Quick release soft gel formulations

Abstract

A quick release soft gel capsule formulation, the formulation comprising: 15% to 60% by mass of one or more film-forming polymers; 1% to 30% by mass of one or more disintegrants; from 5% to 30% by mass of one or more plasticizers or co-solvents; and 10% to 45% by mass of one or more solvents. A method for making a quick release soft gel capsule, the method comprising: (a) preparing a gel mass composition comprising one or more film-forming polymers, one or more disintegrants, one or more plasticizers or co-solvents, and one or more solvents to form a gel mass; (b) heating the gel mass to form a uniform and degassed gel mass; (c) aging the homogenous and degassed gel mass to form an aged gel mass; (d) casting the aged gel mass into a film or tape using a thermally controlled drum or surface; (e) transferring the homogenized filling solution to a packaging line; (f) encapsulating the homogenized filling solution within a gel block film or tape using a rotating mold encapsulation to form a capsule; (g) drying and finishing the capsule; (h) optionally, coating the capsule with a coating and drying; and (i) post-processing and packaging.

Description

Background Technology

[0001] Soft gel capsules are widely popular and accepted due to their attractive and transparent gelatin shells. Furthermore, soft gel capsules are uniform, stable, and dissolve relatively quickly, allowing for use in liquid formulations and making them easier for most subjects to swallow. Soft gel capsules are typically formed from a capsule shell encapsulating a liquid matrix filler. The matrix filler can be aqueous or oil-based, depending on the solubility of the active pharmaceutical ingredient (API).

[0002] There is a growing interest in developing rapidly dissolving soft gel capsules. The need is for soft gel capsules that dissolve or break easily and release APIs quickly. Summary of the Invention

[0003] One embodiment described herein is a rapid-release soft gel capsule formulation comprising: about 15% to 60% by mass of one or more film-forming polymers; about 1% to 30% by mass of one or more disintegrants; about 5% to 30% by mass of one or more plasticizers or cosolvents; and about 10% to 45% by mass of one or more solvents. Optionally, the formulation further comprises about 1% to 20% by mass of one or more viscosity-modifying polymers. In one aspect, the one or more film-forming polymers include gelatin, gelatin hydrolysate, collagen, carrageenan, or agar. In another aspect, the one or more film-forming polymers include gelatin with a Bloom value of about 50 to about 200 Bloom. In another aspect, the gelatin has a Bloom value of about 150 Bloom. In another aspect, the formulation comprises about 20% to 40% by mass of one or more film-forming polymers. In another aspect, the one or more disintegrants include sodium carboxymethyl starch, croscarmellose sodium, crospovidone, calcium silicate, magnesium aluminum silicate, or croscarmellose. In another aspect, the formulation comprises about 5% to 25% by mass of one or more disintegrants. In another aspect, the formulation comprises about 8% to 12% by mass of one or more disintegrants. In another aspect, the formulation comprises about 15% to 25% by mass of one or more disintegrants. In another aspect, one or more plasticizers or cosolvents comprise solutions of polyols, monosaccharides, disaccharides, oligosaccharides, blended hydrophilic molecules, glycerol, sorbitol, polyethylene glycol, or maltitol. In another aspect, the formulation comprises about 10% to 20% by mass of one or more plasticizers or cosolvents. In another aspect, one or more solvents comprise water. According to claim 1, the formulation further comprises a colorant, an opacifier, a flavoring agent or sweetener, a humectant, a preservative, a coating, a viscosity modifier, a filler or extender, an active pharmaceutical ingredient, a viscosity-modifying polymer, or one or more of a buffer salt and an acid. In another aspect, the formulation comprises about 0.01% to 10% by mass of one or more colorants, which include synthetic dyes, natural dyes, or combinations thereof. In another aspect, the formulation comprises about 0.01% to 1% by mass of one or more light-blocking agents, including titanium dioxide, zinc oxide, calcium carbonate, or combinations thereof. In another aspect, the formulation comprises about 0.01% to 1% by mass of one or more flavoring agents or sweeteners. In another aspect, the formulation comprises about 1% to 20% by mass of one or more viscosity-modifying polymers. In another aspect, the formulation comprises 5% to 15% by mass of one or more viscosity-modifying polymers, or about 10% by mass of one or more viscosity modifiers. In another aspect, the formulation comprises one or more viscosity-modifying polymers comprising hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and dextran. In another aspect, the capsule ruptures within about 3 to 9 minutes at 37°C in a USP device II.On the other hand, the capsule ruptured within approximately 5 minutes in the USP device II at 37°C.

[0004] Another embodiment described herein is a method for manufacturing fast-release soft gel capsules, the method comprising: preparing a gel block composition comprising one or more film-forming polymers, one or more disintegrants, one or more plasticizers or cosolvents, and one or more solvents to form a gel block, and optionally comprising one or more viscosity-modifying polymers; heating the gel block to form a homogeneous and degassed gel block; aging the homogeneous and degassed gel block to form an aged gel block; casting the aged gel block into a film or tape using a heat-controlled roller or surface; transferring a homogenized filling solution to an encapsulation line; encapsulating the homogenized filling solution within the gel block film or tape using a rotary die to form a capsule; drying and trimming the capsule; optionally coating the capsule with a coating agent and drying it; and post-processing and packaging. In one aspect, the gel block comprises: about 15% to 60% by mass of one or more film-forming polymers; about 1% to 30% by mass of one or more disintegrants; about 5% to 30% by mass of one or more plasticizers or cosolvents; and about 10% to 45% by mass of one or more solvents. In another aspect, heating the gel block in step (b) involves maintaining a temperature of approximately 57°C to 80°C under vacuum for approximately 15 to 30 minutes to form a homogeneous and degassed gel block. In another aspect, aging the homogeneous and degassed gel block in step (c) involves maintaining a temperature of approximately 65°C to 70°C for approximately 12 to 48 hours to form an aged gel block. In yet another aspect, the capsule is pre-stressed to increase the rupture rate.

[0005] Another embodiment described herein is a fast-release soft gel capsule manufactured by any of the methods described herein.

[0006] Another embodiment described herein is a pharmaceutical dosage form comprising a fast-release soft gel capsule and a matrix filler comprising one or more active pharmaceutical ingredients, wherein the fast-release soft gel capsule ruptures within approximately 3 to 9 minutes at 37°C in a USP device II, releasing the matrix filler comprising one or more active pharmaceutical ingredients. In one aspect, the dosage form ruptures within approximately 5 minutes at 37°C in a USP device II. In another aspect, the fast-release soft gel capsule comprises: approximately 15% to 60% by mass of one or more film-forming polymers; approximately 1% to 30% by mass of one or more disintegrants; approximately 5% to 30% by mass of one or more plasticizers or co-solvents; and approximately 10% to 45% by mass of one or more solvents.

[0007] Another embodiment described herein is a pharmaceutical dosage form comprising a fast-release soft gel capsule and an encapsulated tablet containing one or more active pharmaceutical ingredients, wherein the fast-release soft capsule ruptures in a USP device II at 37°C within approximately 3 to 9 minutes, releasing the encapsulated tablet containing one or more active pharmaceutical ingredients. In one aspect, the dosage form ruptures in a USP device II at 37°C within approximately 5 minutes. In another aspect, the fast-release soft gel capsule comprises: approximately 15% to 60% by mass of one or more film-forming polymers; approximately 1% to 30% by mass of one or more disintegrants; approximately 5% to 30% by mass of one or more plasticizers or co-solvents; approximately 10% to 45% by mass of one or more solvents; and optionally approximately 1% to 20% by mass of one or more viscosity-modifying polymers.

[0008] Another embodiment described herein is a method for rapidly delivering one or more active pharmaceutical ingredients to a subject in need, comprising administering to the subject a pharmaceutical dosage form comprising a fast-release soft gel capsule and a matrix filler comprising one or more active pharmaceutical ingredients, wherein the fast-release soft gel capsule ruptures within approximately 3 to 9 minutes after administration and releases the matrix filler comprising one or more active pharmaceutical ingredients to the subject. In one aspect, the dosage form ruptures within approximately 5 minutes after administration.

[0009] Another embodiment described herein is a method for treating a subject in need with one or more active pharmaceutical ingredients, comprising administering to the subject a pharmaceutical dosage form comprising a fast-release soft gel capsule and a matrix filler comprising one or more active pharmaceutical ingredients, wherein the fast-release soft gel capsule ruptures within approximately 3 to 9 minutes after administration and releases the matrix filler comprising one or more active pharmaceutical ingredients to the subject. In one aspect, the dosage form ruptures within approximately 5 minutes after administration. Attached Figure Description

[0010] Figure 1 A flowchart of an exemplary method for preparing rapid-release soft gel capsules is shown.

[0011] Figure 2 The results of the fracture test performed on the experimental and control samples at 37°C are shown.

[0012] Figure 3 The results of the fracture test performed on the experimental and control samples at 22°C are shown.

[0013] Figure 4 The results of the fracture test performed on the experimental and control samples at 37°C are shown.

[0014] Figures 5A to 5BThe results of dissolution tests performed on experimental and control samples at 37°C are shown. Figure 5A The results for rapid-release capsules containing acetaminophen are shown compared to the control. Figure 5B The dissolution rates of acetaminophen control capsules are shown in normal dissolution media and in enzyme-containing media. Detailed Implementation

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For example, any nomenclature described herein in conjunction with pharmaceutical formulations, medicinal chemistry, biochemistry, molecular biology, immunology, microbiology, genetics, cell and tissue culture, and protein and nucleic acid chemistry, as well as techniques in these fields, are well known and commonly used in the art. In case of conflict, this disclosure (including definitions) shall prevail. While methods and materials similar to or equivalent to those described herein may be used to practice or test the embodiments and aspects described herein, exemplary methods and materials are described below.

[0016] As used herein, the terms “amino acid,” “nucleotide,” “polynucleotide,” “carrier,” “peptide,” and “protein” have their common meanings as will be understood by a biochemist of ordinary skill in the art. Standard single-letter nucleotides (A, C, G, T, U) and standard single-letter amino acids (A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y) are used herein.

[0017] As used herein, terms such as “comprising,” “including,” “containing,” and “having” mean “comprising.” This disclosure also contemplates other embodiments that “comprise” the embodiments or elements presented herein, “consistently comprise” the embodiments or elements presented herein, and “comprise” the embodiments or elements presented herein, whether or not explicitly stated.

[0018] As used herein, the terms “a,” “an,” “the,” and similar terms used in the context of this disclosure (especially in the context of the claims) should be interpreted to cover both singular and plural forms, unless otherwise stated herein or the context clearly contradicts this. Furthermore, unless otherwise stated, “a,” “an,” or “the” means “one or more.”

[0019] As used in this article, the term "or" can be a conjunction or a disjunctive word.

[0020] As used in this article, the term "and / or" refers to both conjunctive and disjunctive phrases.

[0021] As used in this article, the term “substantially” refers to a large or significant degree, but not entirely.

[0022] As used herein, when the term “about” or “approximately” is applied to one or more values ​​of interest, it refers to a value similar to the stated reference value, or a value within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, such as limitations of the measurement system. In one aspect, the term “about” refers to any value, including integer and fractional components within a variation of up to ±10% of the value modified by the term “about.” Alternatively, according to practice in the art, “about” may mean within 3 or more standard deviations. Alternatively, as with respect to biological systems or processes, the term “about” may mean within an order of magnitude, within 5 times the value in some embodiments, and within 2 times the value in some embodiments. As used herein, the symbol “~” signifies “about” or “approximately.”

[0023] All ranges disclosed herein include the two endpoints as discrete values ​​and all integers and fractions specified within that range. For example, the range 0.1–2.0 includes 0.1, 0.2, 0.3, 0.4…2.0. If the endpoints are modified by the term “about,” the specified range is extended by ±10% of any value (including the endpoints) within that range or by three or more standard deviations.

[0024] As used herein, the terms “control” or “reference” are used interchangeably. A “reference” or “control” level can be a predetermined value or range used as a baseline or benchmark for evaluating measurement results. “Control” also refers to a control experiment or control cells.

[0025] As used herein, “treatment” or “curing” means preventing, inhibiting, suppressing, reversing, mitigating, improving, or suppressing the progression of a biological process, including a disorder or disease, or completely eliminating a disease. Treatment can be performed in an acute or chronic manner. The term “treatment” also refers to reducing the severity of a disease or symptom associated with a disease before the onset of the disease. “Suppressing” or “improving” a disease, disorder, or symptom involves administering the cells, compositions, or compounds described herein to a subject after the clinical onset of the disease, disorder, or symptom. “Preventing” or “avoiding” a disease, disorder, or symptom involves administering the cells, compositions, or compounds described herein to a subject before the onset of the disease, disorder, or symptom. “Inhibiting” a disease or disorder involves administering the cells, compositions, or compounds described herein to a subject after the induction of the disease or disorder but before the onset of its clinical manifestations or symptoms.

[0026] As used herein, the term “prevention” means preventing or reducing the progression of a barrier to a statistically significant degree or to a degree that is detectable by a person skilled in the art.

[0027] As used herein, the term "effective dose" or "therapeutic effective dose" refers to a substantially nontoxic but sufficient amount of action, agent, composition, or cells administered to a subject that will, to some extent, prevent, treat, or improve one or more symptoms of an ongoing or predisposing disease or condition. The result may be a reduction or relief of signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. Effective doses may be based on individual subject factors, including but not limited to the subject's age, body size, type or severity of disease, stage of disease, route of administration, type or extent of complementary therapy used, ongoing disease process, and type of treatment required.

[0028] As used herein, the terms “inhibition,” “inhibitory effect,” or “inhibitory” refer to the reduction or suppression of a given biological process, condition, symptom, disorder, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0029] As used herein, the term "subject" refers to an animal. Typically, a subject is a mammal. A subject also refers to primates (e.g., humans, males or females; infants, adolescents, or adults), non-human primates, rats, mice, rabbits, pigs, cattle, sheep, goats, horses, dogs, cats, fish, birds, etc. In one implementation, the subject is a primate. In another implementation, the subject is a human.

[0030] As used in this article, a subject "needs treatment" if the subject will benefit biologically, medically, or in terms of quality of life from the treatment. Subjects who need treatment do not necessarily exhibit symptoms, especially in the case of preventative or preventive treatment.

[0031] As used herein, the terms “active ingredient” or “active pharmaceutical ingredient” or “active pharmaceutical agent” or “API” or “medicine” refer to a pharmaceutical agent, active ingredient, compound or substance, composition or mixture thereof that provides a pharmacological (generally beneficial) effect. When referring to a particular active ingredient, where appropriate, this includes the active ingredient and any pharmaceutically acceptable salt or ester thereof. In some embodiments, one or more active pharmaceutical ingredients may be incorporated into a matrix filler as described herein. In some embodiments, one or more active pharmaceutical ingredients may be incorporated into a compressed tablet as described herein. In some embodiments, one or more active pharmaceutical ingredients may be incorporated into a soft gel capsule formulation as described herein.

[0032] The terms "dosage" or "application amount" refer to any form of active ingredient formulation or composition containing an amount sufficient to induce or produce a therapeutic effect through at least one or more administrations. The dosage forms used herein are for oral administration. A preferred oral dosage form is a soft capsule.

[0033] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one active ingredient, nutrient, or nutritional vitamin. In some embodiments described herein, the pharmaceutical composition comprises, for example, a soft capsule shell formed by encapsulation using a rotary die, comprising one or more polyunsaturated fatty acids, and optionally having one or more vitamins, antioxidants, or other active ingredients.

[0034] As used herein, the terms “formulation” or “composition” refer to an active pharmaceutical ingredient or drug in combination with pharmaceutically acceptable excipients. This includes formulations that can be administered orally as well as formulations that can be administered by other means. The terms “formulation” and “composition” are used interchangeably herein.

[0035] As used in this article, the term "room temperature" refers to the common ambient temperature in a pharmaceutical laboratory, ranging from approximately 20°C to approximately 27°C.

[0036] As used herein, the terms “weight percentage,” “% wt,” “mass percentage,” or “mass %” refer to the percentage by which a particular component of the composition is present in the total mass of the composition (assuming 100%). The term “percentage (or %)…wet mass” refers to the percentage by which the composition contains a significant amount of solvent (typically water). Similarly, “percentage (or %)…dry mass” refers to the percentage by which the composition contains only or primarily dry components.

[0037] As used herein, the terms "wet shell mass" or "wet capsule mass" refer to the mass of the capsule during formulation and manufacturing, but prior to drying. During the manufacturing process, the soft gel capsules are dried, and a portion of the solvent (typically water) evaporates. This increases the integrity and rigidity of the capsule shell. Therefore, the relative mass percentage of the non-volatile components increases proportionally with the decrease in the amount of solvent evaporated during drying. "Dry shell mass" or "dry shell mass percentage" is difficult to measure, but these values ​​can be estimated based on the difference in mass between the capsule immediately after manufacturing and after drying, assuming the difference is solely due to solvent evaporation.

[0038] As used herein, the term “release” or “releasing” refers to the release of a portion of the active ingredient from the soft gel matrix into a medium such as a buffer or gastric juice.

[0039] As used herein, the term "rapid release" or "rapid releasing" refers to the rapid release of a portion of the active ingredient from the softgel matrix filler into the medium, compared to a typical softgel capsule. In one aspect, "rapid release" means that the softgel capsule rapidly releases a portion of the active ingredient from the matrix filler into the medium within approximately 0.5 minutes, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes. One embodiment described herein is a rapid-release softgel capsule.

[0040] As used in this article, the term “rupture” refers to the initial opening of a soft gel capsule, in which the contents begin to be released from the matrix and dissolve into the medium.

[0041] As used herein, the terms "rapid rupture" or "rapid rupturing" refer to the rapid rupture of a soft gel capsule in a medium compared to a standard soft gel capsule. In one aspect, "rapid rupture" means that the soft gel capsule rapidly releases a portion of the active ingredient from the matrix filler into the medium within approximately 0.5 minutes, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes. One embodiment described herein is a rapid-rupture soft capsule.

[0042] As used herein, the term "dissolution" refers to the solvation of a soft gel capsule. Unbound by any particular theory, the soft gel capsule shell begins to slowly dissolve upon introduction into a medium (such as a buffer or gastric juice). As the capsule shell dissolves, the capsule typically ruptures at a weak point (such as a manufacturing seam). The capsule matrix begins to release filler from the initial rupture opening, while the medium enters the rupture and begins to solvate the remaining matrix within the capsule. Simultaneously, the capsule shell continues to dissolve, and the rupture opening enlarges as the matrix is ​​released. After a period of time, both the matrix and the capsule shell are completely solvated, and the capsule dissolves.

[0043] As used herein, the terms "rapid dissolution" or "rapid dissolution" refer to the rapid dissolution of a soft gel capsule in a medium compared to a standard soft gel capsule. In one aspect, "rapid dissolution" means that the soft gel capsule dissolves rapidly within approximately 0.5 minutes, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, or 60 minutes. One embodiment described herein is a rapidly dissolving soft gel capsule.

[0044] As used herein, the term "typical soft gel capsule" or "standard soft gel capsule" refers to a soft gel capsule having a shell containing one or more film-forming polymers (e.g., gelatin), a plasticizer (e.g., glycerin), and water, and manufactured by encapsulation using a rotary mold.

[0045] Typical soft gel capsules do not contain disintegrants as described herein. Typical soft gel capsules containing aqueous (non-oil) fillers typically rupture within 15 to 20 minutes in a buffered medium and dissolve completely within 30 to 45 minutes.

[0046] Typical soft gel capsules, due to their specific formulation requirements, also do not contain viscosity-modifying polymers. The primary purpose of soft gel capsules is to provide an easily swallowable dosage form that delivers APIs in a consistent and controlled manner. The presence of viscosity-modifying polymers can interfere with the flow properties of a liquid or semi-solid core, making it difficult to fill the capsule uniformly and consistently.

[0047] Furthermore, viscosity-modifying polymers can affect the dissolution and bioavailability of APIs, which in turn can impact drug efficacy and pharmacokinetics. For example, gelatin is well-regarded for use in soft gel capsules due to its excellent gelling and film-forming properties, making it ideal for encapsulation purposes. On the other hand, viscosity-modifying polymers may not always be compatible with gelatin in terms of physical and chemical properties. Depending on the amount of viscosity-modifying polymer, it may not miscible with gelatin, leading to problems such as phase separation, instability, or impaired capsule integrity. Therefore, viscosity-modifying polymers can reduce the stability of the shell composition when improperly added. Consequently, typical soft gel capsules are formulated without the addition of viscosity-modifying polymers.

[0048] As used herein, the rupture test, dissolution test, comparative dissolution, and similar experiments were performed in accordance with protocols established in the United States Pharmacopeia (USP), including the USP disintegration method. <701> and USP General Rules <2040> The teachings on this subject are incorporated herein by reference. Specific device descriptions are found in the USP General Rules. <711> Dissolution rate is determined by the following components: Apparatus I - Basket Apparatus; Method II - Paddle Apparatus; Method III - Reciprocating Cylindrical Apparatus; and Method IV - Flow Cell. See USP General Rules. <711> Dissolution, Phase 6 Harmonization, United States Pharmacopeia (2011), which is incorporated herein by reference for such teachings.

[0049] As used herein, the term "film-forming polymer" refers to a water-soluble polymeric agent capable of forming a film that enhances the integrity of the outer shell of a soft gel capsule. Typical film-forming polymers include gelatin, gelatin hydrolysates, and collagen.

[0050] As used herein, the term "plasticizer" refers to an agent that imparts extensibility, dispensability, flexibility, elasticity, rigidity, softness, and / or enhanced mechanical properties to the shell of a soft gel capsule through interaction with the film-forming polymer. Plasticizers can minimize the brittleness and breakage of the soft gel capsule shell. As used herein, the term "co-solvent" refers to an agent that contributes to the solubility of the soft gel capsule.

[0051] As used herein, the term "disintegrant" or "disintegrant agent" refers to an agent that, in an aqueous environment, promotes the breakdown, disintegration, or rupture of a soft gel capsule into smaller fragments, thereby increasing the available surface area and facilitating a more rapid release of the capsule's matrix-filling components.

[0052] As used herein, the term "viscosity-modifying polymer" refers to an agent that adjusts the viscosity of a soft gel capsule, thereby improving the capsule's stability without delaying the release rate of the capsule matrix filling components. Viscosity-modifying polymers can be viscosity reducers used to lower the viscosity or consistency of capsules. Therefore, the viscosity-modifying polymers described herein (i.e., water-soluble polymers and / or having low molecular weights) are used as viscosity reducers rather than binders. Other commonly known types of viscosity-reducing excipients include L-arginine, L-phenylalanine, L-ornithine monohydrochloride, benzenesulfonic acid, pyridoxine hydrochloride, and thiamine phosphate chloride dihydrate.

[0053] As used herein, the term "solvent" refers to an aqueous reagent used to dissolve the various components of a soft gel capsule formulation.

[0054] As used in this article, the term " C max "" refers to the maximum observed blood (plasma, serum, or whole blood) concentration or the maximum blood concentration calculated or estimated based on a concentration-time curve, and is expressed in mg / L or ng / mL, as appropriate.

[0055] As used in this article, the term " C min "" refers to the minimum observed blood (plasma, serum, or whole blood) concentration or the minimum blood concentration calculated or estimated based on a concentration-time curve, and is expressed in mg / L or ng / mL, as appropriate.

[0056] As used in this article, the term " C avg "AUC" refers to the blood (plasma, serum, or whole blood) concentration of the drug within the dosing interval, calculated as AUC / dosing interval, and expressed in mg / L or ng / mL, depending on the situation.

[0057] As used in this article, the term " T max"refers to after application" C max The time of occurrence, expressed in hours (h) or minutes (min), depending on the context.

[0058] As used in this article, the term "AUC" 0→τ "" refers to the time interval from time zero to time tau within the dosing interval under steady state. τ The area under the blood (plasma, serum, or whole blood) concentration-time curve, where tau is the length of the dosing interval and is expressed in h·mg / L or h·ng / mL, as appropriate. For example, the term AUC is used as in this document. 0→12 It refers to the area under the concentration-time curve from 0 hours to 12 hours.

[0059] As used in this article, the term "AUC" 0→∞ "" refers to the area under the blood (plasma, serum, or whole blood) concentration-time curve from time 0 hours to infinity, and is expressed in h·mg / L or h·ng / mL, depending on the situation.

[0060] As used in this article, the term "AUC" overall "AUC" refers to the area under the blood (plasma, serum, or whole blood) concentration-time curve for at least one or more doses of the pharmaceutical composition described herein, and is expressed in h·mg / L (or h·ng / mL). In one aspect, "AUC" overall "" refers to the area under the blood concentration-time curve for at least two doses of the pharmaceutical composition described herein.

[0061] As used herein, the term "gel reactor" refers to a specialized container or apparatus used for the production of soft gel capsules. It is designed to facilitate the mixing, blending, and formation of gels by providing controlled conditions for the gelation process. A gel reactor typically comprises a container or tank that holds the gel formulation. It is equipped with mixing mechanisms, such as impellers, blades, or stirrers, which are responsible for generating the necessary shear forces to mix and disperse the gel components. The design of the reactor can vary depending on the specific requirements of the gel formulation and the desired end product, i.e., gelation kinetics and viscosity.

[0062] Capsule Composition

[0063] One embodiment described herein is a formulation for a rapid-release soft gel capsule. Exemplary rapid-release capsule compositions are shown in Table 1.

[0064]

[0065] Examples of film-forming polymers that can be used to form soft capsules as described herein include gelatin, including bone gelatin, lime bone gelatin, bovine hide gelatin, pigskin gelatin, chicken skin gelatin, fish gelatin, acid-treated skin gelatin, gelatin hydrolysates, collagen, or combinations thereof. Gelatin can be type A or type B gelatin. Type A gelatin is derived from the acid hydrolysis of collagen (e.g., bone gelatin or pigskin gelatin), while type B gelatin (e.g., lime bone gelatin) is derived from the alkaline hydrolysis of collagen. Traditionally, bovine bone and hide have been used as raw materials for the manufacture of both type A and type B gelatin, while pigskin is widely used for the manufacture of type A gelatin. Furthermore, at neutral pH, type A gelatin (acid-treated gelatin) is typically net cationic (e.g., isoelectric point of about 7-9), and type B gelatin (alkali-treated gelatin) is typically net anionic (e.g., isoelectric point of about 4.5-5.3). Type A gelatin typically has higher plasticity and elasticity than Type B gelatin; Type B gelatin typically has higher gel strength than Type A gelatin.

[0066] The strength of a gelatin composition is typically defined by its Bloom strength or grade. A Bloom test measures the weight (in grams) required for a 0.5-inch diameter probe to deflect the gel surface 4 mm without causing it to break. The result is expressed as “Bloom” or “Bloom strength.” The gelatin used in the soft capsules described herein has a Bloom strength ranging from about 20 Bloom to about 400 Bloom, including every integer within the specified range. In one embodiment, the soft capsules described herein have a Bloom strength of about 50 Bloom to about 250 Bloom, including every integer within the specified range. In some embodiments, the gelatin Bloom strength is about 50 Bloom, about 80 Bloom, about 100 Bloom, about 120 Bloom, about 150 Bloom, about 180 Bloom, about 200 Bloom, or about 250 Bloom. In one embodiment, the gelatin Bloom strength is 100 Bloom. In another embodiment, the gelatin Bloom strength is 150 Bloom. In another embodiment, the gelatin Bloom strength is 175 Bloom. In yet another embodiment, the gelatin Bloom strength is 200 Bloom.

[0067] Examples of film-forming polymers that can be used to form the non-animal / non-gelatin soft capsules described herein are κ carrageenan, ι carrageenan, λ carrageenan, or combinations thereof.

[0068] As described herein, examples of film-forming anionic polysaccharides include polygalacturonic acid, carboxymethyl branched starch, carboxymethyl cellulose, hyaluronic acid, cellulose phthalate, cellulose succinate, alginate, sodium alginate and pectin, acrylic acid and methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate (HPMCP), alginates (such as sodium alginate or potassium alginate), or shellac. Poly(methacrylic acid-co-methyl methacrylate) anionic copolymers based on methacrylic acid and methyl methacrylate are particularly stable and are preferred in some embodiments. They can be traded under the name EUDRAGIT. ® The poly(meth)acrylate (methacrylic acid copolymer) obtained by Evonik Industries AG, Essen, Germany is supplied in powder or aqueous dispersion form. In one aspect, the methacrylic acid copolymer can be EUDRAGIT. ® L 30 D-55; EUDRAGIT ® L 100-55; EUDRAGIT ® L 100; EUDRAGIT ® L 12.5; EUDRAGIT ® S 100; EUDRAGIT ® S 12.5; EUDRAGIT ® FS 30 D; EUDRAGIT ® E 100; EUDRAGIT ® E 12.5; EUDRAGIT ® E PO; EUDRAGIT ® RL 100; EUDRAGIT ® RL PO; EUDRAGIT ® RL 30 D; EUDRAGIT ® RL 12.5; EUDRAGIT ® RS 100; EUDRAGIT ® RS PO; EUDRAGIT ® RS 30 D; EUDRAGIT ® RS 12.5; EUDRAGIT ® NE 30 D; EUDRAGIT ® NE 40 D; EUDRAGIT ® NM30 D; or other poly(meth)acrylate polymers.

[0069] The film-forming polymer typically constitutes approximately 15% to 60% of the total wet mass of the casing, including every integer and fraction within the specified range. For example, one or more film-forming polymers may constitute approximately 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the total wet mass of the casing, or approximately 15% to 20%, 15% to 25%, 15% to 30%, 15% to 35%, 15% to 40%, 15% to 45%, 15% to 50%, 15% to 55%, 20% to 25%, 20% to 30%, 20% to 35%, 20% to 40%, 20% to 45%, 20% to 50%, 20% to 55%, 20% to 60%, 25% to 30%, 25% to 35%, and 25% to 45% of the total wet mass of the casing. 25% to 50%, 25% to 55%, 25% to 60%, 30% to 35%, 30% to 40%, 30% to 45%, 30% to 50%, 30% to 55%, 30% to 60%, 35% to 40%, 35% to 45%, 35% to 50%, 35% to 55%, 35% to 60%, 40% to 45%, 40% to 50%, 40% to 55%, 40% to 60%, 45% to 50%, 45% to 55%, 45% to 60%, 50% to 55%, 50% to 60%, or 55% to 60% by mass, including every integer and fraction within these specified values ​​and ranges. In some embodiments, one or more film-forming polymers may constitute about 20% to 40% of the total wet mass of the casing, including every integer and fraction within that specified range. In one non-limiting embodiment, one or more film-forming polymers may account for about 35% to 45% or about 35% to 40% of the total wet mass of the casing, including every integer and fraction within these specified ranges.

[0070] The plasticizer and / or cosolvent that can be used to form soft capsules as described herein is maltitol (hydrogenated corn syrup; for example, Lycasin). ® Roquette), sorbitol, glycerol, partially dehydrated sorbitol, d-sorbitol, 1,4-dehydrated sorbitol, mannitol and water blends; for example, Sorbitol Special ® (SPI Pharma); Anidrisorb ® or Polysorb ®Roquette, corn syrup, xylitol, mannitol, propylene glycol, low molecular weight polyethylene glycol, polyols having 3 to 6 carbon atoms, or combinations thereof. Plasticizers and / or co-solvents typically constitute approximately 5% to 30% of the total wet mass of the shell, including every integer and fraction within the specified range. For example, one or more plasticizers or co-solvents may constitute about 5%, 8%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, or 30% of the total wet weight of the casing, or about 5% to 8%, 5% to 10%, 5% to 12%, 5% to 15%, 5% to 18%, 5% to 20%, 5% to 22%, 5% to 25%, 5% to 28%, 8% to 10%, 8% to 12%, 8% to 15%, 8% to 18%, 8% to 20%, 8% to 22%, 8% to 25%, 8% to 28%, 8% to 30%, 10% to 12%, 10% to 15%, 10% to 18%, 10% to 20%, 10% to 22%, 10% to 25%, 10% to 28%, 10% The percentage of quality up to 30%, 12% to 15%, 12% to 18%, 12% to 20%, 12% to 22%, 12% to 25%, 12% to 28%, 12% to 30%, 15% to 18%, 15% to 20%, 15% to 22%, 15% to 25%, 15% to 28%, 15% to 30%, 18% to 20%, 18% to 22%, 18% to 25%, 18% to 28%, 18% to 30%, 20% to 22%, 20% to 25%, 20% to 28%, 20% to 30%, 22% to 25%, 22% to 28%, 22% to 30%, 25% to 28%, 25% to 30%, or 28% to 30%, including every integer and fraction within these specified values ​​and ranges. In some embodiments, one or more plasticizers or co-solvents may constitute about 10% to 20% of the total wet mass of the shell, including every integer and fraction within that specified range. In a non-limiting embodiment, one or more plasticizers or co-solvents may constitute about 15% to 20% or about 15% to 18% of the total wet mass of the shell, including every integer and fraction within these specified ranges. Adjusting the weight ratio between the film-forming polymer, plasticizer, and / or co-solvent to the solvent allows the gel block to flow and become less viscous, and enables the formation of soft capsules using a rotary encapsulation method.

[0071] Disintegrants that can be used to form soft capsules as described herein include, but are not limited to, sodium carboxymethyl starch (“SSG”), croscarmellose sodium, crospovidone, calcium silicate, magnesium aluminum silicate, croscarmellose, or combinations thereof. In one aspect, the disintegrant is sodium carboxymethyl starch. The disintegrant typically constitutes approximately 1% to 40% of the total wet mass of the shell, including every integer and fraction within the specified range. For example, one or more disintegrants may constitute about 1%, 2%, 2.5%, 5%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 15%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 25%, 30%, 35%, or 40% of the total wet mass of the shell, or about 1% to 2%, 1% to 2.5%, 1% to 5%, 1% to 7.5%, 1% to 8%, or 1% to 8.5% of the total wet mass of the shell. 1% to 9%, 1% to 9.5%, 1% to 10%, 1% to 10.5%, 1% to 11%, 1% to 11.5%, 1% to 12%, 1% to 12.5%, 1% to 13%, 1% to 13.5%, 1% to 15%, 1% to 17.5%, 1% to 18%, 1% to 18.5%, 1% to 19%, 1% to 19.5%, 1% to 20%, 1% to 20.5%, 1% to 21%, 1% to 21.5%, 1% to 22%, 1% to 22.5%, 1% to 25%, 1% to 30%, 1% to 35%, 2% to 2.5%, 2% to 5%, 2% to 7.5% 2% to 8%, 2% to 8.5%, 2% to 9%, 2% to 9.5%, 2% to 10%, 2% to 10.5%, 2% to 11%, 2% to 11.5%, 2% to 12%, 2% to 12.5%, 2% to 13%, 2% to 13.5%, 2% to 15%, 2% to 17.5%, 2% to 18%, 2% to 18.5%, 2% to 19%, 2% to 19.5%, 2% to 20%, 2% to 20.5%, 2% to 21%, 2% to 21.5%, 2% to 22%, 2% to 22.5%, 2% to 25%, 2% to 30%, 2% to 35%, 2% to 40% 2.5% to 5%, 2.5% to 7.5%, 2.5% to 8%, 2.5% to 8.5%, 2.5% to 9%, 2.5% to 9.5%, 2.5% to 10%, 2.5% to 10.5%, 2.5% to 11%, 2.5% to 11.5%, 2.5% to 12%, 2.5% to 12.5%, 2.5% to 13%, 2.5% to 13.5%, 2.5% to 15%, 2.5% to 17.5%, 2.5% to 18%, 2.5% to 18.5%, 2.5% to 19%, 2.5% to 19.5%, 2.5% to 20%, 2.5% to 20.5%, 2.5% to 21%, 2.5% to 21.5%, 2.5% to 22%, 2.5% to 22.5%, 2.5% to 25%, 2.5% to 30%, 2.5% to 35%, 2.5% to 40%, 5% to 7.5%, 5% to 8%, 5% to 8.5%, 5% to 9%, 5% to 9.5%, 5% to 10%, 5% to 10.5%, 5% to 11%, 5% to 11.5%, 5% to 12%, 5% to 12.5%, 5% to 13%, 5% to 13.5%, 5% to 15%, 5% to 17.5%, 5% to 18%, 5% to 18.5%, 5% to 19%, 5% to 19.5%, 5% to 20%, 5% to 20.5%, 5% to 21%, 5% to 21 0.5%, 5% to 22%, 5% to 22.5%, 5% to 25%, 5% to 30%, 5% to 35%, 5% to 40%, 7.5% to 8%, 7.5% to 8.5%, 7.5% to 9%, 7.5% to 9.5%, 7.5% to 10%, 7.5% to 10.5%, 7.5% to 11%, 7.5% to 11.5%, 7.5% to 12%, 7.5% to 12.5%, 7.5% to 13%, 7.5% to 13.5%, 7.5% to 15%, 7.5% to 17.5%, 7.5% to 18%, 7.5% to 18.5%, 7.5% to 19%, 7.5% to 19.5%, 7.5% to 20%, 7.5% to 20.5%, 7.5% to 2 1%, 7.5% to 21.5%, 7.5% to 22%, 7.5% to 22.5%, 7.5% to 25%, 7.5% to 30%, 7.5% to 35%, 7.5% to 40%, 8% to 8.5%, 8% to 9%, 8% to 9.5%, 8% to 10%, 8% to 10.5%, 8% to 11%, 8% to 11.5%, 8% to 12%, 8% to 12.5%, 8% to 13%, 8% to 13.5%, 8% to 15%, 8% to 17.5%, 8% to 18%, 8% to 18.5%, 8% to 19%, 8% to 19.5%, 8% to 20%, 8% to 20.5%, 8% to 21%, 8% to 21.5%, 8% to 22%, 8% to 22.5% %, 8% to 25%, 8% to 30%, 8% to 35%, 8% to 40%, 8.5% to 9%, 8.5% to 9.5%, 8.5% to 10%, 8.5% to 10.5%, 8.5% to 11%, 8.5% to 11.5%, 8.5% to 12%, 8.5% to 12.5%, 8.5% to 13%, 8.5% to 13.5%, 8.5% to 15%, 8.5% to 17.5%, 8.5% to 18%, 8.5% to 18.5%, 8.5% to 19%, 8.5% to 19.5%, 8.5% to 20%, 8.5% to 20.5%, 8.5% to 21%, 8.5% to 21.5%, 8.5% to 22%, 8.5% to 22.5%, 8.5% to 25%, 8.5% to 30%, 8.5% to 35%, 8.5% to 40%, 9% to 9.5%, 9% to 10%, 9% to 10.5%, 9% to 11%, 9% to 11.5%, 9% to 12%, 9% to 12.5%, 9% to 13%, 9% to 13.5%, 9% to 15%, 9% to 17.5%, 9% to 18%, 9% to 18.5%, 9% to 19%, 9% to 19.5%, 9% to 20%, 9% to 20.5%, 9% to 21%, 9% to 21.5%, 9% to 22%, 9% to 22.5%, 9% to 25%, 9% to 30%, 9% to 35%, 9% to 40%, 9.5% to 10%, 9.5% to 10% 0.5%, 9.5% to 11%, 9.5% to 11.5%, 9.5% to 12%, 9.5% to 12.5%, 9.5% to 13%, 9.5% to 13.5%, 9.5% to 15%, 9.5% to 17.5%, 9.5% to 18%, 9.5% to 18.5%, 9.5% to 19%, 9.5% to 19.5%, 9.5% to 20%, 9.5% to 20.5%, 9.5% to 21%, 9.5% to 21.5%, 9.5% to 22%, 9.5% to 22.5%, 9.5% to 25%, 9.5% to 30%, 9.5% to 35%, 9.5% to 40%, 10% to 10.5%, 10% to 11%, 10% to 11.5% 10% to 12%, 10% to 12.5%, 10% to 13%, 10% to 13.5%, 10% to 15%, 10% to 17.5%, 10% to 18%, 10% to 18.5%, 10% to 19%, 10% to 19.5%, 10% to 20%, 10% to 20.5%, 10% to 21%, 10% to 21.5%, 10% to 22%, 10% to 22.5%, 10% to 25%, 10% to 30%, 10% to 35%, 10% to 40%, 10.5% to 11%, 10.5% to 11.5%, 10.5% to 12%, 10.5% to 12.5%, 10.5% to 13%, 10.5% to 13.5%, 10.5% to 12%. 10.5% to 15%, 10.5% to 17.5%, 10.5% to 18%, 10.5% to 18.5%, 10.5% to 19%, 10.5% to 19.5%, 10.5% to 20%, 10.5% to 20.5%, 10.5% to 21%, 10.5% to 21.5%, 10.5% to 22%, 10.5% to 22.5%, 10.5% to 25%, 10.5% to 30%, 10.5% to 35%, 10.5% to 40%, 11% to 11.5%, 11% to 12%, 11% to 12.5%, 11% to 13%, 11% to 13.5%, 11% to 15%, 11% to 17.5%, 11% to 18%, 11% to 18%.5%, 11% to 19%, 11% to 19.5%, 11% to 20%, 11% to 20.5%, 11% to 21%, 11% to 21.5%, 11% to 22%, 11% to 22.5%, 11% to 25%, 11% to 30%, 11% to 35%, 11% to 40%, 11.5% to 12%, 11.5% to 12.5%, 11.5% to 13%, 11.5% to 13.5%, 11.5% to 15%, 11.5% to 17.5%, 11.5% to 18%, 11.5% to 18.5%, 11.5% to 19%, 11.5% to 19.5%, 11.5% to 20%, 11.5% to 20.5%, 11.5% to 21%, 1 1.5% to 21.5%, 11.5% to 22%, 11.5% to 22.5%, 11.5% to 25%, 11.5% to 30%, 11.5% to 35%, 11.5% to 40%, 12% to 12.5%, 12% to 13%, 12% to 13.5%, 12% to 15%, 12% to 17.5%, 12% to 18%, 12% to 18.5%, 12% to 19%, 12% to 19.5%, 12% to 20%, 12% to 20.5%, 12% to 21%, 12% to 21.5%, 12% to 22%, 12% to 22.5%, 12% to 25%, 12% to 30%, 12% to 35%, 12% to 40%, 12.5% ​​to 13% 12.5% ​​to 13.5%, 12.5% ​​to 15%, 12.5% ​​to 17.5%, 12.5% ​​to 18%, 12.5% ​​to 18.5%, 12.5% ​​to 19%, 12.5% ​​to 19.5%, 12.5% ​​to 20%, 12.5% ​​to 20.5%, 12.5% ​​to 21%, 12.5% ​​to 21.5%, 12.5% ​​to 22%, 12.5% ​​to 22.5%, 12.5% ​​to 25%, 12.5% ​​to 30%, 12.5% ​​to 35%, 12.5% ​​to 40%, 13% to 13.5%, 13% to 15%, 13% to 17.5%, 13% to 18%, 13% to 18.5%, 13% to 19%, 13% to 19.5%, 1 3% to 20%, 13% to 20.5%, 13% to 21%, 13% to 21.5%, 13% to 22%, 13% to 22.5%, 13% to 25%, 13% to 30%, 13% to 35%, 13% to 40%, 13.5% to 15%, 13.5% to 17.5%, 13.5% to 18%, 13.5% to 18.5%, 13.5% to 19%, 13.5% to 19.5%, 13.5% to 20%, 13.5% to 20.5%, 13.5% to 21%, 13.5% to 22%, 13.5% to 22.5%, 13.5% to 25%, 13.5% to 30%, 13.5% to 35%, 13.5% to 40%, 15% to 17.5%, 15% to 18%, 15% to 18.5%, 15% to 19%, 15% to 19.5%, 15% to 20%, 15% to 20.5%, 15% to 21%, 15% to 21.5%, 15% to 22%, 15% to 22.5%, 15% to 25%, 15% to 30%, 15% to 35%, 15% to 40%, 17.5% to 18%, 17.5% to 18.5%, 17.5% to 19%, 17.5% to 19.5%, 17.5% to 20%, 17.5% to 20.5%, 17.5% to 21%, 17.5% to 21.5%, 17.5% to 22%, 17.5% to 22.5%, 1 7.5% to 25%, 17.5% to 30%, 17.5% to 35%, 17.5% to 40%, 18% to 18.5%, 18% to 19%, 18% to 19.5%, 18% to 20%, 18% to 20.5%, 18% to 21%, 18% to 21.5%, 18% to 22%, 18% to 22.5%, 18% to 25%, 18% to 30%, 18% to 35%, 18% to 40%, 18.5% to 19%, 18.5% to 19.5%, 18.5% to 20%, 18.5% to 20.5%, 18.5% to 21%, 18.5% to 21.5%, 18.5% to 22%, 18.5% to 22.5%, 18.5% to 25% 18.5% to 30%, 18.5% to 35%, 18.5% to 40%, 19% to 19.5%, 19% to 20%, 19% to 20.5%, 19% to 21%, 19% to 21.5%, 19% to 22%, 19% to 22.5%, 19% to 25%, 19% to 30%, 19% to 35%, 19% to 40%, 19.5% to 20%, 19.5% to 20.5%, 19.5% to 21%, 19.5% to 22%, 19.5% to 22.5%, 19.5% to 25%, 19.5% to 30%, 19.5% to 35%, 19.5% to 40%, 20% to 20.5%, 20% to 21% 20% to 21.5%, 20% to 22%, 20% to 22.5%, 20% to 25%, 20% to 30%, 20% to 35%, 20% to 40%, 20.5% to 21%, 20.5% to 21.5%, 20.5% to 22%, 20.5% to 22.5%, 20.5% to 25%, 20.5% to 30%, 20.5% to 35%, 20.5% to 40%, 21% to 21.5%, 21% to 22%, 21% to 22.5%, 21% to 25%, 21% to 30%, 21% to 35%, 21% to 40%, 21.5% to 22%, 21.5% to 22.5%, 21.5% to 25%, 21.5% to 30%, 21.5% to 35%, 21.5% to 40%, 22% to 22.5%, 22% to 25%, 22% to 30%, 22% to 35%, 22% to 40%, 22.5% to 25%, 22.5% to 30%, 22.5% to 35%, 22.5% to 40%, 25% to 30%, 25% to 35%, 25% to 40%, 30% to 35%, 30% to 40%, or 35% to 40% by mass, including every integer and fraction within these specified values ​​and ranges. In some embodiments, one or more disintegrants may constitute about 1% to 30%, about 5% to 25%, about 8% to 12%, or about 15% to 25% by mass of the total wet mass of the casing, including every integer and fraction within these specified ranges. In some embodiments, one or more disintegrants may constitute up to about 10%, about 15%, about 20%, or about 30% by mass of the total wet mass of the casing. In one non-limiting embodiment, one or more disintegrants may constitute about 8% to 10% or about 8.5% to 9.5% of the total wet mass of the casing, including every integer and fraction within these specified ranges.

[0072] In some embodiments, the solvent comprises about 10% to about 45% by mass of the soft gel capsule composition, including all integers and fractions within the specified range. In one embodiment, the solvent is water (e.g., purified water and / or additional purified water). The amount of water in the composition varies depending on the amount of other ingredients. For example, the amount of additional ingredients such as opacifiers, colorants, flavorings, or other excipients can change the percentage of water present in the composition. In one embodiment, the weight percentage of water is sufficient to make the total mass percentage reach 100% (i.e., adequate; qs). In another embodiment, water comprises about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45% by mass of the soft gel capsule composition. In another embodiment, water comprises about 35% to about 40% of the soft gel capsule composition. In one embodiment, water comprises about 37% by mass of the composition. The solvent typically comprises about 10% to 45% by mass of the total wet mass of the shell, including every integer and fraction within that specified range. For example, the solvent may constitute about 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45% of the total wet mass of the casing, or about 10% to 15%, 10% to 20%, 10% to 25%, 10% to 30%, 10% to 35%, 10% to 40%, 15% to 20%, 15% to 25%, 15% to 30%, 15% to 35%, 15% to 40%, 15% to 45%, 20% to 25%, 20% to 30%, 20% to 35%, 20% to 40%, 20% to 45%, 25% to 30%, 25% to 35%, 25% to 40%, 25% to 45%, 30% to 35%, 30% to 40%, 30% to 45%, 35% to 40%, 35% to 45%, or 40% to 45% of the mass of these specified values ​​and ranges, including every integer and fraction within these specified values ​​and ranges. In some embodiments, the solvent may constitute about 25% to 40% of the total wet mass of the casing, including every integer and fraction within that specified range. In a non-limiting embodiment, the solvent may constitute about 30% to 40% or about 35% to 40% of the total wet mass of the casing, including every integer and fraction within those specified ranges.

[0073] Other suitable shell additives include plasticizers, opacifiers, colorants, humectants, preservatives, viscosity modifiers, flavoring agents, and buffer salts and acids. Other suitable shell additives may also include viscosity-modifying polymers. Unlike viscosity modifiers, viscosity-modifying polymers act as viscosity reducers rather than binders. Viscosity-modifying polymers reduce the viscosity of gel formulations while maintaining similar shell stability and do not affect shell breakage time or disintegration time.

[0074] When the encapsulating active agent is photosensitive, a light-blocking agent can be used to make the capsule shell opaque. Suitable light-blocking agents include titanium dioxide, zinc oxide, calcium carbonate, and combinations thereof. When included in a soft gel capsule composition as described herein, the light-blocking agent typically constitutes about 0.01% to 1% by weight of the total wet weight of the shell, including every fraction within that specified range. For example, one or more opaque agents may constitute about 0.01%, 0.1%, 0.25%, 0.5%, 0.75%, 0.9%, or 1% of the total wet mass of the casing, or about 0.01% to 0.1%, 0.01% to 0.25%, 0.01% to 0.5%, 0.01% to 0.75%, 0.01% to 0.9%, 0.1% to 0.25%, 0.1% to 0.5%, 0.1% to 0.75%, 0.1% to 0.9%, 0.1% to 1%, 0.25% to 0.5%, 0.25% to 0.75%, 0.25% to 0.9%, 0.25% to 1%, 0.5% to 0.75%, 0.5% to 0.9%, 0.5% to 1%, 0.75% to 0.9%, 0.75% to 1%, or 0.9% to 1% by mass, including each fraction within these specified values ​​and ranges. In some embodiments, one or more light-blocking agents may constitute about 0.01% to 1% of the total wet mass of the housing, including each fraction within that specified range.

[0075] Colorants can be used for marketing and product identification / differentiation purposes. Suitable colorants include synthetic and natural dyes, as well as combinations thereof. When included in soft gel capsule compositions as described herein, colorants typically constitute about 0.01% to 10% by weight of the total wet weight of the shell, including every integer and fraction within that specified range. For example, one or more colorants may comprise about 0.01%, 0.1%, 0.25%, 0.5%, 1%, 2%, 2.5%, 5%, 7.5%, or 10% of the total wet weight of the casing, or about 0.01% to 0.1%, 0.01% to 0.25%, 0.01% to 0.5%, 0.01% to 1%, 0.01% to 2%, 0.01% to 2.5%, 0.01% to 5%, 0.01% to 7.5%, 0.1% to 0.25%, 0.1% to 0.5%, 0.1% to 1%, 0.1% to 2%, 0.1% to 2.5%, 0.1% to 5%, 0.1% to 7.5%, 0.1% to 10%, 0.25% to 0.5%, and 0.25% to 1% of the total wet weight of the casing. The percentage by mass of 0.25% to 2%, 0.25% to 2.5%, 0.25% to 5%, 0.25% to 7.5%, 0.25% to 10%, 0.5% to 1%, 0.5% to 2%, 0.5% to 2.5%, 0.5% to 5%, 0.5% to 7.5%, 0.5% to 10%, 1% to 2%, 1% to 2.5%, 1% to 5%, 1% to 7.5%, 1% to 10%, 2% to 2.5%, 2% to 5%, 2% to 7.5%, 2% to 10%, 2.5% to 5%, 2.5% to 7.5%, 2.5% to 10%, 5% to 7.5%, 5% to 10%, or 7.5% to 10%, including every integer and fraction within these specified values ​​and ranges. In some embodiments, one or more colorants may constitute about 0.01% to 10% of the total wet mass of the casing, including every integer and fraction within that specified range.

[0076] Humectants can be used to suppress the water activity of soft gels. Suitable humectants include glycerin and sorbitol, which are often components of plasticizer compositions. Because dry, properly stored soft gel capsules have low water activity, the greatest risk to microorganisms comes from molds and yeasts. Therefore, preservatives can be incorporated into the capsule shell. Suitable preservatives include alkyl esters of parabens, such as methyl, ethyl, propyl, butyl, and heptyl esters (collectively, "parabens"), or combinations thereof.

[0077] Flavoring agents, or "edible flavorings," can be used to mask unpleasant odors and tastes in filling formulations. Suitable flavoring agents include both synthetic and natural flavorings. The use of flavoring agents can be problematic due to the presence of aldehydes that can crosslink gelatin. Therefore, buffer salts and acids can be used in combination with aldehyde-containing flavoring agents to inhibit the crosslinking of gelatin. When included in soft gel capsule compositions as described herein, flavoring agents typically constitute about 0.01% to 1% by weight of the total wet weight of the shell, including every fraction within that specified range. For example, one or more flavorings may constitute about 0.01%, 0.1%, 0.25%, 0.5%, 0.75%, 0.9% or 1% of the total wet mass of the shell, or about 0.01% to 0.1%, 0.01% to 0.25%, 0.01% to 0.5%, 0.01% to 0.75%, 0.01% to 0.9%, 0.1% to 0.25%, 0.1% to 0.5%, 0.1% to 0.75%, 0.1% to 0.9%, 0.1% to 1%, 0.25% to 0.5%, 0.25% to 0.75%, 0.25% to 0.9%, 0.25% to 1%, 0.5% to 0.75%, 0.5% to 0.9%, 0.5% to 1%, 0.75% to 0.9%, 0.75% to 1% or 0.9% to 1% by mass, including each fraction within these specified values ​​and ranges. In some embodiments, one or more flavorings may comprise about 0.01% to 1% of the total wet mass of the shell, including every fraction within that specified range.

[0078] Examples of suitable viscosity modifiers include guar gum, locust bean gum, xanthan gum, agar, and gellan gum.

[0079] If desired, fillers or extenders may be added to the shell composition. Available fillers or extenders include hydroxypropyl starch phosphate, gum arabic, alginate, microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethyl cellulose, pregelatinized starch, potato starch, cassava starch, rice starch, corn starch, wheat starch, pea starch, modified starch, pregelatinized starch, microcrystalline cellulose, hydroxypropyl methylcellulose, lactose, glucose binders, dextrin, dextran, maltodextrin, glucose, sucrose, powdered sugar, sucrose syrup, mannitol, gums (such as xanthan gum, tragacanth gum, guar gum, gum arabic, acacia gum, asafoetida gum, frankincense gum, aquilaria seed gum, citrus gum, okra gum, cassia seed gum), kaolin, talc, bentonite, calcium phosphate, calcium carbonate, magnesium carbonate, magnesium oxide, calcium sulfate, sodium chloride, potassium chloride, combinations or mixtures thereof, and other substances known in the art. Another available filler is N-Lok. ® (Sodium octenyl succinate starch), Hi-Cap ™ and Ultra Sperse ®M.

[0080] Viscosity-modifying polymers can be added to adjust the viscosity of the shell composition and modify the formulation. Polymers can be added to the shell of a soft gel to alter the gel viscosity, specifically reducing or decreasing it, thereby strengthening the gelatin tape and maintaining shell stability. These viscosity-modifying polymers can be low molecular weight. They can also be water-soluble. Examples of viscosity-modifying polymers include, but are not limited to, HPMC, PVP, PVA, and dextran.

[0081] When included in a soft gel capsule composition, the polymer typically constitutes a mass percentage of about 1% to 20% of the total wet mass of the shell, including every fraction within that specified range. For example, one or more viscosity-modifying polymers may constitute about 1%, 5%, 10%, 15%, 20% or about 1% to 5%, 1% to 10%, 1% to 15%, 1% to 20%, 5% to 10%, 5% to 15%, 5% to 20% of the total wet mass of the shell, including every fraction within these specified values ​​and ranges. For example, about 1% to 20% of the total wet mass of low molecular weight PVP may be added to the shell to reduce its viscosity. Table 20 shows the addition of PVP at 5% (0.5%), 10% (1%), and 15% (1.5%), respectively.

[0082] For Table 20, the average viscosity (CP) of the compositions with 0%, 5%, and 15% PVP was 214,800, 71,700, and 11,440 at T=0, respectively, and 182,100, 41,040, and 7,950 at T=24 hours, respectively. The disintegration times (gel samples at 72 hours) in water at 37°C were 16.37 minutes (0% PVP), 8.5 minutes (5% PVP), and 4.38 minutes (15% PVP).

[0083] Further capsule rupture / disintegration tests were performed on 5% PVP and 10% PVP with MCT and PEG fillers. The results (in minutes) of the average capsule rupture and disintegration times for MCT and PEG are shown in Table 21.

[0084] In some embodiments, the soft gel capsule shell composition comprises a top coating or moisture-proof layer applied to the capsule shell. In one embodiment, the moisture-proof layer comprises one or more polyvinyl alcohols (PV) and suitable pharmaceutically acceptable excipients. In one embodiment, the moisture-proof layer comprises polyvinyl alcohol, sodium lauryl sulfate, glyceryl monocaprylate-capric acid, and talc. In one aspect, the moisture-proof layer helps maintain the aesthetic appearance of the dosage form by preventing dents, sticking, or other defects caused by processing or storage. The top coating may also comprise a sealant. In one aspect, the sealant may be a methacrylic acid copolymer, hydroxypropyl methylcellulose, or a proprietary sealant such as Kollicoat. ® Protect (BASF).

[0085] A coating, topcoat, or undercoat is applied to soft capsules using various methods known in the art. The coating is typically prepared as a suspension and sprayed onto the capsules in a perforated coating pan through one or more nozzles at a specific temperature. The coating solution or dispersion can be applied at a spray rate between 100 g / min and 400 g / min. For coatings with higher solids content, the spray rate can be increased proportionally, while for thinner dispersions, the spray rate can be decreased proportionally. In one embodiment, a disc coater is used to coat the capsules. After the coating suspension is applied, the coated capsules are dried in the disc coater at a specific temperature for a period of time.

[0086] In some embodiments, as described herein, soft gel capsules may coat or encapsulate compressed tablets containing one or more active pharmaceutical ingredients to make it easier for a subject to swallow the compressed tablet. As used herein, “coating” generally refers to coating a compressed tablet with a soft gel capsule formulation to form a “coated tablet.” As used herein, “encapsulation” generally refers to coating a compressed tablet with a soft gel capsule formulation to form an “encapsulated tablet,” wherein additional components or excipients may be present in the encapsulated tablet.

[0087] In some embodiments, in addition to or in place of a matrix filler, soft gel capsules as described herein may have one or more active pharmaceutical ingredients incorporated into the soft gel capsule formulation.

[0088] In some implementations, the rapid-release softgel capsules described herein can be used in chewable softgel capsules containing solid, semi-solid, gel, or liquid fillers, such as Chewels. ® Or LiquiSoft ®(PatheonSoftgels Inc.). See, for example, U.S. Patent Nos. 8,097,279, 8,241,665, 8,765,174, 8,414,916, 9,072,677, 9,668,976, 9,861,586, 10,342,763, 9,867,779, and 10,555,901, each of which is incorporated herein by reference with respect to such teachings.

[0089] In some implementations, the rapid-release soft gel capsule may also be prestressed to increase the release rate. Exemplary examples of prestressing include laser drilling, mechanical drilling, scoring, or other known methods of prestressing the gel capsule.

[0090] Filler Composition

[0091] The filling compositions used in the soft gel capsules described herein can be aqueous or oil-based fillers. In addition to the API, aqueous fillers typically contain one or more polyethylene glycols, solubilizers, and other pharmaceutical excipients. In addition to the API, oil-based fillers contain oils, waxes, surfactants, and other pharmaceutical excipients. Exemplary filling compositions are shown in Table 2.

[0092]

[0093] In one embodiment, the filler contains one or more hydrophilic mediators, which may be anhydrous and compatible with soft gelatin capsules. Non-limiting exemplary mediators include Capmul. ® MCM, Captex ® 355, Cremophor ® RH 40, crosslinked carboxymethyl cellulose, crosspovidone, crosspovidone CL, crosspovidone CL-F, crosspovidone CL-M, Imwitor ® 742, Kollidon ® CL, Kollidon ® CL-F, Kollidon ® CL-M, Labrafac ™ Lipophile WL 1349, Labrafil ® M2125CS, Labrasol ® Lutrol ® F 68, Maisine ™ 35-1, Mannitol, Miglyol ® 812, Pearlitol ® Flash, Peceol ®Plurol ® Oleique CC 497, povidone K 17, povidone K 30, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 2000, polyethylene glycol 3350, propylene glycol, glycerin, Lycasin 80 / 55, special sorbitol, xylitol, maltitol, or mixtures thereof. In one embodiment, the hydrophilic medium comprises one or more hydroalcohols, including polyethylene glycols with a molecular weight in the range of about 200 to about 8000, or mixtures or combinations thereof.

[0094] In another embodiment, the hydrophilic medium may include a hygroscopic polymer. In one embodiment, the hygroscopic polymer includes polyvinylpyrrolidone, crospovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, and polyethylene oxide. Suitable hygroscopic polymers include copolymers of polyvinyl alcohol, polyvinylpyrrolidone and polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, and polyethylene oxide (such as POLYOX). ™ 100,000–600,000 MW), gum arabic, dextrin, cyclodextrin, starch, hydroxyethyl polymethyl methacrylate, water-soluble nonionic polymethyl methacrylate or copolymers thereof, modified cellulose, modified polysaccharides, nonionic gums or nonionic polysaccharides.

[0095] In another embodiment, the filler may include one or more lipid or lipophilic mediators. In one aspect, the lipid or lipophilic mediator may be a liquid, solid, or semi-solid lipid or lipophilic mediator. Suitable non-limiting liquid lipid or lipophilic mediators include olive oil, soybean oil, sunflower oil, canola oil, palmitoleic acid, oleic acid, myristone acid, linoleic acid, arachidonic acid, paraffin oil, mineral oil, or mixtures or combinations thereof. The lipid or lipophilic mediator may be a semi-solid lipophilic mediator, such as polyethylene glycol glycerol esters, for example, Gelucire. ® 33 / 01, Gelucire ® 37 / 02, Gelucire ® 39 / 01, Gelucire ® 43 / 01, Gelucire ® 44 / 14, Gelucire ® 50 / 02, Gelucire ® 50 / 13, Gelucire ® 53 / 10 or Gelucire ® 62 / 02; paraffin wax, carnauba wax, or beeswax.

[0096] In another embodiment, the filler may include a release regulator, such as a fatty acid salt, fatty acid ester, or fatty acid polyoxyethylene derivative. The release regulator may also be a surfactant with a hydrophilic / lipophilic balance (HLB) value between about 2 and about 40. The HLB characteristics of the surfactant can be determined according to… Physical Pharmacy:Physical Chemical Principles in the Pharmaceutical Sciences ", 4th edition, pp. 371-373, edited by A. Martin, Lippincott Williams & Wilkins, Philadelphia (1993), which is used to determine that such teachings are incorporated into this article by reference."

[0097] In another embodiment, the filler may include an emulsifier or solubilizer, such as gum arabic, cholesterol, diethanolamine, glyceryl monostearate, lanolin alcohol, lecithin, monoglycerides and diglycerides, monoethanolamine, oleic acid, oleyl alcohol, poloxamer, polyoxyethylene 50 stearate, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 10 oleate ether, polyoxyethylene 20 cetearyl ether, polyoxyethylene 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol diacetate, propylene glycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid, dimethyl silicone oil, triethanolamine, emulsifying wax, or combinations thereof.

[0098] Other suitable solvents include surfactants and copolymers of polyethylene glycol with molecular weights ranging from about 200 to about 8000. Optionally, glycerol, PVP, or propylene glycol (PPG) may be added to enhance the solubility of the agent.

[0099] In another embodiment described herein, the matrix filler comprises one or more flavoring agents. In one embodiment, the one or more flavoring agents comprise citric acid, lactic acid, sodium citrate, anethole, benzaldehyde, ethyl vanillin, eucalyptol, glycine, menthol, methyl salicylate, monosodium glutamate, neroli oil, peppermint, peppermint oil, peppermint extract, rose oil, concentrated rose water, thymol, toluene balsam tincture, vanilla, vanilla tincture, vanillin, or combinations thereof. In one aspect, the flavoring agent comprises one or more of citric acid, acetic acid, lactic acid, malic acid, tartaric acid, or combinations thereof. In another aspect, the flavoring agent comprises citric acid, lactic acid, or combinations thereof.

[0100] In another embodiment, the matrix filler comprises at least one or more sweeteners. In one embodiment, the one or more sweeteners include mannitol, kiwifruit protein, glycyrrhizate, maltitol, sucralose, acesulfame potassium, and steviol glycosides (e.g., Stevia). ® Truvía ® Sweeteners include saccharin, calcium saccharin, sodium saccharin, aspartame, acesulfame potassium, agave nectar, high fructose corn syrup, honey, glucose binders, dextrose, excipient dextrose, and monosaccharides (such as glucose, fructose, sucrose, sucralose, lactose), or combinations thereof. In one aspect, sweeteners include mannitol, maltitol (e.g., Lycasin), and maltitol. ® Xylitol, sucralose, kiwifruit protein (e.g., Talin) ® ), glycyrrhizic acid salt (MagnaSweet) ® (or one or more of their combinations)

[0101] In another embodiment, the matrix filler includes at least one solvent. In one aspect, the solvent is water.

[0102] The matrix filler may optionally include one or more pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients include buffers such as phosphate buffers, citrate buffers, and buffers containing other organic acids; antioxidants, including ascorbic acid; low molecular weight (less than about 10 residues) peptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN. ® (ICI, Inc.; Bridgewater, New Jersey) and PLURONICS ™ (BASF; Florham Park, NJ). Commonly used diluents in the art can also be encapsulated in a shell, including water or other solvents, solubilizers, and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofurfuryl alcohol, and fatty acid esters of sorbitol, as well as mixtures of these substances.

[0103] Pharmaceutical excipients that can be used in matrix fillers include, for example, the following: acidifiers (acetic acid, glacial acetic acid, citric acid, fumaric acid, hydrochloric acid, dilute hydrochloric acid, malic acid, nitric acid, phosphoric acid, dilute phosphoric acid, sulfuric acid, tartaric acid); alkalizing agents (ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine); defoamers (polydimethylsiloxane, dimethyl silicone oil); and antimicrobial preservatives (benzalkonium chloride). Ammonium, benzalkonium chloride solution, benzyl chloride, benzoic acid, benzyl alcohol, butyl paraben, hexadecylpyridine chloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid, ethyl paraben, methyl paraben, sodium methyl paraben, phenol, phenethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propyl paraben, sodium propyl paraben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal Thymol); Antioxidants (ascorbic acid, palmitic acid ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphite, monothioglycerol, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol excipients); Buffers (acetic acid, ammonium carbonate, ammonium phosphate, boric acid, citric acid, lactic acid, phosphoric acid, potassium citrate, potassium metaphosphate, potassium dihydrogen phosphate, sodium acetate, sodium citrate, sodium lactate solution, disodium hydrogen phosphate, sodium dihydrogen phosphate); Chelating agents (disodium ethylenediaminetetraacetate, ethylenediaminetetraacetic acid and its salt, ethylenediaminetetraacetic acid); Coating agents (sodium carboxymethyl cellulose, cellulose acetate, cellulose phthalate acetate, ethyl cellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, methacrylic acid copolymer, methyl cellulose, polyvinyl acetate). Phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein; colorants (caramel, red, yellow, black or blends, iron oxide); complexing agents (ethylenediaminetetraacetic acid and its salt (EDTA), edetate, gentianoacetic acid ethanolamide, hydroxyquinoline sulfate); desiccants (calcium chloride, calcium sulfate, silicon dioxide); emulsifiers and / or solubilizers (gum arabic, cholesterol, diethanolamine (auxiliary agent), glyceryl monostearate, lanolin alcohol, monoglycerides and diglycerides, monoethanolamine (auxiliary agent), lecithin, oleic acid (auxiliary agent)). Oleyl alcohol (stabilizer), poloxamer, polyoxyethylene 50 stearate, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 10 oil ether, polyoxyethylene 20 cetearyl ether, polyoxyethylene 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, diacetate, monostearate, sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid, triethanolamine, emulsifying wax);Filter aids (powdered cellulose, purified diatomaceous earth); flavorings and fragrances (anesinol, benzaldehyde, ethyl vanillin, menthol, methyl salicylate, monosodium glutamate, neroli oil, peppermint, peppermint oil, peppermint extract, rose oil, concentrated rose water, thymol, toluene balsam tincture, vanilla, vanilla tincture, vanillin); humectants (glycerin, hexanediol, sorbitol); plasticizers (e.g., castor oil, diacetylated monoglycerides, diethyl phthalate, glycerin, monoacetylated and diacetylated monoglycerides, propylene glycol, triacetin, triethyl citrate); polymers (e.g., cellulose acetate, alkyl cellulose, hydroxyalkyl, acrylic polymers and copolymers); solvents (acetone, alcohols, diluted alcohols, pentene hydrate, benzyl benzoate, butanol). Carbon tetrachloride, chloroform, corn oil, cottonseed oil, ethyl acetate, glycerin, hexanediol, isopropanol, methanol, dichloromethane, methyl isobutyl ketone, mineral oil, peanut oil, propylene carbonate, sesame oil, water for injection, sterile water for injection, sterile rinsing water, purified water; adsorbents (powdered cellulose, charcoal, purified diatomaceous earth); carbon dioxide adsorbents (barium hydroxide lime, soda lime); hardening agents (hydrogenated castor oil, cetearyl alcohol, cetyl alcohol, cetyl ester wax, stearin, paraffin wax, polyethylene additives, stearyl alcohol, emulsified wax, white wax, yellow wax); suspending agents and / or thickeners (gum arabic, agar, alginic acid, aluminum monostearate, bentonite, purified bentonite, magma bentonite, carbomer, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose, etc.). Sodium methylcellulose, carrageenan, microcrystalline cellulose and sodium carboxymethyl cellulose, dextrin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminum silicate, methylcellulose, pectin, polyethylene oxide, polyvinyl alcohol, povidone, alginate, silica, colloidal silica, sodium alginate, tragacanth gum, xanthan gum; sweeteners (aspartame, glucose binder, dextrose, excipient dextrose, fructose, mannitol, saccharin, calcium saccharin, sodium saccharin, sorbitol, sorbitol solution, sucrose, compressible sugar, powdered sugar, syrup); tablet binders (gum arabic, alginate, sodium carboxymethyl cellulose, microcrystalline cellulose, dextrin, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose). Vitamins, methylcellulose, polyethylene oxide, povidone, pregelatinized starch, syrup; tablet and / or capsule diluents (calcium carbonate, dicalcium phosphate, tricalcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, glucose binder, dextrin, dextran excipient, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, powdered sugar); tablet disintegrants (alginic acid, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacolin potassium, sodium carboxymethyl starch, starch, pregelatinized starch); tablet and / or capsule lubricants (calcium stearate, glyceryl behenate, magnesium stearate, light mineral oil, sodium stearoyl fumarate, stearic acid, purified stearic acid, talc, hydrogenated vegetable oil, zinc stearate);Penetrating agents (dextrose, glycerin, mannitol, potassium chloride, sodium chloride); Medium: Flavoring and / or sweetening (aromatic elixirs, compound benzaldehyde elixirs, isool elixirs, peppermint water, sorbitol solution, syrup, toluene balsam syrup); Medium: Oils (almond oil, corn oil, cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, mineral oil, light mineral oil, myristol, octyldodecyl alcohol, olive oil, peanut oil, peach kernel oil, sesame oil, soybean oil, squalane); Medium: Solid carrier (glucose globules); Medium: Sterile (antibacterial water for injection, antibacterial sodium chloride injection); Thickening agents (see suspending agents); Waterproofing agents (cyclic polymethylsiloxane, ... Polydimethylsiloxane, dimethyl silicone oil; and / or solubilizers (benzalkonium chloride, benzyl chloride, cetylpyridine chloride, sodium docusate, nonylphenyl alcohol ether 9, nonylphenyl alcohol ether 10, octylphenyl polyol 9, poloxamer, polyoxyethylene 35 castor oil, polyoxyethylene 40, hydrogenated castor oil, polyoxyethylene 50 stearate, polyoxyethylene 10 oil ether, polyoxyethylene 20, cetearyl ether, polyoxyethylene 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate, dehydrated sorbitan monolaurate, dehydrated sorbitan monooleate, dehydrated sorbitan monopalmitate, dehydrated sorbitan monostearate, teroxaprol). This list is not intended to be exclusive, but rather represents only the categories and specific excipients that can be used in soft gel dosage forms as described herein.

[0104] In one embodiment, the matrix filler may include a release regulator, such as a fatty acid salt, fatty acid ester, or fatty acid polyoxyethylene derivative. The release regulator may also be a surfactant with a hydrophilic / lipophilic balance (HLB) value between about 2 and about 40. The HLB characteristics of the surfactant can be determined according to… Physical Pharmacy:Physical Chemical Principles in the Pharmaceutical Sciences The 4th edition, 371-373, edited by A. Martin, Lippincott Williams & Wilkins, Philadelphia (1993) is used to determine that its teachings of this kind are incorporated herein by reference.

[0105] In one embodiment, the matrix filler may include one or more hydrophilic carriers. Examples of hydrophilic carriers are all natural, synthetic, or semi-synthetic products, which can be defined as aqueous carriers that are not miscible with oil or can only be partially miscible with oil. All components may be used individually or, if possible, in mixtures of different percentages. The aqueous components may be used as the dispersing phase or as the dispersed phase.

[0106] Examples of aqueous solutions of hydrophilic polymers with various properties of water solubility or water dispersibility include polyethylene glycol, polyvinylpyrrolidone, polyacrylic acid, and derivatives such as Carbopol. ® 971. Polymethyl methacrylate polyoxyethylene polyoxypropylene copolymer (e.g., Poloxamer) ® Lutrol ™ Various hydrophilic polysaccharides, such as dextran, xanthan gum, stearin, acacia gum, guar gum, chitosan, cellulose or starch derivatives.

[0107] In one embodiment, the matrix filler may include a neutralizing agent. In one aspect, the neutralizing agent includes an organic acid, ester, or salt. In another aspect, the neutralizing agent includes at least one of lactate, fumarate, caprylate, decanoate, oleate, maleate, succinate, tartrate, citrate, glutamate, gluconate, their esters or salts, or combinations thereof.

[0108] In one embodiment, the matrix filler may comprise a hydrophilic internal phase and a lipid or lipophilic external phase. The internal phase of the matrix filler may comprise a plasticizer, such as propylene glycol, or a solubility enhancer, such as polyethylene glycol with a molecular weight in the range of about 200 g / mol to about 8000 g / mol. In another embodiment, the internal phase may comprise a cellulose derivative, a hydrophilic polymer, a polyacrylate, polyacrylic acid, and derivatives such as Carbopol. ™ ), polyethylene polymer, chitosan, or a combination thereof in an aqueous alcohol solution.

[0109] In another embodiment, the inner phase of the matrix filler may include polymers such as methylcellulose, hydroxypropyl methylcellulose, polymethyl methacrylate, or polyvinylpyrrolidone (PVP). The inner phase of the matrix filler may also be structured. As used herein, a “structured” inner phase of a matrix filler refers to a solid, semi-solid, or gel that is relatively stable in shape and generally does not aggregate to form large beads. Therefore, the structured inner phase of the matrix filler provides controlled drug release and stabilizes the physical state of the matrix. Without being bound by any theory, it is believed that the structured nature of the matrix filler hinders the solubilization and / or diffusion of the active pharmaceutical ingredient from the matrix filler. In another embodiment, the outer phase of the matrix filler may include vegetable oils, hydrogenated vegetable oils (including shortening), fatty acids, fatty acid esters, waxes, beeswax, soybean oil, or combinations thereof. In another embodiment, the active pharmaceutical ingredient may be dispersed in the inner phase of the matrix filler as a suspension.

[0110] In one embodiment, the matrix filler is a liquid (e.g., a solution, suspension, or dispersion) or a semi-solid (e.g., a paste or gel). In one aspect, the active pharmaceutical ingredient may be inherently liquid or semi-solid. In another aspect, the active ingredient can be prepared as a liquid or semi-solid, for example, by dissolving or otherwise mixing the active ingredient and optionally one or more pharmaceutical adjuvants in a carrier to form a solution. The carrier may be, for example, water, saline, dextran aqueous solution, glycerol, glycol (e.g., propylene glycol), ethanol, fatty acids, glycerides, oils, sterols, phospholipids, etc.

[0111] In one embodiment described herein, the matrix filler comprises a lipid or lipophilic medium that provides a suspension of an active pharmaceutical ingredient having a defined size. In one aspect, a soft capsule containing a suspension of the active pharmaceutical ingredient provides rapid release delivery of the active pharmaceutical ingredient.

[0112] In one embodiment described herein, the pharmaceutical composition provides a matrix filler of an active pharmaceutical ingredient or a derivative thereof based on a lipid or lipophilic material. The described matrix has a hydrophobic (lipophilic) surface that contacts a hydrophilic soft capsule shell to minimize any potential shell-filler interactions, such as when the soft capsule is filled with a hydrophilic material.

[0113] API

[0114] Examples of active pharmaceutical ingredients that may be included include agents classified as, for example, the following: corticosteroids, corticosteroid inhibitors, aldosterone antagonists, amino acids, anabolic steroids, androgens, antagonists, anthelmintics, anti-acne agents, antiadrenergic agents, anti-allergic agents, anti-amoebic agents, anti-androgens, anti-anemia agents, antianginal agents, anti-arthritis agents, anti-asthmatic agents, anti-atherosclerotic agents, antibacterial agents, anti-cholelithiasis agents, anticholinergic agents, anticoagulants, anticoccidial agents, antidiabetic agents, antidiarrheal agents, antidiuretics, antitoxins, antiestrogens, antifibrinolytic agents, antifungal agents, antiglaucoma agents, antihemophilic agents, antihemorrhagic agents, and anti-inflammatory agents. Histamines, antihypertensives, antihyperlipoproteinemia agents, antihypertensives, antiedema agents, anti-infectives, anti-inflammatory agents, antikeratinizing agents, antimalarial agents, antimicrobial agents, antimitotic agents, antifungal agents, antineurodynia agents, antiparasitic agents, anti-peristaltic agents, anti-Pneumocystis agents, antiproliferative agents, anti-benign prostatic hyperplasia agents, antiprotozoal agents, antiallergic agents, antipsoriatic agents, antirheumatic agents, antisteroids, antiseborrheic agents, antisecretive agents, anticonvulsants, antithrombotic agents, antitussives, antiulcer agents, antilithiasis agents, antiviral agents, appetite suppressants, benign prostatic hyperplasia treatment agents, bone resorption inhibitors, bronchodilators, carbonic anhydrase inhibitors, cardiac depressants, heart... Organ protectants, cardiotonics, cardiovascular agents, choleretics, cholinergic agents, cholinergic agonists, cholinesterase inactivators, anticoccidial agents, contrast agents, diagnostic aids, diuretics, ectoparasite-killing agents, enzyme inhibitors, estrogens, fibrinolytic agents, oxygen free radical scavengers, glucocorticoids, gonadotropins, hair growth stimulants, hemostatic agents, hormones, cholesterol lowering agents, blood sugar lowering agents, blood lipid lowering agents, anti-edema agents, imaging agents, immunomodulators, immunomodulatory factors, immunostimulants, immunosuppressants, adjunctive agents for erectile dysfunction treatment, inhibitors, keratolytic agents, LHRH agonists, liver disease treatment agents, luteinizing agents, mucolytics, mydriatics, nasal decongestants, neuromuscular blocking agents. Discontinued drugs, non-steroidal steroid derivatives, non-steroidal anti-inflammatory drugs, oxytocin, plasminogen activator, platelet-activating factor antagonist, platelet aggregation inhibitor, potentiator, thyroid-stimulating hormone, prostaglandins, prostate growth inhibitors, prothyroid-stimulating hormone, radioactive agents, modulators, relaxants, redistribution agents, scabies eliminators, sclerosing agents, selective adenosine A1 antagonists, steroids, inhibitors, symptomatic multiple sclerosis, steroids, thyroid hormones, thyroid suppressants, thyroid-stimulating agents, amyotrophic lateral sclerosis agents, Paget's disease agents, unstable angina agents, uricosuric agents, vasoconstrictors, vasodilators, diuretics, wound healing agents, and xanthine oxidase inhibitors. Further examples of suitable drug ingredients include those listed in the Merck Index (13th edition, Wiley, 2001), the United States Pharmacopeia-National Formulary (USP–NF), and the FDA Orange Book, each incorporated herein by reference into the teachings on drug active ingredients.

[0115] The formulation may contain any therapeutic, diagnostic, preventative, or nutritional agent. Exemplary agents include, but are not limited to, stimulants; analgesics; anesthetics; anti-asthmatics; anti-arthritis agents; anticancer agents; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiabetic agents; antidiabetic agents; antiemetics; anthelmintic agents; antihistamines; antilipidemics; antihypertensives; anti-infectives; anti-inflammatory agents; anti-migraine agents; antitumor agents; anti-Parkinson's drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; antituberculosis agents; antiulcer agents; antiviral agents; anxiolytics; appetite suppressants (anorexia nervosa); and agents for attention deficit disorder and attention deficit hyperactivity disorder. Drugs for movement disorders; cardiovascular drugs, including calcium channel blockers, antianginal drugs, central nervous system (“CNS”) drugs, beta-blockers and antiarrhythmic agents; central nervous system stimulants; diuretics; genetic material; electrolytes; hypnotics; hypoglycemic agents; immunosuppressants; muscle relaxants; anesthetic antagonists; nicotine; nutritional supplements; parasympathetic blocking agents; peptide drugs; psychostimulants; sedatives; salivary promoters; steroids; smoking cessation agents; sympathomimetic drugs; tranquilizers; vasodilators; beta-agonists; and uterine contraction inhibitors.

[0116] The first class of drugs is selected based on the presence of weakly acidic, basic, or amphoteric groups in the molecule that can form salts. Any drug containing acidic or basic functional groups, such as amines, imines, imidazols, guanidines, piperidinyls, pyridinyls, quaternary ammonium groups or other basic groups, or carboxylic acids, phosphoric acids, phenols, sulfuric acids, sulfonic acids or other acidic groups, can react with deionizing agents.

[0117] Certain drugs containing acidic or basic functional groups and thus convertible into the corresponding salts used in the described formulations include, but are not limited to, acetaminophen, acetylsalicylic acid, alendronate, alosetron, amantadine, amlodipine, anagrelide, argatroban, atomoxetine, atorvastatin, azithromycin, balsalazine, bromocriptine, bupropion, candesartan, carboplatin, ceftriaxone, clavulanic acid, clindamycin, simmetidine, dehydrocholic acid, dextromethorphan, diclofenac, bicycloamine, diflunisal, diltiazem, donepezil, doxorubicin, doxepin, epirubicin, etodoxacin, ethacrynic acid, fenprofen, fluoxetine, flurbiprofen, furosemide, gemfibrozil, hydroxyzine, ibuprofen, imipramine, indomethacin, ketoprofen, and levothyroxine. Maprotiline, Meclizine, Methadone, Methylphenidate, Minocycline, Mitoxantrone, Flufloxacin, Mycophenolic acid, Naphazoline, Nifluoxate, Ofloxacin, Ondansetron, Pantoprazole, Paroxetine, Pergolitide, Pramipexole, Phenytoin, Pravastatin, Probenecid, Rabeprazole, Risedronate, Retinic Acid, Ropinirole, Selegiline, Sulindac, Tamsulosin, Tilmide Sartan, Terbinafine, Theophylline, Tiludrotic Acid, Tinzaheparin, Ticarcillin, Tometrine, Valproic Acid, Salicylic Acid, Sevelamer, Ziprasidone, Zoledronic Acid, Acetaminophen, Salbutamol, Amotriptan, Amitriptyline, Amphetamine, Atracurium, Beclomethasone, Benzophenamine, Biperidone, Bosentan, Bromhexine, Brompheniramine, Carbazamine, Caffeine, Capecitabine Cabergoline, Cetirizine, Chlorpheniramine, Chlorpheniramine, Chlorpromazine, Citalopram, Clavulanate Potassium, Ciprofloxacin, Clomastine, Clomiphene, Clonidine, Clopidogrel, Codeine, Cyclobenzaline, Cyproheptadine, Deraviridine, Amfepramone, Valproic acid, Desipramine, Dextromethorphan, Dextromethorphan, Dextrochlorpheniramine, Dextromethorphan, Amphetamine, Dextromethorphan Amphetamine, dextromethorphan, flunisal, phenylenediamine methylsulfate, diphenhydramine, dolasetron, doxylamine, enoxaparin, ergotamine, ertepenem, eprosartan, escitalopram, esomeprazole, fentanyl, fexofenadine, flufenamic acid, fluvastatin, flufenazine, fluticasone, fosinopril, fultriptan, gabapentin, galata Gatifloxacin, Gemcitabine, Haloperidol, Hyaluronic Acid, Hydrocodone, Hydroxychloroquine, Hyoscine, Imatinib, Imipenem, Ipatopeptide, Lisinopril, Leuprorelin, Levoprooxyfen, Losartan, Mephenazone, Mefenazate, Meperazolium, Pethidine, Mefenbutatin, Mephenazine, Mesorazine, Mesorazine, Metoprolol, Metformin, Metazidine, Metformin Scopolamine, Mesimergot, Metoprolol, Metronidazole, Mibeprazole, Montelukast, Morphine, Mometasone, Naratriptan, Nefenavir, Nortriptan, Noscapine, Nilindrine, Omeprazole, Ophenazine, Oseltamivir, Oxybutynin, Papaverine, Pentazocine, Benzotrazine, Phentermine, Pioglitazone, Pilocarpine, Prochlorperazine, Piramine, QuetinibRanitidine, rivastigmine, rosiglitazone, salmeterol, sertalin, sotalol, sumatriptan, tazobactam, tacrolimus, tamoxifen, ticlopidine, topiramate, tolterodine, triptorelin, triptorelin, triptolide, tramadol, trifloxacin, ursodeoxycholic acid, promethazine, propranolol, pseudoephedrine, piracetam, quinidine, sodium benzoate, sermorrelin, tacrolimus, tigesteroids, teriparin, tolterodine, triptorelin dihydroxynaphthyl acid, scopolamine, venlafaxine, zamivir, aminocaproic acid, aminosalicylic acid, hydromorphone, isoseltrine, levonorgestrel, mehalazoline, nalidixic acid, and para-aminosalicylic acid.

[0118] In one embodiment, the composition described herein comprises one or more active pharmaceutical ingredients that can be used to treat, delay progression, postpone onset, prevent, relieve or reduce symptoms of pain, inflammation, fever, or symptoms caused by cough or cold. In one embodiment described herein, the active pharmaceutical ingredient comprises one or more of the following: astemizole, azelastine, atazatidine, brompheniramine, carbixamine, cetirizine, chlorpheniramine, chlormastine, cyproheptadine, desloratadine, dextrobromopheniramine, dextrochlorpheniramine, diphenhydramine, fexofenadine, hydroxyzine, levocetirizine, loratadine, indamine, pheniramine, bentoxamine, promethazine, Piramine, Terfenadine, Trapinalamine, Triptorelin, Acetyldihydrocodeine, Benzophenone, Benzoate, Benzylmorphine, Biphenyl bromide, Butaminoate, Butorphanol, Pentoxyverine, Chlorbenzanol, Chlorbutenol, Chlorfenapyrol, Clopidogrel, Codeine, Dextromethorphan, Diacetylmorphine, Dibuprofen, Dihydrocodeine, Dimethomorphine, Dimethoxypentane, Diphenhydramine, Hydroxypropiconazole, Hydroxypropiconazole, Ethylmorphine, Non- Drosophila, Glaucin, Hydrocodone, Hydromorphone, Isobutylamine, Opioids, Levopropiperazine, Levomethadone, Levopropoxyphene, Mepitex, Methadone, Morclofen, Napilone, Nicocodone, Nicotinic acid, Normethadone, Norscarpine, Oxycladine, Osoramine, Pentoxyverine, Pholcodone, Piperazate, Diethylpiperidinedione, Pronodizine, Tiperidine, Zipeppropanol, Acetylcysteine, Marshmallow Root, Ambroxol Antimony pentasulfide, bromhexine, carboxymethylcysteine, eucalyptol, compound preparations, compound preparations, creosote, denbromocriptine hydrochloride, domiocol, alfa-chain enzyme, ipramone, erdostatin, guaiacol sulfonate, guaiacol, ivy leaf, ipecac, letostrine, levogeranione, mannitol, forsythoside, netinibine, potassium iodide, cornus officinalis, sobromol, spronin, thiopronin, polyethylene glycol, or combinations thereof. In one aspect, the active pharmaceutical ingredient includes one or more of dextromethorphan hydrobromide, menthol, or combinations thereof.

[0119] In one embodiment described herein, the active pharmaceutical ingredient is an anti-allergy agent. Exemplary anti-allergy agents include pseudoephedrine, cetirizine, loratadine, fexofenadine, diphenhydramine, levocetirizine, desloratadine, or combinations thereof.

[0120] In one embodiment described herein, the active pharmaceutical ingredient is an oral rinse. Exemplary oral rinses include phenol, ethanol, thymol, eucalyptol, methyl salicylate, chlorhexidine gluconate, hexadecylpyridine chloride, cyclohexidine, triclosan, hydrogen peroxide, doxorubicin, or combinations thereof. In one embodiment described herein, the active pharmaceutical ingredient includes an oral rinse comprising one or more of ethanol (about 20% to about 30%), menthol (0.042%), thymol (0.064%), methyl salicylate (0.06%), and eucalyptol (0.092%).

[0121] In one embodiment described herein, the active pharmaceutical ingredient is an antidiarrheal or antacid comprising bismuth subsalicylate, loperamide hydrochloride, aluminum hydroxide, magnesium hydroxide, dimethyl silicone oil, aluminum carbonate, calcium carbonate, sodium bicarbonate, magnesium aluminum silicate, hydrotalcite, magnesium aluminate hydrate, cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, omeprazole, esomeprazole, rabeprazole, pantoprazole, dexlansoprazole, or combinations thereof. In one embodiment described herein, the active pharmaceutical ingredient comprises bismuth subsalicylate (approximately 17.6 mg), benzoic acid, D&C Red 22, D&C Red 28, flavoring agent, magnesium aluminum silicate, methylcellulose, sodium saccharin, salicylic acid, sodium salicylate, sorbic acid, and one or more of water.

[0122] In another embodiment, the active pharmaceutical ingredient is an irritable bowel syndrome (IBS) therapeutic agent. Exemplary non-limiting active pharmaceutical ingredients that can be used to treat IBS include antidiarrheal drugs, such as atropine and lomotil. ® ), bicyclic amine (Bentyl) ® loperamide (Imodium) ® Xifaxan ® Lotronex ® ); bile acid binders, such as cholestyramine (Prevailite) ® Constipation treatments, such as linaclotide (Linzess) ® (or Lubiprostone (Amitiza) or a combination thereof.)

[0123] In one embodiment described herein, the active pharmaceutical ingredient is a constipation treatment agent, such as linazesin. ® ) or Lubiprostone (Amitiza® ), methylcellulose, polycarboxylic acid, psyllium husk, mineral oil, glycerin, sodium docusate, sodium bicarbonate, sodium phosphate, magnesium citrate, magnesium oxide, magnesium sulfate, bisacodyl, sennoside, senna leaves, castor oil, or combinations thereof.

[0124] In another embodiment described herein, the active pharmaceutical ingredient comprises one or more corticosteroids used to treat inflammatory diseases and conditions, as well as gastrointestinal inflammation (including, but not limited to, esophagitis). In one embodiment described herein, the active pharmaceutical ingredient comprises one or more corticosteroids, including but not limited to aclomethasone, ancinonide, beclomethasone, betamethasone, budesonide, cicotinide, clobetasol, clobetasol, clocolone, chlorpromazine, cotinazole, diffluxol, deoxycorticosterone, desonide, desoxymethasone, dexamethasone, difluralasone, diflucolone, difluprednisolone, fluchloron, fludrocortisone, fluoxetine, fluoxetine, flunicolone acetonide, fluocin ... Cod, fluocinolone, fluocinolone, fluocinolone, fluticasone, fluticasone propionate, fluprednisolone, formocatal, halometasone, hydrocortisone acetate propionate, hydrocortisone butyrate, hydrocortisone butyrate, chlorpromazine, methylprednisolone, methylprednisolone, methylprednisolone acetate propionate, mometasone furoate, permethasone, prednicarbamate, prednisone, prednisolone, prednisolone, rimexolone, tecristosol, triamcinolone, urobetasol, combinations thereof, or pharmaceutically acceptable salts or esters thereof.

[0125] In another embodiment described herein, the active pharmaceutical ingredient includes one or more of 5-fluorouracil, 5-fluorodeoxyuridine, capecitabine, derivatives thereof, or combinations thereof for the treatment of tumor formation (including but not limited to head and neck tumor formation).

[0126] In another embodiment described herein, the active pharmaceutical ingredient includes one or more of calcium supplements or calcium mimics, including but not limited to cinacalcet, its derivatives or combinations thereof, for the treatment of hyperthyroidism, hypercalcemia, hyperparathyroidism, parathyroid carcinoma or combinations thereof.

[0127] In some implementations, the active pharmaceutical ingredient is a hypnotic drug. Examples of hypnotic drugs include, but are not limited to, doxylamine, diphenhydramine hydrochloride, melatonin, L-theanine, or combinations thereof.

[0128] In some embodiments, the active pharmaceutical ingredient is an oral saliva substitute, such as monofluorophosphate, lactoferrin, lysozyme, lactoperoxidase, glucose oxidase, polysaccharidase, dextranase, glycerol, or combinations thereof.

[0129] In some embodiments, the active pharmaceutical ingredient is a teeth bleaching agent or teeth whitening agent, including but not limited to urea peroxide, sodium bicarbonate, silica hydrate, silica, polyvinylpyrrolidone, potassium nitrate, sodium monofluorophosphate, sodium tripolyphosphate, strontium chloride, or combinations thereof.

[0130] In another embodiment, the active pharmaceutical ingredient is an enamel strengthener. Exemplary enamel strengtheners include potassium nitrate, strontium acetate, strontium chloride, sodium calcium phosphosilicate, or combinations thereof.

[0131] In another embodiment, the active pharmaceutical ingredient is an oral anesthetic, including but not limited to benzocaine, lidocaine, clove oil, or combinations thereof.

[0132] In one embodiment, the active pharmaceutical ingredient is an effervescent tablet, including but not limited to sodium bicarbonate, citric acid, tartaric acid, or combinations thereof. The effervescent tablet may be combined with one or more of the following medications: cold, cough, allergy, nasal decongestant, antitussive, expectorant, antihistamine, stimulant, sedative, anti-inflammatory, antibiotic, antiviral, anti-asthmatic, anti-migraine, hypnotic, narcotic analgesic, or narcotic antagonist active pharmaceutical ingredients, or other combinations thereof.

[0133] In one embodiment described herein, the active pharmaceutical ingredient is one or more nonsteroidal anti-inflammatory drugs (NSAIDs). Non-limiting examples of active pharmaceutical ingredients for NSAIDs include aspirin, ibuprofen, aceclofenac, acyclophrine, azapromide, diphenhydramine, bromofenac, carprofen, celecoxib, magnesium choline salicylate, diclofenac, diflunisal, etodoxacin, edoxoxac, faxamine, fenbufen, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketoprofen, lornoxicam, cloxoprofen, meloxicam, meclofenamic acid, meloxicam, memidazole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenylbutazone, acetaminophen, parecoxib, phenylbutazone, piroxicam, salicylates, sulindac, sulfinpyrazone, sulofen, tenoxac, thiamethoxam, tometetin, vardicoxib, or combinations thereof.

[0134] In another embodiment, suitable active pharmaceutical ingredient may include analgesics such as: acetylsalicylic acid, aloxipine, aminopyrine, anilines, benorilate, benzomorphan derivatives, benzilamide, buccolol, buprenorphine, butorphanol, calcium carbadate, salicylcholine, codeine, atoramide, atropropoxyphene, atorcinol, diacetylmorphine, diflunisal, dihydrocodeine, dihydrocodone, dihydromorphine, diphenylpropylamine derivatives, dipyridocetyl alcohol, ethylbenzamide, fentanyl, flutafenine, flupirtine, gelafenimine, guanecitelsal, hydrocodone, hydrocodone bitartrate, hydromorphone hydrochloride, imidazole salicylate, ketopromidone, sodium aminopyrine, methadone. Morphine derivatives, morphine, morphine sulfate pentahydrate, morphine-6-glucuronic acid, salicylate morpholine, nalbuphine, natural opioid alkaloids, nefopam, nicotinic morphine, nitfinazone, norhydrocodone, noroxycodone, opioids, opium, papaverine derivatives, hydroxycodeine, oxycodone, oxycodone hydrochloride, hydroxymorphone, papaverine, pentazocine, meperidine, phenacetin, phenazocine, phenacetin, phenylpiperidine derivatives, pyridine, potassium salicylate, propatematidine, imipramine, pyrazolone, limazol, salicylamide, salicylic acid derivatives, disodium salicylate, sodium salicylate, tapentadone, teridine, tramadol, viminol, ziconopeptide, or combinations thereof.

[0135] In another embodiment, the active pharmaceutical ingredient disclosed herein includes an opioid substance selected from buprenorphine, codeine, dextromethorphan, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, morphine, pentazocine, hydroxycodeine, oxycodone, hydroxymorphone, norhydrocodone, noroxycodone, morphine-6-glucuronide, tramadol, tapentadol, dihydromorphine, or combinations thereof.

[0136] In one embodiment described herein, the active pharmaceutical ingredient is a probiotic. Exemplary probiotics include Bifidobacterium infantis (Bifidobacterium infantis). Bifidobacterium infantis 35624, Bifidobacterium lactis ( Bifidobacterium lactis HN019, Lactobacillus reuteri ( Lactobacillus reuteri ATCC55730, Lactobacillus rhamnosus ( Lactobacillus rhamnosus Lactobacillus casei ( Lactobacillus casei DN-114 001, Bifidobacterium lactis ( Bifidobacterium lactis Bb-12 or combinations thereof.

[0137] In another embodiment, the active pharmaceutical ingredient comprises an active pharmaceutical ingredient for treating addiction disorders, such as: nicotine, nicotine ion exchange resin complex, bupropion, varenicline, disulfiram, calcium carbamate, acampolic acid, naltrexone, buprenorphine, methadone, levonorgestrel, lofexidine, betahistine, cinnarizine, flunarizine, acetylleucine, gangliosides, ganglioside derivatives, teilazadeh, riluzole, thaliplatin, hydroxybutyric acid, amipyridine, or combinations thereof. In one embodiment described herein, the active pharmaceutical ingredient comprises one or more of nicotine (about 2 mg), potassium acetaminophen, magnesium oxide, menthol, peppermint oil, xylitol, sodium bicarbonate, sodium carbonate, or combinations thereof.

[0138] In another embodiment, the active pharmaceutical ingredient may include those present in energy drinks, including caffeine, taurine, ginkgo, glucuronide, inositol, niacin, nicotinamide, d-panthenol, ginseng root extract, pyridoxine hydrochloride, vitamin B12, cyanocobalamin, riboflavin, guarana, L-carnitine, or combinations thereof.

[0139] In another embodiment, the pharmaceutical composition may comprise a vitamin or a mineral. As used herein, “vitamin” refers to a nutritional or pharmaceutical ingredient comprising organic matter that is generally considered essential for the normal growth and activity of a subject (e.g., a human or non-human animal patient to whom the composition is administered). Non-limiting examples of vitamins include, but are not limited to, vitamins A (retinol), B1 (thiamine), B2 (riboflavin), B complex, B6 (pyridoxine), B12 (cobalamin), C (ascorbic acid), D (cholecalciferol), E (tocopherol), F (linoleic acid), G, H (biotin), and K, as well as choline, folic acid, inositol, niacin, pantothenic acid, para-aminobenzoic acid, or combinations thereof.

[0140] Vitamins may also include naturally occurring inorganic substances (such as minerals) that are generally considered essential for the normal growth and activity of the subject (e.g., a human or non-human animal patient to whom the composition is administered). Examples of minerals include, but are not limited to, boron, calcium, chromium, copper, iron, magnesium, manganese, molybdenum, nickel, phosphorus, selenium, silicon, tin, vanadium, or zinc.

[0141] In some implementations, the active pharmaceutical ingredient is a pharmaceutical nutrient. Examples of nutrient products include, but are not limited to, amino acids, terpenoids (e.g., carotenoid terpenoids and non-carotenoid terpenoids), herbal supplements, homeopathic supplements, glandular supplements, polyphenols, flavonoid polyphenols, phenolic acids, curcumin, resveratrol, lignans, glucosinolates, isothiocyanates, indoles, thiosulfinates, phytosterols, anthraquinones, capsaicin, piperine, chlorophyll, betaine, oxalic acid, acetyl-L-carnitine, allantoin, androstenediol, androstenedione. Betaine (trimethylglycine), caffeine, calcium pyruvate (pyruvate), carnitine, carnosine, carotene, carotenoids, choline, chlorogenic acid, cholic acid, chondroitin sulfate, chondroitin sulfate, cholesterol, succinate, coenzyme Q10, conjugated linoleic acid, corosolic acid, creatine, dehydroepiandrosterone, dichlorophenol, diindolemethane, dimethylglycine, dimercaptosuccinic acid, ebuselenline, ellagic acid, enzymes, fisetone, monazine, gluconic acid (glucosidate), glucosamine (hydrochloric acid or sulfate), glucosamine ( N -Acetyl), glutathione, hesperidin, hydroxy-3-methylbutyric acid, 5-hydroxytryptophan, indole-3-methanol, inositol, isothiocyanate, linolenic acid-γ, lipoic acid (α), melatonin, methanesulfonylmethane, minerals, naringin, pancreatic enzymes, para-aminobenzoic acid, para-hydroxybenzoic acid esters (methyl or propyl), phenols, phosphatidylcholine, phosphatidylserine, phospholipids, phytosterols, progesterone, dienoyl ketones, ω-3 fatty acids, quercetin, resveratrol, d-ribose, rutin, S-adenosylmethionine, salicylic acid, sulforaphane, tartaric acid, piracetam, tetrahydrobenzene Parbutin, theophylline, theobromine, tebuconazole, troxazepam, tryptophan, tocotrienols (α, β, and γ), zeaxanthin, ginkgo, ginger, cat's claw herb, St. John's wort, aloe vera, evening primrose, garlic, ginseng, chili pepper, angelica, ginseng, white chrysanthemum, fenugreek, echinacea, green tea, marshmallow, saw palmetto, tea tree oil, fish oil, plantain seed, calamari, licorice root, Mahonia japonica, hawthorn, turmeric, witch hazel, yohimbine, vacuolar thiol protease, mistletoe, blueberry, bee pollen, peppermint oil, β-carotene, genistein, lutein, lycopene, polyphenols, etc. Other examples of suitable nutritional supplements include... Handbook of Nutraceuticals and Functional Foods Those listed in Robert EC Wildman, ed., CRC Press (2001), are incorporated herein by reference for educational purposes related to nutritional supplements.

[0142] Other available pharmaceutical ingredients or nutritional supplements that may be included as active ingredients include fish oil, egg oil, squid oil, krill oil, nut oil, seed oil; soybean oil, avocado oil, sea buckthorn seed or berry oil, sage seed oil, algae oil, flaxseed oil, sacha inchi oil, blue thistle oil, hemp oil, omega-3 fatty acids, polyunsaturated omega-3 fatty acids, hexadecanoic acid (HTA), alpha-linolenic acid (ALA), octadecanoic acid (SDA), eicosapentaenoic acid (ETE), eicosapentaenoic acid (ETA), eicosapentaenoic acid (EPA, codole), docosapentaenoic acid (HPA), docosapentaenoic acid (DPA, stigmata), docosahexaenoic acid (DHA, oleic acid), docosapentaenoic acid, docosahexaenoic acid (Nysenoic acid), and free acids, their vinyl esters or other esters or salts. In one aspect, the pharmaceutical ingredient is a highly purified omega-3 fatty acid, its ester or salt.

[0143] In one embodiment described herein, the active pharmaceutical ingredient is the only active ingredient in the pharmaceutical composition. In another embodiment, the active ingredient or pharmaceutical ingredient may be an active pharmaceutical ingredient, its derivatives, or a combination thereof.

[0144] In one embodiment, the pharmaceutical composition described herein is suitable for water-soluble as well as slightly soluble or insoluble active pharmaceutical substances.

[0145] In another embodiment, the pharmaceutical composition described herein may comprise a pharmaceutically acceptable salt of any of the above-described active pharmaceutical ingredients. The term "pharmaceutically acceptable salt" for active pharmaceutical ingredient includes alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; and salts formed with organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, succinic acid, tartaric acid, methanesulfonic acid, toluenesulfonic acid, etc. In another embodiment, the active pharmaceutical ingredient may also be in the form of its pharmaceutically acceptable salt, uncharged or charged molecules, molecular complexes, solvates, or anhydrous forms, and may, if applicable, be a single isomer, enantiomer, racemic mixture, or mixture thereof.

[0146] In another embodiment, the active pharmaceutical ingredient may be any of its crystalline, polymorphic, semi-crystalline, amorphous or polyamorphous forms or mixtures thereof.

[0147] In one embodiment described herein, the ratio of the active ingredient or drug substance to the total matrix filler (e.g., matrix filler components and active drug substance) may be from about 1:50 to about 1:1 by weight, including all ratios within the specified range. In another embodiment described herein, the ratio of the active ingredient to the total matrix filler may also be from about 1:16 to about 1:1 by weight, including all ratios within the specified range. The ratio of the active ingredient to the total matrix filler may also be about 1:16; about 1:9; about 1:3; about 1:2; or about 1:1, including all ratios within the specified range.

[0148] In one embodiment described herein, the active ingredient or drug constitutes about 5% to about 80% of the matrix filler mass, including all iterations of integers within the specified range. In one aspect described herein, the active ingredient or drug constitutes about 80% of the matrix filler mass. In another aspect, the active ingredient or drug constitutes about 60% of the matrix filler mass. In another aspect, the active ingredient or drug constitutes about 40% of the matrix filler mass. In another aspect, the active ingredient or drug constitutes about 6% of the matrix filler mass.

[0149] In another embodiment described herein, the active ingredient or drug constitutes about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 15%, about 10%, about 5%, about 2%, or about 1% of the matrix filler mass.

[0150] In one embodiment described herein, the weight ratio of the active pharmaceutical ingredient to the matrix filler material ranges from about 1:20 to about 10:1. In one aspect, the weight ratio of the active pharmaceutical ingredient to the matrix filler material is about 1:3. In another aspect, the weight ratio of the active pharmaceutical ingredient to the matrix filler material is about 1:9. In yet another aspect, the weight ratio of the active pharmaceutical ingredient to the matrix filler material is about 1:17.

[0151] In some implementations, one or more active pharmaceutical ingredients may be incorporated into soft gel capsules as described herein.

[0152] In one embodiment, the composition described herein provides a dose of the active ingredient for administration. The dosage form can be administered, for example, to a subject or a subject in need. In one aspect, the subject can be a mammal or a mammal in need. In another aspect, the dosage form can be administered, for example, to a human or a person in need. In yet another aspect, the human subject or a human subject in need is a medical patient.

[0153] In one embodiment, the pharmaceutical composition described herein comprises about 0.01 mg to about 2000 mg of an active pharmaceutical ingredient, including all integers within the specified range. In one aspect, the active pharmaceutical ingredient is about 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, or about 280 mg. mg, approximately 290mg, approximately 300mg, approximately 310mg, approximately 320mg, approximately 330mg, approximately 340mg, approximately 350mg, approximately 360mg, approximately 370mg, approximately 380mg, approximately 390mg, approximately 400mg, approximately 410mg, approximately 420mg, approximately 430mg, approximately 440mg, approximately 450mg, approximately 460mg, approximately 470mg, approximately 480mg, approximately 490mg, approximately 500mg, approximately 510mg, approximately 520mg, approximately 530mg, approximately 540mg, approximately 550mg, approximately 560mg, approximately 570mg, approximately 580mg, approximately 590mg, approximately 600mg, approximately 610mg, approximately 6 20mg, approximately 630mg, approximately 640mg, approximately 650mg, approximately 660mg, approximately 670mg, approximately 680mg, approximately 690mg, approximately 700mg, approximately 710mg, approximately 720mg, approximately 730mg, approximately 740mg, approximately 750mg, approximately 760mg, approximately 770mg, approximately 780mg, approximately 790mg, approximately 800mg, approximately 810mg, approximately 820mg, approximately 830mg, approximately 840mg, approximately 850mg, approximately 860mg, approximately 870mg, approximately 880mg, approximately 890mg, approximately 900mg, approximately 910mg, approximately 920mg, approximately 930mg, approximately 940mg, approximately 950mg Approximately 960mg, approximately 970mg, approximately 980mg, approximately 990mg, approximately 1000mg, approximately 1010mg, approximately 1020mg, approximately 1030mg, approximately 1040mg, approximately 1050mg, approximately 1060mg, approximately 1070mg, approximately 1080mg, approximately 1090mg, approximately 1100mg, approximately 1110mg, approximately 1120mg, approximately 1130mg, approximately 1140mg, approximately 1150mg, approximately 1160mg, approximately 1170mg, approximately 1180mg, approximately 1190mg, approximately 1200mg, approximately 1210mg, approximately 1220mg, approximately 1230mg, approximately 1240mg, approximately 1250mg.Approximately 1260mg, approximately 1270mg, approximately 1280mg, approximately 1290mg, approximately 1300mg, approximately 1310mg, approximately 1320mg, approximately 1330mg, approximately 1340mg, approximately 1350mg, approximately 1360mg, approximately 1370mg, approximately 1380mg, approximately 1390mg, approximately 1400mg, approximately 1410mg, approximately 1420mg, approximately 1430mg, approximately 1440mg Approximately 1450mg, approximately 1460mg, approximately 1470mg, approximately 1480mg, approximately 1490mg, approximately 1500mg, approximately 1510mg, approximately 1520mg, approximately 1530mg, approximately 1540mg, approximately 1550mg, approximately 1560mg, approximately 1570mg, approximately 1580mg, approximately 1590mg, approximately 1600mg, approximately 1610mg, approximately 1620mg, approximately 1630mg g, approximately 1640mg, approximately 1650mg, approximately 1660mg, approximately 1670mg, approximately 1680mg, approximately 1690mg, approximately 1700mg, approximately 1710mg, approximately 1720mg, approximately 1730mg, approximately 1740mg, approximately 1750mg, approximately 1760mg, approximately 1770mg, approximately 1780mg, approximately 1790mg, approximately 1800mg, approximately 1810mg, approximately 1820mg mg, approximately 1830 mg, approximately 1840 mg, approximately 1850 mg, approximately 1860 mg, approximately 1870 mg, approximately 1880 mg, approximately 1890 mg, approximately 1900 mg, approximately 1910 mg, approximately 1920 mg, approximately 1930 mg, approximately 1940 mg, approximately 1950 mg, approximately 1960 mg, approximately 1970 mg, approximately 1980 mg, approximately 1990 mg, approximately 2000 mg or even more.

[0154] Manufacturing method

[0155] In one aspect, soft gel capsules are prepared using a rotary mold apparatus as described in U.S. Patent Nos. 5,459,983, 5,146,730, and 6,482,516, each of which is incorporated herein by reference for such teachings.

[0156] Another embodiment described herein includes a process for manufacturing soft gel capsules, comprising the methods described herein. The process includes preparing a gel block composition comprising a film-forming water-soluble polymer, one or more disintegrants, a suitable plasticizer or co-solvent and solvent, optionally one or more viscosity-modifying polymers; casting the gel block into a film or strip using a heat-controlled roller or surface; and manufacturing soft capsules containing a matrix filler using a rotary die technique. The thickness of the film or strip forming the soft capsule shell is from about 0.010 inches (≈0.254 mm) to about 0.050 inches (≈1.27 mm), including all integers within the specified range. The shell thickness can be about 0.010 inches (≈0.254 mm), about 0.015 inches (≈0.381 mm), about 0.02 inches (≈0.508 mm), about 0.03 inches (≈0.762 mm), about 0.04 inches (≈1.02 mm), or about 0.05 inches (≈1.27 mm). In one embodiment, the thickness includes approximately 0.02 inches (≈0.508 mm) to approximately 0.040 inches (≈1.02 mm). In one embodiment, the housing thickness is approximately 0.028 inches (≈0.711 mm). In another embodiment, the housing thickness is approximately 0.033 inches (≈0.838 mm). In yet another embodiment, the housing thickness is approximately 0.038 inches (≈0.965 mm).

[0157] In one embodiment described herein, the soft capsule shell encapsulates a matrix filler as described herein. In another embodiment described herein, the soft capsule shell and the encapsulating matrix filler have an external dimension of about 2 ellipses to about 30 ellipses, including all iterations of capsule sizes within a specified range (e.g., 2 ellipses, 3 ellipses, 4 ellipses, 5 ellipses, 6 ellipses, 7 ellipses, 8 ellipses, 10 ellipses, 12 ellipses, 16 ellipses, 20 or 30 ellipses). In yet another embodiment described herein, the soft capsule shell and the encapsulating matrix filler have an external dimension of about 2 circles to about 28 circles, including all iterations of capsule sizes within a specified range (e.g., 2 circles, 3 circles, 4 circles, 5 circles, 6 circles, 7 circles, 8 circles, 10 circles, 12 circles, 16 circles, 20 circles or 28 circles). In another embodiment described herein, the soft capsule shell and encapsulation matrix filler have an external dimension of about 2 elongated ellipses to about 22 elongated ellipses, including all iterations of capsule sizes within a specified range (e.g., 2 elongated ellipses, 3 elongated ellipses, 4 elongated ellipses, 5 elongated ellipses, 6 elongated ellipses, 7 elongated ellipses, 8 elongated ellipses, 10 elongated ellipses, 11 elongated ellipses, 12 elongated ellipses, 14 elongated ellipses, 16 elongated ellipses, 20 elongated ellipses, or 22 elongated ellipses). The size specifications of soft capsules and tablets are known to those skilled in the art. See also Remington's Essentials of Pharmaceutics PharmaceuticalPress Publishing Company, London, UK, 1st edition, 2013, which incorporates such teachings hereby.

[0158] In one non-limiting exemplary embodiment, the soft capsule can be manufactured by the following steps:

[0159] (a) Preparing a gel block composition comprising one or more film-forming polymers, one or more disintegrants, one or more plasticizers or cosolvents and one or more solvents to form a gel block; optionally, the gel block composition further comprises one or more viscosity-modifying polymers.

[0160] (b) Heat the gel block under vacuum at 57°C to 80°C for 15 to 30 minutes to form a uniform and degassed gel block;

[0161] (c) Aged uniformly and degassed gel blocks at 65°C to 70°C for 12 to 48 hours to form aged gel blocks;

[0162] (d) Cast aged gel blocks into films or strips using heat-controlled rollers or surfaces;

[0163] (e) Transfer the homogenized filler solution to the encapsulation line;

[0164] (f) Encapsulation of homogenized filling solution within gel block membranes or strips using a rotary die to form capsules;

[0165] (g) Drying and trimming the capsules;

[0166] (h) Optionally, the capsule is coated and dried; and

[0167] (i) Post-processing and packaging.

[0168] Figure 1 A flowchart of an exemplary method for manufacturing fast-release soft gel capsules as described above is provided. Additional processing aids that may be used during the manufacturing process are shown in Table 3. Nitrogen is used to purge oxygen from the gel mass. Medium-chain triglycerides and lecithin are used as lubricants to prevent the gel strip from adhering to the spreader box and rotary die-packing machinery. The capsules are also lubricated to prevent adhesion during post-manufacturing processing.

[0169]

[0170] When manufacturing soft gel capsules, they are typically dried for a period of time. This allows water to evaporate from the capsule shell, increasing rigidity and strength. Approximately 5% to 30% by mass of water from the shell can evaporate. Therefore, as water evaporates and is lost, the relative mass percentage of other shell components increases. Furthermore, when fillers with low water content are encapsulated, water from the capsule shell can migrate from the shell into the filler through permeation. This can also lead to water loss from the shell. Table 4 shows the mass of the filler, shell, and total capsules immediately after manufacturing and after drying (for oil-filled capsules).

[0171]

[0172] In some embodiments, the fast-release softgel capsules may also be prestressed to improve the release rate. Exemplary examples of prestressing include laser drilling, mechanical drilling, notching, or other known methods of prestressing the gel capsules. In one embodiment, the fast-release softgel capsules may be prestressed during manufacturing by laser drilling or other known methods, regardless of the specific softgel capsule formulation or filling formulation. In other embodiments, the fast-release softgel capsules may be prestressed during manufacturing with a specific softgel capsule formulation as described herein.

[0173] It should be understood that the gel reactor plays a crucial role throughout the manufacturing process. It is responsible for mixing, blending, and dispersing high-viscosity gels. High-viscosity gels can be difficult to handle due to their viscous consistency, making uniform mixing and dispersion challenging. Specific types of gel reactors must be used to accommodate high-viscosity gels, such as those with high-shear mixing mechanisms. Therefore, high-shear mixing involves using specialized equipment that applies strong mechanical forces to break down the viscosity and form a uniform gel mass. This method ensures that all components of the formulation are thoroughly mixed and dispersed, resulting in a consistent and homogeneous gel.

[0174] When handling high-viscosity gels, transferring the gel from the gel reactor to the gel holding tank can present additional challenges. The viscous consistency of the gel can make it difficult to transfer via nozzles or piping systems. In such cases, additional pumps, particularly positive displacement pumps, are typically required. Positive displacement pumps are designed to handle viscous fluids and provide the necessary pressure to efficiently transfer the gel. However, including additional pumps increases the overall cost of the manufacturing process. Therefore, reducing viscosity is advantageous. Incorporating one or more viscosity-modifying polymers into the soft gel capsule formation allows for easier mixing and transfer, eliminating the need for high-shear mixing or additional pumps, or restrictions on the type of gel reactor used.

[0175] Application method

[0176] Dosage forms can be used, for example, 1x, 2x, 3x, 4x, 5x, 6x, or even more daily. One or more dosage forms can be administered, for example, for 1, 2, 3, 4, 5, 6, 7 days, or even longer. One or more dosage forms can be administered, for example, for 1, 2, 3, 4 weeks, or even longer. One or more dosage forms can be administered, for example, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or even longer. One or more dosage forms can be administered until the patient, subject, mammal, mammal in need, human, or person in need no longer requires treatment, prevention, or improvement of any disease or condition.

[0177] The dosage form can be administered once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID) or other dosing regimens, such as X capsules every Y hours, where X is the number of capsules and Y is the hourly interval.

[0178] In one embodiment, the dosage form described herein is administered simultaneously in multiple doses. For example, two or more identical doses are administered at one time. In another embodiment, two or more different doses are administered at one time. Such dual or different simultaneous dosing can be used to provide an effective amount of the pharmaceutical composition to a subject in need.

[0179] In another embodiment, the dosage form described herein may be administered with or without food. In one aspect, the dosage form described herein may be administered with food. In another aspect, the dosage form described herein may be administered without food.

[0180] reagent kits and packaging

[0181] Another embodiment described herein is a kit for dispensing oral pharmaceutical compositions, comprising at least one fast-release soft capsule and at least one container comprising tamper-evident, moisture-proof packaging, including blister packs or strip envelopes, aluminum blister packs, transparent or opaque polymer blister packs with pouches, polypropylene tubes, colored blister materials, tubes, bottles, and bottles optionally containing child-safe features, optionally containing a desiccant such as molecular sieves or silica gel; and optionally, inserts containing instructions or prescription information for the active pharmaceutical ingredient. In one aspect, tamper-evident packaging includes: bottles, film packaging materials, blister packs or strip envelopes, bubble wrap, heat-shrink tape or packaging materials, foil, paper or plastic bags, internal seals at the container opening, tape seals, fragile caps, sealed metal tubes or plastic heat-sealable tubes, sealed cartons, aerosol containers, cans including metal and composite materials, or any combination thereof. The packaging may also include labels, appropriate prescription instructions, instructions for use, warnings, or other appropriate information.

[0182] In some embodiments, the packaging may include bottles and / or blister packs with moisture-proof properties. In one aspect, high-density polyethylene (HDPE) or aluminum bottles with moisture-proof properties may be used to package kits containing soft gel capsules as described herein. In some embodiments, the packaging may also include the use of a desiccant. In one aspect, the desiccant may include silicone packaging, which is typically provided in the form of 1-gram capsules. The use of desiccants and moisture-proof bottles and blister packs in the packaging helps prevent the soft gels from clumping and nesting.

[0183] One embodiment described herein is a rapid-release soft gel capsule formulation comprising: about 15% to 60% by mass of one or more film-forming polymers; about 1% to 30% by mass of one or more disintegrants; about 5% to 30% by mass of one or more plasticizers or cosolvents; and about 10% to 45% by mass of one or more solvents, optionally, about 1% to 20% by mass of one or more viscosity-modifying polymers. In one aspect, the one or more film-forming polymers include gelatin, gelatin hydrolysate, collagen, carrageenan, or agar. In another aspect, the one or more film-forming polymers include gelatin with a Bloom value of about 50 to about 200 Bloom. In another aspect, the gelatin has a Bloom value of about 150 Bloom. In another aspect, the formulation comprises about 20% to 40% by mass of one or more film-forming polymers. In another aspect, the one or more disintegrants include sodium carboxymethyl starch, croscarmellose sodium, crospovidone, calcium silicate, magnesium aluminum silicate, or croscarmellose. In another aspect, the formulation comprises about 5% to 25% by mass of one or more disintegrants. In another aspect, the formulation comprises about 8% to 12% by mass of one or more disintegrants. In another aspect, the formulation comprises about 15% to 25% by mass of one or more disintegrants. In another aspect, one or more plasticizers or cosolvents comprise solutions of polyols, monosaccharides, disaccharides, oligosaccharides, blended hydrophilic molecules, glycerol, sorbitol, polyethylene glycol, or maltitol. In another aspect, the formulation comprises about 10% to 20% by mass of one or more plasticizers or cosolvents. In another aspect, one or more solvents comprise water. In another aspect, the formulation comprises about 1% to 20% by mass of one or more viscosity-modifying polymers. According to claim 1, the formulation further comprises a colorant, an opacifier, a flavoring agent or sweetener, a humectant, a preservative, a coating, a viscosity modifier, a filler or extender, an active pharmaceutical ingredient, a viscosity-modifying polymer, or one or more of a buffer salt and an acid. In another aspect, the formulation comprises about 0.01% to 10% by mass of one or more colorants, which include synthetic dyes, natural dyes, or combinations thereof. In another aspect, the formulation contains about 0.01% to 1% by mass of one or more light-blocking agents, including titanium dioxide, zinc oxide, calcium carbonate, or combinations thereof. In another aspect, the formulation contains about 0.01% to 1% by mass of one or more flavoring agents or sweeteners. In another aspect, the capsule ruptures in USP device II at 37°C within about 3 to 9 minutes. In another aspect, the capsule ruptures in USP device II at 37°C within about 5 minutes.

[0184] Another embodiment described herein is a method for manufacturing fast-release soft gel capsules, the method comprising: preparing a gel block composition comprising one or more film-forming polymers, one or more disintegrants, one or more plasticizers or cosolvents, and one or more solvents to form a gel block; heating the gel block to form a homogeneous and degassed gel block; aging the homogeneous and degassed gel block to form an aged gel block; casting the aged gel block into a film or tape using a heat-controlled roller or surface; transferring a homogenized filling solution to an encapsulation line; encapsulating the homogenized filling solution within the gel block film or tape using a rotary die to form a capsule; drying and trimming the capsule; optionally, coating the capsule with a coating agent and drying it; and post-processing and packaging. In one aspect, the gel block comprises: about 15% to 60% by mass of one or more film-forming polymers; about 1% to 30% by mass of one or more disintegrants; about 5% to 30% by mass of one or more plasticizers or cosolvents; and about 10% to 45% by mass of one or more solvents. In another aspect, heating the gel block in step (b) involves maintaining a temperature of approximately 57°C to 80°C under vacuum for approximately 15 to 30 minutes to form a homogeneous and degassed gel block. In another aspect, aging the homogeneous and degassed gel block in step (c) involves maintaining a temperature of approximately 65°C to 70°C for approximately 12 to 48 hours to form an aged gel block. In yet another aspect, the capsule is pre-stressed to increase the rupture rate.

[0185] Another embodiment described herein is a fast-release soft gel capsule manufactured by any of the methods described herein.

[0186] Another embodiment described herein is a pharmaceutical dosage form comprising a fast-release soft gel capsule and a matrix filler comprising one or more active pharmaceutical ingredients, wherein the fast-release soft gel capsule ruptures within approximately 3 to 9 minutes at 37°C in a USP device II, releasing the matrix filler comprising one or more active pharmaceutical ingredients. In one aspect, the dosage form ruptures within approximately 5 minutes at 37°C in a USP device II. In another aspect, the fast-release soft gel capsule comprises: approximately 15% to 60% by mass of one or more film-forming polymers; approximately 1% to 30% by mass of one or more disintegrants; approximately 5% to 30% by mass of one or more plasticizers or co-solvents; and approximately 10% to 45% by mass of one or more solvents.

[0187] Another embodiment described herein is a pharmaceutical dosage form comprising a fast-release soft gel capsule and an encapsulated tablet containing one or more active pharmaceutical ingredients, wherein the fast-release soft capsule ruptures in a USP device II at 37°C within approximately 3 to 9 minutes, releasing the encapsulated tablet containing one or more active pharmaceutical ingredients. In one aspect, the dosage form ruptures in a USP device II at 37°C within approximately 5 minutes. In another aspect, the fast-release soft gel capsule comprises: approximately 15% to 60% by mass of one or more film-forming polymers; approximately 1% to 30% by mass of one or more disintegrants; approximately 5% to 30% by mass of one or more plasticizers or co-solvents; and approximately 10% to 45% by mass of one or more solvents.

[0188] Another embodiment described herein is a method for rapidly delivering one or more active pharmaceutical ingredients to a subject in need, comprising administering to the subject a pharmaceutical dosage form comprising a fast-release soft gel capsule and a matrix filler comprising one or more active pharmaceutical ingredients, wherein the fast-release soft gel capsule ruptures within approximately 3 to 9 minutes after administration and releases the matrix filler comprising one or more active pharmaceutical ingredients to the subject. In one aspect, the dosage form ruptures within approximately 5 minutes after administration.

[0189] Another embodiment described herein is a method for treating a subject in need with one or more active pharmaceutical ingredients, comprising administering to the subject a pharmaceutical dosage form comprising a fast-release soft gel capsule and a matrix filler comprising one or more active pharmaceutical ingredients, wherein the fast-release soft gel capsule ruptures within approximately 3 to 9 minutes after administration and releases the matrix filler comprising one or more active pharmaceutical ingredients to the subject. In one aspect, the dosage form ruptures within approximately 5 minutes after administration.

[0190] It will be apparent to those skilled in the art that suitable modifications and adaptations can be made to the compositions, formulations, methods, processes, and applications described herein without departing from the scope of any embodiment or aspect thereof. The compositions and methods provided are exemplary and not intended to limit the scope of any specified embodiment. All the various embodiments, aspects, and options disclosed herein can be combined in any variation or iteration. The scope of the compositions, formulations, methods, and processes described herein includes all actual or potential combinations of the embodiments, aspects, options, examples, and preferences described herein. Exemplary compositions and formulations described herein may omit any component, substitute for any component disclosed herein, or include any component disclosed elsewhere herein. The mass ratio of any component of any composition or formulation disclosed herein to the mass of any other component in the formulation or to the total mass of the other components in the formulation is disclosed herein as if they were explicitly disclosed. If the meaning of any term in any patent or publication incorporated by reference conflicts with the meaning of the term used in this disclosure, the meaning of the term or phrase in this disclosure shall prevail. Furthermore, the foregoing discussion discloses and describes only exemplary embodiments. All patents and publications referenced herein are incorporated herein by reference for their specific teaching.

[0191] Various embodiments and aspects of the invention described herein are summarized by the following terms:

[0192] Clause 1. A fast-release soft gel capsule formulation, said formulation comprising:

[0193] About 15% to 60% by mass of one or more film-forming polymers;

[0194] About 1% to 30% by mass of one or more disintegrants;

[0195] About 5% to 30% by mass of one or more plasticizers or cosolvents; and

[0196] One or more solvents, ranging from about 10% to 45% by mass.

[0197] Clause 2. The formulation according to Clause 1, wherein the one or more film-forming polymers comprise gelatin, gelatin hydrolysate, collagen, carrageenan, or agar.

[0198] Clause 3. The formulation according to Clause 1 or 2, wherein the one or more film-forming polymers comprise gelatin with a Bloom value of about 50 Bloom to about 200 Bloom.

[0199] Clause 4. The formulation according to any one of Clauses 1 to 3, wherein the gelatin has a Bloom value of about 150.

[0200] Clause 5. The formulation according to any one of Clauses 1 to 4, wherein the formulation comprises about 20% to 40% by mass of the one or more film-forming polymers.

[0201] Clause 6. The formulation according to any one of Clauses 1 to 5, wherein the one or more disintegrants comprises sodium carboxymethyl starch, croscarmellose sodium, cross-linked carboxymethyl cellulose, crospovidone, calcium silicate, magnesium aluminum silicate, or croscarmellose.

[0202] Clause 7. A formulation according to any one of Clauses 1 to 6, wherein the formulation comprises about 5% to 25% by mass of the one or more disintegrants.

[0203] Clause 8. A formulation according to any one of Clauses 1 to 7, wherein the formulation comprises about 8% to 12% by mass of the one or more disintegrants.

[0204] Clause 9. A formulation according to any one of Clauses 1 to 8, wherein the formulation comprises about 15% to 25% by mass of the one or more disintegrants.

[0205] Clause 10. The formulation according to any one of Clauses 1 to 9, wherein the one or more plasticizers or cosolvents comprise solutions of polyols, monosaccharides, disaccharides, oligosaccharides, blended hydrophilic molecules, glycerol, sorbitol, polyethylene glycol, or maltitol.

[0206] Clause 11. A formulation according to any one of Clauses 1 to 10, wherein the formulation comprises about 10% by mass to 20% by mass of the one or more plasticizers or cosolvents.

[0207] Clause 12. The formulation according to any one of Clauses 1 to 11, wherein the one or more solvents comprise water.

[0208] Clause 13. The formulation according to any one of Clauses 1 to 12, wherein the formulation further comprises one or more of a colorant, an opacifier, a flavoring agent or sweetener, a humectant, a preservative, a coating, a viscosity modifier, a filler or extender, an active pharmaceutical ingredient or a buffer salt and an acid.

[0209] Clause 14. A formulation according to any one of Clauses 1 to 13, wherein the formulation comprises about 0.01% by mass to 10% by mass of one or more colorants, said one or more colorants comprising synthetic dyes, natural dyes, or combinations thereof.

[0210] Clause 15. The formulation according to any one of Clauses 1 to 14, wherein the formulation comprises about 0.01% by mass to 1% by mass of one or more light-blocking agents, said one or more light-blocking agents including titanium dioxide, zinc oxide, calcium carbonate, or combinations thereof.

[0211] Clause 16. A formulation according to any one of Clauses 1 to 15, wherein the formulation comprises about 0.01% by mass to 1% by mass of one or more flavoring agents or sweeteners.

[0212] Clause 17. The formulation according to any one of Clauses 1 to 16, wherein the capsule ruptures in about 3 to 9 minutes at 37°C in a USP device II.

[0213] Clause 18. The formulation according to any one of Clauses 1 to 17, wherein the capsule ruptures in about 5 minutes at 37°C in a USP device II.

[0214] Clause 19. A method for manufacturing a fast-release soft gel capsule, the method comprising:

[0215] (a) Preparing a gel block composition comprising one or more film-forming polymers, one or more disintegrants, one or more plasticizers or cosolvents and one or more solvents to form a gel block;

[0216] (b) Heating the gel block to form a uniform and degassed gel block;

[0217] (c) The homogeneous and degassed gel block is aged to form an aged gel block;

[0218] (d) Cast the aged gel block into a film or strip using a heat-controlled roller or surface;

[0219] (e) Transfer the homogenized filler solution to the encapsulation line;

[0220] (f) Encapsulating the homogenized filling solution within the gel block membrane or strip using a rotary die to form a capsule;

[0221] (g) Drying and trimming the capsules;

[0222] (h) Optionally, the capsule is coated and dried; and

[0223] (i) Post-processing and packaging.

[0224] Clause 20. The method according to Clause 19, wherein the gel block comprises:

[0225] From about 15% to 60% by mass of the one or more film-forming polymers;

[0226] From about 1% to 30% by mass of the one or more disintegrants mentioned above;

[0227] About 5% to 30% by mass of the one or more plasticizers or cosolvents; and

[0228] From about 10% to 45% by mass of the one or more solvents.

[0229] Clause 21. The method according to Clause 19 or 20, wherein heating the gel block in step (b) comprises maintaining a temperature of about 57°C to 80°C under vacuum for about 15 to 30 minutes to form the homogeneous and degassed gel block.

[0230] Clause 22. The method according to any one of Clauses 19 to 21, wherein aging the homogeneous and degassed gel block in step (c) comprises maintaining a temperature of about 65°C to 70°C for about 12 hours to 48 hours to form the aged gel block.

[0231] Clause 23. The method according to any one of Clauses 19 to 22, wherein the capsule is prestressed to increase the rupture rate.

[0232] Clause 24. A fast-release soft gel capsule, said fast-release soft gel capsule being manufactured by the method according to any one of Clauses 19 to 23.

[0233] Clause 25. A pharmaceutical dosage form comprising a fast-release soft gel capsule and a matrix filler containing one or more active pharmaceutical ingredients, wherein the fast-release soft gel capsule ruptures in a USP device II at 37°C within approximately 3 to 9 minutes, releasing the matrix filler containing the one or more active pharmaceutical ingredients.

[0234] Clause 26. The pharmaceutical dosage form as described in Clause 25, wherein the dosage form breaks down within approximately 5 minutes in a USP device II at 37°C.

[0235] Clause 27. The pharmaceutical dosage form according to Clause 25 or 26, wherein the rapid-release soft gel capsule comprises:

[0236] From about 15% to 60% by mass of the one or more film-forming polymers;

[0237] From about 1% to 30% by mass of the one or more disintegrants mentioned above;

[0238] About 5% to 30% by mass of the one or more plasticizers or cosolvents; and

[0239] From about 10% to 45% by mass of the one or more solvents.

[0240] Clause 28. A pharmaceutical dosage form comprising a rapid-release soft gel capsule and an encapsulated tablet containing one or more active pharmaceutical ingredients, wherein the rapid-release soft gel capsule ruptures in a USP device II at 37°C within approximately 3 to 9 minutes, releasing the encapsulated tablet containing the one or more active pharmaceutical ingredients.

[0241] Clause 29. The pharmaceutical dosage form as described in Clause 28, wherein the dosage form breaks down within approximately 5 minutes in a USP device II at 37°C.

[0242] Clause 30. The pharmaceutical dosage form according to Clause 28 or 29, wherein the rapid-release soft gel capsule comprises:

[0243] From about 15% to 60% by mass of the one or more film-forming polymers;

[0244] From about 1% to 30% by mass of the one or more disintegrants mentioned above;

[0245] About 5% to 30% by mass of the one or more plasticizers or cosolvents; and

[0246] From about 10% to 45% by mass of the one or more solvents.

[0247] Clause 31. A method for rapidly delivering one or more active pharmaceutical ingredients to a subject in need, the method comprising administering to the subject a pharmaceutical dosage form comprising a rapid-release soft gel capsule and a matrix filler containing the one or more active pharmaceutical ingredients, wherein the rapid-release soft gel capsule ruptures within approximately 3 to 9 minutes after administration and releases the matrix filler containing the one or more active pharmaceutical ingredients to the subject.

[0248] Clause 32. The method according to Clause 31, wherein the dosage form breaks down within approximately 5 minutes after application.

[0249] Clause 33. A method of treating a subject in need with one or more active pharmaceutical ingredients, the method comprising administering to the subject a pharmaceutical dosage form comprising a fast-release soft gel capsule and a matrix filler containing the one or more active pharmaceutical ingredients, wherein the fast-release soft gel capsule ruptures within approximately 3 to 9 minutes after administration and releases the matrix filler containing the one or more active pharmaceutical ingredients to the subject.

[0250] Clause 34. The method according to Clause 33, wherein the dosage form breaks down within approximately 5 minutes after application.

[0251] Example

[0252] Example 1

[0253] Exemplary soft gel shell compositions are prepared as shown in Table 5.

[0254]

[0255] Four prototype softgel batches using 150 Bloom bovine gelatin were manufactured using sodium carboxymethyl starch (SSG) at a weight percentage of 8.6% (w / w) based on the gelatin formulation. Capsules were manufactured using 8.6% SSG, with gelatin aged for approximately 24 to 48 hours, and gelatin strip thickness varying from 0.028 inches to 0.035 inches (0.7112 mm to 0.889 mm) in all four batches, with two batches using a strip thickness between 0.032 inches and 0.035 inches (0.8128 mm to 0.889 mm). Additionally, three control batches of gelatin were manufactured without SSG, using a gelatin strip thickness between 0.032 inches and 0.035 inches (0.8128 mm to 0.889 mm). Orange organic essential oil (sweet) was used as a filler in each of the listed batches.

[0256] Example 2

[0257] Using the USP breakdown method <701> The disintegration / rupture of the soft gel capsule samples prepared in Example 1 were analyzed at 37°C and 22°C, according to USP General Rules. <2040> A burst test was performed. Six soft-shell capsules were tested directly in 500 mL of degassed purified water. The test was conducted at 50 RPM using a USP apparatus II (paddle apparatus; Distek) at 37 ± 0.5 °C or 22 ± 0.5 °C. The capsules were observed, and the time to shell burst was recorded. The burst test was continued until all samples burst or stopped after 30 minutes. Data from the experiments at 37 °C and 22 °C are shown in Tables 6-7, 8-9, and 9, respectively. Figures 2 to 3 middle.

[0258]

[0259]

[0260]

[0261]

[0262] Example 3

[0263] Prepare the following fast-release capsules containing acetaminophen or medium-chain triglyceride fillers, wherein varying amounts of disintegrant (10% to 29.5% sodium carboxymethyl starch) are incorporated into the capsule shell.

[0264] The capsule fillers are shown in Tables 10 and 11.

[0265]

[0266] Acetaminophen filler was prepared under yellow light and stored under nitrogen at ambient conditions. Polyethylene glycol 600 was preheated to 60°C, transferred to a mixing container, cooled, and maintained at 42°C to prevent curing. Polyethylene glycol 400, povidone K-30, and purified water were added, the mixture was stirred, and heated at 40°C until a clear solution was obtained. Acetaminophen was added and mixed. The resulting mixture was degassed and maintained at 34.5°C. The mixture was then degassed and transferred to a holding container, and stored under nitrogen at ambient temperature until encapsulation.

[0267]

[0268] Medium-chain triglyceride fillers were prepared by combining medium-chain triglycerides in a mixing tank. The mixture was degassed and transferred to a holding tank, and stored under nitrogen at ambient temperature until encapsulation.

[0269] The rapid-release capsule compositions are shown in Tables 12 to 15, followed by the preparation of gel blocks for each formulation.

[0270]

[0271] Preparation of 10% SSG gel blocks

[0272] In a preheated jacketed gelation vessel at 50°C, the shell components gelatin, glycerin, lycasin, sodium carboxymethyl starch, and purified water were blended with gentle stirring. The mixture was vacuum-cooked at 50°C to 70°C for 2 hours and aged overnight at 70°C. The gel block was transparent, free of bubbles and particles. The gel block was maintained at 70°C before and during encapsulation.

[0273]

[0274] Preparation of 15% SSG gel blocks

[0275] In a jacketed heated gelatin tank at 40°C, the outer shell components—gelatin, glycerin, lycasin, sodium carboxymethyl starch, and purified water—were blended. A gel block was formed by heating under vacuum at 70°C to 75°C for 2 hours and then aged overnight at 72°C to 74°C. The gel block was transparent, free of bubbles and particles. The gel block was maintained at 72°C to 74°C before and during encapsulation.

[0276]

[0277] Preparation of 20% SSG gel blocks

[0278] In a jacketed heated gelation vessel, the outer shell components—gelatin, glycerin, lycasin, sodium carboxymethyl starch, and purified water—are blended. A gel block is formed by heating under vacuum at 60°C to 70°C for 2 hours, followed by aging overnight at 70°C to 72°C. The gel block is transparent, free of bubbles and particles. The gel block is maintained at 70°C to 72°C before and during encapsulation.

[0279]

[0280] Preparation of 29.5% SSG gel blocks

[0281] In a preheated jacketed gelatin tank at 55°C, the outer shell components—gelatin, glycerin, lycasin, sodium carboxymethyl starch, and purified water—were blended. A gel block was formed by heating under vacuum at 55°C to 72°C for 2 hours and then aged overnight at 70°C. The gel block was transparent, free of bubbles and particles. The gel block was maintained at 70°C before and during encapsulation.

[0282] Capsules were manufactured using a rotary die for encapsulation. A summary of the production results is shown in Table 16. Successful capsules were made from formulations containing 10%, 15%, and 20% sodium carboxymethyl starch (SSG). The capsule formulation containing 20% ​​SSG was very viscous, but capsules were successfully manufactured. The capsule formulation containing 29.5% SSG could not be successfully manufactured because the capsules could not be sealed.

[0283]

[0284] Example 4

[0285] The rupture and dissolution of capsules containing 10%, 15%, and 20% sodium carboxymethyl starch (SSG) prepared as in Example 3 were compared with those of the control capsules.

[0286] rupture

[0287] Using the USP breakdown method <701> The disintegration / rupture of the acetaminophen soft gel capsules prepared in Example 3 was analyzed at 37°C, according to USP General Rules. <2040> Perform a burst test. Six soft-shell capsules were tested directly in 500 mL of degassed purified water. The test was conducted at 100 RPM using a USP apparatus II (paddle apparatus; Distek) at 37 ± 0.5 °C. The capsules were observed, and the time to shell burst was recorded. The burst test was continued until all samples burst or stopped after 30 minutes. Data are shown in Table 17 and... Figure 4 middle.

[0288]

[0289] Comparison of dissolution

[0290] Using the USP dissolution method <711> The dissolution rate of the acetaminophen soft gel capsules prepared in Example 3 was analyzed using apparatus II (paddle apparatus) at 100 RPM at 37°C in a suitable degassing medium (0.1 N HCl) at pH ~1.2. Dissolution rate data are shown in Table 18 and... Figure 5A middle.

[0291]

[0292] The acetaminophen control appeared to have a shell cross-linking issue. To validate the dissolution profile of the control, a dissolution experiment was performed using an enzyme (pepsin) present in the dissolution medium (0.1N HCl; pH ~1.2). The data are shown in Table 19 and... Figure 5B The experiment showed that the dissolution rate of the control in normal culture medium was almost the same as that in culture medium containing the enzyme.

[0293]

[0294] Regarding the above-described embodiments, aspects, and examples, viscosity-modifying polymers can be incorporated as shown in the exemplary formulations in Table 20 below. In each formulation, PVP is added as the viscosity-modifying polymer, and the mass of other excipients is adjusted accordingly.

[0295]

[0296]

Claims

1. A rapid-release soft gel capsule formulation, the formulation comprising: About 15% to 60% by mass of one or more film-forming polymers; About 1% to 30% by mass of one or more disintegrants; About 5% to 30% by mass of one or more plasticizers or cosolvents; and One or more solvents, ranging from about 10% to 45% by mass.

2. The formulation according to claim 1, wherein the one or more film-forming polymers comprise gelatin, gelatin hydrolysate, collagen, carrageenan, or agar.

3. The formulation according to claim 1 or 2, wherein the one or more film-forming polymers comprise gelatin with a Bloom value of about 50 Bloom to about 200 Bloom.

4. The formulation according to claim 3, wherein the gelatin has a Bloom value of about 150.

5. The formulation according to any of the preceding claims, wherein the formulation comprises about 20% to 40% by mass of the one or more film-forming polymers.

6. The formulation according to any of the preceding claims, wherein the one or more disintegrants comprises sodium carboxymethyl starch, croscarmellose sodium, cross-linked carboxymethyl cellulose, crospovidone, calcium silicate, magnesium aluminum silicate, or croscarmellose.

7. The formulation according to any of the preceding claims, wherein the formulation comprises about 5% to 25% by mass of the one or more disintegrants.

8. The formulation of claim 7, wherein the formulation comprises about 8% to 12% by mass of the one or more disintegrants.

9. The formulation of claim 7, wherein the formulation comprises about 15% to 25% by mass of the one or more disintegrants.

10. The formulation according to any of the preceding claims, wherein the one or more plasticizers or cosolvents comprise a solution of polyols, monosaccharides, disaccharides, oligosaccharides, blended hydrophilic molecules, glycerol, sorbitol, polyethylene glycol, or maltitol.

11. The formulation according to any of the preceding claims, wherein the formulation comprises about 10% to 20% by mass of the one or more plasticizers or cosolvents.

12. The formulation according to any of the preceding claims, wherein the one or more solvents include water.

13. The formulation according to any of the preceding claims, wherein the formulation further comprises one or more of a colorant, an opacifier, a flavoring agent or sweetener, a humectant, a preservative, a coating, a viscosity modifier, a filler or extender, an active pharmaceutical ingredient, a viscosity-modifying polymer or a buffer salt and an acid.

14. The formulation of claim 13, wherein the formulation comprises about 0.01% to 10% by mass of one or more colorants, said one or more colorants comprising synthetic dyes, natural dyes, or combinations thereof.

15. The formulation of claim 13, wherein the formulation comprises about 0.01% to 1% by mass of one or more light-blocking agents, said one or more light-blocking agents comprising titanium dioxide, zinc oxide, calcium carbonate, or combinations thereof.

16. The formulation of claim 13, wherein the formulation comprises about 0.01% to 1% by mass of one or more flavoring agents or sweeteners.

17. The formulation according to any of the preceding claims, wherein the formulation further comprises 1% to 20% by mass of one or more viscosity-modifying polymers.

18. The formulation of claim 17, wherein the formulation comprises about 5% to 15% by mass of the one or more viscosity-modifying polymers.

19. The formulation of claim 17, wherein the formulation comprises about 10% by mass of the one or more viscosity modifiers.

20. The formulation according to claims 17 to 19, wherein the one or more viscosity-modifying polymers comprise hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and dextran.

21. The formulation according to any of the preceding claims, wherein the capsule ruptures at 37°C within about 3 to 9 minutes.

22. The formulation according to any of the preceding claims, wherein the capsule ruptures within about 5 minutes at 37°C.

23. A method for manufacturing a fast-release soft gel capsule, the method comprising: (a) Preparing a gel block composition comprising one or more film-forming polymers, one or more disintegrants, one or more plasticizers or cosolvents and one or more solvents to form a gel block; (b) Heating the gel block to form a uniform and degassed gel block; (c) The homogeneous and degassed gel block is aged to form an aged gel block; (d) Cast the aged gel block into a film or strip using a heat-controlled roller or surface; (e) Transfer the homogenized filler solution to the encapsulation line; (f) Encapsulating the homogenized filling solution within the gel block membrane or strip using a rotary die to form a capsule; (g) Drying and trimming the capsules; (h) Optionally, the capsule is coated and dried; as well as (i) Post-processing and packaging.

24. The method of claim 23, wherein the preparation of the gel block composition to form the gel block further comprises about 1% to 20% by mass of one or more viscosity-modifying polymers.

25. The method of claim 23, wherein the gel block comprises: From about 15% to 60% by mass of the one or more film-forming polymers; From about 1% to 30% by mass of the one or more disintegrants mentioned above; About 5% to 30% by mass of the one or more plasticizers or cosolvents; and From about 10% to 45% by mass of the one or more solvents.

26. The method according to claims 23 to 25, wherein heating the gel block in step (b) comprises maintaining a temperature of about 57°C to 80°C under vacuum for about 15 to 30 minutes to form the homogeneous and degassed gel block.

27. The method according to claims 23 to 26, wherein aging the homogeneous and degassed gel block in step (c) comprises maintaining a temperature of about 65°C to 70°C for about 12 hours to 48 hours to form the aged gel block.

28. The method according to claims 23 to 27, wherein the capsule is prestressed to increase the rupture rate.

29. A fast-release soft gel capsule, said fast-release soft gel capsule being manufactured by the method according to claims 23 to 28.

30. A pharmaceutical dosage form comprising a fast-release soft gel capsule and a matrix filler comprising one or more active pharmaceutical ingredients, wherein the fast-release soft gel capsule ruptures at 37°C within about 3 to 9 minutes and releases the matrix filler comprising the one or more active pharmaceutical ingredients.

31. The pharmaceutical dosage form according to claim 30, wherein the dosage form breaks down within about 5 minutes at 37°C.

32. The pharmaceutical dosage form according to claim 30 or 31, wherein the rapid-release soft gel capsule comprises: About 15% to 60% by mass of one or more film-forming polymers; About 1% to 30% by mass of one or more disintegrants; About 5% to 30% by mass of one or more plasticizers or cosolvents; and One or more solvents, ranging from about 10% to 45% by mass.

33. The pharmaceutical dosage form according to claim 32, further comprising: about 1% to 20% by mass of one or more viscosity-modifying polymers.

34. A pharmaceutical dosage form comprising a fast-release soft gel capsule and an encapsulated tablet containing one or more active pharmaceutical ingredients, wherein the fast-release soft gel capsule ruptures at 37°C within about 3 to 9 minutes and releases the encapsulated tablet containing the one or more active pharmaceutical ingredients.

35. The pharmaceutical dosage form according to claim 34, wherein the dosage form breaks down within about 5 minutes at 37°C.

36. The pharmaceutical dosage form according to claim 34 or 35, wherein the rapid-release soft gel capsule comprises: From about 15% to 60% by mass of the one or more film-forming polymers; From about 1% to 30% by mass of the one or more disintegrants mentioned above; About 5% to 30% by mass of the one or more plasticizers or cosolvents; and From about 10% to 45% by mass of the one or more solvents.

37. The pharmaceutical dosage form of claim 36, wherein the rapid-release soft gel capsule further comprises: about 1% to 20% by mass of one or more viscosity-modifying polymers.

38. A method for rapidly delivering one or more active pharmaceutical ingredients to a subject in need, the method comprising administering to the subject a pharmaceutical dosage form comprising a fast-release soft gel capsule and a matrix filler comprising the one or more active pharmaceutical ingredients, wherein the fast-release soft gel capsule ruptures within approximately 3 to 9 minutes after administration and releases the matrix filler comprising the one or more active pharmaceutical ingredients to the subject.

39. The method of claim 38, wherein the dosage form breaks down within approximately 5 minutes after administration.

40. A method of treating a subject in need with one or more active pharmaceutical ingredients, the method comprising administering to the subject a pharmaceutical dosage form comprising a fast-release soft gel capsule and a matrix filler comprising the one or more active pharmaceutical ingredients, wherein the fast-release soft gel capsule ruptures within approximately 3 to 9 minutes after administration and releases the matrix filler comprising the one or more active pharmaceutical ingredients to the subject.

41. The method of claim 40, wherein the dosage form breaks down within approximately 5 minutes after administration.

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