WO2012093977A1 - Water soluble pharmaceutical formulations comprising ibandronate and an inorganic salt for use in treatment of bone diseases - Google Patents
Water soluble pharmaceutical formulations comprising ibandronate and an inorganic salt for use in treatment of bone diseases Download PDFInfo
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- WO2012093977A1 WO2012093977A1 PCT/TR2012/000008 TR2012000008W WO2012093977A1 WO 2012093977 A1 WO2012093977 A1 WO 2012093977A1 TR 2012000008 W TR2012000008 W TR 2012000008W WO 2012093977 A1 WO2012093977 A1 WO 2012093977A1
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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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
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
Definitions
- the present invention relates to water soluble formulations so as to be used in treatment and/or prevention of bone diseases such as hypercalcaemia, osteoporosis, tumoral osteolysis, malignant hypercalcaemia, metastatic bone disease, periprostatic bone loss, Paget' s disease, and production methods thereof.
- bone diseases such as hypercalcaemia, osteoporosis, tumoral osteolysis, malignant hypercalcaemia, metastatic bone disease, periprostatic bone loss, Paget' s disease, and production methods thereof.
- Bone diseases such as hypercalcaemia, osteoporosis, tumoral osteolysis, Paget' s disease are the most common diseases after cardiovascular diseases and cancer in the world.
- Particularly osteoporosis is a stealthily progressive disease which affects postmenopausal women and arises when the bones are weakened and very susceptible to fracture because of low bone mass and deterioration of bone quality.
- Osteoporosis is seen three times more likely in women than men; and the disease which is seen more common in old age is not a disease seen only in old age. Osteoporosis-related bone fractures have gradually become a serious public health concern.
- the group of drugs frequently used in treatment of bone diseases including osteoporosis is bisphosphonates.
- the bisphosphonate group of drugs causes decrease in number and activity of the cells called osteoclasts which are responsible for bone resorption; and by this means, they provide to preserve and even increase bone mass and strength.
- the most common drugs of this group are alendronate, etidronate, risedronate, ibandronate and zoledronic acid.
- Ibandronate (Formula I) is a potent third generation bisphosphonate. It is known that, when compared to placebo, ibandronate treatment wherein 2.5 mg daily ibandronate is administered to the patients with osteoporosis reduces risk for vertebral fracture in 3 -year-period from approximately 10% to 5% and reduces risk for symptomatic vertebral fractures from 5.3% to 2.8%.
- Ibandronate marketed under the trade names BONVIVA® and BONDRONAT® is in film coated tablet and intravenous forms.
- Bisphosphonates generally have low bioavailability; therefore, it is recommended that orally used bisphosphonates are taken on an empty stomach.
- Intravenous ibandronate is a form only used in treatment of cancer- related bone diseases.
- the dosage used is a single dose in every 3-4 weeks though it changes according to the stage of the disease.
- Oral ibandronate tablet form is not a good option for ibandronate which already has low bioavailability.
- Intravenous form which was improved as alternative to solid dosage forms is the most difficult treatment method to comply with for patients. Many patients, especially the group of patients over 50 years of age, do not want to take the drug in intravenous form which is administered with a sterile needle. Furthermore, intravenous dosage forms require an expert medical practitioner for administration and this situation is disadvantageous for the patient. Many patients do not prefer intravenous administration due to these reasons.
- EP 1820497 discloses effervescent bisphosphonate dosage forms.
- the effervescent dosage forms in this application are composed of at least one acid, one source of carbonate, a binder and a lubricant.
- ibandronate cannot remain stable sufficiently in water soluble formulations.
- the chemical structure of the active agent which is susceptible to degradation causes the formulations to unexpectedly disintegrate and stability of the formulation remains lower than the expected level especially in formulations having a pH value in the range of 3.5 to 4.
- dosage forms having low pH are disadvantageous for ibandronate which causes susceptibility in gastrointestinal canal since they can increase this susceptibility in oral use.
- the present invention discloses water soluble pharmaceutical formulations comprising ibandronate and/or its pharmaceutically acceptable salts, hydrates, amorphous or crystalline forms or combinations thereof as active agent; production and areas of use thereof.
- the water soluble formulations of the present invention can be formulated in powder or granule form and can be presented as filled into bottles, sachet as well as in tablet or capsule for obtainment of the required dosage form.
- formulations of the present invention are formulated in powder form.
- formulations of the present invention are formulated in granule form.
- the dosage form preferred is prepared as sachet dosage form designed to prevent the active agent granules from being affected from environmental factors such as heat, moisture, light.
- Ibandronate or its pharmaceutically acceptable salt used in the pharmaceutical formulations of the present invention is preferably ibandronate sodium salt.
- active agent in monohydrate or dihydrate form can also be used.
- Powder or granule formulations prepared within the scope of the present invention can be effervescent or non-effervescent; the formulations preferred are non-effervescent formulations.
- One characteristic feature of the water soluble formulations of the present invention is that at least one inorganic salt is used in the formulations.
- the inventors have found that use of at least one pharmaceutically acceptable inorganic salt in the range of 1 to 40% by weight, preferably in the range of 5 to 35% by weight, more preferably in the range of 8 to 33% by weight in the formulations causes an unexpected positive effect in the stability of the end product.
- Ibandronate formulations produced in this way can remain stable in aqueous solution for a longer time as compared to the formulations in the prior art.
- the inorganic salt which is used has provided that the solution comprising active agent is taken by the patients more easily and it reduces the risk of gastrointestinal irritation by adjusting pH value of the formulation in the range of 5.5 to 7.
- the inorganic salts of the present invention can be selected from a group comprising sodium carbonate, sodium bicarbonate, sodium acetate, sodium chloride, potassium chloride, potassium carbonate, potassium bicarbonate.
- the inorganic salt used in the formulations is sodium or potassium carbonates or bicarbonates.
- the inorganic salt used in the formulations is sodium bicarbonate.
- the water soluble formulations of the present invention can comprise at least one pharmaceutically acceptable excipient selected from a group comprising filling agents, binders, lubricants, disintegrants, diluents, stabilizing agents, sweeteners, taste regulating agents, inorganic salts, flavouring agents.
- Another characteristic feature of the formulations of the present invention is that suitable substance combination and suitable amounts thereof are used for ibandronate formulations having sufficient stability.
- Another characteristic feature of the formulations of the present invention is that said formulations are basically composed of following components;
- Ibandronate sodium in the range of 10 to 90% by weight, preferably in the range of 10 to 70% by weight, more preferably in the range of 10 to 50% by weight;
- At least one pharmaceutically acceptable filling agent minimum 50% by weight, preferably in the range of 50 to 80 % by weight, more preferably in the range of 50 to 60% by weight;
- At least one pharmaceutically acceptable sweetener 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;
- At least one pharmaceutically acceptable inorganic salt in the range of 1 to 40% by weight, preferably in the range of 5 to 35% by weight, more preferably in the range of 8 to 33% by weight.
- the formulations of the present invention can optionally comprise at least one other pharmaceutically acceptable excipient in addition to the specified ones above.
- the filling agents that can be used in the formulations of the present invention are preferably from the group of water soluble sugar alcohols though they are selected from sorbitol, mannitol, xylitol, erythrol, isomalt, starch hydrolysates or combinations thereof.
- One characteristic feature of the formulations of the present invention is that the formulations comprise at least one filling agent minimum 50% by weight, preferably in the range of 50 to 80 % by weight, more preferably in the range of 50 to 60% by weight.
- the sweeteners that can be used in the water soluble formulations of the present invention 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. More than one sweetener can be used in the formulations of the present invention.
- formulations of the present invention comprise at least one sweetener 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 diluents that can be used in the water soluble formulations of the present invention can be selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, xylitol or the combinations thereof.
- the lubricants that can be used in the water soluble formulations of the present invention can be selected from a group comprising 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 oil, leucine, polyethylene glycols, metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc and/or hydrates thereof.
- 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
- the disintegrants that can be used in the water soluble formulations of the present invention can be selected from a group comprising highly dispersive polymers, for instance cross linked hydroxypropyl cellulose, polyvinylpyrrolidone, high-molecular weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, alginic acid, sodium alginate or the combinations thereof.
- highly dispersive polymers for instance cross linked hydroxypropyl cellulose, polyvinylpyrrolidone, high-molecular weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, alginic acid, sodium alginate or the combinations thereof.
- the water soluble formulations of the present invention can optionally comprise flavouring agents; said flavouring agents can have banana flavour, strawberry flavour, lemon flavour, orange flavour, peach flavour, vanilla flavour or a similar natural fruit flavour or an aromatic plant flavour.
- water soluble formulations of the present invention preferably comprise ibandronate sodium in the range of 50 to 300 mg, preferably in the range of 50 to 200 mg per unit dosage form.
- Said dosage forms can be used once a month or at least once a day according to the type of the disease to be treated. For instance, in the case that the disease to be treated is osteoporosis, it is recommended for use once a month; in treatment/prevention of the diseases such as tumoral osteolysis, malignant hypercalcaemia, metastatic bone disease,it is recommended for use at least once a day.
- the dosage forms of the present invention are preferably taken as dissolved in sufficient amount of water, preferably in 150 ml of water, preferably just before the first meal of the day. Dissolution time of the formulations of the present invention in 150 ml water is in the range of 15 to 60 seconds, preferably in the range of 15 to 45 seconds.
- formulations of the present invention can be produced with any methods in the prior art; these methods can be dry granulation, dry blending, direct compression or wet granulation.
- the method preferred for production of the formulations of the present invention is dry blending method and this method is applied as follows;
- the method to be used for production of ibandronate sodium sachet formulations given above is dry blending method which is described in the description part in detail.
- the pharmaceutical powder formulation obtained by dry blending and sieving steps is sent to the sachet filling machine and final product is obtained in sachet form.
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Abstract
The present invention relates to water soluble formulations so as to be used in treatment and/or prevention of bone diseases such as hypercalcaemia, osteoporosis, tumoral osteolysis, Paget' s disease and production methods thereof.
Description
WATER SOLUBLE PHARMACEUTICAL FORMULATIONS COMPRISING IBANDRONATE AND AN INORGANIC SALT FOR USE IN TREATMENT OF BONE DISEASES
The present invention relates to water soluble formulations so as to be used in treatment and/or prevention of bone diseases such as hypercalcaemia, osteoporosis, tumoral osteolysis, malignant hypercalcaemia, metastatic bone disease, periprostatic bone loss, Paget' s disease, and production methods thereof.
The Prior Art
Bone diseases such as hypercalcaemia, osteoporosis, tumoral osteolysis, Paget' s disease are the most common diseases after cardiovascular diseases and cancer in the world. Particularly osteoporosis is a stealthily progressive disease which affects postmenopausal women and arises when the bones are weakened and very susceptible to fracture because of low bone mass and deterioration of bone quality. Osteoporosis is seen three times more likely in women than men; and the disease which is seen more common in old age is not a disease seen only in old age. Osteoporosis-related bone fractures have gradually become a serious public health concern.
The group of drugs frequently used in treatment of bone diseases including osteoporosis is bisphosphonates. The bisphosphonate group of drugs causes decrease in number and activity of the cells called osteoclasts which are responsible for bone resorption; and by this means, they provide to preserve and even increase bone mass and strength. The most common drugs of this group are alendronate, etidronate, risedronate, ibandronate and zoledronic acid.
Ibandronate (Formula I) is a potent third generation bisphosphonate. It is known that, when compared to placebo, ibandronate treatment wherein 2.5 mg daily ibandronate is administered to the patients with osteoporosis reduces risk for vertebral fracture in 3 -year-period from approximately 10% to 5% and reduces risk for symptomatic vertebral fractures from 5.3% to 2.8%.
Ibandronate marketed under the trade names BONVIVA® and BONDRONAT® is in film coated tablet and intravenous forms. Bisphosphonates generally have low bioavailability; therefore, it is recommended that orally used bisphosphonates are taken on an empty stomach.
Intravenous ibandronate, on the other hand, is a form only used in treatment of cancer- related bone diseases. The dosage used is a single dose in every 3-4 weeks though it changes according to the stage of the disease.
However, said dosage forms in the prior art cannot meet patient requirements effectively. Oral ibandronate tablet form is not a good option for ibandronate which already has low bioavailability.
Intravenous form which was improved as alternative to solid dosage forms is the most difficult treatment method to comply with for patients. Many patients, especially the group of patients over 50 years of age, do not want to take the drug in intravenous form which is administered with a sterile needle. Furthermore, intravenous dosage forms require an expert medical practitioner for administration and this situation is disadvantageous for the patient. Many patients do not prefer intravenous administration due to these reasons.
As seen, there is need for highly bioavailable new approaches which appeal to a wider profile of patients for pharmaceutical formulations comprising ibandronate. In this respect, various studies are available in the prior art. For instance, the European Patent application numbered EP 1820497 discloses effervescent bisphosphonate dosage forms. The effervescent dosage forms in this application are composed of at least one acid, one source of carbonate, a binder and a lubricant.
However, as a result of the studies they conducted in order to develop new dosage forms, the inventors have found that ibandronate cannot remain stable sufficiently in water soluble formulations.
The chemical structure of the active agent which is susceptible to degradation causes the formulations to unexpectedly disintegrate and stability of the formulation remains lower than the expected level especially in formulations having a pH value in the range of 3.5 to 4.
In other aspect, dosage forms having low pH are disadvantageous for ibandronate which causes susceptibility in gastrointestinal canal since they can increase this susceptibility in oral use.
In addition, choosing suitable excipient combination in all formulations to be developed for susceptible active agents such as ibandronate is significantly important in terms of the stability of the formulation to be obtained. To this respect, effervescent formulations in the prior art are not suitable for ibandronate.
Therefore, there is need for new and improved formulations that
• can provide more superior patient compliance,
· are easy to use,
• are highly bioavailable,
• enable use of as few excipients as possible and are stable for ibandronate formulations.
As a result of the studies they conducted in line with this requirement, the inventors have developed new water soluble formulations comprising ibandronate and/or its pharmaceutically acceptable salts, hydrates, amorphous or crystalline forms or combinations thereof as active agent in order to be used in treatment and/or prevention of bone diseases such as hypercalcaemia, osteoporosis, tumoral osteolysis, Paget' s disease.
Detailed Description of the Invention The present invention discloses water soluble pharmaceutical formulations comprising ibandronate and/or its pharmaceutically acceptable salts, hydrates, amorphous or crystalline forms or combinations thereof as active agent; production and areas of use thereof.
The water soluble formulations of the present invention can be formulated in powder or granule form and can be presented as filled into bottles, sachet as well as in tablet or capsule for obtainment of the required dosage form.
One characteristic feature of the present invention is that the formulations of the present invention are formulated in powder form.
Another characteristic feature of the formulations of the present invention is that said formulations are formulated in granule form.
The dosage form preferred is prepared as sachet dosage form designed to prevent the active agent granules from being affected from environmental factors such as heat, moisture, light. Ibandronate or its pharmaceutically acceptable salt used in the pharmaceutical formulations of the present invention is preferably ibandronate sodium salt. Optionally, active agent in monohydrate or dihydrate form can also be used.
Powder or granule formulations prepared within the scope of the present invention can be effervescent or non-effervescent; the formulations preferred are non-effervescent formulations.
One characteristic feature of the water soluble formulations of the present invention is that at least one inorganic salt is used in the formulations.
As a result of the studies they conducted within the scope of the present invention, the inventors have found that use of at least one pharmaceutically acceptable inorganic salt in the range of 1 to 40% by weight, preferably in the range of 5 to 35% by weight, more preferably in the range of 8 to 33% by weight in the formulations causes an unexpected positive effect in the stability of the end product.
Ibandronate formulations produced in this way can remain stable in aqueous solution for a longer time as compared to the formulations in the prior art. In addition, the inorganic salt which is used has provided that the solution comprising active agent is taken by the patients more easily and it reduces the risk of gastrointestinal irritation by adjusting pH value of the formulation in the range of 5.5 to 7.
The inorganic salts of the present invention can be selected from a group comprising sodium carbonate, sodium bicarbonate, sodium acetate, sodium chloride, potassium chloride, potassium carbonate, potassium bicarbonate.
One characteristic feature of the formulations of the present invention is that the inorganic salt used in the formulations is sodium or potassium carbonates or bicarbonates.
One characteristic feature of the formulations of the present invention is that the inorganic salt used in the formulations is sodium bicarbonate.
The water soluble formulations of the present invention can comprise at least one pharmaceutically acceptable excipient selected from a group comprising filling agents, binders, lubricants, disintegrants, diluents, stabilizing agents, sweeteners, taste regulating agents, inorganic salts, flavouring agents.
Another characteristic feature of the formulations of the present invention is that suitable substance combination and suitable amounts thereof are used for ibandronate formulations having sufficient stability. Another characteristic feature of the formulations of the present invention is that said formulations are basically composed of following components;
1. Ibandronate sodium in the range of 10 to 90% by weight, preferably in the range of 10 to 70% by weight, more preferably in the range of 10 to 50% by weight;
2. At least one pharmaceutically acceptable filling agent minimum 50% by weight, preferably in the range of 50 to 80 % by weight, more preferably in the range of 50 to 60% by weight;
3. At least one pharmaceutically acceptable sweetener 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;
4. At least one pharmaceutically acceptable inorganic salt in the range of 1 to 40% by weight, preferably in the range of 5 to 35% by weight, more preferably in the range of 8 to 33% by weight.
The formulations of the present invention can optionally comprise at least one other pharmaceutically acceptable excipient in addition to the specified ones above. The filling agents that can be used in the formulations of the present invention are preferably from the group of water soluble sugar alcohols though they are selected from sorbitol, mannitol, xylitol, erythrol, isomalt, starch hydrolysates or combinations thereof.
One characteristic feature of the formulations of the present invention is that the formulations comprise at least one filling agent minimum 50% by weight, preferably in the range of 50 to 80 % by weight, more preferably in the range of 50 to 60% by weight.
The sweeteners that can be used in the water soluble formulations of the present invention 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. More than one sweetener can be used in the formulations of the present invention.
One characteristic feature of the formulations of the present invention is that the formulations comprise at least one sweetener 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 diluents that can be used in the water soluble formulations of the present invention can be selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, xylitol or the combinations thereof.
The lubricants that can be used in the water soluble formulations of the present invention can be selected from a group comprising 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 oil, leucine, polyethylene glycols, metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc and/or hydrates thereof.
The disintegrants that can be used in the water soluble formulations of the present invention can be selected from a group comprising highly dispersive polymers, for instance cross linked hydroxypropyl cellulose, polyvinylpyrrolidone, high-molecular weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, alginic acid, sodium alginate or the combinations thereof.
The water soluble formulations of the present invention can optionally comprise flavouring agents; said flavouring agents can have banana flavour, strawberry flavour, lemon flavour,
orange flavour, peach flavour, vanilla flavour or a similar natural fruit flavour or an aromatic plant flavour.
One characteristic feature of the water soluble formulations of the present invention is that said formulations preferably comprise ibandronate sodium in the range of 50 to 300 mg, preferably in the range of 50 to 200 mg per unit dosage form.
Said dosage forms can be used once a month or at least once a day according to the type of the disease to be treated. For instance, in the case that the disease to be treated is osteoporosis, it is recommended for use once a month; in treatment/prevention of the diseases such as tumoral osteolysis, malignant hypercalcaemia, metastatic bone disease,it is recommended for use at least once a day.
The dosage forms of the present invention are preferably taken as dissolved in sufficient amount of water, preferably in 150 ml of water, preferably just before the first meal of the day. Dissolution time of the formulations of the present invention in 150 ml water is in the range of 15 to 60 seconds, preferably in the range of 15 to 45 seconds.
The formulations of the present invention can be produced with any methods in the prior art; these methods can be dry granulation, dry blending, direct compression or wet granulation.
The method preferred for production of the formulations of the present invention is dry blending method and this method is applied as follows;
1. Mixing ibandronate sodium, at least one pharmaceutically acceptable filling agent, at least one sweetener and at least one inorganic salt,
2. Sieving the mixture,
3. Sending the mixture to the related filling machines for obtainment of the dosage form required.
The examples of the formulations of the present invention are given below. The formulations of the present invention are not limited to these examples.
EXAMPLES
Example I. Sachet Formulation
Example II. Sachet Formulation
The method to be used for production of ibandronate sodium sachet formulations given above is dry blending method which is described in the description part in detail.
The pharmaceutical powder formulation obtained by dry blending and sieving steps is sent to the sachet filling machine and final product is obtained in sachet form.
Claims
1. A water soluble formulation comprising ibandronate or its salts, hydrates, amorphous or crystalline forms or the combinations thereof characterized in that said formulations comprise at least one pharmaceutically acceptable inorganic salt.
2. The water soluble formulation according to claim 1 characterized in that the formulations comprise at least one inorganic salt in the range of 1 to 40% by weight.
3. The water soluble formulation according to claims 1-2 characterized in that the formulations comprise at least one inorganic salt in the range of 5 to 35% by weight.
4. The water soluble formulation according to claims 1-3 characterized in that the formulations comprise at least one inorganic salt in the range of 8 to 33% by weight.
5. The water soluble formulation according to claims 1-4 characterized in that the inorganic salt comprised in the formulations is selected from a group comprising sodium carbonate, sodium bicarbonate, sodium acetate, sodium chloride, potassium chloride, potassium carbonate, potassium bicarbonate.
6. The water soluble formulation according to claim 5 characterized in that the inorganic salt comprised in the formulations is selected from a group comprising sodium or potassium carbonates or bicarbonates.
7. The water soluble formulation according to claim 6 characterized in that the inorganic salt comprised in the formulations is sodium bicarbonate.
8. The water soluble formulation according to any preceding claims characterized in that ibandronate comprised in the formulations is in sodium salt form.
9. The water soluble formulation according to claim 8 characterized in that the formulation comprises ibandronate sodium in the range of 10 to 90% by weight.
10. The water soluble formulation according to claim 9 characterized in that the formulation comprises ibandronate sodium in the range of 10 to 70% by weight.
11. The water soluble formulation according to claim 10 characterized in that the formulation comprises ibandronate sodium in the range of 10 to 50% by weight.
12. The water soluble formulation according to any preceding claims characterized in that the formulation is in powder or granule form.
13. The water soluble formulation according to claim 12 characterized in that the formulations are filled into bottles, capsules, sachet or compressed in tablet form for obtainment of the dosage form required.
14. The water soluble formulation according to claim 13 characterized in that the formulations are in sachet form.
15. The water soluble formulation according to claim 1 characterized in that the formulation comprises at least one pharmaceutically acceptable excipient selected from a group comprising filling agents, binders, lubricants, disintegrants, diluents, stabilizing agents, sweeteners, taste regulating agents, flavouring agents.
16. The water soluble formulation according to claim 15 characterized in that the formulations comprise at least one pharmaceutically acceptable filling agent.
17. The water soluble formulation according to claim 15 characterized in that the formulations comprise at least one pharmaceutically acceptable sweetener.
18. The water soluble formulation according to claim 1 characterized in that the formulation is used in treatment and/or prevention of the bone diseases such as hypercalcaemia, osteoporosis, tumoral osteolysis, malignant hypercalcaemia, metastatic bone disease, periprostatic bone loss, Paget' s disease.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2011/00151A TR201100151A2 (en) | 2011-01-06 | 2011-01-06 | Ibandronate formulation. |
| TR2011/00151 | 2011-01-06 | ||
| TR2011/10526A TR201110526A2 (en) | 2011-01-06 | 2011-10-24 | Water-soluble pharmaceutical formulations for use in the treatment of bone diseases. |
| TR2011/10526 | 2011-12-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2012093977A1 true WO2012093977A1 (en) | 2012-07-12 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2012/000008 Ceased WO2012093977A1 (en) | 2011-01-06 | 2012-01-03 | Water soluble pharmaceutical formulations comprising ibandronate and an inorganic salt for use in treatment of bone diseases |
Country Status (2)
| Country | Link |
|---|---|
| TR (1) | TR201110526A2 (en) |
| WO (1) | WO2012093977A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006002348A2 (en) * | 2004-06-23 | 2006-01-05 | Teva Pharmaceutical Industies Ltd. | Solid and crystalline ibandronic acid |
| US20070049557A1 (en) * | 2005-08-24 | 2007-03-01 | Hashim Ahmed | Solid pharmaceutical dosage forms comprising bisphosphonates and modified amino acid carriers |
| EP1820497A2 (en) | 1996-05-17 | 2007-08-22 | Merck & Co., Inc. | Effervescent bisphosphonate formulation |
| WO2008131160A1 (en) * | 2007-04-19 | 2008-10-30 | Dr. Reddy's Laboratories Ltd. | Ibandronate sodium polymorphs |
| US20090118239A1 (en) * | 2007-11-05 | 2009-05-07 | Teva Pharmaceutical Industries Ltd. | Amorphous and crystalline forms of ibandronate disodium |
-
2011
- 2011-10-24 TR TR2011/10526A patent/TR201110526A2/en unknown
-
2012
- 2012-01-03 WO PCT/TR2012/000008 patent/WO2012093977A1/en not_active Ceased
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1820497A2 (en) | 1996-05-17 | 2007-08-22 | Merck & Co., Inc. | Effervescent bisphosphonate formulation |
| WO2006002348A2 (en) * | 2004-06-23 | 2006-01-05 | Teva Pharmaceutical Industies Ltd. | Solid and crystalline ibandronic acid |
| US20070049557A1 (en) * | 2005-08-24 | 2007-03-01 | Hashim Ahmed | Solid pharmaceutical dosage forms comprising bisphosphonates and modified amino acid carriers |
| WO2008131160A1 (en) * | 2007-04-19 | 2008-10-30 | Dr. Reddy's Laboratories Ltd. | Ibandronate sodium polymorphs |
| US20090118239A1 (en) * | 2007-11-05 | 2009-05-07 | Teva Pharmaceutical Industries Ltd. | Amorphous and crystalline forms of ibandronate disodium |
Also Published As
| Publication number | Publication date |
|---|---|
| TR201110526A2 (en) | 2012-07-23 |
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