WO2021223824A1 - Flowpack for oral delivery of active ingredients - Google Patents

Flowpack for oral delivery of active ingredients Download PDF

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Publication number
WO2021223824A1
WO2021223824A1 PCT/DK2021/050136 DK2021050136W WO2021223824A1 WO 2021223824 A1 WO2021223824 A1 WO 2021223824A1 DK 2021050136 W DK2021050136 W DK 2021050136W WO 2021223824 A1 WO2021223824 A1 WO 2021223824A1
Authority
WO
WIPO (PCT)
Prior art keywords
particles
sugar alcohol
alcohol particles
flowpack
population
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/DK2021/050136
Other languages
English (en)
French (fr)
Inventor
Helle Wittorff
Christine PEDERSEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fertin Pharma AS
Original Assignee
Fertin Pharma AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fertin Pharma AS filed Critical Fertin Pharma AS
Priority to JP2022567653A priority Critical patent/JP7830352B2/ja
Priority to EP21727077.6A priority patent/EP4146164B1/en
Priority to ES21727077T priority patent/ES3031420T3/es
Priority to CA3174693A priority patent/CA3174693C/en
Priority to AU2021268062A priority patent/AU2021268062B2/en
Priority to MYPI2022006144A priority patent/MY210445A/en
Priority to DK21727077.6T priority patent/DK4146164T3/da
Priority to BR112022021602A priority patent/BR112022021602A2/pt
Priority to CN202180033517.9A priority patent/CN115515563A/zh
Publication of WO2021223824A1 publication Critical patent/WO2021223824A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • A61K2800/524—Preservatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/92—Oral administration

Definitions

  • the present invention relates to the field of flowpacks comprising a powder delivery system suitable for oral delivery of active ingredients.
  • the invention relates to a sugar alcohol delivery system with one or more active ingredients.
  • Oral tablets have traditionally been preferred for administration of active pharmaceutical ingredients and active ingredients having health improving benefits. Both in terms of convenience and compliance, oral tablets have certain benefits compared to other delivery vehicles for oral administration of active ingredients. Additional benefits include uniformity of content which is of particular importance for active pharmaceutical ingredients where lack of safety and appropriate delivery may become fatal in alleviating or treating medical conditions.
  • Oral tablets for gastrointestinal and oromucosal delivery of active ingredients are also commonly preferred with respect to securing an appropriate route of adminstration.
  • Such oral tablets are made by direct compression or compaction methods where a powder tablet material and an active ingredient are pressed into defined tablets with appropriate strength to provide a pharmacological effect to a patient in need thereof in medical formulations or to provide a health benefit for consumers in nutraceutical formulations.
  • a formulation is provided that may also help in obtaining improved sensorial properties of active ingredient delivery.
  • important sensorial properties include mouthfeel, melting sensation, flavor sensation, salivation, cooling sensation, and off-note sensation associated with active ingredients. These properties are both relevant from a convenience perspective in oral administration, but certainly also in order to support an appropriate delivery of active ingredients and avoid adverse side effects of active ingredients.
  • mouthfeel is one of the more important sensorial properties of active ingredient delivery apart from efficacy.
  • the present invention pertains to a new powder delivery system that is not in tablet form but contained in a flowpack.
  • a flowpack for oral delivery of active ingredients comprising a population of particles and one or more active ingredients, the population of particles including at least two types of sugar alcohol particles, wherein at least one of said two types of sugar alcohol particles comprises i) granulated sugar alcohol particles.
  • the powder system of the present invention unlike traditional oral tablets may be associated with various benefits in terms of sensorial properties and various other properties, such as release properties.
  • the powder system is designed to encompass a synergistic combination of different types of sugar alcohol particles. Combined, the different types of sugar alcohol particles serve to both deliver active ingredients with improved effect and to accommodate various sensorial benefits compared to conventional oral tablets, including improved mouthfeel. Also, the powder system is aimed to be superior compared to simpler and less intricate powder systems available for administration of active ingredients.
  • the inventors of the present invention did not expect that combining at least two types of sugar alcohol particles according to the invention would solve various of the prior art issues with oral tablets and more simple powder delivery systems. Such issues include improved saliva generation, appropriate delivery of active ingredients combined with beneficial sensorial properties.
  • the present invention may help in obtaining a release characteristic of active ingredients that offers increased convenience and effectiveness.
  • One of these release characteristics is increased generation of saliva.
  • Increased saliva generation and particularly an experience of increased saliva generation upon administration may for instance have some pronounced benefits for delivery of active ingredients to mucosal surfaces.
  • the present invention may help in obtaining improved sensorial properties of active ingredient delivery.
  • important sensorial properties include mouthfeel, melting sensation, flavor sensation, salivation, cooling sensation, and off- note sensation associated with active ingredients or processing aids.
  • mouthfeel e.g., melting sensation, flavor sensation, salivation, cooling sensation, and off- note sensation associated with active ingredients or processing aids.
  • the present invention may help in improving taste-masking of off- notes during administration. The taste masking challenge is more profound when a higher release of such active ingredients are provided which is generally the case for the powder delivery system of the present invention.
  • a flowpack for oral delivery of active ingredients comprising a population of particles and one or more active ingredients, the population of particles including at least two types of sugar alcohol particles, wherein at least one of said two types of sugar alcohol particles comprises i) granulated sugar alcohol particles, and wherein the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles.
  • the combination of granulated sugar alcohol particles with non-directly compressible (non-DC) sugar alcohol particles according to the invention may provide advantages that conventional powder systems may not provide.
  • One of such advantages is improved mouthfeel.
  • Another is improved generation of saliva.
  • the powder delivery system may turn into liquid relatively fast, i.e. liquifies relatively fast.
  • Other advantages may include improved melting sensation, flavor sensation, cooling sensation, and off-note sensation associated with active ingredients.
  • a flowpack for oral delivery of active ingredients comprising a population of particles and one or more active ingredients, the population of particles including at least two types of sugar alcohol particles, wherein at least one of said two types of sugar alcohol particles comprises i) granulated sugar alcohol particles, and wherein the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles.
  • DC directly compressible
  • the combination of granulated sugar alcohol particles with directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles according to the invention may provide advantages that conventional powder systems may not provide.
  • One of such advantages is improved mouthfeel.
  • Another is improved cooling.
  • Other advantages may include improved melting sensation, salivation, flavor sensation, and off-note sensation associated with active ingredients.
  • a flowpack for oral delivery of active ingredients comprising a population of particles and one or more active ingredients, the population of particles including at least two types of sugar alcohol particles, wherein at least one of said two types of sugar alcohol particles comprises i) granulated sugar alcohol particles, and wherein the population of particles includes at least three types of sugar alcohol particles comprising i) granulated sugar alcohol particles, ii) non-directly compressible (non-DC) sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles.
  • the unique combination of granulated sugar alcohol particles with non-directly compressible (non-DC) sugar alcohol particles and directly compressible (non-DC) sugar alcohol particles that are not granulated sugar alcohol particles according to the invention may provide additional advantages that conventional powder systems may not provide.
  • One of such advantages is improved mouthfeel.
  • Another is improved generation of saliva.
  • Yet another is improved cooling sensation.
  • Other advantages may include improved melting sensation, flavor sensation, and off-note sensation associated with active ingredients.
  • mouthfeel involves various factors of the population of particles that combined contribute to the overall impression of mouthfeel.
  • Objective criteria are set up for test panels that evaluvate mouthfeel according to the invention. Among these criteria are elements such as roughness impression, texture impression and a sandy impression.
  • the general aim of the invention may be to improve these elements to obtain an improved mouthfeel of the population of particles. Combined with improved release and improved sensations as mentioned above, the invention may ascertain synergistic benefits compared to conventional tablets or more simple powder delivery systems known in the art.
  • the powder delivery system when the powder delivery system is mentioned to be “dry and flowable”, the intended meaning is that the system behaves as a powder in the way that the water content is suitably low for a skilled person within powder technology to consider it “dry” for the purpose of the invention and being able to “flow” for a skilled person within powder technology to consider it “flowable” for the purpose of the invention.
  • the system does not need to have a certain water content of 0.0% but may have a content of water to a degree that it behaves like a powder for the purpose of the invention, such as less than 10.0% by weight, 8.0% by weight, 6.0% by weight, 4.0% by weight, 2.0% by weight water content, 1.5% by weight water, such as less than 1.0% by weight water content.
  • the powder delivery system according to the invention in some embodiments does not need to be “free-flowing”. In some embodiments it is adequate that the powder is able to “flow” in the sense that certain agglomerations of particles are allowed and that not all types of particles in the powder delivery system is to be free-flowing. For instance, agglomeration to some extent during storage may be allowed, just that the powder may be gently handled to make the powder flowable to some extend.
  • a tablet is not considered “flowable” in the present context.
  • the powder delivery system according to the invention is not a tablet or comprised in a tablet, such as a chewable tablet or orally disintegrating tablet according to the invention.
  • the powder delivery system is a dry and substantially free-flowing population of particles.
  • the powder delivery system is a dry and free- flowing population of particles.
  • At least one of the at least two types of sugar alcohol particles with different particle size distributions is substantially free- flowing. In some embodiments of the invention, at least one of the at least two types of sugar alcohol particles with different particle size distributions is free-flowing.
  • At least two of the at least two types of sugar alcohol particles with different particle size distributions are substantially free- flowing.
  • At least two of the at least two types of sugar alcohol particles with different particle size distributions are free-flowing.
  • all of the at least two types of sugar alcohol particles with different particle size distributions are substantially free-flowing.
  • all of the at least two types of sugar alcohol particles with different particle size distributions are free-flowing.
  • the meaning of “swishable” in the present context is to be understood as forcing either the powder delivery system around in the oral cavity or the liquid generated after a short period of time around in the oral cavity.
  • the term “swishable” can also cover “gargling”, “swirling” or “pushing around” or similar expressions.
  • the idea is that the powder delivery system and the fluid generated is to be distributed in the oral cavity, both to oral mucosa, tongue and teeth in a way that it secures contact to the surfaces in the oral cavity.
  • the portion of liquid generated is not to be swallowed during the operation, although a low amount is allowed to be swallowed while maintaining a major part of the saliva generated in the oral cavity in order to resemble a liquid mouthwash.
  • the system is strong enough to avoid adding additional water.
  • water may be added to some extent but would not be required in order to deliver the advantages of the present invention.
  • “fluid” or “fluid generation” or similar wording is to be understood in context with the invention as “saliva” or “saliva generation” as a result of the administration of the powder delivery system according to the invention.
  • standard saliva generation is not the intended meaning, but excess saliva generation directly triggered by the powder delivery system is part of the context.
  • the intended meaning is that enough liquid is generated to attribute the same or improved oral care benefits as in liquid mouthwashes.
  • the same amount of liquid as used in a liquid mouthwash is not needed according to the invention, just as long as the amount of saliva generated would be manageable to be “swished”. In some instances, however, the amount of saliva generated may be on the same level as by using a liquid mouthwash.
  • oral care benefits As used in the present context, it is noted that these effects would be understood by a person skilled in the art to cover certain benefits, such as stain removal benefits, bad breath, plaque removal benefits, whitening benefits, alleviation or treatment of gingivitis, or the like. These conditions may be addressed altogether according to the invention, or one or more of the conditions may be addressed. Additionally, not only “oral care benefits” may be convered in the present context. Also, conditions in the throat may be addressed, and conditions in the gastrointestinal tract may be addressed by the present invention.
  • swishing said powder delivery system is characterised by forcing the powder delivery system around the oral cavity for a period of time.
  • swishing said powder delivery system is characterised by forcing the powder delivery system around the oral cavity for at least 5 seconds. In some embodiments of the invention, swishing said powder delivery system is characterised by forcing the powder delivery system around the oral cavity for at least 10 seconds. In some embodiments of the invention, swishing said powder delivery system is characterised by forcing the powder delivery system around the oral cavity for at least 15 seconds. In some embodiments of the invention, swishing said powder delivery system is characterised by forcing the powder delivery system around the oral cavity for at least 20 seconds.
  • At least a portion of the fluid generated by swishing said powder delivery system is forced around the oral cavity for a period of time.
  • the powder delivery system in some embodiments was able to dissolve relatively quickly after oral administration in the oral fluid generated upon administration.
  • the powder delivery system dissolve within 15 seconds.
  • the powder delivery system dissolve within 10 seconds.
  • the powder delivery system dissolve within 8 seconds.
  • the powder delivery system dissolve within 5 seconds.
  • At least a portion of the saliva generated by swishing said powder delivery system is forced around the oral cavity for at least 10 seconds. In some embodiments of the invention, at least a portion of the saliva generated by swishing said powder delivery system is forced around the oral cavity for at least 20 seconds. In some embodiments of the invention, at least a portion of the saliva generated by swishing said powder delivery system is forced around the oral cavity for at least 30 seconds.
  • At least a portion of the fluid generated by swishing said powder delivery system is forced around the oral cavity for a period of time prior to swallowing or spitting out said portion of fluid to provide an oral care benefit.
  • oral care benefits are obtained by swishing said powder delivery system and/or at least a portion of the fluid generated in the oral cavity for at least 10 seconds.
  • oral care benefits are obtained by swishing said powder delivery system and/or at least a portion of the fluid generated in the oral cavity for at least 10 seconds for at least 20 seconds.
  • oral care benefits are obtained by swishing said powder delivery system and/or at least a portion of the fluid generated in the oral cavity for at least 30 seconds.
  • the powder delivery system is a dry and flowable population of particles that is swished upon oral administration and generates fluid in the oral cavity, optionally adding water, and thereby resembling a liquid mouthwash.
  • the Hausner ratio of the powder delivery system is between 1.00 and 1.59. Generally, a ratio above 1.59 is considered poor in the present context.
  • the Hausner ratio is known by a person skilled in the art to be the ratio between stamped powder (g/mL) and unstamped powder (g/mL) according to known methods. The ratio expresses the ratio between the bulk density of the stamped and unstamped powder.
  • the Hausner ratio is usually categorized according to a compressibility index and expresses the flow character of a powder. Best flow character is obtained with a Hausner ratio of 1.00 and the higher the Hausner ratio, the less flowing is the powder.
  • the Hausner ratio of the powder delivery system is between 1.00 and 1.45. In some embodiments of the invention, the Hausner ratio of the powder delivery system is between 1.00 and 1.34.
  • the Hausner ratio of the powder delivery system is less than 1.59, such as less than 1.45.
  • the Hausner ratio of the powder delivery system is less than 1.34, such as less than 1.25.
  • the powder delivery system generates more than 1.5 mL fluid in the oral cavity within a period from 30 to 90 seconds from onset of administration.
  • the powder delivery system generates more than 1.5 mL fluid in the oral cavity within a period from 90 to 180 seconds from onset of administration.
  • the powder delivery system generates more than 1.5 mL fluid in the oral cavity within a period from 180 to 300 seconds from onset of administration.
  • the powder delivery system provides an improved cooling effect compared to a powder delivery system without at least one of the at least two types of sugar alcohol particles with different particle size distributions.
  • the powder delivery system provides an improved watering effect compared to a powder delivery system without at least one of the at least two types of sugar alcohol particles with different particle size distributions.
  • the powder delivery system provides an improved mouthfeel compared to a powder delivery system without at least one of the at least two types of sugar alcohol particles with different particle size distributions, the improved mouthfeel including at least one of less sandy mouthfeel, less dusty mouthfeel, less roughness mouthfeel, less sticky or improved texture.
  • the granulated sugar alcohol particles according to the invention may in itself provide various advantages compared to more simple powder delivery systems known in the art.
  • One of these advantages of the granulated sugar alcohol particles according to the invention is that they provide an improved mouthfeel despite having relatively large particle size.
  • the surface morphology and/or chemical composition of granulated sugar alcohol particles according to the invention may also work in synergy with the non-directly compressible (non-DC) sugar alcohol particles and/or directly compressible (non- DC) sugar alcohol particles that are not granulated sugar alcohol particles according to the invention.
  • advantages from all three types of particles may contribute to the overall benefits of the invention, and the combination may provide further unexpected synergistic properties of the powder delivery system of the invention.
  • the term “types of particles” or similar wording is intended to mean that the particles are different in either surface morphology or chemical composition.
  • two types of sugar alcohol particles may be granulated sugar alcohol particles and non-granulated sugar alcohol particles.
  • the two types of sugar alcohol particles may both be granulated sugar alcohol particles, but different in either surface morphology or chemical composition.
  • non-directly compressible (non-DC) sugar alcohol particles when non-directly compressible (non-DC) sugar alcohol particles are present, or when directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles are present, then the two types of particles are different sugar alcohols, such as granules of xylitol and erythritol respectively sorbitol.
  • the two types of particles may also comprise xylitol in granulated form and xylitol in non-granulated form.
  • the granulated sugar alcohol particles i) are directly compressible (DC) sugar alcohol particles.
  • DC sugar alcohol particles refers to particles of direct compressible (DC) sugar alcohol. It is noted that the terms “DC sugar alcohol particles” and “DC particles” are used interchangeably.
  • DC sugar alcohol particles may be obtained by granulating non-DC sugar alcohol with e.g. other sugar alcohols or binders for the purpose of obtaining so-called direct compressible particles (DC). This may be done in a process such as a wet granulation process, or in a dry granulation process. Also, granulation of non-DC sugar alcohol with water as binder is considered to result in DC sugar alcohol particles in the present context. Agglomeration of particles into a single particle is also within the intended meaning.
  • DC sugar alcohol particles typically have a surface morphology with a rough surface morphology when seen in a scanning electron microscope.
  • “granulation” or “granulated” “or agglomeration” or similar wording is not intended to involve milling, comminuting, or grinding of larger crystalline particles into smaller particles.
  • DC sugar alcohol particles that are not granulated sugar alcohol partices refers to particles of direct compressible (DC) sugar alcohol, which have not been granulated but are DC by nature. Sorbitol particles is an example of such particles. Dextrose that has not been granulated is also considered an example of such particles, such as dextrose that has not been granulated with an average particles size below 250 microns, such as below 210 microns, such as below 180 microns, such as below 150 microns. In the present context, “granulation” or “granulated” or similar wording is not intended to involve milling, comminuting, or grinding of larger crystalline particles into smaller particles. In one embodiment of the invention, the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles.
  • non-DC sugar alcohol particles refers to particles of non-directly compressible (non-DC) sugar alcohol. It is noted that the terms “non-DC sugar alcohol particles” and “non-DC particles” are used interchangeably.
  • the non-DC sugar alcohol particles refer to particles which have not been preprocessed by granulation with e.g. other sugar alcohols or binders for the purpose of obtaining so-called direct compressible particles (DC).
  • non-DC sugar alcohol particles include particles obtained by crystallization, optionally followed by milling, comminuting, or grinding, which does not involve other sugar alcohols or binders. Thus, non-DC sugar alcohol particles are considered as particles consisting of non-DC sugar alcohol.
  • non-DC sugar alcohol particles are considered as non-granulated sugar alcohol particles.
  • non-DC sugar alcohol particles have a surface morphology with a smooth surface morphology when seen in a scanning electron microscope compared to DC sugar alcohol particles.
  • non-DC sugar alcohol particles include crystalline sugar alcohol particles obtained by a crystallization process, optionally followed by milling, communuting, or grinding, which does not involve other sugar alcohols or binders.
  • crystalline is intended to mean that the individual particles are composed of a coherent crystal structure and not for instance a micro-crystalline structure where small crystalline particles are gathered to larger particles.
  • One advantage of the invention is a surprisingly strong saliva generation compared to conventional formulations.
  • the non-DC particles surprisingly induce a remarkable generation of saliva.
  • Increased generation of saliva may have a huge impact on the delivery of the one or more active ingredients.
  • increased generation of saliva may increase exposure of the one or more active ingredinets to mucosal surfaces and thereby contribute to an increased uptake in the oral mucosa.
  • the one or more active ingredients may relatively quickly be exposed to mucosal surfaces and thereby relatively quickly deliver a desired effect.
  • Non-DC erythritol is an example of a sugar alcohol that may contribute significantly to increased generation of saliva.
  • One unexpected advantage over the prior art is that the saliva generation is surprisingly sustained even after a user has swallowed the bulk-portion of the non- DC sugar alcohols. This sustaining of the salivation generation may be advantageous in relation to many applications of the formulation ranging from mouthfeel, taste, flavor perception, etc.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles.
  • the population of particles includes at least three types of sugar alcohol particles comprising i) granulated sugar alcohol particles, ii) non-directly compressible (non-DC) sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles having a particle size with more than 80% of the particles being below 500 microns.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles having a particle size with more than 50% of the particles being below 400 microns.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles having a particle size with more than 80% of the particles being below 400 microns.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles having a particle size with more than 50% of the particles being below 250 microns.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles having a particle size with more than 80% of the particles being below 250 microns.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles having a particle size with more than 95% of the particles being below 250 microns.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles having a particle size with more than 80% of the particles being below 500 microns.
  • DC directly compressible
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles having a particle size with more than 95% of the particles being below 500 microns.
  • DC directly compressible
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles having a particle size with more than 80% of the particles being below 400 microns.
  • DC directly compressible
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles having a particle size with more than 95% of the particles being below 400 microns.
  • DC directly compressible
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles having a particle size with more than 80% of the particles being below 300 microns.
  • DC directly compressible
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles having a particle size with more than 95% of the particles being below 300 microns.
  • DC directly compressible
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles having a particle size with more than 70% of the particles being below 100 microns.
  • DC directly compressible
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles having a particle size with more than 80% of the particles being below 100 microns.
  • DC directly compressible
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles having a particle size with more than 95% of the particles being below 100 microns.
  • DC directly compressible
  • the population of particles includes at least three types of sugar alcohol particles comprising i) granulated sugar alcohol particles, ii) non-directly compressible (non-DC) sugar alcohol particles having a particle size with more than 80% of the particles being below 250 microns and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles having a particle size with more than 80% of the particles being below 300 microns.
  • the population of particles includes at least three types of sugar alcohol particles comprising i) granulated sugar alcohol particles, ii) non-directly compressible (non-DC) sugar alcohol particles having a particle size with more than 95% of the particles being below 250 microns and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles having a particle size with more than 80% of the particles being below 100 microns.
  • the population of particles includes at least three types of sugar alcohol particles comprising i) granulated sugar alcohol particles, ii) non-directly compressible (non-DC) sugar alcohol particles having a particle size with more than 95% of the particles being below 250 microns and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles having a particle size with more than 70% of the particles being below 100 microns.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 10% by weight of the population of particles.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 20% by weight of the population of particles.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 25% by weight of the population of particles. In one embodiment of the invention, the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 30% by weight of the population of particles.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 40% by weight of the population of particles.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 10% by weight of the population of particles and ii) non-directly compressible (non-DC) sugar alcohol particles in an amount of at least 10% by weight of the population of particles.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 20% by weight of the population of particles and ii) non-directly compressible (non-DC) sugar alcohol particles in an amount of at least 20% by weight of the population of particles.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 25% by weight of the population of particles and ii) non-directly compressible (non-DC) sugar alcohol particles in an amount of at least 25% by weight of the population of particles.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 30% by weight of the population of particles and ii) non-directly compressible (non-DC) sugar alcohol particles in an amount of at least 30% by weight of the population of particles.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 10% by weight of the population of particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles in an amount of at least 10% by weight of the population of particles.
  • DC directly compressible
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 20% by weight of the population of particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles in an amount of at least 20% by weight of the population of particles.
  • DC directly compressible
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 25% by weight of the population of particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles in an amount of at least 25% by weight of the population of particles.
  • DC directly compressible
  • the population of particles includes at least three types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 10% by weight of the population of particles, ii) non-directly compressible (non-DC) sugar alcohol particles in an amount of at least 10% by weight of the population of particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles in an amount of at least 10% by weight of the population of particles.
  • the population of particles includes at least three types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 20% by weight of the population of particles, ii) non-directly compressible (non-DC) sugar alcohol particles in an amount of at least 20% by weight of the population of particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles in an amount of at least 20% by weight of the population of particles.
  • the population of particles includes at least three types of sugar alcohol particles comprising i) granulated sugar alcohol particles in an amount of at least 25% by weight of the population of particles, ii) non-directly compressible (non-DC) sugar alcohol particles in an amount of at least 25% by weight of the population of particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles in an amount of at least 25% by weight of the population of particles.
  • At least 80% by weight of said population of particles have a particle size below 500 microns.
  • At least 95% by weight of said population of particles have a particle size below 500 microns.
  • At least 80% by weight of said population of particles have a particle size below 400 microns.
  • At least 95% by weight of said population of particles have a particle size below 400 microns.
  • At least 80% by weight of said population of particles have a particle size below 300 microns. In one embodiment of the invention, at least 95% by weight of said population of particles have a particle size below 300 microns. In one embodiment of the invention, at least 30% by weight of said population of particles have a particle size below 250 microns.
  • At least 50% by weight of said population of particles have a particle size below 250 microns.
  • At least 60% by weight of said population of particles have a particle size below 250 microns.
  • At least 20% by weight of said population of particles have a particle size below 100 microns.
  • At least 30% by weight of said population of particles have a particle size below 100 microns.
  • the population of particles includes at least 20% of one type of sugar alcohol particles having a particle size with more than 80% of the particles being below 250 microns and at least 20% of another type of sugar alcohol particles having a particle size with more than 80% of the particles being below 250 microns.
  • the population of particles includes at least 20% of one type of sugar alcohol particles having a particle size with more than 80% of the particles being below 250 microns and at least 20% of another type of sugar alcohol particles having a particle size with more than 80% of the particles being below 300 microns. In one embodiment of the invention, the population of particles includes at least 20% of one type of sugar alcohol particles having a particle size with more than 80% of the particles being below 250 microns and at least 20% of another type of sugar alcohol particles having a particle size with more than 80% of the particles being below 100 microns.
  • the granulated sugar alcohol particles i) are wet granulated sugar alcohol particles or dry granulated sugar alcohol particles.
  • the granulated sugar alcohol particles i) are dry granulated sugar alcohol particles.
  • the granulated sugar alcohol particles i) comprise a binder, such as a carboxymethyl cellulose (CMC) binder.
  • the binder is gummi arabicum or maltodextrine.
  • Suitable binders include Gum Arabic, Methyl Cellulose, Liquid glucose, Tragacanth, Ethyl Cellulose, Gelatin, Hydroxy Propyl Methyl Cellulose (HPMC), Starches, Hydroxy Propyl Cellulose (HPC), Pregelatinized Starch, Sodium Carboxy Methyl Cellulose (NaCMC), Alginic Acid, Polyvinyl Pyrrolidone (PVP), Maltodextrine (MD); Cellulose, Polyethylene Glycol (PEG), Polyvinyl Alcohols, Polymethacrylates, Copovidone or Microcrystalline Cellulose (MCC), alone or in combination.
  • the granulated sugar alcohol particles i) comprise a wet binder, such as water.
  • the granulated sugar alcohol particles i) are selected from granulated particles of xylitol, maltitol, isomalt, mannitol, erythritol, lactitol, dextrose or combinations thereof. In one embodiment of the invention, the granulated sugar alcohol particles i) are selected from granulated particles of xylitol, maltitol, isomalt, mannitol, erythritol, lactitol or combinations thereof.
  • the granulated sugar alcohol particles i) are selected from granulated particles of xylitol, maltitol, isomalt, mannitol, erythritol or combinations thereof.
  • the granulated sugar alcohol particles i) are selected from granulated particles of xylitol, maltitol, isomalt, erythritol or combinations thereof.
  • the granulated sugar alcohol particles i) are selected from granulated particles of xylitol, maltitol, isomalt or combinations thereof.
  • the granulated sugar alcohol particles i) comprise granulated particles of maltitol.
  • the granulated sugar alcohol particles i) comprise granulated particles of xylitol.
  • the granulated sugar alcohol particles i) are granulated particles of xylitol.
  • the granulated sugar alcohol particles i) comprise granulated particles of dextrose.
  • more than 80% of the granulated sugar alcohol particles i) are within the range of 100 to 500 microns, such as more than 50% within a range of 100 to 400 microns. In one embodiment of the invention, more than 80% of the granulated sugar alcohol particles i) are within the range of 100 to 500 microns. In one embodiment of the invention, more than 80% of the granulated sugar alcohol particles i) are within the range of 100 to 400 microns. In one embodiment of the invention, more than 80% of the granulated sugar alcohol particles i) are within the range of 200 to 500 microns. In one embodiment of the invention, more than 80% of the granulated sugar alcohol particles i) are within the range of 200 to 400 microns.
  • the granulated sugar alcohol particles i) provide the population of particles with free-flowing properties.
  • the granulated sugar alcohol particles i) provide the other types of sugar alcohol particles in the population of particles with free- flowing properties.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles, and wherein the non- directly compressible (non-DC) sugar alcohol particles ii) are selected from non-DC particles of xylitol, maltitol, isomalt, mannitol, erythritol, lactitol or combinations thereof.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles, and wherein the non- directly compressible (non-DC) sugar alcohol particles ii) are selected from non-DC particles of xylitol, maltitol, isomalt, mannitol, erythritol or combinations thereof.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles, and wherein the non- directly compressible (non-DC) sugar alcohol particles ii) are selected from non-DC particles of xylitol, isomalt, mannitol, erythritol or combinations thereof.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles, and wherein the non- directly compressible (non-DC) sugar alcohol particles ii) are selected from non-DC particles of mannitol, erythritol or combinations thereof.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles, and wherein the non- directly compressible (non-DC) sugar alcohol particles ii) comprise non-DC particles of mannitol.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles, and wherein the non- directly compressible (non-DC) sugar alcohol particles ii) comprise non-DC particles of erythritol.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles, and wherein the non- directly compressible (non-DC) sugar alcohol particles ii) are non-DC particles of erythritol.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles, and wherein the non- directly compressible (non-DC) sugar alcohol particles provide the population of particles with a salivation effect upon oral administration of the population of particles.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles, and wherein the directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles iii) comprise sorbitol.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles, and wherein the directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles iii) is sorbitol.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles, and wherein the directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles iii) comprise dextrose, such as dextrose with an average particle size below 250 microns, such as below 210 microns, such as below 180 microns, such as below 150 microns.
  • dextrose such as dextrose with an average particle size below 250 microns, such as below 210 microns, such as below 180 microns, such as below 150 microns.
  • the non-granulated dextrose iii) has an average particle size below 250 microns. In some embodiments of the invention, the non-granulated dextrose iii) has an average particle size below 210 microns. In some embodiments of the invention, the non-granulated dextrose iii) has an average particle size below 180 microns. In some embodiments of the invention, the non- granulated dextrose iii) has an average particle size below 150 microns.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles, and wherein the directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles iii) is dextrose, such as dextrose with an average particle size below 250 microns, such as below 210 microns, such as below 180 microns, such as below 150 microns.
  • dextrose such as dextrose with an average particle size below 250 microns, such as below 210 microns, such as below 180 microns, such as below 150 microns.
  • Sorbitol is an example of a sugar alcohol, which is considered DC grade, when provided as particles consisting of sorbitol, i.e. in its pure form.
  • dextrose that has not been granulated is an example of such a sugar alcohol that is considered DC grade, i.e. in its pure form, such as non-granulated dextrose with an average particle size below 250 microns, such as below 210 microns, such as below 180 microns, such as below 150 microns.
  • several other sugar alcohols are considered non-DC grade if providing them as particles consisting of the specific sugar alcohol. Therefore, such non-DC sugar alcohols are conventionally processed into DC grade sugar alcohols, e.g. by granulating them with e.g. a binder.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles, and wherein the directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles iii) provide the population of particles with a cooling effect upon oral administration of the population of particles.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles, and wherein the directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles iii) provide the population of particles with a cooling effect upon oral administration of the population of particles on the same level or more as xylitol based on weight percentage.
  • DC directly compressible sugar alcohol particles
  • the population of particles includes at least three types of sugar alcohol particles comprising i) granulated sugar alcohol particles, ii) non-directly compressible (non-DC) sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles, and wherein the non-directly compressible (non-DC) sugar alcohol particles ii) is non-DC particles of erythritol and the directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles iii) is particles of sorbitol.
  • the population of particles includes at least three types of sugar alcohol particles comprising i) granulated sugar alcohol particles, ii) non-directly compressible (non-DC) sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles, and wherein the non-directly compressible (non-DC) sugar alcohol particles ii) is non-DC particles of erythritol and the directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles iii) is particles of dextrose, such as dextrose with an average particle size below 250 microns, such as below 210 microns, such as below 180 microns, such as below 150 microns.
  • dextrose such as dextrose with an average particle size below 250 microns, such as below 210 microns, such as below 180 microns, such as below 150 microns.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles in a weight ratio between i) and ii) of between 0.2 and 5.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles in a weight ratio between i) and ii) of between 0.3 and 4.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and ii) non-directly compressible (non-DC) sugar alcohol particles in a weight ratio between i) and ii) of between 0.5 and 3.
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles in a weight ratio between i) and iii) of between 0.2 and 5.
  • DC directly compressible
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles in a weight ratio between i) and iii) of between 0.3 and 4.
  • DC directly compressible
  • the population of particles includes at least two types of sugar alcohol particles comprising i) granulated sugar alcohol particles and iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles in a weight ratio between i) and iii) of between 0.5 and 3.
  • DC directly compressible
  • the active ingredient comprises an active pharmaceutical ingredient. In one embodiment of the invention, the active ingredient comprises an active nutraceutical ingredient or a dietary supplement. In one embodiment of the invention, the active ingredient comprises zinc citrate.
  • the flowpack further comprising one or more flavoring agents.
  • the flowpack further comprising one or more high-intensity sweeteners.
  • Preferred high intensity sweeteners include, but are not limited to sucralose, aspartame, salts of acesulfame, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside (natural high intensity sweetener) and the like, alone or in combination.
  • Encapsulation of sweetening agents can also be provided using another component such as a resinous compound.
  • usage level of the high intensity sweetener will vary considerably and will depend on factors such as potency of the sweetener, rate of release, desired sweetness of the product, level and type of flavor used and cost considerations.
  • the active level of high intensity sweetener may vary from about 0.001 to about 8% by weight (preferably from about 0.02 to about 8% by weight).
  • the usage level of the encapsulated sweetener will be proportionately higher.
  • Combinations of sugar and/or non-sugar sweeteners may be used in the formulation.
  • the amount of flavor may e.g. be from 0.1 to about 10% by weight of the formulation, such as 0.1 to about 6% by weight of the formulation.
  • Usable flavors include almond, almond amaretto, apple, Bavarian cream, black cherry, black sesame seed, blueberry, brown sugar, bubblegum, butterscotch, cappuccino, caramel, caramel cappuccino, cheesecake (graham crust), chili, cinnamon redhots, cotton candy, circus cotton candy, clove, coconut, coffee, clear coffee, double chocolate, energy cow, ginger, glutamate, graham cracker, grape juice, green apple, Hawaiian punch, honey, Jamaican rum, Kentucky bourbon, kiwi, koolada, lemon, lemon lime, tobacco, maple syrup, maraschino cherry, marshmallow, menthol, milk chocolate, mocha, Mountain Dew, peanut butter, pecan, peppermint, raspberry, banana, ripe banana, root beer, RY 4, spearmint, strawberry, sweet cream, sweet tarts, sweetener, toasted almond, tobacco, tobacco blend, vanilla bean ice cream, vanilla cupcake, vanilla swirl, vanillin, waffle, Belgian waffle, watermelon, whipped cream
  • the flavor is a powder flavor.
  • the formulation further comprising at least one dissolution modifier selected from the group consisting of acacia, agar, alginic acid or a salt thereof, carbomer, carboxymethylcellulose, carrageenan, cellulose, chitosan, copovidone, cyclodextrins, ethylcellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hypromellose, inulin, methylcellulose, pectin, polycarbophil or a salt thereof, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, pullulan, starch, tragacanth, trehalose, xanthan gum and mixtures thereof.
  • a dissolution modifier selected from the group consisting of acacia, agar, alginic acid or a salt thereof, carbomer, carboxymethylcellulose, carrageenan, cellulose, chitosan, copovidone, cyclo
  • the at least one dissolution modifier is selected from the group consisting of sodium alginate, calcium polycarbophil, xanthan gum and mixtures thereof.
  • the formulation further comprising at least one viscolising agent that when hydrated forms a gel having positive surface electrical charge and at least one viscolising agent that when hydrated forms a gel having negative surface electrical charge.
  • the flowpack further comprising fillers, such as calcium carbonate and/or talc. In one embodiment of the invention, the flowpack further comprising calcium carbonate. In one embodiment of the invention, the flowpack further comprising talc.
  • the flowpack further comprising flow promoting agents.
  • the flowpack further comprising silicon dioxide as a flow promoting agent.
  • the flowpack further comprising rice hulls as a flow promoting agent.
  • the flowpack further comprising cellulosic agents as flow promoting agents, such as Jelucel.
  • the flow promoting agent is applied in an amount of less than 2.0% by weight of the powder mixture, such as less than 1.5% by weight, such as below 1.0% by weight.
  • the population of particles includes gum base particles. In one embodiment of the invention, the population of particles includes chewing gum particles. In one embodiment of the invention, the flowpack comprising an outer package material enclosing the population of particles and the one or more active ingredients. In one embodiment of the invention, the flowpack comprising an outer aluminium package material enclosing the population of particles and the one or more active ingredients.
  • the flowpack comprising an outer oxygen impermeable package material enclosing the population of particles and the one or more active ingredients.
  • the population of particles is administered directly in the mouth.
  • the population of particles is poured into water and the water is administered in the mouth.
  • the flowpack further comprising an effervescence system.
  • the flowpack further comprising an effervescence system of a base and an acid. In one embodiment of the invention, the flowpack further comprising an effervescence system of a base and an organic acid. In one embodiment of the invention, the flowpack further comprising an effervescence system of a carbonate base and an organic acid.
  • the population of particles is dry and flowable. In one embodiment of the invention, the population of particles provides an improved cooling effect compared to a powder mixture without the at least one of said at least two types of sugar alcohol particles comprising iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles.
  • DC directly compressible
  • the population of particles provides an improved watering effect compared to a powder mixture without the at least one of the at least two types of sugar alcohol particles comprising ii) non-directly compressible (non-DC) sugar alcohol particles.
  • the population of particles provides an improved mouthfeel compared to a powder mixture without the at least one of the at least two types of sugar alcohol particles.
  • the population of particles provides an improved mouthfeel compared to a powder mixture without the at least one of the at least two types of sugar alcohol particles, the improved mouthfeel including at least one of less sandy mouthfeel, less dusty mouthfeel, less roughness mouthfeel, less sticky or improved texture.
  • the population of particles provides faster dissolution compared to a powder mixture without the at least one of the at least two types of sugar alcohol particles.
  • the population of particles provides faster dissolution compared to a powder mixture without ii) non-directly compressible (non-DC) sugar alcohol particles. In one embodiment of the invention, the population of particles provides faster dissolution compared to a powder mixture without iii) directly compressible (DC) sugar alcohol particles that are not granulated sugar alcohol particles.
  • the active ingredient comprises acetaminophen. In one embodiment of the invention, the active ingredient comprises ibuprofen. In one embodiment of the invention, the active ingredient comprises phenylephrine. In one embodiment of the invention, the active ingredient comprises dextrometorphan. In one embodiment of the invention, the active ingredient comprises guaifenesin. In one embodiment of the invention, the active ingredient comprises diphenhydramine. In one embodiment of the invention, the active ingredient comprises acetaminophen, phenylephrine, and dextromethorphan. In one embodiment of the invention, the active ingredient comprises acetaminophen, phenylephrine, dextromethorphan, and guaifenesin.
  • the active ingredient comprises oral care agents including zinc salts, such as zinc acetate or zinc gluconate. In one embodiment of the invention, the active ingredient comprises zinc acetate. In one embodiment of the invention, the active ingredient comprises zinc gluconate. In one embodiment of the invention, the active ingredient comprises zinc citrate.
  • the active ingredient comprises oral care agents for oral care benefits including bad breath, plaque, gingivitis, whitening, or combinations of two or more thereof. In one embodiment of the invention, the active ingredient comprises oral care agents for oral care benefits including one or more probiotic agents.
  • the active ingredient comprises anti-septics. In one embodiment of the invention, the active ingredient comprises anti-septics including cetyl pyridinium chloride (CPC). In one embodiment of the invention, the active ingredient comprises anti-septics including essential oils. In one embodiment of the invention, the active ingredient comprises anti-septics including essential oils selected from the group consisting of menthol, methyl salicylate, cineole, thymol, limonene, and any combination thereof. In one embodiment of the invention, the essential oils include menthol, methyl salicylate, cineole, and thymol.
  • the population of particles is a dosis of about 0.5 to 5.0 g. In one embodiment of the invention, the population of particles is a dosis of about 0.5 to 4.0 g. In one embodiment of the invention, the population of particles is a dosis of about 1.0 to 3.0 g. In one embodiment of the invention, the population of particles is a dosis of about 1.0 to 2.0 g.
  • the population of particles is at least partially dissolved in water and the solution or dispersion is administered in the mouth.
  • a flowpack for oral delivery of active ingredients comprising a population of particles, an outer package material enclosing the population of particles, and one or more active ingredients, the population of particles including at least two types of sugar alcohol particles, wherein at least one of said two types of sugar alcohol particles comprises i) granulated sugar alcohol particles.
  • the flow pack may comprise a population of particles, an outer package material enclosing the population of particles, and one or more active ingredients, according to embodiments of the invention.
  • a flowpack as a powder delivery system for improving saliva generation. Once the powder system is introduced into the mouth according to this aspect of the invention, saliva may be generated to a higher degree than by using conventional types of sugar alcohol particles. In one aspect of the invention, there is provided a flowpack as a powder delivery system for administration of active ingredients.
  • a flowpack as a powder delivery system for a mouthwash.
  • the powder delivery system generates saliva and the user may force at least a portion of the saliva generated around the oral cavity, for example, by swishing, rinsing, washing, etc., to provide an oral care benefit.
  • a flowpack as a powder delivery system for a toothpaste.
  • the powder delivery system generates saliva and the user may force at least a portion of the saliva generated around the oral cavity, for example, by swishing, rinsing, washing, etc., to provide a tooth paste cleaning benefit.
  • a method of achieving oral care benefits comprising the steps of: a) providing a flow pack comprising a population of particles according to any one of the preceding embodiments, the powder delivery system being a dry and flowable population of particles contained in an outer flowpack material, b) resembling a liquid mouthwash by swishing said population of particles, thereby generating fluid in the oral cavity without adding water.
  • a method of achieving oral care benefits comprising the steps of: a) providing a flow pack comprising a population of particles according to any one of the preceding embodiments, the powder delivery system being a dry and flowable population of particles contained in an outer flowpack material, b) subjecting the population of particles into water, thereby obtaining an at least partly dissolved swishable powder delivery system, and c) swishing the at least partly dissolved swishable powder delivery system, thereby generating fluid in the oral cavity.
  • the present invention provides a flowpack for oral delivery of active ingredients comprising a population of particles and one or more active ingredients, the population of particles including at least two types of sugar alcohol particles, wherein at least one of said two types of sugar alcohol particles comprises i) granulated sugar alcohol particles.
  • the term “approximately” or “about” in reference to a number are generally taken to include numbers that fall within a range of 5%, 10%, 15%, or 20% in either direction (greater than or less than) of the number unless otherwise stated or otherwise evident from the context (except where such number would be less than 0% or exceed 100% of a possible value).
  • the phrase “population of particles” refers to a statistical population of particles.
  • the population of particles may be characterized by a number of different parameters, e.g. statistical parameters such as distribution of particles, average particle size, particle size distribution width, etc.
  • the population of particles may have subpopulations, such as DC sugar alcohol particles and non-DC sugar alcohol particles.
  • particle size relates to the ability of the particles to move through or be retained by sieve holes of a specific size.
  • particle size refers to the average particle size as determined according to European Pharmacopoeia 9.1 when using test method 2.9.38 particle size distribution estimation by analytical sieving, unless otherwise specifically is mentioned.
  • particle or similar wording is intended to denote a single, discrete composition of solid matter, such as a granule or individual elements in powder, having a certain size that may deviate considerable.
  • the powder system provided in the present invention is generally provided as a powder where the individual particles are not further processed, such as in a direct compression process or compaction process. Hence, the powder system is not in form of a tablet or similar aggregation of powders. However, some degree of agglomeration of the particles of the present invention may occur either during storage of the powder system in the flow pack or to a minor degree during processing of the particles.
  • flow pack is intended to mean a wrapping containing the powder system according to the present invention, where the package is generally given the meaning in the field of flowpack technology.
  • the powder system is applied during “flow” of the wrapping material in a machinery that allows an efficient process with high speed.
  • Stick packs and sachets are examples of flow packs.
  • binder system “powder delivery system” or “formulation” is intended to be understood as the entire content of matter filled into the flowpack according to the invention, i.e. excluding the package or wrapping material surrounding the content.
  • a “powder system”, “powder delivery system” or a “formulation” includes the “population of particles” as a subsection as well as the one or more active ingredients but it may also include additional ingredients or particles.
  • dissolve is the process where a particle enters a solvent (oral saliva) to yield a solution. Unless otherwise stated, dissolving implies a full dissolving of the compound in question. In some embodiments, the dissolution rate of the active ingredient is measured and shows an improvement compared to conventional powder formulations.
  • in vivo release or “in vivo testing of release” or similar wording intends to mean that the formulation is tested as outlined in the examples.
  • in vitro release or “in vitro testing of release” or similar wording intends to mean that the formulation is tested according to the examples, in particular according to General Monograph 2.9.25 in European Pharmacopoeia, 5th ed.
  • release in the present context is intended to mean under “in vitro” conditions if not stated otherwise.
  • the “release rate” during a certain period of time is intended to mean the amount in percentage of active ingredient that is released during the period.
  • the process of releasing a substance corresponds to the substance being dissolved in saliva.
  • sustained release or “extended release” is herein intended to mean prolonged release over time.
  • rapid release or “quick release” or “high release” is herein intended to mean a higher content released for a given period of time.
  • the term “turn into liquid” is intended to mean that the population of particles are either suspended or dissolved in saliva, perceived as liquid by a test person in accordance with the test procedure of induced saliva generation.
  • delivery to the oral mucosa intends to mean that the formulation is tested according to the examples.
  • biologically active ingredient refers to a substance that is biologically active and has a physiological effect on the human body for the benefit of the human body or part thereof. Active ingredients include active pharmaceutical ingredients, but also other active substances, such as nutraceuticals, dietary supplements or oral care ingredients.
  • suitable for active pharmaceutical ingredients refers to the formulation as a suitable vehicle for e.g. inclusion and delivery of active pharmaceutical ingredients.
  • the powder system may or may not include active pharmaceutical ingredients.
  • water-insoluble gum base or “gum base” or “gum base matrix” or similar wording is meant the mainly water-insoluble ingredients and hydrophobic gum base ingredients.
  • the “gum base” may contain gum base polymers and plasticizers, waxes, emulsifiers, fats and/or fillers.
  • non-DC is easily understood within the field of technology. Suppliers of sugar alcohol provides clear guidance to the user as for the ability for use in relation to compression of tablets.
  • a non-DC particle in this connection is referred to as a particle which is not expressly recommended by the supplier for compression. Examples of a non-DC grade of erythritol includes Zerose (TM) erythritol 16952F and Zerose erythritol 16961 supplied by Cargill.
  • non-DC sugar alcohol particles include non-DC xylitol as Xivia C from Dupont, non-DC isomalt as Isomalt GS from Beneo Paltinit, non-DC mannitol as C*Pharm Mannidex 16700 from Cargill, non DC maltitol as Maltisorb P200 from Roquette.
  • Examples of a direct compressible (DC) grade of erythritol include ZeroseTM DC 16966 also supplied by Cargill.
  • DC sugar alcohols include sorbitol particles provided as e.g. Neosorb ® P 300 DC from Roquette, mannitol particles provided as e.g.
  • Pearlitol ® 300DC or Pearlitol 200 SD from Roquette maltitol provided as e.g. SweetPearl ® P 300 DC, xylitol provided as e.g. Xylisorb ® 200 DC or Xylitab from Dupont.
  • Non-direct compressible (non-DC) sugar alcohols may include non-DC grades of Xylitol, non-DC grades of Erythritol, non-DC grades of Mannitol, non-DC grades of maltitol, non-DC grades of Lactitol, non-DC grades of Isomalt, or other suitable non- DC grades of sugar alcohols.
  • Direct compressible (DC) sugar alcohols may include sorbitol, which is DC by nature, DC grades of Xylitol, DC grades of Erythritol, DC grades of Mannitol, DC grades of maltitol, DC grades of Lactitol, DC grades of dextrose, DC grades of Isomalt or other suitable DC grades of sugar alcohols.
  • sorbitol which is DC by nature, DC grades of Xylitol, DC grades of Erythritol, DC grades of Mannitol, DC grades of maltitol, DC grades of Lactitol, DC grades of dextrose, DC grades of Isomalt or other suitable DC grades of sugar alcohols.
  • the formulation comprises further ingredients selected from the group consisting of flavors, dry -binders, anti-caking agents, emulsifiers, antioxidants, enhancers, mucoadhesives, absorption enhancers, high intensity sweeteners, softeners, colors, active ingredients, water-soluble indigestible polysaccharides, water-insoluble polysaccharides or any combination thereof.
  • the emulsifiers may be selected from the group consisting of sucrose ester of fatty acids (such as sucrose mono stearate), polyethylene glycol esters or ethers (PEG) (such as caprylocaproyl macrogol-8 glycerides and lauroyl macrogol-32-glycerides), mono- and diglyceride of fatty acids (such as glycerol monostearate, glycerol monolaurate, glyceryl behenate ester), acetic acid esters of mono- and diglycerides of fatty acids (Acetem), polyoxyethylene alkyl ethers, diacetyl tartaric ester of monoglycerides, lactylated monoglycerides, glycerophospholipids (such as lecithin), poloxamer (non-ionic block copolymer of ethylene oxide and propylene oxide), cyclodextrins, fatty acid esters of sorbito
  • flavors may be selected from the group consisting of coconut, coffee, chocolate, vanilla, grape fruit, orange, lime, menthol, liquorice, caramel aroma, honey aroma, peanut, walnut, cashew, hazelnut, almonds, pineapple, strawberry, raspberry, tropical fruits, cherries, cinnamon, peppermint, wintergreen, spearmint, eucalyptus, and mint, fruit essence such as from apple, pear, peach, strawberry, apricot, raspberry, cherry, pineapple, and plum essence.
  • the essential oils include peppermint, spearmint, menthol, eucalyptus, clove oil, bay oil, anise, thyme, cedar leaf oil, nutmeg, and oils of the fruits mentioned above.
  • Antioxidants suitable for use include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), betacarotenes, tocopherols, acidulants such as Vitamin C (ascorbic acid or corresponding salts (ascorbates)), propyl gallate, catechins, green tea extract other synthetic and natural types or mixtures thereof.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • betacarotenes betacarotenes
  • tocopherols acidulants
  • acidulants such as Vitamin C (ascorbic acid or corresponding salts (ascorbates)), propyl gallate, catechins, green tea extract other synthetic and natural types or mixtures thereof.
  • High intensity sweetening agents can also be used according to preferred embodiments of the invention.
  • Preferred high intensity sweeteners include, but are not limited to sucralose, aspartame, salts of acesulfame, alitame, neotame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, monk fruit extract, advantame, stevioside and the like, alone or in combination.
  • Encapsulation of sweetening agents can also be provided using another formulation component such as a resinous compound.
  • usage level of the high-intensity sweetener will vary considerably and will depend on factors such as potency of the sweetener, rate of release, desired sweetness of the product, level and type of flavor used and cost considerations.
  • the active level of artificial sweetener may vary from about 0.001 to about 8% by weight (preferably from about 0.02 to about 8% by weight).
  • the usage level of the encapsulated high-intensity sweetener will be proportionately higher.
  • the invention may include one or more fillers/texturizers including as examples, magnesium- and calcium carbonate, sodium sulphate, ground limestone, silicate compounds such as magnesium- and aluminum silicate, kaolin and clay, aluminum oxide, silicium oxide, talc, titanium oxide, mono-, di- and tri-calcium phosphates, cellulose polymers, such as wood, and combinations thereof.
  • one preferred filler/texturizer is calcium carbonate.
  • the formulation according to the invention comprises a pharmaceutically, cosmetically or biologically active substance.
  • active substances include drugs, dietary supplements, antiseptic agents, pH adjusting agents, anti-smoking agents and substances for the care or treatment of the oral cavity and the teeth such as hydrogen peroxide and compounds capable of releasing urea during chewing.
  • useful active substances in the form of antiseptics include salts and derivatives of guanidine and biguanidine (for instance chlorhexidine diacetate) and the following types of substances with limited water-solubility: quaternary ammonium compounds (e.g.
  • ceramine, chi or oxy lend, crystal violet, chloramine), aldehydes (e.g. paraformaldehyde), derivatives of dequaline, polynoxyline, phenols (e.g. thymol, p- chlorophenol, cresol), hexachlorophene, salicylic anilide compounds, triclosan, halogenes (iodine, iodophores, chloroamine, dichlorocyanuric acid salts), alcohols (3,4 dichlorobenzyl alcohol, benzyl alcohol, phenoxyethanol, phenylethanol), cf. also Martindale, The Extra Pharmacopoeia, 28th edition, pages 547-578; metal salts, complexes and compounds with limited water-solubility, such as aluminum salts,
  • active substances in the form of agents adjusting the pH in the oral cavity include: acids, such as adipic acid, succinic acid, fumaric acid, or salts thereof or salts of citric acid, tartaric acid, malic acid, acetic acid, lactic acid, phosphoric acid and glutaric acid and acceptable bases, such as carbonates, hydrogen carbonates, phosphates, sulphates or oxides of sodium, potassium, ammonium, magnesium or calcium, especially magnesium and calcium.
  • acids such as adipic acid, succinic acid, fumaric acid, or salts thereof or salts of citric acid, tartaric acid, malic acid, acetic acid, lactic acid, phosphoric acid and glutaric acid and acceptable bases, such as carbonates, hydrogen carbonates, phosphates, sulphates or oxides of sodium, potassium, ammonium, magnesium or calcium, especially magnesium and calcium.
  • Active ingredients may comprise the below mentioned compounds or derivates thereof but are not limited thereto: Acetaminophen, Acetylsalicylic acid, Buprenorphine, Bromhexin, Celcoxib, Codeine, Diphenhydramin, Diclofenac, Etoricoxib, Ibuprofen, Indometacin, Ketoprofen, Lumiracoxib, Morphine, Naproxen, Oxycodon, Parecoxib, Piroxicam, Pseudoefedrin, Rofecoxib, Tenoxicam, Tramadol, Valdecoxib, Calciumcarbonat, Magaldrate, Disulfiram, Bupropion, Nicotine, Azithromycin, Clarithromycin, Clotrimazole, Erythromycin, Tetracycline, Granisetron, Ondansetron, Prometazin, Tropisetron, Brompheniramine, Ceterizin, leco-Ceterizin, Chlorcyclizine, Chlorphen
  • Chloride Benzeth. Chloride, Cetylpyrid. Chloride, Chlorhexidine, Ecabet-sodium, Haloperidol, Allopurinol, Colchinine, Theophylline, Propanolol, Prednisolone, Prednisone, Fluoride, Urea, Actot, Glibenclamide, Glipizide, Metformin, Miglitol, Repaglinide, Rosiglitazone, Apomorfm, Cialis, Sildenafil, Vardenafil, Diphenoxylate, Simethicone, Cimetidine, Famotidine, Ranitidine, Ratinidine, cetrizin, Loratadine, Aspirin, Benzocaine, Dextrometorphan, Phenylpropanolamine, Pseudoephedrine, Cisapride, Domperidone, Metoclopramide, Acyclovir, Dioctylsulfosucc
  • the invention is suitable for increased or accelerated release of active agents selected among the group of dietary supplements, oral and dental compositions, antiseptic agents, pH adjusting agents, anti-smoking agents, sweeteners, flavorings, aroma agents or drugs. Some of those will be described below.
  • the active agents to be used in connection with the present invention may be any substance desired to be released from the powder.
  • the active agents, for which a controlled and/or accelerated rate of release is desired are primarily substances with a limited water-solubility, typically below 10 g/100 mL inclusive of substances which are totally water-insoluble. Examples are medicines, dietary supplements, oral compositions, anti-smoking agents, highly potent sweeteners, pH adjusting agents, flavorings etc.
  • active ingredients are, for instance, paracetamol, benzocaine, cinnarizine, menthol, carvone, caffeine, chi orhexi dine-di-acetate, cyclizine hydrochloride, 1,8- cineol, nandrolone, miconazole, mystatine, sodium fluoride, nicotine, cetylpyridinium chloride, other quaternary ammonium compounds, vitamin E, vitamin A, vitamin D, glibenclamide or derivatives thereof, progesterone, acetylsalicylic acid, dimenhydrinate, cyclizine, metronidazole, sodium hydrogen carbonate, the active components from ginkgo, the active components from propolis, the active components from ginseng, methadone, oil of peppermint, salicylamide, hydrocortisone or astemizole.
  • active agents in the form of dietary supplements are for instance salts and compounds having the nutritive effect of vitamin B2 (riboflavin), B12, folinic acid, folic acid, niacine, biotine, poorly soluble glycerophosphates, amino acids, the vitamins A, D, E and K, minerals in the form of salts, complexes and compounds containing calcium, phosphorus, magnesium, iron, zinc, copper, iodine, manganese, chromium, selenium, molybdenum, potassium, sodium or cobalt.
  • vitamin B2 riboflavin
  • B12 riboflavin
  • folinic acid folinic acid
  • folic acid niacine
  • biotine poorly soluble glycerophosphates
  • amino acids amino acids
  • the vitamins A, D, E and K minerals in the form of salts, complexes and compounds containing calcium, phosphorus, magnesium, iron, zinc, copper, iodine, manganese, chro
  • active agents in the form of antiseptics are for instance salts and compounds of guanidine and biguanidine (for instance chlorhexidine diacetate) and the following types of substances with limited water-solubility: quaternary ammonium compounds (for instance ceramine, chloroxylenol, crystal violet, chloramine), aldehydes (for instance paraformaldehyde), compounds of dequaline, polynoxyline, phenols (for instance thymol, para chlorophenol, cresol) hexachlorophene, salicylic anilide compounds, triclosan, halogenes (iodine, iodophores, chloroamine, dichlorocyanuric acid salts), alcohols (3,4 dichlorobenzyl alcohol, benzyl alcohol, phenoxyethanol, phenylethanol), cf.
  • quaternary ammonium compounds for instance ceramine, chloroxylenol, crystal violet, chloramine
  • aldehydes for instance paraform
  • metal salts, complexes and compounds with limited water-solubility such as aluminum salts, (for instance aluminum potassium sulphate A1K(S04)2,12H20) and furthermore salts, complexes and compounds of boron, barium, strontium, iron, calcium, zinc, (zinc acetate, zinc chloride, zinc gluconate), copper (copper chloride, copper sulfate), lead, silver, magnesium, sodium, potassium, lithium, molybdenum, vanadium should be included; other compositions for the care of mouth and teeth: for instance; salts, complexes and compounds containing fluorine (such as sodium fluoride, sodiummonofluorophosphate, amino fluorides, stannous fluoride), phosphates, carbonates and selenium.
  • fluorine such as sodium fluoride, sodiummonofluorophosphate, amino fluorides, stannous fluoride
  • active agents in the form of agents adjusting the pH in the oral cavity include for instance: acceptable acids, such as adipic acid, succinic acid, fumaric acid, or salts thereof or salts of citric acid, tartaric acid, malic acid, acetic acid, lactic acid, phosphoric acid and glutaric acid and acceptable bases, such as carbonates, hydrogen carbonates, phosphates, sulfates or oxides of sodium, potassium, ammonium, magnesium or calcium, especially magnesium and calcium.
  • acceptable acids such as adipic acid, succinic acid, fumaric acid, or salts thereof or salts of citric acid, tartaric acid, malic acid, acetic acid, lactic acid, phosphoric acid and glutaric acid
  • acceptable bases such as carbonates, hydrogen carbonates, phosphates, sulfates or oxides of sodium, potassium, ammonium, magnesium or calcium, especially magnesium and calcium.
  • active agents in the form of anti-smoking agents include for instance: nicotine, tobacco powder or silver salts, for instance silver acetate, silver carbonate and silver nitrate.
  • active agents are medicines of any type.
  • active agents in the form of medicines include caffeine, salicylic acid, salicyl amide and related substances (acetylsalicylic acid, choline salicylate, magnesium salicylate, sodium salicylate), paracetamol, salts of pentazocine (pentazocine hydrochloride and pentazocinelactate), buprenorphine hydrochloride, codeine hydrochloride and codeine phosphate, morphine and morphine salts (hydrochloride, sulfate, tartrate), methadone hydrochloride, ketobemidone and salts of ketobemidone (hydrochloride), beta-blockers, (propranolol), calcium antagonists, verapamil hydrochloride, nifedinpine as well as suitable substances and salts thereof mentioned in Pharm.
  • active ingredients include beta-lupeol, Letigen®, Sildenafil citrate and derivatives thereof.
  • active ingredients include dental products including Carbamide, CPP Caseine Phospho Peptide; Chlorhexidine, Chlorhexidine di acetate, Chlorhexidine Chloride, Chlorhexidine di gluconate, Hexetedine, Strontium chloride, Potassium Chloride, Sodium bicarbonate, Sodium carbonate, Fluor containing ingredients, Fluorides, Sodium fluoride, Aluminum fluoride.
  • active ingredients include Ammonium fluoride, Calcium fluoride, Stannous fluoride, Other fluor containing ingredients Ammonium fluorosilicate, Potassium fluorosilicate, Sodium fluorosilicate, Ammonium monofluorphosphate, Calcium monofluorphosphate, Potassium monofluorphosphate, Sodium monofluorphosphate, Octadecentyl Ammonium fluoride, Stearyl Trihydroxy ethyl Propylenediamine Dihydrofluoride
  • active ingredients include vitamins.
  • Vitamins include A, Bl, B2, B6, B12, Folinic acid, Folic acid, niacin, Pantothenic acid, biotine, C, D, E, K.
  • Minerals include Calcium, phosphor, magnesium, iron, Zinc, Copper, Iod, Mangan, Crom, Selene, Molybden.
  • Other active ingredients include:
  • active ingredients include migraine drugs such as Serotonin antagonists: Sumatriptan, Zolmitriptan, Naratriptan, Rizatriptan, Eletriptan; nausea drugs such as Cyclizin, Cinnarizin, Dimenhydramin, Difenhydrinat; hay fever drugs such as Cetrizin, Loratidin, pain relief drugs such as Buprenorfm, Tramadol, oral disease drugs such as Miconazol, Amphotericin B, Triamcinolonaceton; and the drugs Cisaprid, Domperidon, Metoclopramid.
  • the invention relates to the release of Nicotine and its salts.
  • the active ingredient is selected from active ingredients for the throat selected from acetylcysteine, ambroxol, amylmetacresol, benzocaine, bisacodyl, bismuth subsalicylate, bromhexine, cetirizine, cetylpyridinium, chlorhexidine, dextromethorphan hydrobromide, 2,4- dichlorobenzyl alcohol, doxylamine succinate, eucalyptus oil, flurbiprofen, glycerin, hexylresorcinol, lidocaine, menthol, myrrh, paracetamol, pectin, peppermint oil, phenol, phenylephrine, povidone-iodine, pseudoephedrine, ranitidine, simethicone, sodium docusate, spearmint, zinc, or any combination thereof; active ingredients for the gastrointestinal tract selected from alginate, atenolol,
  • the active ingredient may also be one or more cannabinoids selected from: cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCV A). More preferably the one or more cannabinoid is CBD or THC.
  • CBD cannabichromene
  • CBDV cannabichromenic acid
  • CBD cannabidiol
  • the formulation comprises particles comprising gum base, and wherein the formulation is designed to be masticated into a coherent residual containing water-insoluble components.
  • the application of gum may in the present context may invoke a delay of release for active ingredients and this may again promote the buccal and upper throat absorption of active pharmaceutical ingredient when this is released from the formulation during mastication.
  • the formulation contains particles comprising gum base, and wherein the gum base comprises at least 5% by weight of elastomer.
  • gum base typically constitute from about 5 to about 95% by weight, more typically about 20 to about 80% by weight such as 30 to 70% or 30 to 60% by weight of the formulation.
  • the formulation further comprises, beside the already described sugar alcohols, materials selected from the group consisting of bulk sweeteners, flavors, dry-binders, anti-caking agents, emulsifiers, antioxidants, enhancers, absorption enhancers, buffers, high intensity sweeteners, softeners, colors, or any combination thereof.
  • Different sugar alcohols were fractionized according to particle size by performing analyses of the particle size distribution of the various raw materials.
  • the analyses were performed on a Retsch AS 200 control sieve shaker with a stack of 4-5 sieves. The mesh sizes were selected based on the raw material.
  • the procedure for the fractioning was as follows: The sieves were stacked on the shaker with the largest mesh size on top and descending sizes downwards. Two small balls were added to each sieves with a mesh size of 250 pm or less to increase the distribution of fine particles on the sieve.
  • a sample of 100 g sugar alcohol was placed on top of the sieve stack, the lid was fastened, and the shaker was started. The sample was shaken for 15 min with an amplitude of 1,5 mm.
  • the content of each sieve was determined giving the particle size distribution of the raw material.
  • Xylitol sugar alcohol particles Xylitol in different grades was provided and was fractionized according to Example 1. Table 1 below indicates the various xylitol particles applied.
  • Granulated directly compressible (DC) xylitol was provided by DuPont under the trade name Xylitab® 200.
  • the product is a commercially available product that has been granulated in a wet-granulation process with 2% sodium carboxymethylcellulose as binder.
  • Crystalline non-directly compressible (non-DC) xylitol was provided by DuPont under the trade name Xivia C. This xylitol grade was milled to provide a milled crystalline xylitol grade.
  • Granulated DC maltitol was provided by Roquette under the trade name SweetPearl® P300 DC.
  • the product is a commercially available product.
  • Crystalline non-DC maltitol was provided by Roquette under the trade name SweetPearl® P200.
  • the product is a commercially available product.
  • Table 2 Flow properties of different maltitol grades provided.
  • the product is a commercially available product.
  • Crystalline non-DC isomalt was provided by Beneo Palatinit under the trade name Isomalt GS.
  • the product is a commercially available product.
  • Granulated DC isomalt was provided by Beneo Palatinit under the trade name galenlQTM 720.
  • the product is a commercially available product.
  • Granulated DC dextrose was provided by Caldic under the trade name Royal-T ® Dextrose with Maltodextrin 020510.
  • the product is a commercially available product.
  • the particles size distribution measured by sieving specifies a max of 5.0% by weight of the particles on 1.19 mm (#16 mesh), max of 35.0% by weight of the particles thru 177 microns (#80 mesh), and max of 25.0% by weight of the particles thru 149 microns (#100 mesh). In the following, these particles are denoted sample 24A.
  • the particles has good flow properties.
  • Erythritol with different particle size distributions was provided and further combined with one or more additional sugar alcohol particles according to the invention.
  • Table 4 below indicates the various erythritol particles applied.
  • Non-DC erythritol particles were provided by Cargill under the trade name ZeroseTM 16952.
  • the product is a commercially available product that has been processed by fermentation of carbohydrates. This grade was further fractionized according to Example 1.
  • Non-DC erythritol particles were provided by Jungbunzlauer under the trade name ERYLITE ®.
  • the product is a commercially available product that has been processed by fermentation of carbohydrates.
  • Non-DC erythritol particles were provided by Cargill under the trade name ZeroseTM 16961.
  • the product is a commercially available product that has been processed by fermentation of carbohydrates.
  • Mannitol was provided and further combined with one or more additional sugar alcohol particles according to the invention.
  • Table 5 indicates the various mannitol particles applied.
  • Non-DC mannitol particles were provided by Cargill under the trade name C*Pharm Mannidex 16700.
  • the product is a commercially available product. This grade was further fractionized according to Example 1.
  • Sorbitol with different particle size distributions was provided and further combined with one or more additional sugar alcohol particles according to the invention.
  • Table 6 indicates the various sorbitol particles applied.
  • Sorbitol sugar alcohol particles were provided by PharmSorbidex from Cargill under the trade name C*PharmSorbidex P 16656.
  • the product is a commercially available product that has been processed by hydrogenation of sugars. This grade was further fractionized according to Example 1.
  • Sorbitol sugar alcohol particles were provided by Cargill under the trade name C*SorbidexTM S 16607.
  • the product is a commercially available product that has been processed by hydrogenation of sugars.
  • Table 6 Flow properties of different sorbitol grades provided and fractions hereof
  • Dextrose particles were provided from Cargill under the trade name C* DexTM 02001.
  • the product is a commercially available product. This grade was further fractionized according to Example 1.
  • Various types of two sugar alcohol particles from Examples 2-7 and 4A were mixed in a 1:1 weight ratio.
  • the two types of sugar alcohol particles were mixed according to the following procedure: An exact and equal amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each).
  • the two types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly.
  • granulated sugar alcohol particles from Examples 2-4 and 4A were combined with non-directly compressible sugar alcohol particles from Examples 5-6.
  • Various types of two sugar alcohol particles from Examples 2-7 and 4A were mixed in different weight ratio.
  • the two types of sugar alcohol particles were mixed according to the following procedure: An exact amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each).
  • the two types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly.
  • the weight ratios between granulated sugar alcohol particles from Examples 2-4 and 4A, and non-directly compressible sugar alcohol particles from Examples 5-6 were respectively 0.1, 0.2, 0.5, 1, 3, 5 and 6.
  • Combination of two sugar alcohol particles Various types of two sugar alcohol particles from Examples 2-7 were mixed in a 1:1 weight ratio. The two types of sugar alcohol particles were mixed according to the following procedure: An exact and equal amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each). The two types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly. In this example granulated sugar alcohol particles from Examples 2-4 were combined with non-directly compressible sugar alcohol particles from Examples 5-6. Table 7 A: Different combinations of granulated sugar alcohol particles and non-DC sugar alcohol particles.
  • Combination of two sugar alcohol particles Various types of two sugar alcohol particles from Examples 2-7, 4A and 7A were mixed in a 1:1 weight ratio. The two types of sugar alcohol particles were mixed according to the following procedure: An exact and equal amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each). The two types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly. In this example granulated sugar alcohol particles from Examples 2-4 and 4A were combined with sorbitol sugar alcohol particles from Example 7 or dextrose particles from Example 7A.
  • Example 10B Various types of two sugar alcohol particles from Examples 2-7, 4A and 7A were mixed in different weight ratio.
  • the two types of sugar alcohol particles were mixed according to the following procedure: An exact amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each).
  • the two types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly.
  • the weight ratios between granulated sugar alcohol particles from Examples 2-4 and 4A, and sorbitol sugar alcohol particles from Example 7 as well as dextrose particles from Example 7A were respectively 0.1, 0.2, 0.5, 1, 3, 5 and 6.
  • Example 10B Example 10B
  • Various types of two sugar alcohol particles from Examples 2-7 were mixed in a 1:1 weight ratio.
  • the two types of sugar alcohol particles were mixed according to the following procedure: An exact and equal amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each).
  • the two types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly.
  • granulated sugar alcohol particles from Examples 2-4 were combined with sorbitol sugar alcohol particles from Example 7.
  • Three sugar alcohol particles from Examples 2-7, 4A and 7A were mixed in a 1:1:1 weight ratio.
  • the three types of sugar alcohol particles were mixed according to the following procedure: An exact and equal amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each).
  • the three types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly.
  • Three sugar alcohol particles from Examples 2-7 were mixed in a 1:1:1 weight ratio.
  • the three types of sugar alcohol particles were mixed according to the following procedure: An exact and equal amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each).
  • the three types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly.
  • Table 9B Different combinations of sugar alcohol particles.
  • Combination of three sugar alcohol particles Various types of two sugar alcohol particles from Examples 2-7 were mixed in different weight ratio.
  • the three types of sugar alcohol particles were mixed according to the following procedure: An exact amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each).
  • the three types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly.
  • Example 11 The samples from Example 11 were tested with different flow promoting agents. All samples were tested with a) silicium dioxide in an amount of 1% by weight of the sample and b) silicium dioxide in an amount of 2% by weight of the sample. Also, all samples were tested with c) rice hulls provided by Ribus under the brand name Nu- Flow in an amount of 2% by weight of the sample. These rice hulls have a particles size of below 74 microns.
  • Three sugar alcohol particles from Examples 2-7 were mixed in a 1:1:1 weight ratio.
  • the three types of sugar alcohol particles were mixed according to the following procedure: An exact and equal amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each).
  • the three types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly. Further additives were included in order to enhance the sweetness profile and obtain different flavor directions.
  • the powder delivery system were included in a flow-pack according to Example 8.
  • Table 10 Different combinations of sugar alcohol particles including high-intensity sweeteners and flavors.
  • Three sugar alcohol particles from Examples 2-7 were mixed in a 1:1:1 weight ratio.
  • the three types of sugar alcohol particles were mixed according to the following procedure: An exact and equal amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each).
  • the three types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly. Further effervescence ingredients were included in order to generate a fizzy sensation in the mouth. In addition, to some of the samples other active ingredients were added.
  • the powder delivery system were included in a flow-pack according to Example 8.
  • Table 11 Different combinations of sugar alcohol particles and further components.
  • the three types of sugar alcohol particles were mixed according to the following procedure: An exact and equal amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each). The three types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly. Further immune active ingredients were included in order to attain an immune enhancing effect.
  • the powder delivery system were included in a flow-pack according to Example 8.
  • Table 12 Different combinations of sugar alcohol particles and active ingredients.
  • Combination of three sugar alcohol particles with oral care active ingredients Various types of three sugar alcohol particles from Examples 2-7 were mixed in a 1:1:1 weight ratio.
  • the three types of sugar alcohol particles were mixed according to the following procedure: An exact and equal amount of each type of sugar alcohol particles was measured by weight (between 1-3 g of each).
  • the three types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly. Further oral care active ingredients were included in order to attain oral benefits like caries protection, remineralization, and plaque removal.
  • the powder delivery system were included in a flow-pack according to Example 8.
  • Various types of three sugar alcohol particles from Examples 2-7 were mixed in a 1:1:1 weight ratio.
  • the three types of sugar alcohol particles were mixed according to the following procedure: An exact and equal amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each).
  • the three types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly.
  • caffeine and a pre blend of the B-vitamins: B6, niacin and B12 were included in order to obtain an energizing effect.
  • flavor and HIS were added to enhance the sweetness profile and obtain different flavor directions.
  • the powder delivery system were included in a flow-pack according to Example 8.
  • Table 14 Different combinations of sugar alcohol particles and active ingredients.
  • Three sugar alcohol particles from Examples 2-7 were mixed in a 1:1:1 weight ratio.
  • the three types of sugar alcohol particles were mixed according to the following procedure: An exact and equal amount of 500 mg of each type of sugar alcohol particles was measured by weight for a total weight of 1500 mg.
  • the three types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly.
  • the powder delivery system were included in a flow-pack according to Example 8.
  • Table 14A Different combinations of sugar alcohol particles and active ingredients.
  • Non-DC Xylitol Xivia C from Dupont
  • test panel of 8 test persons has been used for this test.
  • Test subject abstain from eating and drinking at least 30 minutes before initiation of any test.
  • the test subject swallows.
  • the test subject refrains from chewing and swallowing during the test.
  • the test subjects let the powder dissolve for 10 seconds without moving it around.
  • saliva and any remains of the powder delivery system is moved around in the mouth without chewing and after 1 minute after starting the test, the test subject discards saliva including any powder delivery system fragments into a plastic cup, which is weighted.
  • the test is repeated with a new powder delivery system under the same conditions as for the 1 minute test but instead of discarding saliva after 1 minute, the saliva is moved around and kept for 3 minutes in the mouth without swallowing before the test subject discards saliva including any powder delivery system fragments into a plastic cup, which is weighted.
  • the saliva samples collected were analyzed for content of active ingredient.
  • the saliva was positioned in a flask and weighted. Subsequently, a solvent was added for dissolution and dilution purposes.
  • the solution was injected directly into an HPLC system and analyzed by an assay method by a HPLC method.
  • the saliva were subject to 3 triple measurements for each of the 8 test persons, giving a total of 24 measurement for each sample. An average of the 24 measurements was calculated. By comparing the amount of active ingredient released (100%), and the amount of active ingredient in the saliva, the amount of active ingredient delivered to the oral mucosa could be estimated.
  • the Hausner ratio was measured on example blends.
  • the Hausner ratio is known by a person skilled in the art to be the ratio between stamped powder (g/mL) and unstamped powder (g/mL) according to known methods. The ratio expresses the ratio between the bulk density of the stamped and unstamped powder.
  • the Hausner ratio is usually categorized according to a compressibility index and expresses the flow character of a powder. Best flow character is obtained with a Hausner ratio of 1.00 and the higher the Hausner ratio, the less flowing is the powder.
  • Various types of three sugar alcohol particles from Examples 2-7 were mixed in a 1:1 or 1:1:1 weight ratio.
  • the three types of sugar alcohol particles were mixed according to the following procedure: An exact and equal amount of each type of sugar alcohol particles was measured by weight (between 3-5 g of each).
  • the types of sugar alcohol particles were combined in a 70x100 mm plastic bag at ambient conditions and the content in the bag was mixed thoroughly.
  • the powder delivery system were included in a flow-pack according to Example 8.
  • Table 14B Different combinations of sugar alcohol particles. *CaC03 added in 5% by weight. **Si02 in 2% byweight.
  • Sensorial evaluation test set-up Sensorial tests were performed on all examples to reveal very important characteristics and properties of the powder delivery system. These sensorial parameters are important as indicators of the structure of the powder delivery system composition.
  • the structure is the underlying guidance as to how the powder delivery system resembles the structure of a comparative powder delivery system, which is used as a reference in the test series, i.e. the powder delivery systems are compared to each other in the test series of preferably 5 samples.
  • the test set-up was composed of 8 test persons in a test panel. Each of the test persons were healthy individuals appointed on an objective basis according to specified requirements.
  • the sensory analysis was performed according to ISO 4121-2003 in testing conditions following ISO 8589. The result is an average of the results of the 8 individuals.
  • test persons gave a rating from “+” to “+++++”, where “+” is poor and “+++++” is excellent compared to the reference sample.
  • the reference sample is given the rating “++” for all the parameters, i.e. “+++++” means that the powder delivery system was far better than the reference and “+” means that the powder delivery system was inferior to the reference. “0“ indicated that it was not tested.
  • “Mouthfeel” the general impression of the powder delivery system when placed in the mouth with respect to elements such as roughness, texture and a sandy or dusty feeling.
  • “Melting” the impression of the powder delivery system when placed in the mouth. For instance, a feeling that the powder delivery system melts on the tongue with a resulting sticking feeling gave a low rating, whereas a less sticky experience gave a higher rating. A slow melting powder deliver system gave a low rating, whereas a fast meting give a high rating.
  • “Flavor” the overall impression of the powder delivery system with respect to flavor including the sweetness profile. For instance, a very low flavor experience gave a very low rating and a too high flavor also gave a very low rating.
  • Off-notes - the overall impression of the off-note from the active ingredients in the composition. For instance, if off-notes (grass, bitter notes, irritation in the throat) were experienced in the throat, a low rating was given and if other uncomfortable sensations was experienced, a low rating was also given.
  • Example 21 The results of the samples above correspond to an illustration of selected samples that were tested with respect to sensorial evaluation according to the set up in Example 19. The additional samples provided in the previous examples were also tested in the same way with respect to the same parameters, and the results were in the same way considered to be advantageous.
  • Example 21 The results of the samples above correspond to an illustration of selected samples that were tested with respect to sensorial evaluation according to the set up in Example 19. The additional samples provided in the previous examples were also tested in the same way with respect to the same parameters, and the results were in the same way considered to be advantageous.
  • Table 16 Evaluation of mouthfeel and other sensorial properties.

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EP21727077.6A EP4146164B1 (en) 2020-05-08 2021-04-30 Flowpack for oral delivery of active ingredients
ES21727077T ES3031420T3 (en) 2020-05-08 2021-04-30 Flowpack for oral delivery of active ingredients
CA3174693A CA3174693C (en) 2020-05-08 2021-04-30 Flowpack for oral delivery of active ingredients
AU2021268062A AU2021268062B2 (en) 2020-05-08 2021-04-30 Flowpack for oral delivery of active ingredients
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DK21727077.6T DK4146164T3 (da) 2020-05-08 2021-04-30 Flowpack til oral afgivelse af aktive ingredienser
BR112022021602A BR112022021602A2 (pt) 2020-05-08 2021-04-30 Embalagem flowpack para entrega oral de ingredientes ativos
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