Ambroxol Liquid Preparation

Abstract

In certain embodiments, liquid formulations for oral administration are disclosed, comprising an amphiphilic material and ambroxol or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the priority of U.S. Provisional Patent Application No. 63 / 471,352, filed on June 8, 2023, the entire content of which is incorporated herein by reference in its entirety.

[0002] The present invention relates to ambroxol liquid formulations, and in certain embodiments to soft - gel capsules, which comprise a shell composition and a filling composition. Methods of preparing such formulations and methods of using them are also disclosed.

Background Art

[0003] Ambroxol is commonly used as an expectorant in wet coughs associated with lung and bronchial diseases. Commercially available pharmaceutical formulations containing ambroxol are oral liquids, syrups, tablets, and lozenges.

[0004] Liquid dosage forms are convenient formulations for the delivery of active agents. Liquids allow for accurate dosing for individual administration. They also provide an alternative for patients who have difficulty swallowing standard oral dosage forms such as tablets.

[0005] Capsule dosage forms are generally used for the oral administration of various pharmaceuticals. Capsules can be, for example, soft gelatin shells or hard shells (animal or plant types). Soft - gel capsules offer many advantages, including rapid dissolution, taste masking, ease of swallowing, fewer excipients compared to tablets, solubilization and improved oral bioavailability of slightly hydrophilic compounds via delivery of a liquid matrix, delivery of low - dose and ultra - low - dose compounds, delivery of low - melting - point compounds, and minimization of dust generation during manufacture, thus improving the safety of manufacturing personnel.

[0006] Soft capsules, such as soft gelatin or carrageenan capsules (or softgel capsules), offer a dosage form that is more readily accepted by patients because the capsule is easy to swallow and does not require flavoring to mask the unpleasant taste of the active ingredient. Softgel encapsulation of drugs further offers the potential to improve the bioavailability of pharmaceuticals. For example, the active ingredient can be rapidly released in liquid or solution form as soon as the gelatin shell ruptures.

[0007] In this technology field, there continues to be a need for new formulations of ambroxol that can provide one or more of the following: improved compliance, therapeutic outcomes, ease of swallowing, or maintenance of stability. [Overview of the Initiative]

[0008] This invention advances the latest technology by developing a liquid formulation of ambroxol in a specific embodiment.

[0009] In certain embodiments, the present invention relates to a liquid formulation containing ambroxol and one or more amphiphilic materials, such as lipids, surfactants, amphiphilic block polymers, or amphiphilic proteins or peptides or combinations thereof.

[0010] In alternative embodiments, the liquid formulation may be administered as a liquid, or the liquid may be incorporated into an oral solid dosage form such as a softgel or hard capsule, or into primary packaging such as a bottle or syringe.

[0011] In certain embodiments, the present invention relates to a softgel capsule comprising a filler material and a shell composition, wherein the filler material comprises ambroxol.

[0012] In one embodiment of the present disclosure, an oral solid dosage form, such as a softgel capsule, is suitable for being swallowed as is for release in the gastrointestinal system.

[0013] In other embodiments of the present disclosure, oral solid dosage forms, such as softgel capsules, are suitable for chewing in the oral cavity.

[0014] In certain embodiments, the present invention relates to a process for producing a pharmaceutical formulation disclosed herein, for example, a liquid or a softgel. In certain embodiments, the process includes encapsulating the ambroxol liquid disclosed herein in a shell composition to form a softgel capsule, and drying the softgel capsule.

[0015] In certain embodiments, the present invention relates to the treatment of lung diseases, comprising administering the pharmaceutical formulations disclosed herein to patients in need thereof. The treatment may include, for example, loosening phlegm and treating cough. [Brief explanation of the drawing]

[0016] The diagram shows the manufacturing process from softgel capsule encapsulation to bulk packaging. [Modes for carrying out the invention]

[0017] The present invention advances the latest technology by developing a liquid formulation of ambroxol in certain embodiments. In certain embodiments, the liquid ambroxol comprises an amphiphilic material, such as a lipid material. In other embodiments, the liquid ambroxol formulation can be incorporated into a softgel capsule. The softgel capsule may comprise (a) a filling material comprising a lipid material including a triglyceride, a hydrophobic surfactant, a hydrophilic surfactant, a hydrophilic solvent, or a combination thereof, and ambroxol or a pharmaceutically acceptable salt thereof, and (b) a shell composition.

[0018] As used herein, “pharmaceutical active ingredient” refers to a drug or compound that may be used to diagnose, cure, alleviate, treat, or prevent a condition. The terms “condition” or “conditions” refer to a medical condition that can be treated or prevented by administering an effective amount of the active agent to the target.

[0019] As used herein, the term “active ingredient” refers to any substance intended to produce a therapeutic, prophylactic, or other intended effect, whether or not it has been approved by a government agency for that purpose. With respect to a particular drug, this term includes the pharmaceutically active drug, as well as all pharmaceutically acceptable salts, solvates, and crystalline forms thereof, which are pharmaceutically active.

[0020] As used herein, the terms “therapeutably effective” and “effective dose” refer to the amount of active agent or the rate at which it is administered required to produce the desired therapeutic outcome.

[0021] As used herein, “shell” or “shell composition” refers to the shell of a softgel capsule that encloses a filler material.

[0022] All references to wt% throughout the specification and claims refer to the weight of the component relative to the total weight of the composition, and may also be referred to as w / w.

[0023] As used herein, “filling material” or “filling” refers to a composition encapsulated by a capsule shell and containing at least one pharmaceutically active ingredient.

[0024] As used herein, "about" refers to any value within a variation of ±10%, and "about 10" includes 9 to 11. As used herein, "a", "an", or "the" refers to one or more, unless otherwise specified. Thus, for example, reference to "an excipient" includes not only a single excipient but also mixtures of two or more different excipients.

[0025] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context.

[0026] The use of any and all examples or exemplary language (e.g., "such as") provided herein is merely intended to clarify particular materials and methods and is not limiting of the scope. No language in this specification should be construed as indicating any non-claimed element essential to the practice of the disclosed materials and methods.

[0027] In certain embodiments, oral solid dosage forms such as soft gels are suitable for swallowing whole and can be formulated for, for example, gastric delivery, intestinal delivery, or combinations thereof.

[0028] In certain embodiments, oral solid dosage forms such as soft gels are suitable for chewing and can be swallowed for gastrointestinal absorption, absorbed in the oral cavity, or combinations thereof. As used herein, "oral" can refer to absorption in the region of the mouth.

[0029] In certain soft gel embodiments, the shell composition includes gelatin, carrageenan, or combinations thereof.

[0030] In certain embodiments of softgels, the shell composition comprises about 10% to about 85% by weight of gelatin, about 45% to about 75% by weight of gelatin, or about 15% to about 45% by weight of gelatin.

[0031] In certain embodiments of softgels, the gelatin is selected from the group consisting of type A gelatin, type B gelatin, and mixtures thereof.

[0032] In certain embodiments of softgels, the gelatin is selected from the group consisting of fish gelatin, skin gelatin, bone gelatin, pig gelatin, bovine gelatin, and mixtures thereof.

[0033] In certain embodiments of the softgel, the shell composition contains carrageenan and does not contain any animal-derived ingredients.

[0034] In certain embodiments of soft gels, the shell composition includes a plasticizer. The plasticizer may include about 10% to about 75% by weight, about 20% to about 50% by weight, or about 30% to about 60% by weight.

[0035] In certain embodiments of soft gels, the plasticizer is selected from the group consisting of glycerin, propylene glycol, aqueous sorbitol and sorbitan solutions, and combinations thereof.

[0036] In certain embodiments, the shell further comprises starch. In some embodiments, the starch may include potato starch, corn starch, or tapioca starch. In some embodiments, the shell composition may contain starch in amounts of about 5% to about 20% by weight, about 8% to about 15% by weight, or about 6% to about 10% by weight, based on the total weight of the shell composition.

[0037] Examples of amphiphilic materials that can be used in the present invention include lipids, surfactants, amphiphilic block polymers, amphiphilic proteins or peptides, and combinations thereof.

[0038] Lipids may include, but are not limited to, saturated and unsaturated lipids; neutral, cationic or anionic lipids; or natural or synthetic lipids. In other embodiments, lipids may be one or more mixtures from any of the classes including, but not limited to, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidic acid (PA), and sphingomyelin (SM). In alternative embodiments, lipid materials may include triglycerides. Triglycerides may include, for example, medium-chain triglycerides, caprylic acid triglycerides, capric acid triglycerides, myristic acid triglycerides, stearate triglycerides, and combinations thereof. In further embodiments, the lipids may be, for example, neutral lipids—dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), egg phosphatidylcholine (egg PC), soy phosphatidylcholine (soy PC), partially or fully hydrogenated phosphatidylcholine (PHSPC or HSPC), palmitoyl-oleoylphosphatidylcholine (POPC), stearyl-oleoylphosphatidylcholine (SOPC); and anionic lipids—dioleoylphosphatidylglycerol (DOPG), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylglycerol (DSPG). The lipid may be a PEG (polyethylene glycol)-lipid, such as mPEG-DPPE, mPEG-DMPE, mPEG-DSPE, mPEG-ceramide-DSPE, or mPEG-DS. In alternative embodiments, antioxidant lipid agents such as vitamin E, α-tocopherol, or ascorbic acid can be used.

[0039] In certain embodiments, the liquid formulation further comprises at least one surfactant in addition to, or instead of, the lipid. The surfactant may be a nonionic surfactant such as, for example, caprylocaproyl macrogol-8-glyceride, caprylic / capric triglyceride, polyoxyl hydrogenated castor oil, PEGylated castor oil, or a combination thereof. In some embodiments, the surfactant may include a hydrophobic surfactant or a hydrophilic surfactant.

[0040] In certain embodiments of the dosage forms of the present invention, the dosage form may also include surfactants. Surfactants useful according to the present invention include, for example, ionic and nonionic surfactants or wetting agents commonly used in pharmaceutical formulations, such as castor oil derivatives, cholesterol, polyglycolated glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polysorbates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene compounds, monoglycerides or their ethoxylated derivatives, diglycerides or their polyoxyethylene derivatives, sodium docusate, sodium lauryl sulfate, cholic acid or its derivatives, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, and polyoxypropylene compounds. This includes, but is not limited to, propoxylated alcohols, ethoxylated / propoxylated block polymers, propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glycerol esters, polyglycerol fatty acid esters, SPAN (e.g., sorbitan esters), TWEEN (i.e., sucrose esters), glucose (dextrose) esters, alkali metal sulfates, quaternary ammonium compounds, amidoamines, and amineimides, simethicone, lecithin, alcohols, phospholipids, and mixtures thereof.

[0041] Examples of useful mixed surfactants / wetting agents according to the present invention include sodium lauryl sulfate / polyethylene glycol (PEG) 6000 and sodium lauryl sulfate / PEG 6000 / stearic acid.

[0042] Block copolymer surfactants (e.g., Pluronic® surfactant or Pluronic® surfactant F-127) or sorbitan ester structuring agents (e.g., Span® 80, Sigma Aldrich Chemical Co.) can also be used.

[0043] In certain embodiments, the liquid formulation further comprises thickeners, such as acacia, agar, alginic acid, aluminum monostearate, bentonite, purified bentonite, magma bentonite, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium carboxymethylcellulose 12, carrageenan, microcrystalline and sodium carboxymethylcellulose, dextrin, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, methylcellulose, pectin, polyethylene oxide, polyvinyl alcohol, povidone, alginate, silicon dioxide, colloidal silicon dioxide, sodium alginate, tragacanth, and xanthan gum.

[0044] In other embodiments, the liquid formulation may contain sweeteners or flavoring agents, such as aspartame, dextrose, dextrose excipients, fructose, mannitol, saccharin, calcium saccharin, sodium saccharin, sorbitol, sorbitol solution, sucrose, compressible sugar, powdered sugar, syrup, etc.

[0045] In certain embodiments, the liquid formulation further comprises emulsifiers, such as lecithin, monoglycerides, sucrose / fatty acid esters, polyglycerol / fatty acid esters, sorbitan / fatty acid esters, potassium and sodium salts of rosin acid and higher fatty acids, as well as sulfates and sulfonates of these acids, amine salts of hydroxylamines of long-chain fatty acid esters, quaternary ammonium salts such as stearyl-dimethylbenzylammonium chloride and tridecylbenzenehydroxyethylimidazole chloride, phosphate esters of higher alcohols such as caprylic and octyl alcohol, as well as monoesters of oleic acid and pentaerythritol such as sorbitan monooleate, and mixtures thereof.

[0046] In certain embodiments, the liquid formulation comprises medium-chain triglycerides, caprylic / capric / myristic / stearate triglycerides, caprylic / capric triglycerides, and caprylocaproyl macrogol-8-glycerides.

[0047] In other embodiments, the liquid formulation comprises medium-chain triglycerides, PEG-40 castor oil, caprylic / capric / myristic / stearic acid triglycerides, soy lecithin, flavorings, and sweeteners.

[0048] In certain embodiments, the liquid formulation comprises about 5% to about 15% ambroxol hydrochloride, about 20% to about 50% medium-chain triglycerides, about 15% to about 45% caprylic / capric / myristic / stearic acid triglycerides, about 5% to about 25% caprylic / capric acid triglycerides, and about 1% to about 10% caprylocaproylmacrogol-8-glyceride.

[0049] In certain embodiments, the liquid formulation contains approximately 5% to 15% ambroxol hydrochloride, approximately 30% to 60% medium-chain triglycerides, approximately 0.5% to 5% PEG-40 castor oil, approximately 10% to 40% caprylic / capric / myristic / stearic acid triglycerides, approximately 0.5% to 5% soy lecithin, flavorings, and sweeteners.

[0050] In a specific softgel embodiment, the present invention provides at least about 10% ambroxol dissolution in 500 mL of 0.1 N HCl using a Type II (propeller) apparatus at 37°C and 50 rpm in 5 minutes.

[0051] In a specific softgel embodiment, the present invention provides at least about 60% ambroxol dissolution in 500 mL of 0.1 N HCl in 10 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm.

[0052] In a specific softgel embodiment, the present invention provides at least about 80% ambroxol dissolution in 500 mL of 0.1 N HCl in 15 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm.

[0053] In a specific softgel embodiment, the present invention provides at least about 90% ambroxol dissolution in 500 mL of 0.1 N HCl, using a Type II (propeller) apparatus at 37°C and 50 rpm in 20 minutes.

[0054] In a specific softgel embodiment, the present invention provides at least about 15% ambroxol dissolution in 5 minutes using a Type III apparatus (reciprocating cylinder) at 30 deep per minute in 500 mL of phosphate buffer pH 6.8.

[0055] In a specific softgel embodiment, the present invention provides at least about 65% ambroxol dissolution in 10 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of phosphate buffer pH 6.8.

[0056] In a specific softgel embodiment, the present invention provides at least about 70% ambroxol dissolution in 15 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of phosphate buffer pH 6.8.

[0057] In a specific softgel embodiment, the present invention provides at least about 80% ambroxol dissolution in 20 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of phosphate buffer pH 6.8.

[0058] In a specific softgel embodiment, approximately 92% of the ambroxol was recovered after 3 months of storage at 40°C / 75% relative humidity, compared to T0 using HPLC analysis.

[0059] In certain softgel embodiments, at least approximately 95% of ambroxol is recovered after 3 months of storage at 40°C / 75% relative humidity, compared to T0 using HPLC analysis.

[0060] In certain softgel embodiments, at least approximately 97% of ambroxol is recovered after 3 months of storage at 40°C / 75% relative humidity, compared to T0 using HPLC analysis.

[0061] In certain softgel embodiments, at least approximately 92% of ambroxol is recovered after 3 months of storage at 30°C / 65% relative humidity, compared to T0 using HPLC analysis.

[0062] In certain softgel embodiments, at least approximately 95% of ambroxol is recovered after 3 months of storage at 30°C / 65% relative humidity, compared to T0 using HPLC analysis.

[0063] In certain softgel embodiments, at least approximately 97% of ambroxol is recovered after 3 months of storage at 30°C / 65% relative humidity, compared to T0 using HPLC analysis.

[0064] In a specific softgel embodiment, after storage at 40°C / 75% relative humidity for 3 months, at least about 5% ambroxol dissolution is achieved in 500 mL of 0.1N HCl using a Type II (propeller) apparatus at 37°C and 50 rpm in 5 minutes.

[0065] In a specific softgel embodiment, after storage at 40°C / 75% relative humidity for 3 months, at least about 50% ambroxol dissolution is achieved in 500 mL of 0.1 N HCl using a Type II (propeller) apparatus at 37°C and 50 rpm in 10 minutes.

[0066] In a specific softgel embodiment, after storage at 40°C / 75% relative humidity for 3 months, at least about 75% ambroxol dissolution is achieved in 500 mL of 0.1 N HCl in 15 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm.

[0067] In a specific softgel embodiment, after storage at 40°C / 75% relative humidity for 3 months, at least about 90% ambroxol dissolution is achieved in 500 mL of 0.1 N HCl using a Type II (propeller) apparatus at 37°C and 50 rpm in 20 minutes.

[0068] In a specific softgel embodiment, after storage at 30°C / 65% relative humidity for 3 months, at least approximately 50% ambroxol dissolution is achieved in 5 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of pH 6.8 phosphate buffer.

[0069] In a specific softgel embodiment, after storage at 30°C / 65% relative humidity for 3 months, at least approximately 60% ambroxol dissolution is achieved in 10 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of pH 6.8 phosphate buffer.

[0070] In a specific softgel embodiment, after storage at 30°C / 65% relative humidity for 3 months, at least approximately 70% ambroxol dissolution is achieved in 15 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of pH 6.8 phosphate buffer.

[0071] In a specific softgel embodiment, after storage at 30°C / 65% relative humidity for 3 months, at least approximately 80% ambroxol dissolution is achieved in 20 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of pH 6.8 phosphate buffer.

[0072] In certain embodiments, the total impurity of ambroxol, as measured by HPLC, does not exceed about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, or about 0.01%.

[0073] In certain embodiments, the present invention relates to a process for manufacturing soft gel capsules, comprising encapsulating a filling composition in a shell composition to form a soft gel capsule, and drying the soft gel capsule.

[0074] In certain embodiments, a method for manufacturing softgel capsules according to the present disclosure is provided. As described herein, the filling of a softgel capsule may be prepared so that the capsule can be swallowed or chewed. The method includes preparing a gelatin mass using an automated process. The automated process may be carried out in a melt reactor. The melt reactor may be controlled by a programmable logic controller using predetermined parameters. The parameters may include predetermined temperature, mixing rate, vacuum, and duration.

[0075] In some embodiments, the method may include adding a plasticizer and water to a melt reactor and heating them while mixing them. The method may also include adding gelatin to a melt reactor and mixing it under heat and vacuum to melt, blend and degas the molten gelatin.

[0076] In some embodiments, the molten mass may be discharged into a heated storage container. The temperature of the storage container may be about 50°C to about 65°C.

[0077] In some embodiments, an opaque agent can be added to the gelatin mass. The mixture is mixed until a homogeneous gelatin mass is formed. The gelatin mass may be stored in a heated container until the end of the encapsulation process of the manufacturing.

[0078] In some embodiments, the gelatin mass may be filtered before being used in the encapsulation machine.

[0079] In certain embodiments, a encapsulation machine is used to form soft gel capsules using the gel mass and filler of any of the above preparations. In some embodiments, the encapsulation machine is a rotary die machine. After the capsules are discharged from the encapsulation machine, they are dried.

[0080] In certain embodiments, the present invention relates to a method for treating a cough, comprising administering a formulation, for example, a softgel capsule disclosed herein. The treatment may include, for example, loosening phlegm. In other embodiments, the cough is associated with a lung or bronchial disease.

[0081] Other embodiments relate to liquid pharmaceutical dosage forms comprising an amphiphilic material and ambroxol or a pharmaceutically acceptable salt thereof. The liquid can be administered directly to the patient or incorporated into dosage forms such as softgels, hard capsules, or lozenges.

[0082] In other embodiments, the liquid formulation may include additional filling components, such as flavoring agents, sweeteners, colorants and fillers, antioxidants or other pharmaceutically acceptable excipients, or additives, such as synthetic dyes and inorganic oxides.

[0083] In some embodiments, the antioxidant may be butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), alpha-tocopherol, vitamin E TPGS, propyl gallate, cysteine, sodium metabisulfite, or a combination thereof.

[0084] In some embodiments, the liquid formulation may contain the pharmaceutically active ingredient, i.e., ambroxol, in amounts of about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or about 120 mg, or any range of these values. In some embodiments, the liquid formulation may contain the pharmaceutically active ingredient, ambroxol, in amounts of about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 40 mg to about 50 mg, or any sub-range or value within these ranges.

[0085] In some embodiments, the liquid composition may contain an antioxidant. The antioxidant may be present in an amount of about 0.001 parts by weight to about 2 parts by weight, based on 100 parts by weight of the filling composition.

[0086] In one embodiment, the shell composition contains dextrose. In one embodiment, the amount of dextrose in the shell composition is about 0.005% to about 5% by weight, or about 0.01% to about 4% by weight, or about 0.01% to about 3% by weight, or about 0.01% to about 2% by weight, or about 0.01% to about 1% by weight, or about 0.1% to about 3% by weight, or about 0.1% to about 2% by weight, or about 0.15% to about 1% by weight, or about 0.15% to about 2% by weight, or about 0.15% to about 1% by weight. Dextrose may be added to the capsule shell to mitigate a potential decrease in gel strength. The concentration of dextrose in the shell composition may be an effective amount to improve enteric coating, but not high enough to prevent the softgel capsule from rupturing.

[0087] In one embodiment, the shell composition may also include a plasticizer. In some embodiments, the plasticizer in the shell composition may include glycerin, aqueous solutions of sorbitol and sorbitan, and combinations thereof. Other suitable plasticizers include, but are not limited to, sugar alcohol plasticizers, e.g., isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol or mannitol; or polyol plasticizers, e.g., diglycerin, dipropylene glycol, polyethylene glycol up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine; and mixtures thereof. Other exemplary plasticizers may include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, singleblock polymers, citrate ester-type plasticizers, and triacetins. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, as well as mixtures thereof.

[0088] In one embodiment, the amount of plasticizer in the shell composition is about 2% to about 40% by weight, or about 5% to about 35% by weight, or about 10% to about 30% by weight, or about 15% to about 25% by weight.

[0089] In one embodiment, the shell composition may also include a gelling agent. In some embodiments, the gelling agent may be gellan gum, agar, alginate, guar gum, or locus bean gum. For example, the gellan gum may be low-acyl gellan gum, such as Kelcogel CG-LA.

[0090] The shell composition may also contain water. In some embodiments, water may be included in the shell composition before processing the soft gel in an amount of 5% to about 35% by weight, or about 10% to about 25% by weight, or about 15% to about 20% by weight, based on the whole shell composition.

[0091] In one embodiment, the shell composition may optionally contain further agents, such as colorants, flavoring agents, sweeteners, fillers, antioxidants, diluents, pH adjusters, or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and inorganic oxides.

[0092] Examples of suitable colorants include, but are not limited to, white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown. In certain embodiments, the color of the dosage form may indicate the contents it contains (e.g., one or more active ingredients).

[0093] Examples of suitable flavoring agents include, but are not limited to, “flavoring extracts” obtained by extracting raw materials, such as parts of animal or plant materials, often using a solvent such as ethanol or water; and natural extracts obtained by extracting essential oils from flowers, fruits, roots, or the whole plant.

[0094] Further exemplary flavoring agents that may be present in the dosage form include, but are not limited to, menthol, spearmint and cinnamon, coffee beans, other flavors or fragrances, breath-freshening compounds such as fruit flavors (e.g., cherry, orange, grape, etc.), especially those used for oral hygiene, and active substances used in dental and oral cleansing, such as quaternary ammonium bases. The flavoring effect may be enhanced using flavor enhancers such as tartaric acid, citric acid, and vanillin.

[0095] Examples of sweeteners may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof. Examples of artificial sweeteners include acesulfame and its various salts, e.g., potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), aspartame-acesulfame salts (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, e.g., sodium salt (available as Sweet'N Low®), stevia, chloro derivatives of sucrose, e.g., sucralose (available as Kaltame® and Splenda®), and mogrosides. Examples of natural sweeteners include glucose, dextrose, reverse sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®); stevia rebaudiana (stevioside); natural concentrated sweeteners such as Lo Han Kuo; and polyols such as sorbitol, mannitol, xylitol, and erythritol.

[0096] In some embodiments, the shell composition may contain a methacrylic copolymer. In one embodiment, the shell composition may contain an amount of methacrylic copolymer of about 0.1% to about 5% by weight, or about 1% to about 4% by weight, or about 2% to about 3% by weight, based on the total weight of the shell composition. In some embodiments, the methacrylic copolymer may be Kollicoat MAE 100P. Although not limited to theory, the inventors believe that the methacrylic copolymer enhances the enteric coating of the shell composition.

[0097] In some embodiments, softgel capsules can provide delayed or modified release of the active drug.

[0098] In some embodiments, the stability of the softgel capsule may be at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least 96%, at least 97%, at least about 98%, or at least 99% when tested at 25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months. In some embodiments, the stability of the softgel capsule may be at about 90% to about 110%, at about 92% to about 108%, at about 94% to about 106%, at about 96% to about 104%, at about 98% to about 102%, or at about 99% to about 101% when tested at 25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0099] In some embodiments, the stability of the softgel capsules may be at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least 96%, at least 97%, at least about 98%, or at least 99% when tested at 30°C / 65%RH for 1 month, 2 months, 3 months, 6 months, or 12 months.

[0100] In some embodiments, the stability of the softgel capsules may be at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least 96%, at least 97%, at least about 98%, or at least 99% when tested at 40°C / 75%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0101] In certain embodiments, any of the compositions described herein may exhibit any of the above-described chemical stabilization when stored for a long period of time (e.g., one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months, or any sub-range or single value) at a relative humidity in the range of about 20% to about 75%.

[0102] In some embodiments, the capsules described herein may be stored in packaging. The packaging may include a plastic bottle, such as a high-density polyethylene (HDPE) bottle, or a blister pack.

[0103] In certain embodiments, any of the compositions described herein may exhibit physical stability when stored for a long period of time (e.g., one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months, or any sub-range or single value) at a relative humidity in the range of about 20% to about 75%.

[0104] The encapsulation of the filler material can be achieved by any conventional method. For example, rotary die encapsulation can be used. In some embodiments, the filler composition can be encapsulated using gel conversion. In some embodiments, the gel conversion comprises a shell composition, an opacifier, and a colorant. The opacifier may be titanium dioxide. The colorant may include FD&C Yellow #6. Water may also be included in the gel conversion. In some embodiments, the colorant may be present in an amount of about 0.5 g to about 2.5 g per kilogram of shell composition. In some embodiments, the opacifier may be present in an amount of about 2 g to about 10 g per kilogram of shell composition. In other embodiments, water may be present in an amount of about 40 g to about 60 g per kilogram of shell composition.

[0105] According to one embodiment, a softgel capsule is prepared by (a) preparing a filling composition, wherein the filling composition contains a pharmaceutically active ingredient, and (b) encapsulating the filling composition in a shell composition. The encapsulation process may also include a sub-step of preparing the shell composition by mixing, for example, gelatin, dextrose, and optionally a plasticizer. The shell composition may further undergo gel conversion before encapsulation by adding a colorant and water.

[0106] The softgel capsules of this disclosure may be packaged in blister packs, bottles, or volume packs. item 1. A liquid formulation comprising an amphiphilic material and ambroxol or a pharmaceutically acceptable salt thereof. 2. The liquid formulation according to item 1, wherein the amphiphilic material comprises a lipid, a surfactant, an amphiphilic block polymer, or an amphiphilic protein or peptide, or a combination thereof. 3. A liquid formulation as described in item 2, wherein the lipids include saturated lipids, unsaturated lipids, neutral lipids, cationic lipids, anionic lipids, natural lipids, synthetic lipids, triglycerides, PEG (polyethylene glycol)-lipids, or antioxidant lipid agents. 4. A liquid formulation as described in item 2, wherein the surfactant comprises an ionic surfactant, a nonionic surfactant, or a humectant. 5. The liquid formulation according to item 1, wherein the amphiphilic material comprises a medium-chain triglyceride, caprylic / capric / myristic / stearate triglyceride, caprylic / capric triglyceride, and caprylocaproyl macrogol-8-glyceride. 6. A liquid formulation as described in item 1, wherein the amphiphilic material comprises medium-chain triglycerides, PEG-40 castor oil, caprylic / capric / myristic / stearic acid triglycerides, soy lecithin, flavorings, and sweeteners. 7. A liquid formulation according to any of items 1 to 6, wherein the liquid formulation contains approximately 20% to 50% medium-chain triglycerides, approximately 15% to 45% caprylic / capric / myristic / stearic acid triglycerides, approximately 5% to 25% caprylic / capric acid triglycerides, and approximately 1% to 10% caprylocaproylmacrogol-8-glycerides. 8. A liquid formulation as described in any of items 1 to 6, comprising approximately 5% to 15% ambroxol hydrochloride, approximately 30% to 60% medium-chain triglycerides, approximately 0.5% to 5% PEG-40 castor oil, approximately 10% to 40% caprylic / capric / myristic / stearic acid triglycerides, approximately 0.5% to 5% soy lecithin, flavorings, and sweeteners. 9. A liquid formulation according to any of the preceding claims, wherein the ambroxol or pharmaceutically acceptable salt comprises ambroxol hydrochloride. 10. The liquid formulation described in item 9, containing ambroxol hydrochloride in an amount of approximately 5% to approximately 15% based on the total weight of the liquid formulation. 11. A softgel capsule for oral administration comprising (a) a filler material comprising a lipid material and ambroxol or a pharmaceutically acceptable salt thereof, and (b) a shell composition. 12. Softgel capsules as described in item 11, which are suitable for swallowing whole. 13. Softgel capsules as described in item 11 or 12, formulated for gastric delivery, intestinal delivery, or a combination thereof. 14. Softgels as described in item 11 or 13, for which the capsule is suitable for chewing. 15. A softgel formulated for oral administration, as described in item 14. 16. A softgel capsule according to any of items 11 to 15, wherein the shell composition comprises gelatin, carrageenan, or a combination thereof. 17. The soft gel according to item 16, wherein the shell composition comprises about 10% to about 85% by weight of gelatin. 18. The soft gel according to item 16, wherein the shell composition comprises about 45% to about 75% by weight of gelatin. 19. The soft gel according to item 16, wherein the shell composition contains about 15% to about 45% by weight of gelatin. 20. A softgel capsule according to any of items 16-19, wherein the gelatin is selected from the group consisting of type A gelatin, type B gelatin, and mixtures thereof. 21. A softgel capsule according to any of items 16-19, wherein the gelatin is selected from the group consisting of fish gelatin, skin gelatin, bone gelatin, pig gelatin, bovine gelatin, and mixtures thereof. 22. A softgel capsule according to any one of items 11 to 16, wherein the shell composition contains a plasticizer. 23. The soft gel according to item 22, wherein the shell composition contains about 10% to about 75% by weight of a plasticizer. 24. The soft gel according to item 22, wherein the shell composition contains about 20% to about 50% by weight of a plasticizer. 25. The soft gel according to item 22, wherein the shell composition contains about 30% to about 60% by weight of a plasticizer. 26. Softgel capsules as described in items 22-25, containing carrageenan as a plasticizer and free of animal-derived ingredients. 27. A softgel capsule according to any of items 22 to 25, wherein the plasticizer is selected from the group consisting of glycerin, propylene glycol, aqueous sorbitol and sorbitan solutions and combinations thereof. 28. A softgel capsule according to any of items 11 to 27, wherein the shell composition contains about 0.01% to about 1.0% by weight of dextrose. 29. Softgel capsules as described in any of items 11-28, the shell further containing starch. 30. A softgel capsule as described in any of items 11-29, wherein the lipid material contains triglycerides. 31. Softgel capsules as described in item 30, wherein the triglycerides include medium-chain triglycerides, caprylic acid triglycerides, capric acid triglycerides, myristic acid triglycerides, stearate triglycerides, and combinations thereof. 32. A softgel capsule according to any one of items 11 to 31, wherein the filling material further comprises at least one surfactant. 33. A softgel capsule as described in item 32, wherein the surfactant is a nonionic surfactant. 34. Softgel capsules as described in item 33, wherein the nonionic surfactant comprises caprylocaproyl macrogol-8-glyceride, caprylic / capric triglyceride, polyoxyl hydrogenated castor oil, PEGylated castor oil, or a combination thereof. 35. A soft gel as described in any of items 11-34, wherein the filling material further contains an emulsifier. 36. Softgel capsules as described in item 35, wherein the emulsifier contains lecithin. 37. A softgel capsule according to any of items 11 to 37, wherein the filling material comprises medium-chain triglycerides, caprylic / capric / myristic / stearic acid triglycerides, caprylic / capric acid triglycerides, and caprylocaproyl macrogol-8-glycerides. 38. Softgel capsules as described in any of items 11-37, whose filling material includes medium-chain triglycerides, PEG-40 castor oil, caprylic / capric / myristic / stearic acid triglycerides, soy lecithin, flavorings, and sweeteners. 39. A softgel capsule as described in any of items 11-37, wherein the filling material comprises approximately 5% to 15% ambroxol hydrochloride, approximately 20% to 50% medium-chain triglycerides, approximately 15% to 45% caprylic / capric / myristic / stearic acid triglycerides, approximately 5% to 25% caprylic / capric acid triglycerides, and approximately 1% to 10% caprylocaproyl macrogol-8-glycerides. 40. Softgel capsules as described in any of items 11-37, the filling material comprising approximately 5% to 15% ambroxol hydrochloride, approximately 30% to 60% medium-chain triglycerides, approximately 0.5% to 5% PEG-40 castor oil, approximately 10% to 40% caprylic / capric / myristic / stearic acid triglycerides, approximately 0.5% to 5% soy lecithin, flavorings, and sweeteners. A softgel capsule according to any of items 11-40, providing at least about 10% ambroxol dissolution in 41,500 mL of 0.1 N HCl, using a Type II (propeller) apparatus at 37°C and 50 rpm for 5 minutes. A softgel capsule according to any of items 11-41, which provides at least about 60% ambroxol dissolution in 42,500 mL of 0.1 N HCl in 10 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm. A softgel capsule according to any of items 11-42, providing at least about 80% ambroxol dissolution in 43,500 mL of 0.1 N HCl in 15 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm. A softgel capsule according to any of items 11-43, which provides at least about 90% ambroxol dissolution in 20 minutes using a Type II (propeller) apparatus in 44,500 mL of 0.1 N HCl at 37°C and 50 rpm. A softgel capsule as described in any of items 11-40, dissolving at least approximately 15% ambroxol in 5 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 45.500 mL of phosphate buffer pH 6.8. A softgel capsule according to any of items 11-40 and 45, providing at least about 65% ambroxol dissolution in 10 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 46.500 mL of phosphate buffer pH 6.8. Softgel capsules as described in any of items 11-40 and 45-46, which provide at least about 70% ambroxol dissolution in 15 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 47.500 mL of phosphate buffer pH 6.8. Softgel capsules as described in any of items 11-40 and 45-47, which provide at least about 80% ambroxol dissolution in 20 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 48.500 mL of phosphate buffer pH 6.8. 49. Softgel capsules as described in any of items 11-48, in which at least approximately 92% of ambroxol is recovered after 3 months of storage at 40°C / 75% relative humidity, compared to T0 using HPLC analysis. 50. Softgel capsules as described in any of items 11-48, in which at least approximately 95% of ambroxol is recovered after 3 months of storage at 40°C / 75% relative humidity, compared to T0 using HPLC analysis. 51. Softgel capsules as described in any of items 11-48, in which at least approximately 97% of ambroxol is recovered after 3 months of storage at 40°C / 75% relative humidity, compared to T0 using HPLC analysis. 52. Softgel capsules as described in any of items 11-48, in which at least approximately 92% of ambroxol is recovered after 3 months of storage at 30°C / 65% relative humidity, compared to T0 using HPLC analysis. 53. Softgel capsules as described in any of items 11-48, in which at least approximately 95% of ambroxol is recovered after 3 months of storage at 30°C / 65% relative humidity, compared to T0 using HPLC analysis. 54. Softgel capsules as described in any of items 11-48, in which at least approximately 97% of ambroxol is recovered after 3 months of storage at 30°C / 65% relative humidity, compared to T0 using HPLC analysis. Softgel capsules as described in any of items 11-48, which, after being stored for 3 months at 55.40°C / 75% relative humidity, provide at least about 5% ambroxol dissolution in 500 mL of 0.1N HCl using a Type II (propeller) apparatus at 37°C and 50 rpm. Softgel capsules as described in any of items 11-48, which, after being stored for 3 months at 56.40°C / 75% relative humidity, provide at least about 50% ambroxol dissolution in 10 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm in 500 mL of 0.1 N HCl. Softgel capsules as described in any of items 11-48, which, after being stored at 57.40°C / 75% relative humidity for 3 months, provide at least approximately 75% ambroxol dissolution in 500 mL of 0.1 N HCl in 15 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm. Softgel capsules as described in any of items 11-48, which, after being stored for 3 months at 58.40°C / 75% relative humidity, provide at least about 90% ambroxol dissolution in 20 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm in 500 mL of 0.1N HCl. Softgel capsules as described in any of items 11-48, which, after being stored for 3 months at 59.30°C / 65% relative humidity, provide at least approximately 50% ambroxol dissolution in 5 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of phosphate buffer pH 6.8. Softgel capsules as described in any of items 11-48, which, after being stored for 3 months at 60.30°C / 65% relative humidity, provide at least approximately 60% ambroxol dissolution in 10 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of phosphate buffer pH 6.8. Softgel capsules as described in any of items 11-48, which, after being stored for 3 months at 61.30°C / 65% relative humidity, provide at least approximately 70% ambroxol dissolution in 15 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of phosphate buffer pH 6.8. Softgel capsules as described in any of items 11-48, which, after being stored for 3 months at 62.30°C / 65% relative humidity, provide at least approximately 80% ambroxol dissolution in 20 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of phosphate buffer pH 6.8. 63. Softgel capsules as described in any of items 11-62, wherein the total amount of ambroxol impurities, as measured by HPLC, does not exceed approximately 0.5%, approximately 0.4%, approximately 0.3%, approximately 0.2%, approximately 0.1%, or approximately 0.01%. 64. A process for manufacturing a softgel capsule according to any one of items 1 to 63, comprising encapsulating a filling composition in a shell composition to form a softgel capsule, and drying the softgel capsule. 65. A method for treating a cough, comprising administering any of the liquid or softgel capsules described in items 1 through 63. 66. The method described in item 65, including treatment that loosens phlegm. 67. The method described in item 65 or 66, in which the cough is accompanied by a lung or bronchial disease. 68. The method described in any of items 65-67, in which the softgel is swallowed whole. 69. The softgel is chewed, as described in any of items 65-67. 70. A liquid pharmaceutical dosage form comprising a lipid material and ambroxol or a pharmaceutically acceptable salt thereof. 71. A lozenge pharmaceutical dosage form comprising a lipid material and ambroxol or a pharmaceutically acceptable salt thereof. 72. A process for manufacturing a swallowable softgel capsule, comprising: preparing a gel mass for a shell composition; preparing a filling composition comprising ambroxol; and inserting the gel mass and the filling composition into a encapsulation machine. 73. The process described in item 72, wherein the sealing machine is a rotary die machine. 74. The process according to item 72 or 73, wherein the preparation of the gel mass comprises mixing a plasticizer with water and then adding gelatin while mixing to form a gel mass. 75. The gel mass is stored in a storage container at a temperature of approximately 50°C to 65°C, following any of the processes described in items 72 to 74. 76. The process according to any one of items 72 to 75, wherein the preparation of the filling composition comprises forming an active pharmaceutical premix containing ambroxol and a second premix. 77. The process described in item 76, wherein the active pharmaceutical premix comprises the first portion of a medium-chain triglyceride and ambroxol or a pharmaceutically acceptable salt thereof. 78. The process according to item 76 or 77, wherein the second premix comprises mixing further triglycerides, surfactants, and emollients in a homogeneous mixer. 79. The process described in any one of items 76-78, in which the active pharmaceutical premix and the second premix are mixed in a homogeneous mixer at a temperature of approximately 20°C to approximately 25°C for approximately 15 minutes. 80. The process described in any one of items 72-79 for manufacturing softgel capsules using an encapsulation machine. 81. The process described in any one of items 72 to 80, further comprising drying the softgel capsules in a rotary dryer. 82. A process for manufacturing a chewable softgel capsule, comprising: preparing a gel mass for a shell composition; preparing a filling composition comprising ambroxol; and inserting the gel mass and the filling composition into a encapsulation machine. 83. The process according to item 82, wherein the preparation of the gel mass comprises forming a first premix comprising starch, glycerol, and water, and forming a second premix comprising a plasticizer and water. 84. The process described in item 83, wherein the first premix and the second premix are added to an automatic mixer to form a gel mass. 85. The gel mass is stored in a storage container at a temperature of approximately 50°C to 65°C, following any of the processes described in items 82 to 84. 86. The process according to any one of items 82 to 85, wherein the preparation of the filling composition comprises forming a first active pharmaceutical ingredient (API) premix comprising ambrolox and a first portion medium-chain triglyceride, a second premix comprising lecithin, citric acid, sugar and a second portion medium-chain triglyceride, and a third premix comprising a flavoring agent and a third portion medium-chain triglyceride. 87. The process described in any of items 83 to 86, in which the second premix is ​​mixed in a homogeneous mixer at a temperature of approximately 40°C for approximately 5 minutes, and then the homogeneous mixer is cooled to a temperature of approximately 20°C to approximately 25°C. 88. Next, add the first API premix to a homogeneous mixer and mix for about 5 minutes, following the process described in item 87. 89. The process according to item 87 or 88, wherein the third premix is ​​added to a homogeneous mixer and mixed for about 5 minutes to form a filling composition. 90. The process described in any one of items 82-89, wherein the sealing machine is a rotary die machine. 91. A process described in any one of items 82-90 for manufacturing softgel capsules using an encapsulation machine. 92. The process described in any of items 82 to 91, further comprising drying the softgel capsules in a rotary dryer.

[0107] Examples Next, the present invention will be described more fully with reference to the attached examples. However, it should be understood that the following description is illustrative and should not be construed as limiting the present invention. Example 1: Manufacturing process for liquid formulations The liquid formulation is prepared by mixing the components listed in Table 1 below. Table 1 [Table 1] Example 1A The liquid formulation is prepared by mixing the components listed in Table 1A below. Table 1A [Table 2]

[0108] Example 2: Manufacturing process for swallowable softgel capsules A method for preparing swallowable softgel capsules containing ambroxol was developed. The softgel capsules were prepared by forming a gelatin mass for the shell composition and a filling material (liquid formulation of Example 1), which were then used in a encapsulation machine to form the capsules. The manufacturing process is described herein and illustrated in the figures.

[0109] Gelatin mass preparation Gelatin mass preparations were prepared using an automated process employing a melt reactor controlled by a programmable logic controller (PLC). The gelatin masses were prepared to form the shell compositions described in Table 2. Table 2: Shell composition of swallowable softgel capsules [Table 3]

[0110] The gelatin mass preparation was prepared using an automated process that utilizes a melting reactor controlled by a programmable logic controller (PLC).

[0111] Enclosure method After the formation of the gel mass and liquid formulation, an encapsulation method was performed. The encapsulation machine was of the rotary die type and provided continuous forming, filling, and sealing operations.

[0112] The machine was supplied by two receivers. One receiver contained the molten gel mass used to form the shell as described above, and the second receiver contained the filling solution as described above.

[0113] The first drying process was performed immediately after encapsulation in a rotary dryer system physically connected to the encapsulation machine, in which the soft gelatin capsules were rotated for a predetermined period of time.

[0114] Drying process After being discharged from the rotary dryer, the capsules were spread out on shallow drying trays. These trays were placed in a drying tunnel, and low-humidity air was circulated over the capsules. The manufacturing process described herein is shown in the figure.

[0115] Example 2: Production of chewable softgel capsules A method for preparing chewable softgel capsules containing ambroxol was developed. The softgel capsules were prepared by forming a gelatin mass for the shell composition and a filling material (liquid formulation of Example 1A), which were then used in a encapsulation machine to form the capsules. The manufacturing process is described herein.

[0116] Gelatin mass preparation Gelatin mass preparations were prepared using an automated process employing a melt reactor controlled by a programmable logic controller (PLC). The gelatin masses were prepared to form the shell compositions described in Table 3. Table 3: Shell composition of chewable softgel capsules [Table 4]

[0117] Encapsulation process The sealing machine was of the rotary die type and provided continuous forming, filling, and sealing operations.

[0118] The machine was supplied by two receivers. One contained the molten gel mass used to form the shell as described above, and the second contained the filling solution as described above.

[0119] The first drying process takes place immediately after encapsulation in a rotary dryer system physically connected to the encapsulation machine, where the soft gelatin capsules are rotated for a predetermined period of time.

[0120] Drying process After being discharged from the rotary dryer, the capsules were spread out on shallow drying trays. These trays were placed in a drying tunnel, and low-humidity air was circulated over the capsules. Each encapsulation line had its own drying tunnel. The manufacturing process described herein is shown in the figure.

[0121] Dissolution test In vitro dissolution tests were conducted between ambroxol tablets and the softgel capsules described above. The dissolution medium for the swallowable capsules was HCl 0.1 N, while the dissolution medium for the chewable capsules was phosphate buffer pH 6.8.

[0122] The dissolution conditions for the swallowable capsules were determined using a Type II propeller at 50 rpm in 500 mL of water at a temperature of 37°C. One capsule was placed in each of six dissolution vessels containing the dissolution medium. After each time point, 1.5 mL of the sample was collected and filtered through a 0.45 μm nylon filter with a diameter of 25 mm.

[0123] The dissolution conditions for the chewable capsules were determined using a Type III reciprocating cylinder at a rate of 30 depths / minute at 37°C in 900 mL of fluid. One capsule was placed in each of six dissolution vessels containing the dissolution medium. After each time point, 5.0 mL of sample was collected and filtered through a 0.45 μm nylon filter with a diameter of 25 mm.

[0124] The results of the dissolution test are shown in Tables 4 to 6 below. Table 4 - Tablet dissolution results [Table 5] Table 5 - Dissolution results of swallowable capsules [Table 6] Table 6 - Dissolution results of chewable capsules [Table 7]

[0125] The results show that 100% (w / w) ambroxol HCl was released after 15 minutes in the tablets and after 20 minutes in both the swallowable and chewable capsules.

[0126] Chemical and physical stability testing The swallowable and chewable softgel capsules in blister packs were subjected to chemical and physical stability tests for 3 months under storage conditions of 40°C / 75%RH, 30°C / 65%RH, and 25°C / 60%RH. After 3 months, no impurities were detected, and the ambroxol recovery rate against T0 (HPLC analysis) was 98% for the swallowable capsules at 40°C / 75%RH and 98% for the chewable capsules at 30°C / 65%RH.

[0127] The dissolution results revealed that 100% (w / w) ambroxol HCl was released 20 minutes after 3 months at 40°C / 75%RH in swallowable capsules, and 20 minutes after 3 months at 30°C / 65%RH in chewable capsules. No delay in API release was observed, and no cross-linking phenomenon was observed after 3 months of storage.

[0128] The results of this test are shown in Tables 7 and 8. Table 7 - Drug release percentage of swallowable capsules [Table 8] Table 8 - Drug release percentage of chewable capsules [Table 9]

[0129] Stability testing Further stability tests were conducted on swallowable and chewable softgel capsules in blister packaging and HDPE bottles. The results of the 12-month stability tests are shown in Tables 9 to 11. Table 9: Ambroxol HCl 30 mg, oval-shaped, swallowable softgel capsules. [Table 10] Table 10: Ambroxol HCl 30 mg, oval 5, 6 CHEW, blister-packed chewable softgel capsules. [Table 11] Table 11: Ambroxol HCl 30 mg, oval 5, 6 CHEW, chewable softgel capsules in HDPE bottle packaging. [Table 12]

Claims

1. A liquid formulation comprising an amphiphilic material and ambroxol or a pharmaceutically acceptable salt thereof.

2. The liquid formulation according to claim 1, wherein the amphiphilic material comprises a lipid, a surfactant, an amphiphilic block polymer, or an amphiphilic protein or peptide, or a combination thereof.

3. The liquid formulation according to claim 2, wherein the lipid comprises saturated lipids, unsaturated lipids, neutral lipids, cationic lipids, anionic lipids, natural lipids, synthetic lipids, triglycerides, PEG (polyethylene glycol)-lipids, or antioxidant lipid agents.

4. The liquid formulation according to claim 2, wherein the surfactant comprises an ionic surfactant, a nonionic surfactant, or a wetting agent.

5. The liquid formulation according to claim 1, wherein the amphiphilic material comprises a medium-chain triglyceride, caprylic / capric / myristic / stearic acid triglyceride, caprylic / capric acid triglyceride, and caprylocaproyl macrogol-8-glyceride.

6. The liquid formulation according to claim 1, wherein the amphiphilic material comprises a medium-chain triglyceride, PEG-40 castor oil, caprylic / capric / myristic / stearic acid triglyceride, soy lecithin, flavorings, and sweeteners.

7. The liquid formulation according to claim 1, wherein the liquid formulation comprises about 20% to about 50% medium-chain triglycerides, about 15% to about 45% caprylic / capric / myristic / stearic acid triglycerides, about 5% to about 25% caprylic / capric acid triglycerides, and about 1% to about 10% caprylocaproylmacrogol-8-glycerides.

8. The liquid formulation according to claim 1, wherein the liquid formulation comprises about 5% to about 15% ambroxol hydrochloride, about 30% to about 60% medium-chain triglycerides, about 0.5% to about 5% PEG-40 castor oil, about 10% to about 40% caprylic / capric / myristic / stearic acid triglycerides, about 0.5% to about 5% soy lecithin, flavorings and sweeteners.

9. The liquid formulation according to claim 1, wherein the ambroxol or pharmaceutically acceptable salt comprises ambroxol hydrochloride.

10. The liquid formulation according to claim 9, wherein the ambroxol hydrochloride is contained in an amount of about 5% to about 15% based on the total weight of the liquid formulation.

11. A softgel capsule for oral administration comprising (a) a filling material comprising a lipid material and ambroxol or a pharmaceutically acceptable salt thereof, and (b) a shell composition.

12. The softgel capsule according to claim 11, wherein the softgel is suitable for swallowing whole.

13. A softgel capsule according to claim 12, formulated for gastric delivery, intestinal delivery, or a combination thereof.

14. The soft gel according to claim 11, wherein the capsule is suitable for chewing.

15. A soft gel according to claim 14, formulated for oral administration.

16. The softgel capsule according to claim 11, wherein the shell composition comprises gelatin, carrageenan, or a combination thereof.

17. The soft gel according to claim 16, wherein the shell composition comprises about 10% to about 85% by weight of gelatin.

18. The soft gel according to claim 12, wherein the shell composition comprises about 45% to about 75% by weight of gelatin.

19. The soft gel according to claim 14, wherein the shell composition comprises about 15% to about 45% by weight of gelatin.

20. The softgel capsule according to claim 16, wherein the gelatin is selected from the group consisting of type A gelatin, type B gelatin, and mixtures thereof.

21. The softgel capsule according to claim 16, wherein the gelatin is selected from the group consisting of fish gelatin, skin gelatin, bone gelatin, pig gelatin, bovine gelatin, and mixtures thereof.

22. The soft gel capsule according to claim 11, wherein the shell composition contains a plasticizer.

23. The soft gel capsule according to claim 22, wherein the shell composition comprises about 10% to about 75% by weight of a plasticizer.

24. The soft gel capsule according to claim 12, wherein the shell composition comprises about 20% to about 50% by weight of a plasticizer.

25. The soft gel capsule according to claim 14, wherein the shell composition comprises about 30% to about 60% by weight of a plasticizer.

26. The softgel capsule according to claim 22, wherein the plasticizer contains carrageenan and does not contain any animal-derived components.

27. The soft gel capsule according to claim 22, wherein the plasticizer is selected from the group consisting of glycerin, propylene glycol, aqueous sorbitol and sorbitan solution and combinations thereof.

28. The soft gel capsule according to claim 11, wherein the shell composition comprises about 0.01% to about 1.0% by weight of dextrose.

29. The soft gel capsule according to claim 14, wherein the shell further contains starch.

30. The soft gel capsule according to claim 11, wherein the lipid material comprises a triglyceride.

31. The softgel capsule according to claim 30, wherein the triglyceride comprises medium-chain triglycerides, caprylic acid triglycerides, capric acid triglycerides, myristic acid triglycerides, stearate triglycerides, and combinations thereof.

32. The soft gel capsule according to claim 11, wherein the filling material further comprises at least one surfactant.

33. The soft gel capsule according to claim 32, wherein the surfactant is a nonionic surfactant.

34. The softgel capsule according to claim 33, wherein the nonionic surfactant comprises caprylocaproyl macrogol-8-glyceride, caprylic / capric triglyceride, polyoxyl hydrogenated castor oil, PEGylated castor oil, or a combination thereof.

35. The soft gel capsule according to claim 11, wherein the filling material further comprises an emulsifier.

36. The soft gel capsule according to claim 35, wherein the emulsifier comprises lecithin.

37. The softgel capsule according to claim 12, wherein the filling material comprises a medium-chain triglyceride, caprylic / capric / myristic / stearic acid triglyceride, caprylic / capric acid triglyceride, and caprylocaproyl macrogol-8-glyceride.

38. The softgel capsule according to claim 14, wherein the filling material comprises medium-chain triglycerides, PEG-40 castor oil, caprylic / capric / myristic / stearic acid triglycerides, soy lecithin, flavorings, and sweeteners.

39. The softgel capsule according to claim 12, wherein the filling material comprises about 5% to about 15% ambroxol hydrochloride, about 20% to about 50% medium-chain triglycerides, about 15% to about 45% caprylic / capric / myristic / stearic acid triglycerides, about 5% to about 25% caprylic / capric acid triglycerides, and about 1% to about 10% caprylocaproyl macrogol-8-glycerides.

40. The softgel capsule according to claim 14, wherein the filling material comprises about 5% to about 15% ambroxol hydrochloride, about 30% to about 60% medium-chain triglycerides, about 0.5% to about 5% PEG-40 castor oil, about 10% to about 40% caprylic / capric / myristic / stearic acid triglycerides, about 0.5% to about 5% soy lecithin, flavorings and sweeteners.

41. The softgel capsule according to claim 12, which provides at least about 10% ambroxol dissolution in 500 mL of 0.1 N HCl in 50 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm.

42. The softgel capsule according to claim 12, which provides at least about 60% ambroxol dissolution in 500 mL of 0.1 N HCl in 10 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm.

43. The softgel capsule according to claim 12, which provides at least about 80% ambroxol dissolution in 500 mL of 0.1 N HCl in 15 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm.

44. The softgel capsule according to claim 12, which provides at least about 90% ambroxol dissolution in 500 mL of 0.1 N HCl in 20 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm.

45. The softgel capsule according to claim 14, which provides at least about 15% ambroxol dissolution in 5 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of phosphate buffer pH 6.

8.

46. The softgel capsule according to claim 14, which provides at least about 65% ambroxol dissolution in 10 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of phosphate buffer pH 6.

8.

47. The softgel capsule according to claim 14, which provides at least about 70% ambroxol dissolution in 15 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of phosphate buffer pH 6.

8.

48. The softgel capsule according to claim 14, which provides at least about 80% ambroxol dissolution in 20 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of phosphate buffer pH 6.

8.

49. The softgel capsule according to claim 12, wherein at least about 92% of ambroxol is recovered after storage at 40°C / 75% relative humidity for 3 months, compared to T0 using HPLC analysis.

50. The softgel capsule according to claim 12, wherein at least about 95% of the ambroxol is recovered after storage at 40°C / 75% relative humidity for 3 months, as compared to T0 using HPLC analysis.

51. The softgel capsule according to claim 12, wherein at least about 97% of ambroxol is recovered after storage at 40°C / 75% relative humidity for 3 months, compared to T0 using HPLC analysis.

52. The softgel capsule according to claim 14, wherein at least about 92% of ambroxol is recovered after storage at 30°C / 65% relative humidity for 3 months, as compared to T0 using HPLC analysis.

53. The softgel capsule according to claim 14, wherein at least about 95% of the ambroxol is recovered after storage at 30°C / 65% relative humidity for 3 months, as measured by HPLC analysis compared to T0.

54. The softgel capsule according to claim 14, wherein at least about 97% of the ambroxol is recovered after storage at 30°C / 65% relative humidity for 3 months, as measured by HPLC analysis compared to T0.

55. The softgel capsule according to claim 12, which, after being stored at 40°C / 75% relative humidity for 3 months, provides at least about 5% ambroxol dissolution in 500 mL of 0.1 N HCl using a Type II (propeller) apparatus at 37°C and 50 rpm in 5 minutes.

56. The softgel capsule according to claim 12, which, after being stored at 40°C / 75% relative humidity for three months, provides at least about 50% ambroxol dissolution in 500 mL of 0.1 N HCl in 10 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm.

57. The softgel capsule according to claim 12, which, after being stored at 40°C / 75% relative humidity for 3 months, provides at least about 75% ambroxol dissolution in 500 mL of 0.1 N HCl in 15 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm.

58. The softgel capsule according to claim 12, which, after being stored at 40°C / 75% relative humidity for three months, provides at least about 90% ambroxol dissolution in 500 mL of 0.1 N HCl in 20 minutes using a Type II (propeller) apparatus at 37°C and 50 rpm.

59. The softgel capsule according to claim 14, which, after being stored at 30°C / 65% relative humidity for 3 months, provides at least about 50% ambroxol dissolution in 5 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of pH 6.8 phosphate buffer.

60. The softgel capsule according to claim 14, wherein after being stored at 30°C / 65% relative humidity for 3 months, at least about 60% ambroxol is dissolved in 500 mL of phosphate buffer pH 6.8 at a rate of 30 depths / min using a Type III apparatus (reciprocating cylinder) for 10 minutes.

61. The softgel capsule according to claim 14, which, after being stored at 30°C / 65% relative humidity for 3 months, provides at least about 70% ambroxol dissolution in 15 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of pH 6.8 phosphate buffer.

62. The softgel capsule according to claim 14, which, after being stored at 30°C / 65% relative humidity for 3 months, provides at least about 80% ambroxol dissolution in 20 minutes using a Type III apparatus (reciprocating cylinder) at 30 depths / min in 500 mL of pH 6.8 phosphate buffer.

63. The softgel capsule according to claim 11, wherein the total amount of ambroxol impurities, as measured by HPLC, does not exceed about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, or about 0.01%.

64. A process for producing a soft gel capsule according to claim 11, comprising: encapsulating the filling composition in the shell composition to form the soft gel capsule; and drying the soft gel capsule.

65. A method for treating a cough, comprising administering a softgel capsule according to any of claim 11.

66. The method according to claim 65, wherein the treatment includes loosening phlegm.

67. The method according to claim 65, wherein the cough is accompanied by a lung disease or bronchial disease.

68. The method according to claim 65, wherein the soft gel is swallowed whole.

69. The method according to claim 65, wherein the soft gel is chewed.

70. A liquid pharmaceutical dosage form comprising a lipid material and ambroxol or a pharmaceutically acceptable salt thereof.

71. A lozenge pharmaceutical dosage form comprising a lipid material and ambroxol or a pharmaceutically acceptable salt thereof.

72. A process for manufacturing a swallowable softgel capsule, comprising: preparing a gel mass for a shell composition; preparing a filling composition comprising ambroxol; and inserting the gel mass and the filling composition into a encapsulation machine.

73. The process according to claim 72, wherein the sealing machine is a rotary die machine.

74. The process according to claim 72, wherein the preparation of the gel mass comprises mixing a plasticizer with water and then adding gelatin while mixing to form a gel mass.

75. The process according to claim 74, wherein the gel mass is stored in a storage container at a temperature of approximately 50°C to approximately 65°C.

76. The process according to claim 72, wherein the preparation of the filling composition comprises forming an active pharmaceutical premix containing ambroxol and a second premix.

77. The process according to claim 76, wherein the active pharmaceutical premix comprises a first portion of a medium-chain triglyceride and ambroxol or a pharmaceutically acceptable salt thereof.

78. The process according to claim 77, wherein the second premix comprises mixing further triglycerides, surfactants, and emollients in a homogeneous mixer.

79. The process according to claim 76, wherein the active pharmaceutical premix and the second premix are mixed in the homogeneous mixer at a temperature of about 20°C to about 25°C for about 15 minutes.

80. The process according to claim 72, wherein the soft gel capsule is manufactured using the encapsulation machine.

81. The process according to claim 72, further comprising drying the soft gel capsules in a rotary dryer.

82. A process for manufacturing a chewable softgel capsule, comprising: preparing a gel mass for a shell composition; preparing a filling composition comprising ambroxol; and inserting the gel mass and the filling composition into a encapsulation machine.

83. The process according to claim 82, wherein the preparation of the gel mass comprises forming a first premix comprising starch, glycerol, and water, and forming a second premix comprising a plasticizer and water.

84. The process according to claim 83, wherein the first premix and the second premix are added to an automatic mixer to form the gel mass.

85. The process according to claim 84, wherein the gel mass is stored in a storage container at a temperature of approximately 50°C to approximately 65°C.

86. The process according to claim 82, wherein the preparation of the filling composition comprises forming a first active pharmaceutical ingredient (API) premix comprising ambrolox and a first portion of a medium-chain triglyceride, a second premix comprising lecithin, citric acid, sugar and a second portion of a medium-chain triglyceride, and a third premix comprising a flavoring agent and a third portion of a medium-chain triglyceride.

87. The process according to claim 86, wherein the second premix is ​​mixed in a homogeneous mixer at a temperature of approximately 40°C for approximately 5 minutes, and then the homogeneous mixer is cooled to a temperature of approximately 20°C to approximately 25°C.

88. The process according to claim 87, wherein the first API premix is ​​then added to the homogeneous mixer and mixed for about 5 minutes.

89. The process according to claim 88, wherein the third premix is ​​added to the homogeneous mixer and mixed for about 5 minutes to form the filling composition.

90. The process according to claim 82, wherein the sealing machine is a rotary die machine.

91. The process according to claim 82, wherein the soft gel capsule is manufactured using the encapsulation machine.

92. The process according to claim 91, further comprising drying the soft gel capsules in a rotary dryer.

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