Title of Invention

"SUSTAINED-RELEASE MICROGRANULES CONTAINING GINKGO BILOBA EXTRACT AND THE PROCESS FOR PREPARATION THEREOF"

Abstract

The present invention related to sustained release microgranules containing a Ginkgo biloba extract comprising a neutral core coated with a layer containing Ginkgo biloba extract with at least one pharmaceutically acceptable excipient, a water-repellent layer, coating said core, comprising at least a polymer or a thermoplastic excipient, and an outer polymeric layer which sustain the release of said extract from the active layer. The invention also relates to a process for preparing the sustained release microgranules.

Full Text

The subject of the present invention is a new stable formulation, in the form of sustained-release microgranules containing Ginkgo Biloba extract as well as the process for preparing it. More precisely, the present invention relates to microgranules in the form of a core containing Ginkgo Biloba extract with at least one pharmaceutically acceptable excipient, an intermediate layer coating said core, and an outer layer, which enables sustained release of Ginkgo Biloba from the core. Ginkgo Biloba extract contains flavone glycosides (flavonoids), such as quercetin, kaemferol, isorhamnetin and terpenes (heterosides) such as Bilobadide, ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J. Flavonoids are known to have anti Platelet-activiting Factor properties, thus terpenes have corticoid-like, anti-ischaemic properties and are known to be antagonists of peripherical benzodiapine receptors, inducing anti stress activity. Powders extracted from plant substances are usually very hygroscopic and they therefore pump moisture from the granules and from the gelatin capsule, which become brittle. This leads to poor stability properties. Plant extracts have poor flowability and compressibility properties. Thus, formulation of such extracts in the form of sustained release tablets is not possible, as it requires homogeneous mixtures of extracts with pharmaceutical excipients during all compression steps. WO 00/69414 relates to granules containing at least one plant substance, characterized in that they each comprise a neutral core, which has a grain size of. between 200 and 4 000 µm and which is coated with a layer containing the plants substance, combined with a pliarmaceutically suitable excipient. The multiparticulate form of the invention maikes it possible to obtain a stable and reproducible sustained release multiparticulate dosage form comprising Ginkgo Biloba extract, with the advantage of boing stable during storage, particularly in accelerated storage conditions, defined in ICH as 40°C for temperature and 75% for relative humidity. According to the present invention, the sustained release micx'ogranules contain a Ginkgo Biloba extract, characteriaed by the release of total flavone glycosides having the following profile of dissolution rates, measured at 37.0°C + 0.5°C/ with a Dissolution Test Apparatus I (Basket method at 100 rpm, 900 mL of purified water, UV Detection : 272 nm) : (Table Removed) More specifically, the sustained release microganules are characterized by the following prrofile ; (Table Removed) These granules containing Ginkgo Biloba extract are further characterized in that they comprise : a neutral core coated with a. layer containing Ginkgo Biloba extract, with at least one pnartnaceutically acceptable excipient, an optionnal water-repellent layer, coating said core, comprising at least a polymer or a thermoplastic excipient, an outer polymeric layer which sustain the release of said extract from the active core. Ginkgo Biloba extract may be in a concentrated preparation which are liquid, solid or of intermediate consistency, generally obtained from dried plant raw materials, preferably leaves, or in a powder-form. Fluid extracts are liquid preparations of which, in general, a pox Lion 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 coneialency 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 title or water is used. Soft extracts have in general a dry residue which is not less than 70 per cent by weight. 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 dx-y residue which is not less than 95 per cent by weight . 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. Ginkgo Biloba extracts contain up to 40% by weight of flavonoids, and up 10% by weight of terpenes. Preferred Ginkgo Biloba extracts contain 24% by weight of flavonoids and 6% by weight of terpenes. The neutral core consists of a substance? chosen, from sugar, starch, mannitol, sorbitol, xylitol, cellulose, talc and mixtures thereof. The neutral core may also consist of a starch/sucrose core in 80/20 mass ratios which as 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 Ginkgo Biloba extract contains at least one pharmaceutically acceptable excipient, selected from the group comprising a binder, an antistatic agent or a lubricant, preferably a binder. The binder is selected from the group consisting of cellulosic polymers, such as ethylcellulose, hydroxypropylcellulose and hydroxypropylmethyl cellulose, acrylic polymers, such as insoluble acrylate ammoniomethacrylate copolymer, polyacrylate as polyroethacrylic copolymer, povidones, copovidones, polyvinylalcohols, shellac, alginic acid, sodium alginate, starch, pregelatinized starch, sucrose and its derivatives, guar gum, polyethylene glycol, preferably polyvinylpyrrolidone (PVP) or shellac. The binder is used in proportions of at most about 50%, preferably at most 20% by weight of Ginko Biloba extract. The antistatic agent, which can be used as flow aid, is selected from the group consisting of micronised or non micronised talc, fumed silica {Aerosila R972), colloidal silica (Aerosil®200), precipitated silica (Sylold® FP244) and mixtures thereof. The antistatic agent is used in proportions of at most 5%, preferably 2% by weight relative to the weight of said granules of GB extract. The lubricant is selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, micronised polyoxyethyleneglycol (micronised Macrogol 6000), ieukine, sodium benzoate and mixtures thereof. The amount of lubricant is from 0 to 3 %, preferably from 1 to 2 % by weight, based on the weight of the granules. In order to prevent sticking between granules, mainly due to Ginkgo Biloba extract, it is necessary to optionally appiy an intermediate layer between the active layer- comprising the Ginkgo Biloba extract and the polymeric layer ensuring sustained release of said extract. Said intermediate water-repellent layer-comprises at least a polymer or a thermoplastic excipient. Microgranules can be manufactured by a number of different processes, for example extrusion-spheronisationf fluid air bed process or a coating-pan method. Extrusion-Spheronization is suitable for pellets with high content of active substance, but need more equipment. For the manufacture of the granules of the invention, the coating-pan method is preferred, as it requires only simple equipment and operation. Good sphericity and appropriate size of microgranule benefit to control drug release by coat ing film and to achieve good stability of the finished product. The process for the preparation of sustained-release microgranulea containing Ginkgo Biloba extract comprises the successive steps consisting in; Applying over a neutral core, a layer comprising Ginkgo Biloba extract, and at least one pnarmaceutical excipient, preferably a binder. Coating said core with an intermediate; Layer over the thus obtained granules by spraying thereon a suspension, or a solution comprising a polymer or a thermoplastic excipient Coating the thus coated granules with an outer layer by spraying a suspension, a. dispersion or a solution of a sustained-release coating composition, Drying the thus obtained coated granules. In this process, all stepa can be performed in different or in the same equipment, each step being performed in the presence of a mixture of excipients which are identical or different. The prepared coating liquid is either water-based or prepared using organic solvents, preferably isopropylic alcohol. According to an advantageous embodiment, this coating liquid is suitable to be sprayed with conventional spray layering equipment, as for example a coating pan or a fluidized air bed equipped with a top insert or bottom (wurster) insert . According to the process of the invention, the cores are obtained by powder-coat ing, advantageously carried out by alternately spraying an alcoholic or aqueous-alcoholic solution comprising at least one pharmaceutical excipient, preferably a binder, and the Ginkgo Biloba extract. 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. In the examples below, the following excipients are used : - Ginkgoi Biloba extract containing 24% by weight cf flavone glycosides and 6% by weight (Table Removed) Dissolution Test Method This method was developed in order to detect release of total flavone glycosides from microgranulee containing Ginkgo Biloba extract, - Apparatus : Dissolution Test Apparatus I (Basket method) - Speed : 10O rpm - Volume : 900 mL of purified water - Temperature : 37.0°C t0.5°C - Sampling (mL): 10 ml - UV Detection : UV at 272 nm Water content assay Water content is determined using Karl Fischer Water determination. Content assay method This method was developed in order to assay total flavone glycosides content from micro-granules containing Ginkgo Biloba extract, and specifically assay quercetin, kaemfortol and isohamnetin content from granules. Source : Chinese Pharmacopeia 2000 Part One, Appendix VI D - Apparatus : HP 1100 Liquid Chromatograph f im ,;dlng quaternary pump, uv detector, diode array detector," chemical work station) , Chxomatographic conditions I HPLC Column : C18 4,6*250 nm 15 jam Beijing Dima Mobile Phase : methanol, 0,4%v/v phosphoric acid solution (50/50) Sampling : 10 µl UV Detection : 360 nm Example 1 step 1 - drug loading 84 Grams of neutral cores are placed in a A 10% (w/w) binding solution of shellac, dissolveo in i.oDropyl alcohol is prepared, then sprayed over neutral core, as Ginkgo Biloba extract is gradually added at the same time. Granules are then sieved and dried for 10 hour at 60°C. Step 2 - Intermediate water-repellent coating 4,8 grams of monosterate glycerides are dissolved in isopropyl alcohol at 10% (w/w) and the resulting solution is sprayed over granules from step 1. Step 3 - Sustained -release coating The thus obtained granules, were coated by spraying thereon a water dispersion of Aquacoat ECD30 at 16 % (weight/weight) containing dibutyl sebacate as plasticizer (25% versus dry polymer). The amount of coating was of 8 % by weight with respect to the weight of the granules from step 2. Coated microgranules are then sieved and dried in a coating pan at. 65°C for 10 hours. The sustained-release microgranules resulting from, the process have the following formula (table l) : Example 2 ; Step 1 - drug loading 498 grams of neutral cores are placed in a coating-pan, A 10% (w/w) binding solution of PVP K30, dissolved in isopropyl alcohol is prepared, then sprayed over neutral core as Ginkgo Biloba extract is gradually added at the same time. Granules are then sieved and dried for 10 hour at 60°C. Step 2 - Sustained -release coating A 10% (w/w) coating solution containing 14 grams of shellac in isopropyl alcohol is prepared and sprayed on the microgranules with spraying gun, alternatively with addition of an appropriate quantity of talc. Coated microgranules are then sieved and dried in a coating pan at 65°C for 10 hours, The sustained-release microgranules resulting from the process have the following formula : Table 3 (Table Removed) The dissolution rates of total flavone glycosides from the sustained-release granules were measured. according to the Chinese Pharmacopeia method : The results are given in following Table 4 : IT (h) % released(w/w) 20, 7% 38. 1% 54.4% 62.3% 12 69. 1% Example 3 Sustained release microgranules comprising Ginkgo Blloba are prepared according the process of example to example 2 (see table 5) : Table 5 (Table Removed) Microgranules thus obtained are encapsulated in hard-gelatin capsules, each containing 120 mg of Ginkgo Biloba extract, said capsules being packed in PVC/Alu blisters. Stability of the resulting product was tested in long term conditions (25°C ± 2°C/HR 60% + 10%) and in-accelerated conditions (40°C ± 2°C/HR 75% ± 5%) , as defined, by ICH, Results are summarized in tables 6 and 7. Conclusion ; After 3 months, results comply with, specifications. The microgranules remain stable in both storage conditions. We claim 1. Sustained release microgranules containing a Ginkgo biloba extract, characterized by the release of total flavone glycosides having the following profile of dissolution rates measured at 37.0 °C ± 0.5°C, with a Dissolution Test Apparatus I (Basket method at 100 rpm, 900mL of purified water UV Detection: 272 nm): 2. (Table Removed) wherein comprising: -a neutral core coated with a layer containing Ginkgo biloba extract with at least one pharmaceutically acceptable excipient, - a water-repellent layer, coating said core, comprising at least a polymer or a thermoplastic excipient, and -an outer polymeric layer which sustain the release of said extract from the active layer. Sustained release microgranules as claimed in claim 1 characterized by the following profile: (Table Removed) 3.Sustained release microgranules as claimed in anyone of claims 1 and 2, wherein the neutral core consists of a substance chosen from sugar, starch, mannitol, sorbitol, xylitol, cellulose, talc and mixtures thereof. 4. Sustained release microgranules as claimed in claim 3 wherein the neutral core consists of a starch/sucrose core in 80/20 mass ratios. 5. Sustained release microgranules as claimed in any one of claims 1 to 4 wherein the Ginkgo Biloba extract contains up to 40% by weight of flavonoids, and up to 10 % by weight of terpenes. 6. Sustained release microgranules as claimed in claim 5 wherein the Ginkgo Biloba extract preferably contains up to 24% by weight of flavonoids, and up to 6% by weight of terpenes. 7. Sustained release microgranules as claimed in anyone of claims 2 to 6 wherein the layer containing the Ginkgo Biloba extract contains at least one pharmaceutically acceptable excipient, selected from the group comprising a binder, an antistatic agent or a lubricant, preferably a binder. 8. Sustained release microgranules as claimed in claim 7 wherein the binder is selected from the group consisting of cellulosic polymers, such as ethylcellulose, hydroxypropylcellulose and hydroxypropylmethyl cellulose, acrylic polymers, such as insoluble acrylate ammoniomethacrylate copolyrner, polyacrylate as polymethacrylic copolyrner, povidones, copovidones, polyvinylalcohols, shellac, alginic acid, sodium alginate, starch pregelatinized starch, sucrose and its derivatives, guar gum, polyethylene glycol, preferably polyvinylpyrrolidone (PVP) or shellac. 9. Sustained release microgranules as claimed in claim 8 wherein the binder is used in proportions of at most 50%, preferably at most 20% by weight of Ginkgo Biloba extract. 10. Sustained release microgranules as claimed in any one of claims 7 to 9, wherein the antistatic agent, which can be used as flow aid, is selected from the group consisting of micronised or non micronised talc, fumed silica, colloidal silica, precipitated silica and mixtures thereof. 11. Sustained release microgranules as claimed in claim 10 wherein the antistatic agent is used in proportions of at most 5%, preferably 2% by weight relative to the weight of said granules of Ginkgo Biloba. 12. Sustained release microgranules as claimed in any one of claims 7 to 11 wherein the lubricant is selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, micronised polyoxyethyleneglycol, leukine, sodium benzoate and mixtures thereof. 13. Sustained release microgranules as claimed in claim 12 wherein the amount of lubricant is from 0 to 3%, preferably from 1 to 2% by weight, based on the weight of the granules. 14. Sustained release microgranules as claimed in any one of claims 2 to 13 wherein the intermediate water-repellent layer comprises at least a polymer or a thermoplastic excipient. 15. Sustained release microgranules as claimed in claim 14 wherein the polymer is selected from the group consisting of cellulosic polymers, such as ethylcellulose, hydroxypropylcellulose and hydroxypropylmethyl cellulose, acrylic polymers, such as insoluble acrylate ammoniomethacrylate copolymer, polyacrylate as polymethacrylic copolymer, povidones, copovidones, polyvinylalcohols, shellac, alginic acid, sodium alginate, starch, pregelatinized starch, sucrose and its derivatives, guar gum, polyethylene glycol, preferably polyvinylpyrrolidone (PVP) or shellac. 16. Sustained release microgranules as claimed in any one of claims 2 to 15 wherein the outer polymeric layer contains at least one coating agent selected from the group consisting of cellulosic polymers, acrylic polymers, shellac and mixtures thereof. 17. Sustained release microgranules as claimed in claim 16 wherein the cellulosic polymer is selected among ethylcellulose, hydroxypropylcellulose and/or hydroxypropylmethylcellulose. 18. Sustained release microgranules as claimed in 16 wherein the acrylic polymer is selected from insoluble acrylate ammonio-methacrylate copolymer, polyacrylate, or methacrylic copolymers, and combinations thereof. 19. Sustained release microgranules as claimed in claim 18 wherein the outer polymeric layer additionally contains a plasticizer, a surfactant, an antistatic agent and/or a lubricant. 20. Sustained release microgranules as claimed in claim 19 wherein the plasticizer is selected from the group consisting of dibutyl sebacate, triacetine, triethylacetate, triethylcitrate, ethylphtalate, or mixtures thereof. 21. Sustained release microgranules as claimed in claim 20 wherein the plasticizer is used in proportions of at most 30%, preferably 10% by weight of the coating polymers. 22. Sustained release microgranules as claimed in any one of claims 7 to 21 wherein the antistatic agent is selected from the group comprising micronised or non micronised talc, fumed silica, colloidal silica, precipitated silica and mixtures thereof. 23. Sustained release microgranules as claimed in claim 22 wherein the antistatic agent is used in proportions of at most 10%, preferably between 0 and 3% by weight, more preferably less than 1% by weight. 24. A process for the preparation of sustained release microgranules as claimed in any one of claims 1 to 23 wherein comprising the successive steps of - applying over a neutral core, a layer comprising Ginkgo Biloba extract, and at least one pharmaceutical excipient, preferably a binder. coating said core with an intermediate layer over the thus obtained granules by spraying thereon a suspension, or a solution comprising a polymer or a thermoplastic excipient. coating the thus coated granules with an outer layer by spraying a suspension, a dispersion or a solution of a sustained-release coating composition, drying the thus obtained coated granules. 25. The process for the preparation of sustained release microgranules as claimed in claim 24 wherein the layer is applied over the neutral cores by spraying a coating alcoholic or aqueous alcoholic solution containing the Ginkgo Biloba extracts and the excipient. 26. The process for the preparation of sustained release microgranules as claimed in claim 25 wherein the alcoholic or aqueous alcoholic solution contains isopropylic alcohol. 27. The process for the preparation of sustained release microgranules as claimed in claim 25 wherein the layer applied over the neutral cores is a 10% w/w binding solution of shellac dissolved in isopropyl alcohol. 28. The process for the preparation of sustained release microgranules as claimed in any one of claims 24 to 27 wherein the outer coating layer is a water dispersion of ethycellulose at 16% w/w containing 25% w/w of dibutyl sebacate versus dry polymer.

Documents:

1841-DELNP-2006-Abstract-(18-11-2008).pdf

1841-delnp-2006-abstract.pdf

1841-DELNP-2006-Claims-(18-11-2008).pdf

1841-delnp-2006-claims.pdf

1841-DELNP-2006-Correspodence Others-(27-06-2011).pdf

1841-DELNP-2006-Correspondence-Others-(04-11-2008).pdf

1841-DELNP-2006-Correspondence-Others-(17-02-2009).pdf

1841-DELNP-2006-Correspondence-Others-(18-11-2008).pdf

1841-DELNP-2006-Correspondence-Others-(27-06-2008).pdf

1841-delnp-2006-correspondence-others.pdf

1841-DELNP-2006-Description (Complete)-(18-11-2008).pdf

1841-delnp-2006-description (complete).pdf

1841-DELNP-2006-Form-1-(18-11-2008).pdf

1841-DELNP-2006-Form-1-(27-06-2011).pdf

1841-delnp-2006-form-1.pdf

1841-DELNP-2006-Form-18-(18-11-2008).pdf

1841-delnp-2006-form-18.pdf

1841-DELNP-2006-Form-2-(18-11-2008).pdf

1841-DELNP-2006-Form-2-(27-06-2011).pdf

1841-delnp-2006-form-2.pdf

1841-DELNP-2006-Form-3-(04-11-2008).pdf

1841-delnp-2006-form-3.pdf

1841-DELNP-2006-Form-5-(18-11-2008).pdf

1841-delnp-2006-form-5.pdf

1841-delnp-2006-gpa.pdf

1841-delnp-2006-pct-101.pdf

1841-DELNP-2006-PCT-210.pdf

1841-DELNP-2006-PCT-301.pdf

1841-delnp-2006-pct-304.pdf

1841-DELNP-2006-PCT-306.pdf

1841-delnp-2006-pct-308.pdf

1841-DELNP-2006-Petition Othors-(27-06-2011).pdf

1841-DELNP-2006-Petition-137-(17-02-2009).pdf