EFFERVESCENT FORMULATIONS COMPRISING CEFACLOR

Present invention relates to pharmaceutical formulations in effervescent form comprising cefaclor.

Prior Art

Cefaclor is a semi-synthetic, wide spectrum, second generation cephalosporin antibiotic which is shown with Formula (I) and which is disclosed in US3925372 (A) for the first time by Eli Lilly.

Formula (I)

Cefaclor, which is physically in white or slightly yellow and in the powder form, slightly dissolve in water but does not dissolve in methanol and methylene chloride. The product sold in the market under the tradename CECLOR ^® is present in capsule and suspension forms.

Cefaclor is used for treatment of infections caused by gram positive microorganisms; staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus pneumonia, Streptococcus pyogenes (group A streptococci), gram negative microorganisms; Haemophilus parainfluenzea, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, Escherichia coli, Klebsiella pneumonia, respiratory tract infections caused by Proteus mirabilisin such as (pneumonia, bronchitis, acute inflammations of chronic bronchitis, pharangitis, tonsilitis), middle-ear infections, sinusitis, skin and soft tissue infections and urinary tract infections (cystitis and pyelonephritis).

Formulations comprising cefaclor are commonly present in the forms of tablet, oral suspension and capsule. These dosage forms, where large amounts of antibiotic are formulated with the excipients, become bigger in size and this affects the usage negatively. Alternatively, the use of reliable and user-friendly effervescent forms is suggested. In the patent application numbered in WO2006078241, the manufacture of a medicament comprising a cephalosporin antibiotic like cephalothin in the effervescent form is disclosed.In this patent application, compared to the total weight of the composition, maximum 1.5%, preferably 0.5-1% of lubricant is used and additionally maximum 60%, preferably 10-40% of binder is used.

However, when effervescent formulations comprising cefaclor as active agent and said amounts of lubricant and binder are prepared, the smooth flow of the mixture can not be obtained since the free flow of granules is not provided and the possible friction between the interface of the tablets is not decreased. Therefore, in cases where the formulations are compressed into tablets, this problem causes a change in tablet weight and increase the relative standard deviation. The weight uniformity can not be provided due to the observed deviations in tablet weight and this causes some problems for the producer in the production and quality control stages.

As is seen, it is necessary to provide weight uniformity for an effective treatment and any problem related to the weight uniformity observed in production and quality control stages should be prevented. For this purpose, it is necessary to develop new approaches for obtaining the drug in effervescent form in which inappropriate changes in unit dosage weight will not be observed.

As a result of the studies toward this requirement, the inventors have found that the developed formulations for the preparation of effervescent forms comprising cefaclor have an effect on the relative standard deviation of the drug dosage weight and the problems in the prior art can be solved by these formulations.

Description of the Invention

The present invention is related to effervescent formulations comprising cefaclor and process for the preparation of these formulations. Surprisingly, when the formulations, in which the amount of lubricant used in the granulation solution is in the range of 2-10%, preferably 2- 8%, more preferably 2-5% and additionally the amount of binder is in the range of 0.3-8%, preferably 0.35-7%, more preferably 0.4-4%, are prepared in solid dosage form, preferably tablet form, it is seen that the relative standard deviation decreases and the weight uniformity can be provided by preventing the changes in the weight of effervescent dosage form. The inventors have studied the relative standard deviation of dosage weight by changing the ratios of lubricant and binder in order to find the effect of the lubricant and binder ratios on the changes of weight and thus the weight uniformity. Accordingly, the ratios of lubricant and binder compared to the total weight of unit dosage and the values of relative standard deviation (RSD%) are given in Table 1. As it is seen in Table 1, the values of RSD% are obtained as under 2% when the amount of binder is in the range of 0.4-4 % and the amount of lubricant is in the range of 2-5 %. Therefore, when the lubricant and binder are used in said amounts in the granulation solution, they have found that the value of relative standard deviation is low and the weight unformity is provided.

Table 1 : The lubricant and binder ratios compared to the total weight of the unit dosage and accordingly the values of relative standard deviation.

Accordingly, the first aspect of the present invention is that the granulation solution prepared in the effervescent formulations comprising cefaclor comprises 2-10%, preferably 2-8%, more preferably 2-5% of lubricant and 0.3-8%, preferably 0.35-7%, more preferably 0.4-4% of binder.

Binder used in the effervescent formulation in accordance with the present invention can be selected from, but not limited with, a group comprising; alginic acid, chitosan, carbomer, carboxymethyl cellulose sodium, dextrin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, gelatine, hypromellose, magnesium aluminium silicate, maltodextrin, polyethylene oxide and povidone or a combination thereof. Preferably povidone is used.

Lubricant used in the effervescent formulation in accordance with the present invention can be selected from a group comprising PEG 6000, sodium benzoate, calcium stearate, glyceryl monostearate, magnesium stearate, polyvinyl alcohol, potassium benzoate, stearic acid and talc. Preferably, PEG 6000 is used.

In another aspect, the present invention is related to the effervescent formulations in which granulation solution that is used for the preparation of said formulations comprises 2-10%, preferably 2-8%, more preferably 2-5% of PEG 6000 and 0.3-8%, preferably 0.35-7%, more preferably 0.4-4% of povidone.

In the effervescent formulation in accordance with the present invention, cefaclor and/or its pharmaceutically acceptable salts, hydrates, solvates and/or a combination thereof can be used.

Cefaclor that is used in the present invention can be present in one of the forms of monohydrate, dihydrate, trihydrate and/or anhydrous. Preferably, it is used in monohydrate form.

Another aspect of the present invention is that the effervescent formulation comprises cefaclor in an amount in the range of 1-55 %, preferably 5-50 % and more preferably 10-40 % compared to the total dosage weight.

Another aspect of the present invention is pharnaceutical composition comprising cefaclor, at least one binder, at least one lubricant and in addition to these at least one pharmaceutically acceptable excipient.

Pharmaceutical composition formulated in the effervescent form in accordance with the present invention comprises cefaclor as active agent, at least one binder, preferably povidone, at least one lubricant, preferably PEG 6000 and additionally one or more of pharmaceutically acceptable excipients selected from a group comprising effervescent couple including effervescent acid and base, sweetener and/or taste regulator, flavoring agent, glidant, diluents, disintegrant, coloring agent, surfactant, anti-foaming agent, humectants, acidic agent and basic agent. Effervescent acid that is used in the effervescent formulation according to the present invention is selected from a group comprising citric acid, tartaric acid, malic acid, fumaric acid, ascorbic acid, acetic acid, adipic acid, succinic acid, acetylsalicylic acid and/or sodium citrate, sodium acetate, sodium dihydrogen phosphate, sodium acid pyrophosphate and sodium acid sulphite. Preferably, citric acid is used.

Effervescent base that can be used in the effervescent formulation according to the present invention can be selected from sodium hydrogen carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium hydrogen carbonate, sodium glycine carbonate, lysine carbonate, arginine carbonate and calcium carbonate. Preferably, sodium hydrogen carbonate is used.

Sweetener and/or taste regulator that can be used in effervescent formulations of the present invention can be selected from, but not limited with, a group containing acesulfame, aspartame, dextrose, fructose, sucralose, sucrose, saccharin, saccharin sodium, lactitol, maltitol, maltose, sorbitol, sodium cyclamate, sucrose and xylitol or a combination thereof.

Flavoring agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, natural aroma oils (peppermint oil, oil of wintergreen, oil of cloves, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, menthane, anethole, methyl salicylate, eucalyptole, cinnamon, 1 -methyl acetate, sage, eugenol, oxanon, alpha- irison, marjoram, lemon, orange, blackberry, propenyl guaethol acethyl, cinnamon, vanilla, thymol, linalol, cinnamalaldehyde glycerol acethal, N-quadric p-menthan-3-carboxamide, 3,1- methoxy propane 1,2-diol or a combination thereof.

Glidant that can be used in effervescent formulations of the present invention can be selected from, but not limited with, sodium lauryl sulfate, sodium benzoate, sodium chloride, sodium acetate, sodium acetate, sodium fumarate, carbowax 4000, L-leucine(17), PEG or a combination thereof.

Diluent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, a group comprising calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch and xylitol or combinations thereof. Disintegrant that can be used in effervescent formulations of the present invention can be selected from, but not limited with, a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, povidone, magnesium aluminium silicate and starch or a combination thereof.

Coloring agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, caratenoids or chlorophyl or a combination thereof.

Surfactant that can be used in effervescent formulations of the present invention can be selected from, but not limited with, sodium lauryl sulfate, sodium sulfate anhydrous and magnesium lauryl sulfate and a combination thereof.

Anti-foaming agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, simethicone and dimethyl siloxane, silicone oil or a combination thereof.

Humectant that can be used in effervescent formulations of the present invention can be selected from, but not limited with, anhydrous sodium sulphate, silica gel and potassium carbonate or combinations thereof.

Acidic agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or combinations thereof.

Basic agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate, or combinations thereof.

The term "Effervescent couple" refers to use of acidic agent and basic agent together.

The term "Effervescent formulations" comprises effervescent tablets, effervescent granules and effervescent powder. Effervescent formulations comprising cefaclor in accordance with the present invention is preferably compressed in the form of tablets.

In the effervescent pharmaceutical composition according to the present invention, with respect to the total weight of unit dosage; cefaclor is present in an amount of 1-55%, effervescent acid in an amount of 5-80 %, effervescent base in an amount of 5-30 %, surfactant in an amount of 1-25 %, binder in an amount of 0.3-7 %, lubricant in an amount of 2-10 %, sweetener and/or taste regulator in an amount of 0.5-6% and flavoring agent in an amount of 1-5 % can be used.

In the effervescent cefaclor formulation in accordance with the present invention, optionally a second active agent can be used. The second active agent can be selected from beta lactamase and cephalasporins, preferably clavulanic acid or its pharmaceutically acceptable derivatives are used.

Clavulanic acid used in the effervescent cefaclor formulation in accordance with the present invention, can be present in the form of its solvates, hydrates, enetiomers, racemates, organic salts, inorganic salts, polymorphs, crystal and amorphous forms or in free form and/or as a combination of these. Preferably, potassium clavulanate is used.

Clavulanic acid and derivatives thereof (for example potasium clavulanate) are very sensitive to moisture. Therefore, in the pharmaceutical composition according to the present invention, potassium clavulanate is preferably used together with a humidity absorbing agent in a ratio of 1:1.

One or more than one of the following substances can be used as a humidity absorbing agent; silica; colloid silica, for instance colloidal silica anhydrous, magnesium trisilicate, powder cellulose, magnesium oxide, calcium silicate, Syloid®, starch, microcrystalline cellulose and talc.

In the effervescent cefaclor formulation in accordance with the present invention, potasium clavulanate is preferably used with syloid or microcrystalline cellulose in a ratio of 1 : 1.

In the effervescent cefaclor formulation in accordance with the present invention, with respect to the total weight of the unit dose, 1-85%, preferably 5-75%, of clavulanic acid or pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an amount equivalent to that can be used.

Another aspect of the present invention is that the pharmaceutical composition prepared according to the invention is used for the treatment of the diseases relative to the upper respiratory tract infections such as pharangitis, tonsillitis, otitis media; lower respiratory tract infections such as acute pneumonia, acute and chronic broncihia and urinary tract infections such as acute cystitis and cystourethritis. Another aspect of the present invention is the process for the preparation of the effervescent formulations comprising cefaclor in accordance with the present invention, which comprises the steps of;

1. Obtaining the granulation solution by mixing at least one binder, at least one lubricant and deionized water

2. Sieving the effervescent acid and base and granulating them with the granulation solution

3. Adding granules cefaclor, sweetener and flavoring agent after drying and sieving the granules obtained in the second step and mixing them to obtain the final mixture.

,In cases where effervescent formulations comprising cefaclor comprise a second active agent, for example potassium clavulanate, in the process used for the preparation of said formulation; potassium clavulanate: humidity absorbing agent (1:1) mixture is added along with cefaclor, sweetener and flavoring agent, in step 3 described above.

The obtained final mixture is optionally compressed in the form of tablets in the tablet pressing machine or filled into sachets.

Accordingly, another aspect the present invention is use of granulation solution comprising with respect to the total weight of the unit dose, more than 2%, preferably 2-8%, more preferably 2-5% of lubricant and more than 0.3%, preferably 0.35-7%, more preferably 0.4- 4% of binder in the effervescent formulations comprising cefaclor.

In another aspect, the inventors have found that the possible bitter taste of cefaclor can be prevented and the drug in the effervescent form can have a pleasent taste by adding two different sweeteners after drying stage in the process for the preparation of the effervescent formulations comprising cefaclor in accordance with the present invention.

Though not limited with these examples, effervescent formulations according to present invention can be prepared according to the examples given below.

Examplel: Formulation and process for preparation of effervescent tablet

A granulation solution comprising binder, lubricant and deionized water is prepared. Effervescent acid, base and surfactant are granulated with the granulation solution by adding them into fluid bed dryer. Cefaclor, sweetener and flavoring agent are added into the obtained mixture and this mixture is dried. Finally, the dried mixture is compressed into tablets.

Example2: Formulation and process for preparation of effervescent tablet

A granulation solution comprising binder, lubricant and deionized water is prepared. Effervescent acid, base and surfactant are granulated with the granulation solution by adding them into fluid bed dryer. Cefaclor, potassium clavulanate:humidity absorbing agent (1:1) mixture, sweetener and flavoring agent are added into the obtained mixture and this mixture is dried. Finally, the dried mixture is compressed into tablets.