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

Abstract

The invention relates to a pharmaceutical or dietary supplement composition in the form of a soft gel capsule comprising a solid fill and a shell, wherein the fill comprises a moisture sensitive active ingredient and at least one excipient with a melting temperature of at least 35ºC at an amount of at least 3.5% (w / w) as well as methods for preparing such soft gel capsules. The invention furthermore relates to methods of stabilizing said moisture sensitive active ingredient.

Description

[0001] Stable soft capsule preparations with solid 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 solid fill and a shell, wherein the fill comprises a moisture sensitive active ingredient and at least one excipient with a melting temperature of at least 35°C at an amount of at least 3.5% (w / w) as well as methods for preparing such soft gel capsules. 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. 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 final product. But, for the moisture sensitive actives, these negative effects may appear under standard conditions. Thus, both migration phenomena can then compromise any moisture sensitive pharmaceuticals located therein.

[0008] 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, i.e. , 3% for extended- release tablets and delayed-release tablets and 8% for effervescent tablets. Currently, ASA soft gel capsules are not marketed due to the high degradation rate. Therefore, no specific limits for the SA content are defined for soft gel capsules. However, 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.

[0009] 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.

[0010] 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 and overcome these problems; however, these forms can act more slowly after ingestion than ASA itself and are not as effective. In W02008 / 068276 the liquid or semi-solid (pasty) fill of the disclosed soft gel capsules comprises an internal lipophilic phase with 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 as help with locking or trapping the water present in their structure.

[0011] US 2014 / 335171 discloses soft gelatine capsules with liquid or semi-solid lipophilic-based fills (such as omega-3 fatty acids as lipophilic vehicle) comprising ASA and additional compounds like amylose or high-amylose starch as stabilizer trapping the water molecules protecting the ASA against hydrolysis to SA. This stabilization effect is improved in the presence of an acid such as citric acid, tartaric acid or the like which can be added into the liquid or semisolid fill.

[0012] 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.

[0013] W00059475A1 discloses a soft gelatin capsule formulation comprising a liquid fill having a hydrophobic pharmaceutical with at least one ionizable functional group, and a carrier, such as non-ionic hydrophilic surfactants having a hydrophilic-lipophilic balance (HLB) value greater than or equal to about 10, ionic hydrophilic surfactants, or hydrophobic surfactants having an HLB value less than 10. It is disclosed that the carriers are capable of solubilizing and delivering a wide variety of ionizable hydrophobic pharmaceuticals including aspirin.

[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.

[0015] Whilst the above cited prior art documents focus on providing the moisture sensitive active ingredients in liquid or semisolid fills, W02020081649 describes solidification as a concept to improve the stability of moisture sensitive active ingredients regardless of hydrophilic-lipophilic balance of fill material, where the solidification has been achieved by UV induced polymerization of the fill after its encapsulation. However, also this solution requires the addition of polymerizable compounds into the fill as well as an extra step of polymerization during the production of the soft gels under high energy consumption, increasing the manufacturing time and cost. In addition, this polymeric technology shows many challenges with respect to product quality and safety. Especially important are the safety limitations due to the nature of polymerizable compounds described. After the polymerization process the suitability of the final polymerized matrix and also the residual levels of polymerizable compounds for human consumption should be ensured.

[0016] Given the aforementioned situation and 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.

[0017] 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 encapsulation process and the following steps of standard soft gel production, and also over the shelf-life of the final product.

[0018] 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.

[0019] SUMMARY

[0020] 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 solid fill and a shell, wherein the solid fill comprises a) at least one moisture sensitive active ingredient; and b) at least one excipient with a melting temperature of at least 35°C at an amount of at least 3.5% (w / w); wherein the shell comprises an edible polymer and / or plasticizer, and optionally an opacifier and / or colorants.

[0021] The fill of the pharmaceutical or dietary supplement composition in the form of a soft gel capsule of present invention is solid at room temperature (25°C ± 5°C).

[0022] The fill of the pharmaceutical or dietary supplement composition in the form of a soft gel capsule of present invention is solid at a temperature of less than 35°C.

[0023] 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 nonsteroidal anti-inflammatory 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, Ibuprofen, 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.

[0025] In one embodiment the solid fill comprises at least one excipient with a melting temperature of at least 35°C at an amount of at least 5.0% (w / w).

[0026] In one embodiment the solid fill comprises at least one excipient with a melting temperature of at least 35°C at an amount of at least 6.0% (w / w).

[0027] In one embodiment the solid fill comprises at least one excipient with a melting temperature of at least 35°C at an amount of at least 10.0% (w / w). In one embodiment of present invention the at least one excipient has a melting temperature of between 35°C to 80°C, preferably between 40°C to 60°C.

[0028] In a further embodiment of the pharmaceutical or dietary supplement composition of present invention the at least one excipient or additive has an HLB of equal to or less than 20, preferably equal or less than 15.

[0029] In one embodiment of the pharmaceutical or dietary supplement composition of present invention at least one excipient is selected from the group consisting of Gelucire 50 / 13, Gelucire 48 / 16, Gelucire 59 / 14, Novata BC PH, Novata BCF PH, Gelucire 44 / 14, beeswax, Candelilla wax, WITEPSOL H37, WITEPSOL E76, Gelucire 43 / 01 , Precirol, Geleol and Compritol 888.

[0030] In a preferred embodiment the at least one excipient is selected from the group consisting of Gelucire 44 / 14, beeswax, Candelilla wax, WITEPSOL H37, WITEPSOL E76, Gelucire 43 / 01 , Precirol, Geleol and Compritol 888.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] In one embodiment the colorants are selected from synthetic colorants or natural colorants.

[0035] In a further aspect the present invention relates to a method for preparing a pharmaceutical or dietary supplement composition in the form of a soft gel capsule with a solid fill, comprising the steps of a) providing a liquid or semi-solid fill composition, said fill composition comprising at least 3.5% (w / w) of at least one excipient with a melting temperature of at least 35°C, b) formulating an active ingredient into the liquid or semi-solid fill composition, c) encapsulating the composition of b) with a shell composition, d) solidifying the fill composition by reducing the temperature of the fill composition to a temperature below the melting temperature of the at least one excipient in a).

[0036] In one embodiment of the method for preparing a pharmaceutical or dietary supplement composition of present invention the solidification is done by rapid reduction of the temperature below the melting temperature of the at least one excipient in a).

[0037] In one embodiment of the method for preparing a pharmaceutical or dietary supplement composition of present invention in step d) reducing the temperature is performed in less than 2 minutes. In a more preferred embodiment in step d) reducing the temperature is performed in less than 1 .5 minutes, less than 1 minute, or even less than 45 seconds. Most preferred in less than 30 seconds.

[0038] In one embodiment of the method for preparing a pharmaceutical or dietary supplement composition of present invention the solidification is done by rapid reduction of the temperature to room temperature (25°C ± 5°C).

[0039] In a preferred embodiment reducing the temperature in step d) is achieved by cooling the soft gel capsule with or in a cooling device.

[0040] In a further aspect the present invention relates to a method of stabilizing moisture sensitive active ingredient in the fill of a soft gel capsule, wherein at least one excipient with a melting temperature of at least 35°C is added to the liquid fill at an amount at least 3.5% (w / w) and the liquid fill is solidified after encapsulation by reducing the temperature of the fill to a temperature below the melting temperature of the at least one excipient.

[0041] DESCRIPTION OF THE FIGURES

[0042] FIG.1 : 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 from the different formulations as prepared in Example 1 depicted as a function of their melting temperature. The results of different formulations which includes excipient with similar melting temperatures were pooled, as shown in Table 1 and Figure 1. DESCRIPTION OF THE INVENTION

[0044] 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.

[0045] 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.

[0046] 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.

[0047] For a successful, rapid and economic manufacture of high quality and safe soft gel capsules the fill shall be present in liquid or semisolid form (such as pasty) so that the material can be easily formulated and injected. In fact, the physicochemical properties, such as the viscosity and fluidity parameters, of this fill material are critical for the manufacturing and filling processes, The liquids or semi-solid fills must have adequate viscosity and fluidity values to ensure the homogeneity of fill formulation along the manufacturing process but also an accurate dosing of the product by displacement pumps at a temperature of approximately 35°C or below (see e.g. G. Reich, in Pharmaceutical Capsules, (Eds: F. Podzeck, B. Jones), Pharmaceutical Press, London 2004, 201). However, maintaining sensitive active ingredients in such liquid or semisolid fill is not optimal for their stability as water from shell material or environment may migrate into the fill material promoting its degradation.

[0048] The inventors could show that after the encapsulation process one of the key parameters for keeping the moisture sensitive active ingredient in the fill material stable is a rapid solidification of the fill material, regardless of hydrophilic-lipophilic balance of fill material and the absence of stabilization molecules that trap the water molecules avoiding its interaction with the sensitive active ingredient. The solidification of the fill material after its encapsulation into the shell cover, acts as a physical barrier to the water migration from the shell to the inner part avoiding the hydrolysis reaction. The inventors have therefore developed novel formulations comprising specific excipients at a certain amount in the fill formulation that can on the one hand simplify the production process and on the other hand provide high stability to the moisture sensitive active ingredients throughout the production and storage. 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 solid fill and a shell, wherein the solid fill comprises e) at least one moisture sensitive active ingredient; and f) at least one excipient with a melting temperature of at least 35°C at an amount of at least 3.5% (w / w);

[0049] 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.

[0050] The term “stable soft gel capsule” as used herein refers to a capsule adapted for selfadministration 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 insolubilization or denaturing, 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 one month in final product.

[0051] As used herein the term “solid fill” refers to a fill having a solid, not liquid or not fluid state at room temperature (20°C to 30°C) as assessed by visual inspection of its macroscopic appearance or by other mechanical properties such as its viscosity or fluidity. It is to be understood that the term “solid fill” does not include fill formulations that having a liquid or semi-solid state, such as pasty, at room-temperature.

[0052] In one embodiment the fill of the pharmaceutical or dietary supplement composition in the form of a soft gel capsule of present invention is solid at a temperature of less than 35°C, less than less than 36°C, less than 37°C, less than 38°C, less than 39°C, less than 40°C.

[0053] 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.

[0054] 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. As used herein the terms “moisture sensitive actives” 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. Water may also facilitate the conversion of an amorphous drug into its less soluble crystalline form, affecting its solubility and bioavailability.

[0055] As used herein the term “melting temperature” refers to the temperature at which the solid and liquid forms of a pure substance can exist in equilibrium. As heat is applied to a solid, its temperature will increase until the melting point is reached. More heat then will convert the solid into a liquid with no temperature change.

[0056] Excipients

[0057] Suitable excipients of present invention have a melting temperature of at least 35°C, such as for example Gelucire 50 / 13, Gelucire 48 / 16, Gelucire 59 / 14, Novata BC PH, Novata BCF PH, Gelucire 44 / 14, beeswax, Candelilla wax, WITEPSOL H37, WITEPSOL E76, Gelucire 43 / 01 , Precirol, Geleol or Compritol 888. The inventors could show that these excipients 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. In long term stability studies, some excipients provided for less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or even less than 3% degradation over one year and even two years.

[0058] In a preferred embodiment the at least one excipient is therefore selected from the group consisting of Gelucire 44 / 14, beeswax, Candelilla wax, WITEPSOL H37, WITEPSOL E76, Gelucire 43 / 01 , Precirol, Geleol and Compritol 888.

[0059] In one embodiment of present invention the at least one excipient has a melting temperature of between 35°C to 80°C, of between 35°C to 75°C, between 35°C to 70°C, between 35°C to 65°C, between 35°C to 60°C, between 35°C to 55°C, between 35°C to 50°C, between 35°C to 40°C, between 40°C to 80°C, between 40°C to 75°C, between 40°C to 70°C, between 40°C to 65°C, between 40°C to 60°C, between 40°C to 55°C, between 40°C to 50°C or between 50°C to 60°C.

[0060] In a preferred embodiment the at least one excipient has a melting temperature of between 40°C to 60°C, most preferred between 40°C to 50°C. In one embodiment the at least one excipient has a melting temperature of at least 60°C, preferably between 60°C to 80°C.

[0061] The amount of excipient in the fill formulation is a further essential factor for the advantageous properties of the fill formulations of present invention. The inventors have found that the required amount varies with the melting temperature of the excipient. For example, if the excipient has a melting temperature of more than 60°C, such as for example beeswax, then the fill formulation needs to comprise at least 3.5% (w / w) of this excipient to be in a solid state at room temperature as shown in example 3. If the excipient has a melting temperature of 35°C to 40°C, such as for example WITEPSOL H37, then the fill formulation needs to comprise at least 32.5% (w / w) of this excipient to be in a solid state at room temperature.

[0062] In one embodiment when the at least one excipient has a melting temperature of at least 60°C, preferably between 60°C to 80°C, the fill formulation comprises at least 3.5% (w / w) of this excipient.

[0063] In one embodiment when the at least one excipient has a melting temperature of 35°C to 40°C, the fill formulation comprises at least 32.5% (w / w) of this excipient.

[0064] The excipient in the fill formulation may therefore be present in varying amounts depending on the excipient used. The excipient may be present in an amount of least 3.5% (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 12.5% (w / w), at least 15% (w / w), at least 17.5% (w / w), at least 20% (w / w), at least 22.5% (w / w), at least 25% (w / w), at least 27.5% (w / w), at least 30% (w / w), at least 32.5% (w / w), at least 35% (w / w), at least 37.5% (w / w), at least 40% (w / w), at least 42.5% (w / w), at least 45% (w / w), at least 47.5% (w / w), at least 50% (w / w), at least 52.5% (w / w), at least 55% (w / w), at least 57.5% (w / w), at least 60% (w / w), at least 62.5% (w / w), at least 65% (w / w), at least 67.5% (w / w), at least 70% (w / w), at least 72.5% (w / w), at least 75% (w / w), at least 77.5% (w / w), at least 80% (w / w), at least 82.5% (w / w), at least 85% (w / w), at least 87.5% (w / w), at least 90% (w / w), at least 92.5% (w / w), at least 95% (w / w), at least 97.5% (w / w), at least 99% (w / w) based on the total weight of the fill.

[0065] In one embodiment the solid fill comprises at least one excipient with a melting temperature of at least 35°C at an amount of at least 5.0% (w / w).

[0066] In one embodiment the solid fill comprises at least one excipient with a melting temperature of at least 35°C at an amount of at least 6.0% (w / w).

[0067] In one embodiment the solid fill comprises at least one excipient with a melting temperature of at least 35°C at an amount of at least 10.0% (w / w). In one embodiment the solid fill comprises at least one excipient with a melting temperature of at least 35°C at an amount of at least 3.5% (w / w), wherein if one of the at least one excipients with a melting temperature of at least 35°C is beeswax, the fill comprises at least 5.0% (w / w) or at least 6.0% (w / w), or at least 10.0% (w / w) of the said beeswax.

[0068] In one embodiment of present invention the fill does not comprise any further stabilizers. The fact that the fill of present invention is solid obviates the necessity for further stabilization of the moisture sensitive active ingredient as described for liquid, semi-solid and pasty fills disclosed in the prior art, which require additional stabilizers for avoiding the hydrolyzation of the active ingredient in the fill.

[0069] Such stabilizers can be selected from solid polyhydroxylated organic compound, such as for example trehalose, trehalose dihydrate, cyclodextrin, sorbitol, chondroitin sulphate, carrageenan or anhydrous calcium chloride, and water- soluble hygroscopic salts, such as for example calcium sulphate hemihydrate or anhydrous calcium chloride, or combinations thereof.

[0070] In one embodiment of present invention the solid fill does therefore not comprise any one of trehalose, trehalose dihydrate, cyclodextrin, sorbitol, chondroitin sulphate, carrageenan, calcium sulphate hemihydrate and / or anhydrous calcium chloride, or any combinations thereof.

[0071] Such stabilizers can furthermore be selected from starch, such as pre-gelatinized starch, amylose or high-amylose starch, such as high-amylose starch comprising 40-90% amylose, specifically comprising 50% or 70% amylose.

[0072] In one embodiment of present invention the solid fill does therefore not comprise any one of starch, such as for example pre-gelatinized starch, amylose and / or high-amylose starch, preferably high-amylose starch comprising 40-90% amylose, specifically comprising 50% or 70% amylose.

[0073] In one embodiment of present invention the solid fill does not comprise an acid, such as for example citric acid, anhydrous citric acid, tartaric acid or combinations thereof.

[0074] In one embodiment the solid fill of present invention does not comprise oils, such as for example fish oil, hydrogenated coconut oil and / or refined palm oil, or combinations thereof.

[0075] The inventors have furthermore found that for the choice of the excipient in addition to the melting temperature, also its HLB plays a role.

[0076] As used herein the term “HLB” is the acronym for the Hydrophilic-Lipophilic Balance. The HLB is calculated from the weight percentage of the hydrophilic groups to the hydrophobic groups in a molecule, with values ranging from 1-20 (Kraiova and Sjdblom, 2009). As is well known in the art, the terms "hydrophilic" and "hydrophobic" are relative terms. To function as a surfactant, a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moiety, i.e. , a surfactant compound must be amphiphilic. An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.

[0077] Using HLB values as a rough guide, hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, hydrophobic surfactants are compounds having an HLB value less than about 10.

[0078] For the present invention the preferred excipients have an HLB up to 20, up to 15, up to 10 or up to 5. The excipients can have an HLB of between 0 to 15, or between 0 to 10. The excipients can have an HLB of less than 5 (see Example 1 , Table 1).

[0079] As such, in a further embodiment of the pharmaceutical or dietary supplement composition of present invention the at least one excipient has an HLB of up to 20, up to 15, up to 10 or up to 5.

[0080] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the at least one excipient has an HLB of between 0 to 15, or between 0 to 10.

[0081] In one embodiment of the pharmaceutical or dietary supplement composition of present invention the at least one excipient has an HLB less than 5.

[0082] In some embodiments of present invention, the excipient in the liquid fill may 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.

[0083] Active ingredients

[0084] 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 nonsteroidal anti-inflammatory drug (NSAID), Itraconazole, Ketoconazole, Erythromycin, Acyclovir or Omeprazole. 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.

[0085] 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 1 B®), 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.

[0086] Shell formulation

[0087] 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.

[0088] 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. 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] In another preferred embodiment the plasticizer can be a mixture of glycerine, sorbitol and sorbitan.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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. 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.

[0102] 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 film-coating. In other embodiments, the coating is a pharmaceutical glaze. In other embodiments, the coating comprises food-grade shellac.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] METHOD

[0108] As described above one key factor for the successful production of soft gel capsules of present invention is the rapid solidification of the fill material after encapsulation. The process mostly used for preparation of soft gel capsules comprising a liquid or semi-solid fill (such as pasty) which is encapsulated into a soft-shell cover is the rotary die process. This process does not envisage a step of solidifying the fill composition after the fill has been encapsuled by the process, but the resulting soft gel capsules maintain their liquid or semi-solid fill after production. However, present invention comprises a further step of solidifying the fill composition after encapsulation, ideally directly after encapsulation, by reducing the temperature of the fill composition to a temperature below the melting temperature of the at least one excipient comprised in the fill.

[0109] In a further aspect the present invention therefore relates to a method for preparing a pharmaceutical or dietary supplement composition in the form of a soft gel capsule with a solid fill, comprising the steps of a) providing a liquid or semi-solid fill composition, said fill composition comprising at least 3.5% (w / w) of at least one excipient with a melting temperature of at least 35°C, b) formulating an active ingredient into the liquid or semi-solid fill composition, c) encapsulating the composition of b) with a shell composition, d) solidifying the fill composition by reducing the temperature of the fill composition to a temperature below the melting temperature of the at least one excipient in a).

[0110] In one embodiment of the method of present invention the at least one excipient has a melting temperature of between 35°C to 80°C, of between 35°C to 75°C, between 35°C to 70°C, between 35°C to 65°C, between 35°C to 60°C, between 35°C to 55°C, between 35°C to 50°C, between 35°C to 40°C, between 40°C to 80°C, between 40°C to 75°C, between 40°C to 70°C, between 40°C to 65°C, between 40°C to 60°C, between 40°C to 55°C, between 40°C to 50°C or between 50°C to 60°C.

[0111] In a preferred embodiment the at least one excipient has a melting temperature of between 40°C to 60°C, most preferred between 40°C to 50°C.

[0112] In one embodiment the at least one excipient has a melting temperature of at least 60°C, preferably between 60°C to 80°C.

[0113] In one embodiment when the at least one excipient has a melting temperature of at least 60°C, preferably between 60°C to 80°C, the fill formulation comprises at least 3.5% (w / w) of this excipient.

[0114] In one embodiment when the at least one excipient has a melting temperature of 35°C to 40°C, the fill formulation comprises at least 32.5% (w / w) of this excipient.

[0115] The excipient in the fill formulation may be present in varying amounts depending on the excipient used. The excipient may be present in an amount of least 3.5% (w / w), at least 5% (w / w), at least 10% (w / w), at least 15% (w / w), at least 20% (w / w), at least 25% (w / w), at least 30% (w / w), at least 32.5% (w / w), at least 35% (w / w), at least 40% (w / w), at least 45% (w / w), at least 50% (w / w), at least 55% (w / w), at least 60% (w / w), at least 65% (w / w), at least 70% (w / w), at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w) based on the total weight of the fill.

[0116] In one embodiment of the method for preparing a pharmaceutical or dietary supplement composition of present invention the solidification is performed by rapid reduction of the temperature below the melting temperature of the at least one excipient in a).

[0117] In one embodiment of the method for preparing a pharmaceutical or dietary supplement composition of present invention in step d) reducing the temperature is performed in less than 2 minutes. In a more preferred embodiment in step d) reducing the temperature is performed in less than 1.5 minutes, less than 1 minute or even less than 45 seconds. Most preferred is the rapid reduction in less than 30 seconds. As can be readily understood the extremely fast reduction in temperature leading to a fast solidification of the fill keeps the time in which the active ingredient in the liquid or semisolid fill can be subjected to degradation at a minimum. This fast reduction in temperature therefore leads to an increase in the amount of intact active ingredient in the final capsule.

[0118] In a preferred embodiment reducing the temperature is performed with a cooling device, such as a Mator Spot Cooler-6.200.

[0119] In a further aspect the present invention relates to a method of stabilizing moisture sensitive active ingredient in the fill of a soft gel capsule, wherein at least one excipient with a melting temperature of at least 35°C is added to the liquid or semisolid fill at an amount at least 3.5% (w / w) and the liquid fill is solidified after encapsulation by reducing the temperature of the fill to a temperature below the melting temperature of the at least one excipient.

[0120] 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. Horn 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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. 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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%).

[0130] EXAMPLES

[0131] Example 1 : Development of a formulation to encapsulate Aspirin (ASA) in a soft gelatine capsule

[0132] The different formulations for a total weight of 16 g were manufactured in the lab facilities, with different types of excipients, which properties are described in the Table 1 , and aspirin as an example of sensitive moisture active were manufactured. The below procedure was used:

[0133] 1 . Melt the excipient at the temperature required in an oven and mix for homogenization: a. For excipients Soy oil and PEG 400: room temperature. b. For excipients Novata BC PH, Novata BCF PH, Witepsol H37 and Witepsol E76: 40°C. c. For excipients Gelucire 43 / 01 , Gelucire 44 / 14, Gelucire 48 / 16, Gelucire 50 / 13, Precirol, Geleol and Gelucire 59 / 14: 60°C. d. For excipients Compritol 888, Beeswax and Candelilla wax: 80°C.

[0134] 2. Weighing of 14.83 g of excipient and 1.17 g of Aspirin in a glass vial.

[0135] 3. Stir in a vortex until complete homogenization.

[0136] 4. Fill formulation has been in contact with gelatin shell.

[0137] 5. Let the formulations cool at room temperature until they completely solidify.

[0138] 6. Place the glass vials in the climatic chamber at 25°C 160% RH for the stability study.

[0139] PEG 400 and soy oil formulations have been used as a reference excipient for standard hydrophilic and lipophilic liquid or semi-solid formulations to compare with solid fill formulations.

[0140] Table 1 : Melting temperature and HLB of excipients used in the formulations of present invention. EXCIPIENTS TESTED:

[0141] 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 to 8 °C; HLB 9.7.

[0142] Soy oil - A vegetable oil extracted from the seeds of the soybean (Glycine max). Melting point -16°C; HLB 4.

[0143] Beeswax - Consists of 70-75% of a mixture of various esters of straight-chain monohydric alcohols with even-numbered carbon chains from C24 to C36 esterified with straight-chain acid.

[0144] Beeswax is used as thickening agent to prevent settling out of particulate matter. Beeswax is regarded as an essentially nontoxic and nonirritant material. It is included in the FDA Inactive Ingredients Database. Melting range 62.0 - 65.0°C; HLB 9.

[0145] Candelilla wax - A wax derived from the leaves of the small Candelilla shrub native to northern Mexico and the southwestern United States, Euphorbia antisyphilitica, from the family Euphorbiaceae. Melting range 68.5 - 72.5°C; HLB 14.

[0146] Gelucire® 43 / 01 - (Mono-, di- and triglyceride ester of fatty acids (C8 to C18), the triester fraction being predominant) A glyceride with an intermediate melting point used as a matrix agent for sensitive APIs and a viscosity-increasing agent in oral and topical formulations. Melting range:42 - 46°C; HLB 1.

[0147] Gelucire® 44 / 14 - (Lauroyl polyoxyl-32 glycerides, lauroyl PEG-32 glycerides) A nonionic water- dispersible surfactant for lipid-based formulations to solubilize and increase oral bioavailability of poorly water-soluble APIs. Self-emulsifies in aqueous media forming a fine dispersion, i.e., microemulsion (SMEDDS). Consists of a small fraction of mono, di- and triglycerides and mainly PEG-32 (MW 1500) mono- and diesters of lauric acid (C12). Melting range: 42.5 - 47.5°C; HLB 11.

[0148] Gelucire® 50 / 13 - (Stearoyl macrogol-32 glycerides, PEG-32 hydrogenated palm glycerides) A nonionic water-dispersible surfactant for lipid-based formulations to solubilize and increase oral bioavailability of poorly water-soluble APIs. Self-emulsifies in aqueous media forming a fine dispersion, i.e., microemulsion (SMEDDS). Consists of mono, di- and triglycerides and PEG-32 (MW 1500) mono- and diesters of palmitic (C16) and stearic (C18) acids. Melting range: 46 - 51°C; HLB 11. Gelucire® 59 / 14 - (Lauroyl PEG-32 Glycerides, Polyethylene Glycol 6000) A non-ionic water- dispersible surfactant for lipid-based formulations to solubilize and increase oral bioavailability of poorly water-soluble APIs. Self-emulsifies in aqueous media forming a fine dispersion, i.e. , microemulsion (SMEDDS). Consists of a small fraction of mono, di- and triglycerides and mainly PEG-32 (MW 1500) mono- and diesters of lauric acid (C12) and of PEG-150 (MW6000). Melting range: 57 - 62°C; HLB 14 ± 1.

[0149] Gelucire® 48 / 16 - (Macrogol-32 stearate (type I) EP, PEG-32 STEARATE) A non-ionic pure surfactant for lipid-based formulation to solubilize and increase oral bioavailability of poorly soluble API. Forms micellar solution in aqueous media. Consists of PEG-32 (MW 1500) esters of palmitic (C16) and stearic (C18) acids. Melting range: 46 - 50°C; HLB 12.

[0150] Compritol® 888 ATO - (Aka Glycerol dibehenate) A glyceride with a high melting point used as a modified release agent or lubricant in tablets. Consists of mono-, di- and triesters of behenic acid (C22), the diester fraction being predominant. Melting range: 65 - 77°C; HLB 2.

[0151] Precirol® ATO 5 - (Glyceryl distearate) A glyceride with an intermediate melting point used as lubricant and flow aid in powder blends for capsule filling and as a coating agent for taste masking. Consists of esters of palmitic (C16) and stearic (C18) acids, the diester fraction being predominant. Melting range: 50 - 60°C; HLB 2.

[0152] WITEPSOL® H 37 - (Hard fat or saturated fat, which are a type of lipid consisting of triesters of glycerol and fatty acids or triglycerides, with a solid consistency at room temperature) WITEPSOL® H grades are hard fats with a low hydroxyl value of max. 15. They comprise mainly of triglycerides with portions of max. 15% of diglycerides and max. 1 % of monoglycerides. Melting Point ~ 37°C. HLB 1.

[0153] WITEPSOL® E 76 - (Hard fat or saturated fat, which are a type of lipid consisting of triesters of glycerol and fatty acids or triglycerides, with a solid consistency at room temperature) WITEPSOL® E grades are hard fats with a melting range above body temperature. Melting Point ~ 38°C. HLB 1.

[0154] Geleol™ mono and diglycerides NF - (Glycerol monostearate 40-55 (Type I)) sold by Gattefosse is a modified release matrix former for capsule. It can be used as coating agent for taste masking or as a consistency agent. Safety of use is inferred by GRAS status and precedence of use in approved pharmaceutical products. Melting range: 54 - 64°C; HLB 3.

[0155] NOVATA BC PH - (Hard fat or saturated fat, which are a type of lipid consisting of triesters of glycerol and fatty acids or triglycerides, with a solid consistency at room temperature) sold by BASF Pharma is a hard fat offering a sharp melting point for suppository applications. It can be added to oil phases to modify the emollient or sensory properties of topical semi-solid emulsions. Melting Point ~ 33°C. HLB 20.

[0156] NOVATA BCF PH - (Hard fat or saturated fat, which are a type of lipid consisting of triesters of glycerol and fatty acids or triglycerides, with a solid consistency at room temperature) sold by BASF Pharma is a hard fat offering a sharp melting point for suppository applications. It can be added to oil phases to modify the emollient or sensory properties of topical semi-solid emulsions. Melting Point ~ 36°C. HLB 20.

[0157] Example 2: Stability study

[0158] A stability study was carried out at long term storage conditions (25°C / 60% RH) with the following sampling points: time zero, 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.

[0159] The results of the stability study are shown in Figure 1. As can be seen the highest amount of degradation (100% of AS 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 85% of the API stable for 30 days. However, the preferred excipients with less than 8% degradation were Gelucire 44 / 14, beeswax, Candelilla wax, WITEPSOL H37, WITEPSOL E76, Gelucire 43 / 01 , Precirol, Geleol and Compritol 888.

[0160] As demonstrated in the Figure 2, stability results from the different formulations as prepared in Example 1 depicted as a function of their melting temperature, regardless of its hydrophilic- lipophilic balance (HLB). Solid fill at lower 35°C avoids Aspirin degradation, obtaining lower degradation product Salicylic acid content.

[0161] As confirmation of these good results, the stability study of one of this formula (Gelucire 43 / 01) was extended for two years. The results of this stability study are shown in Table 2. After two years of stability, fill formula designed provide for less than 8% degradation, very far from the current specification for SA component of effervescent tablets comprising ASA.

[0162] Table 2: Stability results of the fill formulation with Gelucire 43 / 01 at 25°C / 60% RH Example 3: Titration of excipients in fill formulation

[0163] In order to assess the amount of the excipient required for obtaining a solid matrix the following fill compositions were prepared with the process as described in Example 2. As the two exemplary excipients one was chosen with a high melting temperature (beeswax with more than 60°C) and the other was chosen from the excipients with a very low melting temperature

[0164] (Whitepsol H37 with a melting temperature of 35-40°C). The remaining amount up to 100% (w / w) was filled with soy oil, no active ingredient was included in the fill formulation.

[0165] To determine if the formulation was solid or liquid, the formulations were analyzed by visual inspection of the macroscopic appearance. As can be seen in Table 3 and Table 4, at least 3.5% (w / w) of beeswax and 32.5% (w / w) of Whitepsol H37 were required to obtain a solid fill formulation at room temperature.

[0166] Table 3: State of fill formulation with beeswax at room temperature

[0167] Table 4: State of fill formulation with Whitepsol H37 at room temperature

Claims

CLAIMS1 . A pharmaceutical or dietary supplement composition in the form of a soft gel capsule comprising a solid fill and a shell, wherein the solid fill comprises a) at least one moisture sensitive active ingredient; and b) at least one excipient with a melting temperature of at least 35°C at an amount of at least 3.5% (w / w); 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 antiinflammatory 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, Ibuprofen, 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.

4. The pharmaceutical or dietary supplement composition of any one of the preceding claims, wherein the at least one excipient has a melting temperature of between 35°C to 80°C, preferably between 40°C to 60°C.

5. The pharmaceutical or dietary supplement composition of any one of the preceding claims, wherein the at least one excipient has an HLB of up to 20.

6. 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 Gelucire 50 / 13, Gelucire 48 / 16, Gelucire 59 / 14, Novata BC PH, Novata BCF PH, Gelucire 44 / 14, beeswax, Candelilla wax, WITEPSOL H37, WITEPSOL E76, Gelucire 43 / 01 , Precirol, Geleol and Compritol 888, preferably Gelucire 44 / 14, beeswax, Candelilla wax, WITEPSOL H37, WITEPSOL E76, Gelucire 43 / 01 , Precirol, Geleol and Compritol 888.

7. 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.

8. 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.

9. 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.

10. A method for preparing a pharmaceutical or dietary supplement composition in the form of a soft gel capsule with a solid fill, comprising the steps of a. providing a liquid or semi-solid fill composition, said fill composition comprising at least 3.5% (w / w) of at least one excipient with a melting temperature of at least 35°C, b. formulating an active ingredient into the liquid or semi-solid fill composition, c. encapsulating the composition of b) with a shell composition, d. solidifying the fill composition by reducing the temperature of the fill composition to a temperature below the melting temperature of the at least one excipient in a).

11. The method of claim 10, wherein in step d. reducing the temperature is achieved by cooling the soft gel capsule with or in a cooling device.

12. The method of claims 10 or 11 , wherein the at least one excipient is selected from the group consisting of Gelucire 50 / 13, Gelucire 48 / 16, Gelucire 59 / 14, Novata BC PH, Novata BCF PH, Gelucire 44 / 14, beeswax, Candelilla wax, WITEPSOL H37, WITEPSOL E76, Gelucire 43 / 01 , Precirol, Geleol and Compritol 888, preferably Gelucire 44 / 14, beeswax, Candelilla wax, WITEPSOL H37, WITEPSOL E76, Gelucire 43 / 01 , Precirol, Geleol and Compritol 888.

13. A method of stabilizing moisture sensitive active ingredient in the fill of a soft gel capsule, wherein at least one excipient with a melting temperature of at least 35°C is added to the liquid or semisolid fill at an amount at least 3.5% (w / w) and the fill is solidified afterencapsulation by reducing the temperature of the fill to a temperature below the melting temperature of the at least one excipient.

Images