WO2004074235A1 - Transdermal penetration enhancers - Google Patents

Transdermal penetration enhancers Download PDF

Info

Publication number
WO2004074235A1
WO2004074235A1 PCT/CZ2004/000010 CZ2004000010W WO2004074235A1 WO 2004074235 A1 WO2004074235 A1 WO 2004074235A1 CZ 2004000010 W CZ2004000010 W CZ 2004000010W WO 2004074235 A1 WO2004074235 A1 WO 2004074235A1
Authority
WO
WIPO (PCT)
Prior art keywords
per cent
skin
penetration enhancers
general formula
alkyl
Prior art date
Application number
PCT/CZ2004/000010
Other languages
French (fr)
Inventor
Katerina Vavrova
Alexandr Hrabalek
Pavel Dolezal
Tomas Holas
Original Assignee
UNIVERZITA KARLOVA V PRAZE Farmaceuticka Fakulta V Hradci Kralové
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by UNIVERZITA KARLOVA V PRAZE Farmaceuticka Fakulta V Hradci Kralové filed Critical UNIVERZITA KARLOVA V PRAZE Farmaceuticka Fakulta V Hradci Kralové
Publication of WO2004074235A1 publication Critical patent/WO2004074235A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/49—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to transdermal penetration enhancers intended for enhancement of permeation of physiologically active substances applied to either human or animal skin to reach therapeutic concentrations of active substances either in deeper skin layers or in systemic circulation.
  • Transdermal drug delivery has many advantages including prevention of the first- pass effect, limitation of the adverse effects of drugs, and drug and food interactions, more stable plasmatic concentrations, possibility of immediate termination of drug administration and non-invasive administration, leading thus to better patient compliance.
  • transdermal penetration enhancers e.g. Buyuktimkin, N., Buyuktimkin, S., Rytting, J.H. Chemical means of transdermal permeation enhancement.
  • transdermal penetration enhancers e.g. Buyuktimkin, N., Buyuktimkin, S., Rytting, J.H. Chemical means of transdermal permeation enhancement.
  • transdermal and Topical Drug Delivery Systems Ghosh, T. K., Pfister, W. R., (Eds.), Interpharm Press, Buffalo Grove, Illinois, 1997, 357-476; Williams, A. C, Bany. B. W.: Skin absorption enhancers. CRC Critical Reviews in Therapeutic Drug Carrier Systems, 9 (3,4), 1992, 305-353; Santus, G. C, Baker, R. W.: Transdermal enhancer patent literature. J.
  • the structure of the present compounds was designed upon the knowledge of the ceramide biosynthesis that originates from L-serine. Also the requirement of low toxicity and possible biodegradability of the enhancers into non-toxic metabolites in lower epidermal layers was taken into consideration. Thus the compounds of the invention were designed as amino acid esters.
  • the objects of the present invention are ceramide analogues based on amino acid esters of the general formula (I),
  • these compounds consist of a polar head and two hydrophobic chains, similarly to ceramides.
  • the polar head is formed by amino acids glycine and/or serine, optionally by maleic or tartaric acid.
  • the hydrophobic chains are formed by Cg - C 16 alkyl, optionally by C 7 - C 15 acyl or oleoyl.
  • Processes for the preparation of the ceramide analogues include common methods of peptide synthesis and are briefly described in examples.
  • Ceramide analogues of the general formula (I) can be used as enhancers of skin permeation of active ingredients in transdermal or topical pharmaceutical or cosmetic compositions. These compounds can be used to enhance permeation of active agents through the skin into the systemic circulation or into deeper skin layers.
  • the ceramide analogues of the general formula (I) are used in transdermal or topical pharmaceutical or cosmetic compositions in an amount from 0.1 to 5.0 w/w per cent.
  • the compounds are applied dispersed in a hydrophilic vehicle in the amount from 0.1 to 1.0 w/w per cent in relation to the total weight of the preparation.
  • the present ceramide analogues are stable substances with the advantage that they can be prepared in high purity both in a small scale in a laboratory and in a larger scale in industry. Thus they are economically feasible.
  • the advantage of using the substances according to the present invention as penetration enhancers is that they are effective at relatively low concentrations, namely in the range from 0.1 to 5.0 w/w per cent, preferably from 0.1 to 1.0 w/w per cent in relation to the total weight of the preparation.
  • the advantage of these substances is also in that the possible degradation by epidermal enzymes will lead to non-toxic metabolites, namely ⁇ -amino acids, maleic acid, tartaric acid, fatty acids and fatty alcohols.
  • the enhancement ability of the ceramide analogues according to the invention was evaluated in vitro using Franz diffusion cell and either human or porcine skin (Franz, T. J. Percutaneous absorption: on the relevance of in vitro data. J. Invest. Dermatol. 64, 3, 1975, 190-195). The amount of the tested model drug (permeant) permeated through the skin was determined by HPLC.
  • Glycine dodecyl ester was prepared by reaction of glycine with dodecanol and dry hydrogen chloride under nitrogen according to Limanov (Limanov, V. E.; Svitova, I. R.; Kruchenok, T. B.; Tsvirova, I. M.; Yaroslavskaya, L. A. Pharm. Chem. J. 1984, 18, 10, 708) (yield 91 %) and the hydrochloride salt reacted with triethylamine.
  • the resulting glycine dodecyl ester was acylated with N- dodecanoylsuccinimide (prepared according to Lapidot, Y.; Rappoport, S.; Wolman, Y. J. Lip. Res. 1967, 8, 142) in chloroform, product was crystallised from chloroform- diethyl ether mixture (yield 82 %).
  • ER 5.5 ⁇ 2.1 for permeation of theophylline tlirough full- thickness porcine skin from an aqueous vehicle containing 5 per cent of theophylline and 1 per cent of enhancer.
  • Glycine decyl ester hydrochloride was prepared by reaction of glycine and decanol in the presence of toluene sulphonic acid (yield 75 %). After reaction of the hydrochloride salt with triethylamine the resulting glycine decyl ester was acylated with N-decanoylsuccinimide in chloroform and the product was obtained by column chromatography (yield 76 %). White crystals, mp: 70,5 °C - 72 °C.
  • Glycine octyl ester hydrochloride was prepared by reaction of glycine and octanol in the presence of toluene sulphonic acid (yield 76%). After reaction of the hydrochloride salt with triethylamine the resulting glycine octyl ester was acylated with N-octanoylsuccinimide in chloroform and the product was obtained by column chromatography (yield 70 %). White crystals, mp: 55,5 °C - 56 °C.
  • This dipeptide analogue was prepared by condensation of N-dodecanoyl glycine (Lapidot, Y.; Rappoport, S.; Wolman, Y. J. Lip. Res. 1967, 8, 142) and glycine dodecyl ester (see Example 1) via mixed anhydride method (Boissonnas, R. A. Helv. Chim. Acta. 1951, 34, 874) (yield 35 %).
  • ER 2.7 ⁇ 0.7 for permeation of theophylline through human skin (thickness 300 ⁇ m) from an aqueous vehicle containing 5 per cent of theophylline and 0.5 per cent of enhancer.
  • the invention is usable in pharmaceutical and cosmetic industry in production of transdermal and topical pharmaceutical and cosmetic compositions.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides compounds based on ceramide analogues of the general the general formula (I), wherein R1= H or CH2OH; R2 = C8 to C16 alkyl; R3 = C7 to C15 alkyl, cis-heptadec-8­-en-1-yl, CH(R1)NHCOR4, CH=CHCOOR4 or CH(OH)CH(OH)COOR4; R4 = C7 to C16 alkyl. The compounds of the general formula (I) are used as transdermal penetration enhancers. Pharmaceutical and cosmetic compositions, containing ceramide analogues of the general formula (I) in the amount from 0.1 to 5.0 w/w percent, preferably in the amount from 0.1 to 1.0 w/w percent.

Description

Transdermal penetration enhancers
Technical Field
The invention relates to transdermal penetration enhancers intended for enhancement of permeation of physiologically active substances applied to either human or animal skin to reach therapeutic concentrations of active substances either in deeper skin layers or in systemic circulation.
Background Art
Transdermal drug delivery has many advantages including prevention of the first- pass effect, limitation of the adverse effects of drugs, and drug and food interactions, more stable plasmatic concentrations, possibility of immediate termination of drug administration and non-invasive administration, leading thus to better patient compliance.
However, only a limited number of drugs are able to permeate through the skin barrier to reach the necessary therapeutic concentrations. This extremely low skin permeability has been contributed to lipid lamellae in the intercellular spaces of the stratum corneum, particularly to their main component, the ceramides.
The most widely utilized approach to reversibly increase skin permeability for a given drug is the use of transdermal penetration enhancers (e.g. Buyuktimkin, N., Buyuktimkin, S., Rytting, J.H. Chemical means of transdermal permeation enhancement. In: Transdermal and Topical Drug Delivery Systems. Ghosh, T. K., Pfister, W. R., (Eds.), Interpharm Press, Buffalo Grove, Illinois, 1997, 357-476; Williams, A. C, Bany. B. W.: Skin absorption enhancers. CRC Critical Reviews in Therapeutic Drug Carrier Systems, 9 (3,4), 1992, 305-353; Santus, G. C, Baker, R. W.: Transdermal enhancer patent literature. J. Control. Release 25, 1993, 1 - 20). These compounds are capable to interact with stratum corneum components and disorder their arrangement leading to easier drug permeation (Marjukka Suhonen, T., Bouwstra, J. A. and Urtti. A. Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations. J. Control. Release 59, 1999, 149). However, hitherto known enhancers are often showing adverse effects, particularly skin irritability (Moser, K., Kriwet, K., Naik, A., Kalia, Y. N. and Guy, R. H. Passive skin penetration enhancement and its quantification in vitro, Eur. J. Pharm. Biopharm., 52, 2, 2001, 103-112). Therefore the current research in this field has focused to compounds derived from natural skin components - e.g. pyrrolidone derivatives (Yoneto, K; Ghanem, A H; Higuchi, W I; Peck, K D; Li, S K Mechanistic studies of the l-alkyl-2-pyrrolidones as skin permeation enhancers, J. Pharm. Sci., 84, 3, 1995, 312-317), urea (Williams, A.C. and Barry, B. W. Urea analogues in propylene glycol as penetration enhancers in human skin, Int. J. Pharm. 56, 1, 1989, 43-50), or fatty acids (Williams, A. C, Barry, B. W.: Skin absorption enhancers. CRC Critical Reviews in Therapeutic Drug Carrier Systems, 9 (3,4), 1992, 305-353).
Disclosure of Invention
Since the mode of action of the most active penetration enhancers is based on the interaction with ceramides we have chosen ceramide analogues as the target structure.
The structure of the present compounds was designed upon the knowledge of the ceramide biosynthesis that originates from L-serine. Also the requirement of low toxicity and possible biodegradability of the enhancers into non-toxic metabolites in lower epidermal layers was taken into consideration. Thus the compounds of the invention were designed as amino acid esters.
The objects of the present invention are ceramide analogues based on amino acid esters of the general formula (I),
Figure imgf000003_0001
(/)
wherein Ri = H or CH2OH; R2= C8 - C16 alkyl;
R3 = C7 - C15 alkyl, cis-heptadec-8-en-l-yl, CH(Rι)NHCOR4, CH=CHCOOR4 or CH(OH)CH(OH)COOR4 and R4 = C7 - C16 alkyl. In general, these compounds consist of a polar head and two hydrophobic chains, similarly to ceramides. The polar head is formed by amino acids glycine and/or serine, optionally by maleic or tartaric acid. The hydrophobic chains are formed by Cg - C16 alkyl, optionally by C7 - C15 acyl or oleoyl.
Processes for the preparation of the ceramide analogues include common methods of peptide synthesis and are briefly described in examples.
Ceramide analogues of the general formula (I) can be used as enhancers of skin permeation of active ingredients in transdermal or topical pharmaceutical or cosmetic compositions. These compounds can be used to enhance permeation of active agents through the skin into the systemic circulation or into deeper skin layers.
The ceramide analogues of the general formula (I) are used in transdermal or topical pharmaceutical or cosmetic compositions in an amount from 0.1 to 5.0 w/w per cent. Preferably, the compounds are applied dispersed in a hydrophilic vehicle in the amount from 0.1 to 1.0 w/w per cent in relation to the total weight of the preparation.
The present ceramide analogues are stable substances with the advantage that they can be prepared in high purity both in a small scale in a laboratory and in a larger scale in industry. Thus they are economically feasible.
The advantage of practical use of the compounds according to the present invention as penetration enhancers is that they are technologically easily workable with the majority of liquid and semisolid vehicles commonly used for the production of pharmaceutical and cosmetic compositions.
The advantage of using the substances according to the present invention as penetration enhancers is that they are effective at relatively low concentrations, namely in the range from 0.1 to 5.0 w/w per cent, preferably from 0.1 to 1.0 w/w per cent in relation to the total weight of the preparation.
The advantage of these substances is also in that the possible degradation by epidermal enzymes will lead to non-toxic metabolites, namely α-amino acids, maleic acid, tartaric acid, fatty acids and fatty alcohols. The enhancement ability of the ceramide analogues according to the invention was evaluated in vitro using Franz diffusion cell and either human or porcine skin (Franz, T. J. Percutaneous absorption: on the relevance of in vitro data. J. Invest. Dermatol. 64, 3, 1975, 190-195). The amount of the tested model drug (permeant) permeated through the skin was determined by HPLC. To express the activity of the compounds according to the invention as transdermal penetration enhancers, mean values of enhancement ratio, ER's, as the ratios of the drug (permeant) flux through the skin with and without enhancer were used. Selected ER values showing the enhancement of penetration of active substances found by in vitro experiments using excided human skin or porcine skin, respectively, are proving the effectiveness of the compounds according to the invention as penetration enhancers in sense of increasing the topical or transdermal bioavailability of active substances and are briefly stated in the examples.
The invention is further demonstrated by examples however they do not limit its extent.
Examples
Example 1
N-Dodecanoylglycine dodecyl ester
Synthesis: Glycine dodecyl ester was prepared by reaction of glycine with dodecanol and dry hydrogen chloride under nitrogen according to Limanov (Limanov, V. E.; Svitova, I. R.; Kruchenok, T. B.; Tsvirova, I. M.; Yaroslavskaya, L. A. Pharm. Chem. J. 1984, 18, 10, 708) (yield 91 %) and the hydrochloride salt reacted with triethylamine. The resulting glycine dodecyl ester was acylated with N- dodecanoylsuccinimide (prepared according to Lapidot, Y.; Rappoport, S.; Wolman, Y. J. Lip. Res. 1967, 8, 142) in chloroform, product was crystallised from chloroform- diethyl ether mixture (yield 82 %). White crystals, mp: 81 °C - 82 °C.
IR (KBr): vmax 3450, 3333, 2918, 2849, 1740, 1641, 1548, 1473, 1463, 1244, 730, 719 cm"1. 1H NMR (300 MHz, CDC13): δ 5.97 (1H; bs; NH); 4.14 (2H; t; J = 6.9 Hz; COO-
CH2); 4.03 (2H; d; J = 4.9 Hz; CH2NH); 2.23 (2H; t; J = 7.6 Hz; COCH2); 1.70 - 1.55 (4H; m; 2 CH2); 1.40 - 1.15 (34H; m; 17 CH2); 0.87 (6H; t; J = 6.6 Hz; 2 CH3). 13C NMR (75 MHz, CDC13): δ 173.2; 170.2; 65.7; 41.3; 36.4; 31.9; 29.6; 29.5; 29.5; 29.4; 29.3; 29.2; 28.5; 25.8; 25.6; 22.7; 14.1
Enhancing activity: ER = 12.5 ± 0.5 for permeation of theophylline through human skin (tl ickness 300 μm) from an aqueous vehicle containing 5 per cent of theophylline and 1 per cent of enhancer. ER = 5.5 ± 2.1 for permeation of theophylline tlirough full- thickness porcine skin from an aqueous vehicle containing 5 per cent of theophylline and 1 per cent of enhancer.
Example 2
N-Decanoylglycine decyl ester
Synthesis: Glycine decyl ester hydrochloride was prepared by reaction of glycine and decanol in the presence of toluene sulphonic acid (yield 75 %). After reaction of the hydrochloride salt with triethylamine the resulting glycine decyl ester was acylated with N-decanoylsuccinimide in chloroform and the product was obtained by column chromatography (yield 76 %). White crystals, mp: 70,5 °C - 72 °C.
IR (KBr): vmax 3428, 3332, 2919, 2850, 1740, 1641, 1548, 1473, 1464, 1243, 729, 719 cm"1. 1H NMR (300 MHz, CDC13): δ 5.98 (1H; bs; NH); 4.14 (2H; t; J = 6.7 Hz; COO- CH2); 4.03 (2H; d; J = 5.0 Hz; CH2NH); 2.23 (2H; t; J = 7.7 Hz; COCH2); 1.75 - 1.50 (4H; m; 2 CH2); 1.40 - 1.10 (26H; m; 13 CH2); 0.95 - 0.75 (6H; m; 2 CH3). 13C NMR (75 MHz, CDC13): δ 173.2; 170.2; 65.7; 41.3; 36.4; 31.9; 29.6; 29.5; 29.5; 29.4; 29.3; 29.2; 28.5; 25.8; 25.6; 22.7; 14.1
Enhancing activity: ER = 4.2 ± 0.6 for permeation of theophylline through full- thickness porcine skin from an aqueous vehicle containing 5 per cent of theophylline and 2 per cent of enhancer. Example 3
N-Octylglycine octyl ester
Synthesis: Glycine octyl ester hydrochloride was prepared by reaction of glycine and octanol in the presence of toluene sulphonic acid (yield 76%). After reaction of the hydrochloride salt with triethylamine the resulting glycine octyl ester was acylated with N-octanoylsuccinimide in chloroform and the product was obtained by column chromatography (yield 70 %). White crystals, mp: 55,5 °C - 56 °C.
IR (KBr): vmax 3428, 3331, 2923, 2851, 1740, 1641, 1548, 1473, 1463, 1243, 729, 720 cm"1. !H NMR (300 MHz, CDC13): δ 5.97 (1H; bs; NH); 4.14 (2H; t; J = 6.7 Hz; COO- CH2); 4.03 (2H; d; J - 5.2 Hz; CH2NH); 2.23 (2H; t; J = 7.7 Hz; COCH2); 1.75 - 1.55 (4H; m; 2 CH2); 1.40 - 1.15 (18H; m; 9 CH2); 0.95 - 0.75 (6H; m; 2 CH3). 13C NMR (75 MHz, CDC13): δ 173.2; 170.2; 65.7; 41.3; 36.4; 31.7; 31.6; 29.2; 29.1; 29.0; 28.5; 25.8; 25.6; 22.6; 22.6; 14.1
Enhancing activity: ER = 2.2 ± 0.2 for permeation of theophylline through full- thickness porcine skin from an aqueous vehicle containing 5 per cent of theophylline and 0.5 per cent of enhancer.
Example 4
N-Dodecanoylglycylglycine dodecyl ester
Synthesis: This dipeptide analogue was prepared by condensation of N-dodecanoyl glycine (Lapidot, Y.; Rappoport, S.; Wolman, Y. J. Lip. Res. 1967, 8, 142) and glycine dodecyl ester (see Example 1) via mixed anhydride method (Boissonnas, R. A. Helv. Chim. Acta. 1951, 34, 874) (yield 35 %). White crystals, mp: 120,5 °C - 121 °C.
IR (KBr): vmax 3420, 3308, 3085, 2918, 2850, 1746, 1637, 1559, 1467, 1215, 1037, 721 cm"1. 1H NMR (300 MHz, CF3COOD): δ 4.55 - 4.15 (6H; m; 2 CH2N, CH2O; overlapped); 2.65 (2H; t; J = 7.1 Hz; COCH2); 1.90 - 1.65 (4H; m; 2 CH2); 1.60 - 1.15 (34H; m; 17 CH2); 1.00 - 0.80 (6H; m; 2 CH3). 13C NMR (75 MHz, CF3COOD): δ 174.5; 173.3; 70.2; 45.4; 43.6; 36.9; 33.7; 31.4; 31.3; 31.3; 31.2; 31.1; 30.9; 30.7; 29.9; 27.6; 27.3; 24.3; 14.6. In the HMBC spectrum, CH2N proton signals at 4.3 ppm show strong correlation with carbonyl carbons at 174.5 a 173.3 ppm.
Enhancing activity: ER = 2.3 ± 0.6 for permeation of theophylline through human skin (thickness 300 μm) from an aqueous vehicle containing 5 per cent theophylline and 0.5 per cent of enhancer.
Example 5
N-Dodecanoyl-L-serine dodecyl ester
Synthesis: L-Serine was first reacted with dodecanol and dry hydrogen chloride under nitrogen according to Limanov (Limanov, V. E.; Svitova, I. R.; Kruchenok, T. B.; Tsvirova, I. M.; Yaroslavskaya, L. A. Pharm. Chem. J. 1984, 18, 10, 708) (yield 85 %). After reaction of the hydrochloride salt with triethylamine the resulting L-serine dodecyl ester was acylated with N-dodecanoylsuccinimide (see Example 1) in chloroform, product was crystallized from chloroform-diethyl ether mixture (yield 55 %). White crystals, mp: 85 °C - 86 °C. Optical rotation: [ ]2^ = 12,5° (1,0; chloroform). IR (KBr): vmax 3436, 3315, 2919, 2850, 1734, 1649, 1548, 1467, 1282, 1242, 1082, 721 cm"1. 1H NMR (300 MHz, CDC13): δ 6.51 (1H; d; J = 7.1 Hz; NH); 4.70 - 4.60 (1H; m; CHNH); 4.16 (2H; t; J = 6.7 Hz; COO-CH2); 3.94 (2H; d; J = 3.6 Hz; CH2OH); 2.96 (1H; bs; OH); 2.26 (2H; t; J - 7.7 Hz; COCH2); 1.75 - 1.55 (4H; m; 2 CH2); 1.40 - 1.10 (34H; m; 17 CH2); 0.87 (6H; t; J = 6.6 Hz; 2 CH3). 13C NMR (75 MHz, CDC13): δ 173.9; 170.6; 66.1; 63.8; 54.8; 36.5; 31.9; 29.6; 29.5; 29.5; 29.5; 29.3; 29.2; 29.2; 28.4; 25.8; 25.6; 22.7; 14.1
Enhancing activity: ER = 2.7 ± 0.7 for permeation of theophylline through human skin (thickness 300 μm) from an aqueous vehicle containing 5 per cent of theophylline and 0.5 per cent of enhancer. Example 6
N-Oleoyl-L-serine hexadecyl ester
Synthesis: This analogue was prepared by reaction of L-serine hexadecyl ester (see
Example 5) with N-oleoyloxysuccinimide (Lapidot, Y.; Rappoport, S.; Wolman, Y. J. Lip. Res. 1967, 8, 142) in chloroforai, product was purified by column chromatography (yield 75 %). White crystals, mp: 65,5 °C - 66 °C. Optical rotation:
[a] C = 10,5° (1,0; chloroform).
IR (KBr): vmax 3432, 3312, 3009, 2921, 2851, 1718, 1649, 1546, 1467, 1283, 1084, 722 cm"1. 1H NMR (300 MHz, CDC13): δ 6.41 (IH; d; J = 6.9 Hz; NH); 5.40 - 5.20 (2H; m; CH=CH); 4.70 - 4.65 (IH; m; CHNH); 4.15 (2H; t; J = 6.7 Hz; COO-CH2); 4.00 - 3.85 (2H; m; CH2OH); 2.70 (IH; t; J = 5.9 Hz; OH); 2.24 (2H; t; J = 7.7 Hz; COCH2); 2.10 - 1.85 (4H; m; 2 CH2CH=); 1.75 - 1.50 (4H; m; 2 CH2); 1.40 - 1.10 (46H; m; 19 CH2); 0.85 (6H; t; J= 6.7 Hz; 2 CH3). 13C NMR (75 MHz, CDC13): δ 173.8; 170.6; 130.0; 129.7; 66.1; 63.9; 54.9; 36.5; 31.9; 31.9; 29.7; 29.7; 29.7; 29.6; 29.5; 29.5; 29.3; 29.3; 29.2; 29.2; 29.1; 28.5; 27.2; 27.1; 25.8; 25.5; 22.7; 14.1
Enhancing activity: ER = 1.3 ± 0.2 for permeation of theophylline through human skin (thickness 300 μm) from an aqueous vehicle containing 5 per cent theophylline and 0.5 per cent of enhancer.
Example 7
N-(Dodecyloxycarbonylmethyl)maleinamic acid dodecyl ester
Synthesis: Maleic acid monododecyl ester (prepared according to Huber; Lutton. J. Amer. Chem. Soc. 1957, 79, 3919) was reacted with glycine dodecyl ester (see Example 1) via mixed anhydride method (Boissonnas, R. A. Helv. Chim. Acta. 1951, 34, 874) (yield 91 %). White crystals, mp: 50 °C - 53 °C.
IR (KBr): vmax 3433, 3366, 3058, 2919, 2851, 1747, 1730, 1668, 1635, 1538, 1472, 1465, 1244, 1198, 720 cm"1. 1H NMR (300 MHz, CDC13): δ 8.87 (IH; s; NH); 6.32 (IH; d; J = 12.9 Hz; CH=); 6.15 (IH; d; J = 13.2 Hz; CH=); 4.20 - 4.05 (6H; m; 2 COOCH2; CH2N; overlapped); 1.70 - 1.55 (4H; m; 2 CH2); 1.40 - 1.15 (36H; m; 18 CH2); 0.84 (6H; t; J = 6.7 Hz; 2 CH3). 13C NMR (75 MHz, CDC13): δ 169.6; 166.2; 164.0; 137.7; 126.1; 65.9; 65.6; 41.7; 31.9; 29.6; 29.5; 29.5; 29.3; 29.2; 28.4; 28.3; 25.8; 25.8; 22.7; 14.1
Enhancing activity: ER = 6.6 ± 1.8 for permeation of theophylline through full- thickness porcine skin from an aqueous vehicle containing 5 per cent of theophylline and 1 per cent of enhancer.
Example 8
N-( 1 -Dodecyloxycarbonyl-2-hydroxyethyl)-2,3 -dihydroxysuccinamic acid dodecyl ester
Synthesis: The title compound was prepared by oxidation of N-(l- dodecyloxycarbonyl-2-hydroxyethyl)maleinamic acid dodecyl ester (prepared similarly as compound of Example 7) by potassium permanganate in dichloromethane in the presence of crown-ether DH-18-C-6 (Mukaiyama, T.; Tabusa, F.; Suzuki, K. Chem. Lett. 1983, 173). White crystals, mp: 93,5 °C - 96,5 °C.
IR (KBr): vmax 3412, 2922, 2852, 1736, 1663, 1534, 1467, 1217, 721 cm"1. 1H NMR (300 MHz, CDC13): δ 7.75 (IH; d; J = 7.7 Hz; NH); 4.85 - 4.65 (IH; m; CHNH); 4.65 - 4.50 (3H; m; 3 OH); 4.50 - 4.35 (IH; m; CHOH); 4.30 - 4.05 (4H; m; 2 COO-CH2); 4.05 - 3.85 (2H; m; CH2OH); 3.85 - 3.65 (IH; m; CHOH); 1.75 - 1.50 (4H; m; 2 CH2); 1.40 - 1.10 (36H; m; 18 CH2); 0.87 (6H; t; J - 6.6 Hz; 2 CH3). 13C NMR (75 MHz, CDCI3): δ 171.5; 170.7; 170.3; 73.8; 72.8 66.4; 66.2; 62.6; 54.7; 31.9; 29.6; 29.6; 29.6; 29.5; 29.3; 29.2; 28.4; 28.4; 25.8; 22.7 14.1
Enhancing activity: ER = 1.4 ± 0.1 for permeation of theophylline through human skin (thickness 300 μm) from an aqueous vehicle containing 5 per cent of theophylline and 0.5 per cent of enhancer. Industrial applicability
The invention is usable in pharmaceutical and cosmetic industry in production of transdermal and topical pharmaceutical and cosmetic compositions.

Claims

Claims
1. Transdermal penetration enhancers based on ceramide analogues of the general formula (I),
Figure imgf000012_0001
(/)
wherein R1 = H or CH2OH;
Rι= C8 - Ciβ alkyl; R3 = C7 - C15 alkyl, cw-heptadec-8-en-l-yl, CH(Rι)NHCOR4, CH=CHCOOR4 or CH(OH)CH(OH)COOR4 and R4 = C7 - C16 alkyl.
2. Use of the ceramide analogues of the general formula (I) according to claim 1 as transdermal penetration enhancers in transdermal or topical pharmaceutical and cosmetic compositions.
3. Pharmaceutical and cosmetic compositions comprising ceramide analogues of the general formula (I) as transdermal penetration enhancers.
4. Pharmaceutical and cosmetic compositions according to claim 3 comprising ceramide analogues of the general formula (I) in the amount from 0.1 to 5.0 w/w per cent.
5. Pharmaceutical and cosmetic compositions according to claim 4 comprising ceramide analogues of the general formula (I) in a hydrophilic vehicle in the amount from 0.1 to 1.0 w/w per cent.
PCT/CZ2004/000010 2003-02-24 2004-02-23 Transdermal penetration enhancers WO2004074235A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2003-540 2003-02-24
CZ2003540A CZ293989B6 (en) 2003-02-24 2003-02-24 Transdermal penetration accelerants

Publications (1)

Publication Number Publication Date
WO2004074235A1 true WO2004074235A1 (en) 2004-09-02

Family

ID=32875831

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2004/000010 WO2004074235A1 (en) 2003-02-24 2004-02-23 Transdermal penetration enhancers

Country Status (2)

Country Link
CZ (1) CZ293989B6 (en)
WO (1) WO2004074235A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ298319B6 (en) * 2006-06-23 2007-08-22 Univerzita Karlova v Praze, Farmaceutická fakultav Hradci Králové Pseudoceramides and pharmaceutical and/or cosmetic compositions intended for application to skin in which the pseudoceramides are comprised
JP2010528985A (en) * 2007-05-04 2010-08-26 エムディーアールエヌエー，インコーポレイテッド Amino acid lipids and uses thereof
CN110305030A (en) * 2019-07-01 2019-10-08 昆明理工大学 Amino acid ester hydrochlorides and the preparation method and application thereof
CN112341354A (en) * 2020-09-24 2021-02-09 湖北泓肽生物科技有限公司 PMS synthesis method

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4980378A (en) * 1988-06-01 1990-12-25 Odontex, Inc. Biodegradable absorption enhancers
EP0552405A1 (en) * 1992-01-24 1993-07-28 LINTEC Corporation A percutaneous absorption promoter, a tape plaster and a method of promoting percutaneous absorption
WO1999018177A1 (en) * 1997-10-07 1999-04-15 Reckitt & Colman France Detergent composition
EP0928608A2 (en) * 1997-12-25 1999-07-14 Ajinomoto Co., Inc. Cosmetic composition
WO1999036032A1 (en) * 1998-01-15 1999-07-22 Lavipharm Laboratories, Inc. Plant polar lipid permeation enhancer in a cosmetic pad for improving skin appearance
JP2000355524A (en) * 1999-06-14 2000-12-26 Ajinomoto Co Inc Cosmetic composition

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4980378A (en) * 1988-06-01 1990-12-25 Odontex, Inc. Biodegradable absorption enhancers
EP0552405A1 (en) * 1992-01-24 1993-07-28 LINTEC Corporation A percutaneous absorption promoter, a tape plaster and a method of promoting percutaneous absorption
WO1999018177A1 (en) * 1997-10-07 1999-04-15 Reckitt & Colman France Detergent composition
EP0928608A2 (en) * 1997-12-25 1999-07-14 Ajinomoto Co., Inc. Cosmetic composition
WO1999036032A1 (en) * 1998-01-15 1999-07-22 Lavipharm Laboratories, Inc. Plant polar lipid permeation enhancer in a cosmetic pad for improving skin appearance
JP2000355524A (en) * 1999-06-14 2000-12-26 Ajinomoto Co Inc Cosmetic composition

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BARTEL, M. ET AL: "Synthesis of enantiomerically pure, sn-1 modified sn-2-deoxy-2-amido- glycero-3-phospholipids", CHEMISTRY AND PHYSICS OF LIPIDS, vol. 107, no. 1, 2000, pages 121 - 129, XP002284920 *
BIOORGANICHESKAYA KHIMIYA, vol. 20, no. 10, 1994, pages 1101 - 1106 *
CHEMISTRY LETTERS, no. 3, 1993, pages 567 - 570 *
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ISHII, HIROHARU ET AL: "Cosmetics containing N-long-chain acyl neutral or acidic amino acid esters and water- or alcohol-soluble polymers", XP002284924, retrieved from STN Database accession no. 2000:907026 *
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SEBYAKIN, YU. L. ET AL: "Synthesis of amphiphilic L-serine derivatives", XP002284925, retrieved from STN Database accession no. 1995:304551 *
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SHIMIZU, TOSHIMI ET AL: "Polymorphism of model glycosphingolipids evidenced by calorimetric and polarizing microscopic study", XP002284926, retrieved from STN Database accession no. 1993:472967 *
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SUZUKI, EIJI ET AL: "Transdermal absorption accelerators containing amino acids", XP002284923, retrieved from STN Database accession no. 1993:132150 *
VAVROVA, KATERINA ET AL: "L-Serine and glycine based ceramide analogs as transdermal permeation enhancers : polar head size and hydrogen bonding", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 13, no. 14, 21 July 2003 (2003-07-21), pages 2351 - 2353, XP002284921 *
VAVROVA, KATERINA ET AL: "Synthetic ceramide analogues as skin permeation enhancers : structure-activity relationships", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 11, no. 24, 1 December 2003 (2003-12-01) - 5381, pages 5390, XP002284922 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ298319B6 (en) * 2006-06-23 2007-08-22 Univerzita Karlova v Praze, Farmaceutická fakultav Hradci Králové Pseudoceramides and pharmaceutical and/or cosmetic compositions intended for application to skin in which the pseudoceramides are comprised
WO2007147370A2 (en) * 2006-06-23 2007-12-27 UNIVERZITA KARLOVA V PRAZE Farmaceuticka Fakulta V Hradci Kralové Pseudoceramides and pharmaceutical and/or cosmetic compositions designed for administration to the skin containing the same
WO2007147370A3 (en) * 2006-06-23 2008-03-06 Univerzita Karlova V Praze Far Pseudoceramides and pharmaceutical and/or cosmetic compositions designed for administration to the skin containing the same
JP2010528985A (en) * 2007-05-04 2010-08-26 エムディーアールエヌエー，インコーポレイテッド Amino acid lipids and uses thereof
CN110305030A (en) * 2019-07-01 2019-10-08 昆明理工大学 Amino acid ester hydrochlorides and the preparation method and application thereof
CN110305030B (en) * 2019-07-01 2021-10-15 昆明理工大学 Amino acid ester hydrochloride and preparation method and application thereof
CN112341354A (en) * 2020-09-24 2021-02-09 湖北泓肽生物科技有限公司 PMS synthesis method
CN112341354B (en) * 2020-09-24 2022-06-10 湖北泓肽生物科技有限公司 PMS synthesis method

Also Published As

Publication number Publication date
CZ2003540A3 (en) 2004-09-15
CZ293989B6 (en) 2004-09-15

Similar Documents

Publication Publication Date Title
Vavrova et al. Amphiphilic transdermal permeation enhancers: structure-activity relationships
US20060240097A1 (en) TRPV1 agonist compounds and methods for making and using the same
JP6480025B2 (en) Ionic compounds and compositions and uses thereof
JP5140224B2 (en) Phospholipid derivatives of valproic acid and mixtures thereof
DE69636058T2 (en) BOUND PREPARATIONS OF MEDICINAL PRODUCTS BASED ON COVALENCY LINKING WITH GLUTATHIONAL ANALOGS
Vávrová et al. L-Serine and glycine based ceramide analogues as transdermal permeation enhancers: polar head size and hydrogen bonding
CN101157612B (en) Organic acid menthol derivative and transdermal drug delivery preparation having the same
US7183261B2 (en) Galactosylceramide analogs, and β-glucocerebrosidase activators, external skin preparations and method of activating β-glucocerebrosidase using the analogs
Coufalová et al. New propanoyloxy derivatives of 5β-cholan-24-oic acid as drug absorption modifiers
CA2050484A1 (en) Sialic acid-containing glycolipid derivatives
WO2004074235A1 (en) Transdermal penetration enhancers
JPH0211570B2 (en)
US7173021B2 (en) Synthesis of temozolomide esters as potent anticancer pro-drugs for topical and transdermal applications in treatments of cancers
Vávrová et al. Biodegradable derivatives of tranexamic acid as transdermal permeation enhancers
EP2792670A1 (en) Positively charged water-soluble prodrugs of mustards and related compounds with very high skin penetration rates
EP0973710B1 (en) Omega-amino acid derivatives, processes of their preparation and their use
EP1340740B1 (en) Carboxylic acid type lipid
Mrózek et al. New polyfluorothiopropanoyloxy derivatives of 5β-cholan-24-oic acid designed as drug absorption modifiers
Doležal et al. ε-Aminocaproic acid esters as transdermal penetration enhancing agents
Holas et al. Synthesis and transdermal permeation-enhancing activity of carbonate and carbamate analogs of Transkarbam 12
JP2911287B2 (en) N-acyl amino acid compound and method for producing the same
DE69802908T2 (en) SALICYLIC ACID - SPHINGOIDBASE DERIVATIVES AND THEIR USE
CN110305030B (en) Amino acid ester hydrochloride and preparation method and application thereof
Vávrová et al. Amino acid-based transdermal penetration enhancers
Shah et al. Enhancement of in vitro skin permeation of verapamil

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase