CA2189991C - Active substance controlled release devices and process for producing the same - Google Patents
Active substance controlled release devices and process for producing the same Download PDFInfo
- Publication number
- CA2189991C CA2189991C CA002189991A CA2189991A CA2189991C CA 2189991 C CA2189991 C CA 2189991C CA 002189991 A CA002189991 A CA 002189991A CA 2189991 A CA2189991 A CA 2189991A CA 2189991 C CA2189991 C CA 2189991C
- Authority
- CA
- Canada
- Prior art keywords
- active substance
- containing matrix
- mass
- erodible
- thickness
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000013543 active substance Substances 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 26
- 230000008569 process Effects 0.000 title claims abstract description 21
- 238000013270 controlled release Methods 0.000 title claims abstract description 7
- 239000011159 matrix material Substances 0.000 claims abstract description 25
- 239000007787 solid Substances 0.000 claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 238000003825 pressing Methods 0.000 claims 1
- 230000001737 promoting effect Effects 0.000 claims 1
- 239000000243 solution Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229920001169 thermoplastic Polymers 0.000 description 4
- 239000004416 thermosoftening plastic Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 3
- 238000007493 shaping process Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000002318 adhesion promoter Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Moulds For Moulding Plastics Or The Like (AREA)
Abstract
A process for the production of devices for the controlled release of active substances, consisting of an active substance-containing matrix and an erodible mass of solids at least partially covering the matrix, with the thickness of the erodible mass across its extension being determined by thickness gradients, and the active substance-containing matrix itself being produced with thickness gradients which determine the thickness gradients of the erodible mass, is characterized in that in a first step the active substance-containing matrix is formed in the form of pressed articles having thickness gradients, and in a second step It is transferred onto a laminated tablet-compressing machine where it is compressed with the erodible mass.
Description
Active Substance Controlled Release Devices ahd Process for Producing the Same SP~C1FICATIQN
The present invention relates to a process for the production of devices for the controlled release of active substances in liquid media; the devices have an active substance-containing matrix and an erodible mass of solids covering the matrix at least partially, the thickness of the mass being determined by gradients.
Devices of this kind serve to release active substances in liquid media, e.g, body fluids, in a controlled manner, i.a, with a given velocity profile. An important field of application of these devices is the peroral administration of drugs. Here the frequent objective is to administer active substances having a short biological half-life in such a manner that even plasma concentrations are maintained connected with a low taking frequency.
In these devices the velocity profile of the active substance release is particularly influenced by the thickness gradients of the erodible mass of solids which covers the active substance-containing matrix at least partially first. In the course of the release a pragresstve erosion of this mass of solids takes place, causing the contact surface between the active substance-containing matrix and the liquid medium, in which the device is present, to enlarge as a function of its thickness gradients. Through this effect, provided that the thickness gradients have been chosen adequately, a relatively constant release rate - as is frequently desired in sustained-release drugs - can be maintained, for example.
The present invention relates to a process for the production of devices for the controlled release of active substances in liquid media; the devices have an active substance-containing matrix and an erodible mass of solids covering the matrix at least partially, the thickness of the mass being determined by gradients.
Devices of this kind serve to release active substances in liquid media, e.g, body fluids, in a controlled manner, i.a, with a given velocity profile. An important field of application of these devices is the peroral administration of drugs. Here the frequent objective is to administer active substances having a short biological half-life in such a manner that even plasma concentrations are maintained connected with a low taking frequency.
In these devices the velocity profile of the active substance release is particularly influenced by the thickness gradients of the erodible mass of solids which covers the active substance-containing matrix at least partially first. In the course of the release a pragresstve erosion of this mass of solids takes place, causing the contact surface between the active substance-containing matrix and the liquid medium, in which the device is present, to enlarge as a function of its thickness gradients. Through this effect, provided that the thickness gradients have been chosen adequately, a relatively constant release rate - as is frequently desired in sustained-release drugs - can be maintained, for example.
Owing to the novel constructional conception there is no prior art description of possibilities to manufacture devices of this kind. In particular, the problem of combining masses for the formation of an active substance-containing matrix with an erodible mass of solids in a manner by which thickness gradients are formed in the erodible solids mass is not solved in the art. Accordingly, it is the object of the present invention to provide a process for the pro-duction of the devices, which offers a solution for this problem and is efficient.
According to the present invention this object is achieved by (a) combining the erod~,ble mass with the active substance-containing matrix after formation of the same or (b) combining and forming the active substance-containing matrix and the erodible mass in one process step.
In this connection, there are several process technological meth-ods which can contribute to the solution of this problem. For in-stance, tableting which is frequently preferred in pharmaceutical process technology can realize solution (a). To this effect, an ac-tive substance-containing pressed article representing the active substance-containing matrix is formed first. Preferably, the shape of this pressed piece is already adjusted to the desired thickness gradients of the erodible solids mass. This is possible in that the pressed article itself contains thickness gradients which tend to be complementary to the thickness gradients of the erodible mass of solids. These pressed articles are transferred to laminated tablet-compressing machines where they are compressed with the erod-3ble mass. The use of mantle-core presses is particularly advan-tageous for this purpose since, provided that they are constructed accordingly, they are able to transfer the prefabricated pressed pieces automatically and continuously into the die bores in which the second compression cycle takes place.
~
~18999I
According to the present invention this object is achieved by (a) combining the erod~,ble mass with the active substance-containing matrix after formation of the same or (b) combining and forming the active substance-containing matrix and the erodible mass in one process step.
In this connection, there are several process technological meth-ods which can contribute to the solution of this problem. For in-stance, tableting which is frequently preferred in pharmaceutical process technology can realize solution (a). To this effect, an ac-tive substance-containing pressed article representing the active substance-containing matrix is formed first. Preferably, the shape of this pressed piece is already adjusted to the desired thickness gradients of the erodible solids mass. This is possible in that the pressed article itself contains thickness gradients which tend to be complementary to the thickness gradients of the erodible mass of solids. These pressed articles are transferred to laminated tablet-compressing machines where they are compressed with the erod-3ble mass. The use of mantle-core presses is particularly advan-tageous for this purpose since, provided that they are constructed accordingly, they are able to transfer the prefabricated pressed pieces automatically and continuously into the die bores in which the second compression cycle takes place.
~
~18999I
In particular for large scale manufacture,producing devices of the above-mentioned type according to the process described herein by means of tableting is very economical. However, in case the active substance or other required components of the device can-not be tabletted, as is the case with liquid substances or solid substances having a low melting point, or if tableting is to be omitted for other reasons, forming of the active substance-con-taining matrix and/or of the erodible mass of solids may be effect-ed by means of an alternative method. When thermoplastic start-ing materials are used, processes utilizing the thermoplasticity and forming the materials by melting, casting, injecting or extruding are suitable.
According to the present invention it will be preferred in many cases to conduct the process continuously and to form the active substance-containing matrix in the form of a web, tape or rope-shaped body first. Into this material depressions or thickness gra-dients may be made by stamping or rolling - optionally when still in hot condition. During the subsequent combination with the erodable mass of solids these depressions or thickness gradients substantially influence the thickness gradients of the solids mass.
Devices of the above-mentioned type may subsequently be sepa-rated by cutting or punching.
Even if the starting materials do not exhibit distinct thermoplastic properties, a similar process is possible according to the present invention. In this case, shaping may also be effected by using a liquid phase, i.e., by processing a solution, a gel, a suspension, or a paste. For instance, supporting films may be coated with solu-tions and suspensions and web-shaped bodies may be produced by subsequent drying. These are to be finished in correspondence to the bodies formed by thermoplastic shaping. Also, it is possible to premix powdery materials up to a pasty condition, to obtain the active substance-containing matrix therefrom by extru-sion and to conduct further processing as described above.
A process according to the present invention for the production of devices of the above-mentioned type may also include the combi-nation of different process steps. For instance, it may be advanta-geous to manufacture the active substance-containing matrix by one or several consecutive coating processes first, to emboss de-pressions by means of stamps and then inject the erodible mass in molten condition into these depressions.
It may be necessary to apply one or several adhesion promoters on the contact surface between the individual components of the device prior to joining the active substance-containing matrix with the erodible mass. The application of the adhesive adjuvants is preferably effected by applying a solution of these substances by means of a coating, spraying or dipping processes.
As an alternative to the above-mentioned embodiments of the pro-cess, the active substance-containing matrix and the erodible mass of solids may be formed simultaneously and the combination may be carried out in one process step. This manner of production is in particular suitable when the active substance-containing ma-trix and the erodible mass of solids may be manufactured by sim-ilar processes and under similar process conditions. If, for in-stance, all components of the device to be manufactured may be produced through thermoplastic shaping at the same or a similar temperature, coextrusion of the components is a preferred pro-cess.
Irrespective of the embodiment of the production method, all op-tions described also apply when devices for the controlled release of active substances are to be manufactured which have more than one active substance-containing matrix and an erodable mass of solids covering these matrices at least partially.
According to the present invention it will be preferred in many cases to conduct the process continuously and to form the active substance-containing matrix in the form of a web, tape or rope-shaped body first. Into this material depressions or thickness gra-dients may be made by stamping or rolling - optionally when still in hot condition. During the subsequent combination with the erodable mass of solids these depressions or thickness gradients substantially influence the thickness gradients of the solids mass.
Devices of the above-mentioned type may subsequently be sepa-rated by cutting or punching.
Even if the starting materials do not exhibit distinct thermoplastic properties, a similar process is possible according to the present invention. In this case, shaping may also be effected by using a liquid phase, i.e., by processing a solution, a gel, a suspension, or a paste. For instance, supporting films may be coated with solu-tions and suspensions and web-shaped bodies may be produced by subsequent drying. These are to be finished in correspondence to the bodies formed by thermoplastic shaping. Also, it is possible to premix powdery materials up to a pasty condition, to obtain the active substance-containing matrix therefrom by extru-sion and to conduct further processing as described above.
A process according to the present invention for the production of devices of the above-mentioned type may also include the combi-nation of different process steps. For instance, it may be advanta-geous to manufacture the active substance-containing matrix by one or several consecutive coating processes first, to emboss de-pressions by means of stamps and then inject the erodible mass in molten condition into these depressions.
It may be necessary to apply one or several adhesion promoters on the contact surface between the individual components of the device prior to joining the active substance-containing matrix with the erodible mass. The application of the adhesive adjuvants is preferably effected by applying a solution of these substances by means of a coating, spraying or dipping processes.
As an alternative to the above-mentioned embodiments of the pro-cess, the active substance-containing matrix and the erodible mass of solids may be formed simultaneously and the combination may be carried out in one process step. This manner of production is in particular suitable when the active substance-containing ma-trix and the erodible mass of solids may be manufactured by sim-ilar processes and under similar process conditions. If, for in-stance, all components of the device to be manufactured may be produced through thermoplastic shaping at the same or a similar temperature, coextrusion of the components is a preferred pro-cess.
Irrespective of the embodiment of the production method, all op-tions described also apply when devices for the controlled release of active substances are to be manufactured which have more than one active substance-containing matrix and an erodable mass of solids covering these matrices at least partially.
Claims (3)
1. A process for the production of a device for the controlled release of active substances, consisting of an active substance-containing matrix and an erodible mass of solids at least partially covering the matrix, with the thickness of the erodible mass across its extension being determined by thickness gradients, and the active substance-containing matrix itself being produced with thickness gradients which determine the thickness gradients of the erodible mass, said process comprising the steps of:
a) pressing the active substance containing matrix into the form of pressed articles having thickness gradients; and b) transferring the pressed article to a laminated tablet-compressing machine where it is compressed with the erodible mass.
a) pressing the active substance containing matrix into the form of pressed articles having thickness gradients; and b) transferring the pressed article to a laminated tablet-compressing machine where it is compressed with the erodible mass.
2. The process according to claim 1, characterized in that the device for the controlled release of active substances is produced with more than one active substance-containing matrix.
3. The process according to any one of claims 1 or 2, characterized in that prior to combination of active substance-containing matrix and erodible mass, a solution of an adhesion promoting auxiliary is applied on the contact surface between the two components.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002489809A CA2489809C (en) | 1994-05-13 | 1995-05-08 | Active substance controlled release devices and process for producing the same |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4416926.4 | 1994-05-13 | ||
| DE4416926A DE4416926C2 (en) | 1994-05-13 | 1994-05-13 | Process for the manufacture of devices for the controlled release of active substances |
| PCT/EP1995/001725 WO1995031185A1 (en) | 1994-05-13 | 1995-05-08 | Active substance controlled release devices and process for producing the same |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002489809A Division CA2489809C (en) | 1994-05-13 | 1995-05-08 | Active substance controlled release devices and process for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2189991A1 CA2189991A1 (en) | 1995-11-23 |
| CA2189991C true CA2189991C (en) | 2006-09-12 |
Family
ID=6518074
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002189991A Expired - Fee Related CA2189991C (en) | 1994-05-13 | 1995-05-08 | Active substance controlled release devices and process for producing the same |
Country Status (10)
| Country | Link |
|---|---|
| EP (2) | EP0758884B1 (en) |
| JP (1) | JPH10500118A (en) |
| AT (2) | ATE271855T1 (en) |
| CA (1) | CA2189991C (en) |
| DE (3) | DE4416926C2 (en) |
| DK (1) | DK0758884T3 (en) |
| ES (2) | ES2224505T3 (en) |
| GR (1) | GR3035533T3 (en) |
| PT (1) | PT758884E (en) |
| WO (1) | WO1995031185A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19524753A1 (en) * | 1995-07-07 | 1997-01-23 | Lohmann Therapie Syst Lts | Layered tablet for the controlled release of active ingredients |
| DE19640062B4 (en) | 1996-09-28 | 2006-04-27 | Lts Lohmann Therapie-Systeme Ag | Oral preparation comprising in a matrix swellable in an aqueous medium at least one pharmaceutical active substance |
| US20050037052A1 (en) * | 2003-08-13 | 2005-02-17 | Medtronic Vascular, Inc. | Stent coating with gradient porosity |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1237904B (en) * | 1989-12-14 | 1993-06-18 | Ubaldo Conte | CONTROLLED SPEED RELEASE TABS OF ACTIVE SUBSTANCES |
| JPH07507564A (en) * | 1992-09-30 | 1995-08-24 | ファイザー・インク． | Articles containing a core and a coating of variable thickness |
| CN1029660C (en) * | 1993-02-17 | 1995-09-06 | 杨吉田 | Drug non-plane membranous agent and its preparation technology |
| DE4341442C2 (en) * | 1993-12-04 | 1998-11-05 | Lohmann Therapie Syst Lts | Device for the controlled release of active substances and their use |
-
1994
- 1994-05-13 DE DE4416926A patent/DE4416926C2/en not_active Expired - Fee Related
-
1995
- 1995-05-08 AT AT99114947T patent/ATE271855T1/en not_active IP Right Cessation
- 1995-05-08 DK DK95920805T patent/DK0758884T3/en active
- 1995-05-08 WO PCT/EP1995/001725 patent/WO1995031185A1/en active IP Right Grant
- 1995-05-08 DE DE59508911T patent/DE59508911D1/en not_active Expired - Fee Related
- 1995-05-08 ES ES99114947T patent/ES2224505T3/en not_active Expired - Lifetime
- 1995-05-08 CA CA002189991A patent/CA2189991C/en not_active Expired - Fee Related
- 1995-05-08 EP EP95920805A patent/EP0758884B1/en not_active Expired - Lifetime
- 1995-05-08 DE DE59510932T patent/DE59510932D1/en not_active Expired - Fee Related
- 1995-05-08 AT AT95920805T patent/ATE198151T1/en not_active IP Right Cessation
- 1995-05-08 ES ES95920805T patent/ES2155131T3/en not_active Expired - Lifetime
- 1995-05-08 JP JP7529327A patent/JPH10500118A/en not_active Withdrawn
- 1995-05-08 PT PT95920805T patent/PT758884E/en unknown
- 1995-05-08 EP EP99114947A patent/EP0965337B1/en not_active Expired - Lifetime
-
2001
- 2001-03-09 GR GR20010400372T patent/GR3035533T3/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0965337A1 (en) | 1999-12-22 |
| ATE271855T1 (en) | 2004-08-15 |
| GR3035533T3 (en) | 2001-06-29 |
| DE59510932D1 (en) | 2004-09-02 |
| DK0758884T3 (en) | 2001-04-30 |
| EP0758884A1 (en) | 1997-02-26 |
| EP0758884B1 (en) | 2000-12-20 |
| DE4416926A1 (en) | 1995-11-16 |
| ATE198151T1 (en) | 2001-01-15 |
| JPH10500118A (en) | 1998-01-06 |
| EP0965337B1 (en) | 2004-07-28 |
| WO1995031185A1 (en) | 1995-11-23 |
| DE59508911D1 (en) | 2001-01-25 |
| CA2189991A1 (en) | 1995-11-23 |
| PT758884E (en) | 2001-06-29 |
| DE4416926C2 (en) | 2000-01-13 |
| ES2155131T3 (en) | 2001-05-01 |
| ES2224505T3 (en) | 2005-03-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |