Title of Invention

"MELT-FORMULATED, MULTIPARTICULATE ORAL DOSAGE FORM"

Abstract A melt-formulated, multiparticulate, oral dosage form containing clavulanic acid and/or at least one of the physiologically acceptable salts thereof and at least one sucrose fatty acid ester and optionally at least one further physiologically acceptable auxiliary substance wherein the proportions by weight of the clavulanate calculated as free acid, is 1 to 90 wt %, the weight ratio of the sucrose fatty acid ester component is 1 to 50 wt% and the weight ratio of the physiologically acceptable auxiliary substance is 1 to 60 wt %, wherein the sucrose fatty acid esters have a hydrophilic lipophilic balance value (HLB value) of 1 to 3 and wherein the dosage form optionally contains at least one ß-lactam antibiotic.
Full Text The present invention relates to a melt-formulated, multiparticulate, oral dosage form.
The present invention relates to a melt-formulated, multiparticulate, oral dosage form containing clavulanic acid and/or one or more of the physiologically acceptable salts thereof and one or more sucrose fatty acid esters and optionally further physiologically acceptable auxiliary substances, to a process for the production thereof and to the use thereof.
Clavulanic acid, in particular in the form of potassium clavulanate, is frequently used in combination with a ß-lactam antibiotic, such as for example amoxicillin, for the treatment of bacterial infections by Gram negative and Gram positive ß-lactam-resistant pathogens. Due to the combination with clavulanic acid, which is capable of cleaving ß-lactamases, these pathogens, despite initial resistance, again become sensitive to treatment with amoxicillin. This combination is used inter alia for the treatment of otitis media in children. Treatment involves the administration of different dose combinations of clavulanic acid to amoxicillin, with ratios of 1:4, 1:7 or 1:8 being the commonest.
One major problem in the production of pharmaceutical preparations comprising clavulanate, preferably K clavulanate, is this compound's elevated susceptibility to hydrolysis. Even over the course of processing and storage of the compound under normal conditions (ambient temperature of 25°C and 60% rel. atmospheric humidity), increasing hydrolysis of the clavulanic acid occurs within a few hours to days, this being accompanied by an intense discoloration and release of CO2.
Decomposition of the compound is accelerated as temperature and humidity increase and furthermore proceeds autocatalytically, a cascade of different decomposition products possibly arising. This decomposition is described in greater detail in WO 94/16696.
As a consequence of this susceptibility to hydrolysis, when processing potassium clavulanate, which is conventionally already commercially available as a mixture with a grade of microcrystalline cellulose which is in a particularly desiccated form or with dry silicon dioxide, it is necessary both to exclude moisture (relative atmospheric
humidity of the direct surroundings of less than 20%) and to keep the room or ambient temperature below 20°C.
Already known powders for suspension and film coated tablets are thus based on powder mixtures with silicon dioxide or on a dry compacted form of the clavulanate, wherein the auxiliary substances used must also be dried before use. When coating the tablets with a film, special low-moisture processes are used, as are for example described in WO 95/28927.
Since pellets are conventionally produced using aqueous solutions or with the assistance of lipophilic matrix materials, such a formulation method is not suitable for formulating mixtures containing clavulanate to yield pellets. Due to clavulanate's susceptibility to moisture, no aqueous solutions can be used and, due to the delaying action on active ingredient release which conventionally occurs, no lipophilic matrix materials may be used either. This is in particular contrary to the therapeutic goal, according to which rapid release and availability in the body are to be achieved.
The object of the present invention was accordingly to provide storage-stable dosage forms containing clavulanate in multiparticulate form, preferably as pellets, which preferably as pellets have no influence on the release profile of the active ingredient in comparison with, for example, a tablet obtained by dry compaction of the active ingredient powder, together with corresponding processes for the production of such a dosage form.
Said object is achieved by the provision of the melt-formulated, multiparticulate, oral dosage form according to the invention containing clavulanic acid and/or at least one of the physiologically acceptable salts thereof and at least one sucrose fatty acid ester and optionally at least one further physiologically acceptable auxiliary substance.
These melt-formulated dosage forms according to the invention are multiparticulate, preferably in the form of granules or pellets, and are accordingly not obtained by any kind of spinning of a corresponding melt which contains active ingredient. The dosage forms according to the invention are accordingly melt-formulated with the exception of melt-formulation by any kind of spinning.

Due to the use of the sucrose fatty acid ester component, the dosage forms according to the invention do not exhibit any delaying action on active ingredient release. Accordingly, no or no additional delay to active ingredient release from the dosage forms according to the invention is observed due to the use of the sucrose fatty ester component.
Preferred dosage forms are those containing potassium clavulanate or sodium clavulanate, particularly preferably potassium clavulanate, as the physiologically acceptable salt of clavulanic acid.
The active ingredient and all further components of the dosage forms according to the invention must be used in anhydrous form due to clavulanic acid's susceptibility to moisture. The dosage form according to the invention must itself also be protected from moisture.
The clavulanate, calculated as free acid, is present in the dosage forms according to the invention preferably in a quantity of 1 to 90 wt.%, very particularly preferably in a quantity of 30 to 80 wt.%, relative to the total weight of the composition of the dosage form.
The sucrose fatty acid esters used are preferably mono-, di-, tri- or polyesters of sucrose with at least one fatty acid, preferably a saturated or unsaturated Ci2-Ca2 fatty acid, particularly preferably a saturated Ci2-C22 fatty acid, or a mixture of at least two of the above-stated sucrose fatty acid esters, particularly preferably a mixture of mono- to poly-esters of sucrose with fatty acids. Particularly suitable sucrose fatty acid esters are those which are derived from palmitic acid and/or stearic acid.
Of the stated sucrose fatty acid esters, those which are in particular suitable are those exhibiting an HLB value (hydrophilic-lipophilic balance value) of 1 to 3, preferably of 1 to 2, very particularly preferably of about 1. The HLB value is determined by the ratio of mono-, di-, tri- and/or polyesters in the sucrose fatty acid ester component. The sucrose fatty acid esters used are distinguished by a melting range in the range from 50 to 80°C, preferably a melting range in the range from 55

to 65°C. Depending on the ratio of mono-, di-, tri- and or poly-esters in the sucrose fatty acid ester component, the melting range varies in the above-stated range.
Use of the sucrose fatty acid esters used according to the invention has no effect on the release of the active ingredient(s) from the dosage form according to the invention.
Sucrose fatty acid esters are approved food additives worldwide and are suitable for the production of pharmaceutical preparations for oral administration. They are commercially available products.
The sucrose fatty acid component is preferably present in the dosage forms according to the invention in a quantity of 1 to 50 wt.%, particularly preferably of 5 to 30 wt.%, very particularly preferably of 10 to 25 wt.%, relative to the total weight of the composition of the dosage form.
It is, of course, known to the person skilled in the art that the sum of all the components of the dosage form according to the invention must always be 100 wt.%.
The dosage forms according to the invention exhibit a release profile of the active ingredient clavulanic acid which corresponds to that of a tablet which has been produced from a dry mixture by press-moulding. This is surprising because the prior art, in particular WO 01/66081 (page 12 et seq.) teaches that the use of sucrose fatty acid esters with a low HLB value, i.e. an HLB value of The dosage form according to the invention may preferably contain at least one physiologically acceptable, preferably anhydrous, auxiliary substance selected from among the group comprising lactose, microcrystalline cellulose, silicon dioxide (Aerosil or Syloid), kaolin, talcum, titanium dioxide, mannitol, CaHPO4 and pH regulators, such as anhydrous citric acid, NaaHPCXt and ascorbic acid. Kaolin, CaHP04 and/or Syloid are particularly preferred. The auxiliary substances, like the

active ingredient, must have any residues of water removed from them and be used in the driest possible form.
If at least one physiologically acceptable auxiliary substance is present in the dosage form according to the invention, said substance may preferably be used in a quantity of 1 to 60 wt.%, particularly preferably of 3 to 45 wt.%, very particularly preferably of 5 to 15 wt.%, relative to the total weight of the composition of the dosage form.
The multiparticulate dosage forms according to the invention are preferably present as granules, particularly preferably as pellets, such as melt-formulated granules or pellets, and may be packaged in this form in capsules, sachets, in a bottle and in a drinking straw with a barrier device and/or controller, as is described, for example, in WO 00/45888. The corresponding disclosure in the stated WO specification is hereby deemed to be part of the present disclosure and is hereby introduced as a reference. They may also be press-moulded into tablets.
The dosage forms according to the invention may surprisingly be produced by preferably anhydrous melt-formulation of the corresponding composition, without the storage stability of the dosage form according to the invention consequently being impaired. There were in fact grounds to fear that the input of heat required for melt-formulation would initiate decomposition of the clavulanic acid.
However, when stored with exclusion of moisture, the dosage forms according to the invention are as stable as the above-mentioned dry preparations.
The melt-formulated, multiparticulate dosage forms according to the invention, preferably corresponding pellets or granules, may thus be stored at room temperature and at elevated temperatures, such as for example 30°C or 40°C under ICH stability conditions, without there being any discoloration of the dosage form and reduction in active ingredient content brought about by decomposition of the clavulanic acid. This is the case when other binders conventional for melt granulation, such as for example polyethylene glycol, are used.
The present invention accordingly also provides a process for the production of the multiparticulate dosage form according to the invention by preferably anhydrous melt-

formulation of a mixture containing clavulanic acid and/or one of the physiologically acceptable salts thereof and at least one sucrose fatty acid ester and optionally at least one further physiologically acceptable auxiliary substance, wherein all components are preferably used in the predried state, i.e. as anhydrous as possible.
According to the invention, formulation of the melt is not taken to mean any kind of spinning of the molten composition of the dosage form according to the invention. Melt-formulation does, however, also include only softening of the binder component, sucrose fatty acid ester, without complete fusion, such that the dosage form according to the invention may also be produced, i.e. formulated, by sintering.
The multiparticulate dosage form according to the invention is preferably produced by at least partially softening the sucrose fatty acid ester component by input of energy to such an extent that it provides its binder action, optionally cooling it, mixing it with the clavulanic acid and/or with at least one of the physiologically acceptable salts thereof and at least one further, optionally present physiologically acceptable auxiliary substance, granulating the mixture, optionally rounding and cooling it, wherein mixing of the components and softening or melting may proceed in any desired order.
The process according to the invention is preferably performed with exclusion of moisture (relative atmospheric humidity of the surroundings less than 20%) and at a room or ambient temperature of below 25°C.
If one further auxiliary substance is present in the composition of the dosage form according to the invention, said auxiliary substance, preferably kaolin and/or Syloid, is mixed with the sucrose fatty acid ester component, the mixture is melted, cooled, mixed with the optionally heated clavulanic acid or the corresponding salt, the mixture is maintained during granulation at a product temperature of preferably 60° to 70°C and the resultant melt-granules or the resultant melt-pellets are rapidly cooled.
The sucrose fatty acid component is softened or melted by optionally mixing it with further components, heating it to a temperature of 50 to 80°C, preferably of 55 to 75°C, particularly preferably of 60 to 65°C, and preferably cooling it again before

granulation of the complete mixture is begun and carried out, preferably at these temperatures.
The granules containing clavulanic acid or the pellets obtained by rounding the granules are rapidly cooled directly after the production thereof, for example by means of direct addition of dry ice or introduction of liquid nitrogen into the reaction product, preferably to a temperature below the melting temperature of the sucrose fatty acid component used, preferably to a temperature of below 35°C.
Cooling preferably proceeds by introduction of liquid nitrogen which, on contact with the hot granules or the pellets, vaporises and spreads throughout the entire mass of granules so resulting in flash cooling, i.e. cooling within less than one minute, of the granules or pellets to temperatures of at most 30°C. This procedure additionally assists in ensuring the gentlest possible treatment of the clavulanic acid.
Double-walled high speed mixers may preferably be used for the entire production of the dosage form according to the invention by simultaneously or successively mixing all the components and performing heating, granulation and optionally subsequent pelletisation and cooling in said apparatus.
Conventional commercially available high speed mixers, which are preferably operated at a peripheral speed of 7-15 m/sec, are used as the mixers.
To this end, rotational speeds in the range preferably from 800 to 2000 revolutions per minute, particularly preferably from 950 to 1050 revolutions per minute, are maintained for mixing the components and/or for granulation in the mixer and the chopper is preferably also operated at least until granules are obtained. The rotational speeds required depend on the size of the granulator and should be selected such that the above-stated peripheral speed is achieved. The period which elapses until granules or pellets are formed depends on mixer size, rotational speed and load level and is familiar to the person skilled in the art. Rounding of the granules may be achieved with the assistance of the mixer without also turning the chopper on.
The granules containing clavulanic acid and/or clavulanate obtained by the process according to the invention are surprisingly already virtually spherical without a separate downstream rounding step and are distinguished by a relatively narrow particle size distribution, i.e. > 80% of the particles are in the range from 250 to 710 l^m. The granules accordingly preferably already assume the form of pellets, such that no corresponding rounding is necessary. Size classification of the particles is determined by screening.
Tablets may also be produced from the melt-formed particles according to the invention by press-moulding granules obtained according to the invention into tablets, or packaging them in sachets or capsules or in a drinking straw, as is disclosed in WO 00/54888.
It is furthermore possible, with the assistance of melt extruders, to heat the mixture of the components, which have already been mixed either outside the extruder or in the extruder, or granules, which have been produced as stated above, at least up to the softening point or until a melt is obtained, to perform extrusion and rapidly to cool the extruded strand as stated above and to chop it in conventional manner.
The multiparticulate, melt-formed dosage forms according to the invention may be provided in known manner with a coating, preferably for flavour masking. The coating material is preferably applied as a solution in an organic solvent or under aqueous conditions, as disclosed in WO 95/28927, or in a molten state.
The dosage forms according to the invention are furthermore ideally suitable for the preparation of a pharmaceutical combined preparation with a (3-lactam antibiotic, preferably amoxicillin.
The present invention accordingly also provides a pharmaceutical preparation comprising the combination of the dosage form according to the invention of clavulanic acid and/or at least one corresponding physiologically acceptable salt and a separately formulated, oral, preferably multiparticulate dosage form of a (3-lactam antibiotic. The (3-lactam antibiotic preferably contains amoxicillin and/or a corresponding physiologically acceptable salt and/or solvate as the antibiotic, preferably a corresponding hydrate, very particularly preferably amoxicillin trihydrate.
Separately formulated is taken according to the invention to mean that the antibiotic is not formulated together with the clavulanic acid to yield a dosage form, but is instead obtained in a distinct production or formulation process and, to produce the combined preparation, is packaged in a container, such as a capsule, a sachet or a drinking straw for administration to patients in the same manner as the separately formulated dosage forms containing clavulanic acid.
In the pharmaceutical combined preparation according to the invention, the ratio by weight of the clavulanic acid-containing dosage form according to the invention to the amoxicillin-containing dosage form, in each case respectively calculated on the basis of the free acid or as amoxicillin, amounts to 1:2 to 1:14, preferably 1:4 to 1:8, particularly preferably 1:4, 1:7 or 1:8.
The pharmaceutical combined preparation according to the invention is highly suitable for the treatment of bacterial infections. The present invention also provides the use of the melt-formulated, multiparticulate dosage forms according to the invention for the production of a pharmaceutical combined preparation with a further separately formulated oral, preferably solid, multiparticulate dosage form of a (3-lactam antibiotic, preferably amoxicillin, for the treatment of bacterial infections, preferably of bacterial infections in children, in particular for the treatment of otitis media, for the treatment in humans of airways diseases or for the treatment of urinary tract diseases.
The release profile of preparations produced in the Examples was determined as follows:
The preparations were placed in a paddle stirrer apparatus in accordance with the European Pharmacopoeia at a temperature of 37°C and a rotational speed of 100 min"1 or 150 min"1 in 300 ml of artificial gastric juice (pH 2) for 10 minutes, wherein in the case of determination in artificial gastric juice the samples taken for measurement were rebuffered to a pH of 5, in order to prevent decomposition of the clavulanic acid prior to the HPLC determination, or in 900 ml of artificial intestinal juice (pH 6.8) for 15 minutes. This pH value was maintained until the test. The quantity of the active ingredient clavulanic acid released at each point in time was determined by HPLC. The stated values are means from in each case 6 samples.
The invention is explained below with reference to Examples. These explanations are given merely by way of example and do not restrict the general concept of the invention.
Examples: Example 1:
Pellets with the following composition were produced in a room with atmospheric humidity of less than 20% and a room temperature of below 25°C:
(Table Removed)
The components are virtually anhydrous due to drying.
A 2 I mixer (Diosna), fitted with a chopper, was heated to 60°C. The sucrose stearic acid ester, kaolin and the mixture of potassium clavulanate with microcrystalline cellulose were placed in this mixer. The resultant powder mixture was mixed and granulated with heating at 1300 revolutions per minute mixing power with the chopper turned on at 2000 revolutions per minute chopper speed. Once the power uptake of the mixer blades had dropped, the chopper was turned off and the mixer operated for a further 3 minutes at the stated rotational speeds.
The pellets obtained were cooled in a bowl cooled with dry ice.
The pellets had a particle size distribution determined by screening of 3% of the pellets 250 urn, 88% 250 to 710 jim, 9% 710 urn.
The storage stability of the pellets containing clavulanic acid was tested by packaging the pellets in aluminium pouches directly after cooling and the sealed pouches were stored at room temperature (25°C) or at 30°C or 40°C. Storage stability was ascertained by determining the content of potassium clavulanate by HPLC measurement. The corresponding stability data are listed in the following Table, entitled "Storage stability".
Example 2
Clavulanic acid pellets with the following composition were produced under the ambient conditions stated in Example 1:

(Table Removed)
All components were anhydrous.
The pellets with the above composition were produced by preheating a 25 I Diosna mixer to 60°C and then mixing the sucrose ester and kaolin at 650 revolutions per minute mixing power and 200 revolutions per minute chopper speed until the mixture was melted. The mixture was cooled to RT (25°C) and added to the K clavulanate, which had been heated to approx. 60°C, and granulated and rounded at 65°C, 700 revolutions per minute mixing power and 1000 revolutions per minute chopper speed. The finished pellets were rapidly cooled within 3 min to 30°C by introduction of liquid N2 while occasionally being mixed without turning on the chopper. The resultant pellets exhibited a narrow size distribution, wherein 18% of the pellets were 250 |um, 80% of the pellets were in the range from 250 to 710 u,m and 2% of the pellets were 710 jam.
Some of the pellets were packaged in aluminium pouches and the sealed pouches were stored at room temperature (25°C), 30°C or 40°C in order to determine the stability of the clavulanic acid pellets. Stability data are stated in the following Table, entitled "Storage stability".
Release of the clavulanic acid from the pellets in gastric juice (pH 2) or in intestinal juice (pH 6.8) was as follows:

(Table Removed)
Example 3
Clavulanic acid pellets with the following composition were produced under the ambient conditions stated in Example 1:
(Table Removed)

All components were anhydrous.
The pellets with the above composition were produced by preheating a 2 I Diosna mixer to 60°C and then melting sucrose ester at 650 revolutions per minute mixing power and 200 revolutions per minute chopper speed. K clavulanate and citric acid were added to the melted sucrose ester and granulated and rounded at 65°C, 700 revolutions per minute mixing power and 1000 revolutions per minute chopper speed. The finished pellets were rapidly cooled to The resultant pellets exhibited a narrow size distribution, wherein > 80% of the pellets were in the range from 250 to 710 (xm. Testing of storage stability of the pellets stored in aluminium pouches proceeded as stated in Example 1 . The values are shown in the Table "Storage stability".
Example 5
Clavulanic acid pellets with the following composition were produced under the ambient conditions stated in Example 1 :
(Table Removed)
All components were anhydrous.
The pellets with the above composition were produced by preheating a 2 I Diosna mixer to 60°C and then mixing sucrose ester and kaolin at 650 revolutions per minute mixing power and 200 revolutions per minute chopper speed until the mixture was melted. K clavulanate, citric acid and sodium carbonate were added to the mixture and granulated and rounded at 65°C, 700 revolutions per minute mixing power and 1000 revolutions per minute chopper speed. The finished pellets were rapidly cooled to 30°C by introduction of liquid N2 while occasionally being mixed without turning on the chopper.
The resultant pellets exhibited a narrow size distribution, wherein 80% of the pellets were in the range from 250 to 710 urn. The storage stability of the pellets stored in the aluminium pouch is shown in the Table "Storage stability".
Example 6
Clavulanic acid pellets with the following composition were produced under the ambient conditions stated in Example 1, 125 mg of clavulanic acid being present in each dose:

(Table Removed)
Batch size was 600 g
The pellets with the above composition were produced by preheating a 4 I Diosna mixer to 60°C and then mixing sucrose ester and kaolin at 650 revolutions per minute mixing power and 1000 revolutions per minute chopper speed until the mixture was melted. The mixture was cooled to RT (25°C) and added to the mixture of K clavulanate and SiO2, which had been heated to approx. 60°C, and granulated and rounded at 65°C, 500-700 revolutions per minute mixing power and 1000 revolutions per minute chopper speed. The finished pellets were rapidly cooled within The resultant pellets exhibited a narrow size distribution, wherein 18% of the pellets were 710 urn.
Example 7
Clavulanic acid pellets with the following composition were produced under the ambient conditions stated in Example 1, 125 mg of clavulanic acid being present in each dose:

(Table Removed)
Batch size was 600 g.
All components were anhydrous.
The pellets with the above composition were produced by preheating a 4 I Diosna mixer to 60°C and then mixing sucrose ester and a proportion of the CaHP04 at 650 revolutions per minute mixing power and 1000 revolutions per minute chopper speed until the mixture was melted. This mixture was cooled to RT (25°C) and added to the mixture of K clavulanate and the remainder of the CaHPO4, which had been heated to approx. 60°C, and granulated and rounded at 65°C, 500 revolutions per minute mixing power and 1000 revolutions per minute chopper speed. The finished pellets were rapidly cooled within 3 min to 30°C by introduction of liquid N2 while occasionally being mixed without turning on the chopper.
The resultant pellets exhibited a narrow size distribution, wherein 18% of the pellets were 250 urn, 80% of the pellets were in the range from 250 to 710 jam and 2% of the pellets were 710 jim.
Some of the pellets were packaged in drinking straws according to WO 00/45888 and stored in sealed vials at room temperature (25°C), 30°C or 40°C in order to determine the stability of the clavulanic acid pellets. Stability data are stated in the following Table, entitled "Storage stability".
Release of the clavulanic acid from the pellets in gastric juice (pH 2) at 37°C/100 rpm determined by HPLC was as follows:

(Table Removed)
Release in intestinal juice (pH 6.8) at 37°C/150 rpm was:


(Table Removed)
Example 8
Clavulanic acid pellets with the following composition were produced under the ambient conditions stated in Example 1, 125 mg of clavulanic acid being present in each dose:

(Table Removed)
Batch size was 600 g.
The pellets with the above composition were produced by preheating a 4 I Diosna mixer to 60°C and then mixing sucrose ester and a proportion of the kaolin at 650 revolutions per minute mixing power and 1000 revolutions per minute chopper speed until the mixture was melted. This mixture was cooled to RT (25°C) and added to the mixture of K clavulanate, lactose and the remainder of the kaolin, which had been heated to approx. 60°C, and granulated and rounded at 65°C, 500 revolutions per minute mixing power and 1000 revolutions per minute chopper speed. The finished pellets were rapidly cooled within 3 min to 30°C by introduction of liquid N2 while occasionally being mixed without turning on the chopper.
The resultant pellets exhibited a narrow size distribution, wherein 18% of the pellets were 250 urn, 80% of the pellets were in the range from 250 to 710 |im and 2% of the pellets were 710
The stability the clavulanic acid pellets was determined by storing some of the pellets as stated in Example 7. Stability data are stated in the following Table, entitled "Storage stability".
Release of the clavulanic acid from the pellets in intestinal juice (pH 6.8) at 37°C/150 rpm determined by HPLC was as follows:

(Table Removed)
Example 9
Clavulanic acid pellets with the following composition were produced under the ambient conditions stated in Example 1,125 mg of clavulanic acid being present in each dose:

(Table Removed)
All components were anhydrous.
The pellets with the above composition were produced by preheating a 4 I Diosna mixer to 60°C and then mixing sucrose ester and kaolin at 650 revolutions per minute mixing power and 1000 revolutions per minute chopper speed until the mixture was melted. The mixture was cooled to RT (25°C) and added to the mixture of K clavulanate and CaHPO4, which had been heated to approx. 60°C, and granulated and rounded at 65°C, 700 revolutions per minute mixing power and 1000 revolutions
per minute chopper speed. The finished pellets were rapidly cooled within 3 min to 30°C by introduction of liquid Na while occasionally being mixed without turning on the hopper.
The resultant pellets exhibited a narrow size distribution, wherein 18% of the pellets were 250 um, 80% of the pellets were in the range from 250 to 710 |um and 2% of the pellets were 710 jam.
The stability the clavulanic acid pellets was determined by storing some of the pellets as stated in Example 7. Stability data are stated in the following Table, entitled "Storage stability".
Release of the clavulanic acid from the pellets in intestinal juice (pH 6.8) at 37°C/150 rpm determined by HPLC was as follows:
(Table Removed)
Storage stability

(Table Removed)
* Initial concentration of clavulanic acid determined by HPLC.
** Concentration of clavulanic acid measured with HPLC after the stated storage time
and temperature.
Example 10
A bioequivalence study relative to Augmentin® sachets containing amoxicillin/clavulanic acid (1000 mg/125 mg) was carried out using the pellets obtained from Example 2 containing 125 mg of clavulanic acid, which were packaged in a drinking straw with separately formulated pellets containing amoxicillin (1000mg).
Twelve test subjects participated in this study, the test and reference being administered in accordance with a crossover trial design.
For the purpose of administration, the sachets were suspended in 200 ml of water for approx. 10 minutes, the clavulanic acid dissolving completely. This suspension was then administered to the test subjects. The pellets packaged in the drinking straw were taken by the test subjects with the assistance of 200 ml of water.
The reference used was Augmentin® sachets from France with a dosage of 1000 mg of amoxicillin to 125 mg of clavulanate, i.e. in a ratio of 8:1. The relative bioavailability the test formulation relative to the reference is shown in the following Table:
Clavulanic acid (125 mg) pellets in a drinking straw relative to Augmentin® sachets



'max

93%



AUC

94%

The availability of the clavulanic acid from pellets according to the invention is comparable with that of the clavulanic acid solution of the reference product, i.e. the solid dosage form in the form of pellets exhibits in vivo release and comparable in vivo stability such that it is bioequivalent to a clavulanic acid reference administered as a solution.



We claim:
1. A melt-formulated, multiparticulate, composition containing clavulanic acid and/or at least one of the physiologically acceptable salts thereof and at least one sucrose fatty acid ester and optionally at least one further physiologically acceptable auxiliary substance wherein the proportions by weight of the clavulanate calculated as free acid, is 1 to 90 wt %, the weight ratio of the sucrose fatty acid ester component is 1 to 50 wt% and the weight ratio of the physiologically acceptable auxiliary substance is 1 to 60 wt %, wherein the sucrose fatty acid esters have a hydrophilic lipophilic balance value (HLB value) of 1 to 3 and wherein said composition is optionally combined with a separately formulated composition containing at least one ß-lactam antibiotic in a weight ratio of clavulanic acid containing composition to the P-lactam antibiotic containing composition in each case respectively calculated on the basis of the free clavulanic acid and of amoxicillin in a range from 1:2 to 1:14.
2. A composition as claimed in claim 1, wherein potassium clavulanate and/or sodium clavulanate, preferably potassium clavulanate, is present as the physiologically acceptable salt of clavulanic acid.
3. A composition as claimed in claim 1, wherein it contains 30 to 80 wt.%, of clavulanate, calculated as free acid, relative to the total weight of the composition.
4. A composition as claimed in any one of claims 1 to 3, wherein it contains a mono-, di-, tri- or polyester of sucrose with at least one fatty acid or a mixture of at least two of the above-stated sucrose fatty acid esters, preferably a mixture of all the stated sucrose fatty acid esters.
5. A composition as claimed in any one of claims 1 to 4, wherein the sucrose fatty acid esters are derived from saturated or unsaturated C12-C22 fatty acids, preferably from saturated C12-C22 fatty acids.
6. A composition as claimed in any one of claims 1 to 5, wherein the sucrose fatty acid ester(s) is/are derived from stearic acid and/or palmitic acid.
7. A composition as claimed in any one of claims 1 to 6, wherein the sucrose fatty acid ester has an HLB value of less than or equal to 2.
8. A composition as claimed in any one of claims 1 to 7, wherein the sucrose fatty acid ester has an HLB value of about 1.
9. A composition as claimed in any one of claims 1 to 8, wherein the sucrose fatty acid ester(s) has/have a melting range of 50°C to 80°C, preferably of 55°C to 65°C.
10. A composition as claimed in any one of claims1 to 9, wherein the sucrose fatty acid ester(s) has/have no influence on release of the clavulanic acid.
11. A composition as claimed in any one of claims 1 to 10, wherein the proportion by weight of the sucrose fatty acid ester(s), relative to the total weight of the composition, amounts to 1 to 50 wt.%, preferably to 5 to 30 wt.%, particularly preferably to 10 to 25 wt.%.
12. A composition as claimed in any one of claims 1 to 11, wherein it contains water-soluble and/or water-insoluble fillers and/or nucleating agents as one or more physiologically acceptable auxiliary substances.
13. A composition as claimed in any one of claims 1 to 12, wherein it contains at least one auxiliary substance selected from among the group comprising lactose, microcrystalline cellulose, silicon dioxide, CaHP04, kaolin, talcum, titanium dioxide, mannitol, pH, regulators, preferably citric acid, Na2HPO4 or ascorbic acid, preferably kaolin, CaHPO4 and/or silicon dioxide as the physiologically acceptable auxiliary substances.
14. A composition as claimed in any one of claims 1 to 13, wherein the proportion by weight of the physiologically acceptable auxiliary substance(s), relative to the total weight of the
composition, amounts to 1 to 60 wt.%, preferably to 3 to 45 wt.%, particularly preferably to 5 to 15 wt.%.
15. A composition as claimed in any one of claims 1 to 14, wherein said composition assumes the form of pellets or granules, preferably of melt-granules or melt-pellets.
16. A composition as claimed in any one of claims 1 to 15, wherein it assumes a form packaged in a capsule, in a sachet, in a bottle or in a drinking straw or press-moulded into tablets.
17. A composition as claimed in any one of claims 1 to 16 combined with a separately formulated composition comprising at least one ß-lactam antibiotic, preferably amoxicillin, as the pharmaceutical active ingredient.
18. A composition as claimed in claim 17, wherein amoxicillin, optionally in the form a physiologically acceptable salt and/or in the form of a solvate, preferably in the form of a hydrate, particularly preferably in the form of the trihydrate, is present in the separately formulated composition as the P-lactam antibiotic.
19. A composition as claimed in claim 17 or claim 18 wherein the ratio by weight of the clavulanic acid-containing composition to the P-lactam antibiotic-containing composition, in each case respectively calculated on the basis of the free clavulanic acid or of the amoxicillin, preferably in the range from 1:4 to 1:8, particularly preferably at 1:4, 1:7 or 1:8.
20. A composition as claimed in any of the preceding claims as and when used for the preparation of a medicament in the treatment of bacterial infections preferably in children, otitis media, airway diseases or urinary tract diseases
21. A process for the production of a composition as claimed in one or more of claims 1 to 16, wherein the sucrose fatty acid ester component is at least partially softened.
preferably by energy input, to such an extent that it provides its binder action, is optionally cooled, is mixed with the clavulanic acid and/or with at least one of the physiologically acceptable salts thereof and at least one further, optionally present physiologically acceptable auxiliary substance, is granulated optionally rounded and cooled, wherein mixing and energy input may proceed in any desired time sequence.
22. A process for the production of a composition as claimed in claim 21, wherein the sucrose fatty acid ester component is optionally mixed with an auxiliary substance, melted and cooled, the cooled component or mixture is mixed with the optionally heated clavulanic acid, is partially melted with energy input, preferably at a product temperature of 60°C to 70°C, is granulated, optionally rounded and cooled.
23. A process for the production of a composition as claimed in claim 21 or claim 22, wherein the clavulanic acid and optional auxiliary substances is/are heated to a temperature of 50°C to 80°C, preferably of 55°C to 75°C, particularly preferably of 60°C to 65 °C, prior to granulation.
24. A process for the production a composition as claimed in any one of claims 21 to 23, wherein the clavulanic acid-containing granules or the corresponding pellets are rapidly cooled, preferably by addition of dry ice or by introduction of liquid nitrogen, preferably liquid nitrogen, directly after the production thereof


Documents:

1080-DELNP-2006-Abstract (28-01-2010).pdf

1080-delnp-2006-abstract.pdf

1080-delnp-2006-Claims (27-09-2011).pdf

1080-DELNP-2006-Claims (28-01-2010).pdf

1080-delnp-2006-claims.pdf

1080-DELNP-2006-Correspondence-Others (11-02-2010).pdf

1080-DELNP-2006-Correspondence-Others (12-02-2010).pdf

1080-delnp-2006-Correspondence-others (27-09-2011).pdf

1080-DELNP-2006-Correspondence-Others (28-01-2010).pdf

1080-delnp-2006-correspondence-others.pdf

1080-delnp-2006-correspondence-others1.pdf

1080-DELNP-2006-Description (Complete) (28-01-2010).pdf

1080-delnp-2006-description (complete).pdf

1080-DELNP-2006-Form-1 (28-01-2010).pdf

1080-delnp-2006-form-1.pdf

1080-delnp-2006-form-18.pdf

1080-DELNP-2006-Form-2 (28-01-2010).pdf

1080-delnp-2006-form-2.pdf

1080-DELNP-2006-Form-3-(11-02-2010).pdf

1080-delnp-2006-form-3.pdf

1080-delnp-2006-form-5.pdf

1080-DELNP-2006-GPA (28-01-2010).pdf

1080-delnp-2006-gpa.pdf

1080-delnp-2006-pct-210.pdf

1080-delnp-2006-pct-308.pdf

1080-DELNP-2006-Petition 137-(11-02-2010).pdf


Patent Number 249872
Indian Patent Application Number 1080/DELNP/2006
PG Journal Number 47/2011
Publication Date 25-Nov-2011
Grant Date 17-Nov-2011
Date of Filing 01-Mar-2006
Name of Patentee GRUNENTHAL GMBH
Applicant Address 6,D-52078 AACHEN, GERMANY,
Inventors:
# Inventor's Name Inventor's Address
1 IRIS ZIEGLER IM DICKENBRUCH 6, 51259 ROTGEN, GERMANY,
2 JOHANNES BARTHOLOMAUS, IN DEN ATZENBENDEN 54,52080 AACHEN, GERMANY.
3 DIETER SCHATEIKIS WINTERSTR. 13,52223 STOLBERG, GERMANY,
PCT International Classification Number A61K 9/00
PCT International Application Number PCT/EP2004/009530
PCT International Filing date 2004-08-26
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 103 41 264.6 2003-09-04 Germany