CA1338467C - Pharmaceutical composition, pharmaceutical granulate and process for their preparation - Google Patents
Pharmaceutical composition, pharmaceutical granulate and process for their preparationInfo
- Publication number
- CA1338467C CA1338467C CA000560356A CA560356A CA1338467C CA 1338467 C CA1338467 C CA 1338467C CA 000560356 A CA000560356 A CA 000560356A CA 560356 A CA560356 A CA 560356A CA 1338467 C CA1338467 C CA 1338467C
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- CA
- Canada
- Prior art keywords
- antibiotic
- granulate
- weight
- cellulose
- tablet
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- 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
Abstract
A pharmaceutical tablet is provided containing an amphoteric beta-lactam antibiotic, microcrystalline or microfine cellulose or a mixture of both and a second disintegrant, being low-substituted hydroxypropylcellulose which fully disintegrates in water within 60 seconds. When swallowed it shows a bioavailability as good as a pharmacy prepared suspenison of the antibiotic. The tablet is compressed from a mixture containing a new granulate which is prepared from the antibiotic substance, microcrystalline and/or microfine cellulose and water only.
Such tablets can also be prepared by using other know tablet disintegrants as the second disintegrant.
Such tablets can also be prepared by using other know tablet disintegrants as the second disintegrant.
Description
Pharmaceutical tablet, pharmaceutical granulate and process for their preparation.
The invention relates to a pharmaceutical composition comprisiny an amphoteric beta-lactam antibiotic.
More particularly, the invention relates to a pharmaceutical tablet which disintegrates quickly when immerse-d in water and 5 which, when ingested, provides a high bioavailability of antibiotic. The invention further relates to a process for the preparation of this tablet by wet granulation.
Background of the invention The therapeutic action of a medicine in a living organism depends to a considerable extent on its formulation.
~hen drugs are administered orally, hi~h demands are made uron the pharmaceutical formulation.
The first demand is a high bioavailability: the medicine in the composition should be made available to the organism in as high an amount as possible and the optirnum blood levels should be reached within the shortest possible time.
20 This is a typical demand in the treatment of infections with an antibiotic composition with which the present invention is concerned.
A second demand made upon pharmaceutical formulations is that it allows adrninistration to the patient 25 without problems. However, the formulation with the best bioavailability is seldom easy to use and on the other hand, one which is easy to use often does not have satisfactory bioavailability.
The invention relates to a pharmaceutical composition comprisiny an amphoteric beta-lactam antibiotic.
More particularly, the invention relates to a pharmaceutical tablet which disintegrates quickly when immerse-d in water and 5 which, when ingested, provides a high bioavailability of antibiotic. The invention further relates to a process for the preparation of this tablet by wet granulation.
Background of the invention The therapeutic action of a medicine in a living organism depends to a considerable extent on its formulation.
~hen drugs are administered orally, hi~h demands are made uron the pharmaceutical formulation.
The first demand is a high bioavailability: the medicine in the composition should be made available to the organism in as high an amount as possible and the optirnum blood levels should be reached within the shortest possible time.
20 This is a typical demand in the treatment of infections with an antibiotic composition with which the present invention is concerned.
A second demand made upon pharmaceutical formulations is that it allows adrninistration to the patient 25 without problems. However, the formulation with the best bioavailability is seldom easy to use and on the other hand, one which is easy to use often does not have satisfactory bioavailability.
By way of example: amoxicillin is the most prescribed beta-lactam antibiotic. A considerable amount of amoxicillin is delivered as an aqueous suspension as this shows the best bioavailability. However, such suspensions have 5 serious drawbacks:
They have to be prepared by the pharmacist shortly before delivery to the patient. The suspension should be kept cool in a refrigerator because otherwise it is liable to deterioration. When administered it has to be measured with a 10 spoon or a cup with inherent inaccuracy of the dosage volume.
Another inconvenience to the patient is the discomfort caused by the sticky sugary liquid and the tacky container.
To overcome these drawbacks other dosage forms, e.g. capsules or tablets, have been made available. However, -~ lS many patients have serious problems with swallowing such a solid dosage form, especially the larger ones. Moreover the bioavailability and maximum concentration of antibiotic in blood and the time wherein this concentration is reached are inferior to those of the aqueous suspension.
~then developing a new harmaceutical composition, particularly in tablet form, there is still a third category of requirements which has to be met: the ingredients should satisfy the demands of the pharmaceutical production process.
Amoxicillin, for example, presents a very bad flow pattern and ` 25 this, combined with its sensitivity to moisture, places serious restrictions on its formulation.
It is also important that the tablet should possess appropriate physico-chemical properties relatin~ to hardness, stability, friability, disintegration time and so on.
To meet these various requirements pharmacy has at its disposal a great variety of adjuvants subdivided as diluents, binders and adhesives, disinte~rants, lubricants, glidants and flow promoters as well as colours, flavours and sweeteners. It is the task of pharmacy to develop 35 pharmaceutical formulations which have certain specified properties.
~ 3 ~ 1 3 3 8 4 6 7 One of the com~on pharmaceutic~l operations is preparing intimate mixtures of several ingredients. These ingredients may interact with each other during formulation and therefore one cannot predict in detail the physico-chemical 5 characteristics of the resulting pharmaceutical composition which may have surprising ~roperties.
State of the art One way to improve the bioavailability of the antibiotic in tablets is to have them disintegrate faster when immersed in water. I~ith the aid of disintegrants, dispersible tablets have been developed which disintegrate in a few minutes or less when irl~ersed in water.
Belgian patent 817515 describes a tableted beta-lactam antibiotic which i5 said to disintegrate fast in the stomach. ~he mixture to be tableted contains the beta-lactam antibiotic and urea. Binders or diluents have been omitted because these appear to slow down the disintegration. The 20 resulting tablet is said to disinteqrate relatively fast, so that the active ingredient is liberated in about 13 minutes.
~ ritish patent 2084016 describes an amoxicillin containing tablet, which is prepared with two disintegrants, microcrystalline`cellu]ose and either sodium starch glycolate 25 or cross-linked polyvinylpyrrolidone. ~-~owever, there is no mention of favourable disintegration behaviour or of unexpectedly good absorption.
Dispersible tablets containing disintegrants form a special category. ~7hen put into a glass of water they 30 disintegrate fast into a fine dispersion which can be subsequently ingested.
However, existing dispersible tablets for beta-lactam antibiotics are large with respect to the dose of antibiotic and do not show gooA disintegration behaviour. A well known 35 500 mg amoxicillin containing tablet weighs 1260 mg. It disintegrates within 2 minutes and the dispersion contains coarse lumps.
_ 4 _ 1 33 8 4 ~7 Summary of the invention After extensive experimentation, we have developed a tablet suited for amphoteric beta-lactam antibiotics which utilizes the combination of the disintegrants, micro-crystalline cellulose and low-substituted hydroxypropyl-cellulose. Microfine cellulose may partially or fully sub-stitute the microcrystalline cellulose without affecting the invention process or the properties of the invention products.
Such a tablet can either be easily swallowed as such or after being dispersed in water can be drunk. This formu-lation has a bioavailability of the antibiotic which equals that of the corresponding pharmacy prepared aqueous suspension and which is the same for the tablet either swallowed as such or drunk as a suspension.
These tablets may be prepared by compressing a granulate which is mixed with several adjuvants. The granu-late contains the beta-lactam antibiotic and microcrystalline and/or microfine cellulose. No substantial amount of wet binder is present in the tablet, at least less than 0.5 wt %
preferably 0-0.1 wt % based on the weight of the antibiotic.
A part of the microcrystalline and/or microfine cellulose is mixed with the active substance and granulated with water.
The other part is admixed to the granulate together with a second disintegrant, preferably low-substituted hydroxypropyl-cellulose or cross-linked polyvinylpyrrolidone and, optionally, other adjuvants. The resulting mixture possesses a good flow and can be processed smoothly in the tableting press.
Details of the invention The developed dispersible tablet contains an am-photeric beta-lactam antibiotic and two different disinte-grants, one of which is a cellulose product viz. microcry-stalline cellulose or microfine cellulsoe or a mixture of both ~ 1 338467 the other one is low-substituted hydroxypropylcellulose.
Microcrystalline cellulose is the common name for purified, partially depolymerized cellulose occuring as a crystalline powder composed of porous particles. It is a widely used adjuvant, known e.g. under the brand name AVICEL.
Low-substituted hydroxypropylcellulose (l-HPC) is the common name of cellulose which is partially substituted with 2-hydroxypropoxy groups. The substitution grade for the socalled low-substituted variant, a common pharmaceutical adjuvant, is less than 25% and preferably is 7-16%. Micro-fine cellulose (e.g. ELCEMA), also denoted as powdered cellu-lose, is a mechanically processed alpha-cellulose from fibrous plant materials. It is a common pharmaceutical binder and disintegrant in this description and the appending claims "cellulose product" refers partially to microcrystalline cellulose and microfine cellulose and to mixtures of them.
The invented tablet exhibits a new and valuable combination of outstanding properties. The most important and surprising one is that the bioavailability of the anti-biotic when swallowed as such is as good as when it is dis-persed in water before taking it. The amount of active substance absorbed into the blood is the same in both cases.
The bioavailability equals that of the known pharmacy prepared aqueous suspensions. This bioavailability is demonstrated in the following data collected for a 500 mg amoxicillin-containg tablet in accordance with this invention:
Cmax Tmax bioava lability 30 invention tablet swallowed as such 9.2 68 19.0 invention tablet taken as a dispersion in water 9.2 58 18.7 known ready suspenion 9.5 61 17.8 Cmax is the ~x;mum concentration of the antibiotic expressed in micrograms per ml of blood after administration.
Tma is the time in minutes when the Cmax is attained.
* Trade-mark A - ~
The bioavailability is expressed as a number proportional with the area under the graphic curve (AUC) which graph represents the blood concentration progressing with time.
Whèn emmersed in water, the tablet of the invention fully disintegrates with 60 seconds into an excellent aqueous dispersion. However, its disintegration proceeds sufficiently slowly for swallowing it easily.
Since it is know from literature that a standard amoxicillin preparation shows a wide variation in bioavail-ability between individuals, it is surprising that the inven-tion tablet exhibits only a small inter-individual variation, irrespective whether the tablet was swallowed as such or drunk as an aqueous dispersion. This additional advantage could be a consequence of the much improved disintegration behaviour of the tablet.
The tablets of the invention preferably contain 2-20 wt%, of low-substituted hydroxypropylcellulose, more pre-ferably 7-10 wt%, the percentage being based on the weight of antibiotic.
A further aspect of the invention is that only small amounts of disintegrants and other excipients are necessary which results in a considerably smaller tablet, which is easier to swallow, as compared with prior art dispersible tablets containing the same amount of antibiotic. A 500 mg amoxicillin containing tablet of the invention has a weight for example of 937 mg, whereas the comparable prior art tablet would weigh 1260 mg.
Therefore, according to another feature of the inven-tion, the tablet contains a high percentage of active substance, which can be 20-70 wt%, but is preferably 50-65 wt%.
The fact that the tablet of the invention can be taken, at the patientschoice, either as a solid tablet or as a liquid dispersion contributes to better patient compliance.
There is a lower risk that the therapy fails because the patient is reluctant to take the prescribed medicine.
There is also an economic advantage in that only one dosage form needs to be produced and kept in store.
Suspensions, capsules, sachets, effervescent tablets etc.
become obsolete for the antibiotics which are formulated in accordance with this invention.
The new tablet satisfies all common pharmaceutical standards with respect to hardness, friability and stability.
The disintegration time of the larger, high dose tablet is hardly any longer than that of the smaller, low dose tablet.
The tablet of the invention is designed for amphoteric beta-lactam antibiotics. Beta-lactam antibiotics comprise the penicillins and the cephalosporins. Amphoteric means that the molecule contains the same number of free amino groups as of free carboxyl groups. Examples are ampicillin, cefalexin and cefradin, but preferably amoxicillin is used.
Usually amoxicillin trihydrate is employed.
The material for compressing consists of a granu-late mixed with several adjuvants. The granulate contains the beta-lactam antibiotic and microcrystalline and/or micro-fine cellulose. A suitable amount of microcrystalline and/or microfine cellulose in the granulate is 20-50 wt%, prefer-ably 35-45 wt% based on the weight of antibiotic. Microcry-stalline and/or microfine cellulose, low-substituted hydroxy-propylcellulose and optionally further adjuvants are then mixed with the granulate. A suitable further amount of microcrystalline and/or microfine cellulose is 4-20 wt%, pre-ferably 8-15 wt% based on the weight of the antibiotic. A
suitable amount of low-substituted hydroxypropylcellulose is 2-20 wt%, preferably 7-lO wt% based on the weight of the antibiotic.
A further aspect of the invention is a process for the preparation of tablets containing an amphoteric beta-lactam antibiotic together with two different disintegrants, one of which is a cellulose product, viz. microcrystalline cellulose or microfine cellulose or a mixture of both. The process comprises preparing a granulate, mixing the granulate with the further ingredients, and compressing the resulting mixture into tablets.
- The necessary granulate is obtained using a process comprising the following steps:
The beta-lactam antibiotic is mixed with a part of the disintegrant microcrystalline and/or microfine cellulose as sole adjuvant and granulated with water. It is important that the remainder of the disintegrant is retained to be added to the granulate when formed.
The resulting wet mass is further treated in the usual way. The obtained granules are milled, dried, milled again and sieved. The wet granules are thoroughly dried in a fluidized bed dryer at a temperature of less than 70C and preferably less than 45C.
The particle size distribution in the granulate appears to contribute to the disintegration behaviour of the tablet. A suitable distribution is: 100%<0.7 mm, with not more than 30% (preferably 10%) >0.5 mm and not more than 50%
(preferably 20-40%) <0.15 mm.
A good granulate is obtained which can be easily processed, and shows an excellent disintegration pattern.
This is surprising because microcrystalline cellulose, when used in wet granulation, according to the prior artj is always combined with another adjuvant, particularly the binder lactose. Moreover for beta-lactam antibiotics, especially amoxicillin, wet granulation is avoided in the prior art because these antibiotics are generally moisture sensitive.
The resulting granulate is then mixed with the remaining part of the microcrystalline and/or microfine cellulose, the second disintegrant and optionally, other adjuvants and compressed into tablets. Usual other adjuvants aré lubricants as magnesium stearate, flow promoters as colloidal silica and flavours and sweeteners.
The quality of the granulate is best when using 20-50 wt% of microcrystalline and/or microfine cellulose, preferably 35-45 wt%, mixed with 40-80 wt% of water, preferably 50-70 wt%, all percentages with respect to the weight of the antibiotic.
It is a further advantage of the inventon that an organic solvent, with all its safety hazards, as granulation liquid is avoided.
The proportion of granulate used in the tableting mixture is such that the total mixture contains 20-70 wt%, preferably 50-65 wt% of the antibiotic.
The amount of microcrystalline and/or microfine cellulose added to the granulate is 4-20 wt%, preferably 8-15 wt% based on the weight of antibiotic.
The use of the second disintegrant in the tableting mixture is essential for proper disintegration of the tablet.
The optimum disintegrating behaviour is achieved when 2-20 wt%, preferably 7-10 wt% of the second disintegrant is used, based on the weight of the antibiotic.
Examples of compounds which can be used as the second disintegrant are cross-linked polyvinylpyrrolidone te.g.
Kollidon CL), cross-linked sodium carboxymethylcellulose (e.g.
Ac-Di-Sol), starch or starch derivatives such as sodium starch glycolate (e.g. Éxplotab), or combinations with starch (e.g.
Primojel), swellable ion-exchange resins, such as Amberlite IRP 88, formaldehyd-casein (e.g. Esma Spreng), alginates, but preferably the second disintegrant is low-substituted hydroxypropylcellulose or cross-linked polyvinylpyrrolidone.
The former substance also enhances the cohesiveness of the tablet.
A further ~a~istic of the invention is that wet binders are avoided in the tablet. These substances, used for their binding properties in wet granulation, in amounts of about 1-10 wt% based on the weight of the active substance, comprise acacia gum, gelatin, polyvinylpyrrolidone, starch (paste and pre-gelatinized), sodium alginate and alginate derivatives, sorbitol, glucose and other sugars, tragacanth, and soluble celluloses like methylcellulose, hydroxypropyl-methylcellulose and hydroxypropylcellulose. If present, * Trade-mark ~a~
L ~`~
- lo - 1 3 3 ~ 4 6 7 their amount is less than 0.5 wt%, preferably 0-0.1 wt%
based on the weight of the antibiotic.
The process is suited for all amphoteric beta-lactam antibiotics but is most advantageously applied for amoxicillin.
The invention is further illustrated by the following examples, which should not be conceived to be a limitation of the invention.
Reported disintegration times have been measured according to Example 39.
Example 1 Granulate containing amoxicillin 5 Amoxicillin trihydrate 720 g Microcrystalline cellulose 28~ g '~later 420 ml The solid components were mixed thoroughly and granulated with 10 the water. The wet mass was kneaded for 20 minutes, then milled and dried with air of 70C in a fluidized bed drier until the granulate contained not l,lore than 10.5 % of water.
The dried granules were passed through a 0.8 ~m sieve and collected.
Example 2 Granulate containing amoxicillin 20 Amoxicillin trihydrate 750 g Microcrystalline cellulose 150 g Water 345 ml.
A granulate was obtained from these components by following 25 the procedure of Example 1.
Example 3 Tablets containing amoxicillin Granulate from Example 1 500 g Microcrystalline cellulose 30 g Low-substituted hydroxypropylcellulose 20 g Saccharin 3.5 g 35 Flavours 4.0 g Colloidal silic~ 1.5 g Magnesium stearate 7.5 g The granulate was mixed for 10 minute~. ~ith the other excipients, after w~ich the obtained mixture was com~ressed into tablets on a rotary press. The characteristics of tablets with various amounts of amoxicillin were:
dosa~e amoxicillin weight diameter hardness disintegration (as free acid) time 125 mg 234 mg 9 mm 137 N 30 sec 10250 mg 4~9 mg 11 rnm 9~ N 50 sec 500 mg 937 mg 15 mm137 N 35 sec 1000 mg 1~74 mg 20 ~m137 L~ 45 sec - 15 Example 4 Tablets containing amoxicillin Granulate from Example 2 ~00 g 20 ~licrocrystalline cellulose 100 g Low-substituted hydroxypropylcellulose 50 g ~accharin g g Flavours 11 g Colloidal silica 1.5 g 25 Magnesium stearate 7.5 g Tablets were obtained from these components by following the procedure of Example 3. Tablets with varying dosage levels of amoxicillin may be prepared. The 1000 mg amoxicillin tablet 30 for example has a weight of 1~30 mg, a hardness of 137 N and it disintegrates within 60 seconds in water.
~ - 13 -1 3 3 8 4 67 Examples 5-10 Tablets containing amoxicillin 5 Granulate from Example 1 100 g Microcrystalline cellulose 6.18 g ~isintegrant (see TabLe below)6.18 g Colloidal silica 0.19 g Magnesium stearate 0.93 g Tablets containing about 592 mg amoxicilin trihydrate were obtained frorn these components by following t'ne procedure o~ Exar,~.ple 3.
Depending on the specific clisintegrant t~le 15 resulting tablets showed tlle following characteristics:
Example Disinte~rant Weig~t Hardness Disintegration time Amberlite IRP ~ 939 mg 105 N 60 sec 6 Potato starch 964 mg 113 N 57 sec 7 Kollidon CL 955 mg 107 N 26 sec 8 Esma Spren~ 925 mg 123 N 56 sec 259 Fxplotab 939 mg 11~ N 51 sec L-HPC ~25 mg 103 N 33 sec Friability: 0.2-0.4%
~' - 14 - 1 338467 Example 11 Granulate containing cefalexin monohydrate 5 Cefalexin monohydrate 720 g Microcrystalline cellulose 2~B g Water 420 ml A granulate was obt.ained from these components by 10 following the procedure of ~xa~ple 1.
Examples 12-19 Tablets containing cefal.exin monohydrate Granulate from Example 11 50 g Microcrystalline cellulose 3.09 g Disintegrant (see la~le below) 3.09 g Colloidal silica 0.10 20 Flavours Apricot 0.56 Vanillin 0.06 g Saccharin 0.56 g ~qagnesium stearate 0.470 g mablets containing about 500 mg cefalexin monohydrate were obtained from these components by following the nrocedure of Example 3. Depending on the specific disintegrant the resulting tablets showed the following 30 characteristics:
Example Disintegrant Weight ~ardness Disintegration time 12 Amberlite IRP 8~ 817 mg 100 rN 30 sec 13 Potato starch 819 my120 N 30 sec 14 Ac~ Sol 811 mg110 N 40 sec Kollidon CL 812 mg120 N 30 sec 16 Esma Srreng 813 mg90 N 55 sec 17 Explotab 810 mg130 N 35 sec 18 Primojel 813 mg130 N 40 sec 19 L-HPC 811 mg120 r.~ 30 sec Friability: less than 1 Example 20 &ranulate containing ampicillin anhydrate 20 Ampicillin anhydrate 720 g Microcrystalline cellulose 28~ g Water 420 ml A granulate was obtained from these components by 25 following the procedure of ~xample 1.
Examples 21-25 Tablets containing ampicillin anhydrate 5 Granulate from Example 20 50 Microcrystalline cellulose3.09 g Disintegrant (see ~able below) 3.09 g Colloidal silica O.lO g Flavours Apricot 0.56 g Vanillin 0.06 g Saccharin 0.56 g Magnesium stearate 0.470 g 15 Tablets contai.ning about 480 mg ampicillin anhydrate were obtained frorn these components hy fo].lowing the procedure of Example 3. Depen~ing on the specific disintegrant the resulting ta~lets s11owe(1 the f~llowing characteristics:
Exarnple ~isintegrant ~7eight I1ar-lness ~isintegration time 21 Ac-Di-Sol 782 mg90 N 43 sec 25 22 Kollidon CL 777 mg90 .N 30 sec 23 Explotab 7~6 mg~9 N 45 sec 24 Primojel 785 mglOl N 44 sec L-HPC 766 mglO0 N 44 sec 30 Friability: O.l-0.2%
~xample 26 Granulate containing ampicillin trihydrate 5 AmpiciLlin trihydrate 720 g Microcrystalline cellulose 28~ g ~later 470 ml A granulate was obtained from these components by 10 following tlle procedure of Example 1.
Examples 27-34 Tablets containing am~icillin trihydrate Granulate from Example 26 50 Microcrystalline cellulose 3.09 g Disintegrant (see Table below) 3.09 g Colloidal silica 0.10 g 20 Flavours Apricot 0.56 Vanillin 0.06 g Saccharin 0.5~ g Magnesium stearate 0.470 g Tablets containing about 555 mg ampicillin trihydrate were obtained from these components by following the procedure of Example 3. Depending on the specific disintegrant the resulting tablets showed the following 30 characteristics:
Example Disintegrant ',leiyhtHardness Disintegration time 27 Amberlite IRP ''8 910 mg 8$ ~:l 53 sec 28 Potato starc~ '331 mg 115 IN 41 sec 29 Ac-Di-Sol 90G mg 102 N 46 sec Kollidon CL 902 mg 91 N 21 sec 31 Esrna Spreng 893 mg 90 N 42 sec 32 Explotab 890 mg 99 N 33 sec 33 Primojel 913 mg 103 N 23 sec 34 L-HPC 897 mg 103 N 24 sec Friability: 0.1-0.2%
Example 35 (~ranulate containing cefradin Cefradin 720 g 20 r~icrocrystalline cellulose 28~ g ~ater ~35 ml A granulate was obtained frol-n tllese components by following the }:~rocedure of Example 1.
Examples 36-38 Tablets containing cefradin 5 Granulate from Example 35 50 g ~icrocrystalline cellulose3.0'3 g Disintegrant ( see Table below)3.0'3 g Colloidal silica 0.10 g Flavours Apricot 0.5G g Vanillin 0.06 C3 Saccharin 0.5~ ~
Magnesium stearate 0.470 g ~ablets containing about 500 mg cefradin were obtained from these components hy fo]lowing the procedure of Example 3. Depending on the specific disintegrant the resulting tahlets showed the foll.owirlc3 characteristics:
Example Disintegrant ~eight Hardness Disintegration tirne 36 Kollidon CL ~88 mg108 N 32 sec 37 Explotab 881 mg107 N 60 sec 38 L-EiPC 879 rng111 N 62 sec Friability: 0.5%
Example 39 Measurement of the tablet disintegration time 5 The tablet to be tested is immersed in 50 ml water of 20C.
After 30 sec the vessel is swinged so that the liquid starts whirling and not yet disintegrated lumps become visible. As soon as all large lumps have disappeared time is read and the suspension is poured through a 0.71 mm sieve. The reported 10 values are the average of at least two measurements.
Example 40 200 g of amoxicillin trihydrate were mixed with 15 80 g of microfine cellulose (ELCEMA G4003 and 150 ml of water. The resulting wet mass was kneaded for 20 minutes, sieved through a 2 mm mesh sieve and dried in a fluidized bed dryier at about 60C during about one hour until the granulate contained not more than 10.5 wt% of water. The obtained dry 20 granulate was sieved through a 0.8 mm sieve and collected.
Example 41 50 g granulate from Example 40 3.09 g microfine cellulose (ELCE~ G400) 3.09 g l-HPC
0.1 g colloidal silica 0.56 g saccharin 0.62 g flavours 0.47 g magnesium stearate The granulate was mixed for 10 minutes with the other excipients, after which the obtained mixture was compressed into tablets on a rotary press. The prepared 960 mg 35 tablets had a har~ness of 106 ~ and disintegrated in water within 40 seconds.
., ... .
They have to be prepared by the pharmacist shortly before delivery to the patient. The suspension should be kept cool in a refrigerator because otherwise it is liable to deterioration. When administered it has to be measured with a 10 spoon or a cup with inherent inaccuracy of the dosage volume.
Another inconvenience to the patient is the discomfort caused by the sticky sugary liquid and the tacky container.
To overcome these drawbacks other dosage forms, e.g. capsules or tablets, have been made available. However, -~ lS many patients have serious problems with swallowing such a solid dosage form, especially the larger ones. Moreover the bioavailability and maximum concentration of antibiotic in blood and the time wherein this concentration is reached are inferior to those of the aqueous suspension.
~then developing a new harmaceutical composition, particularly in tablet form, there is still a third category of requirements which has to be met: the ingredients should satisfy the demands of the pharmaceutical production process.
Amoxicillin, for example, presents a very bad flow pattern and ` 25 this, combined with its sensitivity to moisture, places serious restrictions on its formulation.
It is also important that the tablet should possess appropriate physico-chemical properties relatin~ to hardness, stability, friability, disintegration time and so on.
To meet these various requirements pharmacy has at its disposal a great variety of adjuvants subdivided as diluents, binders and adhesives, disinte~rants, lubricants, glidants and flow promoters as well as colours, flavours and sweeteners. It is the task of pharmacy to develop 35 pharmaceutical formulations which have certain specified properties.
~ 3 ~ 1 3 3 8 4 6 7 One of the com~on pharmaceutic~l operations is preparing intimate mixtures of several ingredients. These ingredients may interact with each other during formulation and therefore one cannot predict in detail the physico-chemical 5 characteristics of the resulting pharmaceutical composition which may have surprising ~roperties.
State of the art One way to improve the bioavailability of the antibiotic in tablets is to have them disintegrate faster when immersed in water. I~ith the aid of disintegrants, dispersible tablets have been developed which disintegrate in a few minutes or less when irl~ersed in water.
Belgian patent 817515 describes a tableted beta-lactam antibiotic which i5 said to disintegrate fast in the stomach. ~he mixture to be tableted contains the beta-lactam antibiotic and urea. Binders or diluents have been omitted because these appear to slow down the disintegration. The 20 resulting tablet is said to disinteqrate relatively fast, so that the active ingredient is liberated in about 13 minutes.
~ ritish patent 2084016 describes an amoxicillin containing tablet, which is prepared with two disintegrants, microcrystalline`cellu]ose and either sodium starch glycolate 25 or cross-linked polyvinylpyrrolidone. ~-~owever, there is no mention of favourable disintegration behaviour or of unexpectedly good absorption.
Dispersible tablets containing disintegrants form a special category. ~7hen put into a glass of water they 30 disintegrate fast into a fine dispersion which can be subsequently ingested.
However, existing dispersible tablets for beta-lactam antibiotics are large with respect to the dose of antibiotic and do not show gooA disintegration behaviour. A well known 35 500 mg amoxicillin containing tablet weighs 1260 mg. It disintegrates within 2 minutes and the dispersion contains coarse lumps.
_ 4 _ 1 33 8 4 ~7 Summary of the invention After extensive experimentation, we have developed a tablet suited for amphoteric beta-lactam antibiotics which utilizes the combination of the disintegrants, micro-crystalline cellulose and low-substituted hydroxypropyl-cellulose. Microfine cellulose may partially or fully sub-stitute the microcrystalline cellulose without affecting the invention process or the properties of the invention products.
Such a tablet can either be easily swallowed as such or after being dispersed in water can be drunk. This formu-lation has a bioavailability of the antibiotic which equals that of the corresponding pharmacy prepared aqueous suspension and which is the same for the tablet either swallowed as such or drunk as a suspension.
These tablets may be prepared by compressing a granulate which is mixed with several adjuvants. The granu-late contains the beta-lactam antibiotic and microcrystalline and/or microfine cellulose. No substantial amount of wet binder is present in the tablet, at least less than 0.5 wt %
preferably 0-0.1 wt % based on the weight of the antibiotic.
A part of the microcrystalline and/or microfine cellulose is mixed with the active substance and granulated with water.
The other part is admixed to the granulate together with a second disintegrant, preferably low-substituted hydroxypropyl-cellulose or cross-linked polyvinylpyrrolidone and, optionally, other adjuvants. The resulting mixture possesses a good flow and can be processed smoothly in the tableting press.
Details of the invention The developed dispersible tablet contains an am-photeric beta-lactam antibiotic and two different disinte-grants, one of which is a cellulose product viz. microcry-stalline cellulose or microfine cellulsoe or a mixture of both ~ 1 338467 the other one is low-substituted hydroxypropylcellulose.
Microcrystalline cellulose is the common name for purified, partially depolymerized cellulose occuring as a crystalline powder composed of porous particles. It is a widely used adjuvant, known e.g. under the brand name AVICEL.
Low-substituted hydroxypropylcellulose (l-HPC) is the common name of cellulose which is partially substituted with 2-hydroxypropoxy groups. The substitution grade for the socalled low-substituted variant, a common pharmaceutical adjuvant, is less than 25% and preferably is 7-16%. Micro-fine cellulose (e.g. ELCEMA), also denoted as powdered cellu-lose, is a mechanically processed alpha-cellulose from fibrous plant materials. It is a common pharmaceutical binder and disintegrant in this description and the appending claims "cellulose product" refers partially to microcrystalline cellulose and microfine cellulose and to mixtures of them.
The invented tablet exhibits a new and valuable combination of outstanding properties. The most important and surprising one is that the bioavailability of the anti-biotic when swallowed as such is as good as when it is dis-persed in water before taking it. The amount of active substance absorbed into the blood is the same in both cases.
The bioavailability equals that of the known pharmacy prepared aqueous suspensions. This bioavailability is demonstrated in the following data collected for a 500 mg amoxicillin-containg tablet in accordance with this invention:
Cmax Tmax bioava lability 30 invention tablet swallowed as such 9.2 68 19.0 invention tablet taken as a dispersion in water 9.2 58 18.7 known ready suspenion 9.5 61 17.8 Cmax is the ~x;mum concentration of the antibiotic expressed in micrograms per ml of blood after administration.
Tma is the time in minutes when the Cmax is attained.
* Trade-mark A - ~
The bioavailability is expressed as a number proportional with the area under the graphic curve (AUC) which graph represents the blood concentration progressing with time.
Whèn emmersed in water, the tablet of the invention fully disintegrates with 60 seconds into an excellent aqueous dispersion. However, its disintegration proceeds sufficiently slowly for swallowing it easily.
Since it is know from literature that a standard amoxicillin preparation shows a wide variation in bioavail-ability between individuals, it is surprising that the inven-tion tablet exhibits only a small inter-individual variation, irrespective whether the tablet was swallowed as such or drunk as an aqueous dispersion. This additional advantage could be a consequence of the much improved disintegration behaviour of the tablet.
The tablets of the invention preferably contain 2-20 wt%, of low-substituted hydroxypropylcellulose, more pre-ferably 7-10 wt%, the percentage being based on the weight of antibiotic.
A further aspect of the invention is that only small amounts of disintegrants and other excipients are necessary which results in a considerably smaller tablet, which is easier to swallow, as compared with prior art dispersible tablets containing the same amount of antibiotic. A 500 mg amoxicillin containing tablet of the invention has a weight for example of 937 mg, whereas the comparable prior art tablet would weigh 1260 mg.
Therefore, according to another feature of the inven-tion, the tablet contains a high percentage of active substance, which can be 20-70 wt%, but is preferably 50-65 wt%.
The fact that the tablet of the invention can be taken, at the patientschoice, either as a solid tablet or as a liquid dispersion contributes to better patient compliance.
There is a lower risk that the therapy fails because the patient is reluctant to take the prescribed medicine.
There is also an economic advantage in that only one dosage form needs to be produced and kept in store.
Suspensions, capsules, sachets, effervescent tablets etc.
become obsolete for the antibiotics which are formulated in accordance with this invention.
The new tablet satisfies all common pharmaceutical standards with respect to hardness, friability and stability.
The disintegration time of the larger, high dose tablet is hardly any longer than that of the smaller, low dose tablet.
The tablet of the invention is designed for amphoteric beta-lactam antibiotics. Beta-lactam antibiotics comprise the penicillins and the cephalosporins. Amphoteric means that the molecule contains the same number of free amino groups as of free carboxyl groups. Examples are ampicillin, cefalexin and cefradin, but preferably amoxicillin is used.
Usually amoxicillin trihydrate is employed.
The material for compressing consists of a granu-late mixed with several adjuvants. The granulate contains the beta-lactam antibiotic and microcrystalline and/or micro-fine cellulose. A suitable amount of microcrystalline and/or microfine cellulose in the granulate is 20-50 wt%, prefer-ably 35-45 wt% based on the weight of antibiotic. Microcry-stalline and/or microfine cellulose, low-substituted hydroxy-propylcellulose and optionally further adjuvants are then mixed with the granulate. A suitable further amount of microcrystalline and/or microfine cellulose is 4-20 wt%, pre-ferably 8-15 wt% based on the weight of the antibiotic. A
suitable amount of low-substituted hydroxypropylcellulose is 2-20 wt%, preferably 7-lO wt% based on the weight of the antibiotic.
A further aspect of the invention is a process for the preparation of tablets containing an amphoteric beta-lactam antibiotic together with two different disintegrants, one of which is a cellulose product, viz. microcrystalline cellulose or microfine cellulose or a mixture of both. The process comprises preparing a granulate, mixing the granulate with the further ingredients, and compressing the resulting mixture into tablets.
- The necessary granulate is obtained using a process comprising the following steps:
The beta-lactam antibiotic is mixed with a part of the disintegrant microcrystalline and/or microfine cellulose as sole adjuvant and granulated with water. It is important that the remainder of the disintegrant is retained to be added to the granulate when formed.
The resulting wet mass is further treated in the usual way. The obtained granules are milled, dried, milled again and sieved. The wet granules are thoroughly dried in a fluidized bed dryer at a temperature of less than 70C and preferably less than 45C.
The particle size distribution in the granulate appears to contribute to the disintegration behaviour of the tablet. A suitable distribution is: 100%<0.7 mm, with not more than 30% (preferably 10%) >0.5 mm and not more than 50%
(preferably 20-40%) <0.15 mm.
A good granulate is obtained which can be easily processed, and shows an excellent disintegration pattern.
This is surprising because microcrystalline cellulose, when used in wet granulation, according to the prior artj is always combined with another adjuvant, particularly the binder lactose. Moreover for beta-lactam antibiotics, especially amoxicillin, wet granulation is avoided in the prior art because these antibiotics are generally moisture sensitive.
The resulting granulate is then mixed with the remaining part of the microcrystalline and/or microfine cellulose, the second disintegrant and optionally, other adjuvants and compressed into tablets. Usual other adjuvants aré lubricants as magnesium stearate, flow promoters as colloidal silica and flavours and sweeteners.
The quality of the granulate is best when using 20-50 wt% of microcrystalline and/or microfine cellulose, preferably 35-45 wt%, mixed with 40-80 wt% of water, preferably 50-70 wt%, all percentages with respect to the weight of the antibiotic.
It is a further advantage of the inventon that an organic solvent, with all its safety hazards, as granulation liquid is avoided.
The proportion of granulate used in the tableting mixture is such that the total mixture contains 20-70 wt%, preferably 50-65 wt% of the antibiotic.
The amount of microcrystalline and/or microfine cellulose added to the granulate is 4-20 wt%, preferably 8-15 wt% based on the weight of antibiotic.
The use of the second disintegrant in the tableting mixture is essential for proper disintegration of the tablet.
The optimum disintegrating behaviour is achieved when 2-20 wt%, preferably 7-10 wt% of the second disintegrant is used, based on the weight of the antibiotic.
Examples of compounds which can be used as the second disintegrant are cross-linked polyvinylpyrrolidone te.g.
Kollidon CL), cross-linked sodium carboxymethylcellulose (e.g.
Ac-Di-Sol), starch or starch derivatives such as sodium starch glycolate (e.g. Éxplotab), or combinations with starch (e.g.
Primojel), swellable ion-exchange resins, such as Amberlite IRP 88, formaldehyd-casein (e.g. Esma Spreng), alginates, but preferably the second disintegrant is low-substituted hydroxypropylcellulose or cross-linked polyvinylpyrrolidone.
The former substance also enhances the cohesiveness of the tablet.
A further ~a~istic of the invention is that wet binders are avoided in the tablet. These substances, used for their binding properties in wet granulation, in amounts of about 1-10 wt% based on the weight of the active substance, comprise acacia gum, gelatin, polyvinylpyrrolidone, starch (paste and pre-gelatinized), sodium alginate and alginate derivatives, sorbitol, glucose and other sugars, tragacanth, and soluble celluloses like methylcellulose, hydroxypropyl-methylcellulose and hydroxypropylcellulose. If present, * Trade-mark ~a~
L ~`~
- lo - 1 3 3 ~ 4 6 7 their amount is less than 0.5 wt%, preferably 0-0.1 wt%
based on the weight of the antibiotic.
The process is suited for all amphoteric beta-lactam antibiotics but is most advantageously applied for amoxicillin.
The invention is further illustrated by the following examples, which should not be conceived to be a limitation of the invention.
Reported disintegration times have been measured according to Example 39.
Example 1 Granulate containing amoxicillin 5 Amoxicillin trihydrate 720 g Microcrystalline cellulose 28~ g '~later 420 ml The solid components were mixed thoroughly and granulated with 10 the water. The wet mass was kneaded for 20 minutes, then milled and dried with air of 70C in a fluidized bed drier until the granulate contained not l,lore than 10.5 % of water.
The dried granules were passed through a 0.8 ~m sieve and collected.
Example 2 Granulate containing amoxicillin 20 Amoxicillin trihydrate 750 g Microcrystalline cellulose 150 g Water 345 ml.
A granulate was obtained from these components by following 25 the procedure of Example 1.
Example 3 Tablets containing amoxicillin Granulate from Example 1 500 g Microcrystalline cellulose 30 g Low-substituted hydroxypropylcellulose 20 g Saccharin 3.5 g 35 Flavours 4.0 g Colloidal silic~ 1.5 g Magnesium stearate 7.5 g The granulate was mixed for 10 minute~. ~ith the other excipients, after w~ich the obtained mixture was com~ressed into tablets on a rotary press. The characteristics of tablets with various amounts of amoxicillin were:
dosa~e amoxicillin weight diameter hardness disintegration (as free acid) time 125 mg 234 mg 9 mm 137 N 30 sec 10250 mg 4~9 mg 11 rnm 9~ N 50 sec 500 mg 937 mg 15 mm137 N 35 sec 1000 mg 1~74 mg 20 ~m137 L~ 45 sec - 15 Example 4 Tablets containing amoxicillin Granulate from Example 2 ~00 g 20 ~licrocrystalline cellulose 100 g Low-substituted hydroxypropylcellulose 50 g ~accharin g g Flavours 11 g Colloidal silica 1.5 g 25 Magnesium stearate 7.5 g Tablets were obtained from these components by following the procedure of Example 3. Tablets with varying dosage levels of amoxicillin may be prepared. The 1000 mg amoxicillin tablet 30 for example has a weight of 1~30 mg, a hardness of 137 N and it disintegrates within 60 seconds in water.
~ - 13 -1 3 3 8 4 67 Examples 5-10 Tablets containing amoxicillin 5 Granulate from Example 1 100 g Microcrystalline cellulose 6.18 g ~isintegrant (see TabLe below)6.18 g Colloidal silica 0.19 g Magnesium stearate 0.93 g Tablets containing about 592 mg amoxicilin trihydrate were obtained frorn these components by following t'ne procedure o~ Exar,~.ple 3.
Depending on the specific clisintegrant t~le 15 resulting tablets showed tlle following characteristics:
Example Disinte~rant Weig~t Hardness Disintegration time Amberlite IRP ~ 939 mg 105 N 60 sec 6 Potato starch 964 mg 113 N 57 sec 7 Kollidon CL 955 mg 107 N 26 sec 8 Esma Spren~ 925 mg 123 N 56 sec 259 Fxplotab 939 mg 11~ N 51 sec L-HPC ~25 mg 103 N 33 sec Friability: 0.2-0.4%
~' - 14 - 1 338467 Example 11 Granulate containing cefalexin monohydrate 5 Cefalexin monohydrate 720 g Microcrystalline cellulose 2~B g Water 420 ml A granulate was obt.ained from these components by 10 following the procedure of ~xa~ple 1.
Examples 12-19 Tablets containing cefal.exin monohydrate Granulate from Example 11 50 g Microcrystalline cellulose 3.09 g Disintegrant (see la~le below) 3.09 g Colloidal silica 0.10 20 Flavours Apricot 0.56 Vanillin 0.06 g Saccharin 0.56 g ~qagnesium stearate 0.470 g mablets containing about 500 mg cefalexin monohydrate were obtained from these components by following the nrocedure of Example 3. Depending on the specific disintegrant the resulting tablets showed the following 30 characteristics:
Example Disintegrant Weight ~ardness Disintegration time 12 Amberlite IRP 8~ 817 mg 100 rN 30 sec 13 Potato starch 819 my120 N 30 sec 14 Ac~ Sol 811 mg110 N 40 sec Kollidon CL 812 mg120 N 30 sec 16 Esma Srreng 813 mg90 N 55 sec 17 Explotab 810 mg130 N 35 sec 18 Primojel 813 mg130 N 40 sec 19 L-HPC 811 mg120 r.~ 30 sec Friability: less than 1 Example 20 &ranulate containing ampicillin anhydrate 20 Ampicillin anhydrate 720 g Microcrystalline cellulose 28~ g Water 420 ml A granulate was obtained from these components by 25 following the procedure of ~xample 1.
Examples 21-25 Tablets containing ampicillin anhydrate 5 Granulate from Example 20 50 Microcrystalline cellulose3.09 g Disintegrant (see ~able below) 3.09 g Colloidal silica O.lO g Flavours Apricot 0.56 g Vanillin 0.06 g Saccharin 0.56 g Magnesium stearate 0.470 g 15 Tablets contai.ning about 480 mg ampicillin anhydrate were obtained frorn these components hy fo].lowing the procedure of Example 3. Depen~ing on the specific disintegrant the resulting ta~lets s11owe(1 the f~llowing characteristics:
Exarnple ~isintegrant ~7eight I1ar-lness ~isintegration time 21 Ac-Di-Sol 782 mg90 N 43 sec 25 22 Kollidon CL 777 mg90 .N 30 sec 23 Explotab 7~6 mg~9 N 45 sec 24 Primojel 785 mglOl N 44 sec L-HPC 766 mglO0 N 44 sec 30 Friability: O.l-0.2%
~xample 26 Granulate containing ampicillin trihydrate 5 AmpiciLlin trihydrate 720 g Microcrystalline cellulose 28~ g ~later 470 ml A granulate was obtained from these components by 10 following tlle procedure of Example 1.
Examples 27-34 Tablets containing am~icillin trihydrate Granulate from Example 26 50 Microcrystalline cellulose 3.09 g Disintegrant (see Table below) 3.09 g Colloidal silica 0.10 g 20 Flavours Apricot 0.56 Vanillin 0.06 g Saccharin 0.5~ g Magnesium stearate 0.470 g Tablets containing about 555 mg ampicillin trihydrate were obtained from these components by following the procedure of Example 3. Depending on the specific disintegrant the resulting tablets showed the following 30 characteristics:
Example Disintegrant ',leiyhtHardness Disintegration time 27 Amberlite IRP ''8 910 mg 8$ ~:l 53 sec 28 Potato starc~ '331 mg 115 IN 41 sec 29 Ac-Di-Sol 90G mg 102 N 46 sec Kollidon CL 902 mg 91 N 21 sec 31 Esrna Spreng 893 mg 90 N 42 sec 32 Explotab 890 mg 99 N 33 sec 33 Primojel 913 mg 103 N 23 sec 34 L-HPC 897 mg 103 N 24 sec Friability: 0.1-0.2%
Example 35 (~ranulate containing cefradin Cefradin 720 g 20 r~icrocrystalline cellulose 28~ g ~ater ~35 ml A granulate was obtained frol-n tllese components by following the }:~rocedure of Example 1.
Examples 36-38 Tablets containing cefradin 5 Granulate from Example 35 50 g ~icrocrystalline cellulose3.0'3 g Disintegrant ( see Table below)3.0'3 g Colloidal silica 0.10 g Flavours Apricot 0.5G g Vanillin 0.06 C3 Saccharin 0.5~ ~
Magnesium stearate 0.470 g ~ablets containing about 500 mg cefradin were obtained from these components hy fo]lowing the procedure of Example 3. Depending on the specific disintegrant the resulting tahlets showed the foll.owirlc3 characteristics:
Example Disintegrant ~eight Hardness Disintegration tirne 36 Kollidon CL ~88 mg108 N 32 sec 37 Explotab 881 mg107 N 60 sec 38 L-EiPC 879 rng111 N 62 sec Friability: 0.5%
Example 39 Measurement of the tablet disintegration time 5 The tablet to be tested is immersed in 50 ml water of 20C.
After 30 sec the vessel is swinged so that the liquid starts whirling and not yet disintegrated lumps become visible. As soon as all large lumps have disappeared time is read and the suspension is poured through a 0.71 mm sieve. The reported 10 values are the average of at least two measurements.
Example 40 200 g of amoxicillin trihydrate were mixed with 15 80 g of microfine cellulose (ELCEMA G4003 and 150 ml of water. The resulting wet mass was kneaded for 20 minutes, sieved through a 2 mm mesh sieve and dried in a fluidized bed dryier at about 60C during about one hour until the granulate contained not more than 10.5 wt% of water. The obtained dry 20 granulate was sieved through a 0.8 mm sieve and collected.
Example 41 50 g granulate from Example 40 3.09 g microfine cellulose (ELCE~ G400) 3.09 g l-HPC
0.1 g colloidal silica 0.56 g saccharin 0.62 g flavours 0.47 g magnesium stearate The granulate was mixed for 10 minutes with the other excipients, after which the obtained mixture was compressed into tablets on a rotary press. The prepared 960 mg 35 tablets had a har~ness of 106 ~ and disintegrated in water within 40 seconds.
., ... .
Claims (25)
1. Pharmaceutical tablet comprising an amphoteric beta-lactam antibiotic, and as disintegrants, a cellulose product and low-substituted hydroxypropyl-cellulose in which the cellulose product is micro-crystalline cellulose or microfine cellulose or a mixture of both.
2. Tablet according to claim 1, comprising 24-70 wt%, preferably 43-60 wt% of the cellulose product and 2-20 wt%, preferably 7-10 wt% of low-substituted hydroxy-propylcellulose, the percentages being based on the weight of the antibiotic.
3. Tablet according to claim 1, characterized in that 0 wt% up to 0.1 wt% of a wet binding substance is present, based on the weight of the antibiotic.
4. Tablet according to claim 2, characterized in that 0 wt% up to 0.1 wt% of a wet binding substance is present, based on the weight of the antibiotic.
5. Tablet according to claim 1, 2, 3 or 4, characterized in that it contains 20-70 wt% of the antibiotic substance, based on the weight of the tablet.
6. Tablet according to claim 1, 2, 3 or 4, characterized in that it contains 50-65 wt% of the antibiotic substance, based on the weight of the tablet.
7. Pharmaceutical granulate comprising an amphoteric beta-lactam antibiotic, a cellulose product and 0 wt% up to 0.5 wt% of a wet binding substance, based on the weight of the antibiotic in which the cellulose product is microcrystalline cellulose or microfine cellulose or a mixture of both.
8. Granulate according to claim 7, characterized in that it comprises 0 wt% up to 0.1 wt% of a wet binding substance, based on the weight of the antibiotic.
9. Granulate according to claim 7 or 8, characterized in that it contains 20-50 wt% of the cellulose product based on the weight of the antibiotic.
10. Granulate according to claim 7 or 8, characterized in that it contains 35-45 wt% of the cellulose product based on the weight of the antibiotic.
11. Process for the preparation of a granulate containing an amphoteric beta-lactam antibiotic, comprising:
(a) mixing the antibiotic with microcrystalline or microfine cellulose or a mixture of both and water, and granulating the resulting wet mass to form a granulate, and (b) milling, drying, milling and sieving the granulate.
(a) mixing the antibiotic with microcrystalline or microfine cellulose or a mixture of both and water, and granulating the resulting wet mass to form a granulate, and (b) milling, drying, milling and sieving the granulate.
12. Process according to claim 11, characterized in that the mixture to be granulated contains 20-50 wt%
of the cellulose product based on the weight of the antibiotic.
of the cellulose product based on the weight of the antibiotic.
13. Process according to claim 11, characterized in that the mixture to be granulated contains 35-45 wt%
of the cellulose product based on the weight of the antibiotic.
of the cellulose product based on the weight of the antibiotic.
14. Process according to claim 11, 12 or 13 characterized in that the mixture to be granulated contains 0 wt% up to less than 0.1 wt% of a wet binding substance, based on the weight of the antibiotic.
15. Process for the preparation of a tablet containing an amphoteric beta-lactam antibiotic, comprising:
(a) mixing the granulate according to claim 7, 8, 9 or 10 or prepared according to claim 11, 12, 13 or 14 with the disintegrant microcrystalline or microfine cellulose or a mixture of both, a second disintegrant and optionally other excipients, and (b) tableting the mixture.
(a) mixing the granulate according to claim 7, 8, 9 or 10 or prepared according to claim 11, 12, 13 or 14 with the disintegrant microcrystalline or microfine cellulose or a mixture of both, a second disintegrant and optionally other excipients, and (b) tableting the mixture.
16. Process according to claim 15, characterized in that the tableting mixture contains 50-65 wt% of the antibiotic based on the weight of the mixture.
17. Process according to claim 15, characterized in that the second disintegrant is low-substituted hydroxypropylcellulose.
18. Process according to claim 16, characterized in that the second disintegrant is low-substituted hydroxypropylcellulose.
19. Process according to claim 15, characterized in that the second disintegrant is cross-linked poly-vinylpyrrolidone.
20. Process according to claim 16, characterized in that the second disintegrant is cross-linked polyvinylpyrrolidone.
21. Process according to claim 15, characterized in that the granulate is mixed with 4-20 wt%, preferably 8-15 wt% of the cellulose product based on the weight of the antibiotic.
22. Process according to claim 16, 17, 18, 19 or 20, characterized in that the granulate is mixed with 4-20 wt%, preferably 8-15 wt% of the cellulose product based on the weight of the antibiotic.
23. Process according to claim 15, characterized in that the granulate is mixed with 2-20 wt%, preferably 7-10 wt% of low-substituted hydroxypropylcellulose or cross-linked polyvinylpyrrolidone based on the weight of the antibiotic.
24. Process according to claim 16, 17, 18, 19, 20 or 21, characterized in that the granulate is mixed with 2-20 wt%, preferably 7-10 wt% of low-substituted hydroxy-propylcellulose or cross-linked polyvinylpyrrolidone based on the weight of the antibiotic.
25. Process according to claim 22 characterized in that the granulate is mixed with 2-20 wt%, preferably 7-10 wt% of low-substituted hydroxypropylcellulose or cross-linked polyvinylpyrrolidone based on the weight of the antibiotic.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP87200357 | 1987-03-02 | ||
| EP87200357.9 | 1987-03-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1338467C true CA1338467C (en) | 1996-07-23 |
Family
ID=8197583
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000560356A Expired - Lifetime CA1338467C (en) | 1987-03-02 | 1988-03-02 | Pharmaceutical composition, pharmaceutical granulate and process for their preparation |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4950484A (en) |
| EP (1) | EP0281200B1 (en) |
| JP (1) | JPS63301820A (en) |
| KR (1) | KR960009182B1 (en) |
| CN (1) | CN1036763C (en) |
| AU (1) | AU603870B2 (en) |
| CA (1) | CA1338467C (en) |
| DE (1) | DE3887179T2 (en) |
| DK (1) | DK175508B1 (en) |
| ES (1) | ES2061623T3 (en) |
| FI (1) | FI94214C (en) |
| IE (1) | IE70907B1 (en) |
| IL (1) | IL85594A (en) |
| NO (1) | NO174996C (en) |
| NZ (1) | NZ223711A (en) |
| PT (1) | PT86870B (en) |
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| US5211958A (en) * | 1987-11-30 | 1993-05-18 | Gist-Brocades, N.V. | Pharmaceutical composition and process for its preparation |
| DE3868245D1 (en) * | 1987-11-30 | 1992-03-12 | Gist Brocades Nv | PHARMACEUTICAL COMPOSITION AND METHOD FOR THE PRODUCTION THEREOF. |
| EP0330284B1 (en) * | 1988-02-25 | 1994-07-27 | Yamanouchi Europe B.V. | Process for the preparation of a pharmaceutical granulate |
| FR2638971B1 (en) * | 1988-11-15 | 1993-01-08 | Vacher Dominique | INSTANTLY AND / OR INSTANT DISSOLUTION TABLET |
| US5814337A (en) * | 1992-10-07 | 1998-09-29 | Beecham Group Plc | Pharmaceutical formulation |
| GB9007945D0 (en) * | 1990-04-07 | 1990-06-06 | Beecham Group Plc | Pharmaceutical formulation |
| CA2039742A1 (en) * | 1990-04-23 | 1991-10-24 | Andrew B. Dennis | Tablet composition and method for problem pharmaceutical materials |
| DE59106133D1 (en) * | 1990-10-19 | 1995-09-07 | Spirig Ag | Solid, quick-soluble pharmaceutical preparation containing S- (carboxymethyl) -L-cysteine and / or N-acetylcysteine. |
| NL9220009A (en) * | 1991-01-30 | 1993-11-01 | Wellcome Found | WATER-DISPERSIBLE TABLETS. |
| US5629016A (en) * | 1991-01-30 | 1997-05-13 | Glaxo Wellcome Inc. | Water-dispersible tablets |
| US5861172A (en) * | 1991-05-08 | 1999-01-19 | Laboratorios Beecham Sa | Pharmaceutical formulations of compacted granulates of β-lactam antibiotics |
| GB9109862D0 (en) * | 1991-05-08 | 1991-07-03 | Beecham Lab Sa | Pharmaceutical formulations |
| US5464632C1 (en) * | 1991-07-22 | 2001-02-20 | Prographarm Lab | Rapidly disintegratable multiparticular tablet |
| FR2679451B1 (en) * | 1991-07-22 | 1994-09-09 | Prographarm Laboratoires | MULTIPARTICLE TABLET WITH RAPID DELIVERY. |
| GB9215908D0 (en) * | 1992-07-27 | 1992-09-09 | Wellcome Found | Water dispersible tablets |
| US5698226A (en) * | 1993-07-13 | 1997-12-16 | Glaxo Wellcome Inc. | Water-dispersible tablets |
| ES2079327B1 (en) * | 1994-12-13 | 1996-08-01 | Lilly Sa | PHARMACEUTICAL FORMULATIONS OF CEFACLOR. |
| MX9706062A (en) * | 1995-02-08 | 1997-10-31 | Yamanouchi Europ Bv | ORAL DOSAGE-FORMS CONTAINING A 'beta'-LACTAM ANTIBIOTIC. |
| US20030109503A1 (en) * | 1995-06-06 | 2003-06-12 | Smithkline Beecham P.L.C. | Pharmaceutical formulations comprising clavulanic acid alone or in combination with other beta-lactam antibiotics |
| ATE208618T1 (en) | 1995-09-07 | 2001-11-15 | Smithkline Beecham Corp | USE OF A PEDIATRIC PHARMACEUTICAL FORMULATION CONTAINING AMOXICILLIN AND CLAVULANATE |
| US6423341B1 (en) * | 1996-02-29 | 2002-07-23 | Fujisawa Pharmaceutical Co., Ltd. | β-lactam antibiotic-containing tablet and production thereof |
| AT407214B (en) * | 1996-03-13 | 2001-01-25 | Biochemie Gmbh | Process for the preparation of excipient-free agglomerates of beta-lactam antibiotics |
| TWI225402B (en) | 1996-03-13 | 2004-12-21 | Biochemie Gmbh | Auxiliary-free agglomerates |
| US5837292A (en) * | 1996-07-03 | 1998-11-17 | Yamanouchi Europe B.V. | Granulate for the preparation of fast-disintegrating and fast-dissolving compositions containing a high amount of drug |
| SK3999A3 (en) * | 1996-07-16 | 1999-07-12 | Gist Brocades Nv | 'beta'-lactam granules free of organic solvents |
| WO1998034598A2 (en) * | 1997-02-07 | 1998-08-13 | Gist-Brocades B.V. | Homogeneous granulated formulations for dose sipping technology |
| US20030124187A1 (en) * | 1997-02-14 | 2003-07-03 | Smithkline Beecham Laboratoires Pharmaceutiques, | Pharmaceutical formulations comprising amoxycillin and clavulanate |
| FR2766089B1 (en) * | 1997-07-21 | 2000-06-02 | Prographarm Lab | IMPROVED MULTIPARTICULAR TABLET WITH RAPID DELIVERY |
| EP1023065A1 (en) * | 1997-08-29 | 2000-08-02 | Dsm N.V. | Granules free of excipients |
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-
1988
- 1988-02-26 EP EP88200366A patent/EP0281200B1/en not_active Expired - Lifetime
- 1988-02-26 DE DE3887179T patent/DE3887179T2/en not_active Expired - Lifetime
- 1988-02-26 ES ES88200366T patent/ES2061623T3/en not_active Expired - Lifetime
- 1988-02-29 FI FI880928A patent/FI94214C/en active IP Right Grant
- 1988-03-01 AU AU12520/88A patent/AU603870B2/en not_active Expired
- 1988-03-01 NO NO880904A patent/NO174996C/en not_active IP Right Cessation
- 1988-03-01 DK DK198801088A patent/DK175508B1/en not_active IP Right Cessation
- 1988-03-01 PT PT86870A patent/PT86870B/en active IP Right Grant
- 1988-03-01 IL IL85594A patent/IL85594A/en not_active IP Right Cessation
- 1988-03-02 JP JP63049440A patent/JPS63301820A/en active Pending
- 1988-03-02 CN CN88101104A patent/CN1036763C/en not_active Expired - Lifetime
- 1988-03-02 NZ NZ223711A patent/NZ223711A/en unknown
- 1988-03-02 KR KR1019880002170A patent/KR960009182B1/en not_active IP Right Cessation
- 1988-03-02 IE IE58488A patent/IE70907B1/en not_active IP Right Cessation
- 1988-03-02 US US07/162,834 patent/US4950484A/en not_active Expired - Lifetime
- 1988-03-02 CA CA000560356A patent/CA1338467C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| DK108888A (en) | 1988-09-03 |
| DE3887179T2 (en) | 1994-06-16 |
| CN1036763C (en) | 1997-12-24 |
| EP0281200B1 (en) | 1994-01-19 |
| CN88101104A (en) | 1988-12-21 |
| FI94214B (en) | 1995-04-28 |
| DK175508B1 (en) | 2004-11-15 |
| IE70907B1 (en) | 1997-01-15 |
| FI94214C (en) | 1995-08-10 |
| FI880928A (en) | 1988-09-03 |
| IL85594A (en) | 1992-11-15 |
| NO174996C (en) | 1994-08-17 |
| AU603870B2 (en) | 1990-11-29 |
| KR880010757A (en) | 1988-10-24 |
| PT86870B (en) | 1992-05-29 |
| JPS63301820A (en) | 1988-12-08 |
| NO174996B (en) | 1994-05-09 |
| AU1252088A (en) | 1988-09-01 |
| NO880904D0 (en) | 1988-03-01 |
| ES2061623T3 (en) | 1994-12-16 |
| PT86870A (en) | 1988-04-01 |
| KR960009182B1 (en) | 1996-07-16 |
| DE3887179D1 (en) | 1994-03-03 |
| DK108888D0 (en) | 1988-03-01 |
| NZ223711A (en) | 1989-08-29 |
| FI880928A0 (en) | 1988-02-29 |
| NO880904L (en) | 1988-09-05 |
| US4950484A (en) | 1990-08-21 |
| EP0281200A1 (en) | 1988-09-07 |
| IE880584L (en) | 1988-09-02 |
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