WO2014007774A1

WO2014007774A1 - Water soluble formulations comprising a piperidine derivative active agent

Info

Publication number: WO2014007774A1
Application number: PCT/TR2013/000202
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Individual
Current assignee: Individual
Priority date: 2012-07-02
Filing date: 2013-07-02
Publication date: 2014-01-09
Anticipated expiration: 2015-01-02

Description

WATER SOLUBLE FORMULATIONS COMPRISING A PIPERIDINE DERIVATIVE ACTIVE AGENT

The present invention is related to water soluble formulations comprising (+/-) 2,3-Dihydro-5,6- dimethoxy-2-[( l-(phenylmethyl)-4-piperidinyl]methyl]-l H-inden-l-one that shall be used in the symptomatic treatment of types of Alzheimer's Disease varying from mild to moderate.

Donepezil (formula I), which has the chemical name +/-) 2,3-Dihydro-5,6-dimethoxy-2-[(l - (phenylmethyI)-4-piperidinyI]methyI]-l H inden-l-one, is a cholinesterase inhibitor and first disclosed in the patent application US4895481.

Formula I. Donepezil

Donepezil is marketed in film tablet and orodispersible tablet forms. These formulations are indicated for treatment of Alzheimer's disease. General symptoms of Alzheimer's disease can be listed as memory loss, mental confusion and increase in behavioral changes.

The active agent is a crystalline powder which dissolves well in water. However, a significant problem for formulations comprising donepezil is low stability of the active agent in spite of its high water solubility.

As given in the patent numbered EP2127651, this problem is tried to be solved by adding a stabilizing agent to formulations comprising donepezil. The stabilizing agents in said patent application are agents such as edetate, sulfite, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). BHA and BHT are synthetic antioxidants which are frequently used in cosmetics, food and pharmaceutical sector. However, the studies have shown that these compounds used to provide stability cause serious health problems in users due to their oxidative nature. For instance, use of these two agents induces allergic reaction on skin¹. The studies conducted on animals have proved that use of high doses of BHT causes impairments on liver, kidney and lung functions². On the other hands, many international authorities include these compounds in potential carcinogenic compounds and restrict their use³. The references given below show toxic and carcinogenic effects of these compounds used for their antioxidant characteristics. I. U.S. National Library of Medicine, in Haz-Map: Occupational Exposure to Hazardous Agents, 2010, http://hazmap. nlm. nih. gov.

2. UNEP and OECD, 2, 6-di-tert-butyl-p-cresol (BHT) Screening Information Data Set: Initial Assessment Report (Paris: OECD, 2002),

http://www. inchem. org/ documents/ sids/sids/l 28370.pdf.

3. Study on Enhancing the Endocrine Disrupter Priority List with a Focus on Low Production Volume Chemicals, Revised Report to DG Environment (Hersholm. Denmark: DHI Water and Environment, 2007),

^■ http://ec. europa. ew 'environment/endocrine/documents/ final ' report 2007.pdf. 4. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans vol. 17 (Paris:

International Agency for Research on Cancer), vol. 40 (1986).

Therefore, it is seen that there is need for other solutions which are not harmful to human health in order to provide stability in donepezil formulations.

The patent application numbered EP 1086706 explains stable formulations comprising an organic acid such as tosylic, mesylic, benzoic, salicylic acid in addition to an anti-dementia agent such as donepezil. In the formulations of the invention, sensitivity of the active agent especially to light is prevented by use of the given acids in formulations. However, stability of the active agent to moisture and storage conditions should also be provided. Thus, the solution provided in scope of the patent is not sufficient. As a result of the studies they conducted, the inventors have managed to prepare stabile donepezil formulations without need to use any stabilizing agent. The formulations of the present invention do not have any negative effect on human health as they do not comprise a stabilizing agent.

Another advantage of the formulations is that said formulations can preserve their stability for long periods of time under storage conditions. The formulations of the present invention have been prepared in water soluble form since they appeal to a wide patient profile and provide high bioavailability. Water soluble forms are more advantageous compared to conventional forms due to their fast dispersion. These formulations release the active agent/agent into aqueous liquid fast and simultaneously. Time spent between adding the formulations into water and its dispersion and intake of the solution is relatively shorter and a possible stability problem that can appear in the formulations is minimized this way. At the same time, pharmaceutical formulations in water soluble forms are advantageous as they provide ease of use for the ones who cannot swallow solid pharmaceutical forms. A characteristic feature of the water soluble donepezil formulations of the present invention is that formulations do not comprise a stabilizing agent. The term "stabilizing agent" used herein refers to compounds such as antioxidant edetate and sulfite group compounds, BHA and BHT, propyl gallate, ascorbyl palmitate, alpha tocopherol, ascorbic acid. In a more specific way, another feature of the water soluble donepezil formulations of the present invention is that said formulations do not comprise a compound selected from a group comprising antioxidant edetate and sulfite group compounds, BHA and BHT as the stabilizing agent.

As a result of development studies they conducted in scope of the invention, the inventors have surprisingly discovered that use of a dextrin group compound in the formulations which do not== comprise any stabilizing agent influence the stability of the formulations under storage conditions positively.

Dextrins are a group of low-molecular-weight carbohydrate molecules basically produced by the - acidic hydrolysis of starch and used in very different areas for different purposes in the prior art. They can be used as binder, diluent and/or sweetener in pharmaceutical formulations. Primary dextrin compounds are maltodextrin, cyclodextrin or amylodextrin.

On the other hand, use of a dextrin group compound in the water soluble donepezil formulations of the present invention is advantageous since it provides a pleasant taste to the formulations. With this improved taste, there appears no need for use of high amounts of sweetener and/or flavoring agent in order to suppress the bitter taste of the active agent. By this means, both large sizes of dosage forms which would prevent swallowing and the increase of production costs are impeded.

A characteristic feature of water soluble donepezil formulations of the invention is that said formulations comprise;

> Donepezil, ¾

> A dextrin group excipient selected from a group comprising maltodextrin, cyclodextrin and/or amylodextrin and

"At lea^st^otheTpRarmaceutically acceptable excipient!

Another characteristic feature of the water soluble formulations of the present invention is that said ^" formulations comprise a dextrin group excipient selected from a group comprising maltodextrin, cyclodextrin and/or amylodextrin in the range of 1% and 15% by weight. Another characteristic feature of the water soluble formulations of the present invention is that said formulations comprise a dextrin group excipient selected from a group comprising maltodextrin, cyclodextrin and/or amylodextrin in the range of 1 % and 10% by weight. Another chkracteristic feature of the water soluble formulations of the present invention is that said formulations comprise a dextrin group excipient selected from a group comprising maltodextrin, cyclodextrin and/or amylodextrin in the range of 2% and 8% by weight.

Results of the stability study conducted in scope of the present invention and given below in detail indicate that the highest stability in the water soluble donepezil formulations of the present invention is enabled by use of maltodextrin.

According to this, the characteristic of the water soluble formulations of the present invention is that the dextrin group excipient is maltodextrin.

Donepezil used in water soluble formulations of the present invention can be in the form of donepezil or its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof.

The water soluble donepezil formulations of the present invention can comprise donepezil in the range of 1 and 50 mg, preferably in the range of 1 and 45 mg, more preferably in the range of 1 and 40 mg per unit dosage form. - The formulations can optionally be used in combination with another active agent.

The second active agent can be selected from antacid, antihistaminic, 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 Bi_, vitamin C, vitamin E, vitamin B¾ ; vitamin B_2, vitamin , calcium, potassium, sodium, /.inc. magnesium, fluoride, selenium. - · · - - - _— .- -

The water soluble formulations of the present invention can optionally be formulated in effervescent form.

The excipients that can be comprised in the formulations are selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple composed of 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. The disintegrant that can be used in the water soluble formulations of the present invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methylcellulose, chitosan, starch, sodium starch glycolafe. The diluent that can be used in the water soluble formulations of the present invention can be selected from a group comprising can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol. The lubricant that can be used in the water soluble formulations of the present invention can be selected from a group comprising can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, talc, stearic acid, zinc stearate.

The glidant that can be used in the water soluble formulations of the present invention 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 water soluble formulations of the present invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methylcellulose, povidone, starch.

The acidic agent comprised in the effervescent couple composed of at least one acidic agent and at least one basic agent that can be used in the water soluble formulations of the present invention can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid or pharmaceutically acceptable salts of these acids; 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 water soluble formulations of the present invention can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.

The surfactant that can be used in the water soluble formulations of the present invention can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.

The stabilizing agent that can be used in the water soluble formulations of the present invention 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 water soluble formulations of the present invention 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 flavoring agent that can be used in the water soluble formulations of the present invention can be selected from menthol, lemon, orange, vanilla, strawberry,^~raspberry, caramel and simitar flavors.

The formulations of the present invention can be produced by any methods in the prior art such as dry blending methods, wet or dry granulation methods; however, the method preferred in the present invention is wet granulation method. —„_ :— __-_._: _; _ — - — ._^ ^._^^..-.. -^ This method is applied by wet-granulating the dry mixture comprising the active agent and at least another excipient with the granulation solution comprising a pharmaceutically acceptable solvent and optionally at least another excipient and optionally adding at least another excipient into -the obtained granules and giving the granules their final shape.

The dextrin group excipient comprised in the water soluble formulations of the present and selected from a group comprising maltodextrin, cyclodextrin and/or amylodextrin can be comprised in any step of the production method. For instance, it can be added to the content of active agent mixture or granulation solution or some part of it can be comprised in the granulation solution while the rest is in the active agent mixture.

The water soluble formulations of the present invention and their preparation methods can be explained by the examples below yet they should not restrict to them.

Examples:^"

Example 1: Water soluble formulations comprising a dextrin group excipient

Production Method:

1. Donepezil, the carrier, dextrin group compound and the sweetener are mixed,

2. The mixture is wet-granulated with a pharmaceutically acceptable solvent,

3. The granules are dried and sieved,

4. The flavoring agent is added to the sieved granules,

5. The obtained granules are formed in a desired shape.

Comparison Example:

Stability Study and Results

The water soluble formulations given above were subjected to a stability study under the conditions given below; the samples taken at specific intervals were analyzed by HPLC (High Performance Liquid Chromatography) and the results obtained were listed.

Stability Study Conditions

Diluent Methanol and 0,1 mol/L hydrochloric acid mixture (1 : 1)

Injection Volume 50 μί,

Analysis Time 30 minutes

Results

As a result of the stability study;

1. Stability of the formulations which do not comprise a dextrin group compound appeared to be the lowest.

2. Stability of the formulations comprising 5% amylodextrin by weight was found to be higher than the formulations comprising 5% cyclodextrin.

3. The highest stability could be provided in the formulations comprising 5% maltodextrin.

The inventors discovered that use of a dextrin group compound in formulations which do not comprise any stabilizing agent influences the stability of the formulations I positively.

Claims

CLAIMS *

1. Water-soluble formulations, characterized in that said formulations comprise

i. Donepezil as the active agent,

ii. A dextrin group excipient selected from a group comprising maltodextrin, cyclodextrin and/or amylodextrin and

iii. At least another pharmaceutically acceptable excipient.

2. The water soluble formulations according to claim 1 , characterized in that said formulations comprise a dextrin group excipient selected from a group comprising maltodextrin, cyclodextrin and/or amylodextrin in the range of 1% and 15% by weight.

3. The water soluble formulations according to claim 2, characterized in that said formulations comprise a dextrin group excipient selected from a group comprising maltodextrin, cyclodextrin and/or amylodextrin in the range of 1% and 10% by weight.

4. The water soluble formulations according to claim 3, characterized in that said formulations comprise a dextrin group excipient selected from a group comprising maltodextrin, cyclodextrin and/or amylodextrin in the range of 2% and 8% by weight.

5. The water soluble formulations according to any preceding claims, characterized in that the excipient that said formulations comprise is maltodextrin.

6. The water soluble formulations according to any preceding claims, characterized in that donepezil comprised in said formulations is in the form of donepezil or its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, disatereomers or combinations thereof.

7. The water soluble formulations according to any preceding claims, characterized in that said formulations comprise the active agent in the range of 1 mg and 50 mg per unit dosage form.

8. The water soluble formulations according to claim 7, characterized in that said formulations comprise the active agent in the range of 1 mg and 45 mg per unit dosage form.

9. The water soluble formulations according to claims 7-8, characterized in that said formulations comprise the active agent in the range of 1 mg and 40 mg per unit dosage form.

10. The water soluble formulations according to any preceding claims, characterized in that the excipients are selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple composed of 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.

1 1. A method for production of water soluble formulations according to any preceding claims, characterized in that said method is selected from dry blending methods, wet or dry granulation methods.

12. The method selected for production of water soluble formulations according to claim 1 1, * wherein said method is wet granulation method.

13. The method for production of water soluble formulations according to claim 12, characterized in that said method is composed of the steps of;

i. Dry-mixing donepezil and at least one excipient,

ii. Wet-granulating the dry mixture with a granulations solution comprising a pharmaceutically acceptable solvent and optionally at least another excipient, iii. Optionally adding at least another excipient into the obtained granules

iv. Giving the granules a final shape.

14. The method for production of water soluble fpnnuktipns according to claim 13, characterized in that a dextrin group excipient selected from a group comprising maltodextrin, cyclodextrin and/or amylodextrin is comprised in any step of the production method.

15. The water soluble formulations according to any preceding claims, characterized in that said formulations comprise at least a second active agent in addition to donepezil selected from a group comprising antacid, antihistaminic, 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, vitamin C, vitamin E, vitamin B₆ vitamin B_2j vitamin , calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.

16. The water soluble formulations according to any preceding claims, characterized in that said formulations are formulated in effervescent form.