Branched amino acid surfactant for use in healthcare products

Abstract

To provide a healthcare product formulated together with a surfactant.SOLUTION: Provided is a solid formulation comprising at least one active ingredient and at least one surfactant represented by, for example, the following formula.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Provisional Patent Application No. 63 / 051,190, filed July 13, 2020, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to branched surfactants for use in health care products. Such branched surfactants may include siloxane derivatives of amino acids that have surface active properties. [Background technology]

[0003] Surfactants (molecules with surface active properties) are widely used in commercial applications in a variety of formulations, from detergents to hair care products and cosmetics. Compounds with surface active properties are often added to formulations intended to improve the health of humans and animals. Some health care products include medicines, functional foods, vitamin and / or mineral supplements, and wound dressings. Surfactants are important components of many health care or related formulations, at least in part because some surfactants help increase the amount of active ingredients, stabilizers, fillers, excipients, adjuvants, etc. that can be included in a conveniently sized dose, and / or because the inclusion of surfactants in a formulation is useful in the manufacture and / or packaging of the product.

[0004] Surfactants can be nonionic, zwitterionic, cationic, or anionic. In principle, any surfactant class (e.g., cationic, anionic, nonionic, amphoteric) is suitable for cleansing or cleaning applications, but in practice many personal care cleansers and household cleaning products are formulated with a combination of two or more surfactants from two or more surfactant classes.

[0005] Surfactants are often amphiphilic molecules with a relatively water-insoluble hydrophobic "tail" group and a relatively water-soluble hydrophilic "head" group. These compounds can adsorb at interfaces, such as the interface between two liquids, between gas and liquid, or between solid and liquid. In a system that includes a relatively polar component and a relatively non-polar component, the hydrophobic tail preferentially interacts with the relatively non-polar component, while the hydrophilic head preferentially interacts with the relatively polar component. In the case of an interface between water and oil, the hydrophilic head group preferentially extends into the water, while the hydrophobic tail preferentially extends into the oil. When added to an air-water interface, the hydrophilic head group preferentially extends into the water, while the hydrophobic tail preferentially extends into the gas. The presence of the surfactant disrupts at least some of the intermolecular interactions between the water molecules, replacing at least some of the interactions between the water molecules with a generally weaker interaction between at least some of the water molecules and the surfactant. This results in a reduction in surface tension and may also act to stabilise the interface.

[0006] At high enough concentrations, surfactants can form aggregates that act to limit the exposure of the hydrophobic tails to polar solvents. One such aggregate is a micelle. In a typical micelle, the molecules are arranged in a sphere, with the hydrophobic tails of the surfactant preferentially located inside the sphere and the hydrophilic heads of the surfactant preferentially located outside the micelle to preferentially interact with the more polar solvent. The effect that any compound has on surface tension and the concentration at which it forms micelles can be useful as a defining feature of a surfactant. Summary of the Invention

[0007] The present disclosure provides health care products formulated with surfactants, including, but not limited to, tablets, powders, liquids, salves, ointments, cleansers, and / or wipes for use on the body, and wound dressings, which may be formulated to include one or more surfactants from one or more of the surfactant classes disclosed herein.

[0008] The present disclosure provides surfactants for use in health care products in the form of siloxane derivatives of amino acids with surface active properties. The amino acids may be natural or synthetic amino acids, or may be obtained via ring-opening reactions of molecules such as lactams, for example caprolactam. The amino acids may be functionalized with different types of siloxane groups to form compounds with surface active properties. Characteristically, these compounds may have a low critical micelle concentration (CMC) and / or the ability to reduce the surface tension of liquids.

[0009] The present disclosure provides a formulation for delivering an active agent to a patient, comprising at least one surfactant of formula I,

[0010] [ka]

[0011] In the formula, R 1 and R 2 are independently selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; n is an integer from 2 to 5, inclusive; R 3 is C5~C 12 is alkyl, R 4 is C3~C 10 alkyl, and the terminal nitrogen is R 5 may be further substituted with, in which case R 5 is selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; an optional counterion may be present associated with the compound, which counterion, if present, may be selected from the group consisting of chloride, bromide, iodide, and 4-methylbenzenesulfonate; a surfactant; and at least one active ingredient.

[0012] The present disclosure further provides a formulation for delivering an active agent to a patient, comprising at least one surfactant of formula I,

[0013] [ka]

[0014] In the formula, R 1 and R 2 are independently selected from hydrogen, an oxygen atom, and C1-C6 alkyl, where C1-C6 alkyl is carboxylate, hydroxyl, sulfonyl, or sulfo. n is an integer from 2 to 5, inclusive; R 3 is C5~C 12 is alkyl, R 4 is C3~C 10 alkyl, and the terminal nitrogen is R 5 may be further substituted with, in which case R 5 is selected from hydrogen, oxygen, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; an optional counter ion may be present associated with the compound, which counter ion, if present, may be selected from the group consisting of chloride, bromide, iodide, and 4-methylbenzenesulfonate; a surfactant; and at least one active ingredient is selected from the group consisting of at least one drug selected from the group consisting of, but not limited to, analgesics, antibiotics, antihypertensives, chemotherapeutics, antipsychotics, antidepressants, tranquilizers, proton pump inhibitors, and antifungals.

[0015] The present disclosure further provides a solid form formulation for delivery of an active agent to a patient, comprising at least one surfactant of formula I,

[0016] [ka]

[0017] In the formula, R 1 and R 2 are independently selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; n is an integer from 2 to 5, inclusive; R 3 is C5~C 12 is alkyl, R 4 is C3~C 10 alkyl, and the terminal nitrogen is R 5 may be further substituted with, in which case R 5 is selected from hydrogen, oxygen, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; an optional counter ion may be associated with the compound, which, if present, may be selected from the group consisting of chloride, bromide, iodide, and 4-methylbenzenesulfonate; a surfactant, at least one active ingredient, and at least one excipient selected from the group consisting of binders, disintegrants, lubricants, colorants, and / or flavoring agents.

[0018] The present disclosure also provides a formulation in liquid form for delivering an active agent, comprising at least one surfactant of formula I,

[0019] [ka]

[0020] In the formula, R 1 and R 2 are independently selected from hydrogen, an oxygen atom, and C1-C6 alkyl, where C1-C6 alkyl is carboxylate, hydroxyl, sulfonyl, or sulfo. n is an integer from 2 to 5, inclusive; R 3 is C5~C 12 is alkyl, R 4 is C3~C 10alkyl, and the terminal nitrogen is R 5 may be further substituted with, in which case R 5 is selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate, and an optional counter ion may be associated with the compound, which, if present, may be selected from the group consisting of chloride, bromide, iodide, and 4-methylbenzenesulfonate; a surfactant, at least one active ingredient, and either or both of the aqueous and non-aqueous phases, and optionally at least one colorant and / or at least one flavorant.

[0021] The present disclosure further provides a formulation in the form of an emulsion for delivering an active agent, comprising at least one surfactant of formula I,

[0022] [ka]

[0023] In the formula, R 1 and R 2 are independently selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; n is an integer from 2 to 5, inclusive; R 3 is C5~C 12 is alkyl, R 4 is C3~C 10 alkyl, and the terminal nitrogen is R 5 may be further substituted with, in which case R 5is selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; an optional counterion may be associated with the compound, which, if present, may be selected from the group consisting of chloride, bromide, iodide, and 4-methylbenzenesulfonate; a surfactant, at least one active ingredient in the aqueous phase, and optionally at least one colorant and / or at least one flavorant.

[0024] The present disclosure further provides a formulation in the form of an emulsion for delivering an active agent, comprising at least one surfactant of formula I,

[0025] [ka]

[0026] In the formula, R 1 and R 2 may be the same or different and comprise at least one group selected from the group consisting of C1-C6 alkyl, optionally C1-C6 alkyl may comprise one or more of oxygen, nitrogen, or sulfur atoms or groups containing at least one of these atoms, and the alkyl chain may optionally comprise hydroxyl, amino, and n is an integer from 1 to 12, and the terminal nitrogen is optionally substituted with one or more substituents selected from the group consisting of amide, sulfonyl, sulfonate, carbonyl, carboxyl, and carboxylate, and the terminal nitrogen is optionally substituted with one or more substituents selected from the group consisting of R 3 may be further substituted with, in which case R 3 comprises a surfactant selected from the group consisting of hydrogen, oxygen, hydroxyl, and C1-C6 alkyl, optionally present and, if present, a counterion associated with this compound selected from the group consisting of chloride, bromide, and iodide ions, at least one active ingredient in a non-aqueous phase, and optionally at least one colorant and / or at least one flavorant.

[0027] The above and other features of the present disclosure, as well as the methods of achieving the same, will become more apparent and better understood by referring to the following description of the embodiments taken in conjunction with the accompanying drawings. [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 shows a plot of surface tension versus concentration measured at pH=7 as described in Example 1B, where the Y-axis represents surface tension (γ) in millinewtons per meter (mN / m) and the X-axis represents concentration (c) in millimoles (mM). [Figure 2A] FIG. 2A shows a plot of surface tension versus concentration measured at pH=7 as described in Example 2B, where the Y-axis represents surface tension (γ) in milliNewtons per meter (mN / m) and the X-axis represents concentration (c) in millimoles (mM). [Figure 2B] FIG. 2B shows a plot of dynamic surface tension as change in surface tension versus time, as described in Example 2C, where the Y-axis represents surface tension in milliNewtons per meter (mN / m) and the X-axis represents surface elapsed time in milliseconds (ms). [Diagram 3] FIG. 3 shows a plot of surface tension versus concentration measured at pH=7 as described in Example 3B, where the Y-axis represents surface tension (γ) in milliNewtons per meter (mN / m) and the X-axis represents concentration (c) in millimoles (mM). [Figure 4A] FIG. 4A shows a plot of surface tension versus concentration measured at pH=7 as described in Example 4B, where the Y-axis represents surface tension (γ) in milliNewtons per meter (mN / m) and the X-axis represents concentration (c) in millimoles (mM). [Figure 4B] FIG. 4B shows a plot of dynamic surface tension as change in surface tension versus time, as described in Example 4C, where the Y-axis represents surface tension in milliNewtons per meter (mN / m) and the X-axis represents surface elapsed time in milliseconds (ms). [Figure 5A]FIG. 5A shows a plot of surface tension versus concentration measured at pH=7 as described in Example 5B, where the Y-axis represents surface tension (γ) in milliNewtons per meter (mN / m) and the X-axis represents concentration (c) in millimoles (mM). [Figure 5B] FIG. 5B shows a plot of dynamic surface tension as change in surface tension versus time, as described in Example 5C, where the Y-axis represents surface tension in milliNewtons per meter (mN / m) and the X-axis represents surface elapsed time in milliseconds (ms). [Figure 6A] FIG. 6A shows a plot of surface tension versus concentration measured at pH=7 as described in Example 6B, where the Y-axis represents surface tension (γ) in milliNewtons per meter (mN / m) and the X-axis represents concentration (c) in millimoles (mM). [Figure 6B] FIG. 6B shows a plot of dynamic surface tension as change in surface tension versus time, as described in Example 6C, where the Y-axis represents surface tension in milliNewtons per meter (mN / m) and the X-axis represents surface elapsed time in milliseconds (ms). [Figure 7A] FIG. 7A shows a plot of surface tension versus concentration measured at pH=7 as described in Example 7B, where the Y-axis represents surface tension (γ) in milliNewtons per meter (mN / m) and the X-axis represents concentration (c) in millimoles (mM). [Figure 7B] FIG. 7B shows a plot of dynamic surface tension as change in surface tension versus time, as described in Example 7C, where the Y-axis represents surface tension in milliNewtons per meter (mN / m) and the X-axis represents surface elapsed time in milliseconds (ms). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] I. Definition As used herein, the phrase "within any range using these endpoints" literally means that any range may be selected from any two of the values ​​listed before the phrase, regardless of whether the values ​​are toward the lower value of the list or toward the higher value of the list. For example, a pair of values ​​may be selected from the two lower values, the two higher values, or a lower value and an upper value.

[0030] As used herein, the term "alkyl" means any saturated carbon chain, which may be straight or branched.

[0031] As used herein, the phrase "surface active" means that the associated compound is capable of lowering the surface tension of the medium in which it is at least partially dissolved and / or the interfacial tension with other phases, and thus may at least partially adsorb to air-liquid interfaces and / or other interfaces. The term "surfactant" may be applied to such compounds.

[0032] With respect to terms of imprecision, the terms "about" and "approximately" may be used interchangeably and may be used to mean a measurement that includes the stated measurement and includes any measurement that is reasonably close to the stated measurement. A measurement that is reasonably close to the stated measurement deviates from the stated measurement by a reasonably small amount that is understood and readily ascertained by one of ordinary skill in the art. Such deviations may be attributed, for example, to measurement error or small adjustments made to optimize performance. In cases where one of ordinary skill in the art would determine that values ​​for such reasonably small differences are not readily ascertainable, the terms "about" and "approximately" may be understood to mean plus or minus 10% of the stated value.

[0033] When a range of values ​​is given, each intervening value between the upper and lower limits of the range, and any other stated or intervening values ​​within the stated range, are intended to be encompassed by the present disclosure. For example, if a range of 1 μm to 8 μm is stated, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm are also expressly disclosed, as well as a range of values ​​above 1 μm and below 8 μm. As used herein, the term "about" means ±5%, ±10%, or ±20% of the modified value.

[0034] The term "emulsion" or "emulsion formulation" refers to a colloidal dispersion of two immiscible liquids in the form of droplets, generally ranging in size from 10 nanometers to 100 microns. Emulsions are represented by the symbols O / W (oil-in-water) when the continuous phase is an aqueous solution and W / O (water-in-oil) when the continuous phase is an oil. Other examples of emulsions, such as O / W / O (oil-in-water-in-oil), contain oil droplets contained within aqueous droplets dispersed in a continuous oil phase. A "physically stable" emulsion is one that meets the U.S. Food and Drug Administration (FDA) guidelines, which set the general limits of (1) a mean droplet size not exceeding 500 nm or 0.5 μm, and (2) a population of large-diameter fat globules, expressed as the volume-weighted fraction of fat >5 μm (PFAT5), not exceeding 0.05% over a specified storage period at 5° C. or room temperature. SP <729> In addition, a physically stable emulsion will not have visible crystallization of the active agent upon storage at 5° C. or at room temperature for a specified period of time. Crystals are considered visible when viewed at 4× to 10× magnification. The emulsion meets the criteria of USP <729> and is physically stable if no visible crystals of the active agent are observed upon storage at 5° C. or room temperature for a period of at least 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 6 months, 1 year, or 2 years.

[0035] A "chemically stable" emulsion of the present disclosure is one in which the concentration of the active ingredient (i.e., the therapeutically active agent to be delivered) does not change by more than about 20% over a period of at least one month under appropriate storage conditions. In certain embodiments, the concentration of the active agent in an emulsion of the present disclosure does not change by more than about 5%, 10%, 15%, or 20% over a period of at least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, or 24 months under appropriate storage conditions, or over a period of at least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, or 24 months under storage conditions.

[0036] In one example, the stable emulsion composition of the present disclosure is stable over a wide range of temperatures, such as from -20° C. to 40° C. The composition of the present disclosure may be stored at about 5° C. to about 25° C.

[0037] "Oil phase" in a water-in-oil emulsion refers to all components in the formulation that individually exceed their solubility limit in the aqueous phase; these are generally substances that have a solubility of less than 1% in distilled water, although aqueous phase components such as salts may reduce the solubility of certain oils, resulting in their partitioning into the oil phase. Oil phase refers to the non-aqueous portion of a water-in-oil emulsion.

[0038] "Aqueous phase" or "water phase" in a water-in-oil emulsion means water present and any components 45 that are water soluble, i.e., do not exceed their solubility limit in water. "Aqueous phase" as used herein includes water-containing liquids that may contain pharma- ceutically acceptable additives such as acidifiers, alkalinizers, buffers, chelating agents, complexing agents, and solubilizers, antioxidants and antimicrobial preservatives, hygroscopic agents, suspending agents and / or viscosity modifiers, tonicity agents and humectants, or other biocompatible materials. Aqueous phase refers to the non-oil portion of a water-in-oil emulsion.

[0039] By "emulsifier" is meant a compound that prevents separation of an injectable emulsion into separate oil and aqueous phases. Emulsifiers that are useful in the present disclosure are generally: (1) compatible with the other ingredients of the stable emulsions of the present disclosure, (2) do not interfere with the stability or efficacy of the drug contained in the emulsion, (3) are stable and do not degrade in the formulation, and (4) are non-toxic.

[0040] As used herein, the terms "active agent or agents" or "active ingredient or ingredients" refer to compounds that act or are believed to act beneficially on humans and / or animals, and these terms may be used interchangeably as used herein. Such compounds include, but are not limited to, pharmaceuticals, antibodies, graft materials, transplant materials, functional foods, vitamins, and the like. Active agents include vitamins, minerals, and mineral supplements, and such active agents may be formulated alone or in combination with other active agents.

[0041] As used herein, "native particles" refers to particles of a compound without any other added components, i.e., native particles of an active agent are particles that contain an active agent and no other added excipients. "Drug-containing particles" refers to preformed particles that contain "native particles of an active agent" and one or more excipients. Drug-containing particles are necessarily larger in size than native particles. Drug-containing particles may be granules, beads, pellets, or other engineered particles or agglomerates that otherwise incorporate smaller primary drug particles themselves and are capable of withstanding conventional powder handling in flow and transport.

[0042] As used herein, unless otherwise specified, "particle size" and "actual particle size" refer to It means the particle size of the compound without any other components in the formulation, i.e. the particle size of unmodified particles of the active agent or the particle size of particles containing the active agent, some of which may be referred to as "drug-in particles".

[0043] II. Solid Dosage Formulations Comprising at Least One Active Agent Solid dosage formulations include, but are not limited to, at least one active agent formulated as a powder, as a tablet formed by printing a matrix or compressing a solid in the presence or absence of at least one liquid, or as a capsule.

[0044] Some embodiments include tablets or capsules, in which the active agent or active agent particles are formulated in the presence of at least one other inactive agent selected from the group consisting of surfactants, dispersants, excipients, binders, sweeteners, and flavoring agents.

[0045] Some embodiments include tablets, in which the active agent or active agent particles are formulated by compressing at least one active agent with at least one inactive agent selected from the group consisting of surfactants, dispersants, excipients, binders, sweeteners, and flavoring agents.

[0046] Some embodiments include a capsule, in which the active agent of the active agent particles is formulated by entrapping at least one active agent within the same casing as at least one inactive agent selected from the group consisting of surfactants, dispersants, excipients, binders, sweeteners, and flavoring agents.

[0047] Some embodiments of the present invention are formulations containing high concentrations of at least one active compound, some of which can exhibit low friability and sufficient hardness to withstand storage and handling, while also exhibiting a very rapid disintegration rate and a generally acceptable taste when administered orally.

[0048] In some embodiments, the fast dispersing solid dosage form may comprise a porous three-dimensional printed matrix comprising drug-containing particles of an active agent and a bulk material comprising specific excipients such as at least one disintegrant and at least one binder and at least one surfactant. The bulk material may further comprise at least one additional excipient such as a lubricant, a sweetener, and / or a flavoring agent.

[0049] In some embodiments, the matrix may be formed by depositing a printing fluid onto a powder, whereby the particles of the powder become bound by a binder. The matrix may be porous with a given overall bulk density, disintegration (dispersion) time in aqueous fluid, dissolution time in aqueous fluid, and water content. Some matrices exhibit a good balance of hardness, low friability, and fast dispersion rate when contacted or immersed in a small amount of aqueous liquid. Some embodiments of the invention include: a) embodiments in which the matrix has a hardness in the range of about 1 to about 7 kiloponds (kp), about 1 to about 3 kp; b) embodiments in which the matrix disperses in 10 seconds or less when placed in 15 ml of water or saliva; c) embodiments in which the binder is introduced into the matrix by the printing fluid used to form the matrix; d) embodiments in which the binder is introduced into the matrix by the bulk powder used to form the matrix; e) embodiments in which the matrix includes about 150 mg to about 600 mg of active agent; f) embodiments in which the matrix includes 10-40 printed incremental layers; g) embodiments in which the thickness (height) of the incremental layers is within the range of 0.006-0.014 inches or 0.008-0.012 inches; and h) embodiments in which the matrix is ​​porous and uncompressed.

[0050] In some embodiments, the active agent is present in a crystalline form, all polymorphs of which are contemplated. The crystallinity of the active agent, or any other material, can be determined by differential scanning calorimetry (DSC) to determine the presence of amorphous material. In some embodiments, the active agent is present in the bulk powder or matrix in amorphous form.

[0051] Some embodiments provide an orodispersible dosage form comprising a three-dimensionally printed matrix comprising a sweetener, a binder, a disintegrant, a surfactant, and drug-containing particles of an active agent, the binder binding the matrix. The matrix may or may not be bound to the active agent itself. When the formulation is formed by printing fluid, ideally the printing fluid does not dissolve any substantial amount of the active agent during the three-dimensional printing process.

[0052] In some embodiments, the active agent-containing particles include at least one active agent and at least one, at least two, at least three, at least four, or at least five pharmaceutical excipients. In some embodiments, the drug-containing particles include an active agent, at least one binder, at least one surfactant, and at least one disintegrant. The active agent-containing particles may further include a sweetener and / or a flavoring agent. In some embodiments, the drug-containing particles include OXC, at least two binders, at least one surfactant, and at least one disintegrant. Some embodiments of the present invention include: a) embodiments in which the content of the drug-containing particles in the matrix is ​​generally within the range of 55-85 wt%, 60-80 wt%, or 65-70 wt%, based on the total weight of the matrix in the final dosage form; b) embodiments in which the drug-containing particles comprise unmodified particles of a disintegrant, a binder, a surfactant, and an active agent; c) embodiments in which the content of unmodified particles of OXC in the drug-containing particles is within the range of 55-85 wt%, 60-80 wt%, or 65-70 wt%, based on the final weight of the drug-containing particles; d) embodiments in which the drug-containing particles include unmodified particles of OXC, based on the final weight of the drug-containing particles; e) embodiments in which the content of the binder in the drug-containing particle is within the range of 0-10 wt%, 1-7 wt%, or 2-5 wt%, based on the final weight of the drug-containing particle; f) embodiments in which the content of the surfactant in the drug-containing particle is within the range of 0-10 wt%, 1-5 wt%, or 1.4-4.2 wt%, based on the final weight of the drug-containing particle; and g) embodiments in which the drug-containing particle is produced by wet granulation.

[0053] One aspect of the present invention provides an orodispersible three-dimensional printed matrix comprising at least one active agent, at least one sweetener, at least one binder, at least one disintegrant, at least one surfactant, and at least one lubricant, wherein the matrix comprises particles bound by the binder, the matrix is ​​porous and uncompressed, the matrix disperses in less than 15 seconds in a volume of 15 ml of aqueous fluid, the active agent is contained in drug-containing particles comprising small particles of the active agent and at least one pharmaceutical excipient as a carrier, and the content of the active agent in the matrix is ​​in the range of 35-60% by weight based on the total weight of the matrix.

[0054] Drug-containing particles, particularly granules produced by wet granulation, can be used to produce a fast-dispersing 3DP matrix containing an active agent, with a hardness in the range of 1-3 kP and a dispersion time in water of 15 seconds or less, or 10 seconds or less. Suitable drug-containing particles contain 65-70% by weight of active agent, 21.5-23% by weight of diluent / disintegrant, such as microcrystalline cellulose, 3-5% by weight of a super-disintegrant, such as ecoscarmellose, 1-4.5% by weight of a surfactant, such as sodium lauryl sulfate, and 2.5-5% by weight of a binder, such as hydroxypropyl cellulose. Drug-containing particles produced by high shear wet granulation had a DVO.5 of about 60-100 microns.

[0055] In some embodiments, the matrix disperses (disintegrates) rapidly in small amounts of aqueous fluid. Some embodiments of the present invention include those in which the matrix disperses in about 30 seconds or less, about 20 seconds or less, about 15 seconds or less, about 10 seconds or less, or about 5 seconds or less when placed in a small amount of aqueous fluid. In some embodiments, the disintegration time is within the USP <701> is identified according to

[0056] 1. Activator Active agents may include any compound that has or is believed to have a beneficial effect on the health of a human or animal, including, but not limited to, pharmaceutical compounds that may be available by prescription only or without a prescription, supplements such as vitamins, minerals, infant formulas, and complete meals, energy drinks, and / or bars.

[0057] The active agent-containing particles have an average, mean, or median particle size within the range of about 50 to about 400 microns, about 50 to about 300 microns, about 50 to about 250 microns, about 60 to about 250 microns, about 60 to about 100 microns, or about 75 to about 250 microns. Yes.

[0058] In some embodiments, the active agent unmodified particles have an average, mean, or median particle size within the range of about 1 to about 90 microns, about 1 to about 75 microns, about 1 to about 50 microns, about 1 to about 30 microns, about 1 to about 15 microns, about 1 to about 10 microns, about 2 to about 14 microns, about 10 to about 80 microns, about 20 to about 70 microns, about 20 to about 60 microns, or about 30 to about 50 microns. In some embodiments, the OXC native particles have a particle size distribution of less than about 100 microns, less than about 90 microns, less than about 75 microns, less than about 50 microns, and / or less than about 75 microns, less than about 50 microns, less than about 40 microns, less than about 30 microns, less than about 20 microns, less than about 10 microns, less than about 5 microns, between about 1 and about 40 microns, between about 1 and about 30 microns, between about 1 and about 20 microns, between about 5 and about 15 microns, and / or less than about 30 microns, less than about 20 microns, less than about 10 microns, less than about 5 microns, less than about 1 micron. All combinations of these DV10, DV50, and DV90 values ​​and ranges are contemplated. The native particle size distribution and / or effective particle size distribution may be unimodal, bimodal, or multimodal. The active agent may be present as a mixture of two or more different native drug powders, each having its own native particle size distribution and / or manufacturing method. The drug-containing particles may be present as a mixture of two or more different powders, each having its own effective particle size distribution and / or manufacturing method. In some embodiments, the active agent comprises a milled first form and a micronized second form. The amount of the first form may be in the range of 0-25%, 10-15%, or 13-15% by weight, respectively, and the amount of the second form may be in the range of 100-75%, 90-85%, or 97-85% by weight.

[0059] Some embodiments of the invention include those in which the active agent-containing matrix comprises about 150 to about 1200 mg, about 150 mg, about 300 mg, about 450 mg, about 600 mg, about 750 mg, about 900 mg, about 1050 mg, or about 1200 mg of active agent.

[0060] 2. Excipients Excipients in health care formulations are generally defined as inert compounds added to solid formulations to act as vehicles and / or fillers in the formulation. Most pharma- ceutically acceptable excipients, both small molecules and polymers, can be used that can loosely accommodate the pharma- ceutically active ingredient in a porous structure (a matrix of bound particles) susceptible to rapid dispersion in the presence of a suitable aqueous fluid, such as saliva. The three-dimensional Some of these excipients suitable for use in the printing process are listed in the Handbook of Pharmaceutical They are listed in Excipients (Eds. A. Wade and P.J. Weller, Second edition, American Pharmaceutical Association, The Pharmaceutical Press, London, 1994).

[0061] Unless expressly stated otherwise, excipients, as used herein, may refer to compounds used or commonly referred to as fillers, diluents, bulking agents, etc., with the understanding that these names are not exhaustive and that they are not exclusive, e.g., a particular excipient may act as both a diluent and a filler. Unless expressly stated otherwise, excipients, as used herein, may refer to compounds used or commonly referred to as binders, coatings, disintegrants, sweeteners, flavoring agents, and lubricants.

[0062] Excipients may affect the stability, organoleptic properties, and / or physical properties of a given formulation. The weight ratio of an active agent to excipients in a given formulation may be varied to modify the therapeutic, physical, appearance, and / or organoleptic properties of a given formulation.

[0063] Types of excipients suitable for solid dosage forms include binders, disintegrants, dispersants, fillers, sweeteners, lubricants, flavoring agents, surfactants, hygroscopic agents, preservatives, and diluents. Conventional pharmaceutical excipients may be used, but they do not necessarily function in exactly the same way as they do in conventional pharmaceutical processes.

[0064] Adding at least one excipient into the formulation of active agent can affect the properties of the formulation, such as hardness, dispersion time, friability, dosage form size, and drug dosage in the dosage form.If the content of excipient in the drug-containing particle is too low, the function of dosage may be sacrificed.If the content of excipient in the drug-containing particle is too high, the dosage form size may need to be increased in order to contain the appropriate dosage of active agent therein.

[0065] 3. Binder Binders are a subclass of excipients that can be added to solid formulations. Solid formulations of active agents often have binders, which are compounds that promote the association between particles in solid formulations, such as the same or other active agents, and other ingredients, including other excipients such as sweeteners, flavorings, and preservatives. Suitable binders that can be used in the formulations of the present invention include, but are not limited to, gelatin, cellulose, derivatives of cellulose, polyvinylpyrrolidone, starch, and sugars. Exemplary binders include, but are not limited to, spray-dried lactose, fructose, sucrose, dextrose, sorbitol, mannitol, and xylitol.

[0066] One or more binders may be included in the printed matrix. The binder may be included in the bulk powder, the drug-containing particles, and / or in the printing fluid ejected through the print head. The binder is selected independently for each presence. Adhesion of the particles to and / or by the binder occurs when the binder contacts the printing fluid from the print head or when the binder is present (i.e., soluble) in the printing fluid. The binder is preferably water-soluble, aqueous-fluid soluble, partially water-soluble, or partially aqueous-fluid soluble. In some embodiments, the printing fluid includes 0-10% by weight of the binder. In some embodiments, the bulk powder includes >0-50%, 10%-45%, 20%-45%, 25-40%, 25-35% by weight of the binder. In some embodiments, the drug-containing particles comprise >0-10%, 2-10%, 2-7%, or 2-5% by weight of binder. In some embodiments, the printed matrix comprises >0-50%, 10%-45%, 20%-45%, or 25-40% by weight of binder. In some embodiments, the binder is , not present in the printing fluid, or not present in the bulk material.

[0067] Suitable binders include water-soluble synthetic polymers, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropyl-methylcellulose, sorbitol, mannitol, xylitol, lactitol, erythritol, pregelatinized starch, modified starch, arabinogalactan. Preferred binders include polyvinylpyrrolidone (povidone), mannitol, hydroxypropylcellulose, or combinations thereof.

[0068] 4. Surfactants The solid oral dosage formulation of the present invention may include one or more surfactants. Surfactants may be included in the formulation of the present invention to increase the disintegration rate of the solid oral dosage form when contacted with the inside of the recipient's mouth and / or when further ingested by the patient. The solid oral dosage formulation of the present invention may include at least one surfactant, which may be an amphoteric surfactant, a zwitterionic surfactant, a cationic surfactant, a non-ionic surfactant, and optionally at least one other surfactant, which may be an amphoteric surfactant, a zwitterionic surfactant, a cationic surfactant, a non-ionic surfactant, or a combination thereof. Such surfactants should be physically and chemically compatible with the essential ingredients described herein or should not otherwise unduly impair the stability, aesthetics, or performance of the product.

[0069] Some embodiments of the present invention include solid formulations, wherein a) at least one surfactant is present in an amount ranging from 0.5 to 7.0% by weight, based on the final weight of the dosage form; b) at least one sweetener is present in an amount ranging from 0.01 to 2.0% by weight, based on the final weight of the dosage form; c) at least one binder is present in an amount ranging from 5 to 15% by weight, based on the final weight of the dosage form; d) at least one disintegrant is present in an amount ranging from 10 to 30% by weight, based on the final weight of the dosage form; and / or e) at least one lubricant is present in an amount ranging from 0 to 2% by weight, based on the final weight of the dosage form.

[0070] Surfactants suitable for use in the solid oral dosage formulations of the present disclosure include one or more surfactants and / or co-surfactants of Formula I,

[0071] [ka]

[0072] In the formula, R 1 and R 2are independently selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; n is an integer from 2 to 5, inclusive; R 3 is C5~C 12 is alkyl, R 4 is C3~C 10 alkyl, and the terminal nitrogen is R 5 may be further substituted with, in which case R 5 is selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate, and an optional counter ion may be associated with the compound, which, if present, may be selected from the group consisting of chloride, bromide, iodide, and 4-methylbenzenesulfonate.

[0073] In particular, suitable surfactants or co-surfactants may include any one or more of Surfactants 1-7 described herein.

[0074] The concentration of the surfactant system in a solid oral dosage formulation should be sufficient to provide a formulation that is easy to manufacture, store, and administer to a human or animal patient.

[0075] In a printed solid formulation, the inclusion of a surfactant in the printing fluid, bulk powder, and active agent-containing particles helps ensure rapid dispersion of the 3DP dosage form in a minimal amount of water. The surfactant may act to enhance wetting of the particles. The surfactant only needs to be present in an amount sufficient to enhance dispersion compared to another 3DP dosage form formulated without the surfactant. However, if the surfactant is present in too much amount, it may negatively affect the texture, performance, and / or physical properties of the dosage form. The surfactant may be included in the active agent-containing granules, bulk powder, and / or printing fluid. In some embodiments, the total amount of surfactant present in the drug-containing particles is within the range of about 0-5%, >0-5%, 1-4.2%, 2-3% by weight based on the weight of the drug-containing particles. In some embodiments, the amount of surfactant present in the bulk powder, excluding the active agent-containing particles, is within the range of about 0-5%, >0-5%, 1-4.2%, 2-3% by weight based on the weight of the bulk powder.

[0076] 5. Disintegrants Disintegrants are a type of excipient that are added to solid formulations to adjust the physical properties of the formulation. Many solid formulations contain at least one binder and at least one disintegrant, which are important ingredients for controlling the hardness, friability, and dispersion time of the matrix. In general, the higher the amount of binder, the higher the hardness, lower the friability, and slower the dispersion time of the solid formulation. On the other hand, increasing the amount of disintegrant will result in lower hardness, increased friability, and faster dispersion time. Therefore, solid formulations can contain a balanced amount of binder and disintegrant.

[0077] Suitable disintegrants include microcrystalline cellulose (MCC), croscarmellose (crosslinked carboxymethylcellulose), powdered cellulose, or combinations thereof. Preferred disintegrants include microcrystalline cellulose, such as AVICEL® PH 101, a combination of two grades of microcrystalline cellulose, and croscarmellose. Suitable grades of AVICEL® are summarized in the table below. The dosage form may contain one or a combination of the grades specified. All such embodiments containing a single grade or a combination of grades are envisioned.

[0078] In the case of solid formulations formed by printing a matrix of ingredients, the formulation may include one or more disintegrants that may be included in the printed matrix. The disintegrants may be present in the bulk powder and / or in the drug-containing particles. The disintegrants are selected independently for each presence. In some embodiments, the bulk powder includes 3-20 wt%, 3-15 wt%, 4-12 wt%, or 10-16 wt% disintegrant. In some embodiments, the drug-containing particles include 15-35 wt%, 20-30 wt%, or 25-30 wt% disintegrant.

[0079] 6. Sweeteners Sweeteners are a type of excipient that can be added to a formulation to change its sensory properties. One or more sweeteners can be included in a solid formulation, for example, a solid formulation that includes a printed matrix. The sweetener can be present in the bulk powder, the drug-containing particles, and / or in a fluid, such as a printing fluid, used to form the solid. By printing a solid matrix, In the formulation thus formed, better taste masking is observed when at least one sweetener is present at least in the printing fluid. The sweetener may be selected independently depending on the presence of each. The printing fluid, the drug-containing particles, and / or the bulk powder may have at least one sweetener in common. In some embodiments, the bulk powder comprises >0-5 wt%, or >0-2 wt%, or >0-1.5 wt% of a sweetener. In some embodiments, the printing fluid comprises >0-5 wt%, >0-4 wt%, >0-3 wt%, >0-2 wt%, 0.1-5 wt%, 0.1-4 wt%, 0.1-3 wt%, 0.1-2 wt%, 0.5-3 wt%, or 1-3 wt% of a sweetener. In some embodiments, the drug-containing particles comprise 0-5 wt% of a sweetener.

[0080] Suitable sweeteners may be selected from the group consisting of glycyrrhizic acid derivatives, such as magnasweet (monoammonium glycyrrhizinate), sucralose, and combinations thereof. A preferred sweetener in the printing fluid is sucralose. The sweetener is present in at least the printing fluid, but may also be present in the bulk powder.

[0081] 7. Flavoring agents Flavoring agents are a type of excipient that can be added to a formulation to change its sensory properties. One or more flavoring agents can be included in the matrix. Flavoring agents can be present in the bulk powder, the drug-containing particles, and / or the printing fluid. Flavoring agents are preferably water-soluble, aqueous fluid soluble, partially water-soluble, or partially aqueous fluid soluble. If present in the bulk powder, the flavoring agent is preferably present in a form that is applied to the carrier powder prior to the manufacture of the bulk powder. Suitable carrier powders can include starch, modified starch, cellulose, and other powders that can absorb, adsorb, accommodate, or encapsulate the flavoring agent. In some embodiments, the printing fluid includes 0-5 wt%, 0.01-1.0 wt%, or 0.05-0.5 wt% flavoring agent. In some embodiments, the bulk powder includes 0.1-10 wt%, or 1-10 wt%, 2-8 wt%, 3-7 wt% flavoring agent-containing carrier powder. In some embodiments, the printed matrix comprises 0-10% by weight, 0.01 10% by weight of flavoring. In some embodiments, the flavoring is not present in the printing fluid or is not present in the bulk material. Suitable flavorings include peppermint, spearmint, mint, vanilla, orange, lemon, citrus, lime, grape, cherry, strawberry, chocolate, coffee, or combinations thereof.

[0082] III. Methods of Manufacturing Solid Dosage Formulations Tablets containing at least one active agent may be manufactured by any means known in the art. Exemplary methods include direct compression, dry granulation, and wet granulation. The steps in these processes may include any of the following steps performed in a sequence known in the art. These steps include mixing solid raw ingredients with each other or with a small enough amount of liquid to form a final dry formulation. Another commonly used step is granulation, which is a process commonly used to produce particles of uniform and ideally similar size and shape. Depending on the formulation, the granulation step may be performed on the individual components of the final formulation, on a mixture of the components of the final formulation, or on the final formulation.

[0083] If the manufacturing process for a solid formulation involves first producing a liquid, gel, or paste, or if the formulation involves mixing at least one solid ingredient with at least one liquid ingredient, the process of forming a tablet will likely involve drying the formulation. The appropriate drying process will depend on the ingredients of the formulation and the desired final product. Suitable drying processes include vacuum drying, spray drying, fluidized bed drying, freeze drying, pan or tray drying, and any method known in the art. Conventional means known in the art for producing tablets include compressing a mixture containing the desired final composition of the formulation. Machines commonly used to form tablets include stamping and rolling. Tablets are generally sized and shaped to facilitate easy oral administration to the intended patient population.

[0084] Yet another exemplary method for formulating a tablet involves three-dimensional printing of a matrix containing at least one active agent. A summary of some variations of this process will be found in the Examples section.

[0085] IV. Liquid Formulations Liquid formulations may include formulations made with the active ingredient in a liquid, the active ingredient dissolved in a suitable solvent, such as water, the active ingredient formulated into a gel or paste, or the active ingredient in the form of particles suspended in a liquid, paste, lotion, or ointment.

[0086] V. Emulsions Containing at Least One Active Agent Some compounds that are useful in health care applications are not particularly soluble in solvents suitable for use in or on a human or animal patient, and furthermore, some compounds that are useful in cleansing formulations for particular use in health care applications may not be very soluble in solvents that would otherwise be useful for such applications. Some such compounds can be formulated into emulsions suitable for use in health care applications.

[0087] The emulsion containing the active agent may be used as or contained in a topical agent intended for direct application onto a patient, including, but not limited to, salves, ointments, suppositories, lotions, drops, and scrubs. The active agent may be formulated into an emulsion that may be administered to a patient orally, anally, or by inhalation. The active agent may be formulated into an emulsion suitable for intravenous or parenteral administration.

[0088] The active agent may also be encapsulated, and once encapsulated, the active agent may be formulated into a liquid suspension for topical application and / or internal administration to a patient.

[0089] A useful emulsion formulation must be physically stable. USP <729> The droplet size limits set forth in are generally applied throughout the specified storage period. All real emulsions are thermodynamically unstable and may undergo various processes over time that tend to increase the droplet size. These include direct droplet coalescence, where two droplets collide to form a new single droplet, and agglomeration, where droplets stick together to form a larger mass. Agglomeration may in some cases be a precursor to further coalescence into larger droplets. These processes may result in large aggregates that rise to the surface of the container, a phenomenon known as "creaming", and ultimately result in free oil visible on the emulsion surface, known as "cracking".

[0090] Emulsion formulations must also be chemically stable. Drug substances can degrade; for example, lipophilic drugs will partition into the oil phase, which may provide some protection, but hydrolytic degradation may still occur at the oil-water interface. Possible chemical degradation in parenteral fat emulsions includes oxidation of unsaturated fatty acid residues present in triglycerides and lecithin, and hydrolysis of phospholipids resulting in the formation of free fatty acids (FFAs) and lysophospholipids. Such degradation can decrease the pH, which can promote further degradation. Therefore, pH should be controlled during manufacturing, and parenteral emulsion formulations may contain buffers to obtain further control. Any decrease in pH over the specified storage period may be an indication of chemical degradation.

[0091] In some aspects of the invention, emulsion formulations are manufactured and characterized to identify formulations and processes that can incorporate active agents into emulsions for intradermal administration and also maintain stability during the shelf life of the formulation.

[0092] In one embodiment, the composition has an intensity-weighted mean particle size, as determined by dynamic light scattering (DLS), of about 50 nm to 1000 nm, 5 In another embodiment, the average droplet size is maintained at less than 500 nm at room temperature for a period of at least 1 month, 3 months, 6 months, 9 months, 12 months, 2 years, or 3 years.

[0093] In another embodiment, the average droplet size is maintained below 500 nm at 5° C. for a period of at least 1 month, 3 months, 6 months, 9 months, 12 months, 2 years, or 3 years.

[0094] Some embodiments provide emulsions suitable for parenteral administration. Some embodiments provide emulsions suitable for intravenous administration. Some embodiments provide emulsions suitable for subdermal and / or subcutaneous administration.

[0095] 1. Activator Some stable pharmaceutical compositions containing at least one active agent also contain a surfactant or mixture of surfactants, co-surfactants, oils along with an aqueous phase. The compositions are in the form of oil-in-water emulsions that remain stable over long periods of time and are suitable for dilution and intravenous administration.

[0096] 2. Non-aqueous phase The active agent may be present in the oil phase, which comprises emulsifier, co-emulsifier, and oil. The oil phase is then combined with the aqueous phase, which comprises water and tonicity agent, as described below, to produce a stable emulsion. In some formulations, the oil phase has an oil containing at least one active agent in a ratio of about 13:1. This ratio can produce a more stable emulsion when mixed with the aqueous phase, compared to emulsions in which the oil phase is less than about 12:1 or 11:1, and / or has an oil:active agent ratio of about 15:1, 20:1, or more than 11:1, and / or more than about 15:1, 20:1, or more than 30:1.

[0097] The oil (hydrophobic) phase comprises an oil. Triglycerides are exemplary oils for use in the compositions described herein. In certain embodiments, the oil is or comprises a vegetable oil. By "vegetable oil" is meant oil obtained from the seeds or nuts of plants. Vegetable oils are typically "long chain triglycerides" (LCTs) formed by three fatty acids (usually 14-22 carbons in length with varying numbers and positions of unsaturated bonds depending on the oil source) forming ester bonds with three hydroxyl groups on glycerol. In certain embodiments, highly refined grades (also referred to as "ultra-purified") of vegetable oils are used to ensure the safety and stability of the oil-in-water emulsion. In certain embodiments, hydrogenated vegetable oils produced by controlled hydrogenation of vegetable oils may be used. Exemplary vegetable oils include, but are not limited to, almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, olive oil, peanut oil, palm oil, palm kernel oil, rapeseed oil, safflower oil, soybean oil, sunflower oil, and sesame oil. Hydrogenated and / or partially hydrogenated forms of these oils may also be used. In a specific embodiment, the oil is or includes safflower oil, sesame oil, corn oil, olive oil, and / or soybean oil. In a more specific embodiment, the oil is or includes safflower oil and / or soybean oil. The oil may be present in the emulsion. , is present at about 9% w / w, but this may vary from about 5% to 12% w / w, or from 9% to 10% w / w.

[0098] 3.Aqueous phase The aqueous phase of the active agent emulsion may be a mixture of water and a tonicity agent, including but not limited to sucrose, mannitol, glycerin, or dextrose, or mixtures thereof. The aqueous phase also includes a pH adjusting agent. In some examples of the present invention, sodium oleate may be used to adjust the pH of the emulsion to about 6-9, depending on the emulsion formulation desired. The aqueous phase is prepared by mixing water with sodium oleate as a tonicity agent and pH adjusting agent. Other pH adjusting agents that may be used include but are not limited to sodium hydroxide, potassium hydroxide, magnesium hydroxide, Tris, sodium carbonate, and sodium linoleate. The pH adjusting agent used is effective to adjust the pH of the emulsion to a preferred pH of about 6-9, 7-8, or about 6, 7, 8, or 9. The aqueous phase can be easily formed by mixing at room temperature.

[0099] The aqueous phase may also contain a buffer to promote the stability of the emulsion formulation. Drug substances may degrade, for example lipophilic drugs may partition into the oil phase, which may provide some protection, but hydrolytic degradation may still occur at the oil-water interface. Possible chemical degradation in parenteral fat emulsions includes oxidation of unsaturated fatty acid residues present in triglycerides and lecithin, and hydrolysis of phospholipids resulting in the formation of free fatty acids (FFAs) and lysophospholipids. Such degradation reduces the pH, which may promote further degradation. Therefore, pH should be controlled during manufacturing, and emulsion formulations may contain a buffer to obtain further control. Any decrease in pH over the specified storage period may be an indication of chemical degradation.

[0100] 4. Buffers Suitable buffers are known to those skilled in the art and include, but are not limited to, phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer, or borate buffer. Tris buffer is used in some exemplary formulations to adjust the pH of the emulsion to about 8-9. In certain embodiments, the buffer is selected from the group of phosphate buffered saline (PBS), modified PBS (PBS-mod), and citrate buffer. In some embodiments, the aqueous phase comprises a buffer that, when mixed with the oil phase, results in a substantially isotonic oil-in-water emulsion.

[0101] Buffers useful in the compositions described herein include, but are not limited to, phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer, or borate buffer. In certain embodiments, the buffer is selected from the group of phosphate buffered saline (PBS), modified PBS (PBS-mod), and citrate buffer. In some embodiments, the aqueous phase comprises a buffer that, when mixed with the oil phase, results in a substantially isotonic oil-in-water emulsion. In some embodiments, when the aqueous phase contains a buffer, the aqueous phase does not comprise a tonicity agent. Also, when a buffer is added to the aqueous phase, a pH adjusting agent may not be added to the aqueous phase. It is understood that the buffer may be added to the aqueous phase or the buffer may be added to the emulsion.

[0102] 5.Isotonic agent In some embodiments, the aqueous phase contains a tonicity agent, such as sucrose. The tonicity agent is added to the aqueous phase to have about 0%-30%, 0%-25%, or about 20% (w / w) of the tonicity agent. Surprisingly, about 20% (w / w) of sucrose in the aqueous phase is not significantly different from the isotonicity agent. It has been found that compositions containing cellulose produce emulsions that are particularly stable as determined by freeze-thaw testing. Thus, preferred embodiments include emulsions in which the aqueous phase contains a tonicity agent that confers greater chemical and / or physical stability compared to emulsions in which the aqueous phase contains less than about 10%, 15%, or 20% (w / w) of the tonicity agent, or more than about 30%, 40%, or 50% (w / w) of the tonicity agent.

[0103] In some formulations, the aqueous phase further comprises dexamethasone sodium phosphate (also referred to as "dexamethasone phosphate"). Dexamethasone sodium phosphate is a corticosteroid that is highly soluble in water. The daily dose of dexamethasone sodium phosphate is within the range of about 0.5 mg to 20 mg, more preferably about 14 mg to 18 mg, or 16 mg, depending on the severity of the disease or disorder. Thus, an active agent emulsion further comprising dexamethasone may contain dexamethasone sodium phosphate in the aqueous phase. Thus, the aqueous phase of an emulsion suitable for intravenous administration may contain about 0.5 mg to 20 mg, about 14 mg to 18 mg, or 16 mg of dexamethasone sodium phosphate.

[0104] In some formulations, a solution of dexamethasone sodium phosphate may be mixed into the fine emulsion, followed by sterile filtration to produce an emulsion containing dexamethasone sodium phosphate in its aqueous phase.

[0105] Several methods for preparing emulsions suitable for intravenous administration.

[0106] Such formulations may be manufactured following conventional sterile techniques used for the manufacture of active agents intended for subdermal administration.

[0107] 6. Preservatives Preservatives that may be added to any of the liquid formulations disclosed herein include bactericides, fungicides, and antioxidants.

[0108] 7. Surfactants The emulsion may include at least one surfactant, which may be an amphoteric surfactant, a zwitterionic surfactant, a cationic surfactant, a nonionic surfactant, and, optionally, at least one other surfactant, which may be an amphoteric surfactant, a zwitterionic surfactant, a cationic surfactant, a nonionic surfactant, or a combination thereof.

[0109] Surfactants suitable for use in the conditioner formulations of the present disclosure include one or more surfactants and / or co-surfactants of formula I,

[0110] [ka]

[0111] In the formula, R 1 and R 2 are independently selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; n is an integer from 2 to 5, inclusive; R 3 teeth, C5~C 12 is alkyl, R 4 is C3~C 10 alkyl, and the terminal nitrogen is R 5 may be further substituted with, in which case R 5 is selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate, and an optional counter ion may be associated with the compound, which, if present, may be selected from the group consisting of chloride, bromide, iodide, and 4-methylbenzenesulfonate.

[0112] In particular, suitable surfactants or co-surfactants may include any one or more of Surfactants 1-7 described herein.

[0113] VI. Method for Producing Emulsions In one such exemplary emulsion formulation, the aqueous phase is combined with the oil phase under high speed homogenization to produce a coarse emulsion. As described in Examples 1, 2, 3, 4, 5, and 6, the combined aqueous and oil phases are homogenized using an IKA Ultra-Turrax T25 dispersing device at a speed of 20000 rpm for 1 minute. The speed used in this first homogenization step can vary, for example, from 2000 rpm to 25000 rpm, or from 15000 rpm to 22000 rpm. The duration of the homogenization step can also vary, for example, from 0.5 minutes to 1 hour, or from 1 minute to 45 minutes. This coarse emulsion is then homogenized into a fine emulsion by a high pressure homogenizer, which can be a microfluidizer. The interaction chamber and cooling coil part of the microfluidizer are cooled with water, such as by an ice bath. The temperature of the ice bath may be about 0°-10°C or about 2-6°C. The temperature of the emulsion discharged from the high pressure homogenization may be about 0°-60°C, 15°-60°C, 20°-40°C, or about 25°C. The microfluidizer is first primed with water, and then the crude emulsion is introduced. The homogenizer discharge is initially flushed to wastewater to remove the priming water and the mixture of priming water and emulsion, and then collected in a clean container when the flow has a consistent appearance. The cycle of the high pressure homogenizer may be repeated to sufficiently reduce the oil droplet size. The pressure used for homogenization may vary. The pressure may be 40 5000-30000 psi. The number of passes through the microfluidizer may be varied to achieve the desired droplet size. The number of passes can be about 2-20, 2-15, 4-15, 4-12, or 7-8.

[0114] The pharmaceutical formulation may then be passed through a filter system at room temperature and / or autoclaved to achieve sterilization. The filter used to achieve sterilization may have a nominal pore size of 0.2 μm, as selected by one skilled in the art. The filter material used may vary. In one embodiment, the filter is nylon. In another embodiment, the filter is a Posidyne® filter (a covalently charge-modified nylon 6,6 membrane that exhibits a net positive zeta potential in aqueous solutions). For large-scale production, the above method may need to be modified. One skilled in the art may also combine these materials in different orders and with different processing equipment to achieve the desired end result.

[0115] In one embodiment of the present disclosure, homogenization may be performed in repeated cycles with intermediate cooling of the homogenized product to a temperature of less than about 25° C. to obtain an emulsion with an oil particle / droplet size of less than 2 microns (μm).

[0116] The final emulsion comprises an oil portion (oil phase) dispersed in an aqueous portion (aqueous phase). The ratio of ingredients in the oil phase to the active agent is an important property of the emulsion, which can affect the stability of the formulation prepared for injection. As described herein, the oil phase is a phase that contains the active agent. , oils, and emulsifiers, examples of which are provided herein.

[0117] In some formulations, the final active agent emulsion contains 0.7% w / w active agent, but may be within the range of about 0.2%-1.5%, 0.4%-1.0%, or 0.6%-0.7% w / w. Emulsions containing about 130 mg of active agent have been produced, but formulations containing about 100 mg-1000 mg, 100 mg-500 mg, 250 mg-750 mg, or 100-200 mg of active agent may be produced in accordance with the present disclosure.

[0118] In one embodiment, the ratio of oil:active agent (wt%:wt%) in the oil phase is within the range of about 11:1 to 15:1, 12:1 to 14:1, 13:1 to 13.5:1, 13:1 to 14:1, or 12:1 to 15:1. In another embodiment, the ratio of oil:active agent is about 11:1, 11.5:1, 12:1, 12.5:1, 13:1, 13.5:1, 14:1, 14.5:1, or 15:1.

[0119] The ratio of emulsifier to active agent may also vary. For example, the ratio of emulsifier:active agent (wt%:wt%) in the oil portion is within the range of about 15:1 to 30:1, 20:1 to 25:1, 18:1 to 22:1, or 10:1 to 30:1. In one embodiment, the ratio of emulsifier:active agent (wt%:wt%) is about 15:1, 18:1, 19:1, 20:1, 21:1, 22:1, or 23:1.

[0120] The ratio of ingredients in the oil phase can alternatively be expressed as (emulsifier plus oil):active agent (wt%:wt%). Ratios contemplated in this disclosure can be within the range of about 20:1 to 40:1, 25:1 to 35:1, 30:1 to 35:1, or 33:1 to 37:1, or can be, for example, about 30:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, or 40:1.

[0121] VII. Preparations for Intravenous Infusion Intravenous emulsions often have very small droplet sizes to allow them to circulate through the bloodstream without causing capillary blockage or embolism. Such size limits are set forth below in the USP <729> USP33-NF28 General Chapter <729> A representative example is the International Standard for Globule Size Distribution in Lipid Injectable Emulsions, which sets the following overall limits: (1) the mean droplet size is not to exceed 500 nm or 0.5 μm, and (2) the population of large fat droplets, expressed as the volume-weighted fraction of fat > 5 μm (OFAT5), is not to exceed 0.05%, regardless of the final lipid concentration.

[0122] Some aspects of the invention relate to formulations suitable for health care applications, which comprise an active agent in the form of a pharma- ceutically acceptable base or acid salt, solubilized in a mixture of alcohol and at least one surfactant, and in some formulations, the surfactant may comprise Macrogol 15 hydroxystearate and / or the surfactant of the invention disclosed herein, in a weight ratio of surfactant / alcohol ranging from 25 / 75 to 80 / 20, preferably 73 / 27 to 77 / 23.0012. In some embodiments, the active agent may be solubilized in a mixture of ethanol and a surfactant comprising a mixture of polyethoxylated mono- and diesters of 12-hydroxystearic acid as described hereinafter.

[0123] 1. Solvent A suitable solvent for a liquid formulation is any liquid that is recognized as safe and effective for ingestion, administration, or injection into or onto a patient, either human or animal. It is understood in the art that some solvents, when present in small amounts in the formulation, are suitable for use in the formulations of the invention, regardless of unknown or known toxicity when administered to a patient in high concentrations. It is understood that commonly used solvents include those liquids designated as Generally Regarded as Safe (GRAS) by the U.S. Food and Drug Administration. Some suitable solvents include, but are not limited to, water, alcohol, and glycerol.

[0124] 2. Surfactants In some formulations, the surfactant comprises about 35% to about 55% by weight of monoesters and diesters, and about 30% to about 40% of polyethylene glycol H(OCHCH),OH, and additional surfactants. It comprises, as the main components, 35% to 55% by weight of monoesters and diesters, and 30% to 40% of polyethylene glycol H(OCHCH),OH, and other compounds as desired to make up the remainder 100%. It comprises, by weight, 10% to 20% of monoesters, 25% to 35% of diesters, and 30% to 40% of polyethylene glycol H(OCHCH)-OH, and other compounds in amounts to make up the remainder 100%.

[0125] The surfactant / ethanol ratio is in the range of 73 / 27 to 77 / 23, and the concentration of the compound of formula (I) is in the range of 5 to 25 mg / ml.

[0126] The pharmaceutical formulation may be intended to be diluted to form an irrigation solution.

[0127] VIII. Method for producing healthcare perfusion fluid Some embodiments of the present invention include a method of formulating at least one active agent for use in a formulation that can be administered to a human or animal by perfusion. Such a method can include at least some of the following steps: heating at least one surfactant until it is liquid, and / or adding a surfactant that is liquid at room temperature or that is suitably soluble in a suitable solvent at room temperature; adding at least one alcohol; optionally cooling the mixture to ambient temperature and adding at least one active agent to the formulation; and sterilizing the formulation, for example by filtration.

[0128] Some aspects of the invention also relate to a perfusion solution comprising at least one active agent in the form of a pharma- ceutically acceptable base or acid salt, obtained by diluting 1 volume of a pharmaceutical solution into 20-500 volumes of an isotonic solution. In some formulations, the active agent is present in a concentration in the range of 0.01-1.2 mg / ml, a surfactant in a concentration in the range of 0.48-37 mg / ml, and ethanol in a concentration in the range of 0.35-35 mg / ml, are diluted in the isotonic solution. The perfusion solution is intended to be administered to humans or animals.

[0129] Some embodiments of the present invention relate to a method for producing a perfusion solution that consists essentially of diluting one volume of a pharmaceutical solution into 20-500 volumes of an isotonic solution.

[0130] In some aspects of the invention, the pharmaceutical formulation may contain at least one other additive conventionally used in liquid pharmaceutical formulations, which may be, for example, an antioxidant, a preservative, a buffer, etc. According to another embodiment of the invention, the pharmaceutical formulation contains only a surfactant, an alcohol, and an active agent.

[0131] IX. Surfactants Healthcare formulations may include one or more surfactants selected from one or more types of surfactants collectively referred to as a surfactant system, which function as emulsifiers in O / W emulsions.

[0132] Surfactants suitable for use in the inventive health care formulations of the present disclosure include one or more surfactants and / or co-surfactants of formula I,

[0133] [ka]

[0134] In the formula, R 1 and R 2are independently selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; n is an integer from 2 to 5, inclusive; R 3 is C5~C 12 is alkyl, R 4 is C3~C 10 alkyl, and the terminal nitrogen is R 5 may be further substituted with, in which case R 5 is selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate, and an optional counter ion may be present associated with the compound, which, if present, may be selected from the group consisting of chloride, bromide, iodide, and 4-methylbenzenesulfonate.

[0135] One specific compound provided by the present disclosure (Surfactant 1) has the following formula:

[0136] [ka]

[0137] The compound is 6-((2-butyloctyl)oxy)-N,N,N-trimethyl-6-oxohexan-1-aminium iodide having the formula:

[0138] A second specific compound provided by the present disclosure (Surfactant 2) has the following formula:

[0139] [ka]

[0140] The compound is 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexan-1-aminium 4-methylbenzenesulfonate having the formula:

[0141] A third specific compound provided by the present disclosure (Surfactant 3) has the following formula:

[0142] [ka]

[0143] The compound is 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium chloride having the formula:

[0144] A fourth specific compound (Surfactant 4) provided by the present disclosure has the following formula:

[0145] [ka]

[0146] The compound is 4-((6-((2-butyloctyl)oxy)-6-oxohexyl)dimethylammonio)butane-1-sulfonate having the formula:

[0147] A fifth specific compound (surfactant 5) provided by the present disclosure has the following formula:

[0148] [ka]

[0149] The compound is 2-butyloctyl 6-(dimethylamino)hexanoate N-oxide.

[0150] A sixth specific compound (surfactant 6) provided by the present disclosure has the following formula:

[0151] [ka]

[0152] The compound is 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium chloride having the formula:

[0153] A seventh specific compound (surfactant 7) provided by the present disclosure has the following formula:

[0154] [ka]

[0155] The compound is 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium 4-methylbenzenesulfonate having the formula:

[0156] These surfactants can be synthesized by various methods. One such method involves ring-opening a lactam to obtain an amino acid with an N-terminus and a C-terminus. The N-terminus can be reacted with one or more alkylating agents and / or acids to obtain a quaternary ammonium salt. Alternatively, the N-terminus can be reacted with an oxidizing agent to obtain an amine N-oxide. The C-terminus can be reacted with an alcohol in the presence of an acid to obtain an ester.

[0157] The amino acids may be natural or synthetic, or may be derived from a ring-opening reaction of a lactam such as caprolactam. The ring-opening reaction may be either acid or alkali catalyzed, an example of an acid catalyzed reaction is shown in Scheme 1 below.

[0158] [ka]

[0159] Amino acids have as few as one or as many as 12 carbons between the N-terminus and C-terminus. The alkyl chain may be branched or straight. The alkyl chain may be interrupted by nitrogen, oxygen, or sulfur. The alkyl chain may be further substituted with one or more substituents selected from the group consisting of hydroxyl, amino, amido, sulfonyl, sulfonate, carboxyl, and carboxylate. The N-terminal nitrogen may be acylated or alkylated with one or more alkyl groups. For example, the amino acid may be 6-(dimethylamino)hexanoic acid or 6-aminohexanoic acid.

[0160] Surfactant 1 can be synthesized as shown below in Scheme 2. As shown, the N-terminus of 2-butyloctyl 6-(dimethylamino)hexanoate is alkylated with methyl iodide in the presence of sodium carbonate.

[0161] [ka]

[0162] Surfactant 2 can be synthesized as shown in Scheme 3 below. As shown, the C-terminus of 6-(dimethylamino)hexanoic acid is treated with 2-butyloctanol in the presence of p-toluenesulfonic acid (PTSA) in toluene to give the corresponding ester, 2-butyloctyl 6-(dimethylamino)hexanoate, as the 4-methylbenzenesulfonate salt.

[0163] [ka]

[0164] Surfactant 3 can be synthesized as shown in Scheme 4 below. As shown, 2-butyloctyl 6-(dimethylamino)hexanoate is treated with one equivalent of hydrochloric acid to give 2-butyloctyl 6-(dimethylamino)hexanoate as the chloride salt.

[0165] [ka]

[0166] Surfactant 4 can be synthesized as shown below in Scheme 5. As shown, the N-terminus of 2-butyloctyl 6-(dimethylamino)hexanoate is treated with 1,4-butanesultone in refluxing ethyl acetate to give the desired sulfonate.

[0167] [ka]

[0168] Surfactant 5 can be synthesized as shown in Scheme 6 below. As shown, the N-terminus of 2-butyloctyl 6-(dimethylamino)hexanoate is treated with hydrogen peroxide in water to give the desired N-oxide.

[0169] [ka]

[0170] Surfactant 6 can be synthesized as shown below in Scheme 7. As shown, the N-terminus of 2-butyloctyl 6-aminohexanoate is treated with one equivalent of hydrochloric acid to give the corresponding chloride salt.

[0171] [ka]

[0172] Surfactant 7 can be synthesized as shown in Scheme 8 below. As shown, 6-Aminohexanoic acid is treated with 2-butyloctanol and p-toluenesulfonic acid (PTSA) in benzene to give the corresponding 4-methylbenzenesulfonate salt.

[0173] [ka]

[0174] The compounds of the present disclosure exhibit surface active properties. These properties can be measured and expressed by various methods. One way that surfactants can be expressed is by the critical micelle concentration (CMC) of the molecule. CMC can be defined as the concentration of surfactant that forms micelles, and at a higher concentration, any additional surfactant is incorporated into the micelle.

[0175] As the surfactant concentration increases, the surface tension decreases. When the surface is completely covered with surfactant molecules, micelles start to form. This point represents the CMC, or minimum surface tension. Adding more surfactant does not further affect the surface tension. The CMC can therefore be measured by observing the change in surface tension as a function of surfactant concentration. One such method for measuring this value is the Wilhelmy plate method. A Wilhelmy plate is usually a thin iridium-platinum plate attached to a balance by wires and positioned perpendicular to the air-liquid interface. The balance is used to measure the force exerted on the plate by wetting. This value is then used to calculate the surface tension (γ) according to equation 1: Equation 1: γ = F / l cosθ where l is equal to the wetted perimeter (2w+2d, where w and d are the thickness and width of the plate, respectively), and for cosθ, the contact angle between the liquid and the plate is assumed to be 0 in the absence of existing literature values.

[0176] Another parameter used to evaluate the performance of surfactants is the dynamic surface tension. Dynamic surface tension is the value of the surface tension over time for a particular surface or interface. For liquids to which surfactants have been added, this may differ from the equilibrium value. Immediately after the surface is created, the surface tension is equal to that of the pure liquid. As mentioned above, surfactants are surface tension reducers, so the surface tension decreases until it reaches an equilibrium value. The time required to reach equilibrium depends on the diffusion and adsorption rates of the surfactant.

[0177] One way to measure dynamic surface tension is with a maximum bubble pressure tensiometer. This device measures the maximum internal pressure of a bubble formed in a liquid by a capillary. The measured value corresponds to the surface tension at a certain surface time, which is the time from the start of bubble formation to the maximum pressure. The dependence of surface tension on surface time can be measured by varying the rate at which the bubbles are generated.

[0178] Surface active compounds can also be evaluated by their wetting ability on solid substrates, measured by contact angle. When a liquid drop contacts a solid surface in a third medium, such as air, a three-phase line is formed between the liquid, the gas, and the solid. The angle between the surface and the unit vector of surface tension, which plays a role in the three-phase line and is tangent to the drop, is expressed as the contact angle. Contact angle (also called wetting angle) Wetting angle (also known as contact angle) is a measure of the wettability of a solid by a liquid. In the case of complete wetting, the liquid spreads completely over the solid and the contact angle is 0°. Wetting properties are typically measured at concentrations between 1 and 10 x CMC for any compound, although measurements of wetting properties may be measured at higher or lower concentrations as it is not a concentration dependent property.

[0179] In one method, an optical contact angle goniometer can be used to measure contact angles. This instrument uses a digital camera and software to determine the contact angle by analyzing the contour shape of a stationary drop of liquid on a surface.

[0180] Potential applications for the surface active compounds of the present disclosure include formulations for use as shampoos, hair conditioners, detergents, spot free rinse solutions, floor and carpet cleaners, cleaners for graffiti removal, wetting agents for crop protection, adjuvants for crop protection, and wetting agents for aerosol spray coatings.

[0181] Those skilled in the art will appreciate that small differences between compounds can lead to significantly different surfactant properties, and therefore different compounds may be used with different substrates in different applications.

[0182] The following non-limiting embodiments are provided to illustrate the different properties of different surfactants. Table 1 below provides the association between surfactant abbreviations and their corresponding chemical structures.

[0183] [Table 1-1]

[0184] [Table 1-2]

[0185] Each of the seven compounds is effective as a surface active agent and is useful as a wetting or foaming agent, dispersing agent, emulsifying agent, and detergent, among other applications.

[0186] Surfactant 1, Surfactant 2, Surfactant 3, Surfactant 6, and Surfactant 7 are cationic. These surfactants are useful for both the applications mentioned above and for some further special applications, such as personal hair care products, as surface treatments, and can also be used to create water repellent surfaces.

[0187] Surfactant 4 is zwitterionic. These surfactants are useful as co-surfactants in all of the applications mentioned above.

[0188] Surfactant 5 is non-ionic and can be used in shampoos, detergents, hard surface cleaners, and a variety of other surface cleaning formulations.

[0189] Working Example Nuclear magnetic resonance (NMR) spectroscopy was performed on a Bruker 500 MHz spectrometer. The critical micelle concentration (CMC) was determined by the Wilhelmy plate method using a tensiometer (DCAT 11, DataPhysics Instruments GmbH) equipped with a Pt-Ir plate at 23 °C. The dynamic surface tension was determined using a maximum bubble pressure tensiometer (Kruss BP100, Kruss GmbH) at 23 °C. The contact angle was determined using an optical contact angle goniometer (OCA 15 Pro, DataPhysics GmbH) equipped with a digital camera.

[0190] Example 1a: Synthesis of 6-((2-butyloctyl)oxy)-N,N,N-trimethyl-6-oxohexan-1-aminium iodide 2-Butyloctyl 6-(dimethylamino)hexanoate (2.04 mmol, 700 mg) was dissolved in acetonitrile (10 mL). Sodium carbonate (2.44 mmol, 259 mg) was added and the mixture was stirred at room temperature for 10 min. Methyl iodide (6.12 mmol, 0.38 mL) was added and the mixture was heated to 40° C. for 24 h and then cooled to room temperature. The mixture was filtered and the solvent removed in vacuo to give 6-((2-butyloctyl)oxy)-N,N,N-trimethyl-6-oxohexan-1-aminium iodide as a yellow solid in 90% yield. 1 H NMR(500MHz,DMSO) δ3.93(d,J=5.7Hz,2H),3.29-3.22(m,2H),3.04(s,9H),2.34(t,J=7.4Hz,2H),1.73-1.53(m,5H),1.33-1.25(m,18H),0.88-0.85(m,6H).

[0191] Example 1b: Identifying the Critical Micelle Concentration (CMC) The critical micelle concentration (CMC) of 6-((2-butyloctyl)oxy)-N,N,N-trimethyl-6-oxohexan-1-aminium iodide from Example 1a was tested. From the plot of results shown in FIG. 1, it is clear that at concentrations as high as 10 mg / mL, the CMC value cannot be clearly identified and the surface tension asymptotically approaches a value of about 27 mN / m. FIG. 1 is a plot of these results, showing surface tension versus concentration. From the plot of results, it is clear that the surface tension at the CMC is about 27 mN / m or less.

[0192] Example 2a: Synthesis of 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexan-1-aminium 4-methylbenzenesulfonate 6-(Dimethylamino)hexanoic acid was treated with 2-butyloctan-1-ol and p-toluenesulfonic acid in benzene for 12 hours at 120° C. 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexan-1-aminium 4-methylbenzenesulfonate was isolated as a white waxy solid and recrystallized from acetone in 49% yield. 1 H NMR(500MHz,DMSO) δ7.48(dd,J=8.4,0.6Hz,2H),7.12(dd,J=8.4,0.6Hz,1H),3.93(d,J=5.7Hz,2H),3.02-3.00(m,2H),2.76 (d,J=5.0Hz,6H),2.37-2.25(m,6H),1.59-1.53(m,5H),1.25-1.29(m,18H),0.87(td,J=6.8,2.7Hz,6H).

[0193] Example 2b: Identifying the Critical Micelle Concentration (CMC) The critical micelle concentration (CMC) of 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexan-1-aminium 4-methylbenzenesulfonate from Example 2a was tested. From the surface tension with concentration in water, the CMC was determined to be about 0.97 mmol. The minimum surface tension plateau value achievable with this surfactant is about 27 mN / m, i.e., 27 mN / m±3 mN / m. FIG. 2A is a plot of these results, showing surface tension versus concentration. From the resulting plot, the surface tension at the CMC is about 30 mN / m or less.

[0194] Example 2c: Determination of dynamic surface tension The dynamic surface tension of 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexan-1-aminium 4-methylbenzenesulfonate from Example 2a was determined with a maximum bubble pressure tensiometer, which measures the change in surface tension of a freshly created air-water interface over time. Figure 2B shows a plot of surface tension versus time, which shows that in the time interval of 10-100 ms, the surface tension drops rapidly from about 46 mN / m to about 30 mN / m. In the time interval of 100-8000 ms, the surface tension drops slowly from 30 mN / m to about 27 mN / m, asymptotically approaching the saturation value of surface tension at the CMC.

[0195] Example 2d: Identification of wetting properties In addition to surface tension and surface kinetics, the wetting properties of 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium 4-methylbenzenesulfonate from Example 2a were tested on various surfaces. For example, hydrophobic substrates such as polyethylene-HD exhibit a surface wetting with a contact angle of 24.3°. On oleophobic and hydrophobic substrates such as Teflon, the measured contact angle was 48.2°, much lower than the contact angle of water of 119° (Table 2).

[0196] [Table 2]

[0197] Example 3a: Synthesis of 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium chloride 2-Butyloctyl 6-(dimethylamino)hexanoate was treated with one equivalent of hydrochloric acid to give 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexan-1-aminium chloride.

[0198] Example 3b: Identifying the Critical Micelle Concentration (CMC) The critical micelle concentration (CMC) of 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium chloride from Example 3a was tested. From the surface tension varying with concentration in water, the CMC was determined to be about 27.47 mmol. The minimum surface tension achievable with this surfactant is about 29 mN / m, i.e., 29 mN / m±3 mN / m. FIG. 3 is a plot of these results, showing surface tension versus concentration. From the resulting plot, it can be seen that at concentrations as high as 27.4 mmol, the CMC value cannot be clearly determined, and the surface tension asymptotically approaches a value of about 29 mN / m. Example 4a: Synthesis of 4-((6-((2-butyloctyl)oxy)-6-oxohexyl)dimethylammonio)butane-1-sulfonate 2-Butyloctyl 6-(dimethylamino)hexanoate (2.04 mmol, 700 mg) was dissolved in ethyl acetate (30 mL). 1,4-butanesultone (3.06 mmol, 0.31 mL) was added. The mixture was heated to reflux for 12 h, followed by evaporation of the solvent. The resulting white waxy solid was washed with acetone to give 4-((6-((2-butyloctyl)oxy)-6-oxohexyl)dimethylammonio)butane-1-sulfonate in 89% yield. 1H NMR(500MHz,DMSO) δ3.93(d,J=5.7Hz,2H),3.30-3.28(m,4H),2.97(s,3H),2.49-2.43(m,2H),2. 34(t,J=7.4Hz,2H),1.96-1.76(m,9H),1.27-1.25(m,18H),0.88-0.85(m,6H).

[0199] Example 4b: Identifying the Critical Micelle Concentration (CMC) The critical micelle concentration (CMC) of 4-((6-((2-butyloctyl)oxy)-6-oxohexyl)dimethylammonio)butane-1-sulfonate from Example 4a was tested. From the surface tension with concentration in water, the CMC was determined to be about 0.54 mmol. The minimum surface tension plateau value achievable with this surfactant is about 32 mN / m, i.e., 32 mN / m±3 mN / m. FIG. 4A is a plot of these results, showing surface tension versus concentration. From the resulting plot, the surface tension at the CMC is about 32 mN / m or less.

[0200] Example 4c: Determination of dynamic surface tension The dynamic surface tension of 4-((6-((2-butyloctyl)oxy)-6-oxohexyl)dimethylammonio)butane-1-sulfonate from Example 4a was determined with a maximum bubble pressure tensiometer, which measures the change in surface tension of a freshly created air-water interface over time. Figure 4B shows a plot of surface tension versus time, which shows that in the time interval from 10 to 100 ms, the surface tension drops rapidly from about 66 mN / m to about 36 mN / m. In the time interval from 100 to 8000 ms, the surface tension drops slowly from 36 mN / m to about 32 mN / m, asymptotically approaching the saturation value of surface tension at the CMC.

[0201] Example 4d: Identification of wetting properties In addition to surface tension and surface kinetics, the wetting properties of 4-((6-((2-butyloctyl)oxy)-6-oxohexyl)dimethylammonio)butane-1-sulfonate from Example 4a were tested on various surfaces. For example, a hydrophobic substrate such as polyethylene-HD exhibits surface wetting with a contact angle of 44.4°. On oleophobic and hydrophobic substrates such as Teflon, the measured contact angle was 62.2°, much lower than the contact angle of water of 119° (Table 3).

[0202] [Table 3]

[0203] Example 5a: Synthesis of 2-butyloctyl 6-(dimethylamino)hexanoate N-oxide 2-Butyloctyl 6-(dimethylamino)hexanoate was treated with hydrogen peroxide in water at 70° C. for 24 hours to give 2-butyloctyl 6-(dimethylamino)hexanoate N-oxide as an oil in 90% yield. 1 H NMR(500MHz,DMSO) δ3.93(d,J=5.7Hz,2H),3.30-3.28(m,4H),2.97(s,3H),2.49-2.43(m,2H),2. 34(t,J=7.4Hz,2H),1.96-1.76(m,9H),1.27-1.25(m,18H),0.88-0.85(m,6H).

[0204] Example 5b: Identifying the Critical Micelle Concentration (CMC) The critical micelle concentration (CMC) of 2-butyloctyl 6-(dimethylamino)hexanoate N-oxide from Example 5a was tested. From the surface tension with concentration in water, the CMC was determined to be about 0.29 mmol. The plateau value of the minimum surface tension achievable with this surfactant is about 28 mN / m, i.e., 28 mN / m±3 mN / m. Figure 5A is a plot of these results, showing surface tension versus concentration. From the resulting plot, the surface tension at the CMC is about 28 mN / m or less.

[0205] Example 5c: Determination of dynamic surface tension The dynamic surface tension of 2-butyloctyl 6-(dimethylamino)hexanoate N-oxide from Example 5a was determined with a maximum bubble pressure tensiometer, which measures the change in surface tension of a freshly created air-water interface over time. Figure 5B shows a plot of surface tension versus time, which shows that in the time interval of 10-1000 ms, the surface tension drops rapidly from about 60 mN / m to about 30 mN / m. In the time interval of 1000-8000 ms, the surface tension drops slowly from 30 mN / m to about 28 mN / m, asymptotically approaching the saturation value of surface tension at the CMC.

[0206] Example 5d: Identification of wetting properties In addition to surface tension and surface kinetics, the wetting properties of 2-butyloctyl 6-(dimethylamino)hexanoate N-oxide from Example 5a were tested on various surfaces. For example, hydrophobic substrates such as polyethylene-HD exhibit a surface wetting with a contact angle of 31.6°. On oleophobic and hydrophobic substrates such as Teflon, the measured contact angle was 41.5°, much lower than the contact angle of water, 119° (Table 4).

[0207] [Table 4]

[0208] Example 6a: Synthesis of 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium chloride 2-Butyloctyl 6-(dimethylamino)hexanoate was treated with one equivalent of hydrochloric acid to give 6-((2-butyloctyl)oxy)-6-oxohexan-1-aminium chloride.

[0209] Example 6b: Identifying the Critical Micelle Concentration (CMC) The critical micelle concentration (CMC) of 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium chloride from Example 6a was tested. From the surface tension with concentration in water, the CMC was determined to be about 0.15 mmol. The plateau value of the minimum surface tension achievable with this surfactant is about 27 mN / m, i.e., 27 mN / m±3 mN / m. FIG. 6A is a plot of these results, showing surface tension versus concentration. From the resulting plot, the surface tension at the CMC is about 30 mN / m or less.

[0210] Example 6c: Determination of dynamic surface tension The dynamic surface tension of 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium chloride from Example 6a was determined with a maximum bubble pressure tensiometer, which measures the change in surface tension of a freshly created air-water interface over time. Figure 6B shows a plot of surface tension versus time, showing a slow decrease in surface tension from about 69 mN / m to about 29 mN / m over the time interval from 10 to 8000 ms, approaching a saturation value of surface tension at the CMC, with a slight plateau of about 49 mN / m at a surface lapse time of 1000 ms.

[0211] Example 6d: Identification of wetting properties In addition to surface tension and surface kinetics, the wetting properties of 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium chloride from Example 6a were tested on various surfaces. For example, hydrophobic substrates such as polyethylene-HD exhibit a surface wetting with a contact angle of 25.8°. On oleophobic and hydrophobic substrates such as Teflon, the measured contact angle was 48.7°, much lower than the contact angle of water, 119° (Table 5).

[0212] [Table 5]

[0213] Example 7a: Synthesis of 6-((2-butyloctyl)oxy)-6-oxohexan-1-aminium 4-methylbenzenesulfonate 6-Aminohexanoic acid (38.11 mmol, 5 g) was dissolved in benzene (50 mL) in a 100 mL round bottom flask equipped with a Dean Stark trap. p-Toluenesulfonic acid monohydrate (38.11 mmol, 7.25 g) and 2-butyloctanol (38.11 mmol, 7.1 g, 8.5 mL) were added and the mixture was heated to reflux for 1 week until no more water separated in the Dean Stark trap. The solvent was removed in vacuo and the product was crystallized from acetone at -20°C to remove residual unreacted alcohol. The resulting white waxy solid was filtered to give 2-butyloctyl)oxy)-6-oxohexan-1-aminium 4-methylbenzenesulfonate in 82% yield. 1 H NMR(500MHz,DMSO) δ7.49(d,J=8.0Hz,2H),7.12(dd,J=8.4,0.6Hz,2H),3.93(d,J=5.7Hz,2H),2.79-2.73 (m,2H),2.31-2.28(m,5H),1.55-1.50(m,5H),1.31-1.25(m,18H),0.88-0.85(m,6H).

[0214] Example 7b: Identifying the Critical Micelle Concentration (CMC) The critical micelle concentration (CMC) of 6-((2-butyloctyl)oxy)-6-oxohexan-1-aminium 4-methylbenzenesulfonate from Example 7a was tested. From the surface tension change with concentration in water, the CMC was determined to be about 2.12 mmol. The minimum surface tension plateau value achievable with this surfactant is about 27 mN / m, i.e., 27 mN / m±3 mN / m. Figure 7A is a plot of these results, showing surface tension versus surface tension. From the resulting plot, the surface tension at the CMC is about 30 mN / m or less, and at concentrations of about 1.0 mmol or greater the surface tension is about 28.5 mN / m or less.

[0215] Example 7c: Determination of dynamic surface tension The dynamic surface tension of 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium 4-methylbenzenesulfonate from Example 7a was determined with a maximum bubble pressure tensiometer, which measures the change in surface tension of a freshly created air-water interface over time. Figure 7B shows a plot of surface tension versus time, which shows that in the time interval from 10 to 100 ms, the surface tension drops rapidly from about 46 mN / m to about 30 mN / m. In the time interval from 100 to 8000 ms, the surface tension drops slowly from 30 mN / m to about 27 mN / m, asymptotically approaching the saturation value of surface tension at the CMC.

[0216] Example 7d: Identification of wetting properties In addition to surface tension and surface kinetics, the wetting properties of 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium 4-methylbenzenesulfonate from Example 7a were tested on various surfaces. For example, hydrophobic substrates such as polyethylene-HD exhibit a surface wetting with a contact angle of 14.6°. On oleophobic and hydrophobic substrates such as Teflon, the measured contact angle was 49.4°, much lower than the contact angle of water, 119° (Table 6).

[0217] [Table 6]

[0218] Example 8: Formulation of solid oral dosage forms In this example, a formulation for use in a solid oral dosage form is described. The formulation contains at least one active agent, such as a drug, and is useful for obtaining a solid oral dosage form that is easy to manufacture, store, and administer to and by a human or animal patient. The components of the formulation are shown in Table 5 below. In addition, the formulation may contain other compounds, such as sweeteners, flavoring compounds, etc.

[0219] The following process is used to prepare drug-containing particles of the active agent oxcarbazepine: The following raw ingredients are used in the amounts listed:

[0220] [Table 7]

[0221] [Table 8]

[0222] Exemplary drug-containing particles are manufactured by wet granulation at scales from 4 L to 200 L. The following equipment and operating parameters were used:

[0223] [Table 9]

[0224] All powders were weighed and charged into the bowl of the high shear granulator. The dry powders were mixed at low speed for 1 minute. With the mixer and chopper on low speed, a total of 1164 g water (25.5% of the final wet weight) was added at a rate of 95 mL / min. The granulator was stopped once during the process to scrape the bowl. The wet granulation was dried in a fluid bed dryer at 50° C. to an LOD of 1-2%. The dried material was milled through a series of screens using a Comil at 3000 rpm to reduce the particle size to the range acceptable for 3DP. Milling began through a 050G screen and ended through a 018R screen. Most batches had a pass through an intermediate screen (016C) to prevent clogging.

[0225] Example 9: Fabrication of 3D printed orodispersible dosage forms The following process is used to manufacture taste masked three-dimensional printed orodispersible dosage forms comprising a matrix containing bound drug-containing particles of oxcarbazepine. The raw ingredients for the printing fluid and bulk powder are used in the amounts listed below.

[0226] [Table 10]

[0227] Any three-dimensional printer device known or mentioned herein may be used. A bulk powder incremental layer of a predetermined thickness is spread over the previous powder layer, and printing fluid is applied to the incremental layer as droplets according to a predetermined saturation level, line spacing, and printing fluid flow rate to bond the particles in the layer. This two-step process is completed when the matrix has a targeted amount of printed incremental layers. The following printing parameters are used on a Z-Corp lab-scale printer (Model Z310): The printer is equipped with an HP-10 print head, which is run at a scan speed with a drop size of 30-60 um and line spacing of 450-600 um. A solid print pattern is used throughout the dosage form. A specified combination of printing fluid formulation and bulk powder formulation is used. A layer thickness of 0.008-0.011 inches is used. A saturation of 90-116% is used. Printing fluid IA is used. Many different combinations of drug-containing particles numbered 1-12 and bulk powder formulations IIA-II-T are used. 4. Separate the printed matrix from the loose, unprinted powder and dry the printed matrix by any suitable means. The final 3D orodispersible dosage form is produced by reducing the amount of solvent and water to the desired level. The dosage form is then characterized for dispersion time, surface texture (smoothness), and hardness.

[0228] Example 10: Fabrication of taste-masked 3D-printed orodispersible dosage forms with different structures in incremental layers Following the 3DP process described above, it can be carried out in several different ways to produce dosage forms with different structures with varying hardness and composition of incremental layers. The following process provides dosage forms with higher hardness on the top and bottom surfaces compared to the hardness of the interior of the dosage form. This strategy helps to create sections of different mechanical properties in the dosage form. Using this approach, dosage forms are designed with upper and lower layers having different compositions than the middle layer. This design allows the dosage form to have stronger upper and lower layers, which can increase hardness and reduce friability, as well as a large central portion with lower hardness, which allows the dosage form to disperse quickly.

[0229] Method A: This process varies the amount of binder deposited in different incremental layers or in different predefined areas within the same incremental layer. These dosage forms are manufactured according to the process of Example 6, except that the amount of binder deposited on the powder by the printing fluid is varied between incremental powder layers by using printing fluids with different binder concentrations.

[0230] Method B: These dosage forms are manufactured according to the process defined above, except that the amount of printing fluid deposited on the powder is varied between incremental powder layers, with the upper and lower incremental layers receiving a larger amount of printing fluid and the central incremental layer receiving a smaller amount of printing fluid.

[0231] Method C: In this process, the printing pattern used for the upper and lower incremental layers of the dosage form is a solid pattern.

[0232] Method D: In this process, the printing pattern used for the upper and lower incremental layers of the dosage form is a solid pattern. The printing pattern for the incremental layer in the middle portion is an annular / hollow high saturation printing. This is called "saturation printing," and the area surrounded by the ring is not printed.

[0233] Method E: In this process, the printing pattern used for the upper and lower incremental layers of the dosage form is a solid pattern. The printing pattern for the central incremental layer is a combination of an inner grayscale printing surrounded by an outer highly saturated printing.

[0234] Example 11: Manufacturing of emulsions for intravenous injection To prepare the aprepitant emulsion, an oil phase was first prepared by combining 750 mg of the active agent aprepitant and 15.0 g of egg lecithin (LIPOID E 80) with 12.0 ml of ethanol. The mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solution, 10.0 g of soybean oil was added. Heating at 60° C. and stirring at 200 rpm were continued for another 15 minutes. An aqueous phase was prepared by dissolving 5.60 g of sucrose and 0.500 g of the surfactant of the present invention in 70.0 ml of water for injection. The mixture was stirred at 300 rpm at room temperature for 30 minutes. The aqueous phase was then added to the oil phase, followed by stirring at a speed of 20,000 rpm for 1 minute. For high speed homogenization (Ultra-Turrax® IKA T25) A coarse emulsion was produced by subjecting the mixture to a 500 mL / min centrifuge at 100° C. for 1 hour. The coarse emulsion was then passed 8 times through an ice-cooled high pressure microfluidizer (Microfluidizer® M-11OL, F12Y interaction chamber) at a pressure of 18,000 psi. The resulting fine emulsion was sterilized by passing it through a 0.2 μm nylon syringe filter (Coming). The emulsion composition is detailed in Table 11 below. Intensity-weighted particle size analyzed by dynamic light scattering (Malvern® Zetasizer Nano) using non-negative least squares (NNLS) fitting gave a peak 1 diameter of 99 nm. Intensity-weighted mean particle size determined using cumulant fitting gave a Z-mean diameter of 87 nm. Zeta potential was measured by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS) to be −43 mV. The pH of the injectable emulsion was 8.74. This aprepitant-containing emulsion can be injected as is or diluted with 5% dextrose or 0.9% saline for infusion.

[0235] [Table 11]

[0236] Example 12: Manufacturing of emulsions for intravenous injection To prepare an emulsion of the active agent aprepitant, an oil phase was first prepared by combining 450 mg of aprepitant and 9.00 g of egg lecithin (LIPOID E 80) with 4.0 ml of ethanol. The mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solution, 6.00 g of soybean oil was added. Heating at 60° C. and stirring at 200 rpm were continued for another 15 minutes. An aqueous phase was prepared by dissolving 3.36 g of sucrose and 0.300 g of surfactant in 42.0 ml of water for injection. The mixture was stirred at 300 rpm at room temperature for 30 minutes. The aqueous phase was then added to the oil phase, followed by high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute, A coarse emulsion was produced. This coarse emulsion was then passed through an ice-cold high pressure microfluidizer (Microfluidizer® M-IIOL, F12Y interaction chamber) eight times at a pressure of 18000 psi. The resulting fine emulsion was sterilized by passing through a 0.2 μm nylon syringe filter (Coming). Details of the emulsion composition are shown in Table 10. NNLS fitting was performed via analysis by dynamic light scattering (Malvern® Zetasizer Nano). The intensity-weighted particle size analyzed using 100% ethanolamine gave a peak 1 diameter of 127 nm. The intensity-weighted mean particle size determined using cumulant fitting gave a Z-mean diameter of 101 nm. The zeta potential was measured by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS) to be -47 mV. The pH of the injectable emulsion was 8.77. The aprepitant-containing emulsion can be injected as is or diluted with 5% dextrose or 0.9% saline.

[0237] [Table 12]

[0238] Aspects Aspect 1 is a solid health care formulation comprising at least one surfactant of the following formula:

[0239] [ka]

[0240] In the formula, R 1 and R 2 are independently selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; n is an integer from 2 to 5, inclusive; R 3 is C5~C 12 is alkyl, R 4 is C3~C 10 alkyl, and the terminal nitrogen is R 5 may be further substituted with, in which case R 5 is selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; an optional counterion may be associated with the compound, which, if present, may be selected from the group consisting of chloride, bromide, iodide, and 4-methylbenzenesulfonate; a surfactant; and at least one active ingredient.

[0241] Aspect 2 is the formulation of Aspect 1, wherein the at least one active agent is selected from the group consisting of drugs, proteins, cells, tissues, vitamins, supplements, and minerals.

[0242] Aspect 3 is the formulation of aspect 1 or aspect 2, further comprising one or more excipients.

[0243] Aspect 4 is the formulation of Aspect 3, wherein the one or more excipients are selected from the group consisting of binders, fillers, disintegrants, salts, colorants, sweeteners, and flavoring agents.

[0244] Aspect 5 is the formulation of any one of Aspects 1-4, configured as a powder, tablet, or capsule.

[0245] Aspect 6 is a method for preparing a surfactant having the following formula:

[0246] [ka]

[0247] 6. The formulation according to any one of Aspects 1 to 5, wherein the compound is 6-((2-butyloctyl)oxy)-N,N,N-trimethyl-6-oxohexane-1-aminium iodide having the formula:

[0248] Aspect 7 is a method for preparing a surfactant having the following formula:

[0249] [ka]

[0250] 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium 4-methylbenzenesulfonate having the formula:

[0251] In an eighth aspect, the surfactant has the following formula:

[0252] [ka]

[0253] 6. The formulation according to any one of Aspects 1 to 5, wherein the compound is 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium chloride having the formula:

[0254] Aspect 9 is directed to a surfactant having the following formula:

[0255] [ka]

[0256] 6. The formulation of any one of Aspects 1-5, wherein the compound is 4-((6-((2-butyloctyl)oxy)-6-oxohexyl)dimethylammonio)butane-1-sulfonate having the formula:

[0257] Aspect 10 is directed to a surfactant having the following formula:

[0258] [ka]

[0259] 6. The formulation according to any one of Aspects 1 to 5, wherein the compound is 2-butyloctyl 6-(dimethylamino)hexanoate N-oxide having the formula:

[0260] In an eleventh aspect, the surfactant has the following formula:

[0261] [ka]

[0262] 6. The formulation according to any one of Aspects 1 to 5, wherein the compound is 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium chloride having the formula:

[0263] Aspect 12 is directed to a surfactant having the following formula:

[0264] [ka]

[0265] 6. The formulation according to any one of Aspects 1 to 5, wherein the compound is 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium 4-methylbenzenesulfonate having the formula:

[0266] Aspect 13 is a liquid formulation for healthcare, comprising at least one surfactant of the following formula:

[0267] [ka]

[0268] In the formula, R 1 and R 2 are independently selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; n is an integer from 2 to 5, inclusive; R 3 is C5~C 12 is alkyl, R 4 is C3~C 10 alkyl, and the terminal nitrogen is R 5 may be further substituted with, in which case R 5 is selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; an optional counterion may be associated with the compound, which, if present, may be selected from the group consisting of chloride, bromide, iodide, and 4-methylbenzenesulfonate; a surfactant, at least one active ingredient, and an aqueous component.

[0269] Aspect 14 is the formulation of aspect 13, further comprising a buffering agent.

[0270] Aspect 15 is a formulation according to any of aspect 13 or aspect 14, further comprising one or more of a sweetening agent, a flavoring agent, a coloring agent, and / or a preservative.

[0271] Aspect 16 is the formulation of any one of aspects 13-15, further comprising a viscosity enhancing agent.

[0272] Aspect 17 is the formulation of aspect 16, which is one of a drop, a paste, a salve, a lotion, or an ointment.

[0273] An eighteenth aspect is a method for preparing a surfactant comprising the steps of:

[0274] [ka]

[0275] 18. The formulation according to any one of Aspects 13 to 17, wherein the compound is 6-((2-butyloctyl)oxy)-N,N,N-trimethyl-6-oxohexane-1-aminium iodide having the formula:

[0276] Aspect 19 is directed to a surfactant having the following formula:

[0277] [ka]

[0278] 18. The formulation according to any one of Aspects 13 to 17, wherein the compound is 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium 4-methylbenzenesulfonate having the formula:

[0279] Aspect 20 is directed to a surfactant having the following formula:

[0280] [ka]

[0281] 18. The formulation according to any one of Aspects 13 to 17, wherein the compound is 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium chloride having the formula:

[0282] Aspect 21 is directed to a surfactant having the following formula:

[0283] [ka]

[0284] 18. The formulation of any one of Aspects 13-17, wherein the compound is 4-((6-((2-butyloctyl)oxy)-6-oxohexyl)dimethylammonio)butane-1-sulfonate having the formula:

[0285] Aspect 22 is directed to a surfactant having the following formula:

[0286] [ka]

[0287] 18. The formulation according to any one of Aspects 13 to 17, wherein the compound is 2-butyloctyl 6-(dimethylamino)hexanoate N-oxide having the formula:

[0288] Aspect 23 is directed to a surfactant having the following formula:

[0289] [ka]

[0290] 18. The formulation according to any one of Aspects 13 to 17, wherein the compound is 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium chloride having the formula:

[0291] Aspect 24 is directed to a surfactant having the following formula:

[0292] [ka]

[0293] 18. The formulation according to any one of Aspects 13 to 17, wherein the compound is 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium 4-methylbenzenesulfonate having the formula:

[0294]

[0033] Aspect 25 is an emulsion for health care, comprising at least one surfactant of the following formula:

[0295] [ka]

[0296] In the formula, R 1 and R 2 are independently selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; n is an integer from 2 to 5, inclusive; R 3 is C5~C 12 is alkyl, R 4 is C3~C 10 alkyl, and the terminal nitrogen is R 5 may be further substituted with, in which case R 5 is selected from hydrogen, an oxygen atom, and C1-C6 alkyl, which may be substituted with carboxylate, hydroxyl, sulfonyl, or sulfonate; an optional counterion may be associated with the compound, which, if present, may be selected from the group consisting of chloride, bromide, iodide, and 4-methylbenzenesulfonate; a surfactant; and at least one active ingredient; an aqueous phase; and a non-aqueous phase.

[0297] Example 26 is the emulsion of example 25, further comprising a buffer.

[0298] Aspect 27 is the emulsion of any of aspect 25 or aspect 26, further comprising one or more of a sweetening agent, a flavoring agent, a coloring agent, and / or a preservative.

[0299] Aspect 28 is directed to a surfactant having the following formula:

[0300] [ka]

[0301] 28. The formulation according to any one of Aspects 25 to 27, wherein the compound is 6-((2-butyloctyl)oxy)-N,N,N-trimethyl-6-oxohexane-1-aminium iodide having the formula:

[0302] Aspect 29 is directed to a surfactant having the following formula:

[0303] [ka]

[0304] 28. The formulation according to any one of Aspects 25 to 27, wherein the compound is 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium 4-methylbenzenesulfonate having the formula:

[0305] Aspect 30 is directed to a surfactant having the following formula:

[0306] [ka]

[0307] 28. The formulation of any one of Aspects 25 to 27, wherein the compound is 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium chloride having the formula:

[0308] Aspect 31 is directed to a surfactant having the following formula:

[0309] [ka]

[0310] 28. The formulation of any one of Aspects 25 to 27, wherein the compound is 4-((6-((2-butyloctyl)oxy)-6-oxohexyl)dimethylammonio)butane-1-sulfonate having the formula:

[0311] Aspect 32 is directed to a surfactant having the following formula:

[0312] [ka]

[0313] 28. The formulation of any one of Aspects 25 to 27, wherein the compound is 2-butyloctyl 6-(dimethylamino)hexanoate N-oxide having the formula:

[0314] Aspect 33 is directed to a surfactant having the following formula:

[0315] [ka]

[0316] 28. The formulation of any one of Aspects 25 to 27, wherein the compound is 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium chloride having the formula:

[0317] Aspect 34 is directed to a surfactant having the following formula:

[0318] [ka]

[0319] 28. The formulation according to any one of Aspects 25 to 27, wherein the compound is 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium 4-methylbenzenesulfonate having the formula:

Claims

1. 1. A solid formulation for health care comprising: The formula: 【Chemistry 1】 6-((2-butyloctyl)oxy)-N,N,N-trimethyl-6-oxohexan-1-aminium iodide having the formula The formula: 【Chemistry 2】 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium 4-methylbenzenesulfonate having the formula The formula: 【Chemistry 3】 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium chloride having the formula The formula: 【Chemistry 4】 4-((6-((2-butyloctyl)oxy)-6-oxohexyl)dimethylammonio)butane-1-sulfonate having the formula The formula: 【Chemistry 5】 2-butyloctyl 6-(dimethylamino)hexanoate N-oxide having the formula The formula: 【Chemistry 6】 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium chloride having the formula The formula: 【Chemistry 7】 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium 4-methylbenzenesulfonate having the formula At least one surfactant, comprising at least one of At least one active ingredient, 13. A solid formulation comprising:

2. 2. The formulation of claim 1, wherein the at least one active ingredient is selected from the group consisting of drugs, proteins, cells, tissues, vitamins, supplements, and minerals.

3. 10. The formulation of claim 1, further comprising one or more excipients selected from the group consisting of binders, fillers, disintegrants, colorants, sweeteners, and flavoring agents.

4. The formulation of claim 1 , wherein the formulation is configured as a powder, tablet, or capsule.

5. A liquid formulation for healthcare comprising: The formula: 【Chemistry 8】 6-((2-butyloctyl)oxy)-N,N,N-trimethyl-6-oxohexan-1-aminium iodide having the formula The formula: 【Chemistry 9】 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium 4-methylbenzenesulfonate having the formula The formula: 【Chemistry 10】 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium chloride having the formula The formula: 【Chemistry 11】 4-((6-((2-butyloctyl)oxy)-6-oxohexyl)dimethylammonio)butane-1-sulfonate having the formula The formula: 【Chemistry 12】 2-butyloctyl 6-(dimethylamino)hexanoate N-oxide having the formula The formula: 【Chemistry 13】 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium chloride having the formula The formula: 【Chemistry 14】 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium 4-methylbenzenesulfonate having the formula at least one surfactant, At least one active ingredient, and aqueous component, 13. A liquid formulation comprising:

6. The formulation of claim 5 further comprising a buffering agent.

7. 6. The formulation of claim 5, further comprising one or more of a sweetening agent, a flavoring agent, a coloring agent, and / or a preservative.

8. The formulation of claim 5 further comprising a viscosity enhancing agent.

9. 6. The formulation of claim 5, which is one of a drop, a paste, a salve, a lotion, or an ointment.

10. 1. An emulsion for health care comprising: The formula: 【Chemistry 15】 6-((2-butyloctyl)oxy)-N,N,N-trimethyl-6-oxohexan-1-aminium iodide having the formula The formula: 【Chemistry 16】 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium 4-methylbenzenesulfonate having the formula The formula: 【Chemistry 17】 6-((2-butyloctyl)oxy)-N,N-dimethyl-6-oxohexane-1-aminium chloride having the formula The formula: 【Chemistry 18】 4-((6-((2-butyloctyl)oxy)-6-oxohexyl)dimethylammonio)butane-1-sulfonate having the formula The formula: 【Chemistry 19】 2-butyloctyl 6-(dimethylamino)hexanoate N-oxide having the formula The formula: 【Chemistry 20】 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium chloride having the formula The formula: 【Chemistry 21】 6-((2-butyloctyl)oxy)-6-oxohexane-1-aminium 4-methylbenzenesulfonate having the formula at least one surfactant, At least one active ingredient, an aqueous phase, and non-aqueous phase, , an emulsion.

11. 11. The emulsion of claim 10 further comprising a buffer.

12. 11. The emulsion of claim 10, further comprising one or more of a sweetening agent, a flavoring agent, a coloring agent, and / or a preservative agent.

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