CAPSULES FOR ORAL AND NASAL ADMINISTRATION OF PHARMACEUTICAL PRODUCTS

Abstract

The invention describes a method including the administration of a pharmaceutical composition. The administration includes dispensing a pharmaceutical filler composition comprising an active agent from a soft gel capsule into a patient's nasal cavity for nasal absorption or into the patient's oral cavity for pregastric absorption.

Description

CAPSULES FOR ORAL AND NASAL DELIVERY OF PHARMACEUTICALPRODUCTSCross Reference to Related Application(s)

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 545.340, filed on October 23, 2023. The entire contents of which are incorporated in its entirety.Technical Field of the Invention

[0002] The present invention relates to a method of administering a pharmaceutical composition. The method includes dispensing a pharmaceutical fill composition comprising an active agent from a softgel capsule to the nasal cavity' of a patient for nasal absorption or the oral cavity' of the patient for pre-gastric absorption.Background of the Invention

[0003] In the field of perfumery and cosmetics, it is common practice to distribute to the public free samples which contain a single-dose of the product in order to offer a chance to try the product. In addition, nutritional supplements or pharmaceutical agents in liquid carriers are also often distributed in single-dose containers. These single-dose forms have many advantages over other dosage forms such as bulk liquid preparations. For example, the content in a single-dose form can be individually fully identifiable and the integrity of the dosage form is protected until the actual moment of administration. If the content, e.g. cosmetics, nutritional supplements, pharmaceuticals, etc., is not used and the container is intact, the container may be retrieved and used with its integrity' preserved.

[0004] In the pharmaceutical industry, a softgel capsule can be used to deliver a pharmaceutical active ingredient. Softgel capsules are typically administered by swallowing the capsule whole via the oral route. However, some patients have difficulties swallowing the capsule whole.

[0005] Furthermore, supplying a pharmaceutical agent in a single-dose container allows accurate delivery' of a unit dose. This is important and advantageous when relatively small amounts of the pharmaceutical agent must be delivered. Additionally, some pharmaceutical active ingredients are required to be delivered to the buccal cavity or nasal cavity forlocalized action or buccal or nasal absorption. Such uniformity is more difficult to achieve via a tableting process where solids must be uniformly mixed and compressed, or via incorporation of the total dose of active ingredient into a bulk liquid carrier which then requires precise measurement of each dose prior to each administration. Thus, alternative ways of delivering the drug products are necessary' to meet the need of patients.

[0006] Single-dose cosmetics, nutritional supplements, or pharmaceuticals are traditionally packaged in small bottles with a removable stopper, a spray device, or in sachets with a tearable tab or with a line of weakness for delivering these products. These single-dose containers often need to be opened by tearing or twisting using one's hands. Such containers may be difficult to handle for some people in that they require two hands to open. In addition, many such containers that provide sprayable delivery are not biodegradable while many containers that are biodegradable do not provide sprayable delivery, which is advantageous for many applications.

[0007] Thus, there is a need to provide an alternative way to achieve the deliver}' of drug products orally, to buccal or nasal cavities and / or to deliver an active agent for pre-gastric absorption or buccal absorption, and eliminate the need for swallowing the whole capsule, improving the patient compliance.Summary of the Invention

[0008] In an embodiment of the present invention, a method is provided. The method may include administering a pharmaceutical composition. In some embodiments, the administering may include dispensing a pharmaceutical fill composition may include an active agent from a softgel capsule to the nasal cavity of a patient for nasal absorption or the oral cavity of the patient for gastric absorption.

[0009] In some embodiments, the pharmaceutical fill composition may be dispensed to the nasal cavity' of the patient. In other embodiments, the pharmaceutical fill composition may be dispensed to the oral cavity of the patient.

[0010] In some embodiments, the administering of the pharmaceutical composition bypasses first pass hepatic metabolism in the patient.

[0011] In some embodiments, the pharmaceutical fill composition may be dispensed buccally or sublingually.

[0012] In some embodiments, the softgel capsule may include a shell and the pharmaceutical fill composition. The shell may include a shell composition including at least one gellingagent selected from a protein and a polysaccharide. The shell may further include an area having a first shell thickness, wherein the area having the first shell thickness being oblongshaped and having two protrusions that define a border. In some embodiments, the shell may include one or more areas of reduced shell thickness relative to the first shell thickness, wherein the one or more areas of reduced shell thickness is located with the border defined by the two protrusions. In some embodiments, the one or more areas of reduced shell thickness being configured to rupture by exertion of a compression force on the oblong-shaped portion of the shell to provide an opening in the one or more areas of reduced thickness of the shell through which the pharmaceutical fill composition may be dispensed to the naval cavity or the oral cavity, and the opening in the one or more areas of reduced thickness of the shell may be limited by the border defined by the two protrusions.

[0013] In some embodiments, the active agent may be subject to first pass hepatic metabolism upon gastric absorption. In some embodiments, at least 95% of the pharmaceutical fill composition may be dispersed from the softgel capsule.

[0014] In some embodiments, the pharmaceutical fill composition may include a hydrophilic or lipophilic excipient. In some embodiments, the hydrophilic or lipophilic excipient may include polyethylene glycol 400, polyethylene glycol 600, propylene glycol, medium chain triglyceride, a vegetable oil or a combination thereof.

[0015] In some embodiments, the pharmaceutical fill composition may further include an antioxidant. In some embodiments, the pharmaceutical fill composition may further include a surfactant. The surfactant may include vitamin E TPGS, polysorbate 20, polysorbate 80, Span 80, Labrafil, lecithin, or a combination thereof.

[0016] In some embodiments, the pharmaceutical fill composition may further include a flavoring agent. The flavoring agent may include Wintergreen, peppermint oil, lemon oil, or a combination thereof.

[0017] In some embodiments, the pharmaceutical fill composition may further include a sweetening agent.

[0018] In some embodiments, the one or more areas of reduced thickness may include a deepest point in the shell between the protrusions. In some embodiments, the one or more area of reduced thickness may be an area of reduced seal thickness. In some embodiments, the one or more areas of reduced thickness may be convex relative to an area inside of the softgel capsule and adjacent to the one or more areas of reduced thickness. In some embodiments, the two protrusions may be concave relative to an area inside of the softgel capsule to the one or more areas of reduced thickness.

[0019] In some embodiments, the protrusions may create a back pressure on the one or more areas of reduced thickness. In some embodiments, the one or more areas of reduced thickness may be from about 30% to about 70% thinner than the first thickness of the shell.

[0020] In some embodiments, the protrusions and the one or more areas of reduced thickness dispense the pharmaceutical fill composition as a spray. In some embodiments, the shell may have two or more areas of reduced thickness, wherein the spray may be dispensed as a plurality of streams.

[0021] In some embodiments, the one or more areas of reduced thickness may be sized to provide a desired dispensing to the oral cavity or the naval cavity7.

[0022] In some embodiments, the softgel capsule may be biodegradable.

[0023] In some embodiments, the one or more areas of reduced thickness may be circular or linear. In some embodiments, each protrusion may extend less than about 0.55 mm from the area of the shell having the first thickness.

[0024] In some embodiments, the softgel capsule may have an internal volume of from about 0.005 to about 5 ml.

[0025] In some embodiments, the at least one gelling agent of the shell composition may be a protein-based gelling agent selected from the group consisting of collagen, gelatin, egg whites, and milk-based proteins. In some embodiments, the at least one gelling agent of the shell composition may be a polysaccharide-based gelling agent selected from the group consisting of cellulose-based materials, starches, modified starches, pectins, gums, dextrins, alginates, carrageenans, and mixtures thereof.

[0026] In some embodiments, the at least one gelling agent may be gelatin, where the gelatin may be included in an amount of about 25% to about 45% by weight based on total weight of the shell. In some embodiments, the gelatin may be an animal-based gelatin or a plant-based gelatin.

[0027] In some embodiments, the shell composition may further include carrageenan, starch pullulan, cellulose, maltodextrin, or a combination thereof.

[0028] In some embodiments, the softgel capsule may further include an air hole located in a central area of the softgel capsule.

[0029] In some embodiments, the softgel capsule may have a shape include oval, oblong or a tear drop.

[0030] In some embodiments, a method of preparing a softgel capsule is included. The method may include encapsulating a fill composition in a shell composition using a rotary die to form a capsule; and drying the capsule, wherein the encapsulating creates an area ofreduced thickness in a shell of the softgel capsule. In some embodiments, the area of reduced thickness may be an area of reduced seal thickness.Brief Description of the Drawings

[0031] Figure 1 is a schematic representation of a softgel capsule according to an embodiment of the present disclosure;

[0032] Figure 2 is a schematic representation of a softgel capsule with a protrusion, according to an embodiment of the present disclosure;

[0033] Figures 3A-3B illustrate different embodiments of areas of reduced thickness of softgel capsules as viewed from the right side of Figure 1.

[0034] Figure 3C illustrates an area of reduced thickness on a softgel capsule with the area of reduced thickness circumscribing a portion of the softgel capsule; and

[0035] Figure 3D illustrates an embodiment of a softgel capsule that has two protrusions, wherein the area of reduced thickness is located between the two protrusions (cat ear shape).Detailed Description

[0036] The detailed description set forth below is intended to merely as a description of the presently preferred embodiments of the invention, and is not intended to represent the only form in which the present invention may constructed or utilized. The description sets forth the functions, means, and methods of implementing the invention in connection with the illustrated embodiments. It is to be understood, however, that the same or equivalent functions and features may be accomplished by different embodiments that are also intended to be encompassed within the spirit and scope of the claims.

[0037] As used herein, the singular forms “a,” 'an." and “the” include plural references unless the context clearly indicates otherwise. Thus, for example, reference to “a pharmaceutical active ingredient” includes a single pharmaceutical active ingredient as well as a mixture of two or more different pharmaceutical active ingredients, and reference to an “excipient” includes a single excipient as well as a mixture of two or more different excipients, and the like.

[0038] As used herein, the term “about” in connection with a measured quantity, refers to the normal variations in that measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and the precision of the measuring equipment. In certain embodiments, theterm “about’' includes the recited number ±5%, such that “about 10” would include from 9.5 to 10.5.

[0039] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0040] The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to illuminate certain materials and methods and does not pose a limitation on scope. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods.

[0041] As used herein, the terms “active agent,” “active ingredient,” “active pharmaceutical ingredient,” “pharmaceutical active ingredient,” “API,” and “drug” refer to any material that is intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a government agency for that purpose. These terms with respect to specific agents include all pharmaceutically active agents, all pharmaceutically acceptable salts thereof, complexes, stereoisomers, crystalline forms, co-crystals, ether, esters, hydrates, solvates, and mixtures thereof, where the form is pharmaceutically active.

[0042] As used herein, the term “gastric absorption” refers to the absorption of an API in the stomach and intestines. For example, APIs formulated in enteric dosage forms such as tablets, capsules, or liquids are absorbed via gastric absorption. With gastric absorption, the API is absorbed from the intestines and brought directly into the liver, where it may be metabolized by hepatic enzymes into metabolites that are eliminated in the urine and / or feces. This elimination is referred to as “first-pass” metabolism or the “first-pass” effect in the liver and it can significantly reduce the bioavailability of an API.

[0043] As used herein, the term “pre-gastric absorption” refers to the absorption of an API into the portion of the alimentary canal before reaching the stomach, and includes nasal delivery (i.e., absorption via the nasal mucosa) and delivery’ to the oral cavity’ (i. e.. absorption via the buccal mucosa and / or the sublingual mucosa). Accordingly, an API that is delivered via pre-gastric absorption avoids first-pass metabolism and its harmful effects on the API’s bioavailability.

[0044] In an embodiment of the present disclosure, a method for administering a pharmaceutical composition to a patient is provided. Administering of the pharmaceutical composition includes dispensing a pharmaceutical fill composition including an active agentfrom a softgel capsule to the nasal cavity of a patient for nasal absorption or to the oral cavity of the patient for pre-gastric absorption.

[0045] In some embodiments, the pharmaceutical fill composition may be dispensed to the nasal cavity of the patient. In some embodiments, the pharmaceutical fill composition may be dispensed to the oral cavity of the patient. In some embodiments, the administering of the pharmaceutical composition bypasses first pass hepatic metabolism in the patient. In other embodiments, the pharmaceutical fill composition may be dispersed buccally or sublingually.

[0046] In some embodiments of the method, the softgel capsule may include a shell and the pharmaceutical fill composition. In some embodiments, the shell may include a shell composition including at least one gelling agent selected from a protein and a polysaccharide.

[0047] In some embodiments, the shell may include an area having a first shell thickness. The area having the first shell thickness may be oblong-shaped and have two protrusions that define a border. The shell may further include one or more areas of reduced shell thickness relative to the first shell thickness. The one or more areas of reduced shell thickness may be located within the border defined by the two protrusions. In some embodiments, the one or more areas of reduced shell thickness may be configured to rupture by exertion of a compression force on the oblong-shaped portion of the shell to provide an opening in the one or more areas of reduced thickness of the shell through which the pharmaceutical fill composition may be dispensed to the naval cavity or the oral cavity. The opening in the one or more areas of reduced thickness of the shell may be limited by the border defined by the two protrusions.

[0048] In some embodiments, the at least one gelling agent may be a protein-based gelling agent selected from the group consisting of collagen, gelatin, egg whites, and milk-based proteins. As used herein, “collagen” refers to a protein of connective tissue in animals. “Gelatin” refers to a translucent, colorless, odorless, brittle, nearly tasteless solid protein substance, derived from the collagen by partial hydrolysis. Generally, gelatin is classified into alkaline gelatin, acidic gelatin, or enzymatic gelatin. Alkaline gelatin is obtained from the treatment of collagen with a base such as calcium hydroxide. Acidic gelatin is obtained from the treatment of collagen with an acid such as hydrochloric acid. Enzymatic gelatin is generated from treatment of collagen with a hydrolase. In the context of the present disclosure, “gelatin” may also include substantially equivalent substances such as synthetic analogues of natural gelatin.

[0049] In some embodiments, the at least one gelling agent may be a polysaccharide-based gelling agent. The polysaccharide-based gelling agents may be commonly derived from aplant source, such as starch or cellulose. The polysaccharide-based gelling agent may be selected from cellulose or cellulose derivatives, such as microcrystalline cellulose, sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, starch and starch derivatives, pectin, gum, dextrins, alginates and carrageenans. Exemplary starches include arracacha starch, arrowroot starch, banana starch, barley starch, breadfruit starch, buckwheat starch, canna starch, cassava starch, colacasia starch, com starch, katakuri starch, kudzu starch, malanga starch, millet starch, oat starch, oca starch, pea starch, Polynesian arrowroot starch, potato starch, rice starch, rye starch, sago starch, sorghum starch, sweet potato starch, taro starch, water chestnut starch, wheat starch, yam starch, and mixtures thereof.

[0050] The starch of the present disclosure may be a modified starch. The term '’modified starch” refers to derivatives prepared by chemical treatment of starches, for example, acid treatment starches, enzyme treatment starches, oxidized starches, cross-bonding starches, and other starch derivatives. It is preferred that the modified starches be derivatized where their side chains are modified with hydrophilic or hydrophobic groups to thereby form a more complicated structure with a stronger interaction between side chains comparing with unmodified starches. Exemplary modified starch ethers and esters include carboxymethylated starch, hydroxypropylated starch, and hydroxypropylated carboxymethyl crosslinked starch.

[0051] “Modified starch ester” refers to a starch in which one or more of the hydroxyl groups have been reacted to form ester groups. The reaction usually involves a reaction to replace the hydrogen of the OH group on the starch with a -O-(C=O)-CH3 or -O-(C=O)-R group (where R is an aliphatic group).

[0052] “Modified starch ether” refers to a starch in which one or more of the hydrogens on the starch has been replaced by the carbon of an organic groups. For example methylation of a starch replaces the OH group with an OCH3 group.

[0053] The polysaccharide-based gelling agent may also be a gum. Exemplary' gums include acacia gum, agar, carrageenans, cassia gum, cellulose gum, furcellaran, gellan gum. guar gum. gum ghatti. karay a gum. larch gum, locust bean gum, pectin, plantago. tara gum, tragacanth, xanthan gum, or a combination thereof.

[0054] “Gum” refers to polysaccharides of natural origin, capable of causing a large viscosity increase in solution, even at small concentrations. They are used as thickening agents, gelling agents, emulsifiers, and stabilizers. Most often, these gums are found in the woody elements of plants or in seed coatings.

[0055] The polysaccharide-based gelling agent of the present disclosure may be pectin. "Pectin” refers to the complex set of polysaccharides that are present in most primary cell walls and particularly abundant in the non-woody parts of terrestrial plants. The characteristic structure of pectin is a linear chain of a-(l-4)-linked D-galacturonic acid that forms the pectin-backbone, a homogalacturonan. Into this backbone, there are regions where galacturonic acid is replaced by (l-2)-linked L-rhamnose. From the rhamnose residues, side chains of various neutral sugars branch off.

[0056] The pectin may include not only purified or isolated pectates, but also crude natural pectin sources, such as apple, citrus or sugar beet residues which have been subjected, when necessary, to esterification or de-esterification, e.g.. by alkali or enzymes. Preferably, the pectins used in this disclosure may be derived from citrus fruits such as lime, lemon, grapefruit, and orange.

[0057] The polysaccharide-based gelling agent may be dextrin. “Dextrin” refers to a group of low-molecular-weight carbohydrates produced by the hydrolysis of starch or glycogen. Dextrin is a mixture of polymers of D-glucose units linked by a-(l - +4) or a-(l - +6) glycosidic bonds.

[0058] The polysaccharide-based gelling agent of the present disclosure may be alginate. “Alginate” refers to an anionic polysaccharide distributed widely in the cell walls of brown algae, where through binding with water, it forms a viscous gum. Alginate is a linear copolymer with homopolymeric blocks of (l-4)-linked -D-mannuronate (M) and its C-5 epimer a-L- guluronate (G) residues, respectively, covalently link together in different sequences or blocks. Its color ranges from white to yellow ish-brown. It is sold in filamentous, granular, or powdered fonris.

[0059] The polysaccharide-based gelling agent of the present disclosure may be a carrageenan. In some embodiments, carrageenan may provide particular advantages. "Carrageenan" refers to a family of polysaccharide gums extracted from red seaweed. They consist of linear sulfated high molecular weight polysaccharides made up of repeating galactose units and 3, 6 anhydrogalactose (3,6-AG), both sulfated and nonsulfated. The units are joined by alternating alpha 1-3 and beta 1-4 glycosidic linkages.

[0060] In some embodiments, the shell composition may include both a modified starch and iota-carrageenan. In an embodiment, the w eight ratio of the modified starch to the iota- carrageenan is at least about 1.5:1. or about 1.5:1 to about 4: 1, or from about 2: 1 to about 3: 1. A gel forming composition with the above weight ratio is capable of fusion, under pressure, in the range of about 207 kPa to about 2070 kPa (about 30 to about 300 psi) and attemperatures in the range of from about 25 to about 80 °C. In an embodiment, the capsule shell 5, according to the present disclosure, has a melting temperature of from about 2 to about 25 °C, from about 3 to about 15°C, or from about 4 to about 9 °C above its fusion temperature.

[0061] The iota-carrageenans may be conformed to the specification laid down by the USA and European regulatory authorities. The iota-carrageenan is not degraded and should conform to minimum viscosity standards, which correspond to a molecular weight of about 100K Daltons. Standardized iota-carrageenans are preferred. A particular preferred standardized iota- carrageenan is commercially available from the FMC Corporation of Princeton, N.J., known as VISCARIN® SD389, standardized with 15 % by weight dextrose. Other useful iota- carrageenans include a non-standardized iota-carrageenan from SKW BioSystems of Baupt, France known as XPU-HGI and a non-standardized iota- carrageenan from FMC.

[0062] The iota-carrageenan may be used in an amount that, in combination with the modified starch, effectively causes the gel forming compositions to have the required gelatin-like functional properties. As those skilled in the art will appreciate, the gel has what is known as a wet shell composition and a dry shell composition. The dry shell composition results from the evaporation or removal of w ater from the wet shell composition during the manufacturing process for making the softgel capsule. The dry shell composition may still contain some water. The amount of iota-carrageenan may range from about 6-12 % by w eight of the wet shell composition, about 7-12% by weight of the wet shell composition, 9-1 1% by w eight of the wet shell composition, or about 10% by weight of the et shell composition.

[0063] In some embodiments, the shell may be formed using one gelling agent. The one gelling agent may be gelatin. In some embodiments, the gelatin is mammalian gelatin. The shell may contain about 25% to about 45% by weight of gelatin. In some embodiments, the shell may include about 25% to about 40%, about 30% to about 45%, about 30% to about 40%, or about 30% to about 35%, based on weight of the shell composition. Such gelatin-based gel may be strong enough to survive manipulation in the encapsulation machine, provide good sealing properties at temperatures below the meltingpoint of the film, and have sufficient elasticity to allow for the formation of the softgel capsule.

[0064] The shell composition may further include at least one optional component selected from a plasticizer, a preservative, a flavoring agent, an opacifying agent, a buffer, an embrittlement inhibiting agent, a colorant, a disintegrant, a perfume, a flavoring, a shell texturing ingredient and / or pearlescent and / or glittering pigment, and water.

[0065] The plasticizers may include glycerol, polyglycerol, glycerin, propylene glycol, polyethylene glycol, xylitol, sorbitol, non-crystalizing solutions of sorbitol, glucose, fructose, and glucose syrups. These plasticizers may be used alone or in combination with each other. In a combination of plasticizers including glycerol, the glycerol typically comprises at least 30 % by weight of the combination, or in the range of about 30-70 % by weight. In some embodiments, the glycerol may be included in an amount of about 30% to about 70% by weight, about 35% to about 65%, about 40% to about 60%, or about 45% to about 55% by weight. An alternative combination may be ANIDRISORB (a proprietary mixture of Sorbitol, Sorbitans, Maltitol, and Mannitol, available from Roquette Freres). Other plasticizers may include saccharides and polysaccharides. The saccharides and polysaccharides suitable for use as a plasticizer herein may be produced by hydrolysis and / or hydrogenation of a simple or complex polysaccharides.

[0066] When a plasticizer is included, the plasticizer may be used in amounts of up to about 60 % by weight of the dry shell composition or up to about 30 % by weight of the wet shell composition used to make the softgel capsule. In some embodiments, the compositions may include a plasticizer in an amount of about 10 % to about 25 % by weight, about 12% to about 22% by weight or about 15% to about 20% based on the weight of the wet shell composition and from about 30 % to about 50 % by weight, about 35% to about 50% by weight, or about 40% to about 45% of the dry shell composition.

[0067] In some embodiments, the shell composition may include a preservative. Preservatives may be antimicrobial preservatives, which inhibit the growth of microbes, or an antioxidant, such as oxygen absorbers, which inhibit the oxidation of the pharmaceutical fill composition within the softgel capsule. Common antimicrobial preservatives include sorbic acid and its salts, benzoic acid and its salts, calcium propionate, sodium nitrite, sulfites (sulfur dioxide, sodium bisulfite, potassium hydrogensulfite, etc ), and disodium ethylenediaminetetraacetic acid (EDTA). Antioxidants may include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert - butylhydroquinone (TBHQ) and propyl gallate. Other preservatives include ethanol and methylchloroisothiazolinone.

[0068] In some embodiments, the shell composition may further include an embrittlement inhibiting agent. The embrittlement inhibiting agent may include a mixture of sorbitol and one or more sorbitans.

[0069] In some embodiments, a buffer system may be used in the shell composition. The buffer system may include a phosphate buffer.

[0070] In some embodiments, the shell composition may include a plant-based gelling agent. In some embodiments, the shell composition including a plant-based gelling agent includes one or more of carrageenan, starch, pullulan, a plasticizer, water and maltodextrin. In some embodiments, carrageenan may be included in an amount of about 3 to about 20 wt%, about 5 to about 15 wt%, or about 8 wt% to about 12 wt%, based on weight of the wet shell composition. In some embodiments, starch may be included in an amount of about 10 to about 40 wt%, about 15 to about 35 wt%, or about 20 to about 30 wt%, based on weight of the wet shell composition. In some embodiments, pullulan may be included in an amount of about 5 to about 50 wt%, about 10 to about 45 wt%, about 15 to about 40 wt%, or about 20 to about 35 wt% based on weight of the wet shell composition. In some embodiments, a plasticizer may be included in an amount of about 10 to about 40 wt%, about 15 to about 35 wt%, or about 20 to about 30 wt%. based on weight of the wet shell composition. In some embodiments, water may be included in an amount of about 5 to about 25 wt%, or about 10 to about 20 wt%, based on weight of the wet shell composition. In some embodiments, maltodextrin may be included in an amount of about 5 to about 50 wt%, about 10 to about 45 wt%, about 15 to about 40 wt%, or about 20 to about 35 wt%, based on weight of the w et shell composition.

[0071] In some embodiments, the shell composition may include gelatin as the gelling agent. In some embodiments, the shell composition including gelatin includes one or more of gelatin, glycerin, sorbitol sorbitan solution, water, opacifier, or a colorant. In some embodiments, gelatin may be included in an amount of about 10 to about 60 wt%, about 15 to about 55 wt%. 20 to about 50 wt%, about 25 to about 45 wt%. or about 30 wt% to about40 wt%, based on weight of the wet shell composition. In some embodiments, glycerin may be included in an amount of about 5 to about 40 wt%, about 15 to about 35 wt%. or about 20 to about 30 wt%, based on weight of the wet shell composition. In some embodiments, sorbitol sorbitan solution may be included in an amount of about 5 to about 50 wt%, about 10 to about 45 wt%, about 15 to about 40 wt%, or about 20 to about 35 wt% based on weight of the wet shell composition. In some embodiments, an opacifer may be included in an amount of about 1 to about 10 wt%, about 2 to about 8 wt%, or about 3 to about 6 wt%, based on weight of the wet shell composition. In some embodiments, water may be included in an amount of about 5 to about 25 wt%, or about 10 to about 20 wt%, based on weight of the wet shell composition. In some embodiments, a colorant may be included in an amount of about 0.5 to about 5 wt%, about 1 to about 4 wt%, or about 2 to about 3 wt%, based on weight of the wet shell composition.

[0072] In some embodiments, the softgel capsule may have a total capsule weight of about 0.3 grams to 2 grams, about 0.5 grams to about 1.8 grams, about 0.7 grams to about 1.5 grams, or about 1 gram to about 1.2 grams. In some embodiments, the softgel capsule may have a total capsule weight of about 0.2 grams to about 0.5 grams, about 0.25 grams to about 0.45 grams, or about 0.3 grams to about 0.4 grams. In some embodiments, the softgel capsule may have a shell weight of about 0.05 grams to about 0.5 grams, about 0. 1 grams to about 0.45 grams, about 0.15 grams to about 0.4 grams, or about 0.2 grams to about 0.35 grams. In some embodiments, the softgel capsule may have a shell weight of about 0.05 grams to about 0.3 grams, about 0.1 grams to about 0.25 grams, or about 0.15 grams to about 0.2 grams. In some embodiments, the fill weight of the softgel capsule may be about 0.1 gram to about 0.75 grams, about 0.2 grams to about 0.7 grams, about 0.25 grams to about 0.6 grams, or about 0.3 grams to about 0.5 grams. In some embodiments, the fill weight of the softgel capsule may be about 0.1 grams to about 0.4 grams, about 0.2 grams to about 0.3 grams, or about 0.2 grams to about 0.25 grams.

[0073] In some embodiments, the active agent may be subject to first pass hepatic metabolism upon gastric absorption. In some embodiments, at least 95% of the pharmaceutical fill composition may be dispersed from the softgel capsule. In other embodiments, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% of the pharmaceutical fill composition may be dispersed from the softgel capsule.

[0074] In some embodiments, the pharmaceutical fill composition may include a hydrophilic or lipophilic excipient. In some embodiments, the hydrophilic or lipophilic excipient may include polyethylene glycol, such as polyethylene glycol 400 or polyethylene 600, propylene glycol, medium chain triglyceride, a vegetable oil, or a combination thereof. In some embodiments, a vegetable oil may be com oil, soybean oil, olive oil, or peanut oil.

[0075] In some embodiments, the pharmaceutical fill composition may include an antioxidant. The antioxidant may include butylated hydroxy toluene (BHT), butylated hydroxyanisole (BHA), or a combination thereof.

[0076] In some embodiments, the pharmaceutical fill composition may include a surfactant. In some embodiments, the surfactant may include vitamin E TPGS, polysorbate 20, polysorbate 80, Span 90, Labrafil, lecithin, or a combination thereof.

[0077] In some embodiments, the pharmaceutical fill composition may further include a flavoring agent. In some embodiments, the flavoring agent may include wintergreen, peppermint oil, lemon oil, or a combination thereof. Exemplary7suitable flavoring agents may include, but not be limited to, “flavor extract” obtained by extracting a part of a raw material, e.g., animal or plant material, often by using a solvent such as ethanol or water; natural essences obtained by extracting essential oils from the blossoms, fruit, roots, etc., or from the whole plants.

[0078] Additional exemplary flavoring agents that may be in the dosage form may include, but not be limited to, breath freshening compounds like menthol, spearmint, and cinnamon, coffee beans, other flavors or fragrances such as fruit flavors (e.g., cherry, orange, grape, etc.), especially those used for oral hygiene, as well as actives used in dental and oral cleansing such as quaternary ammonium bases. The effect of flavors may be enhanced using flavor enhancers like tartaric acid, citric acid, vanillin, or the like.

[0079] In some embodiments, the pharmaceutical fill composition may further include a sweetening agent. Exemplary7sweetening agents may include, but not be limited to, one or more artificial sweeteners, one or more natural sweeteners, or a combination thereof. Artificial sweeteners include, e.g., acesulfame and its various salts such as the potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), salt of aspartame-acesulfame (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate,saccharin and its various salts such as the sodium salt (available as Sweet'N Low®), stevia, chloro derivatives of sucrose such as sucralose (available as Kaltame® and Splenda®), and mogrosides. Natural sweeteners include, e.g., glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®); Stevia rebaudiana (Stevioside), natural intensive sweeteners, such as Lo Han Kuo, polyols such as sorbitol, mannitol, xylitol, ery thritol, and the like.

[0080] In some embodiments, the softgel capsule may optionally comprise additional agents such as coloring agents, flavorings agents, sweetening agents, fillers, antioxidants, diluents, pH modifiers or other pharmaceutically acceptable excipients or additives such as synthetic dyes and mineral oxides.

[0081] Exemplary suitable coloring agents may include, but not be limited to, colors such as e.g., white, black, yellow, blue, green, pink, red, orange, violet, indigo, and brown. In specific embodiments, the color of the dosage form can indicate the contents (e.g., one or more active ingredients) contained therein. It is to be understood by one of skill in the art that the coloring agent of the compressed mass may be separate and distinct from that of the marking component.

[0082] The thickening agent may be a starch, a starch derivative or a modified starch. The starch or starch derivative may be hydroxypropylated tapioca starch, hydroxypropylated com starch, potato starch, or pregelatinized modified com starches. The modified starch includes such starces as hydroxypropylated starches, acid thinned starches and the like. In general, modified starches are products prepared by chemical treatment of starches, for example, acid treatment starches, enzyme treatment starches, oxidized starches, cross-bonding starches, and other starch derivatives

[0083] The buffer and / or an alkalizing agent may be, but is not limited to, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate and / or disodium phosphate. In one embodiment, the buffer is disodium phosphate.

[0084] The softgel capsule may further include water, acry lates copolymer, xanthan gum, glycerin, butylene glycol, aminomethyl propanol, aloe barbaensis leaf extract, active ingredient, a lipid, or a combination thereof.

[0085] In some embodiments, the lipid may7be selected, without limitations, from the group consisting of , almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil. colza oil, com oil. cottonseed oil. grape seed oil, hazelnut oil, hemp oil. hydroxylated lecithin, lecithin, linseed oil. macadamia oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palmoil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil. rice bran oil. safflower oil, sesame oil. shea butter, soybean oil, sunflower oil. hydrogenated vegetable oil, walnut oil, and watermelon seed oil. Other oil and fats may include, but not be limited to, fish oil (omega-3), krill oil, animal or vegetable fats, e.g., in their hydrogenated form, free fatty acids and mono-, di-, and tri-glycerides with C8-, CIO-, Cl 2-, Cl 4-, Cl 6-, Cl 8-, C20- and C22-fatty acids, and combinations thereof.

[0086] In some embodiments, the softgel capsule may include a plasticizer. In some embodiments, the plasticizer may include glycerol, glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or combinations thereof. In some embodiments, the plasticizer may be glycerol.

[0087] Any pharmaceutically active ingredient subject to first pass hepatic metabolism upon gastric absorption may be used for purposes of the present invention. Additional active agents may include sublingual drugs. Suitable active agents include, without limitation, cardiovascular drugs, steroids, barbiturates, benzodiazepines, opioid analgesics, THC, CBD, proteins, vitamins, and minerals. Some examples include nitroglycerin, morphine, diazepam, midazolam, buprenorphine, buprenorphine / naloxone, zolpidem, ergotamine, desmopressin, apomorphine, asenapine, melatonin, vitamin Bl 2, or vitamin D.

[0088] In some embodiments, the active agent may include analgesics and anti-inflammatory7agents, antacids, anthelmintic, anti-arrhythmic agents, anti-bacterial agents, anti-coagulants, anti-depressants, anti-diabetics, anti-diarrheal, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarial, anti-migraine agents, anti -muscarinic agents, anti-neoplastic agents and immunosuppressants, anti-protozoal agents, anti-rheumatics, antithyroid agents, antivirals, anxiolytics, sedatives, hypnotics and neuroleptics, beta-blockers, cardiac inotropic agents, corticosteroids, cough suppressants, cytotoxics, decongestants, diuretics, enzymes, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and anti- anginal agents, nutritional agents, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, and combinations thereof.

[0089] In some embodiments, the active pharmaceutical ingredient may be selected, without limitations, from the group consisting of dabigatran, dronedarone, ticagrelor, iloperidone, ivacaftor, midostaurine, asimadoline, beclomethasone, apremilast, sapacitabine, linsitinib, abiraterone, vitamin D analogs (e.g., calcifediol. calcitriol, paricalcitol, doxercalciferol),COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, lubiprostone. pharmaceutically acceptable salts thereof, and combinations thereof.

[0090] According to certain embodiments, active agents may include lipid-lowering agents including, but not limited to, statins (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin), fibrates (e.g, clofibrate, ciprofibrate, bezafibrate, fenofibrate, and gemfibrozil), niacin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, and the pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof, mixtures of any of the foregoing, and the like.

[0091] Suitable nutraceutical active agents may include, but are not limited to, 5- hy dr oxy try ptophan, acetyl L-camitine, alpha lipoic acid, alpha-ketoglutarates, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate. charcoal, chitosan, choline, chondroitin sulfate, coenzy me Q10, collagen, colostrum, creatine, cyanocobalamin (Vitamin 812), dimethylaminoethanol, fumaric acid, germanium sequioxide, glandular products, glucosamine HCI, glucosamine sulfate, hydroxyl methyl butyrate, immunoglobulin, lactic acid, L-Carnitine, liver products, malic acid, maltose-anhydrous, mannose (d- mannose), methyl sulfonyl methane, phytosterols, picolinic acid, pyruvate, red yeast extract. S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0092] Suitable nutritional supplement active agents may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements or a combination thereof.

[0093] Suitable vitamin active agents may include, but are not limited to, the following: ascorbic acid (Vitamin C), B vitamins, biotin, fat soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbates, mixed tocopherols, niacin (Vitamin B3), orotic acid, paraaminobenzoic acid, panthothenates, panthothenic acid (Vitamin B5), pyridoxine hydrochloride (Vitamin B6), riboflavin (Vitamin B2), synthetic vitamins, thiamine (Vitamin Bl), tocotrienols, vitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin oils and oil soluble vitamins.

[0094] Suitable herbal supplement active agents may include, but are not limited to, the following: arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginko biloba, ginseng, goldenrod, haw thorn, kava-kava, licorice, milk thistle, psyllium, rauowolfia, senna, soybean, St. John's wort, saw- palmetto, turmeric, valerian.

[0095] Minerals active agents may include, but are not limited to, the following: boron, calcium, chelated minerals, chloride, chromium, coated minerals, cobalt, copper, dolomite,iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvate, zinc and other minerals.

[0096] Examples of other possible active agents include, but are not limited to, antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), non-steroidal anti-inflammatory agents (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen. indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, fluprofen, bucloxic acid, indomethacin, sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam. isoxicam, aceclofenac, aloxiprin, azapropazone, benorilate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lomoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesuhde, oxyphenbutazone, parecoxib. phenylbutazone, salicyl salicylate, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin. pharmaceutically acceptable salts thereof and mixtures thereof) and acetaminophen, anti-emetics (e.g., metoclopramide, methylnaltrexone), anti-epileptics (e.g., phenyloin, meprobmate and nitrazepam), vasodilators (e.g.. nifedipine, papaverine, diltiazem and nicardipine), anti-tussive agents and expectorants (e.g. codeine phosphate), anti-asthmatics (e.g. theophylline), antacids, anti-spasmodics (e.g. atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid, bendrofluthiazide), anti -hypotensives (e.g., propranolol, clonidine), antihypertensives (e.g., clonidine, methyldopa), bronchodilatiors (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants (e.g. pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine) and cannabinoids, as well as pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof.

[0097] The active agent that may also be a benzodiazepine, barbiturate, stimulants, or mixtures thereof. The term “benzodiazepines” refers to a benzodiazepine and drugs that are derivatives of a benzodiazepine that are able to depress the central nervous system. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam,nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and mixtures thereof. Benzodiazepine antagonists that can be used as active agent include, but are not limited to, flumazenil as well as pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.

[0098] The term “barbiturates” refers to sedative-hypnotic drugs derived from barbituric acid (2, 4, 6,-trioxohexahydropynmidine). Barbiturates include, but are not limited to. amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Barbiturate antagonists that can be used as active agent include, but are not limited to, amphetamines as well as pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.

[0099] The term “stimulants” includes, but is not limited to, amphetamines such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, as well as pharmaceutically acceptable salts, hydrates, and solvates and mixtures thereof. Stimulant antagonists that can be used as active agent include, but are not limited to. benzodiazepines, as well as pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.

[0100] The dosage forms according to the disclosure include various active agents and their pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p- toluenesulfonate. and the like; amino acid salts such as arginate, asparginate. glutamate and the like, and metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N.N'-dibenzylethylenediamine salt and the like.

[0101] In some embodiments, the softgel capsule may have a hardness of about 1.5 N to about 10 N, about 2 N to about 9 N, about 2.5 N to about 8N, about 3 N to about 7 N, or about 4 N to about 6 N. In some embodiments, the hardness of the softgel capsule may be about 1 N to about 5 N, about 2 to about 4.5 N, or about 2.5 N to about 4 N. In some embodiments, the water activity (aw) of the softgel capsule may be 0. 1 to about 1. about 0. 15 to about 0.9, about 0.2 to about 0.8, about 0.25 to about 0.75, about 0.3 to about 0.6, or about0.4 to about 0.5. In some embodiments, the water activity of the softgel capsule may be about 0.1 to about 0.5, about 0.2 to about 0.45, or about 0.3 to about 0.4. In some embodiments, the burst strength of the softgel capsule may be about 8 kg to about 18 kg, about 9 kg to about 17 kg, about 10 kg to about 15 kg, or about 12 kg to about 14 kg. In some embodiments, the burst strength of the softgel capsule may be about 9 kg to about 15 kg, about 9.5 kg to about 14.5 kg, or about 10 kg to about 13 kg. In some embodiments, the softgel capsule delivers the fill material after squeezing in an amount of at least about 85%, at least about 88%, at least about 90%, at least about 92%, at least about 95%, at least about 97%, at least about 98%, at least about 99% or at least about 99.5%.

[0102] Referring now to the Figures, FIG. 1 illustrates a softgel capsule according to an embodiment of the present disclosure. In FIG. 1, a softgel capsule 100 includes a capsule shell 5. The capsule shell 5 includes one or more areas of reduced thickness 3 that enable opening of the softgel capsule 100 by compressing the softgel capsule 100 to cause rupture of the capsule shell 5 at the one or more areas of reduced thickness 3. A fdl contained in the softgel capsule 100 can be reliably dispensed from the softgel capsule 100 via the one or more ruptured areas of reduced thickness 3 by being sprayed or squeezed out of the capsule shell 5 to an intended dispensing location, such as the oral cavity or the nasal cavity.

[0103] The capsule shell 5 of the softgel capsule may be impermeable to the fill therein, but could be permeable to other solvents, such as water. The softgel capsule 100 may provide a single-dose product and is small in size. The volume of the softgel capsule 100 may be from about 0.05 mL to about 5 mL, from about 0. 1 mL to about 3 mL, about 0.2 to about 2 mL, or about 0.25 mL to about 1 mL.

[0104] The softgel capsule 100 may have a variety of shapes including spheres, oblong shapes, elongated tubes, disks, squares, rectangles, cylindrical shapes, ellipsoidal shapes, cat ear shapes, or other geometrical shapes. The softgel capsule 100 may also have shapes that are customized for a specific product or vender.

[0105] The one or more areas of reduced thickness 3 may be located any where on the capsule shell 5. In some embodiments, the area of reduced thickness may be offset from the center of the capsule shell 5 to provide a large portion of the capsule shell 5 that can be compressed to rupture the area of reduced thickness 3. In some embodiments, the area of reduced thickness 3 may be located at an end or a comer of the softgel capsule 100 where the softgel capsule 100 has an end or a comer (such as rectangular shape or spheroidal shape, Figure 1). In some embodiments, two areas of reduced thickness 3, or three areas of reduced thickness 3, or four or more areas of reduced thickness, may be provided as a cluster on thecapsule shell 5. The plurality of areas of reduced thickness 3 may be used to provide a spray of plurality of streams of the fill when dispensed from the softgel capsule 100 that might be useful when spreading the fill over an area is desired.

[0106] In Figure 3D, a cat ear shaped softgel capsule 100 is illustrated. The cat ear shape softgel capsule 100 of Figure 3D may include an air hole located in a central area of the capsule 100. In a preferred shape, the area of reduced thickness 3 is a decreased land or surface area bounded by two protrusions 2 such as in the cat ear shape shown in Figure 3D. The land or surface area may be decreased in the sense that the protrusions 2 define borders of the land or surface area within which the area of reduced thickness 3 may be located, thereby decreasing the potential size of an opening created by exerting pressure on the area of reduced thickness 3, relative to a similar package without the protrusions 2. These two protrusions 2 stabilize the fill material in the capsule and create a back pressure directly on the area of reduced thickness 3. The pressure may rupture the area of reduced thickness 3 to express the fill material. The area of reduced thickness 3 also provides a specific start point for the expression, as well as fanning the fill material between the two protrusions 2.

[0107] The walls of the softgel capsule may be shaped, as shown in Fig. 3D. to help direct compressive force applied to the softgel capsule 100 to the area of reduced thickness 3 to facilitate both opening the capsule 100 and dispensing of the contents of the capsule 100, particularly for spray dispensing to an oral cavity or nasal cavity.

[0108] The area of reduced thickness 3 may be a dot. a line, or multiple lines that are parallel or intersecting as shown in Figures 3A-3D. In some embodiments, the area of reduced thickness 3 may have a shape such as fantasy shapes, animals, flowers, a sun, other natural patterns or portions thereof, preferably located in a decreased land area between two protrusions 2, where the two protrusions 2 have the shape of, for example, ears, tails, hands, noses and the like. The area of reduced thickness may be of different lengths or widths in order to customize the rate or pattern of dispensing of the fill from the softgel capsule 100.

[0109] The area of reduced thickness 3 may be more fragile than the remainder of the capsule shell 5 and thus may preferentially ruptured when a sufficient compression force is applied to the softgel capsule 100. The pressure may be applied via hand or finger pressure such as by squeezing the package. The pressure may also be applied by a device designed for use with the softgel capsule of the invention such as a small appliance provided with structure that can exert a compressive force on the softgel capsule 100. The appliances may be able to squeeze the capsule 100 following an established rhythm / path to provide the desired dispensing from capsule 100.

[0110] The ruptured area of reduced thickness 3 may become an ejection orifice for the fill of the softgel capsule 100 which provides a channel through capsule shell 5 for dispensing the fill. The fill may be dispensed as a spray and / or by squeezing the fill from the softgel capsule 100 in a predetermined direction. The fill may be sprayed or squeezed into the oral cavity or nasal cavity7.

[0111] In an embodiment, the softgel capsule 100 may be in the form of an oblong / tear shape. In this embodiment, the application of pressure on the sides where the sealing line resides provides an excellent spray effect. In addition, this embodiment is easy to use and facilitates control of the spray effect. The extended radius on each side of the break point causes the fill material to find the center location during application of pressure. The area of reduced wall thickness 3 enhances the break and allows fill material to express at the center point. The area of reduced thickness 3 may be sized to provide a desired dispensing such as a fine spray.

[0112] In some embodiments, the softgel capsule 100 may have a main body 1 and a protrusion 2 as shown in Figure 2. The main body 1 may have any shape such as a shape of a sphere, a spheroidal shape, an ellipsoidal shape, a rectangular shape, a cylindrical shape or a cubic shape. The protrusion 2 extends, preferably radially outwardly, from the main body 1. The protrusion 2 may be any shape such as a bulge, a cylindrical protrusion, a finger-like shape, or in the form of a likeness of an ear, tail, hand, nose, and the like. In some embodiments, the protrusion 2 may extend less than about 0.5 mm, or less about 0.4 mm, or less than about 0.3 mm, or less than about 0.2 mm from the main body 1 .

[0113] The area of reduced thickness 3 may be located on the protrusion 2. The user may compress the main body 1 of softgel capsule 100 in order to rupture the area of reduced thickness 3 on the protrusion 2. Placing the area of reduced thickness 3 on the protrusion 2, at the tip or in a decreased land area of protrusion 2, may offer convenience for dispensing the fill to certain locations such as inside of the ears, nose, or mouth. The protrusions help direct the fill to flow to the location of the area of reduced thickness 3 in order to facilitate dispensing and, in some embodiments, to help focus the exertion of pressure on the area of reduced thickness 3 to facilitate opening the softgel capsule 100.

[0114] In some embodiments, a plurality of protrusions 2 may be present on the softgel capsule 100 each with an area of reduced thickness 3. In some embodiments, the softgel capsule 100 may have two protrusions 2 where the area of reduced thickness 3 is located in a decreased land area between the two protrusions 2. The plurality of protrusions 2 may form a cluster on the softgel capsule 100. In some embodiments, plurality of protrusions2 with plurality of areas of reduced thickness 3 may provide a plurality of dispensing streams when it is desirable to spray the fill out of the softgel capsule 100 over a relatively large area.

[0115] Optionally, at least a portion of the surface of the capsule shell 5 may be textured by providing textured areas 4 as shown Figure 2. The texturing may be provided by, for example, a raised pattern on the surface of the softgel capsule 100 such as ridges, stripes, bars, bands, streaks, strips, spots, striations, ribs, and combinations thereof, and combinations thereof. This texturing may be applied to capsule shells that comprise gelatin. The texturing may also be provided by one or more indentations in the surface of the softgel capsule 100 of any suitable size or shape though care must be taken not to create an area of weakness that could rupture during compression. A user may hold and compress the softgel capsule 100 at the textured areas 4 for ease of handling and / or to improve grip on the softgel capsule 100 during compression of the softgel capsule 100 for dispensing. The texture 4 may be preferably imparted to the softgel capsule 100 during the manufacturing process by, for example, use of a die that provides texture to the film used to form the capsule shell 5.

[0116] The softgel capsule shell 5 of the softgel capsule 100 may be formed from at least one gelling agent. In some embodiments, the softgel capsule shell 5 may be formed from a combination of two gelling agents. The gelling agents of the present invention may be selected from protein- based gelling agents and polysaccharide-based gelling agents as descried herein.LIST OF ITEMS1. A method comprising administering a pharmaceutical composition, wherein the administering comprises dispensing a pharmaceutical fill composition comprising an active agent from a softgel capsule to the nasal cavity of a patient for nasal absorption or to the oral cavity of the patient for pre-gastric absorption.2. The method of item 1, wherein the pharmaceutical fill composition is dispensed to the nasal cavity' of the patient.3. The method of item 1, wherein the pharmaceutical fill composition is dispensed to the oral cavity of the patient.4. The method of any one of the preceding items, wherein the administering of the pharmaceutical composition bypasses first pass hepatic metabolism in the patient.5. The method of item 1, wherein the fill composition is dispensed buccally or sublingually.6. The method of any one of the preceding items, wherein the softgel capsule includes a shell and the pharmaceutical fill composition, wherein the shell comprises a shell composition comprising at least one gelling agent selected from a protein and a polysaccharide, and the shell comprises an area having a first shell thickness, the area having the first shell thickness being oblong-shaped and having two protrusions that define a border, and one or more areas of reduced shell thickness relative to the first shell thickness, the one or more areas of reduced shell thickness being located with the border defined by the two protrusions; the one or more areas of reduced shell thickness being configured to rupture by exertion of a compression force on the oblong-shaped portion of the shell to provide an opening in the one or more areas of reduced thickness of the shell through which the pharmaceutical fill composition is dispensed to the naval cavity or the oral cavity, and the opening in the one or more areas of reduced thickness of the shell is limited by the border defined by the two protrusions.7. The method of any one of the preceding items, wherein the active agent is subject to first pass hepatic metabolism upon gastric absorption.8. The method of any one of the preceding items, wherein at least 95% of the pharmaceutical fill composition is dispersed from the softgel capsule.9. The method of any one of the preceding items, wherein the pharmaceutical fill composition comprises a hydrophilic or lippophilic excipient.The method of item 9, wherein the hydrophilic or lippophilic excipient comprises polyethylene glycol 400, polyethylene 600. propylene glycol, medium chain triglyceride, a vegetable oil, or a combination thereof. The method of any one of the preceding items, wherein the pharmaceutical fill composition further comprises an antioxidant. The method of any one of the preceding items, wherein the pharmaceutical fill composition further comprises a surfactant. The method of item 12, wherein the surfactant comprises vitamin E TPGS, polysorbate 20, polysorbate 80, Span 80, Labrafil, lecithin, or a combination thereof. The method of any one of the preceding items, wherein the pharmaceutical fill composition further comprises a flavoring agent. The method of item 14, wherein the flavoring agent comprises wintergreen, peppermint oil, lemon oil, or a combination thereof. The method of any one of the preceding items, wherein the pharmaceutical fill composition further comprises a sweetening agent. The method of item 6, wherein the one or more areas of reduced thickness comprise a deepest point in the shell between the protrusions. The method of item 17, wherein the one or more areas of reduced thickness are convex relative to an area inside of the softgel capsule and adjacent to the one or more areas of reduced thickness. The method of item 18, wherein the two protrusions are concave relative to an area inside of the softgel capsule to the one or more areas of reduced thickness. The method of item 6, wherein the protrusions create a back pressure on the one or more areas of reduced thickness.The method of item 6. wherein the one or more areas of reduced thickness are from about 30% to about 70% thinner than the first thickness of the shell. The method of item 6, wherein the protrusions and the one or more areas of reduced thickness dispense the fill composition as a spray. The method of item 22, wherein the shell has two or more areas of reduced thickness, wherein the spray is dispensed as a plurality of streams. The method of item 6, wherein the one or more areas of reduced thickness are sized to provide a desired dispensing to the oral cavity or the naval cavity. The method of any one of the preceding items, wherein the softgel capsule is biodegradable. The method of item 6, wherein the one or more areas of reduced thickness are circular or linear. The method of item 6. wherein each protrusion extends less than about 0.5 mm from the area of the shell having the first thickness. The method of item 1, wherein the softgel capsule has an internal volume of from about 0.05 to about 5 ml. The method of item 6, wherein the at least one gelling agent is a protein-based gelling agent selected form the group consisting of collagen, gelatin, egg whites, and milkbased proteins. The method of item 6, wherein the at least one gelling agent is a polysaccharide-based gelling agent selected from the group consisting of cellulose-based materials, starches, modified starches, pectins, gums, dextrins, alginates, carrageenans, and mixtures thereof.31. The method of item 6, wherein the at least one gelling agent is gelatin and the gelatin is included in an amount of about 25% to about 45% by weight based on total weight of the softgel capsule shell.32. The method of item 31, wherein the gelatin is an animal-based gelatin or a plantbased gelatin.33. The method of any one of the preceding items, wherein the shell further comprises carrageenan, starch, pullulan, cellulose, maltodextrin, or a combination thereof.34. The method of item 6. further comprising an air hole located in a central area of the softgel capsule.35. The method of any one of the preceding items, wherein the softgel capsule has a shape including oval, oblong or a tear drop.36. A method of preparing a softgel capsule comprising: encapsulating a fill composition in a shell composition using a rotary' die to form a capsule; and drying the capsule, wherein the encapsulating creates an area of reduced thickness in a shell of the softgel capsule.EXAMPLES

[0117] Specific embodiments of the invention will now be demonstrated by reference to the following examples. It should be understood that these examples are disclosed solely by way of illustrating the invention and should not be taken in any way to limit the scope of the present invention.

[0118] An example of the softgel capsule as described herein will now be described. It is understood that the example is an illustrative example and is not meant to be limiting.

[0119] The softgel capsules of the present disclosure are used as a container to deliver a pharmaceutical or nutraceutical products to oral and nasal cavity or to skin surface. The capsules were manufactured in a way to create a weak spot created on the tip of thecapsule while ensuing the capsule staying intact during normal storage. During administration of the pharmaceutical composition, the content of the capsule may be delivered to the intended location, either the oral cavity or the nasal cavity by squeezing the capsule. Upon squeezing, the tip of the capsule will burst and release the content of the softgel capsule. The shell can then be discarded as biodegradable waste.

[0120] In Table 1, a shell composition to form a shell of the softgel capsule including a plant based shell is shown.Table 1 : Plant-based Shell Composition

[0121] In Table 2, a shell composition to form a shell of the softgel capsule including gelatin is shown.Table 2: Gelatin-based Shell Composition

[0122] The fill material may include a prescription or over the counter druge product, nutraceutical product that is both hydrophobic or hydrophilic in nature. The manufacturing steps for preparing the softgel capsules as described herein are as follows:1. Gel mass preparation is performed using a gel melter. All excipients for the gel mass are mixied at elevated temperatures of 60 to 95 C to dissolve the solid excipients and form a homogenous flowable gel mass.2. The fill material containing the drug substance is dissolved or suspended in solvents or suspending liquid with mixing. The fill is then deaerated to remove air.3. A rotary die encapsulation machine is employed to encapsulate the fill material. Specially designed dies are used to create the weak spot on the tip of the capsule during the capsule sealing process. This may be achieved where the cutting edge is made thinner than the rest of the die.4. The wet capsules are dried, inspected and packaged into bulk cartons.5. Finished capsules are packaged into bottles or blisters.Fill Weight Study

[0123] A study was performed to test the fill weight of the softgel capsule after dispensing the pharmaceutical composition. In Table 3, the results of the study are shown. In the standard operating procedure, a whole softgel capsule including the fill material was weighed. Then, the fill material was discarded, and the shell was cleaned using solvent. The softgel capsule was then re-weighed. The difference between the whole capsule and the shell weight is calculated as the fill weight.Table 3: Fill Weight of SOP study

[0124] A study was performed to test the delivered fdl quantity of the softgel capsule after squeezing the softgel capsule. In Table 4, the results of this study are shown. In the squeeze test, the whole softgel capsule including the fill material was weighed. The fill material was then squeezed out, where the leftover shell without any cleaning is reweighed. The difference between the whole capsule weight and the shell weight is the amount of fill material discharged.Table 4: Fill Weight of Squeeze testForce Required to Squeeze the Fill Out of Capsule

[0125] A study was performed to investigate the relationship between the force required to squeeze the fill out of capsule and capsule hardness and water activity. The force required to squeeze the fill out of capsule was measured as the burst strength using a Texture Analyzer. The capsule hardness was determined using a hardness tester. The water activity was measured using a water activity meter. Table 5 summarizes the study results.Table 5. Force Required to Squeeze the Fill Out of Capsule as Function of Capsule Hardness and Water ActivityP 2,1 | 0,4775 | 9,756 |

[0126] From this study, the harder the capsule was, and the lower the water activity was, the higher force (burst strength) was required to squeeze out the fill content.

[0127] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.

[0128] The embodiments, illustratively described herein, may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0129] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0130] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also therebydescribed in terms of any individual member or subgroup of members of the Markush group.

[0131] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any- listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a nonlimiting example, each range discussed herein can be readily broken own into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,'’ “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

Claims

What is claimed:

1. A method comprising administering a pharmaceutical composition. wherein the administering comprises dispensing a pharmaceutical fill composition comprising an active agent from a softgel capsule to the nasal cavity of a patient for nasal absorption or to the oral cavity of the patient for pre-gastric absorption.

2. The method of claim 1, wherein the pharmaceutical fill composition is dispensed to the nasal cavity of the patient.

3. The method of claim 1, wherein the pharmaceutical fill composition is dispensed to the oral cavity of the patient.

4. The method of claim 1, wherein the administering of the pharmaceutical composition bypasses first pass hepatic metabolism in the patient.

5. The method of claim 1. wherein the fill composition is dispensed buccally or sublingually.

6. The method of claim 1, wherein the softgel capsule includes a shell and the pharmaceutical fill composition. wherein the shell comprises a shell composition comprising at least one gelling agent selected from a protein and a polysaccharide, and the shell comprises an area having a first shell thickness, the area having the first shell thickness being oblong-shaped and having two protrusions that define a border, and one or more areas of reduced shell thickness relative to the first shell thickness, the one or more areas of reduced shell thickness being located with the border defined by the two protrusions; the one or more areas of reduced shell thickness being configured to rupture by exertion of a compression force on the oblong-shaped portion of the shell to provide an opening in the one or more areas of reduced thickness of the shell through which the pharmaceutical fill composition is dispensed to the naval cavity or the oral cavity, and the opening in the one or more areas of reduced thickness of the shell is limited by the border defined by the two protrusions.

7. The method of claim 1, wherein the active agent is subject to first pass hepatic metabolism upon gastric absorption.

8. The method of claim 7, wherein at least 95% of the pharmaceutical fill composition is dispersed from the softgel capsule.

9. The method of claim 8, wherein the pharmaceutical fill composition comprises a hydrophilic or lippophilic excipient.

10. The method of claim 9. wherein the hydrophilic or lippophilic excipient comprises polyethylene glycol 400, polyethylene 600, propylene glycol, medium chain triglyceride, a vegetable oil, or a combination thereof.

11. The method of claim 8, wherein the pharmaceutical fill composition further comprises an antioxidant.

12. The method of claim 8, wherein the pharmaceutical fill composition further comprises a surfactant.

13. The method of claim 12, wherein the surfactant comprises vitamin E TPGS, polysorbate 20, polysorbate 80, Span 80, Labrafil, lecithin, or a combination thereof.

14. The method of claim 7, wherein the pharmaceutical fill composition further comprises a flavoring agent.

15. The method of claim 14, wherein the flavoring agent comprises wintergreen, peppermint oil. lemon oil, or a combination thereof.1 . The method of claim 7, wherein the pharmaceutical fill composition further comprises a sweetening agent.

17. The method of claim 6, wherein the one or more areas of reduced thickness comprise a deepest point in the shell between the protrusions.

18. The method of claim 17, wherein the one or more areas of reduced thickness are convex relative to an area inside of the softgel capsule and adjacent to the one or more areas of reduced thickness.

19. The method of claim 18, wherein the two protrusions are concave relative to an area inside of the softgel capsule to the one or more areas of reduced thickness.

20. The method of claim 6, wherein the protrusions create a back pressure on the one or more areas of reduced thickness.

21. The method of claim 6, wherein the one or more areas of reduced thickness are from about 30% to about 70% thinner than the first thickness of the shell.

22. The method of claim 6, wherein the protrusions and the one or more areas of reduced thickness dispense the fill composition as a spray.

23. The method of claim 22, wherein the shell has two or more areas of reduced thickness, wherein the spray is dispensed as a plurality of streams.

24. The method of claim 6, wherein the one or more areas of reduced thickness are sized to provide a desired dispensing to the oral cavity or the naval cavity'.

25. The method of claim 1, wherein the softgel capsule is biodegradable.

26. The method of claim 6, wherein the one or more areas of reduced thickness are circular or linear.

27. The method of claim 6, wherein each protrusion extends less than about 0.5 mm from the area of the shell having the first thickness.

28. The method of claim 1, wherein the softgel capsule has an internal volume of from about 0.05 to about 5 ml.

29. The method of claim 6, wherein the at least one gelling agent is a protein-based gelling agent selected form the group consisting of collagen, gelatin, egg whites, and milk-based proteins.

30. The method of claim 6, wherein the at least one gelling agent is a polysaccharide- based gelling agent selected from the group consisting of cellulose-based materials, starches, modified starches, pectins, gums, dextrins, alginates, carrageenans, and mixtures thereof.

31. The method of claim 6, wherein the at least one gelling agent is gelatin and the gelatin is included in an amount of about 25% to about 45% by weight based on total weight of the softgel capsule shell.

32. The method of claim 31, wherein the gelatin is an animal -based gelatin or a plantbased gelatin.

33. The method of claim 6, wherein the shell further comprises carrageenan, starch, pullulan, cellulose, maltodextrin, or a combination thereof.

34. The method of claim 6, further comprising an air hole located in a central area of the softgel capsule.

35. The method of claim 1, wherein the softgel capsule has a shape including oval, oblong or a tear drop.

36. A method of preparing a softgel capsule comprising: encapsulating a fill composition in a shell composition using a rotary' die to form a capsule; and drying the capsule, wherein the encapsulating creates an area of reduced thickness in a shell of the softgel capsule.