CA1282331C - Pharmaceutical composition containing cefuroxime axetil - Google Patents
Pharmaceutical composition containing cefuroxime axetilInfo
- Publication number
- CA1282331C CA1282331C CA000519257A CA519257A CA1282331C CA 1282331 C CA1282331 C CA 1282331C CA 000519257 A CA000519257 A CA 000519257A CA 519257 A CA519257 A CA 519257A CA 1282331 C CA1282331 C CA 1282331C
- Authority
- CA
- Canada
- Prior art keywords
- tablet
- film
- rupture
- film coat
- pharmaceutical
- 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.)
- Expired - Lifetime
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Classifications
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
ABSTRACT
Pharmaceutical Composition A pharmaceutical tablet is described which comprises a tablet core containing the antibiotic cefuroxime axetil and a film coat which serves to mask the bitter taste of the cefuroxime axetil upon oral administration. It has been found that conventional film-coated tablets reduce the bioavailability of cefuroxime axetil and the invention overcomes this by control of the film coat rupture time and use of a tablet core which disintegrates immediately following rupture of the film coat.
Pharmaceutical Composition A pharmaceutical tablet is described which comprises a tablet core containing the antibiotic cefuroxime axetil and a film coat which serves to mask the bitter taste of the cefuroxime axetil upon oral administration. It has been found that conventional film-coated tablets reduce the bioavailability of cefuroxime axetil and the invention overcomes this by control of the film coat rupture time and use of a tablet core which disintegrates immediately following rupture of the film coat.
Description
33~
Pharmaceutical Composition This invention is concerned with pharmaceutical compositions containing the l-acetoxyethyl ester of cefuroxime which has the approved name 'cefuroxime axetil'.
Cefuroxime, as disclosed in British Patent Specification No.1453049, is a valuable broad spectrum antibiotic characterised by high activity against a wide range of gram-positive and gram-negative micro-organisms, this property being enhanced by the very high stability of the compound to ~-lactamases produced by a range of gram-negative microorganisms. Cefuroxime and its salts are principally of value as injectable antibiotics since they are poorly absorbed from the gastro-intestinal tract.
We have found that esterification of the carboxyl group of cefuroxime as a l-acetoxyethyl ester to give cefuroxime axetil improves the effectiveness on oral administration as disclosed in British Patent Specification No. 1571683. The presence of the 1-acetoxyethyl esterifying group results in significant absorption of the compound from the gastro-intestinal tract, whereupon the esterifying group is hydrolysed by enzymes present in, for example, serum and body tissues to yield the antibiotically active acid.
It is particularly advantageou~ to employ ce~uroxime axetil in an amorphous form as di~closed in~British Patent Speciication No. 2127401.
Cefuroxime axetil has therefore extended the valuable therapeutic potential of cefuroxime by making available a form of the antibiotic which may be admini-stered orally rather than by injection only.
A convenient means of presenting cefuroxime axetil for oral administration is as a tablet. However, 33~
cefuroxime axetil has an extremely bitter taste which is long lasting and which cannot be adequately masked by the ad~ition of sweeteners and flavours. In order to provide tablets of cefuroxime axetil which do not have the significant disadvantage of th~ bitter taste, it has been found necessary to use tablets which are film coated.
~ hen tablets of cefuroxime axetil were film coated in conventional manner, it was found that they complied with the standard disintegration tests (with discs) specified in the British and United States Pharmacopeias rBri~ish Pharmacopeia (1980) XIIA, AII3; United States Pharmacopeia XXI, p 1243]
However, it was found that when such film-coated tablets were administered to human volunteers low levels of absorption of cefuroxime axetil were obtained from the gastro-intestinal tract.
We have now discovered that cefuroxime axetil once in contact with aqueous media can form a gelatinous mass. This gelling effect is temperature dependent but does occur at temperatures of about 37C, i.e.
at the physiological temperatures at which the disinte-gration of orally administered tablets takes place.
We have further found that, with the relatively slow permeation of moisture though the film coat to the core which occurs upon administration of tablets of cefuroxime axetil provided with conventional film coats, the cefuroxime axetil present in the tablet core may gelO This gel formation leads to poor disinte-gration of the tablet core and hence to poor dissolution of cefuroxime axetil; thus the absorption from the gastro-intestinal tract is greatly reduced. This occurs with both the crystalline and amorphous forms of cefuroxime axetil referred to above.
We have further discovered that the problem of gelling may be overcome and the high bioavailability of cefuroxime axetil maintained by prepQring a film 33~
coated tablet in which, upon contact with gastro-intestinal fluid, the film coating ruptures very rapidly and the core then immediately disintegrates thus allowing dispersion and dissolution of the cefuroxime axetil in the gastro-intestinal tract before any gelling effect can occur.
According to one feature of the invention there is thus provided a pharmaceutical tablet for oral administration which comprises a tablet core containing an effective amount of cefuroxime axetil as active ingredient and a film coat which serves to mask the bitter taste of cefuroxime axetil upon oral administration, the film coat having a rupture time of less than 40 seconds, preferably less-than 25 seconds and more preferably less than 15 seconds when measured by the rupture test as herein defined and the tablet core disintegrating immediately following rupture of the film coat in the said rupture test.
In the rupture test as herein defined the film-coated tablet is placed in a beaker of still hydrochloricacid (0.07M) at 37C. The rupture time is measured as the time which elapses before the core of the tablet first becomes visible to ~he naked eye through the ruptured film coat. Figs. 1 to 8 of the accompanying drawings illustrate the rupture of the film coat followed by the immediate disintegration o the core of a film coated tablet according to the invention having a rupture time of less than about 5 seconds.
It has been found useful to define the film coats of tablets according to the invention in terms of mean rupture times for representative batches of film coated tablets.
Thus according to a further feature of the invention there is provided a pharmaceutical tablet for oral administration which comprises a tablet core containing an effective amount of cefuroxime axetil as active ingredient and a film coat which 3~
~ 4 --serves to mask the bitter taste of cefuroxime axetil upon oral administration, the film coat having a mean rupture time for a batch of 20 tablets of less than 35 seconds, preferably less than 25 seconds and more preferably less than 15 seconds, when measured by the rupture test as herein defined and the tablet core disintegrating immediately following ru~ture of the film coa~ in the said rupture test.
According to a still further feature of the invention there is Provided a pharmaceutical tablet for oral administration which comprises a tablet core containing an effective amount of cefuroxime axetil as active ingredient and a film coat which serves to mask the bitter taste of cefuroxime axetil upon oral administration, the film coat having a mean rupture time for a batch of 100 tablets of less than 30 seconds, preferably less than 20 seconds and more preferably less than 12 seconds, when measured by the rupture test as herein defined and the tablet core distintegrating immediately following rupture of the film coat in the said rupture test.
In order to obtain film coats which rupture rapidly in accordance with the present invention, it is preferred to apply a relatively thin coat of the film-forming composition on to the tablet core.
In order to obtain tablet cores which disintegrate immediately following rupture of the film coat in the rupture test, it is convenient to incorporate into the core an effective amount of a disintegrant.
According to a yet still further feature of the invention, there is thus provided a process for the preparation of a film coated tablet according to the invention as hereinbefore defined in which a cefuroxime axetil-containing tablet core is coated with a film-forming composition, the said film-forming composition being applied in an amount whereby the rupture time of the film coated tablet is in accordance 33~
with the invention as hereinbefore defined and the tablet core containing an effective amount of a disin-tegrant whereby it disintegrates immediately following rupture of the film coat in the rupture test as herein defined.
The film-forming composition is preferably an aqueous solution of a water-soluble film-forming agent but solutions of film-forming agents in other solvents can if desired be used. The film-forming agent may for example be a polymeric substance with suitable film-forming properties, such polymeric substances preferably have a number average molecular weight of not more than 15,000. Film-forming agents which are useful include hydroxyalkylcelluloses (e.g.
hydroxypropyl cellulose, or hydroxypropylmethylcelluloses such as hydroxypropylmethylcellulose 5 or 6 or hydroxy-propylmethylcellulose 15) and other cellulose-based polymers (e.g. hydroxypropoxy and methyl ethers on cellulose substrates, such as Sepifilm~002) which . 20 may be used in both aqueous and non-aqueous solvent systems, alkylcelluloses such as methyl- or ethylcellu-lose, which may be used in aqueous systems; polyvinyl-pyrrolidone (aqueous or non-aqueous solvents); polyvinyl-acetate phthalate, shellac and zein (all of which require non-aqueous solvent sys~ems); and polymer systems based on methacrylic acid and esters thereof, such as Eudragit E and Eudragit E30D. Hydroxypropylmethyl-cellulose 5 or 6 is particularly preferred.
The film-forming compositions may also conveniently contain excipients such as plasticisers (e.g. propylene glycol, polyethylene glycol, glycerol and sorbitol, all of which can be used in aqueous sytems; glycerol triacetate, diethyl phthalate and ~riethyl citrate, all of which can be used in non~aqueous systems), preservatives (e.g. methyl and propyl hydroxybenzoates) and colouring aqents (e.g. titanium dioxide pigments with lake colours and iron oxide pigments~. The incorporation of such excipients in general reduces 1~4de Irl~r~
33~L
the tensile strength of film coats formed using the film-forming compositions and this has the useful effect of also reducing the rupture time o~ the film coats, thereby enabling film coats of greater thickness to be used while stil providing the rupture times required by the present invention. The weight o~
the film coats applied to tablets according ~o the invention is preferably in the range lmg per 10 to 70mm2, and more preferably lmg per 12 to 35mm2, of the surface area of the tablet.
The tablet core may be ormulated such that it disintegrates immediately following rupture of the film coat, using methods well known in the art.
This may generally be achieved by using disintegrants.
Disintegrants which may be used to provide the desired disintegration properties include for example potato starch, sodium starch glycolate, defatted soybean extract, cross linked polyvinyl-pyrrolidone and cross linked carboxymethylcelluloses, with sodium carboxymethyl celluloses (croscarmellose sodium) being particularly preferred. The tablet cores conveniently comprise from 2 to 15% by weight o~ disintegrant, preferably from 4 to 10% by weight.
Examples of other pharma~eutically acceptable excipients which may be present in the core of the ilm coated tablets of the invention are binding agents, eOg. pregelatinised maize starch, polyvinyl-pyrrolidone and hydroxypropylmethylcelluloses such as hydro~ypropylmethylcellulose 5 or 6 fillers, e.g. starch, lactose, micro-crystalline cellulose and calcium phosphates; lubricants and ~low aids, e.g. hydrogenated vegetable oils, talc and silica;
and wetting agents e.g. sodium lauryl sulphate.
The tablet cores may conveniently be prepared by blending together the active ingredient and the excipients, followed by compaction (for example roller compaction) to give sheets or direct compression to give tablet slugs. The compacted sheets or tablet 3~
slugs may then be broken down to produce granules.
Granulation may be achieved by, for example, passing the tablet slugs or compacted sheets through a sieve or an oscillating granulator. The granules may if desired be blended with additional excipients, for example disintegrants and flow aids, before being compressed into tablet cores using for example conven-tional punches, to give the desired core weight.
The tablet core may be film coated with the film-forming composition using aqueous or solvent methods well known in the art. The tablets may be coated in conventional coating machines such as the Manesty Accelacota, the Driam coating machine or the Hi-coater. When, for example, using a 24" Manesty Accelacota with a load of 44,000 tablets as described in Example 1 below the rate of application of the film-forming composition to the tablet core will conveniently be in the range 10 to 40ml/min, preferably about 20 to 30ml/min, in order to provide a preferred weight of film coat as referred to above. The temperature of the incoming air will conveniently be controlled to 40 to 70C, preferably to 50 to 55C. The humidity of the incoming air will conveniently be up to 30~
relative humidity. It will be understood by those skilled in the art that the coating operation is controlled within the above parameters to avoid overwetting with consequent local disintegration and surface pitting and overdrying during spraying with consequent poor coverage from reduced adhesion of the dry droplets.
It will be appreciated that modification of the Manesty Accelacota equipment, e.g. by changing the baffle arrangement, or the use of different equipment may change the optimum conditions for production of the film coats.
The coated tablets may be dried, for example by leaving them in the coating machine after coating or by transferring them to a drying oven or hot air ~2~q~,~
- ~ -drier.
The cefuroxime axetil incorporated into the tablet cores will preferably be in amorphous form, as described in British Patent Specification No 2127401.
The tablets according to the invention will preferably contain from 30-95% more preerably from 50-85~ by weight of cefuroxime axetil. Each tablet core conveniently contains 50-500 mg of cefuroxime as cefuroxime axetil. Doses employed for human treatment will typically be in the range 100-3000mg cefuroxime per day, e.g. 250 to 2000mg cefuroxime per day for adults and 125 to 1000mg cefuroxime per day for children, although the precise dose will depend on, inter alia, the frequency of administration.
The following Examples illustrate the invention.
The cefuroxime axetil used in the Examples was highly pure and amorphous material prepared as described in British Patent Specification No. 2127401.
Opaspray pigments are based on titanium dioxide with lake colours and were supplied by Colorcon Ltd of Orpington, Kent, United Kingdom.
All percentages herein are by weight unless otherwise specified:-Example 1 Tablet Core mg / tablet -Cefuroxime axetil equivalent to 125.00mg cefuroxime 30 Miarocrystalline celIulose 47.51 Croscarmellose sodium type A 20.00 Sodium lauryl sulphate 2.25 Silicon dioxide 0.63 Hydrogenated vegetable oil 4.25 All the ingredients with the exception of the silicon dioxide and half of the croscarmellose soAium were 3~
g blended together and compacted using a roller compactor.
The compacted material was comminuted using an oscilla-ting granulator and the resultant granules were blended with the remaining excipients and then compressed using a conventional tabletting machine.
Film-forming composition ~ w/v Hydroxypropylmethylcellulose 5 or 6 10.00 10 Propylene glycol 0.60 Methyl hydroxybenzoate 0.10 Opaspray~white m-1-7120 7.00 Propyl hydroxybenzoate 0.08 Distilled water to 100%.
The film-forming composition was prepared by dispersing the ingredients in distilled water. It was then applied to approximately 44,000 tablets in a 24" Manesty Accelacota with a target coat weight of approximately lmg per 27mm2 on the tablets. The rate of application of the film-forming composition was maintained in the range 20 to 30 ml/min and the temperature of the incoming air was maintained in the range 50 to 55C with the humidi~y of the incoming air not being permitted to exceed 30%. Adjustments of the rate of application and temperature of the incoming air within the above ranges were made as necessary during the course of the spraying operation to avoid either overwetting or overdrying as previously described.
Mean film coat rupture time ~100 tablets3 = 4.9 seconds.
~rade ~a~
~X~
Example 2 Tablet Core mq / tablet Ceiuroxime axetil equivalent to 250.00mg cefuroxime Microcrystalline cellulose 95.02 Croscarmellose sodium type ~ 40.00 Sodium lauryl sulphate 4.50 10 Silicon dioxide 1.25 Hydrogenated vegetable oil 8.5 All the ingredients with the exception of the silicon dioxide and half of ~he croscarmellose sodium were lS blended together and compacted using a roller compactor.
The compacted material was comminuted using an oscillating granulator and the resultant granule was blended with the remaining excipients and then compressed using a conventional tabletting machine.
Film-formin~ co~position % w/v Hydroxypropylmethylcellulose 5 or 6 10.00 Propylene glycol 0.60 25 Methyl hydroxybenzoate 0.10 Opaspray blue M-1-4395B 12.00 Propyl hydroxybenzoate 0.08 Distilled water to 100%.
The ~ilm-forming composition was prepared by dispersing the ingredients in distilled water. It was then applied to approximately 22,000 tablets in a 24" Manesty Accelacota with a target coat weight of approximately lmg per 32mm2 on the tablets under conditions as described in Example 1.
Mean film coat rupture time tlOO tablets) = 3.5 seconds.
~ ' ~ ~, '.' ' ~233~L
Example 3 Tablet Core mg / tablet Ceuroxime axetil equivalent to250.00mg cefuroxime Microcrystalline cellulose 94.55 Croscarmellose sodium type A 15.50 Sodium lauryl sulphate 4.50 10 Silicon ~ioxide 1.25 Hydrogenated vegetable oil 8.50 All the ingredients except the silicon dioxide are blended together and compacted using a roller compactor.
The compacted material is comminuted using an oscilla-ting granulator and the resultant granule is blended with the silicon dioxide and compressed using a conven-tional tabletting machine.
Film-forminq composition % w/v Hydroxypropylmethylcellulose 5 or 6 10.00 Propylene glycol 0.60 Methyl hydroxybenxoate 0.10 25 Propyl hydroxy~enzoate 0.08 Opaspray blue M-1-4395B 12.00 Distilled water to 100%.
The film coat is prepared by dispersing the ingredients in distilled water. Tablets are coated using the film coating technique described in Examples 1 and 2 with a target coat weight of approximately lmg per 32mm2.
33~
Example 4 Tablet Core mg / tablet Cefuroxime axetil equivalent to 500.00mg cefuroxime 5 Microcrystalline cellulose 190.04 Croscarmellose sodium type A 80.00 Sodium lauryl sulphate 9.00 Silicon dioxide 2.50 Hydrogenated vegetable oil 17.00 All the ingredients with the exception of the silicon dioxide and half of the croscarmellose sodium were blended together and compacted using a roller compactor.
The compacted material was comminuted using an oscilla-ting granulator and the resultant granule was blended with the remaining excipients and then compressed using a conventional tabletting machine.
Film-forminq composition % w/v Hydroxypropylmethylcellulose 5 or 6 10.00 Propylene glycol 0.60 Methyl hydroxybenzoate 0.10 Opaspray blue M-1-4399 12.00 25 Propyl hydroxybenzoate 0.08 Distilled water to 100~.
The film-forming composition was prepared by dispersing the ingredients in distilled water. It was then applied to approximately 11,000 tablets in a 24"
Manesty Accelacota with a target c~at weight of approximately lmg per 27mm on the tablets under conditions as described in Example 1.
Mean film coat rupture time (100 tablets) -2.5 seconds.
Pharmaceutical Composition This invention is concerned with pharmaceutical compositions containing the l-acetoxyethyl ester of cefuroxime which has the approved name 'cefuroxime axetil'.
Cefuroxime, as disclosed in British Patent Specification No.1453049, is a valuable broad spectrum antibiotic characterised by high activity against a wide range of gram-positive and gram-negative micro-organisms, this property being enhanced by the very high stability of the compound to ~-lactamases produced by a range of gram-negative microorganisms. Cefuroxime and its salts are principally of value as injectable antibiotics since they are poorly absorbed from the gastro-intestinal tract.
We have found that esterification of the carboxyl group of cefuroxime as a l-acetoxyethyl ester to give cefuroxime axetil improves the effectiveness on oral administration as disclosed in British Patent Specification No. 1571683. The presence of the 1-acetoxyethyl esterifying group results in significant absorption of the compound from the gastro-intestinal tract, whereupon the esterifying group is hydrolysed by enzymes present in, for example, serum and body tissues to yield the antibiotically active acid.
It is particularly advantageou~ to employ ce~uroxime axetil in an amorphous form as di~closed in~British Patent Speciication No. 2127401.
Cefuroxime axetil has therefore extended the valuable therapeutic potential of cefuroxime by making available a form of the antibiotic which may be admini-stered orally rather than by injection only.
A convenient means of presenting cefuroxime axetil for oral administration is as a tablet. However, 33~
cefuroxime axetil has an extremely bitter taste which is long lasting and which cannot be adequately masked by the ad~ition of sweeteners and flavours. In order to provide tablets of cefuroxime axetil which do not have the significant disadvantage of th~ bitter taste, it has been found necessary to use tablets which are film coated.
~ hen tablets of cefuroxime axetil were film coated in conventional manner, it was found that they complied with the standard disintegration tests (with discs) specified in the British and United States Pharmacopeias rBri~ish Pharmacopeia (1980) XIIA, AII3; United States Pharmacopeia XXI, p 1243]
However, it was found that when such film-coated tablets were administered to human volunteers low levels of absorption of cefuroxime axetil were obtained from the gastro-intestinal tract.
We have now discovered that cefuroxime axetil once in contact with aqueous media can form a gelatinous mass. This gelling effect is temperature dependent but does occur at temperatures of about 37C, i.e.
at the physiological temperatures at which the disinte-gration of orally administered tablets takes place.
We have further found that, with the relatively slow permeation of moisture though the film coat to the core which occurs upon administration of tablets of cefuroxime axetil provided with conventional film coats, the cefuroxime axetil present in the tablet core may gelO This gel formation leads to poor disinte-gration of the tablet core and hence to poor dissolution of cefuroxime axetil; thus the absorption from the gastro-intestinal tract is greatly reduced. This occurs with both the crystalline and amorphous forms of cefuroxime axetil referred to above.
We have further discovered that the problem of gelling may be overcome and the high bioavailability of cefuroxime axetil maintained by prepQring a film 33~
coated tablet in which, upon contact with gastro-intestinal fluid, the film coating ruptures very rapidly and the core then immediately disintegrates thus allowing dispersion and dissolution of the cefuroxime axetil in the gastro-intestinal tract before any gelling effect can occur.
According to one feature of the invention there is thus provided a pharmaceutical tablet for oral administration which comprises a tablet core containing an effective amount of cefuroxime axetil as active ingredient and a film coat which serves to mask the bitter taste of cefuroxime axetil upon oral administration, the film coat having a rupture time of less than 40 seconds, preferably less-than 25 seconds and more preferably less than 15 seconds when measured by the rupture test as herein defined and the tablet core disintegrating immediately following rupture of the film coat in the said rupture test.
In the rupture test as herein defined the film-coated tablet is placed in a beaker of still hydrochloricacid (0.07M) at 37C. The rupture time is measured as the time which elapses before the core of the tablet first becomes visible to ~he naked eye through the ruptured film coat. Figs. 1 to 8 of the accompanying drawings illustrate the rupture of the film coat followed by the immediate disintegration o the core of a film coated tablet according to the invention having a rupture time of less than about 5 seconds.
It has been found useful to define the film coats of tablets according to the invention in terms of mean rupture times for representative batches of film coated tablets.
Thus according to a further feature of the invention there is provided a pharmaceutical tablet for oral administration which comprises a tablet core containing an effective amount of cefuroxime axetil as active ingredient and a film coat which 3~
~ 4 --serves to mask the bitter taste of cefuroxime axetil upon oral administration, the film coat having a mean rupture time for a batch of 20 tablets of less than 35 seconds, preferably less than 25 seconds and more preferably less than 15 seconds, when measured by the rupture test as herein defined and the tablet core disintegrating immediately following ru~ture of the film coa~ in the said rupture test.
According to a still further feature of the invention there is Provided a pharmaceutical tablet for oral administration which comprises a tablet core containing an effective amount of cefuroxime axetil as active ingredient and a film coat which serves to mask the bitter taste of cefuroxime axetil upon oral administration, the film coat having a mean rupture time for a batch of 100 tablets of less than 30 seconds, preferably less than 20 seconds and more preferably less than 12 seconds, when measured by the rupture test as herein defined and the tablet core distintegrating immediately following rupture of the film coat in the said rupture test.
In order to obtain film coats which rupture rapidly in accordance with the present invention, it is preferred to apply a relatively thin coat of the film-forming composition on to the tablet core.
In order to obtain tablet cores which disintegrate immediately following rupture of the film coat in the rupture test, it is convenient to incorporate into the core an effective amount of a disintegrant.
According to a yet still further feature of the invention, there is thus provided a process for the preparation of a film coated tablet according to the invention as hereinbefore defined in which a cefuroxime axetil-containing tablet core is coated with a film-forming composition, the said film-forming composition being applied in an amount whereby the rupture time of the film coated tablet is in accordance 33~
with the invention as hereinbefore defined and the tablet core containing an effective amount of a disin-tegrant whereby it disintegrates immediately following rupture of the film coat in the rupture test as herein defined.
The film-forming composition is preferably an aqueous solution of a water-soluble film-forming agent but solutions of film-forming agents in other solvents can if desired be used. The film-forming agent may for example be a polymeric substance with suitable film-forming properties, such polymeric substances preferably have a number average molecular weight of not more than 15,000. Film-forming agents which are useful include hydroxyalkylcelluloses (e.g.
hydroxypropyl cellulose, or hydroxypropylmethylcelluloses such as hydroxypropylmethylcellulose 5 or 6 or hydroxy-propylmethylcellulose 15) and other cellulose-based polymers (e.g. hydroxypropoxy and methyl ethers on cellulose substrates, such as Sepifilm~002) which . 20 may be used in both aqueous and non-aqueous solvent systems, alkylcelluloses such as methyl- or ethylcellu-lose, which may be used in aqueous systems; polyvinyl-pyrrolidone (aqueous or non-aqueous solvents); polyvinyl-acetate phthalate, shellac and zein (all of which require non-aqueous solvent sys~ems); and polymer systems based on methacrylic acid and esters thereof, such as Eudragit E and Eudragit E30D. Hydroxypropylmethyl-cellulose 5 or 6 is particularly preferred.
The film-forming compositions may also conveniently contain excipients such as plasticisers (e.g. propylene glycol, polyethylene glycol, glycerol and sorbitol, all of which can be used in aqueous sytems; glycerol triacetate, diethyl phthalate and ~riethyl citrate, all of which can be used in non~aqueous systems), preservatives (e.g. methyl and propyl hydroxybenzoates) and colouring aqents (e.g. titanium dioxide pigments with lake colours and iron oxide pigments~. The incorporation of such excipients in general reduces 1~4de Irl~r~
33~L
the tensile strength of film coats formed using the film-forming compositions and this has the useful effect of also reducing the rupture time o~ the film coats, thereby enabling film coats of greater thickness to be used while stil providing the rupture times required by the present invention. The weight o~
the film coats applied to tablets according ~o the invention is preferably in the range lmg per 10 to 70mm2, and more preferably lmg per 12 to 35mm2, of the surface area of the tablet.
The tablet core may be ormulated such that it disintegrates immediately following rupture of the film coat, using methods well known in the art.
This may generally be achieved by using disintegrants.
Disintegrants which may be used to provide the desired disintegration properties include for example potato starch, sodium starch glycolate, defatted soybean extract, cross linked polyvinyl-pyrrolidone and cross linked carboxymethylcelluloses, with sodium carboxymethyl celluloses (croscarmellose sodium) being particularly preferred. The tablet cores conveniently comprise from 2 to 15% by weight o~ disintegrant, preferably from 4 to 10% by weight.
Examples of other pharma~eutically acceptable excipients which may be present in the core of the ilm coated tablets of the invention are binding agents, eOg. pregelatinised maize starch, polyvinyl-pyrrolidone and hydroxypropylmethylcelluloses such as hydro~ypropylmethylcellulose 5 or 6 fillers, e.g. starch, lactose, micro-crystalline cellulose and calcium phosphates; lubricants and ~low aids, e.g. hydrogenated vegetable oils, talc and silica;
and wetting agents e.g. sodium lauryl sulphate.
The tablet cores may conveniently be prepared by blending together the active ingredient and the excipients, followed by compaction (for example roller compaction) to give sheets or direct compression to give tablet slugs. The compacted sheets or tablet 3~
slugs may then be broken down to produce granules.
Granulation may be achieved by, for example, passing the tablet slugs or compacted sheets through a sieve or an oscillating granulator. The granules may if desired be blended with additional excipients, for example disintegrants and flow aids, before being compressed into tablet cores using for example conven-tional punches, to give the desired core weight.
The tablet core may be film coated with the film-forming composition using aqueous or solvent methods well known in the art. The tablets may be coated in conventional coating machines such as the Manesty Accelacota, the Driam coating machine or the Hi-coater. When, for example, using a 24" Manesty Accelacota with a load of 44,000 tablets as described in Example 1 below the rate of application of the film-forming composition to the tablet core will conveniently be in the range 10 to 40ml/min, preferably about 20 to 30ml/min, in order to provide a preferred weight of film coat as referred to above. The temperature of the incoming air will conveniently be controlled to 40 to 70C, preferably to 50 to 55C. The humidity of the incoming air will conveniently be up to 30~
relative humidity. It will be understood by those skilled in the art that the coating operation is controlled within the above parameters to avoid overwetting with consequent local disintegration and surface pitting and overdrying during spraying with consequent poor coverage from reduced adhesion of the dry droplets.
It will be appreciated that modification of the Manesty Accelacota equipment, e.g. by changing the baffle arrangement, or the use of different equipment may change the optimum conditions for production of the film coats.
The coated tablets may be dried, for example by leaving them in the coating machine after coating or by transferring them to a drying oven or hot air ~2~q~,~
- ~ -drier.
The cefuroxime axetil incorporated into the tablet cores will preferably be in amorphous form, as described in British Patent Specification No 2127401.
The tablets according to the invention will preferably contain from 30-95% more preerably from 50-85~ by weight of cefuroxime axetil. Each tablet core conveniently contains 50-500 mg of cefuroxime as cefuroxime axetil. Doses employed for human treatment will typically be in the range 100-3000mg cefuroxime per day, e.g. 250 to 2000mg cefuroxime per day for adults and 125 to 1000mg cefuroxime per day for children, although the precise dose will depend on, inter alia, the frequency of administration.
The following Examples illustrate the invention.
The cefuroxime axetil used in the Examples was highly pure and amorphous material prepared as described in British Patent Specification No. 2127401.
Opaspray pigments are based on titanium dioxide with lake colours and were supplied by Colorcon Ltd of Orpington, Kent, United Kingdom.
All percentages herein are by weight unless otherwise specified:-Example 1 Tablet Core mg / tablet -Cefuroxime axetil equivalent to 125.00mg cefuroxime 30 Miarocrystalline celIulose 47.51 Croscarmellose sodium type A 20.00 Sodium lauryl sulphate 2.25 Silicon dioxide 0.63 Hydrogenated vegetable oil 4.25 All the ingredients with the exception of the silicon dioxide and half of the croscarmellose soAium were 3~
g blended together and compacted using a roller compactor.
The compacted material was comminuted using an oscilla-ting granulator and the resultant granules were blended with the remaining excipients and then compressed using a conventional tabletting machine.
Film-forming composition ~ w/v Hydroxypropylmethylcellulose 5 or 6 10.00 10 Propylene glycol 0.60 Methyl hydroxybenzoate 0.10 Opaspray~white m-1-7120 7.00 Propyl hydroxybenzoate 0.08 Distilled water to 100%.
The film-forming composition was prepared by dispersing the ingredients in distilled water. It was then applied to approximately 44,000 tablets in a 24" Manesty Accelacota with a target coat weight of approximately lmg per 27mm2 on the tablets. The rate of application of the film-forming composition was maintained in the range 20 to 30 ml/min and the temperature of the incoming air was maintained in the range 50 to 55C with the humidi~y of the incoming air not being permitted to exceed 30%. Adjustments of the rate of application and temperature of the incoming air within the above ranges were made as necessary during the course of the spraying operation to avoid either overwetting or overdrying as previously described.
Mean film coat rupture time ~100 tablets3 = 4.9 seconds.
~rade ~a~
~X~
Example 2 Tablet Core mq / tablet Ceiuroxime axetil equivalent to 250.00mg cefuroxime Microcrystalline cellulose 95.02 Croscarmellose sodium type ~ 40.00 Sodium lauryl sulphate 4.50 10 Silicon dioxide 1.25 Hydrogenated vegetable oil 8.5 All the ingredients with the exception of the silicon dioxide and half of ~he croscarmellose sodium were lS blended together and compacted using a roller compactor.
The compacted material was comminuted using an oscillating granulator and the resultant granule was blended with the remaining excipients and then compressed using a conventional tabletting machine.
Film-formin~ co~position % w/v Hydroxypropylmethylcellulose 5 or 6 10.00 Propylene glycol 0.60 25 Methyl hydroxybenzoate 0.10 Opaspray blue M-1-4395B 12.00 Propyl hydroxybenzoate 0.08 Distilled water to 100%.
The ~ilm-forming composition was prepared by dispersing the ingredients in distilled water. It was then applied to approximately 22,000 tablets in a 24" Manesty Accelacota with a target coat weight of approximately lmg per 32mm2 on the tablets under conditions as described in Example 1.
Mean film coat rupture time tlOO tablets) = 3.5 seconds.
~ ' ~ ~, '.' ' ~233~L
Example 3 Tablet Core mg / tablet Ceuroxime axetil equivalent to250.00mg cefuroxime Microcrystalline cellulose 94.55 Croscarmellose sodium type A 15.50 Sodium lauryl sulphate 4.50 10 Silicon ~ioxide 1.25 Hydrogenated vegetable oil 8.50 All the ingredients except the silicon dioxide are blended together and compacted using a roller compactor.
The compacted material is comminuted using an oscilla-ting granulator and the resultant granule is blended with the silicon dioxide and compressed using a conven-tional tabletting machine.
Film-forminq composition % w/v Hydroxypropylmethylcellulose 5 or 6 10.00 Propylene glycol 0.60 Methyl hydroxybenxoate 0.10 25 Propyl hydroxy~enzoate 0.08 Opaspray blue M-1-4395B 12.00 Distilled water to 100%.
The film coat is prepared by dispersing the ingredients in distilled water. Tablets are coated using the film coating technique described in Examples 1 and 2 with a target coat weight of approximately lmg per 32mm2.
33~
Example 4 Tablet Core mg / tablet Cefuroxime axetil equivalent to 500.00mg cefuroxime 5 Microcrystalline cellulose 190.04 Croscarmellose sodium type A 80.00 Sodium lauryl sulphate 9.00 Silicon dioxide 2.50 Hydrogenated vegetable oil 17.00 All the ingredients with the exception of the silicon dioxide and half of the croscarmellose sodium were blended together and compacted using a roller compactor.
The compacted material was comminuted using an oscilla-ting granulator and the resultant granule was blended with the remaining excipients and then compressed using a conventional tabletting machine.
Film-forminq composition % w/v Hydroxypropylmethylcellulose 5 or 6 10.00 Propylene glycol 0.60 Methyl hydroxybenzoate 0.10 Opaspray blue M-1-4399 12.00 25 Propyl hydroxybenzoate 0.08 Distilled water to 100~.
The film-forming composition was prepared by dispersing the ingredients in distilled water. It was then applied to approximately 11,000 tablets in a 24"
Manesty Accelacota with a target c~at weight of approximately lmg per 27mm on the tablets under conditions as described in Example 1.
Mean film coat rupture time (100 tablets) -2.5 seconds.
Claims (25)
1. A pharmaceutical tablet for oral administration which comprises a tablet core containing an effective amount of cefur-oxime axetil as active ingredient and a film coat which serves to mask the bitter taste of cefuroxime axetil upon oral administra-tion, the film coat having a rupture time of less than 40 seconds when measured by a rupture test wherein the tablet is placed in a beaker of still 0.07 M hydrochloric acid at 37°C, the rupture time being measured as the time which elapses before the core of the tablet first becomes visible to the naked eye through the ruptured film coat and the tablet core disintegrating immediately following rupture of the film coat in the said rupture test.
2. A pharmaceutical tablet as claimed in claim 1 wherein the film coat rupture time is less than 25 seconds.
3. A pharmaceutical tablet as claimed in claim 2 wherein the film coat rupture time is less than 15 seconds.
4. A pharmaceutical tablet for oral administration which comprises a tablet core containing an effective amount of cefur-oxime axetil as active ingredient and a film coat which serves to mask the bitter taste of cefuroxime axetil upon oral administra-tion, the film coat having a mean rupture time for a batch of 20 tablets of less than 35 seconds, when measured by a rupture test wherein the tablet is placed in a beaker of still 0.07 M hydro-chloric acid at 37°C, the rupture time being measured as the time which elapses before the core of the tablet first becomes visible to the naked eye through the ruptured film coat and the tablet core disintegrating immediately following rupture of the film coat in the said rupture test.
5. A pharmaceutical tablet as claimed in claim 4 wherein the mean rupture time for a batch of 20 tablets is less than 25 seconds.
6. A pharmaceutical tablet as claimed in claim 5 wherein the mean rupture time for a batch of 20 tablets is less than 15 seconds.
7. A pharmaceutical tablet for oral administration which comprises a tablet core containing an effective amount of cefur-oxime axetil as active ingredient and a film coat which serves to mask the bitter taste of cefuroxime axetil upon oral administra-tion, the film coat having a mean rupture time for a batch of 100 tablets of less than 30 seconds when measured by a rupture test wherein the tablet is placed in a beaker of still 0.07 M hydro-chloric acid at 37°C, the rupture time being measured as the time which elapses before the core of the tablet first becomes visible to the naked eye through the ruptured film coat and the tablet core disintegrating immediately following rupture of the film coat in the said rupture test.
- 14a - 20208-1293
- 14a - 20208-1293
8. A pharmaceutical tablet as claimed in claim 7 wherein the mean rupture time for a batch of 100 tablets is less than 20 seconds.
9. A pharmaceutical tablet as claimed in claim 8 wherein the mean rupture time for a batch of 100 tablets is less than 12 seconds.
10. A pharmaceutical tablet as claimed in claim 1 wherein the film coat comprises a hydroxyalkylcellulose as a film-forming agent.
11. A pharmaceutical tablet as claimed in claim 10 wherein the film-forming agent is a hydroxypropylmethylcellulose.
12. A pharmaceutical tablet as claimed in claim 11 wherein the film-forming agent is hydroxypropylmethylcellulose 5 or 6.
13. A pharmaceutical tablet as claimed in claim 1 wherein the weight of the film coat is 1 mg per 10 to 70 mm2 of the surface area of the tablet.
14. A pharmaceutical tablet as claimed in claim 13 wherein the weight of the film coat is 1 mg per 12 to 35 mm2 of the surface area of the tablet.
15. A pharmaceutical tablet as claimed in claim 1, 2 or 3 wherein the tablet core contains cefuroxime axetil in amorphous form.
16. A pharmaceutical tablet as claimed in claim 1 containing from 30 to 95% by weight of cefuroxime axetil.
17. A pharmaceutical tablet as claimed in claim 16 contain-ing from 50 to 85% by weight of cefuroxime axetil.
18. A pharmaceutical tablet as claimed in claim 1, 2 or 3 containing from 50 to 500 mg of cefuroxime as cefuroxime axetil in the tablet core.
19. A pharmaceutical tablet as claimed in claim 1 wherein the tablet core contains a disintegrant.
20. A pharmaceutical tablet as claimed in claim 19 wherein the disintegrant comprises a cross-linked carboxymethylcellulose.
21. A process for the preparation of a pharmaceutical tablet as claimed in claim 1 in which a cefuroxime axetil-containing tablet core is coated with a film-forming composition, the said film-forming composition being applied in an amount whereby the rupture time of the film coated tablet is as defined in claim 1 and the tablet core containing an effective amount of a disin-tegrant whereby it disintegrates immediately following rupture of the tablet coating in the rupture test as defined in claim 1.
22. A process as claimed in claim 21 wherein the tablet core is produced by compressing granules comprising cefuroxime axetil and one or more pharmaceutical carriers or excipients.
23. A process as claimed in claim 21 wherein the granules contain a disintegrant.
24. A process as claimed in claim 22 or claim 23 wherein a disintegrant is mixed with the granules prior to compression.
25. A process as claimed in claim 21, 22 or 23 wherein the film-forming composition comprises an aqueous solution of a water-soluble film-forming agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8524001 | 1985-09-30 | ||
| GB858524001A GB8524001D0 (en) | 1985-09-30 | 1985-09-30 | Pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1282331C true CA1282331C (en) | 1991-04-02 |
Family
ID=10585921
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000519257A Expired - Lifetime CA1282331C (en) | 1985-09-30 | 1986-09-29 | Pharmaceutical composition containing cefuroxime axetil |
Country Status (29)
| Country | Link |
|---|---|
| US (1) | US4897270A (en) |
| EP (1) | EP0223365B1 (en) |
| JP (1) | JP2661662B2 (en) |
| KR (1) | KR940000233B1 (en) |
| AT (1) | AT393081B (en) |
| AU (1) | AU594082B2 (en) |
| BE (1) | BE905518A (en) |
| CA (1) | CA1282331C (en) |
| CH (1) | CH672736A5 (en) |
| CY (1) | CY1563A (en) |
| DE (2) | DE3677710D1 (en) |
| DK (1) | DK175349B1 (en) |
| ES (1) | ES2002382A6 (en) |
| FR (1) | FR2591597B1 (en) |
| GB (2) | GB8524001D0 (en) |
| GR (1) | GR862464B (en) |
| HK (1) | HK84990A (en) |
| IE (1) | IE59089B1 (en) |
| IL (1) | IL80165A (en) |
| IT (1) | IT1196644B (en) |
| LU (1) | LU86613A1 (en) |
| NL (1) | NL8602466A (en) |
| NO (1) | NO173636C (en) |
| NZ (1) | NZ217720A (en) |
| PH (1) | PH25702A (en) |
| PT (1) | PT83459B (en) |
| SA (1) | SA91120189B1 (en) |
| SE (1) | SE8604114L (en) |
| ZA (1) | ZA867318B (en) |
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| US4880636A (en) * | 1988-05-13 | 1989-11-14 | Franz Robert M | Film coated tablet of ranitidine HCl |
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| CA2239331C (en) * | 1998-05-29 | 1999-11-30 | Bernard Charles Sherman | Pharmaceutical tablets comprising cefuroxime axetil |
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-
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- 1985-09-30 GB GB858524001A patent/GB8524001D0/en active Pending
-
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- 1986-09-25 ZA ZA867318A patent/ZA867318B/en unknown
- 1986-09-26 IL IL80165A patent/IL80165A/en not_active IP Right Cessation
- 1986-09-29 DK DK198604624A patent/DK175349B1/en not_active IP Right Cessation
- 1986-09-29 CA CA000519257A patent/CA1282331C/en not_active Expired - Lifetime
- 1986-09-29 GR GR862464A patent/GR862464B/en unknown
- 1986-09-29 NO NO863863A patent/NO173636C/en unknown
- 1986-09-29 GB GB8623340A patent/GB2181052B/en not_active Expired
- 1986-09-29 CH CH3900/86A patent/CH672736A5/de not_active IP Right Cessation
- 1986-09-29 IE IE256486A patent/IE59089B1/en not_active IP Right Cessation
- 1986-09-29 IT IT48492/86A patent/IT1196644B/en active Protection Beyond IP Right Term
- 1986-09-29 ES ES8602263A patent/ES2002382A6/en not_active Expired
- 1986-09-29 SE SE8604114A patent/SE8604114L/en not_active Application Discontinuation
- 1986-09-29 DE DE8686307459T patent/DE3677710D1/en not_active Expired - Lifetime
- 1986-09-29 FR FR8613539A patent/FR2591597B1/en not_active Expired
- 1986-09-29 KR KR1019860008131A patent/KR940000233B1/en not_active IP Right Cessation
- 1986-09-29 EP EP86307459A patent/EP0223365B1/en not_active Expired - Lifetime
- 1986-09-29 NZ NZ217720A patent/NZ217720A/en unknown
- 1986-09-29 AU AU63232/86A patent/AU594082B2/en not_active Expired
- 1986-09-29 PT PT83459A patent/PT83459B/en unknown
- 1986-09-29 PH PH34308A patent/PH25702A/en unknown
- 1986-09-30 BE BE0/217227A patent/BE905518A/en not_active IP Right Cessation
- 1986-09-30 AT AT2609/86A patent/AT393081B/en not_active IP Right Cessation
- 1986-09-30 JP JP61230233A patent/JP2661662B2/en not_active Expired - Lifetime
- 1986-09-30 LU LU86613A patent/LU86613A1/en unknown
- 1986-09-30 NL NL8602466A patent/NL8602466A/en not_active Application Discontinuation
- 1986-09-30 DE DE19863633292 patent/DE3633292A1/en not_active Withdrawn
-
1988
- 1988-12-30 US US07/291,364 patent/US4897270A/en not_active Expired - Lifetime
-
1990
- 1990-10-18 HK HK849/90A patent/HK84990A/en not_active IP Right Cessation
-
1991
- 1991-05-17 CY CY1563A patent/CY1563A/en unknown
- 1991-10-13 SA SA91120189A patent/SA91120189B1/en unknown
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