EP2416756A2 - Stable pharmaceutical compositions with high bioavailibility - Google Patents

Stable pharmaceutical compositions with high bioavailibility

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Publication number
EP2416756A2
EP2416756A2 EP10731618A EP10731618A EP2416756A2 EP 2416756 A2 EP2416756 A2 EP 2416756A2 EP 10731618 A EP10731618 A EP 10731618A EP 10731618 A EP10731618 A EP 10731618A EP 2416756 A2 EP2416756 A2 EP 2416756A2
Authority
EP
European Patent Office
Prior art keywords
strontium
treatment
pharmaceutical composition
sodium
composition according
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.)
Withdrawn
Application number
EP10731618A
Other languages
German (de)
French (fr)
Inventor
Mahmut Bilgic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bilgic Mahmut
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Individual
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Filing date
Publication date
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Publication of EP2416756A2 publication Critical patent/EP2416756A2/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Withdrawn legal-status Critical Current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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • the present invention relates to pharmaceutical compositions comprising an active agent alone or in combination with another active agent which is used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or effective as a supplement.
  • the present invention provides a pharmaceutical composition which is used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or effective as a supplement
  • Strontium is an earth-alkali metal that has high chemical reactivity. It was first discovered by Thomas Charles Hope in 1798. Strontium ranelate (Formula I) was first described in United States Patent application 5128367 (European Patent number 0415850 is also a member of the patent family). The process for the preparation of strontium ranelate and its use for the treatment of bone disorder, especially for osteoporosis, are described in this patent.
  • Strontium is an element which has a high affinity to the bone tissue. Due to its high chemical and physical similarity to calcium, it can be used instead of calcium and can show the same activity. Its anti-osteoporotic effect is suggested to demonstrate itself with a dual mechanism of bone production improvement and bone resorption reduction.
  • 89 Sr is a radiopharmaceutical used for bone pain secondary to metastatic bone cancer. The strontium acts like calcium and is preferentially incorporated into bone at sites of increased osteogenesis. This localization focuses the radiation exposure on the cancerous lesion.
  • 90 Sr is used as radiotherapy in cancer treatment due to its beta emission and long half-life characteristics.
  • Strontium ranelate being one of the strontium compounds is effective in bone growth, increasing bone density and lessening bone fractures and the use of granule form of strontium ranelate for oral suspension is approved in Europe.
  • Vitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D 2 (or ergocalciferol) and vitamin D 3 (or cholecalciferol). There are also D 1 , D 4 and D 5 forms. The term vitamin D also refers to these metabolites and other analogues of these substances. Vitamin D 3 is a vitamin D form with the chemical name (3 ⁇ ,5Z,7E)-9,10-secocholesta- 5,7,10(19)-trien-3-ol (Formula II).
  • Vitamin D 3 is the form of vitamin D that is synthesized naturally in the body. It is synthesized in the skin from 7-dehydrocholesterol, a sterol present in the mammalian skin, under the action of ultraviolet light. Vitamin D 3 can be obtained partially from animal products. Vitamin D 3 is hydroxylated in the liver and kidney, and becomes calcitriol (1,25- dihydroxyvitamin D 3 ).
  • Calcitriol plays an important role in the maintenance of the calcium balance and the parathyroid hormone regulation. It stimulates the renal reabsorption of calcium, and increases the intestinal absorption of calcium and phosphorus and their mobilization from the bone to the plasma. It is believed that the absorption of calcium in the intestines is achieved by the calcitriol by binding to specific receptors in the cytoplasm of intestinal mucosa cells. Then calcium is absorbed by formation of a calcium binding protein. When calcium and phosphorus levels of plasma reach saturation, mineralization occurs in the bone. Vitamin D affects the absorption of strontium in the same way as it affects calcium absorption. Hence, Vitamin D can be added to a strontium composition to be used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or as a supplement.
  • the present invention relates to pharmaceutical compositions which are effective for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or as a supplement.
  • the mentioned compositions comprise a strontium compound alone or in combination with vitamin D.
  • the object of the invention is to provide a composition comprising the active agent or agents in a pharmaceutically acceptable, non-toxic and therapeutically effective amount according to the invention and the formulation of these active agent/agents to achieve this desired effect.
  • European Patent No. 1534305 describes the use of strontium malonate with a solubility of 1- 100 g/1 at room temperature, for prevention and/or treatment of various bone conditions.
  • European Patent No. 1534305 European Application No. 1745791 describes the use of some strontium salts also with a solubility of 1-100 g/1 at room temperature, for prevention and/or treatment of various bone conditions. It has been indicated in these patents that these novel salts encounter no solubility problems.
  • vitamin D The tendency of vitamin D to degrade when exposed to heat, light, air, moisture, oxidizing agents or an acidic environment raises the problem of stability with the formulations comprising vitamin D. This situation raises the necessity of using an auxiliary agent to ensure the stability of vitamin D in the tablet.
  • the present invention provides stable, highly soluble and hence bioavailable pharmaceutical compositions comprising a strontium compound alone or in combination with Vitamin D to formulate the composition for maintaining the "desired effect".
  • the present invention relates to the use of pharmaceutical compositions comprising a strontium compound alone or in combination with vitamin D, in the manufacture of a medicament used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or as a supplement in a liquid dosage form or a solid dosage form which transforms into liquid form just before administration.
  • the present invention is directed to obtain stable, highly soluble and hence bioavailable pharmaceutical compositions comprising a strontium compound alone or in combination with Vitamin D to formulate the composition for maintaining the "desired effect".
  • Strontium ranelate a strontium salt effective in the treatment of osteoporosis, released to market in Europe in the form of granules for oral suspension.
  • the present invention is directed to solution formulations which are preferred instead of suspension formulations in order to increase the bioavailability of pharmaceutical compositions comprising a strontium compound.
  • These previously mentioned solution compositions might be either in a liquid dosage form or in a solid dosage form which transforms into liquid phase just before administration.
  • the pharmaceutical compositions of the invention preferably in the effervescent tablet form highly improve the bioavailability because they are already administered in dissolved form and already provide the use of active agent in high amounts.
  • the pharmaceutical formulation composition of the present invention are characterized in that they provide formulations comprising a high dose of a strontium compound in effervescent form to improve solubility, thus bioavailability; instead of restrictive and complicated methods, which require both time and capital, such as use of a solubility enhancing agent, preparation of novel strontium salts with improved solubility, addition of at least two strontium salts to enhance bioavailability and enhancement of the release characteristics of tablet dosage form.
  • Strontium carbonate can be used alone or in combination with other strontium compounds because of the fact that the effervescent formulations of the invention are effective as a carbondioxide source and improve bioavailability by increasing active agent dose.
  • the pharmaceutical compositions preferably in tablet dosage form may also comprise a small amount of sweetener and/or flavoring agent as taste promoter.
  • compositions of the present invention may be formulated comprising a strontium compound alone or also a strontium compound in combination with vitamin D as an active agent.
  • a strontium compound alone or also a strontium compound in combination with vitamin D as an active agent.
  • the stability problem arises due to vitamin D.
  • Pharmaceutical compositions of the invention in effervescent form comprise disintegrants which cause tablets to disintegrate, in other words to dissolve, thus increasing the bioavailability and also providing the stability of the composition.
  • Pharmaceutical compositions of the invention preferably in effervescent form can also comprise at least one stabilizing agent.
  • compositions comprising a strontium compound alone or in combination with vitamin D, in liquid or solid dosage form which transforms into liquid form just before administration, preferably in effervescent tablet form, and optionally comprising an additive selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, surfactants, stabilizing agents, sweeteners and flavoring agents, have improved solubility, bioavailability and stability characteristics and the pharmaceutical compositions are used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or effective as a supplement.
  • the term "used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or as a supplement” used herein refers to the use of treatment of osteoporosis; treatment of osteoporosis by reducing the risk of post-menopausal bone fractures of the spine and hip bones in women; treatment of osteoporosis for reducing the risk of bone fractures in men; treatment of idiopathic osteoporosis; treatment of various disease related osteoporosis; treatment of steroid and glucocorticoid related osteoporosis; treatment of osteoarthritis; treatment of osteopetrosis; treatment of osteopenia; treatment of osteomalacia; treatment of osteodystrophy; treatment of osteogenesis imperfecta; treatment of osteochondrodysplasia; treatment of Sudeck's atrophy, treatment of rheumatoid arthritis, treatment of Paget's disease, treatment of Bechterew's disease, treatment of Behcet's disease, treatment of periodon
  • the pharmaceutical compositions contain strontium compound in the range of 0.1-75% by weight and an amount of vitamin D in the range of 100-100000 IU to achieve the desired therapeutic effect.
  • strontium compound indicates strontium adipate, strontium alendronate, strontium alginate, strontium acetate, strontium ascorbate, strontium aspartate, strontium benzenesulfonate, strontium benzoate, strontium borate, strontium bromate, strontium bromide, strontium butanoate, strontium butirate, strontium decanoate, strontium ethanesulfonate, strontium etidronate, strontium fluoride, strontium formate, strontium phosphate, strontium fumarate, strontium glyconate, strontium glycocholate, strontium glutamate, strontium glutarate, strontium hexanoate,
  • the pharmaceutically acceptable diluents can be selected from the group of lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, caolin, lactitol, powdered cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol and xylitol.
  • the diluent is present in the formulation preferably in a range of 0-85% by weight, more preferably in a range of 0.1-75% by weight.
  • the pharmaceutically acceptable binders can be selected from the group of starch (e.g. potato starch, cornstarch or wheat starch), sucrose, glucose, dextrose, lactose, sugars like maltodexrin, natural and synthetic gums (e.g. acacia tree), gelatin, cellulose derivatives (e.g. microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose), polyethylene glycol (PEG), waxes, calcium carbonate, calcium phosphate, alcohols (e.g. sorbitol, xylitol and mannitol) and water.
  • the binder is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.
  • the pharmaceutically acceptable disintegrants can be selected from the group of starch (e.g. potato starch, cornstarch or wheat starch), sodium starch glycolate, pregelatinized starch, cellulose derivatives (such as croscarmellose sodium or microcrystalline cellulose), polyvinylpyrrolidone (PVP), crospovidone, alginic acid, sodium alginate, clays (such as Xanthan gum or Veegum), ion-exchange resins and effervescent systems (alkali or alkaline earth metal carbonates (e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, and strontium carbonate), water-soluble organic acids and salts (e.g.
  • starch e.g. potato starch, cornstarch or wheat starch
  • sodium starch glycolate e.g. potato starch, cornstarch or wheat starch
  • pregelatinized starch e.g. potato starch, cornstarch or wheat starch
  • the disintegrant is present in the formulation preferably in a range of 0-85% by weight, more preferably in a range of 0.1-75% by weight.
  • the pharmaceutically acceptable lubricants can be selected from the group of metallic stearates (e.g. magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (e.g. sodium stearyl fumarate), fatty acids (e.g. stearic acid), fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (e.g. sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate and sodium acetate.
  • metallic stearates e.g. magnesium stearate, calcium stearate, aluminum stearate
  • fatty acid esters e.g. sodium stearyl fumarate
  • fatty acids e.g. stearic acid
  • fatty alcohols e.g. glyceryl behenate
  • mineral oils e
  • the lubricant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.
  • the pharmaceutically acceptable glidants can be selected from the group of silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate.
  • the weight % of the glidant in the formulation is lower than 1%.
  • the pharmaceutically acceptable surfactants can be selected from the group of polyoxyethylene sorbitan fatty acid (polysorbates), sodium lauryl sulphate, sodium stearyl fumarate, polyoxyethylene castor oil derivatives, docusate sodium, quatenary ammonia compounds, amino acids like L-leucine, sugar esters of fatty acids and glycerides of fatty acids.
  • the lubricant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.
  • the stabilizing agent(s) and antioxidants can be selected from the group of chelating agents, alkalizing agents and photoprotectors.
  • the stabilizing agent is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.
  • the antioxidants can be selected from the group of butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulphite, gallates (e.g. propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbyl palmitate, ethylenediamine tetraacetate.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • gallates e.g. propyl gallate
  • tocopherol citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbyl palmitate, ethylenediamine tetraacetate.
  • the chelating agents can be selected from the group of disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate and combinations.
  • the alkalizing agents can be selected from the group of alkali metal salts like sodium hydrogen carbonate, sodium dihydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; earth alkali salts like 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; primary, secondary and tertiary amines, cyclic amines, N 5 N'- dibenzylethylenediamine, diethanolamin, ethylenediamine, meglumine, monosodium glutamate, polacrilin sodium and sodium alginate.
  • alkali metal salts like sodium hydrogen carbonate, sodium dihydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate
  • earth alkali salts
  • the photoprotectors can be selected from the group of titanium oxide, iron oxide and zinc.
  • the pharmaceutically acceptable sweeteners can be selected from the group of sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, levulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythriol, lactitol, isomalt, corn syrup, saccarine, saccarine salts, acesulfame potassium, aspartam, D-tryptophan, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamate.
  • the sweeteners are present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.
  • the pharmaceutically acceptable flavoring agents can be selected from the following group; natural aroma oils (peppermint oil, partridge currant oil, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil, etc.), menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, 1 -methyl acetate, sage, eugenol, oxanone, ⁇ -irisone, marjoram, lemon, orange, propenyl guaethol acetyl, vanillin, thymol, linalool, cinnamaldehyde glycerol acetal, N- substituted-p-menthane-3-carboxamide, 3,1-methoxy propane- 1,2-diol.
  • the flavoring agent is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1 -5% by weight.
  • solubility modulators In addition to these, solubility modulators, electrolytes, colorants and coatings can be used as other pharmaceutical excipients in the formulation.
  • Example 1 Example 2.

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Abstract

The present invention relates to pharmaceutical compositions comprising a strontium compound alone or in combination with vitamin D which is used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or effective as a supplement.

Description

STABLE PHARMACEUTICAL COMPOSITIONS WITH HIGH BIOAVAILIBILITY
Field of the Invention
The present invention relates to pharmaceutical compositions comprising an active agent alone or in combination with another active agent which is used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or effective as a supplement.
Background of the Invention The present invention provides a pharmaceutical composition which is used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or effective as a supplement The term "desired effect" as used herein, refers to this effect of the composition comprising a strontium compound alone or in combination with vitamin D.
Strontium (Sr) is an earth-alkali metal that has high chemical reactivity. It was first discovered by Thomas Charles Hope in 1798. Strontium ranelate (Formula I) was first described in United States Patent application 5128367 (European Patent number 0415850 is also a member of the patent family). The process for the preparation of strontium ranelate and its use for the treatment of bone disorder, especially for osteoporosis, are described in this patent.
Strontium is an element which has a high affinity to the bone tissue. Due to its high chemical and physical similarity to calcium, it can be used instead of calcium and can show the same activity. Its anti-osteoporotic effect is suggested to demonstrate itself with a dual mechanism of bone production improvement and bone resorption reduction. 89Sr is a radiopharmaceutical used for bone pain secondary to metastatic bone cancer. The strontium acts like calcium and is preferentially incorporated into bone at sites of increased osteogenesis. This localization focuses the radiation exposure on the cancerous lesion. 90Sr is used as radiotherapy in cancer treatment due to its beta emission and long half-life characteristics. Strontium ranelate being one of the strontium compounds is effective in bone growth, increasing bone density and lessening bone fractures and the use of granule form of strontium ranelate for oral suspension is approved in Europe.
Vitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol). There are also D1, D4 and D5 forms. The term vitamin D also refers to these metabolites and other analogues of these substances. Vitamin D3 is a vitamin D form with the chemical name (3β,5Z,7E)-9,10-secocholesta- 5,7,10(19)-trien-3-ol (Formula II).
Vitamin D3 is the form of vitamin D that is synthesized naturally in the body. It is synthesized in the skin from 7-dehydrocholesterol, a sterol present in the mammalian skin, under the action of ultraviolet light. Vitamin D3 can be obtained partially from animal products. Vitamin D3 is hydroxylated in the liver and kidney, and becomes calcitriol (1,25- dihydroxyvitamin D3).
Calcitriol plays an important role in the maintenance of the calcium balance and the parathyroid hormone regulation. It stimulates the renal reabsorption of calcium, and increases the intestinal absorption of calcium and phosphorus and their mobilization from the bone to the plasma. It is believed that the absorption of calcium in the intestines is achieved by the calcitriol by binding to specific receptors in the cytoplasm of intestinal mucosa cells. Then calcium is absorbed by formation of a calcium binding protein. When calcium and phosphorus levels of plasma reach saturation, mineralization occurs in the bone. Vitamin D affects the absorption of strontium in the same way as it affects calcium absorption. Hence, Vitamin D can be added to a strontium composition to be used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or as a supplement.
The present invention relates to pharmaceutical compositions which are effective for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or as a supplement. The mentioned compositions comprise a strontium compound alone or in combination with vitamin D. The object of the invention is to provide a composition comprising the active agent or agents in a pharmaceutically acceptable, non-toxic and therapeutically effective amount according to the invention and the formulation of these active agent/agents to achieve this desired effect.
However, a solubility problem arises with most of the pharmaceutical compositions comprising such a strontium compound. This solubility problem significantly affects the bioavailability of the drug, hence its efficiency.
European Patent No. 1534305 describes the use of strontium malonate with a solubility of 1- 100 g/1 at room temperature, for prevention and/or treatment of various bone conditions. The divisional application of European Patent No. 1534305, European Application No. 1745791 describes the use of some strontium salts also with a solubility of 1-100 g/1 at room temperature, for prevention and/or treatment of various bone conditions. It has been indicated in these patents that these novel salts encounter no solubility problems.
In the International Patent Application with publication number WO 2004/098617, controlled release compositions comprising at least one strontium salt in tablet form, which is suitable for administration once daily, are described. It has been indicated in this application that these tablets with altered release characteristics encountered no solubility problems.
International Patent Application with publication number WO2007/003200 describes the method for synthesis of some strontium salts (strontium malonate, strontium-di-L-ascorbate, strontium fumarate, strontium salicylate, strontium succinate, strontium di-ibuprofenate and strontium maleate) from strontium carbonate, at low temperatures. It is stated in this application that strontium salts prepared with the mentioned method encountered no solubility problems.
International Patent Application with publication number WO2007/003200 describes pharmaceutical compositions comprising at least two strontium salts (preferably strontium carbonate and strontium chloride). It is stated in this application that the mentioned pharmaceutical compositions comprising at least two strontium salts encountered no problems with solubility or bioavailability.
As a result, some methods such as manufacturing of novel strontium salts with improved solubility to enhance the solubility of the strontium compounds, new manufacturing process to obtain these salts, invention of suitable salt combinations and altering the release characteristic of tablets which include these salts have been tried in the prior art. The course of preparation of novel salts with improved solubility and invention of suitable salt combinations require both time and capital, limiting appropriate salt forms. Thus the search for a better solution still continues. Finding a solution that would only cover the solubility problem is not preferred, since the enhancement of the release characteristics of tablet dosage form requires a complicated production method.
The tendency of vitamin D to degrade when exposed to heat, light, air, moisture, oxidizing agents or an acidic environment raises the problem of stability with the formulations comprising vitamin D. This situation raises the necessity of using an auxiliary agent to ensure the stability of vitamin D in the tablet.
The present invention provides stable, highly soluble and hence bioavailable pharmaceutical compositions comprising a strontium compound alone or in combination with Vitamin D to formulate the composition for maintaining the "desired effect".
Summary of the Invention
The present invention relates to the use of pharmaceutical compositions comprising a strontium compound alone or in combination with vitamin D, in the manufacture of a medicament used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or as a supplement in a liquid dosage form or a solid dosage form which transforms into liquid form just before administration.
The present invention is directed to obtain stable, highly soluble and hence bioavailable pharmaceutical compositions comprising a strontium compound alone or in combination with Vitamin D to formulate the composition for maintaining the "desired effect". Strontium ranelate, a strontium salt effective in the treatment of osteoporosis, released to market in Europe in the form of granules for oral suspension. However since the absorption of suspensions last longer than solutions, they have lower bioavailability. The present invention is directed to solution formulations which are preferred instead of suspension formulations in order to increase the bioavailability of pharmaceutical compositions comprising a strontium compound. These previously mentioned solution compositions might be either in a liquid dosage form or in a solid dosage form which transforms into liquid phase just before administration. The pharmaceutical compositions of the invention preferably in the effervescent tablet form highly improve the bioavailability because they are already administered in dissolved form and already provide the use of active agent in high amounts.
The pharmaceutical formulation composition of the present invention are characterized in that they provide formulations comprising a high dose of a strontium compound in effervescent form to improve solubility, thus bioavailability; instead of restrictive and complicated methods, which require both time and capital, such as use of a solubility enhancing agent, preparation of novel strontium salts with improved solubility, addition of at least two strontium salts to enhance bioavailability and enhancement of the release characteristics of tablet dosage form. Strontium carbonate can be used alone or in combination with other strontium compounds because of the fact that the effervescent formulations of the invention are effective as a carbondioxide source and improve bioavailability by increasing active agent dose. The pharmaceutical compositions preferably in tablet dosage form may also comprise a small amount of sweetener and/or flavoring agent as taste promoter.
Pharmaceutical compositions of the present invention may be formulated comprising a strontium compound alone or also a strontium compound in combination with vitamin D as an active agent. However, at this point the stability problem arises due to vitamin D. Pharmaceutical compositions of the invention in effervescent form comprise disintegrants which cause tablets to disintegrate, in other words to dissolve, thus increasing the bioavailability and also providing the stability of the composition. Pharmaceutical compositions of the invention preferably in effervescent form can also comprise at least one stabilizing agent.
According to the invention, pharmaceutical compositions comprising a strontium compound alone or in combination with vitamin D, in liquid or solid dosage form which transforms into liquid form just before administration, preferably in effervescent tablet form, and optionally comprising an additive selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, surfactants, stabilizing agents, sweeteners and flavoring agents, have improved solubility, bioavailability and stability characteristics and the pharmaceutical compositions are used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or effective as a supplement. The term "used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or as a supplement" used herein refers to the use of treatment of osteoporosis; treatment of osteoporosis by reducing the risk of post-menopausal bone fractures of the spine and hip bones in women; treatment of osteoporosis for reducing the risk of bone fractures in men; treatment of idiopathic osteoporosis; treatment of various disease related osteoporosis; treatment of steroid and glucocorticoid related osteoporosis; treatment of osteoarthritis; treatment of osteopetrosis; treatment of osteopenia; treatment of osteomalacia; treatment of osteodystrophy; treatment of osteogenesis imperfecta; treatment of osteochondrodysplasia; treatment of Sudeck's atrophy, treatment of rheumatoid arthritis, treatment of Paget's disease, treatment of Bechterew's disease, treatment of Behcet's disease, treatment of periodontal disease, treatment of malignant bone metastases tumors and related bone pain, treatment of cancer therapy related bone abnormalities, treatment of implant instability, treatment of hyperostosis, treatment of hypercalcemia or hyperthyroidism; to strengthen the muscle tissue and especially as nutritional supplements to maintain pre- and postmenopausal bone health in women during puberty, pregnancy or breast-feeding.
According to the invention, the pharmaceutical compositions contain strontium compound in the range of 0.1-75% by weight and an amount of vitamin D in the range of 100-100000 IU to achieve the desired therapeutic effect. The term "strontium compound" used herein, indicates strontium adipate, strontium alendronate, strontium alginate, strontium acetate, strontium ascorbate, strontium aspartate, strontium benzenesulfonate, strontium benzoate, strontium borate, strontium bromate, strontium bromide, strontium butanoate, strontium butirate, strontium decanoate, strontium ethanesulfonate, strontium etidronate, strontium fluoride, strontium formate, strontium phosphate, strontium fumarate, strontium glyconate, strontium glycocholate, strontium glutamate, strontium glutarate, strontium hexanoate, strontium heptanoate, strontium hydrochloride, strontium hydroxide, strontium ibandronate, strontium iodide, strontium camphorate, strontium carbonate, strontium chlordronate, strontium chlorate, strontium chloride, strontium cholate, strontium chromate, strontium lactate, strontium laurate, strontium linoleate, strontium malate, strontium maleate, strontium malonate, strontium methanesulfonate, strontium myristate, strontium nitrate, strontium nitrite, strontium nonanoate, strontium oxide, strontium octanoate, strontium oxalate, strontium oleate, strontium palmitate, strontium pentanoate, strontium periodate, strontium peroxide, strontium pyruvate, strontium propionate, strontium ranelate, strontium risedronate, strontium salicylate, strontium selenate, strontium silicate, strontium cinnamate, strontium citrate, strontium sorbate, strontium stearate, strontium succinate, strontium sulfate, strontium sulfide, strontium sulfonate, strontium tartrate, strontium taurocholate, strontium titanate, strontium treonate, strontium valerate and preferably strontium ranelate and/or strontium carbonate.
The pharmaceutically acceptable diluents can be selected from the group of lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, caolin, lactitol, powdered cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol and xylitol. The diluent is present in the formulation preferably in a range of 0-85% by weight, more preferably in a range of 0.1-75% by weight.
The pharmaceutically acceptable binders can be selected from the group of starch (e.g. potato starch, cornstarch or wheat starch), sucrose, glucose, dextrose, lactose, sugars like maltodexrin, natural and synthetic gums (e.g. acacia tree), gelatin, cellulose derivatives (e.g. microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose), polyethylene glycol (PEG), waxes, calcium carbonate, calcium phosphate, alcohols (e.g. sorbitol, xylitol and mannitol) and water. The binder is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.
The pharmaceutically acceptable disintegrants can be selected from the group of starch (e.g. potato starch, cornstarch or wheat starch), sodium starch glycolate, pregelatinized starch, cellulose derivatives (such as croscarmellose sodium or microcrystalline cellulose), polyvinylpyrrolidone (PVP), crospovidone, alginic acid, sodium alginate, clays (such as Xanthan gum or Veegum), ion-exchange resins and effervescent systems (alkali or alkaline earth metal carbonates (e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, and strontium carbonate), water-soluble organic acids and salts (e.g. sodium hydrogen sulfate, potassium hydrogen sulfate, sodium dihydrogen phosphate, succinic acid, tartaric acid, adipic acid, fumaric acid , citric acid and malic acid). The disintegrant is present in the formulation preferably in a range of 0-85% by weight, more preferably in a range of 0.1-75% by weight.
The pharmaceutically acceptable lubricants can be selected from the group of metallic stearates (e.g. magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (e.g. sodium stearyl fumarate), fatty acids (e.g. stearic acid), fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (e.g. sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate and sodium acetate. The lubricant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight. The pharmaceutically acceptable glidants can be selected from the group of silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate. The weight % of the glidant in the formulation is lower than 1%.
The pharmaceutically acceptable surfactants can be selected from the group of polyoxyethylene sorbitan fatty acid (polysorbates), sodium lauryl sulphate, sodium stearyl fumarate, polyoxyethylene castor oil derivatives, docusate sodium, quatenary ammonia compounds, amino acids like L-leucine, sugar esters of fatty acids and glycerides of fatty acids. The lubricant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight. The stabilizing agent(s) and antioxidants can be selected from the group of chelating agents, alkalizing agents and photoprotectors. The stabilizing agent is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.
The antioxidants can be selected from the group of butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulphite, gallates (e.g. propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbyl palmitate, ethylenediamine tetraacetate.
The chelating agents can be selected from the group of disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate and combinations.
The alkalizing agents can be selected from the group of alkali metal salts like sodium hydrogen carbonate, sodium dihydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; earth alkali salts like 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; primary, secondary and tertiary amines, cyclic amines, N5N'- dibenzylethylenediamine, diethanolamin, ethylenediamine, meglumine, monosodium glutamate, polacrilin sodium and sodium alginate.
The photoprotectors can be selected from the group of titanium oxide, iron oxide and zinc.
The pharmaceutically acceptable sweeteners can be selected from the group of sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, levulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythriol, lactitol, isomalt, corn syrup, saccarine, saccarine salts, acesulfame potassium, aspartam, D-tryptophan, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamate. The sweeteners are present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.
The pharmaceutically acceptable flavoring agents can be selected from the following group; natural aroma oils (peppermint oil, partridge currant oil, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil, etc.), menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, 1 -methyl acetate, sage, eugenol, oxanone, α-irisone, marjoram, lemon, orange, propenyl guaethol acetyl, vanillin, thymol, linalool, cinnamaldehyde glycerol acetal, N- substituted-p-menthane-3-carboxamide, 3,1-methoxy propane- 1,2-diol. The flavoring agent is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1 -5% by weight.
In addition to these, solubility modulators, electrolytes, colorants and coatings can be used as other pharmaceutical excipients in the formulation.
The formulation examples of the invention are given below. These examples are given only to explain the invention and the invention is not limited to these examples.
Example 1. Example 2.
Example 3. Example 4.
♦Equal to 880 IU Vitamin D3
Example 5.
Equal to 1400 IU Vitamin D3
Example 6.
"Equal to 2800 IU Vitamin D3

Claims

Claims
1. A pharmaceutical composition for the manufacture of a medicament for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or as a supplement characterized in that the composition comprises a strontium compound alone or in combination with vitamin D in a liquid dosage form or a solid dosage form which transforms into liquid form just before administration.
2. A pharmaceutical composition used for the manufacture of a medicament for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or as a supplement comprising
- a strontium compound of 0.1 -75% by weight and optionally
- at least one pharmaceutically acceptable additive selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, surfactants, stabilizing agents, sweeteners and flavoring agents in a liquid dosage form or a solid dosage form which transforms into liquid form just before administration.
3. A pharmaceutical composition used for the manufacture of a medicament for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or as a supplement comprising a strontium compound of 0.1 -75% by weight,
- vitamin D in a range of 100- 100,000 IU,
- and optionally, at least one pharmaceutically acceptable additive selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, surfactants, stabilizing agents, sweeteners and flavoring agents in a liquid dosage form or a solid dosage form which transforms into liquid form just before administration.
4. The pharmaceutical composition according to claims 1 to 3 characterized in that the composition is preferably in the form of effervescent tablet.
5. The use of a pharmaceutical composition according to claims 1 to 3 characterized in that the composition is used for the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or as a supplement indicating to the use of treatment of osteoporosis; treatment of osteoporosis by reducing the risk of post-menopausal bone fractures of the spine and hip bones in women; treatment of osteoporosis for reducing the risk of bone fractures in men; treatment of idiopathic osteoporosis; treatment of various disease related osteoporosis; treatment of steroid and glucocorticoid related osteoporosis; treatment of osteoarthritis; treatment of osteopetrosis; treatment of osteopenia; treatment of osteomalacia; treatment of osteodystrophy; treatment of osteogenesis imperfecta; treatment of osteochondrodysplasia; treatment of Sudeck's atrophy, treatment of rheumatoid arthritis, treatment of Paget's disease, treatment of Bechterew's disease, treatment of
Behcet's disease, treatment of periodontal disease, treatment of malignant bone metastases tumors and related bone pain, treatment of cancer therapy related bone abnormalities, treatment of implant instability, treatment of hyperostosis, treatment of hypercalcemia or hyperthyroidism; to strengthen the muscle tissue and especially as nutritional supplements to maintain pre- and postmenopausal bone health in women during puberty, pregnancy or breast-feeding.
6. The pharmaceutical composition according to claims 1 to 3 characterized in that the strontium compound is selected from the group of strontium adipate, strontium alendronate, strontium alginate, strontium acetate, strontium ascorbate, strontium aspartate, strontium benzenesulfonate, strontium benzoate, strontium borate, strontium bromate, strontium bromide, strontium butanoate, strontium butirate, strontium decanoate, strontium ethanesulfonate, strontium etidronate, strontium fluoride, strontium formate, strontium phosphate, strontium fumarate, strontium glyconate, strontium glycocholate, strontium glutamate, strontium glutarate, strontium hexanoate, strontium heptanoate, strontium hydrochloride, strontium hydroxide, strontium ibandronate, strontium iodide, strontium camphorate, strontium carbonate, strontium chlordronate, strontium chlorate, strontium chloride, strontium cholate, strontium chromate, strontium lactate, strontium laurate, strontium linoleate, strontium malate, strontium maleate, strontium malonate, strontium methanesulfonate, strontium myristate, strontium nitrate, strontium nitrite, strontium nonanoate, strontium oxide, strontium octanoate, strontium oxalate, strontium oleate, strontium palmitate, strontium pentanoate, strontium periodate, strontium peroxide, strontium pyruvate, strontium propionate, strontium ranelate, strontium risedronate, strontium salicylate, strontium selenate, strontium silicate, strontium cinnamate, strontium citrate, strontium sorbate, strontium stearate, strontium succinate, strontium sulfate, strontium sulfide, strontium sulfonate, strontium tartrate, strontium taurocholate, strontium titanate, strontium treonate, strontium valerate and preferably strontium ranelate and/or strontium carbonate.
7. The pharmaceutical composition according to claims 1 to 3 characterized in that vitamin D is in vitamin D3 form.
8. The pharmaceutical composition according to claims 1 to 3 characterized in that the diluents is selected from the group of lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, caolin, lactitol, powdered cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol and xylitol.
9. The pharmaceutical composition according to claim 8 characterized in that the diluent is present in the composition preferably in a range of 0-85% by weight, more preferably in a range of 0.1-75% by weight.
10. The pharmaceutical composition according to claims 1 to 3 characterized in that the binder is selected from the group of starch (e.g. potato starch, cornstarch or wheat starch), sucrose, glucose, dextrose, lactose, sugars like maltodexrin, natural and synthetic gums (e.g. acacia tree), gelatin, cellulose derivatives (e.g. microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose), polyethylene glycol (PEG), waxes, calcium carbonate, calcium phosphate, alcohols (e.g. sorbitol, xylitol and mannitol) and water.
11. The pharmaceutical composition according to claim 10 characterized in that the binder is present in the composition preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.
12. The pharmaceutical composition according to claims 1 to 3 characterized in that the disintegrant is selected from the group of starch (e.g. potato starch, cornstarch or wheat starch), sodium starch glycolate, pregelatinized starch, cellulose derivatives (such as croscarmellose sodium or microcrystalline cellulose), polyvinylpyrrolidone (PVP), crospovidone, alginic acid, sodium alginate, clays (such as Xanthan gum or Veegum), ion-exchange resins and effervescent systems (alkali or alkaline earth metal carbonates (e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, and strontium carbonate), water- soluble organic acids and salts (e.g. sodium hydrogen sulfate, potassium hydrogen sulfate, sodium dihydrogen phosphate, succinic acid, tartaric acid, adipic acid, fumaric acid, citric acid and malic acid).
13. The pharmaceutical composition according to claim 12 characterized in that the" disintegrant is present in the composition preferably in a range of 0-85% by weight, more preferably in a range of 0.1-75% by weight.
14. The pharmaceutical composition according to claims 1 to 3 characterized in that the lubricant is selected from the group of metallic stearates (e.g. magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (e.g. sodium stearyl fumarate), fatty acids (e.g. stearic acid), fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (e.g. sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate and sodium acetate
15. The pharmaceutical composition according to claim 14 characterized in that the lubricant is present in the composition preferably in a range of 0-10% by weight, more preferably in a range of 0.1 -5% by weight.
16. The pharmaceutical composition according to claims 1 to 3 characterized in that the glidant is selected from the group of silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate.
17. The pharmaceutical composition according to claim 16 characterized in that the weight % of the glidant in the composition is lower than 1%.
18. The pharmaceutical composition according to claims 1 to 3 characterized in that the surfactant is selected from the group of polyoxyethylene sorbitan fatty acid (polysorbates), sodium lauryl sulphate, sodium stearyl fumarate, polyoxyethylene castor oil derivatives, docusate sodium, quatenary ammonia compounds, amino acids like L-leucine, sugar esters of fatty acids and glycerides of fatty acids.
19. The pharmaceutical composition according to claim 18 characterized in that the lubricant is present in the composition preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.
20. The pharmaceutical composition according to claims 1 to 3 characterized in that the composition comprises antioxidants as stabilizing agent selected from the group of butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulphite, gallates (e.g. propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbyl palmitate, ethylenediamine tetraacetate.
21. The pharmaceutical composition according to claims 1 to 3 characterized in that the composition comprises chelating agents as stabilizing agent selected from the following group; disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate and combinations.
22. The pharmaceutical composition according to claims 1 to 3 characterized in that the pharmaceutical composition comprises alkalizing agents as stabilizing agent selected from the group of alkali metal salts like sodium hydrogen carbonate, sodium dihydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; earth alkali salts like 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; primary, secondary and tertiary amines, cyclic amines, N,N'-dibenzylethylenediamine, diethanolamin, ethylenediamine, meglumine, monosodium glutamate, polacrilin sodium and sodium alginate.
23. The pharmaceutical composition according to claims 1 to 3 characterized in that the composition comprises photoprotectors as stabilizing agent selected from the group of metal oxides such as titanium oxide, iron oxide and zinc oxide.
24. The pharmaceutical composition according to claims 20-23 characterized in that the stabilizing agent is present in the composition preferably in a range of 0-85% by weight, more preferably in a range of 0.1-75% by weight.
25. The pharmaceutical composition according to claims 1 to 3 characterized in that the sweetener is selected from the group of sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, levulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythriol, lactitol, isomalt, corn syrup, saccarine, saccarine salts, acesulfame potassium, aspartam, D-tryptophan, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamate.
26. The pharmaceutical composition according to claim 25 characterized in that the sweetener is present in the composition preferably in a range of 0-5% by weight, more preferably in a range of 0.1 -3% by weight.
27. The pharmaceutical composition according to claims 1 to 3 characterized in that the flavoring agent is selected from the group of natural aroma oils (peppermint oil, Partridge currant oil, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil, etc.), menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, 1 -methyl acetate, sage, eugenol, oxanone, α-irisone, marjoram, lemon, orange, propenyl guaethol acetyl, vanillin, thymol, linalool, cinnamaldehyde glycerol acetal, N- substituted-p-menthane-3-carboxamide, 3,1-methoxy propane- 1,2-diol.
28. The pharmaceutical composition according to claim 27 characterized in that the flavoring agent is present in the composition preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.
EP10731618A 2009-04-10 2010-04-09 Stable pharmaceutical compositions with high bioavailibility Withdrawn EP2416756A2 (en)

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