EP4153143A1 - Process for preparing an active liposome, related compositions and uses - Google Patents
Process for preparing an active liposome, related compositions and usesInfo
- Publication number
- EP4153143A1 EP4153143A1 EP21732514.1A EP21732514A EP4153143A1 EP 4153143 A1 EP4153143 A1 EP 4153143A1 EP 21732514 A EP21732514 A EP 21732514A EP 4153143 A1 EP4153143 A1 EP 4153143A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- weight
- lecithin
- liposome
- active
- granulation
- 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.)
- Pending
Links
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- 238000012360 testing method Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- 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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/29—Berberidaceae (Barberry family), e.g. barberry, cohosh or mayapple
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
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- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- A61K9/1277—Processes for preparing; Proliposomes
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Definitions
- the present invention relates to a process for preparing an active liposome which comprises an active ingredient in a liposome. Furthermore, the present invention relates to said active liposome as such (per se), or obtained from said process.
- the present invention relates to a composition comprising said active liposome and, optionally, food-grade or pharmaceutical-grade additives and/or excipients.
- the present invention relates to a composition comprising said active liposome and, optionally, food-grade or pharmaceutical-grade additives and/or excipients, for use in a method for:
- the presence on the market of a vast range of finished products is known, for example food products, or products for food supplements, or products for medical devices under Reg. (EU) 2017/745, all the foregoing in various pharmaceutical forms of administration, such as for example tablets, capsules, granules or solutions or dispersions.
- the finished products present on the market can contain, among other things, various types of active ingredients such as for example botanical extracts, alkaloids extracted from various plants, molecules of plant origin such as for example bioflavonoids, or enzymes, such as for example the enzymes present in the juice of some fruits.
- nutraceuticals and supplements for example, products for food supplements or products for medical devices
- increasingly high- performing working processes such as for example particular extraction techniques, in order to be capable of preparing active ingredients and, therefore, finished products, that have a very high concentration, in a manner which is repeatable and standardizable.
- liposomes are also chemical forms known and used in the sector of food supplements and medical devices.
- liposomes are microscopic vesicles which are obtained from molecules of phospholipids in an aqueous environment. Liposomes can be used to store substances of various types (antiblastic and immuno stimulant drugs, in particular). If injected into an organism intravenously, they are assimilated by the cells of the reticuloendothelial system which degrade them, allowing the substances they contain to be freed. Liposomes find application in the field of experimental pharmacology, as vehicles for the administration of drugs of which liposomes reduce the toxicity.
- the prior art document EP0736299A1 discloses a method of preparing a solid liposomal formulation by way of using an organic solvent.
- the prior art document W098/36735A1 discloses an aqueous pharmaceutical composition that comprises a component that is highly insoluble in water, wherein a dispersion containing said component is subjected to a series of freeze-drying steps.
- the prior art document EP0488142A1 discloses a process for encapsulating solid or liquid lipophilic active ingredients in liposomes with an average size distribution of less than 200 nm.
- the known liposomal forms and liposomes do not always make it possible to make the active ingredients encapsulated or contained therein to be bioavailable within a short length of time (in particular: within two hours, preferably within approximately one hour) after administration, and at a concentration that is useful and effective.
- An object of the present invention is a process for preparing an active liposome which comprises an active ingredient in a liposome, having the features according to the appended claims.
- An object of the present invention is said active liposome as such (per se), i.e. obtained from said process, having the features according to the appended claims.
- An object of the present invention is a composition comprising said active liposome and, optionally, food-grade or pharmaceutical-grade additives and/or excipients, which has the features according to the appended claims.
- An object of the present invention is a composition comprising said active liposome and, optionally, food-grade or pharmaceutical-grade additives and/or excipients, for use in a treatment method according to the appended claims.
- An object of the present invention is an active liposome comprising berberine, as an active ingredient, in a lecithin-based liposome, for use in a method for (a) treating and/or improving and/or regulating the digestive function, the hepatic function, intestinal transit, the functionality of the digestive system, or the functionality of the cardiovascular apparatus, which has the features according to the appended claims.
- An object of the present invention is an active liposome comprising bromelain, as an active ingredient, in a liposome, for example based on lecithin, for use in a method for (b) treating and/or improving and/or regulating the digestive function, drainage of bodily liquids (heaviness in the legs), the micro-circulation functionality, or to combat the blemishes of cellulite, which has the features according to the appended claims.
- An object of the present invention is an active liposome comprising diosmin, as an active ingredient, in a liposome, for example based on lecithin, for use in a method for (c) treating chronic venous insufficiency (CVI), hemorrhoids and varicose veins, which has the features according to the appended claims.
- CVI chronic venous insufficiency
- hemorrhoids hemorrhoids and varicose veins
- composition(s) means a pharmaceutical composition, a food supplement composition, a food product composition, or a composition for medical devices under Reg. (EU) 2017/745.
- FIG. 1 is a flowchart of a process according to the present invention, according to a possible embodiment
- FIG. 2 is an exemplary chromatogram of a sample at 120 minutes and a standard sample, showing the two traces for each sample corresponding to berberine (transition 336>291) and benzanilide (198>105);
- FIG. 3 is a diagram of the absorption speed of an active liposome according to the present invention, containing berberine as an active ingredient, with respect to the absorption speed of a prior art 97% berberine solution in water;
- FIGS. 4 and 5 are, respectively, two 63 Ox enlargements of the active ingredient in the form of a prior art 97% berberine solution in water and of the active liposome according to the present invention dispersed in water, containing berberine as an active ingredient, taken in an optical microscope using a Moticam instrument (Moticam, Hong Kong);
- FIGS. 6 and 7 show two SEM images, respectively at 500x and 1500x, of a sample in powder form of crystalline berberine, deposited on a stub and then metalized; the samples in powder form were deposited on a stub, metalized and then observed using a scanning electron microscope.
- the instrument used is a Leica Stereoscan 410. These are respectively samples of a dry extract of Berberis aristata bark, titrated to 97% berberine, and of a granular liposome containing the same extract and having a titer of 20% berberine;
- FIGS. 8 and 9 are two SEM images, respectively at lOOx and 500x, of a sample in powder form of an active liposome according to the present invention dispersed in water containing berberine, deposited on a stub and then metalized; the samples in powder form were deposited on a stub, metalized and then observed using a scanning electron microscope.
- the instrument used is a Leica Stereoscan 410. These are respectively samples of a dry extract of Berberis aristata bark, titrated to 97% berberine, and of a granular liposome containing the same extract and having a titer of 20% berberine.
- the Applicant has devised a process for preparing an active liposome, which comprises an active ingredient in a liposome, wherein said process comprises the following steps of:
- At least one active ingredient selected from the group comprising or, alternatively, consisting of: berberine, diosmin, bromelain, or salts thereof, or mixtures thereof;
- At least one coating agent selected from the group comprising or, alternatively, consisting of: phospholipids, phosphoglycerides, sphingophospholipids, lecithin, phosphatidylcholines, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol, or mixtures thereof;
- step (ii) subjecting said granulation mixture or granulating solution, obtained from step (i), to a step of granulation carried out in a fluid bed granulator, preferably by way of nebulization or spraying, bringing said granulation mixture or granulating solution into contact with said coating agent (step ii(a)) or, alternatively, with a granulation aid in solid form so as to obtain a wet granulate;
- step (iii) subjecting said wet granulate, obtained from step (ii), to a step of drying, (or desiccation) by bringing said wet granulate into contact with a heat source so as to obtain an active liposome in granular form.
- the active ingredient (a) is preferably selected from the group comprising or, alternatively, consisting of: berberine, diosmin, bromelain, and/or salts thereof and/or mixtures thereof.
- Berberine (CAS N. 633-66-9) is a quaternary ammonium salt belonging to the group of benzylisoquinoline alkaloids, which has antimicrobial effects on bacteria, viruses, fungi, protozoa, helminths, and chlamydia.
- the active ingredient (a) is a dry extract of berberine obtained from a plant of the Berberis genus, more preferably an extract of the root, rhizome, stalk and/or bark of a plant of the Berberis genus, even more preferably a dry extract of the bark of Berberis aristata DC.
- Berberis Aristata root bark in dry extract form can be an extract of 97% berberine (analysis method by titration) in the form of a fine, yellow-colored powder.
- 90% of the powder passes through a mesh size of from 40 to 60 mesh and can have a humidity content lower than 12% by weight, preferably lower than 8% by weight, and an ash residue lower than 8% by weight, preferably lower than 4% by weight.
- Bromelain is a generic term used to refer to two proteolytic enzymes (i.e. capable of degrading the proteins in amino acids) that are extracted from Ananas comosus , a plant of the Bromeliaceae family originating from South America. In addition to their proteolytic activity, several other effects have been attributed to these enzymes (anti-inflammatory and anti thrombotic).
- the first form of bromelain is found in the pineapple fruit, while the second is found in the stem; since in the stem the amounts of the enzyme are larger, for commercial purposes it is preferred to use this latter source.
- the bromelain is an extract of the fruit and/or of the stem of Ananas comosus , preferably a dry extract.
- a bromelain with 2500 GDU/g of proteolytic activity can be obtained from the stem of Ananas comosus by extraction with water solvent and can have a bulk density of 0.2-0.8 and a particle size of 100% (40 mesh). It takes the form of a hygroscopic powder, white in color.
- Diosmin (CAS N. 520-27-4) is obtained from plant sources, or as a semi-synthetic molecule, modified starting from the hesperidin molecule, which belongs to the flavonoid family.
- Diosmin is a phlebotropic medicine used for vascular protection.
- Diosmin is considered a vascular protection agent, used to help improve chronic venous insufficiency (CVI), hemorrhoids, lymphedema and varicose veins.
- a diosmin can be in the form of a light yellow hygroscopic powder, practically insoluble in water, soluble in dimethyl sulfoxide DMSO, insoluble in 96% ethanol, and can be dissolved in diluted solutions of alkali hydroxides.
- the active liposome, prepared according to the process of the present invention is in solid granulate, flake, pellet or powder form, preferably the active liposome is in granular form.
- the active liposome, prepared according to the present invention has a phospholipid bilayer.
- the granulation mixture prepared in step (i) can be obtained, in a first embodiment, by mixing the components (a), (b) and (c) and, optionally, (d) all together, in any order and proportion, in a container provided with heating and agitation means, such as for example a mixer with rotating blades, so as to obtain a granulation mixture [(a)+(b)+(c) and optionally (d)].
- the components (a), (b), (c) and, optionally, (d) can all be, or only some of them can be, in liquid form, for example aqueous liquid; liquid extract, for example aqueous extract; suspension, for example aqueous suspension; dispersion, for example aqueous dispersion; or in solid or semi solid form, for example powder, granules, flakes or pellets.
- the granulation mixture [(a)+(b)+(c) and optionally (d)] can be in liquid or suspension or gel or solid or semi-solid form, preferably it is in solid or semi-solid form.
- the components (a), (b) and (c) are present in a quantity by weight (a):(b):(c) comprised from 1:1:1 to 1:1:15, preferably comprised from 1:1:15 to 1:1:10, for example 1:1:8, for example 200 g of extract of 97% Berberis aristata (see above), 200 g of lecithin in powder form, for example a sunflower lecithin in powder form, and 1600 g of water.
- the components (a), (b) and (c) are present in a quantity by weight (a):(b):(c) comprised from 1:2:4 to 1:6:12, for example 1:4:8; for example 200 g of extract of 97% Berberis aristata , 200 g of lecithin in powder form, for example a sunflower lecithin in powder form (step (i)) and 600 g of lecithin in powder form, for example of a sunflower lecithin in powder form (step (ii)) and 1600 g of water.
- the granulation mixture prepared in step (i) can be obtained, in a second embodiment, by mixing the components (a) and (b) together, in a container provided with heating and agitation means, such as for example a mixer with rotating blades, so as to obtain a mixture [(a)+(b)], for example in liquid or solid or semi-solid form. Then, subsequently, the water component (c) is added to this mixture [(a)+(b)], and, optionally, also the component (d) so as to obtain a granulation mixture [(a)+(b)+(c)+ optionally
- the components (a), (b), (c) and, optionally, (d) can all be, or only some of them can be, in liquid form, for example aqueous liquid; liquid extract, for example aqueous extract; suspension, for example aqueous suspension; dispersion, for example aqueous dispersion; or in solid or semi solid form, for example powder, granules, flakes or pellets.
- the granulation mixture [(a)+(b)+(c) and optionally (d)] can be in liquid or suspension or gel or solid or semi-solid form, preferably it is in solid or semi-solid form.
- the components (a) and (b) are present in a quantity by weight (a):(b) comprised from 1:3 to 3:1, preferably 1:2, or 1:1; for example 200 g of extract of 97% Berberis aristata and 200 g of lecithin in powder form, for example a sunflower lecithin in powder form.
- the water component (c) is added so as to obtain [(a)+(b)+(c)] where the components (a), (b) and (c) are present in a quantity by weight comprised (a):(b):(c) of 1:1:8; for example 200 g of extract of 97% Berberis aristata and 200 g of lecithin in powder form, for example a sunflower lecithin in powder form and 1600 g of water.
- the components (a), (b) and (c) are present in a quantity by weight comprised (a):(b):(c) of 1:4:8; for example 200 g of extract of 97% Berberis aristata , 200g of lecithin in powder form, for example a sunflower lecithin in powder form (step (i)) and 600 g of lecithin in powder form, for example a sunflower lecithin (step (ii)) and 1600 g of water.
- the granulation mixture is prepared preferably at an external pressure of 1 Atm, using water, preferably at a temperature from 10°C to 40°C, even more preferably from 15°C to 30°C.
- the granulation mixture is prepared preferably at an external pressure of 1 Atm and maintaining a temperature, preferably at a temperature from 10°C to 40°C, even more preferably from 15°C to 30°C, for a mixing time preferably from 5 minutes to 240 minutes, even more preferably from 30 minutes to 180 minutes, for example from 60 minutes to 120 minutes, so as to obtain a granulation mixture with a water content from 55% to 85% by weight, preferably from 65% to 75% by weight, of the total weight of the granulation solution.
- step (ii) this granulation mixture, obtained from step (i), is subjected to a step of granulation (step (ii)) which can be carried out in two ways: a step ii(a) or a step ii(b).
- step ii(a) the granulation mixture, obtained from step (i), is brought into contact with a granulation aid which is represented by the same coating agent used in step (i), such as for example a lecithin, preferably in powder form, so as to obtain a wet granulate.
- step ii(b) the granulation mixture, obtained from step (i), is brought into contact with a granulation aid in solid form so as to obtain a wet granulate.
- the granulation aid in solid form is selected from the group comprising or, alternatively, consisting of an inorganic aid like silica (Si0 2 ); plant fibers selected from: inulin, maltodextrin, FOS, GOS, XOS; a cellulose-derived polymer selected from: carboxymethylcellulose, carboxyethylcellulose, carboxypropylcellulose; a natural rubber selected from: gum Arabic, guar gum, tara gum or Xanthan gum; polyalcohols; lecithin, such as for example soya, maize or sunflower lecithin, or mixtures thereof.
- an inorganic aid like silica Si0 2
- plant fibers selected from: inulin, maltodextrin, FOS, GOS, XOS
- a cellulose-derived polymer selected from: carboxymethylcellulose, carboxyethylcellulose, carboxypropylcellulose
- a natural rubber selected from: gum Arabic, guar gum, tara gum or Xanthan gum
- the wet granulate prepared in step (ii) can be obtained by addition of this granulation mixture, preferably in the form of aqueous solution (granulating solution), to a granulation aid.
- the granulation aid is selected from the group comprising or, alternatively, consisting of an inorganic aid like silica (Si0 2 ); plant fibers selected from: inulin, maltodextrin, FOS, GOS, XOS; a cellulose-derived polymer selected from: carboxymethylcellulose, carboxyethylcellulose, carboxypropylcellulose; a natural rubber selected from: gum Arabic, guar gum, tara gum or Xanthan gum; polyalcohols; lecithin, such as for example soya, maize or sunflower lecithin, or mixtures thereof.
- the quantity by weight [(a)+(b)+(c)+ optionally (d)] : [(granulation aid)] is from 12:1 to 1:1, preferably from 6:1 to 1:1, even more preferably from 3:1 to 1:1.
- step (ii)) is preferably carried out using a fluid bed granulator, in the presence of said granulation aid which is represented by the same coating agent (step (ii(a))) used in step (i), such as for example a lecithin, preferably in powder form, so as to obtain a wet granulate to be subjected to step (iii).
- a fluid bed granulator in the presence of said granulation aid which is represented by the same coating agent (step (ii(a))) used in step (i), such as for example a lecithin, preferably in powder form, so as to obtain a wet granulate to be subjected to step (iii).
- step (ii)) is preferably carried out using a fluid bed granulator, in the presence of said granulation aid (step (ii(b))) in solid form so as to obtain a wet granulate to be subjected to step (iii).
- the fluid bed granulator can use hot air, at a temperature from 25°C to 50°C, preferably from 30°C to 45°C, even more preferably from 35°C to 40°C in order to facilitate the evaporation of the aqueous solvent (c) contained in the granulation mixture (i) and the formation of the granules in the wet granulate to be subjected to the step of drying (iii).
- the wet granulate prepared in step (ii) contains a quantity of water comprised between 10% and 30% by weight, preferably between 15% and 25% by weight, with respect to the weight [(a)+(b)+(c)+ optionally (d)]: [(granulation aid)] .
- step (iii) said wet granulate, obtained from the step of granulation (ii), is subjected to a step of drying (step (iii)) which brings said wet granulate into contact with a source of heat in order to eliminate the excess water or humidity, so as to obtain an active liposome in granular form.
- the step of dehydration (step (iii)) is represented by a step of drying which is preferably carried out using a fluid bed granulator, using hot air at a temperature from 25°C to 60°C, preferably from 30°C to 55°C, even more preferably from 35°C to 50°C in order to eliminate the residual water present in the wet granulate, so as to obtain an active liposome in granular form.
- the active liposome in granular form contains water in a quantity by weight from 1% to 15%; preferably from 3% to 12%; even more preferably from 5% to 10%; of the total weight of said active liposome.
- the active liposome in granular form contains a quantity of said at least one active ingredient, for example berberine, from 5% to 45%; preferably from 10% to 35%; even more preferably from 15% to 25%, of the total weight of said active liposome.
- the final titer, or the final quantity of liposomal granulate, obtained according to the process of the present invention, is determined using qualitative/quantitative techniques of high performance liquid chromatography (HPLC).
- step (ii) and the step of dehydration (step (iii)), preferably step of drying can also be carried out together in the fluid bed granulator, as a function of the operating conditions adopted.
- a mixture comprising or, alternatively, consisting of: (a) at least one active ingredient (also named hydrophobic active ingredient), (b) at least one coating agent (also named encapsulation agent), preferably a phospholipid agent; and (c) optional technological additives/excipients.
- active ingredient also named hydrophobic active ingredient
- coating agent also named encapsulation agent
- a phospholipid agent preferably a phospholipid agent
- optional technological additives/excipients optional technological additives/excipients.
- both (a) and (b) are independently in solid form, or in liquid form or in semi-liquid form (meaning in an intermediate physical state between a solid and a fluid); more preferably, (a) and (b) are both in solid form.
- a weight ratio (a):(b) is preferably comprised between 1.5:1 and 1:10, preferably comprised between 1.1:1 and 1:8, even more preferably comprised between 1 : 1 and 1 :4.
- a quantity of active ingredient (a) in the mixture of step (i) is from 5% to 20%, by weight, preferably from 10% to 15% by weight, of the total weight of the mixture.
- Said at least one coating agent (b) is preferably a phospholipid.
- Phospholipids are complex lipids in which one or more fatty acid molecules are linked to a phosphoric group or to a nucleobase. Based on their chemical structure, phospholipids can be divided into two classes: phosphoglycerides (also phosphoglycerols or glycerophospholipids) and sphingophospholipids (also sphingolipids or sphingophosphatids). In phosphoglycerides, unlike triglycerides, only two hydroxyls of glycerol are esterified with corresponding glycerol molecules, while the third hydroxyl is esterified with orthophosphoric acid (or phosphoric acid).
- Lecithin belongs to the class of phosphoglycerides. In lecithin, the phosphoric group is linked to choline, an amino alcohol choline, and it is for this reason that sometimes they are also called phosphatidylcholines. Depending on the hydroxyl to which the phosphoric group is linked, the lecithin is alpha-lecithin (more common) or beta- lecithin. Other phospholipids belonging to the class of phosphoglycerides which have interesting characteristics are phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol.
- said coating agent (b) comprises or, alternatively, consists of lecithin, even more preferably soya lecithin, sunflower lecithin, maize lecithin, or mixtures thereof, in an aqueous solution or in powder form.
- the optional technical additives (c) are preferably present in the mixture of step (i) in a quantity from 1% to 50%, preferably from 5% to 40%, more preferably from 10% to 30%, by weight, of the total weight of such mixture.
- the technical additives (c) that can be used in step (i) are selected from the group comprising or, alternatively, consisting of: emulsifiers, suspending agents, coating agents for modified release.
- the active liposome obtained from the preparation process described above contains a quantity of active ingredient (a) - determined by high performance liquid chromatography or HPLC/DAD - preferably comprised between 5% and 45% by weight, preferably comprised between 10% and 35% by weight, even more preferably comprised between 15% and 25% by weight.
- Said active liposome has an average size distribution - determined by laser light scattering analysis - comprised between 150 nm and 1800 nm, preferably comprised between 250 nm and 1500 nm, even more preferably comprised between 550 nm and 660 nm. More preferably, a polydispersity index of said active liposome is comprised between 0.3 and 0.4, even more preferably comprised between 0.320 and 0.350.
- said average size distribution may be determined by laser light scattering analysis (correlation spectroscopy) using a 90 Plus Instrument (Brookhaven, USA), in aqueous suspension at a temperature of 25°C, using a laser beam at the wavelength of 638 nm at 90°.
- a percentage average size distribution per size class may be as indicated in Table 1 below.
- a further object of the present invention is an active liposome obtained by said method of preparation in the aqueous phase.
- At least one active ingredient selected from the group comprising or, alternatively, consisting of: berberine, diosmin, bromelain, or salts thereof, or mixtures thereof;
- At least one coating agent selected from the group comprising or, alternatively, consisting of: phospholipids, phosphoglycerides, sphingophospholipids, lecithin, phosphatidylcholines, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol, or mixtures thereof;
- step (ii) subjecting said granulation mixture or granulating solution, obtained from step (i), to a step of granulation carried out in a fluid bed granulator, preferably by way of nebulization or spraying, bringing said granulation mixture or granulating solution into contact with said coating agent (step ii(a)) or, alternatively, with a granulation aid in solid form (step ii(b)) so as to obtain a wet granulate;
- step (iii) subjecting said wet granulate, obtained from step (ii), to a step of drying (or desiccation), by bringing said wet granulate into contact with a heat source so as to obtain an active liposome in granular form.
- said at least one active ingredient (a) is berberine, preferably an extract of Berberis aristata 97%
- said at least one coating agent is lecithin, preferably a lecithin of soya, maize, sunflower, or mixtures thereof
- step (ii) a step of granulation
- step (ii) a step of granulation
- step (ii) preferably carried out in a step ii(a) wherein the granulation mixture, obtained from step (i), is brought into contact with a granulation aid which is represented by the same coating agent used in step (i), preferably a lecithin, preferably a lecithin in powder form, even more preferably a lecithin of soya, maize or sunflower, or mixtures thereof, so as to obtain a wet granulate.
- a granulation aid which is represented by the same coating agent used in step (i), preferably a lecithin, preferably a lecithin in powder form, even more preferably a lecithin of soya, maize or sunflower, or mixtures thereof, so as to obtain a wet granulate.
- step (iii) a step of drying (step (iii)) which is preferably conducted using a fluid bed granulator, using hot air at a temperature comprised between 25°C and 60°C, preferably between 30°C and 55°C, even more preferably between 35°C and 50°C in order to eliminate the residual water present in the wet granulate so as to obtain an active liposome in granular form that has a quantity by weight of water comprised between 1% and 15%; preferably comprised between 3% and 12%; even more preferably comprised between 5% and 10%; with respect to the total weight of said active liposome.
- step (iii) preferably conducted using a fluid bed granulator, using hot air at a temperature comprised between 25°C and 60°C, preferably between 30°C and 55°C, even more preferably between 35°C and 50°C in order to eliminate the residual water present in the wet granulate so as to obtain an active liposome in granular form that has a quantity by
- An active liposome obtainable from a process according to any one of El -8; preferably containing berberine as the active ingredient (a), preferably an extract of Berberis aristata 91% in a quantity by weight comprised between 5% and 45%, of the total weight of said active liposome, and a lecithin as the coating agent, preferably a lecithin of soya, maize, sunflower, or mixtures thereof, and water.
- a composition comprising a mixture comprising or, alternatively, consisting of an active liposome according to E9, and optionally a food- grade or pharmaceutical-grade additive and/or excipient; said composition being for use in a method for (a) treating and/or improving and/or regulating the digestive function, the hepatic function, intestinal transit, the functionality of the digestive system, or the functionality of the cardiovascular apparatus.
- Example 1 Preparation of a liposome with a phospholipid bilayer encapsulating berberine (active ingredient) which comprises a dry extract of 97% Berberis aristata in berberine; lecithin of soya and water.
- Example 2 Pharmacokinetics of an active liposome encapsulating berberine.
- the project entails the pharmacokinetic analysis of the berberine in rat blood samples taken at 10, 30, 60, 120 and 480 minutes from oral administration via stomach tube of a 20% formulation of berberine (Berberina PhytobilayerTM, batch 2017030048) prepared as per Figure 1 and 97% berberine hydrochloride (batch DNBAJ20161205) used as a control.
- the pharmacokinetics were measured after administration via stomach tube of 50 mg/kg of 97% berberine and Berberine PhytobilayerTM (the subject matter of the present invention) with equidose of berberine. Both were suspended in water at a concentration of 12.5 mg/ml of berberine equivalents and used for oral administration.
- the blood samples were taken after 10, 30, 60, 120 and 480 minutes from administration.
- 500 microliters of heparinized blood are added to 500 microliters of benzanilide solution in methanol (900 ng/ml), 3 ml of water are added, and mixed. 5 ml of ethyl acetate are added and extraction is carried out.
- Figure 2 shows an exemplary chromatogram of a sample at 120 minutes and a standard sample, showing the two traces for each sample corresponding to berberine (transition 336>291) and benzanilide (198>105).
- berberine transition 336>291
- benzanilide 198>105
- TQDMS triple quadrupole detector
- the 336>291 transition was used; for benzanilide 198>105.
- the LOD and LOQ are 0.3 ng/ml and 0.9 ng/ml respectively.
- Table 5 gives the results of the pharmacokinetic analyses expressed in ng/ml, shown in graphic form in the accompanying Figure 3. Table 5
- Example 3 Stability tests of an active liposome encapsulating berberine.
- the active liposome encapsulating berberine was subjected to an evaluation of physical stability over time when stored for one year, at two different temperatures (4°C and 22°C). A dry extract of 97% berberine was used for comparison. From these tests it becomes clear that the dry extract of 97% berberine exhibits some changes that could be correlated to the hygroscopicity of the dry extract and to the tendency of berberine to crystallize in hydrated form.
- Figures from 4 to 9 show optical microscope images and SEM analyses conducted on the various samples.
- the active liposome according to the present invention allows to increase the bioavailability of the active ingredients encapsulated therein, and to obtain a longer release of such active ingredients over time.
- the active liposome obtained with the process according to the present invention allows to obtain a greater solubility in water of active ingredients that otherwise have poor solubility or are even insoluble.
- the active liposome obtained with the process according to the present invention allows to mask the flavors of the encapsulated active ingredients.
- the active liposome obtained with the process according to the present invention has a high stability over time.
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