EP2661270A1 - Water-soluble dosage forms comprising ibandronate - Google Patents

Water-soluble dosage forms comprising ibandronate

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Publication number
EP2661270A1
EP2661270A1 EP12704937.7A EP12704937A EP2661270A1 EP 2661270 A1 EP2661270 A1 EP 2661270A1 EP 12704937 A EP12704937 A EP 12704937A EP 2661270 A1 EP2661270 A1 EP 2661270A1
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EP
European Patent Office
Prior art keywords
formulation
comprised
formulation according
sodium
agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP12704937.7A
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German (de)
French (fr)
Inventor
Mahmut Bilgic
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Individual
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Individual
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Publication date
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Publication of EP2661270A1 publication Critical patent/EP2661270A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • 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
    • A61K9/145—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 organic compounds

Definitions

  • the present invention discloses water soluble dosage forms comprising ibandronate and/or any pharmaceutically suitable derivative thereof which are developed to be used in prevention and treatment of bone loss and diseases associated with bone loss.
  • Bone loss or in other words "osteoporosis” is defined as a disease characterized by low bone mass and susceptibility to bone fragility as a result of distortion in microstructure of bone tissue and increased risk in bone fracture. The disease does not generally result in death; however, it appears as a major health problem affecting quality of life in the world.
  • Bisphosphonates are pharmaceutical agents which are commonly used in prevention and treatment of bone loss and diseases associated with bone loss. The studies conducted have shown that starting bisphosphonate treatment reduces risk of bone fracture when there appears osteoporosis or nontraumatic bone fracture in postmenopausal period (Fink HA the Fracture Intervention Trial (FIT) 2003).
  • Ibandronate which is a bisphosphonate having the chemical name of l-hydroxy-3-N-methyl- N-pentyl aminopropy 1-1.1- diphosphonic acid was firstly disclosed in the patent numbered DE3623397. It is known that ibandronate is used in treatment of bone diseases, calcium metabolism disorders, osteoporosis, tumor osteolysis or Paget' s disease. Ibandronate should be administered frequently, intermittently and for a long period of time in treatment of said diseases; therefore, the aim of ibandronate administration should be oral administration which is much more accepted by lots of patients in addition to intravenous administration.
  • Ibandronate formulations marketed today are in the form of oral formulations (tablet) and solutions for intravenous injection or infusion which have been improved in accordance with this requirement.
  • the first characteristic feature of the formulation of the present invention is that the formulation is formulated as water soluble dosage forms.
  • the inventors have surprisingly found that water soluble dosage forms comprising ibandronate have higher bioavailability as compared to existing oral formulations and overcome gastrointestinal irritations and said difficulties of use observed in oral formulations.
  • the formulation of the present invention is more advantageous as compared to formulations which are administered intravenously since the patient can use the drug easily by oneself without need of any medical practitioner and this method is painless.
  • the present invention relates to water soluble dosage forms comprising ibandronate and/or a pharmaceutical derivative thereof.
  • Ibandronate comprised in the formulation of the present invention is in the form of its pharmaceutically acceptable hydrates, solvates, esters, enantiomers, polymorphs, crystalline forms, amorphous forms, salts or free base form and/or a combination thereof.
  • Ibandronate comprised in the formulation of the present invention is preferably in salt form.
  • These salts can be selected from organic acid salts such as hydrochloride, hydrobromide, sulphate, phosphate, formate, acetate, trifluoroacetate, methanesulphonate, benzenesulphonate, toluenesulfonate; alkaline metal salts such as sodium, potassium; alkaline earth salts such as calcium, magnesium; organic amine salts such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or a combination thereof.
  • Ibandronate comprised in the formulation of the present invention is in sodium salt form.
  • Ibandronate comprised in the formulation of the present invention is preferably in hydrate form.
  • hydrates can be selected from hydrates such as anhydrate, monohydrate, dihydrate, trihydrate, hemihydrate, 1 ⁇ 4 hydrate, 1 ⁇ 2 hydrate, 3 ⁇ 4 hydrate, 3 ⁇ 4 hydrate, 5 / 4 hydrate, hydrate, 5 / 2 hydrate and V 2 hydrate.
  • Ibandronate comprised in the effervescent formulation of the present invention is preferably in monohydrate or anhydrate form.
  • the amount of ibandronate comprised in the formulation of the present invention is in the range of 1-1000 mg, preferably in the range of 10-500 mg, more preferably in the range of 25- 250 mg.
  • Ibandronate comprised in the formulation of the present invention is in the range of 1-60 % by weight, preferably in the range of 5-40 % by weight.
  • the water soluble formulation of the present invention is in the form of powder, granule, pellet, micro tablet or tablet.
  • the inventors have encountered effective dissolution and dissolution time problems in the present formulation which are usually encountered in water soluble formulations.
  • the inventors have seen that the rate of pH agent used in the formulation has importance for effective dissolution and dissolution time.
  • pH agent used in the range of 5-40% provides effective dissolution and dissolution time.
  • the formulation of the present invention comprising pH agent in the range of 5-40% forms a homogeneous mixture by dissolving in water in less than 60 seconds.
  • pH agent used in the formulation of the present invention is sodium hydrogen carbonate.
  • the formulation of the present invention can optionally comprise one or more of the following excipients: effervescent couple, binder, lubricant, glidant, diluent, disintegrant, filling agent, flavouring agent, sweetener, colouring agent, surfactant, antifoaming agent, viscosity agent, stabilizing agent.
  • excipients effervescent couple, binder, lubricant, glidant, diluent, disintegrant, filling agent, flavouring agent, sweetener, colouring agent, surfactant, antifoaming agent, viscosity agent, stabilizing agent.
  • excipients effervescent couple, binder, lubricant, glidant, diluent, disintegrant, filling agent, flavouring agent, sweetener, colouring agent, surfactant, antifoaming agent, viscosity agent, stabilizing agent.
  • ' 'effervescent couple' ' refers to use of an
  • the effervescent couple comprised in the effervescent formulation of the present invention is in the range of 0-80% by weight.
  • the acidic agent mentioned herein can be selected from a group composed of acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or a combination thereof.
  • the basic agent mentioned herein can be selected from a group composed of potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen citrate or a combination thereof.
  • the binder mentioned herein 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; gelatin; cellulose derivatives such as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or a combination thereof.
  • the lubricant mentioned herein can be selected from sodium lauryl sulphate, sodium benzoate, sodium chloride, sodium acetate, sodium fumarate, carbowax 4000, L-leucine(17), PEG or a combination thereof.
  • the glidant mentioned herein can be selected from talc, magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycol, leucine, alanine, glycine, sodium benzoate, sodium acetate, fumaric acid or a combination thereof.
  • the diluent mentioned herein can be selected from lactose, maltose, dextrin, maltodextrin, mannitol, sorbitol, starch or a combination thereof.
  • the disintegrant mentioned herein can be selected from starches such as potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate; cellulose derivatives such as croscarmellose sodium or microcrystalline cellulose; polyvinylpyrrolidone; crospovidone; alginic acid and its salts; chyles such as xanthan gum and veegum; ion exchange resins or a combination thereof.
  • the filling agent mentioned herein can be selected from sorbitol, lactose, mannitol or other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulphate, ethyl cellulose, polyacrylates, calcium hydrogen phosphate, sodium hydrogen phosphate, citric acid or a combination thereof.
  • the amount of filling agent used in the formulation of the present invention is in the range of 10-80% by weight, preferably in the range of 40-60% by weight.
  • the filling agent used in the formulation of the present invention is preferably mannitol.
  • the flavouring agent mentioned herein 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.
  • natural aroma oils such as peppermint oil, oil of wintergreen, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil
  • the sweetener mentioned herein can be selected from sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrine, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharine, saccharine salts, acesulphame potassium, aspartame, D-tryptophan, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamates or a combination thereof.
  • the colouring agent mentioned herein can be selected from carotenoids and chlorophyll or a combination thereof.
  • the surfactant mentioned herein can be selected from sodium lauryl sulphate and magnesium lauryl sulphate or a combination thereof.
  • the antifoaming agent mentioned herein can be selected from simethicone emulsion and dimethyl siloxane, silicone oil or a combination thereof.
  • the viscosity agent mentioned herein can be selected from carboxymethyl cellulose, methyl cellulose, xanthan gum, gummi tragacanthae, gum arabic, aerosil 200, colloidon, agar-agar, bentonite, hydroxyethyl cellulose or a combination thereof.
  • the stabilizing agent and/or agents mentioned herein can be selected from antioxidants, chelating agents, alkalinizing agents and photo protective agents.
  • the antioxidants can be selected from substances such as butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulphite, gallates (such as propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbyl palmitate, ethylenediamine tetraacetate or a combination thereof.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • gallates such as propyl gallate
  • tocopherol citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbyl palmitate, ethylenediamine tetraacetate or a combination thereof.
  • the chelating agents can be selected from disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or a combination thereof.
  • the alkalizing agents can be selected from alkali metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen ortophosphate, sodium aluminate; earth alkali metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate and organic compounds such as primary, secondary and tertiary amines, cyclic amines, N-N'-dibenzylethylenediamine, diethanolamine, ethylenediamine, meglumine, monosodium glutamate, polyacryline sodium, sodium alginate or a combination thereof.
  • alkali metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen ortophosphate
  • the photoprotective agents can be selected from metal oxides such as titanium oxide, iron oxide or zinc oxide or a combination thereof.
  • the formulation of the present invention comprises
  • the formulation of the present invention can be used in treatment of osteoporosis; in order to reduce risk of bone fracture in women including spine bone and hipbone; in order to reduce risk of bone fracture in men; in treatment of diseases such as idiopathic osteoporosis; osteoporosis induced by various diseases; steroid and glucocorticoid-induced osteoporosis ; osteopenia, osteomalacia, osteogenesis imperfecta, osteochondrodysplasia, sudeck atrophy, rheumatoid arthritis, Paget's disease, bone metastasis of malignant tumors, hypercalcaemia or hyperthyroidism; and particularly in adolescence, pregnant or nursing women in premenopausal and postmenopausal period in order to preserve bone health as nutrition reinforcement.
  • diseases such as idiopathic osteoporosis; osteoporosis induced by various diseases; steroid and glucocorticoid-induced osteoporosis ; osteopenia, osteo
  • Ibandronate sodium, pH agent, the filling agent and the other excipients are mixed in a container.
  • the mixture obtained is loaded into sachet filling machines and sachet filling is performed.

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Abstract

The present invention discloses water soluble dosage forms comprising ibandronate and/or any pharmaceutically suitable derivative thereof which are developed to be used in prevention and treatment of bone loss and diseases associated with bone loss.

Description

WATER - SOLUBLE DOSAGE FORMS COMPRISING IBANDRONATE
Technical Field
The present invention discloses water soluble dosage forms comprising ibandronate and/or any pharmaceutically suitable derivative thereof which are developed to be used in prevention and treatment of bone loss and diseases associated with bone loss.
The prior art
Bone loss or in other words "osteoporosis" is defined as a disease characterized by low bone mass and susceptibility to bone fragility as a result of distortion in microstructure of bone tissue and increased risk in bone fracture. The disease does not generally result in death; however, it appears as a major health problem affecting quality of life in the world.
Bisphosphonates are pharmaceutical agents which are commonly used in prevention and treatment of bone loss and diseases associated with bone loss. The studies conducted have shown that starting bisphosphonate treatment reduces risk of bone fracture when there appears osteoporosis or nontraumatic bone fracture in postmenopausal period (Fink HA the Fracture Intervention Trial (FIT) 2003).
Ibandronate which is a bisphosphonate having the chemical name of l-hydroxy-3-N-methyl- N-pentyl aminopropy 1-1.1- diphosphonic acid was firstly disclosed in the patent numbered DE3623397. It is known that ibandronate is used in treatment of bone diseases, calcium metabolism disorders, osteoporosis, tumor osteolysis or Paget' s disease. Ibandronate should be administered frequently, intermittently and for a long period of time in treatment of said diseases; therefore, the aim of ibandronate administration should be oral administration which is much more accepted by lots of patients in addition to intravenous administration.
Ibandronate formulations marketed today are in the form of oral formulations (tablet) and solutions for intravenous injection or infusion which have been improved in accordance with this requirement.
In addition, actually oral treatment often poses problems since bisphosphonates, particularly amino bisphosphonates, cause irritations of gastrointestinal system in general (Fleisch H. Bisphosphonates in bone disease, Bern 1993, p. 126-131). These gastrointestinal irritations can be listed as erosion, ulcer and similar irritations of epithelial and mucosal layer of the mouth, buccal cavity, pharynx, larynx and esophagus. In addition, it is also known that movement disorders can occur in upper gastrointestinal system and/or tablets to be taken might get stuck in esophagus depending on the anatomic situation of esophagus. This situation causes suffocation along with painful swallowing. This situation is more frequently seen in elderly patients or in patients who has to take the tablets required in lying position due to their diseases.
Another problem which is encountered during oral administration of bisphosphonates is that sufficient bioavailability cannot be ensured depending on low absorption in gastrointestinal system. For instance, only 0.5% to 5% of the drug is absorbed and only 20% to 50% of the drug absorbed is bound to bone tissue and show efficiency in tablet form. In this respect, it is seen that solutions for intravenous injection or infusion are more advantageous as compared to orally administered bisphosphonate formulations. However, intravenous administration is not preferred by the patients since the patient cannot administer the drug by oneself, absolutely needs a medical practitioner in order to take the drug and administration method is painful. When the prior art is taken into consideration, it is obviously seen that ibandronate is a therapeutically effective agent in treatment and prevention of bone loss and diseases associated with bone loss. In addition, there is need for development of new formulations due to the reasons of low bioavailability, severe gastrointestinal irritation and use of existing dosage forms only by a limited number of patients. Description of the Invention
The first characteristic feature of the formulation of the present invention is that the formulation is formulated as water soluble dosage forms. The inventors have surprisingly found that water soluble dosage forms comprising ibandronate have higher bioavailability as compared to existing oral formulations and overcome gastrointestinal irritations and said difficulties of use observed in oral formulations. Furthermore, the formulation of the present invention is more advantageous as compared to formulations which are administered intravenously since the patient can use the drug easily by oneself without need of any medical practitioner and this method is painless.
In this respect, the present invention relates to water soluble dosage forms comprising ibandronate and/or a pharmaceutical derivative thereof. Ibandronate comprised in the formulation of the present invention is in the form of its pharmaceutically acceptable hydrates, solvates, esters, enantiomers, polymorphs, crystalline forms, amorphous forms, salts or free base form and/or a combination thereof.
Ibandronate comprised in the formulation of the present invention is preferably in salt form. These salts can be selected from organic acid salts such as hydrochloride, hydrobromide, sulphate, phosphate, formate, acetate, trifluoroacetate, methanesulphonate, benzenesulphonate, toluenesulfonate; alkaline metal salts such as sodium, potassium; alkaline earth salts such as calcium, magnesium; organic amine salts such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or a combination thereof. Ibandronate comprised in the formulation of the present invention is in sodium salt form.
Ibandronate comprised in the formulation of the present invention is preferably in hydrate form.
These hydrates can be selected from hydrates such as anhydrate, monohydrate, dihydrate, trihydrate, hemihydrate, ¼ hydrate, ½ hydrate, ¾ hydrate, ¾ hydrate, 5/4 hydrate, hydrate, 5/2 hydrate and V2 hydrate.
Ibandronate comprised in the effervescent formulation of the present invention is preferably in monohydrate or anhydrate form.
The amount of ibandronate comprised in the formulation of the present invention is in the range of 1-1000 mg, preferably in the range of 10-500 mg, more preferably in the range of 25- 250 mg.
Ibandronate comprised in the formulation of the present invention is in the range of 1-60 % by weight, preferably in the range of 5-40 % by weight.
The water soluble formulation of the present invention is in the form of powder, granule, pellet, micro tablet or tablet. The inventors have encountered effective dissolution and dissolution time problems in the present formulation which are usually encountered in water soluble formulations. The inventors have seen that the rate of pH agent used in the formulation has importance for effective dissolution and dissolution time. As a result of the studies conducted in line with this purpose, the inventors have found that pH agent used in the range of 5-40% provides effective dissolution and dissolution time.
The formulation of the present invention comprising pH agent in the range of 5-40% forms a homogeneous mixture by dissolving in water in less than 60 seconds. pH agent used in the formulation of the present invention is sodium hydrogen carbonate.
The formulation of the present invention can optionally comprise one or more of the following excipients: effervescent couple, binder, lubricant, glidant, diluent, disintegrant, filling agent, flavouring agent, sweetener, colouring agent, surfactant, antifoaming agent, viscosity agent, stabilizing agent. The term ' 'effervescent couple' ' refers to use of an acidic agent and a basic agent together.
The effervescent couple comprised in the effervescent formulation of the present invention is in the range of 0-80% by weight.
The acidic agent mentioned herein can be selected from a group composed of acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or a combination thereof.
The basic agent mentioned herein can be selected from a group composed of potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen citrate or a combination thereof.
The binder mentioned herein 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; gelatin; cellulose derivatives such as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or a combination thereof. The lubricant mentioned herein can be selected from sodium lauryl sulphate, sodium benzoate, sodium chloride, sodium acetate, sodium fumarate, carbowax 4000, L-leucine(17), PEG or a combination thereof. The glidant mentioned herein can be selected from talc, magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycol, leucine, alanine, glycine, sodium benzoate, sodium acetate, fumaric acid or a combination thereof.
The diluent mentioned herein can be selected from lactose, maltose, dextrin, maltodextrin, mannitol, sorbitol, starch or a combination thereof.
The disintegrant mentioned herein can be selected from starches such as potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate; cellulose derivatives such as croscarmellose sodium or microcrystalline cellulose; polyvinylpyrrolidone; crospovidone; alginic acid and its salts; chyles such as xanthan gum and veegum; ion exchange resins or a combination thereof.
The filling agent mentioned herein can be selected from sorbitol, lactose, mannitol or other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulphate, ethyl cellulose, polyacrylates, calcium hydrogen phosphate, sodium hydrogen phosphate, citric acid or a combination thereof. The amount of filling agent used in the formulation of the present invention is in the range of 10-80% by weight, preferably in the range of 40-60% by weight.
The filling agent used in the formulation of the present invention is preferably mannitol.
The flavouring agent mentioned herein 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 sweetener mentioned herein can be selected from sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrine, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharine, saccharine salts, acesulphame potassium, aspartame, D-tryptophan, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamates or a combination thereof. The colouring agent mentioned herein can be selected from carotenoids and chlorophyll or a combination thereof.
The surfactant mentioned herein can be selected from sodium lauryl sulphate and magnesium lauryl sulphate or a combination thereof. The antifoaming agent mentioned herein can be selected from simethicone emulsion and dimethyl siloxane, silicone oil or a combination thereof.
The viscosity agent mentioned herein can be selected from carboxymethyl cellulose, methyl cellulose, xanthan gum, gummi tragacanthae, gum arabic, aerosil 200, colloidon, agar-agar, bentonite, hydroxyethyl cellulose or a combination thereof. The stabilizing agent and/or agents mentioned herein can be selected from antioxidants, chelating agents, alkalinizing agents and photo protective agents.
The antioxidants can be selected from substances such as butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulphite, gallates (such as propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbyl palmitate, ethylenediamine tetraacetate or a combination thereof.
The chelating agents can be selected from disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or a combination thereof.
The alkalizing agents can be selected from alkali metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen ortophosphate, sodium aluminate; earth alkali metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate and organic compounds such as primary, secondary and tertiary amines, cyclic amines, N-N'-dibenzylethylenediamine, diethanolamine, ethylenediamine, meglumine, monosodium glutamate, polyacryline sodium, sodium alginate or a combination thereof.
The photoprotective agents can be selected from metal oxides such as titanium oxide, iron oxide or zinc oxide or a combination thereof. The formulation of the present invention comprises
- ibandronate or a pharmaceutically acceptable derivative thereof in the range of 1-60% by weight
- pH agent in the range of 5-40% by weight
- the filling agent in the range of 10-80% by weight
- the other excipients in the range of 1-50% by weight.
The formulation of the present invention can be used in treatment of osteoporosis; in order to reduce risk of bone fracture in women including spine bone and hipbone; in order to reduce risk of bone fracture in men; in treatment of diseases such as idiopathic osteoporosis; osteoporosis induced by various diseases; steroid and glucocorticoid-induced osteoporosis ; osteopenia, osteomalacia, osteogenesis imperfecta, osteochondrodysplasia, sudeck atrophy, rheumatoid arthritis, Paget's disease, bone metastasis of malignant tumors, hypercalcaemia or hyperthyroidism; and particularly in adolescence, pregnant or nursing women in premenopausal and postmenopausal period in order to preserve bone health as nutrition reinforcement.
The examples required are given below in order to render the formulation of the present invention more comprehensible. Yet, the subject of the present invention should not be limited to these examples.
EXAMPLES
Example 1
Ibandronate sodium, pH agent, the filling agent and the other excipients are mixed in a container. The mixture obtained is loaded into sachet filling machines and sachet filling is performed.
Example 2

Claims

1. The formulation comprising ibandronate and/or a pharmaceutically suitable derivative thereof characterized in that said formulation is formulated in the form of water soluble dosage forms.
2. The formulation according to claim 1 characterized in that ibandronate comprised in said formulation is in the form of its pharmaceutically acceptable hydrates, solvates, esters, enantiomers, polymorphs, crystalline forms, amorphous forms, salts or free base form and/or a combination thereof.
3. The formulation according to claim 2 characterized in that ibandronate comprised in said formulation is in salt form.
4. The formulation according to claim 3 characterized in that ibandronate salt comprised in said formulation is selected from organic acid salts such as hydrochloride, hydrobromide, sulphate, phosphate, formate, acetate, trifluoroacetate, methanesulphonate, benzenesulphonate, toluenesulfonate; alkaline metal salts such as sodium, potassium; alkaline earth salts such as calcium, magnesium; organic amine salts such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or a combination thereof.
5. The formulation according to claim 3 or 4 characterized in that ibandronate comprised in said formulation is in sodium salt form.
6. The formulation according to claim 2 characterized in that ibandronate comprised in said formulation is in hydrate form.
7. The formulation according to claim 6 characterized in that ibandronate hydrate form comprised in said formulation is selected from hydrates such as anhydrate, monohydrate, dihydrate, trihydrate, hemihydrate, ¼ hydrate, ½ hydrate, ¾ hydrate, ¾ hydrate, V4 hydrate, 4/3 hydrate, 5/2 hydrate and 3/2 hydrate.
8. The formulation according to claim 6 or 7 characterized in that ibandronate comprised in said formulation is in monohydrate or anhydrate form.
9. The formulation according to claim 1 characterized in that the amount of ibandronate comprised in said formulation is in the range of 1-1000 mg, preferably in the range of 10-500 mg, more preferably in the range of 25-250 mg.
10. The formulation according to claim 1 characterized in that the amount of ibandronate comprised in the formulation is in the range of 1-60% by weight, preferably in the range of 5-40% by weight.
11. The formulation according to claim 1 characterized in that water soluble formulation is formulated in the form of powder, granule, pellet, micro tablet or tablet.
12. The formulation according to claim 1 characterized in that said formulation comprises pH agent in addition to the active agent ibandronate.
13. The formulation according to claim 12 characterized in that the amount of pH agent comprised in said formulation is in the range of 5-40% by weight.
14. The formulation according to claim 13 characterized in that the amount of pH agent comprised in said formulation is sodium hydrogen carbonate.
15. The formulation according to claim 1 characterized in that said formulation optionally comprises one or more of the excipients of effervescent couple, binder, lubricant, glidant, diluent, disintegrant, flavouring agent, sweetener, colouring agent, surfactant, antifoaming agent, viscosity agent, stabilizing agent.
16. The formulation according to claim 15 characterized in that the effervescent couple comprised in said formulation is composed of acidic agent and basic agent.
17. The formulation according to claim 16 characterized in that effervescent couple comprised in said formulation is in the range of 0-80% by weight.
18. The formulation according to claim 16 characterized in that the acidic agent comprised in said formulation is selected from a group which is composed of acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or a combination thereof.
19. The formulation according to claim 16 characterized in that the basic agent comprised in said formulation is selected from a group which is composed of potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen citrate or a combination thereof.
20. The formulation according to claim 1 characterized in that the binder comprised in said formulation is 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, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or a combination thereof.
21. The formulation according to claim 15 characterized in that the lubricant comprised in said formulation is selected from sodium lauryl sulphate, sodium benzoate, sodium chloride, sodium acetate, sodium fumarate, carbowax 4000, L-leucine(17), PEG or a combination thereof.
22. The formulation according to claim 15 characterized in that the glidant comprised in said formulation is selected from talc, magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycol, leucine, alanine, glycine, sodium benzoate, sodium acetate, fumaric acid or a combination thereof.
23. The formulation according to claim 15 characterized in that the diluent comprised in said formulation is selected from lactose, maltose, dextrin, maltodextrin, mannitol, sorbitol, starch or a combination thereof.
24. The formulation according to claim 15 characterized in that the disintegrant comprised in said formulation is selected from starches such as potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate; cellulose derivatives such as croscarmellose sodium or microcrystalline cellulose; polyvinylpyrrolidone; crospovidone; alginic acid and its salts; chyles such as xanthan gum and veegum; ion exchange resins or a combination thereof.
25. The formulation according to claim 15 characterized in that the filling agent comprised in said formulation is selected from sorbitol, lactose, mannitol or other sugars, microcrystalline cellulose, pectin, gelatine, calcium sulphate, ethyl cellulose, polyacrylates, calcium hydrogen phosphate, sodium hydrogen phosphate, citric acid or a combination thereof.
26. The formulation according to claim 25 characterized in that the filling agent comprised in said formulation is mannitol.
27. The formulation according to 25 or 26 characterized in that the amount of the filling agent comprised in said formulation is in the range of 10-80% by weight, preferably in the range of 40-60% by weight.
28. The formulation according to claim 15 characterized in that the flavouring agent comprised in said formulation is 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, linalool, cinnamaldehyde glycerol acetal, N-substituted p-menthane-3-carboxamide, 3.1-methoxy propane 1.2-diol or a combination thereof.
29. The formulation according to claim 15 characterized in that the sweetener comprised in said formulation is selected from sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrine, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharine, saccharine salts, acesulphame potassium, aspartame, D-tryptophan, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamates or a combination thereof.
30. The formulation according to claim 15 characterized in that the colouring agent comprised in said formulation is selected from carotenoids and chlorophyll or a combination thereof.
31. The formulation according to claim 15 characterized in that the surfactant comprised in said formulation is selected from sodium lauryl sulphate and magnesium lauryl sulphate or a combination thereof.
32. The formulation according to claim 15 characterized in that the antifoaming agent comprised in said formulation is selected from simethicone emulsion and dimethyl siloxane, silicone oil or a combination thereof.
33. The formulation according to claim 15 characterized in that the viscosity agent comprised in said formulation is selected from carboxymethyl cellulose, methyl cellulose, xanthan gum, gummi tragacanthae, gum arabic, aerosil 200, colloidion, agar-agar, bentonite, hydroxyethyl cellulose or a combination thereof.
34. The formulation according to claim 15 characterized in that the stabilizing agent and/or agents comprised in said formulation is selected from antioxidants, chelating agents, alkalinizing agents and photo protective agents.
EP12704937.7A 2011-01-06 2012-01-06 Water-soluble dosage forms comprising ibandronate Withdrawn EP2661270A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2011/00151A TR201100151A2 (en) 2011-01-06 2011-01-06 Ibandronate formulation.
PCT/TR2012/000010 WO2012093979A1 (en) 2011-01-06 2012-01-06 Water-soluble dosage forms comprising ibandronate

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CN104922060B (en) * 2015-05-23 2017-10-20 河北仁合益康药业有限公司 A kind of Ibandronate composition
CN107670103A (en) * 2017-09-15 2018-02-09 天津大学 The bone cement and preparation method that polyethylene pyrrole network alkanone is modified

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DE3623397A1 (en) 1986-07-11 1988-01-14 Boehringer Mannheim Gmbh NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
JP2000511178A (en) * 1996-05-17 2000-08-29 メルク エンド カンパニー インコーポレーテッド Effervescent bisphosphonate preparation
US5853759A (en) * 1996-05-17 1998-12-29 Merck & Co.. Inc. Effervescent alendronate formulation
US20060034921A1 (en) * 2004-01-05 2006-02-16 Katdare Ashok V Effervescent bisphosphonate formulation
US20070087052A1 (en) * 2005-10-19 2007-04-19 Katdare Ashok V Effervescent bisphosphonate formulation

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