Transdermal therapeutic system comprising buprenorphine

Abstract

The invention is concerned with a transdermal therapeutic system (TTS) comprising buprenorphine and a method of manufacturing such a TTS. The transdermal therapeutic system is used for the transdermal administration of buprenorphine and analogues thereof. In particular, the invention relates to the use of a transdermal therapeutic system (TTS) for analgesic purposes. The TTS according to the invention comprises a transdermal drug delivery composition comprising buprenorphine and an adhesive component, which is a mixture of a crosslinked and a non-crosslinked acrylic polymer and a penetration enhancer comprising a keto acid.

Claims

1. A transdermal therapeutic system comprising: 1) a backing layer, 2) at least one drug containing adhesive layer containing a transdermal drug delivery composition consisting of: i. 5 to 15% by weight of buprenorphine, based on the total weight of the composition, ii. an adhesive component, which preferably forms an amorphous mass, comprising 20 to 50% by weight of a crosslinked acrylic polymer and 5 to 25% by weight of a non-crosslinked acrylic polymer, based on the total weight of the composition, in a ratio of 80 to 20 parts by weight to 60 to 40 parts by weight, iii. and 5 to 15% by weight of levulinic acid, based on the total weight of the composition, iv. 10 to 20% by weight of oleyl oleate, based on the total weight of the composition, and v. 5 to 15% by weight of polyvinyl pyrrolidone, based on the total weight of the composition; and 3) optionally at least one further adhesive layer, and 4) further optionally, a release liner, wherein the crosslinked acrylic polymer is obtained from one or more non-functional monomers and one or more functional monomers, the functional monomer comprising a carboxy group, an epoxy group and/or a hydroxy group, wherein the transdermal therapeutic system releases buprenorphine in an amount sufficient to achieve a constant blood plasma of at least 200 pg/ml for up to 4 days.

2. The transdermal therapeutic system according to claim 1, wherein the functional monomer is selected from the group consisting of acrylic acid, methacrylic acid, (meth)acrylic acid hydroxy alkylester, 2-hydro-xylethyl acrylate and glycidyl methacrylate.

3. The transdermal therapeutic system according to claim 1, wherein the non-crosslinked acrylic polymer is obtained from monomers comprising one or more (meth)acrylic acid alkyl esters, optionally one or more of a n-alkyl acrylamide, and further optionally one or more of a vinyl ester, or mixtures thereof.

4. The transdermal therapeutic system according to claim 3, wherein: the (meth)acrylic acid alkyl ester is selected from the group consisting of 2-ethylhexyl acrylate, butyl acrylate, methyl acrylate and methyl methacrylate, the monomers further comprise an n-alkylacrylamide comprising t-octyl acrylamide, and the monomers further comprise a vinyl ester comprising vinyl acrylate.

5. The transdermal therapeutic system according to claim 1, wherein the crosslinked acrylic polymer and the non-crosslinked acrylic polymer are present in a ratio of crosslinked : non-crosslinked of 78:22 to 65:35 parts by weight.

6. The transdermal therapeutic system according to claim 1, wherein the crosslinked acrylic polymer and the non-crosslinked acrylic polymer are present in a ratio of crosslinked : non-crosslinked of 76:24 to 67:33 parts by weight.

7. The transdermal therapeutic system according to claim 1, wherein the crosslinked acrylic polymer and the non-crosslinked acrylic polymer are present in a ratio of crosslinked : non-crosslinked of about 70:30 parts by weight.

Description

DESCRIPTION OF FIGURES

(1) The invention are further illustrated in FIGS. 1 and 2.

(2) FIG. 1 shows buprenorphine blood plasma concentration in blood samples of patients wearing patches containing inventive and comparative buprenorphin compositions.

(3) FIG. 2 shows a comparison of in vitro buprenorphine skin permeation through dermatomised human skin of inventive and comparative compositions.

(4) The invention will further be described in the following examples, which are included for purposes of illustrating the invention and are not intended, in any way, to be limiting of the scope of invention.

EXAMPLES

(5) 1) Manufacture of a Transdermal Therapeutic System

Example 1

(6) 48.125 g of a self-crosslinkable polyacrylate solution having a solid content of 48 wt. % and obtained from a monomer mixture comprising vinyl acetate, 2-ethylhexyl acrylate and acrylic acid in ethyl acetate, 2-propanol, heptane, toluol and 2,4-pentandion as solvents, 23.571 g of a non-crosslinkable polyacrylate solution having a solid content of 42 wt. % and obtained from 2-ethylhexyl acrylate, butyl acrylate, t-octyl acrylamide and methylmethacrylate solved in ethyl acetate, 6 g levulinic acid, 9 g oleyl oleate, 6 g polyvinyl pyrrolidone, 19.95 g 2-propanol, 39.98 g ethyl acetate and 6 g buprenorphine base were homogenized. It was stirred for about 2 h and controlled visually, whether all solids were solved. The homogenous solution was then coated on a transparent polyester foil of a width of 280 mm, resulting in a coating weight per unit area of about 80 g/m.sup.2. The siliconized polyester layer served as a backing layer or as a release liner. The solvents were removed by drying with heated air, which was streamed over the wet coating. The adhesive coating was then covered with a polyester foil of a thickness of 15 μm. An area of 10 cm.sup.2 was then cut by appropriate cutting tools. The edges between distinct systems were removed.

Example 2

(7) 55 g of a self-crosslinkable polyacrylate solution having a solid content of 48 wt. % and obtained from a monomer mixture comprising vinyl acetate, 2-ethylhexyl acrylate and acrylic acid as monomers in ethyl acetate 2-propanol, heptane, toluol and 2,4-pentandion as solvent, 15.741 g of a non-crosslinkable polyacrylate solution having a solid content of 42 wt. % and obtained from 2-ethylhexyl acrylate, butyl acrylate, t-octyl acrylamide and methylmethacrylate solved in ethyl acetate, 6 g levulinic acid, 9 g oleyl oleate, 6 g polyvinyl pyrrolidone, 19.95 g 2-propanol, 39.98 g ethyl acetate and 6 g buprenorphine base were homogenized. It was stirred for about 2 h and controlled visually, whether all solids were solved. The homogenous solution was then coated on a transparent polyester foil of a width of 280 mm, resulting in a coating weight per unit area of about 80 g/m.sup.2. The siliconized polyester layer served as a backing layer or as a release liner. The solvents were removed by drying with heated air, which was streamed over the wet coating. The adhesive coating was then covered with a polyester foil of a thickness of 15 μm. An area of 10 cm.sup.2 was then cut by appropriate cutting tools. The edges between distinct systems were removed.

Example 3

(8) 48.125 g of a self-crosslinkable polyacrylate solution having a solid content of 48 wt. % and obtained from a monomer mixture comprising vinyl acetate, 2-ethylhexyl acrylate and acrylic acid in ethyl acetate, 2-propanol, heptane, toluol and 2,4-pentandion as solvents, 23.571 g of a non-crosslinkable polyacrylate solution having a solid content of 42 wt. % and obtained from 2-ethylhexyl acrylate, butyl acrylate, t-octyl acrylamide and methylmethacrylate solved in ethyl acetate, 6 g 5-oxohexanoic acid, 9 g oleyl oleate, 6 g polyvinyl pyrrolidone, 19.95 g 2-propanol, 39.98 g ethyl acetate and 6 g buprenorphine base were homogenized. It was stirred for about 2 h and controlled visually, whether all solids were solved. The homogenous solution was then coated on a transparent polyester foil of a width of 280 mm, resulting in a coating weight per unit area of about 80 g/m.sup.2. The siliconized polyester layer served as a backing layer or as a release liner. The solvents were removed by drying with heated air, which was streamed over the wet coating. The adhesive coating was then covered with a polyester foil of a thickness of 15 μm. An area of 10 cm.sup.2 was then cut by appropriate cutting tools. The edges between distinct systems were removed.

(9) 2) Evaluation of Buprenorphine Release from TTS Patches and Evaluation of Adhesive Force

(10) The following commercially available compounds have been used in the following Examples:

(11) Kollidon 90 F®: a non-crosslinked polyvinyl pyrrolidone available from BASF.

(12) Cetiol PH®: oleyl oleate available from Cognis Europe.

(13) The crosslinked acrylic polymer was obtained from a monomer mixture comprising acrylic acid, 2-ethylhexyl acrylate and vinyl acetate, supplied in a solvent mixture of ethyl acetate, heptane, isopropylalcohol, toluene and 2,4-pentanedion containing 0.4% of aluminium acetyl acetonate as crosslinker.

(14) The non-crosslinked acrylic polymer was obtained from a monomer mixture comprising 2-ethylhexyl acrylate, butyl acrylate, t-octyl acrylamide and methyl methacrylate, supplied in ethyl acetate as solvent.

(15) Transdermal therapeutic buprenorphine systems (also designated in the following as “patches”) were prepared according to the method of manufacture as described for Example 1 (all percentages are on a weight basis).

(16) Compositions 1 and 2 were according to the subject invention, thus, the adhesive component of the transdermal drug delivery composition forming the drug containing adhesive layer included a mixture of a crosslinked and a non-crosslinked acrylic polymer. Moreover, the adhesive component formed an amorphous mass.

(17) The resulting compositions were as described in Table 1:

(18) TABLE-US-00001 TABLE 1 Reference Reference Reference Reference Composition 1 Composition 2 Composition 1 Composition 2 Composition 3 Composition 4 Buprenorphine 10% 10% 10% 10% 10% 10% Enhancer 1 10% levulinic 10% levulinic acid 10% levulinic acid 10%, AMEE.sup.1 12.5% caprylic acid 20% caprylic acid acid monoglyceride monoglyceride Enhancer 2 15% Cetiol ® PH 15% isopropyl 15% Cetiol ® PH 15% Cetiol ® PH 12.5% isopropyl 20% isopropyl myristate myristate myristate Solubilizer 10% Kollidon ® 10% Kollidon ® 90 F 10% Kollidon ® 90 F 10% Kollidon ® 90 F 10% Kollidon ® 90 F 5% silicate 90 F acrylic polymer 55% crosslinked/ 55% crosslinked/ 55% crosslinked 55% crosslinked 55% crosslinked/ 55% crosslinked/ adhesive non-crosslinked.sup.2 non-crosslinked.sup.2 non-crosslinked.sup.2 non-crosslinked.sup.2 .sup.1Adipinic acid monoethyl ester .sup.2ratio crosslinked: non-crosslinked acrylic polymer was 70:30 on a weight basis
2.1 In Vivo Studies for Evaluation of Buprenorphine Blood Plasma Concentrations

(19) Samples of patches of Composition 1 and Reference Compositions 1 and 2 were used in a single-center, randomized, single-dose, four-treatment, four-period crossover study. Healthy adult subjects were randomly assigned to one of 4 treatment sequences. There was a washout period of 14 days between treatment arms. The system was removed 168 hours after application. Blood samples (1×5 ml) were collected in blood collection tubes containing heparin sodium before patch application and at the following times thereafter: 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 (following patch removal), 172, 180, 192, and 204 hours. Blood samples were analyzed for buprenorphine concentration levels and are as shown in FIG. 1.

(20) It can be seen by FIG. 1 that the TTS according to the invention (Composition 1) leads to increased blood plasma concentrations of the active ingredient compared to the comparative TTS (Reference Compositions 1 and 2). In particular, the TTS of the invention releases buprenorphine in an amount sufficient to obtain a blood plasma level of at least 100 pg ml over a period of more than 144 h and a blood plasma level of at least 200 pg ml over a period of more than 96 h. The Reference Composition 1 comprising only crosslinked acrylic polymer as single adhesive component and levulininc acid as enhancer shows significantly reduced blood plasma concentrations. Thus, it was surprisingly found by the inventors that the combination of a crosslinked and a non-crosslinked acrylic polymer in the drug adhesive layer leads to enhanced blood plasma levels of the active ingredient. Moreover, the Reference Composition 2 having AMEE instead of levulinic acid enhancer merely reaches a maximum buprenorphine blood plasma concentration of 200 pg/ml, which is much lower than in Reference Composition 1 or the inventive Composition 1. In addition the maximum blood plasma concentration rapidly decreases after only 50 h of skin adhesion. Thus, it was not possible with the Reference Composition 2 to reach a constant blood plasma concentration of buprenorphine.

(21) It could thus be surprisingly shown by the present invention that the TTS of the subject invention lead to higher plasma levels of buprenorphine in the blood plasma of patients which remains constant over the required period of time of 3 or 4 to 7 days and which is sufficient to induce analgesia in a patient.

(22) 2.2 In Vitro Evaluation of Buprenorphine Skin Permeation

(23) Skin permeation was evaluated using Compositions 1 and 2 and Reference Compositions 3 and 4 as show in Table 1. Skin permeation measurements were performed according to “ECD Guidelines for the Testing of Chemicals/Section 4: Health Effects, Test No. 428: Skin Absorption: in vitro method; OECD; published by: OECD Publishing, 2004”. Preparation of skin permeation cells were as follows:

(24) TABLE-US-00002 Cell Vertical diffusion cell Medium PBS buffer, pH 5.6 Permeation area 1 cm.sup.2 Acceptor volume 40 ml Sample volume/replacement 1 ml/automatically Sampling After 6, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144 and 168 h Membrane Dermatomised human skin Temperature of water bath 32° C.

(25) The samples were analyzed for buprenorphine using conventional high performance liquid chromatography (HPLC) methods.

(26) TABLE-US-00003 Column Hypersil ® BDS C8, 250 × 4.0 mm, 5 μm Mobile phase 58% 10 mM KH.sub.2PO.sub.4, pH 3.0/42% acetonitrile Flow rate 1 ml/min Detector UV detector, wave length 210 mm

(27) The cumulative amount of buprenorphine penetrating through the skin was calculated and reported as μg/cm.sup.2. The results of the measurements are shown in FIG. 2 as average values. Four samples were measured from each batch of Compositions 1 and 2 and Reference Compositions 3 and 4. However, only three of four measurements could be considered for Reference Composition 3.

(28) Based on the above-results as shown in FIG. 2, the buprenorphine flux could be calculated. The buprenorphine flux corresponds to the amount of buprenorphine penetrating the dermatomised skin per hour reported in μg/(cm.sup.2*h), as shown in Table 2:

(29) TABLE-US-00004 Com- Com- Reference Reference position 1 position 2 Composition 3 Composition 4 Flux 2.25 2.52 1.71 0.66 [μg/(cm.sup.2h)]
2.3 Adhesive Force Measurements

(30) Adhesive force was determined using Compositions 1 and 2 and Reference Compositions 3 and 4 as show in Table 1. Adhesive force measurements were performed according to A.F.E.R.A. method 4001 in which peel test was carried out at 90° peel using stainless steel. Results were as shown in Table 3:

(31) TABLE-US-00005 Com- Com- Reference Reference position 1 position 2 Composition 3 Composition 4 Adhesive force 0.8 1.3 2.2 (—)* [N] *could not be determined due to adhesive composition remaining partially on the release liner upon peeling

(32) FIG. 2 surprisingly shows that skin permeation was significantly higher for Compositions 1 and 2 compared with Reference Compositions 3 and 4. These results could be confirmed by the corresponding flux values, which were also significantly higher for Compositions 1 and 2 compared with Reference Compositions 3 and 4. Both compositions 1 and 2 show a satisfactory adhesive force which is strong enough to provide tackiness over the whole period of use and which can easily be removed from the skin of the patient. In particular, Composition 2 has the benefits of providing high tackiness and a high buprenorphine release.

(33) In contrast, adhesive force for Reference Composition 4 could not be determined since the adhesive composition was too soft and remained partially on the release liner upon peeling. Thus, no meaningful results could be obtained. Moreover, although Reference Composition 3 shows a high adhesive force and the results of the buprenorphine release and flux values were much lower compared with the inventive compositions.

(34) Therefore, only the Compositions 1 and 2 provide a satisfactory balance between buprenorphine release, flux and adhesive force, making the patches particularly suitable to provide a constant and high buprenorphine release over a period of more than three days, and preferably four days.

(35) Further, the combination of the adhesive composition comprising a crosslinked and a non-crosslinked acrylic acid polymer and containing the penetration enhancer according to the subject invention provides improved drug release while at the same time ensures sufficient tackiness of the adhesive composition to provide strong adhesion but also comfortable wear of the TTS.

(36) In summary, the invention provides a transdermal system having one or more of the benefits of (1) a long lasting (more than three days, preferably more than four days) and continuous release of active ingredient, (2) good tolerability by the skin over the entire period of use, (3) reliable efficacy, (4) preventing abuse of the drug contained in the transdermal system, (5) good comfort even after the entire period of use, (6) inexpensive production with a highly reproducibly quality, (7) the dosage can be adjusted by simply varying the size of the skin-contact area, (8) high stability in storage, and (9) high mechanical stability due to the homogeneous structure of the system.