WO2014104989A1

WO2014104989A1 - Pharmaceutical compositions comprising aripiprazole

Info

Publication number: WO2014104989A1
Application number: PCT/TR2012/000232
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Individual
Current assignee: Individual
Priority date: 2011-12-27
Filing date: 2012-12-27
Publication date: 2014-07-03
Anticipated expiration: 2015-06-27
Also published as: WO2014104989A8

Abstract

The present invention relates to pharmaceutical formulations comprising aripiprazole that shall be used in treatment of irritability associated with schizophrenia, bipolar disorder, major depression, autistic disorder.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING ARIPIPRAZOLE

The present invention relates to pharmaceutical formulations comprising aripiprazole that shall be used in treatment of irritability associated with schizophrenia, bipolar disorder, major depression, autistic disorder. Aripiprazole was first disclosed in the application numbered EP367141. In said document, it has been disclosed that aripiprazole is effective in treatment of schizophrenia.

Aripiprazole is available in 5mg, 10 mg, 15 mg, 20 mg and 30 mg tablet forms on the market.

During preparation of the formulations comprising aripiprazole, it is seen that the formulation adheres to machine parts such as inner walls of the die and the punch. This situation causes some part of the medicament to remain on the punches and in the dies, which this brings some problems to the manufacturers during preparation phase of the medicament. In addition, since some part of the medicament remains on the punches and in the dies, the dosage form obtained does not have the desired shape and desired smoothness and this brings some problems at quality control phases. Furthermore, in the case that the formulations are compressed in tablet form, machine parts present corrosion and wear in time due to the friction between tablet surface and punch or inner wall of the die during ejection of the tablets. Therefore, these problems seen during preparation of the formulations comprising aripiprazole pose problems for manufacturers at production and quality control phases and impede to obtain the final product effectively.

As it is seen, there is need for development of new approaches in order to obtain medicaments comprising aripiprazole which are produced in the manner that no problem is observed at production and quality control phases so as to prevent problems such as adhesion of the formulation to the machine parts such as the die and the punch during preparation and possible corrosions that can arise from the friction between tablet surface and the inner wall of the die during tablet production.

As a result of the studies they conducted in line with this requirement, the inventors have found that the problems encountered at production and quality control phases during preparation of the medicaments can be solved by the formulations they have developed for preparation of the dosage forms comprising aripiprazole.

Description of the Invention

The present invention relates to pharmaceutical formulations comprising aripiprazole and preparation methods for said formulations. Surprisingly, the inventors have seen that in the case that the formulations comprising aripiprazole comprise talc, magnesium stearate, PEG 6000, silicone dioxide, sodium benzoate, potassium benzoate, stearic acid, sodium stearyl fumarate and/or a combination thereof as the lubricant, the formulation does not adhere to the punch and inner walls of the die; wear and corrosion resulting from the possible friction in said machine parts are decreased. In this respect, the present invention relates to aripiprazole formulations wherein talc, magnesium stearate, PEG 6000, silicone dioxide, sodium benzoate, potassium benzoate, stearic acid, sodium stearyl fumarate and/or a combination thereof is used as the lubricant.

In a preferred embodiment of the present invention, the lubricant used is magnesium stearate. According to the present invention, dioo value of magnesium stearate used is in the range of 30-250 μη , preferably in the range of 50-200 μηι, more preferably in the range of 75-150 μηι.

According to this, another characteristic feature of the present invention is that magnesium stearate is used as the lubricant and d₁₀₀ value of magnesium stearate used is in the range of 30-250 μπι, preferably in the range of 50-200 μιη, more preferably in the range of 75-150 μπι.

In other aspect, the amount of the lubricant used for preparation of the formulations comprising aripiprazole is an important parameter among characteristics of the formulation to be obtained. In the case that the lubricant is used less than the required amount, this results in adhesion of the formulation prepared to the machine parts and its binding to the hollow punches. Using lubricant more than the required amount, on the other hand, causes increase in dissolution times of the dosage forms obtained. The inventors have seen that formulations are not observed to adhere to the machine parts during preparation and the dosage forms obtained do not have long dissolution times in the case that the amount of the lubricant in the formulations comprising aripiprazole is in the range of 1-20%, preferably in the range of 1- 10%, and more preferably in the range of 1-5 % in proportion to total weight of the formulation. By this means, said problems encountered during both production and use of the formulations comprising aripiprazole have been solved.

In another aspect, the present invention relates to formulations comprising lubricant in the range of 1-20%, preferably in the range of 1-10% and more preferably in the range of 1-5% in proportion to total weight of the formulation.

In a preferred embodiment of the present invention, the formulations comprising aripiprazole are characterized in that said formulations comprise magnesium stearate in the range of 1- 20%, preferably in the range of 1-10% and more preferably in the range of 1-5%.

During the studies they conducted in order to solve adhesion problem of the formulations comprising aripiprazole to the machine parts, the inventors have unexpectedly found that the particle size of aripiprazole and the particle size of the lubricant play a role in solving this problem effectively.

Another characteristic feature of the present invention is that the ratio of d₁₀o value of aripiprazole to di₀₀ value of the lubricant is in the range of 10:1 to 1 : 1 , preferably in the range of 8: 1 to 2:1, and more preferably in the range of 7:1 to 3:1.

- According to a preferred embodiment of the present invention, a pharmaceutical composition comprising aripiprazole is characterized in that said composition comprises lubricant in the range of 1-20 %, preferably in the range of 1-10%, more preferably in the range of 1-5% and

- the ratio of dioo value of aripiprazole to di₀₀ value of the lubricant is in the range of 10:1 to 1 :1, preferably in the range of 8: 1 to 2:1 and more preferably in the range of 7:1 to 3:1 in said composition.

According to another preferred embodiment of the present invention, the pharmaceutical composition comprising aripiprazole is characterized in that

- magnesium stearate is used in the range of 1-20%, preferably in the range of 1-10%, more preferably in the range of 1-5% in said composition and - the ratio of dioo value of aripiprazole to di₀₀ value of the lubricant is in the range of 10:1 to 1 :1, preferably in the range of 8:1 to 2:1 and more preferably in the range of 7:1 to 3:1.

Percentage values of amounts given in scope of the present invention are calculated in proportion to unit dosage weight.

Aripiprazole comprised in the pharmaceutical formulations of the present invention can be in form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; in crystalline, amorphous forms or combinations thereof in terms of polymorphic structure. The pharmaceutical formulations of the present invention comprising aripiprazole and lubricant can be prepared in any dosage form such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, orodispersible tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet. The pharmaceutical formulations of the present invention comprising aripiprazole and lubricant are preferably in powder, tablet and granule forms, more preferably in form of orodispersible tablet, film tablet or effervescent tablet.

In another aspect, the present invention relates to the pharmaceutical formulations comprising aripiprazole and lubricant in form of orodispersible tablet, film tablet or effervescent tablet. The pharmaceutical formulation obtained 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 any 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 of the present invention comprising aripiprazole and lubricant can comprise various excipients in addition to the active agent aripiprazole and the lubricant.

The pharmaceutical formulations of the present invention comprising aripiprazole and lubricant 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, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent in addition to the active agent aripiprazole and the lubricant. The disintegrant that can be used in the pharmaceutical formulations of the present invention comprising aripiprazole and lubricant 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 of the present invention comprising aripiprazole and lubricant 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, D-mannitol, crosspovidone, dibasic calcium phosphate calcium and/or a combination thereof. In the case that the aripiprazol formulation is formulated in tablet form, the solubility of aripiprazol active agent and the dispersion rate of the formulation are important parameters for the effectiveness of the drug, thus an effective treatment. Accordingly, the inventors studied on the solubility of aripiprazol active agent for developing highly soluble and dispersible tablet formulations comprising aripiprozol. Based on these studies, they observed that when a diluent combination comprising two or more diluent agents is used in an amount in the range of 45-95%, preferably 50-90%, more preferably 55-80% in proportion to the total weight of the formulation, high solubility of aripiprazol and rapid dispersion of the formulation can be provided. In another aspect, the present invention relates to the aripiprazol tablet formulations comprising a diluent combination consisting of two or more diluent agents in an amount in the range of 45-95%, preferably 50-90%, more preferably 55-80% in proportion to the total amount of the formulation. In a preferred embodiment of the invention, the diluent combination comprises preferably xylitol, D-mannitol, crosspovidone, dibasic calcium phosphate and microcrystalline cellulose. The inventors have also seen that the ratio of aripiprazol active agent to the diluent combination by weight has a considerable influence on the dispersion of the tablet formulations. They have observed that when the ratio of aripiprazole to the diluent combination is in the range of 1 : 1 - 1 :20, preferably 1:2- 1 :15, more preferably 1:3- 1:12 by weight, the aripiprazol formulations formulated in tablet form can disperse more rapidly and homogeneously.

In another aspect, the present invention relates to the pharmaceutical formulations wherein the ratio of aripiprazole to the diluent combination is in the range of 1:1- 1 :20, preferably 1 :2- 1 :15, more preferably 1:3- 1 :12 by weight.

In a preferred embodiment of the invention, the present invention relates to the pharmaceutical formulations wherein the ratio of aripiprazole to the diluent combination comprising xylitol, D-mannitol, crosspovidone, dibasic calcium phosphate calcium and microcrystalline cellulose is in the range of 1:1- 1:20, preferably 1:2- 1:15, more preferably 1 :3- 1 :12 by weight. The glidant that can be used in the pharmaceutical formulations of the present invention comprising aripiprazole and lubricant 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 of the present invention comprising aripiprazole and lubricant 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 of the present invention comprising aripiprazole and lubricant can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid; and the basic agent 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 of the present invention comprising aripiprazole and lubricant can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.

The surfactant that can be used in the pharmaceutical formulations of the present invention comprising aripiprazole and lubricant 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 of the present invention comprising aripiprazole and lubricant 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 of the present invention comprising aripiprazole and lubricant 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 coloring agent that can be used in the pharmaceutical formulations of the present invention comprising aripiprazole and lubricant can be selected from a group comprising titanium dioxide, chlorophyl, red ferric oxide, betacarotene and other ferric oxides.The flavouring agent that can be used in the pharmaceutical formulations of the present invention comprising aripiprazole and lubricant can be selected from flavours comprising menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavors. According to a preferred embodiment of the present invention, the pharmaceutical composition comprising aripiprazole is characterized in that

- the lubricant is used in the range of 1-20%, preferably in the range of 1-10%, more preferably in the range of 1-5 % in said composition and

- the ratio of di₀₀ value of aripiprazole to d₁₀₀ value of the lubricant is in the range of 10:1 to 1 :1, preferably in the range of 8: 1 to 2:1 and more preferably in the range of

7:1 to 3:1 in said composition

- said composition comprises 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, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent in addition to aripiprazole and the lubricant.

In another preferred embodiment of the present invention, the pharmaceutical composition comprising aripiprazole is characterized in that

- magnesium stearate is used in the range of 1-20%, preferably in the range of 1-10%, more preferably in the range of 1 -5% in said composition and

- the ratio of di₀₀ value of aripiprazole to d₁₀o value of magnesium stearate is in the range of 10:1 to 1 :1, preferably in the range of 8:1 to 2:1 and more preferably in the range of 7:1 to 3:1 in said composition.

The pharmaceutical formulations of the present invention can comprise aripiprazole in the range of 0.1 to 99 % by weight, preferably in the range of 1 to 97 % by weight, more preferably in the range of 5 to 95% by weight.

In a preferred embodiment of the invention, the pharmaceutical formulations of the present invention comprise aripiprazole in an amount in the range of 5-20% by weight. The pharmaceutical formulations of the present invention can comprise 5 to 95% by weight aripiprazol active agent, 1-20% lubricant, 45-95% diluent combination, 0.01- 2% coloring agent, 0.05-1.5% flavoring agent, 0.1- 3% taste regulating agent and 1-15% disintegrant.

The pharmaceutical formulations of the present invention comprising aripiprazole and lubricant can optionally comprise a second active agent in addition to aripiprazole. 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.

The pharmaceutical formulation of the present invention can be obtained by a method comprising the steps of

• stirring the active agent aripiprazole and, if available, the second active agent homogeneously; if required, adding at least one of the abovementioned excipients and the lubricant or

• stirring the active agent aripiprazole and, if available, the second active agent homogeneously after granulated with at least one of the excipients and adding the lubricant or

· stirring the active agent aripiprazole and, if available, the second active agent with at least one of the excipients and at least one of the abovementioned excipients; optionally granulating them with the granulation solution comprising excipient and stirring the granules obtained with the lubricant and optionally at least one excipient or

• using any of the abovementioned methods separately for the active agent compositions and then combining the formulations obtained in the case that two active agents are used. The pharmaceutical formulation of the present invention can be used for prophylaxis and treatment of irritability associated with schizophrenia, bipolar disorder, major depression, autistic disorder.

EXAMPLE: Formulation and process for preparation of orodispersible tablet comprising aripiprazole

In obtainment of the formulation that shall be used in the present invention; aripiprazole, the diluent, the coloring agent, the flavoring agent, the sweetener, and the disintegrant are weighted, stirred in a mixer and sieved. Magnesium stearate is added into this mixture as the lubricant and the mixture is stirred again. The obtained mixture is placed into the compaction machine, compacted, sieved and the same process is reimplemented. After the 2^nd compacting process, the mixture which is sieved again is loaded into the tablet compression machine and compressed in tablet form.

Claims

1. A pharmaceutical formulation comprising aripiprazole, characterized in that said formulation comprises talc, magnesium stearate, PEG 6000, silicone dioxide, sodium benzoate, potassium benzoate, stearic acid, sodium stearyl fumarate and/or a combination thereof as the lubricant.

2. The pharmaceutical formulation comprising aripiprazole according to claim 1, characterized in that the amount of the lubricant is in the range of 1 -20% in proportion to total amount of the formulation.

3. The pharmaceutical formulation comprising aripiprazole according to claim 2, characterized in that the amount of the lubricant is in the range of 1-10% in proportion to total amount of the formulation.

4. The pharmaceutical formulation comprising aripiprazole according to claim 3, characterized in that the amount of the lubricant is in the range of 1-5% in proportion to total amount of the formulation.

5. The pharmaceutical formulation comprising aripiprazole according to any preceding claims, wherein magnesium stearate is used as the lubricant.

6. The pharmaceutical formulation comprising aripiprazole according to any preceding claims, wherein the ratio of d₁₀o value of aripiprazole to di₀₀ value of the lubricant is in the range of 10:1 to 1 :1.

7. The pharmaceutical formulation comprising aripiprazole according to any preceding claims, wherein the ratio of d₁₀₀ value of aripiprazole to di₀₀ value of the lubricant is in the range of 8: 1 to 2:1.

8. The pharmaceutical formulation comprising aripiprazole according to any preceding claims, wherein the ratio of di₀₀ value of aripiprazole to d₁₀₀ value of the lubricant is in the range of 7:1 to 3:1.

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

10. The pharmaceutical formulation comprising aripiprazole according to claim 9, wherein said formulation is in orodispersible tablet, film tablet and effervescent tablet forms.

11. The pharmaceutical formulation comprising aripiprazole according to any preceding claims, wherein aripiprazole is in the form of its pharmaceutically acceptable derivatives; salts, hydrates, solvates, esters, enantiomers, disastereomers or combinations thereof in terms of chemical structure.

12. The pharmaceutical formulation comprising aripiprazole according to any preceding claims, wherein aripiprazole is in amorphous form or crystalline form or a combination thereof in terms of polymorphic structure.

13. The pharmaceutical formulation comprising aripiprazole according to any preceding claims, wherein said formulation comprises pharmaceutically acceptable excipients along with aripiprazole and the lubricant.

14. The pharmaceutical formulation comprising aripiprazole according to claim 13, wherein said formulation comprises 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, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent in addition to aripiprazole and the lubricant.

15. The pharmaceutical formulation comprising aripiprazole according to claim 14 wherein diluent is 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, D-mannitol, crosspovidone, dibasic calcium phosphate calcium and/or a combination thereof.

16. The pharmaceutical formulation comprising aripiprazole according to claim 15 wherein diluent is a diluent combination consisting of two or more diluent agents used in an amount in the range of 45-95% in said formulation.

17. The pharmaceutical formulation comprising aripiprazole according to claims 15- 16 wherein diluent is a diluent combination consisting of two or more diluent agents used in an amount in the range of 50-90% in said formulation

18. The pharmaceutical formulation comprising aripiprazole according to claim 15 and 17 wherein the diluent combination comprises xylitol, D-mannitol, crosspovidone, dibasic calcium phosphate calcium and microcrystalline cellulose.

19. The pharmaceutical formulation comprising aripiprazole according to claims 15-18 wherein the ratio of aripiprazole to the diluent combination is in the range of 1 : 1 - 1 :20.

20. The pharmaceutical formulation comprising aripiprazole according to claim 19 wherein the ratio of aripiprazole to the diluent combination is in the range of 1 :2- 1 :15.

21. The pharmaceutical formulation comprising aripiprazole according to any preceding claims, wherein said formulation comprises the active agent aripiprazole in the range of 0.1 to 99% by weight.

22. The pharmaceutical formulation comprising aripiprazole according to claim 21, wherein said formulation comprises the active agent aripiprazole in the range of 1 to 97% by weight.

23. The pharmaceutical formulation comprising aripiprazole according to claims 21 and 22, wherein said formulation comprises the active agent aripiprazole in the range of 5 to 95% by weight.

24. The pharmaceutical formulation comprising aripiprazole according to claims 21- 23, wherein said formulation comprises the active agent aripiprazole in the range of 5 to 20% by weight.

25. The pharmaceutical formulation comprising aripiprazole according to any preceding claims, wherein said formulation comprise 5 to 95% by weight aripiprazol active agent, 1-20% lubricant, 45-95% diluent combination, 0.01- 2% coloring agent, 0.05- 1.5% flavoring agent, 0.1- 3% taste regulating agent and 1-15% disintegrant.

26. The pharmaceutical formulation comprising aripiprazole according to any preceding claims, wherein said formulation comprises at least a second active agent in addition to aripiprazole 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, anti epileptic, 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 analogs, vitamin B_1; vitamin C, vitamin E, vitamin B_6j vitamin B_2i vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.