WO2013089654A1 - Formulations effervescentes comprenant de la génistéine - Google Patents

Formulations effervescentes comprenant de la génistéine Download PDF

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Publication number
WO2013089654A1
WO2013089654A1 PCT/TR2012/000210 TR2012000210W WO2013089654A1 WO 2013089654 A1 WO2013089654 A1 WO 2013089654A1 TR 2012000210 W TR2012000210 W TR 2012000210W WO 2013089654 A1 WO2013089654 A1 WO 2013089654A1
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WO
WIPO (PCT)
Prior art keywords
effervescent
acid
formulation
range
formulation according
Prior art date
Application number
PCT/TR2012/000210
Other languages
English (en)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2013089654A1 publication Critical patent/WO2013089654A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • phytoestrogens which have estrogenic effect in variable degrees and which are similar to natural estrogens in terms of both structure and shape exert their effects directly through binding to receptors by competing with natural estrogens in the organism.
  • phytoestrogens can change the efficiency of some enzymes having a role in estrogen metabolism.
  • Phytoestrogens are divided into different subclasses according to different resources. These can be listed under four different classes in total: isoflavones, lignans, coumestans and stilbenes. Each class is composed of different compounds itself and resources of these compounds are different from each other in the diet.
  • Genistein is a compound belonging to the class of isoflavones of flavonoids in plants. Furthermore, since isoflavones are plant originated compounds having an estrogen-like biological activity, they are also called phytoestrogens. Isoflavones are present mainly in soybean and soy products. 100 g soybean comprises 111 mg genistein.
  • US512192 discloses production of genistein from a substrate of a soy product by fermentation method.
  • the inventor has developed effervescent form of the active agent formulations, the target population of which is generally women aged over 40. This dosage form is quite beneficial in terms of ease of use, accurate dosing, and high bioavailability.
  • the present invention relates to pharmaceutical formulations in effervescent form comprising genistein in order to be used in treatment and/or prevention of bone diseases particularly such as osteoporosis, osteomalacia and fibrous osteodystrophy seen mostly in post-menopausal period.
  • the effervescent formulations of the present invention comprise genistein minimum at 0.1%, preferably in the range of 0.1 to 5%, more preferably in the range of 0.1 to 2% in proportion to total weight.
  • the effervescent formulations of the present invention comprise genistein in the range of 1 to 200 mg, preferably in the range of 1 to 100 mg per unit dosage form.
  • the effervescent formulations of the present invention comprise genistein having an average particle size (dso) in the range of I to 300 ⁇ , preferably in the range of 1 to 250 ⁇ , more preferably in the range of 1 to 200 ⁇ .
  • average particle size (dso) used herein refers to particle size of 50% of the particles by volume; and it is measured in the device Malvern Mastersizer 2000 S (Scirocco 2000) by dry method.
  • the effervescent formulations of the present invention comprise genistein as the active agent, at least one pharmaceutically acceptable effervescent acid, at least one effervescent base and at least another excipient.
  • excipients that can be used in the effervescent formulations of the present invention can be selected from diluents, binders, sweeteners, lubricants, solvents, flavouring agents, pH regulating agents, colouring agents or combinations thereof.
  • the disintegrants that can be used in the effervescent formulations of the present invention can be selected from a group comprising cellulose derivatives such as cross-linked carboxymethyl cellulose and/or its salts, microcrystalline cellulose, cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, methyl cellulose; sodium starch glycolate, alginic acid, sodium alginate, chitosan, ' colloidal silicone dioxide, starch, pregelatinized starch, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone or combinations thereof.
  • cellulose derivatives such as cross-linked carboxymethyl cellulose and/or its salts, microcrystalline cellulose, cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, methyl cellulose
  • the lubricants that can be used in the effervescent formulations of the present invention can be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc.
  • metallic stearates such as magnesium stearate, calcium stearate, aluminium stearate
  • fatty acid esters such as sodium stearyl fumarate
  • fatty acids such as stearic acid
  • fatty alcohols glyceryl behenate
  • mineral oil such as paraffins, hydrogenated vegetable oils
  • the effervescent formulations of the present invention comprise at least one lubricant in the range of 1 to 5% by weight, preferably in the range of 1 to 4% by weight, more preferably in the range of 1 to 3% by weight.
  • the binders that can be used in the effervescent formulations of the present invention can be selected from starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatine; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or a combination thereof.
  • starches such as potato starch, corn starch, wheat starch
  • sugars such as sucrose, glucose, dextrose, lactose, maltodextrin
  • natural and synthetic gums such as star
  • the effervescent formulations of the present invention comprise at least one binder in the range of 1 to 10% by weight, preferably in the range of 1 to 8% by weight, more preferably in the range of 1 to 5% by weight.
  • the preferred binder is povidone.
  • the diluents that can be used in the effervescent formulations of the present invention can be selected from a group comprising alkaline metal carbonates such as calcium carbonate; alkaline metal phosphates such as calcium phosphate; alkaline metal sulphates such as calcium sulphate; cellulose derivatives such as cellulose, microcrystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, caoline, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and/or anhydrates, hydrates and/or their pharmaceutically acceptable derivatives or combinations thereof.
  • the effervescent formulations of the present invention comprise at least one diluent minimum at 1% by weight, preferably in the range of 1 to 10% by weight, more preferably in the range
  • the sweeteners that can be used in the effervescent formulations of the present invention can be selected from sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharin, saccharin salts, acesulfame potassium, aspartame, D- tryptophan, monoammonium glycyrrhizinate, neohesperidin, dihydrochalcone, thaumatin, neotam, alitam, stevioside and cyclamates or a combination thereof.
  • the effervescent formulations of the present invention comprise at least one sweetener minimum at 0.5% by weight, preferably in the range of 0.5 to 1.5% by weight.
  • natural aroma oils such as peppermint oil, oil of wintergreen, clove bud oil, parsley oil, euca
  • the colouring agents that can be used in the effervescent formulations of the present invention can be selected from a group comprising non-water soluble pigments, iron and titanium oxides, talc, beta carotene or combinations thereof.
  • the solvents that can be used in the effervescent formulations of the present invention can be alcohol or alcohol mixtures or deionised water.
  • the preferred solvent in the formulations of the present invention is deionised water.
  • the effervescent bases that can be used in the effervescent formulations of the present invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen citrate or combinations thereof.
  • the effervescent formulations of the present invention comprise at least one effervescent base minimum at 1% by weight, preferably in the range of 1 to 70% by weight, preferably in the range of 1 to 60%, more preferably in the range of 1 to 50% by weight.
  • the effervescent acids that can be used in the effervescent formulations of the present invention can be selected from a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or their hydrates, anhydrates or combinations thereof.
  • the effervescent formulations of the present invention comprise at least one effervescent acid minimum at 20% by weight, preferably in the range of 20 to 80% by weight, more preferably in the range of 20 to 75% by weight.
  • the formulations of the present invention can be produced by any production methods existing in the prior art. These production methods can be wet granulation, dry granulation, dry blending; though, the method preferred for production of the formulations according to the present invention is wet granulation method.
  • powder mixture comprising the active agent and various excipients which are not fluidal enough causes aggregation in the powder mass due to the effect of cohesive forces.
  • a characteristic feature of the effervescent formulations of the present invention comprising genistein as the active agent, at least one pharmaceutically acceptable effervescent acid, at least one effervescent base and at least one other excipient is that said formulations comprise a) Citric acid anhydrate and b) At least another effervescent acid as the effervescent acid.
  • average particle size (dso) of citric acid anhydrate comprised in said formulations is minimum 400 ⁇ , preferably in the range of 400 to 600 ⁇ , more preferably in the range of 400 to 550 ⁇ .
  • a characteristic feature of the effervescent formulations of the present invention comprising genistein as the active agent, at least one pharmaceutically acceptable effervescent acid, at least one effervescent base and at least one other excipient is that said formulations comprise a) Citric acid anhydrate having an average particle size (dso) of minimum 400 ⁇ , preferably in the range of 400 to 600 ⁇ , more preferably in the range of 400 to 550 ⁇ and b) At least one other effervescent acid as the effervescent acid.
  • the amount of citric acid anhydrate comprised in the effervescent formulations of the present invention is in the range of 20 to 45% by weight, preferably in the range of 20 to 40% by weight, more preferably in the range of 20 to 35% by weight.
  • the amount of at least one effervescent acid comprised in the effervescent formulations of the present invention is minimum at 5% by weight, preferably in the range of 5 to 20% by weight, more preferably in the range of 5 to 15% by weight.
  • the second effervescent acid used herein is preferably malic acid and average particle size (dso) of malic acid is minimum 300 ⁇ , preferably in the range of 1 to 250 ⁇ , more preferably in the range of 1 to 200 ⁇ .
  • ⁇ characteristic feature of the effervescent formulations of the present invention comprising genistein as the active agent, at least one pharmaceutically acceptable effervescent acid, at least one effervescent base and at least one other excipient is that said formulations comprise a) Citric acid anhydrate having an average particle size (d 5 o) of minimum 400 ⁇ , preferably in the range of 400 to 600 ⁇ , more preferably in the range of 400 to 550 ⁇ and b) Malic acid having an average particle size (d 50 ) of minimum 300 ⁇ , preferably in the range of 1 to 250 ⁇ , more preferably in the range of 1 to 200 ⁇ as the effervescent acid.
  • a characteristic feature of the formulations according to the present invention is that the ratio of citric acid anhydrate to malic acid comprised in the formulations is in the range of 1 to 10 by weight, preferably in the range of 1 to 8 by weight, more preferably in the range of 1 to 5 by weight.
  • effervescent acids having a particle size in the ranges given has improved solubility characteristics of effervescent genistein formulations.
  • the effervescent formulations of the present invention can optionally comprise at least one other effervescent acid in addition to the effervescent acids given above.
  • the third effervescent acid that can be used in the formulations can be selected from the group given in the description.
  • the third effervescent acid comprised in the formulations is citric acid anhydrate having an average particle size (d50) preferably minimum 150 ⁇ , preferably in the range of 150 ⁇ to 300 ⁇ , more preferably in the range of 150 ⁇ to 250 ⁇ .
  • a characteristic feature of the effervescent formulations of the present invention comprising genistein as the active agent, at least one pharmaceutically acceptable effervescent acid, at least one effervescent base and at least one other excipient is that said formulations comprise; a) Citric acid anhydrate having an average particle size (d 50 ) of minimum 400 ⁇ , preferably in the range of 400 ⁇ to 600 ⁇ , more preferably in the range of 400 to 550 ⁇ , b) Malic acid having an average particle size (d 50 ) of minimum 300 ⁇ , preferably in the range of 1 ⁇ to 250 ⁇ , more preferably in the range of 1 ⁇ to 200 ⁇ as the effervescent acid and c) Citric acid anhydrate having an average particle size (d 50 ) of minimum 150 ⁇ , preferably in the range of 150 ⁇ to 300 ⁇ , more preferably in the range of 150 ⁇ to 250 ⁇ .
  • the formulations of the present invention can optionally be used with other active agent or agents in combined form.
  • Dosage forms can be taken separately, together or sequentially; though they can also be taken by combining genistein with the other active agent or agents in a single dosage form for combined therapy.
  • the other active agent or agents that can be used together with genistein in combined therapy can be minerals such as calcium, potassium, magnesium, iron, sodium, zinc or their salts such as carbonate, sulphate; vitamins such as vitamin A, B vitamins such as Bl, B12, B6 and/or folic acid, vitamin C, vitamin D, vitamin E.
  • vitamins such as vitamin A, B vitamins such as Bl, B12, B6 and/or folic acid, vitamin C, vitamin D, vitamin E.
  • One or two of the other active agents listed above can be combined with genistein in combined therapy.
  • the present invention comprises binary and ternary combinations of genistein with the other active agents explained above.
  • the other active agent or agents that can be used in combined therapy can be produced together with genistein and by the same production method, though they can also be prepared by producing the active agent formulations separately and then combining them.
  • the second active agent preferred in the effervescent formulations of the present invention is calcium or a pharmaceutically acceptable carbonate or sulphate salt thereof and/or vitamin D.
  • the method wet granulation preferred for production of the formulations according to the present invention is basically composed of the steps of wet granulating the dry mixture comprising effervescent acids and suitable excipients with the granulation solution comprising suitable excipients and solvent, drying the granules, adding active agent and optionally other excipients into the dry granules.
  • the wet granulation method given is implemented by adding citric acid anhydrate portions/fractions having two different particle sizes into the formulation independently from each other in different steps.
  • a characteristic feature of this production method according to the present invention is that the component b) comprised as the effervescent acid in the formulations is added into the formulation before wet granulation process, the component a) is added into the formulation after granulation process.
  • the most appropriate powder fluidity and therefore the least aggregation can be obtained by adding the component b) into the formulation before the wet granulation process, and the component a) after the granulation process.
  • the preferred method for production of the formulations of the present invention is as follows:
  • Effervescent formulations comprising genistein ervescent formulations comprising Genistein and Calcium

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formulations effervescentes comprenant de la génistéine comme agent actif et un anhydrate d'acide citrique comme acide effervescent et au moins un autre acide effervescent.
PCT/TR2012/000210 2011-12-16 2012-12-10 Formulations effervescentes comprenant de la génistéine WO2013089654A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
TR2011/12517 2011-12-16
TR201112518 2011-12-16
TR201112517 2011-12-16
TR2011/12518 2011-12-16

Publications (1)

Publication Number Publication Date
WO2013089654A1 true WO2013089654A1 (fr) 2013-06-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106138005A (zh) * 2016-08-05 2016-11-23 贵州汉方药业有限公司 一种泡腾效果好的碳酸钙维生素c泡腾片及其制作方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US512192A (en) 1894-01-02 harden
WO1999038509A1 (fr) 1998-01-28 1999-08-05 Dusan Miljkovic Formulations isoflavonoides s'administrant par voie orale
WO2002074308A1 (fr) * 2001-03-15 2002-09-26 Roche Vitamins Ag Composition destinee a la prevention de l'osteoporose comprenant une combinaison d'isoflavones et d'acides gras polyinsatures
CN1589786A (zh) * 2003-09-01 2005-03-09 郑州博凯医药保健品有限公司 一种含大豆异黄酮的复合泡腾制剂
WO2010017361A1 (fr) * 2008-08-07 2010-02-11 Phyzz, Inc. Comprimés/granules effervescents
WO2012002918A1 (fr) * 2010-06-03 2012-01-05 Mahmut Bilgic Formulation pour l'ostéoporose
WO2013043142A1 (fr) * 2011-08-08 2013-03-28 Mahmut Bilgic Procédé de production pour formulations pharmaceutiques comprenant une isoflavone

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US512192A (en) 1894-01-02 harden
WO1999038509A1 (fr) 1998-01-28 1999-08-05 Dusan Miljkovic Formulations isoflavonoides s'administrant par voie orale
WO2002074308A1 (fr) * 2001-03-15 2002-09-26 Roche Vitamins Ag Composition destinee a la prevention de l'osteoporose comprenant une combinaison d'isoflavones et d'acides gras polyinsatures
CN1589786A (zh) * 2003-09-01 2005-03-09 郑州博凯医药保健品有限公司 一种含大豆异黄酮的复合泡腾制剂
WO2010017361A1 (fr) * 2008-08-07 2010-02-11 Phyzz, Inc. Comprimés/granules effervescents
WO2012002918A1 (fr) * 2010-06-03 2012-01-05 Mahmut Bilgic Formulation pour l'ostéoporose
WO2013043142A1 (fr) * 2011-08-08 2013-03-28 Mahmut Bilgic Procédé de production pour formulations pharmaceutiques comprenant une isoflavone

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106138005A (zh) * 2016-08-05 2016-11-23 贵州汉方药业有限公司 一种泡腾效果好的碳酸钙维生素c泡腾片及其制作方法
CN106138005B (zh) * 2016-08-05 2021-04-20 贵州汉方药业有限公司 一种泡腾效果好的碳酸钙维生素c泡腾片及其制作方法

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