WO2023049693A2 - Formes posologiques pour l'administration d'un probiotique - Google Patents
Formes posologiques pour l'administration d'un probiotique Download PDFInfo
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- WO2023049693A2 WO2023049693A2 PCT/US2022/076693 US2022076693W WO2023049693A2 WO 2023049693 A2 WO2023049693 A2 WO 2023049693A2 US 2022076693 W US2022076693 W US 2022076693W WO 2023049693 A2 WO2023049693 A2 WO 2023049693A2
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- infant
- bifidobacterium
- billion
- prebiotic
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Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/30—Dietetic or nutritional methods, e.g. for losing weight
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
Definitions
- the present invention generally relates to dosage forms and methods for the delivery of an effective amount of a probiotic including Bifidobacterium to a patient.
- Probiotics are live microorganisms that are intended to have health benefits when consumed or applied to the body. Probiotics may be administered to address a myriad of health conditions including infantile digestive health, colic, and sleep. Probiotics are also increasingly administered to support immune health and prevent atopic diseases, including atopic dermatitis and food allergy (Sestito et al. Front, in Pediatr. 22 December 2020; Henrick et al. Cell 22 July 2021 184(15): p. 1-15).
- Probiotics are found in infant formulas, supplements and food products for babies or children. These probiotics typically consist of Bifidobacterium, including the species B. longum, B. breve, B. bifidum, B. pseudocatenulatum, B. globosum, B. adolescentis, B. moukalabense, B. reuteri, B. pseudoIongum, B. dentium, B. catenulatum, B. sp002742445, B. callitrichos, B. scardovii, B. tissieri, B. subtile, B. gallinarum, B. choerinum, B. angulatum, B. primatium, B.
- Bifidobacterium including the species B. longum, B. breve, B. bifidum, B. pseudocatenulatum, B. globosum, B. adolescentis, B. moukalabense, B. reuter
- kashiwanohense_A B. italicum, B. imperatoris, B. cricetid, B. catulorum, B. callitrichidarum, B. animalis, B. aesculapii, and combinations thereof.
- Bifidobacterium have the ability to break down complex oligosaccharides that are found in human milk (see US Patent No. 8,198,872 and US Pub. No. 2013/01958031; Sela et al, 2008, PNAS, 105(48): p. 18964-69).
- the suitable Bifidobacterium may be those having at least one human milk oligosaccharides (HMO) gene cluster.
- the fermentation product from Bifidobacterium production may be concentrated and freeze dried to provide a concentrated powder.
- the powder may be packaged in a sachet or suspended in an edible oil.
- US Patent No. 10,716,8176 describes a method for obtaining an active Bifidobacterium composition.
- Similac® Probiotic Tri-Blend available from Abbott (Abbott Park, IE) which is a powder containing Bifidobacterium lactis, Bifidobacterium inf antis and Streptococcus thermophilus.
- Evivo® available from Evolve BioSystems (Davis, CA) which contains Bifidobacterium infantis. Evivo is available as a powder or a medium-chain triglyceride oil (MCT oil) suspension.
- MCT oil medium-chain triglyceride oil
- Bifidobacterium and other probiotics may be most effective for their intended purpose when co-administered with a prebiotic, vitamins or supplements and/or food allergen or food introduction products. Accordingly, there is an ongoing need for stable dosage forms that include both a probiotic and one or more additional components and/or kits that include both a probiotic and one or more additional components.
- the Bifidobacterium of the present invention and/or combinations of Bifidobacterium with other probiotics may be incorporated into several different types of dosage forms. These forms include soft gelatin capsules or softgels, wherein the Bifidobacterium is incorporated into the fill material prior to encapsulation in a gelatin based shell or capsule.
- the shell may also be comprised of a shell material which dissolves in liquid other than gelatin, such as a polymer or those derived from starch. Suitable polymers for a shell may include hypromellose, hydroxypropyl cellulose, polymethacrylate(s), pullulan and methylcelllose.
- the soft gel may include a twist off portion, cap or feature to facilitate opening, so as to expose the fill for direct ingestion, incorporation into a food or other edible medium, or for application to the skin of a caregiver, to the oral cavity, cheek or gums of an infant or to the surface of a delivery device such as an artificial nipple or pacifier.
- the Bifidobacterium may also be incorporated into an edible semisolid for ingestion or direct application to the skin.
- This edible semisolid may be in the form of an emulsion, topical gel, cream, paste, ointment or balm and incorporate at least one lipid material.
- This edible semisolid may be fully anhydrous.
- the semisolid is applied to the skin for the ingestion of the Bifidobacterium during infant nursing.
- This application method may comprise different steps.
- the composition may be applied directly to the nipple or surrounding skin area of the caregiver or parent.
- the composition may also be mixed or diluted in a liquid such as infant formula or breastmilk and subsequently applied to the nipple or surrounding skin area.
- the composition may also be applied or pre-applied, e.g. loaded into a pacifier or artificial nipple for ingestion.
- the pacifier or artificial nipple may comprise one portion of the composition such as a prebiotic, wherein the probiotic is administered in a separate portion. This separate portion could be provided through direct oral administration to an infant, or through application to the nipple, surrounding skin or finger.
- the topical gel can be placed on a caregiver’s finger and applied directly to the infant’s gums or cheek.
- the Bifidobacterium may also be incorporated into a solid powder or tablet that is substantially free of lactose. As defined herein free of lactose or lactose-free is defined as less than 1.0 percent, e.g. less than 0.2 percent of lactose by weight of the form.
- Solid dosage forms of the present invention may also include dispersible tablets, or tablets that can be placed into a liquid medium and dissolved prior to administration.
- Solid dosage forms of the present invention may also include dissolvable tablets which can be dissolved in a liquid or semisolid medium prior to administration.
- Other solid dosage forms include powder compositions which can be incorporated directly into a liquid or semisolid medium prior to administration.
- powder compositions may be packaged as individual dose(s) in a sachet, pouch, bottle or blister prior to administration.
- the powder composition may also be incorporated in a hard shell capsule or within a dissolvable capsule shell, which can be opened manually or dissolved in a liquid or semisolid prior to administration.
- Semisolids for the purpose of incorporating the composition or the present invention may include creams, oils, or pureed or blended foods comprising fruits and vegetables.
- an alternative inert powder carrier may be utilized.
- Suitable inert powder carriers include starch(es), cellulose(s), sugars and sugar alcohols.
- the Bifidobacterium is incorporated into dosage forms that contain an antioxidant such as vitamin C, vitamin E, beta-carotene, cysteine, propyl gallate, butylated hydro y toluene (B HT).
- an antioxidant such as vitamin C, vitamin E, beta-carotene, cysteine, propyl gallate, butylated hydro y toluene (B HT).
- the Bifidobacterium containing dosage forms include a prebiotic such as an oligosaccharide or synthetic equivalent.
- the Bifidobacterium containing dosage forms include a vitamin, supplement or mineral.
- the Bifidobacterium containing dosage forms include a food allergen or food introduction product such as an allergen selected from the group of cow milk, egg, peanut, wheat, soy, sesame, fish, shellfish and tree nut.
- probiotic refers to live microorganisms which when administered in adequate amounts confer a health benefit on the host. These probiotic strains generally have the ability to survive the passage through the upper part of the digestive tract. They are non-pathogenic, non-toxic and exercise their beneficial effect on health on the one hand via ecological interactions with the resident flora in the digestive tract, and on the other hand via their ability to influence the immune system positively. Depending on the composition of probiotics, these microorganisms, when given in a sufficient number, have the ability to progress live through the intestine, however they do not cross the intestinal barrier and their primary effects are therefore induced in the lumen and/or the wall of the gastrointestinal tract.
- This colonization allows the probiotic microorganisms to exercise a beneficial effect, such as the repression of potentially pathogenic micro-organisms present in the flora and interactions with the immune system of the intestine.
- the term “effective amount” means an amount sufficient to induce the desired effect.
- safe amount means an amount that is low enough to avoid serious side effects.
- the safe and/or effective amount of the compound, extract, or composition will vary with, e.g., the age, health and environmental exposure of the end user, the duration and nature of the treatment, the specific extract, ingredient, or composition employed, the particular pharmaceutically-acceptable carrier utilized, and like factors.
- “essentially free” or “substantially free” of an ingredient means containing less than 0.1 weight percent, or less than 0.01 weight percent, or none of an ingredient.
- percentages used to express amounts of ingredients are percentage by weight (referred to as “weight %”, “wt%”, “% by weight” or “% (w/volume)”).
- weight ratios used to express relative proportions of ingredients are also determined using percentage by weight (i.e., weight ratios are calculated by dividing the percentage by weight of one ingredient by another).
- the Bifidobacterium species may include B. longum, B. breve, B. bifidum, B. pseudocatenulatum, B. globosum, B. adolescentis, B. moukalabense, B. reuteri, B. pseudoIongum, B. dentium, B. catenulatum, B. sp002742445, B. callitrichos, B. scardovii, B. tissieri, B. subtile, B. gallinarum, B. choerinum, B. angulatum, B. primatium, B. myosotis, B. mongoliense, B. merycicum, B. lemurum, B.
- the Bifidobacterium may be formulated into a composition which is easy to use and allows for consistent dosing.
- the fermentation product from Bifidobacterium production may be concentrated and freeze dried to provide a concentrated powder.
- the composition may contain about 1 million, 500 million, 1 billion, 2 billion, 3 billion, 4 billion, 5 billion, 6 billion, 7 billion, 8 billion, 9 billion, 10 billion or 12 billion to about 8 billion, 9 billion, 10 billion, 20 billion, 30 billion, 40 billion, 50 billion, 60 billion, 70 billion, 80 billion, 90 billion, 100 billion, 200 billion, 250 billion or 500 billion colony forming units (CFU) of Bifidobacterium per gram dry weight.
- CFU colony forming units
- the Bifidobacterium may also be formulated with a prebiotic.
- prebiotic refers to a substance that is indigestible to a host, but can be metabolized by a microorganism, and once metabolized can promote the growth of that microorganism within a host.
- Prebiotic refers to an ingredient that allows specific changes in the composition and/or activity in the gastrointestinal microbiota.
- a prebiotic can be a comestible food or beverage or ingredient thereof.
- Prebiotics can include complex carbohydrates, amino acids, peptides, minerals, or other essential nutritional components for the survival of the bacterial composition.
- Prebiotics include, but are not limited to, amino acids, biotin, fructooligosaccharide, galactooligosaccharides, hemicelluloses (e.g., arabinoxylan, xylan, xyloglucan, and glucomannan), inulin, chitin, lactulose, mannan oligosaccharides, oligofructose-enriched inulin, gums (e.g., guar gum, gum arabic and carregenaan), oligofructose, oligodextrose, tagatose, resistant maltodextrins (e.g., resistant starch), trans-galactooligosaccharide, pectins (e.g., xylogalactouronan, citrus pectin, apple pectin, and rhamnogalacturonan-I), dietary fibers (e.g., soy fiber, sugarbeet fiber, pea
- Prebiotics that can be metabolized by Bifidobacterium include oligosaccharides.
- oligosaccharide refers to a saccharide polymer containing 2 to 20, 2 to 10, 3 to 20 or 3 to 10 monosaccharide units.
- the oligosaccharide may be those naturally found in a mammalian milk (e.g., human, or bovine) known as human milk oligosaccharides, human milk glycans or “HMOs.”
- HMOs human milk oligosaccharides
- the oligosaccharide may be synthesized.
- HMOs There are a number of commercially available HMOs including GlycanTM products offered by DSM Nutritional Products AG.
- Prebiotics that can be metabolized by Bifidobacterium also include synthetic molecules that are structurally distinct from yet functionally equivalent to natural HMOs such as lacto-N-tetraose (LNT) and 2’-fucosyllactose (2’-FL).
- LNT lacto-N-tetraose
- 2’-fucosyllactose 2’-FL
- the composition containing the Bifidobacterium may also contain an auxiliary component.
- auxiliary component are those commonly used in the art and may be selected from metabolites, flow agents or combinations thereof. Examples of flow agents include starch, silicon dioxide, cellulose, sodium bicarbonate, calcium silicate and the like.
- the auxiliary component may also be a milk protein or constituent.
- the auxiliary component may comprise lactose. That is, in such an example, the Bifidobacterium is in powder form mixed with lactose and derivatives thereof. Lactose derivatives may include lactulose, lactitol, lactobionic acid, galacto-oligosaccharides (GOS), lactose monohydrate and tagatose.
- GOS galacto-oligosaccharides
- the composition may also be substantially free of lactose to mitigate lactose sensitivity.
- Suitable lactose substitutes include starch(es), cellulose(s), sugars and sugar alcohols.
- the composition containing the Bifidobacterium may also contain an antioxidant. Examples of antioxidants include vitamin C, vitamin E, beta-carotene, cysteine, propyl gallate, butylated hydroxytoluene (BHT).
- BHT butylated hydroxytoluene
- the final form of the composition containing the antioxidant can be any known in the art.
- the Bifidobacterium may be in dried form (e.g., spray-dried or freeze-dried) as a powder. Said powder may be dosed as a packet, sachet, tablet, foodstuff, capsule, lozenge, tablet, suspension, dry form, etc.
- the final form of the composition may additionally comprise a vitamin, supplement or mineral.
- Suitable vitamins, supplements and minerals may include but are not limited to vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, iron, omega 3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) essential fatty acids, magnesium salts, calcium salts and potassium salts.
- EPA eicosapentaenoic acid
- DHA docosahexaenoic acid
- the final form of the composition may additionally comprise a food allergen or food introduction product.
- suitable food allergens include cow milk, egg, peanut, wheat, soy, sesame, fish, shellfish and tree nut.
- the final form of the composition may be stable up to at least 24 months when stored at 25°C and 65% relative humidity (RH), or at least 12 months when stored at 25°C and 65% relative humidity (RH), or at least 6 months when stored at 25°C and 65% relative humidity (RH) or at least 3 months when stored at 40°C and 75% relative humidity (RH), or at least 1 month when stored at 40°C and 75% relative humidity (RH), or at least 6 months when stored at 50°C.
- the final form of the composition may not comprise added sugar, or may be substantially free of added sugar, or be defined as comprising “no added sugars”. If a prebiotic is added to the composition and wherein the prebiotic portion comprises a carbohydrate or sugar, the probiotic portion may be separate and may not comprise added sugars or be substantially free of added sugar.
- the excipients of the final form of the composition may be derived directly from plants or sourced directly from plants, so as to be defined as “plant-based”.
- the excipients of the final form of the composition may also be sourced from non-genetically modified organisms (“non-GMO”). At least 95% of the excipients of the final form of the composition may be plant-based or non-GMO.
- the emulsion or semi-solid composition containing the Bifidobacterium may also contain ingredients suitable for skin in need of improving skin barrier function and moisturization or for soothing or protecting against skin irritation such as hyaluronic acid, glycerin, petrolatum and propylene glycol.
- skin in need of improving skin barrier function and moisturization means skin that is, but not limited to, lacking in moisture, lacking in sebum, cracked, dry, itchy, scaly, xerodermic, dehydrated, lacks suppleness, lacks radiance, dull, or lacks lipids.
- oils may be used as a carrier within the emulsion or edible semi-solid composition comprising the Bifidobacterium.
- Carriers may include but are not limited to vegetable oils, fish oil, olive oil, soy oil, nut oil, mineral oil, and avocado oil. Additional carriers include glyceryl behenate and glyceryl stearate.
- the composition may comprise 5 percent to 95 percent by weight of the carrier, e.g. 30 percent to about 90 percent by weight of the carrier.
- emulsifier refers to an ingredient that helps keep ingredients (such as oil and water) from separating in an emulsion.
- the composition may comprise emulsifiers such as waxes, beeswax, microcrystalline wax, lecithin, esters (PGE), polysorbates, stearoyl lactylates, propylene glycol esters (PGMS), and sucrose esters.
- the emulsion or edible semi-solid of the present invention may be added to a soft gel.
- the soft gel may be for direct administration, reconstitution in a liquid, or as a carrier for administration to a skin surface.
- the soft gel form has a twist-off portion, cap or feature so as to expose the emulsion or edible semi-solid fill for direct ingestion, incorporation into a food or other edible medium, or for application to the skin of a caregiver, to the oral cavity, cheek or gums of an infant or to the surface of a delivery device such as an artificial nipple or pacifier.
- the portion of the composition which comprises the Bifidobacterium inf antis may be provided in the form of a nanoemulsion or coated particle, so as to protect the Bifidobacterium infantis from oxygen, water or the surrounding composition.
- Suitable coating technologies include microencapsulation compositions, such as those documented in US Patent 11,433,107 documented herein by reference.
- Suitable nanoemulsion compositions include but are not limited to those types documented in US Patent 8,993,019 documented herein by reference.
- the Bifidobacterium may be added to the composition and delivered as a solid form.
- solid form may be defined as an orally disintegrating tablet, a dissolvable tablet or powder composition.
- the solid form may be administered directly to an infant, or dissolved, or mixed in another composition such as a liquid or semi-solid prior to administration.
- the solid form may comprise various excipients.
- suitable excipients include, but are not limited to, fillers, adsorbents, disintegrants, lubricants, glidants, sweeteners, superdisintegrants, flavor and aroma agents, antioxidants, preservatives, texture enhancers, and mixtures thereof.
- One or more of the above ingredients may be present on the same particle of the powder blend.
- Suitable fillers include, but are not limited to, carbohydrates (as discussed herein) and water insoluble plastically deforming materials (e.g., microcrystalline cellulose or other cellulosic derivatives), and mixtures thereof.
- Suitable disintegrants include, but are not limited to, sodium starch glycolate, crosslinked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose, and mixtures thereof.
- Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof.
- Suitable glidants include, but are not limited to, colloidal silicon dioxide.
- sweeteners include, but are not limited to, synthetic or natural sugars; artificial sweeteners such as saccharin, sodium saccharin, aspartame, acesulfame, thaumatin, glycyrrhizin, sucralose, dihydrochalcone, alitame, miraculin, monellin, and stevside; sugar alcohols such as sorbitol, mannitol, glycerol, lactitol, maltitol, and xylitol; sugars extracted from sugar cane and sugar beet (sucrose), dextrose (also called glucose), fructose (also called laevulose), and lactose (also called milk sugar); isomalt, salts thereof, and mixtures thereof.
- artificial sweeteners such as saccharin, sodium saccharin, aspartame, acesulfame, thaumatin, glycyrrhizin, sucralose, dihydr
- superdisintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and cross-linked povidone (crospovidone).
- the tablet contains up to about 5% by weight of such superdisintegrant.
- flavors and aromatics include, but are not limited to, essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit containing mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavor of the fruit (e.g., strawberry, raspberry and black currant); artificial and natural flavors of brews and liquors, e.g., cognac, whisky, rum, gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; spear mint, pepper mint, wintergreen, cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts), almonds
- essential oils including
- antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.
- preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof.
- the solid form contains at least one carbohydrate.
- the carbohydrate can contribute to the dis solvability and mouth feel of the tablet, aid in distributing the meltable binder across a broader surface area, and diluting and cushioning the pharmaceutically active agent.
- carbohydrates include, but are not limited to, water-soluble compressible carbohydrates such as sugars (e.g., dextrose, sucrose, maltose, isomalt, and lactose), starches (e.g., corn starch), sugar-alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, lactitol, and xylitol), and starch hydrolysates (e.g., dextrins, and maltodextrins).
- sugars e.g., dextrose, sucrose, maltose, isomalt, and lactose
- starches e.g., corn starch
- sugar-alcohols e.g., mannitol, sorbitol, maltitol, erythritol, lactitol, and xylitol
- starch hydrolysates e.g.
- the final form of the composition may be packaged into a blister, bottle, vial or sachet and may be packaged under nitrogen.
- the composition may be packaged into a dispenser which does not allow for the composition to come in contact with oxygen or air, or allow for the introduction of air upon dispensing.
- This type of dispensing may be achieved with dispensers such as those supplied by Aptar corporation (Aptarinc), marketed under their “Airless” pump technologies, also documented in US Patent 11,213,843, and documented herein by reference.
- the Bifidobaacterium inf antis are monocoated with polyglyceryl distearate (Plurol Stearique WE1009) according to the process described in Italian Patent Application No. RM2009A000104
- beeswax is melted in soy oil at about 65°C. Soy lecithin is then added to the mixture and the combined formulation cooled at less than or about 25 °C.
- microencapsulated probiotic bacteria were suspended in the cooled suspending formulation of soy oil, bees wax and soy lecithin and mixed at less than 25 °C for 10 minutes.
- the mixed fill is milled while maintaining the temperature below 25 °C for 10 minutes, while under vacuum and under nitrogen to prevent oxidation of the formulation.
- the milled fill is then encapsulated in a soft gelatin capsule using a standard rotary die encapsulation machine as follows: the milled fill and the shell material were loaded into separate receivers connected to the machine.
- the machine prepared from the molten shell material two bands of solid ribbons, which are cooled and lubricated with a mixture of medium chain triglycerides and lecithin.
- the bands are directed into the position of two rotating dies having specific pockets of the required size and shape for formation of the capsule.
- the continuing contra-rotation of the opposed dies form a seal between the two ribbons contacting the dies while the fill material is simultaneously injected into the body of the capsule so formed.
- the continuing rotation of the dies cuts the newly formed capsule from the ribbon.
- Blending The blend(s) is prepared as follows (according to formula in Table 2):
- the coconut oil, shea butter are added to a suitable vessel and preblended until sufficiently uniform at 60°C.
- the corn starch is added while mixing at 100RPM.
- the Bifidobacterium inf antis is added to the mixture from Step 2 and mixed at 25°C until uniform at relatively low speed (less than 100 RPM).
- the blend is added to individual vials under nitrogen and capped.
- Blending The blend(s) is prepared as follows (according to formula in Table 3):
- the magnesium stearate and remaining Pearlitol Flash are passed through a 30 mesh screen and added and blended for additional 5 minutes.
- Part B Compression: The blend is compressed into tablets using round tooling to a hardness of 5.0 kP
- Blending The blend(s) is prepared as follows (according to formula in Table 4):
- Bifidobacterium infantis are passed through a 60 mesh screen to de-lump the materials.
- step 2 The materials from step 1 are placed into a suitable V-blender and blended for 10 minutes. 3. The magnesium stearate is screened through a 30 mesh screen and added and blended for additional 5 minutes. The final blend is discharged into a plastic bag.
- Part B Compression: The blend is compressed into tablets using round tooling to a hardness of 5.0 kP.
- administering refers to providing a given dose of Bifidobacterium to infants as part of their feeding routine (/'. ⁇ ?., it is used as a food supplement).
- the Bifidobacterium may be administered to the infant in the dosage form provided or mixed with any medium that can be consumed by the infant, including breast milk, infant formula, water or food prior to administering the Bifidobacterium to the infant.
- the Bifidobacterium may be mixed into breastmilk.
- the Bifidobacterium may be mixed into infant formula prior to administering the Bifidobacterium to the breastfed infant.
- the Bifidobacterium is mixed with enough infant formula or breastmilk so that the infant is able to completely incorporate the Bifidobacterium and so that the infant is still likely and able to consume the entire dose of Bifidobacterium.
- the Bifidobacterium may be mixed with about 3 to about 5 mL of breastmilk or infant formula prior to administering the Bifidobacterium to the breastfed infant.
- the Bifidobacterium composition may be mixed by any suitable means, including simply stirring (or any other suitable means to obtain a mixture) the composition with the medium (e.g., infant formula, breast milk, water) in a bowl.
- the composition mixed with infant formula or breastmilk may then be fed to the infant by any suitable means.
- Suitable means of feeding to the infant include use of a feeding syringe, spoon, or bottle.
- the Bifidobacterium may be administered prior to feeding the infant when the infant is more likely to be hungry, which is thought to increase the likelihood of the infant consuming the entirety of the dose.
- the Bifidobacterium dosage form may be administered to the infant directly without mixing with breast milk, formula or water.
- the Bifidobacterium dosage form may be applied directly to the mother’s skin prior to breastfeeding.
- the Bifidobacterium dosage form may be applied directly to a bottle nipple or pacifier prior to feeding.
- the Bifidobacterium dosage form may be applied to a finger or flexible dosing device and applied directly inside the infant’s mouth on the gums or cheeks.
- the composition may also be applied or pre-applied, e.g. loaded into a pacifier or artificial nipple for ingestion.
- the pacifier or artificial nipple may comprise one portion of the composition such as a prebiotic, wherein the probiotic is administered in a separate portion. This separate portion could be provided through direct oral administration to an infant, or through application to the nipple, surrounding skin or finger.
- the dose and dosing frequency may be selected as desired.
- the Bifidobacterium may be administered once daily.
- the dose once daily may contain from about 5-15 billion or about 8 billion CFU.
- Splitting the total desired dose into smaller doses is also contemplated. Examples could include smaller doses several times throughout the day (e.g., 2, 3, 4 or 5 times per day).
- the total dose given per day may range from about 1 million, 500 million, 1 billion, 2 billion, 3 billion, 4 billion, 5 billion, 6 billion, 7 billion, 8 billion, 9 billion, 10 billion or 12 billion to about 8 billion, 9 billion, 10 billion, 20 billion, 30 billion, 40 billion, 50 billion, 60 billion, 70 billion, 80 billion, 90 billion, 100 billion, 200 billion, 250 billion or 500 billion colony forming units (CFU) of the Bifidobacterium.
- CFU colony forming units
- the total dose given per day may range from about 5 to about 15 billion CFU, or be about 8 billion CFU. Such total dose values may be given in one dose.
- the Bifidobacterium may be administered beginning on the 1 st , 2 nd , 3 rd , 4 th , 5 th , 6 th day or first week of life, or beginning within the first 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks of life, or beginning with the first 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months of life.
- the term “of life” means after birth.
- the Bifidobacterium may continue to be administered until the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th week of life, or until the 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th or 12th month of life.
- the Bifidobacterium may be first administered within the first 2 weeks of life.
- the Bifidobacterium may be first administered within the first 2 weeks of life and until the 12th week of life.
- the infants may be breastfed infants or formula fed infants or combinations of both.
- the term “breastfed” means that the infant derives at least some of its sustenance from human breastmilk.
- the infant may either nurse or the breastmilk may be expressed e.g., pumped or hand-expressed) and given to the infant.
- the breastfed infant may be at least about 50, 60, 75, 80, 90% or 95% breastfed.
- the remainder of the infant’s sustenance may be derived from infant formula or other food.
- the breastfed infant may be exclusively breastfed.
- the term “exclusively breastfed” means that the infant does not receive infant formula, except that small amounts of infant formula may be used for the sole purpose to mix with the Bifidobacterium and administer to the infant.
- any caloric contribution from other sources during the first 3 months of life, including medicines, the Bifidobacterium composition, or any medium used to deliver the Bifidobacterium, etc. may be considered negligible.
- the Bifidobacterium dosage form contains prebiotics such as oligosaccharides.
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Abstract
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AU2022349055A AU2022349055A1 (en) | 2021-09-24 | 2022-09-20 | Dosage forms for the delivery of a probiotic |
CN202280064737.2A CN118042943A (zh) | 2021-09-24 | 2022-09-20 | 用于递送益生菌的剂型 |
CA3233094A CA3233094A1 (fr) | 2021-09-24 | 2022-09-20 | Formes posologiques pour l'administration d'un probiotique |
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US202163261581P | 2021-09-24 | 2021-09-24 | |
US63/261,581 | 2021-09-24 | ||
US17/933,174 US20230096810A1 (en) | 2021-09-24 | 2022-09-19 | Dosage forms for the delivery of a probiotic |
US17/933,174 | 2022-09-19 |
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