IL272776B1 - Method of rapidly achieving therapeutic concentrations of zolmitriptan for treatment of migraines and cluster headaches - Google Patents
Method of rapidly achieving therapeutic concentrations of zolmitriptan for treatment of migraines and cluster headachesInfo
- Publication number
- IL272776B1 IL272776B1 IL272776A IL27277620A IL272776B1 IL 272776 B1 IL272776 B1 IL 272776B1 IL 272776 A IL272776 A IL 272776A IL 27277620 A IL27277620 A IL 27277620A IL 272776 B1 IL272776 B1 IL 272776B1
- Authority
- IL
- Israel
- Prior art keywords
- microns
- microprojections
- patch
- zolmitriptan
- group
- Prior art date
Links
- UTAZCRNOSWWEFR-ZDUSSCGKSA-N zolmitriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1C[C@H]1COC(=O)N1 UTAZCRNOSWWEFR-ZDUSSCGKSA-N 0.000 title claims 41
- 229960001360 zolmitriptan Drugs 0.000 title claims 41
- 238000000034 method Methods 0.000 title claims 10
- 208000006561 Cluster Headache Diseases 0.000 title claims 4
- 208000019695 Migraine disease Diseases 0.000 title claims 2
- 230000001225 therapeutic effect Effects 0.000 title 1
- 239000008199 coating composition Substances 0.000 claims 34
- 239000007787 solid Substances 0.000 claims 21
- 239000007788 liquid Substances 0.000 claims 19
- 238000001035 drying Methods 0.000 claims 15
- 239000011248 coating agent Substances 0.000 claims 14
- 238000000576 coating method Methods 0.000 claims 14
- 238000009472 formulation Methods 0.000 claims 10
- 238000002493 microarray Methods 0.000 claims 10
- 239000000203 mixture Substances 0.000 claims 10
- 150000003839 salts Chemical class 0.000 claims 10
- 239000000758 substrate Substances 0.000 claims 10
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims 9
- 210000003491 skin Anatomy 0.000 claims 9
- 235000002906 tartaric acid Nutrition 0.000 claims 9
- 239000011975 tartaric acid Substances 0.000 claims 9
- 230000035515 penetration Effects 0.000 claims 8
- 238000010521 absorption reaction Methods 0.000 claims 5
- 208000002193 Pain Diseases 0.000 claims 4
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims 4
- 230000004907 flux Effects 0.000 claims 4
- 210000000434 stratum corneum Anatomy 0.000 claims 4
- 239000010936 titanium Substances 0.000 claims 4
- 239000005414 inactive ingredient Substances 0.000 claims 3
- 210000002381 plasma Anatomy 0.000 claims 3
- 230000036470 plasma concentration Effects 0.000 claims 3
- 229910052719 titanium Inorganic materials 0.000 claims 3
- 206010033546 Pallor Diseases 0.000 claims 2
- 239000013543 active substance Substances 0.000 claims 2
- 238000005452 bending Methods 0.000 claims 2
- 208000018912 cluster headache syndrome Diseases 0.000 claims 2
- 210000004207 dermis Anatomy 0.000 claims 2
- 239000003623 enhancer Substances 0.000 claims 2
- 239000000463 material Substances 0.000 claims 2
- 230000037368 penetrate the skin Effects 0.000 claims 2
- 239000004094 surface-active agent Substances 0.000 claims 2
- 206010015150 Erythema Diseases 0.000 claims 1
- 206010016825 Flushing Diseases 0.000 claims 1
- 206010027603 Migraine headaches Diseases 0.000 claims 1
- 208000001431 Psychomotor Agitation Diseases 0.000 claims 1
- 206010038743 Restlessness Diseases 0.000 claims 1
- 208000036071 Rhinorrhea Diseases 0.000 claims 1
- 206010039101 Rhinorrhoea Diseases 0.000 claims 1
- 229910001069 Ti alloy Inorganic materials 0.000 claims 1
- 239000000853 adhesive Substances 0.000 claims 1
- 230000001070 adhesive effect Effects 0.000 claims 1
- 201000004356 excessive tearing Diseases 0.000 claims 1
- 230000001815 facial effect Effects 0.000 claims 1
- 210000001061 forehead Anatomy 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 229910001000 nickel titanium Inorganic materials 0.000 claims 1
- 239000004033 plastic Substances 0.000 claims 1
- 201000003004 ptosis Diseases 0.000 claims 1
- 210000002966 serum Anatomy 0.000 claims 1
- 239000010935 stainless steel Substances 0.000 claims 1
- 229910001256 stainless steel alloy Inorganic materials 0.000 claims 1
- 230000035900 sweating Effects 0.000 claims 1
- 230000008961 swelling Effects 0.000 claims 1
- 208000024891 symptom Diseases 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- 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
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
Claims (51)
1. An intracutaneous delivery system, comprising a plurality of microprojections that are adapted to penetrate or pierce the stratum corneum of a human patient, the microprojections having a solid coating formulation thereon covering about 10% to 80% of the length of each microprojection measured from the tip to the base, wherein the coating comprises zolmitriptan or a pharmaceutically acceptable salt thereof in an amount of about 1 mg to about 5 mg per system, wherein the solid coating formulation is obtained by applying and drying a liquid coating formulation onto the microprojections, the liquid coating formulation having a viscosity of less than 500 centipoise (cP) prior to drying, and wherein at least 95% of the zolmitriptan is released from the system within about 5 minutes when measured by USP Paddle Over Disk Method (Apparatus 5).
2. The system of claim 1, wherein at least 95% of the zolmitriptan is released within about 1 minute.
3. The system of claim 1 or 2, wherein upon application of the system to a selected area of skin of the patient, the Tmax of a therapeutically effective blood plasma concentration occurs within about 45 minutes of the application, the Cmax is about 5 to about 25 ng/ml, and the AUC0- 2hr is about 5 to about 20 ng/ml*hour.
4. The system of any one of claims 1 to 3, wherein upon application of the system to a selected area of skin of the patient, the Tmax of a therapeutically effective serum concentration occurs within about 30 minutes of the application.
5. The system of any one of claims 1 to 4, wherein the coating covers about 20% to about 70% of the length of each microprojection.
6. The system of claim 5, wherein the coating covers about 30% to about 60% of the length of each microprojection. 272776/3 93
7. The system of any one of claims 1 to 6, wherein the liquid coating formulation, before drying, has a viscosity of about 150 cP to about 350 cP and/or a surface tension of about 50 mNm-1 to about 72 mNm-1 .
8. The system of claim 7, wherein the liquid coating formulation, before drying, has a viscosity of about 200 cP to about 300 cP and/or a surface tension of about 55 mNm-1 to about 65 mNm-1 .
9. The system of any one of claims 1 to 8, wherein the solid coating formulation on each microprojection has an approximate shape of an American football with a thickness that tapers down from a maximum of about 270 μm.
10. The system of claim any one of claims 1 to 9, wherein the microprojections are fabricated of a thin sheet of metal or a rigid material.
11. The system of claim 10, wherein the microprojections are fabricated of a material selected from the group consisting of plastic, stainless steel, titanium, and nickel titanium alloy.
12. The system of claim 11, wherein the microprojections are fabricated of titanium.
13. A patch adhered to a substrate, wherein the substrate comprises an array of microprojections that are coated with a solid formulation comprising zolmitriptan or a pharmaceutically acceptable salt thereof, wherein the solid formulation is obtained by applying and drying a liquid coating formulation onto the microprojections, the liquid coating formulation having a viscosity of less than 500 centipoise (cP) prior to drying, and wherein the patch has at least one of the following features: a. a patch size selected from the group consisting of from about 1 to 20 cm2 , from about 2 to 15 cm2 , from about 4 to 11 cm2 , about 5 cm2 , and about 10 cm2 ; 272776/3 94 b. a substrate size selected from the group consisting of from about 0.5 to 10 cm2 , from about 2 to 8 cm2 , from about 3 to 6 cm2 , about 3 cm2 , about 3.1 cm2 , about 3.13 cm2 , and about 6 cm2 ; c. an array size selected from the group consisting of from about 0.5 to 10 cm2 , from about 2 to 8 cm2 , from about 2.5 to 6 cm2 , about 2.7 cm2 , about 5.5 cm2 , about 2.74 cm2 , and about 5.48 cm2 ; d. a density (microprojections/cm2 ) selected from the group consisting of at least about 10 microprojections/cm2 , from about 200 to 2000 microprojections/cm2 , from about 500 to 1000 microprojections/cm2 , from about 650 to 800 microprojections/cm2 , and about 725 microprojections/cm2 ; e. a number of microprojections/array selected from the group consisting of from about 100 to 4000, from about 1000 to 3000, from about 1500 to 2500, from about 1900 to 2100, about 2000, about 1987, from about 200 to 8000, from about 3000 to 5000, from about 3500 to 4500, from about 4900 to 4100, about 4000, and about 3974; f. a microprojection length selected from the group consisting of from about 25 to 600 microns, from about 100 to 500 microns, from about 300 to 450 microns, from about 320 to 410 microns, about 340 microns, about 390 microns, about 387 microns, less than 1000 microns, less than 700 microns, and less than 500 microns, wherein the microprojections penetrate the skin from about 25 to 1000 microns; g. a tip length selected from the group consisting of from about 100 to 250 microns, from about 130 to about 200 microns, from about 150 to 180 microns, from about 160 to 170 microns, and about 165 microns; h. a microprojection width selected from the group consisting of from about 10 to 500 microns, from about 50 to 300 microns, from about 75 to 200 microns, from about 90 to 160 microns, from about 250 to 400 microns, about 300 microns, about 100 microns, about 110 microns, about 120 microns, about 130 microns, about 140 microns, and about 150 microns; i. a microprojection thickness selected from the group consisting of from about 1 micron to about 500 microns, from about 5 microns to 300 microns, from about 10 microns to 100 microns, from about 10 microns to 50 microns, from about 20 microns to 30 microns, and about 25 microns; 272776/3 95 j. a tip angle selected from the group consisting of about 10-70 degrees, about 20-60 degrees, about 30 to 50 degrees, about 35 to 45 degrees, and about 40 degrees; k. a total amount of zolmitriptan or a pharmaceutically acceptable salt thereof per array selected from the group consisting of from about 0.1 mg to 10 mg, from about 0.5 mg to 5 mg, from about 1 mg to 4 mg, about 1 mg, about 1.9 mg, and about 3.8 mg; l. an amount of inactive ingredient per array selected from the group consisting of from about 0.1 to 10 mg, from about 0.2 to 4 mg, from about 0.3 mg to 2 mg, about 0.6 mg, about 0.63 mg, about 1.3 mg, about 1.26 mg, from one to three times less than an active agent, and from about 0.033 mg to about 3.33 mg; m. a coating thickness selected from the group consisting of from about 100 μm to about 500 μm, from about 200 μm to about 350 μm, from about 250 μm to about 290 μm, and about 270 μm; n. an amount of zolmitriptan or a pharmaceutically acceptable salt thereof per microprojection selected from the group consisting of from about 0.001 to about 1000 μg, from about 0.01 to about 100 μg, from about 0.1 to 10 μg, from about 0.5 to 2 μg, about 1 μg, and about 0.96 μg.
14. The patch of claim 13, having a patch area of about 5 cm2 adhered to a titanium substrate with an area of about 3.1 cm2 and a microprojection thickness of about 25 μm.
15. The patch of claim 13 or 14, wherein the area of the microprojection array is about 2.74 cm2 and contains about 1987 microprojections at a density of about 725 microprojections/cm2 .
16. The patch of claim 14 or 15, wherein the formulation contained on each microprojection has an approximate shape of an American football with a thickness that tapers down from a maximum of about 270 μm, wherein the formulation comprises about 0.96 μg of zolmitriptan and about 0.32 of tartaric acid, or about 1.9 mg of zolmitriptan and about 0.63 mg of tartaric acid per patch. 272776/3 96
17. The patch of any one of claims 13 to 16, wherein the formulation comprises zolmitriptan in an amount of 1.9 mg, and wherein percutaneous absorption of zolmitriptan through ex vivo human torso skin over 300 minutes from a single application results in a mean flux of about 385 ± 96 μg/cm2 /hr at 0.025 hr.
18. The patch of any one of claims 13 to 17, wherein the formulation comprises zolmitriptan in an amount of 1.9 mg, and wherein percutaneous absorption of zolmitriptan through ex vivo human torso skin over 300 minutes from a single application results in a mean flux of about 6.4 ± 0.8 μg/cm2 /hr at 4.75 hr.
19. The patch of any one of claims 13 to 18, wherein the formulation comprises zolmitriptan in an amount of 1.9 mg, and wherein percutaneous absorption of zolmitriptan through ex vivo human torso skin to a receptor solution results in total zolmitriptan absorption of about 83.4 ± 1.3 %.
20. The patch of any one of claims 13 to 19, wherein the formulation comprises zolmitriptan in an amount of 1.9 mg, and wherein percutaneous absorption of zolmitriptan through ex vivo human torso skin over 300 minutes from a single application results in: a. a peak flux at approximately 4 minutes after application, wherein the peak flux is about 849 ± 42 μg/cm2 /hr; and b. a mass balance of about 90% of the applied dose.
21. The patch of claim 13, having a patch area of about 5 cm2 adhered to a titanium substrate with an area of about 6 cm2 and a thickness of about 25 μm.
22. The patch of claim 13 or 21, wherein the area of the microprojection array is about 5.5 cm2 and contains about 4000 microprojections at a density of about 725 microprojections/cm2 .
23. The patch of claim 21 or 22, wherein the formulation contained on each microprojection has an approximate shape of an American football with a thickness that tapers 272776/3 97 down from a maximum of about 270 μm and comprises about 0.96 μg of zolmitriptan and about 0.32 of tartaric acid, or about 3.8 mg of zolmitriptan and about 1.3 mg of tartaric acid per patch.
24. The patch of any one of claims 21 to 23, wherein the microprojections have a length of about 387 ± 13 μm, a width of about 120 ± 13 μm, and a thickness of about 25.4 ± 2.5 μm.
25. The patch of any one of claims 21 to 24, wherein the microprojections are rectangular, with a triangular tip to facilitate penetration and wherein the tip has an angle of 40 ± 5 degrees, and a tip length of about 165 ± 25 microns long.
26. The patch of any one of claims 13 to 25, wherein the microprojections are bent at right angles to the plane of the substrate.
27. The patch of claim 26, wherein the microprojections: a. have a length of about 387 ± 13 μm prior to bending, and b. protrude perpendicular to the substrate about 340 μm after bending.
28. The patch of any one of claims 13 to 27, wherein the formulation does not contain surfactants or other penetration enhancers.
29. A patch for use in a method of treating migraine or cluster headaches in a patient in need thereof, the method comprising applying the patch to a selected area of the skin of the patient, wherein: the patch is adhered to a substrate, wherein the substrate comprises an array of microprojections that are coated with a solid coating formulation comprising zolmitriptan or a pharmaceutically acceptable salt thereof and at least one inactive ingredient, wherein the solid coating formulation is obtained by applying and drying a liquid coating formulation onto the microprojections, the liquid coating formulation having a viscosity of less than 500 centipoise (cP) prior to drying, and wherein the patch has at least one of the following features: 272776/3 98 a. a patch size selected from the group consisting of from about 1 to 20 cm2 , from about 2 to 15 cm2 , from about 4 to 11 cm2 , about 5 cm2 , and about 10 cm2 ; b. a substrate size selected from the group consisting of from about 0.5 to 10 cm2 , from about 2 to 8 cm2 , from about 3 to 6 cm2 , about 3 cm2 , about 3.1 cm2 , about 3.13 cm2 , and about 6 cm2 ; c. an array size selected from the group consisting of from about 0.5 to 10 cm2 , from about 2 to 8 cm2 , from about 2.5 to 6 cm2 , about 2.7 cm2 , about 5.5 cm2 , about 2.74 cm2 , and about 5.48 cm2 ; d. a density (microprojections/cm2 ) selected from the group consisting of at least about 10 microprojections/cm2 , from about 200 to 2000 microprojections/cm2 , from about 500 to 1000 microprojections/cm2 , from about 650 to 800 microprojections/cm2 , and about 725 microprojections/cm2 ; e. a number of microprojections/array selected from the group consisting of from about 100 to 4000, from about 1000 to 3000, from about 1500 to 2500, from about 1900 to 2100, about 2000, about 1987, from about 200 to 8000, from about 3000 to 5000, from about 3500 to 4500, from about 4900 to 4100, about 4000, and about 3974; f. a microprojection length selected from the group consisting of from about 25 to 600 microns, from about 100 to 500 microns, from about 300 to 450 microns, from about 320 to 410 microns, about 340 microns, about 390 microns, about 387 microns, less than 1000 microns, less than 700 microns, and less than 500 microns, wherein the microprojections penetrate the skin from about 25 to 1000 microns; g. a tip length selected from the group consisting of from about 100 to 250 microns, from about 130 to about 200 microns, from about 150 to 180 microns, from about 160 to 170 microns, and about 165 microns; h. a microprojection width selected from the group consisting of from about 10 to 500 microns, from about 50 to 300 microns, from about 75 to 200 microns, from about 90 to 160 microns, from about 250 to 400 microns, about 300 microns, about 100 microns, about 110 microns, about 120 microns, about 130 microns, about 140 microns, and about 150 microns; i. a microprojection thickness selected from the group consisting of from about 1 micron to about 500 microns, from about 5 microns to 300 microns, from about 10 microns to 100 272776/3 99 microns, from about 10 microns to 50 microns, from about 20 microns to 30 microns, and about 25 microns; j. a tip angle selected from the group consisting of about 10-70 degrees, about 20-60 degrees, about 30-50 degrees, about 35 to 45 degrees, and about 40 degrees; k. a total amount of zolmitriptan or a pharmaceutically acceptable salt thereof per array selected from the group consisting of from about 0.1 mg to 10 mg, from about 0.5 mg to 5 mg, from about 1 mg to 4 mg, about 1 mg, about 1.9 mg, and about 3.8 mg; l. an amount of inactive ingredient per array selected from the group consisting of from about 0.1 to 10 mg, from about 0.2 to 4 mg, from about 0.3 mg to 2 mg, about 0.6 mg, about 0.63 mg, about 1.3 mg, about 1.26 mg, from one to three times less than an active agent, and from about 0.033 mg to about 3.33 mg; m. a coating thickness selected from the group consisting of from about 100 μm to about 500 μm, from about 200 μm to about 350 μm, from about 250 μm to about 290 μm, and about 270 μm; n. an amount of zolmitriptan or a pharmaceutically acceptable salt thereof per microprojection selected from the group consisting of from about 0.001 to about 1000 μg, from about 0.01 to about 100 μg, from about 0.1 to 10 μg, from about 0.5 to 2 μg, about 1 μg, and about 0.96 μg.
30. The patch for use of claim 29, wherein the liquid coating formulation comprises: a. zolmitriptan in an amount selected from the group consisting of from 30% w/w to about 60% w/w, from about 40% w/w to about 50% w/w, and about 45% w/w; b. tartaric acid in an amount selected from the group consisting of from about 5% w/w to about 25% w/w, from about 10% w/w to about 20% w/w, and about 15% w/w; and c. a liquid carrier.
31. The patch for use of claim 30, wherein the liquid carrier is water.
32. The patch for use of any one of claims 29 to 31, wherein the liquid coating formulation, prior to drying, has a viscosity selected from the group consisting of: greater than about 3 cP, less than about 400 cP and greater than about 10 cP, less than 300 cP and greater than 272776/3 100 about 50 cP, less than about 250 cP and greater than about 100 cP, more than about 80 cP and less than about 350 cP, more than about 100 cP and less than about 350 cP, more than about 100 cP and less than about 250 cP, at least 20 cP, at least 25 cP, at least about 30 cP, at least about 35 cP, at least about 40 cP, at least about 45 cP, at least about 50 cP, at least about 55 cP, at least about 60 cP, at least about 65 cP, at least about 70 cP, at least about 75 cP, at least about 80 cP, at least about 85 cP, at least about 90 cP, at least about 95 cP, at least about 100 cP, at least about 150 cP, at least about 200 cP, at least about 300 cP, and at least about 400 cP.
33. The patch for use of claim 32, wherein the liquid coating formulation has: a. a viscosity selected from the group consisting of from about 150 cP to about 350 cP, from about 200 cP to about 300 cP, and about 250 cP; and/or b. a surface tension selected from the group consisting of from about 50 mNm-1 to about 72 mNm-1, from about 55 mNm-1 to about 65 mNm-1, and about 62.5 mNm-1 .
34. The patch for use of any one of claims 29 to 33, wherein the solid coating formulation has an average thickness selected from the group consisting of from about 10 to about 400 microns, from about 30 to about 300 microns, from about 100 microns to about 175 microns, from about 115 to about 150 microns, and about 135 microns, as measured from the microprojection surface.
35. The patch for use of any one of claims 29 to 34, wherein the solid coating formulation has a uniform thickness covering the microprojections.
36. The patch for use of any one of claims 29 to 35, wherein the microprojection has a length, a base and a tip; and wherein the solid coating formulation covers at least from about 10% to about 80%, from about 20% to about 70%, from about 30% to about 60%, or from about 40% to about 50% of the length of the microprojection, as measured from the tip to the base of the microprojection.
37. The patch for use of any one of claims 29 to 36, wherein the microprojections have a surface comprising a solid coating formulation disposed thereon, wherein the coating 272776/3 101 comprises about 1.9 mg to about 3.8 mg of zolmitriptan per patch, and about 0.63 mg to about 1.3 mg of tartaric acid per patch.
38. The patch for use of claim 37, wherein the microprojections have a surface comprising a solid coating formulation disposed thereon, wherein the coating comprises about 1.9 mg of zolmitriptan and about 0.63 mg of tartaric acid per patch.
39. The patch for use of claim 37, wherein the microprojections have a surface comprising a solid coating formulation disposed thereon, wherein the coating comprises about 3.8 mg of zolmitriptan and about 1.3 mg of tartaric acid per patch.
40. The patch for use of any one of claims 29 to 36, wherein the microprojections have a surface comprising a solid coating formulation disposed thereon, wherein the coating comprises about 0.96 μg of zolmitriptan and about 0.32 μg of tartaric acid per microprojection.
41. The patch for use of any one of claims 29 to 40, wherein the solid coating formulation does not contain surfactants or other penetration enhancers.
42. An intracutaneous delivery system for use in a method for treating cluster headache in a human patient, the method comprising the steps of: a. providing the intracutaneous delivery system, the system comprising a disposable patch assembly having a plurality of microprojections disposed in an array of about 1 cm2 to about 20 cm2 , the array having a density of about 200 to about 2000 microprojections/cm2 , the microprojections adapted to penetrate or pierce the stratum corneum of a human patient, wherein: i. the microprojections have a solid coating formulation disposed thereon, wherein the coating comprises zolmitriptan or a pharmaceutically acceptable salt thereof in an amount greater than about 0.1 mg/cm2 to less than about 10 mg/cm2 , wherein the solid coating formulation is obtained by applying and drying a liquid coating formulation onto the microprojections, the liquid coating formulation having a viscosity of less than 500 centipoise (cP) prior to drying, and 272776/3 102 ii. the microprojections have a width of about 10 μm to about 500 μm and a tip angle of about 10 to about 70 degrees, and iii. at least 95% of the zolmitriptan is released from the system within about 5 minutes when measured by USP Paddle Over Disk Method (Apparatus 5); and b. applying the microprojections to a selected area of skin of the patient, wherein the patient has pain freedom at about 15 to 30 minutes post-application, and wherein the Tmax of a therapeutically effective blood plasma concentration of zolmitriptan occurs within about 30 minutes of the application, the Cmax is less than about 50 ng/ml and the AUC0-2hr is about 5 to about 20 ng/ml*hour.
43. The intracutaneous delivery system for use of claim 42, wherein the patient is free of one or more of the symptoms selected from the group consisting of excruciating pain, restlessness, excessive tear production and redness in the eye on the affected side, stuffy or runny nose, forehead or facial sweating, pale skin (pallor), facial flushing, swelling around the eye on the affected side, and drooping eyelid, at least 45 minutes post-application.
44. The intracutaneous delivery system for use of claim 42 or 43, wherein the coating has a thickness selected from the group consisting of from about 100 μm to about 500 μm, from about 200 μm to about 350 μm, from about 250 μm to about 290 μm, and about 270 μm.
45. An intracutaneous delivery system for use in a method of treating cluster headache in a population of human patients in need thereof, the method comprising the steps of: a. providing the intracutaneous delivery system, comprising a disposable patch assembly having a plurality of microprojections disposed in an array of about 0.5 to 10 cm2 , the array having a density of about 200 to about 2000 microprojections/cm2 , the microprojections being adapted to penetrate or pierce the stratum corneum of a human patient and having a length of about 25 μm to about 1000 μm, a thickness of about 1 μm to about 500 μm, a width of about 10 μm to about 500 μm, and configured at a tip angle of about 10 to about 70 degrees, wherein: i. the microprojections have a solid coating formulation disposed thereon, wherein the coating comprises zolmitriptan or a pharmaceutically acceptable salt thereof in an amount of from about 0.1 mg to 10 mg per array, 272776/3 103 wherein the solid coating formulation is obtained by applying and drying a liquid coating formulation onto the microprojections, the liquid coating formulation having a viscosity of less than 500 centipoise (cP) prior to drying and ii. wherein at least 95% of the zolmitriptan is released from the system within about 5 minutes when measured by USP Paddle Over Disk Method (Apparatus 5); and b. applying the microprojections to a selected area of skin of each patient, wherein more than about 15% of the patients experience pain freedom at about 15 or 30 minutes postapplication, and wherein the Tmax of a therapeutically effective blood plasma concentration of zolmitriptan occurs within about 30 minutes of the application.
46. The intracutaneous delivery system for use of claim 45, wherein more than about 20% of the patients experience pain freedom at about 15 to 30 minutes post-application.
47. An adhesive dermally-applied microarray (ADAM) coated with a solid coating comprising zolmitriptan or a pharmaceutically acceptable salt thereof, and applied to a penetration site in a subject in need thereof, wherein: a. the microarray comprises microprojections that are about 340 μm long, b. the mean depth of penetration in the penetration site is about 105.4 ± 3.6 μm from stratum corneum into dermis layers of the penetration site, and c. the solid coating is obtained by applying and drying a liquid coating formulation onto the microprojections, the liquid coating formulation having a viscosity of less than 500 centipoise (cP) prior to drying.
48. The zolmitriptan-coated microarray of claim 47, wherein about 96% of the microprojections penetrate the dermis.
49. The zolmitriptan-coated microarray of claim 47 or 48, wherein the microprojections penetrate only about 50% or less of their length. 272776/3 104
50. The zolmitriptan-coated microarray of any one of claims 47 to 49, wherein after the removal of the microarray the mean residue of zolmitriptan on the microarray is about 10% and on the penetration site is about 5%.
51. The zolmitriptan-coated microarray of any one of claims 47 to 50, wherein the microarray is coated with 1.9 mg of zolmitriptan, and the median Tmax for the zolmitriptancoated microarray is 15 minutes.
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| PCT/US2017/048258 WO2019040063A1 (en) | 2017-08-23 | 2017-08-23 | Method of rapidly achieving therapeutic concentrations of zolmitriptan for treatment of migraines and cluster headaches |
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| US11660265B2 (en) | 2018-06-28 | 2023-05-30 | Emergex USA Corporation | Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches |
| US20220241571A1 (en) * | 2019-06-06 | 2022-08-04 | Kindeva Drug Delivery L.P. | Microarray carrier for microarray applicator |
| CA3145203A1 (en) * | 2019-06-28 | 2020-12-30 | Passport Technologies, Inc. | Triptan microporation delivery system |
| CN114699510A (en) * | 2021-12-29 | 2022-07-05 | 浙江湃肽生物有限公司 | Simelide microneedle array and preparation method thereof |
| CN115887903A (en) * | 2022-12-15 | 2023-04-04 | 太平洋康泰科学仪器（济南）有限公司 | Microneedle patch drug delivery assembly and drug delivery method |
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| AU2017428907B2 (en) | 2021-12-16 |
| CA3073442C (en) | 2024-02-06 |
| EP3672570A1 (en) | 2020-07-01 |
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