A FILLING AGENT AND A SWEETENER

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%.

Formula (I)

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 an 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 patients. 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.

The inventors have achieved to produce water soluble ibandronate sodium formulations within the scope of the present invention in line with this need in the prior art.

However, the important problem related to these water soluble formulations is that patients do not want to drink the formulations due to the bitter taste of the active agent.

This problem has been surprisingly solved by selection of the types of the filling agent and the sweetener used in the formulations and adjusting the amounts of these in the formulations.

Masking the bitter taste in this way without need for using high amounts of sweetener enables that the water soluble formulations appeal to a wider profile of patients (for instance diabetic patients). ■ ^■ . / - . ^' J IM

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 the combinations thereof as active agent; production and usage areas thereof.

The purpose of the present invention is to produce easily drinkable, highly bioavailable and easy-to-use water soluble formulations wherein the bitter taste of the active agent is suppressed.

The characteristic feature of the water soluble formulations developed within the scope of the present invention is that the bitter taste can be suppressed without need for using high amounts of sweetener.

One characteristic feature of the formulations of the present invention is that at least one sweetener is used 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 in the formulations.

The sweeteners that can be used in the water soluble formulations of the present invention are selected from a group comprising aspartame, dextrose, fructose, sucralose, sodium cyclamate, mannitol, maltose, sorbitol, saccharin and/or pharmaceutically acceptable salts or the combinations thereof.

Another 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 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 the combinations thereof.

One characteristic feature of the water soluble formulations of the present invention is that the ratio of the filling agent to the sweetener comprised in the formulations by weight is minimum 20, preferably in the range of 20 to 25.

Another characteristic feature of the formulations of the present invention is that the preferred filling agent is mannitol. Another characteristic feature of the formulations of the present invention is that suitable substance combination and suitable ratios thereof are used for ibandronate formulations with suppressed bitter taste.

The pharmaceutical formulations of the present invention are basically composed of the components below;

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.

The formulations of the present invention can optionally comprise at least one other pharmaceutically acceptable excipient in addition to the specified above.

The pharmaceutically acceptable excipients that can be used in the water soluble formulations of the present invention can be selected from a group comprising filling agents, binders, lubricants, disintegrants, diluents, stabilizing agents, sweeteners, taste regulating agents, inorganic salts, flavouring agents.

The inorganic salts that can be used in the formulations 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 formulations of the present invention can comprise an 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 inorganic salt preferred is selected from a group comprising sodium or potassium carbonates or bicarbonates. The inorganic salt which is particularly preferred is sodium bicarbonate.

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 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 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.

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.

One characteristic feature of the formulations of the present invention is that said formulations 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 the 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 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 water soluble formulations of the present invention can be formulated in powder or granule form and presented as filled into bottles, sachet as well as presented in tablet or capsule for obtainment of the dosage form required.

One characteristic feature of the formulations of the present invention is that the formulations are formulated in powder form.

Another characteristic feature of the formulations of the present invention is that the formulations are formulated in granule form.

The dosage form preferred is prepared in sachet dosage form designed to prevent the active agent granules from being affected from the environmental factors such as heat, moisture, light.

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.

The formulations of the present invention can be produced by 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.