CA2197865C - Oestradiol-containing transdermal therapeutic system comprising hydrophylic additives - Google Patents
Oestradiol-containing transdermal therapeutic system comprising hydrophylic additives Download PDFInfo
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- CA2197865C CA2197865C CA002197865A CA2197865A CA2197865C CA 2197865 C CA2197865 C CA 2197865C CA 002197865 A CA002197865 A CA 002197865A CA 2197865 A CA2197865 A CA 2197865A CA 2197865 C CA2197865 C CA 2197865C
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- transdermal therapeutic
- estradiol
- therapeutic system
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- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
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- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
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- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
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- General Health & Medical Sciences (AREA)
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- Diabetes (AREA)
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Abstract
A transdermal therapeutic system with the active substance es-tradiol and, optionally, additional active substances and with a water-binding additive, having a layered structure of a backing layer which is impermeable to active substances and moisture, an active substance-containing matrix layer, and, if necessary, a re-movable protective layer, is characterized by the fact that the water-binding additive is a component of the matrix.
Description
21978~~
Estradiol-TTS havin4 water-binding additives SPECIFICATION
The present invention relates to a transdermal therapeutic system with the active substance estradiol and, optionally, additional ac-tive substances as well as a water-binding additive substance, and with a layered structure of a backing layer which is impermeable to active substances and moisture, an active substance-containing matrix layer, and, in case of need, a removable protective layer covering the matrix layer.
In the pharmaceutical therapy of several diseases, Transdermal Therapeutic Systems (TTS) have been introduced on the market for some time now.
In the following the term "estradiol" is to be understood as the anhydrous substance of 17-~3-estradiol in dissolved or crystalline (anhydrate) form.
In the meantime, TTSs comprising the active substance estradiol have been on the market as therapeutic agent for climacteric com-plaints, and, since a short time ago, also against osteoporosis;
they have proved successful in therapy.
A disadvantage of prior art systems is the insufficient capability of the active substance to permeate through the skin. This cannot be increased beyond a certain limit; the so-called "saturation flow", although several galenic measures with respect to the TTS-con-struction have been taken (use of multilayer systems, use of con-trolling membranes, variation of the active substance 219'865 concentration, modification of the base polymer, and the like).
This finding, i.e., that the transdermal flow of an active substance from the solid, finely dispersed phase cannot be increased further in principle, even if high-dissolving vehicles are used, can already be found in the trailblazing works of Higuchi, e.g., T. Higuchi:
Physical Chemical Analysis of percutaneous process from creams and ointments. J. Soc. Cosmetic Chem. 11, p. 85-97 (1960).
The systems described in EP 0 421 454 comprise estradiol in an acrylate polymer under addition of "crystallization inhibitors" and tackifying resins. Swelling agents are contained to give protection against premature loss of adhesive force.
With a lot of active substances, so-called "enhancers" may be added to the TTS during production. These are usually liquid ad-mixtures improving the absorption properties of human skin; for this reason, they allow the absorption of the active substance from a sufficiently small TTS-surface. In particular readily volatile enhancers, e.g., ethanol used for the active substance estradiol, involve the problem of softening the TTS's adhesive layers to a great extent; above all they require additional bulky compartments in the system, rendering the TTS unacceptably thick. Finally, any additional non-polymeric additive involves the risk of incompatibil-ity reactions on the skin, possibly even that of sensitization. The addition of certain less volatile, however, mostly less active en-hancers (e.g., glycerol esters, cyclic amides, eucalyptol) allows the production of matrix systems comprising the active substance and the absorption-promoting component in one or several monolithic layers.
US 4 863 738 represents one of many examples claiming the ap-plication of active substances, e.g., estradiol, together with a certain enhancer (in this case glycerol monooleate) in an optional TTS-matrix and in an optional concentration.
According to the art, these TTSs do not permit a satisfactory ther-apy either. The reason is that either the active enhancers are poorly tolerated by the skin or that the systems require unac-ceptably large surfaces owing to the still insufficient flow through the skin.
Another possibility of increasing the active substance flow through the skin is that an amount of active substance is dissolved molecularly disperse in the TTS, which exceeds that corresponding to the saturation solubility. With supersaturation of these systems the permeation rate of the skin increases to the same extent.
However, since such states are thermodynamically unstable, these forms of administration are not stable in storage; unforeseeable recrystallization of active substance particles will take place so that the flow rate through the skin gradually decreases to the sat-uration flow level; depending on the starting concentration, this results in losing a great portion of the initially existent therapeutic activity.
This process is a characteristic of estradiol.
At room temperature and normal relative air humidity (20-60%
relative humidity), estradiol i~ not present in ohe of the two known anhydric modifications (I and II) but as a semihydrate (Busetti and Hospital, Acta Cryst. 1972, B28, 5601. Owing to the layered structure stabilized via hydrogen bridges, and because of the dif-fusional compactness of the crystal compound, the semihydrate can be subjected to a short-term heat treatment to .temperatures of about 170°C without decomposition thereof (Kuhnert-Brand-statter and Winkler (1976) Scientia Pharmaceutics 44 (3), 177-190). However, the anhydrous form can quantitatively be obtained already at about 120°C by way of enlarging the crystal surface by means of micronizing. According to own observations, the trans-formation already takes place at about 90°C if heating is con-ducted very slowly (0.2-1 K/min) and in case of a particularly fine-crystalline substance.
219'~8fi5 With decreasing partial water vapor pressure, on the other hand, estradiol has a higher solubility in some polymers, particularly in polyacrylates. According to Fick's law, higher concentrations with otherwise same conditions increase the diffusion flow through the skin; for this reason such a concentration increase is very desir-able in transdermal therapeutic systems. However, the water in-troduced with the estradiol-semihydrate is already sufficient to ini-tiate gradual recrystallization from the solution as estradiol-semi-hydrate (Kuhnert-Brandstatter and Winkler (1976) Scientia Phar-maceutica 44 (3), 177-190). After crystallization, the flow rate from the system to the skin considerably decreases with the di-minishing concentration.
Taking into account these circumstances, transdermal therapeutic systems are known that offer a pharmacotherapeutically satisfying solution by exactly regulating the concentration to little less than the saturation solubility of the estradiol-anhydrate (DE-PS 42 37 453) or by using partially undissolved, disperse estradiol-anhydrate (DE-PS 42 23 360).
Even in consideration of this state of the art, it is important to maintain a sufficiently low atmospheric humidity during production and storage of an estradiol-TTS in order to avoid large-area pre-cipitation of the poorly soluble estradiol-semihydrate. To this end, a waterproof package having a low water-vapor permeability can be used in principle. However, owing to the low estradiol concen-tration contained in today's TTSs, very small amounts of humidity are sufficient to cause precipitation of the estradiol-semihydrate.
If, for example, 2 mg of anEstradiol (anhydrous) are present in a TTS in dissolved form, an amount of only 66.1 erg of water can cause complete precipitation. Using conventional packaging means, it is therefore very difficult to exclude entry of such small quantities of moisture over storage periods of several years.
~19'~~fi~
DE 42 37 453 already proposes to use desiccants in the ready-for-storage package; however, there are no indications with respect to using the water-binding additive as a component of the matrix.
Accordingly, it is the object of the present invention to provide a transdermal therapeutic system comprising estradiol, that protects the system in the package during storage against precipitation of the estradiol-semihydrate, and which, if required, is suitable for a matrix which comprises more active substance in a molecularly disperse dissolved form than corresponds to the saturation solubil-ity.
In a transdermal therapeutic system of the kind mentioned in the introductory part of claim 1, this object is achieved with the pres-ent invention by the fact that the water-binding additive substance is a constituent of the matrix.
Integrating water-binding mineral components in the substance of the matrix according to the present invention can be realized in a TTS in different manners: the most simple form is a single-layer matrix system the matrix of which simultaneously has a pressure-sensitive adhesive function, rendering an additional adhesive layer superfluous.
The mineral components that are contained in the matrix in dis-solved form or which are usually dispersed in solid phase, ensure an equilibrium-moisture content over the storage period that is low enough to render precipitation of the estradiol-semihydrate impos-sible.
If direct contact of the skin with the mineral particles is to be avoided, only the matrix is provided with water-binding mineral components and an adhesive layer which faces the skin and is free from particulate estradiol is applied by lamination.
~l9~ss~
If a membrane which is hardly permeable to estradiol is introduced between such a matrix, which comprises estradiol and water-binding mineral constituents, and the adhesive layer, a modified active substance release is achieved.
In addition to the wide-spread acrylic-acid ester copolymers suit-able for the use with estradiol, other polymers may also be used as base material, for example, polyisobutylene, polyvinyl acetate, and copolymers, synthetic rubber, silicones.
In any case, the characterizing feature of transdermal therapeutic systems according to the present invention is the presence of water-binding mineral components in the matrix. In this connec-tion, the exact amount of said additives in the matrix must be suf-ficiently large since this increases the total moisture-binding ca-pacity in the system. The exact amount of added substances will result for the skilled artisan in a comprehensible manner from the component's binding power for water. Since the water-binding capacity of most of the following exemplary substances generally lies above that of estradiol, an addition in the range of the estra-diol contained - about 1 to 2 percent - may be considered as minimum amount. The upper limit is determined by mechanical values, such as flowability of the matrix, adhesive force, and processibility. In general, a proportion of 10 to 50 percent by weight, preferably between 20 and 35 percent by weight is de-sired.
The following substances may be used as water-binding mineral components, e.g., zinc oxide, silicon dioxide, silica gel (also in modified, e.g., hydrophobized form), talc, phosphorus pentaoxide, alumina, aluminum phosphate, magnesium oxide and hydroxide, calcium oxide and hydroxide; kaolin, molecular sieves, sodium oxide, calcium and magnesium carbonate, magnesium sulfate, calcium sulfate, copper sulfate, manganese oxides, silicates, aluminates, or magnesium perchlorate In this connection, it must be considered that both chemico-reactive processes, such as the reaction of magnesium oxide to magnesium hydroxide, and the physical changes, e.g., inclusion of crystal water into initially anhydrous sodium sulfate, calcium sulfate, or calcium chloride, or also pure, nonstoichiometric hygroscopy or adsorptivity can be utilized; these are commonly known as such to the skilled artisan.
Substances having a high water-binding capacity in case of low humidity (in the range of below about 5% relative humidity) are preferably used. In addition, a high degree of physiological compatibility is desired Fortunately, many hydrates of salts of the alkaline earth metals and alkali metals comply with these conditions, for example, calcium and magnesium carbonate, calcium, sodium, and magnesium sulfate, or many silicates, aluminates, borates, and phosphates of the alkali metals (preferably sodium, potassium, lithium) and alkaline earth metals (calcium and magnesium).
In one embodiment, the present invention provides a transdermal therapeutic system with the active substance estradiol and, optionally, further active substances and, optionally, water-binding additives, having a layered structure comprising a backing layer which is impermeable to active substances and moisture, an active substance-containing matrix layer, and, optionally, a removable protective layer, characterised in that the matrix contains the active substance as water-free estradiol, together with a water-binding additive, said water-binding additive ensuring an equilibrium moisture which prevents the precipitation of estradiol semihydrate.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the matrix exhibits several active substance-containing taming 21290894.1 layers and that at least one of these layers comprises a pharmaceutically acceptable, water-binding mineral additive.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the matrix material comprises the water-binding additive substance in finely dispersed suspension.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the water-binding additive substance is a mineral.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the water-binding additive is the anhydrate of an alkaline-earth or alkali metal salt In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the water-binding additive is the semihydrate or anhydrate ("anhydrite") of calcium sulfate.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the estradiol is present as dispersion of an anhydrous crystallizate.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that more estradiol is comprised in the matrix base material in molecularly disperse dissolved form than corresponds to the saturation solubility.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the proportion of the mineral water-binding additive in the total matrix material amounts to between 1 and 40%-wt., and preferably to 20%-wt.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the matrix base material is a polymer which, under water-free 21290894.1 conditions, has a solubility for the active substance estradiol of between 0.4 and 3.0%
(w/w).
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the matrix base material is a polyacrylate polymer.
In a further embodiment, the present invention provides a process for the production of the transdermal therapeutic system, characterized by the steps:
- preparing a suspension of estradiol-semihydrate and water-binding mineral additive in a solution, dispersion, or melt of the matrix base material, - using this suspension, applying a layer on a sheet-like substrate, - carrying out a conversion of estradiol-semihydrate into anhydrous estradiol in the layer by heating to 90 to 175°C
In an additional embodiment, the process of the present invention is characterized in that the dry layer is heated to 90 to 200°C until a conversion of the hydrous form of the mineral water-binding additive into its anhydrous form has taken place.
In an additional embodiment, the process of the present invention is characterized in that the transdermal therapeutic system is packed into a moistureproof package which comprises a desiccant, if required.
21290894.1 Examples:
Example 1: Production of a system according to the present invention.
2.0 g of 17-(3-estradiol-semihydrate, micronized 60.0 g of CariflexR TR 1107 (styrene-isoprene-styrene block co-polymer) 21290894.1 10 i2a.0 g at Staybelite Ester 5E: ttE~ermoptastic ester gum of toiaphony dari~ratiuesi S4 g of uiscous paraffin S~ g of rslclum sulfate dihydrate are molten in an evacuatable krfeader at 13U°C and brougi~t into . _. , , an extemaily homogeneous form try means of kneading wltt~in ten hours. Under ~ecuurn Mess than 0.02 tsar! heating to 9 65°C i$ ef- ' fectcd far ans hourr while doing so Crygtai water Is driven off the , . active subsiarvce and aaicium sulfate by meant of kneading. , Tfie melt is coolcsl dawn to 120°~; in a continuous coating Line it is subsequently coated ants a siiicarrfaed polyester film of 300 ~rcn thicknøss in such a manner that the weight per ur~it area of the Eager amounts to 200 glm~.
Afterwards g polyest~sr film t5 arm thick is appiied ~aminatedf un-der rot! pressure on the still hot layer, avoidic~g the formation of air hubbies.
TransdermaE systems of 16 Gm' are obtaEned by parching using s vsr2~d punci~.
Exampie 2: Production of a system according to the present En' rrentlon 3.0 g of 't7-~i-estradloE~semlhydrata, micronized , '40b.0 g of acrylic-aold ester copr~lymer solutECn isaEids content b 09~ wlw~
70.0 g of cglcium sulfate, anhydrous ("anhydrite"1 are stirred at roam temperature In a cylindrical glass vessel until a homogeneous suspension is aE~tairrad. Afterwards coating 1s ef~
farted at a slit width of 500pm onto a t~Dpm slliconlzed polyes~
tar fHm. Ztxa cis died a~?S.°yC. at 50°C, at 8d'C an4 at 95°C, each r;~_for I~0 ~aiauces.. A ~5~m poly~gtBrfilm Es immediately applied ~a ~i8minated~ on the dry layer tinder roller pressure, avpiding tha forrnatlon of aEr bu>?bles.
Trsnsdermal systems of t 0 cm' ars obtained by p~unchln~ usErig a wad punch. The3e are tracked into ~ composite packaging material of.paperlaluminum foillhflt-sealing layer under addition of a desic-cant tablet cflmprising 0.3 g of calcium sulfate ~prevloualy pret~ried ~t ~ 80°C~. ~ ~ - . . ' . . _ , .
c ~:
.:~, ..
Estradiol-TTS havin4 water-binding additives SPECIFICATION
The present invention relates to a transdermal therapeutic system with the active substance estradiol and, optionally, additional ac-tive substances as well as a water-binding additive substance, and with a layered structure of a backing layer which is impermeable to active substances and moisture, an active substance-containing matrix layer, and, in case of need, a removable protective layer covering the matrix layer.
In the pharmaceutical therapy of several diseases, Transdermal Therapeutic Systems (TTS) have been introduced on the market for some time now.
In the following the term "estradiol" is to be understood as the anhydrous substance of 17-~3-estradiol in dissolved or crystalline (anhydrate) form.
In the meantime, TTSs comprising the active substance estradiol have been on the market as therapeutic agent for climacteric com-plaints, and, since a short time ago, also against osteoporosis;
they have proved successful in therapy.
A disadvantage of prior art systems is the insufficient capability of the active substance to permeate through the skin. This cannot be increased beyond a certain limit; the so-called "saturation flow", although several galenic measures with respect to the TTS-con-struction have been taken (use of multilayer systems, use of con-trolling membranes, variation of the active substance 219'865 concentration, modification of the base polymer, and the like).
This finding, i.e., that the transdermal flow of an active substance from the solid, finely dispersed phase cannot be increased further in principle, even if high-dissolving vehicles are used, can already be found in the trailblazing works of Higuchi, e.g., T. Higuchi:
Physical Chemical Analysis of percutaneous process from creams and ointments. J. Soc. Cosmetic Chem. 11, p. 85-97 (1960).
The systems described in EP 0 421 454 comprise estradiol in an acrylate polymer under addition of "crystallization inhibitors" and tackifying resins. Swelling agents are contained to give protection against premature loss of adhesive force.
With a lot of active substances, so-called "enhancers" may be added to the TTS during production. These are usually liquid ad-mixtures improving the absorption properties of human skin; for this reason, they allow the absorption of the active substance from a sufficiently small TTS-surface. In particular readily volatile enhancers, e.g., ethanol used for the active substance estradiol, involve the problem of softening the TTS's adhesive layers to a great extent; above all they require additional bulky compartments in the system, rendering the TTS unacceptably thick. Finally, any additional non-polymeric additive involves the risk of incompatibil-ity reactions on the skin, possibly even that of sensitization. The addition of certain less volatile, however, mostly less active en-hancers (e.g., glycerol esters, cyclic amides, eucalyptol) allows the production of matrix systems comprising the active substance and the absorption-promoting component in one or several monolithic layers.
US 4 863 738 represents one of many examples claiming the ap-plication of active substances, e.g., estradiol, together with a certain enhancer (in this case glycerol monooleate) in an optional TTS-matrix and in an optional concentration.
According to the art, these TTSs do not permit a satisfactory ther-apy either. The reason is that either the active enhancers are poorly tolerated by the skin or that the systems require unac-ceptably large surfaces owing to the still insufficient flow through the skin.
Another possibility of increasing the active substance flow through the skin is that an amount of active substance is dissolved molecularly disperse in the TTS, which exceeds that corresponding to the saturation solubility. With supersaturation of these systems the permeation rate of the skin increases to the same extent.
However, since such states are thermodynamically unstable, these forms of administration are not stable in storage; unforeseeable recrystallization of active substance particles will take place so that the flow rate through the skin gradually decreases to the sat-uration flow level; depending on the starting concentration, this results in losing a great portion of the initially existent therapeutic activity.
This process is a characteristic of estradiol.
At room temperature and normal relative air humidity (20-60%
relative humidity), estradiol i~ not present in ohe of the two known anhydric modifications (I and II) but as a semihydrate (Busetti and Hospital, Acta Cryst. 1972, B28, 5601. Owing to the layered structure stabilized via hydrogen bridges, and because of the dif-fusional compactness of the crystal compound, the semihydrate can be subjected to a short-term heat treatment to .temperatures of about 170°C without decomposition thereof (Kuhnert-Brand-statter and Winkler (1976) Scientia Pharmaceutics 44 (3), 177-190). However, the anhydrous form can quantitatively be obtained already at about 120°C by way of enlarging the crystal surface by means of micronizing. According to own observations, the trans-formation already takes place at about 90°C if heating is con-ducted very slowly (0.2-1 K/min) and in case of a particularly fine-crystalline substance.
219'~8fi5 With decreasing partial water vapor pressure, on the other hand, estradiol has a higher solubility in some polymers, particularly in polyacrylates. According to Fick's law, higher concentrations with otherwise same conditions increase the diffusion flow through the skin; for this reason such a concentration increase is very desir-able in transdermal therapeutic systems. However, the water in-troduced with the estradiol-semihydrate is already sufficient to ini-tiate gradual recrystallization from the solution as estradiol-semi-hydrate (Kuhnert-Brandstatter and Winkler (1976) Scientia Phar-maceutica 44 (3), 177-190). After crystallization, the flow rate from the system to the skin considerably decreases with the di-minishing concentration.
Taking into account these circumstances, transdermal therapeutic systems are known that offer a pharmacotherapeutically satisfying solution by exactly regulating the concentration to little less than the saturation solubility of the estradiol-anhydrate (DE-PS 42 37 453) or by using partially undissolved, disperse estradiol-anhydrate (DE-PS 42 23 360).
Even in consideration of this state of the art, it is important to maintain a sufficiently low atmospheric humidity during production and storage of an estradiol-TTS in order to avoid large-area pre-cipitation of the poorly soluble estradiol-semihydrate. To this end, a waterproof package having a low water-vapor permeability can be used in principle. However, owing to the low estradiol concen-tration contained in today's TTSs, very small amounts of humidity are sufficient to cause precipitation of the estradiol-semihydrate.
If, for example, 2 mg of anEstradiol (anhydrous) are present in a TTS in dissolved form, an amount of only 66.1 erg of water can cause complete precipitation. Using conventional packaging means, it is therefore very difficult to exclude entry of such small quantities of moisture over storage periods of several years.
~19'~~fi~
DE 42 37 453 already proposes to use desiccants in the ready-for-storage package; however, there are no indications with respect to using the water-binding additive as a component of the matrix.
Accordingly, it is the object of the present invention to provide a transdermal therapeutic system comprising estradiol, that protects the system in the package during storage against precipitation of the estradiol-semihydrate, and which, if required, is suitable for a matrix which comprises more active substance in a molecularly disperse dissolved form than corresponds to the saturation solubil-ity.
In a transdermal therapeutic system of the kind mentioned in the introductory part of claim 1, this object is achieved with the pres-ent invention by the fact that the water-binding additive substance is a constituent of the matrix.
Integrating water-binding mineral components in the substance of the matrix according to the present invention can be realized in a TTS in different manners: the most simple form is a single-layer matrix system the matrix of which simultaneously has a pressure-sensitive adhesive function, rendering an additional adhesive layer superfluous.
The mineral components that are contained in the matrix in dis-solved form or which are usually dispersed in solid phase, ensure an equilibrium-moisture content over the storage period that is low enough to render precipitation of the estradiol-semihydrate impos-sible.
If direct contact of the skin with the mineral particles is to be avoided, only the matrix is provided with water-binding mineral components and an adhesive layer which faces the skin and is free from particulate estradiol is applied by lamination.
~l9~ss~
If a membrane which is hardly permeable to estradiol is introduced between such a matrix, which comprises estradiol and water-binding mineral constituents, and the adhesive layer, a modified active substance release is achieved.
In addition to the wide-spread acrylic-acid ester copolymers suit-able for the use with estradiol, other polymers may also be used as base material, for example, polyisobutylene, polyvinyl acetate, and copolymers, synthetic rubber, silicones.
In any case, the characterizing feature of transdermal therapeutic systems according to the present invention is the presence of water-binding mineral components in the matrix. In this connec-tion, the exact amount of said additives in the matrix must be suf-ficiently large since this increases the total moisture-binding ca-pacity in the system. The exact amount of added substances will result for the skilled artisan in a comprehensible manner from the component's binding power for water. Since the water-binding capacity of most of the following exemplary substances generally lies above that of estradiol, an addition in the range of the estra-diol contained - about 1 to 2 percent - may be considered as minimum amount. The upper limit is determined by mechanical values, such as flowability of the matrix, adhesive force, and processibility. In general, a proportion of 10 to 50 percent by weight, preferably between 20 and 35 percent by weight is de-sired.
The following substances may be used as water-binding mineral components, e.g., zinc oxide, silicon dioxide, silica gel (also in modified, e.g., hydrophobized form), talc, phosphorus pentaoxide, alumina, aluminum phosphate, magnesium oxide and hydroxide, calcium oxide and hydroxide; kaolin, molecular sieves, sodium oxide, calcium and magnesium carbonate, magnesium sulfate, calcium sulfate, copper sulfate, manganese oxides, silicates, aluminates, or magnesium perchlorate In this connection, it must be considered that both chemico-reactive processes, such as the reaction of magnesium oxide to magnesium hydroxide, and the physical changes, e.g., inclusion of crystal water into initially anhydrous sodium sulfate, calcium sulfate, or calcium chloride, or also pure, nonstoichiometric hygroscopy or adsorptivity can be utilized; these are commonly known as such to the skilled artisan.
Substances having a high water-binding capacity in case of low humidity (in the range of below about 5% relative humidity) are preferably used. In addition, a high degree of physiological compatibility is desired Fortunately, many hydrates of salts of the alkaline earth metals and alkali metals comply with these conditions, for example, calcium and magnesium carbonate, calcium, sodium, and magnesium sulfate, or many silicates, aluminates, borates, and phosphates of the alkali metals (preferably sodium, potassium, lithium) and alkaline earth metals (calcium and magnesium).
In one embodiment, the present invention provides a transdermal therapeutic system with the active substance estradiol and, optionally, further active substances and, optionally, water-binding additives, having a layered structure comprising a backing layer which is impermeable to active substances and moisture, an active substance-containing matrix layer, and, optionally, a removable protective layer, characterised in that the matrix contains the active substance as water-free estradiol, together with a water-binding additive, said water-binding additive ensuring an equilibrium moisture which prevents the precipitation of estradiol semihydrate.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the matrix exhibits several active substance-containing taming 21290894.1 layers and that at least one of these layers comprises a pharmaceutically acceptable, water-binding mineral additive.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the matrix material comprises the water-binding additive substance in finely dispersed suspension.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the water-binding additive substance is a mineral.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the water-binding additive is the anhydrate of an alkaline-earth or alkali metal salt In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the water-binding additive is the semihydrate or anhydrate ("anhydrite") of calcium sulfate.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the estradiol is present as dispersion of an anhydrous crystallizate.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that more estradiol is comprised in the matrix base material in molecularly disperse dissolved form than corresponds to the saturation solubility.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the proportion of the mineral water-binding additive in the total matrix material amounts to between 1 and 40%-wt., and preferably to 20%-wt.
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the matrix base material is a polymer which, under water-free 21290894.1 conditions, has a solubility for the active substance estradiol of between 0.4 and 3.0%
(w/w).
In an additional embodiment, the transdermal therapeutic system of the present invention is characterized in that the matrix base material is a polyacrylate polymer.
In a further embodiment, the present invention provides a process for the production of the transdermal therapeutic system, characterized by the steps:
- preparing a suspension of estradiol-semihydrate and water-binding mineral additive in a solution, dispersion, or melt of the matrix base material, - using this suspension, applying a layer on a sheet-like substrate, - carrying out a conversion of estradiol-semihydrate into anhydrous estradiol in the layer by heating to 90 to 175°C
In an additional embodiment, the process of the present invention is characterized in that the dry layer is heated to 90 to 200°C until a conversion of the hydrous form of the mineral water-binding additive into its anhydrous form has taken place.
In an additional embodiment, the process of the present invention is characterized in that the transdermal therapeutic system is packed into a moistureproof package which comprises a desiccant, if required.
21290894.1 Examples:
Example 1: Production of a system according to the present invention.
2.0 g of 17-(3-estradiol-semihydrate, micronized 60.0 g of CariflexR TR 1107 (styrene-isoprene-styrene block co-polymer) 21290894.1 10 i2a.0 g at Staybelite Ester 5E: ttE~ermoptastic ester gum of toiaphony dari~ratiuesi S4 g of uiscous paraffin S~ g of rslclum sulfate dihydrate are molten in an evacuatable krfeader at 13U°C and brougi~t into . _. , , an extemaily homogeneous form try means of kneading wltt~in ten hours. Under ~ecuurn Mess than 0.02 tsar! heating to 9 65°C i$ ef- ' fectcd far ans hourr while doing so Crygtai water Is driven off the , . active subsiarvce and aaicium sulfate by meant of kneading. , Tfie melt is coolcsl dawn to 120°~; in a continuous coating Line it is subsequently coated ants a siiicarrfaed polyester film of 300 ~rcn thicknøss in such a manner that the weight per ur~it area of the Eager amounts to 200 glm~.
Afterwards g polyest~sr film t5 arm thick is appiied ~aminatedf un-der rot! pressure on the still hot layer, avoidic~g the formation of air hubbies.
TransdermaE systems of 16 Gm' are obtaEned by parching using s vsr2~d punci~.
Exampie 2: Production of a system according to the present En' rrentlon 3.0 g of 't7-~i-estradloE~semlhydrata, micronized , '40b.0 g of acrylic-aold ester copr~lymer solutECn isaEids content b 09~ wlw~
70.0 g of cglcium sulfate, anhydrous ("anhydrite"1 are stirred at roam temperature In a cylindrical glass vessel until a homogeneous suspension is aE~tairrad. Afterwards coating 1s ef~
farted at a slit width of 500pm onto a t~Dpm slliconlzed polyes~
tar fHm. Ztxa cis died a~?S.°yC. at 50°C, at 8d'C an4 at 95°C, each r;~_for I~0 ~aiauces.. A ~5~m poly~gtBrfilm Es immediately applied ~a ~i8minated~ on the dry layer tinder roller pressure, avpiding tha forrnatlon of aEr bu>?bles.
Trsnsdermal systems of t 0 cm' ars obtained by p~unchln~ usErig a wad punch. The3e are tracked into ~ composite packaging material of.paperlaluminum foillhflt-sealing layer under addition of a desic-cant tablet cflmprising 0.3 g of calcium sulfate ~prevloualy pret~ried ~t ~ 80°C~. ~ ~ - . . ' . . _ , .
c ~:
.:~, ..
Claims (18)
1. A transdermal therapeutic system with the active substance estradiol and, optionally, further active substances and water-binding additives, having a layered structure comprising a backing layer which is impermeable to active substances and moisture, an active substance-containing matrix layer, and, optionally, a removable protective layer, characterised in that the matrix contains the active substance as water-free estradiol, together with a water-binding mineral additive, said water-binding mineral additive ensuring an equilibrium moisture which prevents the precipitation of estradiol semihydrate.
2. The transdermal therapeutic system according to claim 1 characterized in that the matrix exhibits several active substance-containing taming layers and that at least one of these layers comprises a pharmaceutically acceptable, water-binding mineral additive.
3. The transdermal therapeutic system according to claim 1 or 2 characterized in that the matrix material comprises the water-binding additive substance in finely dispersed suspension.
4. The transdermal therapeutic system according to any one of claims 1 to 3 characterized in that the water-binding additive is the anhydrite of an alkaline-earth or alkali metal salt.
5. The transdermal therapeutic system according to any one of claims 1 to 4 characterized in that the water-binding additive is the semihydrate or anhydrite ("anhydrite") of calcium sulfate.
6. The transdermal therapeutic system according to any one of claims 1 to 5 characterized in that the estradiol is present as dispersion of an anhydrous crystallizate.
7. The transdermal therapeutic system according to any one of claims 1 to 6 characterized in that more estradiol is comprised in the matrix base material in molecularly disperse dissolved form than corresponds to the saturation solubility.
8. The transdermal therapeutic system according to one or several of claims 1 to 7 characterized in that the proportion of the water-binding mineral additive in the total matrix material amounts to between 1 and 40%-wt.
9. The transdermal therapeutic system according to one or several of claims 1 to 8 characterized in that the matrix base material is a polymer which, under water-free conditions, has a solubility for the active substance estradiol of between 0.4 and 3.0%
(w/w).
(w/w).
10. The transdermal therapeutic system according to claim 9 characterized in that the matrix base material is a polyacrylate polymer.
11. A process for the production of the transdermal therapeutic system according to claim 1, characterized by the steps:
- preparing a suspension of estradiol-semihydrate and water-binding mineral additive in a solution, dispersion, or melt of the matrix base material, and optionally adding further active substances, - using this suspension, applying a layer on a sheet-like substrate to produce said active substance-containing matrix layer, - combining said matrix layer with a backing layer which is impermeable to active substances and moisture, - carrying out a conversion of estradiol-semihydrate into anhydrous estradiol in the matrix layer by heating to 90 to 175°C.
- optionally, covering said matrix layer with a removable protective layer.
- preparing a suspension of estradiol-semihydrate and water-binding mineral additive in a solution, dispersion, or melt of the matrix base material, and optionally adding further active substances, - using this suspension, applying a layer on a sheet-like substrate to produce said active substance-containing matrix layer, - combining said matrix layer with a backing layer which is impermeable to active substances and moisture, - carrying out a conversion of estradiol-semihydrate into anhydrous estradiol in the matrix layer by heating to 90 to 175°C.
- optionally, covering said matrix layer with a removable protective layer.
12 The process according to claim 11 characterized in that the dry layer obtained by subjecting the matrix layer to heating to 90 to 175°C is heated to 90 to 200°C until a conversion of the hydrous form of the water-binding mineral additive into its anhydrous form has taken place.
13. The process according to any one of claims 11 or 12 characterized by a final step in which the transdermal therapeutic system is packed into a moisture-proof package which comprises a desiccant.
14. The process according to claim 11, characterized in that the steps of preparing a suspension and applying a layer are repeated to produce a matrix having several active substance-containing matrix layers, wherein at least one of these layers comprises a pharmaceutically acceptable, water-binding mineral additive.
15. The process according to claim 11, characterized in that the anhydrite of an alkaline-earth or alkali metal salt is used as said mineral additive.
16. The process according to claim 11, characterized in that the semihydrate or anhydrite of calcium sulfate is used as said mineral additive.
17. The process according to any one of claims 11 to 16, characterized in that the water-binding mineral additive is added at a proportion of 1 to 40%-wt., relative to the total matrix material.
18. The process according to any one of claims 11 to 17, characterized in that substances selected from acrylic-acid ester copolymers, polyisobutylene, polyvinyl acetate, synthetic rubbers and silicones are used as said matrix base material.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4429664A DE4429664C2 (en) | 1994-08-20 | 1994-08-20 | Estradiol TTS with water-binding additives and process for its preparation |
| DEP4429664.9 | 1994-08-20 | ||
| PCT/EP1995/003202 WO1996005815A1 (en) | 1994-08-20 | 1995-08-12 | Oestradiol-containing transdermal therapeutic system comprising hydrophylic additives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2197865A1 CA2197865A1 (en) | 1996-02-29 |
| CA2197865C true CA2197865C (en) | 2005-10-25 |
Family
ID=6526229
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002197865A Expired - Fee Related CA2197865C (en) | 1994-08-20 | 1995-08-12 | Oestradiol-containing transdermal therapeutic system comprising hydrophylic additives |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0776197B1 (en) |
| JP (1) | JPH10504314A (en) |
| KR (1) | KR100374476B1 (en) |
| CN (1) | CN1073413C (en) |
| AT (1) | ATE173163T1 (en) |
| AU (1) | AU700119B2 (en) |
| CA (1) | CA2197865C (en) |
| CZ (1) | CZ50897A3 (en) |
| DE (2) | DE4429664C2 (en) |
| DK (1) | DK0776197T3 (en) |
| ES (1) | ES2126308T3 (en) |
| FI (1) | FI118721B (en) |
| HU (1) | HUT77093A (en) |
| IL (1) | IL114948A (en) |
| NO (1) | NO970553D0 (en) |
| NZ (1) | NZ291449A (en) |
| PL (1) | PL180943B1 (en) |
| SI (1) | SI0776197T1 (en) |
| SK (1) | SK280299B6 (en) |
| WO (1) | WO1996005815A1 (en) |
| ZA (1) | ZA956926B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6623763B2 (en) | 1996-01-08 | 2003-09-23 | Lts Lohmann Therape-System Ag | Pharmaceutical preparation adhering to the skin, in particular a transdermal therapeutic system for the release of 17-β-estradiol to the human organism |
| DE19600347A1 (en) * | 1996-01-08 | 1997-07-10 | Lohmann Therapie Syst Lts | Skin-adhering pharmaceutical preparation, in particular TTS for the delivery of 17-beta-estradiol to the human organism |
| GB9720470D0 (en) | 1997-09-25 | 1997-11-26 | Ethical Pharmaceuticals South | Inhibition of crystallization in transdermal devices |
| DE19827732A1 (en) * | 1998-06-22 | 1999-12-23 | Rottapharm Bv | Transdermal patch useful for hormone replacement therapy used for treatment of menopausal symptoms |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991005529A1 (en) * | 1989-10-13 | 1991-05-02 | Watson Laboratories, Inc. | Drug delivery systems and matrix therefor |
| DE4223360C1 (en) * | 1992-07-16 | 1993-04-08 | Lts Lohmann Therapie-Systeme Gmbh & Co Kg, 5450 Neuwied, De | |
| DE4237453C1 (en) * | 1992-11-06 | 1993-08-19 | Lts Lohmann Therapie-Systeme Gmbh & Co Kg, 5450 Neuwied, De | |
| DE4309830C1 (en) * | 1993-03-26 | 1994-05-05 | Lohmann Therapie Syst Lts | Transdermal patches for oestradiol admin. - contg. isopropylidene mono- or di-glycerol as penetration enhancer |
-
1994
- 1994-08-20 DE DE4429664A patent/DE4429664C2/en not_active Expired - Fee Related
-
1995
- 1995-08-12 JP JP8507755A patent/JPH10504314A/en active Pending
- 1995-08-12 SK SK219-97A patent/SK280299B6/en unknown
- 1995-08-12 SI SI9530203T patent/SI0776197T1/en unknown
- 1995-08-12 NZ NZ291449A patent/NZ291449A/en unknown
- 1995-08-12 CZ CZ97508A patent/CZ50897A3/en unknown
- 1995-08-12 CA CA002197865A patent/CA2197865C/en not_active Expired - Fee Related
- 1995-08-12 ES ES95929104T patent/ES2126308T3/en not_active Expired - Lifetime
- 1995-08-12 EP EP95929104A patent/EP0776197B1/en not_active Expired - Lifetime
- 1995-08-12 AU AU32583/95A patent/AU700119B2/en not_active Ceased
- 1995-08-12 KR KR1019970701107A patent/KR100374476B1/en not_active IP Right Cessation
- 1995-08-12 WO PCT/EP1995/003202 patent/WO1996005815A1/en active IP Right Grant
- 1995-08-12 DK DK95929104T patent/DK0776197T3/en active
- 1995-08-12 DE DE59504233T patent/DE59504233D1/en not_active Expired - Lifetime
- 1995-08-12 HU HU9701725A patent/HUT77093A/en unknown
- 1995-08-12 AT AT95929104T patent/ATE173163T1/en active
- 1995-08-12 CN CN95194678A patent/CN1073413C/en not_active Expired - Fee Related
- 1995-08-15 IL IL11494895A patent/IL114948A/en not_active IP Right Cessation
- 1995-08-18 ZA ZA956926A patent/ZA956926B/en unknown
-
1997
- 1997-02-06 NO NO970553A patent/NO970553D0/en not_active Application Discontinuation
- 1997-02-18 PL PL95319014A patent/PL180943B1/en unknown
- 1997-02-19 FI FI970702A patent/FI118721B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| MX9701301A (en) | 1998-05-31 |
| PL180943B1 (en) | 2001-05-31 |
| KR100374476B1 (en) | 2003-04-23 |
| CN1155836A (en) | 1997-07-30 |
| FI970702A (en) | 1997-02-19 |
| IL114948A0 (en) | 1995-12-08 |
| AU700119B2 (en) | 1998-12-24 |
| JPH10504314A (en) | 1998-04-28 |
| NO970553L (en) | 1997-02-06 |
| FI118721B (en) | 2008-02-29 |
| CZ50897A3 (en) | 1997-06-11 |
| SK280299B6 (en) | 1999-11-08 |
| ATE173163T1 (en) | 1998-11-15 |
| KR970705380A (en) | 1997-10-09 |
| CN1073413C (en) | 2001-10-24 |
| SK21997A3 (en) | 1997-07-09 |
| FI970702A0 (en) | 1997-02-19 |
| CA2197865A1 (en) | 1996-02-29 |
| EP0776197A1 (en) | 1997-06-04 |
| DK0776197T3 (en) | 1999-07-26 |
| ZA956926B (en) | 1996-03-25 |
| PL319014A1 (en) | 1997-07-21 |
| DE4429664C2 (en) | 1997-09-11 |
| AU3258395A (en) | 1996-03-14 |
| NZ291449A (en) | 1998-09-24 |
| WO1996005815A1 (en) | 1996-02-29 |
| IL114948A (en) | 2000-10-31 |
| DE59504233D1 (en) | 1998-12-17 |
| SI0776197T1 (en) | 1999-04-30 |
| NO970553D0 (en) | 1997-02-06 |
| ES2126308T3 (en) | 1999-03-16 |
| DE4429664A1 (en) | 1996-02-22 |
| EP0776197B1 (en) | 1998-11-11 |
| HUT77093A (en) | 1998-03-02 |
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