AP328A - Pharmaceutical formulations for oral administration in the treatment of bacterial infections and process for their preparation. - Google Patents
Pharmaceutical formulations for oral administration in the treatment of bacterial infections and process for their preparation. Download PDFInfo
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- AP328A AP328A APAP/P/1992/000382A AP9200382A AP328A AP 328 A AP328 A AP 328A AP 9200382 A AP9200382 A AP 9200382A AP 328 A AP328 A AP 328A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- 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
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- 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
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- 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
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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- 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
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- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Tablet formulations having a structure comprising compacted granulates of a mixture of a medicament and an intra-granular disintergrant, the granulates being compacted together into a tablet with an extra-granular disintegrant and optional extra-granular lubricant and excipients.
Description
PHARMACEUTICAL FORMULATIONS
The present invention relates to pharmaceutical formulations for oral administration in the treatment of bacterial infections, and to processes for the manufacture of such formulations.
It is known to provide formulations for oral administration in the form of water-dispersible granules or tablets which may be swallowed or dispersed in water prior to swallowing.
In one known method of tablet manufacture, an intermediate granulate is prepared comprising an intragranular disintegrant and an active material such as an antibiotic. This granulate is then mixed with an intergranular disintegrant (and optional other additives including a lubricant) and compressed into tablets. Such a process, tablets and granulate are for example described in EP 0281200A, CA 1199871 and JP 3240023A.
It is desirable that such solid formulations should rapidly disperse on immersion in water, for example by rapid disintegration of tablets.
Novel formulations have now been discovered which assist in achieving some of the above-mentioned desirable features.
The invention therefore provides a tablet formulation having a structure comprising compacted granulates; the granulates comprising at least one compacted medicament optionally together with an intra-granular disintegrant; the granulates being compacted together into a tablet form together with an extra-granular disintegrant and optionally also together with an extra-granular lubricant, provided that if a lubricant is present the amount of lubricant is less than 0.5% by weight of the total tablet.
In the tablets of this invention the granulates may be in a crushed state resulting from the compaction of the tablet, and consequently may not have discrete boundaries, or may be sub-divided or broken up into smaller granulates. The invention is intended to include tablets having such a structure containing crushed granulates. Preferably the size of the granulates is in the range 100pm to 2mm, suitably around 1mm ±
0.25mm, maximum dimension.
P30048
-2The medicament is preferably one which is capable of oral absorption, in particular β-lactam antibiotics optionally in combination with a βlactamase inhibitor. A preferred antibiotic is amoxycillin, for example present as a hydrate such as the trihydrate. Amoxycillin may be used alone, or may optionally be used in combination with other β-lactam antibiotics and/or β-lactamase inhibitors such as clavulanic acid or salts (especially the potassium salt) thereof, for example in a weight ratio equivalent to amoxycillin: clavulanic acid in the range 12:1 to 1:1 such as around 4:1 or 2:1. Preferably the proportion of the antibiotic in the tablet is 60-98% by weight of the total tablet, in the case of amoxycillin trihydrate calculated as the weight of the trihydrate. Preferably the particles of antibiotic in the granulates are in the size range lpm to 300pm, especially 10pm to 200pm. A typical suitable size distribution of the antibiotic particles is : >200μ 5% or less, 200-100μ 5-15%, 100-50μ 7.5-15%, <50μ 70% or more.
Suitable intra-granular disintegrants are starches, such as maize starch and rice starch, cross-linked N-vinyl-2-pyrrolidone (CLPVP), sodium starch glycollate, croscarmellose sodium and formaldehyde - casein, or combinations thereof. A preferred intra-granular disintegrant is CLPVP, for example as marketed under the trade names Polyplasdone XL and Polyplasdone XL-10.
The granulate may consist entirely of antibiotic(s), optionally in the case of a β-lactam antibiotic combined with a β-lactamase inhibitor, and an intra-granular disintegrant. Alternatively, particularly when the granulate contains clavulanic acid or a salt thereof, the granulate may also contain a diluent such as silica gel (eg Syloid-Trade Mark). Suitable intra-granular disintegrants for use with antibiotics are CLPVP and sodium starch glycollate. Typically the proportion of intra-granular disintegrant in the granulate may be 0.1 - 10 wt % of the granulate, suitably 1.0 - 8.0wt %, such as 1.25 - 3.5wt %. Typically the proportion of an antibiotic or antibiotic + β-lactamase inhibitor combination in the granulate may be 99.9 - 90wt %, suitably 99 - 92wt %, e.g. 99 - 95wt%, such as 98.75 - 96.5wt % of the weight of the granulate. When the granulate contains a diluent, this may comprise up to 30wt % of the granulate, but is conveniently present in a 1:1 weight ratio with the
P30048
APO 00 32 8
-3amount of clavulanic acid or its salt in the granulate. When the granulate contains a diluent the granulate will contain a correspondingly lower proportion of antibiotic or antibiotic + β-lactamase inhibitor combination, for example 70 - 99.9wt % of the granulate.
The intimate contact between the antibiotic and the intra-granular disintegrant in the granulate appears to assist in improved disintegration and dispersion of the granulate in contact with water to release antibiotic particles in the size range referred to above, and to provide finely dispersed suspensions. Problems are associated with preparation of granulates which include clavulanic acid or its salts, due to their hygroscopicity, and the granulate of the invention facilitates manufacture.
In the tablet formulation the granulate may suitably comprise 70% or more, e.g. 80% or more, 90% or more or 95% or more of the total tablet weight so that a high proportion of medicament is present.
The extra-granular disintegrant may be a conventional disintegrant for example starches such as maize-starch and rice starch, CLPVP, sodium starch glycollate, croscarmellose sodium, microcrystalline or microfine cellulose, low-substituted hydroxypropylcellulose (i.e. cellulose partially substituted with 2-hydroxypropyl groups, e.g. less than 25% substituted, preferably 7-16% substituted), cross-linked sodium carboxymethylcellulose, swellable ion exchange resins, formaldehyde-casein, or alginates. Preferred extra-granular disintegrants are CLPVP, sodium starch glycollate, microfine cellulose and croscarmellose sodium, and combinations thereof. An example of an extra-granular disintegrant combination is a combination of microcrystalline or microfine cellulose with sodium starch glycollate, croscarmellose sodium, or CLPVP, containing 80-90% by weight cellulose.
The proportion of extra-granular disintegrant to total tablet weight may vary between broad limits, for example 0.1-25 weight %. For example if CLPVP or sodium starch glycollate is used as extra-granular disintegrant it may suitably be used as such in a proportion 0.1-5.0 weight %, suitably 0.1 - 3.0 weight %, preferably 0.1-1.5 weight % of the total tablet weight.
If cellulose or a combination containing cellulose is used, e.g. as described above containing around 80-90% by weight of cellulose, the extra-granular
P30048
-4disintegrant may comprise 1-25 weight %, typically around 1-20 weight % of the total tablet.
Suitable lubricants are those conventional to the art, such as long-chain fatty acids, such as stearic acid, or salts thereof, in particular Group II metal salts, such as of magnesium or calcium.
A preferred lubricant is magnesium stearate. It is preferred to use a lubricant proportion as low as possible e.g. 0.35% by weight or preferably lower, e.g. 0.275% or less, e.g. 0.25% or less, preferably using no lubricant at all.
The granulate may also contain an intra-granular lubricant, which may be selected from the same materials as the extra-granular lubricant, such as magnesium stearate. However an advantage of the present tablet formulation is that the granulate and tablet need not contain any lubricant. This can lead to improved wettability and hence improved disintegration of the tablet. Further a reduced lubricant proportion can lead to a lower tablet weight for a given dose of antibiotic and in the case of dispersible formulations can avoid the smeared appearance associated with higher lubricant proportions.
The tablet may also include conventional excipients, typically present up to about 10% of the total tablet weight. These may include flavouring agents, for example flavourings such as menthol, peppermint, vanilla or fruit flavourings, flavouring agents typically being present up to around 0.5-5% by weight of the whole tablet, and sweeteners, e.g. aspartame, present of up to around 15mg per unit dose. Excipients may also include colouring agents, preservatives, suspending aids and fillers such as silicon dioxide, microcrystalline cellulose, dicalcium phosphate, lactose, sorbitol, calcium carbonate or magnesium carbonate. Such excipients are preferably mixed with the extra-granular disintegrant and lubricant (if present). The materials present in the tablets should have low free moisture content and preferably be pre-dried. In some cases, particularly when the medicament is an antibiotic, and includes clavulanic acid or its salts, it may be necessary to include a dessiccant diluent such as silica gel as an excipient, in a proportion of about 1-5% of the weight of the antibiotic, mixed with the antibiotic and intra-granular disintegrant in
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-5the granulates. The particle size of the excipients does not appear to be critical but it is desirable to exclude agglomerates.
The tablet may also contain an effervescent couple of known type, e.g. a 5 solid acid and an alkali metal carbonate or bicarbonate which generates carbon dioxide on contact with water to assist in disintegration of the tablet.
The tablets may be film coated in a conventional manner, e.g. for cosmetic, 10 palatability or production purposes. Suitable coatings include hydroxypropylcellulose, acrylate and/or methacrylate co-polymers, resins etc. Alternatively the coating may be an enteric coating, e.g. which is insoluble in acidic gastric juice but soluble in alkaline digestive juice.
Such a coating enables the antibiotic to pass through the stomach into the duodenum, from where it is absorbed. Suitable enteric coatings include cellulose acetate phthalate.
Preferred combinations of components for the tablets of this aspect of the invention therefore comprise:
P30048
Granulate: Component | Example | |
Medicament | 70-99 | Amoxycillin + Pot.clavulanate |
Disintegrant | 0.1 -4 | CLPVP, Microcryst. cellulose, sodium starch glycollate |
Diluent | 0-30 | Silica gel |
Tablet Component | wt% | Example |
Granulate | 70+ | above |
Disintegrant | 0.1-25 | CLPVP, Microcryst. cellulose, sodium starch glycollate. |
Lubricant | 0 - 0.35 | Magnesium stearate |
Excipients | to 100 | Aspartame, flavour, colour, silicon dioxide |
The invention also provides a process for the manufacture of a tablet in which granulates comprising a compacted mixture of at least one medicament such as a β-lactam antibiotic either alone or in combination with a β-lactamase inhibitor, together with an intra-granular disintegrant are mixed with an extra-granular disintegrant and optionally with an extra-granular lubricant and optionally with any excipients, provided that if a lubricant is present it amounts to less than 0.5% by weight of the mixture, and the mixture is compressed into tablets.
Suitable and preferred antibiotics, intra- and extra-granular disintegrants, lubricants, excipients, granulate and particle sizes, and relative proportions thereof are as discussed above.
The necessary granulate for the process of this aspect of the invention
P30048
AP 0 0 0 3 2 8 •7may be made in a further process by mixing the medicament in a powdered form with the intra-granular disintegrant in a dry state, and compacting the mixture under pressure. Insofar as this further process uses as intra-granular disintegrant CLPVP, sodium starch glycollate, casein-formaldehyde, croscarmellose sodium or combinations thereof, it is believed to be novel, and is a further aspect of this invention.
In this further process, it is desirable to mill and sieve the antibiotic to achieve the desired particle size range. It is also desirable to mill and sieve intra-granular disintegrant to a suitable particle size, for example in the case of CLPVP about 30μ, but particle size does not appear to be critical.
The compaction of the mixture into granulates may be by conventional dry compaction means, for example pressing, rolling, slugging extrusion etc, and a suitable pressure for the compaction process is 30-200KN, e.g. 35-65KN preferably 40-50 KN. The above-described granulate formulations are particularly suited to formation by roller compaction. It may be necessary to mill and sieve the compacted mixture after compaction so as to achieve a suitable size fraction of the granulate. Compression into tablets may be carried out in a conventional manner, e.g. on a conventional tabletting machine. As an optional further step the tablets may be coated as described above.
When the granulates described above contain as a medicament a β-lactam antibiotic such as amoxycillin together in combination with a β-lactamase inhibitor such as clavulanic acid or its salts (especially potassium clavulanate) these granulates are believed to be novel and are a further aspect of this invention. Suitable and preferred features of these granules are as discussed above.
The granulates described above may be suitable for use in the preparation of other pharmaceutical formulations in addition to tablets, for example they may be supplied as a free-flowing granulated formulation in sachets containing a suitable unit dose. This may also for example be dissolved in water together with excipients such as sweetening agents, thickeners, preservatives and buffers such as sodium benzoate, sodium acetate and sodium citrate to form a syrup formulation, for example for administration
P30048
-βίο small children.
The ability of the granulates to form a loose compact, and their rapid dispersion in contact with water makes them particularly suitable for use in encapsulated formulations. Therefore in a further aspect of this invention there is provided an encapsulated formulation comprising such granulates. The encapsulated formulation may optionally include an extra-granular lubricant, which if present is suitably in an amount of less than 0.5% by weight of the granulates, being contained within a pharmaceutical capsule.
The medicament is preferably one which is capable of oral absorption, in particular a β-lactam antibiotic optionally in combination with a βlactamase inhibitor. Suitable and preferred antibiotics, β-lactamase inhibitors, intra-granular disintegrant, extra-granular lubricant, granulate and particle sizes, and relative proportions thereof for a capsule formulation are as discussed above, except that a preferred proportion of lubricant is 0.1-0.5%. particularly 0.32-0.35% by weight of the granulate.
The pharmaceutical capsule may be an entirely conventional capsule, capable of dissolving in the stomach to release its contents, for example made of gelatine.
The formulations described above preferably contain unit doses of antibiotic, for example 375, 500, 750 or lOOOmg of amoxycillin per tablet or capsule. The tablets may be dispersed in water prior to ingestion, or may alternatively be chewed or swallowed whole.
The invention further provides a pharmaceutical formulation as described above, for use as an active therapeutic substance.
The invention further provides a pharmaceutical formulation as described above, in which the medicament is a β-lactam antibiotic optionally in combination with a β-lactamase inhibitor, for use in the treatment of bacterial infections.
The invention futher provides a method of use of a pharmaceutical formulation as described above in which the medicament is a β-lactam
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AP Ο Ο Ο 3 2 8
-9antibiotic optionally in combination with a β-lactamase inhibitor in the manufacture of a medicament for use in the treatment of bacterial infections.
The invention further provides a method of treament of bacterial infections in mammals which comprises the administration to the mammal of an effective amount of a pharmaceutical formulation as described above, in whcih the medicament is a β-lactam antibiotic, optionally in combination with a β-lactamase inhibitor.
The invention will now be described by way of example only.
Example.!; .Granulate.
Amoxycillin trihydrate was milled and sieved using an 0.04 or 0.027 inch (1.0 - 0.7 mm) aperture sieve, and was mixed for 15 minutes in a blender with dried cross-linked polyvinylpyrrolidone having a molecular weight of approximately 1 million and a density of 1.22 mgfem 3 (polyplasdone XL Trade Mark), the mixture containing 3.4% of CLPVP by weight.
The mixture was consolidated using a roller compacter at a controlled pressure of 50KN. The compacted flakes were granulated in a mill, or granulated through a sieve fitted with a 1mm mesh to obtain a suitable size fraction.
Example 2; Tablet,
Tablets were prepared having the composition below;
Component | Weight, mg. | Weights |
Amoxycillin trihydrate | 7501 | 78.95 as granulate of |
example 1 | ||
CLPVP | 26.0 | 2.73, |
Sodium Starch | 21.6 | 2.27 |
Giycollate (Primogel) | ||
Magnesium Stearate | 2.0 | 0.21 extra granulate |
Aspartame | 20.0 | 2.10 |
P30048 ·· ) υ hA
- 10Microcrys tailine 130.4 13.74
Cellulose (Avicel PH102) (1) Expressed or free acid equivalent:
To prepare these tablets, the dried sodium starch glycollate, magnesium stearate and microcrystalline cellulose were sieved, then blended with the granulate of example 1. The aspartame was then added, and this mixture was then blended until homogeneous (5 minutes). The mixture was then compressed into tablets on a conventional tabletting machine.
Example 3: Granulate.
A granulate was prepared using a procedure identical to example 1, comprising 97 weight % of amoxycillin trihydrate and 3 weight % polyplasdone XL, and using a controlled pressure of 40-50 KN.
Example 4;.TableL
Tablets were prepared having the composition below:
Component | wt, mg | wt. mg | wt. mg | wt. mg | wt, % |
Amoxycillin | 375 | 500 | 750 | 1000 | 83.001 |
CLPVP | 17.5 | 23.33 | 35 | 46.65 | 3.782 |
Peppermint | 3 | 4 | 6 | 7.99 | 0.65 |
dry flavour | |||||
Aspartame | 7.5 | 10 | 15 | 19.99 | 1.62 |
Magnesium | 1 | 1.34 | 2 | 2.67 | 0.21 |
stearate (1) As 95 wt. % of amoxycillin trihydrate.
(2) 3% as intra-granular, and 0.78% as extra-granular disintegrant.
To prepare these tablets, the dried flavour, aspartame, magnesium stearate and a weight of CLPVP (polyplasdone XL) corresponding to 0.78 wt. % of the total weight of the mixture was mixed for 5 minutes with the granulate of example 3 to give the wt % indicated above. The mixture was then compressed into tablets on a conventional tabletting machine.
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AP 0 0 0 3 2 8
- 11 Typical tablets of this example containing 750mg of amoxycillin as the trihydrate had the following characteristics:
weight : 925mg ± 5% hardness : > 16 KP time of dispersal: < 1 minute in water friability : <1% presentation : Oval, 17 x 10 x 7mm tablets
Example 5: Granulate
A granulate was prepared using a procedure identical to that of example 1, comprising 97.12 weight % amoxycillin trihydrate together with 2.88 weight % sodium starch glycollate (as Primogel) as intra-granular disintegrant.
Example 6; Tablet
Tablets were prepared having the composition below:
Component# | Weight mg. | Weight % | |
Amoxycillin | 750mgl | 78.95 | as granulate |
Sodium starch glycollate | 21.6 mg | 2.27 | of example 5 |
Magnesium stearate Dried microcrystalline cellulose (Avicel PHI 02) | 2.0mg to 950mg | 0.21 18.5^ | extra granulate |
(1) As free acid equivalent
To prepare these tablets, the granulate of example 5 was sieved using a 1mm sieve, and was then blended with appropriate quantities of the magnesium stearate (lubricant) and microcrystalline cellulose, mixing for 15 minutes. The mixture was then compacted to form tablets having the
P30048
- 12following characteristics:
weight :
hardness :
time of dispersal: in water
950mg
12- 16 KP
10-15 seconds (37°C), 20-25 seconds (20°C)
These tablets could be provided in the above-described uncoated state for dispersion in water prior to swollowing, or could be film coated for swollowing.
Example 7: Encapsulated Formulation
The granulate of example 3 was made up into a loose compact under gentle pressure together with an amount of magnesium stearate lubricant to total 0.34% by weight of the total compact. This loose compact was sealed into gelatin capsules containing the following mixture:
Component Weight mg. Weight %
Amoxycillin trihydrate: 573.91^ 96.8
CLPVP 17 2.9 magnesium stearate 2 0.34 (1) corresponds to 500mg amoxycillin free acid
Example 8: Sachet Formulation
Component
Weight mg.
Weight %
Amoxycillin trihydrate Potassium
2711.1
76.12 granulate clavulanate/syloid AL-1 blend 1:1
Polyplasdone XL dried
Polyplasdone XL dried Lemon dry flavour
13.5
408.0
0.38
11.45 extra granular
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AP Ο Ο Ο 3 2 8
Strawberry dry flavour | 132.0 | 3.71 |
Peach dry flavour | 102.0 | 2.86 |
Aspartame | 45.0 | 1.26 |
Xantham Gum | 150.0 | 4.21 |
Granules were in a manner identical to that of example 1, i.e. by milling and sieving of the granulate components, followed by roller compaction (50KN) and granulation. The granules could be made up into a mixture suitable for a sachet presentation with the extra-granular excipients.
The granulate of this example could be supplied confining appropriate weights of amoxycillin/clavulanate in a sachet, and is also suitable for making up into syrup formulations. For example the weights listed may be made up into 60ml to produce a 156.25mg/5ml syrup or double the listed weights may be made up into 60ml to produce a 312.5mg.5ml syrup. These syrups do not contain any added sugar.
Example 9:. Granulate
Component | Weight mg. | Weight % |
Amoxycillin trihydrate | 581.41 | 64.0* |
Potassium clavulanate | 152.42 | 16.8 as granulate |
Syloid AL-1 | 152.4 | 16.8 |
Polyplasdone XL dried | 22.0 | 2.42 |
(1) corresponds to 500mg amoxycillin free acid.
(2) corresponds to 125mg free clavulanic acid.
Granules are prepared using this mixture in a manner identical to that of example 8. These granules are suitable for supply in a sachet, together with flavour and sucrose in the proportions listed below for the quantity of granules listed above per sachet;
Lemon dry flavour 136.0mg
Strawberry dry flaovur 44. Omg Peach dry flavour 34.Omg
Sucrose to 3500mg
P30048 ιΛ
- 14Sachets containing other weights of amoxycillin, e.g. 250 or 125mg could be made up using proportional amounts of the weights listed and made up to 1750mg total weight with sucrose.
Example 10: Tablet
Component Amoxycillin trihydrate Potassium clavulanate Syloid AL-1 Polyplasdone XL dried | Weight mg- 581.41 152.42 152.4 17.4 | Weight % | |
61.2 16.0 16.0 1.83 | as granulate | ||
Dry flavour (Peppermint or | 6.0 | 0.63 | |
mandarin) | |||
Polyplasdone XL dried | 25.0 | 2.63 | axtra granulate |
Aspartame | 15.0 | 1.58 | |
Colouring | 5.0 | 0.53 | |
Magnesium stearate | 2.5 | 0.26 |
(1) corresponds to 500mg amoxycillin free acid.
(2) corresponds to 125mg free clavulanic acid.
Granules are prepared using this mixture in a manner identical to that of example 8. The flavour, polyplasdone XL, colouring and magnesium stearate were sieved then blended with the granulate. The aspartame was then added, and this mixture was then compressed into tablets on a conventional tabletting machine. This tablet contains 625.0mg of the amoxycillin: clavulanate combination, and the quantities used may be halved to prepare a tablet containing 312.5mg.
P30048
APO00328
- 15Example.ll; Tablet
Component Amoxycillin trihydrate Potassium clavulanate Syloid AL-1 Polyplasdone XL dried | Weight mg. 290.71 152.42 152.4 8.7 | Weight % | |
46.3 24.3 24.3 1.3¾ | as granulate | ||
Dry flavour (Peppermint or | 3.0 | 0.48 | |
mandarin) | |||
Polyplasdone XL dried | 12.5 | 2.00 | extra granulate |
Aspartame | 7.5 | 1.19 | |
Colouring | 2.5 | 0.39 | |
Magnesium stearate | 1.25 | 0.20 |
(1) corresponds to 250mg amoxycillin free acid.
(2) corresponds to 125mg free clavulanic acid.
Tablets were made from this mixture using a procedure identical to that of example 10.
Example 12 : Sachet or Syrup Formulations
Component | Weight mg | y.t % | |
Amoxycillin : potassium clavulanate 4 : 1 w : w + 3 wt% CLPVP | granulate1 | 2255.6 | 63.3 |
CLPVP | 13.5 | 0.38 | |
Lemon dry flavour | 408.0 | 11.46 | |
Strawberry dry flavour | 132.0 | 3.71 | |
Peach dry flavour | 102.0 | 2.86 | |
Silicon dioxide USNF (Syloid AL-1) | 450.0 | 12.64 | |
Aspartame | 45.0 | 1.26 | |
Xantham gum | 150.0 | 4.21 | |
Total weight | 3561.6 | 100.0 |
P30048 'Ί '
- 16(1) amox : clav expressed as free acid.
The granulate was prepared using the procedure of example 8. This formulation could be supplied in a sachet, or could be made up into a 5 syrup, for example at concentrations of 3561.6 mg/60ml or 7123.2 mg/60 ml or 7123.2 mg/60 ml (= 156.25 and 312.5 mg amoxycillin : clavulanate / 5 ml respectively). To adjust the syrup to a suitable viscosity and pH, aerosil 200, succinic acid and/or methocel E - 15 (dry) may be used.
Example 13 : Sachet Formulation
Component | Weight (mg) | w +% | |||
Granulate (Amox:Kclav | |||||
4:1 or 7:1 + 3%PVP) | 500 | 250 | 125 | 875 | 7-25 |
Lemon dry flavour | 136 | 68 | 34 | 136) | |
Strawberry dry flavour | 44 | 22 | 11 | 44) | 3-6.1 |
Peach dry flavour | 34 | 17 | 8.5 | 34) | |
Silicon Dioxide U.S.N.F. | 150 | 75 | 37.5 | 150 | 2.1-4.3 |
(Syloid AL-1) | |||||
Sucrose to | 3500 | 1750 | 1750 | 3500 | to 100 |
(1) weights and Amox/Kclav expressed as free acid.
The granulate was prepared using the procedure of example 8, and was then mixed with the other excipients.
P30048
AP Ο 00 32 8
- 17 Example 14 : Tablet Formulation
Amox : clav^ Ccmponenl | 4 : 1 | 4:1 2:1 weight (mg) | 7 : 1 | w + % | |
Granulate2 | 751.9 | 376.0 | 452.1 | 1201.3 | 70.90 |
Dry Flavour 3 | 6.0 | 3.0 | 3.0 | 8.0 | 0.48 - 0.63 |
Poliplasdone XL) | 100.0 | 50.0 | 66.5 | 110.0 | 8.1 - 10.7 |
dried ) | |||||
Aspartame | 15.0 | 7.5 | 7.5 | 15.0 | 1.1 - 1.6 |
Colouring | 4-5 | 2-2.5 | 2-2.5 | 4-5 | 0.3 - 0.55 |
Mag. Stearate | 2.5 | 1.25 | 1.25 | 3.4 | 0.19-0.26 |
Silicon Dioxide ) | |||||
Syloid AL - 1 ) tfi | 950 | 475 | 628 | 1350 | to 100 |
Π) Amox : clav expressed as weight: weight of amoxycillin :
clavulanate free acid.
(2) Granulate = amox : clav + 3% CLPVP.
(3) Peppermint or mandarin.
The granulate was prepared using the procedure of example 9.
The granulate was prepared using the procedure of example 9. The other excipients except aspartame were sieved and blended then mixed with the granulate. The aspartame was then added, and this mixture was then compressed into tablets in a conventional tabletting machine. This tablet contained 625 mg of the amoxycillin : clavulante blend. Tablets of different strengths could be formulated correspondingly, eg containing 1000, 375 or 312.5 mg of the amoxycillin : clavulanate combination.
P30048
- 18Example 15 : Tablet Formulation
Component Weight (mg) w +%
Granulate (Amox.Kclav) 4:1 or 7:1+ 3% PVP | 751.9 | 376.0 | 188.0 | 1201.3 | 71-83 |
Magnesium stearate Ph. Eur | 2.6 | 1.3 | 0.65 | 3.9 | 0.25 - 0.27 |
Silicon Dioxide USP /NE (Syloid AL-1) | 44.0 | 22.0 | 11.0 | 44.0 | 3 - 4.25 |
Microcrystalline cellulose Avicel pH 112 dried ...to.. | 850.0 | 425.0 | 212.5 | 1275.0 | 1.8-5 |
Organic film coating | yes | yes | yes | yes | to 100 |
Actual weight | 1050.0 | - | - | 1450.0 |
(1) amox : clav expressed as free acid.
The tablet was made up in a manner identical to that of example 14.
The weights and relative proportions of the components of examples 1 to 15 could be varied about the figures listed, but suitably are within ± 10% of those listed, desirably within ± 5%, especially ± 2.5%.
Claims (22)
- ClaimsAP 0 0 ft 32 8- -·: .(tt.co1. A tablet formulation having a structure comprising compacted granulates; the granulates comprising at least one compacted medicament optionally together with an intra-granular disintegrant; the granulates being compacted together into a tablet form together with an extragranular disintegrant and optionally also together with an extra-granular lubricant, provided that if a lubricant is present the amount of lubricant is less than 0.5% by weight of the total tablet.
- 2. A tablet formulation according to claim 1 wherein the medicament is a β-lactam antibiotic, optionally in combination with a β-lactamase inhibitor.
- 3. A tablet formulation according to claim 2 wherein the antibiotic is amoxycillin, optionally in combination with clavulanic acid or a salt thereof in a weight ratio equivalent to amoxycillin : clavulanic acid in the range 12 : 1 to 1: 1.
- 4. A tablet formulation according to claim 1, 2 or 3 wherein the intragranular disintegrant is selected from maize starch, rice starch, cross linked N-vinyl-2-pyrrolidone (CLPVP), sodium starch glycollate, croscarmellose sodium, formaldehyde-casein or combinations thereof.
- 5. A tablet formulation according to any one of the preceding claims wherein the proportion of intra-granular disintegrant is 0.1 to 10 wt % of the weight of the granulate.
- 6. A tablet formulation according to any one of claims 1 to 6 in which the granulate comprises a medicament which is amoxycillin or amoxycillin + clavulanic acid or a salt thereof in combination, an intra-granular disintegrant which is CLPVP or sodium starch glycollate, and optionally one or more diluent(s), in a proportion 70-99 wt % medicament, 1 - 5 wt % disintegrant and up to 30 wt % diluent.
- 7. A tablet formulation according to any one of the preceding claims wherein the granulate comprises 70 wt % or more of the tablet weight.P30048/C- 28. A tablet formulation according to any one of the preceding claims in which the extra-granular disintegrant is selected from maize starch, rice starch, CLPVP, sodium starch glycollate, croscarmellose sodium, microcrystalline or microfine cellulose, low-substituted hydroxypropylcellulose, cross-linked sodium carboxymethylcellulose, swellable ion exchange resins, formaldehyde-casein, or alginates.
- 9. A tablet formulation according to any one of the preceding claims wherein the proportion of extra-granular disintegrant in the tablet is between 0.1 - 25 wt % of the total tablet weight.
- 10. A tablet formulation according to any one of the preceding claims which contains 0 - 0.35 wt % lubricant.
- 11. A pharmaceutical granulate formulation comprising a medicament which is a β-lactam antibiotic together in combination with a β-lactamase inhibitor.
- 12. A formulation according to claim 11 wherein the medicament is amoxycillin in combination with clavulanic acid or a salt thereof in a weight ratio equivalent to amoxycillin: clavulanic acid in the range 12:1 to 1:1.
- 13. A formulation according to claim 11 or 12 wherein the formulation additionally includes an intra-granular disintegrant.
- 14. A formulation according to claim 13 wherein the disintegrant is selected from maize starch, CLPVP, sodium starch glycollate, croscarmellose sodium, formaldehyde-casein or combinations thereof.
- 15. A formulation according to claim 13 or 14 wherein the proportion of intra-granular disintegrant is 0.1 to 10 wt % of the formulation.
- 16. A formulation according to claim 11 in which the granulate comprises a medicament which is amoxycillin plus clavulanic acid or a salt thereof in combination, an intra-granular disintegrant which is CLPVP or sodium starch glycollate, and optionally one or more diluent(s) in a proportion 70-99 wt % medicament, 1-5 wt % disintegrant and up toP30048/CAP 0 0 0 3 2 β-330 wt % diluent.
- 17. A formulation according to any one of claims 11 to 16 or a granulate as defined in claim 1 or a granulate as defined in claim 1 when encapsulated in a pharmaceutical capsule.
- 18. A process for the manufacture of a pharmaceutical tablet, in which granulates comprising at least one compacted medicament optionally together with an intra-granular disintegrant are mixed with an extragranular disintegrant and optionally with an extra granular lubricant and excipients, provided that if a lubricant is present it amounts to less than 0.5 wt % of the mixture, and the mixture is compressed into tablets.
- 19. A process for the manufacture of a pharmaceutical granulate, in which a medicament which is a β-lactam antibiotic together in combination with a β-lactamase inhibitor is compacted under pressure, optionally together with an intra-granular disintegrant.
- 20. A process according to claim 19 wherein the compaction is carried out using roller compaction.
- 21. A pharmaceutical formulation according to any one of claims 1 to 17 for use as an active therapeutic substance.
- 22. A pharmaceutical formulation according to any one of claims 1 to 17, in which the medicament is a β-lactam antibiotic optionally in combination with a β-lactamase inhibitor, for use in the treatment of bacterial infections.
- 23. A method of use of a pharmaceutical formulation according to any one of claims 1 to 17 in which the medicament is a β-lactam antibiotic optionally in combination with a β-lactamase inhibitor, in the manufacture of a medicament for use in the treatment of bacterial infections.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB919109862A GB9109862D0 (en) | 1991-05-08 | 1991-05-08 | Pharmaceutical formulations |
Publications (2)
Publication Number | Publication Date |
---|---|
AP9200382A0 AP9200382A0 (en) | 1992-07-31 |
AP328A true AP328A (en) | 1994-03-23 |
Family
ID=10694582
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
APAP/P/1992/000382A AP328A (en) | 1991-05-08 | 1992-05-06 | Pharmaceutical formulations for oral administration in the treatment of bacterial infections and process for their preparation. |
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US (3) | US6110497A (en) |
EP (3) | EP0783889B1 (en) |
JP (1) | JPH06507396A (en) |
KR (1) | KR100228450B1 (en) |
CN (2) | CN1056277C (en) |
AP (1) | AP328A (en) |
AT (3) | ATE252900T1 (en) |
AU (1) | AU659836B2 (en) |
BR (1) | BR9205948A (en) |
CA (1) | CA2102630C (en) |
CZ (1) | CZ291795B6 (en) |
DE (3) | DE69233464T2 (en) |
DK (1) | DK0585252T3 (en) |
ES (3) | ES2235210T3 (en) |
FI (1) | FI110354B (en) |
GB (1) | GB9109862D0 (en) |
GR (1) | GR3036937T3 (en) |
HU (1) | HU219348B (en) |
IE (1) | IE921472A1 (en) |
IL (1) | IL101795A (en) |
MA (1) | MA22522A1 (en) |
MX (1) | MX9202118A (en) |
MY (1) | MY111879A (en) |
NO (1) | NO312224B1 (en) |
NZ (1) | NZ242625A (en) |
PT (1) | PT100458B (en) |
SA (1) | SA92130069B1 (en) |
SG (1) | SG55163A1 (en) |
SK (1) | SK282333B6 (en) |
TW (1) | TW240172B (en) |
WO (1) | WO1992019227A2 (en) |
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Families Citing this family (102)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9109862D0 (en) * | 1991-05-08 | 1991-07-03 | Beecham Lab Sa | Pharmaceutical formulations |
GB9416600D0 (en) * | 1994-08-17 | 1994-10-12 | Smithkline Beecham Plc | Pharmaceutical formulation |
GB9416599D0 (en) * | 1994-08-17 | 1994-10-12 | Smithkline Beecham Plc | Pharmaceutical formulation |
ES2079327B1 (en) * | 1994-12-13 | 1996-08-01 | Lilly Sa | PHARMACEUTICAL FORMULATIONS OF CEFACLOR. |
GB9501127D0 (en) * | 1995-01-20 | 1995-03-08 | Wellcome Found | Tablet |
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 |
JPH11510811A (en) * | 1995-08-12 | 1999-09-21 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | Pharmaceutical prescription |
IL123563A (en) | 1995-09-07 | 2002-02-10 | Smithkline Beecham Corp | Pharmaceutical formulations comprising amoxycillin and clavulanate in a weight ratio between 14:1 and 16:1 inclusive |
ES2231369T3 (en) * | 1996-02-29 | 2005-05-16 | Fujisawa Pharmaceutical Co., Ltd. | RAPID DISGREGATION GRANULUM OF A SYNTHETIC EDULCORANT CONTAINING SILICON ACID AND / OR SILICON DIOXIDE. |
AT407701B (en) * | 1996-08-12 | 2001-05-25 | Biochemie Gmbh | Mixture which is suitable for direct tableting and contains as essential components amoxicillin trihydrate and the calcium salt of clavulanic acid, and process for preparing this mixture |
TWI225402B (en) * | 1996-03-13 | 2004-12-21 | Biochemie Gmbh | Auxiliary-free agglomerates |
US6893664B1 (en) | 1996-06-17 | 2005-05-17 | Powderject Research Limited | Particle delivery techniques |
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 |
GB9616536D0 (en) | 1996-08-06 | 1996-09-25 | Quadrant Holdings Cambridge | Co-amoxiclav dosage form |
WO1998034598A2 (en) * | 1997-02-07 | 1998-08-13 | Gist-Brocades B.V. | Homogeneous granulated formulations for dose sipping technology |
ES2201468T3 (en) * | 1997-02-14 | 2004-03-16 | Laboratoire Glaxosmithkline S.A.S. | PHARMACEUTICAL PREPARATION THAT INCLUDES AMOXYCLINE AND CLAVULANATE. |
US20030124187A1 (en) * | 1997-02-14 | 2003-07-03 | Smithkline Beecham Laboratoires Pharmaceutiques, | Pharmaceutical formulations comprising amoxycillin and clavulanate |
TR200000529T2 (en) * | 1997-08-29 | 2000-08-21 | Dsm N.V. | Granules without excipients |
DE19820801A1 (en) * | 1998-05-09 | 1999-11-25 | Gruenenthal Gmbh | Oral dosage form for gatifloxacin, providing reproducible decomposition time and drug release |
US6177421B1 (en) | 1999-05-04 | 2001-01-23 | Fuisz International Ltd. | Amoxicillin and clavulanate composition |
WO2000025751A2 (en) * | 1998-10-30 | 2000-05-11 | Fuisz International Ltd. | Improved amoxycillin and clavulanate composition |
IE990159A1 (en) * | 1999-02-26 | 2000-09-20 | Fuisz Internat Ltd | Storage Stable Amoxycillin and Clavulanate Suspension Composition. |
EP1165049B2 (en) | 1999-04-01 | 2011-07-06 | DSM IP Assets B.V. | Agglomerates by crystallisation |
US6294199B1 (en) * | 1999-04-13 | 2001-09-25 | Beecham Pharmaceuticals (Pte) Limited | Method of treating a bacterial infection comprising administering amoxycillin |
US6878386B1 (en) | 1999-04-13 | 2005-04-12 | Beecham Pharmaceuticals (Pte) Limited | Method of treating a bacterial infection comprising amoxycillin and potassium clavulanate |
DE10017883A1 (en) * | 1999-04-13 | 2000-10-26 | Beecham Pharm Pte Ltd | New treatment procedure |
US7250176B1 (en) | 1999-04-13 | 2007-07-31 | Beecham Pharmaceuticals (Pte) Limited | Method of treating a bacterial infection |
US20020006433A1 (en) * | 1999-04-29 | 2002-01-17 | Nigel P. Davidson | Pharmaceutical formulations |
GB9930578D0 (en) * | 1999-12-23 | 2000-02-16 | Smithkline Beecham Plc | Pharmaceutical formulations |
US6565882B2 (en) * | 2000-02-24 | 2003-05-20 | Advancis Pharmaceutical Corp | Antibiotic composition with inhibitor |
US6544555B2 (en) | 2000-02-24 | 2003-04-08 | Advancis Pharmaceutical Corp. | Antibiotic product, use and formulation thereof |
US6756057B2 (en) | 2000-10-12 | 2004-06-29 | Beecham Pharmaceuticals (Pte) Limited | Amoxicillin and potassium clavulanate dosage form |
WO2002030392A2 (en) | 2000-10-12 | 2002-04-18 | Beecham Pharmaceuticals (Pte) Limited | Formulation containing amoxicillin |
US20020068078A1 (en) * | 2000-10-13 | 2002-06-06 | Rudnic Edward M. | Antifungal product, use and formulation thereof |
US6541014B2 (en) * | 2000-10-13 | 2003-04-01 | Advancis Pharmaceutical Corp. | Antiviral product, use and formulation thereof |
WO2002032906A1 (en) * | 2000-10-20 | 2002-04-25 | Biochemie Gesellschaft M.B.H. | Pharmaceutical compositions |
US20020197314A1 (en) * | 2001-02-23 | 2002-12-26 | Rudnic Edward M. | Anti-fungal composition |
US6720000B2 (en) | 2001-03-19 | 2004-04-13 | Three Rivers Pharmaceutical, Llc | Process for producing wet ribavirin pellets |
AT412344B (en) * | 2001-04-12 | 2005-01-25 | Sandoz Ag | Pharmaceutical composition useful for reducing rapid degradation of the active ingredient comprises clavulanate, in the form of granulated and hydrophobised particles, and an active ingredient |
AT413983B (en) * | 2001-04-12 | 2006-08-15 | Sandoz Ag | Pharmaceutical composition useful for reducing rapid degradation of the active ingredient comprises clavulanate, in the form of granulated and hydrophobised particles, and an active ingredient |
WO2003086343A2 (en) * | 2002-04-05 | 2003-10-23 | Cadila Healthcare Limited | Fast disintegrating oral dosage forms |
BR0312728A (en) * | 2002-07-16 | 2005-04-26 | Ranbaxy Lab Ltd | Dispersible tablet formulation and process for its preparation |
US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US7538094B2 (en) | 2002-09-19 | 2009-05-26 | Three Rivers Pharmacueticals, Llc | Composition containing ribavirin and use thereof |
CA2406592C (en) * | 2002-10-04 | 2003-09-30 | Duchesnay Inc. | Method of preparing pharmaceutical dosage forms containing multiple active ingredients |
CA2533292C (en) * | 2003-07-21 | 2013-12-31 | Advancis Pharmaceutical Corporation | Antibiotic product, use and formulation thereof |
CA2533178C (en) * | 2003-07-21 | 2014-03-11 | Advancis Pharmaceutical Corporation | Antibiotic product, use and formulation thereof |
AU2004258944B2 (en) * | 2003-07-21 | 2011-02-10 | Shionogi, Inc. | Antibiotic product, use and formulation thereof |
FR2858556B1 (en) * | 2003-08-06 | 2006-03-10 | Galenix Innovations | DISPERSIBLE AND / OR ORODISPERSIBLE SOLID PHARMACEUTICAL COMPOSITION, NOT PELLETIZED, CONTAINING AT LEAST THE METFORMIN ACTIVE INGREDIENT, AND PROCESS FOR PREPARING THE SAME |
EP1653925A1 (en) | 2003-08-11 | 2006-05-10 | Advancis Pharmaceutical Corporation | Robust pellet |
JP2007502294A (en) | 2003-08-12 | 2007-02-08 | アドバンシス ファーマスーティカル コーポレイション | Antibiotic preparations, their use and preparation |
WO2005021056A1 (en) * | 2003-08-21 | 2005-03-10 | Cns, Inc. | Effervescent delivery system |
WO2005023184A2 (en) * | 2003-08-29 | 2005-03-17 | Advancis Pharmaceuticals Corporation | Antibiotic product, use and formulation thereof |
CA2538064C (en) * | 2003-09-15 | 2013-12-17 | Advancis Pharmaceutical Corporation | Antibiotic product, use and formulation thereof |
WO2005044236A1 (en) * | 2003-10-27 | 2005-05-19 | Control Delivery Systems, Inc. | Suspension delivery system for the sustained and controlled local release of pharmaceuticals |
AU2004308419B2 (en) * | 2003-12-24 | 2011-06-02 | Victory Pharma, Inc. | Enhanced absorption of modified release dosage forms |
AU2005215147B2 (en) * | 2004-02-24 | 2011-05-26 | Sandoz Ag | Amoxicillin instant granulate |
CN1767818A (en) * | 2004-05-31 | 2006-05-03 | 三亚药品株式会社 | Dispersible tablet comprising beta lactam antibiotics and process for preparing the same |
EP1771158A4 (en) * | 2004-07-02 | 2008-03-12 | Advancis Pharmaceutical Corp | Tablet for pulsed delivery |
DE102004054054A1 (en) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines |
CA2598530C (en) | 2005-03-03 | 2014-12-16 | Janssen Pharmaceutica N.V. | Substituted oxa-diaza-spiro-[5.5]-undecanone derivatives and their use as neurokinin antagonists |
EA014239B1 (en) | 2005-03-08 | 2010-10-29 | Янссен Фармацевтика Н.В. | Diaza-spiro-[4.4]-nonane derivatives as neurokinin (nk1) antagonists |
WO2007058397A1 (en) * | 2005-11-17 | 2007-05-24 | Gl Pharmtech Corp. | A dispersible tablet comprising the mixture of amoxicillin and clavulanic acid or its salts and processes for preparing the same |
US8357394B2 (en) | 2005-12-08 | 2013-01-22 | Shionogi Inc. | Compositions and methods for improved efficacy of penicillin-type antibiotics |
US8778924B2 (en) * | 2006-12-04 | 2014-07-15 | Shionogi Inc. | Modified release amoxicillin products |
NZ619413A (en) | 2006-05-04 | 2015-08-28 | Boehringer Ingelheim Int | Polymorphs of a dpp-iv enzyme inhibitor |
EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
PE20110235A1 (en) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | PHARMACEUTICAL COMBINATIONS INCLUDING LINAGLIPTIN AND METMORPHINE |
US8299052B2 (en) | 2006-05-05 | 2012-10-30 | Shionogi Inc. | Pharmaceutical compositions and methods for improved bacterial eradication |
CA2563690C (en) * | 2006-10-12 | 2014-10-07 | Pharmascience Inc. | Pharmaceutical compositions comprising intra- and extra- granular fractions |
FI20070521L (en) | 2006-11-10 | 2008-05-11 | Atacama Labs Oy | Grains, tablets and granulation process |
US8951562B2 (en) | 2006-11-10 | 2015-02-10 | Atacama Labs Oy | Method and apparatus or dry granulation |
ES2601820T3 (en) | 2007-02-23 | 2017-02-16 | Gilead Sciences, Inc. | Modulators of therapeutic properties of pharmacokinetics |
KR20100101574A (en) | 2007-10-26 | 2010-09-17 | 렉산 파마슈티컬스, 인코포레이티드 | Pharmaceutical formulation of clavulanic acid |
AR071175A1 (en) | 2008-04-03 | 2010-06-02 | Boehringer Ingelheim Int | PHARMACEUTICAL COMPOSITION THAT INCLUDES AN INHIBITOR OF DIPEPTIDIL-PEPTIDASA-4 (DPP4) AND A COMPARING PHARMACO |
SI2296633T1 (en) | 2008-05-02 | 2015-11-30 | Gilead Sciences, Inc. | The use of solid carrier particles to improve the processability of a pharmaceutical agent |
WO2009135946A1 (en) | 2008-05-09 | 2009-11-12 | Atacama Labs Oy | Method and apparatus for dry granulation |
UY32030A (en) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN" |
KR20190016601A (en) | 2008-08-06 | 2019-02-18 | 베링거 인겔하임 인터내셔날 게엠베하 | Treatment for diabetes in patients inappropriate for metformin therapy |
US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
AR074689A1 (en) * | 2008-12-19 | 2011-02-02 | Solvay Pharm Bv | PHARMACEUTICAL FORMULATIONS OF FAST DISINTEGRATION PRE-COMPACTED COMPOUNDS WITH LOW ORAL BIOD AVAILABILITY. PREPARATION PROCESS |
JP2012512848A (en) | 2008-12-23 | 2012-06-07 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Salt forms of organic compounds |
AR074990A1 (en) | 2009-01-07 | 2011-03-02 | Boehringer Ingelheim Int | TREATMENT OF DIABETES IN PATIENTS WITH AN INAPPROPRIATE GLUCEMIC CONTROL THROUGH METFORMIN THERAPY |
PT2493312T (en) * | 2009-10-26 | 2021-11-25 | Merck Sharp & Dohme | Solid pharmaceutical compositions containing an integrase inhibitor |
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WO2011080501A2 (en) | 2009-12-29 | 2011-07-07 | Orexo Ab | New pharmaceutical dosage form for the treatment of gastric acid-related disorders |
BR112012028136A2 (en) | 2010-05-05 | 2016-08-09 | Boehringer Ingelheim Int | combination therapy |
AU2011249771A1 (en) * | 2010-05-05 | 2012-11-01 | Boehringer Ingelheim International Gmbh | Pharmaceutical formulations comprising pioglitazone and linagliptin |
EP3725325B1 (en) | 2010-06-24 | 2023-05-31 | Boehringer Ingelheim International GmbH | Diabetes therapy |
US20170087134A1 (en) * | 2010-07-12 | 2017-03-30 | Salix Pharmaceuticals, Ltd | Formulations of rifaximin and uses thereof |
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JP2014079286A (en) * | 2012-10-12 | 2014-05-08 | Hiroaki Koga | Container containing antimicrobial agent |
EP3110449B1 (en) | 2014-02-28 | 2023-06-28 | Boehringer Ingelheim International GmbH | Medical use of a dpp-4 inhibitor |
MX2018015089A (en) | 2016-06-10 | 2019-05-13 | Boehringer Ingelheim Int | Combinations of linagliptin and metformin. |
EP4137132A1 (en) | 2016-09-30 | 2023-02-22 | Salix Pharmaceuticals, Inc. | Solid dispersion forms of rifaximin |
KR20240011873A (en) * | 2016-10-24 | 2024-01-26 | 얀센 사이언시즈 아일랜드 언리미티드 컴퍼니 | Dispersible compositions |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4301149A (en) * | 1977-10-11 | 1981-11-17 | Beecham Group Limited | Pharmaceutical compositions |
US4950484A (en) * | 1987-03-02 | 1990-08-21 | Gist-Brocades N.V. | Pharmaceutical tablet, pharmaceutical granulate and process for their preparation |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1552416A (en) * | 1975-08-12 | 1979-09-12 | Beecham Group Ltd | Pharmaceutical compositions |
DE3134591A1 (en) * | 1981-09-01 | 1983-03-10 | Bayer Ag, 5090 Leverkusen | NEW MEDICINE PREPARATIONS FOR GLYCOSIDE HYDROLASE INHIBITORS |
US5275823A (en) * | 1989-04-27 | 1994-01-04 | Smith Kline & French Laboratories Ltd. | Pharmaceutical compositions |
GB9109862D0 (en) * | 1991-05-08 | 1991-07-03 | Beecham Lab Sa | Pharmaceutical formulations |
US5861172A (en) * | 1991-05-08 | 1999-01-19 | Laboratorios Beecham Sa | Pharmaceutical formulations of compacted granulates of β-lactam antibiotics |
-
1991
- 1991-05-08 GB GB919109862A patent/GB9109862D0/en active Pending
-
1992
- 1992-05-02 AU AU16498/92A patent/AU659836B2/en not_active Ceased
- 1992-05-02 SK SK1127-93A patent/SK282333B6/en unknown
- 1992-05-02 EP EP97200652A patent/EP0783889B1/en not_active Expired - Lifetime
- 1992-05-02 EP EP92909160A patent/EP0585252B1/en not_active Expired - Lifetime
- 1992-05-02 DE DE69233464T patent/DE69233464T2/en not_active Expired - Fee Related
- 1992-05-02 ES ES97200653T patent/ES2235210T3/en not_active Expired - Lifetime
- 1992-05-02 DE DE69231965T patent/DE69231965T2/en not_active Expired - Fee Related
- 1992-05-02 AT AT97200652T patent/ATE252900T1/en not_active IP Right Cessation
- 1992-05-02 DE DE69233239T patent/DE69233239T2/en not_active Expired - Fee Related
- 1992-05-02 DK DK92909160T patent/DK0585252T3/en active
- 1992-05-02 BR BR9205948A patent/BR9205948A/en not_active Application Discontinuation
- 1992-05-02 AT AT97200653T patent/ATE285227T1/en not_active IP Right Cessation
- 1992-05-02 JP JP4508551A patent/JPH06507396A/en active Pending
- 1992-05-02 SG SG1996008480A patent/SG55163A1/en unknown
- 1992-05-02 KR KR1019930703361A patent/KR100228450B1/en not_active IP Right Cessation
- 1992-05-02 WO PCT/EP1992/001024 patent/WO1992019227A2/en active IP Right Grant
- 1992-05-02 EP EP97200653A patent/EP0787487B1/en not_active Expired - Lifetime
- 1992-05-02 AT AT92909160T patent/ATE203400T1/en not_active IP Right Cessation
- 1992-05-02 HU HU9303143A patent/HU219348B/en not_active IP Right Cessation
- 1992-05-02 ES ES92909160T patent/ES2161690T3/en not_active Expired - Lifetime
- 1992-05-02 CZ CZ19932379A patent/CZ291795B6/en not_active IP Right Cessation
- 1992-05-02 CA CA002102630A patent/CA2102630C/en not_active Expired - Fee Related
- 1992-05-02 ES ES97200652T patent/ES2212034T3/en not_active Expired - Lifetime
- 1992-05-05 MY MYPI92000769A patent/MY111879A/en unknown
- 1992-05-06 ZA ZA923272A patent/ZA923272B/en unknown
- 1992-05-06 YU YU47892A patent/YU49069B/en unknown
- 1992-05-06 AP APAP/P/1992/000382A patent/AP328A/en active
- 1992-05-06 PT PT100458A patent/PT100458B/en not_active IP Right Cessation
- 1992-05-06 NZ NZ242625A patent/NZ242625A/en not_active IP Right Cessation
- 1992-05-06 MA MA22807A patent/MA22522A1/en unknown
- 1992-05-06 IL IL10179592A patent/IL101795A/en not_active IP Right Cessation
- 1992-05-06 CN CN92103956A patent/CN1056277C/en not_active Expired - Fee Related
- 1992-05-07 MX MX9202118A patent/MX9202118A/en not_active IP Right Cessation
- 1992-07-01 IE IE147292A patent/IE921472A1/en not_active Application Discontinuation
- 1992-08-15 TW TW081106464A patent/TW240172B/zh active
- 1992-08-18 SA SA92130069A patent/SA92130069B1/en unknown
-
1993
- 1993-11-05 FI FI934914A patent/FI110354B/en not_active IP Right Cessation
- 1993-11-05 NO NO19934009A patent/NO312224B1/en unknown
-
1998
- 1998-12-21 US US09/217,304 patent/US6110497A/en not_active Expired - Lifetime
-
1999
- 1999-11-08 CN CNB991235738A patent/CN1155370C/en not_active Expired - Fee Related
-
2000
- 2000-08-24 US US09/645,001 patent/US6352720B1/en not_active Expired - Lifetime
-
2001
- 2001-10-18 GR GR20010401805T patent/GR3036937T3/en not_active IP Right Cessation
- 2001-11-19 US US10/016,041 patent/US6544558B2/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4301149A (en) * | 1977-10-11 | 1981-11-17 | Beecham Group Limited | Pharmaceutical compositions |
US4950484A (en) * | 1987-03-02 | 1990-08-21 | Gist-Brocades N.V. | Pharmaceutical tablet, pharmaceutical granulate and process for their preparation |
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