WO2013100871A1

WO2013100871A1 - Effervescent rivastigmine formulations

Info

Publication number: WO2013100871A1
Application number: PCT/TR2012/000207
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2011-12-02
Filing date: 2012-12-03
Publication date: 2013-07-04

Abstract

The present invention relates to effervescent formulations to be used in the treatment and/or prevention of memory disorders in patients with Alzheimer's disease or Parkinson's disease.

Description

EFFERVESCENT RIVASTIGMINE FORMULATIONS

The present invention relates to effervescent formulations to be used in the treatment and/or prevention of memory disorders in patients with Alzheimer's or Parkinson's diseases.

The Prior Art Rivastigmine tartrate, chemical name of which is given below, is a highly water-soluble, brain-selective acetylcholinesterase inhibitor drug used by the oral route in the treatment and/or prevention of memory disorders in patients with Alzheimer's disease or Parkinson's disease.

Formula (I). Rivastigmine Tartrate

Rivastigmine Exelon®, which is marketed as tartarate salt, is sold in tablet, solution and transdermal patch dosage forms.

However, these dosage forms present in the prior art have difficulty in meeting the needs of patients. Bioavailability of the tablet dosage forms is lower than the other forms and they mostly lead to swallowing problems in patients with higher averages of age like patients with Alzheimer's or Parkinson's diseases. Swallowing problems considerably affect accurate dosing and consequently the effectiveness of the treatment.

Oral suspension forms suggested as alternatives to tablet dosage form are not preferred most of the time particularly because of the possibility of high and/or uncontrolled dose intake and problems in their physical and chemical stability; high production costs; and the problems during usage and transport. In order to increase the stability of the active agent in oral suspension, stability improving excipients are used most of the time. Using high amounts of excipients in the formulations is not desired as it may cause incompatibility problems as well as increasing the production cost and the physical size of the target dosage form.

Using water-soluble dosage forms as an alternative to above-mentioned dosage forms is also not preferred most of the time because of the low water-solubility of the active agent. Therefore, when the prior art is considered, it is detected that there is a need for new, easy-to- use, stable formulations with high solubility comprising an effective amount of rivastigmine to be used in the treatment and/or prevention of memory disorders in patients with Alzheimer's or Parkinson's diseases.

As a result of the studies conducted in accordance with this need, the inventor has solved these problems in the prior art with the new effervescent formulations within the scope of the present invention.

Description of the Invention

The present invention relates to effervescent formulations comprising rivastigmine as active agent. An advantage of the effervescent formulations of the invention is that said formulations are easy to use and thus appropriate especially for geriatric patients having difficulty in swallowing.

In another aspect, another advantage of the effervescent formulations of the present invention is that they are highly water-soluble. In another aspect, another advantage of the effervescent formulations of the invention is that said formulations preserve their stability for an adequate period of time under storage conditions.

The effervescent rivastigmine formulations of the invention can be in powder and/or granule forms. The obtained powder or granules can optionally be compressed into tablets and/or filled into one-dose packs and/or bottles to be diluted immediately before use. The dosage form preferred according the present invention is effervescent tablet dosage form.

Rivastigmine comprised in the effervescent formulations of the invention can be in the form of its enantiomers, racemates, solvates, hydrates, esters, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or in free form and/or in the form of combinations thereof.

The effervescent formulations of the present invention preferably comprise rivastigmine hydrogen tartrate. The effervescent formulations of the invention comprise rivastigmine hydrogen tartrate in the range of 0.01 to 90%, preferably in the range of 0.01 to 80%, more preferably in the range of 0.01 to 70% in proportion to the total weight of the formulation.

A characteristic of the effervescent formulations of the invention is that the average particle size (d₅₀) of the active agent comprised in said formulations is smaller than 20 μηι, preferably smaller than 17 μηι, more preferably smaller than 15 μηι. The particle size of the active agent is important in terms of providing the adequate solubility characteristics in prepared formulations.

The term "average particle size" used here refers to average particle diameter by volume and is shown as dso in short. In this respect, the term dso means that the volumetric half of said substance has a higher particle size than the value stated with d₅₀; and the other half has a lower particle size than the value stated with dso.

D50 particle size of the active agent comprised in the pharmaceutical compositions of the invention can be measured by one of the common measurement devices, for example with a device measuring particle distribution with laser diffraction (e.g. Malvern Mastersizer etc.). A characteristic of the effervescent formulations of the invention is that said formulations comprise rivastigmine in the range of 0.01 to 90% by weight, at least one effervescent couple and at least one pharmaceutically acceptable excipient.

A characteristic of the effervescent formulations of the invention is that said formulations comprise rivastigmine in the range of 0.01 to 80% by weight, at least one effervescent couple and at least one pharmaceutically acceptable excipient.

A characteristic of the effervescent formulations of the invention is that said formulations comprise rivastigmine in the range of 0.01 to 70% by weight, at least one effervescent couple and at least one pharmaceutically acceptable excipient. The term "effervescent couple" used herein refers to the combination comprising at least one effervescent acid and at least one effervescent base.

A characteristic of the effervescent formulations of the present invention is that the ratio of at least one effervescent acid to at least one effervescent base used in the formulations is in the range of 1 to 10 by weight, preferably in the range of 1 to 8 by weight, more preferably in the range of 1 to 5 by weight.

The pharmaceutically acceptable effervescent acids that can be used in the effervescent formulations of the present invention can be selected from a group comprising citric acid, tartaric acid, adipic acid, succinic acid, ascorbic acid, malic acid, fumaric acid and/or pharmaceutically acceptable salts, hydrates, anhydrates or a combination thereof.

The effervescent formulations according to the present invention comprise at least one pharmaceutically acceptable effervescent acid in the range of 50 to 85 % by weight, preferably 55 to 85 % by weight.

The pharmaceutically acceptable effervescent bases that can be used in the effervescent formulations of the invention can be selected from a group comprising sodium, potassium and calcium bicarbonates, carbonates, glycine carbonates, hydrates or anhydrates or a combination thereof or sodium glycine carbonate.

The effervescent formulations of the present invention comprise at least one pharmaceutically acceptable effervescent base in the range of 15to 40 % by weight, preferably 20 to 40 % by weight.

The excipients that can be comprised in the effervescent formulations of the invention can be selected from a group comprising binders, disintegrants, viscosity enhancing components, filling agents, drying agents, surfactants, stabilizing agents, oiling agents, lubricants, diluents, glidants, wetting agents, coating agents designed to provide various release properties, pH regulating agents, , gelling agents, flavoring agents, sweeteners, emulgators, antifoaming agents, protective agents, solvents or solvent mixtures, coloring agents and complexing agents or combinations thereof.

The excipients particularly preferred in the effervescent formulations of the invention can be selected from a group comprising binders, lubricants, disintegrants, diluents, sweeteners, flavoring agents, effervescent acids or effervescent bases or combinations thereof. The binders that can be used in the effervescent formulations of the invention can be selected from a group comprising potato, wheat or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose and polyvinylpyrrolidone or combinations thereof. The lubricants that can be used in the effervescent formulations of the invention can be selected from a group comprising metallic stearates (magnesium stearate, calcium stearate, aluminum stearate etc.), fatty acid esters (sodium stearyl fumarate etc.), fatty acids ( stearic acid etc.), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols, metallic lauryl sulphate (sodium lauryl sulphate, magnesium lauryl sulphate etc.), sodium chloride, sodium benzoate, sodium acetate, talc and/or hydrates thereof. The formulations of the invention comprise lubricant in the range of 1 to 20% by weight, preferably in the range of 1 to 10% by weight.

The disintegrants that can be used in the effervescent formulations of the invention can be selected from a group comprising highly dispersive polymers, for example cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high molecular-weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, alginic acid, sodium alginate or combinations thereof.

The diluents that can be used in the effervescent formulations of the invention can be selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, xylitol or combinations thereof. The formulations of the invention comprise one or more diluent in the range of 1 to 99%, preferably in the range of 1 to 95% by weight.

The sweeteners that can be used in the effervescent formulations of the invention can be selected from a group comprising aspartame, dextrose, fructose, sucralose, sodium cyclamate, mannitol, maltose, sorbitol, saccharine and/or pharmaceutically acceptable salts or combinations thereof. The formulations of the invention can comprise more than one sweetener. The sweetener amount used in the formulations of the invention is in the range of 1 to 30%, preferably in the range of 1 to 20% by weight.

The flavoring agents that can be used in the effervescent formulations of the invention can be natural fruit flavors such as banana, strawberry, lemon, orange, peach, vanilla or a similar natural fruit flavor or an aromatic plant flavor. The production method for the effervescent formulations of the invention can be any of the methods in the prior art. Wet granulation, dry granulation, dry blending, direct compression or combinations thereof are some of the samples of these methods. However, the preferred method in the present invention is wet granulation method.

The wet granulation method preferred for production of the formulations of the present invention is basically composed of the steps of wet granulating the dry mixture comprising active agent, effervescent couple and suitable excipients with the granulation solution comprising suitable excipients and solvent; drying the granules, sieving them; optionally adding other excipients into the dry granules.

The production method of the invention is preferably as follows:

1. Obtaining the granulation solution by mixing at least one pharmaceutically acceptable binder and at least one solvent,

2. Mixing a pharmaceutically effective amount of rivastigmine hydrogen tartrate and at least another pharmaceutically acceptable excipient dryly,

3. Wet granulating the obtained dry mixture with the granulation solution obtained in the first step,

4. Drying the obtained granules and sieving them,

5. Adding at least one pharmaceutically acceptable sweetener into the dry granules and mixing them,

6. Sending the granules to any one of the tablet compression, bottle filling or sachet filling machines to obtain the desired dosage form.

The inventors have surprisingly found that the effervescent formulations formulated this way and produced according to the above-mentioned method can remain stable during shelf-life.

The amount of (S)- (-)-(l-dimethylaminoethyl) phenol compound, which is the main degradation product, in the effervescent rivastigmine formulations of the invention was measured under accelerated conditions (40 ± 2 °C / 75 ± 5 % relative moisture, for 6 months) and found to be less than 0.4%. This value shows that the formulations can remain stable under storage conditions. The examples for the formulations of the invention are given below. The formulations of the invention are not limited to these examples.

EXAMPLES

1. Effervescent Rivastigmine Tablet Formulation

While any method in the prior art can be used for the production of the effervescent granules given above, the preferred method of the invention is wet granulation method.

According to this method, the active agent and the pharmaceutically acceptable excipients are mixed together; the obtained mixture is wet granulated with a granulation solution preferably comprising a pharmaceutically acceptable sweetener and an adequate amount of deionized water. The effervescent rivastigmine granules obtained this way are preferably sent to tablet compression machine to obtain the desired dosage form.

Claims

1. Pharmaceutical formulations comprising rivastigmine, characterized in that said formulations are in effervescent form.

2. The effervescent formulation according to claim 1, characterized in that said formulation is in powder or granule form.

3. The effervescent formulation according to claims 1 and 2, characterized in that said formulation is prepared in tablet dosage form.

4. The effervescent formulation according to any one of the preceding claims, characterized in that rivastigmine used in the formulations is in the form of its pharmaceutically acceptable salts, enantiomers, racemates, solvates, hydrates, various polymorphic forms, amorphous or crystalline forms or in the form of a combination thereof.

5. The effervescent formulation according to claim 4, characterized in that rivastigmine comprised in said formulations is in the form of its hydrogen tartrate salt.

6. The effervescent formulation according to claim 5, characterized in that said formulations comprise rivastigmine hydrogen tartrate in the range of 0.01 to 90% in proportion to the total weight of the formulation.

7. The effervescent formulation according to claims 5 and 6, characterized in that said formulation comprises rivastigmine hydrogen tartrate in the range of 0.01 to 80% in proportion to the total weight of the formulation.

8. The effervescent formulation according to claims 5 to 7, characterized in that said formulation comprises rivastigmine hydrogen tartrate in the range of 0.01 to 70% in proportion to the total weight of the formulation.

9. The effervescent formulation according to any one of the preceeding claims, characterized in that said formulation comprises at least one effervescent couple and at least one pharmaceutically acceptable excipient.

10. The effervescent formulation according to claim 9, characterized in that the effervescent couple used in the formulations comprises at least one effervescent acid and at least one effervescent base.

11. The effervescent formulation according to claim 10, characterized in that at least one effervescent acid used in the formulations is selected from a group comprising citric acid, tartaric acid, adipic acid, succinic acid, ascorbic acid, malic acid, fumaric acid and/or pharmaceutically acceptable salts, hydrates, anhydrates or combinations thereof.

12. The formulation according to claim 11, characterized in that said formulations comprise at least one effervescent acid in the range of 50 to 85 % by weight.

13. The formulation according to claims 11-12, characterized in that said formulations comprise at least one effervescent acid in the range of 55 to 85 % by weight.

14. The effervescent formulation according to claim 10, characterized in that the effervescent base used in the formulations is selected from a group comprising sodium, potassium and calcium bicarbonates, carbonates, glycine carbonates, hydrates or anhydrates or combinations thereof or sodium glycine carbonate.

15. The effervescent formulation according to claim 14, characterized in that said formulations comprise at least one effervescent base in the range of 15 to 40 % by weight.

16. The effervescent formulation according to claims 14-15, characterized in that said formulations comprise at least one effervescent base in the range of 20 to 40 % by weight.

17. The effervescent formulation according to claims 10-16, characterized in that the ratio of at least one effervescent acid to at least one effervescent base comprised in the formulation is in the range of 1 to 10 by weight.

18. The effervescent formulation according to claim 17, characterized in that the ratio of at least one effervescent acid to at least one effervescent base comprised in the formulation is in the range of 1 to 8 by weight.

19. The effervescent formulation according to claims 17-18, characterized in that the ratio of at least one effervescent acid to at least one effervescent base in the formulation is in the range of 1 to 5 by weight.

20. The effervescent formulation according to claim 9, characterized in that the pharmaceutically acceptable excipients are selected from a group comprising binders, disintegrants, viscosity enhancing components, filling agents, drying agents, surfactants, stabilizing agents, oiling agents, lubricants, diluents, wetting agents, coating agents designed to provide various release properties, pH regulating agents, gelling agents, flavoring agents, sweeteners, emulgators, antifoaming agents, protective agents, solvents or solvent compositions, coloring agents and complexing agents or combinations thereof.

21. The effervescent formulation according to any one of the preceding claims, characterized in that the average particle size of rivastigmine comprised in the formulations is smaller than 20 μη .

22. The effervescent formulation according to claim 21, characterized in that the average particle size of rivastigmine comprised in the formulations is smaller than 17 μηι.

23. The effervescent formulation according to claims 21 and 22, characterized in that the average particle size of rivastigmine comprised in the formulations is smaller than 15 μπι.

24. The effervescent formulation according to any one of the preceding claims, characterized in that said formulation is produced by any one of wet granulation, dry granulation, dry blending and direct compression methods.

25. The method according to claim 24, characterized in that said method is wet granulation method.

26. The method according to claim 25, characterized in that said production method is composed of the following steps;

• Wet- granulating the dry mixture comprising active agent, effervescent couple and suitable excipients with the granulation solution comprising suitable excipients and a solvent;

• Drying the obtained granules, sieving them and optionally adding other excipients into the dry granules.

27. The effervescent formulation according to any one of the preceding claims, characterized in that said formulation is used in the treatment and/or prevention of memory disorders in patients with Alzheimer's disease or Parkinson's disease.