WO2013089654A1 - Effervescent formulations comprising genistein - Google Patents
Effervescent formulations comprising genistein Download PDFInfo
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- 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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- effervescent
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- 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
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- 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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Abstract
The present invention relates to effervescent formulations comprising genistein as the active agent and citric acid anhydrate as the effervescent acid and at least one other effervescent acid.
Description
EFFERVESCENT FORMULATIONS COMPRISING GENISTEIN
The present invention relates to effervescent formulations comprising genistein as the active agent and citric acid anhydrate as the effervescent acid and at least another effervescent acid.
The Prior Art Plant originated estrogens or phenolic compounds having estrogenic effect are called phytoestrogens. 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. In addition, 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.
In recent years, many studies have been conducted on potential protective effects of isoflavones against cardiovascular diseases, menopause symptoms, bone diseases such as osteoporosis, osteomalacia and fibrous osteodystrophy and hormone-associated cancers (breast and prostate cancer).
In the prior art, there are many applications about the methods of obtaining said compounds.
For instance, the application numbered US512192 discloses production of genistein from a substrate of a soy product by fermentation method.
The application numbered WO99/38509, on the other hand, discloses a genistein formulation produced by microemulsion method.
However, the prior art does not refer to use of this plant extract in a pharmaceutically effective dosage form.
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.
Detailed Description of the Invention
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 μηι, preferably in the range of 1 to 250 μιη, more preferably in the range of 1 to 200 μηι. The term "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.
The other 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.
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.
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. 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 of 1 to 8% by weight.
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.
The flavouring agents that can be used in the effervescent formulations of the present invention can be selected from natural aroma oils (such as peppermint oil, oil of wintergreen, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, 1- methyl acetate, sage, eugenol, oxanon, alpha- irisone, marjoram, lemon, orange, blackberry, propenyl guaetol acetyl, cinnamon, vanilla, timole, linalol, cinnamaldehyde glycerol acetal, N-substituted p-menthane-3-carboxamide, 3,1-methoxy propane 1.2-diol or a combination thereof.
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.
However, the inventor has encountered an unexpected problem during production of the effervescent pharmaceutical formulations of the present invention.
According to this, 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.
In the formulations produced this way, unit dose uniformity cannot be obtained. This reduces therapeutically effective dose amount taken by the patient, in other words reduces bioavailability and sufficient quality standard cannot be attained in the final product formulations.
The inventor has solved this problem by adjusting type and particle size of the effervescent acid or acids constituting minimum 20% of the formulations by weight.
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.
Another characteristic feature of the effervescent formulations of the present invention is that average particle size (dso) of citric acid anhydrate comprised in said formulations is minimum 400 μτη, preferably in the range of 400 to 600 μπι, more preferably in the range of 400 to 550 μπι. In other words, 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 μπι, preferably in the range of 400 to 600 μπι, more preferably in the range of 400 to 550 μπι 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 μηι, preferably in the range of 1 to 250 μπι, more preferably in the range of 1 to 200 μπι.
Ά 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 (d5o) of minimum 400 μπι, preferably in the range of 400 to 600 μπι, more preferably in the range of 400 to 550 μηι and b) Malic acid having an average particle size (d50) of minimum 300 μηι, preferably in the range of 1 to 250 μηι, more preferably in the range of 1 to 200 μπι 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.
Furthermore, use of 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 μπι, preferably in the range of 150 μπι to 300 μηι, more preferably in the range of 150 μηι to 250 μπι.
In other words, 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 (d50) of minimum 400 μπι, preferably in the range of 400 μπι to 600 μιη, more preferably in the range of 400 to 550 μπι, b) Malic acid having an average particle size (d50) of minimum 300 μιη, preferably in the range of 1 μπι to 250 μπι, more preferably in the range of 1 μιη to 200 μιη as the effervescent acid and c) Citric acid anhydrate having an average particle size (d50) of minimum 150 μιη, preferably in the range of 150 μηι to 300 μπι, more preferably in the range of 150 μιη to 250 μηι. The formulations of the present invention can optionally be used with other active agent or agents in combined form. The term "other active agent" mentioned herein refers to various vitamins and/or minerals required for human body.
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. One or two of the other active agents listed above can be combined with genistein in combined therapy. In other words, 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.
In the case that citric acid anhydrate having two different particle sizes and malic acid are used in the formulations of the present invention, 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. In other words, 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:
I. Obtaining the granulation solution by mixing at least one pharmaceutically acceptable binder and at least one solvent,
Dry-mixing malic acid -component (b)-, citric acid anhydrate -component (c)- having fine particle size, at least one pharmaceutically acceptable excipient and optionally the second active agent,
Wet-granulating the obtained dry mixture with the granulation solution obtained in the first step,
Granulating the obtained granules with the solvent again and drying the granules,
Adding citric acid anhydrate -component (a)- having coarse particle size and at least one pharmaceutically acceptable sweetener into the dry granules and mixing them,
VI. Adding genistein, optionally one other active agent and other excipients into the mixture and mixing them again,
Optionally compressing the mixture in tablet form.
The examples of the formulation of the present invention are given below. These examples are given in order to elucidate the subject of the present invention, yet the present invention is not limited to these examples.
EXAMPLES
1. Effervescent formulations comprising genistein
ervescent formulations comprising Genistein and Calcium
Content (%) of Amount in Unit Dose
Genistein 31.5
Calcium carbonate 0.7
Vitamin D 0.3
Citric acid anhydrate
45
(Average particle size: 430 μηι)
Malic acid 10
Effervescent base 4
Diluent 3
Binder 1.5
Sweetener 1
Lubricant 2.5
Flavouring agent 0.25
Colouring agent 0.25
Total 100
Content (%) of Amount in Unit Dose
Genistein 31.5
Calcium carbonate 0.7
Vitamin D 0.3
Citric acid anhydrate 25
(Average particle size: 450 μηι)
Citric acid anhydrate 20
(Average particle size: 190 μιη)
Malic acid 10
Effervescent base 4
Diluent 3
Binder 1.5
Sweetener 1
Lubricant 2.5
Flavouring agent 0.25
Colouring agent 0.25
Total 100
The formulations given above can be produced with the production method described description in detail.
Claims
1. An effervescent formulation comprising genistein as the active agent, at least one pharmaceutically acceptable effervescent acid, at least one effervescent base and at least one other excipient, characterized in that said formulation comprises a) Citric acid anhydrate and b) At least one other effervescent acid as the effervescent acid.
2. The effervescent formulation according to claim 1, characterized in that said formulation comprises a) Citric acid anhydrate having an average particle size (dso) of minimum 400 μπι and b) At least one other effervescent acid as the effervescent acid.
3. The effervescent formulation according to claims 1-2, characterized in that said formulation comprises a) Citric acid anhydrate having an average particle size (d50) in the range of 400 to 600 μιη and b) At least one other effervescent acid as the effervescent acid.
4. The effervescent formulation according to claims 1-3, characterized in that said formulation comprises a) Citric acid anhydrate having an average particle size (d50) in the range of 400 to 550 μηι and b) At least one other effervescent acid as the effervescent acid.
5. The effervescent formulation according to any preceding claims, characterized in that the amount of at least one other effervescent acid comprised in the formulation is minimum at 5% by weight.
6. The effervescent formulation according to claims 5, characterized in that the amount of at least one other effervescent acid comprised in the formulation is in the range of 5 to 20% by weight.
7. The effervescent formulation according to claims 5-6, characterized in that the amount of at least one other effervescent acid comprised in the formulation is in the range of 5 to 15% by weight.
8. The effervescent formulation according to any preceding claims, characterized in that other effervescent acid comprised in the formulation is malic acid.
9. The effervescent formulation according to claim 8, characterized in that average particle size (dso) of malic acid comprised in the formulation is minimum 300 μηι.
10. The effervescent formulation according to claims 8-9, characterized in that average particle size (d 0) of malic acid comprised in the formulation is in the range of 1 to 250 μιτι.
11. The effervescent formulation according to claims 8-10, characterized in that average particle size (d5o) of malic acid comprised in the formulation is in the range of 1 to 200 μπι.
12. The effervescent formulation comprising genistein as the active agent, at least one pharmaceutically acceptable effervescent acid, an least one effervescent base and at least one other excipient, characterized in that said formulation comprises a) Citric acid anhydrate having an average particle size (d5o) of minimum 400 μιιι and b) Malic acid having average particle size (d 0) of minimum 300 μιη as the effervescent acid.
13. The effervescent formulation according to claims 8-12, characterized in that the ratio of citric acid anhydrate to malic acid comprised in the formulation is in the range of 1 to 10 by weight.
14. The effervescent formulation according to claim 13, characterized in that the ratio of citric acid anhydrate to malic acid comprised in the formulation is in the range of 1 to 8 by weight.
15. The effervescent formulation according to claim 14, characterized in that the ratio of citric acid anhydrate to malic acid comprised in the formulation is in the range of 1 to 5 by weight.
16. The effervescent formulation according to claims 8-15, characterized in that said formulations comprise a third effervescent acid in addition to malic acid and citric acid anhydrate.
17. The effervescent formulation according to claim 16, characterized in that the third
effervescent acid comprised in the formulation is selected from a group comprising acetic acid, citric acid, lactic acid, malic acid, phopsphoric acid, propionic acid, tartaric acid or their hydrates, anhydrates or combinations thereof.
18. The effervescent formulation according to claim 17, characterized in that the third effervescent acid comprised in the formulation is citric acid anhydrate.
19. The effervescent formulation according to claim 18, characterized in that average particle size (d5o) of citric acid anhydrate comprised in the formulation is minimum 150 μιτι.
20. The effervescent formulation according to claims 18-19, characterized in that average particle size (dso) of citric acid anhydrate comprised in the formulation is in the range of 150 to 300 μπι.
21. The effervescent formulation according to claims 18-20, characterized in that average particle size (d5o) of citric acid anhydrate comprised in the formulation is in the range of 150 ίο 250 μπι.
22. The effervescent formulation according to any preceding claims, characterized in that said formulation comprises a second active agent.
23. The effervescent formulation according to claim 22, characterized in that the second active agent is selected from a group comprising 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 or combinations thereof.
24. The method for production of an effervescent formulation according to any preceding claims, characterized in that said method is wet granulation method.
25. The production method according to claim 24, characterized in that said production method is composed of the steps of wet-granulating the dry mixture comprising effervescent acids and appropriate excipients with the granulation solution comprising appropriate excipients and solvent; drying the granules; adding active agent and optionally other excipients into the dry granules.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2011/12518 | 2011-12-16 | ||
| TR201112518 | 2011-12-16 | ||
| TR2011/12517 | 2011-12-16 | ||
| TR201112517 | 2011-12-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013089654A1 true WO2013089654A1 (en) | 2013-06-20 |
Family
ID=47684004
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2012/000210 Ceased WO2013089654A1 (en) | 2011-12-16 | 2012-12-10 | Effervescent formulations comprising genistein |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2013089654A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106138005A (en) * | 2016-08-05 | 2016-11-23 | 贵州汉方药业有限公司 | Good calcium carbonate vitamin C effervescent tablet of a kind of effervesce effect and preparation method thereof |
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| WO2012002918A1 (en) * | 2010-06-03 | 2012-01-05 | Mahmut Bilgic | Formulation for osteoporosis |
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| US512192A (en) | 1894-01-02 | harden | ||
| WO1999038509A1 (en) | 1998-01-28 | 1999-08-05 | Dusan Miljkovic | Isoflavanoid formulations for oral administration |
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| CN106138005A (en) * | 2016-08-05 | 2016-11-23 | 贵州汉方药业有限公司 | Good calcium carbonate vitamin C effervescent tablet of a kind of effervesce effect and preparation method thereof |
| CN106138005B (en) * | 2016-08-05 | 2021-04-20 | 贵州汉方药业有限公司 | Calcium carbonate vitamin C effervescent tablet with good effervescent effect and preparation method thereof |
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