Title of Invention

GRANULES CONTAINING A PLANT SUBSTANCE COMBINED WITH POLYVINYLPYRROLIDONE AND PROCESS FOR PREPARING THE SAME

Abstract

"GRANULES CONTAINING A PLANT SUBSTANCE COMBINED WITH POLYVINYLPYRROLIDONE AND PROCESS FOR PREPARING THE SAME" The present invention relates to granules containing between 0.1 mg/g and 750 mg/g of at least one plant substance, characterized in that they each comprise a single neutral core having a particle size of between 0.2 and 4 mm coated with a layer containing the plant substance combined with polyvinylpyrrolidone. 8 NOV 2007

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] & The Patents Rule, 2003 COMPLETE SPECIFICATION [See Section 10 and Rule 13] "GRANULES CONTAINING A PLANT SUBSTANCE COMBINED WITH POLYVINYLPYRROLIDONE AND PROCESS FOR PREPARING THE SAME" DBF, a French company of 120, Bureaux de la Colline, 92210 Saint Cloud, France, GRANTED 8-11-2007 The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- ORIGINAL The present invention relates to granules containing a plant substance combined with polyvinylpyrrolidone and process for preparing the same. The subject of the present invention is a new formulation in ±he form of granules containing a plant substance as well as the process for preparing it. More precisely, the present invention relates to granules' containing at least one plant substance and •' each comprising a neutral core coated 'with a layer . containing the said plant substance combined with a pharmaceutically acceptable excipient. The formulations containing plant substances which are already described in the prior art are in the form of powders, granules, tablets or oral solutions. The major' problem with formulations in . powdered form is that the plant powder has to be mixed with excipients which are also in powdered form. A mixture of powders is then obtained which is not very homogeneous and hardly reproducible. Furthermore, powders are very hygroscopic'and they therefore pump moisture from the granules and from the gelatin capsule, which become brittle. This poses .problems of stability, and the proportion in the gelatin capsule is not homogeneous. This problem is solved within the framework v of the present invention by the application of a plant substance in dry or liquid form onto neutral micrograins; in this case, there is no mixing of powder but only the application of dry or liquid substances onto neutral granules. The granules according to the invention have the advantage of being easier to package into gelatin capsules than powders, of being more stable to storage than the formulations of. the prior art and of allowing a reproducible proportion. As for tablets, they have the same problems as powders. Moreover, plant extracts are not always compressible and compressing agents are not always authorized in the food industry.. Finally, the oral fluid forms are often bitter and foul-smelling to the extent that sweeteners and stabilizers need to be added. In addition, the oral fluid forms may exhibit physical or chemical instability during storage, a low content of characteristic plant constituents, and frequently contain ethyl alcohol in a moderately large quantity, which is not generally desirable for the oral administration of medicinal products. The multiparticulate form of the formulation of the invention makes it possible to obtain a uniform and reproducible release profile. In addition, the granules of the invention which each contain a layer of plant substance mounted on a neutral core may be coated with an outer layer so as to modify their properties. The outer layer comprises, for example, an enteric polymer, a polymer intended to prolong the release of the plant substance or a polymer intended to mask the taste or the odour of the plant substance. The formulation according to the invention has the advantage of being stable during storage, of having an enhanced bioavailability, and of being able t.o integrate high doses of plant substance. FR 2,721,512 describes a process for the preparation of granules by extrusion-spheronization from a polymer with absorbent or adsorbent properties. the polymer is sprayed with an aqueous-alcoholic fluid slant extract. The synthetic or natural polymer is optionally combined with' auxiliary substances, such as lactose or PVP, which make it possible to modulate the porosity of the spheroids and their rate of dissolution. The extrusion-spheronization technique has many disadvantages: it requires the addition of a quantity of water at least equal to the quantity of excipients, the grariules obtained by this technique have high moisture levels and their drying takes too. long. In addition, the process described in FR 2, 721,512 uses powder FR 2,616,068 describes a process which consists in granulating a dry or soft plant extract with methyl cellulose or silica. FR 2,682,874 describes a process for the preparation of an extract of active ingredient in dry form from a fluid extract, which consists in adsorbing an aqueous-alcoholic solution of the active ingredient onto porous grains of cellulose or silica. The grains have a particle size which is in the micron range. These grains are then adsorbed onto porous granules 0.1 to 0.5 mm in diameter, which for example consist of sugar. FR 2,737,134 describes a process which consists in coating cores, having a diameter of less than 0.01 mm, consisting of maltisorb or of a sodium bicarbonate/citrate mixture,- with a - compound in powdered form and a compound in solution. The compound in splution is an essential oil and/or a concentrated fluid plant extract. The subjecjt of ' the" present invention is granules which overccjme the disadvantages of the prior art formulations. Thjese granules containing at least one plant substance a|re characterized in that they each comprise a neutral core having a particle size of between 0.2 and 4 mm coated with a layer containing the plant substance combined with a pharmaceutically acceptable excipient. The plant substance may be derived from plants chosen from garlic, Echinacea, Ginkgo biloba, ginseng, harpagophytum, kava, St.-John s-wort, green tea, valerian, Missouri grape, artichoke, hawthorn, burdock, birch, alder buckthorn, blackcurrant, blessed thistle, Fucus, hamamelis, horse chestnut, balm, Orthosiphon, passion . flower, dandelion, horsetail, meadowsweet, sage, spirulina, boldo, nettle, North American palm and mixtures thereof. The neutral core consists of a substance chosen from sugar, starch, mannitol, sorbitol, xylitol, cellulose, talc and mixtures thereof. The neutral cores may also consist of a starch/sucrose core in 20/80 mass ratios which is coated with 80% by weight of starch. In such neutral cores, the proportion by mass of sugar is advantageously less than 20%. The layer containing the plant substance may contain a binder. A sugar such as sucrose, polyvinylpyrrolidone (PVP), lac gum or hydroxypro'pylmethylcellulose is advantageously used as binder. The granules according to the invention may-consist of a neutral core coated with a layer containing the plant substance, itself coated with an outer layer intended to mask the taste and/or the odour of the plant substance, to delay its release or to control its release. When the outer layer is intended to control the release of the plant substance, it advantageously contains lac gum, PVP, a copolymer of methacrylic acid (Eudragit®) or a colloidal dispersion of ethyl cellulose (Aquacoat®) with a plasticizer. When the outer layer is intended to delay the release of the plant substance, it contains a methacrylic acid copolymer, lac gum or a colloidal dispersion of ethyl cellulose (Aquacoat®) with a olasticizer. As polymer intended to mask the taste and/or bhe odour of the plant substance, a copolymer of tiethacrylic acid (Eudragit E 100®), a polyacrylate iispersion (Eudragit NE 30D®) or hydroxypropylmethyl-;ellulose (Pharmacoat®) may be used. It ' is also possible to use, as enteric polymer, lac gum by spraying an alcoholic solution containing 10% by weight of lac gum. At higher concentrations, between 20 and 40%, lac gum fulfils the function of a delayed-release polymer. In the granules., the content of plant substance is between 0.1 mg/g and 750 mg/g. The present invention relates in particular to garlic granules.with masked odour and taste, Ginkgo biloba granules, one daily dose, prolonged-release ginseng granules, enteric Harpagophytum granules, prolonged-release green tea granules, prolonged-release Orthosiphon granules, valerian granules with masked taste and odour and prolonged-release St.-John's-wort granules. The present invention also relates to a process for the preparation of the granules described above. The process according to the invention allows better reproducibility of the proportion. The granules according to the invention may contain several plant substances used in the form of plant powder, of dry, soft or fluid plant extracts or of mixtures thereof. According to the definition given in the pharmacopoeia, plant extracts are concentrated preparations which are liquid, solid or of intermediate consistency, generally obtained from dried plant raw materials. For some preparations, the materials to be extracted may undergo a preliminary treatment such as inactivation of enzymes, grinding or defatting. Fluid extracts are liquid preparations of which, in general, a portion by mass or by volume corresponds to a portion by mass of dried raw material. These preparations are adjusted, if necessary, so as to meet the requirements of content of solvents, of constituents or of dry residue. Soft extracts are preparations having an intermediate consistency between fluid extracts and dry extracts. Soft extracts are prepared by partial evaporation of the solvent which served for their preparation. Only ethanol at an appropriate titre or water are used. Soft extracts have in general a dry residue which is not less - than 70 per cent m/m. They may contain appropriate antimicrobial preservatives . Dry extracts are solid preparations obtained by evaporation of the solvent which served for their production. Dry extracts have' in general a dry residue which is not less than 95 per cent m/m. Appropriate inert substances may be added. . The plant powders are obtained from whole plants or fragmented or cut plant portions, used as they are, in desiccated form. According to the process of the invention, the granules are obtained by powder-coating when the plant substance is in the form of plant powder or of a dry extract. Powder-coating is advantageously carried out by alternately spraying an alcoholic or aqueous-alcoholic solution of a binder, and the plant substance in desiccated form (powder or dry extract). The granules are obtained by spray-coating when the plant substance is in the form of a soft or fluid extract. In the case of a fluid extract, the active layer may. be coated with a layer obtained by spraying a solution of a binder. The fluid extract preferably contains about 30 to 40% alcohol. The process according to the invention advantageously makes it possible to limit the quantity of organic solvent used. During the process of the Invention, 5 to 2 5% by weight of organic solvents are used. The size of the granules used will be chosen as a function of the type of extract used and as a function of the desired proportion. Preferably, the size of the Neutres is between 200 and 900 tim, when the plant substance is in desiccated form (powder or dry extract). The size of the Neutres is between 900 and 1250 μm, when the plant substance is in liquid form (soft or fluid extract). The percentage by mass of plant substance in the form of fluid extract, used in the process of the invention is advantageously between 15 and 5 0% relative to the weight of the granules. The percentage by mass of plant substance in desiccated form (extract, powder) may be as high as 75% relative to the weight of the granules; it is preferably between 35 and 55%. The granules according to the invention are prepared according to coating techniques known in the art, preferably in a pan or in a fluidized air bed. The invention is illustrated without any limitation by the following examples. Example 1; Green tea (dry extract) Green tea granules are prepared according to the following sequence of steps in a conventional pan. The green tea is in the form of a dry extract. QUANTITY (KG) Neutres® 32.5 - 33.5 Coating Dry extract of green tea 40.5 - 41.5 PVP at 2 0% in alcohol 14 - 20 Precoating PVP at 2 0% in alcohol 4 Talc 1.6 Lubrication Talc 0.1 The Neutres used have between 700 and 90 0 mm. - particle size of The green tea coating step may be carried out in a single 'stage or in several stages by alternately spraying the plant extract and a solution of polyvinylpyrrolidone (PVP K30®) at 20% in ethanol. During the coating, precoating and lubricating steps, the granules are sieved at 1.0 - 1.18 mm, 1.18 - 1.25 mm and again at 1.18 - 1.25 mm, respectively, and then dried for 8 hours, respectively at room temperature and 30°C. Granules of the following formula are obtained: Their water content is of the order of 0.7 - 1.5% by mass. Example 2: Harpagophytum (dry extract) *BDLG: Bleached dewaxed lac gum. The Neutres have a particle size of between 700' and 900 microns. The Neutres and the plant extract are sprayed with an alcoholic solution of polyvinylpyrrolidone. The granules are sieved and dried. During a second step, a layer of lac gum is applied still using an alcohol solution of polyvinylpyrrolidone. The granules are again sieved and dried. Finally, the granules are lubricated with talc. Example 3: Harpagophytum (fluid extract) The granules having the following composition are prepared according to the process described below. The Neutres are introduced into the tank and the fluid extract is sprayed in fractions. The granules are sized by sieving and then dried under an air bed. A 33% sucrose solution in an ethanol/water mixture is then applied. The granules are again sieved and dried, and then lubricated with talc. Example 5: Ginkgo biloba (fluid extract) Example 4: Ginkgo biloba (dry extract) The Neutres are introduced into the tank and the fluid extract is sprayed in fractions. The granules are sized by sieving and then dried under an air bed. A solution of polyvinylpyrrolidone in alcohol is then applied. The granules are again sieved and dried, and then lubricated with talc. Example 6; Valerian (dry extract) * substances which disappear during the manufacturing process The manufacturing process can be set out in 2 main steps: application of the valerian dry extract by dusting - over Nei.it.res microgranules using a binder: 2 0% alcoholic solution of PVP, coating of the microgranules with a film-forming agent. The method of applying the active substance is batchwise, composed of a succession of alternate phases of application and phases of sieving and drying during which the microgranules are placed in a hot air stream. The coating phase is carried out by spraying the film-forming agent, in the form of a 3 0% suspension in water, and a proportion of talc (obtained from the formation of aggregates) followed by a sieving and drying phase. Finally, the microgranules are lubricated by addition of talc, reducing the static electricity, facilitating filling into gelatin capsules. Example 7: Passion flower (dry extract) substances which disappear during the manufacturing process The manufacturing process can be set out in 2 main steps: application of the passion flower dry extract by dusting over Neutres microgranules using a binder: 20% alcoholic solution of PVP coating of the microgranules with a film-forming agent. The method of applying the active substance is batchwise composed of a succession of alternate-phases of application and phases of sieving and drying during which the microgranules are placed in a hot air stream. The coating phase is carried out by spraying the film-forming agent, in the form of an alcoholic solution, and a proportion of talc (obtained from the formation of aggregates) followed by a sieving and drying phase. Finally, the microgranules are lubricated by addition of talc, reducing the static electricity, facilitating filling into gelatin capsules. Example 8: Missouri grape (dry extract) substances which disappear during the manufacturing process The manufacturing process can be set out in 2 main steps: , application of the Missouri grape dry extract by dusting over Neutres microgranules using a binder: 20% alcoholic solution of PVP, coating of the microgranules with a film-forming agent. The method of applying the active substance is batchwise, composed of a succession of alternate phases of application and phases of sieving and drying during which the microgranules are placed in a hot air stream. The coating phase is carried out by spraying the film-forming agent, in the form of an aqueous-alcoholic solution, and a proportion of talc (obtained frpm the formation of aggregates) followed by a sieving and. drying phase. Finally, the microgranules are lubricated by addition of talc, reducing the static electricity, -f-ac-i-l-i-ta-ting-.£i11 ing._ln.t,o gelatin capsules . Example 9: Harpagophyturn (dry extract) » Formula: substances which disappear during the manufacturing process The manufacturing process can be set out in 3 main steps: application of the Harpagophytum dry extract by dusting over Neutres microgranules using a binder: 20% alcoholic solution of PVP, precoating with Eudragit® L100, in order to prepare the surface of the microgranules for the coating, - - coating of the microgranules with a film-forming agent: Eudragit® L3 0D supplemented- with a plasticizer, ensuring gastroprotection. The method. of applying the active substance is batchwise, composed of a succession of alternate phases of application and phases of sieving and drying during which the microgranules are placed in a hot air s trearn. The application of the film-forming agents is carried out by spraying (Eudragit® L100, Eudragit® L30D, supplemented with a plasticizer: triethyl citrate) followed by a sieving and drying phase. Finally, the microgranules are lubricated by addition of talc, reducing the static electricity, thus facilitating filling into gelatin capsules. • Results of the gastroprotection trials on 3 batches of Harpagophytum microgranules The 3 batches of microgranules, manufactured according to the process described above, show results in conformity with the specifications: they are gastroprotected. Harpagoside will not be degraded by the gastric juices. Example 10; Reproducibility of the manufacturing process 1.1 Uniformity of the dosage of gelatin capsules of microgranules 1st series of values The quantities of raw materials introduced are found in the finished products: the deviations observed between the theoretical values (quantities introduced) and the measured values (quantities found) are not significant; they are less than 1%. • 2nd series of values ThE three batches studied, of the same formulation, manufactured according to the same procedure, have similar contents of active raw materials. 1.2 Uniformity of mass of the gelatin capsules of microgranules The three batches tested satisfy the test of uniformity of mass: the mean masses are within the acceptance limits and fewer than 2 gelatin capsules exhibit a deviation of plus or minus 7.5% of the mean mass and nO gelatin capsule of plus or minus 15%. The manufacturing process leads to gelatin capsules of constant quality; it is perfectly reproducible. 2. Stability of the formulas Stability results on three batches of gelatin capsules of microgranules of the same formulation, after preservation for 6 months under normal preservation conditions and 6 months under accelerated ageing: The contents of tracers of the three batches tested are similar to the theoretical contents and WE CLAIM: 1. Granules containing between 0.1 mg/g and 750 mg/g of at least one plant substance, characterized in that they each comprise a single neutral core having a particle size of between 0.2 and 4 mm coated with a layer containing the plant substance combined with polyvinylpyrrolidone. 2. Granules as claimed in claim 1, wherein the neutral core consists of a substance chosen from sugar, starch, mannitol, sorbitol, xylitol, cellulose, talc and mixtures thereof. 3. Granules as claimed in claim 1 or 2, wherein the neutral core consists of a starch/sucrose core in 20/80 mass ratios which is coated with 80% by weight of starch. 4. Granules as claimed in any one of the preceding claims, wherein the layer containing the plant substance is coated with an outer layer intended to mask the taste and/or the odour of the plant substance, to delay its release or to control its release. 5. Granules as claimed in claim 4, wherein the outer layer is intended to control the release of the plant substance and contains lac gum, PVP, a copolymer of methacrylic acid or a colloidal dispersion of ethyl cellulose with a plasticizer. 6. Granules as claimed in claim 4, wherein the outer layer is intended to delay the release of the plant substance and contains a copolymer of methacrylic acid, lac gum or a colloidal dispersion of ethyl cellulose with a plasticizer. 7. Granules as claimed in claim 4, wherein the outer layer is intended to mask the taste and/or the odour of the plant substance and contains a polyacrylate dispersion, a copolymer of methacrylic acid or hydroxypropylmethylcellulose. 8. Granules as claimed in any one of the preceding claims, wherein the plant substance is chosen from garlic, Echinacea, Ginkgo biloba, ginseng, Harpagophytum, kava, St. John's-wort, green tea, valerian, Missouri grape, artichoke, hawthorn, burdock, birch, alder buckthorn, blackcurrant, blessed thistle, Fucus, Hamamelis, horse chestnut, balm, Orthosiphon, passion flower, dandelion, horsetail, meadowsweet, sage, spirulina, boldo, nettle, North American palm and mixtures thereof. 9. Process for the preparation of granules as claimed in any one of the preceding claims, comprising coating a neutral core with a layer containing the plant substance, wherein coating of the layer containing the plant substance on the neutral core is performed by powder-coating including spraying an alcoholic solution of polyvinylpyrrolidone as a binder when the plant substance is in the form of a dry extract, or by coating in solution including spraying an alcoholic solution of polyvinylpyrrolidone as a binder when the plant substance is in the form of a soft or fluid extract. 10. Process of preparation as claimed in claim 9, wherein the granules are obtained by powder-coating when the plant substance is in dry form, that is to say in the form of plant powder or dry extract. 11. Process as claimed in claim 9, wherein the fluid extract contains from 30 to 40% alcohol. 12. Process as claimed in any one of claims 9 and 10, wherein the size of the Neutres is between 200 and 900 μm, when the plant substance is in desiccated form. 13. Process as claimed in any one of claims 9 and 11, wherein the size of the Neutres is between 900 and 1250 μm, when the plant substance is in the form of a soft or fluid extract. 14. Process as claimed in any one of claims 9, 11 and 13, wherein the percentage by mass of plant substance in the form of fluid extract used is between 15 and 50% relative to the weight of the granules. 15. Process as claimed in any one of claims 9, 10 and 12 wherein the percentage by mass of plant substance in desiccated from used may be as high as 75% relative to the weight of the granules. 16. Process as claimed in any one of the preceding claims, wherein the granules are prepared in a pan or in a fluidized air bed. Dated this 19th day of May, 2005. [DIPAK MUNDRA] OF REMFRY 8B SAGAR ATTORNEY FOR THE APPLICANTS

Documents:

463-mumnp-2005-abstract(08-11-2007).pdf

463-mumnp-2005-abstract-(8-11-2007).doc

463-mumnp-2005-cancelled pages(08-11-2007).pdf

463-mumnp-2005-claims(granted)-(08-11-2007).pdf

463-mumnp-2005-cliams(granted)-(8-11-2007).doc

463-mumnp-2005-correspondence(17-01-2007).pdf

463-MUMNP-2005-CORRESPONDENCE(2-2-2012).pdf

463-mumnp-2005-correspondence(ipo)-(09-11-2006).pdf

463-mumnp-2005-correspondence-others.pdf

463-mumnp-2005-description (complete).pdf

463-MUMNP-2005-ENGLISH TRANSLATION(2-2-2012).pdf

463-mumnp-2005-form 1(08-11-2007).pdf

463-mumnp-2005-form 13(08-11-2007).pdf

463-mumnp-2005-form 2(granted)-(08-11-2007).pdf

463-mumnp-2005-form 2(granted)-(8-11-2007).doc

463-mumnp-2005-form 3(17-01-2007).pdf

463-mumnp-2005-form 3(18-05-2005).pdf

463-mumnp-2005-form 5(18-05-2005).pdf

463-mumnp-2005-form-1.pdf

463-mumnp-2005-form-18.pdf

463-mumnp-2005-form-2.doc

463-mumnp-2005-form-2.pdf

463-mumnp-2005-form-26.pdf

463-mumnp-2005-form-3-ver-180505.pdf

463-mumnp-2005-form-3.pdf

463-mumnp-2005-form-5.pdf

463-mumnp-2005-form-pct-ib-308.pdf

463-mumnp-2005-form-pct-ipea-409(08-11-2007).pdf

463-mumnp-2005-form-pct-ipea-409.pdf

463-mumnp-2005-form-pct-separate sheet-409.pdf

463-mumnp-2005-petition under rule137(17-01-2007).pdf

463-mumnp-2005-power of authority(08-11-2007).pdf