WO2019221598A1 - Composition comprising dehydrated liposomes with nutritional supplement - Google Patents
Composition comprising dehydrated liposomes with nutritional supplement Download PDFInfo
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- WO2019221598A1 WO2019221598A1 PCT/NL2019/050280 NL2019050280W WO2019221598A1 WO 2019221598 A1 WO2019221598 A1 WO 2019221598A1 NL 2019050280 W NL2019050280 W NL 2019050280W WO 2019221598 A1 WO2019221598 A1 WO 2019221598A1
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- Prior art keywords
- vitamin
- composition according
- vesicles
- nutritional supplement
- composition
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- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 claims description 26
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- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 claims 3
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- QVDYYQXUNAQSNI-UHFFFAOYSA-N ethyl acetate;pentane Chemical compound CCCCC.CCOC(C)=O QVDYYQXUNAQSNI-UHFFFAOYSA-N 0.000 description 1
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- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
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- CONVKSGEGAVTMB-RXSVEWSESA-M potassium-L-ascorbate Chemical compound [K+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] CONVKSGEGAVTMB-RXSVEWSESA-M 0.000 description 1
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- 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
-
- 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
- A23L33/15—Vitamins
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- composition comprising dehydrated liposomes with nutritional supplement
- the current invention relates to a composition for oral administration to a subject, comprising dehydrated liposomal vesicles, wherein the dehydrated liposomal vesicles comprise a nutritional supplement, and to a method for preparing the composition.
- liposomes loaded with drug molecules are commonly prepared as aqueous dispersions.
- a problem with these dispersions is that they only have limited physical stability.
- the liposomes can aggregate and precipitate as sediment. Additionally, on storage the biologically active compounds may be lost into the external aqueous phase.
- US 4830858 discloses a method for preparing a spray-dried mixture of liposomal components which may be stored dry and reconstituted to form a liposome. US 4830858 does not relate to nutritional supplements.
- One object of the present invention is to provide an oral administration form of one or more nutritional supplements. Another object of the present invention is to provide a good bioavailability of the nutritional supplements. A further object of the present invention is to provide a form that is stable during storage.
- the present invention provides a composition for oral administration to a subject, comprising dehydrated liposomal vesicles, wherein the dehydrated liposomal vesicles comprise a nutritional supplement selected from the group consisting of vitamins, minerals, enzymes, proteins, peptides, and/or herbal extracts, preferably wherein the dehydrated liposomal vesicles comprise a bilayer of lecithin extracts, which lecithin extracts comprise at least 25 w% phosphatidylcholine.
- the invention also relates to a method for preparing the composition, the method comprising the steps of:
- step a) a fat-soluble nutritional supplement is added to the solution, and/or in step c) a water-soluble nutritional supplement is added to the solution.
- the dehydrated liposomal vesicles are stable during the
- the resulting composition is a dry (i.e. dehydrated) powder, which can be rehydrated in an appropriate volume of water for oral intake. It may for example be used as a food supplement or a medicament as described below.
- the nutritional supplement is chosen from cannabidiol (CBD), vitamin C, and/or vitamin B12.
- CBD cannabidiol
- the liposomes do not suffer from any disadvantageous effects of the drying step.
- the size of the liposomes before drying as well as after drying and resuspension in water is similar, and the bioavailability of the nutritional supplements does not suffer from any negative effects. Uptake is improved as compared to conventional oral delivery methods such as tablets, powders and capsules (not comprising liposomes), as proven in the experimental section by increased blood plasma levels.
- Cannabidiol is one of the at least 113 cannabinoids identified in cannabis. It is a major phytocannabinoid, which accounts for 40% of the plant’s extract. CBD does not appear to have any psychoactive effects such as those caused by tetrahydrocannabinol (THC). It is believed to have a downregulating impact on disordered thinking and anxiety. Potential uses are the subject of ongoing research. Cannabidiol is insoluble in water but soluble in organic solvents such as pentane and edible oils.
- Vitamin C is also known as ascorbic acid or L-ascorbic acid. Instead of the pure vitamin it may be used in the form of salts like sodium ascorbate, potassium ascorbate and/or any other pharmaceutically acceptable salt. These salts have lesser pH values and are therefore result in lesser gastro-intestinal problems. Vitamin C and it salts are water soluble and an essential nutrient involved in the repair of tissue and the enzymatic production of certain neurotransmitters. Vitamin C is required for the functioning of several enzymes and is important for immune system function. It also functions as an antioxidant. High-dose vitamin C has been studied as a treatment for patients with cancer since the 1970s. When taken by intravenous infusion, vitamin C can reach much higher levels in the blood than when the same amount is taken orally.
- the maximal plasma vitamin C plateau level when taken orally is about 80 mM. This level is obtained by a dosage of 1 to 2.5 g per day, and higher plasma levels do not seem obtainable, even at higher dosages.
- intravenous intake is required. With the present invention, the required high plasma levels are obtainable by oral intake. This eliminates the need for intravenous infusion.
- the nutritional supplement is vitamin B12.
- Vitamin B12 is a vitamin that plays a role in mammalian growth, haematopoiesis, production of epithelial cells, and maintenance of the nervous system. It is quite water-soluble and thus could be expected to be easily available to human subjects. However, the absorption from the gut of normal dietary amounts of vitamin B12 is believed to be dependent on gastric Intrinsic Factor (GIF), and the loss of Intrinsic Factor leads to vitamin B12 deficiency. The loss of ability to absorb vitamin B12 (B12) is the most common cause of adult B12 deficiency.
- GIF gastric Intrinsic Factor
- Such a loss may, for example, be due to pernicious anaemia (with loss of Intrinsic Factor) or to a number of other conditions that decrease production of gastric acid, which also plays a part in absorption of B12 from foods. Deficiency is most significantly linked to inadequate absorption rather than low consumption, as those who consume high amounts of vitamin B12 may still experience deficiency as evidenced by a low blood concentration.
- Vitamin B12 deficiency results in various undesirable conditions such as fatigue, depression, poor memory, etc.
- Other causes of vitamin B12 deficiency include atrophic gastritis (a thinning of the stomach lining), surgery in which part of the stomach and/or small intestine is removed, conditions affecting the small intestine (such as Crohn's disease, celiac disease, bacterial growth, or a parasite), excessive alcohol consumption, autoimmune disorders (such as Graves' disease or systemic lupus erythematosus) and drug abuse.
- intramuscular injections due to low bioavailability of orally ingested (non-liposomal) vitamin B12. Such injection are usually given by a health physician. With the composition of the present invention, intramuscular injections are not necessary. Therefore, visiting a health professional in order to receive the treatment for vitamin B12 deficiency is also not necessary. The subject can administer the vitamin B12 himself. Moreover, as shown in the experiments, the vitamin B12 plasma concentration obtainable with vitamin B12
- vitamin B12 includes cyano-cobalamin, hydroxy- cobalamin, methyl-cobalamin, 5’-deoxyadenosyl-cobalamin, aquacobalamin, glutathionyl- cobalamin and nitrilocobalamin, including the pharmaceutically acceptable salts thereof, and including mixtures thereof.
- the vitamin B12 is methyl-cobalamin.
- Methyl-cobalamin is considered a powerful drug because it decomposes easily in water.
- Methyl-cobalamin is an active form of vitamin B12 in the central nervous system and is absorbed readily into the bloodstream.
- the value of using methyl-cobalamin has not been realized in compositions according to the prior art, i.e. liquid compositions, as methyl-cobalamin cannot be easily stored.
- Pharmaceutical compositions comprising methyl-cobalamin in aqueous solution have to be kept frozen, and therefore a liposomal composition with methyl-cobalamin is not self-evident.
- the pharmaceutically acceptable carrier is chosen from the group consisting of monosaccharides, polysaccharides, maltodextrin, cellulose, aerosil, and starches. More preferably the pharmaceutically acceptable carrier is chosen from the group consisting of maltodextrin, cellulose, aerosil, and starches. These carriers are readily soluble in/miscible with water and have a pleasant taste.
- the composition comprises between 25 and 75 w% of the carrier.
- the dehydrated liposomal vesicles comprise a bilayer of lecithin extracts, which lecithin extracts comprise at least 25 w% phosphatidylcholine.
- the remainder of the lecithin extracts are phospholipids other than phosphatidylcholine.
- vesicles with these compositions have been shown not to suffer from any disadvantageous effects of the drying step.
- the size of the liposomes before drying as well as after drying and resuspension in water is similar.
- the lecithin extracts comprise between 25 - 75 w%
- phosphatidylcholine At lower percentages of phosphatidylcholine, liposomal vesicles are not adequately formed, i.e. the nutritional supplement(s) are largely located outside of the vesicles after step c), or no vesicles are formed at all. At percentages higher than 75 w%, the formed liposomal vesicles may coagulate.
- the dehydrated liposomal vesicles have size of between 50 - 500 nm for a good cellular uptake of the vesicles.
- the dehydrated liposomal vesicles have size of between 50 - 250 nm, to provide for better cellular uptake.
- the dehydrated liposomal vesicles have size of between 50 - 200 nm. Cellular uptake of such vesicles is optimal.
- the composition comprises between 1 - 50 w% of nutritional supplement.
- vitamin B12 deficiency after surgery in which part of the stomach and/or small intestine is removed, Crohn's disease, celiac disease, Graves' disease, systemic lupus erythematosus and migraine.
- treatment of vitamin B12 deficiency is conducted with vitamin B12 injections.
- Vitamin B12 is traditionally administered by intramuscular injections due to low bioavailability of orally ingested (non-liposomal) vitamin B12.
- Literature studies have indicated that with conventional orally ingested vitamin B12 compositions (non-liposomal), plasma levels higher than 400 pmol/L are not obtainable, even after prolonged treatment.
- the composition of the invention is particularly effective for oral treatment of vitamin B12 deficiency, since a single dose was shown to be effective for reaching a plasma level higher than 400 pmol/L.
- the method according to the invention optionally comprises a step c’) of sieving the vesicles to remove large vesicles and aggregates, after between step c) and d). This ensures a homogeneous particles size distribution.
- Figure 1A is a laser diffraction graph of as-prepared liposomes comprising cannabis extract with a high amount (at least 60 w%) of cannabidiol (CBD).
- CBD cannabidiol
- Figure 1 B is a laser diffraction graph of dehydrated and subsequently resuspended liposomes comprising cannabidiol.
- Figure 2A is a laser diffraction graph of as-prepared liposomes comprising vitamin
- Figure 2B is a laser diffraction graph of dehydrated and subsequently resuspended liposomes comprising vitamin B12.
- Figure 3B is a laser diffraction graph of dehydrated and subsequently resuspended liposomes comprising vitamin C.
- Figure 4A is a light microscopy image (400x enlargement) of as-prepared liposomes comprising cannabis extract with a high amount (at least 60 w%) of cannabidiol (CBD).
- CBD cannabidiol
- Figure 4B is a light microscopy image (400x enlargement) of as-prepared liposomes comprising vitamin B12.
- Figure 4C is a light microscopy image (400x enlargement) of as-prepared liposomes comprising vitamin C.
- Figure 5A is a light microscopy image (400x enlargement) of dehydrated and subsequently resuspended liposomes comprising cannabis extract with a high amount (at least 60 w%) of cannabidiol (CBD).
- CBD cannabidiol
- Figure 5B is a light microscopy image (400x enlargement) of dehydrated and subsequently resuspended liposomes comprising vitamin B12.
- Nano sized particles of about 50 - 500 nm are obtained by sonification of the slurry and/or by high pressure extrusion.
- the particles may optionally be sieved through a 0.2 micron sieve in order to separate the particles with a size of 200 nm or less from the larger particles and aggregates.
- the particles are checked with light microscopy (see FIG. 4A, 4B, 4C) and laser diffraction (see FIGS. 1A, 2A, 3A) by checking a liposomal suspension comprising the chosen nutritional supplement in water.
- the suspended particles are dried in the presence of a carrier (e.g. maltodextrine, cellulose, etc.) by either vacuum drying, belt drying and/or spray drying to obtain a powder.
- a carrier e.g. maltodextrine, cellulose, etc.
- This powder is mixed with water and again checked with laser diffraction (see FIGS. 1 B, 2B, 3B) and microscopy (see FIGS. 5A, 5B, and 5C).
- the original liposomes are intact. Partly as separate particles, and partly as clusters of connected particles.
- the size of the particles after rehydration is comparable to the size of the particles before drying for all compositions (CBD, vitamin C, and vitamin B12).
- CBD vitamin C, and vitamin B12
- FIGS. 5A, 5B, and 5C only the large vesicles can be observed. Smaller vesicles are grouped together forming larger particles suggesting that the individual liposomes are still intact.
- Vitamin C 1 kg of lipoid P75 with 75% of phospholipids was used. This material was dissolved in 1 litre of a 50%/50% mixture of methanol and chloroform. After dissolution the mixture was put in a large 5 litre flask of a Buchi Evaporator. All solvents were evaporated under reduced pressure and the phospholipids were left on the wall of the flask. A solution of 25 % (w/v) ascorbic acid in 4 litres of physiological salt solution was put in the flask under heavy mixing using an Ultra-Turrax homogenizer. After that the solution was sonicated with a Hielscher sonicator UP 400 ST.
- the material was homogenized using a Emulsiflex C5 (Avestin) with a pressure of around 5000 - 10000 psi.
- the resulting material was spray dried on a Buchi spray drier B290 with an inlet temperature of 180 °C and an outlet temperature of around 80 °C.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Dispersion Chemistry (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
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Abstract
The present invention relates to a composition for oral administration to a subject, comprising dehydrated liposomal vesicles, wherein the dehydrated liposomal vesicles comprise a nutritional supplement selected from the group consisting of vitamins, minerals, enzymes, proteins, peptides, and/or herbal extracts and to a method for preparing the composition.
Description
Title: Composition comprising dehydrated liposomes with nutritional supplement
Technical Field
The current invention relates to a composition for oral administration to a subject, comprising dehydrated liposomal vesicles, wherein the dehydrated liposomal vesicles comprise a nutritional supplement, and to a method for preparing the composition.
Background Art
A liposome is a spherical vesicle having at least one lipid bilayer. Liposomes are most often composed of phospholipids, but may also include other lipids. The lipid bilayer closely resembles human cell membranes, which is why liposomes can be more readily absorbed in the blood stream. Hydrophilic biologically active components may be dissolved in the core of a liposome, whereas lipophilic components associate with the bilayer. A liposome can hence be loaded with hydrophobic and/or hydrophilic molecules. To deliver the molecules to a site of action, the lipid bilayer can fuse with other bilayers such as the cell membrane. Liposomes are most commonly used in the drug/medicine industry. Compared to conventional (i.e. non-liposomal) oral drug delivery methods, use of drug-loaded liposomes leads to an increased bioavailability of the drugs, and therefore an increased effectivity of the treatment. Use of liposomes for delivery of nutritional supplements is much less common.
In the art, liposomes loaded with drug molecules are commonly prepared as aqueous dispersions. A problem with these dispersions is that they only have limited physical stability. The liposomes can aggregate and precipitate as sediment. Additionally, on storage the biologically active compounds may be lost into the external aqueous phase. Furthermore, depending upon the type of lipid and biologically active compound present in the liposome, there is the potential for chemical degradation of the lipid components and/or the biologically active components in the aqueous dispersion. Thereto, US 4830858 discloses a method for preparing a spray-dried mixture of liposomal components which may be stored dry and reconstituted to form a liposome. US 4830858 does not relate to nutritional supplements.
Summary of Invention
One object of the present invention is to provide an oral administration form of one or more nutritional supplements. Another object of the present invention is to provide a good
bioavailability of the nutritional supplements. A further object of the present invention is to provide a form that is stable during storage.
Thereto, the present invention provides a composition for oral administration to a subject, comprising dehydrated liposomal vesicles, wherein the dehydrated liposomal vesicles comprise a nutritional supplement selected from the group consisting of vitamins, minerals, enzymes, proteins, peptides, and/or herbal extracts, preferably wherein the dehydrated liposomal vesicles comprise a bilayer of lecithin extracts, which lecithin extracts comprise at least 25 w% phosphatidylcholine.
The vitamins, minerals, enzymes, proteins, peptides, and/or herbal extracts may be fat-soluble, water-soluble, and/or both. Even such molecules with relatively low water and fat solubility may be used in a liposomal system.
The invention also relates to a method for preparing the composition, the method comprising the steps of:
a) dissolving lecithin extracts, preferably comprising at least 25 w% phosphatidylcholine, in an organic solvent to form a solution,
b) simultaneously stirring and drying the solution in a vessel under reduced pressure, forming a dry film on the wall of the vessel,
c) adding to the vessel a physiological salt solution and agitating the solution, thereby removing the dry film from the wall of the vessel and creating vesicles,
d) drying the vesicles, optionally in the presence of a pharmaceutically acceptable carrier by vacuum drying, belt drying and/or spray-drying, wherein
in step a) a fat-soluble nutritional supplement is added to the solution, and/or in step c) a water-soluble nutritional supplement is added to the solution.
The preferred lecithin extracts comprising at least 25 w% of phosphatidylcholine result in spray-dryable liposomal vesicles comprising the nutritional supplement(s) after step c). Smaller amounts of phosphatidylcholine result in a suspension of liposomal vesicles wherein a large amount of the nutritional supplement(s) is not located in a vesicle, or even in a suspension without vesicles, such that no liposomal vesicles can be dried/dehydrated.
It is known from Ingvarsson et al., Expert Opinion on Drug Delivery 2011 , 8 (3), 375- 388, that stabilization of liposomes during drying is an issue. Two main stress factors (heat and high shearing forces) are involved in e.g. the spray-drying process and may disrupt the liposomal bilayer structure and result in degradation of the lipid components during the process. The composition of the liposomes should be carefully chosen.
Surprisingly, when the lecithin extracts comprise at least 25 w% of
phosphatidylcholine, the dehydrated liposomal vesicles are stable during the
dehydration/drying process. After dehydration and subsequent resuspension, the vesicles have a similar size as before the dehydration step.
The resulting composition is a dry (i.e. dehydrated) powder, which can be rehydrated in an appropriate volume of water for oral intake. It may for example be used as a food supplement or a medicament as described below.
Description of Embodiments
Preferably, the nutritional supplement is chosen from cannabidiol (CBD), vitamin C, and/or vitamin B12. For these nutritional supplements it has been shown in the invention that the liposomes do not suffer from any disadvantageous effects of the drying step. The size of the liposomes before drying as well as after drying and resuspension in water is similar, and the bioavailability of the nutritional supplements does not suffer from any negative effects. Uptake is improved as compared to conventional oral delivery methods such as tablets, powders and capsules (not comprising liposomes), as proven in the experimental section by increased blood plasma levels.
Cannabidiol (CBD) is one of the at least 113 cannabinoids identified in cannabis. It is a major phytocannabinoid, which accounts for 40% of the plant’s extract. CBD does not appear to have any psychoactive effects such as those caused by tetrahydrocannabinol (THC). It is believed to have a downregulating impact on disordered thinking and anxiety. Potential uses are the subject of ongoing research. Cannabidiol is insoluble in water but soluble in organic solvents such as pentane and edible oils.
Vitamin C is also known as ascorbic acid or L-ascorbic acid. Instead of the pure vitamin it may be used in the form of salts like sodium ascorbate, potassium ascorbate and/or any other pharmaceutically acceptable salt. These salts have lesser pH values and are therefore result in lesser gastro-intestinal problems. Vitamin C and it salts are water soluble and an essential nutrient involved in the repair of tissue and the enzymatic production of certain neurotransmitters. Vitamin C is required for the functioning of several enzymes and is important for immune system function. It also functions as an antioxidant. High-dose vitamin C has been studied as a treatment for patients with cancer since the 1970s. When taken by intravenous infusion, vitamin C can reach much higher levels in the blood than when the same amount is taken orally. As reported in Proc. Natl. Acad. Sci. USA 93 (1996) 3704-3709, Fig. 1C, the maximal plasma vitamin C plateau level when taken orally is about 80 mM. This level is obtained by a dosage of 1 to 2.5 g per day, and higher plasma levels do not seem obtainable, even at higher dosages. When higher plasma levels are desired, intravenous intake is required. With the present invention, the required high plasma levels are obtainable by oral intake. This eliminates the need for intravenous infusion.
More preferably, the nutritional supplement is vitamin B12. Vitamin B12 is a vitamin that plays a role in mammalian growth, haematopoiesis, production of epithelial cells, and maintenance of the nervous system. It is quite water-soluble and thus could be expected to
be easily available to human subjects. However, the absorption from the gut of normal dietary amounts of vitamin B12 is believed to be dependent on gastric Intrinsic Factor (GIF), and the loss of Intrinsic Factor leads to vitamin B12 deficiency. The loss of ability to absorb vitamin B12 (B12) is the most common cause of adult B12 deficiency. Such a loss may, for example, be due to pernicious anaemia (with loss of Intrinsic Factor) or to a number of other conditions that decrease production of gastric acid, which also plays a part in absorption of B12 from foods. Deficiency is most significantly linked to inadequate absorption rather than low consumption, as those who consume high amounts of vitamin B12 may still experience deficiency as evidenced by a low blood concentration.
Vitamin B12 deficiency results in various undesirable conditions such as fatigue, depression, poor memory, etc. Other causes of vitamin B12 deficiency include atrophic gastritis (a thinning of the stomach lining), surgery in which part of the stomach and/or small intestine is removed, conditions affecting the small intestine (such as Crohn's disease, celiac disease, bacterial growth, or a parasite), excessive alcohol consumption, autoimmune disorders (such as Graves' disease or systemic lupus erythematosus) and drug abuse.
Treatment of vitamin B12 deficiency is traditionally accomplished by highly dosed
intramuscular injections due to low bioavailability of orally ingested (non-liposomal) vitamin B12. Such injection are usually given by a health physician. With the composition of the present invention, intramuscular injections are not necessary. Therefore, visiting a health professional in order to receive the treatment for vitamin B12 deficiency is also not necessary. The subject can administer the vitamin B12 himself. Moreover, as shown in the experiments, the vitamin B12 plasma concentration obtainable with vitamin B12
compositions according to the invention greatly exceeds values obtainable in the prior art.
In the present application, the term vitamin B12 includes cyano-cobalamin, hydroxy- cobalamin, methyl-cobalamin, 5’-deoxyadenosyl-cobalamin, aquacobalamin, glutathionyl- cobalamin and nitrilocobalamin, including the pharmaceutically acceptable salts thereof, and including mixtures thereof.
Preferably the vitamin B12 is methyl-cobalamin. Methyl-cobalamin is considered a powerful drug because it decomposes easily in water. Methyl-cobalamin is an active form of vitamin B12 in the central nervous system and is absorbed readily into the bloodstream. The value of using methyl-cobalamin has not been realized in compositions according to the prior art, i.e. liquid compositions, as methyl-cobalamin cannot be easily stored. Pharmaceutical compositions comprising methyl-cobalamin in aqueous solution have to be kept frozen, and therefore a liposomal composition with methyl-cobalamin is not self-evident. In fact, both commercially available solutions that supposedly contained methyl-cobalamin from well- known suppliers that were tested by the inventors (and that were stored by the inventors as prescribed by the respective suppliers) did in fact not contain any methyl-cobalamin, but only
hydroxyl-cobalamin. This is likely due to degradation of methyl-cobalamin to hydroxyl- cobalamin during storage and transport. The composition of the present invention will benefit from improved stability, in particular for methyl-cobalamin.
Preferably, the composition further comprises a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium
phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate, potassium chloride, powdered cellulose, sodium chloride, sorbitol, talc, acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, starch, alginic acid, carboxymethyl cellulose calcium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, aerosil, sodium alginate and sodium starch glycolate.
Preferably, the pharmaceutically acceptable carrier is chosen from the group consisting of monosaccharides, polysaccharides, maltodextrin, cellulose, aerosil, and starches. More preferably the pharmaceutically acceptable carrier is chosen from the group consisting of maltodextrin, cellulose, aerosil, and starches. These carriers are readily soluble in/miscible with water and have a pleasant taste.
Preferably, the composition comprises between 25 and 75 w% of the carrier.
Preferably, the dehydrated liposomal vesicles comprise a bilayer of lecithin extracts, which lecithin extracts comprise at least 25 w% phosphatidylcholine. Preferably, the remainder of the lecithin extracts are phospholipids other than phosphatidylcholine.
Surprisingly, vesicles with these compositions have been shown not to suffer from any disadvantageous effects of the drying step. The size of the liposomes before drying as well as after drying and resuspension in water is similar.
More preferably, the lecithin extracts comprise between 25 - 75 w%
phosphatidylcholine. At lower percentages of phosphatidylcholine, liposomal vesicles are not adequately formed, i.e. the nutritional supplement(s) are largely located outside of the vesicles after step c), or no vesicles are formed at all. At percentages higher than 75 w%, the formed liposomal vesicles may coagulate.
Preferably, the dehydrated liposomal vesicles have size of between 50 - 500 nm for a good cellular uptake of the vesicles. Preferably the dehydrated liposomal vesicles have size of between 50 - 250 nm, to provide for better cellular uptake. Most preferably the
dehydrated liposomal vesicles have size of between 50 - 200 nm. Cellular uptake of such vesicles is optimal.
Preferably, the composition comprises between 1 - 50 w% of nutritional supplement.
The composition according to the invention may be used as a medicament. Notably, the composition wherein the dehydrated liposomal vesicles comprise vitamin B12 is used as a medicament. Most notably, the composition wherein the dehydrated liposomal vesicles comprise methyl-cobalamin is used as a medicament. Specifically, these compositions may be used in the treatment of vitamin B12 deficiency. The vitamin B12 deficiency is any condition where an increased level would be of benefit to the subject, which can be a human or an animal. It may be a condition chosen from pernicious anaemia, autism spectrum disorder, fatigue, memory deficiency, ALS, Alzheimer, deficiency caused by drug abuse, thinning of the stomach lining, vitamin B12 deficiency after surgery in which part of the stomach and/or small intestine is removed, Crohn's disease, celiac disease, Graves' disease, systemic lupus erythematosus and migraine. At present, treatment of vitamin B12 deficiency is conducted with vitamin B12 injections.
Oral use as a medicament of a composition comprising vitamin B12 for treatment of vitamin B12 deficiency is not self-evident. Vitamin B12 is traditionally administered by intramuscular injections due to low bioavailability of orally ingested (non-liposomal) vitamin B12. Literature studies have indicated that with conventional orally ingested vitamin B12 compositions (non-liposomal), plasma levels higher than 400 pmol/L are not obtainable, even after prolonged treatment. The composition of the invention is particularly effective for oral treatment of vitamin B12 deficiency, since a single dose was shown to be effective for reaching a plasma level higher than 400 pmol/L.
The method according to the invention optionally comprises a step c’) of sieving the vesicles to remove large vesicles and aggregates, after between step c) and d). This ensures a homogeneous particles size distribution.
As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the clauses and as a representative basis for teaching one skilled in the art to variously employ the present invention in any appropriately detailed structure. Further, the terms and phrases used herein are not intended to be limiting, but rather, to provide an understandable description of the invention.
The terms "a"/"an", as used herein, are defined as one or more than one. The terms including and/or having, as used herein, are defined as comprising (i.e. , open language, not excluding other elements or steps). The mere fact that certain measures are recited in
mutually different dependent clauses does not indicate that a combination of these measures cannot be used to advantage. All reaction conditions are under atmospheric pressure, unless otherwise indicated.
Brief description of the drawings
Figure 1A is a laser diffraction graph of as-prepared liposomes comprising cannabis extract with a high amount (at least 60 w%) of cannabidiol (CBD).
Figure 1 B is a laser diffraction graph of dehydrated and subsequently resuspended liposomes comprising cannabidiol.
Figure 2A is a laser diffraction graph of as-prepared liposomes comprising vitamin
B12.
Figure 2B is a laser diffraction graph of dehydrated and subsequently resuspended liposomes comprising vitamin B12.
Figure 3A is a laser diffraction graph of as-prepared liposomes comprising vitamin C.
Figure 3B is a laser diffraction graph of dehydrated and subsequently resuspended liposomes comprising vitamin C.
Figure 4A is a light microscopy image (400x enlargement) of as-prepared liposomes comprising cannabis extract with a high amount (at least 60 w%) of cannabidiol (CBD).
Figure 4B is a light microscopy image (400x enlargement) of as-prepared liposomes comprising vitamin B12.
Figure 4C is a light microscopy image (400x enlargement) of as-prepared liposomes comprising vitamin C.
Figure 5A is a light microscopy image (400x enlargement) of dehydrated and subsequently resuspended liposomes comprising cannabis extract with a high amount (at least 60 w%) of cannabidiol (CBD).
Figure 5B is a light microscopy image (400x enlargement) of dehydrated and subsequently resuspended liposomes comprising vitamin B12.
Figure 5C is a light microscopy image (400x enlargement) of dehydrated and subsequently resuspended liposomes comprising vitamin C.
Figure 6 is a graph of the plasma concentration-time profiles of cannabidiol (CBD) following oral administration in liposomal formulation at a dose of 250 mg in 4 test-subjects.
Examples
General protocol
Lecithin extracts comprising at least 25 w% phosphatidylcholine and up to 75 w% other phospholipids (the total adding up to 100 % phospholipids) and any fat-soluble ingredients (e.g. CBD) are dissolved in a flask in an organic solvent such as ethanol, methanol, chloroform, ethyl acetate pentane and/or any other organic solvent which can easily be evaporated.
The organic solvent is removed under reduced pressure while agitating, thereby forming a dry lipid film with fat-soluble active ingredients on the internal wall of the flask. Subsequently the material is diluted with a physiological salt solution, comprising any water- soluble active ingredients (e.g. vitamin C and/or B12). All materials are mixed under firm agitation, thereby creating a slurry.
Nano sized particles of about 50 - 500 nm are obtained by sonification of the slurry and/or by high pressure extrusion. The particles may optionally be sieved through a 0.2 micron sieve in order to separate the particles with a size of 200 nm or less from the larger particles and aggregates.
After sieving, the particles are checked with light microscopy (see FIG. 4A, 4B, 4C) and laser diffraction (see FIGS. 1A, 2A, 3A) by checking a liposomal suspension comprising the chosen nutritional supplement in water.
The suspended particles are dried in the presence of a carrier (e.g. maltodextrine, cellulose, etc.) by either vacuum drying, belt drying and/or spray drying to obtain a powder. This powder is mixed with water and again checked with laser diffraction (see FIGS. 1 B, 2B, 3B) and microscopy (see FIGS. 5A, 5B, and 5C). As can be seen, the original liposomes are intact. Partly as separate particles, and partly as clusters of connected particles. The size of the particles after rehydration is comparable to the size of the particles before drying for all compositions (CBD, vitamin C, and vitamin B12). As can be seen in the figures, almost all particles with CBD were smaller than 200 nm before dehydration (Fig. 1 A). After dehydration and resuspension, almost all particles are smaller than 250 nm (Fig. 1 B). Particles with vitamin B12 and particles with vitamin C have a size of about 200 nm both before as well as after dehydration and resuspension (Figs. 2A, 2B, 3A, and 3B). As can be seen in FIGS. 5A, 5B, and 5C only the large vesicles can be observed. Smaller vesicles are grouped together forming larger particles suggesting that the individual liposomes are still intact.
Comparative example
1 kg of lecithin extracts comprising 10 w% phosphatidylcholine and 90 w% other phospholipids was dissolved in 1 litre of a 50%/50% mixture of methanol and chloroform.
After dissolution the mixture was put in a large 5 litre flask of a Buchi Evaporator. All solvents were evaporated under reduced pressure and the phospholipids were left on the wall of the flask. A solution of 25 % (w/v) sodium ascorbate in 4 litres of water was put in the
flask under heavy mixing using an Ultra-Turrax homogenizer. After that the solution was homogenized using a GEA PANDA homogenizer at a pressure of 300 bar. The mixture formed was not stable, forming a lecithin layer on top of the water. This indicates that no homogeneous liposomal suspension was formed. Thus, no liposomal vesicles were formed.
Experimental details for Vitamin C
For Vitamin C 1 kg of lipoid P75 with 75% of phospholipids was used. This material was dissolved in 1 litre of a 50%/50% mixture of methanol and chloroform. After dissolution the mixture was put in a large 5 litre flask of a Buchi Evaporator. All solvents were evaporated under reduced pressure and the phospholipids were left on the wall of the flask. A solution of 25 % (w/v) ascorbic acid in 4 litres of physiological salt solution was put in the flask under heavy mixing using an Ultra-Turrax homogenizer. After that the solution was sonicated with a Hielscher sonicator UP 400 ST. After that the material was homogenized using a Emulsiflex C5 (Avestin) with a pressure of around 5000 - 10000 psi. The resulting material was spray dried on a Buchi spray drier B290 with an inlet temperature of 180 °C and an outlet temperature of around 80 °C.
Volunteer tests
Cannabidiol
Four volunteers were orally administered liposomal cannabis extract with a high amount (at least 60 w%) of CBD according to the invention at a dose of 250 mg CBD. The powder was ingested by first mixing the powder in a glass of water. The concentration-time profiles of cannabidiol (CBD) in the plasma of the volunteers was recorded over a time interval of 9 hours. From the results in FIG. 6 it can be seen that a maximum concentration is reached within 3.5 hours. This maximum concentration is at least 55 ng/mL. In studies with conventional CBD formulations, as performed by the inventors in a small study with 4 volunteers using CBD mixed with oil, this maximum concentration does not exceed 40 ng/mL. All liposomal products had substantial higher plasma levels as compared to the products dissolved in oil.
Vitamin B12
A volunteer was administered liposomal vitamin B12 (in the form of hydroxyl- cobalamin) according to the invention at a dose of 10 mg. The powder was ingested by first mixing the powder in a glass of water. Within 4 hours the plasma concentration increased from 511 pmol/L to 1175 pmol/L. This is a significant improvement with respect to oral intake of non-liposomal vitamin B12 in tablets and capsules as found in literature, e.g. in Sharabi et
al. , J. Clin. Pharmacol., 56, 635-638. In the latter paper, the plasma concentration did not exceed 400 pmol/L, even after several weeks of treatment. In the present study, a higher level is achieved within only several hours. Vitamin C
A volunteer was administered liposomal vitamin C according to the invention at a dose of 1 g. The powder was ingested by first mixing the powder in a glass of water. Within 4 hours the plasma concentration increased from 23.2 pmol/L to 133.2 pmol/L. This is a significant increase in plasma concentration as compared to conventional oral dosage of vitamin C, such as reported in Proc. Natl. Acad. Sci. USA 93 (1996) 3704-3709. As can be seen in Fig. 1C of this research paper, the maximal plasma vitamin C plateau level is about 80 pM. This level is obtained by a dosage of 1 to 2.5 g per day, and higher plasma levels do not seem obtainable, even at higher dosages. With the present invention, higher plasma levels are obtainable.
Claims
1. Composition for oral administration to a subject, comprising dehydrated liposomal vesicles, wherein the dehydrated liposomal vesicles comprise a nutritional supplement selected from the group consisting of vitamins, minerals, enzymes, proteins, peptides, and/or herbal extracts, and wherein the dehydrated liposomal vesicles comprise a bilayer of lecithin extracts, which lecithin extracts comprise at least 25 w% phosphatidylcholine.
2. Composition according to claim 1 , wherein the nutritional supplement is chosen from cannabidiol, vitamin C, and/or vitamin B12.
3. Composition according to claim 1 or 2, wherein the nutritional supplement is vitamin B12.
4. Composition according to claim 3, wherein the vitamin B12 is methyl-cobalamin.
5. Composition according to any one of the preceding claims, further comprising a pharmaceutically acceptable carrier.
6. Composition according to claim 5, wherein the pharmaceutically acceptable carrier is chosen from the group consisting of monosaccharides, polysaccharides,
maltodextrin, cellulose, aerosil, and starch, preferably wherein the composition comprises between 25 and 75 w% of the carrier.
7. Composition according to any one of the preceding claims, wherein the lecithin extracts comprise between 25 - 75 w% phosphatidylcholine.
8. Composition according to any one of the preceding claims, wherein the remainder of the lecithin extracts are phospholipids other than phosphatidylcholine.
9. Composition according to any one of the preceding claims, wherein the dehydrated liposomal vesicles have size of between 50 - 500 nm, preferably of between 50 - 250 nm, most preferably of between 50 - 200 nm.
10. Composition according to any one of the preceding claims, wherein the composition comprises between 1 - 50 w% of nutritional supplement.
11. Composition according to any one of the preceding claims for use as a medicament.
12. Composition according to claim 11 , for use in the treatment of vitamin B12 deficiency.
13. Method for preparing a composition according to any one of claims 1 - 12, comprising the steps of:
a) dissolving lecithin extracts comprising at least 25 w% phosphatidylcholine in an organic solvent to form a solution,
b) simultaneously stirring and drying the solution in a vessel under reduced pressure, forming a dry film on the wall of the vessel,
c) adding to the vessel a physiological salt solution and agitating the solution, thereby removing the dry film from the wall of the vessel and creating vesicles,
d) drying the vesicles, optionally in the presence of a pharmaceutically acceptable carrier by vacuum drying, belt drying and/or spray-drying, wherein
in step a) a fat-soluble nutritional supplement is added to the solution, and/or in step c) a water-soluble nutritional supplement is added to the solution.
14. Method according to claim 13, comprising a step of
c’) sieving the vesicles to remove large vesicles and aggregates,
between step c) and step d).
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WO2023141658A1 (en) * | 2022-01-24 | 2023-07-27 | Nutraceutical Corporation | Multiple nutrient liposomal supplement and methods of manufacturing the same |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4830858A (en) | 1985-02-11 | 1989-05-16 | E. R. Squibb & Sons, Inc. | Spray-drying method for preparing liposomes and products produced thereby |
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2018
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Patent Citations (1)
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US4830858A (en) | 1985-02-11 | 1989-05-16 | E. R. Squibb & Sons, Inc. | Spray-drying method for preparing liposomes and products produced thereby |
Non-Patent Citations (6)
Title |
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ANONYMOUS: "Liposomal technology, catalogus", 2 March 2017 (2017-03-02), pages 1 - 33, XP055489209, Retrieved from the Internet <URL:https://www.publishpaper.com/issues/b1eee775a2fa0ddd5c1563afe482918c/files/docs/all.pdf> [retrieved on 20180629] * |
INGVARSSON ET AL., EXPERT OPINION ON DRUG DELIVERY, vol. 8, no. 3, 2011, pages 375 - 388 |
PALL THOR INGVARSSON ET AL: "Stabilization of liposomes during drying", EXPERT OPINION ON DRUG DELIVERY, vol. 8, no. 3, 4 February 2011 (2011-02-04), GB, pages 375 - 388, XP055489248, ISSN: 1742-5247, DOI: 10.1517/17425247.2011.553219 * |
PROC. NATL. ACAD. SCI. USA, vol. 93, 1996, pages 3704 - 3709 |
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STEPHEN BURGESS BURGESS: "Liposome Preparation - Avanti Polar Lipids | Sigma-Aldrich", 1 January 1998 (1998-01-01), XP055489240, Retrieved from the Internet <URL:https://www.sigmaaldrich.com/technical-documents/articles/biology/liposome-preparation.html> [retrieved on 20180629] * |
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WO2023141658A1 (en) * | 2022-01-24 | 2023-07-27 | Nutraceutical Corporation | Multiple nutrient liposomal supplement and methods of manufacturing the same |
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