CA2158511A1 - Pharmaceutical formulations of cefaclor - Google Patents
Pharmaceutical formulations of cefaclorInfo
- Publication number
- CA2158511A1 CA2158511A1 CA002158511A CA2158511A CA2158511A1 CA 2158511 A1 CA2158511 A1 CA 2158511A1 CA 002158511 A CA002158511 A CA 002158511A CA 2158511 A CA2158511 A CA 2158511A CA 2158511 A1 CA2158511 A1 CA 2158511A1
- Authority
- CA
- Canada
- Prior art keywords
- weight
- formulation
- set forth
- amount
- cefaclor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Abstract
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 withsuitable 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° - 21°C, and are suitable for the treatment of infections caused by bacteria strains sensitive to cefaclor.
Description
- 21S8all PHARMACEUTICAL FORMULATIONS OF CEFACLOR
FIELD OF THE INVENTION
This invention refers to pharm~ceutical formulations containing cefaclor S suitable for the manufacture of solid pharm~ceutis~1 forms for oral ~lministration.
In particular, the invention refers to pharm~-,euti~1 formulations and dispersible tablets containing cefaclor, and their manufacturing process.
BACKGROUND OF THE INVENTION
Cefaclor or 3-chloro-7-D-(phenylglycinamide)-3-cephem-4-carboxylicacid is a semi-synthetic cephalosporinic antibiotic described for example in US Patent 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, lS particularly Streptococcus and Staphylococcus.
Pharmaceutical forms currently available for a(lmini~tration 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 applopliate precautions.
Moreover, added to this drawback caused by the saccharose content, administration of cefaclor in suspension (phial) has further dlsadvantages which may be summarised as follows:
2158Sll - 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 5 efficacy.
Retard tablets have the drawback of not p~ ing double dosage of the product; moreover, they are not suitable for p~tient~ with difficulties in in~estin~
solid forms.
Existing forms of administration of cefaclor do not in general meet entirely 10 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 asolution 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 ~dministration which must disintegrate in less than three minutes in water at 19C - 21C 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 (British 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 ofcoadjuvant 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 ` 21~511 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 5 incorporate an effervescent pair.
Cefaclor is the active ingredient of the formulations in this invention. As usedin 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 10 total formulation weight. The cefaclor can be prepared as described for example in US Patent 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 15 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 20 weight of the total formulation weight and, for preference, at concentrations between10% and 21%. In addition, mixtures of glycolate sodium starch and sodiumcarboxymethylcellulose 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 25 formulation.
The polymeric derivative of acrylic acid may be of medium or high viscosity, preferably high, and may be used i~ a pr~portion of approximately 10% by weight of the total formulation weight.
The preferred disintegrator is a crospovidone (insoluble polyvinylpyrrolidone 30 [PVP] obtained by polymerization of vinylpyrrolidone). This polymer can be 2158~11 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) whieh means that a very rapid tablet disintegration rate is attained with the resulting S 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 exeipients. The possibility of using the disintegrator in extragranular form enhanees its swelling effect sinee the disintegrating effect is not altered either by wetting or 10 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.
lS 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 20 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 25 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 microcrystallinecellulose may be present in the formulation at between 24% and 46% by weight of total formulation weight, and ` 21~Sll 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 approximately39% 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 S containing microcrystalline cellulose as diluent are prefelr~d.
Rec~llse of the very high pelcentage 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 percel!tages, of the order of 38% to 46%, while with somewhat lower percentages - of the order of 35%-36%
10 - 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 o~ 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 per~entage of less than 5% by weight of the total formulation weight and, for preference, between 0.2% and 1.5 % .
5The 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 l)refe~nce, 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 10of 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 %
15and 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 weight20 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.
25 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 30 incorporate a pair of compounds which produce an effervescent effect. By including S l l 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 earthalkaline metal carbonate or bicarbonate and an acid which, on reacting with the effervescent base, produces carbon dioxide. In the new cefaclor formulations in this S invention, any of the effervescent pairs normally used to make effervescent tablets can be employed, preferably that con~i~ting of citric acid and calcium carbonate.
The cefaclor formulations obtained from this invention may be prep~d easily by screening the appro~l iate amounts of the different excipients and coadjuvants and placing them in a suitable mixer. The active ingredient is then added 10 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 lS 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 20 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 25 rapidly than those made by wet granulation which require the addition of binding agents that slow the disintegration rate.
While direct compression may ca.use 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 ` ` 21~511 varied very little in weight and content of active ingredient. Co~plessibility was acceptable and tablet hardness was within the required Iimits.
Dispersible tablets containing cefaclor may be manufactured by standard processes, for example in a conventional rotary or eccentric complessing machine5 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 10 distributed evenly in the pharmaceutical form and the disintegration rate in water is high (within three minutes in water at 19C - 21C). 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 benefits15 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;
20 - 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 25 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.
` 21~511 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~) [BASF] and microcrystalline cellulose (AVICEL PH 102~) [FMC FORET]. Both high- and medium-viscosity 5 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.
Dispersible tablets were prepared from the following pharmaceutical formulation:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 37.35 Glycolate sodium starch 70.00 5.00 CMC*, AVICEL PH102 612.99 43.78 Stearyl sodium fumarate 14.00 1.00 Colloidal silicon dioxide 70.00 5.00 Aspartame 10.00 0.71 Strawberry fragrance 50.00 3.58 Anhydrous citric acid 50.00 3.58 *CMC Microcrystalline cellulose The process begins with the weighing of all the raw materials separately then screening them as a security measure. After screening, the excipients are placed in 25 a suitable mixer, the cefaclor is then added and re-mixed until homogenous.
The mixed powders are passed several times through a 0.7 mm mesh screen.
Compression follows, with periodlc coatro~s during the process, noting the results obtained on the associated control cards. The powder flows satisfactorily and compresses without difficulties. At the end of the process, representative samples are 21~8~
taken for analysis (from the beginning, middle and end of the batch) using a statistical sampling procedure.
Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1400 mg + 5%
Weight of 10 tablets: 14 g + 3%
Hardness: 7 Kgf Height: approximately 5.6 mm Diameter: 17.15 mm Disintegration in water at 19C - 21C: <3 min Appearance: white with some transparent surface specks Flavor: pleasant (quite neutral) Suspension: once disintegrated and shaken, remains in suspension approximately 2 minutes.
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 41.84 Glycolate sodium starch 62.50 5.00 CMC*, AVICEL PH102 544.49 43.56 Stearyl sodium fumarate 12.50 1.00 Colloidal silicon dioxide 62.50 5.00 Aspartame 5.00 0.40 Strawberry fragrance 40.00 3.20 *CMC Microcrystalline cellulose _ .
Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1250 mg + 5 %
Weight of 10 tablets: 12.5 g + 3%
215~511 Hardness: 7.8 Kgf Height: approximately 5.5 mm Diameter: 17.15 mm Disintegration in water at 19C - 21C: <3 min Flavor: pleasant (quite neutral) Suspension: once disintegrated and shaken, remains in suspension approximately 2 minutes.
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 41.84 Glycolate sodium starch 62.50 5.00 CMC*, AVICEL PHl02 574.49 45.96 Stearyl sodium fumarate 12.50 1.00 Colloidal silicon dioxide 12.50 1.00 Sodium saccharin 5.00 0.40 Strawberry fragrance 60.00 4.80 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1250 mg + 5%
Weight of 10 tablets: 12.5 g + 3%
Hardness: 8 Kgf Height: approximately 5.2 mm Diameter: 17.15 mm Disintegration in water at 19C - 21C: <3 min Appearance: white-ish Flavor: pleasant 21S~31~
Suspension: once disintegrated and shaken, remains in suspension approximately 2 minutes.
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) 5b BY WEIGHT
Cefaclor 523.00 41.84 Glycolate sodium starch 62.50 5.00 CMC*, AVICEL PH102 562.00 44.96 Stearyl sodium fumarate 12.50 1.00 Colloidal silicon dioxide 12.50 1.00 Sodium saccharin 5.00 0.40 Strawberry fragrance 60.00 4.80 Titanium dioxide 12.50 1.00 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1250 mg + 5%
Weight of 10 tablets: 12.5 g + 3%
Hardness: 10 Kgf Height: approximately 5.1 mm Diameter: 17.15 mm Disintegration in water at 19C - 21C: <3 min Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 miF~utes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 45.49 Glycolate sodium starch 115.00 10.00 Dry flowing starch 445.00 38.70 Stearyl sodium fumarate 6.25 0.54 Colloidal silicon dioxide 6.25 0.54 Sodium saccharin 3.00 0.27 Strawberry fragrance 45.00 3.92 Titanium dioxide 6.25 0.54 Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1149.76 mg + 5%
Weight of l0 tablets: 11.5 g + 3%
Hardness: 8 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): 0.9 %
Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 48.29 Glycolate sodium starch 163.00 15.05 21~8511 CMC*, AVICEL PH102 345.00 31.85 Stearyl sodium fumarate 5.60 0.52 Colloidal silicon dioxide - 2.20 0.20 Sodium saccharin 3.00 0.28 Strawberry fragrance 38.00 3.51 Titanium dioxide 3.30 0.30 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1083.11 mg + 5 %
Weight of 10 tablets: 10.8 g + 3%
Hardness: 8 - 9 Kgp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): 0.8 %
Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) ~ BY WEIGHT
Cefaclor 523.01 45.88 Glycolate sodium starch 163.00 14.30 Sodium carboxymethylcellulose 120.00 10.53 CMC*, AVICEL-PH102 ~ .275.00 24.13 Stearyl sodium fumarate 5.60 0.49 Colloidal silicon dioxide 6.00 0.53 Sodium saccharin 2.00 0.17 21~8~11 Strawberry fragrance 42.00 3.68 Titanium dioxide 3.30 0.29 ~CMC Microcrystalline cellulose Dispersible tablets were obtained with the followlng characteristics:
Individual tablet weight: 1139.91 mg + 5%
Weight of 10 tablets: 11.4 g + 3%
Hardness: 8 - 9 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): 0.8~o Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg)% BY WEIGHT
Cefaclor 523.01 45.88 Glycolate sodium starch 110.01 9.65 Calcium carbonate 14.02 1.23 Anhydrous citric acid 40.01 3.51 C M C*, A VIC E L P H 102 390.02 34.21 Stearyl sodium fumarate 5.59 0.50 Colloidal silicon dioxide 11.97 1.05 Sodium saccharin ~2.05 0.18 Strawberry fragrance 40.01 3.50 Titanium dioxide 3.31 0.29 *CMC Microcrystalline cellulose ~ 21~8Sll Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1140 mg + 5%
Weight of 10 tablets: 11.4 g + 3%
Hardness: 9 - 10 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): 0.6%
Appea,~lce: white-ish Flavor: pleasant Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 46.10 Glycolate sodium starch 171.00 15.07 CMC*, AVICEL PH102 345.00 31.35 Stearyl sodium fumarate 17.10 1.50 Colloidal silicon dioxide 17.10 1.50 Sodium saccharin 2.28 0.21 Strawberry fragrance 39.90 3.52 Titanium dioxide 8.55 0.75 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1134.62mg + 5%
Weight of 10 tablets: 11.3 g + 3 %
Hardness: 12.8 Kp Disintegration in water at 19C - 21C: c3 min ` ` ` 2158~11 Friability (10 tablets): < 0.5 %
Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension 5 for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
10 COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 46.10 Glycolate sodium starch 171.00 15.07 CMC*, AVICEL PH102 355.68 31.35 Stearyl sodium fumarate 17.10 1.50 15 Colloidal silicon dioxide 17.10 1.50 Aspartame 2.28 0.21 Strawberry fragrance 39.90 3.52 Titanium dioxide 8.55 0.75 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1134.62 mg + 5 %
Weight of 10 tablets: 11.3 g + 3%
Hardness: 12.8 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): < 0.5 %
Appearance: white-ish Flavor: pleasant .
Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
21S8~11 Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 45.96 Glycolate sodium starch 205.20 18.03 CMC*, AVICEL PH102 324.90 28.55 Stearyl sodium fumarate 17.10 1.50 Colloidal silicon dioxide 17.10 1.50 Sodium saccharin 2.28 0.20 Strawberry fragrance 39.90 3.51 Titanium dioxide 8.55 0.75 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1138.04 mg + 5 %
Weight of 10 tablets: 11.4 g + 3 %
Hardness: 13.0 Kp Disintegration in water at 19C - 21C: C3 min Friability (10 tablets): C 0.5 %
Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure describ~ i~ Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 45.96 Glycolate sodium starch 228.00 20.03 21~8511 CMC*, AVICEL PH102 302.10 26.55 Stearyl sodium fumarate 17.10 1.50 Colloidal silicon dioxide 17.10 1.50 Sodium saccharin 2.28 0.20 Strawberry fragrance 39.90 - 3.51 Titanium dioxide 8.55 0.75 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1138.04 mg + 5 %
Weight of 10 tablets: 11.4 g + 3 %
Hardness: 10.7 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): < 0.5 %
Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg)% BY WEICiHT
Cefaclor - 523.01 46.66 Acrylic derivate (medium viscosity) 114.00 10.17 CMC*, AVICEL PH102 399.00 35.60 Stearyl sodium fumarate 17.10 1.50 Colloidal silicon dioxide ~ 17.10 1.50 Sodium saccharin 2.28 0.21 Strawberry fragrance 39.90 3.56 Titanium dioxide 8.55 0.76 " 2158511 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1120.94 mg + 5 %
Weight of 10 tablets: 11.2 g + 3%
5 - Hardness: 12.27 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): <0.5%
Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical 15 formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 46.26 Acrylic derivate (high viscosity) 114.00 10.08 CMC*, AVICEL PH102 399.00 35.30 Stearyl sodium fumarate 17.10 l.si Colloidal silicon dioxide 17.10 1.51 Sodium saccharin 3.42 0.30 Strawberry fragrance 39.90 3.53 Titanium dioxide 17.10 1.51 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1130.63-~ng + 5 %
Weight of 10 tablets: 11.3 g + 3 ~0 Hardness: 13.65 Kp Disintegration in water at 19C - 21C: <3 min 215~511 Appearance: white-ish Flavor: pleasant Suspension: once di~integl~ted and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
s Dispersible tablets were prel~ared from the following pharm~reutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 46.11 Acrylic derivate (high viscosity) 114.00 10.05 CMC*, AVICEL PH102 399.00 35.17 Stearyl sodium fumarate 17.10 1.51 Colloidal silicon dioxide 17.10 1.51 Sodium saccharin 4.10 0.36 Strawberry fragrance 39.90 3.52 Titanium dioxide 17.10 1.51 Erythrosine 3.00 0.26 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1134.31 mg + 5%
Weight of 10 tablets: 11.3 g + 3 %
Hardness: 13 Kp Disintegration in water at 19C - 21C: ~3 min Friability (10 tablets): < 0.5 %
Appearance: pale rose color Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
21~511 Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 46.24 Acrylic derivate (high viscosity)114.00 10.08 CMC*, AVICEL PH102 400.00 35.07 Stearyl sodium fumarate 17.10 1.51 Colloidal silicon dioxide 17.10 1.51 Sodium saccharin 4.10 0.36 Strawberry fragrance 40.00 3.53 Yellow F, D and C No. 6 4.00 0.35 Erythrosine 4.00 0.35 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1131.31 mg + 5 %
Weight of 10 tablets: 11.3 g + 3%
Hardness: 15.74 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): ~ 0.5 %
Appearance: pale rose color Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were ~repar~d from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 46.48 2158~11 Acrylic derivate (high viscosity) 114.00 10.13 CMC*, AVICEL PH102 - 400.00 35.34 Stearyl sodium fumarate 17.10 1.52 Colloidal silicon dioxide 17.10 1.52 Sodium saccharin 4.10 0.36 Strawberry fragrance 40.00 3.56 Erythrosine 10.00 0.89 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1125.31 mg + 5%
Weight of 10 tablets: 11.2 g + 3 %
Hardness: 15 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): < 0.5 %
Appearance: pale rose color Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) 5'0 BY WEIGHT
Cefaclor 523.01 46.48 Crospovidone 114.00 10.13 CMC*, AVICEL PH102 400.00 35.34 Stearyl sodium fumarate . 17.10 1.52 Colloidal silicon dioxide 17.10 1.52 Sodium saccharin 4.10 0.36 Strawberry fragrance 40.00 3.56 21S8~11 Erythrosine 10.00 0.89 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1125.31 mg + 5%
Weight of 10 tablets: 11.2 g + 3%
Hardness: 14.78 Kp Disintegration in water at 19C - 21C: ~3 min Friability (10 tablets): ~ 0.5 %
Appearance: pale rose color Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
FIELD OF THE INVENTION
This invention refers to pharm~ceutical formulations containing cefaclor S suitable for the manufacture of solid pharm~ceutis~1 forms for oral ~lministration.
In particular, the invention refers to pharm~-,euti~1 formulations and dispersible tablets containing cefaclor, and their manufacturing process.
BACKGROUND OF THE INVENTION
Cefaclor or 3-chloro-7-D-(phenylglycinamide)-3-cephem-4-carboxylicacid is a semi-synthetic cephalosporinic antibiotic described for example in US Patent 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, lS particularly Streptococcus and Staphylococcus.
Pharmaceutical forms currently available for a(lmini~tration 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 applopliate precautions.
Moreover, added to this drawback caused by the saccharose content, administration of cefaclor in suspension (phial) has further dlsadvantages which may be summarised as follows:
2158Sll - 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 5 efficacy.
Retard tablets have the drawback of not p~ ing double dosage of the product; moreover, they are not suitable for p~tient~ with difficulties in in~estin~
solid forms.
Existing forms of administration of cefaclor do not in general meet entirely 10 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 asolution 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 ~dministration which must disintegrate in less than three minutes in water at 19C - 21C 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 (British 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 ofcoadjuvant 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 ` 21~511 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 5 incorporate an effervescent pair.
Cefaclor is the active ingredient of the formulations in this invention. As usedin 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 10 total formulation weight. The cefaclor can be prepared as described for example in US Patent 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 15 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 20 weight of the total formulation weight and, for preference, at concentrations between10% and 21%. In addition, mixtures of glycolate sodium starch and sodiumcarboxymethylcellulose 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 25 formulation.
The polymeric derivative of acrylic acid may be of medium or high viscosity, preferably high, and may be used i~ a pr~portion of approximately 10% by weight of the total formulation weight.
The preferred disintegrator is a crospovidone (insoluble polyvinylpyrrolidone 30 [PVP] obtained by polymerization of vinylpyrrolidone). This polymer can be 2158~11 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) whieh means that a very rapid tablet disintegration rate is attained with the resulting S 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 exeipients. The possibility of using the disintegrator in extragranular form enhanees its swelling effect sinee the disintegrating effect is not altered either by wetting or 10 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.
lS 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 20 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 25 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 microcrystallinecellulose may be present in the formulation at between 24% and 46% by weight of total formulation weight, and ` 21~Sll 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 approximately39% 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 S containing microcrystalline cellulose as diluent are prefelr~d.
Rec~llse of the very high pelcentage 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 percel!tages, of the order of 38% to 46%, while with somewhat lower percentages - of the order of 35%-36%
10 - 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 o~ 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 per~entage of less than 5% by weight of the total formulation weight and, for preference, between 0.2% and 1.5 % .
5The 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 l)refe~nce, 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 10of 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 %
15and 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 weight20 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.
25 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 30 incorporate a pair of compounds which produce an effervescent effect. By including S l l 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 earthalkaline metal carbonate or bicarbonate and an acid which, on reacting with the effervescent base, produces carbon dioxide. In the new cefaclor formulations in this S invention, any of the effervescent pairs normally used to make effervescent tablets can be employed, preferably that con~i~ting of citric acid and calcium carbonate.
The cefaclor formulations obtained from this invention may be prep~d easily by screening the appro~l iate amounts of the different excipients and coadjuvants and placing them in a suitable mixer. The active ingredient is then added 10 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 lS 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 20 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 25 rapidly than those made by wet granulation which require the addition of binding agents that slow the disintegration rate.
While direct compression may ca.use 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 ` ` 21~511 varied very little in weight and content of active ingredient. Co~plessibility was acceptable and tablet hardness was within the required Iimits.
Dispersible tablets containing cefaclor may be manufactured by standard processes, for example in a conventional rotary or eccentric complessing machine5 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 10 distributed evenly in the pharmaceutical form and the disintegration rate in water is high (within three minutes in water at 19C - 21C). 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 benefits15 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;
20 - 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 25 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.
` 21~511 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~) [BASF] and microcrystalline cellulose (AVICEL PH 102~) [FMC FORET]. Both high- and medium-viscosity 5 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.
Dispersible tablets were prepared from the following pharmaceutical formulation:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 37.35 Glycolate sodium starch 70.00 5.00 CMC*, AVICEL PH102 612.99 43.78 Stearyl sodium fumarate 14.00 1.00 Colloidal silicon dioxide 70.00 5.00 Aspartame 10.00 0.71 Strawberry fragrance 50.00 3.58 Anhydrous citric acid 50.00 3.58 *CMC Microcrystalline cellulose The process begins with the weighing of all the raw materials separately then screening them as a security measure. After screening, the excipients are placed in 25 a suitable mixer, the cefaclor is then added and re-mixed until homogenous.
The mixed powders are passed several times through a 0.7 mm mesh screen.
Compression follows, with periodlc coatro~s during the process, noting the results obtained on the associated control cards. The powder flows satisfactorily and compresses without difficulties. At the end of the process, representative samples are 21~8~
taken for analysis (from the beginning, middle and end of the batch) using a statistical sampling procedure.
Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1400 mg + 5%
Weight of 10 tablets: 14 g + 3%
Hardness: 7 Kgf Height: approximately 5.6 mm Diameter: 17.15 mm Disintegration in water at 19C - 21C: <3 min Appearance: white with some transparent surface specks Flavor: pleasant (quite neutral) Suspension: once disintegrated and shaken, remains in suspension approximately 2 minutes.
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 41.84 Glycolate sodium starch 62.50 5.00 CMC*, AVICEL PH102 544.49 43.56 Stearyl sodium fumarate 12.50 1.00 Colloidal silicon dioxide 62.50 5.00 Aspartame 5.00 0.40 Strawberry fragrance 40.00 3.20 *CMC Microcrystalline cellulose _ .
Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1250 mg + 5 %
Weight of 10 tablets: 12.5 g + 3%
215~511 Hardness: 7.8 Kgf Height: approximately 5.5 mm Diameter: 17.15 mm Disintegration in water at 19C - 21C: <3 min Flavor: pleasant (quite neutral) Suspension: once disintegrated and shaken, remains in suspension approximately 2 minutes.
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 41.84 Glycolate sodium starch 62.50 5.00 CMC*, AVICEL PHl02 574.49 45.96 Stearyl sodium fumarate 12.50 1.00 Colloidal silicon dioxide 12.50 1.00 Sodium saccharin 5.00 0.40 Strawberry fragrance 60.00 4.80 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1250 mg + 5%
Weight of 10 tablets: 12.5 g + 3%
Hardness: 8 Kgf Height: approximately 5.2 mm Diameter: 17.15 mm Disintegration in water at 19C - 21C: <3 min Appearance: white-ish Flavor: pleasant 21S~31~
Suspension: once disintegrated and shaken, remains in suspension approximately 2 minutes.
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) 5b BY WEIGHT
Cefaclor 523.00 41.84 Glycolate sodium starch 62.50 5.00 CMC*, AVICEL PH102 562.00 44.96 Stearyl sodium fumarate 12.50 1.00 Colloidal silicon dioxide 12.50 1.00 Sodium saccharin 5.00 0.40 Strawberry fragrance 60.00 4.80 Titanium dioxide 12.50 1.00 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1250 mg + 5%
Weight of 10 tablets: 12.5 g + 3%
Hardness: 10 Kgf Height: approximately 5.1 mm Diameter: 17.15 mm Disintegration in water at 19C - 21C: <3 min Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 miF~utes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 45.49 Glycolate sodium starch 115.00 10.00 Dry flowing starch 445.00 38.70 Stearyl sodium fumarate 6.25 0.54 Colloidal silicon dioxide 6.25 0.54 Sodium saccharin 3.00 0.27 Strawberry fragrance 45.00 3.92 Titanium dioxide 6.25 0.54 Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1149.76 mg + 5%
Weight of l0 tablets: 11.5 g + 3%
Hardness: 8 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): 0.9 %
Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 48.29 Glycolate sodium starch 163.00 15.05 21~8511 CMC*, AVICEL PH102 345.00 31.85 Stearyl sodium fumarate 5.60 0.52 Colloidal silicon dioxide - 2.20 0.20 Sodium saccharin 3.00 0.28 Strawberry fragrance 38.00 3.51 Titanium dioxide 3.30 0.30 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1083.11 mg + 5 %
Weight of 10 tablets: 10.8 g + 3%
Hardness: 8 - 9 Kgp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): 0.8 %
Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) ~ BY WEIGHT
Cefaclor 523.01 45.88 Glycolate sodium starch 163.00 14.30 Sodium carboxymethylcellulose 120.00 10.53 CMC*, AVICEL-PH102 ~ .275.00 24.13 Stearyl sodium fumarate 5.60 0.49 Colloidal silicon dioxide 6.00 0.53 Sodium saccharin 2.00 0.17 21~8~11 Strawberry fragrance 42.00 3.68 Titanium dioxide 3.30 0.29 ~CMC Microcrystalline cellulose Dispersible tablets were obtained with the followlng characteristics:
Individual tablet weight: 1139.91 mg + 5%
Weight of 10 tablets: 11.4 g + 3%
Hardness: 8 - 9 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): 0.8~o Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg)% BY WEIGHT
Cefaclor 523.01 45.88 Glycolate sodium starch 110.01 9.65 Calcium carbonate 14.02 1.23 Anhydrous citric acid 40.01 3.51 C M C*, A VIC E L P H 102 390.02 34.21 Stearyl sodium fumarate 5.59 0.50 Colloidal silicon dioxide 11.97 1.05 Sodium saccharin ~2.05 0.18 Strawberry fragrance 40.01 3.50 Titanium dioxide 3.31 0.29 *CMC Microcrystalline cellulose ~ 21~8Sll Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1140 mg + 5%
Weight of 10 tablets: 11.4 g + 3%
Hardness: 9 - 10 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): 0.6%
Appea,~lce: white-ish Flavor: pleasant Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 46.10 Glycolate sodium starch 171.00 15.07 CMC*, AVICEL PH102 345.00 31.35 Stearyl sodium fumarate 17.10 1.50 Colloidal silicon dioxide 17.10 1.50 Sodium saccharin 2.28 0.21 Strawberry fragrance 39.90 3.52 Titanium dioxide 8.55 0.75 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1134.62mg + 5%
Weight of 10 tablets: 11.3 g + 3 %
Hardness: 12.8 Kp Disintegration in water at 19C - 21C: c3 min ` ` ` 2158~11 Friability (10 tablets): < 0.5 %
Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension 5 for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
10 COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 46.10 Glycolate sodium starch 171.00 15.07 CMC*, AVICEL PH102 355.68 31.35 Stearyl sodium fumarate 17.10 1.50 15 Colloidal silicon dioxide 17.10 1.50 Aspartame 2.28 0.21 Strawberry fragrance 39.90 3.52 Titanium dioxide 8.55 0.75 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1134.62 mg + 5 %
Weight of 10 tablets: 11.3 g + 3%
Hardness: 12.8 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): < 0.5 %
Appearance: white-ish Flavor: pleasant .
Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
21S8~11 Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 45.96 Glycolate sodium starch 205.20 18.03 CMC*, AVICEL PH102 324.90 28.55 Stearyl sodium fumarate 17.10 1.50 Colloidal silicon dioxide 17.10 1.50 Sodium saccharin 2.28 0.20 Strawberry fragrance 39.90 3.51 Titanium dioxide 8.55 0.75 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1138.04 mg + 5 %
Weight of 10 tablets: 11.4 g + 3 %
Hardness: 13.0 Kp Disintegration in water at 19C - 21C: C3 min Friability (10 tablets): C 0.5 %
Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure describ~ i~ Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 45.96 Glycolate sodium starch 228.00 20.03 21~8511 CMC*, AVICEL PH102 302.10 26.55 Stearyl sodium fumarate 17.10 1.50 Colloidal silicon dioxide 17.10 1.50 Sodium saccharin 2.28 0.20 Strawberry fragrance 39.90 - 3.51 Titanium dioxide 8.55 0.75 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1138.04 mg + 5 %
Weight of 10 tablets: 11.4 g + 3 %
Hardness: 10.7 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): < 0.5 %
Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg)% BY WEICiHT
Cefaclor - 523.01 46.66 Acrylic derivate (medium viscosity) 114.00 10.17 CMC*, AVICEL PH102 399.00 35.60 Stearyl sodium fumarate 17.10 1.50 Colloidal silicon dioxide ~ 17.10 1.50 Sodium saccharin 2.28 0.21 Strawberry fragrance 39.90 3.56 Titanium dioxide 8.55 0.76 " 2158511 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1120.94 mg + 5 %
Weight of 10 tablets: 11.2 g + 3%
5 - Hardness: 12.27 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): <0.5%
Appearance: white-ish Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical 15 formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 46.26 Acrylic derivate (high viscosity) 114.00 10.08 CMC*, AVICEL PH102 399.00 35.30 Stearyl sodium fumarate 17.10 l.si Colloidal silicon dioxide 17.10 1.51 Sodium saccharin 3.42 0.30 Strawberry fragrance 39.90 3.53 Titanium dioxide 17.10 1.51 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1130.63-~ng + 5 %
Weight of 10 tablets: 11.3 g + 3 ~0 Hardness: 13.65 Kp Disintegration in water at 19C - 21C: <3 min 215~511 Appearance: white-ish Flavor: pleasant Suspension: once di~integl~ted and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
s Dispersible tablets were prel~ared from the following pharm~reutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 46.11 Acrylic derivate (high viscosity) 114.00 10.05 CMC*, AVICEL PH102 399.00 35.17 Stearyl sodium fumarate 17.10 1.51 Colloidal silicon dioxide 17.10 1.51 Sodium saccharin 4.10 0.36 Strawberry fragrance 39.90 3.52 Titanium dioxide 17.10 1.51 Erythrosine 3.00 0.26 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1134.31 mg + 5%
Weight of 10 tablets: 11.3 g + 3 %
Hardness: 13 Kp Disintegration in water at 19C - 21C: ~3 min Friability (10 tablets): < 0.5 %
Appearance: pale rose color Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
21~511 Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 46.24 Acrylic derivate (high viscosity)114.00 10.08 CMC*, AVICEL PH102 400.00 35.07 Stearyl sodium fumarate 17.10 1.51 Colloidal silicon dioxide 17.10 1.51 Sodium saccharin 4.10 0.36 Strawberry fragrance 40.00 3.53 Yellow F, D and C No. 6 4.00 0.35 Erythrosine 4.00 0.35 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1131.31 mg + 5 %
Weight of 10 tablets: 11.3 g + 3%
Hardness: 15.74 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): ~ 0.5 %
Appearance: pale rose color Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were ~repar~d from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) % BY WEIGHT
Cefaclor 523.01 46.48 2158~11 Acrylic derivate (high viscosity) 114.00 10.13 CMC*, AVICEL PH102 - 400.00 35.34 Stearyl sodium fumarate 17.10 1.52 Colloidal silicon dioxide 17.10 1.52 Sodium saccharin 4.10 0.36 Strawberry fragrance 40.00 3.56 Erythrosine 10.00 0.89 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1125.31 mg + 5%
Weight of 10 tablets: 11.2 g + 3 %
Hardness: 15 Kp Disintegration in water at 19C - 21C: <3 min Friability (10 tablets): < 0.5 %
Appearance: pale rose color Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Dispersible tablets were prepared from the following pharmaceutical formulation, using the procedure described in Example 1:
COMPONENTS WEIGHT (mg) 5'0 BY WEIGHT
Cefaclor 523.01 46.48 Crospovidone 114.00 10.13 CMC*, AVICEL PH102 400.00 35.34 Stearyl sodium fumarate . 17.10 1.52 Colloidal silicon dioxide 17.10 1.52 Sodium saccharin 4.10 0.36 Strawberry fragrance 40.00 3.56 21S8~11 Erythrosine 10.00 0.89 *CMC Microcrystalline cellulose Dispersible tablets were obtained with the following characteristics:
Individual tablet weight: 1125.31 mg + 5%
Weight of 10 tablets: 11.2 g + 3%
Hardness: 14.78 Kp Disintegration in water at 19C - 21C: ~3 min Friability (10 tablets): ~ 0.5 %
Appearance: pale rose color Flavor: pleasant Suspension: once disintegrated and shaken, appears to remain in suspension for a long period (approximately 30 minutes).
Claims (24)
1. A pharmaceutical formulation suitable for manufacturing dispersible tablets by direct compression, with cefaclor as active ingredient in a quantity between 35% and 50% by weight of total formulation weight, with suitable excipients and coadjuvants.
2. A formulation as set forth in claim 1 in which said suitable excipients and coadjuvants comprise disintegrators, diluents, lubricants, antiadherents, sweeteners, fragrances and, optionally, flavorings, opacifiers and colorants.
3. A formulation as set forth in claim 2 in which the disintegrator is glycolatesodium starch, acrylic derivates, mixtures of glycolate sodium starch and carboxymethylcellulose and, for preference, crospovidone.
4. A formulation as set forth in claim 3 comprising glycolate sodium starch in an amount between 5% and 21% by weight of total formulation weight.
5. A formulation as set forth in claim 3 comprising acrylic acid derivates in an amount of approximately 10% by weight of total formulation weight.
6. A formulation as set forth in claim 3 comprising crospovidone in an amount of approximately 10% by weight of total formulation weight.
7. A formulation as set forth in claim 3 comprising a mixture of (i) glycolate sodium starch in an amount of approximately 14% by weight of total formulation weight, and (ii) carboxymethylcellulose in an amount of approximately 10% by weight of total formulation weight, as disintegrator.
8. A formulation as set forth in claim 2 comprising microcrystalline cellulose, dry flowing starch and their mixtures, as diluent.
9. A formulation as set forth in claim 8 comprising microcrystalline cellulose in an amount between 24% and 46% by weight of total formulation weight.
10. A formulation as set forth in claim 9 in which said microcrystalline cellulose has a mean particle size of approximately 90 microns.
11. A formulation as set forth in claim 8 comprising dry flowing starch in an amount of approximately 39% by weight of total formulation weight.
12. A formulation as set forth in claim 2 comprising stearyl sodium fumarate as lubricant, in an amount of less than 2% by weight of total formulation weight.
13. A formulation as set forth in claim 2 comprising colloidal silicon dioxide as antiadherent, in an amount of less than 5% by weight of total formulation weight.
14. A formulation as set forth in claim 2 comprising aspartame, sodium saccharin or their mixtures as sweetener, in an amount of less than 1% by weight of total formulation weight.
15. A formulation as set forth in claim 14 comprising sodium saccharin in an amount between 0.1% and 0.4% by weight of total formulation weight.
16. A formulation as set forth in claim 14 comprising aspartame in an amount between 0.2% and 0.7% by weight of total formulation weight.
17. A formulation as set forth in claim 2 comprising a strawberry fragrance, in an amount between 3% and 5% by weight of total formulation weight.
18. A formulation as set forth in claim 2 comprising anhydrous citric acid as flavoring, in an amount between 2% and 4% by weight of total formulation weight.
19. A formulation as set forth in claim 2 comprising titanium dioxide as opacifier, in an amount of less than 2% by weight of total formulation weight.
20. A formulation as set forth in claim 2 comprising Red F, D and C No.3 -Erythrosine as colorant, in an amount of less than 1% by weight of total formulation weight.
21. A formulation as set forth in claim 1 which includes a pair of compounds producing an effervescent effect.
22. A formulation as set forth in claim 21 wherein said effervescent pair consists of citric acid and calcium carbonate.
23. A dispersible cefaclor tablet obtainable by direct compression of a pharmaceutical formulation from any of claims 1 to 22.
24. A process for the manufacture of a dispersible tablet containing cefaclor, involving the direct compression of a pharmaceutical formulation from any of claims 1 to 22.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES09402530A ES2079327B1 (en) | 1994-12-13 | 1994-12-13 | PHARMACEUTICAL FORMULATIONS OF CEFACLOR. |
| ES9402530 | 1994-12-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2158511A1 true CA2158511A1 (en) | 1996-06-14 |
Family
ID=8288235
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002158511A Abandoned CA2158511A1 (en) | 1994-12-13 | 1995-09-18 | Pharmaceutical formulations of cefaclor |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US5861141A (en) |
| EP (3) | EP1086689A3 (en) |
| JP (1) | JPH08208484A (en) |
| KR (1) | KR100350565B1 (en) |
| CN (1) | CN1136852C (en) |
| AT (1) | ATE201984T1 (en) |
| AU (1) | AU702585B2 (en) |
| BR (1) | BR9504573A (en) |
| CA (1) | CA2158511A1 (en) |
| CO (1) | CO4410176A1 (en) |
| CZ (1) | CZ287248B6 (en) |
| DE (2) | DE716852T1 (en) |
| DK (1) | DK0716852T3 (en) |
| ES (2) | ES2079327B1 (en) |
| FI (1) | FI953887A (en) |
| GR (2) | GR960300062T1 (en) |
| HK (1) | HK1012574A1 (en) |
| HU (1) | HUT73792A (en) |
| IL (1) | IL114642A (en) |
| MY (1) | MY114687A (en) |
| NO (1) | NO309925B1 (en) |
| NZ (1) | NZ272611A (en) |
| PE (1) | PE5196A1 (en) |
| PL (1) | PL181437B1 (en) |
| PT (1) | PT716852E (en) |
| RU (1) | RU2150276C1 (en) |
| SI (1) | SI0716852T1 (en) |
| TR (1) | TR199501165A1 (en) |
| TW (1) | TW492875B (en) |
| UA (1) | UA34479C2 (en) |
| YU (1) | YU60795A (en) |
| ZA (1) | ZA956411B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU227821B1 (en) * | 1996-02-29 | 2012-03-28 | Astellas Pharma Inc | Tablets containing beta-lactam antibiotic and process for producing the same |
| AU1150799A (en) * | 1997-10-10 | 1999-05-03 | Yamanouchi Europe B.V. | Oral compositions containing a cephalosporin antibiotic |
| JP5524435B2 (en) * | 1998-12-01 | 2014-06-18 | ドクター レディーズ ラボラトリーズ リミティド | Novel pharmaceutical composition and process for its preparation |
| DE10005017A1 (en) * | 2000-02-04 | 2001-08-09 | Cognis Deutschland Gmbh | Perfume tablets |
| AP2003002900A0 (en) * | 2001-05-01 | 2003-12-31 | Pfizer Prod Inc | Method for manufacturing a low dose pharmaceutical composition |
| US7151432B2 (en) | 2001-09-19 | 2006-12-19 | Immersion Corporation | Circuit and method for a switch matrix and switch sensing |
| GB0209265D0 (en) | 2002-04-23 | 2002-06-05 | Novartis Ag | Organic compounds |
| TW200404550A (en) * | 2002-07-08 | 2004-04-01 | Sankyo Co | Cepharospolin formulation for oral use |
| JP4526247B2 (en) * | 2002-07-08 | 2010-08-18 | 第一三共株式会社 | Oral cephalosporins |
| US8968768B2 (en) * | 2004-03-29 | 2015-03-03 | Wyeth Llc | Phytosterol nutritional supplements |
| TR201909238T4 (en) * | 2004-03-29 | 2019-07-22 | Wyeth Llc | Multi-vitamin and mineral nutritional supplements. |
| US9198862B2 (en) | 2005-07-22 | 2015-12-01 | Rubicon Research Private Limited | Dispersible tablet composition |
| WO2007018192A1 (en) | 2005-08-10 | 2007-02-15 | Shionogi & Co., Ltd. | Orally disintegratable tablet |
| CN102579455B (en) * | 2012-03-19 | 2014-02-19 | 迪沙药业集团有限公司 | Stable cefaclor chewing composition |
| US10874615B2 (en) * | 2015-09-14 | 2020-12-29 | Merck Patent Gmbh | Formulation having controlled, delayed release of active ingredient |
| CN113750066B (en) * | 2021-10-12 | 2022-12-02 | 上海金城素智药业有限公司 | Cefaclor preparation with clinical advantages and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2259646C2 (en) * | 1972-12-06 | 1984-11-22 | Hoechst Ag, 6230 Frankfurt | High-dose tablets of cephalosporin derivatives, as well as processes for their manufacture |
| US3925372A (en) | 1973-02-23 | 1975-12-09 | Lilly Co Eli | Alpha-aminoacyl-3-halo cephalosporins |
| YU36970B (en) | 1973-02-23 | 1984-08-31 | Lilly Co Eli | Process for obtaining 7-(amino)-acylamido-3-halocephalosporins |
| US4143129A (en) * | 1975-10-11 | 1979-03-06 | Lilly Industries Limited | Cephalexin tablets |
| GB2066662B (en) * | 1979-12-21 | 1984-02-15 | Glaxo Group Ltd | Cephalexin powder compositions containing silicon dioxide |
| NZ198241A (en) * | 1980-09-27 | 1983-12-16 | Beecham Group Ltd | Tablet containing amoxycillin and potassium clavulanate |
| JPS601128A (en) * | 1983-06-15 | 1985-01-07 | Shionogi & Co Ltd | Long-acting cefaclor preparation |
| EP0181966A1 (en) * | 1984-11-13 | 1986-05-28 | Gist-Brocades N.V. | Compression-coated dispersible tablets |
| DE3887179T2 (en) * | 1987-03-02 | 1994-06-16 | Brocades Pharma Bv | Pharmaceutical composition, pharmaceutical granules and process for their preparation. |
| ES2047540T3 (en) * | 1987-11-30 | 1994-03-01 | Brocades Pharma Bv | PHARMACEUTICAL COMPOUND AND PROCEDURE FOR ITS PREPARATION. |
| DE3838431A1 (en) * | 1988-11-12 | 1990-05-17 | Bayer Ag | IBUPROFEN SHOWER PREPARATIONS |
| GB9009473D0 (en) * | 1990-04-27 | 1990-06-20 | Beecham Group Plc | Pharmaceutical formulation |
| FR2669221B1 (en) * | 1990-11-15 | 1993-01-15 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION BY DIRECT COMPRESSION OF TABLETS OF CEPHALOSPORANIC ACID DERIVATIVES. |
| ATE113202T1 (en) * | 1990-11-29 | 1994-11-15 | Wei Ming Pharmaceutical Mfg Co | AUXILIARY BEAM FOR DIRECT PRESSING. |
| RU2106861C1 (en) * | 1991-01-30 | 1998-03-20 | Дзе Веллкам Фаундейшн Лимитед | Water-dispersible tablets, method for theri preparing, and granules and dispersing agent for their production |
| GB9109862D0 (en) * | 1991-05-08 | 1991-07-03 | Beecham Lab Sa | Pharmaceutical formulations |
| IT1251999B (en) * | 1991-11-11 | 1995-05-27 | Opos Biochimica Srl | CRYSTALLINE SHAPE OF A CEPHALOSPORIN ANTIBIOTIC |
| DK0642344T3 (en) * | 1992-04-30 | 1997-07-07 | Schering Corp | Stable dry powder of hydrated cephalosporin for oral suspension formulation. |
| US5503846A (en) * | 1993-03-17 | 1996-04-02 | Cima Labs, Inc. | Base coated acid particles and effervescent formulation incorporating same |
| US5506248A (en) * | 1993-08-02 | 1996-04-09 | Bristol-Myers Squibb Company | Pharmaceutical compositions having good dissolution properties |
| US5616344A (en) * | 1994-06-14 | 1997-04-01 | Fuisz Technologies Ltd. | Apparatus and process for strengthening low density compression dosage units and product therefrom |
| US5622719A (en) * | 1993-09-10 | 1997-04-22 | Fuisz Technologies Ltd. | Process and apparatus for making rapidly dissolving dosage units and product therefrom |
| US5895664A (en) * | 1993-09-10 | 1999-04-20 | Fuisz Technologies Ltd. | Process for forming quickly dispersing comestible unit and product therefrom |
| US5595761A (en) * | 1994-01-27 | 1997-01-21 | The Board Of Regents Of The University Of Oklahoma | Particulate support matrix for making a rapidly dissolving tablet |
| US5605889A (en) * | 1994-04-29 | 1997-02-25 | Pfizer Inc. | Method of administering azithromycin |
-
1994
- 1994-12-13 ES ES09402530A patent/ES2079327B1/en not_active Expired - Lifetime
-
1995
- 1995-07-17 PT PT95304976T patent/PT716852E/en unknown
- 1995-07-17 DE DE0716852T patent/DE716852T1/en active Pending
- 1995-07-17 ES ES95304976T patent/ES2091738T3/en not_active Expired - Lifetime
- 1995-07-17 DE DE69521275T patent/DE69521275T2/en not_active Expired - Fee Related
- 1995-07-17 EP EP00126490A patent/EP1086689A3/en not_active Withdrawn
- 1995-07-17 EP EP00126491A patent/EP1086690A3/en not_active Withdrawn
- 1995-07-17 EP EP95304976A patent/EP0716852B1/en not_active Expired - Lifetime
- 1995-07-17 DK DK95304976T patent/DK0716852T3/en active
- 1995-07-17 SI SI9530516T patent/SI0716852T1/en unknown
- 1995-07-17 AT AT95304976T patent/ATE201984T1/en not_active IP Right Cessation
- 1995-07-18 IL IL11464295A patent/IL114642A/en not_active IP Right Cessation
- 1995-07-18 HU HU9502160A patent/HUT73792A/en unknown
- 1995-07-18 PE PE1995274137A patent/PE5196A1/en not_active Application Discontinuation
- 1995-07-19 NZ NZ272611A patent/NZ272611A/en unknown
- 1995-07-19 CO CO95032103A patent/CO4410176A1/en unknown
- 1995-07-20 AU AU25094/95A patent/AU702585B2/en not_active Ceased
- 1995-08-01 ZA ZA956411A patent/ZA956411B/en unknown
- 1995-08-02 PL PL95309863A patent/PL181437B1/en not_active IP Right Cessation
- 1995-08-03 CZ CZ19951998A patent/CZ287248B6/en not_active IP Right Cessation
- 1995-08-08 KR KR1019950024359A patent/KR100350565B1/en not_active IP Right Cessation
- 1995-08-14 NO NO953192A patent/NO309925B1/en unknown
- 1995-08-17 FI FI953887A patent/FI953887A/en not_active IP Right Cessation
- 1995-08-18 RU RU95113968/14A patent/RU2150276C1/en not_active IP Right Cessation
- 1995-09-02 TW TW084109243A patent/TW492875B/en not_active IP Right Cessation
- 1995-09-18 CA CA002158511A patent/CA2158511A1/en not_active Abandoned
- 1995-09-18 YU YU60795A patent/YU60795A/en unknown
- 1995-09-25 TR TR95/01165A patent/TR199501165A1/en unknown
- 1995-10-13 US US08/542,853 patent/US5861141A/en not_active Expired - Fee Related
- 1995-10-26 BR BR9504573A patent/BR9504573A/en not_active IP Right Cessation
- 1995-11-17 MY MYPI95003503A patent/MY114687A/en unknown
- 1995-12-12 UA UA95125252A patent/UA34479C2/en unknown
- 1995-12-12 JP JP7322647A patent/JPH08208484A/en active Pending
- 1995-12-13 CN CNB951213199A patent/CN1136852C/en not_active Expired - Fee Related
-
1996
- 1996-11-30 GR GR960300062T patent/GR960300062T1/en unknown
-
1998
- 1998-12-17 HK HK98113978A patent/HK1012574A1/en not_active IP Right Cessation
-
2001
- 2001-08-31 GR GR20010401363T patent/GR3036503T3/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |