EP4281043A1 - Microemulsion preconcentrate containing cladribine particularly for oral administration and method of preparation - Google Patents
Microemulsion preconcentrate containing cladribine particularly for oral administration and method of preparationInfo
- Publication number
- EP4281043A1 EP4281043A1 EP22708285.6A EP22708285A EP4281043A1 EP 4281043 A1 EP4281043 A1 EP 4281043A1 EP 22708285 A EP22708285 A EP 22708285A EP 4281043 A1 EP4281043 A1 EP 4281043A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cladribine
- microemulsion preconcentrate
- hydrophilic
- ionogenic
- surfactant
- 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.)
- Pending
Links
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 title claims abstract description 124
- 229960002436 cladribine Drugs 0.000 title claims abstract description 122
- 239000004530 micro-emulsion Substances 0.000 title claims abstract description 77
- 238000002360 preparation method Methods 0.000 title claims description 24
- 238000000034 method Methods 0.000 title claims description 12
- 239000000203 mixture Substances 0.000 claims abstract description 96
- 239000004094 surface-active agent Substances 0.000 claims abstract description 62
- 238000009472 formulation Methods 0.000 claims abstract description 45
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 claims abstract description 37
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 30
- WECGLUPZRHILCT-GSNKCQISSA-N 1-linoleoyl-sn-glycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@@H](O)CO WECGLUPZRHILCT-GSNKCQISSA-N 0.000 claims abstract description 23
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- 239000002798 polar solvent Substances 0.000 claims abstract description 11
- 239000002105 nanoparticle Substances 0.000 claims abstract description 8
- 150000004668 long chain fatty acids Chemical class 0.000 claims abstract description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 70
- 239000002904 solvent Substances 0.000 claims description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 18
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 14
- 150000002632 lipids Chemical class 0.000 claims description 14
- 239000003981 vehicle Substances 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 11
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000008389 polyethoxylated castor oil Substances 0.000 claims description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- 239000012736 aqueous medium Substances 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 6
- 238000012377 drug delivery Methods 0.000 claims description 6
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 claims description 5
- GHHURQMJLARIDK-UHFFFAOYSA-N 2-hydroxypropyl octanoate Chemical compound CCCCCCCC(=O)OCC(C)O GHHURQMJLARIDK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 150000002334 glycols Chemical class 0.000 claims description 4
- -1 polymorphs Substances 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 3
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 claims description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000000796 flavoring agent Substances 0.000 claims description 2
- 235000019634 flavors Nutrition 0.000 claims description 2
- 235000003599 food sweetener Nutrition 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 239000006210 lotion Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000004667 medium chain fatty acids Chemical class 0.000 claims description 2
- 239000006072 paste Substances 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 239000003765 sweetening agent Substances 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims 1
- 230000003078 antioxidant effect Effects 0.000 claims 1
- 230000000699 topical effect Effects 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 37
- 239000006185 dispersion Substances 0.000 abstract description 8
- 239000008240 homogeneous mixture Substances 0.000 abstract description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 43
- 239000002245 particle Substances 0.000 description 31
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 27
- 239000003814 drug Substances 0.000 description 21
- 229940079593 drug Drugs 0.000 description 20
- 239000004615 ingredient Substances 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- 238000010494 dissociation reaction Methods 0.000 description 13
- 230000005593 dissociations Effects 0.000 description 13
- 239000000126 substance Substances 0.000 description 11
- 238000010790 dilution Methods 0.000 description 10
- 239000012895 dilution Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 9
- 230000015556 catabolic process Effects 0.000 description 9
- 238000006731 degradation reaction Methods 0.000 description 9
- 238000011161 development Methods 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 230000007928 solubilization Effects 0.000 description 6
- 238000005063 solubilization Methods 0.000 description 6
- 150000003626 triacylglycerols Chemical class 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 230000002496 gastric effect Effects 0.000 description 5
- 125000005456 glyceride group Chemical group 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 201000006417 multiple sclerosis Diseases 0.000 description 5
- 238000007127 saponification reaction Methods 0.000 description 5
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 229940057917 medium chain triglycerides Drugs 0.000 description 4
- 239000002736 nonionic surfactant Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000001828 Gelatine Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004945 emulsification Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000010587 phase diagram Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- WECGLUPZRHILCT-HZJYTTRNSA-N rac-1-monolinoleoylglycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OCC(O)CO WECGLUPZRHILCT-HZJYTTRNSA-N 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 239000013020 final formulation Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000000771 oncological effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 206010025327 Lymphopenia Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical class C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 231100001125 band 2 compound Toxicity 0.000 description 1
- 231100001127 band 4 compound Toxicity 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 238000005100 correlation spectroscopy Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003413 degradative effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
- 238000010894 electron beam technology Methods 0.000 description 1
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- 230000007515 enzymatic degradation Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000030135 gastric motility Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 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 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000008991 intestinal motility Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 231100001023 lymphopenia Toxicity 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
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- 230000001839 systemic circulation Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 230000007723 transport mechanism Effects 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
Definitions
- the invention relates to a microemulsion preconcentrate comprising cladribine, in particular for oral administration, including a method of preparation and use thereof.
- Cladribine (2-chlorodeoxyadenosine, 2-CdA) was developed in the late 1970s by the Scripps Research Institute (La Jolla, California) and used in the treatment of mainly haemato- oncological diseases. The first registration of a parenteral formulation was granted in 1993 for the treatment of haemato-oncological diseases. It is a synthetic chlorinated analogue of deoxyadenosine with the structure shown in Figure 5.
- cladribine In addition to the originally described chemotherapeutic effect, cladribine also has an immunosuppressive effect, especially on the adaptive component of the immune system, characterized by marked lymphopenia of peripheral B lymphocytes (CD19+), CD4+, and partially also CD8+ T lymphocytes.
- cladribine is a toxic molecule, therefore, hence especially for the treatment of non-oncological indications (multiple sclerosis, possibly myasthenia gravis, autoimmune haemolytic anaemia, rheumatoid arthritis, systemic lupus erythematosus, psoriasis; source: Robak et al., 2006), it is desirable to develop a stable, robust final dosage form that exhibits high bioavailability and thus allows (for) minimised dosing.
- Cladribine for oral administration is currently on the market in 10 mg tablets in the form of a cladribine complex with cyclodextrin. Orally administered cladribine is rapidly absorbed with 40% bioavailability, which is mainly explained by incomplete absorption due to efflux mediated by transport mechanisms (Assessment report MAVENCLAD, 2017).
- cladribine is classified as a BCS (Biopharmaceutical Classification System) class 3 substance, i.e., a high solubility, low permeability substance (NDA 22561 Clinical Pharmacology Amendment Memo).
- BCS Biopharmaceutical Classification System
- drugs are considered highly soluble when the dose corresponding to the highest strength of the dosage form is soluble in ⁇ 250 ml of buffer in the pH range of 1.0 to 7.5.
- EMA European Medicines Agency
- the applicant has decided to base the development of the new oral dosage form containing cladribine on the physicochemical definition of drug solubility as defined by USP 38 and not on the BCS classification.
- cladribine with a maximum water solubility of 6.35 mg/ml can be classified as a sparingly soluble molecule.
- Low water solubility is widely recognized as the main reason for poor oral absorption of many drugs.
- Conventional solubilization approaches based on surfactants, cyclodextrin complexes, synthesis of novel crystal polymorphs and salts, nanoparticles, solid dispersions, lipids and permeation enhancers can be used to increase the oral absorption of drugs.
- LBDDS-based formulations show high potential for improving (i) bioavailability of compounds with low solubility in aqueous media, (ii) membrane permeability, (iii) metabolic problems, or (iv) stability of the active ingredient. High and consistent absorption has been demonstrated with oral administration of the LBDDS-based formulation.
- LBDDS can be divided into four classes including formulations ranging from simple lipid solutions or drug suspensions to emulsions and more complex self-emulsifying, self-micro-emulsifying or self-emulsifying - nanoemulsifying systems (SEDDS/ SMEDDS/ SNEDDS).
- LBCS type II and Illa formulations are generally referred to as SEDDS. They are formulated with mixtures of lipid vehicles, non-ionic surfactants and drug in the absence of water and are assumed to exist as transparent isotropic solutions. These systems have a unique property: they can rapidly self-emulsify in gastrointestinal fluids and form fine oil-in-water emulsions (droplet size diameter ⁇ 300 nm) under gentle agitation provided by gastrointestinal movement. SEDDS are commonly suitable for oral administration in a soft or hard gelatine capsule, a hard hydroxypropylmethylcellulose (HPMC) capsule, or a capsule of other suitable pharmaceutically acceptable material.
- HPMC hard hydroxypropylmethylcellulose
- LBCS Type Illb formulations are commonly referred to as SMEDDS and are defined as isotropic mixtures of oil, surfactant and active ingredient. Such systems form fine oil-in-water microemulsions under gentle agitation provided by gastric and intestinal motility after dilution by the aqueous phase in vivo. SMEDDS differ from SEDDS by the smaller particle size produced by dilution, resulting in a transparent or translucent stable dispersion. The particle size after dilution is ⁇ 100 nm for SMEDDS or ⁇ 300 nm for SEDDS.
- Type IV formulations according to LBCS are oil-free, based only on surfactant and auxiliary solvent mixtures. This type has recently been added to the LBCS. These formulations represent the most hydrophilic type of lipid formulation. They form a very fine dispersion in an aqueous medium sometimes referred to as nanoemulsions (SNEDDS).
- SNEDDS nanoemulsions
- SMEDDS generally contain relatively high concentrations of surfactants (typically 30 to 60% w/w) or hydrophilic solvents. They are often described as microemulsion preconcentrates because microemulsions are formed by dilution in an aqueous environment.
- LBDDS represent the successful strategy for increasing the solubility and improving the bioavailability of poorly soluble drugs, especially for BCS class II and IV groups. They achieve enhanced absorption of poorly soluble drugs by specific mechanisms: prolonged retention time in the stomach, increased solubilization, stimulation of the gastrointestinal lymphatic system, transport and impact on the biochemical and physical barrier of the GIT. However, their efficacy strongly depends on the composition and proportion of all ingredients. Combinations of different types of excipients determine the specific drug delivery system. It is necessary to determine experimentally the appropriate formulation of the selected delivery system for each individual drug to ensure maximum efficacy of the selected LBDDS.
- microemulsions as potential therapeutic systems for oral administration is their specific structure, which allows the incorporation of hydrophilic, amphiphilic and lipophilic drugs to increase their solubility, speed and extent of absorption, to protect labile substances from the gastrointestinal environment, to reduce inter- and intra-individual variability of effect and to mask unpleasant odour and taste.
- the object of the present invention is to provide a liquid formulation of a microemulsion preconcentrate containing cladribine, particularly for oral, administration providing higher stability of the active ingredient at acidic pH, and a method of preparing the same using a robust, cost-effective, safe and easily applied industrial production technology.
- the applicant of the invention considers it crucial to develop a formulation that allows the cladribine molecule to be protected from degradation in the low pH of the stomach, while at the same time increasing solubility so that at any given time the excess of cladribine predominates over its degradative metabolite.
- the optimal solution appears to be to use a liquid formulation with rapid solubility and the ability to protect the degradation of the active ingredient, or at least to allow faster absorption of cladribine from the immediately available higher concentration of the active ingredient.
- the invention presents a microemulsion preconcentrate containing cladribine for administration mainly by the oral route, the essence of which is that it comprises the following components: i) cladribine, ii) at least one aprotic polar solvent, iii) at least one auxiliary organic solvent with an acceptable affinity for water, iv) a non-ionogenic surfactant with a hydrophilic-lipophilic balance > 10 (hereafter referred to as HLB), v) a hydrophobic component comprising (i) a non-ionogenic surfactant with HLB ⁇ 10, or (ii) a lipophilic vehicle with a high proportion of glycerol mono-oleate or glycerol mono- oleate-, or a combination of both (i) and (ii) above.
- HLB hydrophilic-lipophilic balance > 10
- the problem of solubilization of cladribine in LBDDS was solved by a suitable combination of an aprotic solvent with a hydrophilic auxiliary solvent and a mixture of non- ionogenic surfactants with HLB > 10 with a non-ionogenic water-insoluble surfactant with HLB ⁇ 10 and/or with lipophilic vehicles containing a high proportion of long-chain fatty acids, such as glycerol mono-oleate or glycerol mono-linoleate.
- anhydrous microemulsion preconcentrate comprising cladribine: Cladribine dissolved in an aprotic polar solvent (or multiple solvents) and an auxiliary organic solvent (or multiple solvents) having an acceptable affinity for water, and further comprising a mixture of non-ionogenic surfactants having HLB > 10 with a hydrophobic component, which may comprise hydrophobic non-ionic surfactants with HLB ⁇ 10 or lipophilic vehicles containing a high proportion of glycerol mono-oleate or glycerol mono-linoleate, or a combination of non-ionic surfactants with lipophilic vehicles.
- the invention also includes a method of preparing a microemulsion preconcentrate comprising the following process steps:
- step (c) the combination of the components of step (a) and (b) of the said drug solution and the said surfactant system to form a microemulsion preconcentrate.
- Cladribine was first dissolved in the minimum amount of aprotic solvent required and the resulting concentrated solution was diluted with organic solvent to the required viscosity. The resulting solution of cladribine was then mixed with the surfactant solution and possibly with lipophilic vehicles containing a high proportion of glycerol mono-oleate or glycerol monolinoleate or combinations thereof, resulting in optimization of the dispersion properties of the formulation. When the results were evaluated, it was surprisingly found that the resulting formulation significantly increased the resistance of cladribine to low pH while improving the solubility of the formulation.
- microemulsion preconcentrate prepared in this way is that it spontaneously forms nanoparticles containing dissolved cladribine when diluted in an aqueous medium.
- cladribine is dissolved in an aprotic polar solvent (e.g., DMSO, DMFA, DMA) or in organic auxiliary solvents having acceptable affinity for water (e.g., ethanol, Transcutol, glycols).
- hydrophilic surfactants are heated and mixed with the hydrophobic component to form a homogeneous mixture of surfactants.
- This homogeneous mixture is then mixed with a cladribine solution to produce a formulation (microemulsion preconcentrate) that, when introduced into the GIT, spontaneously forms a dispersion of non-ionogenic surfactant nanoparticles.
- a formulation microemulsion preconcentrate
- the invention further provides a method of administering a drug based on a microemulsion preconcentrate comprising cladribine.
- the microemulsions formed in GIT are isotropic, thermodynamically stable transparent (or translucent) systems of water and surfactant or oil, respectively, often in combination with an auxiliary solvent with particle sizes typically in the range of 20-200 nm.
- it is a drug delivery system based on an surfactant, solvent and an excipient which has the ability to form an oil-in-water (o/v) (micro)emulsion after dispersing in the aqueous phase under mild agitation, caused for example by gut and stomach motility.
- microemulsions as potential therapeutic systems for oral administration is their specific structure, which allows the incorporation of hydrophilic, amphiphilic and lipophilic drugs characterized by an increase in their solubility, rate and extent of absorption, to reduce inter and intra individual variability, or to mask unpleasant smell and taste. When administered orally, high and consistent absorption was obtained.
- microemulsion systems have been shown to increase membrane permeability and may protect the incorporated molecules against oxidation and enzymatic degradation.
- composition according to the present invention can be prepared by first dissolving cladribine in a mixture of aprotic and polar auxiliary solvent and then by mixing with a mixture of surfactants.
- cladribine refers to cladribine in the form of pharmaceutically acceptable solvates, hydrates, enantiomers, polymorphs or mixtures thereof.
- cladribine is used in crystalline form.
- An aprotic polar solvent is defined as a polar solvent that does not act as a hydrogen bond donor.
- polar aprotic solvents include dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, N-methylpyrrolidone (NMP), N,N- dimethylacetamide (DMA) and propylene carbonate and/or mixtures thereof.
- any suitable water-miscible organic solvent can preferably be used.
- the selection of a suitable organic solvent will depend in part on the solubility of the active material in the solvent, the extent to which the solvent is miscible with water, and the tolerance of the solvent.
- the solvent should be physiologically acceptable.
- solvents examples include, but are not limited by enumeration, alcohols, glycols, glycerol, propylene glycol, and various polyethylene glycols.
- hydrophobic and hydrophilic non-ionogenic surfactants are mixed together to form a homogeneous mixture that can be heated if necessary.
- the non-ionogenic surfactants are selected for their hydrophilic-lipophilic balance (HLB).
- HLB is not a universal property because it is based solely on the weight percent of polyoxyethylene or polyol in the surfactant molecule, regardless of its molecular weight, the chemical nature of its hydrophilic and lipophilic groups, and the structural properties of the latter.
- HLB values as a rough guide, compounds having an HLB value greater than 10, in particular from 12 to 17, are considered to be hydrophilic surfactants.
- hydrophobic surfactants are compounds having an HLB value of less than 10.
- Hydrophilic non-ionogenic surfactant is more soluble in water than in oil (with HLB higher than 10).
- Preferred representatives in view of the invention are the reaction products of natural or polyethoxylated castor oil and ethylene oxide.
- the ethoxylated castor oil may have a content of 25 to 100 moles of ethylene oxide per molecule, preferably 35 to 60 moles of ethylene oxide per molecule.
- Natural or polyethoxylated castor oil may be reacted with ethylene oxide in a molar ratio of from about 1 :35 to about 1 :60, with the polyethoxylated component possibly removed from the products.
- polyethoxylated castor oils having a saponification number of about 50 to about 60, an acidity number of less than 1, a water content of less than 2%, an nD60 in the range of from 1.453 to 1.457, and an HLB in the range of from 12 to 16.
- polyethoxylated castor oils having a molecular weight of approximately 1630, a saponification number of approximately 65 to 70, an acid number of approximately 2, an iodine number in the approximate range of 28 to 32, an HLB of 16 and an nD25 of 1,471.
- Last in the series are products corresponding to a saponification number in the range of 40 to 50, an acidity number of less than 1, an iodine number of less than 1, a water content in the range of 4,5 % to 5,5 %, an nD25 value of 1,453 to 1,457, while an HLB value in the range of 15 to 17 may also be used.
- Hydrophobic non-ionic surfactant is more soluble in oil than in water (with low HLB).
- Transesterified ethoxylated vegetable oils are particularly suitable.
- transesterified ethoxylated vegetable oils advantageous to the invention are obtained from corn oil and having an acidity number of less than 2, a saponification number of 155 to 175, an HLB value of 3 to 4, and an iodine value of 90 to 110, or from kernel oil and having an acidity number of 2, a saponification number of 145 to 175, an iodine value of 60 to 90, and an HLB value of 4.
- the oil phase usually consists of triglycerides or mixed glycerides (a mixture of mono-, di- and triglycerides) consisting of long- and/or medium-chain fatty acids. Mixtures of lipids and surfactants are often used as solvents or carriers for poorly water-soluble drugs.
- the oil phase influences both the dissolution of hydrophobic drugs, the self-emulsification ability of the formulation, the behaviour of the drug in the GIT, and may contribute to their lymphatic transport.
- lipid excipients are a heterogeneous group of substances, all of which are called by the general name of lipids.
- LCTs long-chain triglycerides
- MCTs medium-chain triglycerides
- propylene glycol esters propylene glycol esters, fatty acids, monoglycerides, di glycerides, and lipid mixtures (Cerpnjak et al. 2013, for review).
- MCTs medium chain triglycerides
- glycerides are fundamentally influenced by the type of glyceride used.
- LBDDS type Illb microemulsion preconcentrate
- the use of mixed mono-, di- and triglycerides has proven to be useful, which, due to their amphiphilic nature, exhibit better self-dispersibility and higher solubilization capacity for poorly water-soluble drugs.
- the formulation according to the present invention is prepared once the mixture of non- ionogenic surfactants is thoroughly mixed with a solution of the active ingredient in an organic solvent/water miscible solvent.
- the formulation according to the present invention when diluted with an aqueous medium or gastric fluids, forms a dispersion of non-ionogenic surfactant nanoparticles, preferably below 50 nm in size. This was measured using the Malvern ZS (Malvern Instruments Ltd, UK, Zetasizer Nano).
- the formulation according to the present invention comprising cladribine dissolved in an aprotic solvent/water miscible solvent produces thermodynamically stable nanoparticle dispersions in aqueous solutions that are resistant to a wide range of temperatures, water hardness and pH.
- cladribine dissolved in an aprotic polar solvent and an auxiliary water-miscible solvent can form desirable drug delivery systems, when used with a carrier consisting of a suitable combination of a hydrophilic component (hydrophilic non-ionogenic surfactant) with a hydrophobic component (hydrophobic non- ionogenic surfactant, mono-, di-glycerides or combinations thereof).
- Preferred embodiments of the invention have the advantage of allowing cladribine to be solubilized and transported through the aqueous GIT environment as a dispersion of non- ionogenic surfactant nanoparticles.
- Cladribine may be present in the system in an amount ranging from 0.001 wt. % to 20 wt. %, preferably 0.01 wt. %. to 20 wt%.
- Additional excipients or additives may preferably be added to the inventive formulation to increase the efficacy of the active ingredient, to reduce side effects and/or toxic effects, to prolong the duration of the active ingredient in the systemic circulation.
- Other additives may also be added to the formulation to increase the stability of the active ingredient or formulation, such as antioxidants.
- Still other additives, such as colorants, flavours, sweeteners, and the like, may be added to the formulation to increase the susceptibility and tolerability of patients or other users of the formulations.
- the formulation according to the present invention is primarily intended for oral administration of pharmaceuticals, e.g., as a solution, soft and hard gelatine capsule, but the invention could also be used for topically administered formulations, e.g., as a cream, paste, lotion, gel, etc.
- Fig. 1 shows the phase diagram used to optimize the evolution of the cladribine-containing microemulsion preconcentrate based on the particle size distribution, where zones with different particle sizes are shown in different shades of grey, with the light grey zone on the left part of the diagram indicating the region with particle size ⁇ 100 nm, then the middle zone indicates the region with particle size >100 nm, and then the dark grey zone in the right part of the diagram indicates the region in which it was not possible to measure the particle size by default, and at the same time the small triangle in the left part of the diagram indicates the region that was selected to optimize the final formulation,
- Fig. 2 shows TEM images of particles formed by dilution of the selected preconcentrate in water (2% v/v),
- Fig. 3 shows a representation of the particle distribution of the selected preconcentrate after dilution in 0.1 M HC1, pH 1 (to obtain the image, x repetitions were performed3 on a Malvern ZS instrument at 20 °C, with a measurement time of 150 s),
- Fig. 4 shows the comparative dissociation profile of the commercial formulation labelled Mavenclad, the preconcentrate containing Labrafil and the preconcentrate containing Maisine auxiliary as the hydrophobic component (Apparatus II, 37 °C, 50 rpm, 900 ml 0.1 M HC1, pH 1.0),
- Fig. 5 shows the structure of the cladribine molecule
- Fig. 6 shows Table 1 - Comparison of AUC and DE of a commercial formulation (Mavenclad) with a microemulsion preconcentrate according to the invention (Apparatus II, 37 °C, 50 rpm, 900 ml 0.1 M HC1, pH 1.0), and Table 2 - Comparison of dissociation profiles based on absolute values of drug released (mg) (Apparatus II, 37 °C, 50 rpm, 900 ml 0.1 M HC1, pH 1.0).
- DMSO dimethylsulfoxide
- DMF dimethylformamide
- NMP N-methylpyrrolidone
- DMA N,N-dimethylacetamide
- propylene carbonate and/or combinations thereof proved to be the most suitable solvents.
- DMSO and DMA have proven to be very suitable solvents in this respect.
- the solubility of cladribine in DMSO was 100 mg/0.2 ml, and the solubility in DMA was 100 mg/0.25 ml.
- the microemulsion system was designed based on preliminary experiments with individual excipients and binary/ternary mixtures of excipients and APIs.
- a ternary phase diagram of the hydrophilic phase (DMSO/Transcutol HP mixture), Cremophor RH40 and Labrafil Ml 944 (Maisine, Peceol, Capryol) was constructed using preconcentrates with different ratios of the individual components.
- a target sub-region of the phase diagram ( Figure 1) was selected to meet the poly dispersity and particle size requirements of the microemulsion in aqueous media.
- ANOVA, residue examination and prediction of external point values were performed to validate the model.
- the final formulation was then selected within the above range of excipients so that higher proportions of organic solvents were present to ensure acceptable appearance and stability of the sample after dilution.
- Microemulsion particles were evaluated by imaging and particle distribution measurements. Using transmission electron microscopy, the presence of round vesicles with a mean diameter of approximately 20 nm was demonstrated ( Figure 2). The vesicles were very sensitive to the electron beam and morphological changes occurred during focusing, which could account for the difference in size measured by LS and TEM.
- Particle size measurements of diluted samples were performed by Photo-Correlation Spectroscopy (PCS) in a Malvern ZS particle size analyser at 20 °C, 150 s measurement time, in water or 0.1 M HC1. Solubilization was performed by gently mixing the pre concentrate in a flask. Z-averaged particle size and poly dispersity were reported as the average of three independent measurements.
- the characteristic particle distribution of the preconcentrate prepared according to the subject patent is shown in Figure 3.
- Example 4 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants
- Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ⁇ 45-60 °C.
- a second beaker dissolve Cremophor RH40, add Labrafil, mix with CLB solution and homogenize.
- the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
- Example 5 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and propylene glycol monocaprylate.
- Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ⁇ 45-60 °C.
- DMSO DMSO
- Transcutol HP when heated to T ⁇ 45-60 °C.
- Cremophor RH40 dissolve Cremophor RH40
- Capryol add Capryol
- the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size after dilution in water or 0.1 M HC1.
- Example 6 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-oleate.
- Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ⁇ 45-60 °C.
- DMSO DMSO
- Transcutol HP when heated to T ⁇ 45-60 °C.
- Cremophor RH40 dissolve Cremophor RH40
- Peceol add Peceol
- CLB solution 0.1 M HC1.
- Example ? Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and non-ionogenic surfactants and glycerol monolinoleate-.
- Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ⁇ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
- Example 8 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and non-ionogenic surfactants and glycerol monolinoleate-.
- Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ⁇ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
- Example 9 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and non-ionogenic surfactants and glycerol monolinoleate-.
- Example 10 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
- Cladribine dissolves in a solution of DMSO and IPA when heated to T ⁇ 45-60 °C.
- a second beaker dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize.
- the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
- Example 11 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
- Cladribine dissolves in a solution of DMSO and MeOH when heated to T ⁇ 45-60 °C.
- DMSO dimethyl methoxysulfoxide
- Cremophor RH40 a compound that can be added to CLB solution and homogenize.
- the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
- Example 12 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
- Cladribine dissolves in a solution of DMSO and EtOH when heated to T ⁇ 45-60 °C.
- DMSO dimethyl sulfoxide
- Cremophor RH40 a compound that can be used to dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize.
- the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
- Example 13 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
- Cladribine dissolves in a solution of DMSO and PEG 400 when heated to T ⁇ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
- Example 14 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
- Cladribine dissolves in DMSO solution when heated to T ⁇ 45-60 °C.
- Cremophor RH40 dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize.
- the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
- Example 15 Preparation of a microemulsion preconcentrate of cladribine containing poly ethoxylated castor oil.
- Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ⁇ 45-60 °C. In a second beaker, dissolve Cremophor RH40, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
- Example 16 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
- Cladribine dissolves in a solution of DMSO and DMA when heated to T ⁇ 45-60 °C.
- a second beaker dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize.
- the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
- Example 17 Comparative dissolution of a microemulsion preconcentrate prepared with a mixture of hydrophilic and hydrophobic non-ionogenic surfactants, a microemulsion preconcentrate prepared from a mixture of a hydrophilic non- ionogenic surfactant and glycerol mono-linoleate with a commercial formulation (Mavenlad).
- the comparative dissolution was carried out under discriminative conditions (acidic pH) in a type II dissolution apparatus, in 900 ml of dissolution medium (0.1 M HC1 pH 1.0), at 50 rpm and 37 °C.
- a 10 mg tablet of a commercially available preparation (Mavenclad, batch number 00015336) was used as a reference sample.
- the tested microemulsion preconcentrate was filled into hard gelatine capsules just before use. The difference in the formulations used partially affected the profile of the dissociation curve but in no way affected the availability of cladribine from the formulations tested. For this reason, conversion to the absolute value of cladribine at each sampling interval was also used in the evaluation of the dissociation efficiency.
- microemulsion preconcentrate-based formulations represent a suitable form of cladribine administration. From the difference between the values of the different preconcentrates, it is evident that the use of a lipid vehicle significantly increases the rate of release of cladribine from the microemulsion preconcentrate-based liquid dosage form and positively affects the dissociation profile at acidic pH.
- microemulsion preconcentrate containing cladribine especially for oral administration and a method of preparation according to the invention will find application in the field of treatment of haemato-oncological diseases, MS, autoimmune diseases and in medical and pharmaceutical research.
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Abstract
The invention relates to an anhydrous microemulsion preconcentrate containing cladribine, comprising: cladribine dissolved in at least one aprotic polar solvent and in at least one auxiliary organic solvent having an acceptable affinity for water, a mixture of a non-ionogenic surfactant having a hydrophilic-lipophilic equilibrium > 10 with a non-ionogenic water-insoluble surfactant having a hydrophilic-lipophilic equilibrium < 10 and/or with lipophilic vehicles containing a high proportion of long-chain fatty acids, such as, e.g. Glycerol mono-oleate or glycerol mono-linoleate. The hydrophilic and hydrophobic components are mixed to form a homogeneous mixture. This homogeneous mixture is then mixed with a cladribine solution to produce a formulation which, when introduced into the gastrointestinal tract, spontaneously forms a dispersion of non-ionogenic surfactant nanoparticles containing dissolved cladribine molecules.
Description
Microemulsion preconcentrate containing cladribine particularly for oral administration and method of preparation
Field of the Invention
The invention relates to a microemulsion preconcentrate comprising cladribine, in particular for oral administration, including a method of preparation and use thereof.
State of the art
Cladribine (2-chlorodeoxyadenosine, 2-CdA) was developed in the late 1970s by the Scripps Research Institute (La Jolla, California) and used in the treatment of mainly haemato- oncological diseases. The first registration of a parenteral formulation was granted in 1993 for the treatment of haemato-oncological diseases. It is a synthetic chlorinated analogue of deoxyadenosine with the structure shown in Figure 5.
In addition to the originally described chemotherapeutic effect, cladribine also has an immunosuppressive effect, especially on the adaptive component of the immune system, characterized by marked lymphopenia of peripheral B lymphocytes (CD19+), CD4+, and partially also CD8+ T lymphocytes.
Interest in the use of cladribine in the treatment of non-cancer diseases has increased with the demonstration of its potential use in selective immune reconstitution therapy (SIRT). The experience with the successful use of the oral formulation of cladribine in the treatment of multiple sclerosis (MS) is the reason for the growing interest in the use of the oral form of cladribine in the treatment of other autoimmune disorders, in which cladribine, like to MS, could be useful as a short-term immunosuppressant in immune reconstitution therapy.
On the other hand, cladribine is a toxic molecule, therefore, hence especially for the treatment of non-oncological indications (multiple sclerosis, possibly myasthenia gravis, autoimmune haemolytic anaemia, rheumatoid arthritis, systemic lupus erythematosus, psoriasis; source: Robak et al., 2006), it is desirable to develop a stable, robust final dosage form that exhibits high bioavailability and thus allows (for) minimised dosing.
Cladribine for oral administration is currently on the market in 10 mg tablets in the form of a cladribine complex with cyclodextrin. Orally administered cladribine is rapidly absorbed with 40% bioavailability, which is mainly explained by incomplete absorption due to efflux mediated by transport mechanisms (Assessment report MAVENCLAD, 2017).
While for the liquid intravenous formulation the bioavailability was 37 to 51% (Lilienmark, 1997), for the current tablet oral formulation the bioavailability is approximately 40% (Assessment report MAVENCLAD,2017). Most of the unabsorbed substance administered in the oral formulation is excreted in the urine. Renal clearance of cladribine administered by tablet represents 51% of the total clearance, while 21 % to 35 % are excreted unchanged in the urine in the case of intravenously administered substance (Liliemark J, 1997, Assessment report MAVENCLAD,2017).
From a comparison of the available data, it appears that the cyclodextrin complex allows the formation of a solid dosage form but does not substantially affect the availability of cladribine compared to the liquid form. One reason for this may be the poor protection of the active substance against degradation by the low pH in the stomach. Although Schlutz et al. described in US 395 the 6194 protection of cladribine from degradation at low pH by forming a complex with cyclodextrin, these results were not confirmed in the range defined in US 7 328888 and US 8 785415.
The aforementioned assumption was clearly confirmed by the results of comparative dissociation of oral cladribine in different dissociation buffers, which were carried out by the applicant of the invention. The 0-25 min AUC values at pH 1.2 decreased approximately by 30% compared to that in pH 6.8 buffer. Almost the same decrease was shown in cladribine dissociation efficiency (Kahn, 1975) in low pH dissociation medium compared to the results from pH 6.8 medium.
Based on the experiments performed, the applicant's invention has confirmed that the cyclodextrin complex, while enabling the production of an oral dosage form in tablet form, provides very little protection of cladribine from degradation at low pH, which may result in low bioavailability of the product.
According to the information available from the manufacturer, cladribine is classified as a BCS (Biopharmaceutical Classification System) class 3 substance, i.e., a high solubility, low permeability substance (NDA 22561 Clinical Pharmacology Amendment Memo). According to the BCS definition, drugs are considered highly soluble when the dose corresponding to the highest strength of the dosage form is soluble in < 250 ml of buffer in the pH range of 1.0 to 7.5.
A close look at the properties of the cladribine molecule shows that cladribine does not clearly meet the above criteria for a highly soluble substance. At a physiological temperature of 37 °C, the t value of i/2cladribine was determined to be 1.6 hours for solutions with pH > 2.0 and only 0.37 hours for solutions with pH 1.2 and below (Tarasiuk et al., 1994). As a result of the high susceptibility to hydrolysis in solutions with pH less than 2 and especially with pH 1.0, the requirement according to the above definition for high solubility cannot be met, since the degradation of the cladribine molecule occurs in parallel with solubility, and in solutions with low pH the complete solubility of the starting molecule cannot be demonstrated due to rapid degradation. Determination of the solubility of cladribine at pH 1,2 is not feasible due to stability problems. Based on the FDA criteria cited above, the drug must be soluble in the pH range of 1,0 to 7,5 at 37 °C and therefore cladribine does not meet these criteria.
According to the 2020 European Medicines Agency (EMA) definition (ICH M9 on biopharmaceutics classification system-based biowaivers, 2020), the solubility of a substance must be tested in at least three solutions at pH 1.2, then 4.5 and then 6.8 in three replicates. If the drug substance is not stable with > 10 % degradation in the solubility range of the assessment, solubility cannot be sufficiently determined and therefore the drug substance cannot be classified.
In view of the above references, the applicant has decided to base the development of the new oral dosage form containing cladribine on the physicochemical definition of drug solubility as defined by USP 38 and not on the BCS classification. According to the USP 38 definition, cladribine with a maximum water solubility of 6.35 mg/ml can be classified as a sparingly soluble molecule.
Low water solubility is widely recognized as the main reason for poor oral absorption of many drugs. Conventional solubilization approaches based on surfactants, cyclodextrin complexes, synthesis of novel crystal polymorphs and salts, nanoparticles, solid dispersions, lipids and permeation enhancers can be used to increase the oral absorption of drugs.
Among others, the Lipid-Based Drug Delivery Systems (LBDDS) represent an interesting option to address the problem of solubility enhancement. LBDDS-based formulations show high potential for improving (i) bioavailability of compounds with low solubility in aqueous media, (ii) membrane permeability, (iii) metabolic problems, or (iv) stability of the active ingredient. High and consistent absorption has been demonstrated with oral administration of the LBDDS-based formulation.
According to the current Lipid Based Classification System (LBCS), LBDDS can be divided into four classes including formulations ranging from simple lipid solutions or drug suspensions to emulsions and more complex self-emulsifying, self-micro-emulsifying or self-emulsifying - nanoemulsifying systems (SEDDS/ SMEDDS/ SNEDDS).
LBCS type II and Illa formulations are generally referred to as SEDDS. They are formulated with mixtures of lipid vehicles, non-ionic surfactants and drug in the absence of water and are assumed to exist as transparent isotropic solutions. These systems have a unique property: they can rapidly self-emulsify in gastrointestinal fluids and form fine oil-in-water emulsions (droplet size diameter < 300 nm) under gentle agitation provided by gastrointestinal movement. SEDDS are commonly suitable for oral administration in a soft or hard gelatine capsule, a hard hydroxypropylmethylcellulose (HPMC) capsule, or a capsule of other suitable pharmaceutically acceptable material.
LBCS Type Illb formulations are commonly referred to as SMEDDS and are defined as isotropic mixtures of oil, surfactant and active ingredient. Such systems form fine oil-in-water microemulsions under gentle agitation provided by gastric and intestinal motility after dilution by the aqueous phase in vivo. SMEDDS differ from SEDDS by the smaller particle size produced by dilution, resulting in a transparent or translucent stable dispersion. The particle size after dilution is < 100 nm for SMEDDS or < 300 nm for SEDDS.
Type IV formulations according to LBCS are oil-free, based only on surfactant and auxiliary solvent mixtures. This type has recently been added to the LBCS. These formulations represent the most hydrophilic type of lipid formulation. They form a very fine dispersion in an aqueous medium sometimes referred to as nanoemulsions (SNEDDS).
SMEDDS generally contain relatively high concentrations of surfactants (typically 30 to 60% w/w) or hydrophilic solvents. They are often described as microemulsion preconcentrates because microemulsions are formed by dilution in an aqueous environment.
LBDDS represent the successful strategy for increasing the solubility and improving the bioavailability of poorly soluble drugs, especially for BCS class II and IV groups. They achieve enhanced absorption of poorly soluble drugs by specific mechanisms: prolonged retention time in the stomach, increased solubilization, stimulation of the gastrointestinal lymphatic system, transport and impact on the biochemical and physical barrier of the GIT. However, their efficacy strongly depends on the composition and proportion of all ingredients. Combinations of different types of excipients determine the specific drug delivery system. It is necessary to determine experimentally the appropriate formulation of the selected delivery system for each individual drug to ensure maximum efficacy of the selected LBDDS.
The advantage of microemulsions as potential therapeutic systems for oral administration is their specific structure, which allows the incorporation of hydrophilic, amphiphilic and lipophilic drugs to increase their solubility, speed and extent of absorption, to protect labile substances from the gastrointestinal environment, to reduce inter- and intra-individual variability of effect and to mask unpleasant odour and taste.
Based on the results of the experiments conducted by the applicant of the invention, the most suitable approach for the development of a new, particularly oral, dosage form containing cladribine was the use of a self-emulsifying microemulsion drug delivery system, abbreviated SMEDDS, sometimes also referred to as a microemulsion preconcentrate.
The object of the present invention is to provide a liquid formulation of a microemulsion preconcentrate containing cladribine, particularly for oral, administration providing higher
stability of the active ingredient at acidic pH, and a method of preparing the same using a robust, cost-effective, safe and easily applied industrial production technology.
Summary of the Invention
For the development of a new, particularly oral, dosage form, the applicant of the invention considers it crucial to develop a formulation that allows the cladribine molecule to be protected from degradation in the low pH of the stomach, while at the same time increasing solubility so that at any given time the excess of cladribine predominates over its degradative metabolite. The optimal solution appears to be to use a liquid formulation with rapid solubility and the ability to protect the degradation of the active ingredient, or at least to allow faster absorption of cladribine from the immediately available higher concentration of the active ingredient. Hence, the potential protection against degradation of cladribine in the acidic pH of the stomach, combined with the increased solubility, were the main motivations for the development of the new dosage form according to the present invention.
The invention presents a microemulsion preconcentrate containing cladribine for administration mainly by the oral route, the essence of which is that it comprises the following components: i) cladribine, ii) at least one aprotic polar solvent, iii) at least one auxiliary organic solvent with an acceptable affinity for water, iv) a non-ionogenic surfactant with a hydrophilic-lipophilic balance > 10 (hereafter referred to as HLB), v) a hydrophobic component comprising (i) a non-ionogenic surfactant with HLB < 10, or (ii) a lipophilic vehicle with a high proportion of glycerol mono-oleate or glycerol mono- oleate-, or a combination of both (i) and (ii) above.
Surprisingly, the problem of solubilization of cladribine in LBDDS was solved by a suitable combination of an aprotic solvent with a hydrophilic auxiliary solvent and a mixture of non- ionogenic surfactants with HLB > 10 with a non-ionogenic water-insoluble surfactant with HLB < 10 and/or with lipophilic vehicles containing a high proportion of long-chain fatty acids, such as glycerol mono-oleate or glycerol mono-linoleate.
As apparent from the foregoing, the invention relates to an anhydrous microemulsion preconcentrate comprising cladribine: Cladribine dissolved in an aprotic polar solvent (or multiple solvents) and an auxiliary organic solvent (or multiple solvents) having an acceptable affinity for water, and further comprising a mixture of non-ionogenic surfactants having HLB > 10 with a hydrophobic component, which may comprise hydrophobic non-ionic surfactants with HLB < 10 or lipophilic vehicles containing a high proportion of glycerol mono-oleate or glycerol mono-linoleate, or a combination of non-ionic surfactants with lipophilic vehicles.
The invention also includes a method of preparing a microemulsion preconcentrate comprising the following process steps:
(a) dissolution of cladribine in at least one aprotic polar solvent and at least one water-soluble organic auxiliary solvent,
(b) the preparation of a mixture of non-ionogenic surfactants with HLB > 10 with a hydrophobic component, which may consist of hydrophobic non-ionogenic surfactants with HLB < 10 or lipophilic vehicles containing a high proportion of glycerol mono-oleate or glycerol mono- oleate-, or a combination of non-ionogenic surfactants with lipophilic vehicles,
(c) the combination of the components of step (a) and (b) of the said drug solution and the said surfactant system to form a microemulsion preconcentrate.
Cladribine was first dissolved in the minimum amount of aprotic solvent required and the resulting concentrated solution was diluted with organic solvent to the required viscosity. The resulting solution of cladribine was then mixed with the surfactant solution and possibly with lipophilic vehicles containing a high proportion of glycerol mono-oleate or glycerol monolinoleate or combinations thereof, resulting in optimization of the dispersion properties of the formulation. When the results were evaluated, it was surprisingly found that the resulting formulation significantly increased the resistance of cladribine to low pH while improving the solubility of the formulation. The advantage of the microemulsion preconcentrate prepared in this way is that it spontaneously forms nanoparticles containing dissolved cladribine when diluted in an aqueous medium.
In the inventive method, cladribine is dissolved in an aprotic polar solvent (e.g., DMSO, DMFA, DMA) or in organic auxiliary solvents having acceptable affinity for water (e.g., ethanol, Transcutol, glycols).
If necessary, the hydrophilic surfactants are heated and mixed with the hydrophobic component to form a homogeneous mixture of surfactants.
This homogeneous mixture is then mixed with a cladribine solution to produce a formulation (microemulsion preconcentrate) that, when introduced into the GIT, spontaneously forms a dispersion of non-ionogenic surfactant nanoparticles.
Preferably, the invention further provides a method of administering a drug based on a microemulsion preconcentrate comprising cladribine. The microemulsions formed in GIT are isotropic, thermodynamically stable transparent (or translucent) systems of water and surfactant or oil, respectively, often in combination with an auxiliary solvent with particle sizes typically in the range of 20-200 nm. Generally, it is a drug delivery system based on an surfactant, solvent and an excipient which has the ability to form an oil-in-water (o/v) (micro)emulsion after dispersing in the aqueous phase under mild agitation, caused for example by gut and stomach motility.
The advantage of microemulsions as potential therapeutic systems for oral administration is their specific structure, which allows the incorporation of hydrophilic, amphiphilic and lipophilic drugs characterized by an increase in their solubility, rate and extent of absorption, to reduce inter and intra individual variability, or to mask unpleasant smell and taste. When administered orally, high and consistent absorption was obtained. In addition, microemulsion systems have been shown to increase membrane permeability and may protect the incorporated molecules against oxidation and enzymatic degradation.
The composition according to the present invention can be prepared by first dissolving cladribine in a mixture of aprotic and polar auxiliary solvent and then by mixing with a mixture of surfactants.. The term cladribine, as used in the present invention application, refers to cladribine in the form of pharmaceutically acceptable solvates, hydrates, enantiomers, polymorphs or mixtures thereof. Preferably, cladribine is used in crystalline form.
An aprotic polar solvent is defined as a polar solvent that does not act as a hydrogen bond donor. Preferably used examples of polar aprotic solvents include dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, N-methylpyrrolidone (NMP), N,N- dimethylacetamide (DMA) and propylene carbonate and/or mixtures thereof.
In the present invention, any suitable water-miscible organic solvent can preferably be used. The selection of a suitable organic solvent will depend in part on the solubility of the active material in the solvent, the extent to which the solvent is miscible with water, and the tolerance of the solvent. The solvent should be physiologically acceptable.
Examples of solvents that may be advantageously used in the present invention include, but are not limited by enumeration, alcohols, glycols, glycerol, propylene glycol, and various polyethylene glycols.
The hydrophobic and hydrophilic non-ionogenic surfactants are mixed together to form a homogeneous mixture that can be heated if necessary. The non-ionogenic surfactants are selected for their hydrophilic-lipophilic balance (HLB). HLB is not a universal property because it is based solely on the weight percent of polyoxyethylene or polyol in the surfactant molecule, regardless of its molecular weight, the chemical nature of its hydrophilic and lipophilic groups, and the structural properties of the latter. Using HLB values as a rough guide, compounds having an HLB value greater than 10, in particular from 12 to 17, are considered to be hydrophilic surfactants. Similarly, hydrophobic surfactants are compounds having an HLB value of less than 10.
Hydrophilic non-ionogenic surfactant is more soluble in water than in oil (with HLB higher than 10). Preferred representatives in view of the invention are the reaction products of natural or polyethoxylated castor oil and ethylene oxide. The ethoxylated castor oil may have a content of 25 to 100 moles of ethylene oxide per molecule, preferably 35 to 60 moles of ethylene oxide per molecule. Natural or polyethoxylated castor oil may be reacted with ethylene oxide in a molar ratio of from about 1 :35 to about 1 :60, with the polyethoxylated component possibly removed from the products.
Particularly suitable in view of the invention are polyethoxylated castor oils having a saponification number of about 50 to about 60, an acidity number of less than 1, a water content of less than 2%, an nD60 in the range of from 1.453 to 1.457, and an HLB in the range of from 12 to 16.
Also preferred are polyethoxylated castor oils having a molecular weight of approximately 1630, a saponification number of approximately 65 to 70, an acid number of approximately 2, an iodine number in the approximate range of 28 to 32, an HLB of 16 and an nD25 of 1,471.
Last in the series, but no less advantageous in effect, are products corresponding to a saponification number in the range of 40 to 50, an acidity number of less than 1, an iodine number of less than 1, a water content in the range of 4,5 % to 5,5 %, an nD25 value of 1,453 to 1,457, while an HLB value in the range of 15 to 17 may also be used.
Hydrophobic non-ionic surfactant is more soluble in oil than in water (with low HLB). Transesterified ethoxylated vegetable oils are particularly suitable.
Examples of transesterified ethoxylated vegetable oils advantageous to the invention are obtained from corn oil and having an acidity number of less than 2, a saponification number of 155 to 175, an HLB value of 3 to 4, and an iodine value of 90 to 110, or from kernel oil and having an acidity number of 2, a saponification number of 145 to 175, an iodine value of 60 to 90, and an HLB value of 4.
The oil phase usually consists of triglycerides or mixed glycerides (a mixture of mono-, di- and triglycerides) consisting of long- and/or medium-chain fatty acids. Mixtures of lipids and surfactants are often used as solvents or carriers for poorly water-soluble drugs. The oil phase influences both the dissolution of hydrophobic drugs, the self-emulsification ability of the formulation, the behaviour of the drug in the GIT, and may contribute to their lymphatic transport.
From a chemical point of view, lipid excipients are a heterogeneous group of substances, all of which are called by the general name of lipids. In terms of categorizing lipids as excipients in oral lipid formulations, it is useful to divide lipids into three basic groups: long-chain
triglycerides (LCTs), medium-chain triglycerides (MCTs), and a group including propylene glycol esters, fatty acids, monoglycerides, di glycerides, and lipid mixtures (Cerpnjak et al. 2013, for review).
From the available literature data, it is clear that medium chain triglycerides (MCTs) were preferred for LBDDS because of their better solubilization properties, self-emulsification ability and better chemical stability of the active ingredients compared to long chain triglycerides (LCTs).
From the perspective of the invention, however, it is not only the chain length that affects the solubility and self-emulsification properties of glycerides. The properties of glycerides are fundamentally influenced by the type of glyceride used. For the preparation of microemulsion preconcentrate (LBDDS type Illb), the use of mixed mono-, di- and triglycerides has proven to be useful, which, due to their amphiphilic nature, exhibit better self-dispersibility and higher solubilization capacity for poorly water-soluble drugs.
It was the above-mentioned properties of the mixed mono-, di- and triglycerides that led to their use for the preparation of a microemulsion preconcentrate containing cladribine according to the present invention. As particularly preferred, preparations containing glycerol monolinoleate, glycerol mono-oleate and propylene glycol monocaprylate were used.
The formulation according to the present invention is prepared once the mixture of non- ionogenic surfactants is thoroughly mixed with a solution of the active ingredient in an organic solvent/water miscible solvent. In the development of the invention, it has been found that the formulation according to the present invention, when diluted with an aqueous medium or gastric fluids, forms a dispersion of non-ionogenic surfactant nanoparticles, preferably below 50 nm in size. This was measured using the Malvern ZS (Malvern Instruments Ltd, UK, Zetasizer Nano).
One advantage of preferred embodiments of the present invention is that the formulation according to the present invention comprising cladribine dissolved in an aprotic solvent/water miscible solvent produces thermodynamically stable nanoparticle dispersions in aqueous solutions that are resistant to a wide range of temperatures, water hardness and pH.
In the development of the invention, it was found that cladribine dissolved in an aprotic polar solvent and an auxiliary water-miscible solvent can form desirable drug delivery systems, when used with a carrier consisting of a suitable combination of a hydrophilic component (hydrophilic non-ionogenic surfactant) with a hydrophobic component (hydrophobic non- ionogenic surfactant, mono-, di-glycerides or combinations thereof).
Preferred embodiments of the invention have the advantage of allowing cladribine to be solubilized and transported through the aqueous GIT environment as a dispersion of non- ionogenic surfactant nanoparticles. Cladribine may be present in the system in an amount ranging from 0.001 wt. % to 20 wt. %, preferably 0.01 wt. %. to 20 wt%.
Additional excipients or additives may preferably be added to the inventive formulation to increase the efficacy of the active ingredient, to reduce side effects and/or toxic effects, to prolong the duration of the active ingredient in the systemic circulation. Other additives may also be added to the formulation to increase the stability of the active ingredient or formulation, such as antioxidants. Still other additives, such as colorants, flavours, sweeteners, and the like, may be added to the formulation to increase the susceptibility and tolerability of patients or other users of the formulations.
The formulation according to the present invention is primarily intended for oral administration of pharmaceuticals, e.g., as a solution, soft and hard gelatine capsule, but the invention could also be used for topically administered formulations, e.g., as a cream, paste, lotion, gel, etc.
Description of Drawings
The said invention will be explained in more detail in the following illustrations, where:
Fig. 1 shows the phase diagram used to optimize the evolution of the cladribine-containing microemulsion preconcentrate based on the particle size distribution, where zones with different particle sizes are shown in different shades of grey, with the light grey zone on the left part of the diagram indicating the region with particle size <100 nm, then the middle zone indicates the region with particle size >100 nm, and then the dark grey zone in the right part of the diagram indicates the region in which it was not possible to
measure the particle size by default, and at the same time the small triangle in the left part of the diagram indicates the region that was selected to optimize the final formulation,
Fig. 2 shows TEM images of particles formed by dilution of the selected preconcentrate in water (2% v/v),
Fig. 3 shows a representation of the particle distribution of the selected preconcentrate after dilution in 0.1 M HC1, pH 1 (to obtain the image, x repetitions were performed3 on a Malvern ZS instrument at 20 °C, with a measurement time of 150 s),
Fig. 4 shows the comparative dissociation profile of the commercial formulation labelled Mavenclad, the preconcentrate containing Labrafil and the preconcentrate containing Maisine auxiliary as the hydrophobic component (Apparatus II, 37 °C, 50 rpm, 900 ml 0.1 M HC1, pH 1.0),
Fig. 5 shows the structure of the cladribine molecule
Fig. 6 shows Table 1 - Comparison of AUC and DE of a commercial formulation (Mavenclad) with a microemulsion preconcentrate according to the invention (Apparatus II, 37 °C, 50 rpm, 900 ml 0.1 M HC1, pH 1.0), and Table 2 - Comparison of dissociation profiles based on absolute values of drug released (mg) (Apparatus II, 37 °C, 50 rpm, 900 ml 0.1 M HC1, pH 1.0).
Examples of preferred embodiment of invention
It is understood that the specific embodiments of the invention described and illustrated below are presented for purposes of illustration and not as a limitation of the invention to the examples provided. Those skilled in the art will find or be able to provide, using routine experimentation, a greater or lesser number of equivalents to the specific embodiments of the invention described herein. An inventive formulation based on the system used in the example embodiments may be made by any suitable method known in the art.
Example 1 : Selection of solvent system
Due to the physicochemical properties of cladribine, it was difficult to find a solvent that would allow it to be dissolved in the volume required to prepare the microemulsion preconcentrate. Aprotic polar solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, N-methylpyrrolidone (NMP), N,N-dimethylacetamide (DMA) and propylene
carbonate and/or combinations thereof proved to be the most suitable solvents. In particular, DMSO and DMA have proven to be very suitable solvents in this respect. The solubility of cladribine in DMSO was 100 mg/0.2 ml, and the solubility in DMA was 100 mg/0.25 ml.
With regard to the low daily limits of DMSO (50 mg/day) and especially DMA (10.5 mg/day), it was necessary to work with very concentrated and viscous solutions that were not technologically suitable for further handling. For this reason, it was necessary to select a suitable auxiliary solvent that would allow dilution of the cladribine concentrate but would not affect its solubility and, in particular, its stability in the dosage form. The use of organic solvents miscible with water proved to be the optimal solution. Although none of the tested organic solvents miscible with water and acceptable in terms of applicability for the development of an oral dosage form was able to dissolve the required amount of cladribine, in combination with an aprotic solvent it significantly affected especially the viscosity of the microemulsion preconcentrate. For this reason, organic water miscible solvents were included in the formulation. C 1.3 alcohols, glycols, glycerol, propylene glycol and various polyethylene glycols were found to be particularly suitable solvents.
Example 2: Selection of excipients
The microemulsion system was designed based on preliminary experiments with individual excipients and binary/ternary mixtures of excipients and APIs. A ternary phase diagram of the hydrophilic phase (DMSO/Transcutol HP mixture), Cremophor RH40 and Labrafil Ml 944 (Maisine, Peceol, Capryol) was constructed using preconcentrates with different ratios of the individual components. For mathematical modelling using DOE, a target sub-region of the phase diagram (Figure 1) was selected to meet the poly dispersity and particle size requirements of the microemulsion in aqueous media. ANOVA, residue examination and prediction of external point values were performed to validate the model. The final formulation was then selected within the above range of excipients so that higher proportions of organic solvents were present to ensure acceptable appearance and stability of the sample after dilution.
Example 3 : Particle morphology
Microemulsion particles were evaluated by imaging and particle distribution measurements. Using transmission electron microscopy, the presence of round vesicles with a mean diameter of approximately 20 nm was demonstrated (Figure 2). The vesicles were very sensitive to the
electron beam and morphological changes occurred during focusing, which could account for the difference in size measured by LS and TEM.
Particle size measurements of diluted samples were performed by Photo-Correlation Spectroscopy (PCS) in a Malvern ZS particle size analyser at 20 °C, 150 s measurement time, in water or 0.1 M HC1. Solubilization was performed by gently mixing the pre concentrate in a flask. Z-averaged particle size and poly dispersity were reported as the average of three independent measurements. The characteristic particle distribution of the preconcentrate prepared according to the subject patent is shown in Figure 3.
Example 4: Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants
Ingredients:
Cladribine 100 mg
Transcutol HP 400 mg
DMSO 350 mg
Cremophor RH40 850 mg
Labrafil 300 mg
Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ~ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Labrafil, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
Other water-soluble solvents can also be used for the preparation of the preconcentrate, but the use of Transcutol HP has significant technological advantages in the drying of soft gelatin capsules.
Example 5: Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and propylene glycol monocaprylate.
Ingredients:
Cladribine 100 mg
Transcutol HP 400 mg
DMSO 350 mg
Cremophor RH40 900 mg
Capryol (propylene glycol monocaprylate) 250 mg
Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ~ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Capryol, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size after dilution in water or 0.1 M HC1.
Example 6: Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-oleate.
Ingredients:
Cladribine 100 mg
Transcutol HP 400 mg
DMSO 350 mg
Cremophor RH40 900 mg
Pecol (glycerol mono-oleate) 250 mg
Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ~ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Peceol, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size after dilution in water or 0.1 M HC1.
Example ?: Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and non-ionogenic surfactants and glycerol monolinoleate-.
Ingredients:
Cladribine 100 mg
Transcutol HP 400 mg
DMSO 350 mg
Cremophor RH40 900 mg
Maisine (glycerol mono-linoleate) 250 mg
Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ~ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
Example 8: Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and non-ionogenic surfactants and glycerol monolinoleate-.
Ingredients:
Cladribine 100 mg
Transcutol HP 500 mg
DMSO 250 mg
Cremophor RH40 900 mg
Maisine (glycerol mono-linoleate) 250 mg
Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ~ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
Example 9: Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and non-ionogenic surfactants and glycerol monolinoleate-.
Ingredients:
Cladribine 100 mg
Transcutol HP 400 mg
DMA 400 mg
Cremophor RH40 900 mg
Maisine (glycerol mono-linoleate) 250 mg
Cladribine dissolves in a solution of DMA and Transcutol HP when heated to T ~ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
Example 10: Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
Ingredients:
Cladribine 100 mg
DMSO 450 mg
2-propanol (IP A) 450 mg
Cremophor RH40 900 mg
Maisine (glycerol mono-linoleate) 250 mg
Cladribine dissolves in a solution of DMSO and IPA when heated to T ~ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
Example 11 : Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
Ingredients:
Cladribine 100 mg
DMSO 450 mg
Methanol (MeOH) 450 mg
Cremophor RH40 900 mg
Maisine (glycerol mono-linoleate) 250 mg
Cladribine dissolves in a solution of DMSO and MeOH when heated to T ~ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and
homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
Example 12: Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
Ingredients:
Cladribine 100 mg
DMSO 450 mg
EtOH anhydrate (EtOH) 450 mg
Cremophor RH40 900 mg
Maisine (glycerol mono-linoleate) 250 mg
Cladribine dissolves in a solution of DMSO and EtOH when heated to T ~ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
Example 13: Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
Ingredients:
Cladribine 100 mg
DMSO 350 mg
PEG 400 400 mg
Cremophor RH40 900 mg
Maisine (glycerol mono-linoleate) 250 mg
Cladribine dissolves in a solution of DMSO and PEG 400 when heated to T ~ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
Example 14: Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
Ingredients:
Cladribine 100 mg
DMSO 200 mg
Cremophor RH40 900 mg
Maisine (glycerol mono-linoleate) 250 mg
Cladribine dissolves in DMSO solution when heated to T ~ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
Example 15: Preparation of a microemulsion preconcentrate of cladribine containing poly ethoxylated castor oil.
Ingredients:
Cladribine 100 mg
DMSO 350 mg
Transcutol HP 400 mg
Cremophor RH40 1200 mg
Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ~ 45-60 °C. In a second beaker, dissolve Cremophor RH40, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
Example 16: Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
Ingredients:
Cladribine 100 mg
DMSO 150 mg
DMA 50 mg
Cremophor RH40 900 mg
Maisine (glycerol mono-linoleate) 250 mg
Cladribine dissolves in a solution of DMSO and DMA when heated to T ~ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
Example 17: Comparative dissolution of a microemulsion preconcentrate prepared with a mixture of hydrophilic and hydrophobic non-ionogenic surfactants, a microemulsion preconcentrate prepared from a mixture of a hydrophilic non- ionogenic surfactant and glycerol mono-linoleate with a commercial formulation (Mavenlad).
The comparative dissolution was carried out under discriminative conditions (acidic pH) in a type II dissolution apparatus, in 900 ml of dissolution medium (0.1 M HC1 pH 1.0), at 50 rpm and 37 °C. A 10 mg tablet of a commercially available preparation (Mavenclad, batch number 00015336) was used as a reference sample. The tested microemulsion preconcentrate was filled into hard gelatine capsules just before use. The difference in the formulations used partially affected the profile of the dissociation curve but in no way affected the availability of cladribine from the formulations tested. For this reason, conversion to the absolute value of cladribine at each sampling interval was also used in the evaluation of the dissociation efficiency. Samples were taken at 5, 10, 15 and 20 min intervals and the cladribine content was determined by HPLC. The dissociation profiles of each formulation were evaluated by the values measured for the levels under the concentration curve (AUC), the dissociation efficiency (DE) and the conversion of the relative values of the dissociation profile to absolute values of dissolved cladribine in the dissociation medium at each time interval.
The results are summarized in Tables 1 and 2 shown in Figure 6 and further the results are summarized in Figure 4 and as can be seen from the results, both the microemulsion formulations showed higher values as compared to the commercially available formulation.
In the case of using a mixture of non-ionogenic surfactants, the AUC of the microemulsion formulation was approximately 12 % higher. In the case of using a combination of a lipophilic non-ionogenic surfactant with a lipophilic vehicle, the difference in values was almost 30 % higher. Similar values were found for DE.
Thus, it can be considered proven that microemulsion preconcentrate-based formulations represent a suitable form of cladribine administration. From the difference between the values of the different preconcentrates, it is evident that the use of a lipid vehicle significantly increases the rate of release of cladribine from the microemulsion preconcentrate-based liquid dosage form and positively affects the dissociation profile at acidic pH.
Industrial applicability
The microemulsion preconcentrate containing cladribine especially for oral administration and a method of preparation according to the invention will find application in the field of treatment of haemato-oncological diseases, MS, autoimmune diseases and in medical and pharmaceutical research.
Claims
PATENT CLAIMS A microemulsion preconcentrate containing cladribine, particularly for oral administration, based on a drug delivery system based on a self-emulsifying microemulsion preconcentrate (SEDDS) containing a mixture of hydrophilic and hydrophobic tensides characterized in that it comprises the following components:
I. cladribine in the form of pharmaceutically acceptable solvates, hydrates, enantiomers, polymorphs, or mixtures thereof, or in crystalline form,
II. at least one aprotic polar solvent from the group consisting of dimethyl sulfoxide (DMSO), dimethylformamide (DMFA), ethyl acetate, N-methylpyrrolidone (NMP), N,N-dimethylacetamide (DMA) and propylene carbonate.
III. at least one water-miscible auxiliary solvent for adjusting the viscosity of the preconcentrate from the group C1.3 alcohols, transcutol, propylene glycol, glycols,
IV. at least one hydrophilic non-ionogenic surfactant, preferably comprising polyethoxylated castor oil, or a combination of polyethoxylated castor oils having a hydrophilic-lipophilic balance value greater than 10, preferably between 12 and 16,
V. at least one lipophilic non-ionogenic component from the group of waterinsoluble surfactants having a hydrophilic-lipophilic balance of less than 10, or a lipid vehicle comprising a high proportion of at least one long-chain or medium-chain fatty acid from the group of glycerol mono-oleate or glycerol mono-linoleate. The microemulsion preconcentrate according to claim 1, characterized in that cladribine is present in an amount of 0,01 wt. %. to 20 % w/w. The microemulsion preconcentrate according to claim 1 or 2, characterized in that it simultaneously comprises mixtures of a hydrophilic surfactant and a hydrophobic surfactant.
The microemulsion preconcentrate according to any one of claims 1 to 3 , characterized in that the component V. further comprises labrafil, or glycerol monolinoleate, or glycerol monooleate, or propylene glycol monocaprylate, and/or combinations thereof. The microemulsion preconcentrate according to any one of claims 1 to 4 , characterized in that the microemulsion preconcentrate is in the form of a transparent dispersed nanoparticle having a size below 50 nm in the aqueous medium. The microemulsion preconcentrate according to any one of claims 1 to 5, characterized in that it further comprises at least one excipient or additive of the group of antioxidant, colour, flavour, sweetener, to increase the stability or efficacy of the active ingredient of the microemulsion preconcentrate, or to increase the susceptibility and tolerability of users of the formulation. The microemulsion preconcentrate according to any one of claims 1 to 6 , characterized in that it is in the form of a solution or capsule for oral application and in the form of a cream, paste, lotion or gel for topical application. A method of manufacturing the microemulsion preconcentrate comprising cladribine, in particular for oral administration, based on a self-emulsifying microemulsion preconcentrate comprising a mixture of hydrophilic and hydrophobic tensides according to any one of claims 1 to 7 , characterized in that comprising the following process steps: (a) dissolving the cladribine in at least one aprotic polar solvent and at least one water-soluble auxiliary organic solvent,
(b) the preparation of a mixture of non-ionogenic surfactants with a hydrophobic component, which may consist of hydrophobic non-ionogenic surfactants with a hydrophilic-lipophilic balance < 10, or lipophilic vehicles containing a high proportion of glycerol mono-oleate or glycerol mono-oleate-, or a combination of non-ionogenic surfactants with lipophilic vehicles,
(c) a combination of the components prepared from steps (a) and (b) to form a microemulsion preconcentrate.
9. The method according to claim 8, characterized in that the hydrophilic surfactant (IV) and the hydrophobic surfactant (V) are mixed at elevated temperature in step b).
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CZ2021-25A CZ309587B6 (en) | 2021-01-22 | 2021-01-22 | Microemulsion preconcentrate containing cladribine and preparing it |
PCT/CZ2022/050005 WO2022156836A1 (en) | 2021-01-22 | 2022-01-21 | Microemulsion preconcentrate containing cladribine particularly for oral administration and method of preparation |
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EP1075252A2 (en) * | 1998-05-07 | 2001-02-14 | ELAN CORPORATION, Plc | Solvent/cosolvent free microemulsion and emulsion preconcentrate drug delivery systems |
FR2873585B1 (en) * | 2004-07-27 | 2006-11-17 | Aventis Pharma Sa | NEW GALENIC FORMULATIONS OF ACTIVE PRINCIPLES |
PL2121139T3 (en) * | 2007-01-16 | 2013-03-29 | Bipar Sciences Inc | Formulations for cancer treatment |
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