CA2449217C - Process for cleaning hard gelatine capsules - Google Patents
Process for cleaning hard gelatine capsules Download PDFInfo
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- CA2449217C CA2449217C CA2449217A CA2449217A CA2449217C CA 2449217 C CA2449217 C CA 2449217C CA 2449217 A CA2449217 A CA 2449217A CA 2449217 A CA2449217 A CA 2449217A CA 2449217 C CA2449217 C CA 2449217C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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Abstract
The invention relates to a process which can be used in the laboratory or on an industrial scale for cleaning the inner wall of hard gelatine capsules, in which the sealed capsules are cleaned with a powder formulation.
Description
1/1213 Prio/ ff 1 78162tra.206 Process for cleaning hard gelatine capsules The invention relates to a process for cleaning the inner wall of hard gelatine capsules.
Background to the invention As a result of the method of manufacturing hard gelatine capsules the inner wall of 1o these capsules is coated with lubricant and/or mould release agents. This leads to an increased adhesion of powder to the inner walls, which cannot be delivered to the patient in the case of capsules for inhalation. In addition, the parameters of "mass delivered" and "inhalable proportion" are subject to a wide range of fluctuations.
1s It is known from the prior art that special capsules, e.g. CONI-SNAP
capsules (Messrs Capsugel), which have a reduced coating of lubricant or mould release agent, can be used for inhalation purposes. This coating can be removed using solvents. However, cleaning with solvents is extremely expensive on an industrial scale and is therefore only suitable under certain conditions. In addition, the residual 20 solvent content has to be checked thereafter.
The aim of the present invention is to provide a simple method of cleaning the inner wall of hard gelatine capsules for use in inhalation therapy.
25 Detailed description of the invention Surprisingly, it has now been found that the coating of lubricant or mould release agent can easily be removed from the inner walls of capsules by using suitable powders as cleaning agents without the addition of solvents.
The invention therefore relates to a process for cleaning the inner wall of hard gelatine capsules for use in inhalation therapy which can be carried out in the laboratory and also on an industrial scale, in which the capsules are cleaned with a powder formulation.
1/1213 Prio/ ff 2 Capsules suitable for the process according to the invention are usually divisible hard gelatine capsules, consisting of an upper and lower part, in which the lower part is filled, then the top part is fitted on and the capsule is sealed. Particularly suitable capsules are hard gelatine snap-in capsules with a closure, preferably polyethyleneglycol-free hard gelatine capsules, more preferably CONI-SNAP
size 3 capsules (made by Capsugel, division of Warner Lambert N.V., Belgium).
In a preferred process the powder formulation is pharmaceutically acceptable.
The powder formulation may contain one or more ingredients. Pharmaceutically to acceptable ingredients include, for example, lactose, lactose monohydrate, glucose, sucrose, mannitol and sorbitol.
Particularly preferred is a process wherein the powder formulation denotes an ingredient of the active substance formulation.
Ingredients of the active substance formulation which are suitable for the powder formulation include, for example, lactose, lactose monohydrate, glucose, sucrose, mannitol and sorbitol, preferably lactose or lactose monohydrate, particularly lactose monohydrate.
Also preferred is a process wherein the powder formulation is the active substance formulation for inhalation.
Powders for inhalation may for example contain the active substances selected from among tiotropium, cromoglycic acid, reproterol, beclomethasone, terbutalin, salbutamol, salmeterol, ketotifen, orciprenaline, fluticasone, insulin, ipratropium, dexamethasone, bambuterol, budesonide, fenoterol, clenbuterol , prednisolone, prednisone, prednylidene, methylprednisolone, formoterol, nedocromil, as well as one of the pharmaceutically acceptable salts or mixtures thereof and another cortisone preparation or atropine derivative suitable for inhalation purposes, preferably ipratropium bromide, tiotropium bromide and tiotropium bromide monohydrate, particularly preferably tiotropium bromide monohydrate.
Typical ingredients of powders for inhalation, apart from the active substance. are lactose, lactose monohydrate or glucose, inter alia.
Particularly preferred is a process wherein the cleaning takes place in sealed capsules.
Of particular importance is a process wherein the cleaning is carried out without the use of solvents.
Also of particular importance is a process wherein the cleaning is carried out in a gravity mixer or on a vibrating table. Gravity mixers which are suitable for the process according to the invention include for example ELTE 650 gyrowheel or SAS 1200 io gyrowheel (Messrs. Engelsmann AG, Frankenthaler StraRe 137 -141, D 6700 Ludwigshafen/Rh), Turbula*T2 C (Messrs. Bachofen AG, Basle, Switzerland) or Turbula T 10 B (Messrs. Bachofen AG, Basle, Switzerland), while Turbula T2 C
or Turbula T 10 B is particularly suitable.
Also of particular importance is a process wherein the cleaning is carried out at a temperature of 15 to 50 C, preferably 17 to 40 C, preferably 19 to 28 C, most preferably about 22 C.
Also preferred is a process wherein the mixing time is 20 to 150 minutes, preferably 50 to 100 minutes, preferably 60 to 90 minutes, most preferably about 30 to 75 minutes.
Also particularly preferred is a process wherein some or all of the grains of the powder formulation accumulate impurities.
Also preferred is a process wherein some or all of the grains of the powder formulation accumulate lubricants and mould release agents. Such lubricants and mould release agents may for example contain stearic acid, magnesium stearate, fats, waxes, oils or emulsifiers such as soya lecithin.
Also particularly preferred is a process wherein the content of powder formulation is from 6 % (v/v) to 50 % (v/v), preferably 10 % (v/v) to 30 % (v/v), preferably 15 %
(v/v) to 25 % (v/v), particularly preferably about 20 % (v/v), of the maximum capacity of the capsule.
*Trade-mark Also particularly preferred is a process wherein the powder formulation contains lactose and/or lactose monohydrate, preferably lactose monohydrate for inhalation purposes, preferably lactose monohydrate 200M for inhalation purposes. Lactose monohydrate may be obtained for example from Messrs. DMV International (Veghel/
Netherlands).
According to the invention a process is preferred wherein the powder formulation contains an excipient with particle sizes of 10 to 50 pm in aerodynamic diameter *
io (measured with an API Aerosizer LD by a flying time method), for example ground lactose monohydrate.
Particularly preferred according to the invention is a process which comprises the successive steps a) to e), wherein a) a powder formulation is subjected to one or more screenings and mixings, b) the powder formulation is transferred into gelatine capsules for inhalation, c) the gelatine capsules are agitated in a mixing container, d) the end of the purification process is monitored visually, optionally by opening capsules, and e) the gelatine capsules are placed directly in the inhaler or optionally emptied and refilled.
The invention further relates to a gelatine capsule containing a tiotropium power formulation, obtainable by shaking the filled capsules in a gravity mixer or on a vibrating table.
The term tiotropium powder formulation refers to powder formulations of the tiotropium salts or the hydrates thereof, preferably the chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methylsuiphate salt or the hydrates thereof, preferably tiotropium bromide or tiotropium bromide monohydrate, most preferably tiotropium bromide monohydrate.
The invention further relates to the use of a capsule prepared by the process according to the invention in a powder inhaler, preferably in a Metered Dose Powder Inhaler (MDPI), particularly preferably in an MDPI as described in WO
94/28958.
*Trade-mark The advantage of the process according to the invention is in the simple and economical cleaning of the inner wall of the capsule, which does not require any 5 additional checking of the content of cleaning agent, e.g. solvent. In the case of pharmacologically acceptable contamination of the inner wall of the capsule the cleaning may be done by the active substance formulation, so that the capsule does not have to be opened again after cleaning, emptied and refilled with the active substance formulation. The cleaning process thus ensures, in this case too, a release io of active substance which is not affected by the adhesion of the formulation to the inner wall of the capsules.
The process according to the invention can be carried out by the general procedure illustrated in the flow chart in Figure 1 and according to the preferred embodiment described hereinafter. These are to be regarded as illustrating the invention without restricting it to their content.
For cleaning the gelatine capsules with a powder formulation using the process according to the invention it is particularly suitable to use powder formulations which contain lactose monohydrate (Al) which has previously been mixed and screened.
For this, lactose monohydrate is screened through a suitable screen (B1), for example a hand-held screen with a mesh size of 0.2 mm to 1 mm, preferably.
about 0.5 mm, or a suitable screening granulator with a mesh size of 0.2 mm to 1 mm, preferably about 0.5 mm to 0.6 mm, into a collecting container or mixing container.
The screened material is homogeneously mixed in a suitable mixer, for example in ELTE 650 gyrowheel or SA 1200 gyrowheel (Messrs. Engelsmann AG, Frankenthaler Stra1 e 137 -141, D 6700 Ludwigshafen/Rh), Turbula T2 C (Messrs.
Bachofen AG, Basle, Switzerland) or Turbula T 10 B (Messrs. Bachofen AG, Basle, Switzerland), over a period of 20 to 150 minutes, preferably 50 to 100 minutes, preferably 60 to 90 minutes, particularly preferably about 30 to 75 minutes, preferably at 5 to 35, preferably 10 to 30, particularly preferably about 20 revolutions per minute-Suitable screening granulators which may be used include for example the QUADRO*
Comil, type: 197 S, 0.5 mm (Intertechnik Elze GmbH & Co KG, Lessingweg 1+2, D
31008 Elze) or Glatt Schnellsiel type TR 80, 0.6 mm (Messrs. Glatt GmbH, D
Binzen / Lorrach).
*Trade-mark During the screening and mixing the room should be maintained at a temperature of 19 C to 28 C, preferably 22 C, and at a relative humidity of 35 % r.h. to 65 % r. h., preferably 50 % r. h..
The screened lactose monohydrate is packed into snap-in gelatine capsules (A2), preferably polyethyleneglycol-free snap-in gelatine capsules, separately or as part of a powder formulation, using a suitable capsule filling and sealing machine (B2), for example type MG2-G100 (Messrs. MG2, Bologna, Italy). The quantity of powder formulation packed in should be 6 % (v/v) to 50 % (v/v), preferably 10 % (v/v) to 30 io % (v/v), preferably 15 % (v/v) to 25 % (v/v), particularly preferably about 20 % (v/v), of the maximum capacity of the capsule. During filling, the climatic conditions in the room should be the same as for the screening and mixing process. The filled and sealed capsules are placed in a suitable mixing container under the climatic conditions described above. The fill level is 50 % to 80 % , preferably 60 %
to 70 most preferably about 65 %, of the height of the container.
The mixing container is then agitated in a suitable mixer (B3), preferably gyrowheel or SA 1200 gyrowheel (Engelsmann AG, Frankenthaler StraRe 137 -141, D 6700 Ludwigshafen/Rh), Turbula*T2 C, or Turbula T 10 B (Messrs Bachofen AG
(Switzerland) at 10 to 30 rpm, preferably at about 20 rpm. The mixing time should be 20 to 150 minutes, preferably 50 to 100 minutes, preferably 60 to 90 minutes, particularly preferably about 30 to 75 minutes. The results of the mixing or cleaning process can be checked by visual inspection, optionally by opening capsules (B4).
The cleaning process is complete as soon as no powder coating can be seen on the inner wall of the capsule. A very slight powder coating on the inner wall of the capsule is also sufficient for the cleaning process to be brought to an end.
The capsules may be emptied and then filled with an active substance formulation. If the active substance formulation itself is used as the powder formulation, there is no need to empty and refill the capsules. They may be used directly for inhalation.
The following Example serves to illustrate the process according to the invention. It is to be regarded as simply an example of procedure without restricting the invention to its content.
*Trade-mark Example About 70 Grade A hard gelatine capsules (reduced content of lubricant and mould release agent), type CONI-SNAP size 3 (Messrs. Capsugel) and about 70 Grade B
(standard) hard gelatine capsules, type CONI-SNAP size 3 (Messrs. Capsugel) were filled with a tiotropium-lactose mixture consisting of about 11 mg/capsule of lactose monohydrate (Pharmatose 200M made by Veghel / NL) and 36 pg/capsule of tiotropium bromide.
Half the capsules were shaken using with a Turbula Mixer type 2C (Messrs Bachofen AG, Basle, Switzerland) for about two hours at a temperature of 22 C.
io Then the parameter "dose delivered ", i.e. the amount of active substance delivered in %, was determined in the shaken and unshaken capsules.
The results in Table 1 show a significant increase in the dose delivered (determined according to TEST Uniformity of dose, a. Uniformity of delivered dose, European is Pharmacopoeia , Third Edition (1997), page 1770, published by the Council of Europe, 67075 Strasbourg Cedex, ISBN: 92-871-2991-6) after the cleaning process by shaking the capsules.
Table 1 Capsule Dose delivered (%]
Grade A unshaken 74 Grade A shaken 82 Grade B unshaken 79 Grade B shaken 83 *Trade-mark
Background to the invention As a result of the method of manufacturing hard gelatine capsules the inner wall of 1o these capsules is coated with lubricant and/or mould release agents. This leads to an increased adhesion of powder to the inner walls, which cannot be delivered to the patient in the case of capsules for inhalation. In addition, the parameters of "mass delivered" and "inhalable proportion" are subject to a wide range of fluctuations.
1s It is known from the prior art that special capsules, e.g. CONI-SNAP
capsules (Messrs Capsugel), which have a reduced coating of lubricant or mould release agent, can be used for inhalation purposes. This coating can be removed using solvents. However, cleaning with solvents is extremely expensive on an industrial scale and is therefore only suitable under certain conditions. In addition, the residual 20 solvent content has to be checked thereafter.
The aim of the present invention is to provide a simple method of cleaning the inner wall of hard gelatine capsules for use in inhalation therapy.
25 Detailed description of the invention Surprisingly, it has now been found that the coating of lubricant or mould release agent can easily be removed from the inner walls of capsules by using suitable powders as cleaning agents without the addition of solvents.
The invention therefore relates to a process for cleaning the inner wall of hard gelatine capsules for use in inhalation therapy which can be carried out in the laboratory and also on an industrial scale, in which the capsules are cleaned with a powder formulation.
1/1213 Prio/ ff 2 Capsules suitable for the process according to the invention are usually divisible hard gelatine capsules, consisting of an upper and lower part, in which the lower part is filled, then the top part is fitted on and the capsule is sealed. Particularly suitable capsules are hard gelatine snap-in capsules with a closure, preferably polyethyleneglycol-free hard gelatine capsules, more preferably CONI-SNAP
size 3 capsules (made by Capsugel, division of Warner Lambert N.V., Belgium).
In a preferred process the powder formulation is pharmaceutically acceptable.
The powder formulation may contain one or more ingredients. Pharmaceutically to acceptable ingredients include, for example, lactose, lactose monohydrate, glucose, sucrose, mannitol and sorbitol.
Particularly preferred is a process wherein the powder formulation denotes an ingredient of the active substance formulation.
Ingredients of the active substance formulation which are suitable for the powder formulation include, for example, lactose, lactose monohydrate, glucose, sucrose, mannitol and sorbitol, preferably lactose or lactose monohydrate, particularly lactose monohydrate.
Also preferred is a process wherein the powder formulation is the active substance formulation for inhalation.
Powders for inhalation may for example contain the active substances selected from among tiotropium, cromoglycic acid, reproterol, beclomethasone, terbutalin, salbutamol, salmeterol, ketotifen, orciprenaline, fluticasone, insulin, ipratropium, dexamethasone, bambuterol, budesonide, fenoterol, clenbuterol , prednisolone, prednisone, prednylidene, methylprednisolone, formoterol, nedocromil, as well as one of the pharmaceutically acceptable salts or mixtures thereof and another cortisone preparation or atropine derivative suitable for inhalation purposes, preferably ipratropium bromide, tiotropium bromide and tiotropium bromide monohydrate, particularly preferably tiotropium bromide monohydrate.
Typical ingredients of powders for inhalation, apart from the active substance. are lactose, lactose monohydrate or glucose, inter alia.
Particularly preferred is a process wherein the cleaning takes place in sealed capsules.
Of particular importance is a process wherein the cleaning is carried out without the use of solvents.
Also of particular importance is a process wherein the cleaning is carried out in a gravity mixer or on a vibrating table. Gravity mixers which are suitable for the process according to the invention include for example ELTE 650 gyrowheel or SAS 1200 io gyrowheel (Messrs. Engelsmann AG, Frankenthaler StraRe 137 -141, D 6700 Ludwigshafen/Rh), Turbula*T2 C (Messrs. Bachofen AG, Basle, Switzerland) or Turbula T 10 B (Messrs. Bachofen AG, Basle, Switzerland), while Turbula T2 C
or Turbula T 10 B is particularly suitable.
Also of particular importance is a process wherein the cleaning is carried out at a temperature of 15 to 50 C, preferably 17 to 40 C, preferably 19 to 28 C, most preferably about 22 C.
Also preferred is a process wherein the mixing time is 20 to 150 minutes, preferably 50 to 100 minutes, preferably 60 to 90 minutes, most preferably about 30 to 75 minutes.
Also particularly preferred is a process wherein some or all of the grains of the powder formulation accumulate impurities.
Also preferred is a process wherein some or all of the grains of the powder formulation accumulate lubricants and mould release agents. Such lubricants and mould release agents may for example contain stearic acid, magnesium stearate, fats, waxes, oils or emulsifiers such as soya lecithin.
Also particularly preferred is a process wherein the content of powder formulation is from 6 % (v/v) to 50 % (v/v), preferably 10 % (v/v) to 30 % (v/v), preferably 15 %
(v/v) to 25 % (v/v), particularly preferably about 20 % (v/v), of the maximum capacity of the capsule.
*Trade-mark Also particularly preferred is a process wherein the powder formulation contains lactose and/or lactose monohydrate, preferably lactose monohydrate for inhalation purposes, preferably lactose monohydrate 200M for inhalation purposes. Lactose monohydrate may be obtained for example from Messrs. DMV International (Veghel/
Netherlands).
According to the invention a process is preferred wherein the powder formulation contains an excipient with particle sizes of 10 to 50 pm in aerodynamic diameter *
io (measured with an API Aerosizer LD by a flying time method), for example ground lactose monohydrate.
Particularly preferred according to the invention is a process which comprises the successive steps a) to e), wherein a) a powder formulation is subjected to one or more screenings and mixings, b) the powder formulation is transferred into gelatine capsules for inhalation, c) the gelatine capsules are agitated in a mixing container, d) the end of the purification process is monitored visually, optionally by opening capsules, and e) the gelatine capsules are placed directly in the inhaler or optionally emptied and refilled.
The invention further relates to a gelatine capsule containing a tiotropium power formulation, obtainable by shaking the filled capsules in a gravity mixer or on a vibrating table.
The term tiotropium powder formulation refers to powder formulations of the tiotropium salts or the hydrates thereof, preferably the chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methylsuiphate salt or the hydrates thereof, preferably tiotropium bromide or tiotropium bromide monohydrate, most preferably tiotropium bromide monohydrate.
The invention further relates to the use of a capsule prepared by the process according to the invention in a powder inhaler, preferably in a Metered Dose Powder Inhaler (MDPI), particularly preferably in an MDPI as described in WO
94/28958.
*Trade-mark The advantage of the process according to the invention is in the simple and economical cleaning of the inner wall of the capsule, which does not require any 5 additional checking of the content of cleaning agent, e.g. solvent. In the case of pharmacologically acceptable contamination of the inner wall of the capsule the cleaning may be done by the active substance formulation, so that the capsule does not have to be opened again after cleaning, emptied and refilled with the active substance formulation. The cleaning process thus ensures, in this case too, a release io of active substance which is not affected by the adhesion of the formulation to the inner wall of the capsules.
The process according to the invention can be carried out by the general procedure illustrated in the flow chart in Figure 1 and according to the preferred embodiment described hereinafter. These are to be regarded as illustrating the invention without restricting it to their content.
For cleaning the gelatine capsules with a powder formulation using the process according to the invention it is particularly suitable to use powder formulations which contain lactose monohydrate (Al) which has previously been mixed and screened.
For this, lactose monohydrate is screened through a suitable screen (B1), for example a hand-held screen with a mesh size of 0.2 mm to 1 mm, preferably.
about 0.5 mm, or a suitable screening granulator with a mesh size of 0.2 mm to 1 mm, preferably about 0.5 mm to 0.6 mm, into a collecting container or mixing container.
The screened material is homogeneously mixed in a suitable mixer, for example in ELTE 650 gyrowheel or SA 1200 gyrowheel (Messrs. Engelsmann AG, Frankenthaler Stra1 e 137 -141, D 6700 Ludwigshafen/Rh), Turbula T2 C (Messrs.
Bachofen AG, Basle, Switzerland) or Turbula T 10 B (Messrs. Bachofen AG, Basle, Switzerland), over a period of 20 to 150 minutes, preferably 50 to 100 minutes, preferably 60 to 90 minutes, particularly preferably about 30 to 75 minutes, preferably at 5 to 35, preferably 10 to 30, particularly preferably about 20 revolutions per minute-Suitable screening granulators which may be used include for example the QUADRO*
Comil, type: 197 S, 0.5 mm (Intertechnik Elze GmbH & Co KG, Lessingweg 1+2, D
31008 Elze) or Glatt Schnellsiel type TR 80, 0.6 mm (Messrs. Glatt GmbH, D
Binzen / Lorrach).
*Trade-mark During the screening and mixing the room should be maintained at a temperature of 19 C to 28 C, preferably 22 C, and at a relative humidity of 35 % r.h. to 65 % r. h., preferably 50 % r. h..
The screened lactose monohydrate is packed into snap-in gelatine capsules (A2), preferably polyethyleneglycol-free snap-in gelatine capsules, separately or as part of a powder formulation, using a suitable capsule filling and sealing machine (B2), for example type MG2-G100 (Messrs. MG2, Bologna, Italy). The quantity of powder formulation packed in should be 6 % (v/v) to 50 % (v/v), preferably 10 % (v/v) to 30 io % (v/v), preferably 15 % (v/v) to 25 % (v/v), particularly preferably about 20 % (v/v), of the maximum capacity of the capsule. During filling, the climatic conditions in the room should be the same as for the screening and mixing process. The filled and sealed capsules are placed in a suitable mixing container under the climatic conditions described above. The fill level is 50 % to 80 % , preferably 60 %
to 70 most preferably about 65 %, of the height of the container.
The mixing container is then agitated in a suitable mixer (B3), preferably gyrowheel or SA 1200 gyrowheel (Engelsmann AG, Frankenthaler StraRe 137 -141, D 6700 Ludwigshafen/Rh), Turbula*T2 C, or Turbula T 10 B (Messrs Bachofen AG
(Switzerland) at 10 to 30 rpm, preferably at about 20 rpm. The mixing time should be 20 to 150 minutes, preferably 50 to 100 minutes, preferably 60 to 90 minutes, particularly preferably about 30 to 75 minutes. The results of the mixing or cleaning process can be checked by visual inspection, optionally by opening capsules (B4).
The cleaning process is complete as soon as no powder coating can be seen on the inner wall of the capsule. A very slight powder coating on the inner wall of the capsule is also sufficient for the cleaning process to be brought to an end.
The capsules may be emptied and then filled with an active substance formulation. If the active substance formulation itself is used as the powder formulation, there is no need to empty and refill the capsules. They may be used directly for inhalation.
The following Example serves to illustrate the process according to the invention. It is to be regarded as simply an example of procedure without restricting the invention to its content.
*Trade-mark Example About 70 Grade A hard gelatine capsules (reduced content of lubricant and mould release agent), type CONI-SNAP size 3 (Messrs. Capsugel) and about 70 Grade B
(standard) hard gelatine capsules, type CONI-SNAP size 3 (Messrs. Capsugel) were filled with a tiotropium-lactose mixture consisting of about 11 mg/capsule of lactose monohydrate (Pharmatose 200M made by Veghel / NL) and 36 pg/capsule of tiotropium bromide.
Half the capsules were shaken using with a Turbula Mixer type 2C (Messrs Bachofen AG, Basle, Switzerland) for about two hours at a temperature of 22 C.
io Then the parameter "dose delivered ", i.e. the amount of active substance delivered in %, was determined in the shaken and unshaken capsules.
The results in Table 1 show a significant increase in the dose delivered (determined according to TEST Uniformity of dose, a. Uniformity of delivered dose, European is Pharmacopoeia , Third Edition (1997), page 1770, published by the Council of Europe, 67075 Strasbourg Cedex, ISBN: 92-871-2991-6) after the cleaning process by shaking the capsules.
Table 1 Capsule Dose delivered (%]
Grade A unshaken 74 Grade A shaken 82 Grade B unshaken 79 Grade B shaken 83 *Trade-mark
Claims (16)
1. Process for cleaning the inner wall of a hard gelatine capsule for use in inhalation therapy, comprising cleaning the capsule with a powder formulation.
2. Process according to claim 1, wherein the powder formulation is pharmaceutically acceptable.
3. Process according to claim 1 or 2, wherein the powder formulation constitutes an ingredient of an active substance formulation.
4. Process according to claim 1 or 2, wherein the powder formulation is an active substance formulation for inhalation.
5. Process according to any one of claims 1 to 4, wherein the cleaning is carried out in a sealed capsule.
6. Process according to any one of claims 1 to 5, wherein the cleaning is carried out without the use of solvents.
7. Process according to any one of claims 1 to 6, wherein the cleaning is carried out in a gravity mixer or on a vibrating table.
8. Process according to any one of claims 1 to 7, wherein the cleaning is carried out at a temperature of 15 to 50 °C.
9. Process according to any one of claims 1 to 8, wherein the cleaning comprises a mixing time of from 20 to 150 minutes.
10. Process according to any one of claims 1 to 9, wherein some or all of the grains of the powder formulation accumulate impurities.
11. Process according to any one of claims 1 to 10, wherein some or all of the grains of the powder formulation accumulate lubricants or mould release agents, or both.
12. Process according to any one of claims 1 to 11, wherein the content of powder formulation is from 6 % to 50 % of the theoretical total capacity of the capsule.
13. Process according to any one of claims 1 to 12, wherein the powder formulation contains at least one excipient with particle size of 10 to 50 µm in aerodynamic diameter.
14. Process according to any one of claims 1 to 13, wherein the powder formulation contains lactose or lactose monohydrate, or both.
15. Process according to any one of claims 1 to 14, which comprises the successive steps a) to e):
a) subjecting the powder formulation to one or more screenings and mixings, b) transferring the powder formulation into the gelatine capsule for inhalation, c) agitating the gelatine capsule in a mixing container, d) monitoring the end of the cleaning process visually, and e) placing the gelatine capsule directly in the inhaler or optionally emptying and refilling the gelatine capsule with an active substance formulation.
a) subjecting the powder formulation to one or more screenings and mixings, b) transferring the powder formulation into the gelatine capsule for inhalation, c) agitating the gelatine capsule in a mixing container, d) monitoring the end of the cleaning process visually, and e) placing the gelatine capsule directly in the inhaler or optionally emptying and refilling the gelatine capsule with an active substance formulation.
16. Use of a capsule prepared by the process according to any one of claims 1 to 15 in a powder inhaler.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10128779A DE10128779A1 (en) | 2001-06-13 | 2001-06-13 | Process for cleaning hard gelatin capsules |
| DE10128779.8 | 2001-06-13 | ||
| PCT/EP2002/006423 WO2002100319A2 (en) | 2001-06-13 | 2002-06-12 | Method for cleaning hard gelatine capsules |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2449217A1 CA2449217A1 (en) | 2002-12-19 |
| CA2449217C true CA2449217C (en) | 2011-03-08 |
Family
ID=7688208
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2449217A Expired - Fee Related CA2449217C (en) | 2001-06-13 | 2002-06-12 | Process for cleaning hard gelatine capsules |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP1399105B2 (en) |
| JP (1) | JP4446334B2 (en) |
| AR (1) | AR034474A1 (en) |
| AT (1) | ATE451904T1 (en) |
| CA (1) | CA2449217C (en) |
| DE (2) | DE10128779A1 (en) |
| ES (1) | ES2337451T5 (en) |
| MX (1) | MXPA03011460A (en) |
| UY (1) | UY27325A1 (en) |
| WO (1) | WO2002100319A2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10128779A1 (en) † | 2001-06-13 | 2003-01-02 | Boehringer Ingelheim Pharma | Process for cleaning hard gelatin capsules |
| US8216610B2 (en) | 2004-05-28 | 2012-07-10 | Imaginot Pty Ltd. | Oral paracetamol formulations |
| EP3449928A1 (en) | 2005-11-28 | 2019-03-06 | Imaginot Pty Ltd. | Oral therapeutic compound delivery system |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB697723A (en) † | 1949-07-25 | 1953-09-30 | John Tye & Son Ltd | Improvements in and relating to capsules |
| GB1122284A (en) † | 1965-03-19 | 1968-08-07 | Fisons Pharmaceuticals Ltd | Inhalation device |
| US3860618A (en) † | 1967-08-08 | 1975-01-14 | Philip Saxton Hartley | Chromone |
| US3653500A (en) † | 1969-07-11 | 1972-04-04 | Lilly Co Eli | Filled capsules |
| US3676958A (en) † | 1970-11-09 | 1972-07-18 | Parke Davis & Co | Vibratory cleaner |
| GB1459426A (en) † | 1973-02-26 | 1976-12-22 | Allen & Hanburys Ltd | Inhalation devices |
| US4069819A (en) † | 1973-04-13 | 1978-01-24 | Societa Farmaceutici S.P.A. | Inhalation device |
| US3948264A (en) † | 1975-05-21 | 1976-04-06 | Mead Johnson & Company | Inhalation device |
| DE3268533D1 (en) † | 1981-07-24 | 1986-02-27 | Fisons Plc | Inhalation drugs, methods for their production and pharmaceutical formulations containing them |
| DE3345722A1 (en) † | 1983-12-17 | 1985-06-27 | Boehringer Ingelheim KG, 6507 Ingelheim | INHALATOR |
| WO1994006498A1 (en) † | 1992-09-23 | 1994-03-31 | Fisons Plc | Inhalation device |
| US5641510A (en) * | 1994-07-01 | 1997-06-24 | Genentech, Inc. | Method for treating capsules used for drug storage |
| GB9902689D0 (en) * | 1999-02-08 | 1999-03-31 | Novartis Ag | Organic compounds |
| KR100488644B1 (en) * | 2000-10-12 | 2005-05-11 | 베링거 잉겔하임 파르마 게엠베하 운트 코 카게 | Novel tiotropium-containing inhalation powder |
| DE10128779A1 (en) † | 2001-06-13 | 2003-01-02 | Boehringer Ingelheim Pharma | Process for cleaning hard gelatin capsules |
-
2001
- 2001-06-13 DE DE10128779A patent/DE10128779A1/en not_active Ceased
-
2002
- 2002-06-10 UY UY27325A patent/UY27325A1/en not_active Application Discontinuation
- 2002-06-12 MX MXPA03011460A patent/MXPA03011460A/en active IP Right Grant
- 2002-06-12 JP JP2003503146A patent/JP4446334B2/en not_active Expired - Lifetime
- 2002-06-12 EP EP02747374.3A patent/EP1399105B2/en not_active Expired - Lifetime
- 2002-06-12 DE DE50214098T patent/DE50214098D1/en not_active Expired - Lifetime
- 2002-06-12 AR ARP020102209A patent/AR034474A1/en not_active Withdrawn
- 2002-06-12 WO PCT/EP2002/006423 patent/WO2002100319A2/en active Application Filing
- 2002-06-12 AT AT02747374T patent/ATE451904T1/en active
- 2002-06-12 CA CA2449217A patent/CA2449217C/en not_active Expired - Fee Related
- 2002-06-12 ES ES02747374T patent/ES2337451T5/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| ES2337451T3 (en) | 2010-04-26 |
| UY27325A1 (en) | 2003-05-30 |
| EP1399105A2 (en) | 2004-03-24 |
| EP1399105B2 (en) | 2018-09-05 |
| WO2002100319A2 (en) | 2002-12-19 |
| DE10128779A1 (en) | 2003-01-02 |
| ES2337451T5 (en) | 2019-03-05 |
| JP2004529729A (en) | 2004-09-30 |
| JP4446334B2 (en) | 2010-04-07 |
| ATE451904T1 (en) | 2010-01-15 |
| DE50214098D1 (en) | 2010-01-28 |
| AR034474A1 (en) | 2004-02-25 |
| CA2449217A1 (en) | 2002-12-19 |
| EP1399105B1 (en) | 2009-12-16 |
| WO2002100319A3 (en) | 2003-03-20 |
| MXPA03011460A (en) | 2004-04-05 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20220301 |
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| MKLA | Lapsed |
Effective date: 20200831 |