WO2013095315A1

WO2013095315A1 - Formulations comprising dexketoprofen (particle size 300-2500 micrometer)

Info

Publication number: WO2013095315A1
Application number: PCT/TR2012/000219
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2011-12-19
Filing date: 2012-12-19
Publication date: 2013-06-27

Abstract

The present invention relates to the preparation of pharmaceutical formulations comprising dexketoprofen that shall be used as antipyretic, analgesic, anti-inflammatory in treatment of mild and moderate pain such as toothache, menstrual pain, post-surgical pain, musculoskeletal pain. The preparation of the pharmaceutical formulations, preferably an effervescent formulation, comprising dexketoprofen is characterized in that the granules comprising dexketoprofen, at least one excipient and optionally the second active agent are sieved or ground in the manner that they have an average particle size in the range of 300-2500 mirometer, said granules are dried and said granules are mixed with at least one excipient. A preferred formulation is an effervescent dexketoprofen formulation.

Description

FORMULATIONS COMPRISING DEXKETOPROFEN (PARTICLE SIZE 300 -2500 MICROMETER)

The present invention relates to pharmaceutical formulations comprising dexketoprofen that shall be used as antipyretic, analgesic, anti-inflammatory in treatment of mild and moderate pains such as toothache, menstrual pain, post-surgical pain, musculoskeletal pain. Dexketoprofen was first disclosed in the application numbered EP0668851. In said document, it has been disclosed that dexketoprofen is effective when used as antipyretic, analgesic, antiinflammatory in treatment of mild and moderate pain such as toothache, menstrual pain, postsurgical pain, musculoskeletal pain.

Dexketoprofen is available in forms of 50 mg/2ml solution for injection, 25 mg film coated tablet and 25 mg effervescent tablet on the market.

In preparation of formulations comprising dexketoprofen, it is seen that formulation mixtures do not have proper flow due to the reasons that free flow of the granules obtained cannot be provided and/or possible friction in interfaces of the granule particles cannot be reduced, therefore homogeneity cannot be provided in the pharmaceutical composition obtained and the mixture loses its homogeneity during the process. Therefore, the problems mentioned result in weight changes in the end product and increase in relative standard deviation values during forming the formulations into any dosage form. Weight and content uniformity cannot be provided in the end product due to these variations observed in weight of the end product obtained and failure to provide formulation homogeneity. This causes producers to encounter problems during production and quality control phases and also causes patients not to be able to take equal amount of drug during their treatment and consequently causes treatment efficiency to decrease due to loss of weight and content uniformity observed in the dosage forms obtained. As it is seen, there is still need to develop new approaches so as to obtain homogeneous dexketoprofen formulations produced in the manner that no weight change is observed in unit dosage for the purpose of performing an effective treatment by preventing the changes observed in weight and content of the end product obtained and preventing the problems arising from loss of weight uniformity during quality and control phases.

As a result of the studies they conducted in line with this requirement, the inventors have found that some physical characteristics of the formulations they have developed in order to prepare the dosage forms comprising dexketoprofen are effective on relative standard deviation in dosage weight of the drug obtained and said problems encountered during both quality control and using phases can be solved with the formulations developed by adjusting physical characteristics.

Description of the Invention The present invention relates to pharmaceutical formulations comprising dexketoprofen and methods for preparation of these formulations. Surprisingly, it has been seen that in the case that the formulations which comprise granules comprising dexketoprofen, at least one excipient and optionally a second active agent and having an average particle size in the range of 300-2500 μιη, preferably in the range of 350-2000 μιη, more preferably in the range of 500-1750 μπι are formed into any solid dosage form; relative standard deviation remains low, a homogeneous pharmaceutical composition is obtained, weight and content uniformity are provided by preventing weight changes.

In this respect, the subject of the present invention is the granules which comprise dexketoprofen, at least one excipient and optionally a second active agent and have an average particle size in the range of 300-2500 μτη, preferably in the range of 350-2000 μπι, more preferably in the range of 500-1750 μιη during preparation of formulations comprising dexketoprofen.

The term "average particle size" refers to volumetric average particle size and it is also shown with d₅₀ in short. In this sense, the term d₅₀ signifies that half of the said substance by volume has a particle size over the value stated with d₅o and the other half of the substance by volume has a particle size below the value stated with d₅₀.

D ₀ value can be measured with one of the known measuring devices, for instance with a device which measures particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.). In another aspect, the present invention relates to a process that shall be used in production of the granules which have an average particle size in the range of 300-2500 μηι, preferably in the range of 350-2000 μ^ηι, more preferably in the range of 500-1750 μηι and comprise dexketoprofen, at least one excipient and optionally a second active agent characterized in that the granules having an average particle size in the range of 300-2500 μηι, preferably in the range of 350-2000 μηι, more preferably in the range of 500-1750 μηι are obtained by

• sieving said granules with an appropriate sieve or

• grinding said granules with devices such as impact mill, jet mill, blade mill etc.

In the case that blade mill is used, grinding process is performed by the effect of rotating blades in the device.

In the case that impact mill is used, grinding process is performed by the effect of rotating hammers in the device.

In the case that jet mill is used, grinding process is performed by providing collision of the particles with each other with the help of high-pressured and high-speed airstream. The pharmaceutical formulation of the present invention can be obtained by a method comprising:

Mixing the granules obtained after granulating the active agent dexketoprofen and, if available, the second active agent with the granulation solution comprising at least one of the excipients homogeneously; and drying the mixture obtained; if required, bringing the granules to an average particle size in the range of 300-2500 μη by an appropriate method and optionally treating them with at least one other excipient or

Mixing the granules obtained after mixing the active agent dexketoprofen and, if available, the second active agent with at least one of the excipients homogeneously and optionally granulating them with the granulation solution comprising at least one excipient; and drying the mixture obtained; if required, bringing the granules to an average particle size in the range of 300-2500 μπι with an appropriate method; and optionally treating them with at least one other excipient or

Using any of the abovementioned methods separately for the active agent compositions and combining the formulations obtained in the case that two active agents are used. In the case that the pharmaceutical formulation is formulated in effervescent tablet form, it is obtained by a method comprising the following steps:

I. A granulation solution is prepared with binder, deionized water and ethyl alcohol, II. Effervescent acid is mixed with the effervescent base, binder and the sweetener, III. The mixture obtained in step II is firstly granulated with the granulation solution obtained in step I and then with ethyl alcohol,

IV. The granules obtained in step III are dried and an amount in the range of 1-15% of said dried granules is set apart,

V. The active agent dexketoprofen is added into the remaining dry granules obtained in step IV and mixed, and then the dry granules set apart are added into this mixture,

VI. Finally, the final mixture is obtained by adding the flavoring agent into the mixture obtained in step V; and

VII. the final mixture is compressed into tablets.

In the case that the pharmaceutical formulation is formulated in effervescent tablet form, the homogenization and dispersion problems are observed. The inventors conducted new studies for eliminating these problems. In step V, when the active agent dexketoprofen is added into the remaining amount of the granules obtained in step IV and 1-15% of the dried granules is added into this mixture, the inventors have observed that a more homogeneous mixture is obtained and the obtained effervescent formulations can disperse more rapidly. In another aspect, the present invention relates to a process that the active agent dexketoprofen is added into the remaining amount of the granules obtained in step IV and then 1-15% of the dried granules, which is set apart, is added into this mixture in step V.

During the studies conducted, the inventors have seen that parameters such as drying temperature and moisture content of the granules obtained are important for obtaining optimum values of hardness, fragility and stability of the granules obtained during preparation of the formulations comprising dexketoprofen and the end product in solid form prepared with the said granules and therefore important for preventing possible problems that can be encountered during quality control and using phases.

According to studies conducted, the inventors surprisingly have seen that the granules obtained according to the process of the present invention as dried at 10-120°C, preferably at 20-100°C and more preferably at 25-70°C present proper flow property and the solid forms prepared with these granules have desired hardness and fragility.

According to this, another aspect of the present invention relates to drying the granules comprising dexketoprofen, at least one excipient and optionally a second active agent at a temperature in the range of 10-120°C, preferably at a temperature in the range of 20-100°C and more preferably at a temperature in the range of 25-70°C in preparation of the formulations comprising dexketoprofen.In line with the studies conducted, the inventors have seen that moisture content of the granules obtained during preparation of the formulations comprising dexketoprofen has effect on the end product obtained in solid form to have desired physical properties and to provide weight certainty and on stability of the product obtained.

According to this, another aspect of the present invention relates to drying the granules comprising dexketoprofen, at least one excipient and optionally a second active agent in the manner that they have moisture content less than 1% by weight, preferably in the range of 0.1-0.9% by weight in preparation of the formulations comprising dexketoprofen. Dexketoprofen comprised in the pharmaceutical formulations prepared according to the process of the present invention is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; it is in amorphous form or crystalline form or a combination thereof in terms of polymorphic structure. Dexketoprofen is preferably in salt form, more preferably in dexketoprofen trometamol form.

The pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can be prepared in any solid dosage form such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enteric coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet.

The pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen are preferably in powder, tablet and granule forms, more preferably in film coated tablet or effervescent tablet forms.

The pharmaceutical formulation obtained according to the present invention can be formed into any abovementioned dosage forms. In the case that the formulation is in tablet form, the tablets obtained can be treated with film coating agents for instance sugar based coating agents, water soluble film coating agents, enteric coating agents, delayed release coating agents or coating compositions comprising any combination thereof.

Saccharose can be used singly or optionally with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof as the sugar based coating agent.

The water soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combinations thereof.

The enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof.

The delayed release coating agents can be selected from cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, emulsion copolymer of ethyl acrylate-methyl methacrylate or combinations thereof.

The pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can comprise various excipients in addition to the active agent dexketoprofen.

The pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen comprise at least one excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic agent and at least one basic agent, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent in addition to the active agent dexketoprofen and the lubricant.

The disintegrant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.

The diluent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.

The glidant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.

The binder that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch.

The acidic agent composing the effervescent couple comprising at least one acidic agent and at least one basic agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid; and the basic agent composing the effervescent couple comprising at least one acidic agent and at least one basic agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.

The pH regulating agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts. The surfactant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.

The stabilizing agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.

The sweetener and/or taste regulating agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.

The flavouring agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours. The pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can comprise dexketoprofen in the range of 0.1 to 99.9 % by weight, preferably in the range of 1 to 99% by weight, more preferably in the range of 5 to 95% by weight.

The pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can optionally comprise a second active agent in addition to dexketoprofen. The second active agent can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant, immunosuppressant, myorelaxant, analgesic, psycholeptic, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin B_1; vitamin C, vitamin E, vitamin B_6> vitamin B_2; vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.

In the case that two active agents are comprised in the same formulation, the pharmaceutical formulations prepared according to the process of the present invention and comprising a second active agent in addition to dexketoprofen can be prepared in any solid dosage form such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet; in the case that the two active agents are in different formulations but in the same dosage form, the pharmaceutical formulations prepared according to the process of the present invention and comprising a second active agent in addition to dexketoprofen can be prepared in dosage forms such as layered tablet, capsule; in the case that the two active agents are in different formulations and dosage forms, the pharmaceutical formulations prepared according to the process of the present invention and comprising a second active agent in addition to dexketoprofen can be prepared in treatment package form comprising a combination of solid dosage forms such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet or in forms of micro tablet and/or capsule comprising micropellet.

The pharmaceutical formulation of the present invention can be used as antipyretic, analgesic, anti-inflammatory in treatment of mild and moderate pain such as toothache, menstrual pain, post-surgical pain, musculoskeletal pain.

EXAMPLE: The effervescent tablets comprising dexketoprofen and preparation method thereof

For obtainment of the formulation that shall be used in the present invention, a granulation solution is prepared by mixing ethyl alcohol, the binder and purified water. The effervescent acid, the effervescent base and the taste regulating agent are mixed and granulated with the granulation solution prepared. The obtained granules are dried and sieved. The sweetener and dexketoprofen mixture is added into the granules dried and sieved, then the mixture is stirred. The mixture obtained is mixed again after the flavouring agent and the lubricant are added and the final mixture is compressed in tablet form.

Claims

A process that shall be used in preparation of the pharmaceutical formulations comprising dexketoprofen, characterized in that

- The granules comprising dexketoprofen, at least one excipient and optionally the second active agent are

- Sieved or ground in the manner that they have an average particle size in the range of 300-2500 μηι,

- Said granules are dried,

- Said granules are mixed with at least one excipient.

The process according to claim 1, characterized in that said process is sieving or grinding the granules comprising dexketoprofen, at least one excipient and optionally the second active agent in the manner that they have an average particle size in the range of 350-2000 μπι.

The process according to claims 1-2, characterized in that said process is sieving or grinding the granules comprising dexketoprofen, at least one excipient and optionally the second active agent in the manner that they have an average particle size in the range of 500-1750 μηι.

The process according to claims 1-3, characterized in that

- Sieved in the manner that they have an average particle size in the range of 300-2500 μηι

- Said granules are dried and

- Said granules are mixed with at least one excipient.

The process according to claims 1-3, characterized in that

The granules comprising dexketoprofen, at least one excipient and optionally the second active agent are

- Ground in the manner that they have an average particle size in the range of 300-2500 μπι

- Said granules are dried and

- Said granules are mixed with at least one excipient.

The process according to claims 1-3,5, characterized in that grinding process is performed by impact mill, jet mill and blade mill.

7. The process according to claims 1-6, characterized in that the granules comprising dexketoprofen, at least one excipient and optionally the second active agent are dried at a temperature in the range of 10-120°C.

8. The process according to claims 1-7, characterized in that the granules comprising dexketoprofen, at least one excipient and optionally the second active agent are dried at a temperature in the range of 20-100°C.

9. The process according to claims 1-8, characterized in that the granules comprising dexketoprofen, at least one excipient and optionally the second active agent are dried at a temperature in the range of 25-70°C.

10. The process according to claims 1-9, characterized in that the granules comprising dexketoprofen, at least one excipient and optionally the second active agent are dried in the manner that they have moisture content less than 1%.

11. The process according to claims 1-10, characterized in that the granules comprising dexketoprofen, at least one excipient and optionally the second active agent are dried in the manner that they have moisture content in the range of 0.1 - 0.9 %.

12. The process according to claims 1-1 1, characterized in that in the case that the pharmaceutical formulation is formulated in effervescent tablet form, it is obtained by a method comprising the following steps:

I. A granulation solution is prepared with binder, deionized water and ethyl alcohol,

II. Effervescent acid is mixed with the effervescent base, binder and the sweetener,

III. The mixture obtained in step II is firstly granulated with the granulation solution obtained in step I and then with ethyl alcohol,

IV. The granules obtained in step III are dried and an amount in the range of 1- 15% of said dried granules is set apart,

VII. the final mixture is compressed into tablets.

13. The process according to claim 12, characterized in that the active agent dexketoprofen is added into the remaining amount of the granules obtained in step IV and then 1-15% of the dried granules, which is set apart, is added into this mixture in step V.

14. A pharmaceutical formulation comprising dexketoprofen prepared in accordance with the process according to claims 1-13, characterized in that

· Said formulation comprises granules comprising dexketoprofen, at least one excipient and optionally the second active agent and

• The granules comprising dexketoprofen, at least one excipient and optionally the second active agent have an average particle size in the range of 300-2500 μηι.

1 . The pharmaceutical formulation comprising dexketoprofen according to claim 14, characterized in that

• Said formulation comprises granules comprising dexketoprofen, at least one excipient and optionally the second active agent and

• The granules comprising dexketoprofen, at least one excipient and optionally the second active agent have an average particle size in the range of 350-2000 μηι.

16. The pharmaceutical formulation comprising dexketoprofen according to claims 14 and 15, characterized in that

• The granules comprising dexketoprofen, at least one excipient and optionally the second active agent have an average particle size in the range of 500-1750 μπι.

17. The pharmaceutical formulation according to any preceding claims, wherein said formulation is prepared in any dosage forms of tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet.

18. The pharmaceutical formulation according to any preceding claims, wherein said formulation is in film coated tablet form or in effervescent tablet form.

19. The pharmaceutical formulation according to any preceding claims, wherein dexketoprofen is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof.

20. The pharmaceutical formulation according to any preceding claims, wherein dexketoprofen is in pharmaceutically acceptable dexketoprofen trometamol form.

21. The pharmaceutical formulation according to any preceding claims, wherein at least one excipient comprised in the formulation in addition to dexketoprofen is selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic agent and at least one basic agent, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent.

22. The pharmaceutical formulation according to any preceding claims, wherein said formulation comprises dexketoprofen used as the active agent in the range of 0.1 to 99.9% by weight.

23. The pharmaceutical formulation according to any preceding claims, wherein said formulation comprises dexketoprofen as the active agent in the range of 1 to 99 % by weight.

24. The pharmaceutical formulation according to any preceding claims, wherein said formulation comprises dexketoprofen used as the active agent in the range of 5 to 95% by weight.

25. The pharmaceutical formulation according to any preceding claims, wherein the second active agent comprised in the formulation that can be used optionally in addition to dexketoprofen is selected from antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti- parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant, immunosuppressant, myorelaxant, analgesic, psycholeptic, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin B_1; vitamin C, vitamin E, vitamin B_6i vitamin B_2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.