MXPA97005663A - Nanoparticulas micela - Google Patents
Nanoparticulas micelaInfo
- Publication number
- MXPA97005663A MXPA97005663A MXPA/A/1997/005663A MX9705663A MXPA97005663A MX PA97005663 A MXPA97005663 A MX PA97005663A MX 9705663 A MX9705663 A MX 9705663A MX PA97005663 A MXPA97005663 A MX PA97005663A
- Authority
- MX
- Mexico
- Prior art keywords
- oil
- micellar
- initiator
- micellar nanoparticle
- group
- Prior art date
Links
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 85
- 239000002105 nanoparticle Substances 0.000 claims abstract description 83
- 239000003999 initiator Substances 0.000 claims abstract description 37
- 239000000203 mixture Substances 0.000 claims abstract description 22
- 239000003381 stabilizer Substances 0.000 claims abstract description 18
- -1 nonylphenol ethers Chemical class 0.000 claims abstract description 15
- 239000007864 aqueous solution Substances 0.000 claims abstract description 13
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 12
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 12
- HMFKFHLTUCJZJO-UHFFFAOYSA-N 2-{2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy}ethyl dodecanoate Chemical group CCCCCCCCCCCC(=O)OCCOCC(OCCO)C1OCC(OCCO)C1OCCO HMFKFHLTUCJZJO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229920001214 Polysorbate 60 Polymers 0.000 claims abstract description 6
- 229960005309 Estradiol Drugs 0.000 claims description 47
- 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 description 46
- 239000003921 oil Substances 0.000 claims description 34
- 235000019198 oils Nutrition 0.000 claims description 34
- 238000002360 preparation method Methods 0.000 claims description 34
- 239000000463 material Substances 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000012071 phase Substances 0.000 claims description 12
- 239000003085 diluting agent Substances 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- 239000011149 active material Substances 0.000 claims description 10
- YYGNTYWPHWGJRM-RUSDCZJESA-N Squalene Natural products C(=C\CC/C(=C\CC/C=C(\CC/C=C(\CC/C=C(\C)/C)/C)/C)/C)(\CC/C=C(\C)/C)/C YYGNTYWPHWGJRM-RUSDCZJESA-N 0.000 claims description 8
- 239000008346 aqueous phase Substances 0.000 claims description 6
- VLPFTAMPNXLGLX-UHFFFAOYSA-N Axona Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 claims description 5
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 5
- 229940031439 Squalene Drugs 0.000 claims description 4
- 239000002480 mineral oil Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 229940093609 tricaprylin Drugs 0.000 claims description 4
- 229940013317 Fish Oils Drugs 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010699 lard oil Substances 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000008158 vegetable oil Substances 0.000 claims description 3
- 235000019498 Walnut oil Nutrition 0.000 claims description 2
- 239000010466 nut oil Substances 0.000 claims description 2
- 239000008170 walnut oil Substances 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims 4
- TWIMUEGVLWNOMO-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-(2-nonylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCC1=CC=CC=C1OCCOCCOCCOCCOCCOCCO TWIMUEGVLWNOMO-UHFFFAOYSA-N 0.000 claims 2
- 235000019488 nut oil Nutrition 0.000 claims 1
- 239000002953 phosphate buffered saline Substances 0.000 claims 1
- 239000002202 Polyethylene glycol Substances 0.000 abstract description 4
- 229920001223 polyethylene glycol Polymers 0.000 abstract description 4
- 239000002245 particle Substances 0.000 description 48
- 239000004094 surface-active agent Substances 0.000 description 14
- 239000000284 extract Substances 0.000 description 13
- 239000003814 drug Substances 0.000 description 12
- 210000002966 Serum Anatomy 0.000 description 9
- 229940079593 drugs Drugs 0.000 description 9
- 230000000699 topical Effects 0.000 description 8
- 241000282560 Macaca mulatta Species 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- 235000019634 flavors Nutrition 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 206010018987 Haemorrhage Diseases 0.000 description 4
- 210000003491 Skin Anatomy 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 230000000740 bleeding Effects 0.000 description 4
- 231100000319 bleeding Toxicity 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000010348 incorporation Methods 0.000 description 4
- 239000000693 micelle Substances 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000004513 sizing Methods 0.000 description 4
- 235000012424 soybean oil Nutrition 0.000 description 4
- 239000003549 soybean oil Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- SNQQPOLDUKLAAF-UHFFFAOYSA-N Nonylphenol Chemical compound CCCCCCCCCC1=CC=CC=C1O SNQQPOLDUKLAAF-UHFFFAOYSA-N 0.000 description 3
- 229940068968 Polysorbate 80 Drugs 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 235000002864 food coloring agent Nutrition 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 230000001225 therapeutic Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 239000000341 volatile oil Substances 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 235000005979 Citrus limon Nutrition 0.000 description 2
- 240000002268 Citrus limon Species 0.000 description 2
- 229940088597 Hormone Drugs 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 240000002799 Prunus avium Species 0.000 description 2
- 206010046910 Vaginal haemorrhage Diseases 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 235000019693 cherries Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 230000001809 detectable Effects 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 244000144725 Amygdalus communis Species 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- 206010002368 Anger Diseases 0.000 description 1
- 229940002010 Banana Extract Drugs 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- GFURAIPDNXHHQY-WAJSLEGFSA-N CCO.OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)O)[C@@H]4[C@@H]3CCC2=C1 Chemical compound CCO.OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)O)[C@@H]4[C@@H]3CCC2=C1 GFURAIPDNXHHQY-WAJSLEGFSA-N 0.000 description 1
- 229940107161 Cholesterol Drugs 0.000 description 1
- 229940019859 Estradiol 100 MG Drugs 0.000 description 1
- 229940071887 Estradiol 50 MG Drugs 0.000 description 1
- 240000001441 Fragaria vesca Species 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 240000001422 Laurus nobilis Species 0.000 description 1
- 235000017858 Laurus nobilis Nutrition 0.000 description 1
- 235000018330 Macadamia integrifolia Nutrition 0.000 description 1
- 235000003800 Macadamia tetraphylla Nutrition 0.000 description 1
- 240000000912 Macadamia tetraphylla Species 0.000 description 1
- 240000006217 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000016247 Mentha requienii Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 240000009023 Myrrhis odorata Species 0.000 description 1
- 235000007265 Myrrhis odorata Nutrition 0.000 description 1
- 229940111617 OREGANO OIL Drugs 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 240000005158 Phaseolus vulgaris Species 0.000 description 1
- 229940067631 Phospholipids Drugs 0.000 description 1
- 235000012550 Pimpinella anisum Nutrition 0.000 description 1
- 239000004153 Potassium bromate Substances 0.000 description 1
- 241000736029 Ruvettus pretiosus Species 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 244000044822 Simmondsia californica Species 0.000 description 1
- 235000004433 Simmondsia californica Nutrition 0.000 description 1
- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical compound OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 235000005212 Terminalia tomentosa Nutrition 0.000 description 1
- 240000008529 Triticum aestivum Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 240000006722 Vanilla planifolia Species 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- NWGKJDSIEKMTRX-HSACVWGTSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (E)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-HSACVWGTSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000006682 bigleaf mint Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 235000021324 borage oil Nutrition 0.000 description 1
- 235000019519 canola oil Nutrition 0.000 description 1
- 239000000828 canola oil Substances 0.000 description 1
- 239000010627 cedar oil Substances 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000010630 cinnamon oil Substances 0.000 description 1
- 239000001926 citrus aurantium l. subsp. bergamia wright et arn. oil Substances 0.000 description 1
- 239000010634 clove oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 231100000223 dermal penetration Toxicity 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000000635 electron micrograph Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000001076 estrogenic Effects 0.000 description 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 239000000576 food coloring agent Substances 0.000 description 1
- 239000003688 hormone derivative Substances 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000000977 initiatory Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 235000021388 linseed oil Nutrition 0.000 description 1
- 239000000944 linseed oil Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000001098 melissa officinalis l. leaf oil Substances 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 230000002906 microbiologic Effects 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 235000006679 mint Nutrition 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 239000010661 oregano oil Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000006678 peppermint Nutrition 0.000 description 1
- 235000015132 peppermint Nutrition 0.000 description 1
- 235000007735 peppermint Nutrition 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229940013712 pineapple extract Drugs 0.000 description 1
- 235000015277 pork Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 235000013533 rum Nutrition 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
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- 239000002600 sunflower oil Substances 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 235000021307 wheat Nutrition 0.000 description 1
Abstract
The present invention relates to a micellar nanoparticle having a diameter of between about 25 and 1000 nm, the micellar nanoparticle comprises a lipophilic phase which includes an oil, a stabilizer and an alcohol-based initiator hydrated with a suitable aqueous solution, wherein the stabilizer is selected from the group consisting of Tween 60, Tween 80, nonylphenol ethers and polyethylene glycol, and mixtures thereof.
Description
MICELAR NANOPARTICLES
BACKGROUND OF THE INVENTION The present invention relates to materials and methods for making "micellar nanoparticles", micelle-like particles with average diameters less than 1000 nanometers (1 miera). These micellar nanoparticles are oil-based particles, with the size of submicrons, the smallest of which is filtered through a 0.2-micron filter as those used in standard form for microbiological purification. The micellar nanoparticles of the invention can be formed in stable dispersions in aqueous solutions and buffer solutions. Micellar nanoparticles have a variety of uses given their small size. Other synthetic particles such as liposomes, non-phospholipid lipid vesicles and microcapsules are usually one or more. In contrast, it is possible to form micellar nanoparticles of the invention in sizes less than 100 nanometers in diameter. Unlike lipid vesicles, some of which can be designed to carry an oil, see, for example, Wallach US Patent No. 4,911,928, the particles herein require at least one oil, one stabilizer / surfactant, an initiator and water or other diluent for its manufacture. However, neither cholesterol nor phospholipids are used. In fact, these nanoparticles can be made using USP or NF grade, food grade materials suitable for human use applications. This is particularly important if these micellar nanoparticles are to be used for the topical delivery of a material into the bloodstream. A specific use of this type of system is the administration of natural or synthetic hormones such as estradiol. These materials often have solubility problems, for example, they are often only soluble in materials such as ethanol, which can be difficult to incorporate into stable particulate systems. The micellar nanoparticles are unique in that they allow materials that are soluble in water, oil or initiator (ie ethanol or methanol) to be incorporated into stable particles with average diameters between about 30 and 1000 nanometers. Most of the preparations have particle diameters between 30 to 500 nanometers, are irascible in water and filterable through 0.2 or 0.45 micron filters. These can be stored between -20 and 25 ° C. Using the materials and methods described, it is possible to produce micellar nanoparticles that do the following: 1. Incorporate into the particles the drugs or drugs soluble in ethanol or methanol. 2. Incorporate in the particles the pesticides soluble in ethanol or methanol. 3. Incorporate adjuvants in the particles. 4. Incorporate proteins in the particles. 5. Incorporate into the particles all viruses that contain intact nucleic acids. However, it should be noted that the smaller particles of the invention are approximately the same size as most viruses. 6. Incorporate flavors extracted with ethanol into the particles. 7. Incorporate volatile oils (flavors and fragrances) into the particles. 8. They incorporate a charge in the particles. 9. They create colorful particles. Of particular importance is the ability to transmit drugs topically. For many years it has been known that small particles, such as those with a diameter smaller than 1 miera, can cross the skin barrier more easily than larger particles. However, the small amount of medication transmitted in small particles has often limited its usefulness. In addition, most of the particles have been limited to only one class of materials they can supply. Accordingly, an object of the invention is to produce submicron-sized particles that can supply a variety of kinds of materials. Another object of the invention is to produce submicron-sized particles that can supply materials soluble in ethanol or methanol but have limited solubility or no solubility in aqueous and oily systems. Another object of the invention is to produce particles below 100 nanometers in diameter that can deliver drugs. Still another object of the invention is to produce a particle for topical delivery of hormones such as estradiol. These and other objects and features of the invention will be apparent from the description and the claims.
SUMMARY OF THE INVENTION The present invention provides micellar nanoparticles and the methods for their preparation. These micellar particles have particular utility as vehicles for drug delivery, with specific applications for the topical delivery of materials that are soluble in ethanol and methanol. However, these micellar nanoparticles can also be used to administer very different kinds of drugs and other materials. The small size of the micellar nanoparticles and their compatibility with the tissue makes them applicable for various uses. The micellar nanoparticles of the invention have diameters of about 10-100 nanometers, with most of the particles having diameters below 100 nanometers. This small particle size allows passage through a 0.2 micron filter. The nanoparticles are made from a lipophilic phase that includes an oil, a stabilizer (or surfactant) and an initiator such as ethanol or methanol. This lipophilic phase is hydrated by an aqueous solution such as water or a buffer solution. Preferred stabilizers are non-phospholipid surfactants, particularly the family of Tween surfactants (polyoxyethylene derivatives of sorbitan fatty acid esters) and the nonylphenol polyethylene glycol ethers. The most preferred surfactants are Tween 60 (polyoxyethylene monostearate sorbitan 20) and Tween 80
(sorbitan monooleate 20), and Tergitol NP-40 (poly (oxy-1,2-ethanediyl), a- (4-nonylphenol) -? - hydroxy, branched [average molecular weight 1980]) Tergitol NP-70 (surfactant mixed -AQ = 70%). The high molecular weight of these surfactants appears to have advantageous properties in the manufacture and stability of the resulting micellar nanoparticles. Preferred initiators in the present invention are ethanol and methanol, but in other circumstances other short chain alcohols and / or amides may be used. Although ethanol or pure methanol is preferred, mixtures of the two, and materials, combined or non-combined, containing at least 50% alcohol can be used. This group of initiators may include flavored initiators such as peppermint, lemon, orange and the like. In addition to the initiator and surfactant of the stabilizer, the micellar particles can be modified or processed according to the customer's conditions by selecting the right oil. Although most oils stop working, the preferred oils are selected from the group consisting of vegetable oils, walnut oils, fish oils, lard oils, mineral oils, squalene, tricaprylin and mixtures thereof. It is possible to add various other materials to the micellar nanoparticles for specific uses of the particles. Volatile oils, such as volatile flavor oils, can be used in place of some of the oils or can be added in addition to the other particulate forming oils. A coloring agent can also be added as a food coloring agent, preferably by adding it to the initiator. The initiator or oil can also carry active ingredients that are incorporated in the final particulate suspension. These assets can be dissolved or suspended in the liquid. A preferred additive is a steroid or hormone such as estradiol which can be dissolved in an ethanol initiator and incorporated into the particle. Since estradiol precipitates in aqueous solutions, the addition of the aqueous phase will precipitate estradiol, which then can be released in a topical preparation. An interesting fact that appears is that the type of crystals that are formed using the methods of the present invention are different in form than the precipitates of the standard aqueous estradiol solutions. The aqueous solution used to hydrate the lipophilic phase is preferably a physiologically compatible solution such as water or a buffer solution, for example, saline solution buffered with phosphate. The aqueous solution may have an active material dissolved or suspended therein for incorporation. The fundamental procedure for the manufacture of the micellar nanoparticles is to mix the oil, the stabilizer / surfactant and the initiator to form a lipophilic phase and mix an excess, preferably around a 4: 1 ratio, of the lipophilic phase with a solution of the aqueous diluent. The combination or hydration of the lipophilic phase with the aqueous phase is preferably carried out using a device that generates a relative velocity of about 50 m / s through a hole diameter of 1/18,000 of an inch. This shear provides particles in the preferred size range while lower shear values, for example, using larger holes or lower speeds can give rise to larger particle size. All the different materials and processes described herein can be modified or selected to control the properties of the resulting micellar nanoparticles. The active ingredients can be carried in the oil, the initiator or the aqueous phase for incorporation into the particles. Although it appears that the particles are micelles, they can be in the form of reverse micelles without changing the scope of the invention. The invention is further illustrated by the following detailed description and drawings. BRIEF DESCRIPTION OF THE DRAWINGS Figure la and Ib are electronic micrographs of the nanoparticles of the invention in two different amplification sizes.; and Figure 2 is a graph of serum estradiol levels in ovariectomized Rhesus monkeys after topical administration of 1 mg of estradiol using 3 different types of vehicles. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to micellar nanoparticles and methods for their preparation. Unlike microcapsules and liposomal systems, the micellar nanoparticles of the present have a population of significant size below 100 nanometers in diameter, while still carrying significant amounts of active ingredients. These micellar nanoparticles are particularly useful as vehicles for the topical administration of drugs given their small size and other characteristics that allow rapid dermal penetration. The micellar nanoparticles are also exceptionally versatile since the active materials that can be ported include those that can be suspended or dissolved in any of the oils, aqueous diluents, or, preferably, the initiator. These properties allow this system to be used with assets that are difficult to use in other management systems. The micellar nanoparticles are formed by first combining at least one oil, preferably an oil selected from Table 1, a stabilizer (surfactant), preferably a surfactant from Table 2, and an initiator, preferably ethanol or methanol. The most preferred stabilizers are Tween 60, Tween 80, Tergitol NP-40 and Tergitol NP-70. Possible additional initiators are shown in Table 3 (alcohols and related compounds) and Table 4 (alcoholic flavor extracts). If any of the flavoring alcohol strata of Table 4 that is less than 50% ethanol is used, a mixture of ethanol and the extract is used to ensure that at least 50% ethanol is used. Volatile oils can also be added to these chemical components (table 5), and colors can also be added to the oil-stabilizer-initiator mixture (table 6). It is possible to introduce a negative charge by adding oleic acid to the oil-stabilizer-initiator mixture. After premixing these materials, water or a suitable buffer solution such as those shown in table 7 is injected maintaining the mixture at a high speed. The preferred ratio of the oil: stabilizer: initiator is 25: 3: 5, respectively, volume to volume. The preferred ratio of the phase containing the pre-mixed oil to the water is 4: 1, respectively. The nanoparticles can be produced with syringe instrumentation on the go and see, continuous flow instrumentation or high speed mixing equipment. The particles that are made in this 4: 1 ratio have a diameter range of 30 to 500 nanometers. These miscible particles in water can then be filtered through a 0.2 or
0. 45 microns. The larger micellar particles can be made by simply increasing the water content, decreasing the oil-stabilizer-initiator content or changing the shear force during the formation of the particles. We have coined the name "micellar nanoparticles" for particles with average diameters less than 1000 nanometers (one miera). Table 1: oils used in the preparation of micellar nanoparticles sweet almond oil chabacano seed oil borage oil canola oil coconut oil corn oil cottonseed oil fish oil jojoba bean oil pork fat linseed oil, boiled macadamia nut oil mineral oil olive oil peanut oil safflower oil sesame oil soybean oil squalene sunflower oil tricaprylin (1, 2, 3-trioctanoyl glycerol) seed oil of wheat Table 2: stabilizers / surfactants that are used in the preparation of micellar nanoparticles. Tween 60 Tween 80 ethers of nonylphenol polyethylene glycol (alkyl phenol-hydroxy polyoxyethylene) 1. Poly (oxy-1,2-ethanediyl), alpha- (4-nonylphenol) -? - hydroxy-branched (ie surfactant Tergitol NP- 40) formula: C95 H? 85 O40 PM (average) = 1980 2. Mixtures of nonylphenol ether polyethylene glycol (ie Tergitol NP-70 (AQ 70%) surfactant] Formula PM: not applicable (mixture) Table 3: Initiators which are used in the preparation of micellar nanoparticles Ethanol methanol Table 4: Flavoring primers (flavor extracts
*) that are used in the preparation of micellar nanoparticles. Pure anise extract (73% ethanol) Imitation banana extract (40% ethanol) Imitation cherry extract (24% ethanol) Chocolate extract (23% ethanol) Pure lemon extract (84% ethanol) Pure extract from orange (80% ethanol) Mint pure extract (89% ethanol) Pineapple extract (42% ethanol) Rum imitation extract (35% ethanol) Strawberry imitation extract (30% ethanol) Pure vanilla extract (35 % of ethanol) * the extracts that are used are food grade materials (MeCormick). Materials can be substituted from other sources. Table 5: Oils or volatile fragrances that are used during the preparation of micellar nanoparticles. Melissa oil Laurel oil Bergamot oil Cedar wood oil Cherry oil Cinnamon oil Clove oil Oregano oil Peppermint oil Table 6: Food colors * used in the preparation of micellar nanoparticles. Green Yellow Red Blue * Food colors used are food grade materials (MeCormick). It is possible to replace materials from other sources. Table 7: List of diluents that are used in the preparation of micellar nanoparticles. Water for saline injection buffered with phosphate The following examples will illustrate the invention and its usefulness more clearly. Example 1- Production of micellar nanoparticles without charge Table 8 contains the materials that are used to produce micellar nanoparticles where the diluent is water. The sizing parameters using an apparatus to measure the size Coulter L130 Laser is shown in Table 9.
Table 8: Preparation of micellar nanoparticles using water as a diluent Chemical component Amount Soybean oil (oil) 25 ml Polysorbate 80 (Tween 80) (stabilizer) 3 ml Ethanol (initiator) 5 ml
The aforementioned oil-stabilizer-initiator components are mixed for 60 sec. 1 ml of water is injected into 4 ml of the mixture using syringe instrumentation with oscillating movement. This instrumentation has two 5 ml syringes connected together through a stainless steel Leurlok connector with a 1/18000 in. Hole. The solutions are propelled between the syringes through the connector for about 100 seconds. The resulting particles were dried on EM reticles stained with uranyl acetate and micrographic electron studies were performed. The Figure shows an electromicrograph of this preparation in an amplification of 60000 X whereas Figure Ib shows the same preparation in an amplification of 150000 X. Each table shows a brief description of the production method of the micellar nanoparticles. Table 9. Dimensioning micellar nanoparticles using water as diluent.
Preparation average diameter LS- range LS-130 130 (nanometers) (nanometers) nanoparticles 312 193-455 micellar (SBO / Tw80 / E / FI
One problem with the use of the LS130 size measuring device is that it is not really possible to accurately measure the size of particles with a diameter smaller than 200 nanometers. Using the figures la and Ib it is determined that most of the particles are between 70 and 90 nanometers in diameter, with only 5% of the particles with a diameter greater than 90 nanometers. Particles in the range of 20-30 nanometers are visible in the larger amplification shown in Figure Ib. Example 2- Incorporation of estradiol in the micellar nanoparticles. Tables 10 and 12 contain the materials used to produce two batches of uncharged micellar nanoparticles in which estradiol has been incorporated in two different concentrations. Both preparations were made using water as a diluent. The materials with the highest concentration of estradiol were used in studies in Rhesus monkeys as described in Example 3 below. 50 or 100 mg of estradiol were solubilized in the initiator (ethanol component) of the preparation before the formation of the micellar nanoparticles. This is necessary since estradiol precipitates in the presence of water. In fact the small amount of water in the reactive grade ethanol appears to be sufficient to precipitate estradiol since the micellar particles that are formed using the materials and methods described herein appear to have estradiol crystals contained therein. However, these crystals appear to have a leaf-like shape instead of the needle shape commonly found in aqueous precipitations. Table 10: Preparation of micellar nanoparticles containing estradiol Chemical component Amount Soy bean oil (Oil) 25 ml Polysorbate 80. { Tween 80) (Stabilizer) 3 ml Ethanol (Initiator) 5 ml Estradiol 50 mg
The micellar nanoparticles were made using the procedures substantially identical to those described in Example 1, except that the estradiol was dissolved (or suspended) in the ethanol initiator before mixing the initiator with the other components. The oil-stabilizer-initiator / estradiol components are mixed by hand or can be mixed for 60 seconds using a vortex mixer. 1 ml of water is injected into 4 ml of the resulting mixture using oscillating syringe instrumentation as described in Example 1. TABLE 11-Sizing data in micellar nanoparticles containing estradiol (50 mg) Preparation Average diameter Range LS-130 LS -130 (nanometers) (nanometers)
Micellar nanoparticles (SBO / Tw80 / EtOH-estradiol / FI 289 174-459
The sizing data in these preparations, measured using an apparatus for measuring the Coulter LS130 Laser size are shown in Tables 11 and 13 respectively for the two preparations. The device for measuring size LS130 can not measure particles of size approximately less than 200 nanometers in diameter. These materials were also dried on EM grids, stained with uranyl acetate and electron micrograph studies were performed. Electron micrographs show that most particles are less than 200 nanometers. The particles in the range of 20-30 nanometers are visible. The crystallized estradiol is easily visible in larger micelles. No crystal of free medication is observed in any of the fields, which suggests the complete incorporation of the drug in the micelles. TABLE 12: Preparation of micellar nanoparticles containing estradiol. Chemical component Amount Soybean oil (Oil) 25 ml Polysorbate 80 (Tween 80) (Stabilizer) 3 ml Ethanol (Initiator) 5 ml Estradiol 100 mg TABLE 13: Sizing data in micellar nanoparticles containing estradiol (100 mg) Preparation Average diameter Range LS-130 LS-130 (nanometer) (nanometer)
Micellar nanoparticles (SBO / Tw80 / EtOH-estradiol / FI 217 151-291 Example 3- Test of preparations containing estradiol in rhesus monkeys 100 mg of the estradiol preparation of Example 2 was tested against an estradiol preparation in standard ethanol To show the efficacy, one milligram of estradiol, in ethanol (Table 14) or in micellar nanoparticles (Table 15), was applied to the skin of groups in four ovariectomized Rhesus monkeys, blood samples were taken in series and the level was determined. of serum estradiol for the next 32 days The serum estradiol data are plotted in Figure 2. No additional drugs were administered to the skin of any animal.The animals were kept under observation for the next 60 days to determine the time of appearance, duration and severity of vaginal bleeding (Table 16).
TABLE 14 Levels of serum estradiol in female ovariectomized monkeys after a single topical application of micellar nanoparticles equivalent to one mg of estradiol.
Time Mono number Average sample group ± D.E. Serum estradiol # 19567 # 21792 # 22366 # 22405 (pg / ml) (pg / ml) (pg / ml) (pg / ml) 0 hour 0.0b 0.0b 0.0 ° 0.0b 0.0 ± 0.0b
0. 5 hours 22.2 49.8 36.9 77.5 46.6 ± 11.7
1 hour 3 377..44 60.9 65.6 108.6 68.1 ± 14.8
2 hours 61.5 80.5 87.3 191.3 105.2 ± 29.2 4 hours 77.2 132.1 120.6 120.4 112.6 ± 12.1 6 hours 89.0 166.3 119.0 158.3 133.2 ± 18.0 8 hours 87.5 157.3 116.1 148.1 127.3 ± 15.9 2 hours 83.0 160.5 100.6 140.3 121.1 ± 17.8 days 90.7 178.0 105.7 132.6 126.8 ± 19.2 2 days 95.5 152.8 90.6 83.5 105.6 ± 15.9
3 days 81.9 122.6 51.1 47.2 75.7 ± 17.5
4 days 91.5 83.9 58.7 50.3 71.1 ± 9.9
days 41.6 74.7 35.1 40.0 47.9 ± 9.1
6 days 45.2 63.7 25.6 40.9 43.9 ± 7.8
7 days 18.3 25.9 21.9 27.0 23.3 ± 2.0
12 days O.Ob O.Ob 0.0b 0.0b 0.0 ± 0.0b
17 days O.O O.Ob 0.0b 0.0b 0.0 ± 0.0b
22 days O.Ofc O.O 0.0 0.0b 0.0 ± 0.0b
27 days 0.0b O.Ob 0.0b 0.0b 0.0 ± 0.0b
32 days O.Ob 0.0b 0.0 0.0b 0.0 ± 0.0b at CDB 3988 = 2.4 mg estradiol / ml Tween / Oil. The dosage volume was 0.42 ml. B 0 = Not detectable. The limit of detection (DE90) for the trial was 13.3 ± 2.4 pg / ml (mean ± D.E., n = 4)
TABLE 15 Levels of serum estradiol in ovariectomized female monkeys after a single topical application of micellar nanoparticles equivalent to one mg of estradiol.
Time Mono number Average sample group ± D.E. Serum estradiol # G-558 # G-603 # E-920 # E-924 (pg / ml) (pg / ml) (pg / ml) (pg / ml) 0 hour 0.0 0.0b 0.0b 0.0b 0.0 ± o.ob 0.5 hour 17.7 97.1 44.8 19.5 44.8 ± 18.5 1 hour 53.2 44.1 88.3 99.9 71.4 ± 13.5
2 hours 144.3 89.4 138.5 155.1 131.8 ± 14.6 4 hours 143.7 202.3 165.1 193.6 176.2 ± 13.4 6 hours 155.8 257.8 173.1 203.7 197.6 ± 22.4 8 hours 114.2 266.1 130.7 130.0 160.3 ± 35.5 12 hours 80.8 219.5 86.4 115.9 125.7 ± 32.2 1 day 92.4 145.2 56.9 109.4 101.0 ± 18.4
2 days 74.1 124.2 55.3 107.2 90.2 ± 15.6
3 days 65.0 67.4 51.9 89.2 68.4 ± 7.7
4 days 70.5 79.6 57.8 90.0 74.5 ± 6.8
days 53.6 53.2 51.6 47.3 51.4 ± 1.4
6 days 60.1 59.0 59.4 53.0 57.9 ± 1.6
7 days 48.7 40.6 50.3 36.6 44.1 ± 3.3
12 days 28.5 24.2 53.3 0.0b 26.4 ± 10.9b
17 days 0.0 0.0b 28.9 0.0b 7.2 ± 7.2b
22 days 0.0b 0.0b 13.8 0.0 3.5 ± 3.5
27 days 0.0b 0.0b 0.0b 0.0b 0.0 ± 0.0b
32 days 0.0b 0.0 0.0b 0.0b 0.0 ± 0.0b CBD 100 = 2.4 mg estradiol / l absolute ethanol. The dosage volume was 0.42 ml. B 0 = Not detectable. The limit of detection (DE90) for the trial was 13.3 ± 2.4 pg / ml (mean ± D.E., n = 4)
The data in Tables 14 and 15 and Figure 2 show that the serum therapeutic levels of estrogen are present in the bloodstream of the ovariectomized animals in both groups one hour after a single application. Average estradiol levels greater than 40 picograms / ml were maintained for 7 days with the ethanol preparation and for 6 days with the preparation of the nanoparticles. When estrogen levels remain low (see Figure 2 and Table 16), vaginal bleeding occurs in both groups. Also of particular interest is the shape of the curves in Figure 2. The ethanol-estradiol preparation produces a very sharp curve that exhibits a high initial action and a sudden drop while the preparation of the micellar nanoparticles produces more than one "mesa" effect "with an almost flat level for a few hours. This "table" effect is usually preferred since some of the problems associated with peak formation can be reduced.
TABLE 16 - ESTROGENIC RETIREMENT OF BLEEDING IN OVARIECTOMIZED RHESUS MONKEYS AFTER ONE TOP APPLICATION OF ESTRADIOL IN ALCOHOL OR NANOPAR MICELAR ICES
CBD No. ESTRADIOL ESTER BLEEDING RETIREMENTS DAYS LATENCY DURATION INTENSITY 100 Solution of 19.5 ± 0.3 4.3 ± 0.9 1.6 ± 0.2 estradiol in alcohol 3988 Formulation0 of 16.5 ± 0.5C 7.3 ± 1.5 1.6 ± 0.1 estradiol 1 Mean intensity of bleeding (1 = sparse, moderate, 3 - abundant) during the period of bleeding b Novavax MN Suspension 11294-2 c Significant difference (p <0.01) of estradiol solution in alcohol based on a one-way analysis of variance followed by a range test Multiple Student Neuman-Keuls.
Thus, this Example demonstrates in a non-human primate that the micellar nanoparticles of the invention can be used to deliver estradiol through the intact skin with maintenance of the therapeutic levels of estradiol in serum for 6 days after a single application. This technology can have numerous therapeutic applications in medicine. The estradiol preparation is also stable at a variety of temperatures. Table 17 shows the thermal stability data for the preparation of micellar nanoparticles of Example 2 at -20 ° C, 25 ° C and 65 ° C. As is clear, although the micellar nanoparticles are unstable at elevated temperatures, they are stable to room temperature and low temperatures.
TABLE 17: Thermal stability of micellar nanoparticles Preparation Average diameter Range LS-130 LS-130 (nanometers) (nanometers; Micellar nanoparticles (SBO / Tw80 / EtOH-estradiol / FI Storage at 25 ° C 361 168-599
Micellar nanoparticles (SBO / Tw80 / EtOH-estradiol / FI Storage at -20 ° C 312 179-510
Micellar nanoparticles (SBO / Tw80 / EtOH-estradiol / FI) Storage at 65 ° C Unstable
In addition, the micellar nanoparticles of the invention can be diluted with aqueous solutions without losing stability. This allows the possibility of using products of high concentration that can be diluted for use as necessary. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents for the specific embodiments of the invention described herein. These equivalents are proposed to be contained by the following claims.
Claims (26)
1. A micellar nanoparticle having a diameter between about 25 and 1000 nm, the micellar nanoparticle comprises a lipophilic phase which includes an oil, a stabilizer and an initiator, hydrated with a suitable aqueous-based solution.
2. The micellar nanoparticle of claim 1, wherein the stabilizer is selected from the group consisting of Tween 60, Tween 80, nonylphenol polyethylene glycol ether and mixtures thereof.
3. The micellar nanoparticle of claim 1, wherein the initiator is selected from the group consisting of alcohol-based materials containing methanol, ethanol, and mixtures thereof.
4. The micellar nanoparticle of claim 3, wherein the initiator is selected from the group consisting of alcohol-based materials containing ethanol, methanol, and mixtures thereof by 50% or greater.
5. The micellar nanoparticle of claim 1, wherein the oil is selected from the group consisting of vegetable oils, walnut oils, fish oils, lard oil, mineral oils, squalene, tricaprylin, and mixtures thereof.
6. The micellar nanoparticle of claim 1, wherein the aqueous solution comprises a physiologically compatible solution.
The micellar nanoparticle of claim 9, wherein the aqueous solution is selected from the group consisting of water and saline buffered with phosphate.
8. The micellar nanoparticle of claim 1, wherein the aqueous phase has an active material dissolved or suspended therein.
9. The micellar nanoparticle of claim 1, wherein the oil has an active material dissolved or suspended therein.
10. The micellar nanoparticle of claim 1, wherein the initiator has an active material dissolved or suspended therein.
11. The micellar nanoparticle of claim 10, wherein the active material comprises estradiol.
12. The micellar nanoparticle of claim 1, wherein the micellar nanoparticle is dispersible in aqueous solution.
13. The micellar nanoparticle of claim 1, wherein the diameter of the micellar nanoparticle allows passage through a 0.2 mm filter.
14. A method for making micellar nanoparticles comprising the steps of: mixing an excess of an oil, together with a stabilizer and an initiator to form a lipophilic phase; the preparation of a diluent solution having a base of aqueous solution; and mixing an excess of the lipophilic phase with the diluent to form the micellar nanoparticles.
15. The method of claim 14, wherein the stabilizer is selected from the group consisting of Tween 60, Tween 80, nonylphenol polyethylene glycol ether and mixtures thereof.
16. The method of claim 14, wherein the initiator is selected from the group consisting of alcohol-based materials containing methanol, ethanol, and mixtures thereof.
The method of claim 16, wherein the initiator is selected from the group consisting of alcohol-based materials containing ethanol, methanol, and mixtures thereof by 50% or greater.
The method of claim 14, wherein the oil is selected from the group consisting of vegetable oils, nut oils, fish oils, lard oil, mineral oils, squalene, tricaprylin and mixtures thereof.
The method of claim 18, wherein the aqueous solution consists of a physiologically compatible solution.
The method of claim 19, wherein the aqueous solution is selected from the group consisting of water and phosphate buffered saline.
21. The method of claim 14, wherein the aqueous phase has an active material dissolved or suspended therein.
22. The method of claim 14, wherein the oil has an active material dissolved or suspended therein.
23. The method of claim 14, wherein the initiator has an active material dissolved or suspended therein.
The method of claim 23, wherein the active material comprises estradiol.
The method of claim 14, wherein the mixture of the lipophilic phase and the diluent is achieved using a relative velocity of about 50 m / s through a 1 / 18,000 in. Orifice.
26. The method of claim 14, wherein the ratio of the lipophilic phase to the aqueous phase is about 4: 1.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US08380942 | 1995-01-31 | ||
US08/380,942 US5629021A (en) | 1995-01-31 | 1995-01-31 | Micellar nanoparticles |
Publications (2)
Publication Number | Publication Date |
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MX9705663A MX9705663A (en) | 1998-07-31 |
MXPA97005663A true MXPA97005663A (en) | 1998-11-09 |
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