WO2002026235A1

WO2002026235A1 - Dispersible pharmaceutical cephalosporin compositions, preparation and use thereof

Info

Publication number: WO2002026235A1
Application number: PCT/FR2001/002959
Authority: WO
Inventors: Claude Laruelle; René Gimet; Dominique Toselli
Original assignee: Cll Pharma
Priority date: 2000-09-29
Filing date: 2001-09-25
Publication date: 2002-04-04
Also published as: FR2814679A1; AU2001291980A1; FR2814679B1

Abstract

The invention concerns dispersible cephalosporin compositions, in particular in the form of tablets, their preparation method and their use for improving sensory perception of patients when such compositions are orally administered.

Description

DISPERSIBLE PHARMACEUTICAL COMPOSITIONS BASED ON CEPHALOSPORINS, THEIR PREPARATION METHOD AND THEIR

USE

The present invention relates to pharmaceutical compositions based on cephalosporins, in particular in the form of dispersible tablets, as well as to their use for improving the sensory perception of patients with the oral administration of such compositions.

In the pharmaceutical industry, cephalosporins are very widely used as anti-bacterial agents and are therefore offered by a very large number of chemical suppliers. Among these cephalosporins, there may be mentioned, by way of example, the active ingredients known under the international nonproprietary names (INNs) cefadroxil, cephadrine or even cefalexin. To date, the active ingredient cefadroxil has been offered by 28 chemical suppliers alone. Cephalosporins and their derivatives can be produced according to various synthetic processes.

Thus, in patent application FR 1 603 618, a process for the preparation of cephalosporin derivatives is described which consists in reacting a derivative of 7-aminodeacetoxycephalosporanic acid (7-ADCA) with an acylating agent. comprising an amino function protected by a protective group which may in particular be a t-butyloxycarbonyl group (t-BOC), the expected cephalosporin derivative then being obtained by hydrolysis of the protective group in an inert solvent. These cephalosporin derivatives are obtained in anhydrous form with a very low yield. In addition, the use of acylating agent comprising a protective group such as t-BOC is very expensive.

US Patent 3,985,741 describes another process for preparing cephalosporins in which the acylating agent used is chosen from compounds in which the alpha-amino group is protected by a β-keto group such as for example methyl acetylate . This acetylating agent is a mixed anhydrous acid obtained by reaction between a carboxylic acid salt (Dane salt) and an ethyl chloroformate in the presence of a catalyst, N-methylmorpholine. Another synthetic process, as described for example in patent application FR 2 365 570, schematically consists of a) silylating the 7-ADCA, then b) acylating the silylated 7-ADCA in step a) with D - (-) - α-amino-α- (p-hydroxyphenyl) acetyl chloride hydrochloride in the presence of an acid acceptor such as triethylamine, dimethylamine, dimethylaniline, quinoline, lutidine or pyridine , then c) cleaving all the silyl groups from the acylation product of step b) to obtain the desired cephalosporanic acid.

The cephalosporins obtainable by these different processes must then undergo one or more stages of crystallization and purification before they can be incorporated into pharmaceutical compositions.

For this purpose, many crystallization techniques using different types of solvents can be used.

Thus it has for example been proposed, in particular in US patent 3,985,741 or in patent application FR 2 365 570, to use a solvent chosen from acetonitrile, methanol, toluene, dimethylformamide ( DMF), dimethylacetamide (DMAC) and mixtures thereof.

Taking into account the diversity of the processes allowing the synthesis, the crystallization and the purification of cephalosporins, the obtained compounds present notable variations as well from the point of view of their structural characteristics in particular crystallographic as of the degree of purity which they present (presence of traces residual solvents).

Medicines based on cephalosporins are generally administered orally and can be presented in various galenical forms such as capsules, granules or powders for oral suspension, dispersible or non-dispersible tablets.

The administration of cephalosporins in the form of capsules or non-dispersible tablets cannot always be envisaged, especially in children and in people suffering from the upper tract of the digestive tract and having difficulty swallowing. Non-dispersible capsules and tablets also have a bioavailability which may be less than that of dispersible powders and tablets. On the other hand, the administration of cephalosporins in the form of powders or granules for oral suspension requires before use the reconstitution of the suspension by addition of water, the agitation of this suspension before each use and the measurement of the dose. appropriate before each administration. All of these different operations are a source of errors regarding the dose of cephalosporin administered.

However, the presentation in the form of dispersible tablets has several advantages:

- the dispersible tablet, which must be dispersed in water before * ingestion, always corresponds to a single and precise dose of the active ingredient to be administered;

- This type of formulation also allows easier administration of the drug in people with swallowing problems, in particular the elderly and children. However, the formulation of active principles in the form of dispersible tablets requires the addition of excipients such as flavors and sweetening agents so as to mask the odor and the taste, possibly unpleasant of the active principle in itself, and thus improve the olfactory and gustatory perception of the drug during ingestion To date, ORACEFAL ® is the only available cephalosporin-based drug which can be in the form of dispersible tablets. These dispersible tablets contain 1 g of active ingredient (cefadroxil) in combination with various excipients necessary for this type of formulation, among which we can notably cite crosslinked polyvinylpyrrolidone (known under the trade name crospovidone ®) and which is a disintegrating agent, cellulose. microcrystalline (binding agent), magnesium stearate (lubricating agent), sweeteners such as gluconate or sodium cyclamate or sodium saccharin and flavors such as orange and grapefruit flavors.

However, despite the presence of sweetening agents and flavors, the presentation of ORACEFAL ® in the form of dispersible tablets is poorly tolerated from a sensory point of view (odor and taste) when ingested. It is in order to remedy these problems that the inventors have developed what is the subject of the invention.

The inventors therefore set themselves the objective of providing a dispersible pharmaceutical composition based on cephalosporin having all the advantages of this type of galenical formulation as well as an improved odor and taste.

The present invention therefore relates to a pharmaceutical composition dispersible in a liquid comprising at least one cephalosporin as active ingredient, alone or in combination with another active ingredient, and at least one disintegrating agent, characterized in that said cephalosporin has an N, N-dimethylacetamide (DMAC) impurity level of less than 21.4 ppm and that said disintegrating agent is crosslinked sodium carboxymethylcellulose (croscarmellose® sodium).

The inventors have in fact demonstrated that the specific association of these two compounds makes it possible to obtain a dispersible pharmaceutical composition having olfactory and gustatory properties markedly improved compared to those of pharmaceutical compositions of the prior art based on cephalosporins, without that it is necessary to act mainly on the flavoring thereof.

The pharmaceutical compositions in accordance with the invention have the additional advantage of disintegrating completely in less than 3 minutes when they are brought into contact with a liquid such as water and thus leading to an oral suspension whose homogeneity can be easily obtained by stirring.

The pharmaceutical composition according to the invention can be in the form of dispersible tablets or dispersible granules.

According to a particularly advantageous embodiment of the invention, the DMAC impurity level of the cephalosporins is less than 5 ppm.

The cephalosporins which can be used as active principle in the pharmaceutical composition in accordance with the invention are preferably chosen from cefadroxil, cephadrine, cefalexin, cefatrizin and cefixime.

These cephalosporins must be prepared according to a synthetic process which does not require the use of dimethylaniline. However, they are preferably prepared according to a synthetic process using a Dane salt, as described for example in US patent 3,985,741.

According to the invention, croscarmellose ® sodium preferably represents from 1 to 25% by weight approximately of the total weight of the pharmaceutical composition and even more particularly from 2 to 10% by weight.

The pharmaceutical composition in accordance with the invention may also contain one or more excipients which can be chosen from flow agents, lubricating agents, binding agents, sweeteners, flavoring agents, flavorings, etc. flow agents which can be used in the pharmaceutical composition in accordance with the invention, mention may in particular be made of precipitated silica dioxide, colloidal silica, talc, stearic acid, magnesium stearate and their mixtures, particularly preferred precipitated silica dioxide. These flow agents are used to prevent the components of the tablets or granules from forming aggregates during the preparation of these tablets or granules and also to reduce friction during compression operations. They are generally present in proportions of between 0.1 and 3% of the total weight of the pharmaceutical composition.

Among the lubricating agents which can be used in the pharmaceutical composition in accordance with the invention, mention may in particular be made of magnesium stearate, calcium stearate and their mixtures. These lubricating agents, the role of which is to reduce friction operations during compression operations, are advantageously present in proportions of between 0.1% and 3% of the total weight of the pharmaceutical composition. Among the binding agents which can be used in the pharmaceutical composition in accordance with the invention, mention may in particular be made of microcrystalline cellulose, lactose, hydroxypropylmethylcellulose (HPC), pregelatinized starch and their mixtures, microcrystalline cellulose being particularly preferred. Binding agents facilitate the compression operations necessary to obtain tablets and give adequate hardness to them. When used, these binding agents preferably represent from 5 to 60% of the total weight of the pharmaceutical composition. The sweeteners can in particular be chosen from aspartame, sodium saccharin, sodium cyclamate, potassium acesulfame, ammonium glycerinate and their mixtures. These sweeteners preferably represent from 1 to 20% of the total weight of the pharmaceutical composition. Although the pharmaceutical composition in accordance with the invention has an improved odor and taste compared to the compositions of the prior art based on cephalosporin, it may nevertheless contain one or more aromas, these being in particular able to be chosen from the aromas fruits such as strawberry, lemon, raspberry, grapefruit, orange, etc. and the aromas of mint, chocolate, vanilla, strawberry, licorice and their mixtures

Of course, those skilled in the art will take care on this occasion that the excipient (s) possibly used are compatible with the intrinsic properties attached to the present pharmaceutical composition.

The invention also relates to a process for the preparation of a dispersible pharmaceutical composition as defined above, said process being characterized in that it comprises: a) a step of premixing at least one cephalosporin having a impurity of N, N-dimethylacetamide less than 21.4 ppm with crosslinked sodium carboxymethylcellulose in the presence, optionally, of a binding agent and / or a flow agent, to obtain a premix (A), b ) a step of mixing any additional excipients such as binding agents, lubricating agents, sweetening agents, flavorings, to obtain a mixture of excipients (B), c) a step of final mixing of the premix (A) and of the mixture of excipients (B), to obtain a final mixture (C), d) a granulation and / or compression step of the final mixture (C) resulting.

According to the invention, steps a) to c) of the process described above are preferably carried out with stirring and can include sub-sieving operations of the various ingredients used and / or mixtures obtained.

Step d) of granulation or compression can be carried out conventionally according to known methods of granulation or compression. Finally, the subject of the invention is the use of at least one dispersible pharmaceutical composition as defined above to improve the sensory perception (olfactory and gustatory) of a patient during the oral administration of such a composition. In addition to the foregoing arrangements, the invention also comprises other arrangements which will emerge from the description which follows, which refers to an example of demonstration of the improvement of sensory perception during the oral administration of a composition. pharmaceutical according to the invention compared to the administration of pharmaceutical compositions not forming part of the invention.

It should be understood, however, that this example is given only by way of illustration of the subject of the invention, of which it in no way constitutes a limitation.

EXAMPLE: DEMONSTRATION OF THE IMPROVEMENT OF SENSORY PERCEPTION DURING THE ADMINISTRATION OF A DISPERSIBLE PHARMACEUTICAL COMPOSITION BASED ON CEPHALOSPORIN

1) Preparation of dispersible tablets based on cefadroxil

Dispersible tablets having the compositions listed in Table I below were prepared (the quantities are given in mg):

Table I

': Comparative composition not forming part of the invention: Composition according to the present invention

A CD 1 dispersible tablet, which serves as a reference and which corresponds to the formulation of the ORACEFAL® 1000 dispersible tablets of the 1996 edition of the VIDAL® dictionary containing 1000 mg of cefadroxil monohydrate, was also studied.

The different excipients mentioned for the CD 4 dispersible tablet correspond to those present in the CD 1 dispersible tablet of ORACEFAL ® 1000.

The CD 2 to CD 4 tablets above were prepared as follows: a) Preparation of a premix A

Cefadroxil, 80% of the total amount of microcrystalline cellulose, croscarmellose ® sodium and half of the silica (CD 2 and CD 3 tablets) were sieved on an oscillating calibrator equipped with a 1 mm grid. These sieved ingredients were then introduced into a TUMBLER type mobile bowl inversion mixer and mixed for 30 minutes at a speed of 19 revolutions / minute. b) Preparation of a mixture of excipients B

The remaining 20% of microcrystalline cellulose, sweetening agents, anhydrous citric acid and the flavors were sieved on an oscillating calibrator equipped with a 0.5 mm grid.

These sieved ingredients were then introduced into a granulator mixer type Lodi ^'ge and mixed for 2 minutes at a speed of 1450 revolutions / minute. c) Preparation of a final mixture C cl) Preparation of a final premix

The mixtures A and B obtained in the preceding steps were calibrated separately on an oscillating calibrator equipped with a 1 mm grid operating at 110 oscillations / minute. The mixtures A and B thus calibrated, as well as the second half of the silica, were introduced into the tank of a mobile tank mixer of the TUMBLER type and mixed for 30 minutes at a speed of 19 revolutions / minute. c.2) Screening of the flow agent

The flow agent, namely magnesium stearate, was sieved on an oscillating calibrator fitted with a 0.25 mm grid. c.3) Lubrication step

The magnesium stearate thus sieved was then added to the final premix obtained above in step c1), in a mobile tank mixer of TUMBLER. The whole was mixed for 5 minutes at 19 rpm. d) Compression of the final mixture C

The final mixture obtained above in step c was then compressed in a rotary tableting machine of the FETTE P2100 type with punches with a diameter of 23 mm, bi-plane faceted with a breakable bar.

The machine was adjusted so as to obtain a tablet mass equal to 2500 mg of hardness between 60 and 180 N, and having the following characteristics:

- Thickness: 6 mm,

- Breaking strength: 60 to 180 N,

- Friability: <1%,

- Disaggregation speed: <1 min.

2) Evaluation of the disintegration time of the tablets

The total disintegration time of each of the above CD 1 to CD 4 tablets was determined after immersion in 100 ml of water per tablet.

The results obtained are shown in Table II below:

Table II

These results show that the tablets containing a disintegrating agent in accordance with the invention, that is to say croscarmellose® sodium have a disintegration time approximately twice as short as the dispersible tablets containing a disintegrating agent which are not part of the invention, namely crospovidone ®.

3) Evaluation of sensory perception during the oral administration of the tablets CD 1 to CD 4

This evaluation was carried out on a panel of 12. volunteer people.

Each person blindly tests the four CD1 to CD4 tablets, each dispersed in half a glass of water, both from the olfactory point of view of the suspension before ingestion and from the point of view of its overall appreciation. (taste, finesse, presence or absence of aftertaste, etc.) during ingestion. Each person assigns a score ranging from 1 to 10 for the olfactory assessment and a score ranging from 1 to 10 for the overall assessment.

This evaluation test makes it possible to take into account the odor after disintegration of the tablet in water. This factor is important because it reflects the desire to bring the glass to the mouth and administer the product.

The results obtained are collated as an average in Table III below:

Table III

These results demonstrate that the CD 2 dispersible tablet according to the invention, that is to say containing the combination of a cephalosporin having a DMAC impurity level of less than 21.4 ppm as a principle active and croscarmellose ® sodium as a disintegrating agent, leads to better results, both from the point of view of odor and of overall appreciation after ingestion, than those obtained with the dispersible tablets CD 1, CD 3 or CD 4 not forming part of the invention.

These results also show that the use of only one of the two elements of this association is not sufficient to improve the sensory perception of a patient during the oral administration of such a composition.

Indeed, a tablet containing the combination of a cephalosporin having a DMAC impurity level greater than 21.4 ppm, in combination with croscarmellose ® sodium as a disintegrating agent (CD 3 tablet) gives results. generally equivalent to the reference (CD 1 tablet). Similarly, a tablet containing the combination of a cephalosporin having a DMAC impurity level of less than 21.4 ppm, in combination with crospovidone ® as a disintegrating agent (CD 4 tablet) also gives results generally equivalent to the reference (CD 1 tablet).

Claims

1. Pharmaceutical composition dispersible in a liquid comprising at least one cephalosporin as active principle, alone or in combination with another active principle, and at least one disintegrating agent, characterized in that the said cephalosporin has an impurity content of N, N-dimethylacetamide less than 21.4 ppm and that said disintegrating agent is crosslinked sodium carboxymethylcellulose.

2. Pharmaceutical composition according to claim 1, characterized in that it is in the form of tablets or granules.

3. Pharmaceutical composition according to claim 1 or 2, characterized in that said cephalosporin has an impurity level of N, N-dimethylacetamide less than 5 ppm.

4. Pharmaceutical composition according to any one of the preceding claims, characterized in that the said cephalosporin is chosen from cefadroxil, cephadrine, cefalexin, cefatrizine and cefixime.

5. Pharmaceutical composition according to any one of the preceding claims, characterized in that the crosslinked sodium carboxymethylcellulose represents from 1 to 25% _. by weight of the total weight of said composition, and preferably from 2 to 10%.

6. Pharmaceutical composition according to any one of the preceding claims, characterized in that it contains one or more excipients chosen from flow agents, lubricants, binding agents, sweeteners, flavoring agents, and the aromas.

7. A method of preparing a dispersible pharmaceutical composition as defined above, said method being characterized in that it comprises: a) a step of premixing at least one cephalosporin having an impurity content of N, N-dimethylacetamide less than 21.4 ppm with crosslinked sodium carboxymethylcellulose in the optional presence of a binding agent and / or a flow agent, to obtain a premix (A), b) a step of mixing any additional excipients such as binding agents, lubricating agents, sweetening agents, flavorings, to obtain a mixture of excipients (B), c) a step of final mixing of the premix (A) and of the mixture excipients (B), to obtain a final mixture (C), d) a granulation or compression step of the resulting final mixture (C).

8. Use of at least one dispersible pharmaceutical composition as defined in any one of claims 1 to 6 for improving the olfactory and gustatory perception of a patient during the oral administration of such a composition.