Pharmaceutical formulations of cefaclor

Pharmaceutical formulations of cefaclor, suitable for the direct-compression manufacture of dispersible tablets, containing the antibiotic cefaclor in an amount between 35% and 50% by weight of the total weight of the formulation, along with suitable excipients and coadjuvants selected from disintegrators, diluents, lubricants, antiadherents, sweeteners, fragrances and, optionally, flavorings, opacifiers and colorants. Said formulations are suitable for the manufacture of dispersible tablets which disintegrate in less than three minutes in water at 19.degree.-21.degree. C., and are suitable for the treatment of infections caused by bacteria strains sensitive to cefaclor.

FIELD OF THE INVENTION 
This invention refers to pharmaceutical formulations containing cefaclor 
suitable for the manufacture of solid pharmaceutical forms for oral 
administration. In particular, the invention refers to pharmaceutical 
formulations and dispersible tablets containing cefaclor, and their 
manufacturing process. 
BACKGROUND OF THE INVENTION 
Cefaclor or 3-chloro-7-D-(phenylglycinamide)-3-cephem-4-carboxylic acid is 
a semi-synthetic cephalosporinic antibiotic described for example in U.S. 
Pat. No. 3,925,372 and German Patent No. DE 2,408,698 (Eli Lilly & Co.). 
Its bactericide action is based on its capacity to inhibit cell wall 
synthesis. Cefaclor is indicated for treatment of infections caused by 
sensitive strains of numerous organisms, particularly Streptococcus and 
Staphylococcus. 
Pharmaceutical forms currently available for administration of cefaclor 
include capsules, retard tablets and suspensions, both in phial and sachet 
form. 
There are a number of limitations and drawbacks to the use of capsules 
affecting the following: 
their administration to the patient, which may be limited because some may 
have problems in swallowing them, particularly children and the elderly 
who may even be unable to do so; and 
the fact that they permit only a single dosage. 
On the other hand, the drawback to cefaclor administration in suspension 
(sachets) is that, due to its saccharose content, its potential use is 
limited in diabetic patients, who must take the appropriate precautions. 
Moreover, added to this drawback caused by the saccharose content, 
administration of cefaclor in suspension (phial) has further disadvantages 
which may be summarised as follows: 
risk of accidental overdose due to uncontrolled consumption, particularly 
in children; and 
the difficulties of handling and transport because of the volume involved, 
leading to some risk of failure to complete the therapy, with the 
attendant loss of efficacy. 
Retard tablets have the drawback of not permitting double dosage of the 
product; moreover, they are not suitable for patients with difficulties in 
ingesting solid forms. 
Existing forms of administration of cefaclor do not in general meet 
entirely satisfactorily some requirements considered desirable in the 
treatment of bacterial infections, for example their application to any 
patient in conditions such as to ensure that the therapy is completed, 
thereby enhancing its efficacy. 
There is thus a requirement for new pharmaceutical forms for administering 
cefaclor which solve these problems, making it easier for the patient to 
administer them, and so that they can be used with diabetic patients 
without causing additional difficulties, so increasing the efficacy of 
treatment. This invention provides a solution to these problems, by 
furnishing new pharmaceutical formulations containing cefaclor which are 
suitable for the manufacture of dispersible tablets. 
Dispersible tablets are solid pharmaceutical forms for oral administration 
which must disintegrate in less than three minutes in water at 19.degree. 
C.-21.degree. C. and disperse evenly in the water. The dispersion 
uniformity trial involves placing two tablets in 100 ml of water and 
shaking them until they are completely disintegrated; they must disperse 
so as to pass through a screen with a nominal mesh size of 710 microns 
(Brtitish Pharmacopea Vol. II, 1988). 
Dispersible tablets are known which contain antibiotics belonging to the 
synthetic penicillins group (amoxycillin) and anti-inflammatories 
(pyroxycam), but none is known which contains an antibiotic belonging to 
the synthetic cephalosporin group, such as cefaclor. 
The subject of this invention is new pharmaceutical formulations containing 
cefaclor suitable for the manufacture of dispersible tablets. A further 
subject of this invention consists of such dispersible tablets containing 
cefaclor, and their manufacturing process. 
A DETAILED DESCRIPTION OF THE INVENTION 
The preparation of formulations suitable for manufacturing dispersible 
tablets requires both study of the physical-chemical incompatibilities of 
the active ingredient and a search for the right excipients making it 
possible to comply with the requirements of the various Pharmacopeas. 
Account must also be taken of the procedure to be used for the manufacture 
of such dispersible tablets, since the excipients and coadjuvants of the 
formulation will in large part depend on the process selected for the 
manufacture of such dispersible tablets. For reasons to be mentioned 
subsequently, direct compression was the process selected for the 
manufacture of the tablets. 
The parameters defining dispersible tablets are as follows: 
i) Their high rate of disintegration in water, and 
ii) The uniform distribution of the particles into which they disintegrate. 
Disintegration rate and uniformity of dispersion are also dependent on both 
the coadjuvants and the active ingredient. Thus disintegration, as a 
measure of the release of the active ingredient in compressed 
pharmaceutical preparations, is the critical parameter for the development 
of dispersible forms. Thus the selection of coadjuvants in the preparation 
of dispersible tablets is the most important phase of the Galenic 
research. The properties and the quality of the finished tablet depend in 
large part on the coadjuvants it incorporates so that the correct choice 
of coadjuvant is of the greatest importance, as is the manufacturing 
process since the type of coadjuvant may be selected depending on the 
technique used. 
New pharmaceutical formulations of cefaclor, suitable for manufacturing 
dispersible tablets provided by this invention, take account of these 
consideration and, in addition to the active ingredient, contain adequate 
amounts of disintegrator, diluents, lubricants, antiadherents, sweeteners, 
fragrances and, optionally, flavorings, flatting agents and colorings. In 
addition, in a particular implementation of this invention, new 
pharmaceutical formulations of cefaclor are provided which incorporate an 
effervescent pair. 
Cefaclor is the active ingredient of the formulations in this invention. As 
used in this description, the term "cefaclor" is intended to include not 
only the free acid form but also its hydrates and pharmaceutically 
acceptable salts. The Cefaclor may be present in the formulation of an 
amount between 35% and 50% by weight of the total formulation weight. The 
cefaclor can be prepared as described for example in U.S. Pat. No. 
3,925,372 and German Patent No. DE 2,408,698 (Eli Lilly & Co.). 
Because the critical parameter of dispersible tablets is their rate of 
disintegration in water, the choice of the right disintegrator is one of 
the most important stages. As used in this description, the term 
"disintegrator" refers to an agent which produces a surface increase so 
that the active ingredient of the tablet is released very quickly. 
Glycolate sodium starch, alone or together with carboxymethylcellulose, 
polymeric derivates of acrylic acid and, preferably, crospovidone are 
suitable disintegrators for the formulations in this invention. 
Glycolate sodium starch can be used in proportions of 5% and more by weight 
of the total formulation weight and, for preference, at concentrations 
between 10% and 21%. In addition, mixtures of glycolate sodium starch and 
sodium carboxymethylcellulose may be used in amounts of approximately 14% 
by weight of glycolate sodium starch and approximately 10% of sodium 
carboxymethylcellulose, in both cases in relation to the total weight of 
the formulation. 
The polymeric derivative of acrylic acid may be of medium or high 
viscosity, preferably high, and may be used in a proportion of 
approximately 10% by weight of the total formulation weight. 
The preferred disintegrator is a crospovidone (insoluble 
polyvinylpyrrolidone PVP! obtained by polymerization of 
vinylpyrrolidone). This polymer can be included in the formulation in a 
proportion of approximately 10% by weight of the total formulation weight. 
It is believed that the high disintegrating action of the reticulated and 
insoluble PVP is due to its hydration capacity (water adsorption) which 
means that a very rapid tablet disintegration rate is attained with the 
resulting improved dissolution of the cefaclor in water. 
On the other hand, the selection of the direct compression technique to 
manufacture dispersible tablets involves a further advantage in the choice 
of excipients. The possibility of using the disintegrator in extragranular 
form enhances its swelling effect since the disintegrating effect is not 
altered either by wetting or by drying. 
In the sense used in this description, the term "diluents" includes 
excipients which facilitate the compression of powdery materials and give 
the tablets strength. Microcrystalline cellulose and dry flowing starch 
and mixtures thereof are suitable diluents. 
The following are examples of suitable diluents for the formulations in 
this invention: 
1) Microcrystalline cellulose, which provides the powder mixture with 
highly appropriate fluidity and compressibility characteristics. This 
diluent makes it possible to manufacture tablets of a high level of 
purity, using the direct compression technique. It also acts as a binder, 
to give strong tablets of suitable hardness, while its absorption capacity 
contributes to short disintegration times. Of the different types of 
microcrystalline cellulose available on the market, AVICEL PH102 (mean 
particle size 90 microns) is preferred; while the others have similar 
characteristics in terms of their capacity to facilitate direct 
compression, AVICEL PH102 makes direct compression more straightforward 
thanks to the fluidity it confers on the mixture and, because of its 
particle size, it facilitates direct compression of fine powder mixtures 
(as in the formulations of this invention). The microcrystalline cellulose 
may be present in the formulation at between 24% and 46% by weight of 
total formulation weight, and 
2) dry flowing starch, due to its diluent and binding capacity in direct 
compression. It may be present in the formulation in a quantity of 
approximately 39% by weight of total formulation weight. However, tablets 
made with this diluent are not very hard, and this affects their 
friability negatively: for this reason, tablets containing 
microcrystalline cellulose as diluent are preferred. 
Because of the very high percentage of microcrystalline cellulose (between 
24% and 46% by weight of total formulation weight) tablets can be obtained 
with weights of between 1140 and 1150 mg, with high cellulose percentages, 
of the order of 38% to 46%, while with somewhat lower percentages--of the 
order of 35%-36%--tablets were obtained with a final weight of the order 
of 1125 mg each. Finally, when the percentage of microcrystalline 
cellulose is approximately 28%, tablets can be obtained with final weights 
of the order of 1130-1140 mg. 
The term "lubricant" as used in this description includes excipients which 
reduce inter-particle friction inside the tablet, reducing the reaction 
forces appearing on the walls of the matrix. Stearyl sodium fumarate, a 
hydrophylic lubricant, may be used for preference as lubricant suitable 
for the formulations in this invention. This coadjuvant can be added to 
the formulations in this invention at a rate of less than 2% by weight in 
relation to the total weight of the formulation and, for preference, 
between 0.4% and 1.5% by weight of the total formulation weight. 
The inclusion of this excipient enhances the slipping of the formulation to 
be compressed. It also ensures even filling of the space in the matrix so 
that there is very little tablet weight variation. 
Standard stearic acid salts are not suitable since, for example, magnesium 
stearate does not adsorb water, giving a solution of most unpleasant 
appearance, with the formation of a "halo" on the surface. 
The term "antiadherent" as used in this description includes excipients 
which prevent particle adhesion, so avoiding or reducing compacting and 
limiting friction between them. Colloidal silicon dioxide can be used as a 
suitable antiadherent for the formulations in this invention: because of 
its large specific surface, this raw material is a very good regulator of 
powder flow and also acts as adsorbent, capturing the humidity which would 
be taken up by the cefaclor, so slowing the degradation of the active 
ingredient by hydrolysis. 
This coadjuvant can be incorporated at a percentage of less than 5% by 
weight of the total formulation weight and, for preference, between 0.2% 
and 1.5%. 
The formulations in this invention may also contain sweeteners, fragrances 
and flavorings. Sodium saccharin may be used as artificial sweetener at 
less than 1% by weight of total weight of the formulation and, for 
preference, between 0.1% and 0.4% by weight, or aspartame at less than 1% 
by weight of total formulation weight and, for preference, between 0.2% 
and 0.75% by weight in relation to total weight of the formulation. 
Strawberry fragrance may be used for preference as fragrance, for example 
that identified as 52,312 AP05.15 Firmenich, at between 3% and 6% by 
weight of the total formulation weight. 
Anhydrous citric acid can be used for preference as flavoring, at between 
2% and 4% by weight of total formulation weight. 
Additionally and optionally, the formulations in this invention may contain 
a flatting agent and a colorant or combination of colorants to enhance the 
physical appearance of the solution to be obtained and to give it a 
uniform color. Titanium dioxide (E-171) may be used as an opacifier, in an 
amount less than 2% by weight of the total formulation weight, and for 
preference approximately 1.5% by weight of total formulation weight. Its 
use is not however essential. 
Individual colorants or combinations may be used, preferably to obtain a 
red-pink solution which can be associated with the fragrance to be used in 
the tablets (strawberry) and which also provide the final suspension with 
a pleasant appearance. These objectives may be attained by including less 
than 1% by weight of the Red F, D and C No. 3--erythrosine (E-127) 
coloring Merck Index, 11th Edition, 1989, Rahway, N.J., USA!. 
On the other hand, in a particular and alternative implementation of this 
invention, new pharmaceutical formulations of cefaclor are provided which 
also incorporate a pair of compounds which produce an effervescent effect. 
By including the effervescent pair, the tablet's disintegration rate can 
be increased. In general, an effervescent pair consists of an effervescent 
base, such as an alkaline or earth alkaline metal carbonate or bicarbonate 
and an acid which, on reacting with the effervescent base, produces carbon 
dioxide. In the new cefaclor formulations in this invention, any of the 
effervescent pairs normally used to make effervescent tablets can be 
employed, preferably that consisting of citric acid and calcium carbonate. 
The cefaclor formulations obtained from this invention may be prepared 
easily by screening the appropriate amounts of the different excipients 
and coadjuvants and placing them in a suitable mixer. The active 
ingredient is then added and mixed until homogeneous, to give a 
free-flowing powder. 
These new formulations can be used to make dispersible tablets containing 
cefaclor as active ingredient. 
As already stated, the manufacturing process for the tablet plays a very 
important role in the design of the pharmaceutical formulation. The 
formation of the tablet casing may be based on a granulate (an 
agglomerated material made of powder particles to which a binder is 
added), or on a previously untreated powder mixture (direct compression). 
Coadjuvants are selected according to the technique selected. Because 
dispersible tablets are very sensitive to damp and their stability is 
compromised by granulation operations, direct compression is the preferred 
technique, being the one which offers most advantages: on the one hand, 
manufacture is rapid, depending neither on granulation or drying and, on 
the other, it avoids possible degradation (due to hydrolysis) of the 
active ingredient during granulation. Risk of contamination is also 
reduced. However, perhaps the most significant advantage is that directly 
compressed tablets normally disintegrate more rapidly than those made by 
wet granulation which require the addition of binding agents that slow the 
disintegration rate. 
While direct compression may cause some drawbacks, such as problems of 
uniformity of mixture and dosage, fluidity and compressibility, 
surprisingly, with the formulations in this invention, none of these 
problems arose. In fact, the tablets varied very little in weight and 
content of active ingredient. Compressibility was acceptable and tablet 
hardness was within the required limits. 
Dispersible tablets containing cefaclor may be manufactured by standard 
processes, for example in a conventional rotary or eccentric compressing 
machine which compresses the prepared and screened pharmaceutical 
formulation fed to the machine. 
Dispersible tablets containing cefaclor provided by this invention are 
solid, intended for oral use, of uniform appearance, and with sufficient 
mechanical strength to withstand possible damage from storage and 
transport. The active ingredient is distributed evenly in the 
pharmaceutical form and the disintegration rate in water is high (within 
three minutes in water at 19.degree. C.-21.degree. C.). Likewise, the 
level of disintegration (or fineness of the particles in to which the 
product disintegrates) is suitable, and in line with the requirements of 
the various Pharmacopeas. 
The use of dispersible tablets containing cefaclor provides a series of 
benefits over known and habitual forms of administration of this active 
ingredient, including the following: 
They are suitable for treating patients with difficulties in ingesting 
solid forms; 
They may be used by diabetic patients since they do not contain saccharose; 
Dosage is flexible and reasonably accurate following dissolution in the 
volume of water desired by the patient. 
The resulting solutions are of suitable organoleptic characteristics, 
acceptable to patients. 
Their shape, size and reduced volume allow them to be presented in blister 
form, which is a benefit to the patient, enhancing ease of handling and 
carrying, to ensure that the patient completes the therapy, thereby 
raising the efficacy of treatment; and 
There is less risk of accidental intoxication due to overdose, making them 
less hazardous, particularly to children. 
The following Examples illustrate specific implementations of the invention 
and should not be construed as limiting it. Said Examples use dry flowing 
starch GORMASO!, crospovidone (KOLLIDON CL.RTM.) BASF! and 
microcrystalline cellulose (AVICEL PH 102.RTM.) FMC FORET!. Both high- 
and medium-viscosity acrylic derivates consist of a copolymer of 
methacrylic acid and methyl methacrylate in a ratio of approximately 7:3, 
made by ROHM PHARMA. The difference between the two types of acrylic 
derivates is due to the different viscosity of the gel they form.