MXPA00012902A - Transdermal therapeutic system containing hormones and crystallization inhibitors - Google Patents
Transdermal therapeutic system containing hormones and crystallization inhibitorsInfo
- Publication number
- MXPA00012902A MXPA00012902A MXPA/A/2000/012902A MXPA00012902A MXPA00012902A MX PA00012902 A MXPA00012902 A MX PA00012902A MX PA00012902 A MXPA00012902 A MX PA00012902A MX PA00012902 A MXPA00012902 A MX PA00012902A
- Authority
- MX
- Mexico
- Prior art keywords
- therapeutic system
- percutaneous therapeutic
- adhesive
- percutaneous
- estradiol
- Prior art date
Links
- 230000001225 therapeutic Effects 0.000 title claims abstract description 28
- 230000005712 crystallization Effects 0.000 title claims abstract description 19
- 238000002425 crystallisation Methods 0.000 title claims abstract description 18
- 239000003112 inhibitor Substances 0.000 title claims abstract description 15
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 14
- 229940088597 Hormone Drugs 0.000 title description 2
- 239000005556 hormone Substances 0.000 title description 2
- 239000000853 adhesive Substances 0.000 claims abstract description 13
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims abstract description 9
- 239000010410 layer Substances 0.000 claims abstract description 9
- 229960005309 Estradiol Drugs 0.000 claims abstract description 8
- 229920000058 polyacrylate Polymers 0.000 claims abstract description 7
- 229920000642 polymer Polymers 0.000 claims abstract description 7
- 230000001070 adhesive Effects 0.000 claims abstract description 6
- 125000003277 amino group Chemical group 0.000 claims abstract description 3
- 239000011241 protective layer Substances 0.000 claims abstract description 3
- 239000004821 Contact adhesive Substances 0.000 claims description 10
- IMONTRJLAWHYGT-ZCPXKWAGSA-N Norethindrone Acetate Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](C#C)(OC(=O)C)[C@@]1(C)CC2 IMONTRJLAWHYGT-ZCPXKWAGSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 6
- 239000004014 plasticizer Substances 0.000 claims description 6
- FHXBMXJMKMWVRG-SLHNCBLASA-N [(8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] acetate Chemical compound C1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCC3=CC(OC(=O)C)=CC=C3[C@H]21 FHXBMXJMKMWVRG-SLHNCBLASA-N 0.000 claims description 5
- 238000010521 absorption reaction Methods 0.000 claims description 4
- 239000003623 enhancer Substances 0.000 claims description 4
- 230000002708 enhancing Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 229960003575 Estradiol acetate Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 229960001652 norethindrone acetate Drugs 0.000 claims description 3
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 claims description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N 2-methyl-2-propenoic acid methyl ester Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004831 Hot glue Substances 0.000 claims description 2
- 230000000111 anti-oxidant Effects 0.000 claims description 2
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- SOGAXMICEFXMKE-UHFFFAOYSA-N butyl 2-methylprop-2-enoate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims description 2
- 229920000768 polyamine Polymers 0.000 claims description 2
- 230000003712 anti-aging Effects 0.000 claims 2
- 230000036881 Clu Effects 0.000 claims 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N Norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229960000993 norethisterone Drugs 0.000 claims 1
- 230000001012 protector Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 210000003491 Skin Anatomy 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000003223 protective agent Substances 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- POILWHVDKZOXJZ-ARJAWSKDSA-M (Z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N 2-(2-Ethoxyethoxy)ethanol Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229940097362 Cyclodextrins Drugs 0.000 description 1
- 229960003851 Estradiol Hemihydrate Drugs 0.000 description 1
- 229920003149 Eudragit® E 100 Polymers 0.000 description 1
- 229940102838 Methylmethacrylate Drugs 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002431 foraging Effects 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- XPXMKIXDFWLRAA-UHFFFAOYSA-N hydrazinide Chemical compound [NH-]N XPXMKIXDFWLRAA-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011068 load Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
Abstract
The invention relates to a transdermal therapeutic system in the form of a patch for controlled release of estradiol in combination with noresthisteron acetate, comprising a backing layer, a reservoir attached thereto and oversaturated with active substances, which is produced using polyacrylate contact-sensitive adhesives and crystallization inhibitors, in addition to a removable protective layer. The inventive system is characterized in that the crystallization inhibitor is a polymer containing an amino group.
Description
PERCUTANEOUS THERAPEUTIC SYSTEM, CONTAINING CRYSTALLIZATION HORMONES AND INHIBITORS
The invention relates to a percutaneous therapeutic system (TTS) for the controlled emission of estradiol, in combination with Norethisteron acetate to human skin.
Estradiol, in combination with Norethisteron acetate, has a very low solubility of saturation in the auxiliary substances that are usually used for the formulation of percutaneous therapeutic systems, such as contact adhesives based on polyacrylate, and "Tackifier", plasticizers and improvers of absorption. This strongly limits the possibility of loading TTS with dissolved active principle, that is to say that during storage, in the event of supersaturation, unwanted crystallisations occur. Due to this, the proportion of active principle dissolved in the matrix is reduced, which negatively affects its release.
In the combined preparations based on estradiol and norethisteron acetate, forms of application were developed, in which the active principles are contained in a percutaneous therapeutic system in separate forms. However, the manufacture of these percutaneous therapeutic systems is very expensive.
The common incorporation of percutaneous therapeutic systems with drying agents in the primary container reduces the risk of recrystallization, but is nevertheless very laborious.
In DE-OS 43 36 557, a percutaneous therapeutic system containing an active principle based on a contact adhesive is described. Said manufacture is carried out in such a way that the components are kneaded in the melt, at temperatures between 100 and 1402C, and then they are coated. These high temperatures for the manufacture of medicaments entail the risk that decomposition products can be formed in a high proportion, which is unacceptable.
WO 95/30409 discloses a topical polymer release system for the administration of certain active ingredients, by means of an aerosol pump that does not have propellant gas. The advantage lies in the absence of adhesives. As additional components, crystallization inhibitors / stabilizers and / or penetration enhancers are used, such as substituted cyclodextrins, Transcutol, urea and isoterpenes, with the particularity that the combination of active principle: estradiol and norethisterone acetate is not claimed.
What is therefore intended with the present invention is to offer a stable patch, that is to say that does not present recrystallization with the active ingredients: estradiol and norethisteron acetate.
Surprisingly, it has been seen that the problem is solved with a percutaneous therapeutic system, with the characteristics of the main claim, to which is added, as a crystallization inhibitor, a polymer containing amino groups. As crystallization inhibitors, polymers based on butyl methacrylate, 2-dimethyl-amino-ethyl-methacrylate and methyl-methacrylate are preferably used, preferably in molar ratio of 1: 2: 1, poly-amino-amide , poly-amino-imidazoline, polyetherurtana-mine, polyamine and polyglucosamine. It has been found that crystallization inhibitors are particularly suitable in a proportion of 0.05 to 30% by weight.
Due to the formation of hydrogen bonds between the basic groups of the crystallization inhibitor and the mobile hydrogen atoms of the estradiol molecule, an immobilization of the estradiol occurs. This reduces the concentration of free estradiol in the matrix and prevents crystallization.
The self-adhesive reservoir contains estradiol and norethisterone acetate in a weight ratio of 1: 2 to 1: 15, preferably 1: 3 to 1: 7, and a total concentration of up to 25% by weight.
The deposit may contain a component of the group of aging protection agents, plasticizers and absorption enhancers, the plasticizer being used in a concentration of 0 to 5% by weight and the protective agent of aging in a concentration of 0.1. to 2% by weight.
DE 37 43 949 describes suitable protective agents for aging as well as plasticizers, antioxidants and absorption enhancers known to the person skilled in the art.
In order to apply the percutaneous therapeutic system on the skin, it is necessary to present self-adhesive properties. To achieve these properties in the percutaneous therapeutic system according to the invention, contact adhesives based on polyacrylate are used in the form of solutions in organic solvents, the so-called solvent-based contact adhesives.
In addition, polyacrylate-based contact adhesives can be used in the form of aqueous dispersions.
Hot-melt adhesives are also suitable.
These have no solvent or dispersant and are applied from the fluid mass.
UV-crosslinkable acrylate-based contact adhesives are also suitable. These lack solvents and are applied using the usual coating method. Next and applying UV radiation, the crosslinking of the polymer chains takes place. This is necessary in order to give the contact adhesive sufficient cohesion.
The deposit of the percutaneous therapeutic system can be constituted by several layers, with equal or different concentrations of active principle.
The layer thickness of the reservoir is from 0.02 mm to 0.500 mm, preferably however 0.030 mm to 0.200 mm.
The tank may be provided with an additional self-adhesive layer or with a self-adhesive edge. This will be needed when the deposit has insufficient self-adhesive properties.
The percutaneous therapeutic system according to the present invention is intended for therapeutic purposes in human medicine.
Next, the invention is explained based on some examples.
Example 1
155.08 g Durotak 387-2287 (National Starch Firm) (Polyacrylate-based contact adhesive), 4.81 g Eudragit E 100 (Firma Rohm) (Polyacrylate) are homogenized by shaking and mixed with the suspension of
2.17 g Eutanol G (Signature Caesar und Loretz) (Long chain fatty alcohol), 0.03 g Aluminum acetylacetonate (Firma Merck-Schuchardt), 1.29 g Estradiol hemihydrate 8.33 g Norethisteron acetate
in the solvent mixture
27.98 g Ethacetate and 27.97 g Ethanol
And stir for 24 hours at room temperature.
The adhesive solution thus obtained is applied to a separable protective layer of Hostaphan RN 100, siliconized on both sides, so that after drying a matrix containing active substance is obtained, with a weight per unit area of 96.3 / m2 . The matrix thus obtained is coated with a subsequent layer, impermeable to the active principles (0.015 mm thick polyester sheet). Next, percutaneous therapeutic systems of 40 cm2 in size are cut.
Examples 2-7 and comparison: The manufacture is carried out in the manner described in example 1, although with the raw materials and the amounts indicated in table 1.
TABLE 1: Composition [g]
The verification of the recrystallization phenomena was carried out microscopically to the light, with an increase of 40.
The results are shown in table 2
TABLE 2: Recrystallization phenomena
As shown in Table 2, by adding crystallization inhibitors, percutaneous therapeutic systems without crystallization are obtained, contrary to the reference example (without crystallization inhibitor), in which considerable crystallization occurs in a period of 3 months.
Claims (1)
- CLAIMS OF THE PATENT Percutaneous therapeutic system in the form of a patch for the controlled emission of estradiol in combination with norethisteron acetate, constituted by a posterior layer, a deposit attached to it, containing estradiol and norethisteron, saturated with active principles, which is made using polyacrylate-based contact adhesives and crystallization inhibitors, and a separable protective layer, which is characterized in that the crystallization inhibitor is a polymer containing amino groups. The percutaneous therapeutic system according to claim 1, characterized in that the crystallization inhibitor is selected from polymers based on butyl methacrylate, 2-dimethylaminoethyl methacrylate and methyl methacrylate, in particular in a molar ratio of 1: 2: 1, polyaminoarnides, polyamino -imidazolines, polyether-urethane inas, polyamines and polyglucosamines. Percutaneous therapeutic system according to one of claims 1 or 2, characterized in that it has one or more crystallization inhibitors in a proportion of 0.05-30% by weight. The percutaneous therapeutic system according to one or more of claims 1-3, characterized in that the reservoir contains estradiol and norethisterone acetate in a weight ratio of 1: 2 to 1:15, preferably 1: 3. at 1: 7, and a total concentration of up to 25% by weight. Percutaneous therapeutic system according to one of claims a-4, characterized in that the reservoir contains a clu L group component of the anti-aging agents, plasticizers, antioxidants and absorption enhancers, the plasticizer being used in a proportion of 0 - 5% by weight and the anti-aging protector in a concentration of 0.1 - 2%. Percutaneous therapeutic system according to one of claims 1-5, characterized in that the contact adhesive is a solvent-based adhesive, a dispersion adhesive, a hot-melt adhesive or a crosslinkable adhesive with UF radiation. Percutaneous therapeutic system according to one or several of claims 1-6, characterized in that the deposit is constituted by several layers. Percutaneous therapeutic system according to one or several of claims 1-7, characterized in that the reservoir has a layer thickness of 0.02 mm, 0.500 mm, preferably 0.030 - 0.200 mm. Percutaneous therapeutic system according to one or several of claims 1-8, characterized in that the reservoir is provided with an additional self-adhesive layer or a self-adhesive edge. Utilization of the percutaneous therapeutic system, according to one or more of claims 1-9, for therapeutic purposes in human medicine.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19828273.7 | 1998-06-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00012902A true MXPA00012902A (en) | 2002-05-09 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6899894B1 (en) | Transdermal therapeutic system containing hormones and crystallization inhibitors | |
| CA2854164C (en) | Dermal delivery compositions and methods | |
| KR100297548B1 (en) | Plaster for transdermal application of steroid hormones containing dexpantenol | |
| JP2002542277A (en) | Transdermal therapeutic system with neutralized acrylic adhesive patch | |
| HU222499B1 (en) | Controlled release pharmaceutical composition containing estradiol penetration intensifier agent for transdermal administration and process for its preparation | |
| SK95297A3 (en) | Plaster containing estradiol | |
| US7332180B2 (en) | Transdermal therapeutic system for administering non-steroidal antiphlogistic agents containing carboxyl groups, and a method for the production of the same | |
| FI118885B (en) | Skopolaminplåster | |
| MXPA00012902A (en) | Transdermal therapeutic system containing hormones and crystallization inhibitors | |
| EP2068847B1 (en) | Preparation and composition of meloxicam transdermal drug delivery system | |
| EP3150205B1 (en) | Transdermal preparation | |
| EP2371360B1 (en) | Selegiline-containing adhesive preparation | |
| HU226959B1 (en) | Oestradiol containing transdermal therapeutic system (tts) comprising glycerin as hygroscopic additive | |
| TWI725147B (en) | Containing zonisamide percutaneous absorption type patch preparation | |
| WO1999066907A1 (en) | Transdermal therapeutic system containing hormones and crystallization inhibitors | |
| CA2144441C (en) | Dexpanthenol-containing plaster for the transdermal application of steroid hormones |