EP2882423A1 - Uncoated tablet comprising granules including a -lactam antibiotic and highly dispersed silicone dioxide - Google Patents

Uncoated tablet comprising granules including a -lactam antibiotic and highly dispersed silicone dioxide

Info

Publication number
EP2882423A1
EP2882423A1 EP13747660.2A EP13747660A EP2882423A1 EP 2882423 A1 EP2882423 A1 EP 2882423A1 EP 13747660 A EP13747660 A EP 13747660A EP 2882423 A1 EP2882423 A1 EP 2882423A1
Authority
EP
European Patent Office
Prior art keywords
granules
weight
tablet
highly dispersed
silicone dioxide
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.)
Withdrawn
Application number
EP13747660.2A
Other languages
German (de)
French (fr)
Inventor
Herwig Jennewein
Franz Schwarz
Johannes Raneburger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AG
Original Assignee
Sandoz AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sandoz AG filed Critical Sandoz AG
Priority to EP13747660.2A priority Critical patent/EP2882423A1/en
Publication of EP2882423A1 publication Critical patent/EP2882423A1/en
Withdrawn legal-status Critical Current

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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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/1611—Inorganic compounds

Definitions

  • Uncoated tablet comprising granules including a ⁇ -Iactam antibiotic and highly dispersed silicone dioxide
  • the invention relates to an uncoated tablet containing granules comprising a ⁇ -lactam antibiotic, highly dispersed silicone dioxide and at most small amounts of other excipients such as disintegrants; as well as to methods for preparing the granules and tablet.
  • Antibiotics such as ⁇ -lactam antibiotics are used to treat infections caused by bacteria which are sensitive to said antibiotics.
  • a ⁇ -!actam antibiotic is amoxicillin or a pharmaceutically acceptable salt or solvate thereof.
  • infections to be treated with amoxicillin are infections of the ear, throat, nose or sinuses; chest infections such as bronchitis and pneumonia; infections of the bladder; prevention of heart infections during mouth or throat surgery; early Lyme disease (from a tick bite) and stomach ulcers caused by the bacterium Helicobacter pylori.
  • the usual dose for adults and children over 12 years is 750 mg to 3000 mg daily in two to three divided doses.
  • Tablets comprising antibiotics are typically swallowed as a whole by the patient or are dispersed in water or other liquids prior to the intake. Children take dosage forms in dispersed form, if they do not want or cannot swallow tablets. Some types of rapidly dispersible tablets can even be dispersed in the mouth without placing them into water before intake, since the tablets are dispersed by small amounts of saliva liquids in the mouth. In countries were pure water is rare, it is desirable to disperse tablets in very small amounts of water or breast milk or even directly administer the tablets to be dispersed in the mouth by saliva liquids. At present, dry syrups comprising powder or granules are typically used for providing drinkable suspensions for infants and children.
  • the dry syrups Prior to use, the dry syrups are supplemented with water in order to provide the desired drug concentration, which often does not provide accurate concentrations. If not completely consumed, the suspension has to be kept refrigerated in order to prevent degradation in suspended state. However, in poor countries such as African countries, refrigerators are not always available.
  • dispersible tablets comprising granules.
  • Such disintegration properties are typically provided by including high amounts of disintegrants into the granules which disintegrants take up water, swell and disintegrate the granules.
  • Disintegrants are typically also used in the extragranular phase of the tablet to further improve disintegration.
  • the use of high amounts of disintegrants results in a big tablet size.
  • tablets comprising antibiotics are sensitive to humidity and prone to degradation during storage. Stability during storage is particularly problematic in countries with high ambient temperatures and high humidity such as in African countries.
  • tablets comprising antibiotics should have a high stability. The less stable the tablets are, the more effort is required to protect the tablets during storage by using expensive packaging materials.
  • tablets which are not highly stable are packaged in fuli aluminum blisters which do not have any water permeability.
  • Coated dispersible tablets comprising amoxicillin trihydrate can be prepared by dry granulation as described in WO 01/37816 A2.
  • Coated tablets comprising 500 mg, 750 mg or 1000 mg of amoxicillin trihydrate (based on the free form of amoxicillin) are distributed by Sandoz under the tradenames "Ospamox 500 mg - losbare Tablette", "Ospamox 750 mg - losbare Tablette” and "Ospamox 1000 mg - losbare Tablette” and are described in the corresponding "Patient Information Leaflet" of said products.
  • US 2006/0110445 Al discloses dispersible tablets with granules including ⁇ -lactam antibiotics and only small amounts of about 1- about 2.5% disintegrants (based on the weight of the tablet) such as croscarmellose sodium, polyvinylpyrolidone, or sodium starch glycolate.
  • EP 0281200 Al discloses dispersible tablets with granules including ⁇ -lactam antibiotics and two different types of disintegrants such as microcrystalline cellulose and low-substituted hydroxypropylcellulose but only small amounts of binding agents.
  • the granulate is prepared by wet granulation.
  • the amount of microcrystalline cellulose is between 20 and 50 wt.-%, based on the weight of the ⁇ -lactam antibiotic.
  • the amount of hydroxypropylcellulose is between 2 and 20 wt.-%, based on the weight of the ⁇ -lactam antibiotic.
  • the document also discloses the use of highly dispersed silicone dioxide in the extragranular phase of the tablet.
  • the high stability of the tablets provides further benefits when breaking the tablets into two or more parts to be separately administered at different time points which poses the problem that one or more parts of the tablet have to be stored outside the package (for example aluminum blister) and may come into contact with humidity.
  • the surface area of the tablets is increased and granules which were formerly embedded in the extragranular phase come into contact with air, wherein the granules themselves may also break during breaking of the tablet.
  • the use of highly dispersed silicone dioxide as granulating agent provides quickly dispersible tablets.
  • the granules contained in the tablet according to the invention provides good dispersibility properties even when using only very small amounts of disintegrants or, unexpectedly, even when using no disintegrants at all.
  • the disintegration may be particularly good when using tablets with small content of active ingredients such as tablets with 250 mg of antibiotic. In this case, only few milliliters such as 1-5 milliliters of water or breast milk may be necessary for dispersing the tablets.
  • the amount of excipients in the extragranular phase can be reduced, e.g. by using only small amounts of highly dispersed silicone dioxide in the extragranular phase.
  • the tablets of the invention having about 250 mg of antibiotic are small sized and can directly be put in the mouth of children where they quickly disperse in the saliva liquids.
  • the invention relates to an uncoated tablet comprising granules as well as to a method for preparing the granules and tablet.
  • the invention relates to an uncoated tablet comprising granules as well as to a method for preparing the granules and tablet.
  • the tablet contains granules comprising a ⁇ -lactam antibiotic, highly dispersed silicone dioxide and at most small amounts of other excipients such as disintegrants (less than 15% by weight of other excipients, based on the weight of the granules).
  • the weight of the components of the tablet refers to the weight of the components in the form, e.g. salt form, or hydrate form, in which they are used for preparing the tablet.
  • the weight of the active agents in their "free form” is the weight of the active moiety of the active agents, e.g. their free base or free acid form, but not the weight of the solvates, salts or other pharmaceutically acceptable forms thereof.
  • the invention thus refers to an uncoated tablet containing granules comprising or preferably consisting of
  • optional further excipients in an amount of 0-15°wt.-%, based on the weight of the granules, wherein said further excipients comprise 0-3 wt.-%, further preferred 0-2.5 wt- %, 0-2 wt.-%, 0-1 wt.-%, or even 0-0.5 wt.-%, of disintegrants, based on the weight of the granules, preferably the excipients including the disintegrants, i.e. any components which are not mentioned in (i) or (ii), are present in an amount of 0-3 wt.-% or 0-2 wt- %, based on the weight of the granules;
  • the total amount of the one or more active agents and the highly dispersed silicone dioxide is at least 85 wt.-%, preferably at least 90 wt.-%, further preferred at least 95 wt.-%, even further preferred at least 98 wt.-%, based on the weight of the granules, and
  • the uncoated tablet described herein comprises, preferably consists of granules and an extragranular phase.
  • the amount of granules in the tablet can for example be 80-95 wt.-%, preferably 85-93 wt.-%, based on the weight of the tablet.
  • the granules may contain excipients such as binding agents, fillers, and disintegrants. Other types of excipients may also be used.
  • the extragranular phase of the tablet also comprises excipients. The granules are embedded in the extragranular phase.
  • the tablet described herein is an "uncoated tablet" which means that the tablet does not comprise an outer coating, such as a taste masking coating, or enteric coating, or any other type of coating.
  • binding agents are excipients which increase the adhesion of the active agents and excipients during granulation.
  • binding agents are: sugars, such as sorbitol, glucose, fructose, disaccharides as saccharose, polysaccharides; acacia gum; cellulose derivatives, such as soluble celluloses like methylcellulose, hydroxypropylmethylcellulose and hydroxypropyiceiluiose; tragacanth; polyvinylpyrrolidone, such as N-vinyipyrroiidone or crospovidone; sodium alginate and alginate derivatives and gelatin.
  • the amount of binding agents in the granules preferably is 0-3 wt.-%, 0-2.5 wt.-%, 0-2 wt.-%, 0- 1.5 wt.-%, 0-1 wt.-% or 0-0.5 wt.-%, based on the weight of the granules.
  • no binding agents are present in the granules.
  • disintegrants are excipients which can take up water and swell and thus improve disintegration of a tablet or granules.
  • examples of disintegrants are: croscarmellose sodium; starch (paste and pre-gelatinized), such as sodium starch glycolate, sodium salt of carboxymethyl starch; methacrylic acid polymer with divinylbenzene, potassium salt, Maltodextrin; crospovidone.
  • the amount of disintegrants in the granules is 0-3 wt.-% 0-2.5 wt.- %, 0-2 wt.-%, 0-1.5 wt.-%, 0-1 wt.-% or 0-0.5 wt.-%, based on the weight of the granules.
  • no disintegrants are present in the granules.
  • the extragranular phase/part of the tablet based on the total weight of the tablet, can comprise 5-15 wt.-%, or 5-10 wt.-%, disintegrants, e.g. croscarmellose sodium, in particular 1.5 wt.-% croscarmellose sodium.
  • lubricants are excipients which reduce the friction between excipients.
  • examples of lubricants are magnesium stearate, magnesiumfumarate, fumaric-acid, and sodiumstearylfumarate.
  • fillers are excipients which increase the volume of the granules or extragranular phase.
  • examples of fillers are mannitol, celluloses such as microcrystalline cellulose, synthetic polymers, Ca-phosphate, inorganic calcium salts, maize starch, polyols and pregelatinzed starch.
  • the amount of fillers in the granules is 0-10 wt.-%, 0-8 wt.-%, 0-6 wt.-%, 0-4 wt.-%, 0- 2 wt.-% or 0-1 wt.-% by weight, based on the weight of the granules.
  • no fillers are present in the granules.
  • Other excipients are known in the art and can be chosen by a skilled person depending on their function.
  • the granules can for example further comprise
  • binding agents in an amount of up to 3% by weight, based on the weight of the granules, or in the amounts as indicated above, and
  • fillers in an amount of up to 10% by weight, based on the weight of the granules, or in the amounts as indicated above.
  • the granules do not contain any binding agents, fillers, disintegrants or any excipients other than highly dispersed silicone dioxide.
  • the granules consist of active agents, preferably a ⁇ -lactam antibiotic or a ⁇ -lactam antibiotic and ⁇ - lactamase inhibitor such as clavulanic acid, and highly dispersed silicone dioxide.
  • the extragranular phase/part of the tablet based on the total weight of the tablet, comprises/consists of:
  • lubricant such as magnesium stearate
  • disintegrant e.g. croscarmellose sodium and/or microcrystalline cellulose, e.g. 1.5 wt.-% croscarmellose sodium and about 7 wt.-% microcrystalline cellulose,
  • the granules can consist of ⁇ - lactam antibiotic, e.g. amoxicillin free form or a pharmaceutically acceptable salt or solvate thereof, and highly dispersed silicone dioxide, for example between 85-99% by weight of ⁇ - lactam antibiotic and between 1 and 15%, or between 3 and 10%, by weight of highly dispersed silicone dioxide, in particular 94-96% or about 95% by weight of ⁇ -lactam antibiotic, for example 100-400 mg or 250 mg ⁇ -lactam antibiotic per tablet, and 4-6% or about 5% by weight of highly dispersed silicone dioxide.
  • ⁇ - lactam antibiotic e.g. amoxicillin free form or a pharmaceutically acceptable salt or solvate thereof
  • highly dispersed silicone dioxide for example between 85-99% by weight of ⁇ - lactam antibiotic and between 1 and 15%, or between 3 and 10%, by weight of highly dispersed silicone dioxide, in particular 94-96% or about 95% by weight of ⁇ -lactam antibiotic, for example 100-400 mg or 250 mg ⁇
  • active agents are ⁇ -lactam antibiotics and for example agents which improve the effect of ⁇ -lactam antibiotics, such as ⁇ -lactamase inhibitors like clavulanic acid or a salt thereof, e.g. the potassium salt of clavulanic acid; as well as any other drug compounds which are administered in combination with ⁇ -lactam antibiotics.
  • the granules comprise a ⁇ -lactamase inhibitor such as clavulanic acid as active agent in addition to the ⁇ -lactam antibiotic, wherein the ⁇ -lactamase inhibitor and ⁇ -lactam antibiotic can be present as the sole active agents or a further antibiotic or other active agent is additionally used.
  • the one or more active agents can for example be a combination of a ⁇ -lactam antibiotic in free form and clavulanic acid or a pharmaceutically acceptable salt or solvate of a ⁇ -lactam antibiotic and clavulanic acid.
  • ⁇ -lactam antibiotic comprises the drug compound in its "free form” as well as in the form of solvates, salts and other pharmaceutically acceptable forms.
  • free form refers to the drug form which is not a sait or solvate.
  • the uncoated tablet contains granules consisting of ⁇ -lactam antibiotic such as amoxicillin free form or a pharmaceutically acceptable salt or solvate thereof or a combination of a ⁇ -lactam antibiotic such as amoxicillin or a pharmaceutically acceptable salt or solvate thereof and clavulanic acid, wherein the weight ratio of clavulanic acid/ ⁇ -lactam antibiotic (in its free form) can for example be 1:2-1:20.
  • Preferred ⁇ -lactam antibiotics are amphoteric ⁇ -lactam antibiotics, preferably the ⁇ -lactam antibiotic is selected from the group consisting of penicillins, such as ampicillin, amoxicillin, oxacillin, cloxacillin, flucoxacillin and dicloxacillin; cephalosporins such as cefaclor, cefixime, cephalexin, cephradine, cefadroxil, cefroxadine, cefdinir, cefpodoxime proxetil, cefuroxime axetil, loracabef, or carbapenems such as imipenem; preferably it is amoxicillin such as amoxicillin trihydrate.
  • antibiotics such as amoxicillin, it is meant to also refer to pharmaceutically acceptable salts and solvates thereof.
  • the active agents may be used in any modification.
  • the ⁇ -lactam antibiotics can be used in amorphous form, semi-crystalline or crystalline form.
  • the amount of ⁇ -lactam antibiotic in the tablet can for example be 50-1500 mg, 100-700, or 100-400 mg, for example 250 mg, based on the free form of the ⁇ -lactam antibiotic.
  • the granules comprise highly dispersed silicone dioxide/silica such as fumed silica or colloidal silica.
  • Colloidal silica is typically used as lubricant in the extragranular phase of tablets with granules.
  • the highly dispersed silicone dioxide is a silicone dioxide having a BET surface area of 50 m 2 or above, e.g. from 50 m 2 to 800 m 2 , preferably 100 m 2 /g above, e.g. 100 m 2 /g to 800 m 2 /g, or the BET surface area is 100-400 m 2 /g, or 200-400 m 2 /g (as e.g. measured by ISO 9277: 2010(E) standard with nitrogen and e.g. static volumetric and multipoint methods.
  • the highly dispersed silicone dioxide can for example have a tapped density of about 30-70 g/l, in particular about 50 g/l, as measured according to DIN EN ISO 787/11, August 1983.
  • the uncoated tablets Upon contact with water, the uncoated tablets disperse in water to provide the granules which themselves disperse to provide the desired finely dispersed suspension.
  • the tablet disperses in water in less than 3 minutes, or less than 2 minutes, preferably in less than 1 minute.
  • the uncoated tablet described herein preferably has a breaking notch.
  • the breaking notch can be provided on one or more sides of the tablet. Typically the breaking notch is provided on two opposing sides of a tablet. Breaking notches are sometimes also referred to as score lines or grooves.
  • breaking notches in a tablet is common technical knowledge in the art.
  • the breaking notch(es) allow(s) splitting the tablet without difficulty by a patient, physician or pharmacist.
  • the breaking notches used herein allow dividing the tablet into at least two parts with substantially equal weight and, thus, substantially equal drug content without applying any technical devices for splitting.
  • the two or more parts can have equal weights, wherein each of the parts is compared with each of the remaining parts, wherein the two parts to be compared have a maximum deviation of +/- 20%calculated as follows: (difference in weight of the two tablet parts to be compared)/(weight of the two tablet parts to be compared)xl00.
  • the breaking notches used herein allow dividing the tablet into two parts with substantially equal weight and, thus, substantially equal drug content without applying any technical devices for splitting.
  • the two parts can have equal weights with a maximum deviation of +/- 20% calculated as follows: (difference in weight of tablet parts)/(full tablet weight)xl00.
  • the invention refers to a packaged product comprising at least 2, or at least 4 or at least 6 tablets described herein, wherein each of the tablets can be divided into two parts according to the invention without using technical devices.
  • splitting of a 250 mg amoxicillin tablet provides two parts with 125 mg drug content each of which parts can either be administered to different patients or to the same patient at different time points. Due to the stability of the tablets described herein, the broken tablet (i.e. the tablet parts) can be stored outside the package.
  • the invention also refers to a process for preparing granules as described herein, comprising the step of
  • step (i) providing a mixture of the highly dispersed silicone dioxide and the one or more active agents and optionally further excipients, wherein the types of the highly dispersed silicone dioxide, the one or more active agents and excipients as well as the amounts thereof are preferably as defined above, wherein the amount of highly dispersed silicone dioxide in step (i) is the full amount of highly dispersed silicone dioxide which is present in the final granules or is only a partial amount thereof, such as 50-95 wt.-%;
  • step (ii) granulating the mixture of step (i) with an aqueous medium, preferably water, while optionally adding further amounts of highly dispersed silicone dioxide during granulating;
  • step (ii) can be dried to reduce the residual water content, wherein the drying can be performed by using a fluid-bed device.
  • Step (ii) of the process can be performed in a high-shear mixer such as a device of the company Diosna.
  • the invention also refers to a process for preparing an uncoated tablet as described herein, comprising the step of
  • step (b) mixing the granules of step (a) with further excipients, and
  • step (c) compressing the mixture of step (b) into tablets.
  • the process does not include any coating steps.
  • One aspect of the invention refers to a packaged product comprising tablets as described herein, wherein the packaged is/comprises a blister pack which is preferably not a full aluminum (alu/alu) blister, i.e. the tablets in the blister are not completely surrounded by aluminum foil. Rather, the blister comprises at least one foil which is not aluminum but is a polymeric material.
  • the blister pack can comprise a material/foil such as made of a polymeric material having a moisture permeability in flat, unformed form of 0.05-5 g/m 2 /24h, 0.1-5 g/m 2 /24h, 0.1-3 g/m 2 /24h, 0.2-5 g/m 2 /24h, 0.3-5 g/m 2 /24h, 0.4-5 g/m /24h or even 1-5 g/m 2 /24h, when measured at 38°C and 90% humidity on a Mocon equipment.
  • the flat, unformed form is the plain material/foil which is then formed to encompass the tablets.
  • blister materials which can generally be used are (moisture permeability in g/m 2 /24h as measured at 38°C and 90% humidity on a Mocon equipment are given in brackets): Mono PVC (unformed 3.71; formed 3.90), Mono PP (unformed 1.20; formed 1.50), 40 g PVdC/ PVC (unformed 0.75; formed 1.10), 20PP/ 120 COC (cycloolefin-copolymer)/ 20PP (unformed 0.76; formed 0.98), 60 g PVdC/ PVC (unformed 0.50; formed 0.80), 20PP/ 190 COC/ 20PP (unformed 0.35; formed 0.71), 20PP/ 240 COC/ 20PP (unformed 0.31; formed 0.57), 90g PVdC/ PE (polyethylene)/PVC (unformed 0.25; formed 0.55), ACLAR ® Rx 160/ PVC (unformed 0.36; formed 0.50), 20PP/ 300 COC/ 20PP (unformed 0.23; formed 0.45), 120 g PVd
  • Preferred materials in terms of manufacturing costs and moisture permeability are foils comprising or consisting of PVC (polyvinyl chloride), PVDC (polyvinylidene chloride) and/or PP (polypropylene). Particularly preferred are PVC/PVDC/aluminum (Al) blisters, one side of the blister being aluminum or PVC/PVDC without aluminum.
  • composition of tablet is Composition of tablet:
  • Amoxicillin trihydrate - 287 mg (which corresponds to 250 mg amoxicillin in its free form);
  • Highly dispersed silicone dioxide (Aerosil ® 200) - 2mg. Amoxicillin and half of the amount of highly dispersed silicone dioxide (used for the granules) were intensively mixed in a high shear mixer (Diosna), then granulated with water and the remaining amount of highly dispersed silicone dioxide used for the granules was added. The obtained granules were dried in a fluid bed dryer at 70°C draught and subsequently equalized using a Frewitt sieve. The obtained granules were mixed with the highly dispersed silicone dioxide of the extragranular phase as well as with the remaining excipients and compressed into tablets.
  • the tablets fully disperse in water (for example in 50 ml of water or for example in only 10 ml of water when using tablets with a drug content of up to 400 mg) in less than 1 minute while the resulting suspension does not contain particles with a size of above 750pm.
  • the obtained tablets have a water uptake of less than 0.5% when stored under open conditions at 25°C/60% relative humidity, 30°C/65% and 30°C/75% and 40°C/75% over at least 24 hours and their physicochemical properties remain almost unchanged.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to an uncoated tablet comprising granules comprising a β-lactam antibiotic, highly dispersed silicone dioxide and at most small amounts of other excipients such as disintegrants; as well as to a method for preparing the granules and tablet. The tablet shows a good dispersibility and high storage stability.

Description

Uncoated tablet comprising granules including a β-Iactam antibiotic and highly dispersed silicone dioxide
The invention relates to an uncoated tablet containing granules comprising a β-lactam antibiotic, highly dispersed silicone dioxide and at most small amounts of other excipients such as disintegrants; as well as to methods for preparing the granules and tablet.
Background prior art
Antibiotics such as β-lactam antibiotics are used to treat infections caused by bacteria which are sensitive to said antibiotics. One example of a β-!actam antibiotic is amoxicillin or a pharmaceutically acceptable salt or solvate thereof. Examples of infections to be treated with amoxicillin are infections of the ear, throat, nose or sinuses; chest infections such as bronchitis and pneumonia; infections of the bladder; prevention of heart infections during mouth or throat surgery; early Lyme disease (from a tick bite) and stomach ulcers caused by the bacterium Helicobacter pylori. The usual dose for adults and children over 12 years is 750 mg to 3000 mg daily in two to three divided doses.
Tablets comprising antibiotics are typically swallowed as a whole by the patient or are dispersed in water or other liquids prior to the intake. Children take dosage forms in dispersed form, if they do not want or cannot swallow tablets. Some types of rapidly dispersible tablets can even be dispersed in the mouth without placing them into water before intake, since the tablets are dispersed by small amounts of saliva liquids in the mouth. In countries were pure water is rare, it is desirable to disperse tablets in very small amounts of water or breast milk or even directly administer the tablets to be dispersed in the mouth by saliva liquids. At present, dry syrups comprising powder or granules are typically used for providing drinkable suspensions for infants and children. Prior to use, the dry syrups are supplemented with water in order to provide the desired drug concentration, which often does not provide accurate concentrations. If not completely consumed, the suspension has to be kept refrigerated in order to prevent degradation in suspended state. However, in poor countries such as African countries, refrigerators are not always available.
One type of tablets on the market are dispersible tablets comprising granules. In order to be suitable for dispersing, such tablets should quickly disintegrate (e.g. in less than 3 minutes) in water so that only small particles of below 750 pm remain. Such disintegration properties are typically provided by including high amounts of disintegrants into the granules which disintegrants take up water, swell and disintegrate the granules. Disintegrants are typically also used in the extragranular phase of the tablet to further improve disintegration. However, the use of high amounts of disintegrants results in a big tablet size.
Furthermore, tablets comprising antibiotics are sensitive to humidity and prone to degradation during storage. Stability during storage is particularly problematic in countries with high ambient temperatures and high humidity such as in African countries. Thus, in addition to the ability to quickly dispers in liquids, tablets comprising antibiotics should have a high stability. The less stable the tablets are, the more effort is required to protect the tablets during storage by using expensive packaging materials. Typically, tablets which are not highly stable are packaged in fuli aluminum blisters which do not have any water permeability.
Coated dispersible tablets comprising amoxicillin trihydrate can be prepared by dry granulation as described in WO 01/37816 A2.
Coated tablets comprising 500 mg, 750 mg or 1000 mg of amoxicillin trihydrate (based on the free form of amoxicillin) are distributed by Sandoz under the tradenames "Ospamox 500 mg - losbare Tablette", "Ospamox 750 mg - losbare Tablette" and "Ospamox 1000 mg - losbare Tablette" and are described in the corresponding "Patient Information Leaflet" of said products.
US 2006/0110445 Al discloses dispersible tablets with granules including β-lactam antibiotics and only small amounts of about 1- about 2.5% disintegrants (based on the weight of the tablet) such as croscarmellose sodium, polyvinylpyrolidone, or sodium starch glycolate.
EP 0281200 Al discloses dispersible tablets with granules including β-lactam antibiotics and two different types of disintegrants such as microcrystalline cellulose and low-substituted hydroxypropylcellulose but only small amounts of binding agents. The granulate is prepared by wet granulation. The amount of microcrystalline cellulose is between 20 and 50 wt.-%, based on the weight of the β-lactam antibiotic. The amount of hydroxypropylcellulose is between 2 and 20 wt.-%, based on the weight of the β-lactam antibiotic. The document also discloses the use of highly dispersed silicone dioxide in the extragranular phase of the tablet.
Despite of the above tablets, there is still a need for tablets having good dispersibility and stability. The present invention thus aims at tablets having good dispersibility and stability. Summary of the invention
It has been found that the use of highly dispersed silicone dioxide as granulating agent confers a high stability against humidity, in particular against a high humidity at a high ambient temperature, to tablets comprising β-lactam antibiotics. The increased stability of the tablets allows packaging the tablets by using cheap packaging materials having a certain moisture permeability compared to a full aluminum blister which has no moisture permeability but is expensive. The high stability provided by the present invention provides particular benefits for small-sized tablets which have a high ratio of tablet surface area/tablet weight compared to the same tablets with bigger size which results in increased contact with air at the tablet surface and thus increased problems due to degradation. Omitting coatings, such as outer coatings for increasing stability or for improving the ease of intake, on the tablet allows preparing the tablets in a simple process and thus reduces the manufacturing costs.
The high stability of the tablets provides further benefits when breaking the tablets into two or more parts to be separately administered at different time points which poses the problem that one or more parts of the tablet have to be stored outside the package (for example aluminum blister) and may come into contact with humidity. In addition, when breaking tablets into two halves, the surface area of the tablets is increased and granules which were formerly embedded in the extragranular phase come into contact with air, wherein the granules themselves may also break during breaking of the tablet.
It has also been found that the use of highly dispersed silicone dioxide as granulating agent provides quickly dispersible tablets. The granules contained in the tablet according to the invention provides good dispersibility properties even when using only very small amounts of disintegrants or, unexpectedly, even when using no disintegrants at all. The disintegration may be particularly good when using tablets with small content of active ingredients such as tablets with 250 mg of antibiotic. In this case, only few milliliters such as 1-5 milliliters of water or breast milk may be necessary for dispersing the tablets.
Moreover, the amount of excipients in the extragranular phase can be reduced, e.g. by using only small amounts of highly dispersed silicone dioxide in the extragranular phase.
Furthermore, the tablets of the invention having about 250 mg of antibiotic are small sized and can directly be put in the mouth of children where they quickly disperse in the saliva liquids.
Thus, the invention relates to an uncoated tablet comprising granules as well as to a method for preparing the granules and tablet. Detailed Description
The invention relates to an uncoated tablet comprising granules as well as to a method for preparing the granules and tablet. The tablet contains granules comprising a β-lactam antibiotic, highly dispersed silicone dioxide and at most small amounts of other excipients such as disintegrants (less than 15% by weight of other excipients, based on the weight of the granules). Unless otherwise indicated, the weight of the components of the tablet refers to the weight of the components in the form, e.g. salt form, or hydrate form, in which they are used for preparing the tablet. In contrast, it is sometimes referred to the weight of the active agents in their "free form", which is the weight of the active moiety of the active agents, e.g. their free base or free acid form, but not the weight of the solvates, salts or other pharmaceutically acceptable forms thereof.
The invention thus refers to an uncoated tablet containing granules comprising or preferably consisting of
(i) one or more active agents, wherein at least one active agent is a β-lactam antibiotic; and
(ii) highly dispersed silicone dioxide in an amount of 1-15 %, or 1-10 %, or 3-10 %, based on the weight of the granules;
(iii) optional further excipients in an amount of 0-15°wt.-%, based on the weight of the granules, wherein said further excipients comprise 0-3 wt.-%, further preferred 0-2.5 wt- %, 0-2 wt.-%, 0-1 wt.-%, or even 0-0.5 wt.-%, of disintegrants, based on the weight of the granules, preferably the excipients including the disintegrants, i.e. any components which are not mentioned in (i) or (ii), are present in an amount of 0-3 wt.-% or 0-2 wt- %, based on the weight of the granules;
wherein the total amount of the one or more active agents and the highly dispersed silicone dioxide is at least 85 wt.-%, preferably at least 90 wt.-%, further preferred at least 95 wt.-%, even further preferred at least 98 wt.-%, based on the weight of the granules, and
Keeping the amounts of excipients in the granules or extragranular phase small allows providing tablets with high drug loading.
The uncoated tablet described herein comprises, preferably consists of granules and an extragranular phase. The amount of granules in the tablet can for example be 80-95 wt.-%, preferably 85-93 wt.-%, based on the weight of the tablet. In addition to the highly dispersed silicone dioxide, the granules may contain excipients such as binding agents, fillers, and disintegrants. Other types of excipients may also be used. The extragranular phase of the tablet also comprises excipients. The granules are embedded in the extragranular phase. The tablet described herein is an "uncoated tablet" which means that the tablet does not comprise an outer coating, such as a taste masking coating, or enteric coating, or any other type of coating.
As used herein, binding agents are excipients which increase the adhesion of the active agents and excipients during granulation. Examples of binding agents are: sugars, such as sorbitol, glucose, fructose, disaccharides as saccharose, polysaccharides; acacia gum; cellulose derivatives, such as soluble celluloses like methylcellulose, hydroxypropylmethylcellulose and hydroxypropyiceiluiose; tragacanth; polyvinylpyrrolidone, such as N-vinyipyrroiidone or crospovidone; sodium alginate and alginate derivatives and gelatin.
The amount of binding agents in the granules preferably is 0-3 wt.-%, 0-2.5 wt.-%, 0-2 wt.-%, 0- 1.5 wt.-%, 0-1 wt.-% or 0-0.5 wt.-%, based on the weight of the granules. Preferably, no binding agents are present in the granules.
As used herein, disintegrants are excipients which can take up water and swell and thus improve disintegration of a tablet or granules. Examples of disintegrants are: croscarmellose sodium; starch (paste and pre-gelatinized), such as sodium starch glycolate, sodium salt of carboxymethyl starch; methacrylic acid polymer with divinylbenzene, potassium salt, Maltodextrin; crospovidone. The amount of disintegrants in the granules is 0-3 wt.-% 0-2.5 wt.- %, 0-2 wt.-%, 0-1.5 wt.-%, 0-1 wt.-% or 0-0.5 wt.-%, based on the weight of the granules. Preferably, no disintegrants are present in the granules. The extragranular phase/part of the tablet, based on the total weight of the tablet, can comprise 5-15 wt.-%, or 5-10 wt.-%, disintegrants, e.g. croscarmellose sodium, in particular 1.5 wt.-% croscarmellose sodium.
As used herein, lubricants are excipients which reduce the friction between excipients. Examples of lubricants are magnesium stearate, magnesiumfumarate, fumaric-acid, and sodiumstearylfumarate.
As used herein, fillers are excipients which increase the volume of the granules or extragranular phase. Examples of fillers are mannitol, celluloses such as microcrystalline cellulose, synthetic polymers, Ca-phosphate, inorganic calcium salts, maize starch, polyols and pregelatinzed starch. The amount of fillers in the granules is 0-10 wt.-%, 0-8 wt.-%, 0-6 wt.-%, 0-4 wt.-%, 0- 2 wt.-% or 0-1 wt.-% by weight, based on the weight of the granules. Preferably, no fillers are present in the granules. Other excipients are known in the art and can be chosen by a skilled person depending on their function.
The granules can for example further comprise
(iii) binding agents in an amount of up to 3% by weight, based on the weight of the granules, or in the amounts as indicated above, and
(iv) fillers in an amount of up to 10% by weight, based on the weight of the granules, or in the amounts as indicated above.
Preferably, the granules do not contain any binding agents, fillers, disintegrants or any excipients other than highly dispersed silicone dioxide. In such an embodiment, the granules consist of active agents, preferably a β-lactam antibiotic or a β-lactam antibiotic and β- lactamase inhibitor such as clavulanic acid, and highly dispersed silicone dioxide.
In one embodiment, the extragranular phase/part of the tablet, based on the total weight of the tablet, comprises/consists of:
0-5 wt.-%, e.g. 0.3 wt.-%, flavoring agents,
0-2 wt.-%, e.g. 0.3 wt.-%, lubricant such as magnesium stearate,
0- 2 wt.-% sweetening agents in particular aspartame,
5-15 wt.-%, e.g. about 9 wt.-%, disintegrant, e.g. croscarmellose sodium and/or microcrystalline cellulose, e.g. 1.5 wt.-% croscarmellose sodium and about 7 wt.-% microcrystalline cellulose,
1- 15 wt.-%, preferably 5-15 wt.-%, e.g. 1.8 wt.-%, filler, e.g. mannit; and
0-2 wt.-%, highly dispersed silicone dioxide. In this embodiment, the granules can consist of β- lactam antibiotic, e.g. amoxicillin free form or a pharmaceutically acceptable salt or solvate thereof, and highly dispersed silicone dioxide, for example between 85-99% by weight of β- lactam antibiotic and between 1 and 15%, or between 3 and 10%, by weight of highly dispersed silicone dioxide, in particular 94-96% or about 95% by weight of β-lactam antibiotic, for example 100-400 mg or 250 mg β-lactam antibiotic per tablet, and 4-6% or about 5% by weight of highly dispersed silicone dioxide.
Within the context of the invention, active agents are β-lactam antibiotics and for example agents which improve the effect of β-lactam antibiotics, such as β-lactamase inhibitors like clavulanic acid or a salt thereof, e.g. the potassium salt of clavulanic acid; as well as any other drug compounds which are administered in combination with β-lactam antibiotics. In one embodiment, the granules comprise a β-lactamase inhibitor such as clavulanic acid as active agent in addition to the β-lactam antibiotic, wherein the β-lactamase inhibitor and β-lactam antibiotic can be present as the sole active agents or a further antibiotic or other active agent is additionally used. Thus, the one or more active agents can for example be a combination of a β-lactam antibiotic in free form and clavulanic acid or a pharmaceutically acceptable salt or solvate of a β-lactam antibiotic and clavulanic acid. The expression "β-lactam antibiotic" comprises the drug compound in its "free form" as well as in the form of solvates, salts and other pharmaceutically acceptable forms.
The expression "free form" as used in the context of an antibiotic refers to the drug form which is not a sait or solvate.
In one embodiment, the uncoated tablet contains granules consisting of β-lactam antibiotic such as amoxicillin free form or a pharmaceutically acceptable salt or solvate thereof or a combination of a β-lactam antibiotic such as amoxicillin or a pharmaceutically acceptable salt or solvate thereof and clavulanic acid, wherein the weight ratio of clavulanic acid/^-lactam antibiotic (in its free form) can for example be 1:2-1:20.
Preferred β-lactam antibiotics are amphoteric β-lactam antibiotics, preferably the β-lactam antibiotic is selected from the group consisting of penicillins, such as ampicillin, amoxicillin, oxacillin, cloxacillin, flucoxacillin and dicloxacillin; cephalosporins such as cefaclor, cefixime, cephalexin, cephradine, cefadroxil, cefroxadine, cefdinir, cefpodoxime proxetil, cefuroxime axetil, loracabef, or carbapenems such as imipenem; preferably it is amoxicillin such as amoxicillin trihydrate. In general, when referring to particular antibiotics, such as amoxicillin, it is meant to also refer to pharmaceutically acceptable salts and solvates thereof. The β-lactam antibiotics used herein typically have a particle size distribution of D50 = 5-50 pm.
The active agents may be used in any modification. For example the β-lactam antibiotics can be used in amorphous form, semi-crystalline or crystalline form. The amount of β-lactam antibiotic in the tablet can for example be 50-1500 mg, 100-700, or 100-400 mg, for example 250 mg, based on the free form of the β-lactam antibiotic.
As mentioned above, the granules comprise highly dispersed silicone dioxide/silica such as fumed silica or colloidal silica. Colloidal silica is typically used as lubricant in the extragranular phase of tablets with granules.
The highly dispersed silicone dioxide is a silicone dioxide having a BET surface area of 50 m2 or above, e.g. from 50 m2 to 800 m2, preferably 100 m2/g above, e.g. 100 m2/g to 800 m2/g, or the BET surface area is 100-400 m2/g, or 200-400 m2/g (as e.g. measured by ISO 9277: 2010(E) standard with nitrogen and e.g. static volumetric and multipoint methods. The highly dispersed silicone dioxide can for example have a tapped density of about 30-70 g/l, in particular about 50 g/l, as measured according to DIN EN ISO 787/11, August 1983. The properties of commercially available types of highly dispersed silicone dioxide are for example described in "Die Tablette: Handbuch der Entwicklung, Herstellung und Qualitatssicherung", 3. edition, 2012, Editio Cantor Verlag, Aulendorf, see pages 108/109 and 126. Preferred materials are distributed under the tradename Aerosil® of the company Evonik, Germany, e.g. Aerosil® 200 Pharma or Aerosil® 300 Pharma. In one embodiment, highly dispersed silicone dioxide is used which has between 50 and 200% of the BET surface are of Aerosil® 200 Pharma, In general, the extragranular phase/part of the tablet, based on the total weight of the tablet, can e.g. comprise 0-5%, or 0-2% highly dispersed silicone dioxide.
Upon contact with water, the uncoated tablets disperse in water to provide the granules which themselves disperse to provide the desired finely dispersed suspension. Preferably, the tablet disperses in water in less than 3 minutes, or less than 2 minutes, preferably in less than 1 minute.
The uncoated tablet described herein preferably has a breaking notch. The breaking notch can be provided on one or more sides of the tablet. Typically the breaking notch is provided on two opposing sides of a tablet. Breaking notches are sometimes also referred to as score lines or grooves.
The provision of breaking notches in a tablet is common technical knowledge in the art. The breaking notch(es) allow(s) splitting the tablet without difficulty by a patient, physician or pharmacist. Preferably, the breaking notches used herein allow dividing the tablet into at least two parts with substantially equal weight and, thus, substantially equal drug content without applying any technical devices for splitting. The two or more parts can have equal weights, wherein each of the parts is compared with each of the remaining parts, wherein the two parts to be compared have a maximum deviation of +/- 20%calculated as follows: (difference in weight of the two tablet parts to be compared)/(weight of the two tablet parts to be compared)xl00.
Preferably, the breaking notches used herein allow dividing the tablet into two parts with substantially equal weight and, thus, substantially equal drug content without applying any technical devices for splitting. The two parts can have equal weights with a maximum deviation of +/- 20% calculated as follows: (difference in weight of tablet parts)/(full tablet weight)xl00.
In one embodiment, the invention refers to a packaged product comprising at least 2, or at least 4 or at least 6 tablets described herein, wherein each of the tablets can be divided into two parts according to the invention without using technical devices.
For example, splitting of a 250 mg amoxicillin tablet provides two parts with 125 mg drug content each of which parts can either be administered to different patients or to the same patient at different time points. Due to the stability of the tablets described herein, the broken tablet (i.e. the tablet parts) can be stored outside the package.
The invention also refers to a process for preparing granules as described herein, comprising the step of
(i) providing a mixture of the highly dispersed silicone dioxide and the one or more active agents and optionally further excipients, wherein the types of the highly dispersed silicone dioxide, the one or more active agents and excipients as well as the amounts thereof are preferably as defined above, wherein the amount of highly dispersed silicone dioxide in step (i) is the full amount of highly dispersed silicone dioxide which is present in the final granules or is only a partial amount thereof, such as 50-95 wt.-%;
(ii) granulating the mixture of step (i) with an aqueous medium, preferably water, while optionally adding further amounts of highly dispersed silicone dioxide during granulating;
(iii) and obtaining said granules.
Subsequently, the granules of step (ii) can be dried to reduce the residual water content, wherein the drying can be performed by using a fluid-bed device. Step (ii) of the process can be performed in a high-shear mixer such as a device of the company Diosna.
The invention also refers to a process for preparing an uncoated tablet as described herein, comprising the step of
(a) providing granules as described herein by using a process as described above;
(b) mixing the granules of step (a) with further excipients, and
(c) compressing the mixture of step (b) into tablets. The process does not include any coating steps. One aspect of the invention refers to a packaged product comprising tablets as described herein, wherein the packaged is/comprises a blister pack which is preferably not a full aluminum (alu/alu) blister, i.e. the tablets in the blister are not completely surrounded by aluminum foil. Rather, the blister comprises at least one foil which is not aluminum but is a polymeric material.
The blister pack can comprise a material/foil such as made of a polymeric material having a moisture permeability in flat, unformed form of 0.05-5 g/m2/24h, 0.1-5 g/m2/24h, 0.1-3 g/m2/24h, 0.2-5 g/m2/24h, 0.3-5 g/m2/24h, 0.4-5 g/m /24h or even 1-5 g/m2/24h, when measured at 38°C and 90% humidity on a Mocon equipment. The flat, unformed form is the plain material/foil which is then formed to encompass the tablets.
Examples of blister materials which can generally be used are (moisture permeability in g/m2/24h as measured at 38°C and 90% humidity on a Mocon equipment are given in brackets): Mono PVC (unformed 3.71; formed 3.90), Mono PP (unformed 1.20; formed 1.50), 40 g PVdC/ PVC (unformed 0.75; formed 1.10), 20PP/ 120 COC (cycloolefin-copolymer)/ 20PP (unformed 0.76; formed 0.98), 60 g PVdC/ PVC (unformed 0.50; formed 0.80), 20PP/ 190 COC/ 20PP (unformed 0.35; formed 0.71), 20PP/ 240 COC/ 20PP (unformed 0.31; formed 0.57), 90g PVdC/ PE (polyethylene)/PVC (unformed 0.25; formed 0.55), ACLAR® Rx 160/ PVC (unformed 0.36; formed 0.50), 20PP/ 300 COC/ 20PP (unformed 0.23; formed 0.45), 120 g PVdC/ PE/PVC (unformed 0.15; formed 0.40), ACLAR® Rx20E/ PVC (unformed 0.27; formed 0.37), ACLAR® SupRx900/ PVC (unformed 0.23; formed 0.30), ACLAR® UltRx 2000/ PVC (unformed 0.11;
formed 0.15), ACLAR® UltRx 3000/ PVC (unformed 0.08; formed 0.11), ACLAR® UltRx 4000/ PVC (unformed 0.05; formed 0.08), Alu/Alu (unformed 0.00; formed 0.00).
Preferred materials in terms of manufacturing costs and moisture permeability are foils comprising or consisting of PVC (polyvinyl chloride), PVDC (polyvinylidene chloride) and/or PP (polypropylene). Particularly preferred are PVC/PVDC/aluminum (Al) blisters, one side of the blister being aluminum or PVC/PVDC without aluminum.
Example - 250 mg tablet
The following example describes the present invention in detail, but is not to be construed to be in any way limiting for the present invention.
Composition of tablet:
Granules:
Amoxicillin trihydrate - 287 mg (which corresponds to 250 mg amoxicillin in its free form);
Highly dispersed silicone dioxide (Aerosil® 200) - 13mg; Extragranular phase:
Orange flavor - lmg;
Magnesium stearate - 1.1 mg;
Aspartame - 1.2 mg;
Sodium croscarmellose - 5 mg;
Mannitol (granulated) - 6 mg;
Microcrystalline cellulose - 25 mg;
Highly dispersed silicone dioxide (Aerosil® 200) - 2mg. Amoxicillin and half of the amount of highly dispersed silicone dioxide (used for the granules) were intensively mixed in a high shear mixer (Diosna), then granulated with water and the remaining amount of highly dispersed silicone dioxide used for the granules was added. The obtained granules were dried in a fluid bed dryer at 70°C draught and subsequently equalized using a Frewitt sieve. The obtained granules were mixed with the highly dispersed silicone dioxide of the extragranular phase as well as with the remaining excipients and compressed into tablets.
The tablets fully disperse in water (for example in 50 ml of water or for example in only 10 ml of water when using tablets with a drug content of up to 400 mg) in less than 1 minute while the resulting suspension does not contain particles with a size of above 750pm.
The obtained tablets have a water uptake of less than 0.5% when stored under open conditions at 25°C/60% relative humidity, 30°C/65% and 30°C/75% and 40°C/75% over at least 24 hours and their physicochemical properties remain almost unchanged.
Cited literature
WO 01/37816 A2;
EP 0281200 Al; and
US 2006/0110445 Al.
"Die Tablette: Handbuch der Entwicklung, Herstellung und Qualitatssicherung", 3. edition, 2012, Editio Cantor Verlag, Aulendorf, pages 108/109 and 126. Patient Information Leaflet of "Ospamox 500 mg - losbare Tablette"/"Ospamox 750 mg losbare Tablette"/ "Ospamox 1000 mg - losbare Tablette".

Claims

Uncoated tablet containing granules, wherein the granules comprise or consist of
(i) one or more active agents, wherein at least one active agent is a β-lactam antibiotic;
(ii) highly dispersed silicone dioxide in an amount of 1-15 wt.-%, based on the weight of the granules; and
(iii) optional further excipients in an amount of 0-15°wt.-%, based on the weight of the granules, wherein said further excipients comprise 0-3 wt.-% of disintegrants, based on the weight of the granules,
wherein the total amount of the active agents and the highly dispersed silicone dioxide is at least 85 wt.-%, based on the weight of the granules.
The uncoated tablet according to claim 1, wherein the excipients in (iii) comprise
(iiia) binding agents in an amount of 0-3 wt.-%, based on the weight of the granules; and
(iiib) fillers in an amount of 0-10 wt.-%, based on the weight of the granules; preferably the excipients in (iii) are present in an amount of 0-3 wt.-%, based on the weight of the granules.
The uncoated tablet according to claim 1, wherein the granules consist of the one or more active agents and the highly dispersed silicone dioxide, wherein preferably the one or more active agents are a β-lactam antibiotic or a combination of a β-lactam antibiotic and a β-lactamase inhibitor.
The uncoated tablet according to any of the preceding claims, wherein the highly dispersed silicone dioxide is a silicone dioxide having a BEET surface area of from 50 m2 to 800 m2, as measured by ISO 9277 with nitrogen.
The uncoated tablet according to any of claims 1, 3 and 4, wherein the granules consist of 85-99 wt.-% by weight of the β-lactam antibiotic and between 1 and 15 wt.-% highly dispersed silicone dioxide, based on the weight of the granules.
6. The uncoated tablet according to any of the preceding claims, wherein the amount of granules in the tablet is 80-95 wt.-%, preferably 85-93 wt.-%, based on the weight of the tablet.
7. The uncoated tablet according to any of the preceding claims, wherein the amount of β- lactam antibiotic in the tablet is 100-400 mg based on the free form of the β-lactam antibiotic, wherein the free form of the β-lactam antibiotic is not a salt or solvate.
8. The uncoated tablet according to any of the preceding claims, wherein
the extragranular part of the tablet, based on the total weight of the tablet, comprises or consists of the following excipients:
0-5 wt.-% flavoring agents;
0-2 wt.-% lubricants in particular magnesium stearate;
0- 2 wt.-% sweetening agents in particular aspartame;
5-15 wt.-% disintegrants in particular including sodium croscarmellose;
1- 15 wt.-% fillers; and
0-2 wt.-% highly dispersed silicone dioxide.
9. The uncoated tablet according to any of the preceding claims, wherein the tablet has at least one breaking notch which allows the tablet to be split into at least two parts having equal weight with a maximum deviation of +/- 20% compared with each remaining part calculated as: (difference in weight of the two tablet parts to be compared)/(weight of the two tablet parts to be compared)xl00.
10. The uncoated tablet according to any of the preceding claims, wherein the one or more active agents is amoxicillin or a pharmaceutically acceptable salt or solvate thereof, or a combination of (a) amoxicillin free form or a pharmaceutically acceptable salt or solvate thereof and (b) clavulanic acid, wherein the weight ratio of clavulanic acid/amoxicillin free form is 1:2-1:20.
11. Process for preparing granules as defined in any of claims 1-10, comprising or consisting of the steps of
(i) providing a mixture of the highly dispersed silicone dioxide and the one or more active agents and optionally further excipients, wherein the types of the highly dispersed silicone dioxide, the one or more active agents and excipients as well as the amounts thereof are preferably as defined in any of claims 1-10, wherein the amount of highly dispersed silicone dioxide in step (i) is the full amount of highly dispersed silicone dioxide which is present in the final granules or is only a partial amount thereof;
(ii) granulating the mixture of step (i) with an aqueous medium while optionally adding the remaining amount of highly dispersed silicone dioxide during the granulation; and
(iii) obtaining the granules.
Process for preparing an uncoated tablet as defined in any of claims 1-10, comprising or consisting of the steps of
(a) providing granules by using a process as defined in claim 11;
(b) mixing the granules of step (a) with further excipients, preferably the excipients as defined in claim 8, and
(c) compressing the mixture of step (b) into tablets.
Packaged product comprising tablets as defined in any of claims 1-10, wherein the packaged product comprises a blister pack which is not a full aluminum/aluminum blister.
The packaged product according to claim 13, wherein the blister pack is formed from flat, umformed materials which form the sides of the blister pack, and wherein the moisture permeability of the flat, unformed material used for at least one side of the blister pack is in the range of 0.05-5 g/m2/24h, when measured at 38°C and 90% humidity.
The packaged product according to claim 13 or 14, wherein the blister pack is made of polyvinyl chloride, polyvinylidene chloride and/or polypropylene, and preferably does not comprise aluminum.
EP13747660.2A 2012-08-07 2013-08-06 Uncoated tablet comprising granules including a -lactam antibiotic and highly dispersed silicone dioxide Withdrawn EP2882423A1 (en)

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PCT/EP2013/066433 WO2014023710A1 (en) 2012-08-07 2013-08-06 UNCOATED TABLET COMPRISING GRANULES INCLUDING A β-LACTAM ANTIBIOTIC AND HIGHLY DISPERSED SILICONE DIOXIDE
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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
US20030124187A1 (en) * 1997-02-14 2003-07-03 Smithkline Beecham Laboratoires Pharmaceutiques, Pharmaceutical formulations comprising amoxycillin and clavulanate
AT413647B (en) * 1998-11-26 2006-04-15 Sandoz Ag USE OF A COPOLYMERISATE OF 1-VINYL-2-PYRROLIDONE AND VINYL ACETATE FOR THE PREPARATION OF CEFUROXIMAXETIL-SUBJECTED TABLETS
AT500063A1 (en) 1999-11-23 2005-10-15 Sandoz Ag COATED TABLETS
AU2003247023A1 (en) * 2002-08-02 2004-02-25 Ranbaxy Laboratories Limited A process for the preparation of dispersible tablet of cephalexin

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