WO2013165330A1

WO2013165330A1 - Stable effervescent formulations

Info

Publication number: WO2013165330A1
Application number: PCT/TR2013/000132
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2012-04-30
Filing date: 2013-04-29
Publication date: 2013-11-07

Abstract

The present invention relates to a pharmaceutical formulation in effervescent form comprising at least one active agent and use of monosodium citrate which has a lower reactivity as compared to citric acid as the effervescent acid in this formulation.

Description

STABLE EFFERVESCENT FORMULATIONS

The present invention relates to effervescent formulations comprising at least one active agent and use of monosodium citrate (also known as sodium hydrogen citrate monobasic) as the effervescent acid in these formulations.

Drugs are composed of many different forms. Tablets, capsules, granules, dragees, sachets comprising powder, chewable tablets and effervescent tablets can be listed among the solid oral dosage forms commonly used nowadays.

Solid oral dosage forms such as tablet or capsule are disadvantageous for paediatric and geriatric patients and people who have swallowing difficulties. Furthermore, they are not preferred by most patients.

Suspension forms that can remove this problem are not mostly preferred due to the possibility of uncontrolled dose intake, bad taste, difficulty of use, high production costs, physical and chemical instability problems, problems seen during use and carrying phases. Although suspension forms have higher bioavailability values as compared to solid dosage forms, it is seen that they are more inconvenient than solid dosage forms when viewed in terms of stability and shelf-life.

When these problems in the prior art are taken into consideration, effervescent formulations which dissolve when combined with water are more advantageous than other dosage forms. Effervescent formulations are composed of an acid and a base couple; they release C0₂ when they dissolve in water; and they form a clear solution for oral use. These formulations are more therapeutically advantageous since they are user-friendly, have fast dissolution and/or dispersion and higher bioavailability as compared to solid dosage forms.

The effervescent formulations comprise at least one pharmaceutically acceptable effervescent couple in order to provide effervescent reaction. However, this mixture which is basically composed of an acid and a base generally poses some problems during production of the formulations since it shows sub-reactions with both components of the formulations and active agents. Eor instance, various problems may be observed in both production and post-production storage phases of the formulations due to high reactivity and hygroscopic characteristics of citric acid which is often used as the effervescent acid in effervescent formulations.

Due to high reactivity of citric acid, the formulations degrade in a shorter time than expected; and due to its hygroscopic characteristics, the formulations adhere to the parts in production line during production and this causes product loss and the product cannot preserve its stability for a long time under storage conditions and it degrades.

When the prior art is taken into consideration, it is seen that there is need for new and improved formulations that can provide easy production and high stability for effervescent forms.

The inventors have surprisingly found that the stability problems existing in the prior art can be removed with use of monosodium citrate having low reactivity as the effervescent acid in the effervescent formulations.

According to this, the present invention discloses effervescent formulations comprising at least one active agent and use of monosodium citrate as effervescent acid in these formulations. The formulations of the present invention can optionally comprise at least one other effervescent acid in addition to monosodium citrate.

In another aspect, the present invention provides a pharmaceutical formulation in effervescent form comprising at least one active agent, an effervescent couple wherein monosodium citrate is used as the effervescent acid and optionally at least one pharmaceutically suitable excipient.

The effervescent formulations of the present invention are preferably used after dissolved in 1 glass of water or another suitable liquid. At this point, it is apparent that water solubility of the formulation is a very important parameter for providing an effective treatment and therefore bioavailability. In the effervescent formulations they conducted in the scope of the present invention, the inventors have found that use of monosodium citrate as the effervescent acid not only improves stability of the formulation but also affects its solubility positively.

The effervescent formulations of the present invention comprises an effervescent couple which is composed of monosodium citrate as the effervescent acid, optionally at least one other effervescent acid and at least one effervescent base. According to this, the term "effervescent couple" refers to mixture of at least one effervescent acid and effervescent base. Both or either of these agents can be in combination form of different types in an effervescent couple. For instance, an effervescent couple comprising two different effervescent acids and one effervescent base or two different effervescent acids and two different effervescent bases can be used.

The amount of the effervescent acid comprised in the effervescent formulations of the present invention is in the range of 80 - 95% in proportion to total formulation weight.

The effervescent formulations of the present invention comprising at least one active agent comprise monosodium citrate in the range of 10% to 80%, preferably in the range of 15% to 75% in proportion to total formulation weight.

The effervescent formulations of the present invention can optionally comprise at least one other effervescent acid in addition to monosodium citrate as the effervescent acid.

The effervescent acids that can be comprised in addition to monosodium citrate in the effervescent formulations of the present invention are selected from a group comprising organic acids such as citric acid, tartaric acid, malic acid or pharmaceutically acceptable hydrates, anhydrates and similar forms of these acids or combinations thereof.

The effervescent bases that can be used in the effervescent formulations of the present invention can be selected from a group comprising alkaline or alkaline-earth metal carbonates or bicarbonates or combinations thereof. Potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate and sodium bicarbonate or combinations thereof can be given as examples to effervescent bases preferred in the formulations of the present invention.

The ratio of at least one pharmaceutically acceptable effervescent acid to effervescent base comprised in the effervescent formulations of the present invention comprising at least one active agent is in the range of 0.1 to 10 by weight.

The terms "effervescent powder, tablet and granule" refer to effervescent tablets, effervescent granules, effervescent powders and effervescent tablets.

The inventors have found that the highest solubility is obtained with the formulations having a di oo particle size equal to or less than 150 μιτι and a d9₀ particle size equal to or less than 85 μηι in the effervescent formulations comprising at least one active agent and monosodium citrate as the effervescent acid.

According to this, di₀₀ particle size of the effervescent acid monosodium citrate comprised in the formulations is equal to or less than 150 μιη. In another aspect, dioo particle size of the effervescent acid monosodium citrate comprised in the formulations is preferably equal to or less than 140 μηι.

In another aspect, d]oo particle size of the effervescent acid monosodium citrate comprised in the formulations is more preferably equal to or less than 130 μηι.

According to this, d₉o particle size of the effervescent acid monosodium citrate comprised in the formulations is equal to or less than 85 μιη.

In another aspect, d₉₀ particle size of the effervescent acid monosodium citrate comprised in the formulations is preferably equal to or less than 80 μηι.

In another aspect, d₉₀ particle size of the effervescent acid monosodium citrate comprised in the formulations is more preferably equal to or less than 75 μηι. In other words, a characteristic feature of the effervescent formulations of the present invention comprising at least one active agent is to comprise

> Monosodium citrate having a dioo particle size equal to 150 μιη, a d₉₀ particle size equal to 80 μπι,

> At least one pharmaceutically acceptable effervescent base and at least one other excipient.

The term "dioo particle size" used throughout the text refers to particle size of 100% of the particles by volume; the term "d₉₀ particle size" refers to particle size of 90% of the particles by volume. Dioo and d₉₀ values 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.).

Another characteristic feature of the effervescent formulations of the present invention is that said formulations comprise at least one pharmaceutically acceptable excipient in addition to the active agent and effervescent couple. The excipients that can be comprised in the effervescent formulations of the present invention can be selected from a group comprising binders, disintegrants, viscosity enhancing agents, filling agents, drying agents, surface active agents, stabilizing agents, oiling agents, lubricants, diluents, glidants, wetting agents, oiling agents, pH regulating agents, gelling agents, flavouring agent, sweeteners, taste regulators, emulsifying agents, anti-foaming agents, anti-oxidants, preservatives, solvent or solvent mixtures, colouring agents and complexing agents or combinations thereof.

The disintegrant that can be used in the effervescent formulations of the present invention comprising at least one active agent and monosodium citrate as the effervescent acid 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 glycolate.

The diluent that can be used in the effervescent formulations of the present invention comprising at least one active agent and monosodium citrate as the effervescent acid 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 effervescent formulations of the present invention comprising at least one active agent and monosodium citrate as the effervescent acid 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 effervescent formulations of the present invention comprising at least one active agent and monosodium citrate as the effervescent acid 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 pH regulating agent that can be used in the effervescent formulations of the present invention comprising at least one active agent and monosodium citrate as the effervescent acid can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.

The surfactant that can be used in the effervescent formulations of the present invention comprising at least one active agent can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.

The stabilizing agents that can be used in the effervescent formulations of the present invention comprising at least one active agent and monosodium citrate as the effervescent acid 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 effervescent formulations of the present invention comprising at least one active agent and monosodium citrate as the effervescent acid can be selected from a group comprising acesulphame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharin, saccharin sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride. The flavouring agent that can be used in the effervescent formulations of the present invention comprising at least one active agent and monosodium citrate as the effervescent acid can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel, blackberry and similar flavours.

The lubricants that can be used in the effervescent formulations of the present invention comprising at least one active agent and monosodium citrate as the effervescent acid can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof.

The active agent that can be used in the effervescent formulations of the present invention comprising at least one active agent and monosodium citrate as the effervescent acid 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 Bj, vitamin C, vitamin E, vitamin B₆, vitamin B₂, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium or binary, ternary and quaternary combinations thereof.

The active agent comprised in the formulations of the present invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; in amorphous or crystalline form or a combination thereof in terms of polymorphic structure.

A characteristic feature of the effervescent formulations of the present invention is that the amount of the active agent comprised in the formulations is in the range of 0.1% to 90% by weight, preferably in the range of 0.1 % to 85% by weight.

The effervescent formulations of the present invention can optionally comprise one or more active agents. The pharmaceutical formulations of the present invention comprising a second active agent in addition to at least one active agent can be prepared in any solid dosage forms of effervescent tablet, effervescent granule, effervescent dry powder dosage forms in the case that two active agents are comprised in the same formulation; layered tablet, capsule in the case that two active agents are comprised in different formulations but in the same dosage form; in a treatment package form wherein the first active agent is in any of effervescent tablet, effervescent granule, effervescent dry powder dosage forms, the second active agent is in any 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 in the case that two active agents are comprised in different formulations and different dosage forms.

The preparation method of the formulations of the present invention comprises formulating the active agent with a suitable excipient combination and giving the required form to said formulation.

Any production method in the prior art can be used in formulating the formulations of the present invention. Wet granulation, dry granulation and dry blending methods can be listed among these production methods. More specifically, the formulations of the present invention can be produced according to any production methods given below:

1. Mixing at least one active agent with at least one pharmaceutically acceptable excipient homogeneously and adding at least one of the abovementioned excipients if required, optionally treating the mixture with at least one pharmaceutically acceptable lubricant, giving the required form to the powder mixture obtained,

2. Wet-granulating the mixture obtained by mixing at least one active agent with at least one pharmaceutically acceptable excipient homogeneously with the granulation solution optionally comprising at least one excipient; drying the granules obtained; optionally adding at least one pharmaceutically acceptable excipient into the dry granules and giving the required form to the granules obtained,

3. Wet-granulating at least one of the abovementioned excipients with the granulation solution optionally comprising at least one excipient; drying the granules obtained; adding at least one active agent and optionally at least one excipient into the dry granules and mixing them; giving the required form to the granules obtained,

4. Dry-granulating the mixture obtained by adding at least one active agent and at least one of the abovementioned excipients and giving the required form to the granules obtained.

5. Preparing two active agents according to any abovementioned production method separately and combining the formulations obtained or storing them in different dosage forms in the case that the formulations comprise a second active agent.

The effervescent formulations of the present invention are prepared according to any abovementioned methods and then they can be

• compressed in tablet form,

• filled into sachets in order to obtain the required dosage form.

The effervescent formulations of the present invention are preferably in tablet form. in another aspect, the present invention relates to administration of the said effervescent formulation to mammals including human. The pharmaceutical formulation of the present invention and preparation methods thereof can be explained with the help of the examples below. Yet, the present should not be limited to these examples.

Examples:

The effervescent formulations given above are produced according to any methods in the prior art which are explained in the description part in detail and presented for use preferably in the tablet form.

Claims

1. Effervescent formulations comprising at least one active agent, at least one pharmaceutically acceptable effervescent acid, at least another effervescent base and at least another excipient, characterized in that said formulations comprise monosodium citrate as the effervescent acid.

2. The effervescent formulations according to claim 1, characterized in that said formulations comprise monosodium citrate in the range of 10% to 80% by weight.

3. The effervescent formulations according to claims 1-2, characterized in that said formulations comprise monosodium citrate in the range of 15% to 75% by weight.

4. The effervescent formulations according to any preceding claims, characterized in that said formulations comprise at least one active agent in the range of 0.1% to 90% by weight.

5. The effervescent formulations according to claim 4, characterized in that said formulations comprise at least one active agent in the range of 0.1% to 85% by weight.

6. The effervescent formulations according to claim 1, characterized in that dioo particle size of monosodium citrate comprised in the formulations is equal to or less than 150 μηι.

7. The effervescent formulations according to claim 6, characterized in that dioo particle size of monosodium citrate comprised in the formulations is equal to or less than 140 μηι.

8. The effervescent formulations according to claims 6-7, characterized in that dioo particle size of monosodium citrate comprised in the formulations is equal to or less than 130 μιη.

9. The effervescent formulations according to claim 1 , characterized in that d₉o particle size of monosodium citrate comprised in the formulations is equal to or less than 85 μπι.

10. The effervescent formulations according to claim 9, characterized in that d₉₀ particle size of monosodium citrate comprised in the formulations is equal to or less than 80 μηι.

1 1. The effervescent formulations according to claims 9-10, characterized in that d₉₀ particle size of monosodium citrate comprised in the formulations is equal to or less than 75 μιτι. ^*

12. The effervescent formulations according to claim 1 , wherein the effervescent base comprised in the formulations is selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate and sodium bicarbonate or combinations thereof.

13. The effervescent formulations according to claim 1 , characterized in that the other excipients comprised in said formulations are selected from a group comprising binders, disintegrants, viscosity enhancing components, filling agents, drying agents, surface active agents, stabilizing agents, oiling agents, lubricants, diluents, glidants, wetting agents, oiling agents, pH regulating agents, gelling agents, flavouring agent, sweeteners, taste regulators, emulsifying agents, anti-foaming agents, anti-oxidants, preservatives, solvent or solvent mixtures, colouring agents and complexing agents or combinations thereof.

14. The effervescent formulation comprising at least one active agent, characterized in that said formulation comprises

> Monosodium citrate having a dioo particle size equal to or less than 150 μηι, a d₉₀ particle size equal to or less than 80 μιη,

> At least one pharmaceutically acceptable effervescent base and at least another excipient.

15. The effervescent formulations according to any preceding claims, characterized in that at least one active agent comprised in the formulations is selected from a group comprising 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 Bi, vitamin C, vitamin E, vitamin B₆, vitamin B₂, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium or binary, ternary and quaternary combinations thereof.