CA2527972C - Measuring device for non-destructively determining the weight-in quantity in capsules - Google Patents
Measuring device for non-destructively determining the weight-in quantity in capsules Download PDFInfo
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- CA2527972C CA2527972C CA2527972A CA2527972A CA2527972C CA 2527972 C CA2527972 C CA 2527972C CA 2527972 A CA2527972 A CA 2527972A CA 2527972 A CA2527972 A CA 2527972A CA 2527972 C CA2527972 C CA 2527972C
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- capsules
- microwave
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- resonator
- weight
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Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01G—WEIGHING
- G01G9/00—Methods of, or apparatus for, the determination of weight, not provided for in groups G01G1/00 - G01G7/00
- G01G9/005—Methods of, or apparatus for, the determination of weight, not provided for in groups G01G1/00 - G01G7/00 using radiations, e.g. radioactive
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
- A61J3/071—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use into the form of telescopically engaged two-piece capsules
- A61J3/074—Filling capsules; Related operations
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01G—WEIGHING
- G01G17/00—Apparatus for or methods of weighing material of special form or property
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01G—WEIGHING
- G01G9/00—Methods of, or apparatus for, the determination of weight, not provided for in groups G01G1/00 - G01G7/00
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N22/00—Investigating or analysing materials by the use of microwaves or radio waves, i.e. electromagnetic waves with a wavelength of one millimetre or more
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J2200/00—General characteristics or adaptations
- A61J2200/70—Device provided with specific sensor or indicating means
- A61J2200/74—Device provided with specific sensor or indicating means for weight
Abstract
The invention relates to a method for conducting nondestructive net weighing of capsules with the aid of microwaves
Description
84474pct MEASURING DEVICE FOR NON-DESTRUCTIVELY DETERMINING THE
WEIGHT-IN QUANTITY IN CAPSULES
The invention relates to a process for the non-destructive net weighing of capsules using microwaves.
Background to the invention In many industrial manufacturing processes it is particularly important to know the net weight of packed goods (e.g. bulk goods, foodstuffs, etc.). When the tare weight is negligibly small compared with the net weight, gross weighing of the packed goods is generally sufficient. However, if the wrappings or packagings are very small, as in the case of pharmaceutical formulations containing active substances, such as capsules, for example, the ratio between the surface area and the volume is shifted considerably towards the surface area, and the tare weight is easily a multiple of the net weight. In such cases, fluctuations in the tare weight cannot be disregarded. The net weight must therefore be determined either by directly weighing the net contents or by weighing the object to be measured before and after packaging (determining the tare and gross weights).
Naturally, net weighing will always be carried out on the filling or packing machine where the actual metering process takes place. The same is also true, however, of gross/tare weighing when operating at high production rates, as otherwise the proper association between the tare and gross measurements of the individual items could only be achieved with difficulty or at considerable expense.
When high production rates (e.g. 100,000 items/hour or more) are required while at the same time small quantities in the mg range are being weighed out, the measuring apparatus is subject to extreme demands in terms of precision and speed. For example, online gross/tare weighing systems on capsule filling machines in which a capacitive measuring system is used are known in the prior art. The substance to be measured is passed through a capacitor before and after filling and the mass introduced is calculated from its change in capacity. However, it has been found that processes of this kind are only suitable for use with amounts of more than 50 mg. Modern gravimetric weighing cells meet significantly higher accuracy requirements. However, they operate at a low speed of only a few capsules per second. Significantly higher throughput speeds could be achieved by providing weighing cells of this kind in parallel, but gravimetric weighing cells have the limitation of being highly sensitive to vibrations and having lobe operated in cycles rather than continuously. Consequently, gravimetric weighing cells can only be used to a very limited extent on continuously operating capsule filling machines.
There is thus a need for a weighing method which - when detached from the filling machine and operating as a stand-alone solution - is capable of determining the contents of filled and sealed capsules.
Description of the invention An embodiment of the invention relates to process for the non-destructive net weighing of a capsule filled with a sample of material, wherein in a first step of the process variable frequency electromagnetic radiation is generated in a microwave generator under the control of a processor and is supplied to a probe applicator in the form of a resonator, a microwave signal leaving the applicator being supplied to a detector diode from whose signals b(0) and f(0) are determined by the processor as primary measurement values by means of an analogue-to-digital converter, b(0) being the half-power width at the resonant frequency f(0) of the applicator which is operatively connected to a measuring probe, wherein the capsule filled with a sample of material is connected to the resonator such that the electric field of the resonator runs generally parallel to the surface on passing into the material of the probe and wherein, from the primary measurement values b(0) and f(0), the measuring signals F = f(L) - f(0) or B = b(0) - b(L) are obtained, where F and B denote the microwave measuring signals of the detuning and propagation of the resonance, with f(L) and b(L) being equal to constant material-dependent reference values, and wherein in a second step gravimetric gross weighing is carried out in order to determine the gross weight signal C = m-1- + MN, wherein the magnitude mT represents the mass of the empty packaging and the magnitude mN represents the net mass to be determined, and finally from the measuring signals F, B and C obtained the net mass mN to be determined is computed according to the following equation mN = aF + r3B + yC + 6 the coefficients a, 3, y and 6 having been determined beforehand by calibration of the measuring system by linear regression from a measuring series with reference samples of known net weight.
Another embodiment of the invention relates to apparatus for carrying out the process as described above, which comprises a hopper from which filled and sealed capsules are guided serially and/or individually by means of a separating unit through the microwave resonator, which also comprises an adjacent distributor unit by means of which the capsules are arranged parallel for transporting and by means of which the capsules are distributed onto several pathways where gravimetric weighing cells are located, and which also comprises a computer-aided data collecting unit which is connected to the microwave resonator, the distributor unit and the gravimetric weighing cells and ensures that the measurements are correctly assigned to the individual capsules and performs the evaluation and which finally has a reject channel through which capsules of the wrong weight are rejected.
The measuring signals F and B may be determined using apparatus as disclosed for example in DE 4004119. Figure 1 shows the diagrammatic structure of such an apparatus.
- 3a -As shown in Figure 1, this apparatus is characterised by a variable-frequency microwave generator (3) which can be digitally tuned by a processor (2), this generator being connected to a coupling probe (5) which is disposed in an applicator (4) for measuring the measuring signals F and B of a sample (11), said applicator (4) having another coupling probe (6) which is connected via a microwave amplifier or attenuator (7) to a detector diode (8) the signal output of which is connected to the processor (2). As shown in Figure 1, the detector diode (8) may be connected to the processor (2) via an analogue-to-digital converter (9). The attenuator (7) may be connected to the processor (2) via a digital-to-analogue converter (10), as shown in Figure 1. A circulator (28) for uncoupling is disposed between the microwave generator (3) and the coupling probe (5) and between the coupling probe (6) and the microwave amplifier or attenuator (7).
To determine the gross weight signal C, gravimetric weighing cells may be used which determine the weight with a standard deviation of 0.1 mg.
Figure 2 shows the diagrammatic plan of the coupling of the microwave process to the gross weighing. Using a separating unit (2') the filled and sealed capsules are guided serially and/or individually from a hopper (1') through the microwave resonator (3'). An adjacent distributor unit (4') as used in current capsule weighing machines arranges the capsules for parallel transportation and distributes them onto several pathways where the gravimetric weighing cells (5') are located. A
computer -aided data collecting unit (7') which is connected to the units (3'), (4') and (5') ensures that the measurements are correctly assigned to the individual capsules and performs the evaluation. Capsules of the wrong net weight are diverted into a reject channel (6').
The term microwave resonator (3') denotes an apparatus according to Figure 1.
This process is suitable for contents in the mg range. It operates at high speed and can be used even when the weight of the packaging or the empty capsule far exceeds the weight of the capsule contents.
The particular value of the process is that the necessary measurement can be carried out at high speed and with precision so that even amounts in the mg range can be processed. Fluctuations in the moisture content of the product or packaging are also compensated by the process according to the invention.
The data sets obtained by the process according to the invention are evaluated as described hereinafter.
The masses of the packaging (tare) and goods for measurement (net weight) are designated mT and mN. Either the packaging or the contents must contain water.
The mass of water contained either in the empty capsule or in the filling is hereinafter designated mina The two measuring signals determined by the microwave measuring method for detuning and propagating the resonance are hereinafter referred to as F = f(L) - f(0) or B = b(0) - b(L) and the result of the gross weighing is designated C.
The detuning of the microwave resonator F and also the propagation of the resonance B are proportional to the mass of the sample introduced into the resonator.
Thus the two microwave measuring signals can be represented in the following form:
F = fTmT + fmommo +
B = bTmT + b1120MH20 hATMN, (2) The coefficients IT, fino , IN and bT, bin , bAr denote the respective substance-specific proportionality constants.
As the microwave attenuation depends primarily on the water content of the product being measured, the measuring signal B is essentially determined by the term bH20111H20 in equation (2). Fluctuations in the moisture content of either the product or the packaging are thus compensated by taking account of the measured value B
For the gross weight ,signal C = mT + M N = (3) After inversion of the linear equation system (1), (2) and (3) and resolution according to the net weight sought, mN is obtained as a linear combination of the measuring data F, B and C obtained, in the form mN = cxF + B + ),C + (4) For calibration the coefficients c4 A y and oin equation (4) are determined by linear regression from a measuring series with reference samples of known net weight.
The coefficient .5 takes account of any possible shift in the calibration caused by other influencing factors (e.g. temperature).
As the microwave detuning F is always proportional to the respective dielectric constant (DC) of the materials introduced into the resonator, the operating principle of the proposed apparatus is guaranteed when the DCs of the packing and contents are sufficiently different.
By capsules are meant, within the scope of the present invention, sealed capsules characterised in that they contain a quantity of a powder. The material from which these capsules are made is selected according to the invention from among gelatine, cellulose derivatives, starch, starch derivatives, chitosan and synthetic plastics. If gelatine is used as the capsule material, it may be used in admixture with other additives selected from among polyethyleneglycol (PEG), preferably PEG 3350, glycerol, sorbitol, propyleneglycol, PEO-PPO block copolymers and other =
polyalcohols and polyethers. Within the scope of the present invention gelatine is used particularly preferably in admixture with PEG, preferably PEG 3350. A
gelatine capsule according to the invention preferably contains PEG in an amount of 1-10% (wt.-%), preferably 3-8 %. Particularly preferred gelatine capsules contain PEG in an amount of 4-6%, a PEG content of about 5% being most preferred according to the invention. If cellulose derivatives are used as the capsule material, it is preferable to use hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxymethylcellulose and hydroxyethylcellulose. In this case, hydroxypropylmethylcellulose (HPMC), particularly preferably HPMC 2910 is used as the capsule material. If synthetic plastics are used as the capsule material, these are preferably selected according to the invention from among polyethylene, polycarbonate, polyester, polypropylene and polyethylene terephthalate.
Particularly preferred synthetic plastics for the capsules for inhalation according to the invention are polyethylene, polycarbonate or polyethylene terephthalate. If polyethylene is used as one of the particularly preferred capsule materials according to the invention, polyethylene with a density of between 900 and 1000 kg/m3, preferably from 940 - 980 kg/m3 , particularly preferably 960 kg/m3 is preferably used (high-density polyethylene).
The empty capsules may be prepared by methods known in the art. For example, possible production methods include the dipping method, blow moulding, injection moulding, extrusion and deep drawing, all of which are known in the art.
The process according to the invention for net weighing capsules is aimed at determining the precise weight or mass mN of the powder contained in the capsules.
This powder is preferably a powder intended for inhalation which contains a pharmaceutically acceptable excipient in addition to an active substance.
Examples of pharmaceutically acceptable excipients include, for example, monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose, trehalose), oligo- and polysaccharides (e.g. dextrane), polyalcohols (e.g.
sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate), or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
The active substances within the scope of the present invention are compounds which are preferably selected from among the anticholinergics, betamimetics, dopamine agonists, antiallergics, leukotriene antagonists and corticosteroids and optionally combinations of active substances thereof.
Examples of preferred anticholinergics are compounds selected from among the tiotropium salts, ipratropium salts, oxitropium salts, salts of the compourids known from WO 02/32899 tropenol N-methyl-2,2-diphenylpropionate, scopine N-methyl-2,2-diphenylpropionate, scopine N-methyl-2-fluoro-2,2-diphenylacetate and tropenol N-methyl-2-fluoro-2,2-diphenylacetate as well as salts of the compounds known from WO 02/32899 tropeno1N-methy1-3,3',4,4'-tetrafluorobenzilate, scopine N-methyl-3,3',4,4'-tetrafluorobenzilate;
scopine N-methyl-4,4'-dichlorobenzilate, scopine N-methyl- 4,41-difluorob enzilate, tropenol N-methyl-3,3'-difluorobenzilate, scopine N-methyl- 3,3'-difluorobenzilate and tropenol N-ethyl-4,4'-difluorobenzilate, optionally in the form of their hydrates and solvates.
By salts are meant those compounds which contain, in addition to the abovementioned cations, as counter-ion, an anion with a single negative charge selected from among the chloride, bromide and methanesulphonate.
Particularly preferably the active substances within the scope of the present invention are the bromides or methanesulphonates of the abovementioned structures.
Of exceptional interest within the scope of the present invention are, for example, the anticholinergics tiotropium bromide, ipratropium bromide, oxitropium bromide, 2,2-diphenylpropionate tropenol-methobromide, scopine 2,2-diphenylpropionate-=
WEIGHT-IN QUANTITY IN CAPSULES
The invention relates to a process for the non-destructive net weighing of capsules using microwaves.
Background to the invention In many industrial manufacturing processes it is particularly important to know the net weight of packed goods (e.g. bulk goods, foodstuffs, etc.). When the tare weight is negligibly small compared with the net weight, gross weighing of the packed goods is generally sufficient. However, if the wrappings or packagings are very small, as in the case of pharmaceutical formulations containing active substances, such as capsules, for example, the ratio between the surface area and the volume is shifted considerably towards the surface area, and the tare weight is easily a multiple of the net weight. In such cases, fluctuations in the tare weight cannot be disregarded. The net weight must therefore be determined either by directly weighing the net contents or by weighing the object to be measured before and after packaging (determining the tare and gross weights).
Naturally, net weighing will always be carried out on the filling or packing machine where the actual metering process takes place. The same is also true, however, of gross/tare weighing when operating at high production rates, as otherwise the proper association between the tare and gross measurements of the individual items could only be achieved with difficulty or at considerable expense.
When high production rates (e.g. 100,000 items/hour or more) are required while at the same time small quantities in the mg range are being weighed out, the measuring apparatus is subject to extreme demands in terms of precision and speed. For example, online gross/tare weighing systems on capsule filling machines in which a capacitive measuring system is used are known in the prior art. The substance to be measured is passed through a capacitor before and after filling and the mass introduced is calculated from its change in capacity. However, it has been found that processes of this kind are only suitable for use with amounts of more than 50 mg. Modern gravimetric weighing cells meet significantly higher accuracy requirements. However, they operate at a low speed of only a few capsules per second. Significantly higher throughput speeds could be achieved by providing weighing cells of this kind in parallel, but gravimetric weighing cells have the limitation of being highly sensitive to vibrations and having lobe operated in cycles rather than continuously. Consequently, gravimetric weighing cells can only be used to a very limited extent on continuously operating capsule filling machines.
There is thus a need for a weighing method which - when detached from the filling machine and operating as a stand-alone solution - is capable of determining the contents of filled and sealed capsules.
Description of the invention An embodiment of the invention relates to process for the non-destructive net weighing of a capsule filled with a sample of material, wherein in a first step of the process variable frequency electromagnetic radiation is generated in a microwave generator under the control of a processor and is supplied to a probe applicator in the form of a resonator, a microwave signal leaving the applicator being supplied to a detector diode from whose signals b(0) and f(0) are determined by the processor as primary measurement values by means of an analogue-to-digital converter, b(0) being the half-power width at the resonant frequency f(0) of the applicator which is operatively connected to a measuring probe, wherein the capsule filled with a sample of material is connected to the resonator such that the electric field of the resonator runs generally parallel to the surface on passing into the material of the probe and wherein, from the primary measurement values b(0) and f(0), the measuring signals F = f(L) - f(0) or B = b(0) - b(L) are obtained, where F and B denote the microwave measuring signals of the detuning and propagation of the resonance, with f(L) and b(L) being equal to constant material-dependent reference values, and wherein in a second step gravimetric gross weighing is carried out in order to determine the gross weight signal C = m-1- + MN, wherein the magnitude mT represents the mass of the empty packaging and the magnitude mN represents the net mass to be determined, and finally from the measuring signals F, B and C obtained the net mass mN to be determined is computed according to the following equation mN = aF + r3B + yC + 6 the coefficients a, 3, y and 6 having been determined beforehand by calibration of the measuring system by linear regression from a measuring series with reference samples of known net weight.
Another embodiment of the invention relates to apparatus for carrying out the process as described above, which comprises a hopper from which filled and sealed capsules are guided serially and/or individually by means of a separating unit through the microwave resonator, which also comprises an adjacent distributor unit by means of which the capsules are arranged parallel for transporting and by means of which the capsules are distributed onto several pathways where gravimetric weighing cells are located, and which also comprises a computer-aided data collecting unit which is connected to the microwave resonator, the distributor unit and the gravimetric weighing cells and ensures that the measurements are correctly assigned to the individual capsules and performs the evaluation and which finally has a reject channel through which capsules of the wrong weight are rejected.
The measuring signals F and B may be determined using apparatus as disclosed for example in DE 4004119. Figure 1 shows the diagrammatic structure of such an apparatus.
- 3a -As shown in Figure 1, this apparatus is characterised by a variable-frequency microwave generator (3) which can be digitally tuned by a processor (2), this generator being connected to a coupling probe (5) which is disposed in an applicator (4) for measuring the measuring signals F and B of a sample (11), said applicator (4) having another coupling probe (6) which is connected via a microwave amplifier or attenuator (7) to a detector diode (8) the signal output of which is connected to the processor (2). As shown in Figure 1, the detector diode (8) may be connected to the processor (2) via an analogue-to-digital converter (9). The attenuator (7) may be connected to the processor (2) via a digital-to-analogue converter (10), as shown in Figure 1. A circulator (28) for uncoupling is disposed between the microwave generator (3) and the coupling probe (5) and between the coupling probe (6) and the microwave amplifier or attenuator (7).
To determine the gross weight signal C, gravimetric weighing cells may be used which determine the weight with a standard deviation of 0.1 mg.
Figure 2 shows the diagrammatic plan of the coupling of the microwave process to the gross weighing. Using a separating unit (2') the filled and sealed capsules are guided serially and/or individually from a hopper (1') through the microwave resonator (3'). An adjacent distributor unit (4') as used in current capsule weighing machines arranges the capsules for parallel transportation and distributes them onto several pathways where the gravimetric weighing cells (5') are located. A
computer -aided data collecting unit (7') which is connected to the units (3'), (4') and (5') ensures that the measurements are correctly assigned to the individual capsules and performs the evaluation. Capsules of the wrong net weight are diverted into a reject channel (6').
The term microwave resonator (3') denotes an apparatus according to Figure 1.
This process is suitable for contents in the mg range. It operates at high speed and can be used even when the weight of the packaging or the empty capsule far exceeds the weight of the capsule contents.
The particular value of the process is that the necessary measurement can be carried out at high speed and with precision so that even amounts in the mg range can be processed. Fluctuations in the moisture content of the product or packaging are also compensated by the process according to the invention.
The data sets obtained by the process according to the invention are evaluated as described hereinafter.
The masses of the packaging (tare) and goods for measurement (net weight) are designated mT and mN. Either the packaging or the contents must contain water.
The mass of water contained either in the empty capsule or in the filling is hereinafter designated mina The two measuring signals determined by the microwave measuring method for detuning and propagating the resonance are hereinafter referred to as F = f(L) - f(0) or B = b(0) - b(L) and the result of the gross weighing is designated C.
The detuning of the microwave resonator F and also the propagation of the resonance B are proportional to the mass of the sample introduced into the resonator.
Thus the two microwave measuring signals can be represented in the following form:
F = fTmT + fmommo +
B = bTmT + b1120MH20 hATMN, (2) The coefficients IT, fino , IN and bT, bin , bAr denote the respective substance-specific proportionality constants.
As the microwave attenuation depends primarily on the water content of the product being measured, the measuring signal B is essentially determined by the term bH20111H20 in equation (2). Fluctuations in the moisture content of either the product or the packaging are thus compensated by taking account of the measured value B
For the gross weight ,signal C = mT + M N = (3) After inversion of the linear equation system (1), (2) and (3) and resolution according to the net weight sought, mN is obtained as a linear combination of the measuring data F, B and C obtained, in the form mN = cxF + B + ),C + (4) For calibration the coefficients c4 A y and oin equation (4) are determined by linear regression from a measuring series with reference samples of known net weight.
The coefficient .5 takes account of any possible shift in the calibration caused by other influencing factors (e.g. temperature).
As the microwave detuning F is always proportional to the respective dielectric constant (DC) of the materials introduced into the resonator, the operating principle of the proposed apparatus is guaranteed when the DCs of the packing and contents are sufficiently different.
By capsules are meant, within the scope of the present invention, sealed capsules characterised in that they contain a quantity of a powder. The material from which these capsules are made is selected according to the invention from among gelatine, cellulose derivatives, starch, starch derivatives, chitosan and synthetic plastics. If gelatine is used as the capsule material, it may be used in admixture with other additives selected from among polyethyleneglycol (PEG), preferably PEG 3350, glycerol, sorbitol, propyleneglycol, PEO-PPO block copolymers and other =
polyalcohols and polyethers. Within the scope of the present invention gelatine is used particularly preferably in admixture with PEG, preferably PEG 3350. A
gelatine capsule according to the invention preferably contains PEG in an amount of 1-10% (wt.-%), preferably 3-8 %. Particularly preferred gelatine capsules contain PEG in an amount of 4-6%, a PEG content of about 5% being most preferred according to the invention. If cellulose derivatives are used as the capsule material, it is preferable to use hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxymethylcellulose and hydroxyethylcellulose. In this case, hydroxypropylmethylcellulose (HPMC), particularly preferably HPMC 2910 is used as the capsule material. If synthetic plastics are used as the capsule material, these are preferably selected according to the invention from among polyethylene, polycarbonate, polyester, polypropylene and polyethylene terephthalate.
Particularly preferred synthetic plastics for the capsules for inhalation according to the invention are polyethylene, polycarbonate or polyethylene terephthalate. If polyethylene is used as one of the particularly preferred capsule materials according to the invention, polyethylene with a density of between 900 and 1000 kg/m3, preferably from 940 - 980 kg/m3 , particularly preferably 960 kg/m3 is preferably used (high-density polyethylene).
The empty capsules may be prepared by methods known in the art. For example, possible production methods include the dipping method, blow moulding, injection moulding, extrusion and deep drawing, all of which are known in the art.
The process according to the invention for net weighing capsules is aimed at determining the precise weight or mass mN of the powder contained in the capsules.
This powder is preferably a powder intended for inhalation which contains a pharmaceutically acceptable excipient in addition to an active substance.
Examples of pharmaceutically acceptable excipients include, for example, monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose, trehalose), oligo- and polysaccharides (e.g. dextrane), polyalcohols (e.g.
sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate), or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
The active substances within the scope of the present invention are compounds which are preferably selected from among the anticholinergics, betamimetics, dopamine agonists, antiallergics, leukotriene antagonists and corticosteroids and optionally combinations of active substances thereof.
Examples of preferred anticholinergics are compounds selected from among the tiotropium salts, ipratropium salts, oxitropium salts, salts of the compourids known from WO 02/32899 tropenol N-methyl-2,2-diphenylpropionate, scopine N-methyl-2,2-diphenylpropionate, scopine N-methyl-2-fluoro-2,2-diphenylacetate and tropenol N-methyl-2-fluoro-2,2-diphenylacetate as well as salts of the compounds known from WO 02/32899 tropeno1N-methy1-3,3',4,4'-tetrafluorobenzilate, scopine N-methyl-3,3',4,4'-tetrafluorobenzilate;
scopine N-methyl-4,4'-dichlorobenzilate, scopine N-methyl- 4,41-difluorob enzilate, tropenol N-methyl-3,3'-difluorobenzilate, scopine N-methyl- 3,3'-difluorobenzilate and tropenol N-ethyl-4,4'-difluorobenzilate, optionally in the form of their hydrates and solvates.
By salts are meant those compounds which contain, in addition to the abovementioned cations, as counter-ion, an anion with a single negative charge selected from among the chloride, bromide and methanesulphonate.
Particularly preferably the active substances within the scope of the present invention are the bromides or methanesulphonates of the abovementioned structures.
Of exceptional interest within the scope of the present invention are, for example, the anticholinergics tiotropium bromide, ipratropium bromide, oxitropium bromide, 2,2-diphenylpropionate tropenol-methobromide, scopine 2,2-diphenylpropionate-=
methobromide, scopine 2-fluoro-2,2-diphenylacetate-methobromide, tropenol 2-fluoro-2,2-diphenylacetate-methobromide, tropenol 3,3,4,4'- tetrafluorob enzilate-methobromide, scopine 3,3',4,4'-tetrafluorobenzilate-methobromide; scopine 4,4'-dichlorobenzilate-methobromide, scopine 4,4'-difluorobenzilate-methobromide, tropenol 3,3'-difluorobenzilate-methobromide, scopine 3,3'-difluorobenzilate-methobromide and tropenol 4,4'-difluorobenzilate-ethylbromide, while tiotropium bromide, ipratropium bromide, tropenol 2,2-diphenylpropionate -methobromide, scopine 2,2-diphenylpropionate-methobromide, scopine 2-fluoro-2,2 -diphenylacetate-methobromide and tropenol 2-fluoro-2,2-diphenylacetate-methobromide are particularly important.
Of outstanding importance here is tiotropium bromide, most particularly in the form of its crystalline monohydrate known from WO 02/30928.
Examples of betamimetics which may be used according to the invention are preferably compounds selected from among bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salbutamol, salmeterol, sulphonterol, terbutaline, tulobuterol, 4-hydroxy-742-{ [2-{ [3-(2-phenylethoxy)propyl]sulphonyl}ethyll-aminolethy1]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxypheny1)-2-[4-(1-benzimidazoly1)-2-methyl-2-butylamino]ethanol, 143-(4-methoxybenzyl-amino)-4-hydroxypheny1]-2-[4-(1-benzimidazoly1)-2-methy1-2-butylamino]ethanol, 142H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-243-(4-N,N-dimethylaminopheny1)-2-methy1-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-243-(4-methoxypheny1)-2-methyl-2-propylaminolethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-243-(4-n-butyloxypheny1)-2-methy1-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-2-{443-(4-methoxypheny1)-1,2,4-triazol-3-y1]-2-methy1-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobuty1)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylpheny1)-2-tert.-butylamino)ethanol and 1-(4-ethoxycarbonylamino-cyano-5-fluoropheny1)-2-(tert.-butylamino)ethanol, optionally in the form of their racemates, their enantiomers, their diastereomers, as well as optionally their pharmacologically acceptable acid addition salts and hydrates. It is particularly preferable to use, as betamimetics, active substances of this kind selected from among fenoterol, formoterol, salmeterol, salbutamol, 1- [3-(4-methoxybenzyl-amino)-4-hydroxypheny1]-214-(1-benzimidazoly1)-2-methyl-2-butylaminoiethanol, 142H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2-3 -(4-N,N-= WO 2004/106870 - 9 -dimethylaminopheny1)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-213-(4-methoxypheny1)-2-methy1-2-propylamino]ethanol, 142H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-243-(4-n-butyloxypheny1)-2-methy1-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-2-(443-(4-methoxypheny1)-1,2,4-triazol-3-y1]-2-methyl-2-butylamino }ethanol, optionally in the form of their racemates, their enantiomers, their diastereomers, as well as optionally their pharmacologically acceptable acid addition salts and hydrates. Of the betamimetics mentioned above, the compounds formoterol and salmeterol, optionally in the form of their racemates, their enantiomers, their diastereomers, as well as optionally their pharmacologically acceptable acid addition salts and hydrates, are particularly important.
For example, the acid addition salts of the betamimetics are selected from among the hydrochloride, hydrobromide, sulphate, phosphate, fumarate, methanesulphonate and xinafoate are preferred according to the invention. In the case of formoterol, the salts selected from among the hydrochloride, sulphate and fumarate are particularly preferred, especially the hydrochloride and fumarate. Of outstanding importance according to the invention is formoterol fumarate. In the case of salmeterol, the salts selected from among the hydrochloride, sulphate and xinafoate are particularly preferred, especially the xinafoate.
Within the scope of the present invention, the corticosteroids which may be used according to the invention are compounds selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864, KSR 592, ST-126 and dexamethasone. The preferred corticosteroids within the scope of the present invention are those selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexamethasone, while budesonide, fluticasone, mometasone and ciclesonide, especially budesonide and fluticasone, are of particular importance. The term steroids may be used on its own, within the scope of the present patent application, instead of the term corticosteroids. Any reference to steroids within the scope of the present invention also includes a reference to salts or derivatives which may be formed from the steroids. Examples of possible salts or derivatives include: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. The corticosteroids may optionally also be in the form of their hydrates.
Within the scope of the present invention, the term dopamine agonists denotes compounds selected from among bromocriptine, cabergolin, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid and viozan. It is preferable within the scope of the present invention to use dopamine agonists selected from among pramipexol, talipexol and viozan, pramipexol being of particular importance. Any reference to the abovementioned dopamine agonists also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts and hydrates thereof which may exist. By the physiologically acceptable acid addition salts thereof which may be formed by the abovementioned dopamine agonists are meant, for example, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.
Examples of antiallergic agents which may be used according to the invention include epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadine, mizolastin, ketotifen, emedastin, dimetinden, clemastine, bamipin, cexchloropheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastin, desloratidine and meclizine. Preferred antiallergic agents which may be used within the scope of the present invention are selected from among epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadine, ebastin, desloratidine and mizolastin, epinastin and desloratidine being particularly preferred. Any reference to the abovementioned antiallergic agents also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof which may exist.
The embodiments that follow serve to illustrate the invention more fully. The following measurements were obtained on a set of 25 capsules filled with an inhalable powder containing tiotropium bromide. The microwave measurements F
and B were measured using a microwave moisture measuring apparatus MW 3010, the microwave electronic evaluator MW 3010 and the resonator E83/8, made and supplied by Messrs TEWS Elektronik (Sperberhorst 10, D-22459 Hamburg). The gross weighings to determine the value C were carried out using an AX105 WO 2004/106870 ¨ 11 - PCT/EP2004/005529 analytical balance made by Messrs Mettler Toledo GmbH (Im Langacher, CH-8606 Greifensee, Switzerland) with a reduced read-off accuracy of 0.1 mg.
In order to calibrate the apparatus and evaluate the accuracy which could be achieved with the process it was necessary to know the true net weights mN of the 25 capsules. For this purpose the capsules were filled manually using -a hand-operated powder pipette. The net weight of the filling was determined by weighing the individual capsules before and after filling on the above-mentioned Mettler analytical balance with a read-off accuracy of 0.01 mg.
Table 1 combines all the measurements and weights obtained. The first 15 samples were used to calibrate the instruments. For this purpose the coefficients a, f3, y and from equation (4) were calculated by linear regression from the measured values F, B, C with the known net weight values mN.
From this the following was obtained as the coming together of the measuring signal and the weight:
nig mg niN = ¨0.18105 _______________ * A+ 0.0438 __ *B +1.470 *C. (5) MHz MHz Gealibration data = 0.33 mg was obtained as the standard deviation between the calibration data and the predictions calculated after calibration (cross calibration).
After the calibration carried out in this way the remaining 10 capsules were used to test the accuracy of the proposed weighing method. The comparison between the true weighed values and the predictions based on the calibration (5) yields a standard deviation of atest samples = 0.68 mg. Fig. 3 brings all the calibration and test data together in the cross-validation diagram.
Tab. 1: Measured values of the 25 calibration and test samples Sample Net [mg] Gross [mg] Tare [mg] Microwave Microwave Gross [mg] Prediction analytical balance analytical balance analytical F [MHz] B [MHz]
C [mg] MN [Mg]
balance according to equation (5) 1 2.44 50.23 47.79 418.8594 103.9680936 50 2.24 2 2.85 51.06 48.21 424.9063 104.6123785 51.1 2.79 3 3.14 50.31 47.17 413.8125 100.6091802 50.3 3.45 4 3.97 52.04 48.07 425.9063 104.3166723 52.1 4.07 4.46 52.29 47.83 424.8594 102.5303456 52.1 4.18 r.) a) 71.' 6 5.19 52.46 47.27 416.9063 98.36373737 52.2 5.58 2 7 5.31 53.51 48.2 429.9063 103.8392956 53.8 ' 5.82 o 8 6.08 54.36 48.28 430.875 102.979476 54.3 6.34 .-46Fi u. 9 6.94 53.2 46.26 421.9375 101.2003059 53.2 6.27 ,o 7.-t-Q.) 10 7.56 54.7 47.14 427.9375 101.101946 54.7 7.38 11 8.23 56.18 47.95 434.9531 101.3368326 56.2 8.33 12 7.21 55.41 48.2 435.9453 102.809727 55.3 6.89 13 8.37 56.63 48.26 434.9375 101.9294894 56.4 8.65 14 8.67 56.97 48.3 440 101.7243854 56.9 8.46 10.08 58.3 48.22 440.9297 101.7071026 58.1 10.06 16 7.16 56.27 49.11 451.0703 111.1018252 56.3 5.98 17 7.16 56.27 49.11 451.1563 111.1708615 56.4 6.12 18 5.56 53.51 47.95 432.0078 107.2317522 53.4 5.00 u) 19 5.56 53.51 47.95 434.0625 107.6035326 53.7 5.09 -a, 2 20 6.38 54.16 47.78 433.0313 106.4290683 54.3 6.10 .,, 21 6.38 54.16 47.78 435.0625 106.8360262 54.1 5.46 cn a) E-1 22 5.42 52.74 47.32 424.0703 103.103133 52.7 5.23 . 23 5.42 52.74 47.32 426.125 103.9186604 53.3 5.77
Of outstanding importance here is tiotropium bromide, most particularly in the form of its crystalline monohydrate known from WO 02/30928.
Examples of betamimetics which may be used according to the invention are preferably compounds selected from among bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salbutamol, salmeterol, sulphonterol, terbutaline, tulobuterol, 4-hydroxy-742-{ [2-{ [3-(2-phenylethoxy)propyl]sulphonyl}ethyll-aminolethy1]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxypheny1)-2-[4-(1-benzimidazoly1)-2-methyl-2-butylamino]ethanol, 143-(4-methoxybenzyl-amino)-4-hydroxypheny1]-2-[4-(1-benzimidazoly1)-2-methy1-2-butylamino]ethanol, 142H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-243-(4-N,N-dimethylaminopheny1)-2-methy1-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-243-(4-methoxypheny1)-2-methyl-2-propylaminolethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-243-(4-n-butyloxypheny1)-2-methy1-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-2-{443-(4-methoxypheny1)-1,2,4-triazol-3-y1]-2-methy1-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobuty1)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylpheny1)-2-tert.-butylamino)ethanol and 1-(4-ethoxycarbonylamino-cyano-5-fluoropheny1)-2-(tert.-butylamino)ethanol, optionally in the form of their racemates, their enantiomers, their diastereomers, as well as optionally their pharmacologically acceptable acid addition salts and hydrates. It is particularly preferable to use, as betamimetics, active substances of this kind selected from among fenoterol, formoterol, salmeterol, salbutamol, 1- [3-(4-methoxybenzyl-amino)-4-hydroxypheny1]-214-(1-benzimidazoly1)-2-methyl-2-butylaminoiethanol, 142H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2-3 -(4-N,N-= WO 2004/106870 - 9 -dimethylaminopheny1)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-213-(4-methoxypheny1)-2-methy1-2-propylamino]ethanol, 142H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-243-(4-n-butyloxypheny1)-2-methy1-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-y1]-2-(443-(4-methoxypheny1)-1,2,4-triazol-3-y1]-2-methyl-2-butylamino }ethanol, optionally in the form of their racemates, their enantiomers, their diastereomers, as well as optionally their pharmacologically acceptable acid addition salts and hydrates. Of the betamimetics mentioned above, the compounds formoterol and salmeterol, optionally in the form of their racemates, their enantiomers, their diastereomers, as well as optionally their pharmacologically acceptable acid addition salts and hydrates, are particularly important.
For example, the acid addition salts of the betamimetics are selected from among the hydrochloride, hydrobromide, sulphate, phosphate, fumarate, methanesulphonate and xinafoate are preferred according to the invention. In the case of formoterol, the salts selected from among the hydrochloride, sulphate and fumarate are particularly preferred, especially the hydrochloride and fumarate. Of outstanding importance according to the invention is formoterol fumarate. In the case of salmeterol, the salts selected from among the hydrochloride, sulphate and xinafoate are particularly preferred, especially the xinafoate.
Within the scope of the present invention, the corticosteroids which may be used according to the invention are compounds selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864, KSR 592, ST-126 and dexamethasone. The preferred corticosteroids within the scope of the present invention are those selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexamethasone, while budesonide, fluticasone, mometasone and ciclesonide, especially budesonide and fluticasone, are of particular importance. The term steroids may be used on its own, within the scope of the present patent application, instead of the term corticosteroids. Any reference to steroids within the scope of the present invention also includes a reference to salts or derivatives which may be formed from the steroids. Examples of possible salts or derivatives include: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. The corticosteroids may optionally also be in the form of their hydrates.
Within the scope of the present invention, the term dopamine agonists denotes compounds selected from among bromocriptine, cabergolin, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid and viozan. It is preferable within the scope of the present invention to use dopamine agonists selected from among pramipexol, talipexol and viozan, pramipexol being of particular importance. Any reference to the abovementioned dopamine agonists also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts and hydrates thereof which may exist. By the physiologically acceptable acid addition salts thereof which may be formed by the abovementioned dopamine agonists are meant, for example, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.
Examples of antiallergic agents which may be used according to the invention include epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadine, mizolastin, ketotifen, emedastin, dimetinden, clemastine, bamipin, cexchloropheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastin, desloratidine and meclizine. Preferred antiallergic agents which may be used within the scope of the present invention are selected from among epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadine, ebastin, desloratidine and mizolastin, epinastin and desloratidine being particularly preferred. Any reference to the abovementioned antiallergic agents also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof which may exist.
The embodiments that follow serve to illustrate the invention more fully. The following measurements were obtained on a set of 25 capsules filled with an inhalable powder containing tiotropium bromide. The microwave measurements F
and B were measured using a microwave moisture measuring apparatus MW 3010, the microwave electronic evaluator MW 3010 and the resonator E83/8, made and supplied by Messrs TEWS Elektronik (Sperberhorst 10, D-22459 Hamburg). The gross weighings to determine the value C were carried out using an AX105 WO 2004/106870 ¨ 11 - PCT/EP2004/005529 analytical balance made by Messrs Mettler Toledo GmbH (Im Langacher, CH-8606 Greifensee, Switzerland) with a reduced read-off accuracy of 0.1 mg.
In order to calibrate the apparatus and evaluate the accuracy which could be achieved with the process it was necessary to know the true net weights mN of the 25 capsules. For this purpose the capsules were filled manually using -a hand-operated powder pipette. The net weight of the filling was determined by weighing the individual capsules before and after filling on the above-mentioned Mettler analytical balance with a read-off accuracy of 0.01 mg.
Table 1 combines all the measurements and weights obtained. The first 15 samples were used to calibrate the instruments. For this purpose the coefficients a, f3, y and from equation (4) were calculated by linear regression from the measured values F, B, C with the known net weight values mN.
From this the following was obtained as the coming together of the measuring signal and the weight:
nig mg niN = ¨0.18105 _______________ * A+ 0.0438 __ *B +1.470 *C. (5) MHz MHz Gealibration data = 0.33 mg was obtained as the standard deviation between the calibration data and the predictions calculated after calibration (cross calibration).
After the calibration carried out in this way the remaining 10 capsules were used to test the accuracy of the proposed weighing method. The comparison between the true weighed values and the predictions based on the calibration (5) yields a standard deviation of atest samples = 0.68 mg. Fig. 3 brings all the calibration and test data together in the cross-validation diagram.
Tab. 1: Measured values of the 25 calibration and test samples Sample Net [mg] Gross [mg] Tare [mg] Microwave Microwave Gross [mg] Prediction analytical balance analytical balance analytical F [MHz] B [MHz]
C [mg] MN [Mg]
balance according to equation (5) 1 2.44 50.23 47.79 418.8594 103.9680936 50 2.24 2 2.85 51.06 48.21 424.9063 104.6123785 51.1 2.79 3 3.14 50.31 47.17 413.8125 100.6091802 50.3 3.45 4 3.97 52.04 48.07 425.9063 104.3166723 52.1 4.07 4.46 52.29 47.83 424.8594 102.5303456 52.1 4.18 r.) a) 71.' 6 5.19 52.46 47.27 416.9063 98.36373737 52.2 5.58 2 7 5.31 53.51 48.2 429.9063 103.8392956 53.8 ' 5.82 o 8 6.08 54.36 48.28 430.875 102.979476 54.3 6.34 .-46Fi u. 9 6.94 53.2 46.26 421.9375 101.2003059 53.2 6.27 ,o 7.-t-Q.) 10 7.56 54.7 47.14 427.9375 101.101946 54.7 7.38 11 8.23 56.18 47.95 434.9531 101.3368326 56.2 8.33 12 7.21 55.41 48.2 435.9453 102.809727 55.3 6.89 13 8.37 56.63 48.26 434.9375 101.9294894 56.4 8.65 14 8.67 56.97 48.3 440 101.7243854 56.9 8.46 10.08 58.3 48.22 440.9297 101.7071026 58.1 10.06 16 7.16 56.27 49.11 451.0703 111.1018252 56.3 5.98 17 7.16 56.27 49.11 451.1563 111.1708615 56.4 6.12 18 5.56 53.51 47.95 432.0078 107.2317522 53.4 5.00 u) 19 5.56 53.51 47.95 434.0625 107.6035326 53.7 5.09 -a, 2 20 6.38 54.16 47.78 433.0313 106.4290683 54.3 6.10 .,, 21 6.38 54.16 47.78 435.0625 106.8360262 54.1 5.46 cn a) E-1 22 5.42 52.74 47.32 424.0703 103.103133 52.7 5.23 . 23 5.42 52.74 47.32 426.125 103.9186604 53.3 5.77
Claims (8)
1. Process for the non-destructive net weighing of a capsule filled with a sample of material, wherein in a first step of the process variable frequency electromagnetic radiation is generated in a microwave generator under the control of a processor and is supplied to a probe applicator in the form of a resonator, a microwave signal leaving the applicator being supplied to a detector diode from whose signals b(0) and f(0) are determined by the processor as primary measurement values by means of an analogue-to-digital converter, b(0) being the half-power width at the resonant frequency f(0) of the applicator which is operatively connected to a measuring probe, wherein the capsule filled with a sample of material is connected to the resonator such that the electric field of the resonator runs generally parallel to the surface on passing into the material of the probe and wherein, from the primary measurement values b(0) and f(0), the measuring signals F = f(L) - f(0) or B = b(0) - b(L) are obtained, where F and B denote the microwave measuring signals of the detuning and propagation of the resonance, with f(L) and b(L) being equal to constant material-dependent reference values, and wherein in a second step gravimetric gross weighing is carried out in order to determine the gross weight signal C = m T + m N, wherein the magnitude m T represents the mass of the empty packaging and the magnitude m N represents the net mass to be determined, and finally from the measuring signals F, B and C obtained the net mass m N to be determined is computed according to the following equation m N = .alpha.F + .beta.B + .gamma.C + .delta.
the coefficients .alpha., .beta., .gamma. and .delta. having been determined beforehand by calibration of the measuring system by linear regression from a measuring series with reference samples of known net weight.
the coefficients .alpha., .beta., .gamma. and .delta. having been determined beforehand by calibration of the measuring system by linear regression from a measuring series with reference samples of known net weight.
2. Process according to claim 1, wherein filled capsules are weighed, the material of which is selected from the group consisting of gelatine, cellulose derivatives, starch, starch derivatives, chitosan and synthetic plastics.
3. Process according to claim 1 or 2, wherein the capsules hold a powder which contains an active substance and optionally a pharmaceutically acceptable excipient.
4. Process according to claim 3, wherein the active substance is selected from the group comprising the anticholinergics, betamimetics, dopamine agonists, antiallergics, leukotriene antagonists and corticosteroids and optionally combinations of active substances thereof.
5. Process according to any one of claims 1 to 4, wherein the measured signal values F and B are determined by means of an apparatus which comprises a variable-frequency microwave generator which can be digitally tuned by the processor, this generator being connected to a coupling probe which is disposed in an applicator for measuring the measuring signals F and B of a sample, said applicator having another coupling probe which is connected via a microwave amplifier or attenuator to a detector diode the signal output of which is connected to the processor.
6. Process according to any one of claims 1 to 5, wherein to determine the gross weight signal C a gravimetric weighing cell is used which determines the weight with a standard deviation of ~ 0.1 mg.
7. Process according to any one of claims 1 to 6, wherein it is carried out using an apparatus which comprises a hopper from which the filled and sealed capsules are guided serially and/or individually by means of a separating unit through the microwave resonator, which also comprises an adjacent distributor unit by means of which the capsules are arranged parallel for transporting and by means of which the capsules are distributed onto several pathways where gravimetric weighing cells are located, and which also comprises a computer-aided data collecting unit which is connected to the microwave resonator, the distributor unit and the gravimetric weighing cells and ensures that the measurements are correctly assigned to the individual capsules and performs the evaluation and which finally has a reject channel through which capsules of the wrong weight are rejected.
8. Apparatus for carrying out the process according to claim 1, which comprises a hopper from which filled and sealed capsules are guided serially and/or individually by means of a separating unit through the microwave resonator, which also comprises an adjacent distributor unit by means of which the capsules are arranged parallel for transporting and by means of which the capsules are distributed onto several pathways where gravimetric weighing cells are located, and which also comprises a computer-aided data collecting unit which is connected to the microwave resonator, the distributor unit and the gravimetric weighing cells and ensures that the measurements are correctly assigned to the individual capsules and performs the evaluation and which finally has a reject channel through which capsules of the wrong weight are rejected.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03012566A EP1484586A1 (en) | 2003-06-03 | 2003-06-03 | Measuring device for non-destructively determining the net weight in tablets |
| EP03012566.0 | 2003-06-03 | ||
| PCT/EP2004/005529 WO2004106870A1 (en) | 2003-06-03 | 2004-05-22 | Measuring device for nondestructively determining the weight-in quantity in capsules |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2527972A1 CA2527972A1 (en) | 2004-12-09 |
| CA2527972C true CA2527972C (en) | 2013-12-03 |
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ID=33155142
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2527972A Expired - Fee Related CA2527972C (en) | 2003-06-03 | 2004-05-22 | Measuring device for non-destructively determining the weight-in quantity in capsules |
Country Status (12)
| Country | Link |
|---|---|
| EP (2) | EP1484586A1 (en) |
| JP (1) | JP4828410B2 (en) |
| AT (1) | ATE333634T1 (en) |
| CA (1) | CA2527972C (en) |
| CY (1) | CY1105406T1 (en) |
| DE (1) | DE502004000995D1 (en) |
| DK (1) | DK1634041T3 (en) |
| ES (1) | ES2268658T3 (en) |
| PL (1) | PL1634041T3 (en) |
| PT (1) | PT1634041E (en) |
| SI (1) | SI1634041T1 (en) |
| WO (1) | WO2004106870A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1669755B1 (en) * | 2004-12-08 | 2007-02-07 | TEWS ELEKTRONIK Dipl.-Ing. Manfred Tews | Method and device for measuring mass and/or moisture of the content of capsules |
| US7755368B2 (en) | 2007-02-06 | 2010-07-13 | Tews Elektronik Dipl.-Ing. Manfred Tews | Method and device for measuring mass and/or moisture of the content of capsules |
| DE102007026646A1 (en) | 2007-06-06 | 2008-12-11 | Körber Ag | Dielectricity measurement device for determining dielectric properties of portioned material of capsule end packaging, has receiving area |
| DE102007024071A1 (en) | 2007-05-22 | 2008-11-27 | Körber Ag | Dielectricity measurement device for determining dielectric properties of portioned material of capsule end packaging, has receiving area for receiving and positioning electrically conductive packaging wall of capsule end packaging |
| WO2008141833A1 (en) * | 2007-05-22 | 2008-11-27 | Mediseal Gmbh | Dielectricity measurement device |
| CA2879366A1 (en) * | 2012-07-20 | 2014-01-23 | President And Fellows Of Harvard College | Fourier transform microwave spectroscopy for enantiomer-specific detection of chiral molecules |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4004119A1 (en) * | 1990-02-10 | 1991-08-14 | Tews Elektronik Dipl Ing Manfr | METHOD FOR MEASURING THE HUMIDITY OF A MEASUREMENT WITH THE AID OF MICROWAVES AND DEVICE FOR IMPLEMENTING THE METHOD |
| IT1258025B (en) * | 1992-07-31 | 1996-02-20 | Mg 2 Spa | METHOD AND DEVICE FOR THE DOSAGE OF A PHARMACEUTICAL PRODUCT INSIDE CAPSULES |
| US6163158A (en) * | 1996-02-20 | 2000-12-19 | Hauni Maschinenbau Ag | Method of and apparatus for ascertaining at least one characteristic of a substance |
| IT1285463B1 (en) * | 1996-02-21 | 1998-06-08 | Ima Spa | APPARATUS FOR AUTOMATIC, CONTINUOUS, RAPID AND PRECISE WEIGHING OF SMALL PRODUCTS, ESPECIALLY OF GELATIN CAPSULES |
| JP3343480B2 (en) * | 1996-08-05 | 2002-11-11 | アンリツ株式会社 | Capsule weight measuring device |
| IT1292645B1 (en) * | 1997-06-27 | 1999-02-08 | Mg 2 Spa | METHOD AND RELATED MACHINE FOR DOSING PHARMACEUTICAL PRODUCTS. |
| ITBO20020432A1 (en) * | 2002-07-04 | 2004-01-05 | Ima Spa | METHOD FOR DETECTION AND CONTROL OF CHARACTERISTICS OF PHARMACEUTICAL ITEMS |
-
2003
- 2003-06-03 EP EP03012566A patent/EP1484586A1/en not_active Withdrawn
-
2004
- 2004-05-22 AT AT04734470T patent/ATE333634T1/en active
- 2004-05-22 PT PT04734470T patent/PT1634041E/en unknown
- 2004-05-22 WO PCT/EP2004/005529 patent/WO2004106870A1/en active IP Right Grant
- 2004-05-22 DE DE502004000995T patent/DE502004000995D1/en active Active
- 2004-05-22 ES ES04734470T patent/ES2268658T3/en active Active
- 2004-05-22 CA CA2527972A patent/CA2527972C/en not_active Expired - Fee Related
- 2004-05-22 EP EP04734470A patent/EP1634041B1/en active Active
- 2004-05-22 PL PL04734470T patent/PL1634041T3/en unknown
- 2004-05-22 SI SI200430087T patent/SI1634041T1/en unknown
- 2004-05-22 DK DK04734470T patent/DK1634041T3/en active
- 2004-05-22 JP JP2006508191A patent/JP4828410B2/en active Active
-
2006
- 2006-09-26 CY CY20061101378T patent/CY1105406T1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP2006526770A (en) | 2006-11-24 |
| WO2004106870A1 (en) | 2004-12-09 |
| DE502004000995D1 (en) | 2006-08-31 |
| DK1634041T3 (en) | 2006-11-13 |
| JP4828410B2 (en) | 2011-11-30 |
| EP1484586A1 (en) | 2004-12-08 |
| CA2527972A1 (en) | 2004-12-09 |
| EP1634041A1 (en) | 2006-03-15 |
| SI1634041T1 (en) | 2006-12-31 |
| PT1634041E (en) | 2006-11-30 |
| ATE333634T1 (en) | 2006-08-15 |
| CY1105406T1 (en) | 2010-04-28 |
| EP1634041B1 (en) | 2006-07-19 |
| PL1634041T3 (en) | 2006-12-29 |
| ES2268658T3 (en) | 2007-03-16 |
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