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WO2015090337A1 - Composition de poudre de nicotine - Google Patents

Composition de poudre de nicotine Download PDF

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Publication number
WO2015090337A1
WO2015090337A1 PCT/DK2014/050444 DK2014050444W WO2015090337A1 WO 2015090337 A1 WO2015090337 A1 WO 2015090337A1 DK 2014050444 W DK2014050444 W DK 2014050444W WO 2015090337 A1 WO2015090337 A1 WO 2015090337A1
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WO
WIPO (PCT)
Prior art keywords
powder composition
nicotine
weight
composition according
solid lipid
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/DK2014/050444
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English (en)
Inventor
Bruno Provstgaard Nielsen
Niels Ramskov BØJE
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
Publication of WO2015090337A1 publication Critical patent/WO2015090337A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/0058—Chewing gums
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5176—Compounds of unknown constitution, e.g. material from plants or animals

Definitions

  • the present invention pertains to the field of powder compositions for oromucosal delivery of nicotine.
  • the present invention pertains to solid lipid powder compositions with a content of nicotine and low water content.
  • Nicotine has been the subject of various attempts to optimize delivery and uptake in the oral cavity.
  • One of the critical issues when nicotine enters the oral cavity is to avoid that most of the nicotine is swallowed and degraded in the gastrointestinal tract. While this may be an advantage for the vast majority of medical active ingredients, the effect of nicotine in oral formulations is mainly obtained by uptake of nicotine in the oral mucosa. Uptake in the oral mucosa and subsequent absorption in the blood stream is critical to deliver nicotine to its receptor target sites in the human brain. This way of uptake will ensure that nicotine will pass directly to the target receptors in the human brain.
  • nicotine has traditionally been formulated for the purpose of sustained delivery in the oral cavity.
  • sustained delivery it has been the expectation in the prior art that a higher ratio of nicotine would be delivered into the blood stream and a lower ratio of nicotine would be swallowed and degraded in the gastrointestinal tract.
  • One such oral delivery vehicle used for sustained delivery of nicotine is nicotine polacrilex resins.
  • the mechanism in these kinds of systems is that ion-bonding of nicotine provides a stable nicotine complex during storage which after entering the oral cavity will slowly deliver nicotine to the oral cavity. It has been the conventional wisdom that the mechanism involves a number of limiting factors, such as concentration limits in the saliva and concentration limits in the oral mucosa, as well as barrier properties through the oral mucosa. By keeping the release rate of nicotine low, it has been conventional thinking that such limiting factors may be optimized.
  • an unexpected and improved powder composition for oromucosal delivery of nicotine comprising a plurality of solid lipid particles, the solid lipid particles having a content of nicotine and at least one surfactant, and the powder composition having a content of water below 10.0% by weight of the powder composition.
  • the present invention provides a method of producing a powder composition for oromucosal delivery of nicotine comprising the steps of providing a liquid suspension of a plurality of solid lipid particles, the solid lipid particles having a content of nicotine and at least one surfactant, and subjecting the liquid suspension to a drying step and thereby obtaining a powder composition having a content of water below 10.0% by weight of the powder composition.
  • the present invention provides an oromucosal delivery system, such as a lozenge or compressed chewing gum, comprising a powder composition according to the invention.
  • FIGURES Figure 1 shows the particle size distribution of a suspension of solid lipid particles.
  • the particle concentrations in this figure is 1,3 % of the total weight of the suspension.
  • Figure 2 shows the particle size distribution of a suspension containing solid lipid particles and 2 % trehalose that has been freeze dried to a powder.
  • the suspension measured in Figure 1 and Figure 2 is the same, and the two figures are thus directly comparable. It is thus a comparison of the suspension before and after the freeze drying process.
  • oral delivery refers to delivery to the oral cavity.
  • solid lipid is a lipid that is solid at room
  • mucoadhesive and “mucoadhesion” refers to the concept of a composition adhering to a mucous membrane. Mucoadhesive compounds may facilitate mucoadhesion by their specific properties.
  • gum base and “gum base matrix” we mean the mainly water insoluble and hydrophobic gum base ingredients that are mixed together before the bulk portion of the chewing gum formulation is added.
  • bulk portion intends to mean the mainly water soluble chewing and hydrophilic gum ingredients that are mixed into the gum base matrix after it has been mixed.
  • a powder composition for oromucosal delivery of nicotine comprising a plurality of solid lipid particles, the solid lipid particles having a content of nicotine and at least one surfactant, and the powder composition having a content of water below 10.0% by weight of the powder composition.
  • the present invention may offer a fast effect of nicotine compared to conventional systems. Contrary to conventional systems where nicotine is delivered to saliva in the oral cavity, nicotine may be delivered directly into the oral mucosa by the present invention. In turn, nicotine may also or alternatively be delivered directly to the epithelium in the oral cavity by the present invention. Without being bound by theory, it is believed that nicotine is protected by the solid lipid particles of the present invention and that this protection offers improved conditions for targeting nicotine to the sites of absorption. Hence, while obtaining conditions that allows for less nicotine being swallowed into the gastrointestinal tract, the present invention may utilize a higher amount of nicotine compared to conventional systems and thereby reduced costs. By incorporating nicotine into solid lipid particles, nicotine may also be stabilized to a high degree.
  • the surfactant of the present invention may facilitate stabilizing nicotine in the solid lipid particles. Accordingly, the concept may be seen as a way to stabilize nicotine and at the same time offer the best conditions for delivery of nicotine to the target site.
  • the solid lipid particles according to the present invention may be an advantage in terms of less burning and unpleasant taste compared to conventional systems for delivery of nicotine since nicotine may provide a burning sensation to target receptors in the oral cavity. Hence, burning may be less pronounced according to the present invention.
  • nicotine is released directly into the oral cavity when using nicotine polacrilex resins and bitterness receptors may be triggered. This direct exposure may be avoided according to the present invention. This would in turn also be the case for systems where nicotine is adsorbed into or onto carriers such as cellulose particles where nicotine is also delivered directly in the oral cavity.
  • bitterness receptors may be less triggered by the present invention and that taste masking is improved.
  • the reason may in part be that the solid lipid particles of the present invention are targeted to the site of action, and in part the solid lipid particles protect nicotine from exposure to bitterness receptors.
  • Another advantage of the present invention is that nicotine may be stabilized by using a relatively low amount of water, i.e. an amount of water of less than 10.0% by weight of the powder composition or even lower. Compared to conventional systems this offers improved conditions for the powder composition according to the present invention. That it was in fact possible to provide a system with such a relative low amount of water was a surprise to the present inventions and completely unexpected. It was in fact expected by the present inventors that such relative low water content would compromise the quality of nicotine and impart problems with evaporation of nicotine either during the process of lowering the amount of water or during storage. However, contrary to expectations, the exact opposite was seen.
  • the content of water of the powder composition is below 5% by weight of the powder composition, such as below 3% by weight of the powder composition. In one embodiment of the invention, the content of water of the powder composition is below 2.5% by weight of the powder composition, such as below 2% by weight of the powder composition, such as below 1.5% by weight of the powder composition.
  • the content of water of the powder composition is between 0.2 and 5.0% by weight of the powder composition, such as between 0.2 and 3.0% by weight of the powder composition.
  • the content of water of the powder composition is between 0.3 and 4.0% by weight of the powder composition, such as between 0.5 and 3.0% by weight of the powder composition, such as between 0.7 and 2.5%) by weight of the powder composition, such as between 0.8 and 2.0% by weight of the powder composition.
  • a particularly preferred embodiment of the present invention may be a powder composition, wherein the average size of the plurality of solid lipid particles is between 20 nm and 100 ⁇ , such as between 20 nm and 20 ⁇ .
  • Such an average size of the particles may provide for improved taste-masking properties of the present invention because less sized particles may be less susceptible for bitterness receptors.
  • less sized particles have been shown to be an advantage in order for the particles to enter the barrier of epithelium. Hence, such less sized particles may provide for an improved uptake or absorption of nicotine into the blood stream and higher effect of nicotine.
  • the size of the particles will have a lower limit. This is partly due to restrictions in the manufacturing process.
  • the average size of the plurality of solid lipid particles is between 50 nm and 20 ⁇ , such as between 70 nm and 15 ⁇ , such as between 100 nm and 15 ⁇ , such as between 200 nm and 15 ⁇ , such as between 300 nm and 15 ⁇ , such as between 400 nm and 12 ⁇ , such as between 500 nm and 10 ⁇ .
  • the average size of the plurality of solid lipid particles is between 50 nm and 15 ⁇ , such as between 70 nm and 12 ⁇ , such as between 100 nm and 10 ⁇ , such as between 200 nm and 5 ⁇ , such as between 300 nm and 3 ⁇ , such as between 400 nm and 2 ⁇ , such as between 500 nm and 1 ⁇ .
  • the solid lipid particles according to the invention may contain additional ingredients, such as a cryoprotectant or an excipient for further handling.
  • additional ingredients such as a cryoprotectant or an excipient for further handling.
  • the size of the particles above may include such additional ingredient.
  • solid lipid particles with a relatively large size may be adsorbed to the epithelium and that the oral mucosa will somehow be of less importance to penetrate.
  • solid lipid particles with a relatively small size may be absorbed into the oral mucosa and thereby reaching the epithelium via uptake in the oral mucosa.
  • both mechanisms would be present. This may be the case for intermediate sizes particles dependent on the thickness of the oral mucosa. This may depend of the affinity of the lipid particle according to the invention to the lipid structures in the oral mucosa and/or the epithelium or the like.
  • lipid is present in an amount of between 20 and 95% by weight of the powder composition, such as between 30 and 80% by weight of the powder composition.
  • lipid is present in an amount of between 25 and 90% by weight of the powder composition, such as between 30 and 75% by weight of the powder composition.
  • the solid lipid particles according to the invention are considered lipid particles. While the amount of lipid is not always 100%, lipid contributes to a major part of the properties of the particles. Hence, lipid will be the major contributor to the properties of the particles. For instance, nicotine may be protected by nearly 100%) lipid, but according to the invention may also be protected by a less amount of lipid because the characteristics of the lipid according to the invention are overwhelming.
  • the amount of lipid may be even lower, such as 15 and 60%> by weight of the powder composition, such as between 20 and 55% by weight of the powder composition, such as between 25 and 50% by weight of the powder composition, such as between 30 and 45% by weight of the powder composition.
  • the at least one surfactant is present in the powder composition in an amount of between 1 and 15% by weight of the powder composition, such as between 1 and 10% by weight of the powder composition.
  • the at least one surfactant is present in the powder composition in an amount of between 2 and 10% by weight of the powder composition, such as between 2 and 8% by weight of the powder composition, such as between 2 and 7% by weight of the powder composition, such as between 1 and 8% by weight of the powder composition, such as between 2 and 7% by weight of the powder composition.
  • the surfactant according to the invention may be used to stabilize the composition with nicotine. While nicotine both contains lipophilic and hydrophilic properties, the surfactant according to the invention may secure an adequate balance in order to provide for a stable and desired amount of nicotine present.
  • the at least one surfactant may be present in the powder composition in an amount of between 1 and 7% by weight of the powder composition, such as between 1 and 6% by weight of the powder composition, such as between 1 and 5% by weight of the powder composition, such as between 1 and 4% by weight of the powder composition.
  • nicotine is present in an amount of between 0.1 and 20% by weight of the powder composition, such as between 0.5 and 10% by weight of the powder composition.
  • nicotine is present in an amount of between 1 and 20%) by weight of the powder composition, such as between 3 and 15%> by weight of the powder composition, such as between 3 and 10%> by weight of the powder composition.
  • nicotine is present in an amount of between 8 and 20% by weight of the powder composition, such as between 10 and 20% by weight of the powder composition, such as between 15 and 20% by weight of the powder composition. In another embodiment of the invention, nicotine is present in an amount of between 5 and 15% by weight of the powder composition, such as between 6 and 14% by weight of the powder composition, such as between 7 and 13% by weight of the powder composition.
  • the amount of nicotine may be influenced by the presence of cryoprotectant and/or additional excipient in the process.
  • the solid lipid particles having a content of nicotine and at least one surfactant may imply that a lower amount of nicotine is necessary for oromucosal delivery of nicotine compared to nicotine polacrilex resins.
  • the lower amount of nicotine may be obtained as nicotine may be delivered directly into the oral mucosa by the present invention.
  • nicotine may alternatively be delivered directly to the epithelium in the oral cavity by the present invention. Without being bound by theory, it is believed that nicotine is protected in the solid lipid particles of the present invention and that this protection offers improved conditions for targeting nicotine to the sites of absorption.
  • the present invention may utilize a higher amount of nicotine compared to conventional systems and thereby reduced costs.
  • the type of nicotine used according to the present invention may be selected from the group consisting of a nicotine base and a salt of nicotine, such as nicotine bitartrate.
  • nicotine base is preferred.
  • said nicotine salts are selected from the group comprising nicotine hydrochloride, nicotine dihydrochloride, nicotine monotartrate, nicotine bitartrate, nicotine sulfate, nicotine zinc chloride, nicotine salicylate, or any combination thereof.
  • a salt of nicotine such as nicotine bitartrate
  • nicotine and the at least one surfactant is distributed within and onto the surface of the solid lipid particles. In another embodiment, nicotine and the at least one surfactant is distributed evenly in the solid lipid particles. In another embodiment, more than 70% nicotine and the at least one surfactant is distributed within the outermost 80% of the solid lipid particles.
  • the solid lipid particles imply an increased stability of nicotine compared to adsorption or absorption of nicotine onto delivery vehicles.
  • nicotine By incorporating nicotine into solid lipid particles, nicotine may also be stabilized to a high degree. Accordingly, the concept may be seen as a way to stabilize nicotine and at the same time offer the best conditions for delivery of nicotine to the target site.
  • the powder composition contains no more than 6% of trans nicotine-N-oxide and no more than 4% of cis nicotine-N-oxide when placed in a sealed plastic bottle and stored for four weeks at 50° C. and 75% relative humidity.
  • the solid lipid particles imply a faster delivery of nicotine compared to nicotine polacrilex resins.
  • the present invention may offer a fast effect of nicotine compared to conventional systems. Contrary to conventional systems where nicotine is delivered to saliva in the oral cavity, nicotine may be delivered directly into the oral mucosa by the present invention. In turn, nicotine may alternatively be delivered directly to the epithelium in the oral cavity by the present invention. Without being bound by theory, it is believed that nicotine is protected in the solid lipid particles of the present invention and that this protection offers improved conditions for targeting nicotine to the sites of absorption. Hence, while obtaining conditions that allows for less nicotine being swallowed into the gastrointestinal tract, the present invention may utilize a higher amount of nicotine compared to conventional systems and thereby reduced costs.
  • the solid lipid particles imply an increased taste masking of nicotine compared to nicotine polacrilex resins.
  • the solid lipid particles imply an increased taste masking of nicotine compared to nicotine bitartrate.
  • the solid lipid particles according to the present invention may be an advantage in terms of less burning and unpleasant taste compared to conventional systems for delivery of nicotine since nicotine may provide a burning sensation to target receptors in the oral cavity. Hence, burning may be less pronounced according to the present invention.
  • nicotine is released directly into the oral cavity when using nicotine polacrilex resins and this direct exposure may be avoided according to the present invention.
  • nicotine is released directly into the oral cavity when nicotine is adsorbed into or onto carriers such as cellulose particles.
  • the powder composition may further comprise at least one mucoadhesive.
  • the advantage of at least one mucoadhesive is that an increased amount of nicotine is targeted to the sites of absorption.
  • the content of the at least one mucoadhesive is between 1 and 15% by weight of the powder composition, such as between 1 and 10% by weight of the powder composition.
  • the content of the at least one mucoadhesive is between 2 and 12% by weight of the powder composition, such as between 3 and 1 1%) by weight of the powder composition, such as between 5 and 10% by weight of the powder composition.
  • the content of the at least one mucoadhesive is between 5 and 15% by weight of the powder composition, such as between 7 and 15%) by weight of the powder composition.
  • the content of the at least one mucoadhesive is between 1 and 9% by weight of the powder composition, such as between 2 and 8%) by weight of the powder composition.
  • the solid lipid particles having a content of nicotine, at least one surfactant and at least one mucoadhesive imply that a lower amount of nicotine is necessary for oromucosal delivery of nicotine compared to nicotine polacrilex resins.
  • the present invention may offer a fast effect of nicotine compared to conventional systems. Contrary to conventional systems where nicotine is delivered to saliva in the oral cavity, nicotine may be delivered directly into the oral mucosa by the present invention. In turn, nicotine may alternatively be delivered directly to the epithelium in the oral cavity by the present invention. Without being bound by theory, it is believed that nicotine is protected in the solid lipid particles of the present invention and that this protection offers improved conditions for targeting nicotine to the sites of absorption. Hence, while obtaining conditions that allows for less nicotine being swallowed into the gastrointestinal tract, the present invention may utilize a higher amount of nicotine compared to conventional systems and thereby reduced costs.
  • the solid lipid particles essentially consist of lipid, nicotine, at least one surfactant and at least one mucoadhesive.
  • the size of the particles are to be low, e.g. in nano size.
  • the solid lipid particles essentially do not contain any content of water.
  • water is substantially present on the outside of the solid lipid particles within the powder composition.
  • the solid lipid particles comprise 20 to 95% lipid, 1 to 15%) surfactant, 0.1 to 20% nicotine and 1 to 15%> mucoadhesive by weight of the powder composition. In one embodiment of the invention, the solid lipid particles comprise 30 to 80%> lipid, 1 to 10%) surfactant, 0.5 to 10%> nicotine and 1 to 10%> mucoadhesive by weight of the powder composition.
  • a cryoprotectant is added and the cryoprotectant being located in the powder composition outside the solid lipid particles.
  • retention of nicotine is above 70% by adding a cryoprotectant, such as above 75% by adding a cryoprotectant, such as above 80% by adding a cryoprotectant. This means that nicotine is not lost by adding a
  • cryoprotectant Retention in this respect means the percentage of nicotine retained during the process.
  • the cryoprotectant is present in an amount of between 4 and 95% by weight of the powder composition, such as between 15 and 65% by weight of the powder composition, such as between 30 and 60% by weight of the powder composition.
  • the cryoprotectant is lactose or trehalose. According to the invention, lactose and trehalose have shown to give particularly good results.
  • cryoprotectant is selected from members known to those skilled in the art to work within the present invention.
  • the solid lipid particles comprise 4 to 95% lipid, 0.1 to 15%) surfactant, 0.1 to 20% nicotine and 0.1 to 15% mucoadhesive, and 4 to 95%) cryoprotectant by weight of the powder composition. In one embodiment of the invention, the solid lipid particles comprise 30 to 80% lipid, 1 to 10%) surfactant, 0.5 to 10% nicotine, 1 to 10% mucoadhesive, and 15 to 65%) cryoprotectant by weight of the powder composition.
  • no cryoprotectant is added. This may be an advantage in case less sized particles are preferred, such as nano-sized particles.
  • the average size of the plurality of solid lipid particles when no cryoprotectant is added is between 20 nm and 1000 nm, such as between 50 nm and 500 nm, such as between 50 nm and 400 nm.
  • the average size of the plurality of solid lipid particles when no cryoprotectant is added is between 50 nm and 300 nm, such as between 75 nm and 250 nm, such as between 75 nm and 200 nm, such as between 75 nm and 150 nm.
  • the average size of the plurality of solid lipid particles without cryoprotectant is less than 5 times the average size when cryoprotectant is added, such as less than 10 times the average size. In another embodiment of the invention, the average size of the plurality of solid lipid particles without cryoprotectant is less than 11 times the average size when cryoprotectant is added, such as less than 15 times the average size.
  • the average size of the plurality of solid lipid particles without cryoprotectant is more than 2 times the average size when cryoprotectant is added, such as more than 3 times the average size, such as more than 4 times the average size
  • the size of the solid lipid particles in part depend of the amount of cryoprotectant added during manufacture.
  • cryoprotectant is added after formation of the solid lipid particles and before drying.
  • the cryoprotectant is instead an excipient.
  • This excipient may be selected from any excipient known to be useful to those skilled in the art, for instance when the particles undergo spray drying.
  • lipid is present in an amount of between 50 and 95% by weight of the solid lipid particles, such as between 50 and 80% by weight of the solid lipid particles.
  • the lipid is selected from the group consisting of fatty acids, fatty esters and fatty mono-, di-, and triglycerides thereof, partial glycerides, fatty alcohols and their esters and ethers, natural and synthetic waxes such as bees wax and carnauba wax, wax alcohols and their esters,
  • the lipid is selected from the group consisting of C8-24 fatty acids and C8-24 fatty mono-, di-, or triglycerides, such as CI 0-22 fatty acids and CI 0-22 fatty mono-, di-, or triglycerides, such as saturated CI 0-22 fatty acids and CI 0-22 fatty mono-, di-, or triglycerides, preferably wherein said at least one lipid is selected from the group consisting of capric, lauric, myristic, palmitic, stearic, and arachidic acids and mono-, di- and triglycerides thereof, preferably trimyristin, tripalmitin, tristearin, tricaprin, myristic acid, palmitic acid, stearic acid, and behenic acid.
  • said at least one lipid is selected from the group consisting of capric, lauric, myristic, palmitic, stearic, and arachidic acids and mono-, di- and triglycerides thereof, preferably selected from trimyristin, tripalmitin, tristearin, tricaprin, myristic acid, palmitic acid, stearic acid, and behenic acid.
  • the lipid is a phospholipid preferably selected from the group consisting of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidic acid (PA), DPG (bisphosphatidyl glycerol), PEOH (phosphatidyl alcohol), cholesterol, ergosterol and lanosterol, preferably phosphatidylcholine (PC).
  • PC phosphatidylcholine
  • PE phosphatidylethanolamine
  • PS phosphatidylserine
  • PG phosphatidylglycerol
  • PI phosphatidylinositol
  • PA phosphatidic acid
  • DPG bisphosphatidyl glycerol
  • PEOH phosphatidyl alcohol
  • cholesterol ergosterol and lanosterol
  • the surfactant is selected from the group consisting of ionic, non-ionic, and amphoteric surfactants, preferably selected from the group consisting of non-ionic surfactants such as polyvinyl alcohol (PVA), polyoxy ethylene esters and ethers, lecithin, sodium docecyl sulfate (SDS), copolymers of polyoxy ethylene oxide and polyoxypropylene oxide.
  • PVA polyvinyl alcohol
  • SDS sodium docecyl sulfate
  • a surfactant may stabilize the particles according to the invention and prevent agglomeration of the individual particles.
  • the use of a surfactant may also control the morphology of the particles produced.
  • Porogen leaching from the particles can be used to control the particles and porosity by selecting suitable amounts of the added porogens, thus further controlling the release over time of nicotine.
  • Modification of porogen surface to volume ratio can be used to optimize the permeability of the particles and thus control the release of nicotine.
  • composition further comprises a compound having mucoadhesive properties in order to further control the delivery of the nicotine and/or flavour component to the desired place of delivery.
  • the mucoadhesive is selected from the group consisting of pectin, chitosan, sodium alginate, polyvinyl alcohol (PVA), polyacrylic acid (PAA), methyl cellulose (MC), sodium carboxy methylcellulose (SCMC), hydroxy propyl cellulose (HPC), preferably selected from the group consisting of pectin, PVA and PAA.
  • the composition comprises nicotine and a flavour component, wherein the nicotine component is immobilized in separate lipid particles from the particles immobilizing the flavour component.
  • the release of both the nicotine component and the flavour component may be controlled to obtain e.g. a fast release of nicotine to satisfy the nicotine craving and a longer lasting flavour release to obtain a pleasant taste in the mouth.
  • the composition further comprises at least one ingredient, preferably wherein said ingredient is a hydrophilic polymer and/or amphiphilic polymer, preferably selected from the group consisting of pectin, chitosan, dextran, pullulan, carrageenan, starch, cellulose acetate, sodium alginate, polyvinyl alcohol (PVA), polyacrylic acid (PAA), polyethylene oxide (PEO), methyl cellulose (MC), sodium carboxy methylcellulose (SCMC), hydroxy propyl cellulose (HPC), preferably selected from the group consisting of pectin, PEO, PVA and PAA.
  • a hydrophilic polymer and/or amphiphilic polymer preferably selected from the group consisting of pectin, chitosan, dextran, pullulan, carrageenan, starch, cellulose acetate, sodium alginate, polyvinyl alcohol (PVA), polyacrylic acid (PAA), polyethylene oxide (PEO), methyl cellulose (MC), sodium carboxy
  • the solid lipid particles are prepared by hot homogenization, such as in the following order:
  • One or more lipids in a melted state are provided, optionally by heating to above the phase transition temperature thereof. Thus heating may not be necessary when the lipid(s) in question is/are in a liquid state at room temperature. However, in other embodiments heating will be applied in order to provide the lipid(s) in a melted state.
  • nicotine is dissolved or dispersed therein.
  • any optional ingredients such as surfactant(s), excipient(s) and/or mucoadhesive compound(s) and/or porogen(s) are added to the lipid dispersion either neat or as a solution, preferably an aqueous solution thereof, and mixed.
  • the solid lipid particles are prepared by hot high shear homogenization and/or ultrasoni cation techniques, such as in the following order:
  • one or more lipids and nicotine is mixed in the melted state, optionally by heating to above the phase transition temperature of the lipid(s).
  • heating may not be necessary when the lipid(s) in question is/are in a liquid state at room temperature.
  • heating will be applied in order to provide the lipid(s) in a melted state
  • any optional ingredients such as surfactant(s), excipient(s) and/or mucoadhesive compound(s) and/or porogen(s) in aqueous solution or dispersion are heated and added to the above lipid-active ingredient mixture
  • the above solution or dispersion is cooled to below the phase transition temperature or below the melting point.
  • the solid lipid particles are prepared by cold homogenization, such as in the following order: 1. one or more lipids in a melted state are provided, optionally by heating to above the phase transition temperature thereof. Thus heating may not be necessary when the lipid in question is/are in a liquid state at room temperature. However, in other embodiments heating will be applied in order to provide the lipid(s) in a melted state 2. the at least one active ingredient is dissolved or dispersed therein and rapidly cooled afterwards
  • the above solid lipid mixture is milled to nano-micron size 4.
  • the above mixture is mixed with any optional ingredients, such as surfactant(s), excipient(s) and/or mucoadhesive compound(s) and/or porogen(s) that are added to the mixture either neat or as a solution, preferably as an aqueous solution thereof, 5. thereafter the mixture obtained is subjected to high pressure homogenisation below the melting temperature of the lipid(s), to obtain the solid lipid particles.
  • the shape of the solid lipid particles is not spherical.
  • the shape may be somehow elongate compared to spherical particles.
  • Another aspect of the present invention is a method of producing a powder composition for oromucosal delivery of nicotine comprising the steps of providing a liquid suspension of a plurality of solid lipid particles, the solid lipid particles having a content of nicotine and at least one surfactant, and subjecting the liquid suspension to a drying step and thereby obtaining a powder composition having a content of water below 10.0% by weight of the powder composition.
  • This method may provide a powder composition according to the invention.
  • the drying step comprises freeze drying in presence of a cryoprotectant.
  • Freeze drying according to the invention includes a number of steps.
  • the material to be dehydrated is frozen at a temperature and speed depending upon the type of material.
  • the frozen material is then placed in a chamber which is evacuated to a degree which also depends upon the nature of the material which is to be freeze dried.
  • the second dehydrating phase which is to say after the greatest part of the free water has been eliminated by sublimation, the remainder of the water (compositional water) is eliminated by evaporation.
  • the water which is freed during dehydration is fixed in a condenser which possesses a chilled surface having a temperature of less than 40 (degree) C and dimensions which are determined by the quantity of water to be fixed.
  • the material which has been dehydrated is then enclosed within a sealed package in which there prevails an evacuated or inert atmosphere.
  • the drying step comprises spray drying in presence of an excipient.
  • Spray drying according to the invention is a rapid, one-step process to obtain the solid lipid particles.
  • the drying gas is air, but nitrogen can also be used for special products needing oxygen-free conditions.
  • the most common feed materials are aqueous-based solutions, emulsions and suspensions, where water is evaporated in the dryer.
  • the liquid feed is fed to an atomizer, which is a device that breaks up the liquid stream into tiny droplets. This atomization takes place within the drying chamber so that the droplets are immediately exposed to hot air that initiates rapid moisture evaporation. The droplets become small particles of powder as the moisture is evaporated and they fall to the bottom of the drying chamber.
  • Pressure nozzles, rotary disks, two-fluid nozzles, and the like are used as the atomizing unit.
  • the drying time is as short as 5 to 30 seconds (see, Handbook of Chemistry and Engineering (1999) revised sixth edition, Maruzen Corporation, p. 770, p. 780).
  • a four-fluid nozzle has also been developed, which has enabled mass-scale spray drying with a liquid droplet having a mean particle size of several micrometers.
  • the spray drying method according to the invention is used in many cases of mass scale production.
  • a solution or slurry is fed at a fast feed rate into a spray dryer, while the inlet temperature of the spray dryer and the outlet temperature thereof are elevated as high as possible, to dry the slurry at a high speed.
  • milk is dried at an inlet temperature of the spray dryer of 150 to 250.deg.C and yeast is dried at the inlet temperature of 300 to 350.deg.C. Drying at such high temperatures may negatively impact the flavor of the raw material itself and produce a dry powder with a burned odor.
  • spray drying at a low temperature to avoid these disadvantages can increase process times and costs. See US 2005/0031769 and US Patent No.
  • a spray dryer with a vertical parallel flow function can be used.
  • the spray dryer should be a system with a dehumidifying and drying function.
  • a spray dryer capable of blowing a high volume of desiccated air with a dew point of less than 5.deg.C is particularly preferable.
  • the spray dryer is inevitably arranged with a dry dehumidifier, e.g., a honeycomb-type rotary dehumidifier (e.g., Nichias Corporation or Sweden PROFLUTE Corporation).
  • Suitable spray dryers include the micromist spray dryer and the hybrid granulator series manufactured by Fujisaki Electric Co., Ltd.; the fluidized spray dryer FSD with internal fluid bed as manufactured by Niro Corporation; the fluid granulation spray dryer and L-8 type spray dryer manufactured by Ogawara (Japan); the type spray dryers manufactured by Yamato Scientific Co., Ltd., and Anhydro Spray Bed Dryer manufactured by SPX Corporation.
  • the outlet temperature of the spray drying apparatus is between 20.deg.C and 60.deg.C, preferably 30 to 60.deg.C, and more preferably 40 to 60.deg.C.
  • the outlet temperature of the spray dryer means the product temperature of the dry powder in the vicinity of the powder collection part of the spray dryer.
  • the outlet temperature means the temperature (exhaust gas temperature) at the exhaust part thereof.
  • the average inlet air temperature of the spray drying apparatus is less than 100 .deg.C. In certain embodiments, the average inlet air temperature of the spray drying apparatus is in the range of 40. deg.C to 99. deg.C, more preferably 60. deg.C to 99. deg.C and most preferably 80. deg.C to 99. deg.C.
  • the average inlet air temperature is a sum total of all inlet air streams, e.g., main chamber inlet air and the inlet air to the fluid bed(s).
  • the solid lipid particles are obtained by spray-drying the mixture or drying the mixture in a fluidized bed (e.g. fluid bed-drying).
  • a fluidized bed e.g. fluid bed-drying
  • nicotine is substantially not degraded during the step of freeze drying or spray drying. In another embodiment of the nicotine is degraded less than 1 % during the step of freeze drying or spray drying, such as less than 2% during the step of freeze drying or spray drying, such as less than 5% during the step of freeze drying or spray drying, such as less than 10% during the step of freeze drying or spray drying.
  • Another aspect of the invention provides for an oromucosal delivery system comprising a powder composition according to the invention.
  • the powder composition is added in an amount of 1 to 70%) by weight of the oromucosal delivery system, such as in an amount of 10 to 50%) by weight of the oromucosal delivery system.
  • the powder composition is added in an amount of 5 to 65%) by weight of the oromucosal delivery system, such as in an amount of 7 to 60%o by weight of the oromucosal delivery system, such as in an amount of 10 to 55%) by weight of the oromucosal delivery system, such as in an amount of 15 to 50%o by weight of the oromucosal delivery system,
  • the powder composition is added in an amount of 2 to 50% by weight of the oromucosal delivery system, such as in an amount of 5 to 40% by weight of the oromucosal delivery system, such as in an amount of 7 to 30% by weight of the oromucosal delivery system, such as in an amount of 10 to 25% by weight of the oromucosal delivery system,
  • the powder composition is added in an amount of 10 to 70% by weight of the oromucosal delivery system, such as in an amount of 20 to 65% by weight of the oromucosal delivery system, such as in an amount of 25 to 60% by weight of the oromucosal delivery system, such as in an amount of 30 to 50% by weight of the oromucosal delivery system,
  • the powder composition is compressed and constitutes the oromucosal delivery system. This embodiment is particularly useful if a whole tablet is to be produced in one step. This saves additional processes and it is believed by the inventors that such a one step process may result in even more stable products.
  • the content of water is between 0.2 and 2.0% by weight of the oromucosal delivery system.
  • the oromucosal delivery system is in form of a lozenge, such as a fast disintegrating oral tablet, or the like.
  • the oromucosal delivery system is in form of a chewing gum.
  • the gum base matrix may comprise two or more ingredients selected from the group consisting of elastomers, elastomer plasticizers, resins, polyvinyl acetate, hydrogenated resins, polyterpene, fillers, fats and waxes, or any combination thereof.
  • a preferred amount of gum base matrix in the chewing gum is above 30 percent by weight of the chewing gum, such as above 35 percent by weight of the chewing gum, such as above 40 percent by weight of the chewing gum, such as above 45 percent by weight of the chewing gum, such as about 40 percent by weight of the chewing gum, such as about 47 percent by weight of the chewing gum.
  • composition of gum base formulations can vary substantially depending on the particular product to be prepared and on the desired masticatory and other sensory characteristics of the final product.
  • typical ranges (% by weight) of the above gum base components are: 5 to 80% by weight elastomeric compounds, 5 to 80%) by weight elastomer plasticizers, 0 to 40% by weight of waxes, 5 to 35% by weight softener, 0 to 50% by weight filler, and 0 to 5% by weight of miscellaneous ingredients such as antioxidants, colourants, etc.
  • the gum base may comprise about 5 to about 95 percent, by weight, of the chewing gum, more commonly the gum base comprises 10 to about 60 percent, by weight, of the gum.
  • Elastomers provide the rubbery, cohesive nature to the gum, which varies depending on this ingredient's chemical structure and how it may be compounded with other ingredients.
  • Elastomers suitable for use in the gum base and gum of the present invention may include natural or synthetic types.
  • Elastomer plasticizers vary the firmness of the gum base. Their specificity on elastomer inter-molecular chain breaking (plasticizing) along with their varying softening points cause varying degrees of finished gum firmness and compatibility when used in base. This may be important when one wants to provide more elastomeric chain exposure to the alkane chains of the waxes.
  • the elastomer compounds may be of natural origin but are preferably of synthetic origin, preferably synthetic polyesters.
  • the elastomers (rubbers) employed in the gum base may vary depending upon various factors such as the type of gum base desired, the texture of gum composition desired and the other components used in the composition to make the final chewing gum product.
  • the elastomer may be any water-insoluble polymer known in the art, and includes those gum polymers utilized for chewing gums and bubble gums.
  • suitable polymers in gum bases include both natural and synthetic elastomers.
  • those polymers which are suitable in gum base compositions include, without limitation, natural substances (of vegetable origin) such as chicle gum, natural rubber, crown gum, nispero, rosidinha, jelutong, perillo, niger gutta, tunu, balata, guttapercha, lechi capsi, sorva, gutta kay, and the like, and mixtures thereof.
  • synthetic elastomers include, without limitation, styrene-butadiene copolymers (SBR), polyisobutylene, isobutylene-isoprene copolymers, polyethylene, polyvinyl acetate and the like, and mixtures thereof.
  • the preferred molecular weight of the elastomers is below 500.000 (MW) to give a homogeneous product which is easiler to manufacture and which provides an optimized release profile of pH, and/or active ingredients.
  • Natural resins may be used according to the invention and may be natural rosin esters, often referred to as ester gums including as examples glycerol esters of partially hydrogenated rosins, glycerol esters of polymerised rosins, glycerol esters of partially dimerized rosins, glycerol esters of tally oil rosins, pentaerythritol esters of partially hydrogenated rosins, methyl esters of rosins, partially hydrogenated methyl esters of rosins, pentaerythritol esters of rosins, synthetic resins such as terpene resins derived from alpha-pinene, beta-pinene, and/or d-limonene
  • the resin comprises terpene resins, e.g. derived from alpha-pinene, beta-pinene, and/or d-limonene, natural terpene resins, glycerol esters of gum rosins, tall oil rosins, wood rosins or other derivatives thereof such as glycerol esters of partially hydrogenated rosins, glycerol esters of polymerized rosins, glycerol esters of partially dimerised rosins, pentaerythritol esters of partially hydrogenated rosins, methyl esters of rosins, partially hydrogenated methyl esters of rosins or pentaerythritol esters of rosins and combinations thereof.
  • terpene resins e.g. derived from alpha-pinene, beta-pinene, and/or d-limonene
  • natural terpene resins e.g. derived from alpha-
  • polyterpene resins may be avoided in order to give a homogeneous product which is easiler to manufacture and which provides an optimized release profile of pH, and/or active ingredients.
  • Double sigma blade mixers are used for mixing the gum base with the other components of the formulation.
  • the gum base may be softened in the mixer. By heat (from the heating jacket) and mixing, the gum base becomes plastic. So, the softened base is mixed with the liquid components, e g flavours, liquid, sorbitol and glycerol, optionally an active ingredient, such as nicotine in base form, and the solid materials, optionally active ingredients, such as nicotine in any form other than in liquid form, buffer, bulk sweetener, color as a powder mixture.
  • the warm mass is discharged from the mixer in form of loaves stacked on trays on a truck and stored in a conditioned area until the next step starts. This is to cool the gum.
  • the gum is extruded into a thick sheet, which is rolled by multiple sets of calender rolls to the correct thickness.
  • the scoring rolls usually two sets, cut the gum into the correct size.
  • the sheets are then transferred to a conditioned area on trays, where the sheets are cooled to make them brittle enough to be broken.
  • the conditioned gum sheets are then 20 passed through a breaker, which is a rotating drum that parts the sheets into separate pieces of gum along the scores.
  • said chewing gum formulation comprises said gum base matrix and one or more chewing gum ingredients.
  • said chewing gum ingredients are selected from the group consisting of bulk sweeteners, flavors, dry-binders, tabletting aids, anti- caking agents, emulsifiers, antioxidants, enhancers, absorption enhancers, buffers, high intensity sweeteners, colors, or any combination thereof.
  • the chewing gum formulation comprise one or more chewing gum ingredients selected from the group consisting of bulk sweeteners, flavors, dry-binders, tabletting aids, anti-caking agents, emulsifiers, antioxidants, enhancers, absorption enhancers, buffers, or any combination thereof.
  • Further useful chewing gum base components include antioxidants, e.g. butylated hydroxytoluene (BHT), butyl hydroxyanisol (BHA), propylgallate and tocopherols, and preservatives.
  • antioxidants e.g. butylated hydroxytoluene (BHT), butyl hydroxyanisol (BHA), propylgallate and tocopherols, and preservatives.
  • chewing gum granules are produced and mixed with chewing gum powder obtained through the following steps:
  • chewing gum granules are produced and mixed with chewing gum powder obtained through the following steps:
  • said chewing gum blend is compressed.
  • the different processes may be overall categorized in basically two different processes; that is chewing gum mechanically mixed on the basis of a gum base compounds or chewing gum compressed on the basis of more or less discrete gum base particles.
  • the first type of chewing gum generally benefits from a very comfortable texture, among several different parameters, most likely due to the mechanically mixing of the polymers and for example the flavors.
  • One disadvantage of such type of process and chewing gum is, however, that the different ingredients, such as encapsulated flavor, active ingredients, etc. may be more or less destroyed or degraded by the mixing process.
  • the second type of chewing gum generally benefits from a relatively gentle handling of vulnerable additives, such as the above-mentioned flavors or active ingredients.
  • WO 03/011045 discloses a technique where the sticking or adhering of the chewing gum mixture to the tableting process equipment is dealt with by controlling the size of the mixture granules.
  • Chewing gum tablets are typically manufactured by applying pressure to an amount of powder by suitable compression means. Suitable compression means will be disclosed and explained below. The powder is then compressed into a compact coherent tablet.
  • the powder may for example comprise so-called primary particles or aggregated primary particles, also referred to as granules. When these are compressed, bonds are established between the particles or granules, thereby conferring a certain mechanical strength to the compressed tablet.
  • powder, primary particles and granules may be somewhat misleading in the sense that the difference between primary particles and granules may very often be looked upon differently depending on the background of the user.
  • a sweetener such as sorbitol
  • sorbitol as a primary particle in spite of the fact that sorbitol due to the typically preprocessing performed on sorbitol when delivered to the customer should rather be regarded as some sort of granule.
  • the definition adopted in the description of this invention is that granules refer to macro-particles comprising more or less preprocessed primary particles. It should, however, be noted that this adoption of terms only relates to the description of background prior art and is not mandatory for defining the scope of the invention.
  • the first thing that happens when a powder is compressed is that the particles are rearranged under low compaction pressures to form a closer packing structure.
  • Particles with a regular shape appear to undergo rearrangement more easily than those of irregular shape. As the pressure increases, further rearrangement is prevented and subsequent volume reduction is obtained by plastic and elastic deformation and/or fragmentation of the tablet particles. Brittle particles are likely to undergo fragmentation, i.e. breakage of the original particles into smaller units. Plastic deformation is an irreversible process resulting in a permanent change of particle shape, whereas the particles resume their original shape after elastic deformation. Evidently, both plastic and elastic deformation may occur, when compressing a chewing gum tablet.
  • the compression technique has been preferred by the pharmaceutical industry for the manufacturing of chewing gum.
  • a problem related to the compression technique is that the nature of chewing gum granules is quite different to that of pure pharmaceutical conventional tablet powder.
  • a further, and even more significant problem is that the required texture is basically completely different from that of a tablet intended for completely dissolving within the mouth of the user.
  • this compression technique has been regarded as inferior with respect to the basic texture properties of therewith obtained chewing gum.
  • the powder composition is added as part of a bulk portion after mixing of a gum base matrix.
  • the gum base matrix constitutes 30 to 80% by weight of the chewing gum.
  • the oromucosal delivery system further comprises a buffering agent, such as a pH controlling agent.
  • the powder composition is compressed together with chewing gum base particles to obtain a compressed chewing gum.
  • the oromucosal delivery system is in form of a mouth spray.
  • the oromucosal delivery system is in form of a pouch.
  • the powder composition is being produced by the method according to the invention.
  • examples 1-8 are normalized to 100 ml for easier comparison.
  • the batch size can be increased within the scope of this invention.
  • This solution containing polysorbate, hydrogenated sunflower oil, stearic/palmitic acid and water is transferred either by a syringe or by pouring immediately to the solution described below.
  • 50 mg of poly-vinyl-alcohol (PVA) provided by Nippon Gohsei is dissolved in 98 ml of water by heating to above the melting temperature of the lipid solution containing nicotine, e.g. 80 °C. After about 10 minutes, when the PVA is dissolved in the beaker, the lipid solution containing nicotine is added to obtain an emulsion.
  • PVA poly-vinyl-alcohol
  • This emulsion is homogenized using an Ultra Turrex or similar high shear mixer.
  • the rpm of the mixer is set to the desired value, e.g. 8000 rpm.
  • the rpm of the mixer is set to the desired value, e.g. 8000 rpm.
  • the emulsion is warmed by a hotplate, to avoid premature solidification of lipids caused by lowered temperatures.
  • the duration of the homogenization is about 30-60 minutes.
  • the high shear mixer is removed and the emulsion is allowed to cool at room temperature for 30 minutes, before being transferred to 5 °C for further cooling. As the emulsion cools, the lipid crystallizes and forms small particles resulting in a suspension of solid lipid particles.
  • PVA poly-vinyl-alcohol
  • the emulsion is homogenized for 1 minute with an Ultra Turrex or other similar instrument. Upon creation of the pre-emulsion the liquid changes to a milky white color, this indicates the presence of small particles.
  • the high pressure homogenizer should be pre-warmed to above the melting point of the lipid solution to avoid clogging by solidifying lipids.
  • the crude pre-emulsion is connected to the inlet tube of the homogenizer and the outlet tube is either connected to the same beaker to establish a continuous flow or to another beaker to ensure that the emulsion is homogenized equally. When the flow is established, the pressure is adjusted to the desired level, e.g. 500-1500 bar.
  • the homogenization process runs for 1-20 cycles or 5-120 minutes. After homogenization the homogenizer is emptied by removing the inlet tube from the emulsion. As the emulsion cools, the lipid crystallizes and forms small particles resulting in a suspension of solid lipid particles.
  • Stearic/palmitic acid e.g. Kolliwax® S 6,68 g
  • Nicotine base 0,416 ml
  • Stearic/palmitic acid e.g. Kolliwax® S 6 6, 17 g
  • Nicotine base 0,416 ml
  • Miglyol 812 supplied by Sasol is added to hydrogenated sunflower oil and Kolliwax S before melting. Following this, the production process is as described in example 2.
  • Miglyol 812 has a melting point below 0 °C and is thus a liquid at room temperature. In the cooled solid lipid particles, the Miglyol will as such still be a liquid.
  • the particles in this example have a main body of solidified lipid, with a small amount of liquid lipid interdispersed between the solidified parts.
  • the mono-/diglyceride emulsifier supplied by Kerry Ingredients & Flavours is mixed with the lipids before melting and the mix is heated to a temperature 10 °C above the melting temperature of the lipids. Following this, the production process is as described in example 2.
  • Stearic/palmitic acid e.g. Kolliwax® S 6,68 g
  • Nicotine base 0,416 ml
  • the SDS is dissolved in water followed by heating of the solution to 10 °C above the melting point of the lipids, e.g. 80°C. Following this, the production process is as described in example 2, where the lipid/nicotine solution is poured into the SDS solution.
  • Producing a powder of solid lipid particles by freeze drying a suspension of solid lipid particles A suspension with the following composition and production process described in example 2 is freeze dried to obtain a powder.
  • Stearic/palmitic acid e.g. Kolliwax® S
  • Nicotine base 0,040 ml
  • the primary drying step of the freeze drying is performed below -35 °C, to ensure that freeze drying is performed below the collapse temperature of the suspension.
  • the suspension is freeze dried to a low water content and the resulting product is a white powder.
  • the freeze drying cycle may include an annealing step prior to the drying step, to optimize the drying process. Below is an example of the freeze drying cycle.
  • Example 10 The product is a non-free flowing white powder.
  • Producing a powder of solid lipid particles by freeze drying a suspension of solid lipid particles A suspension with the composition and production process shown in examples 3-8 is freeze dried. The freeze drying is performed at described in example 9.
  • Producing a powder of solid lipid particles by freeze drying a suspension of solid lipid particles with a cryoprotectant e.g. lactose, trehalose or mannitol.
  • a suspension with the following composition and production process described in example 2 is freeze dried to obtain a powder.
  • Stearic/palmitic acid e.g. Kolliwax® S 800 mg
  • the cryoprotectant is dissolved in the suspension and the suspension is freeze dried in bulk trays.
  • the freeze drying cycle is as described in example 9.
  • the result is a non-free flowing white powder.
  • the effect of adding a cryoprotectant is shown in the table below.
  • the average size of the particles is increased from approximately 400 nm in suspension to 10 ⁇ in the final powder.
  • the degradation of nicotine is not affected by the freeze drying process.
  • Example 12 Producing a powder of solid lipid particles by spray drying a suspension of solid lipid particles.
  • a suspension with the compositions and production process described in examples 1-8 is spray dried to obtain a powder.
  • the suspension of solid lipid particles is fed at a high rate and temperature through a nozzle, which atomizes the suspension.
  • the atomized suspension is subjected to drying by contact with hot air e.g. 100 °C that evaporates the water in the suspension, resulting in a dry powder.
  • hot air e.g. 100 °C that evaporates the water in the suspension, resulting in a dry powder.
  • protectants e.g. lactose or trehalose can be added to the suspension avoid agglomeration of particles.
  • the powder obtained from examples 9-12 can be used in a formulation intended for oral use.
  • This formulation could be a lozenge where the powder is mixed with flavors, sweeteners and buffer systems.
  • the final composition of such a lozenge is shown in the following table.
  • a batch size could be e.g. 1-10 kg equivalent to 2000-20000 tablets.
  • magnesium stearate is added to the tablet machine.
  • the magnesium stearate will be sprayed onto the pistons while tableting.
  • the raw material mixture is filled into the tablet press feed hopper. Tablets are compressed with a speed of 8-12 rpm and a pressure of 25 kN (acceptance criteria 20-30 kN) and the weight is adjusted by means of the filling depth, until the weight of 10 tablets is 5,00 g+/- 0, 12g.
  • the feed hopper continuously filled to ensure that it does not run empty during the compression process.
  • the nicotine contained in the lozenge is released in the oral cavity upon sucking and chewing it.
  • the powder obtained from examples 9-12 can be used in a formulation intended for oral use.
  • This formulation could be a compressed gum, where one layer contains the gum base and the second layer contains flavor and sweetener.
  • the solid lipid particles can be placed in either layer.
  • Table 2 Composition of compressed gum with solid lipid particles in layer 1 Polysorbate 60 3,0
  • a batch size could be e.g. 1-10 kg equivalent to 700-7000 tablets.
  • the two layers are dry mixed separately. First approximately half of the isomalt is added to a mixing bin. The remaining ingredients, including the active pharmaceutical ingredient, are sieved and added to the mixing bin. Finally the last half of isomalt is sieved in to the mixing bin. The powder blend is mixed in by the Turbula for 5 minutes.
  • magnesium stearate is added to the tablet machine.
  • the magnesium stearate will be sprayed onto the pistons while tableting.
  • the raw material mixtures are filled into the tablet press feed hoppers. Tablets are compressed with a speed of 8-12 rpm and a precompression pressure of 2-3 kN and a main compression pressure of 25 kN (acceptance criteria 20-30 kN).
  • the weight is adjusted by means of the filling depth of chamber 2, until the weight of 10 tablets is 14,00 g+/- 0,35g.
  • the feed hoppers continuously filled to ensure that it does not run empty during the compression process. The tableting procedure is stopped when the powder is just above the hopper product censor.

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Abstract

La présente invention concerne des compositions de poudre inattendues et améliorées pour l'administration oromucosale de nicotine, comprenant une pluralité de particules lipidiques solides, les particules lipidiques solides ayant une teneur en nicotine et au moins un tensioactif, et la composition de poudre ayant une teneur en eau inférieure à 10,0 % en poids de la composition de poudre.
PCT/DK2014/050444 2013-12-20 2014-12-18 Composition de poudre de nicotine Ceased WO2015090337A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022216323A1 (fr) * 2021-04-06 2022-10-13 Altria Client Services Llc Nicotine séchée par pulvérisation pour inclusion dans des produits detinés à être utilisés par voie orale
RU2812603C1 (ru) * 2019-10-11 2024-01-30 Фертин Фарма А/С Ионообменная композиция с водорастворимыми мукоадгезивными полимерами
US11896711B2 (en) 2019-12-09 2024-02-13 Nicoventures Trading Limited Process of making nanoemulsion
US12137723B2 (en) 2019-12-09 2024-11-12 Nicoventures Trading Limited Oral products with active ingredient combinations
US12295412B2 (en) 2022-01-28 2025-05-13 Altria Client Services Llc Oral pouch product
USD1081739S1 (en) 2021-04-06 2025-07-01 Altria Client Services Llc Die for gum forming
EP4420529A4 (fr) * 2021-10-19 2025-08-20 Japan Tobacco Inc Composition orale contenant du tréhalose

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999015171A1 (fr) * 1997-09-25 1999-04-01 Pharmacia & Upjohn Ab Compositions de nicotine et leur procede de formulation
WO2007113665A2 (fr) * 2006-04-05 2007-10-11 Transgene Biotek Limited Nanoparticules lipidiques solides polymerisees pour la liberation par voie orale ou muqueuse de proteines et de peptides therapeutiques
WO2007118653A2 (fr) * 2006-04-11 2007-10-25 Koko Kosmetikvertrieb Gmbh & Co. Kg Nanoparticules contenant de la nicotine et/ou de la cotinine, dispersions et leur utilisation
WO2012134380A1 (fr) * 2011-03-29 2012-10-04 Chill Of Sweden Ab Sachet contenant de la nicotine sous forme de sel libre
WO2014135630A1 (fr) * 2013-03-07 2014-09-12 Danmarks Tekniske Universitet Systèmes d'administration par voie oro-muqueuse de nano-microparticules d'un principe actif

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999015171A1 (fr) * 1997-09-25 1999-04-01 Pharmacia & Upjohn Ab Compositions de nicotine et leur procede de formulation
WO2007113665A2 (fr) * 2006-04-05 2007-10-11 Transgene Biotek Limited Nanoparticules lipidiques solides polymerisees pour la liberation par voie orale ou muqueuse de proteines et de peptides therapeutiques
WO2007118653A2 (fr) * 2006-04-11 2007-10-25 Koko Kosmetikvertrieb Gmbh & Co. Kg Nanoparticules contenant de la nicotine et/ou de la cotinine, dispersions et leur utilisation
WO2012134380A1 (fr) * 2011-03-29 2012-10-04 Chill Of Sweden Ab Sachet contenant de la nicotine sous forme de sel libre
WO2014135630A1 (fr) * 2013-03-07 2014-09-12 Danmarks Tekniske Universitet Systèmes d'administration par voie oro-muqueuse de nano-microparticules d'un principe actif

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2812603C1 (ru) * 2019-10-11 2024-01-30 Фертин Фарма А/С Ионообменная композиция с водорастворимыми мукоадгезивными полимерами
US11896711B2 (en) 2019-12-09 2024-02-13 Nicoventures Trading Limited Process of making nanoemulsion
US12137723B2 (en) 2019-12-09 2024-11-12 Nicoventures Trading Limited Oral products with active ingredient combinations
US12318479B2 (en) 2019-12-09 2025-06-03 Nicoventures Trading Limited Process of making nanoemulsion
WO2022216323A1 (fr) * 2021-04-06 2022-10-13 Altria Client Services Llc Nicotine séchée par pulvérisation pour inclusion dans des produits detinés à être utilisés par voie orale
USD1081739S1 (en) 2021-04-06 2025-07-01 Altria Client Services Llc Die for gum forming
EP4420529A4 (fr) * 2021-10-19 2025-08-20 Japan Tobacco Inc Composition orale contenant du tréhalose
US12295412B2 (en) 2022-01-28 2025-05-13 Altria Client Services Llc Oral pouch product
US12484617B2 (en) 2023-12-08 2025-12-02 Altria Client Services Llc Oral pouch product

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