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(12) United States Patent (10) Patent No.: US 7,026,360 B1 Fest0 (45) Date of Patent: Apr

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(12) United States Patent (10) Patent No.: US 7,026,360 B1 Fest0 (45) Date of Patent: Apr USOO702636OB1 (12) United States Patent (10) Patent No.: US 7,026,360 B1 Fest0 (45) Date of Patent: Apr. 11, 2006 (54) PHARMACEUTICAL COMPOSITIONS FOREIGN PATENT DOCUMENTS CONTAINING COMPOUNDS WITH EP O 390 206 10, 1990 ACTIVITY FOR THE ENHANCEMENT OF EP O390206 * 10, 1990 ABSORPTION OF ACTIVE INGREDIENTS EP 0 723 775 T 1996 JP 62-42922 2, 1987 (75) Inventor: Norberto Festo, Lugano (CH) OTHER PUBLICATIONS (73) Assignee: Inpharma S.A., Lugano (CH) Corti, P., et al., “Near infrared reflectance spectroscopy in the study of atopy Part 3. Interactions between the skin and (*) Notice: Subject to any disclaimer, the term of this fomblins.” ANALYST, vol. 123, pp. 2313-2317, 1998. patent is extended or adjusted under 35 Bonina, F., et al., “Three phase emulations for controlled U.S.C. 154(b) by 0 days. delivery in the cosmetic field.” Int. J. Cosmetic Sci, Vol. 14, (21) Appl. No.: 09/673,411 pp. 65-74, 1992. Lehmler, Hans-Joachim, et al., “Liquid Ventilation—A New (22) PCT Filed: Feb. 16, 2000 Way to Deliver Drugs to Diseased Lungs?.” Chemtech, vol. 29, No. 10, 7-12, pp. 1-10 (Oct. 1999). (86). PCT No.: PCT/BOO/OO167 * cited by examiner S 371 (c)(1), Primary Examiner Cecilia J. Tsang (2), (4) Date: Oct. 17, 2000 Assistant Examiner Taylor Victor Oh (74) Attorney, Agent, or Firm—Ladas & Parry LLP (87) PCT Pub. No.: WO00/48636 (57) ABSTRACT PCT Pub. Date: Aug. 24, 2000 The new pharmaceutical compositions contain, apart from (30) Foreign Application Priority Data one or more active ingredient(s), between 0.01 and 60% w/w Feb. 18, 1999 (CH) ..................................... O311/99 of the compounds of formula I (51) Int. Cl. A6 IK3I/02 (2006.01) (52) U.S. Cl. ...................................................... 514/759 (58) Field of Classification Search ................ 568/600, CF 568/615,677,683, 679; 514/759 See application file for complete search history. with n and mid 18 and <46 and with molecular weights between -600 and ~8000 for the enhancement of absorption (56) References Cited of the active ingredient(s). Moreover, such compositions U.S. PATENT DOCUMENTS may contain also between 0.01 and 20% w/w of Phosphati dylcholine. 5,304,334 A 4, 1994 Lahanas et al. 5,376,359 A 12/1994 Johnson 5,686,102 A * 11/1997 Gross et al. ................ 424/450 29 Claims, No Drawings US 7,026,360 B1 1. 2 PHARMACEUTICAL COMPOSITIONS Surprisingly, it was found that inclusion of a quantity of CONTAINING COMPOUNDS WITH PFPE at concentrations between 0.01% w/w and 60% w/w, ACTIVITY FOR THE ENHANCEMENT OF in topical and/or transdermal (drug delivery systems) for ABSORPTION OF ACTIVE INGREDIENTS mulations, increases the percutaneous absorption of active ingredients by over 5–20 times their normal value, thus The invention described herein refers to pharmaceutical enabling improved absorption and optimization of their compositions, to the use of compounds as agents with systemic effects through Suitable pharmaceutical presenta activity for the enhancement of absorption of active ingre tions. dients and to specific compounds. The problems related to percutaneous absorption of active 10 DETAILED DESCRIPTION OF THE ingredients in topical and transdermal pharmaceutical pre INVENTION sentations (drug delivery systems) is known and has been the subject matter of patents 1 Peroutaneous absorption: Comprehension of the invention is facilitated by the mechanisms-methodology-drug delivery, 2 Ed., Bronaugh description of a number of assessments on the percutaneous Maibach, MARCEL DEKKER INC. 15 absorption of certain formulations containing different Among the most significant examples reported In Scien active ingredients. tific literature it is possible to mention the enhancing activity Example A illustrates the increase in permeability by of decylmethylsulfoxide in increasing percutaneous absorp approx. 10 times of a formulation containing Troxerutine tion of idoxuridine 2 Touitou. E. (1988). Int. J. Pharm. and 3% PFPE as compared with that of a reference formu 43:1. The effect of dodecylazacycloheptan-2-one (Lauroca- 20 lation. pram, AZone) in enhancing absorption of various molecules Example B demonstrates the correlation between PFPE was Investigated by Stoughton 3 Stoughton, R. B. (1982), concentration and percutaneous absorption of formulations Arch. Dermatol. 118: 474 and by Sugibayashi 4 Sugiba containing NimeSulide and increasing concentrations of yashi, K., Hosoya, K. Morimoto, Y., and Higuchi, W. 1. PFPE. (1985), J. Pharm. Pharmacol. 37: 578. 25 Substances made available on the market and initially Example C contains a comparison of the permeation used in fields other than the pharmaceutical sector, Subse speed of formulations containing non-steroidal antiinflam quently proved to be of remarkable importance also for the matory drugs versus formulations to which 3% PFPE has pharmaceutical industry. Among these, we can find the been added. Perfluoropolyether class of compounds (PFPE) 5 obtained 30 by polymerization of hexafluoropropene with oxygen acti Example A vated by UV radiation and subsequent treatment to obtain a cosmetic product 6 as an excipient for preparations used in Verification of the percutaneous absorption of TROX the manufacture of products with a barrier effect 7. ERUTINE through pig skin using various formulations 35 containing different types of absorption enhancers. In par SUMMARY OF THE INVENTION ticular, this involved investigation of the release of TROX ERUTINE from formulations containing PFPE, Nor-cheno The following invention consists in the use of PFPE to deoxycolic acid and transcutol, Versus a reference enhance absorption of pharmacologically active ingredients formulation. in topical pharmaceutical presentations and/or in transder- a mal formulations (drug delivery systems) containing mix Experimental Section: tures of at least one active ingredient for the enhancement of Apparatus: Franz Cells (manufacturer: Crown Glass Com absorption. pany Inc., New Jersey) These compounds, if included in pharmaceutical presen tations containing an association or at least one active as Franz diffusion cells are one of the main systems used for ingredient, can modify the permeating capacity of the active the investigation of ex-vivo permeation. This study involved ingredients through the skin, demonstrating a Surprising and the use of three cells each with a 9 mm diameter donor unexpected capacity to promote the penetration of the active compartment corresponding with a diffusion area of 64 ingredient. mm. In accordance with the first aspect of the invention, The receptor compartment has a capacity of 4.8 ml. The inclusion of a quantity of PFPE may be applied in traditional 50 receptor chamber is heated to 37° C. 1. topical formulations such as, for example, but not limited to: Test system: HPLC, Gilson, Mod. 305 with Spectra Physics creams, liquid emulsions, ointments, lotions, microemul detector, Spectra 200 Mod. sions, foams, gels, aspersion powders; and in transdermal Formulations: formulations (drug delivery systems). 55 The term PFPE means molecules with a chemical struc ture A. B C D Troxerutine 3 3 3 3 Phosphatidylcholine 7 7 7 7 CF Tocopherol acetate O.S O.S O.S O.S Sepigel 305 4 4 4 4 Methyl-p-hydroxybenzoate O.15 O.15 O.15 O.15 where n/m=20=40 Propyl-p-hydroxybenzoate O.OS O.OS O.OS O.OS Phenoxyethanol 1 1 1 1 with molecular weights between 650 and 6250, C.A.S. 65 PFPE 3 name: 1-Propene, 1,1,2,3,3,3-hexafluoro-, oxidized and Nor-chenodeoxycolic acid 0.4 polymerized C.A.S. number: 69991-67-9. US 7,026,360 B1 4 various formulations containing different concentrations of -continued PFPE versus a reference formulation. A. B C D Formulations: Transcutol 15 Purified water q.S. to: 100 1OO 100 100 A. B C D Preparation of the Skin Nimesulide 5 5 5 5 The pig skin samples were taken from the internal ear of 10 Lactic acid 2 2 2 2 Ethyl alcohol 95° 4 4 4 4 pigs that had just been sacrificed. Glycerine 5 5 5 5 The samples were soaked in buffer solution at pH 7.4 for PFPE 1.5 3 4.5 24 hours at 4° C. Sepigel 305 4 4 4 4 The sections of connective tissue and muscle were Sub Phosphatidylcholine 2 2 2 2 Methyl-p-hydroxybenzoate O.15 O.15 O.15 O.15 sequently removed from the skin and the sample was cut into 15 Propyl-p-hydroxybenzoate O.OS O.OS O.OS O.OS 2x2 cm Squares. Purified water q.S. to: 100% 100% 100% 100% The skin samples were stored at -20° C. HPLC Operating Test Conditions Results The results on permeability are summarized in the fol Column: KP 18, 5 micron Licrospher 100 lowing table Mobile phase: 20% acetonitrile 80% phosphate buffer at pH 6.6 Flow: 1 ml/min Pressure: 1.52 Kipsi Wavelength: 245 nm. 25 neg of permeated Ninesulide RT: 8.51 TIME (h) A. B C D O.S O.15 O16 O.S9 O.83 Procedure 1 0.27 O.39 O.S9 1.21 The pig skin is placed between the donor compartment 30 2 O.35 0.72 0.97 1.70 and the receptor chamber with the external skin surface 4 O.86 1.14 1.24 1.91 facing the upper compartment. The test formulation is 6 1.15 1.54 2.21 2.38 placed inside the donor compartment. 8 1.54 2.24 3.21 3.73 The receptor chamber is filled with a phosphate buffer 24 3.53 6.OO 9.71 9.86 solution at pH 7.4 and at intervals between 0.5 and 8 hours, 35 2 ml of solution are drawn from this chamber. When each sample is taken fresh buffer solution heated to 37° C. is Conclusions added in order to replenish the initial volume.
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