CA2251353C - Transdermal delivery device for azapirone compounds - Google Patents
Transdermal delivery device for azapirone compounds Download PDFInfo
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- CA2251353C CA2251353C CA002251353A CA2251353A CA2251353C CA 2251353 C CA2251353 C CA 2251353C CA 002251353 A CA002251353 A CA 002251353A CA 2251353 A CA2251353 A CA 2251353A CA 2251353 C CA2251353 C CA 2251353C
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- Prior art keywords
- buspirone
- azapirone
- transdermal
- adhesive
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
Abstract
In accordance with the present invention, a transdermal azapirone device is provided for administering therapeutically effective amounts of an azapirone into the blood at a controlled rate over a prolonged period of time. The present invention is a transdermal device comprising an azapirone and a stabilizing agent effective to inhibit recrystallization of the azapirone within the transdermal device.
Description
TRANSDERMAL DELIVERY DEVICE FOR AZAPIRONE COMPOUNDS
Technical Field The present invention relates to a device and method for transdermal delivery of an azapirone compound and its pharmaceurically acceptable salts. More pai-ticularly, the present invention is a transdermal 1 5 device comprising an azapirone and a stabilizing agent effective to inhibit recrystallization of the azapirone within ttie transdermal device.
Background of the Invention "Azapirone" as used herein encompasses a class of i-elated 2 0 compounds having the formula U1q-(C1'12)4-NR1P,2 wherein Z is ainember selected from the group and R' QS02~ A
acco~ CO R~
CO
with the doted and solid line representing either a single or a double chemical bond; A being selected from the -r-oup consisting of 0, CH23 3 0 CHiCH2 and CH=CH; R3 and R4 being independently selected from hydrogen and C 1-4 alkyl or R3 and R4 can be taken together as a butanediyl or pentanedi.yl chain; and R 1 and R2 are either taken together as O~-N
, N v , or R is hydrogen and R2 is ~ CHz~ O
"Psychogenic symptomatology" as used herein includes, but is not limited to psychological disorders and substance addictions.
Representative of "psychogenic symptomotology" are alcohol addiction, drug addiction, anxiety, nausea and vomiting, panic disorder, depression, short-term memory loss, obsessive-compulsive disorder, sexual dysfunction, schizophrenia, and eating disorders. Representative of a "drug addiction" are habitual use of ***e, habitual use of an opiate, such as methadone, habitual use of amphetamine, habitual use of phencyclidine and habitual use of methylphenidate. "Recrystallization" as used herein means the formation of perceptible to visible crystals. "Stabilizing agent" as used herein means an agent which inhibits recrystallization of an azapirone in a transdermal device.
"Stabilized" as used herein means an azapirone does not crystallize in a 2 5 transdermal device.
Azapirones are effective for treating a vai-iety of psychogenic symptomatologies by their interaction with rnonoaniinergic pathways in discrete areas of the brain. The synthesis of azapirones and the disclosure of their use in treating psychogenic symptomatologies are described in:
1. Y.H. Wu et al., J. Med. Chem., 15:447 (1972).
2. Wu et al., U.S. Patent No. 3,717,634, issued February 20, 1974.
Technical Field The present invention relates to a device and method for transdermal delivery of an azapirone compound and its pharmaceurically acceptable salts. More pai-ticularly, the present invention is a transdermal 1 5 device comprising an azapirone and a stabilizing agent effective to inhibit recrystallization of the azapirone within ttie transdermal device.
Background of the Invention "Azapirone" as used herein encompasses a class of i-elated 2 0 compounds having the formula U1q-(C1'12)4-NR1P,2 wherein Z is ainember selected from the group and R' QS02~ A
acco~ CO R~
CO
with the doted and solid line representing either a single or a double chemical bond; A being selected from the -r-oup consisting of 0, CH23 3 0 CHiCH2 and CH=CH; R3 and R4 being independently selected from hydrogen and C 1-4 alkyl or R3 and R4 can be taken together as a butanediyl or pentanedi.yl chain; and R 1 and R2 are either taken together as O~-N
, N v , or R is hydrogen and R2 is ~ CHz~ O
"Psychogenic symptomatology" as used herein includes, but is not limited to psychological disorders and substance addictions.
Representative of "psychogenic symptomotology" are alcohol addiction, drug addiction, anxiety, nausea and vomiting, panic disorder, depression, short-term memory loss, obsessive-compulsive disorder, sexual dysfunction, schizophrenia, and eating disorders. Representative of a "drug addiction" are habitual use of ***e, habitual use of an opiate, such as methadone, habitual use of amphetamine, habitual use of phencyclidine and habitual use of methylphenidate. "Recrystallization" as used herein means the formation of perceptible to visible crystals. "Stabilizing agent" as used herein means an agent which inhibits recrystallization of an azapirone in a transdermal device.
"Stabilized" as used herein means an azapirone does not crystallize in a 2 5 transdermal device.
Azapirones are effective for treating a vai-iety of psychogenic symptomatologies by their interaction with rnonoaniinergic pathways in discrete areas of the brain. The synthesis of azapirones and the disclosure of their use in treating psychogenic symptomatologies are described in:
1. Y.H. Wu et al., J. Med. Chem., 15:447 (1972).
2. Wu et al., U.S. Patent No. 3,717,634, issued February 20, 1974.
3. L.E. Allen et at., Arzneium. Forsch., 24:917 (1974).
4. G.L. Sathananthan et al., Cur. Therap. Res., 18:701 (1975).
5. Wu et al., U.S. Pat. No. 3,976,776, issued August 24, 1976.
6. Gawin et al., U.S. Patent No. 5,185,329, issued February 9. 1993.
The best known of the azapirones is buspirone and each of the cited references teaches oral administration of buspirone. Although oral buspirone has been shown to be effective in treating a variety of psychogenic symptomatologies, it is poorly absorbed from the gastrointestinal tract. Moreover, it shows a very high first pass metabolism which results in the production of metabolites such as 1-(2-pyrimidinyl)-piperazine (1-PP) which inhibits the pharmacologic effects of buspirone and which may be responsible for the clinical side-effects encountered with oral buspirone. With oral buspirone, less than 4% of a therapeutic dose reaches the systemic circulation unchanged and maximal plasma concentration can vary up to, 10 fold. In addition, the biological half-life of buspirone is short, from 3 to 11 hours, whereas buspirone metabolites such as 1-PP are eliminated much more slowly. These pharmacokinetic properties of buspirone necessitate a frequent dosing regimen which impacts negatively on patient compliance. Moreover, the rapid absorption of oral buspirone and the resultant high peak plasma values cause undesired side effects during initial treatment which further impacts negatively on patient compliance Therefore, what is needed is a device which maintains a therapeutically effective level of an azapirone, such as buspirone, in the systemic circulation over a prolonged period of time and which relies only minimally on patient compliance for its effectiveness.
A transdermal device can provide controlled delivery of an 1 5 azapirone, such as buspirone, into the systemic circulation wherein therapeutically effective levels of the phatmacologically active azapirone are maintained over a prolonged period of time. Such a transdermal device would eliminate the adverse side effects of initial high peak plasma levels and the generation of metabolites such as 1-PP resulting from high first pass 2 0 metabolism. Moreover, when delivery is from a transdermal device, the amount of drug required for treatment can be reduced and transdermal devices rely only minimally on patient compliance for their effectiveness.
A transdermal device can be composites that includes an adhesive layer which contains a drug and which attaches to the skin and a 2 5 backing layer which forms the outer surface of the device and which is impermeable to the drug. A transdermal device also can be composite that includes a matrix layer which contains a drug, an adhesive layer which attaches to the skin and a backing layer which forms the outer surface of the device and which is impermeable to the drug. A tansdermal device also can 3 0 be reservoir which contains a drug and having a microporous layer permeable to the drug, a backing layer impermeable to the drug and an adhesive layer which attaches to the skin. Other forms of transdermal devices are known to those skilled in the art.
A transdermal device can deliver a controlled amount of a drug 3 5 into the systemic circulation over a prolonged period of time and rely only rninimally ori patient cornpliance.. To date, hovl,ever, oniy (imited commercial exploitation of transdermal devieeF, has hcc ri achreved. because of probleins inciuding, but not limited to, difficulty in maintaining a drug in deliverable forni in an adhesive, a matrix or a reservoir, adverse effects of the drug on the adhesive, niatrix or reservoir, ability to control delivery of the drug to the skin and through the stratum corneuni and viable epidermis into the systemic circulation. Moreover, to be useful, a transdermal device must maintain its integrity during long-term storage prior to use..
Summary of the Invention Accordingly in one aspect the present invention seeks to provide a device for the transdermal delivery of therapeutically effective amounts of an azapirone into the systemic circulation over a prolonged period of time. It was a previously unrecognized problem that azapirones dissolved in prior art solvents are not stable and recrystallize within the transdermal device.
As the azapirone recrystallizes, its flux from the transder-mal device into the systemic circulation decreases. Therefore, therapeutically effective amounts of the azapirone cannot be maintained in the systemic circulation over time.
Moreover, this instability of the azapirone within the transdermal device 2 0 means that the transdermal device cannot be stored prior to use. If the transdermal device cannot be stored prior to use, its use as an azapirone delivery device is not practical.
It was completely unexpected that an azapirone can be stabilized in a transdermal device so that therapeutically effective amounts of 2 5 the azapirone are delivered into the systemic circulation over a prolonged period of time. Further, it was completely unexpected that when an azapirone is stabilized in a transdermal device, the transdermal device maintains its integrity during long-term storage prior to use.
The present invention is a transdermal azapirone device, 3 0 comprising an azapirone and a stabilizing agent effective to inhibit recrystallization of the azapirone within the transderrnal device. The present invention also provides a method for administering a therapeutically effective amount of an azapirone to a warm-blooded animal in need of such administration, comprising applying to the skin of the warm-blooded animal 3 5 a transdermal device comprising an azapirone and a stabilizing agent effective to inhibit recrystallization of the azapirone within the transdermal device.
A tansdermal azapirone delivery device, in a first embodiment, can be a three-layer laminate comprising a backing layer, an adhesive layer containing stabilized azapirone and, optionally, a release liner layer; in a second embodiment, can be a four-layer laminate comprising a backing layer, a stabilized azapirone loaded matrix layer, an adhesive layer and, optionally, a release liner layer; and, in a third embodiment, can be a stabilized azapirone loaded reservoir, a microporous membrane permeable to the azapirone, a backing layer impermeable to the azapirone and an adhesive layer. Other transdermal device configurations are known to those skilled in the art.
The aspects, features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiments and the appended claims.
Brief Description of the Figures Fig. 1 is a cross-sectional view of a three-layered transdermal azapirone device.
Fig. 2 is a cross-sectional view of a four-layered transdermal azapirone device.
Fig. 3 (A-D) shows photomicrographs (4X) of transdermal buspirone devices prepared using a prior art solvent alone and prepared using a prior art solvent and a stabilizing agent. Fig. 3A is buspirone 2 5 dissolved in the prior art solvent acetone. Fig. 3B is buspirone dissolved in the prior art solvent acetone and stabilized in isocetyl alcohol. Fig. 3C
is buspirone dissolved in the prior art solvent toluene. Fig. 3D is buspirone dissolved in the prior art solvent toluene and stabilized in isocetyl alcohol.
Fig. 4 shows the flux ( g/sqcm/h) across human cadaver skin 3 0 of buspirone from transdermal devices prepared using a prior art solvent alone and prepared using a prior art solvent and a stabilizing agent. Fig. 4A
compai-es the flux across human cadaver skin of buspirone dissolved in the prior art solvent acetone and of buspirone dissolved in the prior art solvent acetone and stabilized in isocetyl alcohol. Fig. 4B compares the flux across 3 5 human cadaver skin of buspirone dissolved in the prior art solvent toluene and of buspirone dissolved in the prior art solvent toluene and stabilized in isocetyl alcohol.
Fig. 5 shows the flux ( g/sqcm/h) of buspirone across human cadaver skin from transdermal devices prepared using the prior art solvent toluene and the stabilizing agents isocetyl alcohol (E), triglyceride of caprylic/capric acids (F), C 12-C 15 alkyl benzoates (G) and ethoxydiglycol (H).
Fig. 6 compares buspirone serum concentration ( g/ml) in eight healthy adult volunteers using the transdermal buspirone device of the present invention and using oral buspirone tablets.
Fig. 7 compares median plasma concentrations (ng/ml) of buspirone (FIG. 7A) and of the buspirone metabolite 1-(2 pyrimidinyl)-piperazine (1-PP) (FIG. 7B) in 16 healthy adult volunteers using the transdermal buspirone device of the present invention and using oral 1 5 buspirone tablets.
Detailed Description of the Present Invention The present invention is a transdermal azapirone delivery device, comprising an azapirone and a stabilizing agent effective to inhibit 2 0 recrystallization of the azapirone within the transdermal device.
Preferably, the present invention is a transdermal azapirone delivery device comprising an adhesive layer containing an azapirone and a stabilizing agent effective to inhibit recrystallization of the azapirone within the adhesive layer and a backing layer impermeable to the azapirone or a transdermal azaprione 2 5 delivery device comprising a matrix layer and containing an azapirone and a stabilizing agent effective to inhibit recrystallization of the azapirone within the matrix layer, an adhesive layer and a backing layer impermeable to the azapirone. More preferably, the present invention is a transdermal azapirone delivery device comprising an adhesive layer containing an 3 0 azapirone and a stabilizing agent effective to inhibit reci-ystallization of the azapirone within the adhesive layer, the adhesive layer having a first face and a second face, and a backing layer substantially impermeable to the azapirone and contacting the first face of the adhesive layer. It is to be understood that the present invention includes delivery of azapirones by any of the transdermal devices known to those of ordinary skill in the art. The embodiments disclosed herein are meant only as examples.
As illustrated in FIG. 1, the transdermal device 10 of one embodiment of the present invention has an impermeable backing layer 15, a stabilized azapirone loaded adhesive layer 20, and a release liner layer 25.
As illustrated in FIG. 2, the transdermal device 30 of another embodiment of the present invention has an impermeable backing layer 35, a stabilized azapirone loaded matrix layer 40, an adhesive layer 45, and a release liner layer 50.
The azapirone loaded adhesive layer 20 and the azapirone loaded matrix layer 40 each contain a stabilizing agent or combination of agents which inhibit recrystallization of the azapirone in the adhesive layer 20 or in the matrix layer 40. The virtually impermeable 1 5 backing layer 15 and 35 defines the first face of the transdermal delivery device or the side furthermost away from the skin. The impermeable backing layer 15 and 35 protects the transdermal delivery device and prevents the escape of constituents of the adhesive layer 20 or of the matrix layer 40 and the adhesive layer 45 into the environment. Material used for 2 0 the backing layer 15 and 35 of each embodiment shoul.d be impermeable to stabilized azapirone. The backing layer material should form a support to hold the adhesive layer 20 or the matrix layer 40 and the adhesive layer 45 in comfortable contact with the patient's skin.
The invention may include a release liner (peel strip). The 2 5 release liner (peel strip) layer 25 covers the surface of the adhesive or the release liner (peel strip) layer 50 covers the surface of the matrix during storage, protects the adhesive or the matrix and helps maintain drug stability.
Azapirones for use in the present invention include compounds 3 0 having the formula Z -(CHt)4-NRIRZ
The best known of the azapirones is buspirone and each of the cited references teaches oral administration of buspirone. Although oral buspirone has been shown to be effective in treating a variety of psychogenic symptomatologies, it is poorly absorbed from the gastrointestinal tract. Moreover, it shows a very high first pass metabolism which results in the production of metabolites such as 1-(2-pyrimidinyl)-piperazine (1-PP) which inhibits the pharmacologic effects of buspirone and which may be responsible for the clinical side-effects encountered with oral buspirone. With oral buspirone, less than 4% of a therapeutic dose reaches the systemic circulation unchanged and maximal plasma concentration can vary up to, 10 fold. In addition, the biological half-life of buspirone is short, from 3 to 11 hours, whereas buspirone metabolites such as 1-PP are eliminated much more slowly. These pharmacokinetic properties of buspirone necessitate a frequent dosing regimen which impacts negatively on patient compliance. Moreover, the rapid absorption of oral buspirone and the resultant high peak plasma values cause undesired side effects during initial treatment which further impacts negatively on patient compliance Therefore, what is needed is a device which maintains a therapeutically effective level of an azapirone, such as buspirone, in the systemic circulation over a prolonged period of time and which relies only minimally on patient compliance for its effectiveness.
A transdermal device can provide controlled delivery of an 1 5 azapirone, such as buspirone, into the systemic circulation wherein therapeutically effective levels of the phatmacologically active azapirone are maintained over a prolonged period of time. Such a transdermal device would eliminate the adverse side effects of initial high peak plasma levels and the generation of metabolites such as 1-PP resulting from high first pass 2 0 metabolism. Moreover, when delivery is from a transdermal device, the amount of drug required for treatment can be reduced and transdermal devices rely only minimally on patient compliance for their effectiveness.
A transdermal device can be composites that includes an adhesive layer which contains a drug and which attaches to the skin and a 2 5 backing layer which forms the outer surface of the device and which is impermeable to the drug. A transdermal device also can be composite that includes a matrix layer which contains a drug, an adhesive layer which attaches to the skin and a backing layer which forms the outer surface of the device and which is impermeable to the drug. A tansdermal device also can 3 0 be reservoir which contains a drug and having a microporous layer permeable to the drug, a backing layer impermeable to the drug and an adhesive layer which attaches to the skin. Other forms of transdermal devices are known to those skilled in the art.
A transdermal device can deliver a controlled amount of a drug 3 5 into the systemic circulation over a prolonged period of time and rely only rninimally ori patient cornpliance.. To date, hovl,ever, oniy (imited commercial exploitation of transdermal devieeF, has hcc ri achreved. because of probleins inciuding, but not limited to, difficulty in maintaining a drug in deliverable forni in an adhesive, a matrix or a reservoir, adverse effects of the drug on the adhesive, niatrix or reservoir, ability to control delivery of the drug to the skin and through the stratum corneuni and viable epidermis into the systemic circulation. Moreover, to be useful, a transdermal device must maintain its integrity during long-term storage prior to use..
Summary of the Invention Accordingly in one aspect the present invention seeks to provide a device for the transdermal delivery of therapeutically effective amounts of an azapirone into the systemic circulation over a prolonged period of time. It was a previously unrecognized problem that azapirones dissolved in prior art solvents are not stable and recrystallize within the transdermal device.
As the azapirone recrystallizes, its flux from the transder-mal device into the systemic circulation decreases. Therefore, therapeutically effective amounts of the azapirone cannot be maintained in the systemic circulation over time.
Moreover, this instability of the azapirone within the transdermal device 2 0 means that the transdermal device cannot be stored prior to use. If the transdermal device cannot be stored prior to use, its use as an azapirone delivery device is not practical.
It was completely unexpected that an azapirone can be stabilized in a transdermal device so that therapeutically effective amounts of 2 5 the azapirone are delivered into the systemic circulation over a prolonged period of time. Further, it was completely unexpected that when an azapirone is stabilized in a transdermal device, the transdermal device maintains its integrity during long-term storage prior to use.
The present invention is a transdermal azapirone device, 3 0 comprising an azapirone and a stabilizing agent effective to inhibit recrystallization of the azapirone within the transderrnal device. The present invention also provides a method for administering a therapeutically effective amount of an azapirone to a warm-blooded animal in need of such administration, comprising applying to the skin of the warm-blooded animal 3 5 a transdermal device comprising an azapirone and a stabilizing agent effective to inhibit recrystallization of the azapirone within the transdermal device.
A tansdermal azapirone delivery device, in a first embodiment, can be a three-layer laminate comprising a backing layer, an adhesive layer containing stabilized azapirone and, optionally, a release liner layer; in a second embodiment, can be a four-layer laminate comprising a backing layer, a stabilized azapirone loaded matrix layer, an adhesive layer and, optionally, a release liner layer; and, in a third embodiment, can be a stabilized azapirone loaded reservoir, a microporous membrane permeable to the azapirone, a backing layer impermeable to the azapirone and an adhesive layer. Other transdermal device configurations are known to those skilled in the art.
The aspects, features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiments and the appended claims.
Brief Description of the Figures Fig. 1 is a cross-sectional view of a three-layered transdermal azapirone device.
Fig. 2 is a cross-sectional view of a four-layered transdermal azapirone device.
Fig. 3 (A-D) shows photomicrographs (4X) of transdermal buspirone devices prepared using a prior art solvent alone and prepared using a prior art solvent and a stabilizing agent. Fig. 3A is buspirone 2 5 dissolved in the prior art solvent acetone. Fig. 3B is buspirone dissolved in the prior art solvent acetone and stabilized in isocetyl alcohol. Fig. 3C
is buspirone dissolved in the prior art solvent toluene. Fig. 3D is buspirone dissolved in the prior art solvent toluene and stabilized in isocetyl alcohol.
Fig. 4 shows the flux ( g/sqcm/h) across human cadaver skin 3 0 of buspirone from transdermal devices prepared using a prior art solvent alone and prepared using a prior art solvent and a stabilizing agent. Fig. 4A
compai-es the flux across human cadaver skin of buspirone dissolved in the prior art solvent acetone and of buspirone dissolved in the prior art solvent acetone and stabilized in isocetyl alcohol. Fig. 4B compares the flux across 3 5 human cadaver skin of buspirone dissolved in the prior art solvent toluene and of buspirone dissolved in the prior art solvent toluene and stabilized in isocetyl alcohol.
Fig. 5 shows the flux ( g/sqcm/h) of buspirone across human cadaver skin from transdermal devices prepared using the prior art solvent toluene and the stabilizing agents isocetyl alcohol (E), triglyceride of caprylic/capric acids (F), C 12-C 15 alkyl benzoates (G) and ethoxydiglycol (H).
Fig. 6 compares buspirone serum concentration ( g/ml) in eight healthy adult volunteers using the transdermal buspirone device of the present invention and using oral buspirone tablets.
Fig. 7 compares median plasma concentrations (ng/ml) of buspirone (FIG. 7A) and of the buspirone metabolite 1-(2 pyrimidinyl)-piperazine (1-PP) (FIG. 7B) in 16 healthy adult volunteers using the transdermal buspirone device of the present invention and using oral 1 5 buspirone tablets.
Detailed Description of the Present Invention The present invention is a transdermal azapirone delivery device, comprising an azapirone and a stabilizing agent effective to inhibit 2 0 recrystallization of the azapirone within the transdermal device.
Preferably, the present invention is a transdermal azapirone delivery device comprising an adhesive layer containing an azapirone and a stabilizing agent effective to inhibit recrystallization of the azapirone within the adhesive layer and a backing layer impermeable to the azapirone or a transdermal azaprione 2 5 delivery device comprising a matrix layer and containing an azapirone and a stabilizing agent effective to inhibit recrystallization of the azapirone within the matrix layer, an adhesive layer and a backing layer impermeable to the azapirone. More preferably, the present invention is a transdermal azapirone delivery device comprising an adhesive layer containing an 3 0 azapirone and a stabilizing agent effective to inhibit reci-ystallization of the azapirone within the adhesive layer, the adhesive layer having a first face and a second face, and a backing layer substantially impermeable to the azapirone and contacting the first face of the adhesive layer. It is to be understood that the present invention includes delivery of azapirones by any of the transdermal devices known to those of ordinary skill in the art. The embodiments disclosed herein are meant only as examples.
As illustrated in FIG. 1, the transdermal device 10 of one embodiment of the present invention has an impermeable backing layer 15, a stabilized azapirone loaded adhesive layer 20, and a release liner layer 25.
As illustrated in FIG. 2, the transdermal device 30 of another embodiment of the present invention has an impermeable backing layer 35, a stabilized azapirone loaded matrix layer 40, an adhesive layer 45, and a release liner layer 50.
The azapirone loaded adhesive layer 20 and the azapirone loaded matrix layer 40 each contain a stabilizing agent or combination of agents which inhibit recrystallization of the azapirone in the adhesive layer 20 or in the matrix layer 40. The virtually impermeable 1 5 backing layer 15 and 35 defines the first face of the transdermal delivery device or the side furthermost away from the skin. The impermeable backing layer 15 and 35 protects the transdermal delivery device and prevents the escape of constituents of the adhesive layer 20 or of the matrix layer 40 and the adhesive layer 45 into the environment. Material used for 2 0 the backing layer 15 and 35 of each embodiment shoul.d be impermeable to stabilized azapirone. The backing layer material should form a support to hold the adhesive layer 20 or the matrix layer 40 and the adhesive layer 45 in comfortable contact with the patient's skin.
The invention may include a release liner (peel strip). The 2 5 release liner (peel strip) layer 25 covers the surface of the adhesive or the release liner (peel strip) layer 50 covers the surface of the matrix during storage, protects the adhesive or the matrix and helps maintain drug stability.
Azapirones for use in the present invention include compounds 3 0 having the formula Z -(CHt)4-NRIRZ
wherein Z is a member selected from the group A \
O~ OI
::x:1 c0 with the doted and solid line representing either a single or a double chemical bond; A being selected from the group consisting of 0, CH2, CH2CH2 and CH=CH; R3 and R4 being independently selected from hydrogen and C 1_4 alkyl or R3 and R4 can be taken together as a butanediyl or pentanediyl chain; and R 1 and R2 are either taken together as N ~J
1 5 or RI is hydrogen and R2 is -CH7~
O
O~ OI
::x:1 c0 with the doted and solid line representing either a single or a double chemical bond; A being selected from the group consisting of 0, CH2, CH2CH2 and CH=CH; R3 and R4 being independently selected from hydrogen and C 1_4 alkyl or R3 and R4 can be taken together as a butanediyl or pentanediyl chain; and R 1 and R2 are either taken together as N ~J
1 5 or RI is hydrogen and R2 is -CH7~
O
Preferred azapirones for use in the present invention include, but are not limited to Specific Anpirone Compounds STRUCTURE REFERENCE
// US 3.717,634 N-(CH2)4-N N-{ O
\\ N
~ \N
BUSPIRONE
O US 4,423.049 N
/
cH, /"\
N-(CH2)4-N N-{ O
CH3 \\ \N
SEPIRONE
O EP 129,128A
// ~---~ N
N-(CH2)4-N N~O
N
IPSAPIRONE
O US 4,507,303 /~ N
2 ~
C)3 N-(CH2)4-N N- O
N
\\
0 J.Med.Chcm., 1988 31, 2 S \ N-(CH=)a-N/ N--( v 'N
\\
W Y-47,846 O US 4,612.312 /CHZ~ 0 30 /N_CH24_NH
OQ O
The most preferred azapirone for use in the present invention is buspirone.
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The most preferred azapirone for use in the present invention is buspirone.
The preferred range of azapirone for use in the present invention is between approximately 0.1 to 50% dry weight. A more preferred range is between approximately 0.25% to 25% dry weight. A
most preferred range is between approximately 0.5% and 10% dry weight.
The amount of azapirone to be incorporated in the transdermal device will vary depending on the systemic concentration desired, the permeability of the adhesive layer, the thickness of the adhesive layer, the length of time the transdermal device is to remain on the skin and othei- factors which are known to those skilled in this art. To achieve a therapeutic effect, the 1 0 azapirone flux from the transdermal device through the skin should be in a range between 0.1 and 100 g/cm2/h based on a patch size of I to 200 cm2.
A more preferred flux is between approximately 0.5 and 50 g/cm2/h based on a patch size of between approximately 1 to 50 cm2. A most preferred flux is between approximately 1.0 and 10 g/cm2/h based on a patch size of 1 5 1 to 30 cm2. Thus, for example, an acceptable transdermal device will deliver between 0.004 mg and 5 mg per hour of an azapirone which is a minimum of approximately 0. 1 mg of azapirone per 24 hours and a maximum of approximately 120 mg of azapirone per 24 hours.
Stabilizing agents for use in the present invention inhibit 2 0 recrystallization of an azapirone within a transdermal device. Stabilizing agents include, but are not limited to, fatty alcohols such as isocetyl alcohol, glycerides such as triglyceride of caprylic/capric acids, carboxylic acids such as C I 2-C 15 alkyl benzoates and glycols such as ethoxydiglycol. A
preferred stabilizing agent is isocetyl alcohol. Isocetyl alcohol unexpectedly 2 5 stabilizes the azapirones in adhesives and, even at relatively high concentration, does not destroy the adhesive. The preferred range of stabilizing agents for use in the present invention is between approximately 0.1% to 75% dry weight. A more preferred range is between approximately 2% and 40% dry weight. A most preferred range is between approximately 3 0 5% and 25% dry weight. The ratio of azapirone to stabilizing agent may vary between approximately 1:0.02 and 1:200, more preferably between approximately 1:1 and 1:40, and most preferably between approximately 1:5 and 1:20 dry weight.
Dermatologically acceptable adhesives foi- use in the present 3 5 invention include, but are not limited to, natural rubber, synthetic rubber, acrylic, silicone and block copolymer adhesives. A preferred adhesive in the synthetic rubber adhesive polyisobutylene. It is to be understood that the above list of adhesives is only representative of the adhesives that can be used in practicing the present invention and is not meant to be an exhaustive or exclusive list of adhesives. The preferred range of adhesive for use in the present invention is between approximately 5% and 99.8% dry weight.
A more preferred range is between approximately 30% and 98% dry weight. A most preferred range is between approximately 60% and 95%
dry weight. To obtain desirable adhesive properties, tackifiers, plasticizers, fillers, pigments, antioxidants and unsaturated resins, partially saturated resins and fully saturated resins may be added to the adhesive. The kinds and amounts of these to be added to the adhesive are known to those of ordinary skill in the art.
Backing layer material for use in the present invention 1 5 includes, but is not limited to, dermatologically acceptable films such as polyesters, polyurethanes, polyolefins, rubbers, synthetic resins, cloth, foils, and various laminates of these materials. Release liner (peel strip) material for use in the present invention includes, but is not limited to, dermatologically 2 0 acceptable filtns such as polyesters, polyurethanes, polyolefins, rubbers, synthetic resins, cloth, foils, and various laminates of these materials. A
preferred material is polyester.
The transdermal device of the present invention may be assembled by any of the techniques known in the art. The adhesive may be 2 5 processed by casting (pouring into a mold or on a moving flat surface), coating, extrusion, hot melt applications, radiation curing or other methods known in the art. The adhesive layer may be laminated onto the backing layer, onto the release liner (peel strip) layer or onto an intermediary support film to form a multilayered laminate. The multilayered laminate transdermal 3 0 device typically has a thickness in the range of 25 to 10,000 microns.
Patches of the desired size are punched or cut from the laminate. Punched patches can range from approximately 1 to 200 cm2. The more preferable patch size is from I to 50 cm2. The size of the patch will vary according to the amount of azapirone to be delivered over the desired time period. To 3 5 prevent contamination and to maintain the stability of the stabilized azapirone and the adhesive, the punched patches are preferably sealed in individual pouches or other suitable materials until used. It should be noted that the transdermal device which is contemplated as the present invention can be used anywhere on the body where the transdermal device can be applied to the skin.
This invention is further illustrated by the following examples, which are not construed in any way as imposing limitations upon the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.
Example 1 1 5 Transdermal buspirone delivery devices are prepared by dissolving buspirone in a prior art solvent. The dissolved buspirone is divided into aliquots. A stabilizing agent is added to one or more of the aliquots. An adhesive is dissolved in toluene and each aliquot of the dissolved buspirone or of the dissolved and stabilized buspirone is blended 2 0 into the adhesive/toluene. Each preparation is coated onto a layer of release coated polyester film to obtain a thickness of approximately 3 millimeters after drying. The preparations are dried at 600 to 650 C and the dried preparations are laminated to polyester film laminate to form transdermal devices.
Example 2 Transdermal buspirone devices are prepared as in Example 1.
The stability of buspirone in the transdermal device is evaluated microscopically at various times after preparation of the transdermal device.
3 0 The flux of buspirone from a transdermal patch across excised human skin is evaluated chromatographically. Skin samples are prepared by lifting the stratum corneum/epidermis from full thickness human cadaver skin. The transderinal device is adhered onto the stratum corneum side of the skin sample. The skin specimen-transdermal patch is set onto a glass 3 5 diffusion cell with the epidermis side down. The receiver compartment is filled with saline and stirred constantly. The preparation is maintained at a temperature of 320 C. Samples of saline are removed from the receiver compartment after various time periods and are analyzed by high pressure liquid chromatography (HPLC) to determine the amount of buspirone collected over a given time period. The flux of the buspirone from the transdermal device and through the skin specimen into the saline is calculated in g/cm2/h and in g/cm2/24 h.
Example 3 Transdermal devices are prepared as in Example I and are evaluated as in Example 2.
Transdermal device A (TD-A) is buspirone dissolved in the prior art solvent acetone.
1 5 COMPONENTS % WET WEIGHT % D R Y
WEIGHT
Buspirone 0.70 1.50 Acetone 99.7% 9.20 0.00 2 0 Polyisobutylene adhesive 45.05 98.50 Toluene 99.8% 45.05 0.00 Transdermal device B(TD-B) is buspirone dissolved in the 2 5 prior art solvent acetone and stabilized in isocetyl alcohol.
COMPONENTS % WET WEIGHT % D R Y
WEIGHT
Buspirone 0.70 1.50 Acetone 9.80 0.00 3 0 Isocetyl alcohol 100% 6.10 12.50 Polyisobutylene adhesive 41.70 86.00 Toluene 41.700.00 Transdermal device C(TD-C) is buspirone dissolved in the prior art solvent toluene.
COMPONENTS % WET WEIGHT % D R Y
WEIGHT
Buspirone 0.60 2.00 Toluene 5.00 0.00 Polyisobutylene adhesive 29.30 98.00 Toluene 65.10 0.00 Transdermal device D (TD-D) is buspirone dissolved in the prior art solvent toluene and stabilized in isocetyl alcohol.
COMPONENTS % WET WEIGHT % D R Y
WEIGHT
Buspirone 0.50 1.50 1 5 Toluene 7.90 0.00 Isocetyl alcohol 100% 3.80 12.50 Polyisobutylene adhesive 26.40 86.00 Toluene 61.40 0.00 2 0 FIGS. 3A and 3B show the physical appearance of TD-A, buspirone dissolved in acetone (3A), and of TD-B, buspirone dissolved in acetone and stabilized in isocetyl alcohol (3B), 21 days after their preparation. FIGS. 3C and 3D show the physical appearance of TD-C, buspirone dissolved in toluene (3C), and TD-D, buspirone dissolved in 2 5 toluene and stabilized in isocetyl alcohol (3D), 20 months after their preparation.
These photomicrographs show crystals of buspirone in TD-A
(3A) and in TD-C (3C) and no crystals of buspirone in TD-B (3B) and in TD-D (3D). These photomicrographs demonstrate that, in the absence of a 3 0 stabilizing agent, buspirone recrystallizes in the adhesive layer of transdermal devices TD-A and TD-C, whereas in the presence of the stabilizing agent isocetyl alcohol buspirone does not recrystallize in the adhesive layer of transdermal devices TD-B and TD-D.
FIG. 4A compares the flux across excised human skin of 3 5 buspirone from TD-A, buspirone dissolved in acetone and from TD-B, buspirone dissolved in acetone and stabilized in isocetyl alcohol, 48 days after their preparation. The average flux of buspirone from TD-A is 1.71 g/sqcm/h and from TD-B is 4.70 g/sqem/h. The cumulative flux from TD-A is 40.98 g/cm2/24h and from TD-B is 112.98 g/cm2/24h The cumulative flux from TD-B is 275% greater than the cumulative flux from TD-A. FIG. 4B compares the flux across excised human skin of buspirone from TD-C, buspirone dissolved in toluene, and from TD-D, buspirone dissolved in toluene and stabilized in isocetyl alcohol, 20 months after their preparation. The average flux of buspirone from TD-C is 0.64 4g/cm2/h 1 0 and from TD-D is 3.34 g/cm2/h. The cumulative flux from TD-C is 15.49 g/cm2/24h and from TD-D is 80.19 g/cm2/24h The cumulative flux from TD-D is 518% greater than the cumulative flux from TD-C.
These flux data demonstrate that as buspirone, dissolved in the prior art solvents acetone and toluene, recrystallizes within the adhesive 1 5 layer of the transdermal device, it becomes decreasingly available for transdermal delivery. These flux data also demonstrate that as buspirone, dissolved in the prior art solvents acetone and toluene and stabilized in the stabilizinQ agent isocetyl alcohol, does not recrystallize within the adhesive layer of the transdermal device it remains available for transdermal delivery.
2 0 This transdermal flux of stabilized buspirone is unexpected and unpredictable from the prior art.
Example 4 TT-ansdermal devices are prepared as in Example I and flux 2 5 data is evaluated as in Example 2.
Transdermal device E (TD-E) is buspirone dissolved in toluene and stabilized in the fatty alcohol isocetyl alcohol.
COMPONENTS % WET WEIGHT % D R Y
Buspirone 0.20 1.00 Toluene 9.90 0.00 Isocetyl-alcohol 1.50 6.00 Polyisobutylene adhesive 23.00 93.00 3 5 Toluene 65.40 0.00 Transdermal device F (TD-F) is buspirone dissolved in toluene and stabilized in the glyceride triglyceride of caprylic/capric acids.
COMPONENTS % WET WEIGHT % D R Y
WEIGHT
Buspirone 0.20 1.00 Toluene 9.90 0.00 1 0 Triglyceride of caprylic/capric acids 100% 1.50 6.00 Polyisobutylene adhesive 23.00 93.00 Toluene 65.40 0.00 Transdermal device G (TD-G) is buspirone dissolved in toluene and stabilized in the carboxylic acid C 12-C 15 alkyl benzoates.
COMPONENTS % WET WEIGHT % D R Y
WEIGHT
2 0 Buspirone 0.20 1.00 Toluene 9.90 0.00 C 12-C 15 alkyl benzoates 1.50 6.00 (Finsolv) 2 5 Polyisobutylene adhesive 23.00 93.00 Toluene 65.40 0.00 Transdermal device H (TD-H) is buspirone dissolved in toluene and stabilized in the glycol ethoxydiglycol.
COMPONENTS % WET WEIGHT % D R Y
WEIGHT
Buspirone 0.20 1.00 Toluene 9.90 0.00 Ethoxydiglycol 100% 1.50 6.00 (Transcutol) Polyisobutyleile adhesive 23.00 93.00 Toluene 65.4 0.00 Figure 5 shows that the flux across excised human skin of buspirone from TD-E, buspirone stabilized in isocetyl alcohol is 3.16 g/sqcm/h, froin TD-F, buspirone stabilized in triglyceride of caprylic/capric acids is 2.91 g/cm2/h, from TD-G, buspirone stabilized in C 12-C 15 alkyl benzoates is 3.14 g/cm2/h, and from TD-H, buspirone stabilized in ethoxydiglycol is 2.99 g/cm2/h. The transdermal delivery devices prepared with these stabilizing agents remained chemically stable over time. The transdermal flux of buspirone, when a stabilizing agent such 1 0 as isocetyl alcohol, triglyceride of caprylic/capric acids, C 12-C 15 alkyl benzoates and ethoxydiglycol is included in the transdermal device, is unexpected and unpredictable from the prior art. It is the stabilizing agent, which inhibit recrystallization of the buspirone within the transdermal device and, therefore, enables the delivery of therapeutically effective amounts of 1 5 buspirone into the blood at a controlled rate over a prolonged period of time.
Example 5 Transdermal devices are prepared as in Example 1. These devices are 20 cm2, contain 2.5 mg of buspirone stabilized in isocetyl 2 0 alcohol and deliver 1.9 mg buspirone/24 hours. The transdermal buspirone devices are stored for use within 24 months.
One 20 cm2 transdermal buspirone device is applied to the skin of each of 10 healthy adult male volunteers and is left in place for 24 hours. Blood samples are collected prior to application of the transdermal 2 5 device and at 1, 2, 4, 6, 8, 10, 14, 22, 24, 25, 26 and 28 hours subsequent to application of the transdermal device. The amount of buspirone in the serum is determined by gas chromatography. One week later, the same volunteers, after fasting for 12 hours, are given 20 mg of buspirone by mouth. Blood samples are collected prior to the oral buspirone and at 0.5, 3 0 1, 1.5, 2, 3. 4, and 6 hours subsequent to the oral buspirone. The amount of buspirone in the serum is determined by gas chromatography.
FIG. 6 shows the mean serum buspirone levels obtained using transdermal buspirone and using oral buspirone. Table I shows the mean pharmacokinetic parameters for transdermal buspirone and for oral 3 5 buspirone.
most preferred range is between approximately 0.5% and 10% dry weight.
The amount of azapirone to be incorporated in the transdermal device will vary depending on the systemic concentration desired, the permeability of the adhesive layer, the thickness of the adhesive layer, the length of time the transdermal device is to remain on the skin and othei- factors which are known to those skilled in this art. To achieve a therapeutic effect, the 1 0 azapirone flux from the transdermal device through the skin should be in a range between 0.1 and 100 g/cm2/h based on a patch size of I to 200 cm2.
A more preferred flux is between approximately 0.5 and 50 g/cm2/h based on a patch size of between approximately 1 to 50 cm2. A most preferred flux is between approximately 1.0 and 10 g/cm2/h based on a patch size of 1 5 1 to 30 cm2. Thus, for example, an acceptable transdermal device will deliver between 0.004 mg and 5 mg per hour of an azapirone which is a minimum of approximately 0. 1 mg of azapirone per 24 hours and a maximum of approximately 120 mg of azapirone per 24 hours.
Stabilizing agents for use in the present invention inhibit 2 0 recrystallization of an azapirone within a transdermal device. Stabilizing agents include, but are not limited to, fatty alcohols such as isocetyl alcohol, glycerides such as triglyceride of caprylic/capric acids, carboxylic acids such as C I 2-C 15 alkyl benzoates and glycols such as ethoxydiglycol. A
preferred stabilizing agent is isocetyl alcohol. Isocetyl alcohol unexpectedly 2 5 stabilizes the azapirones in adhesives and, even at relatively high concentration, does not destroy the adhesive. The preferred range of stabilizing agents for use in the present invention is between approximately 0.1% to 75% dry weight. A more preferred range is between approximately 2% and 40% dry weight. A most preferred range is between approximately 3 0 5% and 25% dry weight. The ratio of azapirone to stabilizing agent may vary between approximately 1:0.02 and 1:200, more preferably between approximately 1:1 and 1:40, and most preferably between approximately 1:5 and 1:20 dry weight.
Dermatologically acceptable adhesives foi- use in the present 3 5 invention include, but are not limited to, natural rubber, synthetic rubber, acrylic, silicone and block copolymer adhesives. A preferred adhesive in the synthetic rubber adhesive polyisobutylene. It is to be understood that the above list of adhesives is only representative of the adhesives that can be used in practicing the present invention and is not meant to be an exhaustive or exclusive list of adhesives. The preferred range of adhesive for use in the present invention is between approximately 5% and 99.8% dry weight.
A more preferred range is between approximately 30% and 98% dry weight. A most preferred range is between approximately 60% and 95%
dry weight. To obtain desirable adhesive properties, tackifiers, plasticizers, fillers, pigments, antioxidants and unsaturated resins, partially saturated resins and fully saturated resins may be added to the adhesive. The kinds and amounts of these to be added to the adhesive are known to those of ordinary skill in the art.
Backing layer material for use in the present invention 1 5 includes, but is not limited to, dermatologically acceptable films such as polyesters, polyurethanes, polyolefins, rubbers, synthetic resins, cloth, foils, and various laminates of these materials. Release liner (peel strip) material for use in the present invention includes, but is not limited to, dermatologically 2 0 acceptable filtns such as polyesters, polyurethanes, polyolefins, rubbers, synthetic resins, cloth, foils, and various laminates of these materials. A
preferred material is polyester.
The transdermal device of the present invention may be assembled by any of the techniques known in the art. The adhesive may be 2 5 processed by casting (pouring into a mold or on a moving flat surface), coating, extrusion, hot melt applications, radiation curing or other methods known in the art. The adhesive layer may be laminated onto the backing layer, onto the release liner (peel strip) layer or onto an intermediary support film to form a multilayered laminate. The multilayered laminate transdermal 3 0 device typically has a thickness in the range of 25 to 10,000 microns.
Patches of the desired size are punched or cut from the laminate. Punched patches can range from approximately 1 to 200 cm2. The more preferable patch size is from I to 50 cm2. The size of the patch will vary according to the amount of azapirone to be delivered over the desired time period. To 3 5 prevent contamination and to maintain the stability of the stabilized azapirone and the adhesive, the punched patches are preferably sealed in individual pouches or other suitable materials until used. It should be noted that the transdermal device which is contemplated as the present invention can be used anywhere on the body where the transdermal device can be applied to the skin.
This invention is further illustrated by the following examples, which are not construed in any way as imposing limitations upon the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.
Example 1 1 5 Transdermal buspirone delivery devices are prepared by dissolving buspirone in a prior art solvent. The dissolved buspirone is divided into aliquots. A stabilizing agent is added to one or more of the aliquots. An adhesive is dissolved in toluene and each aliquot of the dissolved buspirone or of the dissolved and stabilized buspirone is blended 2 0 into the adhesive/toluene. Each preparation is coated onto a layer of release coated polyester film to obtain a thickness of approximately 3 millimeters after drying. The preparations are dried at 600 to 650 C and the dried preparations are laminated to polyester film laminate to form transdermal devices.
Example 2 Transdermal buspirone devices are prepared as in Example 1.
The stability of buspirone in the transdermal device is evaluated microscopically at various times after preparation of the transdermal device.
3 0 The flux of buspirone from a transdermal patch across excised human skin is evaluated chromatographically. Skin samples are prepared by lifting the stratum corneum/epidermis from full thickness human cadaver skin. The transderinal device is adhered onto the stratum corneum side of the skin sample. The skin specimen-transdermal patch is set onto a glass 3 5 diffusion cell with the epidermis side down. The receiver compartment is filled with saline and stirred constantly. The preparation is maintained at a temperature of 320 C. Samples of saline are removed from the receiver compartment after various time periods and are analyzed by high pressure liquid chromatography (HPLC) to determine the amount of buspirone collected over a given time period. The flux of the buspirone from the transdermal device and through the skin specimen into the saline is calculated in g/cm2/h and in g/cm2/24 h.
Example 3 Transdermal devices are prepared as in Example I and are evaluated as in Example 2.
Transdermal device A (TD-A) is buspirone dissolved in the prior art solvent acetone.
1 5 COMPONENTS % WET WEIGHT % D R Y
WEIGHT
Buspirone 0.70 1.50 Acetone 99.7% 9.20 0.00 2 0 Polyisobutylene adhesive 45.05 98.50 Toluene 99.8% 45.05 0.00 Transdermal device B(TD-B) is buspirone dissolved in the 2 5 prior art solvent acetone and stabilized in isocetyl alcohol.
COMPONENTS % WET WEIGHT % D R Y
WEIGHT
Buspirone 0.70 1.50 Acetone 9.80 0.00 3 0 Isocetyl alcohol 100% 6.10 12.50 Polyisobutylene adhesive 41.70 86.00 Toluene 41.700.00 Transdermal device C(TD-C) is buspirone dissolved in the prior art solvent toluene.
COMPONENTS % WET WEIGHT % D R Y
WEIGHT
Buspirone 0.60 2.00 Toluene 5.00 0.00 Polyisobutylene adhesive 29.30 98.00 Toluene 65.10 0.00 Transdermal device D (TD-D) is buspirone dissolved in the prior art solvent toluene and stabilized in isocetyl alcohol.
COMPONENTS % WET WEIGHT % D R Y
WEIGHT
Buspirone 0.50 1.50 1 5 Toluene 7.90 0.00 Isocetyl alcohol 100% 3.80 12.50 Polyisobutylene adhesive 26.40 86.00 Toluene 61.40 0.00 2 0 FIGS. 3A and 3B show the physical appearance of TD-A, buspirone dissolved in acetone (3A), and of TD-B, buspirone dissolved in acetone and stabilized in isocetyl alcohol (3B), 21 days after their preparation. FIGS. 3C and 3D show the physical appearance of TD-C, buspirone dissolved in toluene (3C), and TD-D, buspirone dissolved in 2 5 toluene and stabilized in isocetyl alcohol (3D), 20 months after their preparation.
These photomicrographs show crystals of buspirone in TD-A
(3A) and in TD-C (3C) and no crystals of buspirone in TD-B (3B) and in TD-D (3D). These photomicrographs demonstrate that, in the absence of a 3 0 stabilizing agent, buspirone recrystallizes in the adhesive layer of transdermal devices TD-A and TD-C, whereas in the presence of the stabilizing agent isocetyl alcohol buspirone does not recrystallize in the adhesive layer of transdermal devices TD-B and TD-D.
FIG. 4A compares the flux across excised human skin of 3 5 buspirone from TD-A, buspirone dissolved in acetone and from TD-B, buspirone dissolved in acetone and stabilized in isocetyl alcohol, 48 days after their preparation. The average flux of buspirone from TD-A is 1.71 g/sqcm/h and from TD-B is 4.70 g/sqem/h. The cumulative flux from TD-A is 40.98 g/cm2/24h and from TD-B is 112.98 g/cm2/24h The cumulative flux from TD-B is 275% greater than the cumulative flux from TD-A. FIG. 4B compares the flux across excised human skin of buspirone from TD-C, buspirone dissolved in toluene, and from TD-D, buspirone dissolved in toluene and stabilized in isocetyl alcohol, 20 months after their preparation. The average flux of buspirone from TD-C is 0.64 4g/cm2/h 1 0 and from TD-D is 3.34 g/cm2/h. The cumulative flux from TD-C is 15.49 g/cm2/24h and from TD-D is 80.19 g/cm2/24h The cumulative flux from TD-D is 518% greater than the cumulative flux from TD-C.
These flux data demonstrate that as buspirone, dissolved in the prior art solvents acetone and toluene, recrystallizes within the adhesive 1 5 layer of the transdermal device, it becomes decreasingly available for transdermal delivery. These flux data also demonstrate that as buspirone, dissolved in the prior art solvents acetone and toluene and stabilized in the stabilizinQ agent isocetyl alcohol, does not recrystallize within the adhesive layer of the transdermal device it remains available for transdermal delivery.
2 0 This transdermal flux of stabilized buspirone is unexpected and unpredictable from the prior art.
Example 4 TT-ansdermal devices are prepared as in Example I and flux 2 5 data is evaluated as in Example 2.
Transdermal device E (TD-E) is buspirone dissolved in toluene and stabilized in the fatty alcohol isocetyl alcohol.
COMPONENTS % WET WEIGHT % D R Y
Buspirone 0.20 1.00 Toluene 9.90 0.00 Isocetyl-alcohol 1.50 6.00 Polyisobutylene adhesive 23.00 93.00 3 5 Toluene 65.40 0.00 Transdermal device F (TD-F) is buspirone dissolved in toluene and stabilized in the glyceride triglyceride of caprylic/capric acids.
COMPONENTS % WET WEIGHT % D R Y
WEIGHT
Buspirone 0.20 1.00 Toluene 9.90 0.00 1 0 Triglyceride of caprylic/capric acids 100% 1.50 6.00 Polyisobutylene adhesive 23.00 93.00 Toluene 65.40 0.00 Transdermal device G (TD-G) is buspirone dissolved in toluene and stabilized in the carboxylic acid C 12-C 15 alkyl benzoates.
COMPONENTS % WET WEIGHT % D R Y
WEIGHT
2 0 Buspirone 0.20 1.00 Toluene 9.90 0.00 C 12-C 15 alkyl benzoates 1.50 6.00 (Finsolv) 2 5 Polyisobutylene adhesive 23.00 93.00 Toluene 65.40 0.00 Transdermal device H (TD-H) is buspirone dissolved in toluene and stabilized in the glycol ethoxydiglycol.
COMPONENTS % WET WEIGHT % D R Y
WEIGHT
Buspirone 0.20 1.00 Toluene 9.90 0.00 Ethoxydiglycol 100% 1.50 6.00 (Transcutol) Polyisobutyleile adhesive 23.00 93.00 Toluene 65.4 0.00 Figure 5 shows that the flux across excised human skin of buspirone from TD-E, buspirone stabilized in isocetyl alcohol is 3.16 g/sqcm/h, froin TD-F, buspirone stabilized in triglyceride of caprylic/capric acids is 2.91 g/cm2/h, from TD-G, buspirone stabilized in C 12-C 15 alkyl benzoates is 3.14 g/cm2/h, and from TD-H, buspirone stabilized in ethoxydiglycol is 2.99 g/cm2/h. The transdermal delivery devices prepared with these stabilizing agents remained chemically stable over time. The transdermal flux of buspirone, when a stabilizing agent such 1 0 as isocetyl alcohol, triglyceride of caprylic/capric acids, C 12-C 15 alkyl benzoates and ethoxydiglycol is included in the transdermal device, is unexpected and unpredictable from the prior art. It is the stabilizing agent, which inhibit recrystallization of the buspirone within the transdermal device and, therefore, enables the delivery of therapeutically effective amounts of 1 5 buspirone into the blood at a controlled rate over a prolonged period of time.
Example 5 Transdermal devices are prepared as in Example 1. These devices are 20 cm2, contain 2.5 mg of buspirone stabilized in isocetyl 2 0 alcohol and deliver 1.9 mg buspirone/24 hours. The transdermal buspirone devices are stored for use within 24 months.
One 20 cm2 transdermal buspirone device is applied to the skin of each of 10 healthy adult male volunteers and is left in place for 24 hours. Blood samples are collected prior to application of the transdermal 2 5 device and at 1, 2, 4, 6, 8, 10, 14, 22, 24, 25, 26 and 28 hours subsequent to application of the transdermal device. The amount of buspirone in the serum is determined by gas chromatography. One week later, the same volunteers, after fasting for 12 hours, are given 20 mg of buspirone by mouth. Blood samples are collected prior to the oral buspirone and at 0.5, 3 0 1, 1.5, 2, 3. 4, and 6 hours subsequent to the oral buspirone. The amount of buspirone in the serum is determined by gas chromatography.
FIG. 6 shows the mean serum buspirone levels obtained using transdermal buspirone and using oral buspirone. Table I shows the mean pharmacokinetic parameters for transdermal buspirone and for oral 3 5 buspirone.
Table I
Parameter Transderm Oral al Area Under the Curve to infinity 13.24 (30)* 4.25 (AUCinf) ng.h/ml (64) Maximum.
Concentration 0.89 (59) 2.18 (Cmax) n /ml (83) Time to Maximum.
(tmax) h 18.5 (49) 0.8 (53) * = mean (coefficient of variation) These data in FIG. 6 and in Table I show that buspirone, stabilized in a transdermal device, is delivered from the transdermal device into the blood at a rate which enables a relatively steady concentration of buspirone to be maintained in the blood over time, whereas oral buspirone results in initial high peak blood concentrations which decline rapidly over time. These data also show that,with a 20 mg buspirone dose, the area under the curve to infinity of transdermal buspirone (13.34 ng=h/ml) is approximately 3 times that of oral buspirone (4.25 ng=h/ml)), that the maximum serum concentration of transdermal buspii-one (0.89 ng/ml) is approximately 2.5 times less than that of oral buspirone (2.18 ng/ml) and that the time to maximum serum concentration for transdermal buspirone 1 5 (18.5h) is approximately 23 times longer than that for oral buspirone (0.8h). Moreover, a 1.9 mg/24h transdermal dose of buspirone provides a serum concentration of buspirone approximately identical to that provided by 20 mg of oral buspirone taken 3X/24h.
Adverse clinical events with transdermal buspirone and with 2 0 oral buspirone are shown in Table II.
Parameter Transderm Oral al Area Under the Curve to infinity 13.24 (30)* 4.25 (AUCinf) ng.h/ml (64) Maximum.
Concentration 0.89 (59) 2.18 (Cmax) n /ml (83) Time to Maximum.
(tmax) h 18.5 (49) 0.8 (53) * = mean (coefficient of variation) These data in FIG. 6 and in Table I show that buspirone, stabilized in a transdermal device, is delivered from the transdermal device into the blood at a rate which enables a relatively steady concentration of buspirone to be maintained in the blood over time, whereas oral buspirone results in initial high peak blood concentrations which decline rapidly over time. These data also show that,with a 20 mg buspirone dose, the area under the curve to infinity of transdermal buspirone (13.34 ng=h/ml) is approximately 3 times that of oral buspirone (4.25 ng=h/ml)), that the maximum serum concentration of transdermal buspii-one (0.89 ng/ml) is approximately 2.5 times less than that of oral buspirone (2.18 ng/ml) and that the time to maximum serum concentration for transdermal buspirone 1 5 (18.5h) is approximately 23 times longer than that for oral buspirone (0.8h). Moreover, a 1.9 mg/24h transdermal dose of buspirone provides a serum concentration of buspirone approximately identical to that provided by 20 mg of oral buspirone taken 3X/24h.
Adverse clinical events with transdermal buspirone and with 2 0 oral buspirone are shown in Table II.
Oral Bus irone Transdermal Bus irone eodv Svstem igS;3f 1neldence Isial lN>dence Or an Class !o %
ARolication Site Disorders Erythema ' 0 0 10 100 r-entral Nervous Sys Disorders Dizziness 6 60 0 0 Sleepy 3 30 0 0 Head Rush 1 10 0 0 Dry Mouth 1 10 0 0 slight redness to redness under the patch (disappeared after patch was removed) These data show that the central nervous system side effects common with oral buspirone unexpectedly are not seen with the transdermal buspirone delivery system of the present invention.
Example 6 In this study, 16 healthy human subjects are randomly assigned to a treatment of either 2.31 mg transdermal buspirone/24 h(30 cm2 patch) 60 mg oral buspirone/24 h (20 mg, 3X) for 3 consecutive days.
After a one week washout, the subject treatments are reversed.
Blood samples for the transdermal treatment are collected prior to and at 24, 48, 49, 50, 52, 54, 56, 58, 62, 64, 66, 70, 72, 73, 74, 76, 79 2 0 and 82 hours after application of the transdermal delivery device. Blood samples for the oral treatment are collected prior to and at 24, 48, 48.5, 49, 49.5, 50, 51, 52, 54, 56, 56.5, 57, 57.5, 58, 62, 64,:64.5, 65, 65.5, 66, 67, 68, 70, and 72 hours after the first oral dose.
FIG. 7A compares the median buspirone plasma concentration 2 5 at steady state after administration of transdermal buspirone and of oral buspirone. These data show that transdermal buspirone provides an approximately constant plasma concentration of buspirone, whereas oral buspirone provides high peaks in plasma concentration after each dose of buspirone which followed by low valleys in plasma concentration of 3 0 buspirone.
FIG 7B compares the median 1-(2-pyrimidinyl)-piperazine (1-PP) plasma concentration at steady state after transdermal and oral administration of buspirone. These data show very low 1-PP plasma concentrations with transdermal administration of buspirone, whereas these 3 5 data show peaks and valleys of 1-PP plasma concentration with oral buspirone. This is because, when oral busprione undergoes first pass metabolism in the liver, it is convenrted to metabolites such as 1-PP. The low 1-PP plasma concentration observed with transdermal delivery of buspirone is especially significant as 1-PP antagonizes buspirone's useful pharmacological actions and may be responsible for the unwanted side effects reported for oral buspirone.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
ARolication Site Disorders Erythema ' 0 0 10 100 r-entral Nervous Sys Disorders Dizziness 6 60 0 0 Sleepy 3 30 0 0 Head Rush 1 10 0 0 Dry Mouth 1 10 0 0 slight redness to redness under the patch (disappeared after patch was removed) These data show that the central nervous system side effects common with oral buspirone unexpectedly are not seen with the transdermal buspirone delivery system of the present invention.
Example 6 In this study, 16 healthy human subjects are randomly assigned to a treatment of either 2.31 mg transdermal buspirone/24 h(30 cm2 patch) 60 mg oral buspirone/24 h (20 mg, 3X) for 3 consecutive days.
After a one week washout, the subject treatments are reversed.
Blood samples for the transdermal treatment are collected prior to and at 24, 48, 49, 50, 52, 54, 56, 58, 62, 64, 66, 70, 72, 73, 74, 76, 79 2 0 and 82 hours after application of the transdermal delivery device. Blood samples for the oral treatment are collected prior to and at 24, 48, 48.5, 49, 49.5, 50, 51, 52, 54, 56, 56.5, 57, 57.5, 58, 62, 64,:64.5, 65, 65.5, 66, 67, 68, 70, and 72 hours after the first oral dose.
FIG. 7A compares the median buspirone plasma concentration 2 5 at steady state after administration of transdermal buspirone and of oral buspirone. These data show that transdermal buspirone provides an approximately constant plasma concentration of buspirone, whereas oral buspirone provides high peaks in plasma concentration after each dose of buspirone which followed by low valleys in plasma concentration of 3 0 buspirone.
FIG 7B compares the median 1-(2-pyrimidinyl)-piperazine (1-PP) plasma concentration at steady state after transdermal and oral administration of buspirone. These data show very low 1-PP plasma concentrations with transdermal administration of buspirone, whereas these 3 5 data show peaks and valleys of 1-PP plasma concentration with oral buspirone. This is because, when oral busprione undergoes first pass metabolism in the liver, it is convenrted to metabolites such as 1-PP. The low 1-PP plasma concentration observed with transdermal delivery of buspirone is especially significant as 1-PP antagonizes buspirone's useful pharmacological actions and may be responsible for the unwanted side effects reported for oral buspirone.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Claims (9)
1. Use of a transdermal delivery device (10) for treating a psychogenic symptomotology, in an animal in need of such treatment, wherein said device (10) comprises:
a. an adhesive layer (20) containing (i) a therapeutically effective amount of an azapirone and (ii an amount of a stabilizing agent effective to inhibit recrystallization of the azapirone within the adhesive layer (20), wherein the dry weight ratio of the azapirone to the stabilizing agent is between approximately 1:5 and 1:20, the adhesive layer (20) having a first face and a second face, and b. a backing layer (15) impermeable to the azapirone and contacting the first face of the adhesive layer (20).
a. an adhesive layer (20) containing (i) a therapeutically effective amount of an azapirone and (ii an amount of a stabilizing agent effective to inhibit recrystallization of the azapirone within the adhesive layer (20), wherein the dry weight ratio of the azapirone to the stabilizing agent is between approximately 1:5 and 1:20, the adhesive layer (20) having a first face and a second face, and b. a backing layer (15) impermeable to the azapirone and contacting the first face of the adhesive layer (20).
2. The use according to claim 1, wherein the psychogenic symptomotology is selected from the group consisting of alcohol addiction, drug addiction, anxiety, nausea and vomiting, panic disorder, depression, short-term memory loss, obsessive-compulsive disorder, sexual dysfunction, schizophrenia, and eating disorders.
3. The use according to claim 2, wherein the drug addiction is selected from the group consisting of habitual use of ***e, habitual use of an opiate, habitual use of amphetamine, habitual use of phencyclidine and habitual use of methylphenidate.
4. The use according to claim 1, wherein the azapirone is selected from the group consisting of buspirone, sepirone, ipsapirone, SM-3997, WY-47,846, and MDL 72832.
5. The use according to claim 1, wherein the stabilizing agent is selected from the group consisting of a fatty alcohol, a carboxylic acid, a glyceride and a glycol.
6. The use according to claim 5, wherein the stabilizing agent is the fatty alcohol isocetyl alcohol.
7. The use according to claim 1, wherein the adhesive is selected from the group consisting of a synthetic rubber adhesive, an acrylic adhesive, a silicone adhesive and a block copolymer adhesive.
8. The use according to claim 7, wherein the adhesive is the synthetic rubber adhesive polyisobutylene.
9. The use according to claim 7, wherein the stabilizing agent is selected from the group consisting of triglycerides of caprylic/capric acids, C12-C15 alkyl benzoates and ethoxydiglycol.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1996/004745 WO1997037659A1 (en) | 1996-04-08 | 1996-04-08 | Transdermal delivery device for azapirone compounds |
| AU55363/96A AU5536396A (en) | 1996-04-08 | 1996-04-08 | Transdermal delivery device for azapirone compounds |
| CA002251353A CA2251353C (en) | 1996-04-08 | 1996-04-08 | Transdermal delivery device for azapirone compounds |
| EP96912595A EP0942727A1 (en) | 1996-04-08 | 1996-04-08 | Transdermal delivery device for azapirone compounds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1996/004745 WO1997037659A1 (en) | 1996-04-08 | 1996-04-08 | Transdermal delivery device for azapirone compounds |
| CA002251353A CA2251353C (en) | 1996-04-08 | 1996-04-08 | Transdermal delivery device for azapirone compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2251353A1 CA2251353A1 (en) | 1997-10-16 |
| CA2251353C true CA2251353C (en) | 2008-10-07 |
Family
ID=25680592
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002251353A Expired - Fee Related CA2251353C (en) | 1996-04-08 | 1996-04-08 | Transdermal delivery device for azapirone compounds |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0942727A1 (en) |
| CA (1) | CA2251353C (en) |
| WO (1) | WO1997037659A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0306859D0 (en) * | 2003-03-25 | 2003-04-30 | Arachnova Therapeutics Ltd | Topical formulation and use of buspirone |
| EP2870962B1 (en) * | 2012-07-05 | 2018-09-12 | SK Chemicals Co., Ltd. | Transdermally absorbable preparation containing rotigotine |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL91451A0 (en) * | 1988-08-30 | 1990-04-29 | Bristol Myers Co | Pharmaceutical compositions comprising azapiron compounds and their use in the treatment of addiction |
| JPH06505712A (en) * | 1990-11-28 | 1994-06-30 | サノ・コーポレーシヨン | Methods and devices for treating tobacco poisoning |
| DK0690715T3 (en) * | 1993-03-26 | 2003-09-22 | Beth Israel Hospital | Topical and systemic application of busphirone or its derivatives for the treatment of pathological conditions associated with immune reactions |
| EP0705097B2 (en) * | 1993-06-25 | 2004-01-14 | Alza Corporation | Incorporating poly-n-vinyl amide in a transdermal system |
-
1996
- 1996-04-08 EP EP96912595A patent/EP0942727A1/en not_active Withdrawn
- 1996-04-08 CA CA002251353A patent/CA2251353C/en not_active Expired - Fee Related
- 1996-04-08 WO PCT/US1996/004745 patent/WO1997037659A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1997037659A1 (en) | 1997-10-16 |
| CA2251353A1 (en) | 1997-10-16 |
| EP0942727A1 (en) | 1999-09-22 |
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