compounds for formulation of the capsule shells to address cultural, religious, and dietary requirements. For example, Hydroxypropyl Methylcellulose as for example used in V - caps, Quali - VC and Vegicaps, as well as pullulan shells (NPCaps) and starch are alternatives that are envisaged as shell material without animal derived products. In a preferred embodiment of present invention, the shell therefore does not comprise any animal derived products. In one embodiment of present invention the shell comprises starch, carrageenan, Seagel® CAP 203, or combinations thereof.

[0109] In some embodiments the outer shell comprises at least about 13 wt%, at least about 14 wt%, at least about 15 wt%, at least about 16 wt%, at least about 17 wt%, at least about 18 wt%, at least about 19 wt%, at least about 20 wt%, at least about 21 wt%, at least about 22% wt%, at least about 23% wt%, or at least about 24% wt% glycerine of the total weight of the outer shell, most preferred being an amount of at least about 25 wt% glycerine.

[0110] In some embodiments, the outer shell comprises colorants such as dyes or pigments. It should be recognized that any food-grade dye known in the art is suitable for use in the outer shell of the present disclosure.

[0111] In addition to dyes, other colorant agents may be included to increase the opacity of the outer shell to provide a more attractive appearance to the soft gel capsule. In other embodiments, the outer shell comprises titanium dioxide, starch, calcium carbonate, zinc oxide, tricalcium phosphate iron oxides, or combinations thereof. In one embodiment, the outer shell comprises a pearlescent pigment. In certain embodiments, the pearlescent pigment comprises a natural silicate or silica in combination with titanium oxide particles and / or iron oxide particles, wherein the particles have a particle size between about 5 microns and about 150 microns. In certain embodiments, the outer shell comprises a Candurin® pigment. In certain other embodiments, the outer shell comprises a silver or gold pearlescent pigment.

[0112] In a further embodiment the present invention also provides for soft gel capsules comprising an inner fill, an outer shell, and a coating, wherein the outer shell encapsulates the inner fill and the coating is applied to the outer shell. Coatings may be applied to the outer shell of the soft gel capsules as described herein for purposes including, but not limited to, further improvements to aesthetic appearance, flavour modification, ease of ingestion, capsule identification, etc. In some embodiments, the coating is a filmcoating. In other embodiments, the coating is a pharmaceutical glaze. In other embodiments, the coating comprises food-grade shellac.

[0113] If it is desired to improve the taste of the soft gel capsule, flavourings and / or sweeteners may be added as a coating to the capsule. In other embodiments, the coating comprises one or more flavourings. In certain embodiments, the coating comprises sugar or an artificial sweetener. The coating may further include ink for labelling and / or identification. In some embodiments, the coating comprises ink. In certain embodiments, the ink comprises polypropylene glycol.

[0114] In one embodiment of present invention the opacifier is selected from starch, titanium dioxide, starch, calcium carbonate, Zinc oxide, tricalcium phosphate, iron oxides, or combinations thereof.

[0115] In one embodiment the colorants are selected from synthetic colorants or natural colorants. Exemplary synthetic colorants 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 colorants include, but are not limited to copper complexes of chlorophylls, carmine, caramel, carotenoids, Carthamus, carrot, xanthophylls, beetroot red, paprika extract, sorghum extract, vegetable carbon.

[0116] The soft shells of the present invention comprising gelatine can be prepared by combining appropriate amounts of gelatine, water, plasticizer, and any optional components in a suitable vessel and agitating and / or stirring while heating to about 65 °C, until a uniform solution is obtained. This soft gelatine shell preparation can then be used for encapsulating the desired quantity of the fill composition employing standard encapsulation methodology to produce one-piece, hermetically sealed, soft gelatine capsules. The gelatine capsules are formed into the desired shape and size so that they can be readily swallowed. The soft gelatine capsules of the instant invention are of a suitable size for easy swallowing and typically contain from about 100 mg to about 2000 mg of the active composition. Soft gelatine capsules and encapsulation methods are described in P. K. Wilkinson et at., "Soft gels: Manufacturing Considerations", Drugs and the Pharmaceutical Sciences, 41 (Specialized Drug Delivery Systems), P. Tyle, Ed. (Marcel Dekker, Inc., New York, 1990) pp.409-449; F. S. Hom et at., "Capsules, Soft", Encyclopedia of Pharmaceutical Technology, vol. 2, J. Swarbrick and J. C. Boylan, eds. (Marcel Dekker, Inc., New York, 1990) pp. 269-284; M. S. Patel et at., "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 gel (Soft Gelatin Capsule) Update", Drug Development and Industrial Pharmacy (Interphex '86 Conference), vol. 12, no. 8 & 9, pp. 1133-1144 (1986); 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 by reference herein in their entirety. The resulting soft gelatine capsule is soluble in water and in gastrointestinal fluids. Upon swallowing the capsule, the gelatine shell rapidly dissolves or ruptures in the gastrointestinal tract thereby introducing the pharmaceutical actives from the liquid core into the physiological system.

[0117] The vegetarian or vegan soft shells of the present invention that do not comprise gelatine from animal sources, can be prepared as described above, the melting temperature being around 95°C.

[0118] Preferably the capsules have an oblong or oval shape to facilitate swallowing. In the case of a capsule containing 125 to 1400 mg of the active ingredients an oblong capsule may be about 10.0 -20.0 mm, preferably 12.0 - 18.0 mm, in particular about 15.0 to 15.5 mm long and have a diameter of about 5.0 to 11.0 mm, preferably 6.0 - 10.0 mm, in particular 8.0-9.0 mm, most preferred 8.8 to 9.0 mm.

[0119] In one embodiment of present invention, the soft gel capsule may be characterized by standard shape and size categories known in the art to describe soft gel capsule forms and fill values.

[0120] In some embodiments, the soft gel capsule may have a shape that is oval, oblong, or round. In certain embodiments, the soft gel capsule may have a size between 12 and 18 minims. In some embodiments, the soft gel capsule has a size of less than or equal to an oval, oblong, or round size 12 minims gel capsule. In certain embodiments, the soft gel capsule has a size and shape of 12 minims oval or 12 minims oblong. In some embodiments, the soft gel capsule has a size and shape of 12 minims oblong. In other embodiments, the soft gel capsule has a size of less than or equal an oval, oblong, or round size 18 minims capsule. In certain embodiments, the soft gel capsule has a size and shape of 18 minims oval or 18 minims oblong. In still other embodiments, the soft gel capsule has a size and shape of 18 minims oblong.

[0121] It is finally contemplated that any features described herein can optionally be combined with any of the embodiments of any method, medical use, kit and use of a kit of the invention; and any embodiment discussed in this specification can be implemented with respect to any of these. It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention.

[0122] 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.

[0123] The use of the word "a" or "an" may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one". The use of the term “another” may also refer to one or more. The use of the term "or" in the claims is used to mean "and / or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive.

[0124] As used in this specification and claim(s), 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 the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. As used herein, the phrase "consisting of’ excludes any element, step, or ingredient not specified in the claim except for, e.g., impurities ordinarily associated with the element or limitation.

[0125] The term "or combinations thereof’ as used herein 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 if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.

[0126] As used herein, words of approximation such as, without limitation, "about", "around”, “approximately” refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating the condition as being present. The extent to which the description may vary will depend on how great a change can be instituted and still have one of ordinary skilled in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodified feature. In general, but subject to the preceding discussion, a numerical value herein that is modified by a word of approximation such as "about" may vary from the stated value by ±1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%. Accordingly, the term “about” may mean the indicated value ± 5% of its value, preferably the indicated value ± 2% of its value, most preferably the term “about” means exactly the indicated value (± 0%).

[0127] Examples

[0128] Manufacturing process

[0129] The different formulations studied in Example 1 and Example 2 for a total weight of 10 g were manufactured in the lab facilities following the below procedure:

[0130] 1. Melt the excipient at the temperature required in an oven and mix for homogenization a. For excipients PEG 400, Soy oil, and Pluronics (except to Pluronic P123, Pluronic F68, Pluronic F108 and Pluronic F127): room temperature. b. For excipients Pluronic P123, Pluronic F68, Pluronic F108 and Pluronic F127: 60°C.

[0131] 2. Weight the excipient(s) in a glass vial. In case of mixture excipient, stir in a vortex until complete homogenization .

[0132] 3. Weight Aspirin in the glass vial. 4. Stir in a vortex until complete homogenization.

[0133] 5. Fill formulation has been in contact with gelatin shell. Let the formulations cool at room temperature if needed.

[0134] 6. Place the glass vials in the climatic chamber at 25°C / 60%RH for the stability study.

[0135] PEG 400 and soy oil formulations have been used as a reference for standard hydrophilic and lipophilic liquid formulations to compare with Pluronic fill formulations.

[0136] Table 1: HLB and %EO groups of excipients used in the formulations of present invention.

[0137] Soy oil - A vegetable oil extracted from the seeds of the soybean (Glycine max). Melting point -16°C;

[0138] HLB 4.

[0139] Macrogol 400 (Polyethylene Glycol 400, PEG 400) - A low-molecular-weight grade of polyethylene glycol. It is a clear, colorless, viscous liquid and is strongly hydrophilic. Due in part to its low toxicity, PEG 400 is widely used in a variety of pharmaceutical formulations. Melting point 4-8°C; HLB 10.

[0140] Pluronic L31 (Pluronic L-31) - A difunctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -1,100 g / mol), with EO-PO-EO structure, 2 EO segments and 16 PO segments (20%EO). It is a colourless viscous liquid, classifies as non-ionic surfactant that is 100% active and relatively nontoxic, excellent w / o emulsification and defoaming properties; thus, it is used for different formulation types as dispersant and emulsifier properties. Melting Point ~32°C; HLB 4.

[0141] Pluronic L35 (Pluronic L-35, Poloxamer 105, Poloxamer P105) - A difimctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -1,900 g / mol), with EO-PO-EO structure, 22 EO segments and 16 PO segments (73%EO). It is a liquid, classified as non-ionic surfactant that is 100% active and relatively nontoxic, it is an effective dispersant, solubilizer and emulsifier that is readily biodegradable; thus, it is used for different formulation types as polymer and surfactant. Melting Point ~7°C; HLB 10.

[0142] Pluronic L61 (Pluronic L-61) - A difunctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -2,000 g / mol), with EO-PO-EO structure, 4 EO segments and 32 PO segments (20%EO). It is a colourless liquid, classified as non-ionic surfactant that is 100% active and relatively nontoxic, that offers good w / o emulsification properties and effective defoamer characteristics; thus, it is used for different formulation types as dispersant, emulsifier and defoamer. Melting Point -29°C; HLB 3.

[0143] Pluronic L62 (Pluronic L-62, Poloxamer 182, Poloxamer P 182) - A difimctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -3,650 g / mol), with EO-PO-EO structure, 8 EO segments and 50 PO segments (24%EO). It is a colourless liquid, classified as non-ionic surfactant that is 100% active and relatively nontoxic, that offers great o / w emulsifier that is readily biodegradable provides, good emulsion stability and is low foaming; thus, it is used for different formulation types as dispersant, emulsifier, surfactant, wetting aid and process aid. Melting Point -4°C; HLB 4.

[0144] Pluronic L64 (Pluronic L-64, Poloxamer 184, Poloxamer P 184) - A difimctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -2,900 g / mol), with EO-PO-EO structure, 14 EO segments and 31 PO segments (47%EO). It is a colourless liquid, classified as non-ionic surfactant that is 100% active and relatively nontoxic. It is used for different formulation types as wetting agent, emulsifier, demulsifier, viscosity control agent, dispersant, antistatic agent, and lubricant. Melting Point 16°C; HLB 15.

[0145] Pluronic L92 (Pluronic L-92) - A difimctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -3,650 g / mol), with EO-PO-EO structure, 6 EO segments and 35 PO segments (26%EO). It is a colourless liquid, classified as non-ionic surfactant that is 100% active and relatively nontoxic, cellent w / o emulsification, wetting and defoaming properties; thus, it is used for different formulation types as wetter, dispersant, emulsifier, and process aid. Melting Point 7°C; HLB 6.

[0146] Pluronic L101 (Pluronic L-101, Poloxamer 331, Poloxamer P331) - A difunctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -3,800 g / mol), with EO-PO-EO structure, 6 EO segments and 59 PO segments (17%EO). It is a colourless liquid, classified as A non-ionic surfactant that is 100% active and relatively nontoxic, excellent emulsification, wetting and defoaming properties.; thus, it is used for different formulation types as wetter, dispersant, emulsifier, and process aid. Melting Point -23°C; HLB 1.

[0147] Pluronic L121 (Pluronic L-121, Poloxamer 401, Poloxamer P401) - A difunctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -4,400 g / mol), with EO-PO-EO structure, 5 EO segments and 62 PO segments (14%EO). It is a liquid, classified as a non-ionic surfactant that is 100% active and relatively nontoxic, is particularly suitable for formulating low-foaming water-in- oil (w / o) emulsions; thus, it is used for different formulation types as dispersant, emulsifier (w / o), process aid, surfactant, and wetting agent. Melting Point 5°C; HLB 1.

[0148] Pluronic P123 (Pluronic P-123, Poloxamer 403, Poloxamer P403) - A difunctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -5,800 g / mol), with EO-PO-EO structure, 20 EO segments and 70 PO segments (36%EO). It is available in paste form and is classified as a non-ionic surfactant that is 100% active and relatively nontoxic. Acting as dispersant, emulsifier (o / w), surfactant and wetting agent. Melting Point 56°C; HLB 8.

[0149] Pluronic F68 (Pluronic F-68, Poloxamer 188, Poloxamer Pl 88, Pluronic PE 6800) - A difimctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -8,400 g / mol), with EO-PO-EO structure, 80 EO segments and 30 PO segments (85%EO). It is available in flakes form and is classified as a non-ionic surfactant that is 100% active and relatively nontoxic, provides emulsion stability good particle dispersion, foaming and associative thickening properties. It is used for different formulation types as dispersant and emulsifier. Melting Point 52°C; HLB 20.

[0150] Pluronic F108 (Pluronic F-108, Poloxamer 338, Poloxamer P338, Synperonic® F108) - A difunctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -14,600 g / mol), with EO-PO-EO structure, 127 EO segments and 48 PO segments (85%EO). It is available in flakes form and is classified as a non-ionic surfactant that is 100% active and relatively nontoxic. It is used in different formulation types as soluhilizer and surfactant. Melting Point 52°C; HLB 20.

[0151] Pluronic F127 (Pluronic F-127, Poloxamer 407, Poloxamer P407, Synperonic PE / F 127) - A difunctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -12,500 g / mol), with EO-PO-EO structure, 100 EO segments and 65 PO segments (75%EO). It is available in flakes form and is classified as a non-ionic surfactant that is 100% active and relatively nontoxic. It is used in different formulation types as solubilizer and surfactant. Melting Point 57°C; HLB 20.

[0152] Pluronic RPE1720 (Pluronic RPE-1720) - A difunctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -2,150 g / mol), with PO-EO-PO structure, 11 EO segments and 22 PO segments (20%EO). It is a liquid, classified as a non-ionic surfactant that is 100% active and relatively nontoxic. It is used in different formulation types as solubilizer and surfactant. HLB 4.

[0153] Pluronic RPE1740 (Pluronic RPE-1740) - A difunctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -2,650 g / mol), with PO-EO-PO structure, 21 EO segments and 16 PO segments (40%EO). It is a liquid, classified as a non-ionic surfactant that is 100% active and relatively nontoxic. It is used in different formulation types as solubilizer and surfactant. HLB 8. Pluronic RPE3110 (Pluronic RPE-3110) - A difunctional EO / PO block copolymer surfactant terminating in primary hydroxyl groups (MW -3,500 g / mol), with PO-EO-PO structure, 9 EO segments and 40 PO segments (10%EO). It is a liquid, classified as a non-ionic surfactant that is 100% active and relatively nontoxic. It is used in different formulation types as solubilizer and surfactant. HLB 2.

[0154] EXAMPLE 1 : Stability of Pluronic / soy oil mixture formulations with Aspirin to select the best amounts of Pluronic

[0155] The stability of Aspirin in various formulations of present invention with different Pluronic L62: soy oil ratios were studied to assess the minimum amount of excipient needed for seeing an effect on the stability of Aspirin. The stability study was carried out at long term storage conditions (25°C / 60% RH) with the following sampling points: time zero, 7 days, 15 days and 30 days. In each sampling point, formulations were analysed by HPLC for the Aspirin (ASA) and its degradation product Salicylic Acid (SA) content.

[0156] The results are shown in Figure 1. As can be seen, an effect of protection from degradation can already be seen when at least 20% (w / w) of the excipient in the liquid fill are Pluronic in the formulation. The higher the percentage of Pluronic based on the total weight of the excipient used in the fill, the better protection against degradation is achieved. When at least 40% (w / w) of the excipient in the liquid fill are Pluronic in the formulation, less than 40% of the API were degraded after 30 days. Increasing the amount of Pluronic to 60% (w / w) resulted in degradation of below 60% after 30 days. Increasing the amount of Pluronic to 80% (w / w) resulted in degradation of below 35% after 30 days, whereas with 90% (w / w) the degradation already decreased to 20%. With 100% (w / w) of Pluronic in the liquid fill, i.e., Pluronic being the only excipient in the fill, less than 10% degradation can be observed. As described above, the usual degradation rate in soft gel capsules of the prior art is no lower than 35%, which is why there exists no accepted standard so far. It is therefore highly surprising that the addition of Pluronic as the main excipient can lower the degradation rate to such a low amount even reaching the 8%, which is the accepted threshold for effervescent tablets.

[0157] EXAMPLE 2: Pluronic formulations with Aspirin vs soy oil or PEG 400 formulations with Aspirin, using the same Aspirin: excipient ratio.

[0158] The stability of Aspirin in various formulations of present invention with different Pluronics as the only excipient (100% (w / w) of excipient) were studied to assess which Pluronics show the best properties for stabilizing the API. These formulations were compared to soy oil and PEG 400 formulations as an example of common hydrophilic and lipophilic excipients used in standard softgels.

[0159] The stability study was carried out at long term storage conditions (25°C / 60% RH) with the following sampling points: time zero, 7 days, 15 days and 30 days. In each sampling point, formulations were analysed by HPLC for the Aspirin (ASA) and its degradation product Salicylic Acid (SA) content. The results of the stability study are shown in Figure 2 and Table 2 (below). As can be seen the highest amount of degradation (100% of SA after 30 days) was observed in the presence of the lipophilic control excipient soy oil. In the presence of PEG400, the hydrophilic control excipient, more than 20% were degraded after 15 days and almost 40% after 30 days of storage. All other excipients kept more than about 80% of the API stable for 30 days. No correlation to % degradation product and HLB of Pluronic excipient was observed. The preferred excipients with less than 8% degradation were Pluronic RPE1720, Pluronic RPE1740, Pluronic RPE3110, Pluronic L31, Pluronic L35, Pluronic L61, Pluronic L62 and Pluronic L92, see Table 2 below.

[0160] Table 2: %SA found in formulation of present invention with different excipients of varying %EO

[0161] The stability study was continued for 3 months, selecting Pluronic formulations with L62 and L35. L35 is a Pluronic with a content of more than 50% EO, whereas L62 is a Pluronic with a content of less than 25% EO, thus covering both ends of the %EO spectrum of the Pluronics used. The results are shown in Figure 3. As can be seen both Pluronics provide for extremely low Aspirin degradation, which is maintained for three months, meaning that Pluronics with a content of less than 25% EO and also Pluronics with a content of more than 50% EO can act as efficient stabilizers. In both cases, the % SA content is far from the values obtained for reference formulations (at least 35% of SA after 1 month). In fact, both formulations even comply with the current acceptance limit fixed for effervescent tablets (<8%).

Claims

CLAIMS1. A pharmaceutical or dietary supplement composition in the form of a soft gel capsule comprising a liquid fill and a shell, wherein the liquid fill comprises a) at least one moisture sensitive active ingredient; and b) at least about 55% (w / w) of at least one excipient comprising or consisting of amphiphilic block copolymers of PEO and PPO groups; wherein the shell comprises an edible polymer and / or plasticizer, and optionally an opacifier and / or colorants.

2. The pharmaceutical or dietary supplement composition of claim 1, wherein the at least one moisture sensitive active ingredient is selected from a non-steroidal anti-inflammatory drug (NSAID), Itraconazole, Ketoconazole, Erythromycin, Acyclovir or Omeprazole.

3. The pharmaceutical or dietary supplement composition of claim 2, wherein the NSAID is selected from the group consisting of Acetyl salicylic acid (Aspirin), Fenoprofen calcium, Flurbiprofen, Suprofen, Benoxaprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin, Diclofenac sodium, Diclofenac potassium, Etodolac, , Ketorolac tromethamine, Ketorolac, Nabumetone, Sulindac, Tolmetin, Meclofenamate sodium, Mefenamic acid, Piroxicam, Diflunisal, Oxyphenbutazone, Phenylbutazone, Acetaminophen, COX-2 inhibitors, or mixtures or combinations thereof.

4. The pharmaceutical or dietary supplement composition of claims, wherein the NSAID is selected from the group consisting of Acetyl salicylic acid (Aspirin), Acetaminophen, Naproxen and Naproxen sodium.

5. The pharmaceutical or dietary supplement composition of any one of the preceding claims, wherein the at least one excipient is a tri-block copolymer of PEO and PPO groups.

6. The pharmaceutical or dietary supplement composition of any one of the preceding claims, wherein the fill comprises at least about 60% (w / w), preferably at least about 70% (w / w), more preferably at least about 80% (w / w), most preferably at least about 90% (w / w) of the at least one excipient.

7. The pharmaceutical or dietary supplement composition of any one of the preceding claims, wherein the fill comprises only one excipient.

8. The pharmaceutical or dietary supplement composition of any one of the preceding claims, wherein the weight percent of the EO chain in the copolymer of the at least one excipient is between about 10 to 85% (w / w).

9. The pharmaceutical or dietary supplement composition of any one of the preceding claims, wherein the copolymer has a Mw of between about 1.100 to 14.600 g / mol.

10. The pharmaceutical or dietary supplement composition of any one of the preceding claims, wherein the at least one excipient is selected from the group consisting of Pluronic L31, Pluronic L35, Pluronic L61, Pluronic L62, Pluronic L64, Pluronic L92, Pluronic L101, Pluronic L121, Pluronic P123, Pluronic F68, Pluronic F108, Pluronic F127, Pluronic RPE1720, Pluronic RPE1740 and Pluronic RPE3110.

11. The pharmaceutical or dietary supplement composition of any one of the preceding claims, wherein the at least one excipient is selected from the group consisting of Pluronic L31, Pluronic L35, Pluronic L61, Pluronic L62, Pluronic L92, Pluronic RPE1720, Pluronic RPE1740 and Pluronic RPE3110, preferably the at least one excipient is selected from Pluronic L35, Pluronic L61, Pluronic L62 and Pluronic L92.

12. The pharmaceutical or dietary supplement composition of any one of the preceding claims, wherein the edible polymer is selected from gelatine, gelatine RXL, gelatine GELITA® RXL R2 and non-animal derived compounds, such as Seagel® CAP 203, carrageenan, vegetable starch, such as for example maize or pea starch, or combinations thereof, preferably gelatine GELITA® RXL R2 or Seagel® CAP 203.

13. The pharmaceutical or dietary supplement composition of any one of the preceding claims, wherein the plasticizer is selected from glycerine, propylene glycol, mannitol, sorbitan, sorbitol, or similar low molecular weight polyols, or combinations thereof.

14. The pharmaceutical or dietary supplement composition of any one of the preceding claims, wherein the opacifier is selected from starch, titanium dioxide, calcium carbonate, zinc oxide, tricalcium phosphate, iron oxides, or combinations thereof.

15. A method of stabilizing a moisture sensitive active ingredient in the liquid fill of a soft gel capsule, wherein at least one excipient comprising or consisting of amphiphilic block copolymers of PEG and PPG groups is added to the liquid fill at an amount of at least about 55% (w / w), preferably at an amount of at least about 60% (w / w).

16. The method of claim 15, comprising the moisture sensitive ingredient according to claims 3 or 4 and the at least one excipient according to any one of claims 5 or 8 to 11.

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