EP1117389A1 - Verfahren zur herstellung von druckempfindlichen klebepflastern enthaltend hydrophyle wirkstoffsalze - Google Patents
Verfahren zur herstellung von druckempfindlichen klebepflastern enthaltend hydrophyle wirkstoffsalzeInfo
- Publication number
- EP1117389A1 EP1117389A1 EP99945640A EP99945640A EP1117389A1 EP 1117389 A1 EP1117389 A1 EP 1117389A1 EP 99945640 A EP99945640 A EP 99945640A EP 99945640 A EP99945640 A EP 99945640A EP 1117389 A1 EP1117389 A1 EP 1117389A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- drug
- hcl
- adhesive
- pressure sensitive
- sensitive adhesive
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000003814 drug Substances 0.000 title claims abstract description 212
- 229940079593 drug Drugs 0.000 title claims abstract description 210
- 239000011159 matrix material Substances 0.000 title claims abstract description 138
- 239000004820 Pressure-sensitive adhesive Substances 0.000 title claims abstract description 125
- 150000003839 salts Chemical class 0.000 title claims abstract description 79
- 238000004519 manufacturing process Methods 0.000 title abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 105
- 238000000034 method Methods 0.000 claims abstract description 90
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 88
- 239000006185 dispersion Substances 0.000 claims abstract description 63
- 239000000203 mixture Substances 0.000 claims abstract description 57
- 230000004907 flux Effects 0.000 claims abstract description 40
- 238000005266 casting Methods 0.000 claims abstract description 18
- 230000037317 transdermal delivery Effects 0.000 claims abstract description 16
- 230000002378 acidificating effect Effects 0.000 claims abstract description 14
- 238000001704 evaporation Methods 0.000 claims abstract description 14
- 238000002425 crystallisation Methods 0.000 claims abstract description 5
- 230000008025 crystallization Effects 0.000 claims abstract description 5
- 230000001965 increasing effect Effects 0.000 claims abstract description 5
- 239000000853 adhesive Substances 0.000 claims description 159
- 230000001070 adhesive effect Effects 0.000 claims description 156
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 claims description 74
- 239000002904 solvent Substances 0.000 claims description 50
- 229960002495 buspirone Drugs 0.000 claims description 34
- 229920002367 Polyisobutene Polymers 0.000 claims description 32
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 claims description 25
- 229960002896 clonidine Drugs 0.000 claims description 24
- 239000010410 layer Substances 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 22
- 239000003961 penetration enhancing agent Substances 0.000 claims description 20
- 229960004384 ketorolac tromethamine Drugs 0.000 claims description 19
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 claims description 14
- 229960001193 diclofenac sodium Drugs 0.000 claims description 14
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 claims description 14
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 11
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 claims description 11
- 239000003522 acrylic cement Substances 0.000 claims description 10
- KYITYFHKDODNCQ-UHFFFAOYSA-M sodium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [Na+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 KYITYFHKDODNCQ-UHFFFAOYSA-M 0.000 claims description 10
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 claims description 8
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000012790 adhesive layer Substances 0.000 claims description 7
- 239000005038 ethylene vinyl acetate Substances 0.000 claims description 7
- 229940057282 albuterol sulfate Drugs 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 claims description 5
- 238000010030 laminating Methods 0.000 claims description 5
- 229960002647 warfarin sodium Drugs 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 claims description 4
- 229960000265 cromoglicic acid Drugs 0.000 claims description 4
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims description 3
- YLXIPWWIOISBDD-NDAAPVSOSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;4-[(1r)-1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.CNC[C@H](O)C1=CC=C(O)C(O)=C1 YLXIPWWIOISBDD-NDAAPVSOSA-N 0.000 claims description 3
- MAUPDHMFNIUWSK-UHFFFAOYSA-N 1-(1h-indol-4-yloxy)-3-(propan-2-ylamino)propan-2-ol;hydrochloride Chemical compound Cl.CC(C)NCC(O)COC1=CC=CC2=C1C=CN2 MAUPDHMFNIUWSK-UHFFFAOYSA-N 0.000 claims description 3
- JSXBVMKACNEMKY-UHFFFAOYSA-N 8-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzoxazepine;hydron;chloride Chemical compound Cl.C1CN(C)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 JSXBVMKACNEMKY-UHFFFAOYSA-N 0.000 claims description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 3
- RGHAZVBIOOEVQX-UHFFFAOYSA-N Metoprolol succinate Chemical compound OC(=O)CCC(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 RGHAZVBIOOEVQX-UHFFFAOYSA-N 0.000 claims description 3
- UBDNTYUBJLXUNN-IFLJXUKPSA-N Oxytetracycline hydrochloride Chemical compound Cl.C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O UBDNTYUBJLXUNN-IFLJXUKPSA-N 0.000 claims description 3
- GFBKORZTTCHDGY-UWVJOHFNSA-N Thiothixene Chemical compound C12=CC(S(=O)(=O)N(C)C)=CC=C2SC2=CC=CC=C2\C1=C\CCN1CCN(C)CC1 GFBKORZTTCHDGY-UWVJOHFNSA-N 0.000 claims description 3
- HOBWAPHTEJGALG-JKCMADFCSA-N [(1r,5s)-8-methyl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate;sulfate Chemical compound [O-]S([O-])(=O)=O.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1 HOBWAPHTEJGALG-JKCMADFCSA-N 0.000 claims description 3
- 229960002576 amiloride Drugs 0.000 claims description 3
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 claims description 3
- 229960002028 atropine sulfate Drugs 0.000 claims description 3
- 229960003108 brompheniramine maleate Drugs 0.000 claims description 3
- SRGKFVAASLQVBO-BTJKTKAUSA-N brompheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Br)C=C1 SRGKFVAASLQVBO-BTJKTKAUSA-N 0.000 claims description 3
- IVHBBMHQKZBJEU-UHFFFAOYSA-N cinchocaine hydrochloride Chemical compound [Cl-].C1=CC=CC2=NC(OCCCC)=CC(C(=O)NCC[NH+](CC)CC)=C21 IVHBBMHQKZBJEU-UHFFFAOYSA-N 0.000 claims description 3
- 229960002179 ephedrine Drugs 0.000 claims description 3
- 229960003157 epinephrine bitartrate Drugs 0.000 claims description 3
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960004207 fentanyl citrate Drugs 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 229960000939 metoprolol succinate Drugs 0.000 claims description 3
- 229960001300 metoprolol tartrate Drugs 0.000 claims description 3
- 229960000805 nalbuphine Drugs 0.000 claims description 3
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 claims description 3
- 229960004127 naloxone Drugs 0.000 claims description 3
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 claims description 3
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 claims description 3
- 229960003086 naltrexone Drugs 0.000 claims description 3
- 229960001802 phenylephrine Drugs 0.000 claims description 3
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 claims description 3
- 229960000395 phenylpropanolamine Drugs 0.000 claims description 3
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 claims description 3
- 229960003712 propranolol Drugs 0.000 claims description 3
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 3
- LACQPOBCQQPVIT-SEYKEWMNSA-N scopolamine hydrobromide trihydrate Chemical compound O.O.O.Br.C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 LACQPOBCQQPVIT-SEYKEWMNSA-N 0.000 claims description 3
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 claims description 3
- KFVSLSTULZVNPG-UHFFFAOYSA-N terbutaline sulfate Chemical compound [O-]S([O-])(=O)=O.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1 KFVSLSTULZVNPG-UHFFFAOYSA-N 0.000 claims description 3
- 229960005105 terbutaline sulfate Drugs 0.000 claims description 3
- WUBVEMGCQRSBBT-UHFFFAOYSA-N tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)C(F)(F)F)=CC1 WUBVEMGCQRSBBT-UHFFFAOYSA-N 0.000 claims description 3
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- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 claims description 3
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- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 claims 3
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- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
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- 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
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- This invention relates to methods of preparing pressure sensitive adhesive matrix patch devices for transdermal drug delivery. More particularly, the invention relates to the preparation of pressure sensitive adhesive matrix patches by dissolving hydrophilic salts of hydrophobic drugs that are crystalline at room temperature in aqueous dispersions of hydrophobic pressure sensitive adhesive polymers. These patches are surprisingly free from drug crystals upon drying and exhibit unusually good physical stability without the use of a solubilizing agent or crystal growth inhibitor. Transdermal delivery of various drugs and pressure sensitive adhesive matrix patches for transdermal delivery of such drugs are well known in the art of drug delivery.
- These matrix patches include a pressure sensitive adhesive layer for affixing the patch to the skin and for carrying the drug and any excipients that are directly incorporated into this adhesive layer.
- These adhesive matrix patches also typically include an inert, impervious backing layer and a release liner that is peeled off and discarded before applying the patch to the skin.
- These patches are distinguished from reservoir patches in that the drug in a reservoir patch is incorporated in a layer or compartment separate from the pressure sensitive adhesive layer.
- An example of a reservoir transdermal patch is described in U.S. Patent No. 5,120,546 to Hansen et al.
- the polymers used to form pressure sensitive adhesives are well known to those skilled in the art and will be discussed in greater detail below.
- Drugs or pharmaceutical agents that are incorporated into pressure sensitive adhesive matrix patches are often available as either hydrophobic water- insoluble free drugs or as hydrophilic water-soluble salts. These hydrophilic drug salt derivatives are well known in the art and are often the forms that are developed for oral delivery.
- the hydrophobic free drug form of a drug and the hydrophilic salt form of a drug may be freely substituted in a transdermal pressure sensitive adhesive matrix patch.
- U. S. Patent No. 5,149,538 to Granger discloses a pressure sensitive adhesive matrix incorporating opioids or their pharmaceutically acceptable salts, however, no mention is made of the means of manufacture or the specific types of adhesives that might be compatible with such opioid drugs or drug salts.
- Free form drugs and their corresponding salts will normally differ in their physico-chemical properties such as solubility and hydrophobicity. Therefore, it is unlikely that the free drug and salt forms can be freely substituted in a given adhesive.
- the free drug form is likely to be insoluble in the water phase of an aqueous emulsion pressure sensitive adhesive, while the hydrophilic salt form is likely to be insoluble in the organic solvents of a solvent-based pressure sensitive adhesive.
- transdermal delivery system suitable for one drug or drug form may not be suitable for use with another drug or drug form.
- U.S. Patent No. 5,633.009 to Kenealy et al. suggests that azapirones and azapirone salts may be freely interchanged in pressure sensitive matrix patches, but discloses only techniques for incorporating hydrophobic azapirone free base in a solvent-based hydrophobic polyisobutylene adhesive.
- ketorolac and ketorolac salts may be freely substituted in transdermal matrix devices, but only discloses techniques for incorporating hydrophobic ketorolac free acid in a hydrophobic solvent-based pressure sensitive acrylic adhesive and techniques for incorporating hydrophilic ketorolac tromethamine in hydrophilic polymers (hydrogels, polyurethane, or pectin/gelatin blends). These examples serve to illustrate that hydrophilic salt forms of drugs are known in the art to be compatible with water- soluble hydrophilic polymers and hydrophobic drug forms are known to be compatible with solvent-based hydrophobic polymers such as are used in typical pressure sensitive adhesives.
- the hydrophilic salt is commonly converted to the hydrophobic free base
- This conversion and subsequent incorporation in a solvent-based hydrophobic pressure sensitive adhesive polymer is well known in the art.
- U.S. Patent No. 5,002,773 to Keshary et al. describes transdermal delivery of a calcium antagonist compound, "TA-3090.” Keshary states that the free base form of TA-3090 can be incorporated in polymeric matrix materials in a higher concentration than the maleate salt of TA-3090 and that the free base form is preferred for transdermal delivery.
- U.S. Patent No. 4,262,003 to Urquhart et al. describes a gelled mineral oil-polyisobutylene-scopolamine free base transdermal patch for the administration of scopolamine base.
- U.S. Patent No. 4,956,171 to Chang provides examples of the conversion of buprenorphine salts into buprenorphine free base for incorporation into an organic solvent-based pressures sensitive adhesive.
- transdermal matrix patch devices that use water-based pressure sensitive adhesive dispersions has been contemplated in the art, but the inco ⁇ oration of hydrophilic salts of crystalline drugs in such dispersions has not been considered.
- U.S. Patent No. 5,230,896 to Yeh et al. discloses a transdermal delivery system for administration of nicotine comprising nicotine base, an acrylic polymer adhesive, a stabilizer, and a polyester film backing. It is stated that a nicotine salt is also contemplated in the practice of the invention. Such a nicotine salt is used to reduce volatility of the drug and is formed in situ by addition of acid. Nicotine is an unusual compound in that the free base is quite hydrophilic and is a liquid at room temperature.
- the water-based adhesive is an acrylic copolymer, ethylene- vinyl acetate copolymer, or polyisobutylene polymer or copolymer that is a two- phase dispersion of water-insoluble polymer particles in water.
- Illustrative drugs that can be inco ⁇ orated into such patches by this method include albuterol sulfate. ketorolac tromethamine, diclofenac sodium, buspirone HC1, lidocaine HC1. clonidine HC1. and warfarin sodium.
- the matrix film can further comprise an effective amount of a permeation enhancer selected from the group consisting of cell envelope disordering compounds, solvents, and mixtures thereof.
- a method of inhibiting crystallization of a drug in a pressure sensitive adhesive matrix patch comprises:
- a method of increasing transdermal flux of an acidic drug comprises applying a pressure sensitive adhesive matrix patch to skin, wherein the matrix patch is prepared by the steps comprising:
- a method of preparing a drug/adhesive layer of a pressure sensitive adhesive matrix patch device comprises the steps of:
- a method of inhibiting crystallization of a drug in a drug/adhesive layer of a pressure sensitive adhesive matrix patch comprises the steps of:
- FIG. 1 shows a schematic sectional view through an illustrative device according to the present invention.
- references to a composition for delivering "a drug” includes reference to two or more of such drugs
- reference to “an adhesive” includes reference to one or more of such adhesives
- reference to “a permeation enhancer” includes reference to two or more of such permeation enhancers.
- hydrophilic salt and similar terms mean an ionic form of a drug or pharmaceutical agent, such as sodium, potassium, ammonium, tromethamine, or other cation salts thereof, sulfate or other anion salts thereof, acid addition salts of basic drugs, and base addition salts of acidic drugs.
- a drug or pharmaceutical agent such as sodium, potassium, ammonium, tromethamine, or other cation salts thereof, sulfate or other anion salts thereof, acid addition salts of basic drugs, and base addition salts of acidic drugs.
- Illustrative examples of such salts include sodium diclofenac, sodium cromolyn, sodium acyclovir, sodium ampicillin, sodium warfarin, ketorolac tromethamine, amiloride HCl, ephedrine HCl, loxapine HCl, thiothixene HCl, trifluoperizine
- HCl naltrexone HCl. naloxone HCl, nalbuphine HCl, buspirone HCl, bupriprion HCl, phenylephrine HCl, tolazoline HCl, chlo ⁇ heniramine maleate, phenylpropanolamine HCl, clonidine HCl, dextrometho ⁇ han HBr, metoprolol succinate, metoprolol tartrate, epinephrine bitartrate. ketotofin fumarate. atropine sulfate, fentanyl citrate, apomo ⁇ hine sulfate.
- propranolol HCl pindolol HCl, lidocaine HCl.
- tetracychne HCl oxytetracycline HCl.
- tetracaine HCl dibucaine HCL terbutaline sulfate, scopolamine HBr, and brompheniramine maleate.
- an effective amount means an amount of a drug or pharmacologically active agent that is nontoxic but sufficient to provide the desired local or systemic effect and performance at a reasonable benefit/risk ratio attending any medical treatment.
- An effective amount of a permeation enhancer as used herein means an amount selected so as to provide the selected increase in skin permeability and rate of administration.
- drug means any chemical or biological material or compound suitable for transdermal administration by the methods previously known in the art and/or by the methods taught in the present invention that induces a desired biological or pharmacological effect.
- the effect can be local, such as providing for a local anaesthetic effect, or it can be systemic.
- This invention is not drawn to novel drugs or new classes of active agents. Rather it relates to the mode of making dosage forms of agents or drugs that exist in the state of the art or that may later be established as active agents and that are suitable for delivery by the present invention.
- Such substances include broad classes of compounds normally delivered into the body, including through body surfaces and membranes, including skin.
- antiinfectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antihelminthics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including potassium and calcium channel blockers, beta-blockers, alpha-blockers.
- antihypertensives diuretics and antidiuretics
- vasodilators including general coronary, peripheral, and cerebral: central nervous system stimulants
- vasoconstrictors cough and cold preparations, including decongestants
- hormones such as estradiol and other steroids, including corticosteroids
- hypnotics immunosuppressives
- muscle relaxants parasympatholytics
- psychostimulants sedatives
- tranquilizers include
- solvent-based pressure sensitive adhesives ' ' are hydrophobic pressure sensitive adhesives that are dissolved in organic solvents
- water-based pressure sensitive adhesives are hydrophobic pressure sensitive adhesives that are water-insoluble and that have been dispersed as water-insoluble particles in water.
- a pressure sensitive adhesive (PSA) is "(a)n adhesive which adheres to a surface at room temperature by temporary application of pressure alone.” Shields, Adhesives Handbook 343 (3d ed., 1984).
- Typical polymers that have been used to form the basis of pressure sensitive adhesives are natural rubbers, block copolymers, synthetic rubbers (butyl rubber and polyisobutylene), styrene-butadiene rubber (SBR), polyacrylates.
- the adhesive In order to be coated onto the face stock material the adhesive must be in the liquid state. This state may be achieved by melting (hot-melt PSAs), dissolving (solvent-based adhesives), or dispersing (adhesive dispersions) the PSAs. . . . Generally, there are aqueous and solvent-based adhesive solutions, and aqueous or solvent-based adhesive dispersions. The most important are the organic solvent solutions of adhesives (solvent-based adhesives) and the water-based dispersions of adhesives (water-based adhesives). I. Benedek & L.J. Heymans, Pressure-Sensitive Adhesives Technology 34 (1997).
- a dispersion is "a two-phase system in which one phase consists of finely divided particles distributed throughout a bulk substance, the particles being the disperse or internal phase and the bulk substance the continuous or external phase.”
- latex is also routinely used to describe such systems in which a polymer is the paniculate phase and water is the continuous phase.
- aqueous and solvent-based adhesive solutions there are aqueous and solvent-based adhesive solutions, and aqueous or solvent-based adhesive dispersions.
- Pressure sensitive adhesives can also be obtained by compounding emulsion-polymerized dispersions of hydrophobic elastomeric polymers (e.g. BASF ACRONAL A217) with tackifiers that are water soluble (e.g. polyvinylmethyl ether; BASF LUTONAL M40) or that are water insoluble particle dispersions in water (e.g. poiyvinylisobutyl ether; BASF
- Dispersions of hydrophobic pressure sensitive adhesive polymers in water can also be formed by polymerizing the monomers (neat or solution polymerization), then removing the solvent and dispersing the polymer in water with the aid of surfactants (e.g. Lord PIB 500 and Lord BL-100).
- surfactants e.g. Lord PIB 500 and Lord BL-100.
- "physical stability" of a drug in a matrix patch includes the lack of recrystallization of the drug in the dried adhesive layer of the patch.
- permeation enhancer refers to compounds and mixtures of compounds that enhance the permeation of a drug across the skin.
- Chemical enhancers are comprised of two primary categories of components, i.e.. cell-envelope disordering compounds and solvents or binary systems containing both cell-envelope disordering compounds and solvents. The latter are well known in the art, e.g. U.S. Patent Nos. 4,863,970 and 4,537,776, inco ⁇ orated herein by reference.
- Cell envelope disordering compounds are known in the art as being useful in topical pharmaceutical preparations.
- cell envelope disordering compounds that can be used as enhancers, without limitation, include saturated and unsaturated fatty acids and their esters, alcohols, monoglycerides, acetates, diethanolamides, and N.N-dimethylamides, such as oleic acid, propyl oleate, isopropyl myristate. glycerol monooleate, glycerol monolaurate, methyl laurate, lauryl alcohol, lauramide diethanolamide, and mixtures thereof. Saturated and unsaturated sorbitan esters, such as sorbitan monooleate and sorbitan monolaurate, can also be used. It is believed that any cell envelope disordering compound is useful for pu ⁇ oses of this invention.
- Suitable solvents include water; diols. such as propylene glycol and glycerol; mono-alcohols, such as ethanol, propanol. and higher alcohols; DMSO; dimethylformamide; N,N-dimethylacetamide; 2-pyrrolidone; N-(2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, l-dodecylazacycloheptan-2-one and other n- substituted-alkyl-azacycloalkyl-2-ones (azones) and the like.
- diols such as propylene glycol and glycerol
- mono-alcohols such as ethanol, propanol. and higher alcohols
- DMSO dimethylformamide
- 2-pyrrolidone N-(2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, l-dodecyl
- a method for manufacturing a pressure sensitive adhesive matrix device for transdermal drug delivery by adding the hydrophilic salt form of the hydrophobic free drug directly to a water-based adhesive (a two-phase aqueous dispersion of a hydrophobic pressure sensitive adhesive polymer) and evaporating the water phase.
- the salt form of the drug is usually hydrophilic and insoluble in organic-solvent-based adhesives and cannot be inco ⁇ orated into organic-solvent-based adhesive patches to provide clinically meaningful skin flux.
- Hydrophilic salt forms of hydrophobic drugs are generally readily soluble in aqueous dispersions of hydrophobic pressure sensitive adhesives because the carrier is water, not an organic solvent.
- Such salt forms of drugs have previously had to be converted to the more hydrophobic free acid or free base form to be soluble and/or compatible in the organic-solvent-based adhesive to obtain clinically meaningful skin flux.
- This prior procedure required additional process steps, wherein the drug was converted from the FDA-approved salt form to an unapproved free acid or free base form, thus introducing additional regulatory and/or toxicological hurdles to developing a matrix patch.
- These problems can be avoided by formulating the salt form of the drug in a water-based pressure sensitive adhesive.
- the drugs inco ⁇ orated into patches prepared in this way are su ⁇ risingly physically stable.
- the present method also has safety and toxicological advantages since the carrier is water and not an organic solvent.
- systems manufactured in this manner are free from drug crystals upon drying and have su ⁇ rising physical stability relative to systems prepared using the conventional manufacturing technique using hydrophobic free drug forms and organic solvent-based pressure sensitive adhesives.
- effective amounts of a crystalline drug or pharmaceutical agent can be dissolved in the carrier of a hydrophobic pressure sensitive adhesive, and the drug will remain dissolved in the dried laminate without the use of a solubilizing agent.
- Drug flux from these patches containing dissolved drug is better than the drug flux from patches that contain undissolved crystalline drug particles in the matrix and is comparable to or better than the skin flux obtained from patches manufactured using the conventional technique by combining the hydrophobic free drug form and a solvent-based adhesive. Comparable skin flux is indicated by relative flux ratios from 0.4 or greater.
- patches manufactured in this manner have improved physical stability relative to systems prepared using the conventional manufacturing technique.
- effective amounts of a crystalline drug or pharmaceutical agent can be dissolved in the carrier of a hydrophobic pressure sensitive adhesive, and the drug will remain dissolved in the dried laminate without the use of a solubilizing agent.
- FIG. 1 shows an exemplary matrix patch 10 that is compatible with the present invention.
- the patch 10 is a laminated composite wherein the backing layer 12 forms the top surface of the composite.
- the drug-containing adhesive matrix layer 14 is immediately below and adjacent to the backing layer.
- the laminate Prior to use, the laminate also includes a strippable protective release liner.
- the release liner can be in the form of two sheets, 16a and 16b. the first sheet 16a partially overlapping the second sheet 16b. Additional structural layers can also be present.
- the backing layer which adheres to the drug-containing adhesive layer, serves as the upper layer of the device during use and functions as the primary structural element of the device.
- the backing layer is made of a sheet or film of a preferably flexible elastomeric material that is substantially impermeable to the drug and any enhancer that may be present. This backing layer is typically about
- the backing layer can also comprise laminates of one or more of the foregoing polymers.
- the release liner is a disposable element that serves only to protect the device prior to application to the skin.
- the release liner is formed from a material impermeable to the drug, enhancer, and other components of the device, and is easily strippable from the pressure sensitive adhesive.
- Release liners can generally be made of the same materials as the backing layer.
- the drug-containing adhesive matrix layer can. in addition to the adhesive, drug, and optional permeation enhancer, also contain other optional ingredients, such as thickeners, excipients, tackifiers. preservatives, defoamers. antioxidants, and the like, which are materials without pharmacological activity that are suitable for administration in conjunction with the presently disclosed and claimed compositions. Such materials are pharmaceutically acceptable in that they are nontoxic, do not interfere with drug delivery, and are not for any other reasons biologically or otherwise undesirable.
- the pressure sensitive adhesives used in accordance with the present invention must also be pharmaceutically acceptable.
- Pressure sensitive adhesive matrix systems described herein were prepared as follows. First, the solids content of a water-based or solvent-based adhesive in liquid form was determined by placing a known weight of liquid in a weighed aluminum dish and evaporating the solvents overnight in a 70° C convection oven. The content of solid adhesive in the liquid was calculated by dividing the adhesive solid weight after drying by the initial total liquid weight.
- the polyisobutylene (PIB) adhesives were prepared from polyisobutylene solids. The solid PIB was first dissolved in heptane to achieve a final solid content of about 30% by weight, and then the exact solid content was determined as described above.
- a weighed quantity of adhesive liquid was added to a glass bottle, and the solid adhesive weight was calculated from the known solid fraction of the given adhesive liquid.
- the drug substance hydrophilic salt or free drug form
- the liquid containing the adhesive polymer drug substance was then mixed overnight. In some cases, the drug substance dissolved completely in the mixture. In other cases, the drug did not completely dissolve, resulting in a liquid containing some drug crystals dispersed in the solution.
- approximately 8 ml of the solution was dispensed on a silanized polyester release liner and film cast using a casting knife with a gap size appropriate to achieve a final dried thickness of approximately 0.05-0.1 mm. The cast was dried in a 70°C convection oven for 15-30 minutes to yield a dried matrix onto which an 0.08 mm thick polyethylene backing film was laminated.
- the silanized release liner was removed from the adhesive matrix system, and the adhesive was affixed to the stratum corneum side of the thawed epidermal membrane, which was then cut to an appropriate size and placed between the two halves of the diffusion cell with the stratum corneum facing the donor compartment.
- the receiver compartment was filled with water or an aqueous buffer appropriate to maintain sink conditions for the drug. All receiver media included 0.02% (w/w) sodium azide to inhibit bacterial growth.
- the diffusion cell was placed in a temperature controlled circulating water bath calibrated to maintain the surface temperature of the skin at 32°C.
- the receiver compartment was constantly stirred by a magnetic stir bar in the receiver compartment agitated by a magnetic stirring module placed under the water bath.
- C ( ⁇ g/cm 3 ) is the concentration of the receiver compartment at sample time t (hours)
- V is the volume of the receiver compartment of the diffusion cell (6.3 cm 3 )
- A is the diffusional area of the cell (0.64 cm 2 ).
- Buspirone is an azapirone anxiolytic drug, and the FDA-approved form of the drug is the hydrochloride (HCl) salt.
- Pressure sensitive adhesive systems were prepared using the methods described above with buspirone hydrochloride and buspirone free base in several different adhesives: (1) MA-24 (Adhesives Research, Glen Rock, PA), an organic solvent-based PIB adhesive; (2) PIB-500 (Lord Co ⁇ oration, Pompano Beach, FA), a comparable water-based PIB; (3) DUROTAK 2979 (National Starch and Chemical Company, Bridgewater, NJ), an organic solvent-based acrylic adhesive; (4) NACOR 72-9965 (National Starch and Chemical Company), a comparable water-based acrylic.
- MA-24 Adhesives Research, Glen Rock, PA
- PIB-500 Lid Co ⁇ oration, Pompano Beach, FA
- DUROTAK 2979 National Starch and Chemical Company, Bridgewater, NJ
- NACOR 72-9965 National Starch and Chemical Company
- the drug substance was mixed with the liquid adhesive in quantities sufficient to obtain a concentration of 5% (w/w) drug in the dried film after film casting.
- the hydrophobic buspirone free base dissolved readily in the organic solvent-based adhesives and the dried films were visibly homogeneous and free from drug crystals.
- the hydrophilic buspirone hydrochloride salt did not dissolve in the organic solvent solution and the resulting dried films were filled with drug crystals that were visible to the naked eye.
- Pressure sensitive matrix systems with buspirone free base were prepared according to the procedure of Example 1 in two organic solvent-based acrylic copolymer adhesives, TSR (Sekisui Chemical Company, Osaka, Japan) and DURO-TAK 2516 (National Starch and Chemical Co.), at concentrations equivalent to 1 % or 2% (w/w) of the HCl salt.
- the HCl salt did not dissolve completely in the organic solvents of these solvent-based adhesives, and the final dried casts contained visible solid drug crystals in the adhesive matrix.
- a matrix system with Buspirone HCl at 1 % or 2% (w/w) was prepared in a comparable water-based acrylic copolymer adhesive dispersion, NACOR 72-9965. The HCl salt dissolved completely in this water-based adhesive dispersion, and the dried adhesive matrix was visibly free of drug crystals.
- Tables 3-5 The results of in vitro skin flux experiments using these systems are summarized in Tables 3-5.
- TSR/buspirone HCl 99%/ 1 % (w/w)
- TSR/buspirone free base 99.1 %/0.9% (w/w)
- NACOR 72-9965/buspirone HCl 99%/l % (w/w)
- TSR buspirone HCl 98%/2% (w/w)
- TSR/buspirone free base 98.2%/ 1.8% (w/w)
- NACOR 72-9965/buspirone HCl 98%/2% (w/w)
- permeation from the matrix prepared with the salt form of the drug and the water-based adhesive was comparable to permeation from the matrix prepared using the more conventional technique of mixing the hydrophobic free base and the organic solvent-based adhesives.
- a buspirone transdermal delivery device was prepared according to techniques known in the art. It has been claimed that devices can be prepared in this manner using either buspirone free base or buspirone salts such as buspirone HCl, therefore devices were prepared using both forms of the drug for comparison.
- Preparation with Buspirone Free Base A transdermal buspirone delivery device was prepared using buspirone free base according to the technique described in WO 97/37659 (Example 3) and U.S. Patent No. 5,633,009 (Example 1). Buspirone free base (0.70 ⁇ 0.01 g) was dissolved in 9.20 g of a prior art solvent (acetone, 99.5%+; Aldrich; Milwaukee, WI).
- This buspirone free base solution was combined with 6.1 ⁇ 0.01 g of isocetyl alcohol (Condea-Vista; Austin, TX).
- the buspirone free-base/acetone/isocetyl alcohol mixture was blended with a commercial organic solution PIB adhesive (MA-24, Adhesives Research, Glen Rock. PA).
- the buspirone free base/acetone/isocetyl alcohol/PIB adhesive mixture was cast on a release coated polymer film (Rexam Release
- the resulting laminate was stored at room temperature and 40°C/70%RH for 3 weeks and the stability of buspirone in the transdermal device was evaluated microscopically. No recrystallization of buspirone occurred, thus supporting the teaching of WO 97/37659 and U.S. Patent No. 5,633,009 when applied to the use of buspirone free base.
- a transdermal buspirone delivery device was prepared using buspirone hydrochloride salt according to the technique described in WO 97/37659 (Example 3) and U.S. Patent No. 5,633,009 (Example 1 ). This approach is based on the premise that all salts of the base compound are included in the term buspirone (U.S. Patent No. 5,633,009 at Col. 8, Lines 23-25).
- Buspirone hydrochloride (0.70 g) was added to 9.2 g of acetone (99.5%+; Aldrich; Milwaukee, WI). The hydrophilic buspirone hydrochloride salt did not completely dissolve in this solvent.
- the buspirone hydrochloride/acetone mixture was combined with 6.1 g of isocetyl alcohol
- the hydrophilic buspirone hydrochloride did not completely dissolve in this mixture.
- the buspirone hydrochloride/acetone/isocetyl alcohol mixture was blended with a commercial organic solvent-based PIB adhesive (MA-24, Adhesives Research, Glen Rock, PA).
- the hydrophilic buspirone hydrochloride also did not completely dissolve in this mixture.
- the buspirone hydrochloride/acetone/isocetyl alcohol/PIB adhesive mixture was cast on a release coated polymer film (Rexam Release Technologies, W. Chicago, IL) to obtain a dried coating weight of approximately 10 mg/ml.
- This film was dried at 60°C in a convection oven for 30 minutes and the dried film was laminated to a polyester film laminate (SCOTCHPACK #1012, 3M Pharmaceuticals; St. Paul, MN).
- the composition of the dried pressure sensitive adhesive matrix film was PIB adhesive/buspirone hydrochloride/isocetyl alcohol 86/1.5/12.5% (w/w).
- buspirone hydrochloride salt cannot be successfully substituted for buspirone free base in the examples of WO 97/37659 and U.S. Patent No. 5,633,009.
- solubilizers such as isocetyl alcohol appears to be operative for the use of buspirone free base, but is not applicable to the use of a hydrophilic buspirone salt.
- hydrophobic pressure sensitive adhesive laminates were manufactured using the method of the present invention with the hydrophilic buspirone hydrochloride salt and an aqueous dispersion of a hydrophobic pressure sensitive adhesive.
- the present method not only provides a method of successfully manufacturing physically stable pressure sensitive adhesive matrix transdermal delivery devices, but also makes unnecessary the use of a solubilizing agent.
- Albuterol is a beta 2 -adrenergic bronchodilator available in the hydrophobic free drug form and also as a hydrophilic sulfate salt.
- Pressure sensitive adhesive systems were prepared with albuterol sulfate and albuterol free base at 10%> (w/w) concentrations in two different adhesives: (1) Sekisui TSR, an organic solvent-based acrylic/vinylpyrrolidone copolymer adhesive solution, (2) National Starch NACOR 9965, a water based acrylic copolymer adhesive dispersion with 5% (w/w) KOLLIDON 90F (a vinylpyrrolidone homopolymer) as a thickening agent. The resulting systems were stored at 40°C/75% RH and observed microscopically for the presence of drug crystals. These observations are summarized in Table 7.
- This example shows that it is feasible to make hydrophobic pressure sensitive adhesive matrix patches with the hydrophilic albuterol sulfate salt and a water based dispersion of a hydrophobic acrylic copolymer pressure sensitive adhesive. Furthermore, this example shows that a system manufactured in this manner has an unexpected physical stability advantage relative to a system manufactured with the hydrophobic albuterol free base and a comparable organic solvent-based pressure sensitive adhesive solution. These results show that the manufacture of albuterol pressure sensitive matrix systems by mixing albuterol sulfate salt with a water based adhesives confers an unexpected advantage with respect to the physical stability of the dried matrix and allows for production of stable matrix systems at relatively high concentration (10%> w/w) without use of a solubilizing agent.
- Ketorolac is an acidic non-steroidal anti-inflammatory drug, and the FDA- approved form of ketorolac is the hydrophilic tromethamine salt (2-amino-2- hydroxymethyl-l,3-propanediol).
- Pressure sensitive matrix systems with ketorolac free acid and ketorolac tromethamine were prepared in an organic solvent-based acrylic pressure sensitive adhesive (TSR) at concentrations equivalent to 1% (w/w) of the tromethamine salt.
- TSR acrylic pressure sensitive adhesive
- the tromethamine salt did not completely dissolve in the organic solvent system, and the dried matrix contained crystallized drug in an acrylic adhesive matrix.
- Ketorolac free acid completely dissolved in the organic solvent system, and the dried matrix was visually free of any crystals.
- TSR/ketorolac tromethamine 99%/ 1% (w/w)
- TSR/ketorolac free acid 99%/0.7% (w/w)
- NACOR 72-9965/ketorolac tromethamine 99%/l % (w/w)
- Example 6 a ketorolac transdermal delivery device was prepared according to techniques described in the art. It is claimed in the art that devices can be prepared in this manner using either ketorolac free acid or ketorolac salts such as ketorolac tromethamine. Therefore devices were prepared using both forms of the drug for comparison. Preparation with Ketorolac Free Acid. Transdermal patches with 10% ketorolac free acid were prepared according to the procedure described in U.S. Patent No. 5,589,498 (Example 2).
- Ketorolac free acid (1.65 g) was added to 0.64 g of propylene glycol (Sigma, Lot # 27H1179) and 0.67 g isopropyl myristate (Nikko Chemicals, Lot # 4123). The mixture was added to 41.05 g of a pressure sensitive acrylic copolymer adhesive in an organic solution (DURO- TAK 2852, formerly DURO-TAK 9852; National Starch and Chemical, Lot 7898-1 17-1, 33.5% solids). The solution was left to mix for 12 hours on a rolling mill. The ketorolac acid-enhancer-adhesive mixture formed a homogeneous solution.
- the drug-enhancer-adhesive mixture was then cast on SCOTCHPAK 1012 polyester backing film (3M, Lot # 138) with a 40 mil (1,016 ⁇ m) casting knife.
- the solvent in the adhesive solution was evaporated at room temperature for 30 minutes and then in an oven at 100° C for 15 minutes.
- the resulting adhesive film was laminated to a release liner (SCOTCHPAK #1022, Lot 640).
- the resulting transdermal laminate was cut into 0.71 cm 2 disks for in vitro evaluation.
- the adhesive matrix was visibly homogeneous and free from crystals upon microscopic examination.
- Ketorolac Tromethamine Transdermal patches with 10% ketorolac (on a free acid basis) were prepared with ketorolac tromethamine salt according to the procedure described in U.S. Patent No. 5,589,498 (Example 2). This approach is based on the premise that all pharmaceutically accepted salts of the ketorolac free acid compound are included in the term ketorolac (U.S. Patent No. 5,589,498 at Col. 4, Lines 46-51).
- Ketorolac tromethamine salt (2.10 g) was added to 0.56 g of propylene glycol (Sigma, Lot # 27H1179) and 0.56 g isopropyl myristate (Nikko Chemicals, Lot # 4123). The mixture was added to 32.6 g of a pressure sensitive acrylic copolymer adhesive in an organic solution (DURO- TAK 2852, formerly DURO-TAK 9852; National Starch and Chemical, 33.5% solids). The solution was left to mix for 12 hours on a rolling mill. The ketorolac tromethamine does not dissolve in the enhancer-acrylic adhesive solution.
- the drug-enhancer-adhesive mixture was then cast on SCOTCHPAK 1012 polyester backing (3M, Lot 138) with a 40 mil (1,016 ⁇ m) casting knife.
- the solvent in the adhesive solution was evaporated at room temperature for 30 minutes and then in an oven at 100°C for 15 minutes.
- the resulting adhesive film was laminated to a release liner (SCOTCHPAK #1022, Lot 640).
- the resulting transdermal laminate was cut into 0.71 cm 2 disks for in vitro evaluation.
- the resulting transdermal laminate was visibly cloudy and extensive crystals were visible upon microscopic examination.
- ketorolac free acid and the ketorolac tromethamine salt give substantially different results when used in an organic solvent-based pressure sensitive acrylic adhesive.
- the salt form cannot be readily substituted for the free acid form because the resulting pressure sensitive adhesive laminate contains undissolved drug crystals and the skin flux performance of the resulting patch is reduced.
- the teaching of U.S. Patent No. 5,589.498 appears valid for use of the ketorolac free acid, but is inoperative when applied to the use of ketorolac tromethamine salt.
- Example 5 of the present application show that using the process described in the present invention, it is possible to make physically stable hydrophobic pressure sensitive adhesive matrix systems using the ketorolac tromethamine salt and that these matrix systems in fact have improved skin flux relative to systems made using the conventional technique of combining the hydrophobic free acid and an organic solvent-based adhesive.
- Diclofenac is an acidic non-steroidal anti-inflammatory drug.
- the FDA- approved form of diclofenac is the hydrophilic sodium salt.
- Pressure sensitive matrix systems with diclofenac free acid and diclofenac sodium were prepared in an organic solvent-based acrylic/vinylpyrrolidone copolymer adhesive, TSR, at molar concentrations equivalent to 1% or 2% (w/w) of diclofenac sodium.
- the sodium salt was not sufficiently soluble in the organic solvent system to dissolve completely, and the dried matrix contained crystallized drug in an acrylic adhesive matrix.
- the free acid of diclofenac completely dissolved in the organic solvent system, and the final dried cast was visually free of drug crystals.
- Pressure sensitive adhesive matrix patches containing 1 % or 2% (w/w) diclofenac sodium also were prepared with water-based dispersions of comparable hydrophobic acrylic copolymer adhesives, NACOR 72-9965 and ROBOND PS20 4386
- TSR diclofenac sodium 99%/l%> (w/w)
- TSR diclofenac free acid 99.1 %/0.9% (w/w)
- NACOR 72-9965/diclofenac sodium 99%/l% (w/w)
- TSR/diclofenac sodium 98%/2% (w/w)
- TSR/diclofenac 98.2% l .8% (w/w)
- ROBOND PS20/KOLLIDON 90/diclofenac Na 96%/2%/2% (w/w)
- the matrix systems manufactured using the sodium salt and the water-based adhesive dispersion had skin flux rates which were unexpectedly 8 to 9-fold higher on average than the skin flux from systems produced using the conventional technique of combining the hydrophobic free acid form with a comparable organic solvent-based pressure sensitive adhesive.
- the systems manufactured with the salt and the water-based adhesive dispersions were stored at room temperature and examined using optical microscopy at 100X magnification for the presence of drug crystals. No crystals were observed after 101 weeks of storage, indicating that these are physically stable systems.
- Warfarin is a widely prescribed anticoagulant.
- the free drug form contains a conjugated alcohol and alkene, which can be used to make a hydrophilic sodium salt through formation of an enolate anion.
- This sodium salt is the form of the drug approved for oral administration.
- Matrix systems were prepared using the free drug form and an organic solvent-based adhesive solution and using the salt form and a comparable aqueous dispersion acrylic copolymer adhesive.
- Warfarin free drug at 12% (w/w) was inco ⁇ orated in an organic solvent-based acrylic/vinylpyrrolidone copolymer adhesive (TSR). The hydrophobic free drug dissolved readily in the organic solvents and the resulting dry film was free from drug crystals, visible and microscopic.
- TSR organic solvent-based acrylic/vinylpyrrolidone copolymer adhesive
- a comparable formulation was prepared with 12% sodium warfarin and a water-based dispersion of a comparable acrylic copolymer adhesive (Nacor 72-9965) thickened with 5.0 % (w/w) of a polyvinylpyrrolidone homopolymer (Kollidon 90F).
- the hydrophilic warfarin sodium salt dissolved readily in water-based dispersion and the resulting dry hydrophobic matrix has been free from visible and microscopic drug crystals.
- Table 1 The results of in vitro skin permeation experiments using these systems are shown in Table 1 1.
- Lidocaine is an analgesic drug that is pharmaceutically approved in both the hydrophilic hydrochloride salt form and the hydrophobic free base forms.
- Pressure sensitive matrix systems with lidocaine free base and lidocaine HCl were prepared in an organic solvent-based hydrophobic acrylic copolymer adhesive, DURO-TAK 2516, at concentrations equivalent to 1% (w/w) of the HCl salt.
- the free base dissolved easily in the organic solvent solution and the resulting dried matrix was visibly free of drug crystals.
- the HCl salt did not dissolve completely in the organic solvent-based adhesive, and the final dried cast contains visible solid drug crystals in the adhesive matrix.
- a matrix system with lidocaine HCl at 1 % (w/w) was also prepared in a comparable water-based acrylic adhesive, NACOR 72-9965.
- the dried matrix produced using the salt and the water-based adhesive dispersion was physically stable and free of drug crystals.
- Table 12 The results of in vitro skin flux experiments using these systems are summarized in Table 12.
- TSR/lidocaine HCl 99%/l% (w/w)
- TSR/lidocaine free base 99.14%/0.86% (w/w)
- NACOR 72-9965/lidocaine HCl 99% l% (w/w)
- Permeation with the physically stable, crystal-free matrix prepared with the salt form of the drug and the water-based adhesive was greater than that obtained with the matrix containing a mixture of dissolved and crystallized drug produced using the salt and the organic solvent-based adhesive.
- the flux from the matrix system prepared using the salt and the water-based adhesive dispersion was also comparable to the flux from the matrix prepared with the free base form of the drug and the organic solvent-based adhesive.
- Clonidine is an antihypertensive drug approved for oral administration as the hydrochloride salt and for transdermal delivery as the free base. In these transdermal systems, conversion to the free base form was required because the salt form was insoluble in the organic solvent-based polyisobutylene adhesive used in the transdermal patch.
- a pressure sensitive adhesive matrix system with clonidine free base at a concentration equivalent to 2% (w/w) of the HCl salt was prepared in a polyisobutylene adhesive blend that had been dissolved in organic solvents, 33% high molecular weight PIB (VISTANEX MM L- 100 ) and 66% low molecular weight PIB (VISTANEX LM- MH), both from Exxon (Houston. Texas).
- the hydrophobic free base dissolved readily in the organic solvent solution and the resulting dry matrix film was free from drug crystals.
- Permeation with the matrix prepared with the salt form of the drug and the water-based PIB dispersion was comparable to that obtained with the matrix prepared using the more conventional technique with the free base form of the drug and the organic solvent-based PIB solution.
- Permeation enhancers can optionally be inco ⁇ orated when matrix systems are prepared using water-based hydrophobic adhesive dispersions and hydrophilic drug salts.
- This example illustrates the inco ⁇ oration of enhancers for an acidic drug (diclofenac sodium) and two basic drugs (buspirone HCl and clonidine HCl).
- Pressure sensitive adhesive matrix systems were prepared with the salt forms of these drugs at a concentration of 2% (w/w) in a water-based acrylic adhesive, NACOR 72-9965. Additional systems were also prepared with 2.5% (w/w) of a non-ionic permeation enhancer, lauryl lactate (CERAPHYL 31; ISP. Van Dyk, N.J.). The results of in vitro skin flux experiments with these systems are shown in Tables 14-16.
- NACOR 72-9965/diclofenac sodium 98%/2% (w/w)
- NACOR 72-9965/diclofenac sodium/lauryl lactate 95.5%/2%/2.5% (w/w)
- NACOR 72-9965/buspirone HCl 98%/2% (w/w)
- NACOR 72-9965/buspirone HCl/lauryl lactate 95.5%/2%/2.5% (w/w)
- NACOR 72-9965/clonidine HCl 98%/2% (w/w)
- NACOR 72-9965/clonidine HCl/lauryl lactate 95.5%/2%/2.5% (w/w)
- Comparable enhanced formulations were prepared by combining the drug and water-based adhesive dispersion mixture with a known permeation enhancer, lauroyl lactylic acid (R.I.T.A. Co ⁇ oration Woodstock, IL) in amounts sufficient to obtain a concentration of 2.4% (w/w) enhancer in the dried film. All systems were thickened for film casting with a polyvinylpyrrolidone copolymer at 5% (w/w) , (Collacral VL30, B.A.S.F., Ludwigshafen am Rhein, Germany). The results of in vitro skin flux experiments with these systems are shown in Tables 17-18. 4386
- Example 13 An additional example of the inco ⁇ oration of a permeation enhancer in a water-based adhesive was prepared using buspirone HCl as a model drug and sucrose laurate, a known permeation enhancer. Pressure sensitive adhesive matrix systems were prepared with buspirone HCl at a concentration of 2% (w/w) and sucrose laurate at 5% (w/w) (Ryoto LWA 1570; Mitubishi-Kagaku Foods Co ⁇ oration, Tokyo, Japan) was mixed with a water-based acrylic adhesive, NACOR 72-9965. The results of in vitro skin flux experiments with this .system are shown in Table 19.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US14952398A | 1998-09-08 | 1998-09-08 | |
US149523 | 1998-09-08 | ||
PCT/US1999/020814 WO2000024386A1 (en) | 1998-09-08 | 1999-09-08 | Method of making pressure sensitive adhesive matrix patches containing hydrophilic salts of drugs |
Publications (1)
Publication Number | Publication Date |
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EP1117389A1 true EP1117389A1 (de) | 2001-07-25 |
Family
ID=22530677
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EP99945640A Withdrawn EP1117389A1 (de) | 1998-09-08 | 1999-09-08 | Verfahren zur herstellung von druckempfindlichen klebepflastern enthaltend hydrophyle wirkstoffsalze |
Country Status (5)
Country | Link |
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EP (1) | EP1117389A1 (de) |
JP (1) | JP2003520191A (de) |
AU (1) | AU5820699A (de) |
CA (1) | CA2343100A1 (de) |
WO (1) | WO2000024386A1 (de) |
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EP1757280A1 (de) * | 2001-03-16 | 2007-02-28 | ALZA Corporation | Transdermales Pflaster zur Verabreichung von Sufentanyl |
US7797375B2 (en) | 2001-05-07 | 2010-09-14 | International Business Machines Corporat | System and method for responding to resource requests in distributed computer networks |
DE10141650C1 (de) | 2001-08-24 | 2002-11-28 | Lohmann Therapie Syst Lts | Transdermales Therapeutisches System mit Fentanyl bzw. verwandten Substanzen |
US20110086086A1 (en) * | 2005-07-26 | 2011-04-14 | Pfizer Inc | Transdermal system for varenicline |
US8383149B2 (en) | 2005-09-23 | 2013-02-26 | Alza Corporation | High enhancer-loading polyacrylate formulation for transdermal applications |
US20070098772A1 (en) | 2005-09-23 | 2007-05-03 | Westcott Tyler D | Transdermal norelgestromin delivery system |
CN105126241B (zh) * | 2008-03-31 | 2018-12-25 | 日东电工株式会社 | 透膜物递送系统及其使用方法 |
EP2349230A2 (de) * | 2008-10-06 | 2011-08-03 | Mylan Technologies, Inc. | Amorphes transdermales system von rotigotin |
FR2963889B1 (fr) | 2010-08-20 | 2013-04-12 | Debregeas Et Associes Pharma | Formulations a base de nalbuphine et leurs utilisations |
US20130211351A1 (en) * | 2012-01-31 | 2013-08-15 | Gruenenthal Gmbh | Pharmaceutical patch for transdermal administration of (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indol]-4-amine |
US20140288481A1 (en) * | 2013-03-15 | 2014-09-25 | G. Chad MORGAN | Transdermal patch with non-water soluble adhesive and anesthetic |
WO2023048192A1 (ja) * | 2021-09-27 | 2023-03-30 | 久光製薬株式会社 | ジクロフェナクインドリノン体の生成を抑制する方法 |
CN117677384A (zh) * | 2021-09-27 | 2024-03-08 | 久光制药株式会社 | 抑制双氯芬酸吲哚酮体的生成的方法 |
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US5310559A (en) * | 1982-09-01 | 1994-05-10 | Hercon Laboratories Corporation | Device for controlled release and delivery to mammalian tissue of pharmacologically active agents incorporating a rate controlling member which comprises an alkylene-alkyl acrylate copolymer |
US5633009A (en) * | 1990-11-28 | 1997-05-27 | Sano Corporation | Transdermal administration of azapirones |
JP2849950B2 (ja) * | 1990-11-30 | 1999-01-27 | 日東電工株式会社 | 経皮吸収製剤 |
US5883115A (en) * | 1992-11-09 | 1999-03-16 | Pharmetrix Division Technical Chemicals & Products, Inc. | Transdermal delivery of the eutomer of a chiral drug |
US5985317A (en) * | 1996-09-06 | 1999-11-16 | Theratech, Inc. | Pressure sensitive adhesive matrix patches for transdermal delivery of salts of pharmaceutical agents |
WO1999055312A2 (en) * | 1998-04-29 | 1999-11-04 | Virotex Corporation | Pharmaceutical carrier device suitable for delivery of pharmaceutical compounds to mucosal surfaces |
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1999
- 1999-09-08 JP JP2000577996A patent/JP2003520191A/ja active Pending
- 1999-09-08 EP EP99945640A patent/EP1117389A1/de not_active Withdrawn
- 1999-09-08 WO PCT/US1999/020814 patent/WO2000024386A1/en not_active Application Discontinuation
- 1999-09-08 CA CA002343100A patent/CA2343100A1/en not_active Abandoned
- 1999-09-09 AU AU58206/99A patent/AU5820699A/en not_active Abandoned
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CA2343100A1 (en) | 2000-05-04 |
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AU5820699A (en) | 2000-05-15 |
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