Propelling active from within a pouch

Abstract

Disclosed is an effervescent composition configured for oral use. The effervescent composition comprises an active ingredient and one or more ingredients for creating an effervescence when contacted by an effervescent permitting liquid, wherein the effervescent composition is contained within a pouch. Also disclosed is a pouched product containing the effervescent composition disclosed herein. Further disclosed is a method for delivery of an active ingredient to a user using the pouched product. In addition, also disclosed is a method of manufacture of the pouched product and process for preparation of an effervescent composition configured for oral use, as disclosed herein. The composition and product can be used for delivery of an active ingredient to a user.

Description

PROPELLING ACTIVE FROM WITHIN A POUCHCROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of and priority to U.S. Provisional patent application No. 63 / 697,757, filed September 23rd, 2024. The content of the above-noted patent application is hereby expressly incorporated by reference into the detailed description hereof.FIELD

[0002] The specification relates to an effervescent composition configured for oral use, a pouched product, a method for delivery of an active ingredient to a user, and a method of manufacture of the pouched product.BACKGROUND

[0003] Buccal absorption in the oral cavity is a well-established route for administering medications to a patient, since the absorbed medications enter into the systemic circulation directly; thus bypassing the portal circulation and the liver. As such, fast responses are expected with medications delivered by buccal absorption. Further, if the administered medication has a high first pass metabolism in the liver, the bioavailability is expected to be higher.

[0004] Currently, numerous medications are formulated for a fast release for buccal absorption. Various dosage formats such as fast dissolving tablets, gum, oral spray, buccal batches, strips (like Listerine®) and others are commercially available. Lozenges are the most common example of this of this dosage form.

[0005] Similar to the above, buccal pouches have also been used as a dosage form. In this dosage format, the active ingredients are contained within a porous pouch. The pouch material is made out of a non-woven fabric or fleece that is porous and allows wetting by saliva; thereby, solubilizing the pouch contents. Once solubilized within the pouch, the active ingredients are released into the oral cavity and absorbed through the oral mucosa which lines the oral cavity. In this dosageformat, a large portion of the released contents is absorbed in the oral cavity through buccal mucosa. In the meantime, a portion is swallowed and absorbed downstream in the gastrointestinal track. This partitioning (portion swallowed and portion absorbed locally) can be assessed accurately by including a contrast material in the pouch such as barium sulfate which can be visualized by X-rays.

[0006] The currently marketed pouches are made out of non-woven fleece material. For fleece manufacturing, the fibers are laid in a random fashion and a heat-sensitive binder is added to adhere the fibers to each other. In the majority of commercial fleeces, the fibers are made out of cellulose, although some non-woven fleeces also contain other types of fibers, such as polyester. Post-manufacturing, the non-woven material is processed to have certain characteristics such as hydrophobic or hydrophilic. Also the non-woven material is available in different weights and binder characteristics.

[0007] Since these non-woven fabrics are three-dimensional, the pore sizes are very variable and cover a wide range. The porosity of these tea-bag-like pouches is determined mainly by air pressure and weight, rather than pore sizes. The current commercial oral pouches are used for consumer products such as multivitamin, energy and nicotine products.

[0008] Use instructions of the current commercial pouches typically state that these pouches are placed in the oral cavity (mainly behind the upper lip) for 15-30 minutes where saliva assists in solubilizing the contents which results in buccal absorption. The whole process of wetting, solubilization and content release is saliva driven and is modulated by simple capillary flow of saliva. Clearly, the release of pouch contents will depend on salivary flow, which is mostly individual-dependent and is a passive process. Although salivary stimulants and absorption enhancers are usually included in the pouch ingredient, a delicate balance is essential to increase salivary flow, but not to the extent that most of the released content are swallowed. A balance needs to be reached to stimulate salivary solubilization while maximizing local buccal absorption.

[0009] Within the time frame of utilization, the amount of active ingredients remaining within the pouch after utilization is significant; amounting to ranges between 30-60%. This large residual is both significant and more importantlyunpredictable. This fact limits the use of these pouches for therapeutic purposes, since bioavailability plays a significant role in drug effectiveness.

[0010] Clearly several factors play a role in determining the release profile of actives from an oral pouch. However, it is not clear which factor(s) plays the most significant role(s) in determining the release profiles of actives from various pouches. Since the mode of release of the active ingredient is saliva dependent and relies on capillary flow, the passivity of this process takes a central role in the solubilization and release process.

[0011] Converting the saliva-driven release pattern from a passive process into an active one where the solubilization is initiated by the saliva flow into the pouch and then driven and controlled by the ingredients within the pouch can help to convert the whole process into a predictable pattern of release and bioavailability, hence reliability of the whole process.

[0012] Utilization of chemical energy to drive chemical reactions and physical processes is well established and used in our daily lives. Propelling various chemical and physical processes through the generation of bubble streams is well known and utilized. Chemical propelling by gas generation as a driving force for solubilization and chemical extraction is also well known in various technical and scientific disciplines.

[0013] The utilization of chemical bubble generation and bubble streams to accelerate and drive the release of active medications in a formulation goes back several decades. These bubble streams are generated by different chemical reactions, the most common of which are the effervescent reactions. Effervescent reactions and their bubble stream generation are extensively utilized in the pharmaceutical industry to assist in solubilization of active ingredients.

[0014] The liberation of carbon dioxide from an effervescent reaction increases the dissolution of the active pharmaceutical ingredient (API). The first utilization of an effervescent reaction and gas generation was in 1957, when the Emerson Drug Company introduced a popular drink tablets, the FIZZIES. Alka- Seltzer was introduced in the early 1970 and became a famous utilization of an effervescent reaction in the pharmaceutical industry. Nowadays, products that employ the effervescent reactions are widely marketed in pharmaceutical,nutraceutical, food, agriculture, detergent and cleaning sectors. In the consumer medical market, the most common examples are effervescent Vitamin C and denture treatment tablets.

[0015] The basic chemistry of effervescent reactions is well-documented in the scientific and patent literature. Effervescent reactions are fundamentally reactions between an acid or acid salt as a proton donor and an alkali metal or an alkaline earth carbonate or bicarbonate as the carbon dioxide donor. Effervescent reactions are initiated by water resulting in generation of carbon dioxide and water, which sustain further driving of the reaction.

[0016] Bubble generation and propelling by a chemical reactions stretches beyond effervescent reactions. Peroxide hydrolysis reactions are another type of chemical reaction to generate a bubble stream. Peroxide hydrolysis reactions employ both by enzymatic and non-enzymatic hydrolysis. Bubble generation by hydrolysis of peroxides is well utilized in both pharmaceutical and laundry industry.

[0017] Although effervescent reactions are known, and their proposed use in a pouch dosage format has been disclosed before, no pouch product having an effervescent composition that is configured for oral use is commercially available.

[0018] There is a need in the art for a composition for delivery of an active pharmaceutical ingredient where the composition is formulated or configured for an oral use in a pouch format with such composition having a predictable active release profile, a product for containing such a composition, a method of delivery of an active ingredient to a user that promotes buccal absorption, and a method of manufacture of such a composition and / or product.

[0019] The background herein is included solely to explain the context of the disclosure. This is not to be taken as an admission that any of the material referred to was published, known, or part of the common general knowledge as of the priority date.SUMMARY

[0020] In one aspect, the specification relates to an effervescent composition configured for oral use, the effervescent composition comprising:

[0021] an active ingredient; and

[0022] one or more ingredients for creating an effervescence when contacted by an effervescent permitting liquid;

[0023] wherein the effervescent composition is contained within a pouch.

[0024] In a second aspect, the specification relates to a pouched product, comprising:

[0025] an effervescent composition comprising an active ingredient and one or more ingredients for creating an effervescence when contacted by an effervescent permitting liquid,

[0026] wherein the effervescent composition is contained in a pouch.

[0027] In a third aspect, the specification relates to a method for delivery of an active ingredient to a user, the method comprising:

[0028] placing the pouched product as disclosed herein in an oral cavity of the user.

[0029] In a fourth aspect, the specification relates to a method of manufacture of the pouched product as disclosed herein, the method comprising:

[0030] placing the effervescent composition as disclosed herein in a pouch; and

[0031] sealing the pouch.

[0032] In a fifth aspect, the specification relates to a process for preparation of an effervescent composition configured for oral use, the process comprising:

[0033] mixing an active ingredient and one or more ingredients for creating an effervescence when contacted by an effervescent permitting liquid.BRIEF DESCRIPTION OF DRAWINGS

[0034] Reference will now be made, by way of example, to the accompanying drawing which shows an example embodiment of the present application, and by which the present application can be further understood from the followingdescription with reference to the Figure. The present application includes a drawing, wherein:

[0035] Figure 1 shows a picture of a pouched product containing the effervescent composition for oral use.DESCRIPTION OF EXAMPLE EMBODIMENTS

[0036] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, the typical materials and methods are described herein. In describing and claiming the present invention, the common terminology generally used is described herein below. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting.

[0037] Many patent applications, patents, and publications are referred to herein to assist in understanding the aspects described. Each of these references are incorporated herein by reference in their entirety.

[0038] When introducing elements disclosed herein, the articles “a”, “an”, “the”, and “said” are intended to mean that there may be one or more of the elements.

[0039] The term "comprising" and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The foregoing also applies to words having similar meanings such as the terms, "including", "having" and their derivatives. It will be understood that any embodiments described as “comprising” certain components may also “consist of” or “consist essentially of,” these components, wherein “consisting of” has a closed- ended or restrictive meaning and “consisting essentially of” means including the components specified but excluding other components except for materials present as impurities, unavoidable materials present as a result of processes used to providethe components, and components added for a purpose other than achieving the technical effects described herein. For example, a composition defined using the phrase “consisting essentially of” encompasses any known acceptable additive, excipient, diluent, carrier, and the like, suitable for the composition described herein. Typically, a composition consisting essentially of a set of components will comprise less than 5% by weight, typically less than 3% by weight, more typically less than 1 % by weight of non-specified components.

[0040] It will be understood that any component defined herein as being included may be explicitly excluded from the claimed invention by way of proviso or negative limitation, such as any specific compounds or method steps, whether implicitly or explicitly defined herein.

[0041] In addition, all ranges given herein include the end of the ranges and also any intermediate range points, whether explicitly stated or not.

[0042] Finally, terms of degree such as "substantially", "about" and "approximately" as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0043] The abbreviation, “e.g.” is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation “e.g.” is synonymous with the term “for example.” The word “or” is intended to include “and” unless the context clearly indicates otherwise.

[0044] The phrase “at least one of” is understood to be one or more. The phrase “at least one of... and...” is understood to mean at least one of the elements listed or a combination thereof, if not explicitly listed. For example, “at least one of A, B, and C” is understood to mean A alone or B alone or C alone or a combination of A and B or a combination of A and C or a combination of B and C or a combination of A, B, and C.

[0045] As noted above, although effervescent reactions are known, their use in a pouch dosage format has been unsuccessful, and no pouch product having an effervescent composition that is configured for oral use is commercially available. It is hypothesized that as effervescent reactions are endothermic, meaning that theyabsorb heat from their surroundings, this results in drop in the local temperature surrounding the effervescent formulation, which leads to a reduction in the solubility, and consequently, release of an active ingredient in saliva. Further, the bubbling effect of an effervescent reaction, rather than leading to a beneficial increase in release could lead to an overall reduction in release and hence availability of the active ingredient. The inventor of the specification has surprisingly uncovered that by reducing and actively controlling the rate of effervescence, the beneficial effects of the effervescence to pump out the active ingredient into the oral cavity, and thereby increase the amount of active ingredients and their dissolution in the saliva can be achieved. The reduction in the rate of effervescence can be achieved by having one or more of the ingredients (that lead to effervescence) to have low solubility in an aqueous environment. This results in a reduction in the amount of ingredient available for the effervescence reaction at any one instant. Rather, the low solubility ingredient(s) for the effervescence reaction is available for a prolonged period of time, which can lead to prolonged bubbling and pumping of the active ingredients into the aqueous environment. A second method to reduce the rate of effervescence is to encapsulate one of the ingredients used in the effervescent reaction. Similar to the first method, this reduces the availability of one of the ingredients for the effervescent reaction, leading to effervescence for a longer period of time. This delay resulted in a higher dissolution of the active ingredients and hence provides a potential path for utilization of the effervescent reaction in an oral pouch product. A further added benefit of controlling the various parameters of the effervescent reaction is the ability to manufacture the formulation and the oral pouch under ambient conditions which reduces the manufacturing costs and also ensure a long shelf life of the pouch formulation.

[0046] In one aspect, the specification relates to an effervescent composition configured or formulated for oral use to deliver an active pharmaceutical ingredient, the effervescent composition comprising one or more ingredients for creating an effervescence when contacted by an effervescent permitting liquid, wherein the effervescent composition is contained within a pouch. In another aspect, the specification relates to a pouched product having the effervescent composition disclosed herein. The above involves the employment of a chemical reaction to generate a bubble stream in an oral pouch and utilizing the propelling action of thisstream to increase and control the release of an active ingredient from the pouch. Reaction partners of a bubble generating reaction are included in the ingredients of the oral pouch, and are activated by absorption of saliva into the pouch. Such reaction partners include one or more ingredients for creating an effervescence when contacted by an effervescent permitting liquid.

[0047] Once initialed, the bubble stream acts as an engine to drive the release of the one or more active ingredients from the oral pouch. Further, in addition to the release of gas by the effervescence reaction, water is also produced, which make the reaction a self-driving reaction. By controlling and manipulating the various parameters of the chemical reactions, the bubble stream generation and its propelling action are modulated and controlled.

[0048] This control over the active ingredient release rate converts the release from a passive process into an active and predictable one. By manipulating the various parameters of this bubble stream, including bubble size, rate of generation and other reaction parameters, the release rate of the active ingredient can be controlled more accurately. Such modulation can impact the release rate and hence the biological impact of absorption of the active ingredient becomes more predictable.

[0049] In one embodiment, the propelling action of a bubble stream is generated within an oral pouch by an effervescent reaction. Effervescent reaction partners are included as ingredients within the oral pouch. This bubble stream acts as an engine to drive and control the release of the active ingredient from the pouch. Various formulation steps and processes are implemented to prevent premature trigger of the effervescent reactions and control the rate of this reaction. Initiating the effervescent reaction starts by saliva and is driven and can be maintained by water produced by the effervescent reaction.

[0050] The term, effervescent composition, is not particularly limited and should be understood by a person of skill in the art. An effervescent composition is a preparation that produces a fizzing or bubbling effect when it is mixed with a liquid that permits an effervescent reaction to occur, leading to the fizzing or bubbling effect. The effervescent reaction, in one embodiment, is the result of reaction between an acid and a carbonate / bicarbonate compound, as described hereinbelow. In another embodiment, the effervescent reaction is the result of hydrolysis of a peroxide, as described herein.

[0051] The term, active ingredient, as used herein is not particularly limited and should be understood by a person of skill in the art. An active ingredient is the substance in a composition, such as a medication, that produces the desired effect or performs a desired function. The active ingredient present in effervescent composition is not particularly limited, and can be varied based on application requirements. In one embodiment, for example and without limitation, the active ingredient is calcium, magnesium, nicotine or caffeine.

[0052] The acid or acid salt used in preparation of the effervescent composition are not particularly limited, should be known to a person of skill in the art or can be determined, and can be varied based on application requirements. Where an acid salt is utilized, the acid salt should have another acidic proton for the effervescent reaction (polyprotic acid). As such, reference to an acid salt herein refers to a compound that has multiple acidic protons and where one of the acidic protons is replaced with a cation to form the acidic salt.

[0053] To control the rate of the effervescent reaction, in one embodiment, for example and without limitation, at least one of the acid and the carbonate / bicarbonate compound (i.e. , the metal carbonate or metal bicarbonate) has low solubility in water or an aqueous environment, such as a buffered solution or saline. The term, low solubility, is not particularly limited and should be understood by a person of skill in the art. In one embodiment, for example and without limitation, low solubility refers to requiring more than 100, 1000 or 10,000 mass units of solvent to dissolve one mass unit of the solute.

[0054] Alternatively, in another embodiment, for example and without limitation, to control the rate of effervescence, one of the acid and the carbonate / bicarbonate compound (i.e., the metal carbonate or metal bicarbonate) is encapsulated to reduce the availability of the encapsulated species for the effervescent reaction.

[0055] As noted herein, the type of acid utilized is not particularly limited and can be varied based on application requirements. In one embodiment, for example and without limitation, the acid is a weak acid. In a second embodiment, for exampleand without limitation, the acid has a paof greater than about 1 , 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5 or 4. The term, pa, should be known to a person of skill in the art. In chemistry, an acid dissociation constant (a) is a quantitative measure of the strength of an acid in solution, while pais the logarithm of the dissociation constant (a). Hence, paand acid strength have an inverse relationship, where a lower pavalue indicates a stronger acid, while a higher pavalue indicates a weaker acid. In particular embodiments, the acid used in the composition disclosed herein has a paof greater than about 2, 2.25, 2.5, 2.75, 3, 3.25 or 3.5. In a further embodiment, for example and without limitation, the acid or acid salt can be an organic acid or salt of the organic acid. Such an organic acid or salt thereof can include, for example and without limitation, a food grade acid. The food grade acid used is also not particularly limited, and can include, for example and without limitation, citric acid, lactic acid, formic acid, propionic acid, sorbic acid or benzoic acid.

[0056] As described herein, the effervescent reaction can result from one or more ingredients that create an effervescence when contacted by an effervescent permitting liquid. The one or more ingredients used for creating effervescence is not particularly limited, and should be known or can be determined by a person of skill in the art. In one embodiment, for example and without limitation, the one or more ingredients (also referred to as effervescent reaction partners) include an alkali metal carbonate, an alkali metal bicarbonate, an alkaline earth metal carbonate, and / or an alkaline earth metal bicarbonate as the carbon dioxide donor and an acid or acid salt as the proton donor. In another embodiment, for example and without limitation, the one or more ingredients include a peroxide and a peroxide hydrolyzing catalyst.

[0057] The alkali metal carbonate, the alkali metal bicarbonate, the alkaline earth metal carbonate, and / or the alkaline earth metal bicarbonate used in preparation of the effervescent composition are not particularly limited and can be varied based on application requirements. In one embodiment, for example and without limitation, these include sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate or potassium bicarbonate.

[0058] As noted herein, in another embodiment, the one or more ingredients include to form the effervescent composition can include a peroxide and a peroxide hydrolyzing catalyst. In such an embodiment, the bubble stream is generated byhydrolysis of the peroxide where a peroxide and its hydrolysis catalyst are included in the pouch ingredients. The peroxide used in not particularly limited, should be known to a person of skill in the art or can be determined, and can be varied based on application requirements. In one embodiment, for example and without limitation, the peroxide is a food grade peroxide. In a further embodiment, for example and without limitation, the peroxide is calcium peroxide. The catalyst used for hydrolyzing the peroxide is not particular limited, should be known to a person of skill in the art or can be determined, and can be varied based on application requirements. In one embodiment, for example and without limitation, the peroxide hydrolyzing catalyst is an enzymatic hydrolyzing catalyst or a non- enzymatic hydrolyzing catalyst. Non-limiting example of a non-enzymatic hydrolyzing catalyst can include a metal salt.

[0059] As disclosed herein, another method to control the rate of effervescence is to encapsulate one of the ingredients of the effervescent reaction. This can involve encapsulation of acid, the carbonate / bicarbonate species (i.e. the metal carbonate or the metal bicarbonate), or both. The materials used for encapsulation are not particularly limited and can be varied based on application requirements and some are commercially available. In one embodiment, the encapsulating material is a water soluble polymer that dissolves in an aqueous solution environment releasing the ingredient needed for the effervescent reaction. In an embodiment, for example and without limitation, the effervescent composition contains an encapsulated acid. In another embodiment, for example and without limitation, the effervescent composition contains an encapsulated metal carbonate or metal bicarbonate. Oil-coated Alkali carbonate is an FDA-authorized and commercially available whitening agent (Avalanche Cloud by Sensient pharmaceuticals). Encapsulated acids are commercially available from many sources and have been used in the baking industry for decades.

[0060] The amount of the ingredients used in the effervescent composition is not particularly limited and can be varied based on application requirements. In one embodiment, for example and without limitation, the molar ratio of the acid to the metal carbonate / bicarbonate is from about 1 :1 to about 1 :4.

[0061] In some embodiments, the effervescent composition, or the one or more ingredients for carrying out the effervescent reaction are present as particulatematerial, forming granules. The size of the particulate material is not particularly limited and can be varied based on application requirements and can have granulates diameters between 1 mm and 10 mm.

[0062] As should be understood by a person of skill in the art, the effervescent compositions are formulated such that the one or more ingredients for the effervescent reaction react in the presence of water or an aqueous solution, such as a buffered solution or saliva. In the context of the subject specification, the term, configured for oral use, refers to the effervescent composition being provided in a pouch (such as shown in Figure 1) that can be placed in the oral cavity of a user, and allowing the effervescent reaction to take place, leading to release of the active ingredients from the pouch into the oral cavity of the user.

[0063] The pouch used and disclosed herein is not particularly limited and should be known to a person of skill in the art. Various pouches configured for oral use are known and available.

[0064] The effervescent composition disclosed herein can further contain, for example and without limitation, one or more a pharmaceutically acceptable diluent, carrier or excipient, or other compounds that aid the stability, safety and delivery of the active ingredient. The pharmaceutically acceptable diluent, carrier or excipient, or other compounds, is not particularly limited, should be known to a person of skill in the art or can be determined, and can be varied based on application requirements.

[0065] A pharmaceutically acceptable excipient is a non-toxic, inert substance added to a composition to increase its bulk. Common examples include lactose, starch, microcrystalline cellulose, and mannitol, chosen for their compatibility with active ingredients, good flowability, and stability to ensure the active ingredients proper form and performance. A pharmaceutically acceptable carrier or excipient is a generally safe, non-toxic, and biologically acceptable substance used in a pharmaceutical composition to deliver the active ingredient. It helps to make the composition safe and effective for human or animal use by serving as a solvent, diluent, stabilizer, or agent to improve drug absorption and targeting. These carriers must not cause undue harm or adverse effects at the prescribed dosages and should not cause any premature trigger of the effervescent reaction.

[0066] The other ingredients that can aid formulating the effervescent composition include, for example and without limitation, flavoring agents, surfactants, sweeteners, taste modifiers (such as bitter blockers), salts, binders, buffering agents, colorants, and the like, which can help to improve the effervescent composition. The other ingredients that can be used are not particularly limited, so long as they do not have a detrimental effect on effervescent reaction and composition, and should be known to a person of skill in the art or can be determined.

[0067] In a further aspect, the specification relates to a method of manufacture of the pouched product as disclosed herein, the method comprising placing the effervescent composition as disclosed herein in a pouch and sealing the pouch. The method utilized for manufacture is not particularly limited and involves steps typically taken in preparation of oral pouches known in the art under ambient conditions. The step of placing the effervescent composition is also not particularly limited and can involve pouring the composition in the pouch. Care should be taken to avoid exposure to excessive moisture that can lead to a premature effervescent reaction triggering resulting in a detrimental effect on the composition. In one embodiment, for example and without limitation, the pouch used is a non-woven fabric or fleece.

[0068] In still another aspect, the specification relates to a process for preparation of an effervescent composition configured for oral use, the process comprising mixing an active ingredient and one or more ingredients for creating an effervescence when contacted by an effervescent permitting liquid. The process for mixing is not particularly limited and can be determined by a person of skill in the art. As should be recognized by a skilled worker, moisture, water, aqueous solutions and the like, that provide a source of water molecules should be controlled to avoid or reduce the effervescent reaction in the composition, as it can effect the efficacy of the effervescent composition. US patent publication number US 2008 / 0003289 (incorporated herein by reference) discloses a method that can be utilized for the process of preparation of the effervescent composition disclosed herein.

[0069] In one embodiment, as disclosed herein, one of the ingredients for creating an effervescence can be encapsulated to control the rate of effervescence. As such, one or more of the acid, metal carbonate / bicarbonate, peroxide and peroxide hydrolyzing catalyst can be encapsulated. The process of encapsulation is not particularly limited and involves coating the ingredient and / or forming granules.In this way, one or more the ingredients is caged and does not readily react to form effervescence. Various means can be used for encapsulation, and can include coating the one or more ingredients with, for example and without limitation, a water soluble polymer or food grade water insoluble polymer.

[0070] The method of coating is also not particularly limited and can involve mixing one of the ingredients used in the effervescent reaction with a coating agent in the presence of a solvent for a sufficient amount of time, along with agitation to coat the ingredient. The solvent can be removed by evaporation or filtration based on the reagents used for encapsulation. This encapsulation ingredient can then be mixed with other ingredients to form the effervescent composition disclosed herein.EXAMPLES

[0071] The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific Examples. These Examples are described solely for purposes of illustration and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the constructs of the present invention and practice the claimed methods. The following working examples therefore, specifically point out the typical aspects of the present invention and are not to be construed as limiting in any way in the remainder of the disclosure. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation.

[0072] In the examples below, Examples 1 - 3 demonstrate effervescence formulations that address the general principles of the invention. While Examples 4 - 27 disclose the influence of various factors and ingredients that impact the effervescence reaction and hence the impact of bubble stream generation on propelling ingredients out of the pouch.

[0073] General experimental condition

[0074] Pouches of non-woven material are manually made and filled with various ingredients to be dissolved. The made pouches have dimensions of 32 mmin length and 14 mm in width. The pouches are filled with about 700-750 mg of material (about 80% capacity).

[0075] The dissolution of the active ingredients in the pouch was carried out under conditions that simulate oral dissolution during utilization in the oral cavity. The pouches were placed in a 20 mL Phosphate Buffered Saline (PBS) buffer @ pH of 6.8 that was kept at 37°C with no agitation. Ingredient dissolution efficiency was assessed by weighing the pouch before dissolution, after dissolution and after oven drying to remove the impact of water absorption by various excipients. Each dissolution experiment was done in at least in triplicates.

[0076] Example 1

[0077] A mixture of the ingredients with portions as noted in Table 1 was blended for 30 minutes in a V-blender. Pouches filled with 700mg of either control or effervescent mixtures. In the control pouches, the effervescent mixture was replaced with sweetener. Two different sets of experimentations were done, where active ingredients within the pouches were solubilised by standard methods (noted herein) for 30 minutes at room temperature and the active ingredients were measured in the solution phase. Pouches were also given to people to use and the active ingredients were measured in the residual of dry pouches using both spectroscopic methods and HPLC. In three repeats of the experiments, the average percentage (%) of active release in the control pouches was 60%. In the pouches with active effervescent partners, the average active release is 72%.Table 1 shows the ingredients used in formulating the effervescent composition.

[0078] Example 2

[0079] A mixture of the ingredients within the specified % range as noted in Table 2 was blended for 30 minutes using a V-Blender. Pouches filled with 700 mg of ingredients of either control or effervescent mixtures. In the control pouches, the effervescent mixture was replaced with sweetener. Pouches were given to different individuals to use by placing for 20 minutes in the oral cavity. Used pouches were recovered and dried. The active ingredients were measured in the residuals of dried pouches using both spectroscopic methods and HPLC. In three repeats of the experiments, the average percentage (%) of active release in the control pouches was 45%. In the pouches with active effervescent partners, the average active release is 66%.Table 2 shows a mixture of the ingredients within the specified % range in formulating the pouched products.

[0080] Example 3

[0081] A mixture of the ingredients with % in the specified range as noted in Table 3 was blended for 30 minutes in a V-Blender. Pouches were filled with 700mg of ingredients of either control or effervescent mixtures. In the control mixtures, the effervescent partners are replaced with excipients or sweetener. Pouches were placed in solubilization solution for 30 minutes at 37°C with mild mixing. Upon conclusion, pouches were dried and the active ingredients were measured in the solution phase and also in the dry pouches. Actives were measured using spectroscopic methods and HPLC.

[0082] In three repeats of the experiments, the average percentage (%) of active release in the control pouches was 65%. In the pouches with active effervescent partners, the average active release is 80%. Table 3 shows a mixture of the ingredients within the specified % range in formulating the pouched products.

[0083] Examples 4 - 10

[0084] In these set of examples, various parameters that influence the effervescence reaction were studied. To demonstrate the impact of effervescent reactions and gas generation on the dissolution efficiency of pouch contents, a base caffeine formation was made and various ingredients known to impact the release of pouch contents were added to this base formulation. These ingredients were added either separately or in combination. In order to keep pouch weight (fill) constant to avoid any weight influences on dissolution efficiency, the weight was supplemented with sugar for a constant pouch weight.

[0085] The ingredients of this control no-effervescent base formulation are detailed in Table 4. The various ingredients supplemented to this base formulation are detailed in Table 4A. The ingredients dissolution efficiency of the base formulation either by itself or after adding ingredients individually or in combinations to the pouch contents is detailed in Tables 5, 6, 7, 8, 9, 10 and 11. In these formulations, inclusion of water absorbing ingredients was avoided in order to get clear dissolution conclusions. Clearly, the average weight loss due to dissolution of ingredients is approximately 40-50%.Table 4 shows the ingredients used in the base formulation without all the ingredients to form an effervescent composition.Table 4A lists the modifiers added to the base formulation shown in Table 4 to assess the affect of the modifiers on release of the active ingredients.Table 5 lists the results of the dissolution study (Example 4) on a composition containing the base composition noted in Table 4 and L-tyrosine.Table 6 lists the results of the dissolution study (Example 5) on a composition containing the base composition noted in Table 4, L-tyrosine and L-theanine.Table 7 lists the results of the dissolution study (Example 6) on a composition containing the base composition noted in Table 4, L-tyrosine, L-theanine and calcium stearate (Ca stearate).Table 8 lists the results of the dissolution study (Example 7) on a composition containing the base composition noted in Table 4, L-tyrosine, L-theanine, calcium stearate (Ca stearate) and 40 mg citric acid.Table 9 lists the results of the dissolution study (Example 8) on a composition containing the base composition noted in Table 4, L-tyrosine, L-theanine, calcium stearate (Ca stearate) and Pluronic F127Table 10 lists the results of the dissolution study (Example 9) on a composition containing the base composition noted in Table 4, L-tyrosine, L-theanine and Pluronic F-127.Table 11 lists the results of the dissolution study (Example 10) on a composition containing the base composition noted in Table 4, L-tyrosine, L-theanine, Pluronic F127 and paraffin wax.

[0086] Examples 11 - 23

[0087] In these set of examples, the impact of specific effervescence reaction as well as the various ingredients that influence these reactions are assessed in order to appreciate the delicate balance required to propel ingredients out of the pouch.

[0088] A base effervescent formulation of ingredients containing a large amount of caffeine was used to demonstrate the impact of effervescent reactions on ingredient dissolution. The following examples illustrate the various parameters influencing the effervescence reactions.

[0089] Examples 11-14: In this set of experiments, the base effervescence formulation is detailed in Table 12 and the weight loss as a result of dissolution of the active ingredients in the pouch is detailed in Table 12B (three repeats, Example 11). In this formulation, the effervescent formulation employed mild partners (chlorogenic acids as the proton donor and calcium carbonate as the carbon dioxide donor). When this base formulation was supplemented with ingredients that influence the effervescent reactions efficiency, a clear impact in pouch residual weight after dissolution is evident. The impact of different ingredients was assessed as described further herein with reference to Examples 12 to 14.Table 12 lists the ingredients and their amounts (mg) in the base effervescent formulation.Chlorogenic acids 25Table 12B shows the result of dissolution of the active ingredients in the pouch using the base effervescent formulation noted in Table 12.

[0090] Example 12 involved studying the impact where the base formulation(as noted in Table 12) was supplemented with 50 mg of calcium phosphate. The formulation is outlined in Table 13, and the results of the dissolution study are provided in Table 13B.Table 13 lists the ingredients and their amounts (mg) in the base effervescent formulation supplemented with 50 mg of calcium phosphate.Table 13B shows the result of dissolution of the active ingredients in the pouch using the effervescent formulation noted in Table 13.

[0091] Example 13 involved studying the impact where the base formulation(as noted in Table 12) was supplemented with 50 mg of medium chain triglyceride (MCT) oil. The formulation is outlined in Table 14, and the results of the dissolution study are provided in Table 14B. Table 14 lists the ingredients and their amounts (mg) in the base effervescent formulation supplemented with 50 mg of MCT oil.Table 14B shows the result of dissolution of the active ingredients in the pouch using the effervescent formulation noted in Table 14.

[0092] Example 14 involved studying the impact where the base formulation(as noted in Table 12) was supplemented with 25 mg of bile salts. Bile salts can act as effective emulsifiers that influence both release of ingredients and their oral absorption, from pouch formulations. The formulation is outlined in Table 15, and the results of the dissolution study are provided in Table 15B.Table 15 lists the ingredients and their amounts (mg) in the base effervescent formulation supplemented with 25 mg of bile salts.Table 15B shows the result of dissolution of the active ingredients in the pouch using the effervescent formulation noted in Table 15.

[0093] It is clear from this set of experiments that the effervescent reactions enhance the dissolution of the ingredients from the oral pouch although the effervescence reactions are hypothermic which is expected to decrease the ingredients solubilisation. Further, it was clear that the impact is due to the effervescence reaction as adding ingredients that hinder that reaction impacted the residual ingredient weight.

[0094] Examples 15 - 18

[0095] A commercial caffeine formulation was supplemented with effervescent reaction partners. In this set of experiments, the ingredients of caffeine formulation(Table 16) were supplemented with a constant amount of carbon dioxide donor (calcium carbonate) and different acids are coupled with the carbon dioxide donor to facilitate effervescence and residual pouch weight was monitored. Sugar was used to make pouches of equal weight. The acids included citric acid (Table 17 and Table 17B) (Example 15), sodium dihydrogen phosphate (Table 18 and 18B) (Example16), chlorogenic acids (Table 19 and 19B) (Example 17) and Malic acid (Table 20 and 20B) (Example 18).Table 16 lists the ingredients and their amounts (mg) of a commercial caffeine formulation.Table 17 lists the amounts (mg) of the commercial caffeine formulation supplemented with citric acid.Table 17B shows the result of dissolution of the active ingredients in the pouch using the formulation noted in Table 17.Table 18 lists the amounts (mg) of the commercial caffeine formulation supplemented with 30 mg of sodium dihydrogen phosphate and sugar.Table 18B shows the result of dissolution of the active ingredients in the pouch using the formulation noted in Table 18.Table 19 lists the amounts (mg) of the commercial caffeine formulation supplemented with 40 mg of chlorogenic acid and sugar.Table 19B shows the result of dissolution of the active ingredients in the pouch using the formulation noted in Table 19.Table 20 lists the amounts (mg) of the commercial caffeine formulation supplemented with 40 mg of malic acid and sugar.Table 20B shows the result of dissolution of the active ingredients in the pouch using the formulation noted in Table 20.

[0096] Examples 19 - 23

[0097] In this set of experiments, combinations of acids were employed with a fixed amount of carbon dioxide donor. Residual Pouch weight was monitored after dissolution of 10 and 20 minutes. In this set of experiments, oral pouches with base formulation that contain the carbon dioxide donor were made (Table 21) and three different acid combinations were tested (Table 21A). The tested acids are malic, citric and combination of both. Upon dissolution, the pouch weight loss was monitored after 10 and 20 minutes of dissolution.

[0098] The weight loss of the control formulation after dissolution of 10 minutes (Table 21 B) or after 20 minutes (Table 21 C) shows the average weight loss of 4 repeats. The effervescent formulations resulted in more weight loss due to dissolution of ingredients at both 10 minutes and 20 minutes when malic acid is used (Table 22 and 22B), citric acid (Table 23 and 23B) or their combination (Table 24and 24B). It is clear that the amount and type of proton donor need to be selected to maximize the release of ingredients.Table 21 lists the ingredients and their amounts (mg) of a base formulation.Table 21 A lists the different effervescence combinations and their amounts (mg) that were added to the base formulation noted in Table 21 .Table 21 B shows the result of dissolution of the active ingredients in the pouch using the formulation noted in Table 21 after 10 minutes.Table 21 C shows the result of dissolution of the active ingredients in the pouch using the formulation noted in Table 21 after 20 minutes.Table 22 shows the result of dissolution of the active ingredients in the pouch using the formulation noted in Table 21 and pump #1 after 10 minutes.Table 22B shows the result of dissolution of the active ingredients in the pouch using the formulation noted in Table 21 and pump #1 after 20 minutes.Table 23 shows the result of dissolution of the active ingredients in the pouch using the formulation noted in Table 21 and pump #2 after 10 minutes.Table 23B shows the result of dissolution of the active ingredients in the pouch using the formulation noted in Table 21 and pump #2 after 20 minutes.Table 24 shows the result of dissolution of the active ingredients in the pouch using the formulation noted in Table 21 and pump #3 after 10 minutes.Table 24B shows the result of dissolution of the active ingredients in the pouch using the formulation noted in Table 21 and pump #3 after 20 minutes.

[0099] Examples 24 - 31

[0100] In this set of examples, a pouch composition was provided that under non-effervescent conditions, ingredient solubilisation was maximized. These compositions included either the poorly soluble calcium carbonate (Table 25) or with the highly soluble sodium bicarbonate (Table 26). The dissolution of these non- effervescent formulations was done under the same previous conditions. Pouch weight was kept constant by supplementing with sugar and was done in 3 replicates.Table 25 lists ingredients of a base composition containing calcium carbonateTable 26 lists ingredients of a base composition containing sodium carbonate

[0101] The results of dissolution results of these two different carbonates when no effervescence is triggered are provided in Tables 25B and 26B for calcium and sodium carbonate, respectively, and clearly demonstrate efficient ingredients solubilisation.Table 25B shows the results of the dissolution of the base composition noted inTable 25, with 240 mg of sugar addedTable 26B shows the results of the dissolution of the base composition noted in Table 26 (one embodiment with 240 mg sugar added and the second where 0 mg of sugar has been added)

[0102] The same base formulations above containing the different carbonates were supplemented with different amounts of same acid mixture (Table 27) to induce effervescence. Again, pouch weight maintained fixed by supplementing with sugar.Table 27 lists the acid mixture added to the two base compositions noted in Table 25 and 26

[0103] When the 2 carbonates of different solubility participate in an effervescence reactions, the outcome of ingredients dissolutions clearly diverge from each other as well as from the control set.

[0104] When the insoluble calcium carbonate is used with the same amount of acid mixture, the efficiency of ingredient solubilisation is impacted to a much lower extent on the amount of used acid mixture (Tables 28 A, 28B and 28C for the same 25%, 50% and 75% of the same mixture).Table 28A shows the dissolution test results of three separate samples of the base composition having calcium carbonate and containing 25% of the acid mixtureTable 28B shows the dissolution test results of three separate samples of the base composition having calcium carbonate and containing 50% of the acid mixtureTable 28C shows the dissolution test results of three separate samples of the base composition having calcium carbonate and containing 75% of the acid mixture

[0105] In contrast, using a fixed amount of the highly water soluble sodium bicarbonate, controlling the reaction rate by varying the amount of acid mixture applied to the effervescence reaction results in different dissolution efficiency (Tables 29 A, 29B and A and table 29C) and poor control over the dissolution results.Table 29A shows the dissolution test results of three separate samples of the base composition having sodium bicarbonate and containing 25% of the acid mixtureTable 29B shows the dissolution test results of three separate samples of the base composition having sodium bicarbonate and containing 50% of the acid mixtureTable 29C shows the dissolution test results of three separate samples of the base composition having sodium bicarbonate and containing 75% of the acid mixture

[0106] All publications, patents and patent applications cited above are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[0107] Although preferred embodiments of the invention have been described herein in detail, it will be understood by those skilled in the art that variations may bemade thereto without departing from the spirit of the invention or the scope of the appended claims.

Claims

WE CLAIM:

1. An effervescent composition configured for oral use, the effervescent composition comprising: an active ingredient; and one or more ingredients for creating an effervescence when contacted by an effervescent permitting liquid; wherein the effervescent composition is contained within a pouch.

2. The effervescent composition of claim 1 , wherein the active ingredient is calcium, magnesium, caffeine or nicotine.

3. The effervescent composition of claim 1 or 2, wherein the one or more ingredients for creating an effervescence comprises (i) an acid and (ii) a metal carbonate or bicarbonate.

4. The effervescent composition of claim 3, wherein at least one of (i) the acid and (ii) the metal carbonate or bicarbonate, has low solubility in water.

5. The effervescent composition of claim 3 or 4, wherein one of (i) the acid and (ii) the metal carbonate or bicarbonate, is encapsulated to reduce the rate of effervescence.

6. The effervescent composition of any one of claims 3 to 5, wherein the acid is a weak acid.

7. The effervescent composition of any one of claims 3 to 6, wherein the acid has a p a of greater than about 1 , 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25 or 3.5.

8. The effervescent composition of any one of claims 3 to 6, wherein the acid is an organic acid.

9. The effervescent composition of claim 8, wherein the organic acid is any food grade acid.

10. The effervescent composition of claim 9, wherein the food grade acid is citric acid, formic acid, propionic acid, sorbic acid or benzoic acid.

11. The effervescent composition of any one of claims 3 to 10, wherein the metal carbonate or the metal bicarbonate is sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate or potassium bicarbonate.

12. The effervescent composition of claim 1 or 2, wherein the one or more ingredients for creating effervescence of bubble stream comprises a food grade peroxide and a peroxide hydrolyzing catalyst.

13. The effervescent composition of claim 12, wherein the peroxide is calcium peroxide and the catalyst is an enzymatic hydrolysis catalyst.

14. The effervescent composition of claim 12, wherein the catalyst is a metal salt.

15. The effervescent composition of any one of claim 1 to 14, further comprising a pharmaceutically acceptable diluent, carrier, or excipient.

16. The effervescent composition of claim 15, wherein the pharmaceutically acceptable excipient is calcium phosphate, microcrystalline cellulose (MCC), alcohol sugar, or starch.

17. A pouched product, comprising: an effervescent composition comprising an active ingredient and one or more ingredients for creating an effervescence when contacted by an effervescent permitting liquid, wherein the effervescent composition is contained in a pouch.

18. The pouched product of claim 17, wherein the active ingredient is calcium, magnesium, caffeine or nicotine.

19. The pouched product of claim 17 or 18, wherein the one or more ingredients for creating an effervescence comprises (i) an acid and (ii) a metal carbonate or bicarbonate.

20. The pouched product of claim 19, wherein at least one of (i) the acid and (ii) the metal carbonate or bicarbonate, has low solubility in water.21 . The pouched product of claim 19 or 20, wherein one of (i) the acid and (ii) the metal carbonate or bicarbonate, is encapsulated to reduce the rate of effervescence.

22. The pouched product of any one of claims 19 to 21 , wherein the acid is a weak acid.

23. The pouched product of any one of claims 19 to 22, wherein the acid has a paof greater than about 1 , 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25 or 3.5.

24. The pouched product of any one of claims 19 to 23, wherein the acid is an organic acid.

25. The pouched product of claim 24, wherein the organic acid is food grade acid.

26. The pouched product of claim 25, wherein the food grade acid is citric acid, lactic acid, formic acid, propionic acid, sorbic acid or benzoic acid.

27. The pouched product of any one of claims 19 to 26, wherein the metal carbonate or the metal bicarbonate is sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate or potassium bicarbonate.

28. The pouched product of claim 17 or 18, wherein the one or more ingredients for creating effervescence of bubble stream comprises a food grade peroxide and a peroxide hydrolyzing catalyst.

29. The pouched product of claim 28, wherein the peroxide is calcium peroxide and the peroxide hydrolyzing catalyst is an enzymatic hydrolysis catalyst.

30. The pouched product of claim 28, wherein the peroxide hydrolyzing catalyst is a metal salt.

31. The pouched product of any one of claim 17 to 30, further comprising a pharmaceutically acceptable diluent, carrier, or excipient.

32. The pouched product of claim 31 , wherein the pharmaceutically acceptable excipient is calcium phosphate, microcrystalline cellulose (MCC), alcohol sugar, or starch.

33. A method for delivery of an active ingredient to a user, the method comprising:placing the pouched product as defined in any one of claims 17 to 32 in an oral cavity of the user.

34. The method of delivery of claim 33, wherein saliva of the user contacts the pouched product causing effervescence for releasing the active ingredient from the pouched product.

35. A method of manufacture of the pouched product as defined in any one of claims 12 to 22, the method comprising: placing the effervescent composition as defined in any one of claims 1 to 11 in a pouch; and sealing the pouch.

36. The method of claim 35, wherein the pouch is a non-woven fabric or fleece.

37. A process for preparation of an effervescent composition configured for oral use, the process comprising: mixing an active ingredient and one or more ingredients for creating an effervescence when contacted by an effervescent permitting liquid.

38. The process of claim 37, wherein the active ingredient is calcium, magnesium, caffeine or nicotine.

39. The process of claim 37 or 38, wherein the one or more ingredients for creating an effervescence comprises (i) an acid and (ii) a metal carbonate or a metal bicarbonate.

40. The process of claim 39, wherein at least one of (i) the acid and (ii) the metal carbonate or bicarbonate, has low solubility in water.

41. The process of claim 39 or 40, further comprising the step of encapsulating one of (i) the acid and (ii) the metal carbonate or bicarbonate, to reduce the rate of effervescence.

42. The process of any one of claims 39 to 41 , wherein the acid is a weak acid.

43. The process of any one of claims 39 to 42, wherein the acid has a paof greater than about 1 , 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25 or 3.

544. The process of any one of claims 39 to 43, wherein the acid is an organic acid.

45. The process of claim 44, wherein the organic acid is food grade acid.

46. The process of claim 45, wherein the food grade acid is citric acid, lactic acid, formic acid, propionic acid, sorbic acid or benzoic acid.

47. The process of any one of claims 39 to 46, wherein the metal carbonate or the metal bicarbonate is sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate or potassium bicarbonate.

48. The process of claim 37 or 38, wherein the one or more ingredients for creating effervescence of bubble stream comprises a food grade peroxide and a peroxide hydrolyzing catalyst.

49. The process of claim 48, wherein the peroxide is calcium peroxide and the catalyst is an enzymatic hydrolysis catalyst.

50. The process of claim 48, wherein the peroxide hydrolyzing catalyst is a metal salt.51 . The process of any one of claim 37 to 50, further comprising a pharmaceutically acceptable diluent, carrier, or excipient.

52. The process of claim 51 , wherein the pharmaceutically acceptable excipient is calcium phosphate, microcrystalline cellulose (MCC), alcohol sugar, or starch.

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