ESKETAMINE-SUSPENSION-TTS

Abstract

The present invention concerns a transdermal therapeutic system, comprising a backing layer, which is not permeable N for the active ingredient, and at least one matrix layer on one side of the backing layer, wherein the matrix layer contains at least one pressure sensitive adhesive and ketamine or a pharmaceutically acceptable salt or solvate thereof, wherein the at least one pressure sensitive adhesive comprises a silicone pressure sensitive adhesive, as well as its use as medicament, in particular for the treatment of depression and pain.

Claims

1. A transdermal therapeutic system comprising: a backing layer, which is not permeable for the active ingredient; and at least one matrix layer on one side of the backing layer; wherein the matrix layer contains at least one pressure sensitive adhesive and ketamine or a pharmaceutically acceptable salt or solvate thereof; and wherein the at least one pressure sensitive adhesive comprises a silicone pressure sensitive adhesive.

2. The transdermal therapeutic system of claim 1, wherein the ketamine is (S)-ketamine or a pharmaceutically acceptable salt or solvate thereof.

3. The transdermal therapeutic system of claim 1, wherein the ketamine is present in the form of the ketamine free base.

4. The transdermal therapeutic system of claim 1, wherein the silicone pressure sensitive adhesive comprises a dimethiconol/trimethylsiloxysilicate crosspolymer and/or a trimethylsilyl treated dimethiconol/trimethylsiloxysilicate crosspolymer.

5. The transdermal therapeutic system of claim 1, wherein the silicone pressure sensitive adhesive is present in the matrix layer in an amount of 70 to 95 wt.-%, based on the total weight of the matrix layer.

6. The transdermal therapeutic system of claim 1, wherein the matrix layer comprises at least one penetration enhancer.

7. The transdermal therapeutic system of claim 6, wherein the at least one penetration enhancer is selected from the group consisting of levulinic acid, valeric acid, hexanoic acid, caprylic acid, nonanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, 3-methylbutanoic acid, neoheptanoic acid, neonanonic acid, isostearic acid, oleic acid, palmitoleic acid, linolenic acid, vaccenic acid, petroselinic acid, elaidic acid, oleic acid, arachidonic acid, gadoleic acid, erucic acid, methyl propionate, methyl valerate, diethyl sebacate, methyl laurate, ethyl laurate, ethyl oleate, isopropyl decanoate, isopropyl myristate, isopropyl palmitate, isopropyl oleate, diethyltoluamide, propylene glycol monocaprylate, propylene glycol, polyethylene glycol, diisopropyl adipate, eugenol, transcutol, lauryl lactate, and/or oleyl alcohol.

8. The transdermal therapeutic system of claim 6, wherein the matrix layer comprises the at least one penetration enhancer in an amount of 1 to 15 wt.-%, based on the total weight of the matrix layer.

9. The transdermal therapeutic system of claim 1, wherein the matrix layer does not comprise any pressure sensitive adhesive that comprises (meth)acrylate groups.

10. The transdermal therapeutic system of claim 1, wherein the matrix layer comprises ketamine in an amount of 1 to 25 wt.-%, based on the weight of the matrix layer.

11. The transdermal therapeutic system of claim 1, wherein the matrix layer comprises at least one antioxidant.

12. The transdermal therapeutic system of claim 1, wherein the matrix layer has an area weight of 30 to 400 g/m.sup.2.

13. The transdermal therapeutic system of claim 1, wherein the transdermal therapeutic system comprises a detachable protective layer on that side of the matrix layer on which the backing layer is not arranged.

14. The transdermal therapeutic system of claim 1 for use as a medicament.

15. The transdermal therapeutic system of claim 1 for use in the treatment of depression and/or pain.

16. The transdermal therapeutic system of claim 3, wherein the ketamine is (S)-ketamine.

17. The transdermal therapeutic system of claim 6, wherein the at least one penetration enhancer comprises methyl laurate.

18. The transdermal therapeutic system of claim 11, wherein the at least one antioxidant comprises alpha-tocopherol, ascorbyl palmitate and/or dibutylhydroxytoluene.

Description

EXAMPLES

[0106] In the following examples, the following ingredients were used.

[0107] BIO-PSA Q7-4201 and BIO-PSA 4301: trimethylsilyl treated dimethiconol/trimethylsiloxysilicate crosspolymer.

[0108] DURO-TAK 387-4287: Pressure sensitive adhesive on the basis of an acrylate vinyl acetate copolymer comprising free hydroxyl groups, obtained without using a crosslinking agent.

[0109] DURO-TAK 387-2054: Pressure sensitive adhesive on the basis of an acrylate vinyl acetate copolymer comprising free carboxyl groups, obtained with using a crosslinking agent.

[0110] Plastoid B: Copolymer of butyl methacylate and methyl methacylate (crystallization inhibitor)

[0111] Transcutol: Diethylene glycol monoethyl ether (enhancer)

[0112] Eutanol HD: 9-Octadecen-1-ol (enhancer)

[0113] HPC/Isopropanol: Hydroxypropyl cellulose dissolved in isopropanol (gelling agent; solid content 2 wt.-%).

[0114] HPC/1,2-Propandiol: Hydroxypropyl cellulose dissolved in 1,2-propandiol (gelling agent; solid content 2 wt.-%)

[0115] Crosspovidone: Crosslinked polyvinylpolypyrrolidone (structure agent)

Example 1

[0116] The formulations of the S-ketamine-containing coating compositions of this example are summarized in Table 1 below.

TABLE-US-00001 TABLE 1 Ingredient Formulation [wt.-%] (Trade Name) Ex. 1a Ex. 1b Ex. 1c Ex. 1d Ex. 1e Ex. 1f S-ketamine base 10.0 10.0 10.0 10.0 10.1 10.0 Silicone adhesive in n-heptane. — 42.3 42.2 42.1 — 44.9 Solids content of 72.6% by weight (DOW CORNING ® BIO-PSA Q7-4201) Silicone adhesive in n-heptane. — 42.5 42.2 42.5 — 44.6 Solids content of 72.3% by weight (DOW CORNING ® BIO-PSA Q7-4301) Acrylic adhesive in ethyl acetate. 73.8 — — — — — Solids content of 38.4% by weight (DURO-TAK ™ 387-4287) Acrylic adhesive in ethyl acetate, — — — — 54.8 — heptanes, isopropanol, 2,4- pentanedione, toluene. Solids content of 47.5% by weight (DURO-TAK ™ 387-2054) Plastoid B — — — — 20.0 — Methyl laurate 10.1  5.1  5.1  5.0 — — Leuvulinic acid  6.1 — — —  5.0 — Eutanol HD — — — —  5.0 — Transcutol — — — —  5.0 — HPC/Isopropanol — —  0.5 — — — HPC/1,2-propandiol — — —  0.5 —  0.5 Area Weight [g/m.sup.2] 78.9 71.0 81.9 78.5 81.5 79.6

[0117] For Example 1a, a beaker was loaded with the S-ketamine base, with the solvent (ethyl acetate), the levulinic acid and the methyl laurate. The acrylic pressure sensitive adhesive polymer DURO-TAK 387-4287 was added and the mixture was then stirred at up to 300 rpm until a homogeneous mixture was obtained (stirring time is about 90 min.).

[0118] For Example 1b, a beaker was loaded with the S-ketamine base, with the solvent (n-heptane) and the methyl laurate. The mixture was stirred for about 30 min at 300 rpm and then the silicone pressure sensitive adhesives DOW CORNING BIO-PSA Q7-4201 and DOW CORNING BIO-PSA Q7-4301 were added. The mixture was then stirred at up to 900 rpm until a homogeneous mixture was obtained (stirring time is about 90 min.).

[0119] For Example 1c, a beaker was loaded with the HPC/Isopropanol solution, the methyl laurate and the S-ketamine base. The mixture was stirred for about 30 min at 300 rpm and then the silicone pressure sensitive adhesives DOW CORNING BIO-PSA Q7-4201 and DOW CORNING BIO-PSA Q7-4301 were added. The mixture was then stirred at up to 900 rpm until a homogeneous mixture was obtained (stirring time is about 90 min.).

[0120] For Example 1d, a beaker was loaded with the HPC/1,2-propandiol solution, the methyl laurate and the S-ketamine base. The mixture was stirred for about 30 min at 300 rpm and then the silicone pressure sensitive adhesives DOW CORNING BIO-PSA Q7-4201 and DOW CORNING BIO-PSA Q7-4301 were added. The mixture was then stirred at up to 900 rpm until a homogeneous mixture was obtained (stirring time is about 90 min.).

[0121] For Example 1e, a beaker was loaded with the S-ketamine base, with the solvent (ethyl acetate), the levulinic acid, the Eutanol HD and the Transcutol. The acrylic pressure sensitive adhesive polymer DURO-TAK 387-2054 was added and the mixture was then stirred at up to 300 rpm for about 30 min. The Plastoid B is added and the mixture is then stirred at up to 350 rpm until a homogeneous mixture was obtained (stirring time is about 120 min.).

[0122] For Example 1f, a beaker was loaded with the HPC/1,2-propandiol solution and the S-ketamine base. The mixture was stirred for about 30 min at 300 rpm and then the silicone pressure sensitive adhesives DOW CORNING BIO-PSA Q7-4201 and DOW CORNING BIO-PSA Q7-4301 were added. The mixture was then stirred at up to 900 rpm until a homogeneous mixture was obtained (stirring time is about 90 min.).

[0123] For Examples 1a and 1e the resulting S-ketamine-containing coating composition was coated on a polyethylene terephthalate film (siliconized, 75 μm thickness, which may function as release liner) and dried for approx. 15 min at room temperature and 15 min at 60° C. The coating thickness gave an area weight of the matrix layer of 78.9 g/m.sup.2 (Example 1a) rsp. 81.5 g/m.sup.2 (Example 1e). The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an S-ketamine-containing self-adhesive layer structure.

[0124] For Examples 1b, 1c, 1d and 1f the resulting S-ketamine-containing coating composition was coated on a polyethylene terephthalate film (fluorpolymerized, 75 μm thickness, which may function as release liner) and dried for approx. 15 min at room temperature and 15 min at 60° C. The coating thickness gave an area weight of the matrix layer of 71.0 g/m.sup.2 (Example 1b). 81.9 g/m.sup.2 (Example 1c), 78.5 g/m.sup.2 (Example 1d) and 79.6 g/m.sup.2 (Example 1f), respectively. The dried film was laminated with a polyethylene terephthalate backing layer (19 μm thickness) to provide an S-ketamine-containing self-adhesive layer structure.

[0125] The individual systems were then punched out from the S-ketamine-containing self-adhesive layer structure. In specific embodiments a TTS as described above can be provided with a further self-adhesive layer of larger surface area, preferably with rounded corners, comprising a pressure-sensitive adhesive matrix layer which is free of active agent. This is of advantage when the TTS, on the basis of its physical properties alone, does not adhere sufficiently to the skin and/or when the S-ketamine-containing matrix layer, for the purpose of avoiding waste, has pronounced corners (square or rectangular shapes). The systems are then punched out and sealed into pouches of the primary packaging material.

[0126] Measurement of Skin Permeation Rate

[0127] The permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 1a-1f were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) and the EMA guideline on quality of transdermal patches (EMA/CHMP/QWP/608924/2014, adopted Oct. 23, 2014), carried out with a 7.0 ml Franz diffusion cell. Split thickness human abdominal skin (female) was used. A dermatome was used to prepare skin to a thickness of 500 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.152 cm.sup.2 were punched from the TTS. The S-ketamine permeated amount in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. was measured after 72 h and the corresponding skin permeation rate [μg/cm.sup.2*h] is calculated. The results are shown in Table 2 and FIG. 1.

TABLE-US-00002 TABLE 2 Skin permeation rate with SD [μg/(cm.sup.2 h)] Elapsed Ex. 1a Ex. 1b Ex. 1c Ex. 1d Ex. 1e Ex. 1f time (n= 3) (n = 3) (n = 3) (n = 3) (n = 3) (n = 3) Δ[h] Rate SD Rate SD Rate SD Rate SD Rate SD Rate SD 0 0 0 0 0 0 0 0 0 0 0 0 0 1.5 11.5 3.40 5.6 1.35 5.7 4.61 8.6 1.70 9.3 2.51 4.3 1.02 4.5 19.1 4.10 10.1 1.88 12.8 1.72 13.0 2.51 15.3 2.72 7.9 1.15 7 21.9 3.73 10.8 3.50 17.7 3.42 14.6 2.46 16.0 2.17 9.1 0.89 9 20.8 3.28 12.6 3.10 17.6 2.65 16.3 3.91 15.7 1.56 9.5 1.25 11 19.8 2.57 14.5 3.39 17.9 2.09 16.1 3.04 15.1 1.25 9.7 1.60 14 17.6 1.82 12.2 2.87 18.4 2.01 16.7 2.90 14.5 1.08 10.3 1.55 20 14.2 0.59 13.4 2.46 18.5 1.56 17.0 2.52 12.3 0.65 10.2 1.22 36 6.7 0.09 7.6 2.19 13.4 0.90 12.4 0.47 8.0 0.41 10.1 0.91 60 4.8 0.37 6.3 1.98 3.7 1.50 3.8 2.16 4.9 0.52 8.2 0.29

[0128] Utilization of S-Ketamine

[0129] The utilization of S-ketamine at 72 h was calculated based on the permeated amount of s-ketamine in the receptor and the initial S-ketamine content in the TTS. The results are shown in Table 3 and FIG. 2.

TABLE-US-00003 TABLE 3 Utilization of S-Ketamine after 72 h [%] Exam- Exam- Exam- Exam- Exam- Exam- ple 1a ple 1b ple 1c ple 1d ple 1e ple 1f (n = 3) (n = 3) (n = 3) (n = 3) (n = 3) (n = 3) 86.0 86.0 97.1 96.1 76.7 82.3

[0130] The results summarized in FIG. 1 to FIG. 2 show an improved utilization of the active ingredient and an improved flux of active ingredient compared to a formulation with an acrylic adhesive.

Example 2

[0131] The formulations of the S-ketamine-containing coating compositions of Examples 2a-d were prepared analogously as described in Example 1 and are summarized in Table 4 below.

TABLE-US-00004 TABLE 4 Ingredient Formulation [wt.-%] (Trade Name) Ex. 2a Ex. 2b Ex. 2c Ex 2d S-ketamine base 10.0 10.0 10.0 10.0 Silicone adhesive in n-heptane. 42.2 39.8 40.0 42.3 Solids content of 72.6% by weight (DOW CORNING ® BIO-PSA Q7- 4201) Silicone adhesive in n-heptane. 42.2 39.8 39.9 42.1 Solids content of 72.3% by weight (DOW CORNING ® BIO-PSA Q7- 4301) Methyl laurate 5.1 10.0 5.1 5.1 HPC/Isopropanol 0.5 0.5 — 0.5 Crosspovidone — — 5.0 — Area Weight [g/m.sup.2] 81.9 81.8 86.8 65.5

[0132] The skin permeation rate was determined analogously to Example 1 and is summarized in FIG. 3.

[0133] Utilization of S-Ketamine

[0134] The utilization of S-ketamine at 72 h was calculated based on the permeated amount of s-ketamine in the receptor and the initial S-ketamine content in the TTS. The results are shown in Table 5 and FIG. 4.

TABLE-US-00005 TABLE 5 Utilization of S-Ketamine after 72 h [%] Example 2a Example 2b Example 2c Example 2d (n = 3) (n = 3) (n = 3) (n = 3) 97.1 93.6 99.0 99.9

[0135] The results summarized in FIG. 3 to Hg. 4 show an improved utilization of the active ingredient by reducing the coating weight and a faster and higher onset of flux by using a higher concentration of enhancer. Crosspovidone is an equivalent alternative compared to HPC.

Example 3

[0136] The formulations of the S-ketamine-containing coating compositions of Examples 3a-h were prepared analogously as described in Example 1 and are summarized in Table 6 below.

TABLE-US-00006 TABLE 6 Ingredient Formulation [wt.-%] (Trade Name) Ex. 3a Ex. 3b Ex. 3c Ex. 3d Ex. 3e Ex. 3f Ex. 3g Ex. 3h S-ketamine base 10.0 10.0 10.0 10.1 10.0 10.0 10.0 10.0 Silicone adhesive in n-heptane. 90.0 — 44.9 — — — — — Solids content of 72.6% by weight (DOW CORNING ® BIO-PSA Q7-4201) Silicone adhesive in n-heptane. — 90.0 45.1 — — — — — Solids content of 72.3% by weight (DOW CORNING ® BIO-PSA Q7-4301) Acrylic adhesive in ethyl acetate. — — — 89.9 — — — — Solids content of 38.4% by weight (DURO-TAK ™ 387-4287) Acrylic adhesive in ethyl acetate, — — — — 90.0 — — — heptanes, isopropanol, 2,4- pentanedione, toluene. Solids content of 47.5% by weight (DURO-TAK ™ 387-2054) Acrylic adhesive in ethyl acetate. — — — — — 90.0 — — Solids content of 36.6% by weight (DURO-TAK ™ 87-9301) Acrylic adhesive in ethyl acetate. — — — — — — 90.0 — Solids content of 39.3% by weight (DURO-TAK ™ 87-4098) Polyisobutylene adhesive in n-heptane. — — — — — — — 90.0 Solids content of 36.6% by weight (DURO-TAK ™ 87-6908) Area Weight [g/m.sup.2] 93.2 91.7 92.9 103.0  98.4 106.4  103.0  95.8

[0137] Skin permeation rate and (S)-Ketamin utilization was analyzed analogously to The respective results are given in FIGS. 5 and 6, respectively.