WO2013074046A1 - Pharmaceutical formulations comprising isoflavone - Google Patents

Pharmaceutical formulations comprising isoflavone Download PDF

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Publication number
WO2013074046A1
WO2013074046A1 PCT/TR2012/000119 TR2012000119W WO2013074046A1 WO 2013074046 A1 WO2013074046 A1 WO 2013074046A1 TR 2012000119 W TR2012000119 W TR 2012000119W WO 2013074046 A1 WO2013074046 A1 WO 2013074046A1
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Prior art keywords
formulation according
formulations
range
weight
pharmaceutical formulation
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PCT/TR2012/000119
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French (fr)
Inventor
Mahmut Bilgic
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Mahmut Bilgic
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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
    • 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 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to water soluble formulations comprising at least one component belonging to the group of isoflavones, preparation methods and area of use thereof.
  • 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 in itself and resources of these compounds in diet are different from each other. Daidzein and genistein are the compounds belonging to the class of isoflavones of flavanoids in plants. Furthermore, since isoflavones are plant originated compounds having an estrogen-like biological activity, they are also called phytoestrogens. Isoflaves are comprised particularly in soybean and soy products. Soybean comprises 84 mg daidzein and 111 mg genistein per 100 g of soybean.
  • isoflavones decreases severity and frequency of vasomotor symptoms arising along with the movement of contraction and dilatation of blood vessels associated with menopause. Particularly, the vessels close to skin surface play an important role particularly in regulating body temperature.
  • Soybean, soy tofu, soy milk, soy sauce, soy mince can be listed among soy products that can be taken in daily diet. However, use of these products is closely associated with food habits of people and the region where they live. Soy products are not included in daily diet of most of the people.
  • tablet formulations comprising sufficient amount of genistein and used as daily food supplement are produced in the prior art.
  • tablet dosage forms are not convenient for use since they pose swallowing problems particularly in geriatric patient group.
  • Problem and solution relations existing in the prior art generally aim at combining the compound with other daily supplements.
  • the compound has a considerably sensitive nature and is considerably hygroscopic and low-soluble as well. This situation makes the selection of excipients, production method and dosage form critical for production of the formulations comprising genistein.
  • special solutions are required.
  • the European patent numbered EP 1392337 discloses formulations comprising a dry plant extract such as genistein.
  • formulations comprising such an active agent are not preferred in soluble form due to their instability against acids and low solubility in water. Therefore, the formulations according to the patent are produced in a solid dosage form, preferably in tablet or capsule form.
  • solid dosage forms cause swallowing problems particularly for geriatric patients as mentioned before. Therefore, there is need for new formulations whose solubility characteristic is improved for formulations comprising genistein, which can remain stable for a long time, which are easy to use and which appeal to a wide patient profile.
  • the inventor has achieved to produce the formulations comprising genistein, a compound belonging to the group of isoflavones, in water soluble form and without causing a solubility and/or stability problem in order to be used in treatment and/or prevention of bone diseases which are generally seen in postmenopausal period such as particularly osteoporosis, osteomalacia and fibrous osteodystrophy.
  • the present invention discloses stable genistein formulations which comprise efficient amounts of genistein and are suitable for oral use. Said formulations are in water soluble form.
  • the formulations of the present invention comprises genistein at least at the ratio of 1%, preferably in the range of 1 to 20%, more preferably in the range of 0.1 to 10% in proportion to total weight.
  • the 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 formulations of the present invention do not comprise a pharmaceutical excipient in order to enhance solubility.
  • these formulations dissolve by forming a clear solution between 0.5 and 5 minutes, preferably between 0.5 and 3 minutes, more preferably between 0.5 to 2 minutes after they are put in water at room temperature.
  • lactose in monohydrate form as the diluent in the formulations.
  • the inventor has produced the formulations in water soluble form comprising genistein, which has a rather low solubility in water, along with lactose monohydrate.
  • lactose monohydrate which causes incompatibility with many substances has not caused any degradation in the formulations of the present invention.
  • the formulations of the present invention comprise lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight.
  • Use of lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight in the formulations of the present invention has surprisingly caused an improvement in solubility of the end product.
  • the present invention relates to water soluble genistein formulations comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight.
  • the water soluble formulations of the present invention are preferably effervescent formulations.
  • the formulations of the present invention can comprise at least one other pharmaceutically acceptable excipient in addition to genistein and lactose monohydrate.
  • the pharmaceutically acceptable excipients which are probable to be comprised in the formulations of the present invention can be selected from disintegrants, sweeteners, effervescent acids, effervescent bases, binders, lubricants, flavouring agents, colouring agents, pH regulators, basic substances or combinations thereof.
  • the disintegrants that can be used in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight can be selected from a group comprising highly dispersive polymers, for instance cross linked hydroxypropyl cellulose, polyvinylpyrrolidone, high- molecular weighted polymers, microcrystalline cellulose, sodium starch glycolate, povidone, alginic acid, sodium alginate or combinations thereof.
  • highly dispersive polymers for instance cross linked hydroxypropyl cellulose, polyvinylpyrrolidone, high- molecular weighted polymers, microcrystalline cellulose, sodium starch glycolate, povidone, alginic acid, sodium alginate or combinations thereof.
  • the pharmaceutically acceptable effervescent acid that can be used in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight can be selected from a group comprising citric acid, tartaric acid, malic acid, fumaric acid, monosodium citrate and/or pharmaceutically acceptable salts, hydrates, anhydrates or a combination thereof.
  • the formulations of the present invention comprise at least one pharmaceutically acceptable effervescent acid in the range of 1 to 90% by weight, preferably in the range of 1 to 80% by weight, more preferably in the range of 1 to 70% by weight.
  • Pharmaceutically acceptable effervescent bases that can be used in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight can be selected from a group comprising sodium, potassium and calcium carbonates, bicarbonates and/or sodium glycine carbonate or a combination thereof.
  • the formulations of the present invention comprise at least one pharmaceutically acceptable effervescent base in the range of 1 to 80% by weight, preferably in the range of 1 to 60% by weight, more preferably in the range of 1 to 50% by weight.
  • binders that can be used in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight can be selected from a group comprising potato, wheat or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose; hydroxypropyl methyl cellulose and polyvinylpyrrolidone or combinations thereof.
  • water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight comprise at least one pharmaceutically acceptable binder in the range of 1 to 5% by weight.
  • the ratio of the binder to lactose monohydrate comprised in the formulations of the present invention is in the range of 0.1 to 5 by weight, preferably in the range of 0.1 to 4 by weight, more preferably in the range of 0.1 to 3 by weight.
  • the binder which is preferred in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight is polyvinylpyrrolidone.
  • the sweeteners that can be used in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight can be selected from a group comprising aspartame, dextrose, fructose, sucralose, sodium cyclamate, mannitol, maltose, sorbitol, saccharin and/or pharmaceutically acceptable salts or combinations thereof.
  • the formulations of the present invention comprise at least one pharmaceutically acceptable sweetener in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight, more preferably in the range of 0.1 to 3 % by weight.
  • flavouring agents that can be used in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight can have banana, strawberry, lemon, orange, peach, vanilla flavours or a similar natural fruit flavour or an aromatic plant flavour.
  • formulations of the present invention are that a solubility and/or stability enhancing substance are not used in the formulations.
  • the formulations of the present invention can be produced by a production method in the prior art, for instance wet granulation, dry granulation and/or dry blending.
  • a method preferred for the formulations of the present invention comprising genistein is dry blending method.
  • Another method preferred for the formulations of the present invention comprising genistein is wet granulation method.
  • formulations of the present invention can optionally be used with at least one other active agent in combined form.
  • other active agent 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 treatment.
  • the active agents can be together with at least one pharmaceutically acceptable excipient in a single formulation, though the active agents can also be formulated separately together with at least one pharmaceutically acceptable excipient in the formulations comprising genistein and at least one other active agent for combined therapy.
  • Different formulations obtained can be combined in a single dosage form or can be prepared in the manner that they are in separate dosage forms.
  • said dosage forms can be same or different.
  • 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; 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 other active agents listed above can be combined with genistein in combined treatment.
  • 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 by combining them.
  • Effervescent formulation comprising genistein
  • the formulation given above is prepared by dry blending method and is preferably compressed into tablets by sending the formulation to tablet compression machine.

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Abstract

The present invention relates to formulations comprising at least one component belonging the group of isoflavones, preparation methods and area of use thereof.

Description

PHARMACEUTICAL FORMULATIONS COMPRISING ISOFLAVONE
The present invention relates to water soluble formulations comprising at least one component belonging to the group of isoflavones, preparation methods and area of use thereof.
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 in itself and resources of these compounds in diet are different from each other. Daidzein and genistein are the compounds belonging to the class of isoflavones of flavanoids in plants. Furthermore, since isoflavones are plant originated compounds having an estrogen-like biological activity, they are also called phytoestrogens. Isoflavons are comprised particularly in soybean and soy products. Soybean comprises 84 mg daidzein and 111 mg genistein per 100 g of soybean. In recent years, many studies have been conducted on potential protective effects of isoflavons against cardiovascular diseases, menopause symptoms, bone diseases such as osteoporosis, osteomalacia and fibrous osteodystrophy and cancers associated with hormones (breast and prostate cancer).
Use of isoflavones decreases severity and frequency of vasomotor symptoms arising along with the movement of contraction and dilatation of blood vessels associated with menopause. Particularly, the vessels close to skin surface play an important role particularly in regulating body temperature.
In the studies, it has been found that use of 60 mg soy protein per day alleviates vasomotor symptoms at the rate of 50%; 70 mg soy protein alleviates vasomotor symptoms at the rate of As a result of 38 clinical studies conducted, it has been seen that total cholesterol decreased at the rate of 9.3%, LDL cholesterol (low density lipoprotein) was reduced at the rate of 12.9% and plasma triglycerides was reduced at the rate of 10.5% in the people who were administered soy protein isolates.
One of the important reasons for preferring phytoestrogens acting like estrogen in treatment of many diseases mentioned above is that use of estrogen hormone directly in said treatments results in various side effects such as increase in risk of thrombosis and breast cancer, and weight gain.
Soybean, soy tofu, soy milk, soy sauce, soy mince can be listed among soy products that can be taken in daily diet. However, use of these products is closely associated with food habits of people and the region where they live. Soy products are not included in daily diet of most of the people.
However, as explained above, there is need for new approaches associated with soy products which appeal to a wide patient profile used in treatment and/or prevention of many diseases from heart diseases to menopause symptoms; from osteoporosis to prostate cancer.
In line with this requirement, tablet formulations comprising sufficient amount of genistein and used as daily food supplement are produced in the prior art. However, tablet dosage forms are not convenient for use since they pose swallowing problems particularly in geriatric patient group. Problem and solution relations existing in the prior art generally aim at combining the compound with other daily supplements. However, the compound has a considerably sensitive nature and is considerably hygroscopic and low-soluble as well. This situation makes the selection of excipients, production method and dosage form critical for production of the formulations comprising genistein. When the compound is desired to be produced particularly in water soluble dosage forms, special solutions are required. The European patent numbered EP 1392337 discloses formulations comprising a dry plant extract such as genistein. This patent discloses that formulations comprising such an active agent are not preferred in soluble form due to their instability against acids and low solubility in water. Therefore, the formulations according to the patent are produced in a solid dosage form, preferably in tablet or capsule form. However, solid dosage forms cause swallowing problems particularly for geriatric patients as mentioned before. Therefore, there is need for new formulations whose solubility characteristic is improved for formulations comprising genistein, which can remain stable for a long time, which are easy to use and which appeal to a wide patient profile.
As a result of the studies he conducted, the inventor has achieved to produce the formulations comprising genistein, a compound belonging to the group of isoflavones, in water soluble form and without causing a solubility and/or stability problem in order to be used in treatment and/or prevention of bone diseases which are generally seen in postmenopausal period such as particularly osteoporosis, osteomalacia and fibrous osteodystrophy.
Detailed Description of the Invention The present invention discloses stable genistein formulations which comprise efficient amounts of genistein and are suitable for oral use. Said formulations are in water soluble form.
The formulations of the present invention comprises genistein at least at the ratio of 1%, preferably in the range of 1 to 20%, more preferably in the range of 0.1 to 10% in proportion to total weight.
The 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 formulations of the present invention do not comprise a pharmaceutical excipient in order to enhance solubility. On the other hand, these formulations dissolve by forming a clear solution between 0.5 and 5 minutes, preferably between 0.5 and 3 minutes, more preferably between 0.5 to 2 minutes after they are put in water at room temperature.
This unexpected effect arises from the use of lactose in monohydrate form as the diluent in the formulations. The inventor has produced the formulations in water soluble form comprising genistein, which has a rather low solubility in water, along with lactose monohydrate. Surprisingly, lactose monohydrate which causes incompatibility with many substances has not caused any degradation in the formulations of the present invention.
The formulations of the present invention comprise lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight. Use of lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight in the formulations of the present invention has surprisingly caused an improvement in solubility of the end product.
In other words, the present invention relates to water soluble genistein formulations comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight.
An advantage of the formulations of the present invention is that they appeal to a wide patient profile since they are in water soluble form. The water soluble formulations of the present invention are preferably effervescent formulations. The formulations of the present invention can comprise at least one other pharmaceutically acceptable excipient in addition to genistein and lactose monohydrate. The pharmaceutically acceptable excipients which are probable to be comprised in the formulations of the present invention can be selected from disintegrants, sweeteners, effervescent acids, effervescent bases, binders, lubricants, flavouring agents, colouring agents, pH regulators, basic substances or combinations thereof.
The disintegrants that can be used in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight can be selected from a group comprising highly dispersive polymers, for instance cross linked hydroxypropyl cellulose, polyvinylpyrrolidone, high- molecular weighted polymers, microcrystalline cellulose, sodium starch glycolate, povidone, alginic acid, sodium alginate or combinations thereof.
The pharmaceutically acceptable effervescent acid that can be used in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight can be selected from a group comprising citric acid, tartaric acid, malic acid, fumaric acid, monosodium citrate and/or pharmaceutically acceptable salts, hydrates, anhydrates or a combination thereof.
The formulations of the present invention comprise at least one pharmaceutically acceptable effervescent acid in the range of 1 to 90% by weight, preferably in the range of 1 to 80% by weight, more preferably in the range of 1 to 70% by weight. Pharmaceutically acceptable effervescent bases that can be used in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight can be selected from a group comprising sodium, potassium and calcium carbonates, bicarbonates and/or sodium glycine carbonate or a combination thereof. The formulations of the present invention comprise at least one pharmaceutically acceptable effervescent base in the range of 1 to 80% by weight, preferably in the range of 1 to 60% by weight, more preferably in the range of 1 to 50% by weight.
The binders that can be used in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight can be selected from a group comprising potato, wheat or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose; hydroxypropyl methyl cellulose and polyvinylpyrrolidone or combinations thereof.
It is important to prevent active agent-excipient and excipient-excipient interactions and ensure stability of the formulation in the formulations of the present invention comprising genistein as well as providing the required solubility characteristics. Therefore, it is required to select the type and amount of the excipients comprised in the formulations meticulously.
According to this, water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight comprise at least one pharmaceutically acceptable binder in the range of 1 to 5% by weight.
The ratio of the binder to lactose monohydrate comprised in the formulations of the present invention is in the range of 0.1 to 5 by weight, preferably in the range of 0.1 to 4 by weight, more preferably in the range of 0.1 to 3 by weight. A possible incompatibility and a possible degradation that can arise from the use of lactose monohydrate and binder together are prevented by the use of two excipients at the given rates.
The binder which is preferred in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight is polyvinylpyrrolidone. The sweeteners that can be used in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight can be selected from a group comprising aspartame, dextrose, fructose, sucralose, sodium cyclamate, mannitol, maltose, sorbitol, saccharin and/or pharmaceutically acceptable salts or combinations thereof. The formulations of the present invention comprise at least one pharmaceutically acceptable sweetener in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight, more preferably in the range of 0.1 to 3 % by weight.
The flavouring agents that can be used in water soluble genistein formulations of the present invention comprising lactose monohydrate in the range of 0.1 to 10% by weight, preferably in the range of 0.1 to 5% by weight can have banana, strawberry, lemon, orange, peach, vanilla flavours or a similar natural fruit flavour or an aromatic plant flavour.
Another advantage of the formulations of the present invention is that a solubility and/or stability enhancing substance are not used in the formulations. The formulations of the present invention can be produced by a production method in the prior art, for instance wet granulation, dry granulation and/or dry blending.
A method preferred for the formulations of the present invention comprising genistein is dry blending method.
Another method preferred for the formulations of the present invention comprising genistein is wet granulation method.
The formulations of the present invention can optionally be used with at least one other active agent 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 treatment.
In other words, the active agents can be together with at least one pharmaceutically acceptable excipient in a single formulation, though the active agents can also be formulated separately together with at least one pharmaceutically acceptable excipient in the formulations comprising genistein and at least one other active agent for combined therapy.
Different formulations obtained can be combined in a single dosage form or can be prepared in the manner that they are in separate dosage forms. In the case that the formulations are in separate dosage forms, said dosage forms can be same or different. 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; 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 other active agents listed above can be combined with genistein in combined treatment. 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 by combining them.
The examples of the formulation of the present invention are 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 formulation comprising genistein
Figure imgf000009_0001
The formulation given above is prepared by dry blending method and is preferably compressed into tablets by sending the formulation to tablet compression machine.
2. Effervescent formulation comprising Genistein and Calcium
Figure imgf000009_0002
escent formulation comprising Genistein, Calcium and Vitamin D
Figure imgf000010_0001

Claims

1. A pharmaceutical formulation comprising genistein, characterized in that said formulation is in water soluble form.
2. The pharmaceutical formulation according to claim 1, characterized in that said formulations comprise lactose monohydrate.
3. The pharmaceutical formulation according to claim 2, characterized in that said formulation comprises lactose monohydrate in the range of 0.1 to 10% by weight.
4. The pharmaceutical formulation according to claim 3, characterized in that said formulation comprises lactose monohydrate in the range of 0.1 to 5% by weight.
5. The pharmaceutical formulation according to any preceding claims, characterized in that said formulation comprises genistein in the range of 0.1 to 10% by weight.
6. The pharmaceutical formulation according to claim 5, characterized in that said formulation comprises genistein in the range of 0.1 to 5% by weight.
7. The formulation according to any preceding claims, characterized in that said formulation is in effervescent form.
8. The pharmaceutical formulation according to any preceding claims, characterized in that said formulation comprises at least one pharmaceutically acceptable binder selected from a group comprising potato, wheat or corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone or combinations thereof.
9. The pharmaceutical formulation according to claim 8, characterized in that the pharmaceutical formulations comprise at least one binder in the range of 1-5% by weight.
10. The pharmaceutical formulation according to claims 2-9, characterized in that the ratio of the binder to lactose monohydrate comprised in the formulations is in the range of 0.1 to 5 by weight.
1 1. The pharmaceutical formulation according to claim 10, characterized in that the ratio of the binder to lactose monohydrate comprised in the formulations is in the range of 0.1 to 4 by weight.
12. The pharmaceutical formulation according to claim 11 , characterized in that the ratio of the binder to lactose monohydrate comprised in the formulations is in the range of 0.1 to 3 by weight.
13. The pharmaceutical formulation according to claims 8-12, characterized in that the binder comprised in the formulations is polyvinylpyrrolidone.
14. The pharmaceutical formulation according to claim 7, characterized in that said formulation comprises at least one pharmaceutically acceptable effervescent acid in the range of 1 to 90% by weight.
15. The pharmaceutical formulation according to claim 14, characterized in that effervescent acid used in the formulations is selected from a group comprising citric acid, tartaric acid, malic acid, fumaric acid, monosodium citrate, tartaric acid and/or pharmaceutically acceptable salts, hydrates, anhydrates or a combination thereof.
16. The formulation according to claim 7, characterized in that said formulation comprises at least one pharmaceutically acceptable effervescent base in the range of 1 to 80% by weight.
17. The formulation according to claim 16, characterized in that the effervescent base used in the formulations is selected from a group comprising sodium, potassium, and calcium carbonates, bicarbonates and/or sodium glycine carbonate or a combination thereof.
18. The formulation according to any preceding claims, characterized in that said formulations are used with at least one other active agent in combined form.
19. The formulation according to claim 18, characterized in that the active agents are taken separately, together or sequentially or by combining genistein with at least one other active agent in a single dosage form in the formulations comprising genistein and at least one other active agent.
20. The formulation according to claims 18-19, characterized in that other active agent or agents are at least one vitamin and/or at least one mineral.
21. The formulation according to claims 18-20, characterized in that the other active agent or agents is selected from a group comprising minerals such as calcium, potassium, magnesium, iron, sodium, zinc; vitamins such as vitamin A, B vitamins such as Bl, B12, B6 and/or folic acid, vitamin C, vitamin D, vitamin E.
22. The formulation according to claim 1, characterized in that said formulation is used in treatment and/or prevention of bone diseases such as osteoporosis, osteomalacia and fibrous osteodystrophy.
PCT/TR2012/000119 2011-08-08 2012-08-07 Pharmaceutical formulations comprising isoflavone WO2013074046A1 (en)

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WO2013089654A1 (en) * 2011-12-16 2013-06-20 Mahmut Bilgic Effervescent formulations comprising genistein
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