DE19825856A1 - New topical formulation which includes active agent as liquid lipid nanoparticles in an oil-in-water emulsion - Google Patents
New topical formulation which includes active agent as liquid lipid nanoparticles in an oil-in-water emulsionInfo
- Publication number
- DE19825856A1 DE19825856A1 DE19825856A DE19825856A DE19825856A1 DE 19825856 A1 DE19825856 A1 DE 19825856A1 DE 19825856 A DE19825856 A DE 19825856A DE 19825856 A DE19825856 A DE 19825856A DE 19825856 A1 DE19825856 A1 DE 19825856A1
- Authority
- DE
- Germany
- Prior art keywords
- preparation according
- lipid
- active ingredient
- skin
- oil
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000002632 lipids Chemical class 0.000 title claims abstract description 25
- 239000007788 liquid Substances 0.000 title claims abstract description 15
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 10
- 239000007764 o/w emulsion Substances 0.000 title claims abstract 3
- 239000013543 active substance Substances 0.000 title claims description 6
- 239000012049 topical pharmaceutical composition Substances 0.000 title description 2
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 16
- 238000009472 formulation Methods 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 12
- 239000007787 solid Substances 0.000 claims abstract description 8
- 230000001839 systemic circulation Effects 0.000 claims abstract description 3
- 230000000699 topical effect Effects 0.000 claims abstract description 3
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims description 31
- 239000004480 active ingredient Substances 0.000 claims description 17
- 229960003604 testosterone Drugs 0.000 claims description 15
- 239000002245 particle Substances 0.000 claims description 11
- 238000000265 homogenisation Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000003098 androgen Substances 0.000 claims description 2
- 229940030486 androgens Drugs 0.000 claims description 2
- 229940011871 estrogen Drugs 0.000 claims description 2
- 239000000262 estrogen Substances 0.000 claims description 2
- 239000003349 gelling agent Substances 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 239000003755 preservative agent Substances 0.000 claims description 2
- 239000000583 progesterone congener Substances 0.000 claims description 2
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 claims description 2
- 238000003892 spreading Methods 0.000 claims description 2
- 230000007480 spreading Effects 0.000 claims description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims 2
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 claims 1
- 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 1
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 claims 1
- 241001465754 Metazoa Species 0.000 claims 1
- 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 1
- 208000018737 Parkinson disease Diseases 0.000 claims 1
- 229940035676 analgesics Drugs 0.000 claims 1
- 239000000730 antalgic agent Substances 0.000 claims 1
- 230000001857 anti-mycotic effect Effects 0.000 claims 1
- 239000002543 antimycotic Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 claims 1
- 229960005309 estradiol Drugs 0.000 claims 1
- 229930182833 estradiol Natural products 0.000 claims 1
- 239000003906 humectant Substances 0.000 claims 1
- 229960004400 levonorgestrel Drugs 0.000 claims 1
- 229960003987 melatonin Drugs 0.000 claims 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 claims 1
- 229960001652 norethindrone acetate Drugs 0.000 claims 1
- 229960002847 prasterone Drugs 0.000 claims 1
- 239000000186 progesterone Substances 0.000 claims 1
- 229960003387 progesterone Drugs 0.000 claims 1
- 239000003381 stabilizer Substances 0.000 claims 1
- 210000003491 skin Anatomy 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- 239000000839 emulsion Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 8
- 150000003904 phospholipids Chemical class 0.000 description 6
- 239000004359 castor oil Substances 0.000 description 5
- 235000019438 castor oil Nutrition 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000003623 enhancer Substances 0.000 description 4
- 230000004907 flux Effects 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000004945 emulsification Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000002047 solid lipid nanoparticle Substances 0.000 description 3
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 229920002799 BoPET Polymers 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000010579 first pass effect Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- ITVGXXMINPYUHD-CUVHLRMHSA-N neohesperidin dihydrochalcone Chemical compound C1=C(O)C(OC)=CC=C1CCC(=O)C(C(=C1)O)=C(O)C=C1O[C@H]1[C@H](O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 ITVGXXMINPYUHD-CUVHLRMHSA-N 0.000 description 2
- 239000008385 outer phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000004584 polyacrylic acid Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010058359 Hypogonadism Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920001363 Polidocanol Polymers 0.000 description 1
- 235000019484 Rapeseed oil Nutrition 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 239000003522 acrylic cement Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- JBTHDAVBDKKSRW-UHFFFAOYSA-N chembl1552233 Chemical compound CC1=CC(C)=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 JBTHDAVBDKKSRW-UHFFFAOYSA-N 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229920006237 degradable polymer Polymers 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 235000008524 evening primrose extract Nutrition 0.000 description 1
- 239000010475 evening primrose oil Substances 0.000 description 1
- 229940089020 evening primrose oil Drugs 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 description 1
- 229960002226 polidocanol Drugs 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
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- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
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- 230000001681 protective effect Effects 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
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- 230000009467 reduction Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- -1 sorbitan fatty acid esters Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 229940073450 sudan red Drugs 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940100640 transdermal system Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
Abstract
Description
Zu Beginn der 80er Jahre wurden von Speiser sowohl Lipidmikropartikel durch Sprüherstarrung als auch Nanopellets für die orale Applikation aus festen Lipiden her gestellt (DE 34 21 468 A1 1985). Später kamen Formulierungen auf Basis von Nano partikeln aus in vivo abbaubaren Polymeren wie Polylaktiden und deren Copolymeren mit Glykolsäure hinzu. Liposomen und Polymer-Nanopartikel waren konkurrierende Systeme, von denen sich zunächst die Liposomen durchgesetzt haben. Unter Nano partikel versteht man sphärische Körper bzw. gefüllte Vesikel mit einem Durchmesser im Bereich von Nanometern (1-1000 nm), üblicherweise in der Größe von 10-800 nm, je nach dem, ob das System injiziert werden soll oder ob die Größe die Bioverfügbarkeit steuert. Mit Präparaten wie Alveofact® und AmBisone® sind liposomale Arzneistoff systeme in den Markt eingeführt worden.At the beginning of the 80s, Speiser was through both lipid microparticles Spray solidification as well as nanopellets for oral application from solid lipids provided (DE 34 21 468 A1 1985). Formulations based on nano came later particles from in vivo degradable polymers such as polylactides and their copolymers with glycolic acid. Liposomes and polymer nanoparticles were competing Systems from which the liposomes first prevailed. Under nano Particles are spherical bodies or filled vesicles with a diameter in the range of nanometers (1-1000 nm), usually in the size of 10-800 nm, each according to whether the system should be injected or whether the size is bioavailability controls. With preparations like Alveofact® and AmBisone® are liposomal drugs systems have been launched on the market.
Während Liposomen sehr gut zur Inkorporation und Freigabe von hydrophilen Arzneistoffen geeignet sind (s. Marktbeispiele) ist die Kapazität zur Beladung von Liposomen mit lipophilen Arzneistoffen begrenzt und beeinflußt die Stabilität der Partikel negativ. Dagegen wären feste Lipid-Nanopartikel (SLN = solid lipid nano particle) zur Verkapselung von lipophilen Arzneistoffen möglich und insofern für Steroidhormone wie Estrogene, Androgene und Gestagene einzusetzen, allerdings sind die genannten Hormone für die orale Applikation ungeeignet, da diese Substanzen einem hohen First Pass Effekt unterliegen. Die orale Applikation ist aber das Haupt- Einsatzgebiet für die SLN; u. a. auch deshalb, weil die SLN-Formulierungen nicht durch das Stratum Corneum der Haut penetrieren, sondern auf der Haut eine Okklusion verursachen. While liposomes are very good for incorporating and releasing hydrophilic Drugs are suitable (see market examples) is the capacity for loading Liposomes with lipophilic drugs limit and affect the stability of the Particles negative. In contrast, solid lipid nanoparticles (SLN = solid lipid nano particle) for the encapsulation of lipophilic drugs possible and in this respect for Steroid hormones such as estrogens, androgens and progestogens are used, however the hormones mentioned are unsuitable for oral administration because these substances are subject to a high first pass effect. Oral application is the main Area of application for the SLN; u. a. also because the SLN formulations are not penetrate through the stratum corneum of the skin, but on the skin one Cause occlusion.
Die erste hepatische Metabolisation (sog. First Pass Effekt) kann durch transdermale Anwendung umgangen werden, da nach epikutaner Absorption der Wirkstoff direkt aus den Kapillargefäßen in den systemischen Kreislauf unter Umgehung der Leber passage gelangt. Nun stellt aber die Haut eine erhebliche Barriere für die Resorption von Arzneisubstanzen dar. Es gilt also ein Arzneimittelfreigabesystem zu konzipieren, daß schlecht permeierende Stoffe in ausreichender Menge und kontrollierter Weise durch die Haut in den Blutkreislauf abgibt. Dieses ist das Einsatzgebiet der Trans dermalen Therapeutischen Systeme. Durch Zusatz von sog. Enhancern wird versucht, die Durchlässigkeit der Haut für Arzneistoffe zu erhöhen. Dieses gelingt auch bis zu einem gewissen Maße, kann aber zu Hautirritationen führen, insbesondere, wenn effektive Enhancer in höheren Konzentrationen angewendet werden. Auch die Mikro emulsionen sind ein Beispiel dafür: die bei dieser Formulierung erforderliche hohe Tensidkonzentration führt oft zu Hautunverträglichkeiten.The first hepatic metabolism (so-called first pass effect) can be caused by transdermal Application bypassed, because after epicutaneous absorption the active ingredient directly from the capillaries into the systemic circulation bypassing the liver passage. However, the skin now represents a significant barrier to absorption of medicinal substances. It is therefore important to design a medication release system that poorly permeable substances in sufficient quantities and in a controlled manner through the skin into the bloodstream. This is the area of application of the Trans dermal therapeutic systems. By adding so-called enhancers, an attempt is made to increase the permeability of the skin to drugs. This also works up to to a certain extent, but can lead to skin irritation, especially if effective enhancers are used in higher concentrations. Even the micro Emulsions are an example of this: the high level required for this formulation Surfactant concentration often leads to skin intolerance.
Die vorliegende Erfindung befaßt sich nun mit einer flüssigen oder halbfesten topischen Formulierung, in der vorwiegend lipophile Arzneistoffe in einer flüssigen Lipid-Phase im Nanometerbereich vorliegen und von einer wäßrigen äußeren Phase umgeben sind. Die Formulierung enthält keine oder nur geringe Enhancer- oder Tensidkonzentrationen und besitzt damit eine gute Hautverträglichkeit. Trotzdem zeigte sich überraschend eine hohe Hautpermeation der verkapselten Wirkstoffe. Die Wirkstoffe werden vorzugsweise in gesättigter oder übersättigter Konzentration in die Formulierung eingearbeitet. Weiter besitzt die Formulierung im Gegensatz zu den festen Lipid-Nanopartikeln den Vorteil, daß die Lipidpartikel nicht erst auf der Haut schmelzen müssen, um den Wirkstoff freizugeben. Flüssige Lipidpartikel geben nach Spreitung bzw. Einreibung in die lipidhaltigen Hautschichten direkt den Wirkstoff in lipidlöslicher Form frei. Dies führt zu verbesserter Wirkstoffabsorption. The present invention is now concerned with a liquid or semi-solid topical formulation in which mainly lipophilic drugs in a liquid Lipid phase in the nanometer range and an aqueous outer phase are surrounded. The formulation contains little or no enhancer or Surfactant concentrations and is therefore well tolerated by the skin. Nevertheless surprisingly, a high skin permeation of the encapsulated active ingredients was shown. The Active substances are preferably in the saturated or supersaturated concentration in the Wording incorporated. In contrast to the, the formulation also has solid lipid nanoparticles have the advantage that the lipid particles do not first touch the skin have to melt to release the active ingredient. Liquid lipid particles give way Spreading or rubbing into the lipid-containing skin layers directly the active ingredient in lipid-soluble form free. This leads to improved drug absorption.
Die erfindungsgemäße topische Zubereitung enthält bis zu 30% eines Lipids, welches bei 32-34°C Hauttemperatur in flüssiger Form vorliegt. Als Lipide sind folgende Sub stanzen beispielsweise verwendbar: pflanzliche Öle wie Sonnenblumenöl, Erdnußöl, Rizinusöl, Rapsöl, Nachtkerzenöl oder synthetische Lipide wie 2-Octyldodecanol, Diisopropyladipat, Ester von Fettsäuren der Kettenlänge C4-C15. Das ausgewählte Lipid muß über eine ausreichende Löslichkeit für den Wirkstoff verfügen, was vorher zu untersuchen ist und woraufhin das Lipid auszuwählen ist. Natürlich muß auch der Wirkstoff eine insgesamt gute Lipidlöslichkeit besitzen. Gut wasserlösliche Wirkstoffe ohne eine ausreichende Lipidlöslichkeit sind für die erfindungsgemäße Zubereitung nicht geeignet. Für Wirkstoffe dieser Art sind andere Systeme wie z. B. Liposomen besser geeignet. Man stellt die Konzentration des Wirkstoffes so ein, daß Sättigung vorliegt bzw. die Löslichkeit geringfügig überschritten wird, um ein schwach übersättigtes System zu erhalten.The topical preparation according to the invention contains up to 30% of a lipid which at 32-34 ° C skin temperature in liquid form. The following are sub-lipids Punching can be used, for example: vegetable oils such as sunflower oil, peanut oil, Castor oil, rapeseed oil, evening primrose oil or synthetic lipids such as 2-octyldodecanol, Diisopropyl adipate, esters of fatty acids with chain length C4-C15. The selected one Lipid must have sufficient solubility for the active substance, which was previously the case is to be examined and then the lipid is to be selected. Of course he has to Active ingredient have an overall good lipid solubility. Well water-soluble active ingredients without sufficient lipid solubility for the preparation according to the invention not suitable. For systems of this type, other systems such as B. Liposomes more suitable. The concentration of the active ingredient is adjusted so that saturation is present or the solubility is slightly exceeded by a weak to get oversaturated system.
Weiter enthält die erfindungsgemäße Zubereitung einen Gehalt an Phospholipiden von 1-15%, vorzugsweise 2-7%. Phospholipide werden aus pflanzlichem Soyalecithin durch sorgfältige Isolation und Aufreinigung in pharmazeutisch reiner Qualität hergestellt. Sie sind z. B. als Phospholipon 80® von Nattermann Phospholipid GmbH, Köln zu be ziehen, welches aus 75-80% des Phospholipids Phosphatidylcholin besteht. Ein Lecithin mit ähnlichen Eigenschaften ist Lipoid S 75 von Lipoid GmbH, Ludwigshafen. Ferner sind auch hydrierte Phopholipide bekannt und einsetzbar, aber für die Verbesserung der Hautpermeation werden die unhydrierten Phospholipide bevorzugt.The preparation according to the invention also contains a phospholipid content of 1-15%, preferably 2-7%. Phospholipids are made from plant-based soyalecithin Careful isolation and purification in pharmaceutically pure quality. You are e.g. B. as Phospholipon 80® from Nattermann Phospholipid GmbH, Cologne pull, which consists of 75-80% of the phospholipid phosphatidylcholine. A lecithin with similar properties is Lipoid S 75 from Lipoid GmbH, Ludwigshafen. Further Hydrogenated phopholipids are also known and can be used, but for improvement unhydrogenated phospholipids are preferred for skin permeation.
Ferner kann die erfindungsgemäße Zubereitung in geringen Mengen andere ober flächenaktive Substanzen (Tenside), auch in Mischungen, enthalten wie z. B. Poly sorbate, Sorbitanfettsäureester, polyoxyethylierte Verbindungen wie Polidocanol in einer Menge unter 5%, vorzugsweise in einer Konzentration unter 3%. In addition, the preparation according to the invention can be used in small amounts surface-active substances (surfactants), also in mixtures, contain such. B. Poly sorbates, sorbitan fatty acid esters, polyoxyethylated compounds such as polidocanol in an amount below 5%, preferably in a concentration below 3%.
Die äußere Phase enthält Wasser und, sofern erforderlich, wasserlösliche derma tologische Hilfsstoffe wie Ethanol, Propylenglykol, Glycerin, Sorbitol etc. sowie Kon servierungsmittel.The outer phase contains water and, if necessary, water-soluble derma technological auxiliaries such as ethanol, propylene glycol, glycerin, sorbitol etc. and Kon preservative.
Wichtig ist die Herstellung eines erfindungsgemäßen Systems zu Nanopartikeln. Hier für werden die lipophilen Bestandteile einschließlich der lipidlöslichen Wirk- und Hilfsstoffe zusammen gegeben, evtl. auf 50-80°C erwärmt und anschließend mit der wäßrigen Phase, die die gleiche Temperatur wie die Lipidphase besitzt, voremulgiert. Anschließend wird aus der Emulsion eine Nanoemulsion erstellt, indem eine mehrmalige Hochdruckhomogenisation durchgeführt wird. Bei Herstellung der erfindungsgemäßen Zubereitung bedient man sich zweckmäßigerweise eines Kolben- Spalt-Homogenisators mit Drücken zwischen 200 bar und 1500 bar wie z. B. eines Gerätes der Firma APV Homogeniser, Lübeck, welche Geräte im Labormaßstab ab 40l/h für den diskontinuierlichen Betrieb (APV Miaon Lab 40) bis hin zum industriellen Produktionsmaßstab mit 1500l/h (kontinuierlicher Betrieb) anbietet. Dieses hat Vorteile gegenüber der Verwendung von beispielsweise Rotor-Stator- Systemen wie UltraTurrax, bei deren Verwendung lediglich Partikelgrößen im µm- Bereich erreicht werden. Anschließend wird das Produkt abgekühlt und abgefüllt. Es ist möglich, das erhaltene erfindungsgemäße System sowohl flüssig in Form eines Sprays oder halbfest wie eine Creme als auch nachträglich angedickt durch Gelbildner (z. B. Cellulosegele, Polyacrylsäuregele) zu applizieren.The production of a system according to the invention for nanoparticles is important. Here for the lipophilic components including the lipid-soluble active and Auxiliaries added together, possibly heated to 50-80 ° C and then with the pre-emulsified aqueous phase, which has the same temperature as the lipid phase. A nanoemulsion is then created from the emulsion by a repeated high pressure homogenization is carried out. When producing the Preparation according to the invention is expediently used using a piston Gap homogenizer with pressures between 200 bar and 1500 bar such as B. one Devices from APV Homogeniser, Lübeck, which devices on a laboratory scale 40l / h for discontinuous operation (APV Miaon Lab 40) up to industrial production scale with 1500l / h (continuous operation). This has advantages over the use of, for example, rotor-stator Systems like UltraTurrax, when using only particle sizes in µm Range can be reached. The product is then cooled and filled. It is possible to obtain the system according to the invention both in the form of a liquid Sprays or semi-solid like a cream as well as subsequently thickened by gelling agents (e.g. cellulose gels, polyacrylic acid gels).
Da zur Zeit für die transdermale Applikation von Testosteron Pflastersysteme einge setzt werden, wurde in der In-vitro-Mäusehautpermeation die erfindungsgemäße Zu bereitung (Zusammensetzung siehe Beispiel 1, 2 und 3) gegen ein handelsübliches Flüssigreservoirpflaster (Vergleich 1) und gegen ein Matrixpflaster (Vergleich 2) ge prüft. Die nachstehende Tabelle gibt eine Zusammenfassung der Ergebnisse. Currently used for the transdermal application of testosterone patch systems are set, was in the in vitro mouse skin permeation according to the invention preparation (composition see examples 1, 2 and 3) against a commercially available Liquid reservoir patch (comparison 1) and against a matrix patch (comparison 2) ge checks. The table below summarizes the results.
Damit ist ersichtlich, daß die erfindungsgemäßen Beispiele 1, 2 und 3 deutlich höhere Fluxraten pro System aufweisen (letzte Spalte) als die als Vergleich 1 und 2 unter suchten transdermalen Systeme. Der Flux pro 24h/cm2 liegt zwar bei Vergleich 1 höher, aber durch die Art des Systems beträgt die Fläche nur 7,5 cm2, wodurch sich die Menge Testosteron, die letztendlich an den Körper abgegeben wird, deutlich reduziert. Die Applikationsfläche, die für die erfindungsgemäße Zubereitung angegeben wird, ergibt sich, wenn man die Menge von 1 g der erfindungsgemäßen Zubereitung auf eine Fläche von ca. 120 cm2 des Körpers einreibt. Ein Transdermalsystem in Form eines Pflasters wäre in dieser Größe nicht akzeptabel.It can thus be seen that Examples 1, 2 and 3 according to the invention have significantly higher flux rates per system (last column) than the transdermal systems examined as Comparison 1 and 2. The flux per 24h / cm 2 is higher in comparison 1, but due to the nature of the system, the area is only 7.5 cm 2 , which significantly reduces the amount of testosterone that is ultimately released to the body. The application area, which is specified for the preparation according to the invention, results when the amount of 1 g of the preparation according to the invention is rubbed into an area of approximately 120 cm 2 of the body. A transdermal system in the form of a patch would not be acceptable in this size.
Ein mit den Beispielen 1, 2 oder 3 erzielbarer Flux ermöglicht damit eine transdermale Anwendung von Testosteron zur Hormonsubstitutionstherapie des Hypogonadismus bei Männern.A flux that can be achieved with Examples 1, 2 or 3 thus enables transdermal Use of testosterone for hormone replacement therapy in hypogonadism in men.
Weiter konnte festgestellt werden, daß die Übersättigung des Systems, die in den Beispielen 1 bis 3 vorliegt, ebenfalls durch diese Herstellmethode und Zusammen setzung gut stabilisiert werden kann, was sich durch eine Verminderung der Re kristallisation des gelösten Wirkstoffs in der Emulsion zeigt. It was also found that the supersaturation of the system in the Examples 1 to 3 are present, also by this production method and together setting can be stabilized well, which is reflected in a reduction in Re crystallization of the dissolved active ingredient in the emulsion shows.
Als weiteren positiven Effekt der erfindungsgemäßen Zubereitung erwies sich die hautpflegende Wirkung, was zur Compliance der Arzneimitteltherapie durch den Patienten beiträgt.The proved to be a further positive effect of the preparation according to the invention skin care effect, leading to compliance of drug therapy by the Contributes to patients.
Um 1 kg der erfindungsgemäßen Formulierung herzustellen, werden 20,0 g Testosteron in 250 g Rizinusöl, 24,0 g Isopropylmyristat und 90,0 g Ethanol 96% unter leichtem Erwärmen und Rühren gelöst. Anschließend werden 50,0 g NAT 8539 (Nattermann Phospholipid GmbH, Köln) und 90,0 g Glycerol anhydricum, sowie 20,0 g Span 20 (Deutsche ICI) zugewogen und unter Rühren homogenisiert. Es werden 456,0 g gereinigtes Wasser unter Rühren zugegeben und es erfolgt eine Homogenisation der Voremulsion durch 10 min Ultra-Turrax. Man erhält eine fast weiße, dünnflüssige homogene Emulsion, die 20 mg Testosteron pro Gramm enthält. Die Teilchengröße eines mit Rotor-Stator-Prinzip homogeniserten Systems enthält zu 76% Partikel in der Größe von 380 bis 450 nm, aber auch noch 12% Partikel von 1,5-1,8 µm und 9% über 2 µm Durchmesser. Da in diesem Beispiel noch kein Hochdruck-Kolben-Spalt Homo genisator eingesetzt wurde, ist infolge der unterschiedlichen Tröpfchengröße in der Emulsion die Lagerfähigkeit begrenzt. Die Übersättigung läßt sich durch vereinzelte Wirkstoffkristalle in den Lipidvesiklen unter dem Mikroskop nach Anfärben mit Sudanrot nachweisen.To produce 1 kg of the formulation according to the invention, 20.0 g Testosterone in 250 g castor oil, 24.0 g isopropyl myristate and 90.0 g ethanol under 96% slightly warming and stirring dissolved. Then 50.0 g of NAT 8539 (Nattermann Phospholipid GmbH, Cologne) and 90.0 g glycerol anhydricum, and 20.0 g Span 20 (German ICI) weighed and homogenized with stirring. There are 456.0 g purified water is added with stirring and there is a homogenization of the Pre-emulsion with 10 min Ultra-Turrax. You get an almost white, thin liquid homogeneous emulsion containing 20 mg testosterone per gram. The particle size of a system homogenized with the rotor-stator principle contains 76% particles in the Size from 380 to 450 nm, but also 12% particles from 1.5-1.8 µm and 9% over 2 µm diameter. Since in this example no high-pressure piston gap Homo was used due to the different droplet sizes in the Emulsion limits shelf life. The supersaturation can be isolated Active ingredient crystals in the lipid vesicles under the microscope after staining with Detect Sudan red.
Um 1 kg der erfindungsgemäßen Formulierung herzustellen, werden 20,0 g Testosteron in 200 g Rizinusöl und 200,0 g Ethanol 96% unter leichtem Erwärmen und Rühren gelöst. Anschließend werden 70,0 g NAT 8539 und 50,0 g Glycerol anhydricum, sowie 20,0 g Span 20 zugewogen, unter Rühren homogenisiert und auf 70°C erwärmt. Es werden 440,0 g gereinigtes Wasser von 70°C unter Rühren zugegeben und es erfolgt eine Voremulgierung unter Rühren. Anschließend wird die Voremulsion mit 4 Durchläufen eines Kolben-Spalt-Homogenisators bei 800 bar homogenisiert. Man erhält eine fast weiße, halbfeste homogene Emulsion, die 20 mg Testosteron pro Gramm enthält. Die Teilchengröße dieses mit Hochdruck-Prinzip homogeniserten Systems enthält Lipid-Nanopartikel in der Größe von 178 nm ± 34% Standardabweichung.To produce 1 kg of the formulation according to the invention, 20.0 g Testosterone in 200 g castor oil and 200.0 g ethanol 96% with gentle heating and Stirring dissolved. Then 70.0 g of NAT 8539 and 50.0 g of glycerol anhydricum, and 20.0 g of Span 20 weighed, homogenized with stirring and on Heated to 70 ° C. 440.0 g of purified water at 70 ° C. are added with stirring and there is a pre-emulsification with stirring. Then the pre-emulsion homogenized with 4 passes of a piston-gap homogenizer at 800 bar. Man receives an almost white, semi-solid homogeneous emulsion containing 20 mg of testosterone per Contains grams. The particle size of this homogenized with the high pressure principle Systems contains lipid nanoparticles in the size of 178 nm ± 34% Standard deviation.
Um 1 kg der erfindungsgemäßen Formulierung herzustellen, werden 11,0 g Testosteron in 200,0 g Rizinusöl und 200,0 g Ethanol 96% unter leichtem Erwärmen und Rühren gelöst. Anschließend werden 70,0 g NAT 8539 und 70,0 g Glycerol anhydricum, sowie 20,0 g Span 20 zugewogen und unter rühren homogenisiert und auf 70°C erwärmt. Es werden 429,0 g gereinigtes Wasser von 70°C unter Rühren zugegeben und es erfolgt eine Voremulgierung unter Rühren. Anschließend erfolgt eine Homo genisation der Voremulsion mit 4 Durchläufen eines Kolben-Spalt-Homogenisators bei 800 bar. Man erhält eine fast weiße, halbfeste homogene Emulsion, die 11 mg Testosteron pro Gramm enthält. Die Teilchengröße dieses mit Hochdruck-Prinzip homogeniserten Systems enthält Lipid-Nanopartikel in der Größe von 165 nm ± 41% Standardabweichung.To produce 1 kg of the formulation according to the invention, 11.0 g Testosterone in 200.0 g castor oil and 200.0 g ethanol 96% with gentle heating and Stirring dissolved. Then 70.0 g of NAT 8539 and 70.0 g of glycerol anhydricum, and 20.0 g of Span 20 weighed and homogenized with stirring and on Heated to 70 ° C. 429.0 g of purified water at 70 ° C. are added with stirring and there is a pre-emulsification with stirring. Then there is a homo Genization of the pre-emulsion with 4 passes of a piston-gap homogenizer 800 bar. An almost white, semi-solid homogeneous emulsion is obtained, 11 mg Contains testosterone per gram. The particle size of this using the high pressure principle homogenized system contains lipid nanoparticles in the size of 165 nm ± 41% Standard deviation.
Um 1 kg der erfindungsgemäßen Formulierung herzustellen, werden 15,0 g Testosteron in 200,0 g Rizinusöl und 200,0 g Ethanol 96% unter leichtem Erwärmen und Rühren gelöst. Anschließend werden 60,0 g Lipoid 575 (Lipoid GmbH, Ludwigshafen) zugewogen, unter Rühren homogenisiert und auf 70°C erwärmt. Es werden 525,0 g gereinigtes Wasser von 70°C unter Rühren zugegeben und es erfolgt eine Voremulgierung unter Rühren. Anschließend wird die Voremulsion mit 4 Durchläufen eines Kolben-Spalt-Homogenisators bei 800 bar homogenisiert. Man erhält eine fast weiße, halbfeste homogene Emulsion, die 15 mg Testosteron pro Gramm enthält.To produce 1 kg of the formulation according to the invention, 15.0 g Testosterone in 200.0 g castor oil and 200.0 g ethanol 96% with gentle heating and Stirring dissolved. Then 60.0 g of Lipoid 575 (Lipoid GmbH, Ludwigshafen) weighed, homogenized with stirring and heated to 70 ° C. There are 525.0 g purified water of 70 ° C is added with stirring and there is a Pre-emulsification with stirring. Then the pre-emulsion with 4 passes a piston-gap homogenizer homogenized at 800 bar. You almost get one white, semi-solid homogeneous emulsion containing 15 mg testosterone per gram.
Hier wurde als Vergleich zur erfindungsgemäßen Formulierung das Handelsprodukt Andropatch® (SmithKline Beecham, UK) eingesetzt. Es enthält ein wässrig-ethano lisches, neutralisiertes Polyacrylsäure-Gel mit Glycerin sowie die Enhancer Methlyl aurat und Glycerolmonooleat. Das Gel ist in ein Reservoir geschlossen, welches eine Fläche von 7,5 cm2 umfaßt. Das Reservoir wird auf der Haut mittels einem Acrylatklebefilm, der 29,5 cm2 beträgt, fixiert. Das System enthält 12,5 mg Testosteron.The commercial product Andropatch® (SmithKline Beecham, UK) was used here as a comparison to the formulation according to the invention. It contains an aqueous, ethical, neutralized polyacrylic acid gel with glycerin as well as the enhancers methyl aurate and glycerol monooleate. The gel is closed in a reservoir which covers an area of 7.5 cm 2 . The reservoir is fixed on the skin using an acrylic adhesive film that measures 29.5 cm 2 . The system contains 12.5 mg testosterone.
Um 1000 cm2 eines Pflasterlaminates als Vergleich zur erfindungsgemäßen Formu lierung herzustellen, werden 0,44 g Testosteron und 0,24 g Neohesperidin DC (erhältlich als Citrosa® von der Firma Denk Feinmittelchemie) in 7,3 ml Ethanol 96% gelöst, nacheinander werden die Kleberlösungen Durotak 387-2287 in 2,89 g und Duro tak 387-1753 in 15,54 g zugewogen und die gesamte Lösung 1h zur Homogenisierung gerührt. Die wirkstoffhaltige Kleberlösung wird in 400 µm Naßschichtdicke mit Erichson Rakel auf eine Schutzfolie (z. B. silikonisierte PET-Folie von der Firma Rexam Release oder Scotchpak der Firma 3M) ausgestrichen, getrocknet von 30°C auf 80°C ansteigend und mit einer Trägerfolie kaschiert (z. B. eine PET-Folie Hostaphan RN 15 von der Fa. Hoechst oder eine flexible Trägerfolie wie Polyurethan, Weich-Polyvinylchlorid, Polyolefin, oder Verbundfolien mit Ethylenvinylacetat). Es werden Pflaster mit einer Größe von 40 cm2, einem Matrix flächengewicht von 80 g/m2 und einem Wirkstoffgehalt von 17,6 mg erhalten.In order to produce 1000 cm 2 of a plaster laminate as a comparison to the formulation according to the invention, 0.44 g of testosterone and 0.24 g of neohesperidin DC (available as Citrosa® from the company Denk Feinmittelchemie) are dissolved in 7.3 ml of 96% ethanol, in succession Weighed the adhesive solutions Durotak 387-2287 in 2.89 g and Duro tak 387-1753 in 15.54 g and the entire solution was stirred for 1 hour for homogenization. The active ingredient-containing adhesive solution is spread in a 400 μm wet layer thickness with an Erichson doctor blade onto a protective film (for example siliconized PET film from Rexam Release or Scotchpak from 3M), dried from 30 ° C. to 80 ° C. and rising with a carrier film laminated (e.g. a Hostaphan RN 15 PET film from Hoechst or a flexible carrier film such as polyurethane, soft polyvinyl chloride, polyolefin, or composite films with ethylene vinyl acetate). Patches with a size of 40 cm 2 , a matrix weight per unit area of 80 g / m 2 and an active substance content of 17.6 mg are obtained.
Claims (12)
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| CN102429912A (en) * | 2011-10-26 | 2012-05-02 | 庞飞 | Pharmaceutical composition prepared with micronized prasterone or sodium prasterone sulfate and use thereof |
| EP2281553A3 (en) * | 2000-08-30 | 2012-11-14 | Unimed Pharmaceuticals, LLC | Pharmaceutical composition and method for treating hypogonadism |
| EP2474307A3 (en) * | 2001-04-25 | 2013-02-20 | Western Center for Drug Development, College of Pharmacy, Western University of Health Sciences | Proliposomal drug delivery system |
| US8466138B2 (en) | 2005-10-12 | 2013-06-18 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
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| DE3225706A1 (en) * | 1982-07-09 | 1984-01-12 | A. Nattermann & Cie GmbH, 5000 Köln | LIQUID ACTIVE INGREDIENTS IN THE FORM OF CONCENTRATES FOR MICROEMULSIONS |
| EP0349150A2 (en) * | 1988-06-20 | 1990-01-03 | Shiseido Company Limited | Transparent compostition |
| EP0361928A2 (en) * | 1988-09-29 | 1990-04-04 | Shiseido Company Limited | Emulsified composition |
| EP0387647A2 (en) * | 1989-03-13 | 1990-09-19 | Desitin Arzneimittel GmbH | High-dispersion pharmaceutical composition |
| EP0406162A2 (en) * | 1989-06-26 | 1991-01-02 | Hans Georg Prof. Dr. Weder | Process for the preparation of a nanoemulsion of oilparticles in an aqueous phase |
| US4992478A (en) * | 1988-04-04 | 1991-02-12 | Warner-Lambert Company | Antiinflammatory skin moisturizing composition and method of preparing same |
| EP0439042A1 (en) * | 1990-01-24 | 1991-07-31 | F. Hoffmann-La Roche AG | Use of pharmaceutical and cosmetic preparations with mixed micellen |
| EP0480690A1 (en) * | 1990-10-10 | 1992-04-15 | Ciba-Geigy Ag | Aqueous ophthalmic microemulsions of tepoxalin |
| DE4038385A1 (en) * | 1990-12-01 | 1992-06-04 | Roecar Holdings Nv | Sitosterol and its glycoside(s) with improved bio-availability - are in the form of microemulsions using lecithin as the carrier, isopropyl-myristate as the emulsifier and isopropanol as co-emulsifier |
| DE4310935A1 (en) * | 1992-04-02 | 1993-11-18 | Zerbini E J Fundacao | Microemulsions esp. for diagnosis and therapy of tumours - are protein-free and contain hydrophobic component of cholesterol ester and phospholipid(s) and opt. tri:glyceride(S) and/or free cholesterol |
| EP0598116A1 (en) * | 1989-11-27 | 1994-05-25 | Nippon Shinyaku Company, Limited | Fat emulsion |
| DE4439888A1 (en) * | 1993-11-19 | 1995-05-24 | Marigen Sa | Ultramicroemulsions of spontaneously dispersible concentrates with antitumoral active xanthophyll esters |
-
1998
- 1998-06-10 DE DE19825856A patent/DE19825856A1/en not_active Withdrawn
Patent Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3212053A1 (en) * | 1981-04-06 | 1982-10-21 | Sandoz-Patent-GmbH, 7850 Lörrach | SKIN-APPLICABLE PHARMACEUTICAL COMPOSITIONS |
| DE3225706A1 (en) * | 1982-07-09 | 1984-01-12 | A. Nattermann & Cie GmbH, 5000 Köln | LIQUID ACTIVE INGREDIENTS IN THE FORM OF CONCENTRATES FOR MICROEMULSIONS |
| US4992478A (en) * | 1988-04-04 | 1991-02-12 | Warner-Lambert Company | Antiinflammatory skin moisturizing composition and method of preparing same |
| EP0349150A2 (en) * | 1988-06-20 | 1990-01-03 | Shiseido Company Limited | Transparent compostition |
| EP0361928A2 (en) * | 1988-09-29 | 1990-04-04 | Shiseido Company Limited | Emulsified composition |
| EP0387647A2 (en) * | 1989-03-13 | 1990-09-19 | Desitin Arzneimittel GmbH | High-dispersion pharmaceutical composition |
| EP0406162A2 (en) * | 1989-06-26 | 1991-01-02 | Hans Georg Prof. Dr. Weder | Process for the preparation of a nanoemulsion of oilparticles in an aqueous phase |
| EP0598116A1 (en) * | 1989-11-27 | 1994-05-25 | Nippon Shinyaku Company, Limited | Fat emulsion |
| EP0439042A1 (en) * | 1990-01-24 | 1991-07-31 | F. Hoffmann-La Roche AG | Use of pharmaceutical and cosmetic preparations with mixed micellen |
| EP0480690A1 (en) * | 1990-10-10 | 1992-04-15 | Ciba-Geigy Ag | Aqueous ophthalmic microemulsions of tepoxalin |
| DE4038385A1 (en) * | 1990-12-01 | 1992-06-04 | Roecar Holdings Nv | Sitosterol and its glycoside(s) with improved bio-availability - are in the form of microemulsions using lecithin as the carrier, isopropyl-myristate as the emulsifier and isopropanol as co-emulsifier |
| DE4310935A1 (en) * | 1992-04-02 | 1993-11-18 | Zerbini E J Fundacao | Microemulsions esp. for diagnosis and therapy of tumours - are protein-free and contain hydrophobic component of cholesterol ester and phospholipid(s) and opt. tri:glyceride(S) and/or free cholesterol |
| DE4439888A1 (en) * | 1993-11-19 | 1995-05-24 | Marigen Sa | Ultramicroemulsions of spontaneously dispersible concentrates with antitumoral active xanthophyll esters |
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| WO2000054733A3 (en) * | 1999-03-12 | 2001-04-05 | Henkel Kgaa | Flexible, absorbent carriers containing nanoparticle dispersions for treating the skin |
| WO2000054733A2 (en) * | 1999-03-12 | 2000-09-21 | Henkel Kommanditgesellschaft Auf Aktien | Flexible, absorbent carriers containing nanoparticle dispersions for treating the skin |
| US9132089B2 (en) | 2000-08-30 | 2015-09-15 | Besins Healthcare Inc. | Pharmaceutical composition and method for treating hypogonadism |
| US9125816B2 (en) | 2000-08-30 | 2015-09-08 | Besins Healthcare Inc. | Pharmaceutical composition and method for treating hypogonadism |
| EP2281553A3 (en) * | 2000-08-30 | 2012-11-14 | Unimed Pharmaceuticals, LLC | Pharmaceutical composition and method for treating hypogonadism |
| FR2817478A1 (en) * | 2000-12-04 | 2002-06-07 | Oreal | Aqueous suspension of nanospheres useful in cosmetic compositions, comprises an amorphous lipophilic active ingredient stabilized with a surfactant |
| WO2002080885A1 (en) * | 2001-04-03 | 2002-10-17 | University Of Florida | Detoxification and decontamination using nanotechnology therapy |
| US8658202B2 (en) | 2001-04-25 | 2014-02-25 | Western University Of Health Sciences | Coated drug delivery formulations |
| US8889180B2 (en) | 2001-04-25 | 2014-11-18 | Western University Of Health Sciences | Coated drug delivery formulations |
| EP2474307A3 (en) * | 2001-04-25 | 2013-02-20 | Western Center for Drug Development, College of Pharmacy, Western University of Health Sciences | Proliposomal drug delivery system |
| WO2007000193A1 (en) * | 2005-06-29 | 2007-01-04 | Dsm Ip Assets B.V. | Isoflavone nanoparticles and use thereof |
| US8951560B2 (en) | 2005-06-29 | 2015-02-10 | Dsm Ip Assets B.V. | Isoflavone nanoparticles and use thereof |
| US8741881B2 (en) | 2005-10-12 | 2014-06-03 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| US8466136B2 (en) | 2005-10-12 | 2013-06-18 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| US8466137B2 (en) | 2005-10-12 | 2013-06-18 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| US8486925B2 (en) | 2005-10-12 | 2013-07-16 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| US8466138B2 (en) | 2005-10-12 | 2013-06-18 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| US8729057B2 (en) | 2005-10-12 | 2014-05-20 | Unimed Pharmaeuticals, LLC | Testosterone gel and method of use |
| US8754070B2 (en) | 2005-10-12 | 2014-06-17 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| US8759329B2 (en) | 2005-10-12 | 2014-06-24 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| CN101249070B (en) * | 2008-04-02 | 2010-07-21 | 郑州大学 | 2-methoxy estradiol vena nano emulsions |
| CN101249071B (en) * | 2008-04-02 | 2010-06-16 | 郑州大学 | Preparation of 2-methoxyl group estradiol vena nano emulsions |
| EP2229936A1 (en) * | 2009-03-09 | 2010-09-22 | PharmaSol GmbH | Nanonized testosterone formulations for improved bioavailability |
| WO2010102737A1 (en) * | 2009-03-09 | 2010-09-16 | Pharmasol Gmbh | Nanonized testosteron formulations for improved bioavailability |
| CN102429912A (en) * | 2011-10-26 | 2012-05-02 | 庞飞 | Pharmaceutical composition prepared with micronized prasterone or sodium prasterone sulfate and use thereof |
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