Soft calcifediol capsules

Abstract

Soft capsule comprising: a) a soft capsule cover; and b) a pharmaceutical composition comprising: - calcifediol, - an oily component selected from the group consisting of a medium-chain triglyceride, isopropyl myristate, a C14-C18 alkyl alcohol, a C14-C18 alkenyl alcohol, lanolin alcohol and mixtures thereof, and - a pharmaceutically acceptable organic solvent selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol, benzyl alcohol and mixtures thereof; wherein the soft capsule shell encapsulates the pharmaceutical composition and wherein said pharmaceutical composition is wax-free.

Description

Calcifediol Softgels Field of invention The present invention relates to calcifediol soft capsules, their use in the treatment or prevention of diseases related to vitamin D deficiency, and their manufacturing process. State of the art Calcifediol, also known as calcidiol, 25-hydroxycholecalciferol, 25-hydroxyvitamin D3 (abbreviated 25(OH)Da) or (6R)-6-[(1R,3aR,4E,7aR)-4-[(2Z)-2-[(5S)-5-hydroxy-2-methylidene-cyclohexylidene]ethylidene]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-1-yl]-2-methylheptan-2-ol, has the chemical structure shown below. Calcifediol s Calcifediol is highly lipophilic and has poor water solubility. Due to these physicochemical properties, it is difficult to formulate calcifediol in an immediate-release pharmaceutical preparation for oral administration that has adequate oral bioavailability. Solubility, dissolution, and gastrointestinal permeability are fundamental parameters that control the rate and extent of drug absorption and its bioavailability. A drug's water solubility is a key property that plays a significant role in its absorption after oral administration. Oral bioavailability depends on several parameters, including water solubility, drug permeability, dissolution rate, first-pass metabolism, and susceptibility to efflux mechanisms. However, for drugs with poor water solubility, the limiting factors for in vivo bioavailability after oral administration are water solubility and dissolution in gastrointestinal fluids. Therefore, the type of pharmaceutical preparation administered orally has a direct influence on the bioavailability of drugs that are poorly soluble in water. In particular, the bioavailability of orally administered preparations decreases in the following order: solutions > suspensions > emulsions > capsules > tablets > coated tablets. Immediate-release calcifediol pharmaceutical preparations of the previous technique for oral administration that have adequate bioavailability are those marketed under the name Hidroferol® (Faes Farma), in which calcifediol is provided as a solution in a medium-chain triglyceride and an antioxidant. An example of such a formulation is a solution consisting of calcifediol (0.266 mg; 15,960 IU of calcifediol), medium-chain triglycerides (1.5 ml), and α-tocopherol acetate (0.266 mg; vitamin E acetate). The oral bioavailability of some hydrophobic drugs, such as cyclosporine A (Gursoy, RN, Benita, S., Biomedicine Pharmacotherapy, 2004, 58, 173-182), has been improved using self-emulsifying drug delivery systems (SEDDS). These systems are isotropic mixtures of oils, surfactants, solvents, and co-solvents / surfactants that rapidly and spontaneously form fine oil-in-water emulsions, microemulsions, or nanoemulsions when introduced into aqueous phases with gentle agitation. Therefore, SEDDS are readily dispersed in the gastrointestinal tract, where the motility of the stomach and small intestine provides the agitation necessary for emulsification.The effectiveness of oral absorption of a drug compound from a self-emulsifying solution (SEDDS) depends on many formulation-related parameters, such as surfactant concentration, oil-to-surfactant ratio, emulsion polarity, droplet size, and charge, among others. Therefore, only highly specific combinations of pharmaceutical excipients will lead to effective self-emulsifying systems. Although many studies have been conducted, only a few drug products have been formulated as SEDDS (comprising the drug and mixtures of oils, surfactants, solvents, and co-solvents / surfactants), confirming the difficulty of formulating hydrophobic drug compounds in such formulations.Other types of oral formulations of calcifediol have been described, such as controlled-release solid formulations comprising calcifediol (WO 2007 / 092755), in which the active compound is provided within a wax matrix that is detachably bonded to the drug. However, the presence of such wax or other detachably bonded components does not allow for the immediate release of calcifediol. Calcifediol in an immediate-release hard gelatin capsule formulation, which does not comprise waxes and includes ethanol, BHT, and Miglyol, is described in WO 2008 / 134512. In view of the above, there is a need to find immediate-release solid oral formulations of calcifediol that have improved bioavailability. Summary of the invention The authors of the present invention have found an immediate-release oral formulation of calcifediol that has improved bioavailability compared to a prior art liquid immediate-release oral formulation of calcifediol (i.e., Hidroferol®). Therefore, according to a first aspect, the present invention relates to a soft capsule comprising: a) a soft capsule cover, wherein the soft capsule cover comprises: - 40 to 80% gelatin by weight, - 10 to 50% by weight of plasticizer selected from the group consisting of glycerol, sorbitol, propylene glycol, polyethylene glycol, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, triacetin, tributyl citrate, triethyl citrate, and mixtures thereof, the quantities being expressed in weight with respect to the total weight of the soft capsule shell; and (b) a pharmaceutical composition comprising: - calcifediol, - an oily component selected from the group consisting of a medium-chain triglyceride, isopropyl myristate, C14-C18 alkyl alcohol, a C14-C18 alkenyl alcohol, lanolin alcohol and mixtures thereof, and - a pharmaceutically acceptable organic solvent selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol, benzyl alcohol and mixtures thereof; wherein the soft capsule shell encapsulates the pharmaceutical composition and wherein said pharmaceutical composition is wax-free. According to a further aspect, the present invention relates to a soft capsule as defined above, for use in medicine. A further aspect of the invention is a soft capsule as defined above, for use in the treatment and / or prevention of a selected disease from the group consisting of vitamin D deficiency, demineralization such as hypocalcemia and hypophosphatemia, renal osteodystrophy, rickets, osteoporosis, osteopenia, osteoarthritis, osteoarthrosis, osteomalacia, hypoparathyroidism, and inflammatory bowel disease. In a further aspect, the invention relates to a method for preparing a soft capsule as defined above, said method comprising: a) preparing a mixture comprising calcifediol; the oily component; and the pharmaceutically acceptable organic solvent; and optionally calcium ions, iron ions, vitamin B12, vitamin B9, levomefolic acid or a pharmaceutically acceptable salt thereof, an essential unsaturated fatty acid and / or a bisphosphonate; b) prepare a mixture comprising gelatin; the plasticizer; water; and optionally a pharmaceutically acceptable opacifying agent and / or a pharmaceutically acceptable coloring agent; c) form a covering from the mixture of step b) ; d) fill the cover with the mixture from step a), and e) dry the capsule obtained in step d) . Figure description Figure 1 shows the time-concentration graphical representation obtained in example 3, i.e., after administration of calcifediol soft capsules according to the invention (triangles) or the reference calcifediol ampoule (circles). Detailed description of the invention In the context of the present invention, the following terms have the detailed meanings below: The term "AUC0-72" refers to the area under the curve (mathematically known as the integral) in a graphical representation of blood plasma drug concentration versus time, starting at the time the drug is administered (0 hours) and ending after 72 hours. The term "Cmax" refers to the maximum (or peak) serum concentration achieved after administration of calcifediol. The term "Cm-CW alkyl alcohol" refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having between 14 and 18 carbon atoms, and being attached to a hydroxyl group (OH) by a single bond, including, for example, myristyl alcohol (C14), cetyl alcohol (Cia), stearyl alcohol (C18), cetostearyl alcohol (a mixture of cetyl and stearyl alcohol as main components). The term "C14-C18 alkenyl alcohol" refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing one, two, or three unsaturations, having between 14 and 18 carbon atoms, and being attached to a hydroxyl group (OH) by a single bond, including, for example, oleyl alcohol (C18). The term "medium-chain triglyceride" or "MCT" refers to triesters of glycerol and Ce-Ci2 fatty acids, examples of which are caproic acid (Ca), caprylic acid (C8), capric acid (C10), and lauric acid (C12). The three fatty acids in the MCT can be the same or different, but preferably two different fatty acids. Preferred medium-chain triglycerides are caprylic / capric triglycerides (marketed as Miglyol® 812 or 810). The term "essential unsaturated fatty acid" refers to a linear chain hydrocarbon having a carboxyl group at one end that has one or more double bonds (C=C), preferably one, two, three, four, five or six double bonds, wherein the first double bond exists at the third carbon-carbon bond from the terminal CH3 end of the carbon chain (omega-3 fatty acid), at the sixth carbon-carbon bond from the terminal CH3 end of the carbon chain (omega-6 fatty acid) or at the ninth carbon-carbon bond from the terminal CH3 end of the carbon chain (omega-9 fatty acid).Examples of essential unsaturated fatty acids are omega-3 fatty acids, such as alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), hexadecatrienoic acid (HTA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), heneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA), tetracosapentaenoic acid and tetracosahexaenoic acid and mixtures thereof; omega-6 fatty acids, such as linoleic acid (LA), Y-linolenic acid (GLA), calendic acid, eicosadienoic acid, dihomo-Y-linolenic acid (DGLA), arachidonic acid (AA), docosadienoic acid, adrenic acid, docosapentaenoic acid, tetracosatetraenoic acid, tetracosapentaenoic acid, and mixtures thereof; omega-9 fatty acids, such as oleic acid, elaidic acid, gondoic acid, Mead's acid, erucic acid and nervonic acid, and mixtures thereof.Preferred omega-3 fatty acids are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and mixtures thereof. Preferred omega-6 fatty acids are linoleic acid (LA), gamma-linolenic acid (GLA), dihomo-Gly-linolenic acid (DGLA), arachidonic acid (AA), and mixtures thereof. Preferred omega-9 fatty acids are oleic acid and erucic acid, with oleic acid being even more preferable. The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not normally produce an adverse allergic or similar reaction, such as gastric upset, dizziness, and the like, when administered to a human or animal. Preferably, as used herein, the term "pharmaceutically acceptable" means authorized by a federal or state government regulatory agency or listed in the United States Pharmacopeia or another generally recognized pharmacopoeia for use in animals, and more particularly in humans. The term "pharmaceutically acceptable salts" refers to acid addition salts, base addition salts, or metallic salts, and they can be synthesized from the parent compound containing a basic or acid moiety using conventional chemical methods. Generally, such salts are prepared, for example, by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate acid or base in water, an organic solvent, or a mixture of the two. Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred. Examples of acid addition salts include mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate.Examples of alkali addition salts include inorganic salts such as ammonium salts and organic alkali salts such as ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, glucamine, and basic amino acid salts. Examples of metallic salts include sodium, potassium, calcium, magnesium, aluminum, and lithium salts. The term "polyethylene glycol" or "PEG" refers to an oligomer or polymer of ethylene oxide with an average molecular weight of 150 to 650 daltons, preferably 150 to 550 daltons, and more preferably 150 to 450 daltons. Polyethylene glycols are also referred to as PEG followed by a number indicating their average molecular weight; for example, PEG 200 refers to a polyethylene glycol with an average molecular weight of 200 daltons. Preferred polyethylene glycols are PEG 200, PEG 400, and mixtures thereof; more preferably PEG 200, PEG 400, and mixtures thereof. The term "soft capsule" is well known in the field and refers to a capsule with a soft capsule shell, as opposed to hard capsules, which have a rigid shell. A soft capsule shell is typically composed of gelatin, water, and plasticizer in various mixtures, which gives elasticity and softness to the walls (shell). Soft capsules are usually formed in one piece, unlike hard capsules, which consist of a two-piece shell that fits together. The term "surfactant" refers to compounds that are amphiphilic, that is, they contain both hydrophobic groups (tail) and hydrophilic groups (head). Therefore, a surfactant contains both a component that is insoluble in water (or soluble in oil), i.e., the tail, and a component that is soluble in water, i.e., the head.Examples of surfactants are polyoxyethylene products of hydrogenated vegetable oils, polyoxyethylene-sorbitan fatty acid esters, and the like, e.g., polyoxyethylene hydrogenated castor oil (50) marketed under the registered trademark Nikkol® (Nikkol HCO-50), polyoxyethylene hydrogenated castor oil (40) (Nikkol HCO-40), polyoxyethylene hydrogenated castor oil (60) (Nikkol HCO-60); polyoxyethylene (20)-sorbitan monolaurate (polysorbate 20) marketed under the trademark Tween® (Tween 20), polysorbate 21 (Tween 21), polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polysorbate 80 (Tween 80), polysorbate 81 (Tween 81) ; sorbitan monooleate (Span 80); polyoxy-35 castor oil (Cremophor® EL); polyoxyethylated glycerides (Labrafil® M2125 Cs), polyoxyethylated oleic glycerides (Labrafil® M1944 Cs); caprylocaproylpolyoxyl-8 glycerides (Labrasol®); Da-tocopheryl polyethylene glycol succinate 1000 (TPGS). The term "wax" refers to a class of chemical compounds that are plastic (malleable) at temperatures near room temperature. Characteristically, they melt above 45°C, yielding a low-viscosity liquid. Waxes are insoluble in water but soluble in nonpolar organic solvents. Waxes may contain esters of carboxylic acids and long-chain alcohols or mixtures of substituted hydrocarbons, such as fatty acids and long-chain primary alcohols (these substituted hydrocarbons having a hydrocarbon chain comprising more than 20 carbon atoms). Synthetic waxes are long-chain hydrocarbons lacking functional groups.Examples of waxes are synthetic wax, microcrystalline wax, paraffin wax, carnauba wax, beeswax, china wax (insect wax), shellac wax (lacquer wax), spermaceti, lanolin (wool wax), ouricuri wax, candelilla wax, esparto grass wax, ozokerite, and lignite wax. Soft capsules In a first aspect, the present invention provides a soft capsule, as defined in claim 1, comprising: a) a soft capsule cover; and b) a pharmaceutical composition comprising: - calcifediol, - an oily component selected from the group consisting of medium-chain triglyceride, isopropyl myristate, CmC-ib alkyl alcohol, CmC-ib alkenyl alcohol, lanolin alcohol and mixtures thereof, and - a pharmaceutically acceptable organic solvent selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol, benzyl alcohol and mixtures thereof; wherein the soft capsule shell encapsulates the pharmaceutical composition and wherein said pharmaceutical composition is wax-free. Preferably, the present invention provides a soft capsule comprising: a) a soft capsule cover; and b) a pharmaceutical composition comprising: - calcifediol, - an oily component selected from the group consisting of a medium-chain triglyceride, isopropyl myristate, an alkenyl alcohol CmC-ib, and mixtures thereof, and - a pharmaceutically acceptable organic solvent selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol, benzyl alcohol and mixtures thereof; wherein the soft capsule shell encapsulates the pharmaceutical composition and wherein said pharmaceutical composition is wax-free. In the present invention, the soft capsule shell comprises gelatin and a plasticizer selected from the group consisting of glycerol, sorbitol, propylene glycol, polyethylene glycol, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, triacetin, tributyl citrate, triethyl citrate, and mixtures thereof; preferably a plasticizer selected from the group consisting of glycerol, sorbitol, and mixtures thereof. The gelatins used to prepare softgel capsule shells are those authorized by local authorities for pharmaceutical or nutritional use. These gelatins are primarily of two different types: either alkaline (type B) or acidic (type A), with medium gel strength (medium Bloom strength, such as 150–200 Bloom). Both types can be used in combination or separately. Preferably, a combination of type A and type B gelatin is used. Examples of type B gelatins are lime-treated bone gelatin and lime-treated leather gelatin. Examples of type A gelatins are pigskin gelatin, acid leather gelatin, and fish gelatin. The soft capsule shell comprises: - 40 to 80% gelatin by weight, - 10 to 50% by weight of plasticizer selected from the group consisting of glycerol, sorbitol, propylene glycol, polyethylene glycol, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, triacetin, tributyl citrate, triethyl citrate, and mixtures thereof, preferably selected from the group consisting of glycerol, sorbitol, and mixtures thereof, The quantities are expressed in weight with respect to the total weight of the soft capsule shell. In one particular embodiment, the soft capsule cover comprises: - 40 to 80% gelatin by weight, - 10 to 30% by weight of glycerol, and - 5 to 15% by weight of sorbitol, the quantities being expressed in weight with respect to the total weight of the cover. In another particular embodiment, the soft capsule cover comprises: - 60 to 70% gelatin by weight, - 15 to 25% by weight of glycerol, and - 5 to 15% by weight of sorbitol, the quantities being expressed in weight with respect to the total weight of the cover. In one embodiment, the softgel shell further comprises a pharmaceutically acceptable opacifying agent and / or a pharmaceutically acceptable coloring agent. Opacifying agents are added to the softgel shell to render it opaque and thereby protect the softgel filling, i.e., the pharmaceutical composition, from light. Suitable opacifying agents are known in the art and include titanium dioxide, talc, and the like. Coloring agents are added to the softgel shell to impart the desired color. Suitable coloring agents are known in the art and include sunset yellow FCF (E-110), indigo carmine (E-132), erythrosine (E-127), quinoline yellow (E-104), and the like. In particular, the soft capsule shell has not undergone any crosslinking procedure. The pharmaceutical composition encapsulated by the soft capsule shell comprises calcifediol; an oily component selected from the group consisting of a medium-chain triglyceride, isopropyl myristate, CmC-ib alkyl alcohol, CmC-ib alkenyl alcohol, lanolin alcohol, and mixtures thereof; and a pharmaceutically acceptable organic solvent selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol, benzyl alcohol, and mixtures thereof. Preferably, the pharmaceutical composition encapsulated by the soft capsule shell comprises calcifediol; an oily component selected from the group consisting of a medium-chain triglyceride, isopropyl myristate, a CmC-ib alkenyl alcohol, and mixtures thereof; and a pharmaceutically acceptable organic solvent selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol, benzyl alcohol and mixtures thereof. In one embodiment, the pharmaceutical composition of the soft capsule of the invention comprises: - from 0.001 to 0.2% by weight of calcifediol, - from 80 to 99.9% by weight of the oily component, and - from 0.3 to 6% by weight of the pharmaceutically acceptable organic solvent; The amounts are expressed in weight with respect to the total weight of calcifediol, the oily component and the pharmaceutically acceptable organic solvent present in the pharmaceutical composition. In one embodiment, the oily component is selected from a medium-chain triglyceride, isopropyl myristate, a C14-C18 alkenyl alcohol, and mixtures thereof. In one embodiment, the oily component is selected from a medium-chain triglyceride and isopropyl myristate, preferably a medium-chain triglyceride, the medium-chain triglyceride being more preferably caprylic / capric triglyceride. In another embodiment, the pharmaceutically acceptable organic solvent is selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol and mixtures thereof, preferably ethanol. In one embodiment, the oily component is a medium-chain triglyceride, preferably caprylic / capric triglyceride, and / or the pharmaceutically acceptable organic solvent is selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol, and mixtures thereof, preferably ethanol. In one particular embodiment, the pharmaceutical composition of the soft capsule of the invention comprises: - from 0.001 to 0.2% by weight of calcifediol, - from 80 to 99.9% by weight of an oily component selected from the group consisting of a medium-chain triglyceride (preferably caprylic / capric triglyceride) and isopropyl myristate, preferably a medium-chain triglyceride (such as caprylic / capric triglyceride), and - from 0.3 to 6% by weight of a pharmaceutically acceptable organic solvent selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol and mixtures thereof, preferably ethanol, The amounts are expressed in weight with respect to the total weight of calcifediol, the oily component and the pharmaceutically acceptable organic solvent present in the pharmaceutical composition. In one particular embodiment, the pharmaceutical composition of the soft capsule of the invention comprises: - from 0.001 to 0.1% by weight of calcifediol, - from 80 to 99.9% by weight of an oily component selected from the group consisting of a medium-chain triglyceride (preferably caprylic / capric triglyceride) and isopropyl myristate, preferably a medium-chain triglyceride (such as caprylic / capric triglyceride), and - from 0.5 to 5% by weight of a pharmaceutically acceptable organic solvent selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol and mixtures thereof, preferably ethanol, The amounts are expressed in weight with respect to the total weight of calcifediol, the oily component and the pharmaceutically acceptable organic solvent present in the pharmaceutical composition. In another particular embodiment, the pharmaceutical composition of the soft capsule of the invention comprises: - from 0.001 to 0.1% by weight of calcifediol, - 95 to 99.9% by weight of an oily component selected from the group consisting of a medium-chain triglyceride (preferably caprylic / capric triglyceride) and isopropyl myristate, preferably a medium-chain triglyceride (such as caprylic / capric triglyceride), and - from 0.5 to 1.5% by weight of a pharmaceutically acceptable organic solvent selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol and mixtures thereof, preferably ethanol, The amounts are expressed in weight with respect to the total weight of calcifediol, the oily component and the pharmaceutically acceptable organic solvent present in the pharmaceutical composition. In another particular embodiment, the pharmaceutical composition of the soft capsule of the invention comprises: - from 0.01 to 0.1% by weight of calcifediol, - 95 to 99.9% by weight of an oily component selected from the group consisting of a medium-chain triglyceride (preferably caprylic / capric triglyceride) and isopropyl myristate, preferably a medium-chain triglyceride (such as caprylic / capric triglyceride), and - from 0.5 to 1.5% by weight of a pharmaceutically acceptable organic solvent selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol and mixtures thereof, preferably ethanol, The amounts are expressed in weight with respect to the total weight of calcifediol, the oily component and the pharmaceutically acceptable organic solvent present in the pharmaceutical composition. In one particular embodiment, the pharmaceutical composition of the soft capsule of the invention comprises: - from 0.01 to 0.5 mg of calcifediol, - 400 to 500 mg of an oily component selected from the group consisting of a medium-chain triglyceride (preferably caprylic / capric triglyceride) and isopropyl myristate, preferably a medium-chain triglyceride (such as caprylic / capric triglyceride), and - 2 to 20 mg of a pharmaceutically acceptable organic solvent selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol and mixtures thereof, preferably ethanol. In another particular embodiment, the pharmaceutical composition of the soft capsule of the invention comprises: - from 0.01 to 0.5 mg of calcifediol, - 400 to 500 mg of a caprylic / capric triglyceride, and - 4 to 6 mg of ethanol, 5 to 10 mg of polyethylene glycol and / or 2 to 8 mg of propylene glycol, preferably 4 to 6 mg of ethanol. In another particular embodiment, the pharmaceutical composition of the soft capsule of the invention comprises: - from 0.2 to 0.4 mg of calcifediol, - 400 to 500 mg of isopropyl myristate, and - 4 to 6 mg of ethanol. In another particular embodiment, the pharmaceutical composition of the soft capsule of the invention comprises: - from 0.2 to 0.4 mg of calcifediol, - 400 to 500 mg of isopropyl myristate, - 3 to 6 mg of ethanol, and - 10 to 25 mg of polyethylene glycol or propylene glycol. In a further embodiment, the pharmaceutical composition of the soft capsule of the invention further comprises calcium or a pharmaceutically acceptable derivative thereof, preferably calcium ions (Ca2+). Calcium and pharmaceutically acceptable derivatives thereof refers to any pharmaceutically acceptable source of calcium or calcium ions, such as pharmaceutically acceptable calcium salts, calcium hydroxide, and hydroxyapatite. Examples of such pharmaceutically acceptable calcium salts include carbonate, chloride, chloride hexahydrate, citrate, formate, glycinate, bisglycinate, glucoheptonate, gluconate, gluconolactate, glutamate, glycerophosphate, hydrogen phosphate, lactate, lactobionate, lactophosphate, levulinate, oleate, monobasic or tribasic phosphate, pidolate, and calcium sulfate. Preferably, the calcium or calcium ion is provided as calcium glycinate, calcium bisglycinate, calcium hydroxide, or mixtures thereof.More preferably, calcium or calcium ion is provided as calcium glycinate, calcium bisglycinate, or mixtures thereof. In a further embodiment, the pharmaceutical composition of the soft capsule of the invention comprises calcium or a pharmaceutically acceptable derivative thereof; iron or a pharmaceutically acceptable derivative thereof; vitamin B12; vitamin B9 (also known as folic acid or folate); levomefolic acid or a pharmaceutically acceptable salt thereof; and / or essential unsaturated fatty acids or mixtures thereof. Iron and derivatives thereof refers to any pharmaceutically acceptable source of iron, such as iron ions (Fe2+ and / or Fe3+), which may be provided as pharmaceutically acceptable iron salts; and elemental iron, which may be provided as a metalloprotein or as a coordination complex, wherein the iron (Fe(III) or Fe(II)) is coordinated by nitrogen, oxygen, or sulfur centers belonging to amino acid residues of a protein or other pharmaceutically acceptable organic compound.Examples of such pharmaceutically acceptable iron salts are ferrous and ferric salts, preferably such as ferric ammonium citrate, ferric phosphate, ferric pyrophosphate, ferritin, ferrocolinate, ferrous ascorbate, ferrous aspartate, ferrous chloride, ferrous sulfate, ferrous tartrate, ferrous fumarate, ferrous gluconate, ferrous gluceptate, ferrous glycine sulfate, ferrous lactate, ferrous oxalate, and ferrous succinate. Examples of such iron metalloproteins or coordination complexes are iron-glycinate complex, iron-glucose complex, iron-fructose complex, iron-polymaltose complex, and iron-sucrose complex. In one particular embodiment, the pharmaceutical composition of the soft capsule of the invention comprises: - calcifediol, - a medium-chain triglyceride, preferably caprylic / capric triglyceride, - ethanol, and - calcium or a pharmaceutically acceptable derivative thereof. In another particular embodiment, the pharmaceutical composition of the soft capsule of the invention comprises: - calcifediol, - a medium-chain triglyceride, preferably caprylic / capric triglyceride, - ethanol, - calcium or a pharmaceutically acceptable derivative thereof, - iron or a pharmaceutically acceptable derivative thereof, - vitamin B12, - vitamin B9, levomefolic acid or a pharmaceutically acceptable salt thereof, and - an essential unsaturated fatty acid. In one embodiment, the pharmaceutical composition of the soft capsule of the invention further comprises a bisphosphonate. Bisphosphonates are well known in the art as a class of drugs that prevent bone loss and have two phosphonate groups. Preferably, the bisphosphonate is selected from the group consisting of alendronic acid, risedronic acid, ibandronic acid, clodronic acid, tiludronic acid, etidronic acid, pamidronic acid, zoledronic acid, and mixtures thereof; more preferably, the bisphosphonate is selected from the group consisting of alendronic acid, ibandronic acid, and mixtures thereof. In another preferred embodiment, the pharmaceutical composition of the soft capsule contains less than 10% water. Preferably less than 5%, more preferably less than 2.5%, even more preferably 1%, and most preferably less than 0.5% water. In one particular embodiment, the pharmaceutical composition of the soft capsule of the invention comprises: - calcifediol, - a medium-chain triglyceride, preferably caprylic / capric triglyceride, - ethanol, and - a bisphosphonate, preferably an alendronic acid, ibandronic acid or a mixture of the same. Surprisingly, the soft capsule of the invention forms SEDDS in the absence of a surfactant, which is known to be one of the essential components of this type of system. Therefore, in a preferred embodiment, the soft capsule of the invention is surfactant-free. In another preferred embodiment, the soft capsule lacks a cellulose polymer. Examples of cellulose polymers include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, and sodium carboxymethylcellulose. The pharmaceutical composition encapsulated in the soft capsule of the present invention may further comprise pharmaceutically acceptable excipients. The term "pharmaceutically acceptable excipient" refers to a vehicle, diluent, or adjuvant administered with the active ingredient. Those skilled in the art are familiar with conventional pharmaceutically acceptable excipients. For example, suitable pharmaceutical excipients are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, 21st edition, 2005. In particular, the pharmaceutical composition encapsulated in the soft capsule of the present invention is a liquid composition. The amount of calcifediol in the soft capsule of the invention is preferably in the range of 200 to 180,000 IU of calcifediol. In one embodiment, the soft capsule of the invention provides a calcifediol Cmax at least 1.2 times greater than the Cmax of an equivalent amount of calcifediol administered as an oral liquid preparation containing calcifediol, a medium-chain triglyceride, and α-tocopherol acetate, preferably at least 1.25 times greater, more preferably at least 1.3 times greater, and more preferably 1.35 times greater. In another embodiment, the soft capsule of the invention provides an AUC0-72 at least 1.2 times greater than the AUC0-72 of an equivalent amount of calcifediol administered as an oral liquid preparation containing calcifediol, a medium-chain triglyceride, and α-tocopherol acetate, preferably at least 1.25 times greater. In a further embodiment, the soft capsule of the invention provides a Cmax of calcifediol at least 1.2 times greater than the Cmax of an equivalent amount of calcifediol administered as an oral liquid preparation containing calcifediol, a medium-chain triglyceride and α-tocopherol acetate, preferably at least 1.25 times greater, more preferably at least 1.3 times greater, more preferably 1.35 times greater; and an AUC0-72 at least 1.2 times greater than the AUC0-72 of an equivalent amount of calcifediol administered as an oral liquid preparation containing calcifediol, a medium-chain triglyceride and α-tocopherol acetate, preferably at least 1.25 times greater. Cmax and AUC0-72 were determined using conventional procedures in accordance with Directive 2001 / 20 / EC. Specifically, these parameters were determined by administering calcifediol, drawing blood samples (3 ml) at baseline (e.g., the mean value obtained at -0.5 h, -0.25 h, and 0 h) and after calcifediol administration (e.g., at 2, 4, 4, 5, 5, 5, 5, 6, 6, 5, 7, 8, 10, 12, 24, 48, and 72 h). The plasma concentration of calcifediol in the blood samples was determined by HPLC-MS. Cmax corresponds to the maximum observed calcifediol concentration, and AUC0-72 is determined by integrating the area under the graphical representation of the drug concentration in blood plasma versus time using common mathematical procedures, such as the trapezoidal rule. The reference oral liquid preparation containing calcifediol, a medium-chain triglyceride, and α-tocopherol acetate is that marketed by Faes Farma under the name Hidroferol®, in which calcifediol is provided as an ampoule comprising a solution consisting of calcifediol (such as 0.266 mg; 15,960 IU of calcifediol; or an amount equivalent to the calcifediol in the soft capsule according to the present invention), medium-chain triglycerides (1.5 ml), and α-tocopherol acetate (0.266 mg; vitamin E acetate). The presence of linearity in the calcifediol dose range (between 0.105 mg and 0.700 mg) (Haddad JG Jr, Rojanasathit S. Acute administration of 25-hydroxycholecalciferol in man, J. Clin. Endocrinol. Metab. 1976; 42 (2):284-90) allows a study dose of 0.532 mg (2x0.266 mg) with adequate exposure separation, ensuring that the comparison is sensitive enough to detect potential differences between formulations. Medical uses of soft capsules Calcifediol has been described for use in the treatment of diseases related to vitamin D deficiency. Therefore, in an additional aspect, the present invention relates to a soft capsule as defined above for use in medicine. An additional aspect of the invention is a soft capsule as defined above, for use in the treatment and / or prevention of a selected disease from the group consisting of vitamin D deficiency, demineralization such as hypocalcemia and hypophosphatemia, renal osteodystrophy, rickets, osteoporosis, osteopenia, osteoarthritis, osteoarthrosis, osteomalacia, hypoparathyroidism, and inflammatory bowel disease. The term "treatment" or "treat" in the context of this specification means the administration of a compound or formulation according to the invention to improve or eliminate the disease or one or more symptoms associated with it. "Treatment" also includes improving or eliminating the physiological sequelae of the disease. The term "improve" in the context of this invention is understood to mean any improvement in the condition of the treated patient. The term "prevention" or "prevent" refers to reducing the risk of acquiring or developing a given disease or disorder, or to reducing or inhibiting the recurrence of a disease or disorder. Specifically, the softgel capsule, as defined above, is for administration once every three months, once every two months, once a month, once every three weeks, once every two weeks, once a week, or once a day. Preferably, the softgel capsule for administration once every three months comprises from 24,000 IU to 16,000 IU of calcifediol. Preferably, the softgel capsule for administration once every two months comprises from 24,000 IU to 16,000 IU of calcifediol. Preferably, the softgel capsule for administration once a month comprises from 24,000 IU to 16,000 IU of calcifediol.Preferably, the soft capsule for once-every-three-week administration comprises from 16,000 IU to 14,000 IU of calcifediol. Preferably, the soft capsule for once-every-two-week administration comprises from 14,000 IU to 12,000 IU of calcifediol. Preferably, the soft capsule for once-weekly administration comprises from 10,000 IU to 8,000 IU of calcifediol, more preferably 9,000 IU of calcifediol. Preferably, the soft capsule for once-daily administration comprises from 1,000 IU to 400 IU of calcifediol. In particular, the soft capsule for use as defined above, wherein the pharmaceutical composition comprising said soft capsule further comprises a bisphosphonate; preferably a bisphosphonate selected from the group consisting of alendronic acid, risedronic acid, ibandronic acid, clodronic acid, tiludronic acid, etidronic acid, pamidronic acid, zoledronic acid, and mixtures thereof; more preferably a bisphosphonate selected from the group consisting of alendronic acid, ibandronic acid, and mixtures thereof. Said soft capsule for use as defined above is for once-monthly or once-weekly administration. Preferably, the soft capsule for once-monthly administration comprises from 24,000 IU to 16,000 IU of calcifediol and 150 mg of ibandronic acid.Preferably, the once-weekly softgel contains 2800 IU to 5600 IU of calcifediol and 70 mg of alendronic acid. These softgels are particularly useful for the treatment and / or prevention of osteoarthritis. Procedure for preparing soft capsules The soft capsules of the present invention can be prepared by any conventional manufacturing process known in the art for the preparation of soft capsules (as described, for example, in Gurava Reddy, R. et al., Int. J. Adv. Pharm. Gen. Res., 2013, 1, 20-29), such as by a rotary die process. In particular, an additional aspect of the present invention relates to a method for preparing a soft capsule as defined above, said method comprising: a) prepare a mixture comprising calcifediol; the oily component; and the pharmaceutically acceptable organic solvent; and optionally calcium or a pharmaceutically acceptable derivative thereof, iron or a pharmaceutically acceptable derivative thereof, vitamin B12, vitamin B9, evomefolic acid or a pharmaceutically acceptable salt thereof, an essential unsaturated fatty acid and / or a bisphosphonate; b) prepare a mixture comprising gelatin; the plasticizer; water; and optionally a pharmaceutically acceptable opacifying agent and / or a pharmaceutically acceptable coloring agent; c) form a covering from the mixture of step b) ; d) fill the cover with the mixture from step a), and e) dry the capsule obtained in step d) . Step a) comprises preparing a mixture comprising the components to be present in the pharmaceutical composition encapsulated by the soft capsule shell, namely, calcifediol, the oily component, and the pharmaceutically acceptable organic solvent. Preferably, this mixture is a solution. Additionally, if further components are present in this pharmaceutical composition, such as calcium or a pharmaceutically acceptable derivative thereof, iron or a pharmaceutically acceptable derivative thereof, vitamin B12, vitamin B9, levomefolic acid or a pharmaceutically acceptable salt thereof, an essential unsaturated fatty acid, and / or a bisphosphonate, these components are also included in the mixture of step a).Preferably, this mixture is prepared by dissolving calcifediol in a pharmaceutically acceptable organic solvent and then adding the resulting solution to the oily components. Any additional components to be present in the pharmaceutical composition are also added to the oily component. Preferably, step a) is carried out under an inert atmosphere such as a nitrogen atmosphere. Step b) comprises preparing an aqueous mixture of the components that will make up the soft capsule shell, namely gelatin and plasticizer; and any additional components that may be present, such as a pharmaceutically acceptable opacifying agent and / or a pharmaceutically acceptable coloring agent. Preferably, this mixture is a solution. Step a) can be performed before step b), step b) can be performed before step a), or steps a) and b) can be performed simultaneously. Step c) comprises forming a cover from the mixture of step b), and step d) comprises filling the cover with the mixture of step a). Preferably, steps c) and d) are carried out simultaneously, for example, by using rotary die-cutting technology that begins with forming two plasticized films called tapes from the mixture of step b), passing each tape over a die, and sealing it to the other tape at the point where the two rotary dies meet while being filled with the mixture of step a). In a particular embodiment, step c) and / or step d) are carried out under controlled relative humidity (RH) conditions, such as 20% to 40% RH, preferably 25% to 35% RH, and more preferably 30% RH. Finally, step (e) comprises drying the capsule obtained in the previous step, generally to approximately 6% remaining water, for example, in a drum dryer and a tunnel dryer. In one particular embodiment, step (e) is carried out under controlled relative humidity (RH) conditions, such as 10% to 30% RH, preferably 15% to 25% RH, and more preferably 22% RH. The present invention will be illustrated more specifically by the following examples. However, it should be understood that the present invention is not limited by these examples in any way. Examples Example 1. Calcifediol soft capsules a) Soft capsule cover *It evaporates when the capsule dries b) Pharmaceutical compositions - Pharmaceutical Composition 1 *caprylic / capric triglyceride - Pharmaceutical Commission 2: *caprylic / capric triglyceride - Pharmaceutical Commission 3: - Pharmaceutical Commission 4: *caprylic / capric triglyceride Soft capsule preparation: 1. Dissolve the calcifediol in the pharmaceutically acceptable organic solvent. 2. The solution from step 1 is added to the oily component under a nitrogen atmosphere. 3. The soft capsule shell component mixture is prepared by providing water, heating to 75°C, adding glycerol and sorbitol, heating to 75°C, adding gelatin, mixing by vacuum and heat, adding sunset yellow and titanium dioxide, and mixing. 4. The mixture obtained in step 2 is dosed into soft capsules, forming a soft capsule shell with the mixture from step 3. Example 2. Reference calcifediol formulation The reference calcifediol formulation was Hidroferol® (Faes Farma), which is a calcifediol solution packaged in ampoules comprising: *caprylic / capric triglyceride Example 3. Pharmacokinetic studies HPLC Method Overview: The method involved a liquid-liquid extraction procedure with n-pentane and subsequent derivatization with 4-phenyl-1,2,4-triazolin-3,5-dione (PTAD). Calcifediol and the internal standard were measured by reversed-phase high-performance liquid chromatography coupled to a tandem mass spectrometry detector (LC / MS / MS). Equipment Instrumental system: The modular liquid chromatography system consisted of: an HTC autosampler (CTC-PAL), a high-pressure binary pump (Agilent 1200 series), a high-pressure pump (Perkin Elmer 200 series), an API 4000 mass spectrometer detector (MDS Sciex), a column heater (CROCO-CIL), and a 10-port switching valve (VICI). Data acquisition and data integration were performed using MDS Sciex Analyst software version 1.4.2. Chromatographic conditions: Separations were performed on a reversed-phase column (Unison UK-C18, 2 x 50 mm, 3 pm, Imtakt). Mobile phase A was 1 mM methylamine and 0.1% formic acid prepared in water, and mobile phase B was 1 mM methylamine and 0.1% formic acid prepared in methanol. Gradient chromatography was performed at 40°C with a flow rate ranging from 0.5 to 1.00 mL / min. Detection conditions: • calcifediol 607.5 ^ 298.0 amu • calcifediol-d6 (internal standard) 613.5 ^ 298.0 amu Extraction method: 100 µL of internal standard working solution were transferred to tubes containing 100 µL of plasma from each sample (study sample, calibration standard, or quality control) and then extracted with n-pentane. Subsequently, derivatization was performed with PTAD. Pharmacokinetic study A randomized, two-step, two-sequence, two-period, crossover clinical trial was conducted to compare the bioavailability of an Example 1 soft capsule comprising pharmaceutical composition 1 (calcifediol soft capsule) with respect to the reference calcifediol formulation of Example 2 (calcifediol ampoule) following single-dose administration to healthy, fasting volunteers. Seventy-two volunteers (38 men and 34 women) aged 18 to 35 years were randomly assigned to two groups, A and B. In the first period (P1: 6 days), group A received two ampoules of calcifediol, while group B received two soft capsules of calcifediol. After a washout period of at least 105 days, group A received two soft capsules of calcifediol and group B received two ampoules of calcifediol during a second period (P2: 8 days). Two volunteers withdrew from the trial before the second period (P2) for personal reasons. Ultimately, 70 volunteers (36 men and 34 women) completed the study. The Cmax and AUC0-72 were determined by measuring the plasma concentration of calcifediol in blood samples using HPLC-MS as described above. Blood samples (3 ml) were taken at baseline (the mean value obtained at -0.5 h, -0.25 h, and 0 h) and after administration of the calcifediol formulation, either as soft capsules or ampoules, at 2, 4, 4, 5, 5, 5, 5, 6, 6, 5, 7, 8, 10, 12, 24, 48, and 72 h. Figure 1 shows the time-plasma concentration plot. Cmax and AUC0-72 were obtained from plasma concentration-time plots using WinNonlin 6.3 software (Pharsight Corporation, Car and, USA). The results are shown in the table below as mean + standard deviation (SD).

Claims

1. Soft capsule comprising: a) a soft capsule shell, wherein the soft capsule shell comprises: - 40 to 80% by weight of gelatin, - 10 to 50% by weight of plasticizer selected from the group consisting of glycerol, sorbitol, propylene glycol, polyethylene glycol, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, triacetin, tributyl citrate, triethyl citrate, and mixtures thereof, the amounts being expressed by weight with respect to the total weight of the soft capsule shell; (b) a pharmaceutical composition comprising: - calcifediol, - an oily component selected from the group consisting of a medium-chain triglyceride, isopropyl myristate, a CmC-ib alkyl alcohol, a CmC-ib alkenyl alcohol, lanolin alcohol and mixtures thereof, and - a pharmaceutically acceptable organic solvent selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol,Benzyl alcohol and mixtures thereof; wherein the soft capsule shell encapsulates the pharmaceutical composition and wherein said pharmaceutical composition is wax-free.

2. Soft capsule according to claim 1, wherein the pharmaceutical formulation comprises: - from 0.001 to 0.2% by weight of calcifediol, - from 80 to 99.9% by weight of the oily component, and - from 0.3 to 6% by weight of the pharmaceutically acceptable organic solvent; the amounts being expressed by weight with respect to the total weight of calcifediol, the oily component, and the pharmaceutically acceptable organic solvent present in the pharmaceutical composition.

3. Soft capsule according to any one of the preceding claims, wherein the oily component is selected from the group consisting of a medium-chain triglyceride, isopropyl myristate, a CmC-ib alkenyl alcohol, and mixtures thereof.

4. Soft capsule according to any one of the preceding claims,wherein the oily component is a medium-chain triglyceride, preferably caprylic / capric triglyceride, and / or wherein the pharmaceutically acceptable organic solvent is selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol, and mixtures thereof, preferably ethanol.

5. A soft capsule according to any one of the preceding claims, wherein it is free of surfactants.

6. A soft capsule according to any one of the preceding claims, wherein the pharmaceutical composition further comprises calcium or a pharmaceutically acceptable derivative thereof.

7. A soft capsule according to any one of the preceding claims, wherein the pharmaceutical composition further comprises iron or a pharmaceutically acceptable derivative thereof, vitamin B12, vitamin B9, levomefolic acid or a pharmaceutically acceptable salt thereof, and / or an essential unsaturated fatty acid.or mixtures thereof.

8. Soft capsule according to any one of the preceding claims, wherein the pharmaceutical composition further comprises a bisphosphonate.

9. Soft capsule according to any one of the preceding claims, wherein the soft capsule shell further comprises a pharmaceutically acceptable opacifying agent and / or a pharmaceutically acceptable coloring agent.

10. Soft capsule according to any one of the preceding claims comprising from 200 to 180,000 IU of calcifediol.

11. Soft capsule according to any one of the preceding claims for use in medicine.

12. Soft capsule according to any one of claims 1 to 10 for use in the treatment and / or prevention of a selected disease from the group consisting of vitamin D deficiency, demineralization such as hypocalcemia and hypophosphatemia, renal osteodystrophy, rickets, osteoporosis, osteopenia, osteoarthritis, osteoarthrosis,osteomalacia, hypoparathyroidism, and inflammatory bowel disease.

13. Soft capsule for use according to claim 12, wherein the soft capsule is for administration once every three months, once every two months, once a month, once every three weeks, once every two weeks, once a week, or once a day.

14. Process for preparing a soft capsule according to any one of claims 1 to 10, said process comprising: a) preparing a mixture comprising calcifediol; the oily component; and the pharmaceutically acceptable organic solvent; and optionally calcium or a pharmaceutically acceptable derivative thereof, iron or a pharmaceutically acceptable derivative thereof, vitamin B12, vitamin B9, levomefolic acid, or a pharmaceutically acceptable salt thereof,an essential unsaturated fatty acid and / or a bisphosphonate; b) preparing a mixture comprising gelatin; the plasticizer; water; and optionally a pharmaceutically acceptable opacifying agent and / or a pharmaceutically acceptable coloring agent; c) forming a shell from the mixture of step b); d) filling the shell with the mixture of step a); and e) drying the capsule obtained in step d).

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