WO2013109201A1

WO2013109201A1 - Pharmaceutical compositions comprising cefprozil and clavulanic acid

Info

Publication number: WO2013109201A1
Application number: PCT/TR2013/000013
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2012-01-18
Filing date: 2013-01-16
Publication date: 2013-07-25

Abstract

The present invention relates to pharmaceutical formulations comprising cefprozil and clavulanic acid to be used in the treatment of diseases caused by upper and lower respiratory tract infections, skin and soft tissue infections and urinary system infections. Said formulations are characterized in being in effervescent form.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING CEFPROZIL AND

CLAVULANIC ACID

Cefprozil was first disclosed in the patent application numbered DE3402642. In said document, cefprozil was indicated to be effective in the treatment of diseases caused by upper and lower respiratory tract infections, skin and soft tissue infections and urinary system infections.

Cefprozil is present in forms for oral administration on the market.

However, these dosage forms of the prior art pose a disadvantage in pediatric and geriatric patients and people with dysphagia; besides they are not preferred by most of the patients.

An alternative to eliminate this problem may be formulating the pharmaceutical composition in suspension form. Yet suspension forms are not preferred most of the time because of the possibility of uncontrolled dose intake; high production costs; problems of physical and chemical instability; and possible problems during use and transport. Although suspension forms have higher bioavailability values as compared to solid dosage forms, they are less efficient in terms of stability and shelf life. In the prior art, pharmaceutical compositions comprising cefprozil were prepared in the form of tablet and suspension. Yet, use of tablet form poses problems for those having dysphagia such as children, elders and the handicapped or for those who do not want to take tablets or capsules. Solution dosage forms, on the other hand, are not preferred since they have the possibility of uncontrolled dose intake; make compliance to the treatment difficult for patients because of bad taste and difficulty of use; have shorter shelf lives due to their low stabilities as compared to solid dosage forms.

When the prior art is considered, a necessity has been observed for new dosage forms comprising cefprozil which have rapid dissolution and effect; are easy to use and appropriate for patients with dysphagia at the same time; and have long shelf lives. Clavulanic acid and its derivatives (e.g. its salts such as potassium clavulanate) are known as beta-lactamase inhibitors fighting against the resistance mechanism based on beta-lactamase by suppressing the activity of beta-lactamase enzymes.

Formulating the active agents cefprozil and clavulanic acid together leads to various problems such as;

• A possible interaction between active agents and excipients during formulating active agents with different excipients to provide necessary solubility and dispersibility properties,

• Obtainment of too large volumes of dosage forms when the two active agents are combined with excipients and the problems this causes to patients in terms of use.

The inventors have discovered that the problems in the prior art can surprisingly be solved with the effervescent formulations prepared in accordance with the invention.

Description of the Invention

The present invention relates to pharmaceutical formulations characterized with effervescent forms comprising cefprozil and clavulanic acid to be used in the treatment of diseases caused by upper and lower respiratory tract infections, skin and soft tissue infections and urinary system infections.

The characteristic of the formulations of the present invention is that they are in the form of effervescent powder, tablet and granule having the advantages of both tablet and suspension forms and they eliminate the problems faced with these dosage forms. Effervescent dosage forms are particularly useful for patients with dysphagia.

The pharmaceutical formulations of the present invention covers effervescent oral dosage forms comprising at least one pharmaceutically acceptable excipient in addition to cefprozil, clavulanic acid and effervescent couple; or comprising only cefprozil, clavulanic acid and effervescent couple.

In an aspect, the invention relates to effervescent oral dosage forms comprising cefprozil, clavulanic acid, effervescent couple and at least one pharmaceutically acceptable excipient. Cefprozil comprised in the formulations of the invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; and in crystalline, amorphous forms or combinations thereof in terms of polymorphic structure. A characteristic of the effervescent formulations of the invention is that the amount of cefprozil comprised in the formulations is in the range of 1% and 90%, preferably in the range of 1% and 85%, more preferably in the range of 1% and 80% by weight.

Another characteristic of the formulations of the invention is being in the form of effervescent powder, tablet and granule. The characteristic of the formulations of the invention is

- being in the form of effervescent powder, tablet and granule; and

- that the amount of cefprozil comprised is in the range of 1% and 90%, preferably in the range of 1% and 85%, more preferably in the range of 1% and 80% by weight.

The effervescent formulations of the invention are used as dissolved preferably in a glass of water or another appropriate liquid. At this point, it is clear that water-solubility of the formulation is an important parameter for providing an effective treatment and thus providing bioavailability.

The inventors have discovered that the highest solubility of the effervescent formulations comprising cefprozil and clavulanic acid is attained with formulations where the average particle size of cefprozil is smaller than 50 μηι

Accordingly, a characteristic of the effervescent formulations of the invention is to comprise cefprozil as active agent with an average particle size smaller than 50 μηι.

In another aspect, another characteristic of the effervescent formulations of the invention is to comprise cefprozil as active agent with an average particle size in the range of 1 μιη and 50 μη .

In another aspect, another characteristic of the effervescent formulations of the invention is to comprise cefprozil as active agent with an average particle size in the range of 1 μπι and 45 μηι. The characteristic of the effervescent formulations of the invention is

- being in the form of effervescent powder, tablet and granule,

- that the amount of cefprozil comprised is in the range of 1 % and 90%, preferably in the range of 1% and 85%, more preferably in the range of 1% and 80% by weight; and - that the average particle size of cefprozil comprised is smaller than 50 μηι, preferably in the range of 1 μπι and 50 μιη and more preferably in the range of 1 μπι and 45 μηι.

The phrase "average particle size" used here refers to volumetric average particle diameter and is shown as d₅₀ in short. In this respect, d₅₀ means that volumetric half of a substance has a particle size above the value indicated by d₅o and the other half has a particle size below the value indicated by d₅₀.

D₅₀ value can be measured with one of the common devices, e.g. a device measuring particle distribution by laser diffraction (e.g. Malvern Mastersizer etc.).

Another characteristic of the effervescent formulations of the invention is that said formulations comprise at least one pharmaceutically acceptable excipient in addition to cefprozil, clavulanic acid and the effervescent couple.

The excipients that can be comprised in the effervescent formulations of the invention can be selected from a group comprising binders, disintegrants, viscosity enhancing agents, filling agents, drying agents, surfactants, stabilizing agents, oiling agents, lubricants, diluents, glidants, wetting agents, oiling agents, pH regulating agents, effervescent acids, effervescent bases, gelling agents, flavoring agents, sweeteners, taste regulating agents, emulsifier, anti- foaming agents, antioxidants, protecting agents, solvents or solvent compositions, coloring agents and complexing agents or combinations thereof.

The disintegrant that can be used in the formulations of the invention comprising cefprozil and clavulanic acid 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 formulations of the invention comprising cefprozil and clavulanic acid 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 oiling agent that can be used in the formulations of the invention comprising cefprozil and clavulanic acid can be selected from a group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc.

The binder that can be used in the formulations of the invention comprising cefprozil and clavulanic acid can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, starch.

The effervescent acids that can be used in the formulations of the invention comprising cefprozil and clavulanic acid can be selected from a group comprising organic acids such as citric acid and acetic acid, tartaric acid, fumaric acid, adipic acid, malic acid or pharmaceutically acceptable hydrates, anhydrates and the like forms thereof; or combinations thereof.

The effervescent bases that can be used in the effervescent formulations of the invention comprising cefprozil and clavulanic acid can be selected from a group comprising alkali or alkaline earth metal carbonates or bicarbonates or combinations thereof. The examples of the effervescent bases used in the formulations of the invention can be potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate and sodium bicarbonate or combinations thereof.

The effervescent formulations of the invention comprise a pharmaceutically acceptable effervescent couple comprising at least an effervescent acid and at least an effervescent base in the range of 10% and 95%, preferably in the range of 15% and 95%, more preferably in the range of 20% and 95% in proportion to the total weight of the formulation.

According to this, "effervescent couple" signifies the combination of at least one effervescent acid and at least one effervescent base. Both or any of these two agents can be in the effervescent couple mixture as a combination of different types. For example; 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 ratio of at least one pharmaceutically acceptable effervescent acid and at least one effervescent base comprised in the effervescent formulations of the invention comprising cefprozil and clavulanic acid is in the range of 0.1 and 10 by weight.

The pH regulating agent that can be used in the effervescent formulations of the invention comprising cefprozil and clavulanic acid can be selected from citrate, phosphate, carbonate tartarate, fumarate, acetate and amino acid salts.

The surfactant that can be used in the effervescent formulations of the invention comprising cefprozil and clavulanic acid can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and the like.

The stabilizing agents that can be used in the effervescent formulations of the invention comprising cefprozil and clavulanic 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 invention comprising cefprozil and clavulanic acid 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 effervescent formulations of the invention comprising cefprozil and clavulanic acid can be selected from flavors such as menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and the like.

The lubricants that can be used in the effervescent formulations of the invention comprising cefprozil and clavulanic 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 excipients that can be used in the effervescent formulations of the invention comprising cefprozil and clavulanic acid can be selected from a group comprising binders, disintegrants, filling agents, surfactants, stabilizing agents, oiling agents, lubricants, diluents, glidants, effervescent acids, effervescent bases, flavoring agents, sweeteners, solvents or solvent compositions or combinations thereof.

Clavulanic acid can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts and free base form, polymorphs, crystalline forms, amorphous forms and esters.

The effervescent formulations of the invention comprising cefprozil preferably comprise potassium clavulanate as a second active agent in addition to cefprozil.

In the case that the two active agents are in the same formulation, the pharmaceutical formulations of the present invention comprising cefprozil and clavulanic acid can be prepared in any of the dosage forms such as effervescent tablet, effervescent granule, effervescent dry powder; in the case that the two active agents are in different formulations but in the same dosage form, said formulations can be prepared in forms such as layered tablet, capsule; in the case that the two active agents are in different formulations and in different dosage forms, the formulations can be prepared in the form of a treatment package where cefprozil can be in any of the dosage forms such as effervescent tablet, effervescent granule, effervescent dry powder, and the second active agent can be in any of the solid dosage forms such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film-coated tablet, enterically coated tablet, dry powder, granule, capsule, extended- release tablet, modified-release tablet, delayed-release tablet. The preparation method for the formulations of the invention comprises the steps of formulating the active agent with an appropriate excipient and giving a desired form to said formulation.

Any production method present in the prior art can be used for formulating the formulations of the invention; wet granulation, dry granulation and dry mixing methods are among these production methods.

More specifically, the formulations of the invention can be produced in accordance with any of the production methods given below:

1. Mixing the active agents cefprozil and clavulanic acid with at least one pharmaceutically acceptable excipient homogeneously and adding at least one of the excipients stated above when necessary; treating the mixture optionally with at least one pharmaceutically acceptable lubricant, giving a desired form to the obtained mixture,

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

3. Wet-granulating at least one of the excipients stated above with the granulation solution optionally comprising at least one excipient; drying the obtained granules; adding cefprozil, clavulanic acid and optionally at least one excipient to the dry granules and mixing them together; giving a desired form to the obtained granules,

4. Dry-granulating the mixture obtained by adding cefprozil, clavulanic acid as active agent and at least one of the excipients stated above and giving a desired form to the obtained granules.

To obtain a desired dosage form after the formulations of the invention are prepared according to any one of the methods above, the formulations

• can be compressed into tablets,

• can be filled into sachets. The effervescent of the invention are preferably in tablet form.

The inventors have observed that water-solubility of the formulations is affected by tablet compression force when these formulations prepared in effervescent form are in tablet dosage form.

Accordingly, the fact that the formulations prepared according to any of the methods above, which are present in the prior art, are compressed into tablets with a compression force in the range of 3 kN and 50 kN, preferably in the range of 4 kN and 45 kN, more preferably in the range of 4 kN and 40 kN leads to an improvement in the solubility of the final product.

The characteristic of the effervescent formulations of the invention is

- being in effervescent form and - that the tablet compression force applied when the formulations are compressed into tablets is in the range of 3 kN and 50 kN, preferably in the range of 4 kN and 45 kN, more preferably in the range of 4 kN and 40 kN.

The pharmaceutical formulations of the invention can be used in the prophylaxis and treatment of upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; and skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases caused by gram positive and gram negative bacteria.

The examples below are given to explain the pharmaceutical compositions of the invention and the preparation methods thereof; the scope of the invention cannot be restricted to these examples.

EXAMPLES Example I.

The effervescent formulation given above is produced according to any of the methods present in the prior art and explained in the description part in detail; and brought into use in a desired dosage form.

Claims

1. A pharmaceutical formulation comprising cefprozil and clavulanic acid, characterized in that said formulation is in effervescent form and the average particle size of cefprozil comprised in the formulation is in the range of 1 μπι and 50 μιη.

2. The formulation according to claim 1, characterized in that the average particle size of cefprozil comprised in the formulation is in the range of 1 μιη and 45 μπι.

3. The formulation according to claim 1, characterized in that cefprozil is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof; in amorphous or crystalline forms or combinations thereof in terms of polymorphic structure.

4. The formulation according to claims 1 and 3, characterized in that the amount of cefprozil comprised in the formulation is in the range of 1% and 90% by weight.

5. The formulation according to claims 1 to 4, characterized in that the amount of cefprozil comprised in the formulation is in the range of 1% and 85% by weight.

6. The formulation according to claims 1 to 5, characterized in that the amount of cefprozil comprised in the formulation is in the range of 1% and 80% by weight.

7. The formulation according to any one of the preceding claims, characterized in that said formulation is in the forms of effervescent powder, tablet and granule.

8. The formulation according to any one of the preceding claims, characterized in that the average particle size of cefprozil comprised in the formulation is smaller than 50 μηι.

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

10. The formulation according to claim 9, characterized in that the excipient that can be comprised in the formulation is selected from a group comprising binders, disintegrants, viscosity enhancing agents, filling agents, drying agents, surfactants, stabilizing agents, oiling agents, lubricants, diluents, glidants, wetting agents, oiling agents, pH regulating agents, effervescent acids, effervescent bases, gel forming agents, flavoring agents, sweeteners, taste regulating agents, emulsifiers, anti-foaming agents, antioxidants, protecting agents, solvents or solvent compositions, coloring agents and complexing agents or combinations thereof.

1 1. The formulation according to claim 10, characterized in that the excipient that can be comprised in the formulation is selected from a group comprising binders, disintegrants, filling agents, surfactants, stabilizing agents, glidants, lubricants, diluents, effervescent acids, effervescent bases, gelling agents, flavoring agents, sweeteners, solvents or solvent compositions, or combinations thereof.

12. The formulation according to claim 1 1, characterized in that the effervescent acids that can be comprised in the formulation are selected from organic acids such as citric acid, acetic acid, tartaric acid, fumaric acid, adipic acid, malic acid; or from a group comprising pharmaceutically acceptable hydrates, anhydrates and the like thereof; or from the combinations thereof.

13. The formulation according to claim 11, characterized in that the effervescent bases that can be comprised in the formulation is selected from a group comprising alkali or alkaline earth metal carbonates or bicarbonates or combinations thereof.

14. The formulation according to claim 1 1, characterized in that the effervescent bases that can be comprised in the formulation is selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate and sodium bicarbonate or combinations thereof.

15. The formulation according to claim 1 1 to 14, characterized in that said formulation comprises an effervescent couple comprising at least one pharmaceutically acceptable effervescent acid and effervescent base in the range of 10% and 95% in proportion to the total weight of the formulation.

16. The formulation according to claim 15, characterized in that said formulation comprises an effervescent couple comprising at least one pharmaceutically acceptable effervescent acid and effervescent base in the range of 15% and 95% in proportion to the total weight of the formulation.

17. The formulation according to claims 15-16, characterized in that said formulation comprises an effervescent couple comprising at least one pharmaceutically acceptable effervescent acid and effervescent base in the range of 20% and 95% in proportion to the total weight of the formulation.

18. The formulation according to claims 15 to 17, characterized in that the ratio of at least one pharmaceutically acceptable effervescent acid and effervescent base is in the range of 0.1 and 10.

19. The formulation according to any one of the preceding claims, characterized in that the second active agent clavulanic acid is in the form of potassium clavulanate.

20. A method for production of a formulation according to any one of the preceding claims, characterized in that said method comprises wet granulation, dry granulation, dry mixing steps or combinations thereof.

21. A tablet form comprising cefprozil and clavulanic acid as active agent, wherein said tablet form

a. is in effervescent form

b. comprises cefprozil in the range of 1 % and 90%

c. is compressed with a compression force in the range of 3 kN and 50 kN.