CA2172401C - Transdermal therapeutic system with acetylsalicylic acid as active substance - Google Patents
Transdermal therapeutic system with acetylsalicylic acid as active substance Download PDFInfo
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- CA2172401C CA2172401C CA002172401A CA2172401A CA2172401C CA 2172401 C CA2172401 C CA 2172401C CA 002172401 A CA002172401 A CA 002172401A CA 2172401 A CA2172401 A CA 2172401A CA 2172401 C CA2172401 C CA 2172401C
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Abstract
Transdermal therapeutic system comprising the active substance acetylsalicylic acid, having a layered structure consisting of a backing layer which is substantially impermeable to active substances and moisture and one or several active substance-containing matrix layers, which is characterized in that at least one of said matrix layers comprises acetylsalicylic acid in mainly crystalline form.
Description
21 ~24C11 SPECIFICATION
The present invention relates to a transdermal therapeutic system for the release of acetylsalicylic acid and optional further sub-stances via the skin to the human body. The system that will be described has an increased chemical hydrolytic stability for the ac-tive substance acetylsalicylic acid.
Transdermal therapeutic systems (TTS) have been established on the market in the medicinal therapy of various diseases.
It is also known that the active substance acetylsalicylic acid has a basic permeativity through the human skin and is therefore suit-able as a component in transdermal therapeutic systems. Rougier et al. (J. Pharm. Sci. 176, 451-454, 1987) have already described that the acetylsalicylic acid-absorption rate into the skin depends (to a rather small extent) on the chosen skin area.
Chen et al. (Zhongguo Yiyuan Yaoxue Zazhi, Vol. 1 1, p. 245-247 (1991 ) give a report on a successful transdermal application of acetylsalicylic acid creams in children suffering from rheumatism.
JP 3 1 12 926 describes an agent for the percutaneous applica-tion, including actetylsalicylic acid, which agent is formed by dis-solution in water and addition of water-swellable additives and is finally used in a silicone polymer in dispersed form.
In this case, there is a great risk of hydrolysis due to the contact with water.
Acetylsalicylic acid has been introduced for some time and is a therapeutically effective drug having a high therapeutic index.
Used in very high doses (more than one gram per day) it is used as an antirheumatic agent, in mean doses (250 to 500 mg) as an :~
2172~~1 antipyretic/analgesic, and in a low dosage (30 to 150 mg per day) as a platelet aggregation inhibitor.
Acetylsalicylic acid already melts at a low temperature (about 139°C) and is noticeably volatile already at this temperature.
Acetylsalicylic acid exists in several polymorphous forms (modifications) which partly melt at only 100°C and also have dif-ferent dissolution behavior.
Because of the unstable ester grouping it is susceptible to hydroly-sis and transesterification. On the way to a stable administration form the following principles have to be observed in general:
- water, alcohols and esters as possible coreactants usually are unsuitable formulation components;
- for the same reason, in consideration of the law of mass ac-tion, it is useful to add potential reaction products, such as acetic acid or water-binding acetic anhydride as stabilizing components;
- since the hydrolysis proceeds slowest at a pH of about 2 to 3, adjustment to this acidity promotes stability;
- also, the use of additional stabilizing inactive ingredients is known, e.g., Luzzi and Ma (U.S.-Patent No. 4,228,162) re-commend to use dimethylisosorbide as stabilizing solvent.
No indications have been found in literature as to how this galenic problem can be applied to the technique of manufacturing a TTS.
First formulations wherein the TTS-matrix - following the state of the art - contained acetylsalicylic acid exclusively in dissolved form proved to be too unstable.
r:..
According to U.S.-Patent No. 4,286,592 a pharmaceutic active substance is used in crystalline form in a TTS in order to control the active substance release via an adhesive layer. A special ratio between the particle size of the crystals and the diffusion proper-ties is important in this case.
However, this application would only be used by those skilled in the art to limit an active substance flow but not for stabilization purposes with simultaneously maintaining the maximum possible release properties.
Although it is usual practice in some cases to load transdermal therapeutic systems with active substance to such a concentration that it crystallizes during the production after having been in com-plete solution initially (EP 0 156 080). By this a particularly long-lasting action is achieved. However, the method involves the dis-advantage that it is difficult to control the procedure of crystalliza-tion and that, in the absence of crystal nuclei, modifications hav-ing a limited storage period are frequently obtained. Thus, the product cannot be manufactured to meet the required pharmaceu-tical quality. Indications as to stabilize active substances by intro-ducing a high crystalline portion into transdermal therapeutic sys-tems cannot be found in literature.
It is the object of the present invention to provide a transdermal therapeutic system with acetylsalicylic acid, which has a sufficient pharmaceutical stability at the maximum achievable release rate to the skin under the circumstances.
According to the present invention this object is achieved by a transdermal therapeutic system comprising the active substance acetylsalicylic acid and optional further substances and having a layered structure consisting of a backing layer which is substan-tially impermeable to active substances and moisture and one or _ ~ 4 2172401 several matrix layers, with at least one of said matrix layers com-prising acetylsalicylic acid in mainly crystalline form.
Normally, an undesired limitation of the release properties in active substance crystals must be expected due to the fact that the dis-solution rate could become lower than the permeation into the skin. Most surprisingly, this is not the case, if according to the present invention - in addition to careful drying of the layered components of the transdermal therapeutic system or other known stabilizing measures - a stabilizing phase of crystalline acetylsali-cylic acid is formed already prior to coating and drying.
As a matter of fact, dry storage conditions are very useful to sta-bilize these properties since hydrolysis is repressed thereby. Such storage conditions can be ensured by gas and moisture resistant packing means and by insertion of one or more moisture-absorbing elements into the package.
The subject matter of the present invention will be illustrated in more detail in the following:
A characterizing and essential feature of the present invention is the presence of undissolved acetylsalicylic acid in a transdermal therapeutic system. In contrast to the prior art, at least a partial amount of the active substance employed prior to the drying pro-cess is maintained in an undissolved condition during the whole fabrication so that at least sufficient seed crystals of the stable ac-tive substance modification may come into the product. Thus, an only temporarily stable, oversaturated condition of the active sub-stance solution - possibly under precipitation of metastable sedi-ments - is avoided; this would involve high risks with respect to stability. In the course of time, uncontrolled recrystallizations will result in a product which no longer corresponds to the initial re-lease rate specification.
_.
,1 217240 The individual form of the present invention may vary within wide ranges. In the most simple case, the system of Figure 1 corre-sponds to a single-layer matrix having pressure sensitive adhesive properties to the skin. The system consists of a backing layer which is substantially impermeable to the active substance, the matrix layer, and a removable protective layer which is to be re-moved prior to application.
Numerous substances standing out for a particular resistance and diffusion stability may be used as backing layer (1 ), among these polyester. But nearly any other plastics suitable for the application on the skin may be used, such as polyvinyl chloride, ethylene vi-nylacetate, vinyl acetate, polyethylene, polypropylene, cellulose derivatives, and many others.ln particular cases an additional layer may be applied, e.g., by metallizing or vapor-plating with other additives forming a diffusion barrier, such as silicon dioxide, alu-minum oxide, and the like. Also, for better acceptance, the outer side of the backing layer is frequently coated with a cuticolor var-nish, or treated otherwise to improve the appearance.
The thickness of the film-like backing layer normally amounts to 8 to 80 Vim, depending - among others - on the stability and per-meability of the chosen material; however, for special purposes it may also be thicker or thinner.
Among others, copolymers comprising acrylic esters, mixtures of rubbers and resins, polyvinyl acetate, silicone polymers and many other base materials compatible with the skin are suitable for the use as matrix layer (2) of the patch according to the present in-vention. The addition of up to 40% of fillers, such as titanium di-oxide, zinc oxide, chalk, activated charcoal, finely divided silicon dioxide, etc. does by no means impair the function according to , .
i the present invention and may result in advantages with respect to the cohesion of the finished system.
The removable protective layer (3) is of less importance for the function; for instance, it may consist of a polyester material. How-ever, any other plastics suitable for the application on the skin may be used, such as polyvinyl chloride, ethylene vinylacetate, vi-nyl acetate, polyethylene, polypropylene, cellulose derivatives, and many others. In particular cases metallizing or vapor-plating with other diffusion-blocking additives, such as silicon dioxide, alumi-num oxide, and the like may be carried out. In any case, the sur-face facing the adhesive matrix must be treated with dehesive (release) materials, such as silicones or fluorine-containing plastics, so that the composite remains easily removable. The thickness of the film-like removable protective layer normally amounts to about 40 to 200 ,um; for special purposes it may be thicker or thinner.
Figure 2 shows as additional embodiment of the present invention the arrangement in two matrix layers, which is also possible; the adhesive layer (4) advantageously comprises smaller and less nu-merous active substance crystals. By this an improved adhesion to the skin can be achieved, as compared to a single-layer system.
With respect to the object of the present invention, it is not expe-dient to dispense completely with crystalline portions even in the adhesive layer, since the diffusion boundary layer could grow ex-cessively wide, resulting in a reduced flow into the skin.
The size of the acetylsalicylic acid crystals is of no importance with respect to the function of the principle according to the pres-ent invention and to the basic advantage of stabilization as such.
Smaller crystals having a diameter of below approximately 50 to 100 Nm are advantageous, if only because of the more homoge-nous visual appearance. If extremely slightly dissolving matrix .._ 217201 base materials, such as masses based on polyisobutylenes and larger crystal diameters (more than 300 ,cam) are used, a release control of the active substance through the skin may take place, involving the advantage that the release rate is controlled by the system, but involving the disadvantage that only part of the theo-retically achievable flow rate can be achieved.
Independently of the construction of the system, volatile additives may be added, e.g., 2-pyrrolidone, benzyl alcohol, butanol and other short-chain alcohols, triglycerides, cholesterol, cineole, delta-tocopherol, diethyleneglycol, diethyleneglycol monoethylether, di-isopropyl adipate, dimethyldecyl phosphoxide, dimethylisosorbide, dimethyllauroyl amide, dimethylsulfoxide, dodecylsulfoxide, acetic acid, ethyl acetate, and other aliphatic and aromatic esters, ethyl-ene glycol, ethyleneglycol monolaurate, and other esters and ethers of ethylene glycol or propylene glycol, 2-octyl dodecanol, thin-bodied paraffin, glycerol, glycerol monooleate, glycerol mono-stearate, hydrogenated castor oil, isopropyl myristate, isopropyl palmitate, lauric acid diethanolamide, menthol or other volatile ter-pene derivatives (which are mixture components of many natural ethereal oils), methyl benzoate, methyloctylsulfoxide, mono- or diethylacetamide, N,N-diethyl-m-toluamide , N-methylpyrrolidone,' 1-octanol and other volatile, medium-chain alcohols, octanoic acid and other medium-chain, aliphatic carboxylic acids, oleyl alcohol, olive oil, oleic acid, oleyl oleate, phenylethanol, propylene glycol, ricinoleic acid, triacetin, but also mixtures of these substances, e.g., oleic acid/propylene glycol.
In special cases, however, the reactivity of the active substance acetylsalicylic acid with esters and acids as well as alcohols must be taken into consideration; this limits the use of such substances.
However, the present invention limits the possible chemical reac-tion to the widest possible extent by means of compartments, thus it represents a stabilization advantage even in this respect.
2 i 72401 In this connection, one alternative is of particular advantage; in this case the matrix layer is divided into two portions to be lami-nated onto each other, both comprising acetylsalicylic acid in mainly crystalline form according to the present invention; one of said portions comprises a highly volatile ingredient (e.g., one of the substances listed in the above paragraph), which remains in the system as a solvent for the residual components, and has been laminated with the second portion of the matrix layer during the production. Thus, after migration of the highly volatile compo-nent, a system having sufficient shear strength and comprising high-volatile additives can be obtained.
The acetylsalicylic acid content of the total matrix of the trans-dermal therapeutic system according to the present invention suit-ably amounts to about 15 to 60%-wt., preferably it is of the order of 35 to 50%-wt. In particular if readily dissolving matrix base ma-terials are used, such as acrylic ester copolymers, exceeding the saturation solubility by factor 2 or even about 5 to 10 can only be achieved with such an extremely high load of the system with ac-tive substance.
It is useful for the system not only to stabilize the active sub-stance against chemical degradation according to the present in-vention, but also to provide for a stabilization against physical age-ing-influences.
This is easily possible with the structure described herein. To this effect, the thermodynamically most stable form of the acetylsali-cylic acid, according to the latest knowledge that having a melting point of above 132°C (depending on the degree of purity about 139°C), is used in the manufacture, taking care in the production that always at least a small portion of the active substance, ho-mogenously divided, remains in this original crystal modification.
r~ 2172401 In extreme cases, it is sufficient to prepare a saturated solution of acetylsalicylic acid and the pharmaceutical auxiliary agents of the matrix base, to disperse therein in crystalline form only about 1 of the acetylsalicylic acid in stable modification, to dry this mass, and to combine it with further sheets andlor matrix components.
Besides the solvent-based production processes it is also possible to use hot-melt methods to manufacture the matrix layer(s), how-ever, in this case too, complete dissolution of the active substance particles must never occur during the process.
To sum it up it can be said that the present invention provides a TTS in which acetylsalicylic acid is present in undissolved form.
The production of a stabilizing phase of crystalline acetylsalicylic acid makes a sufficient stability at a maximum release rate to the skin possible.
Description of the drawings:
Fia. 1 : System according to the present invention having a sin _qle-layer matrix 1 - Backing layer which is impermeable to active substances 2 - Matrix with dissolved and crystalline active substance portion 3 - Removable protective layer.
Fig. 2: Svstem according to the~resent invention according to claim 3 1 - Backing layer which is impermeable to active substances 2 - Matrix with dissolved and crystalline active substance portion 3 - Removable protective layer 4 - Matrix layer ("adhesive layer") with smaller and less frequent acetylsalicylic acid crystals.
Fig. 3: System according to the present invention according to claim 4 1 - Backing layer which is impermeable to active substances 2 - Matrix with dissolved and crystalline active substance portion 3 - Removable protective layer 5 - Matrix layer remote from the skin with acetylsalicylic acid, consisting of a solution of the matrix components in a solvent remaining in the TTS.
The present invention relates to a transdermal therapeutic system for the release of acetylsalicylic acid and optional further sub-stances via the skin to the human body. The system that will be described has an increased chemical hydrolytic stability for the ac-tive substance acetylsalicylic acid.
Transdermal therapeutic systems (TTS) have been established on the market in the medicinal therapy of various diseases.
It is also known that the active substance acetylsalicylic acid has a basic permeativity through the human skin and is therefore suit-able as a component in transdermal therapeutic systems. Rougier et al. (J. Pharm. Sci. 176, 451-454, 1987) have already described that the acetylsalicylic acid-absorption rate into the skin depends (to a rather small extent) on the chosen skin area.
Chen et al. (Zhongguo Yiyuan Yaoxue Zazhi, Vol. 1 1, p. 245-247 (1991 ) give a report on a successful transdermal application of acetylsalicylic acid creams in children suffering from rheumatism.
JP 3 1 12 926 describes an agent for the percutaneous applica-tion, including actetylsalicylic acid, which agent is formed by dis-solution in water and addition of water-swellable additives and is finally used in a silicone polymer in dispersed form.
In this case, there is a great risk of hydrolysis due to the contact with water.
Acetylsalicylic acid has been introduced for some time and is a therapeutically effective drug having a high therapeutic index.
Used in very high doses (more than one gram per day) it is used as an antirheumatic agent, in mean doses (250 to 500 mg) as an :~
2172~~1 antipyretic/analgesic, and in a low dosage (30 to 150 mg per day) as a platelet aggregation inhibitor.
Acetylsalicylic acid already melts at a low temperature (about 139°C) and is noticeably volatile already at this temperature.
Acetylsalicylic acid exists in several polymorphous forms (modifications) which partly melt at only 100°C and also have dif-ferent dissolution behavior.
Because of the unstable ester grouping it is susceptible to hydroly-sis and transesterification. On the way to a stable administration form the following principles have to be observed in general:
- water, alcohols and esters as possible coreactants usually are unsuitable formulation components;
- for the same reason, in consideration of the law of mass ac-tion, it is useful to add potential reaction products, such as acetic acid or water-binding acetic anhydride as stabilizing components;
- since the hydrolysis proceeds slowest at a pH of about 2 to 3, adjustment to this acidity promotes stability;
- also, the use of additional stabilizing inactive ingredients is known, e.g., Luzzi and Ma (U.S.-Patent No. 4,228,162) re-commend to use dimethylisosorbide as stabilizing solvent.
No indications have been found in literature as to how this galenic problem can be applied to the technique of manufacturing a TTS.
First formulations wherein the TTS-matrix - following the state of the art - contained acetylsalicylic acid exclusively in dissolved form proved to be too unstable.
r:..
According to U.S.-Patent No. 4,286,592 a pharmaceutic active substance is used in crystalline form in a TTS in order to control the active substance release via an adhesive layer. A special ratio between the particle size of the crystals and the diffusion proper-ties is important in this case.
However, this application would only be used by those skilled in the art to limit an active substance flow but not for stabilization purposes with simultaneously maintaining the maximum possible release properties.
Although it is usual practice in some cases to load transdermal therapeutic systems with active substance to such a concentration that it crystallizes during the production after having been in com-plete solution initially (EP 0 156 080). By this a particularly long-lasting action is achieved. However, the method involves the dis-advantage that it is difficult to control the procedure of crystalliza-tion and that, in the absence of crystal nuclei, modifications hav-ing a limited storage period are frequently obtained. Thus, the product cannot be manufactured to meet the required pharmaceu-tical quality. Indications as to stabilize active substances by intro-ducing a high crystalline portion into transdermal therapeutic sys-tems cannot be found in literature.
It is the object of the present invention to provide a transdermal therapeutic system with acetylsalicylic acid, which has a sufficient pharmaceutical stability at the maximum achievable release rate to the skin under the circumstances.
According to the present invention this object is achieved by a transdermal therapeutic system comprising the active substance acetylsalicylic acid and optional further substances and having a layered structure consisting of a backing layer which is substan-tially impermeable to active substances and moisture and one or _ ~ 4 2172401 several matrix layers, with at least one of said matrix layers com-prising acetylsalicylic acid in mainly crystalline form.
Normally, an undesired limitation of the release properties in active substance crystals must be expected due to the fact that the dis-solution rate could become lower than the permeation into the skin. Most surprisingly, this is not the case, if according to the present invention - in addition to careful drying of the layered components of the transdermal therapeutic system or other known stabilizing measures - a stabilizing phase of crystalline acetylsali-cylic acid is formed already prior to coating and drying.
As a matter of fact, dry storage conditions are very useful to sta-bilize these properties since hydrolysis is repressed thereby. Such storage conditions can be ensured by gas and moisture resistant packing means and by insertion of one or more moisture-absorbing elements into the package.
The subject matter of the present invention will be illustrated in more detail in the following:
A characterizing and essential feature of the present invention is the presence of undissolved acetylsalicylic acid in a transdermal therapeutic system. In contrast to the prior art, at least a partial amount of the active substance employed prior to the drying pro-cess is maintained in an undissolved condition during the whole fabrication so that at least sufficient seed crystals of the stable ac-tive substance modification may come into the product. Thus, an only temporarily stable, oversaturated condition of the active sub-stance solution - possibly under precipitation of metastable sedi-ments - is avoided; this would involve high risks with respect to stability. In the course of time, uncontrolled recrystallizations will result in a product which no longer corresponds to the initial re-lease rate specification.
_.
,1 217240 The individual form of the present invention may vary within wide ranges. In the most simple case, the system of Figure 1 corre-sponds to a single-layer matrix having pressure sensitive adhesive properties to the skin. The system consists of a backing layer which is substantially impermeable to the active substance, the matrix layer, and a removable protective layer which is to be re-moved prior to application.
Numerous substances standing out for a particular resistance and diffusion stability may be used as backing layer (1 ), among these polyester. But nearly any other plastics suitable for the application on the skin may be used, such as polyvinyl chloride, ethylene vi-nylacetate, vinyl acetate, polyethylene, polypropylene, cellulose derivatives, and many others.ln particular cases an additional layer may be applied, e.g., by metallizing or vapor-plating with other additives forming a diffusion barrier, such as silicon dioxide, alu-minum oxide, and the like. Also, for better acceptance, the outer side of the backing layer is frequently coated with a cuticolor var-nish, or treated otherwise to improve the appearance.
The thickness of the film-like backing layer normally amounts to 8 to 80 Vim, depending - among others - on the stability and per-meability of the chosen material; however, for special purposes it may also be thicker or thinner.
Among others, copolymers comprising acrylic esters, mixtures of rubbers and resins, polyvinyl acetate, silicone polymers and many other base materials compatible with the skin are suitable for the use as matrix layer (2) of the patch according to the present in-vention. The addition of up to 40% of fillers, such as titanium di-oxide, zinc oxide, chalk, activated charcoal, finely divided silicon dioxide, etc. does by no means impair the function according to , .
i the present invention and may result in advantages with respect to the cohesion of the finished system.
The removable protective layer (3) is of less importance for the function; for instance, it may consist of a polyester material. How-ever, any other plastics suitable for the application on the skin may be used, such as polyvinyl chloride, ethylene vinylacetate, vi-nyl acetate, polyethylene, polypropylene, cellulose derivatives, and many others. In particular cases metallizing or vapor-plating with other diffusion-blocking additives, such as silicon dioxide, alumi-num oxide, and the like may be carried out. In any case, the sur-face facing the adhesive matrix must be treated with dehesive (release) materials, such as silicones or fluorine-containing plastics, so that the composite remains easily removable. The thickness of the film-like removable protective layer normally amounts to about 40 to 200 ,um; for special purposes it may be thicker or thinner.
Figure 2 shows as additional embodiment of the present invention the arrangement in two matrix layers, which is also possible; the adhesive layer (4) advantageously comprises smaller and less nu-merous active substance crystals. By this an improved adhesion to the skin can be achieved, as compared to a single-layer system.
With respect to the object of the present invention, it is not expe-dient to dispense completely with crystalline portions even in the adhesive layer, since the diffusion boundary layer could grow ex-cessively wide, resulting in a reduced flow into the skin.
The size of the acetylsalicylic acid crystals is of no importance with respect to the function of the principle according to the pres-ent invention and to the basic advantage of stabilization as such.
Smaller crystals having a diameter of below approximately 50 to 100 Nm are advantageous, if only because of the more homoge-nous visual appearance. If extremely slightly dissolving matrix .._ 217201 base materials, such as masses based on polyisobutylenes and larger crystal diameters (more than 300 ,cam) are used, a release control of the active substance through the skin may take place, involving the advantage that the release rate is controlled by the system, but involving the disadvantage that only part of the theo-retically achievable flow rate can be achieved.
Independently of the construction of the system, volatile additives may be added, e.g., 2-pyrrolidone, benzyl alcohol, butanol and other short-chain alcohols, triglycerides, cholesterol, cineole, delta-tocopherol, diethyleneglycol, diethyleneglycol monoethylether, di-isopropyl adipate, dimethyldecyl phosphoxide, dimethylisosorbide, dimethyllauroyl amide, dimethylsulfoxide, dodecylsulfoxide, acetic acid, ethyl acetate, and other aliphatic and aromatic esters, ethyl-ene glycol, ethyleneglycol monolaurate, and other esters and ethers of ethylene glycol or propylene glycol, 2-octyl dodecanol, thin-bodied paraffin, glycerol, glycerol monooleate, glycerol mono-stearate, hydrogenated castor oil, isopropyl myristate, isopropyl palmitate, lauric acid diethanolamide, menthol or other volatile ter-pene derivatives (which are mixture components of many natural ethereal oils), methyl benzoate, methyloctylsulfoxide, mono- or diethylacetamide, N,N-diethyl-m-toluamide , N-methylpyrrolidone,' 1-octanol and other volatile, medium-chain alcohols, octanoic acid and other medium-chain, aliphatic carboxylic acids, oleyl alcohol, olive oil, oleic acid, oleyl oleate, phenylethanol, propylene glycol, ricinoleic acid, triacetin, but also mixtures of these substances, e.g., oleic acid/propylene glycol.
In special cases, however, the reactivity of the active substance acetylsalicylic acid with esters and acids as well as alcohols must be taken into consideration; this limits the use of such substances.
However, the present invention limits the possible chemical reac-tion to the widest possible extent by means of compartments, thus it represents a stabilization advantage even in this respect.
2 i 72401 In this connection, one alternative is of particular advantage; in this case the matrix layer is divided into two portions to be lami-nated onto each other, both comprising acetylsalicylic acid in mainly crystalline form according to the present invention; one of said portions comprises a highly volatile ingredient (e.g., one of the substances listed in the above paragraph), which remains in the system as a solvent for the residual components, and has been laminated with the second portion of the matrix layer during the production. Thus, after migration of the highly volatile compo-nent, a system having sufficient shear strength and comprising high-volatile additives can be obtained.
The acetylsalicylic acid content of the total matrix of the trans-dermal therapeutic system according to the present invention suit-ably amounts to about 15 to 60%-wt., preferably it is of the order of 35 to 50%-wt. In particular if readily dissolving matrix base ma-terials are used, such as acrylic ester copolymers, exceeding the saturation solubility by factor 2 or even about 5 to 10 can only be achieved with such an extremely high load of the system with ac-tive substance.
It is useful for the system not only to stabilize the active sub-stance against chemical degradation according to the present in-vention, but also to provide for a stabilization against physical age-ing-influences.
This is easily possible with the structure described herein. To this effect, the thermodynamically most stable form of the acetylsali-cylic acid, according to the latest knowledge that having a melting point of above 132°C (depending on the degree of purity about 139°C), is used in the manufacture, taking care in the production that always at least a small portion of the active substance, ho-mogenously divided, remains in this original crystal modification.
r~ 2172401 In extreme cases, it is sufficient to prepare a saturated solution of acetylsalicylic acid and the pharmaceutical auxiliary agents of the matrix base, to disperse therein in crystalline form only about 1 of the acetylsalicylic acid in stable modification, to dry this mass, and to combine it with further sheets andlor matrix components.
Besides the solvent-based production processes it is also possible to use hot-melt methods to manufacture the matrix layer(s), how-ever, in this case too, complete dissolution of the active substance particles must never occur during the process.
To sum it up it can be said that the present invention provides a TTS in which acetylsalicylic acid is present in undissolved form.
The production of a stabilizing phase of crystalline acetylsalicylic acid makes a sufficient stability at a maximum release rate to the skin possible.
Description of the drawings:
Fia. 1 : System according to the present invention having a sin _qle-layer matrix 1 - Backing layer which is impermeable to active substances 2 - Matrix with dissolved and crystalline active substance portion 3 - Removable protective layer.
Fig. 2: Svstem according to the~resent invention according to claim 3 1 - Backing layer which is impermeable to active substances 2 - Matrix with dissolved and crystalline active substance portion 3 - Removable protective layer 4 - Matrix layer ("adhesive layer") with smaller and less frequent acetylsalicylic acid crystals.
Fig. 3: System according to the present invention according to claim 4 1 - Backing layer which is impermeable to active substances 2 - Matrix with dissolved and crystalline active substance portion 3 - Removable protective layer 5 - Matrix layer remote from the skin with acetylsalicylic acid, consisting of a solution of the matrix components in a solvent remaining in the TTS.
Claims (8)
1. A transdermal therapeutic system comprising the active substance acetylsalicylic acid, having a layered structure consisting of a backing layer which is substantially impermeable to active substances and moisture, and one or several active substance-containing matrix layers, at least one of said matrix layers comprising acetylsalicylic acid predominantly in crystalline form, and a removable protective layer, characterized by its production, whereby the acetylsalicylic acid, in a suspension or solution or a melt of the matrix base material selected from the group consisting of acrylic acid ester-containing copolymers, mixtures of rubbers and resins, and polyvinyl acetate, is applied in one layer to said protective layer and is then dried, whereupon the layer is covered by applying a backing layer which is substantially impermeable to active substances and moisture, and the resulting substrate is separated by contour punching or film cutting into separate TTS, and the separated TTS are packed in packaging means sealed in a gas-tight manner, and the packing material withdraws moisture from the transdermal therapeutic system by means of water-absorbing means.
2. The transdermal therapeutic system according to claim 1, characterized in that at least a partial amount of the active substance used prior to the production process is maintained in undissolved, crystalline condition during the whole fabrication so that a sufficient number of seed crystals of the active substance comes into the system.
3. The transdermal therapeutic system according to claim 1 characterized in that acetylsalicylic acid is used which is present as stable, anhydrous modification in crystalline form melting above 132°C.
4. The transdermal therapeutic system according to claim 1 comprising a first matrix layer and a second matrix layer, wherein the first matrix layer faces the skin and is pressure sensitive adhesive, and the second matrix layer is remote from the skin, and comprises anhydrous acetylsalicylic acid in crystalline form, whereas the first matrix layer, comprises fewer acetylsalicylic acid crystals than the second matrix layer.
5. The transdermal therapeutic system according to claim 4, characterized in that both matrix layers comprise anhydrous acetylsalicylic acid in crystalline form and that the second matrix layer which is remote from the skin is the product of a solution of the matrix components in a solvent permanently remaining in the TTS.
6. The transdermal therapeutic system according to any one of claims 1 to 5 characterized in that the portion of acetylsalicylic acid in the matrix material amounts to 15 to 60%-wt., based on the total matrix.
7. The transdermal therapeutic system according to claim 5 characterized in that the solvent comprises permeation enhancers.
8. The transdermal therapeutic system according to claim 6, characterized in that the portion of acetylsalicylic acid in the matrix material amounts to 35 to 50%
wt., based on the total matrix.
wt., based on the total matrix.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4332093.7 | 1993-09-22 | ||
| DE4332093A DE4332093C2 (en) | 1993-09-22 | 1993-09-22 | Transdermal therapeutic system with the active ingredient acetylsalicylic acid and process for its preparation |
| PCT/EP1994/003106 WO1995008330A1 (en) | 1993-09-22 | 1994-09-16 | Transdermal therapeutic system with acetylsalicylic acid as active substance |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2172401A1 CA2172401A1 (en) | 1995-03-30 |
| CA2172401C true CA2172401C (en) | 2005-11-15 |
Family
ID=35520907
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002172401A Expired - Fee Related CA2172401C (en) | 1993-09-22 | 1994-09-16 | Transdermal therapeutic system with acetylsalicylic acid as active substance |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2172401C (en) |
-
1994
- 1994-09-16 CA CA002172401A patent/CA2172401C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2172401A1 (en) | 1995-03-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20130917 |