DESC:The inventions disclosed in provisional patent application No. 201941039876 filed on 02/10/2019 entitled “FREE-FLOWING BERBERINE COMPOSITION AND A METHOD OF PREPARATION OF THE SAME” and provisional patent application No.202041013145 filed on 26/03/2020 entitled “BERBERINE COMPOSITION AND DOSE FORM WITH ENHANCED BIOAVAILABILITY” are cognate of one another. The disclosures of the two provisional patent applications are combined by reference herein in its entirety.
FIELD OF THE INVENTION
The present invention relates to a Medicinal preparations of undetermined constitution containing material from plants such as Berberidaceae (Barberry family). The invention also relates to a Medicinal preparations characterised by special physical form such as coated pills or tablets and polymer coating. The invention also relates method of said composition and special physical form.
BACKGROUND OF THE INVENTION
Berberine is an alkaloid, organic heteropentacyclic compound, which is found in many deciduous, and evergreen shrubs found in temperate and subtropical climates. Berberine is quaternary ammonium that can be synthesised from said plants extracts. One of such plants is Berberis aristata. The most common form of berberine salt is berberis hydrochloride or berberine chloride.
The berberine compounds have an intense yellow colour. One of the first uses of Berberine was as a dye.In recent years berberine compounds are extensively used in pharmaceutical and food supplement industry. Irrespective of the medical benefits berberine compounds possess, it is one difficult product to work with because of the smell and colour. Berberine has a strong bitter smell. The strong smell and colour make it difficult to work with Berberine.
One of the common uses of the berberine compound is as a dye in wood and leather industry, but when the same compound is used in the food and pharmaceutical industry, the colouring property has an adverse effect. Berberine compounds have a staining problem, and because of it much expenditure goes into cleaning and housekeeping in the industry where Berberine is used. Moreover, Berberine is not a userfriendly compound because of the bitter taste and strong smell it holds. Fine powder of Berberine is an irritant for people working around it. Over all this, Berberine has poor flowability. Flow properties of powders are of utmost importance in the pharmaceutical and food industry.The present invention tries to address these problems with Berberine compound.
OBJECTS OF THE INVENTION
The principal object of this invention is to provide a free-flowing berberine composition which does not stain like the regular Berberine, and the composition is free-flowing and free of dust.
Another objective of the invention is to provide a process for manufacturing the free-flowing berberine composition. This process also includes a method to coat berberine salt with an edible polymer.
Another object of the invention is to provide a slow release of Berberine from the delivery system for an extended period, thus allowing the gastrointestinal mucosa to absorb the drug for a longer duration.
Another object of the invention is to provide an intestinal delivery system for Berberine, thus protecting the berberine compound from gastrointestinal fluid and releasing it directly in the intestine.
Another object of the invention is to provide solid dosage form in the form of powder, granules, pellets and tablets capable of delivering the Berberine for a longer duration of time.
SUMMARY OF THE INVENTION
The following disclosure provides a Berberine based composition and product that doesn’t stain equipment and vessels it is stored or subjected. More specifically, the said composition and product does not leave behind dust in any container where it is stored in or produce dust or stain when moved from one vessel to another. While making said Berberine based composition and product user-friendly, the purity of the product is not compromised.
An embodiment of the invention is a stain-free and free-flowing berberine composition comprising of berberine salt and edible polymer and the berberine salt to the edible polymer is blended in 100:1 to 1:1 weight ratio. The berberine composition is in granule, pellets, micro-pellets, beads, or beadlets form, and has a particle size of 10 to 1000micron.
The berberine salt is selected from a group of berberine chloride, berberine tetrahydrate, berberine chloride ethanol solvate hemihydrate, berberine bromide dihydrate, berberine iodide, berberine hydrochloride and bis(Berberine)-sulfate heptahydrate, Berberine palmitate, Berberine dioctyl sulfosuccinate, Berberine p-tosylate, Berberine tetraphenylborate, Berberine laurate and Berberine dodecyl-sulfate or a combination thereof.
In the stain free berberine composition the edible polymer is selected from Hydroxypropyl methylcellulose, starch, and natural gum.
The edible polymer is selected for a group of plant fibre, Gelatin, Sucrose, sodium alginate, Methyl cellulose sodium carboxymethyl cellulose, ethyl cellulose, hydroxy propyl methyl cellulose, polyvinyl pyrrolidone, magnesium aluminium silicates, Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutaniic acid, Glutarnine, Glycine, Histidine, Isoteucine, Leucine, Lysine, Methionine, phenylalanine, Phenylalaninc, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine or a combination thereof.
The natural gum selected from a group comprising of Acacia gum, gum Arabic, gum ghatti, gum tragacanth, karaya gum, guar gum, locust bean gum, beta-glucan, dummar gum, glucomannan, psyllium seed husks, tara gum, gellan gum, xanthan gum, agar, alginic acid and carrageenan.
In some embodiment the berberine composition is coated with an enteric coating material selected from a group of Ethyl cellulose, Sodium Alginate, Methacrylic acid co-polymers, poly (methacrylic acid co-methyl methacrylate), poly(methacrylic acid co-ethyl acrylate), poly(methyl methacrylate-co-methacrylic acid), Cellulose acetate phthalate, polyvinyl acetate phthalate, shellac, Cellulose acetate trimellitate, Hydroxypropyl methylcellulose phthalate and combination thereof.
In another embodiment the berberine salt is extracted from a plant selected from a group comprising of Berberis aristata, Mahonia aquifolium, Hydrastis canadensis, Xanthorhizasimplicissima, Phellodendronamurense, Coptischinensis, Tinosporacordifolia, Argemone Mexicana, andCosciniumfenestratum. In some embodiment the berberine composition is coated over ainert spherical core which is made of carbohydrate, sugar, silica, polymer, starch, and fibre.
Another embodiment of the invention discloses the method of manufacturing a free-flowing berberine composition. The Berberine, edible polymer, and water are combined to forma mixture which is further compressed in a roll compactor to form a thick mixture, followed by granulating the thick mixture in a granulator.
In another embodiment, a berberine composition is coated with an edible polymer. The coated Berberine is free-flowing, has high purity and does not stick to surfaces.
In yet another embodiment under the invention, the method of coating the Berberine with at least a layer of the edible polymer involve, fluidising the free-flowing granule in a confined space, and then selected polymer is dissolved in water and sprayed onto the fluidised granule to obtain coated free flowing granule.
For covering the Berberine with at least a layer of the edible polymer, 100 mass unit of free-flowing granule have to be rolled in a cylindrical pan fixed at an angle about 45 degrees and 3 mass unit of the polymer layer is dissolved in water to obtain a polymer solution of total dissolved solids (TDS) of 5±2%, and the resultant polymer solution is sprayed onto to the rolling granule to obtain coated free flowing granule.
Another embodiment of the invention is the method of manufacturing berberine hydroxide from Berberis aristata, The method comprises charging Berberis aristata plant parts in a reactor andcirculating a hydro-alcohol solvent through the reactor to get a decoction, followed by the addition of HCL into the decoction to precipitate Berberine Hydrochloride.
BRIEF DESCRIPTION OF THE DRAWINGS
Various features and advantages of the present invention should become apparent from the following figures of the accompanying drawings, which demonstrate the process steps involved in various process trials carried under specific preferred embodiment under the invention as well as the findings.
FIG1: Process of extracting berberine compound from plant parts.
FIG2: Process of granulating the berberine compound.
FIG3: Process of coating berberine granules using a fluidised bed.
FIG4: Process of coating berberine granules using a Pan coating machine.
Fig.5: Molecular structure of a) Berberine, and b) Berberine chloride, and c) Berberine sulphate.
DETAILED DESCRIPTION THE INVENTION
The present invention discloses Berberine based composition and product with its various embodiments and each embodiment describes a novel feature of the invention. Through these embodiments, a composition, a formulation and product along with a process of production and method of use shall be disclosed. The embodiments have to be understood in its broadest sense. The illustrations provide the best mode of preparation of the flowing Berberine composition and usage of the same according tothe invention, which can be well understood for a person skilled in the art and does not intend to narrow the scope of any subject matter claimed.
Throughout the description and claims of this specification the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.
Ranges can be expressed herein as from "about" one particular value, and to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it should be understood that the particular value forms another aspect. It should be further understood that the endpoints of each of the ranges are significant both with the other parameter and independently of the other endpoint. It is also understood that when a value is disclosed, then "less than or equal to" the value, "greater than or equal to the value" and possible ranges between values are also disclosed, as appropriately understood by the skilled person in the art. It is also understood that throughout the application, data are provided in many different formats and that these data represent endpoints and starting points and ranges for any combination of the data points.
Berberine includes any structural analogue of the quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids. For illustration purpose, the chemical structure of Berberine, and two other berberine analogue are provided in FIG 5. If not specified otherwise “berberine” mentioned throughout the application refers to a berberine salt, bereberine extract or a berberine analogue.
An aspect of the discloser is a Berberinecomposition which does not leave behind dust in any container in which it is storedand alsodoes not produce dust when moved from one container to another. Berberine composition has a smoother flow in comparison to a berberine salt or a berberin extract derived from a plant.
In one embodiment theBerberine compositionis made up of Berberineand an edible polymer. Berberineto edible polymer in the composition is present in a ratio of 1:1 to 100:1. The purity of Berberine in the composition is 60% to 98%.
In some embodiment said composition disclosed is in the form of granule pellets, micro-pellets, beads, or beadletsform, where the particle size ranges from 100micron to 1000micron more precisely 200micron to 400micron. More specifically, at least 80% to 90% of the granules are in the range of 100micron to 1000micron. More specifically, at least 80% to 90% of the granules are in the range of 200micron to 400micron.
In some embodiment said composition disclosed has a bulk density of 0.5-0.8g/cm3. In another embodiment,said composition disclosed has a bulk density of 0.6-0.8g/cm3. In yet another embodiment,said composition disclosed has a bulk density of 0.6 to 0.7 g/cm3.
In a preferred embodiment, a composition of Berberineand an edible polymer is disclosed. In the said composition, Berberineto edible polymer is present in a ratio of 1:1 to 100:1. The composition disclosed is in granule pellets, micro-pellets, beads, or beadlets form. The particle size ranges from 100micron to 1000micron in the composition. More precisely, at least 80% to 90% of the parts in the composition are in size range of 100micron to 1000micron, preferably 200micron to 400micron. The composition disclosed has a bulk density of 0.5-0.8g/cm3, preferably 0.6 to 0.7 g/cm3.
In a preferred embodiment, a composition of berberine hydrochloride and an edible polymer is disclosed. Berberinehydrochloride to edible polymer is present in a ratio of 1:1 to 100:1 in the said composition. The composition disclosed is in granule pellets, micro-pellets, beads, or beadlets form. The particle size ranges from 100micron to 1000micron in the composition. More precisely, at least 80% to 90% of the parts in the composition are in size range of 100micron to 1000micron. The composition disclosed has a bulk density of 0.5-0.8g/cm3.
In yet another embodiment a composition of berberine hydrochloride and an edible polymer is disclosed. Berberine hydrochloride to edible polymer is present in a ratio of 90:1 to 99:1 in the said composition. The composition disclosed is in granule pellets, micro-pellets, beads, or beadlets form. The particle size ranges from 200micron to 400micron in the composition. More precisely, at least 80% to 90% of the parts in the composition are in size range of 200microns to 400microns. The composition disclosed has a bulk density of 0.6 to 0.7 g/cm3.
In one embodiment a composition is disclosed where Berberine is coated with an edible polymer. In the composition berberineto edible polymer is present in a ratio of 1:1 to 100:1. The purity of Berberine in the composition is 60% to 98%.
In some embodiment said coated berberine composition disclosed is in granule pellets, micro-pellets, beads, or beadlets form, where the particle size ranges from 100microns to 1000micron. More precisely, at least 80% to 90% of the granules are in the range of 100microns to 1000micron.
In some embodiment said coated berberine composition disclosed is in granule, pellets, micro-pellets, beads, or beadlets form, where the particle size ranges from 200microns to 400microns. More precisely, at least 80% to 90% of the granules are in the range of 200microns to 400microns.
In some embodiment said composition disclosed has a bulk density of 0.5-0.8g/cm3. In another embodiment, said composition disclosed has a bulk density of 0.6-0.8g/cm3. In yet another embodiment, said composition disclosed has a bulk density of 0.6 to 0.7 g/cm3.
In a preferred embodiment, a composition of Berberine coated with an edible polymer is disclosed. Berberineto edible polymer is present in a ratio of 1:1 to 100:1 in said composition. The coated composition disclosed is in granule pellets, micro-pellets, beads, or beadlets form. The particle size ranges from 100microns to 1000micron in the composition. More precisely, at least 80% to 90% of the parts in the composition are in size range of 100microns to 1000micron. The composition disclosed has a bulk density of 0.5-0.8g/cm3.
In another preferred embodiment a composition of Berberine coated with an edible polymer is disclosed. Berberineto edible polymer is present in a ratio of 90:1 to 99:1 in said composition. The composition disclosed is in granule pellets, micro-pellets, beads, or beadlets form. The particle size ranges from 200micron to 400micron in the composition. More precisely, at least 80% to 90% of the parts in the composition are in size range of 200microns to 400microns. The composition disclosed has a bulk density of 0.6 to 0.7 g/cm3.
Said edible polymer might be a polysaccharide type, selected from any one or a combination of Hydroxypropyl methylcellulose (HPMC), starch and natural gum. Natural gum may include but not limited to Acacia gum, gum Arabic (acacia), gum ghatti (anogeissus), gum tragacanth (astragalus), karaya gum (sterculia), guar gum (guar beans), locust bean gum, beta-glucan, dummar gum, glucomannan, psyllium seed husks, tara gum, gellan gum, xanthan gum, agar, alginic acid and carrageenan.
The edible polymer may also be a protein type, selected from a group of Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutaniic acid, Glutarnine, Glycine, Histidine, Isoteucine, Leucine, Lysine, Methionine, phenylalanine, Phenylalaninc, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine or a combination thereof. They may further be selected from a group comprising of Acacia gum, plantfibre, Gum tragacanth, Gelatin, Sucrose, Starch, Sodium alginate, Methyl cellulose Sodium carboxymethyl cellulose, Ethyl cellulose, Hydroxy propyl methyl cellulose, Polyvinyl pyrrolidone, Magnesium aluminium silicates, and combination thereof.
Said Berberine might include one or more Berberine based salts selected from but not limited to berberine chloride tetrahydrate, berberine chloride, berberine chloride ethanol solvate hemihydrate, berberine bromide dihydrate, berberine iodide, berberine hydrochloride and bis(Berberine) sulfateheptahydrat. Berberine may also include organic salt of Berberine selected from Berberine palmitate, Berberine dioctylsulfosuccinate, Berberine p-tosylate, Berberine tetraphenylborate, Berberine laurate and Berberine dodecylsulfate.
In some embodiment the berberine composition has entric coating, berberine is blended with a binder such as a edible polymer in 100:1 to 10:1 ratio, the said mixture is compressed to increase the bulk density of the mix, preferably in the range of 0.5-0.8g/cm3. The compressed mixture is granulated using a granulator and the granules are coated with a seal coating. Over the seal coating a layer of enteric coating is provided.
There are multiple methods to coat berberine, and one suchmethod is to mix berberin with a binder such as edible polymer and mould the mixture in to a dosage form such as a tablet, capsule, granule, pills, pellets or any solid dose form. Then the dose form is provided with an enteric coating, in most cases a sealing coat is provided over the dose form prior giving it an enteric coating to prevent the exposer of active ingredient with the acidic coating material.
Since the berberin is sensitive to acidic medium a sub-coat over the active core will be desirable, especially if the enteric coating material is acidic in nature. The sub coat physically separates the acid labile drug from the acidic protective system, and hence improves the stability of the formulation. Preferable sub-coating material are selected from but not limited to hydroxyl propyl methyl cellulose (HPMC), ethyl cellulose, hydroxpropylcellulose, hydroxymethyl cellulose, cellulose acetate phthalate, and combination thereof.
Enteric coating is a coating material which acts as a barrier between the active material and the gastric environment in an oral dosage form. The coating protects the active material from the acidic environment of the stomach. The enteric coating will release the active ingredient in the intestine. The active ingredient in the present application is the berberin salt. Providing enteric coating to berberin salt enhances the activity significantly. The enteric coating material is selected from but not limited to; Ethyl cellulose, Sodium Alginate, Methacrylic acid co-polymers, poly (methacrylic acid co-methyl methacrylate), poly(methacrylic acid co-ethyl acrylate), poly(methyl methacrylate-co-methacrylic acid), Cellulose acetate phthalate, polyvinyl acetate phthalate, shellac, Cellulose acetate trimellitate, Hydroxypropyl methylcellulose phthalate and combination thereof.
In some embodiment the berberine composition will have other active compounds in its core other than berberine salts. The active compounds could be phytochemicals derived from plants, minerals or synthetic compounds. Plant phytochemicals are selected from but not limited to turmeric, emblica, amaranthus, withania somnifera, ginger, green tea, green coffee, Punicagranatum, Carica papaya, boswellia, Salvia rosmarinus, Sesamum, and a combination thereof.
In one embodiment the composition has Berberin extract: 28-32 %, Sucrose (as sugar pellets) : 37%, HPMC : 16% , Ethyl cellulose :12.75%, and Sodium Alginate : 2.25%.
An aspect of the disclosure is the process of extracting Berberine, and manufacturing compositions with berberineand process of coating such composition.
An embodiment of the invention is a method of extracting Berberine for a plant source rich in Berberine. Said method includes extracting a plant parts which is rich in Berberine with hydro-alcoholic solvent. After extraction, the solution is collected and concentrated. To the concentrated extract, an acid is introduced to get precipitate of berberine salt. Preferably HCL is used to precipitate out berberine hydrochloride. The plant source could be anyone or more selected from a group of Berberis aristata, Mahonia aquifolium, Hydrastis canadensis, Xanthorhizasimplicissima, Phellodendronamurense, Coptischinensis, Tinosporacordifolia, Argemone Mexicana, and Cosciniumfenestratum.
In an embodiment, the plant source isBerberis aristataand steams, and barks are the primary plant part used for extraction as raw material. Said extraction process also includes, sorting the plant parts, powdering the plant part, and charging a fixed quantity of the plant part into an extractor, a solvent is added to the extractor, and the plant parts are subjected to the solvent extraction in the extractor at a fixed temperature and pressure. For the extraction for one part of raw material, four to six parts of the solvent is required by weight. After some time when the solvent reaches a fixed concentration, the solvent is removed, and the removed solvent is concentrated to a preferred TDS level to get a concentrated solution. Diluted HCL is added to the solutionto precipitate out berberine hydrochloride. A preferred TDS level would be 6% to 10%.
The Berberine salt derived from plants has a purity of about 1% to 99%, preferably 20% to 70%, more preferably 30 to 60%. In most practical cases the purity of Berberine salt to be used is not less than 50%. Based on the quality of the raw material a standardised extact is prepared which has a consistent yield and purity.
In another embodiment, for every 1000 Kg of powdered plant part charged in the extractor about 5500 litres of hydro-alcoholic solvent is used. The hydro-alcoholic solvent used is in the ratio of 10:90, i.e., 10 part water and 90 part alcohol. The alcohol is selected from methanol, ethanol, isopropanol, butanol, isobutanol, benzyl alcohol and a combination thereof.
In yet another embodiment, the soxhlet extraction is used for the extraction of Berberine and a rising film evaporator (RFE) may be used for this.
In still another embodiment, thepowdered plant part is subjected to solvent extraction until the solvent reaches a total dissolved solid (TDS) about 6% or more. The solvent is further concentrated by stripping out the solvent to make the TDS 10% or more. The solvent can be stripped by distillation or by an evaporator.
In yet another embodiment, the HCL used for precipitation was of 12N. The precipitate is filtered out and dried under vacuum at minimum 550 mm of Hg at 70-75oC. The dried precipitation is then pulverised and packed. The moisture content is less than 3% in the final product. Said dried product has a purity of 10% to 98%, more preferabley it is enriched to 60 to 98%.
According to FIG1 powdered raw material (a) is charged into an extractor (b), followed by the addition of hydro-alcohol solvent (c) into the extractor. The solvent passes through the powdered raw material and flows through a filter into the RFE (d). The solvent gets heated in the RFE, the vapour of the solvent rises andenters intothe extractor (b). The solvent condenses in the extractor, passes through the raw material and trickles down through a filter back to RFE (d). Every time the solvent passes through the raw material in the reactor (b) it leaches out polyphenols from the raw material. At (e) the TDS is tested, to check the state of the extraction. The solvent moves from (d) to (b) and back to (d) in a reflex till the TDS at (e) doesn't reach 6% or higher. Once the TDS reaches 6% or above the vapour outlet (d1) is closed, and a vapour outlet (d3) is opened. The solvent is concentrated in the REF (d). The TDS is tested at (f), if the TDS reaches 10% or more, the concentrated solution is moved to (g) or else the concentration process is continued. HCL 12 N stored in (h) is slowly added in to (g), Berberine hydrochloride is precipitated to form a slurry. The slurry is passed through a filter press (i), and the cake is moved to (k) after discarding the cake. Then the cake is dried in (k) and the product is powdered in (l) to get the final product.
Another embodiment of the invention is the method to make berberine composition with an edible polymer. A fixed quantity of Berberine, a fixed quantity of edible polymer and a fixed quantity of water are mixed in a mixing unit. All the three components are mixed with an agitator to get a mixture. The mixture is passed through a roll compactor to compress the mixture to get compressed flakes. In one embodiment, for about 100 partberberineby weight about 1 to 100 part edible polymer is required. In another embodiment, for about 100 part berberine by weight about 1 to 50 part edible polymer is required. In yet another embodiment, for about 100 part berberine by weight about 1 to 10 part edible polymer is required. In one embodiment, for about 100 part berberineby weight about 1 to 5 part edible polymer is required.
In some embodiment, said compressed flakes are powdered and fed into a tabletting machine with 3mm dies and punched to get 3 mm diameter tablets. For every 90 to 99 part Berberine 1 part of the edible polymer is required to make a mini-tablet.
In another embodiment, said compressed flakes might be granulated using a swaying granulator to obtain granules. The granules are further segregated using mesh to segregate granules of the desired size. Preferred size of granules would be 100 microns to 1000micron, more preferably 200 microns to 400 microns. One part edible polymer is required for 90 to 99 part Berberine.
The granulating process is explained here with the help of FIG2, although the FIG2 is not meant to limit the scope of the process. According to FIG2 a powdered berberine (a) is charged into the wet grinder (b), deionised waterfrom (c) is sprayedon to the powered Berberine in the wet grinder simultaneously. The wet mixture is passed through a roll compactor (d), the flakes coming out of the roll compactor (d) is moved to a granulator (e). From the granulator, the product moves to a fluidised bed dryer (f). The dried granules are passed through sieves (g) for sorting. The granules of the desired size are sorted out at (h), and the rest is recycled. In some embodiment edible polymer is dissolved in (c). In some embodiment, the Berberine is Berberine hydrochloride, and the edible polymer is HPMC type. In some embodiment, the Berberine is Berberine chloride, and the edible polymer is HPMC type.
In yet another embodiment, the 200-micron to 400-micron granules of Berberine is provided with coating using a fluidised bed method. A fixed quantity of edible polymer is dissolved in water to make a 3 to 5% TDS solution. Said fixed quantity of berberine granules are fluidised in a chamber. On to the bed of fluidised granules, the edible polymer solution is sprayed. In one embodiment, in the coated granule for about 100 part granules of Berberine by weight about 1 to 100 part edible polymer is required. In another embodiment, in the coated granule for about 100 part granules of Berberine by weight about 1 to 50 part edible polymer is required. In yet another embodiment, in the coated granule for about 100 part granules of Berberine by weight about 1 to 10 part edible polymer is required. In one embodiment, for about 100 part granules of Berberine by weight about 1 to 5 part edible polymer is required.
In another embodiment, the granules of Berberine are fluidised by hot air, maintained at a temperature of about 50oC. Granules are said to be fluidised when all the parts are in the air, and no particle is overflowing from the chamber.
The fluidised bed coating process is further explained in FIG 3. Berberine granules (a) are charged into a fluidised bedchamber (f). The granules are fluidised when air is purged from the bottom of the chamber. When the granules in the chamber are completely fluidised, the coating material is sprayed on to them through nozzles (f1). Edible coating material (b) and water (c) are mixed well in (d) and filtered in (e). The filtered coating mixture is sprayed on the fluidised bed through the nozzle (f1). The coated granules are dried and sent for sorting in (g). The desired sorted product is taken out in (h).
In yet another embodiment, the 200-micron to 400-micron granules of Berberine are provided with coating using pan coating. A fixed quantity of edible polymer is dissolved in water to make a 3 to 5% TDS solution. A fixed quantity of berberine granules is takenand rolled in a pan fixed at an angle of about 45 degrees. The polymer solution is sprayed into the pan on to the granules to get a coated granule. In one embodiment, in the coated granule for about 100 part granules of Berberine by weight about 1 to 100 part edible polymer is required. In another embodiment, in the coated granule for about 100 part granules of Berberine by weight about 1 to 50 part edible polymer is required. In yet another embodiment, in the coated granule for about 100 part granules of Berberine by weight about 1 to 10 part edible polymer is required. In one embodiment, for about 100 part granules of Berberine by weight about 1 to 5 part edible polymer is required.
Pan coating process is further explained in FIG4. The granules in (a) are charged in a cylindrical pan (d). Edible polymer (b) is mixed with water (c) in (e) to get the coating solution, and the solution is filtered to remove any undissolved particles using a filter (f). The coating solution is pumped through the pipe (1). Inlet air (d1) is also pumped through the pipe (1) into the pan (d). The pan is rotated on its axis, the granules are rolling in the pan continuously, and on to the rolling granules the coating material is sprayed through the pipe (1) in the (d2) stream. Excess air is removed from the pan (d) from the pipe (2). Once the granules are coated thoroughly, they are dried in fluidised bed dryer (g) and sent for sorting in sieve system (h). In some embodiment, the edible polymer is HPMC type. In some embodiment, the edible polymer is starch type. In some embodiment, the edible polymer is a natural gum type. In some embodiment, the edible polymer is a combination of starch and natural gum type. In some embodiment, the edible polymer is combination HPMC and starch type. In some embodiment, the edible polymer is combination HPMC and natural gum type.
In yet another embodiment the method of manufacturing berberine composition involves mixing 150-250Kg berberine extract, 3 to 5Kg edible polymer, and 2 to 4 Kg deionised water to obtain a mixture. The mixture is subject to high pressure compression to obtain flakes, a roll compacter can be used to apply the pressure. The flakes are granulated to obtain the stain-free berberine composition. The berberine extract used in the process has a purity of 10-98% and the granules have a bulk density of 0.5-0.8g/cm3.
Another aspect of the invention is an enteric-coated berberine composition. The Berberine is provided with anenteric coating that can release Berberine only in the intestine and protect Berberine from the gastrointestinal fluid of the stomach. In one embodiment, the bioavailability of Berberine in the blood is increased when delivered directly to the intestine in comparison to when without enteric coating. In some embodiment, the Berberine is delivered directly into the large intestine.
EXAMPLES
The best mode of performing the invention is illustrated in the example below. However, the invention is not limited to the examples, and the examples are only meant for the enablement of a person skilled in the art.
Example 1
Method of extracting Berberine from Berberis aristata
For the extraction process, the raw material chosen was mostly roots and barks of Berberis aristata. Plant parts are sorted, washed, and dried. The dried plant parts are powdered. About 1000Kg of the powdered raw material was charged in the Multifunctional Extractor (MFE). The bottom of MFE was connected to a rising film evaporator (RFE) in such a way that solvent can trickle down from MFE to RFE, and when a solvent was distilled in the RFE, it gets condensed in the MFE.
About 5000L of hydro-alcohol solvent was charged into the MFE. The heat was applied to RFE to distil the hydro-alcohol solvent in it. The distilled solvent is condensed in MFE, and the condensate was allowed totravel back to the RFE. The cycle was maintained in the reflux conditionfor about 16 hours. Sample from an RFE was tested at regular interval for TDS, and when the TDS reaches 6% or more, the RFE was stopped.
The solvent in the RFE was distilled and the distilled out solvent was diverted to a storage tank. The solvent was distilled till the TDS become 10% to get a concentrated solvent extract. The concentrated solvent extract was moved to a different vessel where diluted HCL was added into the concentrated solvent extract. HCL of 12N was slowly added into the vessel which created slurry Berberine Hydrochloride. The slurry was then passed through a filter press. The cake obtained was dried under vacuum at 550 mm of Hg at 70-75oC for 8 hours or till the moisture content was less than 3%. The cake was then pulverised to get Sample-1. Sample-1 has a purity of 87±2% when tested in HPLC.
A part of sample-1 was further purified by dissolving the 1 Kg Sample-1 in 4Kgmethanol. 50gactivated carbon was added to the methanol solution. The solution was stirred for3 hours and then was left to settle for 1 hour. The solution was filtered out. The methanol solution was concentrated, and all the solvent was stripped to leave behind a cake. The cake was powdered to obtain the purified sample-2. Sample-2 has a purity of 95±2% when tested in HPLC.
Example 2
Method to make Berberine granules
The following method can be used to make granules of any berberine. For this specific example, Sample-1 made as per example 1 was taken.
About 200Kg of sample-1 was charged into a wet mixture granulator machine and mixed with water. Deionised water was spread into the wet mixture grinder. About 3 Kg of water was sprayed into the wet mixture grinder. After the water was sprayed, the mixture was agitated for a few more minutes before stopping. The mixture was discharged and fed to a roll compactor. Flakes of sample-1 were obtained from the roll compactor. The flakes were collected and passed through a swaying granulator machine with a 20 mesh perforated plate. The granules were collected and dried in a fluidised bed drier. The dried granules were sieved through 20mesh sieve followed by 60mesh sieve. The underpass of 20 mesh and the overpass of 60 mesh is separated as Product-1. The product had a bulk density of 0.62 g/cm3.
Example 3
Method to make Berberine granules with edible polymer
The following method can be used to make granules of any berberine. For this specific example, Sample-1 made as per example 1 was taken. Also, HPMC was chosen as the edible polymer for the example.
About 200Kg of sample-1 was charged into a wet mixture granulator machine along with 4Kg of HPMC (edible polymer) and mixed. Deionised water was spread into the wet mixture grinder. About 3 Kg of water was sprayed into the wet mixture grinder. After the water was sprayed, the mixture was agitated for a few more minutes before stopping. The mixture was discharged and fed to a roll compactor. Flakes of sample-1 were obtained from the roll compactor. The flakes were collected and passed through a swaying granulator machine with a 20 mesh perforated plate. The granules were collected and dried in a fluidised bed drier. The dried granules were sieved through 20mesh flowed by 60mesh. The underpass of 20 mesh and the overpass of 60 mesh is the desired product, Product-2. The product had a bulk density of 0.64 g/cm3.
Example 4
Method of coating Berberine granules using fluidised bed method
For this specific example, Product-1 made as per example 2 was taken. The method can also be used to coat product-2 in the same manner.
The required amount of Coating material was weighed and slowly added to the required amount of Purified water while it was being stirred until the whole Coating material is dissolved to form a uniform solution with required TDS. Filter the solution in a 250 microns stainless steel filter. About 100kg Product-1 were charged in Fluidised bed coating (FBC) machine. FBC was turned on, and the granules were fluidised, inlet temperature was set at 50oC. The Coating solution was pumped using a Peristaltic pump and was sprayed on the fluidised granules, through the spray nozzle connected at the top of the FBC. Mixer air pressure in the spray nozzle was maintained at 3 kg/cm2. The solution spray rate was adjusted accordingly, to maintain the Exhaust temperature at 41-43oC. After the solution pumping was over, the FBC is turned off, and the product was discharged. The discharged product was sieved through a 16 Mesh stainless steel filter. The underpass product was collected and then sieved through 60 Mesh stainless steel filter. The overpass product of this was the required coated turmeric extract.
Table 1
Parameters of the coating according to the different edible polymer.
Coating material HPMC GUM ACACIA STARCH STARCH: GUM ACACIA 80:20
Required amount 3Kg 1.5Kg 2Kg 1.6Kg
water 57Kg 48.5Kg 64.66Kg 64.66Kg
Coating solution TDS 5% 3% 3% 3%

Example 5
Method of coating Berberine granules using coating pan
For this specific example, Product-1 made as per example 2 was taken. The method can also be used to coat product-2 in the same manner.
The most preferred coating material were HPMC,Gum Acacia, Starch, or a combination of starch and gum acacia.The quntitiy of water required varises based on the coating material.
The required amount of coating material was weighed and slowly added to the required amount of Purified water while it was being stirred until the whole coating material was dissolved to form a uniform solution with a desired TDS. The solution was filtered with a 250 microns stainless steel filter to obtain the coating solution. About 100 kg Product-1 was charged into the Coating Pan. The Coating Pan was turned on, with an Inlet air temperature maintained at 55oC. The coating solution was pumped using a Peristaltic pump and was sprayed on the rolling Curcumin extract in the pan, through the spray nozzle connected inside the top of the Coating Pan. Mixer air pressure in the spray nozzle was maintained at 3 kg/cm2. The solution spray rate was adjusted accordingly to maintain the Exhaust temperature at 41-43 degree centigrade. After the solution pumping was over, the Coating Pan was turned off, and the product was discharged. The discharged product was sieved through a 16 Mesh stainless steel filter. The underpass product was collected and then sieved through 60 Mesh stainless steel filter. The overpass product of this was the required coated turmeric extract.
Table 2
Parameters of the coating process according to the different Edible polymer.
Coating material HPMC Gum Acacia Starch Starch: Gum Acacia 80:20
Required amount 3Kg 1.5Kg 2Kg 1.6Kg
water 57Kg 48.5Kg 64.66Kg 64.66Kg
Coating solution TDS 5% 3% 3% 3%

Example 6
Method of entric coating: on to aninert spherical core.
a. Method of layering of berberine extract on a sugar beadlets.
Purified water (8 Litre) was taken and kept for stirring under a mechanical stirrer. Hydroxyl propyl methyl cellulose (355 g) and Talc (25 g) were added slowly to water to form a uniform suspension. Berberin extract (1750 g) was accurately weighed and added to the suspension with constant stirring for 30 mins. The sugar beadlets are the inert spherical core. About 1936gm sugar beadlets were coated with the prepared suspension using Fluidised Bed Coater (FBC, 300 kg capacity, three spray gun, fully automatic type) to get 110% coating of the extract on the sugar beadlets.
b. Process of sealing of berberin extract layered on a sugar beadlets:
HPMC (406 g) was dissolved in purified water (3.66 L; 10% TDS solution) and kept for stirring under a mechanical stirrer. Stirring was continued for 30 minutes. Berberin extract layered sugar beadlets were coated with the coating solution using Fluidised Bed Coater (FBC).
c. Process of preparing a protective system of Berberine extract layered on a sugar beadlets :
Methacrylic acid co-polymer (1565g) with 30% TDS was added to purified water (14.09 L) to prepare a 10% TDS solution and kept for stirring for 30 minutes under a mechanical stirrer. An aqueous solution of polyethylene glycol with 20% TDS was added to Methacrylic acid co-polymer solution and mixed by stirring under a mechanical stirrer for 30 minutes. The aqueous solution of polyethylene glycol with 20% TDS was prepared by dissolving 201gm of polyethylene glycol in 805ml of purified water and kept for stirring under a mechanical stirrer for 30 minutes. Berberin extract seal coated sugar beadlets were layered with the coating solution using Fluidised Bed Coater (FBC) to get a protective system of Berberin with 15% coating.
Other modifications and variations to the invention are apparent to those skilled in the art from the foregoing disclosure and teachings. The scope of the invention is not limited to the turmeric extract prepared in the above illustrations. Person skilled in the art can use extracts prepared from other known methods. Thus, while only certain embodiments to show case the applicability of the invention have been specifically described herein, it will be apparent that numerous alterations are possible without departing from the spirit and scope of the invention. ,CLAIMS:1. A stain-free berberine composition comprises of berberine salt and edible polymer, wherein the berberine salt to the edible polymer is blended in 100:1 to 1:1 weight ratio.

2. The stain-free berberine composition as claimed in claim 1, wherein the berberine composition is in granule, pellets, micro-pellets, beads, or beadlets form, and has a particle size of 10 to 1000micron.

3. The stain-free berberine composition as claimed in claim 1, wherein the berberine composition is coated over an inert spherical core.

4. The stain-free berberine composition as claimed in claim 1 to 3, wherein the berberine salt is selected from a group of berberine chloride, berberine tetrahydrate, berberine chloride ethanol solvate hemihydrate, berberine bromide dihydrate, berberine iodide, berberine hydrochloride and bis(Berberine)-sulfate heptahydrate, Berberine palmitate, Berberine dioctyl sulfosuccinate, Berberine p-tosylate, Berberine tetraphenylborate, Berberine laurate and Berberine dodecyl-sulfate or a combination thereof.

5. The stain-free berberine composition as claimed in claim 1 to 3, wherein the edible polymer is selected from Hydroxypropyl methylcellulose, starch, and natural gum.

6. The stain-free berberine composition as claimed in claim 5, wherein the natural gum selected from a group comprises of Acacia gum, gum Arabic, gum ghatti, gum tragacanth, karaya gum, guar gum, locust bean gum, beta-glucan, dummar gum, glucomannan, psyllium seed husks, tara gum, gellan gum, xanthan gum, agar, alginic acid and carrageenan.

7. The stain-free berberine composition as claimed in claim 1, wherein the edible polymer is selected for a group comprising of plant fibre, Gelatin, Sucrose, sodium alginate, Methyl cellulose sodium carboxymethyl cellulose, ethyl cellulose, hydroxy propyl methyl cellulose, polyvinyl pyrrolidone, magnesium aluminium silicates, Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutaniic acid, Glutarnine, Glycine, Histidine, Isoteucine, Leucine, Lysine, Methionine, phenylalanine, Phenylalaninc, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine or a combination thereof.

8. The stain-free berberine composition as claimed in claim 1 to 6, wherein the berberine composition is coated with an enteric coating material selected from a group comprises of Ethyl cellulose, Sodium Alginate, Methacrylic acid co-polymers, poly (methacrylic acid co-methyl methacrylate), poly(methacrylic acid co-ethyl acrylate), poly(methyl methacrylate-co-methacrylic acid), Cellulose acetate phthalate, polyvinyl acetate phthalate, shellac, Cellulose acetate trimellitate, Hydroxypropyl methylcellulose phthalate and combination thereof.

9. The stain-free berberine composition as claimed in claim 1 to 8, wherein the berberine salt is from a berberine plant extract selected from a group comprising ofBerberis aristata, Mahonia aquifolium, Hydrastis canadensis, Xanthorhizasimplicissima, Phellodendronamurense, Coptischinensis, Tinosporacordifolia, Argemone Mexicana, andCosciniumfenestratum.

10. The stain-free berberine composition as claimed in claim 1 to 9, wherein the berberine composition comprises of:
i. Barbering plant extract: 28-32% with 10-98% purity;
ii. sugar pellets: 37%;
iii. Hydroxypropyl methylcellulose: 16%.
iv. Ethyl cellulose :12.75%; and
v. Sodium Alginate: 2.25%.
11. A method to manufacture a stain-free berberine composition comprises of: mixing 150-250Kg berberine extract, 3 to 5Kg edible polymer, and 2 to 4 Kg deionised water to obtain a mixture; the mixture is subject to high pressure compression to obtain flakes; the flakes are granulated to obtain the stain-free berberine composition, wherein the berberine extract has a purity of 10-98%; and the granules have a bulk density of 0.5-0.8g/cm3.
12. The method to manufacture a stain-free berberine composition as claimed in claim 11, wherein the berberine composition is provided with an enteric coating by fluidising the berberine composition in a confined space, sparing the fluidised composition with an enteric coating material; wherein the enteric coating material is selected from a group comprising of Ethyl cellulose, Sodium Alginate, Methacrylic acid co-polymers, poly (methacrylic acid co-methyl methacrylate), poly(methacrylic acid co-ethyl acrylate), poly(methyl methacrylate-co-methacrylic acid), Cellulose acetate phthalate, polyvinyl acetate phthalate, shellac, Cellulose acetate trimellitate, Hydroxypropyl methylcellulose phthalate and combination thereof.
13. A berberine beadlet, comprising: an inert spherical core and a coating of a barbering composition over the inert spherical core; wherein the berberine composition comprises of Hydroxyl propyl methyl cellulose, a Berberine extract and talc.
14. The berberine beadlet as claimed in claim 13, wherein the berberine beadlet has a layer of enteric coating over it, wherein the coating material is selected from a group comprising of Ethyl cellulose, Sodium Alginate, Methacrylic acid co-polymers, poly (methacrylic acid co-methyl methacrylate), poly(methacrylic acid co-ethyl acrylate), poly(methyl methacrylate-co-methacrylic acid), Cellulose acetate phthalate, polyvinyl acetate phthalate, shellac, Cellulose acetate trimellitate, Hydroxypropyl methylcellulose phthalate and combination thereof.
15. The berberine beadlet as claimed in claim 13 and 14, wherein the inert spherical core is selected from a group comprises of carbohydrate, sugar, silica, polymer, starch, and fibre.