Field of the Invention
[0001] This invention is in the field of transdermal delivery of levonorgestrel.
Background of the Invention
[0002] Various adhesive matrix compositions have been developed for transdermal delivery of steroid hormones. For example,
U.S. Patent No. 7,384,650 describes a transdermal hormone delivery system that utilizes an adhesive composition comprising a pressure sensitive adhesive (PSA), a humectant, a skin permeation enhancer, an estrogen and a progestin.
[0004] EP 0913158 relates to a transdermal patch comprising a combination of two or more fatty acids or alcohols as permeation enhancers. The document discloses a transdermal matrix system for the percutaneous delivery of levonorgestrel and estradiol in Example 35, which comprises lauric and oleic acid permeation enhancers, a carrier comprising a polyacrylate pressure sensitive adhesive (Duro Tak 87-2852) and BHT antioxidant.
Summary of the Invention
[0005] This invention relates to a polymeric matrix useful in a transdermal delivery system for transdermal delivery of levonorgestrel.
[0006] One aspect of the invention features composition for transdermal delivery of levonorgestrel as defined in the appended claims.
[0007] The above-described composition can also include a humectant. In certain embodiments, the humectant is PVP or a PVP co-polymer, such as PVP/VA.
[0008] In various embodiments of the above-described composition, the levonorgestrel is present in a concentration based on weight of the composition of 0.1% to 3.0% or 0.2% to 2.0% or 0.5% to 1.5%. The skin permeation enhancer can present in a concentration based on weight of the composition of 1% to 50% or 2% to 40%.
[0009] In certain embodiments, the anti-oxidant in the composition includes BHT. The BHT can be present in a concentration based on weight of the hormone of 10% to 500%, 20% to 200%, or 50% to 150%.
[0010] The composition does not comprise an estrogen. In certain embodiments, the anti-oxidant in the composition is pentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate) or tris (2,4-di-tert-butylphenyl) phosphite.
[0011] Another aspect of the invention features a method of improving the stability of levonorgestrel in a levonorgestrel transdermal delivery composition that does not comprise an estrogen as defined in the appended claims.
[0012] In various embodiments of the method, the levonorgestrel is present in the composition in a concentration based on weight of the composition of 0.1% to 3.0% or 0.2% to 2.0% or 0.5% to 1.5%. The skin permeation enhancer is present in a concentration based on weight of the composition of 1% to 50% or 2% to 40%.
[0013] In various embodiments of the method, the anti-oxidant in the composition is BHT. The BHT may present in a concentration based on weight of the hormone of 10% to 500%, 20% to 200%, or 50% to 150%.
[0014] In various embodiments of the method, the anti-oxidant in the composition is pentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate) or tris (2,4-di-tert-butylphenyl) phosphite.
[0015] These and other embodiments are more fully described below.
Detailed Description of the Invention
[0016] The present invention is useful in delivering levonorgestrel to a patient that can benefit from supplementation, i.e., delivery of levonorgestrel without concomitant delivery of an estrogen. In an aspect of the present invention, the levonorgestrel, is stabilized, i.e., protected from degradation, by incorporation of an anti-oxidant as defined in the appended claims.
[0017] As discussed further hereinbelow, certain components of a transdermal composition, such as the transdermal compositions described in
US 7,384,650 and hereinbelow, have been found to contribute to degradation of levonorgestrel. Such components include the polyacrylate pressure sensitive adhesive ("PSA"), the PVP humectant (e.g., PVP/VA), and the dimethyl sulfoxide skin permeation enhancer. Incorporation of an excipient that functions as an antioxidant can protect the levonorgestrel from degradation, i.e., it can slow degradation of the levonorgestrel, and thereby increase the shelf life of the composition.
[0018] Levonorgestrel-containing Transdermal Composition: The composition for transdermal delivery, i.e., systemic delivery through the skin, has a composition as defined in the appended claims. The composition does not comprise an estrogen, and it may be referred to as a "levonorgestrel-only transdermal composition". The composition optionally also comprises excipients such as gelling agents, plasticizers, humectants, buffers, and the like. The composition can be formulated and applied to the skin, for instance, as a gel, an ointment, or a spray, which are not according to the invention, or it can be contained within a transdermal delivery device, such as a patch, in which the composition is contained, for example, within a reservoir by a semipermeable membrane or as a soft polymeric matrix that is in direct contact with the skin, i.e., that is firm enough that a reservoir membrane is not required.
[0019] In an illustrative embodiment of the invention, the composition is a polymeric matrix comprising a polymer pressure-sensitive adhesive (PSA) as a carrier, the levonorgestrel, the anti-oxidant and the skin permeation enhancer. The polymer is a pressure sensitive adhesive ("PSA") that forms a biologically acceptable adhesive polymer matrix capable of forming adhesive active-containing thin films or coatings through which the progestin can pass into the skin. Suitable polymers are biologically and pharmaceutically compatible, nonallergenic, insoluble in and compatible with body fluids or tissues with which the device is contacted. The use of water soluble polymers is generally less preferred since dissolution or erosion of the matrix would affect the release rate of the progestin as well as the capability of the dosage unit to remain in place on the skin. So, in certain embodiments, the polymer is non-water soluble.
[0020] Suitable transdermal compositions not according to the invention are disclosed, e.g., in
US 7,045,145,
US 7,384,650,
US 20100255072,
US 2010292660, and
US 20100178323.
[0021] Polymers used to form a polymer matrix in the progestin-containing layer can have glass transition temperatures below room temperature such that they are soft and pliable at room temperature. The polymers are preferably non-crystalline but may have some crystallinity if necessary for the development of other desired properties. Cross-linkable monomeric units or sites can be incorporated into such polymers. For example, cross-linking monomers that can be incorporated into polyacrylate polymers include polymethacrylic esters of polyols such as butylene diacrylate and dimethacrylate, trimethylol propane trimethacrylate and the like. Other monomers that provide such sites include allyl acrylate, allyl methacrylate, diallyl maleate and the like.
[0022] PSAs used to form the adhesive composition are polyacrylate adhesives. A useful adhesive polymer formulation comprises a polyacrylate adhesive polymer of the general formula (I):
wherein X represents the number of repeating units sufficient to provide the desired properties in the adhesive polymer and R is H or a lower (Ci-Cio) alkyl, such as ethyl, butyl, 2-ethylhexyl, octyl, decyl and the like. The adhesive polymer matrix can comprise, for instance, a polyacrylate adhesive copolymer having a 2-ethylhexyl acrylate monomer and approximately 50-60% w/w of vinyl acetate as a co-monomer. An example of a suitable polyacrylate adhesive copolymer for use in the present invention includes, but is not limited to, that sold under the tradename of Duro Tak® 87-4098 by Henkel Corporation, Bridgewater, N.J., which comprises vinyl acetate co-monomer.
[0023] Levonorgestrel is a potent progestin on a weight-dose basis and may be selected for that or other reasons. The levonorgestrel is typically present in a concentration based on weight of the transdermal composition (i.e., wt%) of 0.1 to 3 % or 0.2 to 2.0 % or 0.5-1.5 %.
[0024] Skin Permeation Enhancers: A number of skin permeation enhancers have been used to improve passage of progestins through the skin and into the blood stream. These include, e.g., alcohols; alkanones; amides and other nitrogenous compounds; 1 -substituted azacycloheptan-2-ones; bile salts; cholesterol; cyclodextrins and substituted cyclodextrins; ethers; saturated and unsaturated fatty acids; saturated and unsaturated fatty acid esters; saturated and unsaturated fatty alcohol esters; glycerides and monoglycerides; organic acids; methyl nicotinate; pentadecalactone; polyols and esters thereof; phospholipids; sulfoxides; surfactants; terpenes; and combinations thereof.
[0025] Of particular interest in the present invention are volatile organic solvents, including one or more of dimethyl sulfoxide (DMSO), a C
8-C
20 alcohol ester of a hydroxyl acid, a C
1-C
4 alkyl ester of a hydroxyl acid and a C
6-C
18 fatty acid.
[0026] The aforementioned combination of skin permeation enhancers may be used to enhance transdermal delivery of steroid hormones from any type of transdermal delivery composition, as discussed above. An adhesive polymer matrix -type system as described in detail herein and in
US 7,045,145,
US 7,384,650,
US 20100255072,
US 2010292660, and
US 20100178323 are illustrative; however, the enhancer combination may also be utilized in non-adhesive polymers, as well as in multi-layer or reservoir-type transdermal delivery systems, gels, ointments, sprays, and lotions, to name a few.
[0027] The skin permeation enhancer is typically present in a concentration of at least 1% or at least 2% by weight of the composition. It may be present in a concentration of up to 50% or up to 40% by weight of the composition. In certain embodiments, the skin permeation enhancer is present in a concentration based on weight of the composition (
i.e., wt%) of 1 to 50 % or 10 to 40 % or 20 to 30 % of the composition.
[0028] Additional Excipients: A number of excipients are employed in transdermal delivery compositions for various purposes. Of particular interest are polymers that function as humectants and/or as plasticizers. Incorporation of a humectant in the formulation allows the dosage unit to absorb moisture from the surface of skin, which in turn helps to reduce skin irritation and to prevent the adhesive polymer matrix of the delivery system from failing to adhere for a sufficient duration. The plasticizer/humectant may be a conventional plasticizer used in the pharmaceutical industry, for example, polyvinyl pyrrolidone (PVP). In particular, PVP/vinyl acetate (PVP/VA) co-polymers, such as those having a molecular weight of from about 50,000, are suitable for use in the present invention. The PVP/VA acts as both a plasticizer, acting to control the rigidity of the polymer matrix, as well as a humectant, acting to regulate moisture content of the matrix. The PVP/VA can be, for example, Plasdone® S-630 Copovidone (International Specialty Products, Inc. (ISP), Wayne, New Jersey), which is a 60:40 PVP:VA co-polymer that has a molecular weight of 24,000 to 30,000 and a glass transition temperature of 106° C. The amount of humectant/plasticizer is directly related to the duration of adhesion of the overlay.
[0029] Anti-oxidants: Anti-oxidants function to prevent or inhibit oxidation of other molecules by themselves becoming oxidized. The composition of the invention comprises an anti-oxidant as defined in the appended claims.
[0030] The pH of the transdermal composition can be maintained at about pH 6 to about pH 8,
e.g., at about pH 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2., 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0. In one embodiment, the composition is maintained at about pH 6.5 to pH7.5. In another embodiment, the composition is maintained at about pH 7. Anti-oxidants that would increase pH, e.g., sodium metabisulfite, are preferably avoided. BHT can be present,
e.g., in a concentration based on the weight of the hormone of at least 10 wt% or at least 20 wt% or at least 30 wt% of the hormone. BHT can be present,
e.g., in a concentration of up to 150 wt% or 200 wt% or 500 wt% of the hormone. In certain embodiments, BHT is present in a concentration based on weight of the hormone of 10 to 500 %, 20 to 200 %, or 50 to 150 % of the hormone. Suitable concentrations of other anti-oxidants are readily ascertainable. For example, suitable concentrations of tris(2,4-di-tert-butylphenyl) phosphite, e.g., Irgafos 168, include concentrations that are similar to those of BHT, although lower or higher concentrations may also be employed; suitable concentrations of pentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate), e.g., Irganox 1010, include similar concentrations although lower or higher concentrations may be employed, e.g., concentrations that are up to about 10%, 20% or 30% higher.
[0031] The following examples are set forth to describe the invention in greater detail. They are intended to illustrate, not limit, the invention.
Examples
Example 1
[0032] A master blend, utilizing the formula listed in Table 1, below, was produced. The master blend was divided and spiked with ethinyl estradiol (reference examples) or known anti-oxidants as shown in Table 3. Each blend was then coated on a release liner at a target coat weight of 133 g/m
2 and dried at 60°C. The sheets were laminated, cut into 15 cm
2 samples, placed between two release liners, pouched, and then stored at 80°C. Samples were evaluated at five time points as shown in Table 2.
Table 1. Master Blend Formula
Levonorgestrel |
0.38% |
Penetration Enhancers, PVP/VA, Ethyl Acetate |
39.0% |
PSA* |
60.5% |
* PSA = polyacrylate adhesive copolymer having a 2-ethylhexyl acrylate monomer and approximately 50-60% w/w of vinyl acetate as a co-monomer |
Table 2. Sampling Plan
Sampling Time Point | Temperature | Number of Samples Tested |
0 days (T0) |
80°C |
3 |
2 days (T2) |
80°C |
3 |
4 days (except Batch 7) (T4) |
80°C |
3 |
6 days (Batch 7 only) (T6) |
80°C |
3 |
8 days (T8) |
80°C |
3 |
Table 3. Test Blends
Batch #1 |
Master Blend |
Batch #2 |
Master Blend + ethinyl estradiol, 1.53 mg/15 cm2 |
Batch #3 |
Master Blend + BHT, 1.14 mg/15 cm2 |
Batch #4 |
Master Blend + BHT, 1.71 mg/15 cm2 |
Batch #5 |
Master Blend + Irganox 1010, 1.11 mg/15 cm2 + Irgafos 168, 0.57 mg/15 cm2 |
Batch #6 |
Master Blend + Irganox 1010, 1.66 mg/15 cm2 + Irgafos 168, 0.85 mg/15 cm2 |
Batch #7 |
Master Blend + ethinyl estradiol, 0.97 mg/15 cm2 |
[0033] The amounts of levonorgestrel in each composition at each time point are shown in Table 4 as an average of 3 samples of each batch as a percentage of the target amount of levonorgestrel ("%TL"), which is 0.868 % based on the weight of the polymeric matrix. Batches #1, #2 and #7 are reference examples.
Table 4. Levonorgestrel Stability as % Target Levonorgestrel
Batch | T0 | T2 | T4 | T6 | T8 |
Batch 1 |
96.9 |
87.1 |
68.5 |
NA |
48.1 |
Batch 2 |
106.6 |
92.8 |
93.3 |
NA |
87.3 |
Batch 3 |
106.8 |
102.0 |
98.1 |
NA |
97.7 |
Batch 4 |
103.4 |
102.2 |
99.7 |
NA |
95.7 |
Batch 5 |
104.3 |
104.3 |
99.4 |
NA |
94.6 |
Batch 6 |
102.6 |
101.1 |
98.5 |
NA |
93.1 |
Batch 7 |
105.4 |
97.1 |
NA |
93.4 |
91.7 |
[0034] These results demonstrate that ethinyl estradiol functions as an anti-oxidant in the composition and that levonorgestrel stability is markedly improved by addition of an anti-oxidant to the composition.
Example 2
[0035] To six batches of a master blend of levonorgestrel, penetration enhancers, polyvinylpyrrolidone/vinyl acetate copolymer, and pressure sensitive adhesive, substantially as described in Example 1, BHT was added at different amounts ranging from 0.02 mgs per patch (each patch contains 300 mgs of master blend) to 1.7 mgs per patch (the value of 1.7 mgs represents the molar equivalent of the amount of levonorgestrel in each patch).
[0036] Each batch was heated to 80°C and analyzed at the time points of 0, 4 and 8 days. All BHT loading values had a positive effect on the stability of levonorgestrel. The amounts of LNG remaining at T = Day 0, T = Day 4, and T = Day 8 are shown in Table 5.
Table 5. Effect of BHT concentration on the degradation of levonorgestrel
BHT (mg/patch) | Day 0 | Day 4 | Day 8 |
0 |
98 |
56 |
56 |
1.7 |
100 |
95 |
91 |
0.3 |
102 |
98 |
91 |
0.15 |
101 |
94 |
85 |
0.075 |
98 |
90 |
69 |
0.040 |
101 |
74 |
62 |
0.020 |
100 |
66 |
66 |
Reference Example 3
[0037] The following test batches were prepared and tested as described.
- a) Levonorgestrel (2.6 mg) was dissolved in 412 mg Duro Tak 87-4098 (hereinbelow, "Carrier"). Drawdowns were made and heated at 80°C for 4 and 8 days. The amounts of levonorgestrel remaining and the percent of degradants for the samples heated at 4 and 8 days were determined.
- b) Levonorgestrel (2.6 mg) and 60 mg of PVP/VA were dissolved in 412 mg of Carrier. Drawdowns were made and heated at 80°C for 4 and 8 days. The amounts of levonorgestrel remaining and the percent of degradants for the samples heated at 4 and 8 days were determined.
- c) Levonorgestrel (2.6 mg), 1.71 mg BHT and 60 mg PVP/VA were dissolved in 412 mg Carrier. Drawdowns were made and heated at 80°C for 4 and 8 days. The amounts of levonorgestrel remaining and the percent of degradants for the samples heated at 4 and 8 days were determined.
- d) The same procedure as described in c) was performed, except 1.14 mg BHT was added.
[0038] The batch formulations are summarized in Table 6.
Table 6. Summary of Batch Formulations
| Carrier (mg) | levonorgestrel(mg) | PVP/VA(mg) | BHT(mg) |
a |
412 |
2.6 |
|
|
b |
412 |
2.6 |
60 |
|
c |
412 |
2.6 |
60 |
1.71 |
d |
412 |
2.6 |
60 |
1.14 |
[0039] HPLC analysis was conducted to identify degradants of levonorgestrel. An aliquot of approximately 200 mg and 100 mg of the sample (exact weight recorded) for 4 and 8 day stability was used. The sample was dissolved in 5 mL of 1:1 tetrahydrofuran:methanol (THF/MeOH). 10 µL was injected for HPLC analysis.
[0040] Levonorgestrel degradants appeared after incubation in the 80°C oven for 4 days and 8 days for samples a and b. No degradant was found for samples c and d. The results are shown in Table 7.
Table 7. Peak Area Percentage of Total Degradants
Sample ID | Total degradants (%) |
4 day | 8 day |
A |
0.48 |
0.75 |
B |
1.26 |
1.28 |
C |
0.00 |
0.00 |
D |
0.00 |
0.00 |
[0041] The peak area percentages of remaining levonorgestrel after incubation in 80°C oven are shown in Table 8.
Table 8. Peak Area Percentage of Remaining Substances
Sample ID | Remaining | Remaining |
4 day | 8 day |
a |
99.52 |
99.25 |
b |
98.74 |
98.72 |
c |
100.00 |
100.00 |
d |
100.00 |
100.00 |
[0042] Note for Table 8: Remaining levonorgestrel percentages were directly obtained from peak area percentages.
[0043] The force degradation study described above indicated that addition of BHT reduced degradation of levonorgestrel, while addition of Povidone (PVP) slightly increased the degradation.
Example 4
[0044] Transdermal delivery patches were prepared comprising penetration enhancers, polyvinylpyrrolidone/vinyl acetate copolymer, pressure sensitive adhesive, and varying amounts of levonorgestrel (LNG) and BHT, as follows (Lot 1 is a reference example):
Lot 1: LNG (2.17 mg, 0.87 wt%) - 12.5 cm2 patch;
Lot 2: LNG (2.6 mg, 0.87 wt%) plus BHT (1.712 mg, 0.57 wt%) - 15 cm2 patch;
Skin flux across human cadaver skin (3 donor skin samples, 3 replicates per skin donor) was compared. Data are reported in Table 9.
Table 9. Cumulative amounts of LNG permeated as a function of time.
Lot # | Cumulative amounts of LNG permeated (ug/cm2) |
| 24 h | 48 h | 72 h | 96 h | 120 h | 144 h | 168 h |
1 |
5.503 +/-1.475 |
12.414 +/-2.456 |
18.787 +/-3.256 |
24.962+/- 3.895 |
30.502 +/-4.569 |
35.767 +/-5.230 |
40.736 +/- 5.770 |
2 |
5.187 +/-1.900 |
11.336+/- 2.755 |
17.092 +/- 3.578 |
22.650 +/-4.286 |
27.795 +/-4.969 |
32.689 +/-5.551 |
37.355 +/- 6.110 |
[0045] The mean steady-state flux of levonorgestrel (ug/cm
2/h) in each batch is shown in the following table.
Table 10. Mean steady-state flux of levonorgestrel (ug/cm
2/h)
Lot 1 |
0.2442 +/- 0.0312 |
Lot 2 |
0.2231 +/- 0.0312 |
[0046] These data show that permeation of levonorgestrel was not impeded by the addition of BHT.
Reference Example 5
[0047] As shown in Table 11, seven transdermal compositions, each comprising approximately 164.8 mg Duro Tak® 87-4098 and 2.6 mg levonorgestrel (LNG), after drying, with and without PVP/VA and DMSO, were prepared to test the oxidative effects of a polyacrylate PSA, PVP, and DMSO.
Table 11. Compositions
Composition # | PVP/VA (mg) | DMSO (mg) |
1 |
None |
none |
2 |
60 mg PVP/VA |
none |
3 |
60 mg PVP/VA |
none |
4 |
60 mg PVP/VA |
none |
5 |
60 mg PVP/VA |
none |
6 |
None |
16mgDMSO |
7 |
60 mg PVP/VA |
16 mg DMSO |
[0048] In the case of compositions 1 - 4 and 6, the PSA was pre-heated at 78°C for 8 hours prior to addition of PVP/VA and DMSO. In the case of preparations 3 and 4, the PVP/VA was pre-heated at 80°C for 48 hours in the presence of air and nitrogen, respectively.
[0049] All preparations were then placed in an oven at 80°C for 4 days and 8 days. Degradants were analyzed by HPLC. Degradant percentage data are provided in Table 12.
Table 12. Peak Area Percentage of Total Degradants
Composition # | Degradants (%) Day 4 | Degradants (%) Day 8 |
1 |
0.32 |
0.47 |
2 |
0.76 |
0.94 |
3 |
0.87 |
0.91 |
4 |
0.78 |
1.16 |
5 |
1.21 |
1.60 |
6 |
1.12 |
1.67 |
7 |
1.65 |
1.78 |
[0050] As shown in Table 12, presence of PVP/VA increased degradants roughly by two-fold. Pretreatment of PVP/VA did not show significant difference. Heating the compositions for 8 days produced slightly more degradants than for 4 days. Pre-heating the PSA reduced the amount of degradants. Addition of DMSO increased the amount of degradants.
Reference Example 6
[0051] A master blend utilizing the formula listed in Table 13 was produced. The master blend was then divided and spiked with BHT as shown in Table 14. Each test blend was then coated on a release liner at a target coat weight of 200 g/m
2 and dried at 60°C for 17.5 mins using a fan speed of 2300 rpm. The sheets were then laminated, cut into 15 cm
2 samples, placed between two release liners, pouched, and then stored at 80°C. Samples were evaluated on Days 0, 4, and 8..
Table 13. Master Blend Formula
Levonorgestrel |
0.378% |
Ethinyl estradiol |
0.333% |
Penetration Enhancers, PVP/VA, Ethyl Acetate |
39.558% |
PSA* |
59.730% |
* PSA = polyacrylate adhesive copolymer having a 2-ethylhexyl acrylate monomer and approximately 50-60% w/w of vinyl acetate as a co-monomer [Duro-Tak 87-4098] |
Table 14. Test Blends
Batch #1 |
Master Blend |
Batch #2 |
Master Blend + BHT, 1.712 mg/15 cm2, 2.481 g/kg |
Batch #3 |
Master Blend + BHT, 1.000 mg/15 cm2, 1.449 g/kg |
Batch #4 |
Master Blend + BHT, 0.428 mg/15 cm2, 0.620 g/kg |
Batch #5 |
Master Blend + BHT, 0.300 mg/15 cm2, 0.435 g/kg |
Batch #6 |
Master Blend + BHT, 0.150 mg/15 cm2, 0.217 g/kg |
[0052] The amounts of levonorgestrel and ethinyl estradiol were determined by HPLC. The results (% LC) for each test blend are shown in Table 15 as an average of 5 samples per test blend, with %-Relative Standard Deviations (%RSD).
Table 15. Results
| Day 0 | Day 4 | Day 8 |
Test Blend | EE | LNG | EE | LNG | EE | LNG |
| (% RSD) | (% RSD) | (% RSD) | (% RSD) | (% RSD) | (% RSD) |
Control |
98.7 |
100.3 |
77.3 |
43.0 |
72.9 |
28.5 |
(1.9) |
(2.1) |
(1.0) |
(3.1) |
(9.1) |
(57.0) |
2 |
98.0 |
98.7 |
91.4 |
72.1 |
85.4 |
57.5 |
(2.2) |
(2.2) |
(1.3) |
(1.5) |
(2.4) |
(8.1) |
3 |
99.1 |
99.6 |
87.8 |
66.7 |
86.9 |
54.4 |
(1.8) |
(2.0) |
(2.6) |
(2.1) |
(2.6) |
(22.8) |
4 |
99.3 |
100.2 |
85.7 |
51.6 |
79.8 |
33.9 |
(3.1) |
(3.0) |
(3.0) |
9.4) |
(5.9) |
(48.6) |
5 |
97.4 |
98.2 |
81.0 |
54.7 |
82.6 |
41.8 |
(1.8) |
(1.9) |
(1.8) |
6.4 |
(3.3) |
(33.6) |
6 |
98.5 |
99.6 |
80.4 |
38.9 |
81.0 |
41.5 |
(1.2) |
(1.1) |
(6.1) |
(51.5) |
(1.6) |
(7.1) |
1. A composition for transdermal delivery of levonorgestrel, which comprises:
a) a carrier comprising a polyacrylate pressure sensitive adhesive (PSA),
b) levonorgestrel,
c) a skin permeation enhancer comprising one or more of: dimethyl sulfoxide (DMSO), a C8-C20 alcohol ester of a hydroxy acid, a C1-C4 alkyl ester of a hydroxy acid, and a C6-C18 fatty acid, and
d) an anti-oxidant selected from one of the following groups:
i) sodium bisulfite, sodium sulfite, isopropyl gallate, Vitamin C and E, pentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), tris (2,4-di-tert-butylphenyl) phosphite or BHT or any combination of two or more of said anti-oxidants; and
ii) a phenolic anti-oxidant;
wherein the composition comprises a component that contributes to degradation of the levonorgestrel, wherein the component is one or more of : (1) DMSO, (2) polyvinyl pyrrolidone (PVP) or a PVP copolymer; wherein the composition does not comprise an estrogen.
2. The composition of claim 1, wherein the PSA is polymerized by free radical polymerization.
3. The composition of any one of the preceding claims, wherein the PSA is a polyacrylate adhesive comprising a 2-ethylhexyl acrylate co-monomer and 50 to 60% w/w vinyl acetate co-monomer.
4. The composition of any one of the preceding claims, comprising PVP or PVP/VA.
5. The composition of any one of the preceding claims, disposed within a transdermal drug delivery device that comprises:
a) the composition, having a skin contacting surface and a non-skin contacting surface;
b) a release liner adjacent the skin contacting surface of the composition; and
c) a backing layer adjacent the non-skin contacting surface.
6. A method of improving the stability of a levonorgestrel in a levonorgestrel transdermal delivery composition that does not comprise an estrogen, which composition comprises a polyacrylate PSA, the levonorgestrel, and a component that contributes to degradation of the levonorgestrel, wherein the component is one or more of (1) DMSO, and (2) PVP or a PVP copolymer, the method comprising adding an anti-oxidant to the composition, wherein the anti-oxidant is selected from one of the following groups:
a) sodium bisulfite, sodium sulfite, isopropyl gallate, Vitamin C and E, pentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), tris (2,4-di-tert-butylphenyl) phosphite or BHT or any combination of two or more of said anti-oxidants; and
b) a phenolic anti-oxidant.
7. The method of claim 6, wherein the polyacrylate PSA is polymerized by free radical polymerization.
8. The method of claim 6 or claim 7, comprising skin permeation enhancer that is one or more of DMSO, a C8-C20 alcohol ester of a hydroxy acid, a C1-C4 alkyl ester of a hydroxy acid, and a C6-C18 fatty acid.
9. The method of any one of claims 6 to 8, wherein the composition comprises PVP or PVP/VA.
10. The method of claim 7, wherein the PSA comprises a 2-ethylhexyl acrylate monomer.
11. The method of claim 10, wherein the polyacrylate adhesive further comprises 3 to 60% w/w vinyl acetate monomer.
1. Zusammensetzung zur transdermalen Lieferung von Levonorgestrel, welche umfasst:
a) einen Träger mit einem Druck-empfindlichen Polyacrylat-Kleber (PSA),
b) Levonorgestrel,
c) einen Haut-Permeationsverstärker, der ein oder mehrere umfasst von Dimethylsulfoxid (DMSO), einem C8-C20-Alkoholester einer Hydroxysäure, einem C1-C4-Alkylester einer Hydroxysäure, und einer C6-C18 Fettsäure, und
d) einem Anti-Oxidationsmittel ausgewählt unter den folgenden Gruppen:
i) Natriumbisulfit, Natriumsulfit, Isopropylgallat, Vitamin C und E, Pentaerythritoltetrakis (3-(3,5-di-tert.-butyl-4-hydroxyphenyl)propionat), Tris(2,4-di-tert.-butylphenyl)phosphit oder BHT oder jeder Kombination von zwei oder mehreren der Antioxidantien; und
ii) einem phenolischen Antioxidans;
worin die Zusammensetzung eine Komponente umfasst, die zum Abbau des Levonorgestrel beiträgt, worin die Komponente eine oder mehrere ist von: (1) DMSO, (2) Polyvinylpyrrolidon (PVP) oder einem PVP-Copolymer; worin die Zusammensetzung kein Östrogen enthält.
2. Zusammensetzung nach Anspruch 1, worin der PSA mittels freier Radikalpolymerisation polymerisiert wird.
3. Zusammensetzung nach einem der vorstehenden Ansprüche, worin der PSA ein Polyacrylat-Kleber mit einem 2-Ethylhexylacrylat-Comonomer und 50 bis 60 Gew.-% Vinylacetat-Comonomer ist.
4. Zusammensetzung nach einem der vorstehenden Ansprüche, welcher PVP oder PVP/V A umfasst.
5. Zusammensetzung nach einem der vorstehenden Ansprüche, welche in einem transdermalen Arzneimittel-Liefergerät vorgesehen ist, welches umfasst:
a) die Zusammensetzung mit einer Haut-Kontaktoberfläche und einer nicht die Haut kontaktierenden Oberfläche;
b) eine Trennfolie neben der Haut-Kontaktoberfläche der Zusammensetzung; und
c) einer Schutzfolie neben der die Haut nicht kontaktierenden Oberfläche.
6. Verfahren zum Verbessern der Stabilität eines Levonorgestrel in einer transdermalen Levonorgestrel-Liefer-Zusammensetzung, die kein Östrogen enthält, worin die Zusammensetzung ein Polyacrylat-PSA, das Levonorgestrel, und eine Komponente enthält, die zum Abbau des Levonorgestrel beiträgt, worin die Komponente eine oder mehrere ist von (1) DMSO, und (2) PVP oder einem PVP-Copolymer, wobei das Verfahren umfasst, Zusetzen eines Antioxidationsmittels zu der Zusammensetzung, worin das Antioxidans ausgewählt ist unter einer der folgenden Gruppen:
a) Natriumbisulfit, Natriumsulfit, Isopropylgallat, Vitamin C und E, Pentaerythritoltetrakis(3-(3,5-di-tert.-butyl-4-hydroxyphenyl)propionat), Tris(2,4-di-tert-butylphenyl)phosphit oder BHT oder jeder Kombination von zwei oder mehreren der Antioxidantien; und
b) einem phenolischen Antioxidans.
7. Verfahren nach Anspruch 6, wobei das Polyacrylat-PSA durch freie Radikalpolymerisation polymerisiert wird.
8. Verfahren nach Anspruch 6 oder Anspruch 7, welches einen Haut-Permeationsverstärker umfasst, der ein oder mehrere ist von DMSO, einem C8-C20 -Alkoholester einer Hydroxysäure, einem C1-C4-Alkylester einer Hydroxysäure, und einer C6-C18-Fettsäure.
9. Verfahren nach einem der Ansprüche 6 bis 8, worin die Zusammensetzung PVP oder PVP/VA umfasst.
10. Verfahren nach Anspruch 7, worin der PSA 2-Ethylhexylacrylat-Monomer umfasst.
11. Verfahren nach Anspruch 10, worin der Polyacrylat-Kleber weiter 3 bis 60 Gew.-% Vinylacetat-Monomer umfasst.
1. Composition pour l'administration transdermique de lévonorgestrel, qui comprend :
a) un support comprenant un adhésif sensible à la pression (« pressure sensitive adhesive » - PSA) polyacrylate ;
b) du lévonorgestrel ;
c) un agent améliorant la pénétration dans la peau comprenant au moins l'un parmi : le diméthyl sulfoxyde (DMSO), un ester d'un alcool en C8-C20 et d'un hydroxy acide, un alkyl en C1-C4 ester d'un hydroxy acide, et un acide gras en C6-C18 ; et
d) un anti-oxydant choisi dans l'un des groupes suivants :
i) le bisulfite de sodium, le sulfite de sodium, le gallate d'isopropyle, la Vitamine C et la Vitamine E, le pentaérythritol tétrakis (3-(3,5-di-tert-butyl-4-hydroxyphényl)propionate), le tris (2,4-di-tert-butylphényl) phosphite ou le BHT ou toute combinaison d'au moins deux desdits anti-oxydants ; et
ii) un anti-oxydant phénolique ;
la composition comprenant un composant qui contribue à la dégradation du lévonorgestrel, le composant étant au moins l'un parmi : (1) le DMSO, (2) la polyvinyl pyrrolidone (PVP) ou un copolymère de PVP ; la composition ne comprenant pas d'oestrogène.
2. Composition selon la revendication 1, dans laquelle le PSA est polymérisé par polymérisation par radicaux libres.
3. Composition selon l'une quelconque des revendications précédentes, dans laquelle le PSA est un adhésif polyacrylate comprenant un comonomère acrylate de 2-éthylhexyle et 50 à 60 % p/p d'un comonomère acétate de vinyle.
4. Composition selon l'une quelconque des revendications précédentes, comprenant de la PVP ou du PVP/VA.
5. Composition selon l'une quelconque des revendications précédentes, disposée dans un dispositif d'administration transdermique de médicament qui comprend :
a) la composition, ayant une surface de contact avec la peau et une surface non de contact avec la peau ;
b) une pellicule anti-adhésive adjacente à la surface de contact avec la peau de la composition ; et
c) une couche de support adjacente à la surface non de contact avec la peau.
6. Procédé pour améliorer la stabilité d'un lévonorgestrel dans une composition d'administration transdermique de lévonorgestrel qui ne comprend pas d'oestrogène, laquelle composition comprend un PSA polyacrylate, le lévonorgestrel et un composant qui contribue à la dégradation du lévonorgestrel, le composant étant au moins l'un parmi (1) le DMSO, et (2) la PVP ou un copolymère de PVP, le procédé comprenant l'addition d'un anti-oxydant à la composition, l'anti-oxydant étant choisi dans l'un des groupes suivants :
a) le bisulfite de sodium, le sulfite de sodium, le gallate d'isopropyle, la Vitamine C et la Vitamine E, le pentaérythritol tétrakis (3-(3,5-di-tert-butyl-4-hydroxyphényl)propionate), le tris (2,4-di-tert-butylphényl) phosphite ou le BHT ou toute combinaison d'au moins deux desdits anti-oxydants ; et
b) un anti-oxydant phénolique.
7. Procédé selon la revendication 6, dans lequel le PSA polyacrylate est polymérisé par polymérisation par radicaux libres.
8. Procédé selon la revendication 6 ou la revendication 7, comprenant un agent améliorant la pénétration dans la peau qui est au moins l'un parmi le DMSO, un ester d'alcool en C8-C20 et d'un hydroxy acide, un alkyl en C1-C4 ester d'un hydroxy acide, et un acide gras en C6-C18.
9. Procédé selon l'une quelconque des revendications 6 à 8, dans lequel la composition comprend de la PVP ou du PVP/VA.
10. Procédé selon la revendication 7, dans lequel le PSA comprend un monomère acrylate de 2-éthylhexyle.
11. Procédé selon la revendication 10, dans lequel l'adhésif polyacrylate comprend en outre 3 à 60 % p/p de monomère acétate de vinyle.