Lecithin-free cold and cough formulation

Abstract

The present disclosure relates to suspension-based pharmaceutical formulations for cold and flu medications, and more specifically to high-concentration suspension formulations and soft gel capsule dosage forms having reduced size, as well as methods of preparing the suspension formulations and soft gel capsules thereof.

Description

LECITHIN-FREE COLD AND COUGH FORMULATIONTechnical Field

[0001] The present application relates to a formulation of a lecithin-free cold and cough pharmaceutical composition.Background

[0002] It is acknowledged that smaller dosage forms facilitate the swallowing of medication and provide a more pleasant experience for the consumer. This is particularly important for over-the-counter cold and cough (or flu) medications, which often need to combine multiple active ingredients to treat the symptoms. Creating new formulations that allow for smaller dosage forms without sacrificing efficacy or other attributes is challenging.

[0003] Smaller dosage forms have been shown to enhance the palatability of cold and cough medications. However, recent efforts to improve palatability have stalled due to challenges in developing formulations with significant size reduction (i.e. , greater than 20% reduction in capsule weight) while maintaining the same or similar stability level. Many smaller dosage forms tend to become unstable, necessitating the use of stabilizing agents such as lecithin.

[0004] Lecithin is a multifunctional ingredient often used as an emulsifier, stabilizer, surfactant, dispersing agent, and wet granulation aid. Its ability to blend oil and water, stabilize mixtures, and improve the bioavailability of active ingredients makes it an effective stabilizing agent in many existing formulations.

[0005] The presence of lecithin presents challenges, such as allergic reactions, particularly in individuals sensitive to soy. The quality of lecithin can vary, affecting its stabilizing effectiveness if not used in sufficient amounts, which would increase the size of the capsule. It may also introduce undesirable taste or texture.

[0006] As such, there is a need to develop new formulations for cold and cough medications that enhance the user experience without compromising on important attributes like stability and efficacy.

[0007] It is understood that the aspects described below are not limited to implementations which solve any or all of the disadvantages of the known approaches described above.Summary

[0008] This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to determine the scope of the claimed subject matter; variants and alternative features which facilitate the working of the invention and / or serve to achieve a substantially similar technical effect should be considered as falling into the scope of the invention disclosed herein.

[0009] It is understood that the pharmaceutical compositions described here can be administered in semisolid form or used to prepare capsules. In one aspect, the pharmaceutical composition may be a capsule encapsulating a matrix fill material.

[0010] Another aspect is a pharmaceutical composition comprising a lecithin-free fill material comprising: a plurality of pharmaceutically active agents in an amount from about 40% to about 50% by weight; at least one solvent in an amount from about 50% to about 60% by weight; and at least one viscosity modifier in an amount less than 1% by weight.

[0011] Another aspect is a soft gelatin capsule comprising a lecithin-free fill material comprising: (a) an analgesic and antipyretic cough suppressant; (b) a cough suppressant; (c) a decongestant or an antihistamine; (d) one or more solvents; and (e) a viscosity modifier.

[0012] Another aspect is a lecithin-free capsule comprising: a lecithin-free fill material of about 65% by weight and a shell composition in an amount of about 35% by weight, wherein the lecithin-free filling material comprising: an acetaminophen in an amount of 325 mg; a dextromethorphan in an amount of 10 mg; a phenylephrine hydrochloride in an amount of 5 mg, doxylamine succinate in an amount of 6.25 mg, or diphenhydramine in an amount of 25 mg; polyethylene glycols in an amount of369.4 mg; and a viscosity modifier is in an amount of 3.69.

[0013] Another aspect is a method for treating cough, nasal congestion, or cold symptoms, comprising administering the pharmaceutical composition of any aspect described herein, to a patient in need thereof.

[0014] Another aspect is a method for making a pharmaceutical composition described herein, the method comprising: (a) mixing together: (i) about 40% to 50% by the mixture weight of a plurality of pharmaceutically active agents comprising at least one analgesic and antipyretic agent, at least one cough suppressant, and at least one decongestant or at least one antihistamine, (ii) about 50% to 60% by the mixture weight of solvent, and (iii) less than about 1% by the mixture weight of a viscosity modifier; and (b) encapsulating the mixture in a gelatin shell composition.

[0015] Another aspect is method for making a lecithin-free fill of a pharmaceutical composition according to any of the aspects described herein, the method comprising: (a) mixing a first portion of one or more solvents with less than about 1% by the mixture weight of a viscosity modifier at 50°C; (b) cooling the mixture to 30°C; (c) adding to the mixture about 40% to 50% by weight of a plurality of pharmaceutically active agents comprising at least one analgesic and antipyretic agent, at least one cough suppressant, and at least one decongestant or at least one antihistamine; (d) rinsing the mixture with said one or more solvents with a second portion of said one or more solvents; (e) mixing the mixture with a third portion of said one or more solvents at 45°C; and (f) cooling the mixture to 25 °C.

[0016] Another aspect is an oral dosage form of the pharmaceutical composition produced by the method described herein. The pharmaceutical composition may be administered to treat cough, nasal congestion, or cold symptoms according to one or more aspects described herein.

[0017] Aspects of the present invention are described below by way of example only. These examples represent the suitable modes of putting the invention into practice that are currently known to the Applicant although they are not the only ways in which this could be achieved.

[0018] The aspects described herein may be combined as appropriate, as would be apparent to a skilled person, and may be combined with any of the other aspects of the present invention.Detailed Description

[0019] Aspects of the present invention are described below by way of example only. These examples represent the suitable modes of putting the invention into practice that are currently known to the Applicant although they are not the only ways in which this could be achieved.

[0020] A soft gel capsule has been developed and described herein, comprising a lecithin-free fill matrix that allows for reduced size compared to any known or existing capsules while maintaining the same therapeutic dose in an appealing form. This soft gel capsule, purposed for cold and flu medications, avoids incorporating certain ingredients (i.e., stabilizing agents) in the matrix fill and, in turn, addresses the processing and quality challenges inherent to existing capsules.

[0021] The soft gel capsule herein described achieves a balance of even distribution, proper dosage ratios, and active pharmaceutical ingredient (API) stability by incorporating sufficient polyethylene glycol (PEG) and povidone to keep the APIs in suspension without the need for additional excipients. The suspension remains stable during the processing stage even without further stabilizing agents like lecithin. This formulation ensures that the APIs retain their chemical purity and therapeutic efficacy throughout the capsule’s lifecycle, including handling, storage, and final administration.

[0022] It is recognized that reducing capsule size is particularly important for cough and cold medications, as smaller dosage forms are easier to swallow and enhance the consumer experience. Many existing formulations rely on stabilizing agents like lecithin, which would inevitably result in increased capsule size. Herein described formulation of the soft gel capsule utilizes precise amounts of PEGs and a viscosity modifier, providing a promising alternative.

[0023] By carefully selecting appropriate grades of PEG, such as PEG 400 and PEG600, in certain aspects, the solubility and bioavailability of active ingredients are enhanced while maintaining formulation integrity without any stabilizing agent. Further, viscosity modifiers like povidone, in minute amounts, improve flow properties and fill uniformity, ensuring consistent dosing and better manufacturability. This precise combination of PEGs and viscosity modifier described herein achieves the desired consistency and stability in smaller dosage forms, minimizing size and eliminating the need for stabilizers like lecithin, which some consumers prefer to avoid.

[0024] Moreover, the combination of PEGs and the viscosity modifier povidone does not require the addition of any buffering agent, such as an acid or base like alkali metal acetate. Povidone, in combination with PEGs, helps control viscosity and ionic strength, potentially eliminating the need for a buffering agent. Adding alkali metal acetates, for example, could interact unpredictably with PEGs or other components, potentially altering viscosity or leading to precipitation if the ionic strength or pH shifts too drastically. This could destabilize the formulation and compromise its performance.

[0025] The same or similar functional purpose of stabilizing agents can be achieved by the combination of PEGs and viscosity modifier(s) in the formulations described herein. The formulations (i.e., matrix fill) are free of stabilizing agents, specifically lecithin-free. It is found that using a low percentage (%) weight of povidone achieves the same stabilizing effect as desired upon adding lecithin in a typical formulation.

[0026] In particular, adding a small amount of povidone, i.e., less than 1% of povidone K30, has been shown to provide the same or similar stabilizing effect. Povidone is known to increase viscosity and could improve the suspension of the API. Thus, in most formulations, an amount much greater than 1% povidone is incorporated, which unavoidably increases the size of the capsule. Accordingly, with viscosity modifier(s) like povidone at less or equal to about 1% of the total dry weight of the capsules, it would effectively result in a reduced overall size.

[0027] It is understood that povidone, even in small amounts, helps stabilize the formulation by enhancing solubility and viscosity, preventing phase separation orsedimentation. While the amount of povidone in the formulation described herein may be much less than in existing formulations (typically higher than 5%), this amount is necessary for maintaining viscosity in combination with PEGs. The benefits of using a lower concentration of povidone include minimizing the excipient load, which reduces potential side effects and interactions, improving cost efficiency, and potentially enhancing bioavailability. Additionally, it helps maintain the formulation's stability without excessively increasing viscosity, which could affect drug delivery or patient comfort.

[0028] The formulation is able to remain homogenous over time, with no signs of phase separation or sedimentation. This may be verifiable through visual inspection or through particle size analysis, showing uniform distribution. Moreover, it is understood that the povidone effectively enhances the solubility of the active ingredient(s) compared to a formulation without povidone, possibly measured through solubility assays (e.g., mg / mL of the active ingredient dissolved in the solution).

[0029] The following sections outline exemplary formulations, methods of their preparation and parameters, and are not intended to limit the scope of the disclosure, but rather to provide examples of potential embodiments and aspects.

[0030] In one aspect is a pharmaceutical composition comprising a lecithin-free fill material comprising: a plurality of pharmaceutically active agents in an amount from about 40% to about 50% by weight; at least one solvent in an amount from about 50% to about 60% by weight; and at least one viscosity modifier in an amount less than 1% by weight. Optionally or additionally, the lecithin-free fill material also comprise

[0031] Another aspect is a soft gelatin capsule comprising a lecithin-free fill material comprising: (a) an analgesic and antipyretic cough suppressant; (b) a cough suppressant; (c) a decongestant or an antihistamine; (d) one or more solvents; and (e) a viscosity modifier.

[0032] Yet another aspect is lecithin-free capsule comprising: a lecithin-free fill material of about 65% by weight and a shell composition in an amount of about 35%by weight, wherein the lecithin-free filling material comprising: an acetaminophen in an amount of 325 mg; a dextromethorphan in an amount of 10 mg; a phenylephrine hydrochloride in an amount of 5 mg, doxylamine succinate in an amount of 6.25 mg, or diphenhydramine in an amount of 25 mg; polyethylene glycols in an amount of 369.4 mg; and a viscosity modifier is in an amount of 3.69.

[0033] As an option, the plurality of pharmaceutically active agents comprising at least one analgesic and antipyretic agent and at least one cough suppressant. Another option, the at least one analgesic and antipyretic agent is acetaminophen. Another option, the acetaminophen is present in an amount of about 45% by weight. Another option said at least one cough suppressant is dextromethorphan; wherein the dextromethorphan is present in an amount from about 1% to 2% by weight. Another option said at least one solvent comprises at least two polyethylene glycol; wherein said at least two polyethylene glycols comprise polyethylene glycol 400 and polyethylene glycol 600 respectively present in amounts about 20% and 30% by weight. Another option, the plurality of pharmaceutically active agents further comprising: at least one decongestant; wherein said at least one decongestant is present in an amount of less than 1% by weight or said at least one decongestant is phenylephrine in an amount of about 0.7% by weight; wherein said at least one decongestant is present in an amount up to about 5% by weight or said at least one decongestant is pseudoephedrine in an amount of about 4% by weight. Another option, the plurality of pharmaceutically active agents further comprising at least one antihistamine with sedative and anti-allergic properties; wherein said at least one antihistamine is present in less than about 1% to about 5% by weight; or said at least one antihistamine is doxylamine succinate in an amount of about 0.9% by weight or said at least one antihistamine is diphenhydramine in an amount of about 3.5% by weight. Another option, the pharmaceutical composition comprises a shell composition in an amount of about 35% by weight of the pharmaceutical composition; wherein the shell composition comprising: a gelatin shell matrix in an amount from about 58% to 68% of the shell composition; and one or more plasticizers in an amount from about 32 to 42% of the shell composition; wherein the shell further comprising: one or more colorants in an amount less than 1% of the shell composition; wherein the shell further comprising: at least one opacifier in anamount less than 1% of the shell composition. Another option, the lecithin-free fill material is without lecithin.

[0034] As an option, the fill material is present in an amount of 720 mg. Another option, the analgesic and antipyretic cough suppressant is acetaminophen in an amount of 325 mg. Another option, the cough suppressant is dextromethorphan in an amount of 10 mg. Another option, the decongestant is phenylephrine in an amount of 5 mg; or the decongestant is pseudoephedrine in an amount of 30 mg; or the antihistamine is doxylamine succinate in an amount of 6.25 mg; or wherein the antihistamine is diphenhydramine in an amount up to 25 mg. Another option, wherein said one or more solvents are polyethylene glycol 400 and polyethylene glycol 600 respectively present in an amount of 147.8 mg and 202.4 mg. Another option, the viscosity modifier is povidone in an amount of 3.69 mg. Another option, the capsule further comprising: a gelatin in an amount from about 220 mg to 260 mg; a glycerin in an amount from about 38 mg to 76 mg; a sorbitol in an amount from about 57 mg to 95 mg; one or more dyes in an amount from about 0.38 mg to 2.28 mg; and a coating mixture of mica flakes coated with metal oxides in an amount from about 1.9 mg to 7.6 mg.

[0035] As an option, the shell composition comprising: a gelatin in an amount from 220 mg to 260 mg; a glycerin in an amount from 38 mg to 76 mg; a sorbitol in an amount from 57 mg to 95 mg; one or more dyes in an amount from 0.38 mg to 2.28 mg; and a coating mixture of mica flakes coated with metal oxides in an amount from 1.9 mg to 7.6 mg. Another option, the mixture is about 65% by weight of the soft gelatin capsule.

[0036] It is understood that any one or more options may be combined with one or more other options or aspects, as one skilled in the art will recognize that numerous combinations of these aspects and options are possible, unless otherwise specified or limited.I. CompositionA. Fill Materials

[0037] The fill material may comprise a plurality of pharmaceutically active agents, solvents, and a viscosity modifier. The fill material does not contain lecithin or is lecithin-free.

[0038] In one aspect, the fill material may comprise a plurality of pharmaceutically active agents in an amount from about 40% to about 50% by weight of the fill material, at least one solvent in an amount from about 50% to about 60% by weight, and at least one viscosity modifier in an amount less than or equal to about 1% by weight.

[0039] The plurality of pharmaceutically active agents may comprise at least one analgesic and antipyretic agent and at least one cough suppressant. Analgesic and antipyretic agents may include but are not limited to acetaminophen, aspirin, ibuprofen, naproxen, diclofenac, ketoprofen, celecoxib, indomethacin, etc. And cough suppressants may include but are not limited to dextromethorphan, codeine, pholcodine, levodropropizine, benzonatate, etc.

[0040] The plurality of pharmaceutically active agents may also include at least one decongestant or at least one antihistamine with sedative and anti-allergic properties. At least one decongestant may include but is not limited to pseudoephedrine, phenylephrine, midodrine, oxymetazoline, tetrahydrozoline, xylometazoline, etc. At least one antihistamine may include but is not limited to doxylamine succinate, diphenhydramine, chlorpheniramine, hydroxyzine, promethazine, loratadine, fexofenadine, cetirizine, etc.

[0041] The plurality of pharmaceutically active agents may comprise about 40% to about 50% by weight of the fill material. For example, acetaminophen: 325 mg, dextromethorphan: 10 mg, and doxylamine succinate: 6.25 mg and up to 25 mg. Another example is acetaminophen: 325 mg, dextromethorphan: 10 mg, and phenylephrine hydrochloride: 5 mg. In yet another example is acetaminophen: 325 mg, dextromethorphan: 15 mg, and phenylephrine hydrochloride: 5 mg. In yet another example, acetaminophen: 325 mg, dextromethorphan HBr: 10 mg, and pseudoephedrine hydrochloride: 30 mg. The total weight for the fill may be about 720 mg, which would include the amount of the plurality of pharmaceutically active agentsor part of the amount of the plurality of pharmaceutically active agents as provided herein.

[0042] In one aspect, acetaminophen may be present in an amount of about 45% by weight. The dextromethorphan may be present in an amount from about 1% to 2% by weight. Less than about 1% by weight of phenylephrine. The phenylephrine may also be less than about 0.7% by weight.

[0043] In another aspect, acetaminophen may be present in an amount of about 45% by weight. The dextromethorphan may be present in an amount from about 1% to 2% by weight. Less than about 1% by weight of doxylamine succinate. The doxylamine succinate may also be about 0.9% by weight.

[0044] In another aspect, acetaminophen may be present in an amount of about 45% by weight. The dextromethorphan may be present in an amount from about 1% to 2% by weight. Up to or equal to about 5% by weight of pseudoephedrine.

[0045] In another aspect, acetaminophen may be present in an amount of about 45% by weight. The dextromethorphan may be present in an amount from about 1% to 2% with less than about 1% by weight of a decongestant and / or an antihistamine.

[0046] In another aspect, acetaminophen may be present in an amount of about 45% by weight. The dextromethorphan may be present in an amount from about 1% to 2% with less than about 5% by weight of a decongestant and / or less than about 1% of an antihistamine.

[0047] The fill material may comprise at least two polyethylene glycols as solvent, polyethylene glycol 400 and polyethylene glycol 600 respectively present in amounts about 20% and 30% by weight. For example, the amount of polyethylene glycol 400 and polyethylene glycol 600, respectively, present in an amount of 147.8 mg and 202.4 mg.

[0048] In one aspect, the acetaminophen may be present in an amount of about 45% by weight. The dextromethorphan may be present in an amount from about 1% to 2% by weight. Less than about 1% by weight of phenylephrine or doxylamine succinate,or less than or equal to about 5% by weight of pseudoephedrine. The polyethylene glycol 400 and polyethylene glycol 600 respectively present in amounts about 20% and 30% by weight.

[0049] The fill material may comprise a viscosity modifier, povidone, where the povidone is less than 1% by weight. For example, the viscosity modifier is povidone in an amount of 3.69 mg. The povidone may have K-value of 30.

[0050] In one aspect, the acetaminophen may be present in an amount of about 45% by weight. The dextromethorphan may be present in an amount from about 1% to 2% by weight. Less than about 1% by weight of phenylephrine or doxylamine succinate may be added; alternatively phenylephrine about 5% by weight of pseudoephedrine may be suitable. The polyethylene glycol 400 and polyethylene glycol 600 respectively present in amounts about 20% and 30% by weight. The povidone is less than about 1% by weight.B. Shell

[0051] The shell matrix / capsule comprising gelatin may be in an amount of about 35% by weight of the pharmaceutical composition. The gelatin shell matrix is in an amount from about 58% to 68% of the shell composition, and one or more plasticizers are in an amount from about 32 to 42% of the shell composition. For example, the pharmaceutical composition may be less than or equal to about 1100 mg, which is the wet capsule weight. The shell along may be about 720 mg.

[0052] The shell matrix may also comprise one or more colorants in an amount less than 1% of the shell composition and at least one opacifier in an amount less than 1% of the shell composition. These may comprise Opatint® Concentrated Color Dispersion DG-110018 Green, which may include but are not limited to FD&C Blue #1 Dye, D&C Yellow #6 Dye, and MICA Based Pearlescent Pigment, along with proprietary amounts of Titanium Dioxide and Mica, all functioning as colorants and opacifiers per CFR standards.

[0053] For example, the shell matrix may comprise gelatin in an amount from about 220 mg to 260 mg, a glycerin in an amount from about 38 mg to 76 mg, a sorbitol inan amount from about 57 mg to 95 mg, one or more dyes in an amount from about 0.38 mg to 2.28 mg, and a coating mixture of mica flakes coated with metal oxides in an amount from about 1.9 mg to 7.6 mg.II. Methods of Preparation

[0054] The soft gel capsule is prepared using an industrial mixing system, Ekato. Ekato is suitable for handling volumes (2000L) of material while providing precise control over mixing, temperature, and atmosphere, ensuring the final product's consistency and quality.

[0055] Process Steps for PEG Heating and Product Manufacturing in 2000L Ekato: the process begins by heating the PEG in a 140°F (60°C) hot box for no less than 24 hours. While the PEG is heating, prepare Portion I by inerting a 200L tank with nitrogen, then adding the PEG to the tank. Povidone K30 is added to this PEG portion, and the tank is set to 50°C. Using a Cowles mixer with an 8-inch or 12-inch blade, mix at 100-300 RPM until the povidone is completely dissolved. After dissolution, cool the tank to 30°C while continuing to mix.

[0056] It is recognized that different K-values of povidone may be used, which can include a combination of multiple K-values to achieve the same effect and optimize the formulation for the desired outcomes. For example, povidone K12 may be used around 4-5 mg to maintain similar solubility enhancement due to its lower viscosity. In contrast, povidone K90 may be used in amounts around 2-2.5 mg, as its higher molecular weight will significantly impact viscosity.

[0057] Once the solution reaches 30°C, weigh the Dextromethorphan and PSE (or PE). These ingredients are slowly added to Portion I while mixing at 200 RPM, ensuring a nitrogen blanket (1-2 SCFM) is maintained. The mixture is stirred for 90 minutes to ensure proper blending. Afterward, rinse the mixer blade with PEG 400 (Portion II), and add the rinse to the 200L tank.

[0058] In another 200L tank, add PEG 600 while continuing to blanket the mixture with nitrogen. The PEG 600 is then vacuum transferred into a 2000L Ekato mixing system, followed by the transfer of PEG 400 (Portion III) into the Ekato, also undernitrogen blanketing. The Ekato's temperature is set to 45°C, and the Paravisc agitator is run at 30 RPM counterclockwise.

[0059] Next, vacuum transfer the Acetaminophen into the Ekato under a nitrogen purge. The mixture is homogenized at 1500 RPM for 15 minutes. After homogenization, change the Paravisc's direction to clockwise. At this point, vacuum transfer the side mix - containing PEG 400, Dextromethorphan, and PSE / PE - into the Ekato. Stir the combined mixture for 30 minutes at 30 RPM clockwise, then homogenize again at 1500 RPM for 30 minutes.

[0060] After homogenization, reduce the Ekato’s temperature to 25°C and lower the Paravisc speed to 10 RPM, this time rotating counterclockwise. The mixture is deaerated for 60 minutes to remove any trapped air. Finally, discharge the product into a nitrogen-purged 700L tank through a 20-mesh Y-strainer to complete the process.

[0061] For example, the below steps may be followed:• Portion I of PEG in a 200L tank inerted with Nitrogen and add Povidone to portion I PEG• Set 200L tank to 50C mix with cowles mixer with a 8” or 12” blade at 100-300 RPM until povidone is dissolved• Cool tank while mixing to 30C• Weigh Dextromethorphan and PSE or PE and slowly add to Portion I while mixing 200RPM and nitrogen blanketing 1-2 SCFM.• Mix for 90 minutes• Rinse the mixer blader with PEG 400 Portion II and add rinse to 200L tank• Into another 200L tank add PEG 600 while blanketing with Nitrogen• Into the 2000L Ekato Vacuum transfer the PEG 600 from the 200L Tank• Transfer PEG 400 Portion III into the EKATO while blanketing with Nitrogen• Set Ekato Temp to 45C and Paravisc speed to 30RPM Counterclockwise• Into Ekato vacuum transfer the Acetaminophen under nitrogen purge• Homogenize at 1500RPM for 15 min• Change Paravisc direction to clockwise• Vacuum transfer the side mix consisting of PEG 400, Dex and PSE / PE• Mix for 30 minutes at 30RPM clockwise and homogenize at 1500 rpm for 30 minutes• Reduce Ekato temp to 25C and decrease Paravisc to 10RPM counterclockwise• De-aerate for 60 min• Discharge into a nitrogen purged 700L tank through a 20 mesh y strainer

[0062] In the production of soft gel capsules, after de-aerating and discharging the mixture into a nitrogen-purged tank, the gel mass may be transferred to a soft gel encapsulation machine. This machine fills the gelatin shell with the prepared formulation. The soft gel capsules are sealed as the liquid fill is enclosed between layers of gelatin. After encapsulation, the soft gel capsules must be dried to reduce moisture content and harden the gelatin shell. Capsules are inspected for defects, such as leaks or deformities, and sorted accordingly. The final step involves packaging the capsules in blister packs, bottles, or other appropriate containers for distribution. These steps ensure the product is ready for consumption and meets quality control standards.

[0063] Following these steps or any other steps described herein, the soft gel capsule may be present at an amount of about 1100 mg with 720 mg of fill material, which is a 20% to 30% reduction in size compared to commercially available cold and cough formulations. At the same time, the product exhibits similar levels of stability and comprises a lecithin-free fill matrix. The fill matrix further comprises one or more solvents encapsulating about 40% to 50% of a plurality of pharmaceutically active agents about by the mixture weight of the fill matrix, where solvents may be polyethylene glycol about 50% to 60% by that weight.

[0064] One aspect of a method for preparing a pharmaceutical composition or a soft gel capsule described herein, in accordance with the steps above or according to any of the aspects described herein, the method may comprise (a) mixing a first portion of one or more solvents with less than about 1% by the mixture weight of a viscosity modifier at 50°C, (b) cooling the mixture to 30°C, (c) adding to the mixture about 40% to 50% by weight of a plurality of pharmaceutically active agents comprising at leastone analgesic and antipyretic agent, at least one cough suppressant, and at least one decongestant or at least one antihistamine, (d) rinsing the mixture with said one or more solvents with a second portion of said one or more solvents, (e) mixing the mixture with a third portion of said one or more solvents at 45°C, and (f) cooling the mixture to 25 °C.

[0065] Another aspect is a method or process for making a pharmaceutical composition or soft gel capsule described herein, the method comprising: the method comprising: (a) mixing together: (i) about 40% to 50% by the mixture weight of a plurality of pharmaceutically active agents comprising at least one analgesic and antipyretic agent, at least one cough suppressant, and at least one decongestant or at least one antihistamine, (ii) about 50% to 60% by the mixture weight of solvent, and (iii) less than about 1% by the mixture weight of a viscosity modifier; and (b) encapsulating the mixture in a gelatin shell composition.

[0066] As an option, further comprising: mixing together (i) a gelatin shell matrix in an amount from about 58% to 68% of the shell composition, and (2) one or more plasticizers in an amount from about 32 to 42% of the shell composition to form the gelatin shell composition. Another option, further comprising: adding one or more colorants in an amount less than 1% of the gelatin shell composition. Another option, adding at least one opacifier in an amount less than 1% of the gelatin shell composition. As an option, further comprising: mixing together (i) a gelatin shell matrix in an amount from about 58% to 68% of the shell composition, and (2) one or more plasticizers in an amount from about 32 to 42% of the shell composition to form the gelatin shell composition. Another option, further comprising: adding one or more colorants in an amount less than 1% of the gelatin shell composition. Another option, adding at least one opacifier in an amount less than 1% of the gelatin shell composition.III. Methods of Use

[0067] Soft gel capsules (lecithin-free) may be used to encapsulate a wide range of cold and cough APIs, some of which are described herein. These soft gel capsules encapsulating the APIs may be administered orally to a patient to deliver the APIs.

[0068] The size of the lecithin-free fill or the overall capsule is reduced by about 20% to 30% compared to existing and known cold and cough products, and moreover, there is no significant increase in the amount / number of degradants of stability testing under the condition of various ICH zone (i.e., I to IV) at room temperature for over 24 hours to 52 weeks.

[0069] It is understood that the soft gel capsules may be administered to patients to treat cough, nasal congestion, or cold symptoms, comprising administering the pharmaceutical composition of any aspect described herein, to a patient in need thereof.

[0070] One aspect is a method for treating cough, nasal congestion, or cold symptoms, comprising administering the pharmaceutical composition of any aspect described herein, to a patient in need thereof.

[0071] Another aspect is a soft gel capsule or pharmaceutical composition for use in a method of treating cough, nasal congestion, or cold symptoms, the method comprising administering the pharmaceutical composition said soft gel capsule or pharmaceutical composition to a patient.EXAMPLES

[0072] Example pharmaceutical formulations are designed for capsule delivery, combining APIs and excipients to achieve specific therapeutic effects for treating colds and coughs, tailored for daytime and nighttime use. For example, the inclusion of phenylephrine or pseudoephedrine is typically associated with daytime formulations, while doxylamine succinate / diphenhydramine can be used for nighttime relief. These formulations also contain acetaminophen, dextromethorphan HBr, and a mixture of PEGs of varying molecular weights to enhance solubility and formulation stability, complemented by povidone or more specifically povidone K30 as a viscosity modifier. Although the total weight of the capsules varies slightly, it is approximately 720 mg. These formulations exemplify a careful balance between APIs without unnecessary excipients such as lecithin. Below are some examples of the formulation described herein.Fil Example 1Fill Material Ingredients Mg / CapsuleAcetaminophen 325.000Dextromethorphan HBr 10.000Pseudoephedrine HCI 30.00Polyethylene Glycol 600 206.664Polyethylene Glycol 400, Portion I 60.000Polyethylene Glycol 400, Portion II 17.784Polyethylene Glycol 400, Portion III 60.000Povidone K30 3.688TOTAL 713.136Fil Example 2Fill Material Ingredients Mg / CapsuleAcetaminophen 325.000Dextromethorphan HBr 10.000Doxylamine Succinate 6.25Polyethylene Glycol 600 220.409Polyethylene Glycol 400, Portion I 60.000Polyethylene Glycol 400, Portion II 19.773Polyethylene Glycol 400, Portion III 68.000Povidone K30 3.688TOTAL 713.12Fil Example 3Fill Material Ingredients Mg / CapsuleAcetaminophen 325.000Dextromethorphan HBr 10.000Phenylephrine 5Polyethylene Glycol 600 221.659Polyethylene Glycol 400, Portion l-lll 147.773Povidone K30 3.688TOTAL 713.12Fil Example 4Fill MaterialIngredients Mg / CapsuleAcetaminophen 325.000Dextromethorphan HBr 15.000Pseudoephedrine HCI 30.00Polyethylene Glycol 600 206.664Polyethylene Glycol 400, Portion I 60.000Polyethylene Glycol 400, Portion II 17.784Polyethylene Glycol 400, Portion III 60.000Povidone K30 3.688TOTAL 718.136Fil Example 5Fill Material Ingredients Mg / CapsuleAcetaminophen 325.000Dextromethorphan HBr 10.000Diphenhydramine 25Polyethylene Glycol 600 220.409Polyethylene Glycol 400, Portion I 60.000Polyethylene Glycol 400, Portion II 19.773Polyethylene Glycol 400, Portion III 68.000Povidone K30 3.688TOTAL 731.87Fil Example 6Fill Material Ingredients Mg / CapsuleAcetaminophen 325.000Dextromethorphan HBr 10.000Polyethylene Glycol 600 221.659Polyethylene Glycol 400, Portion l-lll 147.773Povidone K30 3.688TOTAL 708.12

[0073] It will be understood that the benefits and advantages described above may relate to one aspect or may relate to several aspects. The aspects are not limited to those that solve any or all of the stated problems or those that have any or all of thestated benefits and advantages. Variants should be considered to be included into the scope of the invention.

[0074] Further, it is understood that the disclosed invention is not limited to the particular methodology, protocols, and reagents described as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

[0075] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are as described. Publications cited herein and the materials for which they are cited are specifically incorporated by reference. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0076] Any reference to 'an' item refers to one or more of those items. The term 'comprising' is used herein to mean including the method steps or elements identified, but that such steps or elements do not comprise an exclusive list and a method or apparatus may contain additional steps or elements.

[0077] Further, as used herein, the term "exemplary", "example" or "aspects" is intended to mean "serving as an illustration or example of something". Further, to the extent that the term "includes" is used in either the detailed description or the claims, such term is intended to be inclusive in a manner similar to the term "comprising" as "comprising" is interpreted when employed as a transitional word in a claim.

[0078] As used herein, the term “about” or “approximately” as applied to one or more values of interest, refers to a value that is similar to a stated reference value, or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, such as the limitations of the measurement system. In one aspect, theterm “about” refers to any values, including both integers and fractional components that are within a variation of up to ± 10% of the value modified by the term “about.” Alternatively, “about” can mean within 3 or more standard deviations, per the practice in the art. Alternatively, such as with respect to biological systems or processes, the term “about” can mean within an order of magnitude, in some embodiments within 5- fold, and in some embodiments within 2-fold, of a value. As used herein, the symbol means “about” or “approximately.”

[0079] All ranges disclosed herein include both end points as discrete values as well as all integers and fractions specified within the range. For example, a range of 0.1- 2.0 includes 0.1 , 0.2, 0.3, 0.4 . . . 2.0. If the end points are modified by the term “about,” the range specified is expanded by a variation of up to ±10% of any value within the range or within 3 or more standard deviations, including the end points.

[0080] What has been described above includes examples of one or more aspects. It is, of course, not possible to describe every conceivable modification and alteration of the above devices or methods for purposes of describing the aforementioned aspects, but one of ordinary skill in the art can recognize that many further modifications and permutations of various aspects are possible. Accordingly, the described aspects are intended to embrace all such alterations, modifications, and variations that fall within the scope of the appended

Claims

CLAIMS1. A pharmaceutical composition comprising a lecithin-free fill material comprising: a plurality of pharmaceutically active agents in an amount from about 40% to about 50% by weight; at least one solvent in an amount from about 50% to about 60% by weight; and at least one viscosity modifier in an amount less than 1% by weight.

2. The pharmaceutical composition of claim 1, wherein the plurality of pharmaceutically active agents comprising: at least one analgesic and antipyretic agent and at least one cough suppressant.

3. The pharmaceutical composition of claim 1, wherein the at least one analgesic and antipyretic agent is acetaminophen.

4. The pharmaceutical composition of claim 3, wherein the acetaminophen is present in an amount of about 45% by weight.

5. The pharmaceutical composition of claims 2 to 4, wherein said at least one cough suppressant is dextromethorphan.

6. The pharmaceutical composition of claim 5, wherein the dextromethorphan is present in an amount from about 1% to 2% by weight.

7. The pharmaceutical composition of any preceding claim, wherein said at least one solvent comprises at least two polyethylene glycol.

8. The pharmaceutical composition of claim 7, wherein said at least two polyethylene glycols comprise polyethylene glycol 400 and polyethylene glycol 600 respectively present in amounts about 20% and 30% by weight.

9. The pharmaceutical composition of any preceding claim, wherein the plurality of pharmaceutically active agents further comprising: at least one decongestant.

10. The pharmaceutical composition of claim 9, wherein said at least one decongestant is present in an amount of less than 1% by weight or said at least one decongestant is phenylephrine in an amount of about 0.7% by weight.

11. The pharmaceutical composition of claim 9, wherein said at least one decongestant is present in an amount up to about 5% by weight or said at least one decongestant is pseudoephedrine in an amount of about 4% by weight.

12. The pharmaceutical composition of any preceding claim, wherein the plurality of pharmaceutically active agents further comprising: at least one antihistamine with sedative and anti-allergic properties.

13. The pharmaceutical composition of claim 11 , wherein said at least one antihistamine is present in less than about 1% to about 5% by weight; or said at least one antihistamine is doxylamine succinate in an amount of about 0.9% by weight or said at least one antihistamine is diphenhydramine in an amount of about 3.5% by weight.

14. The pharmaceutical composition of any preceding claim, wherein the pharmaceutical composition comprises a shell composition in an amount of about 35% by weight of the pharmaceutical composition.

15. The pharmaceutical composition of claim 14, wherein the shell composition comprising: a gelatin shell matrix in an amount from about 58% to 68% of the shell composition; and one or more plasticizers in an amount from about 32 to 42% of the shell composition.

16. The pharmaceutical composition of claim 14 or 15, wherein the shell further comprising: one or more colorants in an amount less than 1% of the shell composition.

17. The pharmaceutical composition of claims 14 to 16, wherein the shell furthercomprising: at least one opacifier in an amount less than 1% of the shell composition.

18. The pharmaceutical composition of any preceding claim, wherein the lecithin- free fill material is without lecithin.

19. A method for treating cough, nasal congestion, or cold symptoms comprising administering the pharmaceutical composition of claims 1 to 18 to a patient in need thereof.

20. A soft gelatin capsule comprising a lecithin-free fill material comprising:(a) an analgesic and antipyretic cough suppressant;(b) a cough suppressant;(c) a decongestant or an antihistamine;(d) one or more solvents; and(e) a viscosity modifier.

21. The capsule of claim 20, wherein the fill material is present in an amount of 720 mg.

22. The capsule of claim 20 or 21 , wherein the analgesic and antipyretic cough suppressant is acetaminophen in an amount of 325 mg.

23. The capsule of claims 20 to 22, wherein the cough suppressant is dextromethorphan in an amount of 10 mg.

24. The capsule of claims 20 to 23, wherein the decongestant is phenylephrine in an amount of 5 mg.

25. The capsule of claims 20 to 23, wherein the decongestant is pseudoephedrine in an amount of 30 mg.

26. The capsule of claims 20 to 23, wherein the antihistamine is doxylamine succinate in an amount of 6.25 mg; or wherein the antihistamine is diphenhydramine in an amount up to 25 mg.

27. The capsule of claims 20 to 26, wherein said one or more solvents arepolyethylene glycol 400 and polyethylene glycol 600 respectively present in an amount of 147.8 mg and 202.4 mg.

28. The capsule of claims 20 to 27, wherein the viscosity modifier is povidone in an amount of 3.69 mg.

29. The capsule of claims 20 to 28, wherein the capsule further comprising: a gelatin in an amount from about 220 mg to 260 mg; a glycerin in an amount from about 38 mg to 76 mg; a sorbitol in an amount from about 57 mg to 95 mg; one or more dyes in an amount from about 0.38 mg to 2.28 mg; and a coating mixture of mica flakes coated with metal oxides in an amount from about 1.9 mg to 7.6 mg.

30. A lecithin-free capsule comprising: a lecithin-free fill material of about 65% by weight and a shell composition in an amount of about 35% by weight, wherein the lecithin-free filling material comprising: an acetaminophen in an amount of 325 mg; a dextromethorphan in an amount of 10 mg a phenylephrine hydrochloride in an amount of 5 mg, doxylamine succinate in an amount of 6.25 mg, or diphenhydramine in an amount of 25 mg; polyethylene glycols in an amount of 369.4 mg; and a viscosity modifier is in an amount of 3.69.

31. The capsule of claim 30, wherein the shell composition comprising: a gelatin in an amount from 220 mg to 260 mg; a glycerin in an amount from 38 mg to 76 mg; a sorbitol in an amount from 57 mg to 95 mg; one or more dyes in an amount from 0.38 mg to 2.28 mg; and a coating mixture of mica flakes coated with metal oxides in an amount from 1.9 mg to 7.6 mg.

32. A method for treating cough, nasal congestion, or cold symptoms comprising administering the capsule of claims 20 to 31 to a patient in need thereof.

33. A method for making a soft gelatin capsule, the method comprising:(a) mixing together(i) about 40% to 50% by the mixture weight of a plurality of pharmaceutically active agents comprising at least one analgesic and antipyretic agent, at least one cough suppressant, and at least one decongestant or at least one antihistamine,(ii) about 50% to 60% by the mixture weight of solvent, and(iii) less than about 1% by the mixture weight of a viscosity modifier; and(b) encapsulating the mixture in a gelatin shell composition.

34. The method of claim 33, wherein the mixture is about 65% by weight of the soft gelatin capsule.

35. The method of claim 33 or 34, further comprising: mixing together (i) a gelatin shell matrix in an amount from about 58% to 68% of the shell composition, and (2) one or more plasticizers in an amount from about 32 to 42% of the shell composition to form the gelatin shell composition.

36. The method of claim 35, further comprising: adding one or more colorants in an amount less than 1% of the gelatin shell composition.

37. The method of claims 33 to 36, adding at least one opacifier in an amount less than 1% of the gelatin shell composition.

38. The method for making a lecithin-free fill of a pharmaceutical composition according to claims 1 to 18, the method comprising:(a) mixing a first portion of one or more solvents with less than about 1% by the mixture weight of a viscosity modifier at 50°C;(b) cooling the mixture to 30°C;(c) adding to the mixture about 40% to 50% by weight of a plurality of pharmaceutically active agents comprising at least one analgesic andantipyretic agent, at least one cough suppressant, and at least one decongestant or at least one antihistamine;(d) rinsing the mixture with said one or more solvents with a second portion of said one or more solvents;(e) mixing the mixture with a third portion of said one or more solvents at45°C; and(f) cooling the mixture to 25 °C.

39. The method of claim 38, wherein said one or more solvents comprise polyethylene glycol about 50% to 60% by the mixture weight.40 The method of claim 38 or 39, wherein said plurality of pharmaceutically active agents is about 40% to 50% by the mixture weight.