Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—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

Definitions

• the present invention relates to a device and method for transdermal delivery of an azapirone compound and its pharmaceutically acceptable salts Moie pai ticularly, the present invention is a transdermal device comprising an azapirone and a stabilizing agent effective to inhibit recrvstallization of the azapirone within the transdermal device
• Azapirone as used herein encompasses a class of lelated compounds having the foimula
• Z is a membei selected from the group
• R 3 and R 4 being independently selected from hydrogen and C
• R 1 and R ⁇ are either taken together as
• R ! is hydrogen and R ⁇ is
• Psychogenic symptomatology includes, but is not limited to, psychological disorders and substance addictions.
• Recrystallization 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 recrystallize in a transdermal device.
• Azapirones are effective for treating a variety of psychogenic symptomatologies by their interaction with monoaminergic pathways in discrete areas of the brain.
• the synthesis of azapirones and the disclosure of their use in treating psychogenic symptomatologies arc described in: 1 . Y.H. Wu et al., J. Med. Chem., 15:447 ( 1972).
• 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 l -(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.
• 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 1 1 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.
• a transdermal device can provide controlled delivery of an azapirone, such as buspirone, into the systemic circulation wherein therapeutically effective levels of the pharmacologically active azapirone are maintained over a prolonged period of time.
• an azapirone such as buspirone
• 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 metabolism.
• the amount of drug required for treatment can be reduced and transdermal devices rely only minimally on patient compliance for their effectiveness.
• a transdermal devices can be composites that includes an adhesive layer which contains a drug and 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 transdermal devices 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 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 into the systemic circulation over a prolonged period of time and rely only minimally on patient compliance.
• problems including, but not limited to, difficulty in maintaining a drug in deliverable form in an adhesive, a matrix or a reservoir, adverse effects of the drug on the adhesive, matrix or reservoir, ability to control delivery of the drug to the skin and through the stratum corneum and viable epidermis into the systemic circulation.
• a transdermal device must maintain its integrity during long-term storage prior to use.
• An initial objective of the present invention is 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 transdermal 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 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.
• an azapirone can be stabilized in a transdermal device so that therapeutically effective amounts of 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, comprising an azapirone and a stabilizing agent effective to inhibit recrystallization of the azapirone within the transdermal 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 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
• 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
• 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 ait solvent and a stabilizing agent
• Fig 3A is buspirone 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/sqem/h) across human cadaver skin 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 compares the flux across human cadaver skin of buspnone dissolved in the pnor ait solvent acetone and of buspirone dissolved in the prior art solvent acetone and stabilized in isocetyl alcohol
• Fig 4B compares the flux across human cadaver skin of buspnone 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), t ⁇ glyce ⁇ de of caprylic/cap ⁇ c acids (F), C12-C15 alkyl benzoates (G) and ethoxydiglycol
• 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 l -(2 py ⁇ midinyl)- piperazine ( 1 -PP) (FIG 7B) in 16 healthy adult volunteers using the transdermal buspirone device of the present invention and using oral buspirone tablets
• the present invention is a transdermal azapirone delivery device, comprising an azapirone and a stabilizing agent effective to inhibit recrystallization of the azapirone within the transdermal device
• the present invention is a transdermal azapirone dehveiy device comprising an adhesive layer containing an azapirone and a stabilizing agent effective to inhibit lecrystalhzation of the azapirone within the adhesive layer and a backing layei impermeable to the azapirone or a transdermal azap ⁇ one dehveiy 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
• the present invention is a transdermal azapirone delviery device comprising an adhesive layer containing an azapirone and a stabilizing agent effective to inhibit reciystal zation of the azapirone
• 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
• 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 ot the azapirone in the adhesive layer 20 oi in the matrix layer 40.
• the virtually impermeable backing layei 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 the backing layer 15 and 35 of each embodiment should be impermeable to stabilized azapirone
• the backing layer mate ⁇ al should form a support to hold the adhesive layei 20 oi 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 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 having the formula
• Z is a member selected from the group
• R 3 and R 4 being independently selected from hydrogen and C ] .4 alkyl or R 3 and R 4 can be taken together as a butanediyl or pentanediyl chain, and R' and R ⁇ are either taken together as
• R 1 is hydiogen and R ⁇ is
• Preferred azapirones for use in the present invention include, but are not limited to
• 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 other factors which are known to those skilled in this art.
• the azapirone flux from the transdermal device through the skin should be in a range between 0.1 and 100 ⁇ g/cm ⁇ /h based on a patch size of 1 to 200 cnr
• a more preferred flux is between approximately 0.5 and 50 ⁇ g/cm ⁇ /h based on a patch size of between approximately 1 to 50 cm ⁇ .
• a most preferred flux is between approximately 1.0 and 10 ⁇ g/cm ⁇ /h based on a patch size of 1 to 30 cm ⁇ .
• 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 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 ] 2-C i 5 alkyl benzoates and glycols such as ethoxydiglycol.
• a preferred stabilizing agent is isocetyl alcohol. Isocetyl alcohol unexpectedly 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 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 for use in the present 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 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.
• tackifiers plasticizers, fillers, pigments, antioxidants and unsaturated resins, partially saturated resins and fully saturated resins may be added to the adhesive.
• plasticizers plasticizers
• fillers pigments
• antioxidants unsaturated resins
• unsaturated resins partially saturated resins
• fully saturated resins partially saturated resins
• unsaturated resins partially saturated resins
• unsaturated resins partially saturated resins
• 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 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 acceptable films 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 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 device typically has a thickness in the range of 25 to 10,000 microns.
• Punched patches can range from approximately 1 to 200 cm ⁇ .
• the more preferable patch size is from 1 to 50 cm ⁇ .
• the size of the patch will vary according to the amount of azapirone to be delivered over the desired time period.
• the punched patches are preferably sealed in individual pouches or other suitable materials until used.
• 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.
• 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 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 60° to 65° 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. 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 transdermal device is adhered onto the stratum corneum side of the skin sample. The skin specimen-transdermal patch is set onto a glass 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 32° C.
• Transdermal devices are prepared as in Example 1 and are evaluated as in Example 2.
• Transdermal device A is buspirone dissolved in the prior art solvent acetone. COMPONENTS % WET WEIGHT % D R Y
• Transdermal device B(TD-B) is buspirone dissolved in the prior art solvent acetone and stabilized in isocetyl alcohol
• Transdermal device C (TD-C) is buspirone dissolved in the prior art solvent toluene.
• 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
• 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 toluene and stabilized in isocetyl alcohol (3D), 20 months after their preparation.
• FIG. 4A compares the flux across excised human skin of 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/sqcm/h.
• the cumulative flux from TD-A is 40.98 ⁇ g/cm 2 /24h and from TD-B is 1 12.98 ⁇ g/cm 2 /24h
• the cumulative flux from TD-B is 275% greater than the cumulative flux from
• 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 ⁇ g/cm 2 /h and from TD-D is 3.34 ⁇ g/cm /h.
• the cumulative flux from TD-C is 15.49 ⁇ g/cm 2 /24h and from TD-D is 80.19 ⁇ g/cm 2 /24h
• the cumulative flux from TD-D is 518% greater than the cumulative flux from TD-C.
• Transdermal devices are prepared as in Example 1 and flux data is evaluated as in Example 2.
• Transdermal device E is buspirone dissolved in toluene and stabilized in the fatty alcohol isocetyl alcohol.
• Transdermal device F is buspirone dissolved in toluene and stabilized in the glyceride triglyceride of caprylic/capric acids.
• Triglyceride of caprylic/capric acids 100% 1.50 6.00
• Transdermal device G is buspirone dissolved in toluene and stabilized in the carboxylic acid C12- 5 alkyl benzoates.
• Transdermal device H is buspirone dissolved in toluene and stabilized in the glycol ethoxydiglycol.
• Example 5 Transdermal devices are prepared as in Example 1. These devices are 20 cm 2 , contain 2.5 mg of buspirone stabilized in isocetyl alcohol and deliver 1.9 mg buspirone/24 hours. The transdermal buspirone devices are stored for use within 24 months.
• One 20 cm 2 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 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 arc collected prior to the oral buspirone and at 0.5, 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 1 shows the mean pharmacokinetic parameters for transdermal buspirone and for oral buspirone.
• Table I shows the mean pharmacokinetic parameters for transdermal buspirone and for oral buspirone.
• 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
• 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 and 82 hours after application of the transdermal delivery device.
• FIG 7A compares the median buspirone plasma concentration 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 buspirone.
• FIG 7B compares the median l-(2-py ⁇ m ⁇ d ⁇ nyl)-p ⁇ peraz ⁇ ne (1- PP) plasma concentration at steady state after transdermal and oral administration of buspirone.
• These data show veiy low 1 -PP plasma concentrations with transdermal administration of buspirone, whereas these 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.

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• 1996
  • 1996-04-08 EP EP96912595A patent/EP0942727A1/de not_active Withdrawn
  • 1996-04-08 WO PCT/US1996/004745 patent/WO1997037659A1/en not_active Application Discontinuation
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