WO1992022530A1 - Medicaments precurseurs a base de cetobemidone - Google Patents

Medicaments precurseurs a base de cetobemidone Download PDF

Info

Publication number
WO1992022530A1
WO1992022530A1 PCT/DK1992/000184 DK9200184W WO9222530A1 WO 1992022530 A1 WO1992022530 A1 WO 1992022530A1 DK 9200184 W DK9200184 W DK 9200184W WO 9222530 A1 WO9222530 A1 WO 9222530A1
Authority
WO
WIPO (PCT)
Prior art keywords
ketobemidone
composition according
alkenyl
formula
topical
Prior art date
Application number
PCT/DK1992/000184
Other languages
English (en)
Inventor
Hans Bundgaard
Lona Louring Christrup
Ann Fullerton
Laila Bach Hansen
Original Assignee
H. Lundbeck A/S
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 H. Lundbeck A/S filed Critical H. Lundbeck A/S
Publication of WO1992022530A1 publication Critical patent/WO1992022530A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms

Definitions

  • This invention relates to a class of prodrug derivatives of ketobemidone useful in effecting transdermal delivery of ketobemidone to the systemic circulation of a mammal.
  • prodrug denotes a derivative of ketobemidone which, when administered topically to warm-blooded animals, e.g. humans, is converted into the proven drug, i.e. ketobemidone.
  • Ketobemidone is a well known drug and it is a generally known and an accepted practice to administer ketobemidone to control chronic pain. Ketobemidone plays an important role in the control of pain associated with chronic diseases, especially the chronic pain of cancer, and acute pain, especially the acute pain experienced post-operatively.
  • ketobemidone is subject to some problems.
  • the oral and parenteral administration of ketobemidone for pain control frequently involve variations in the pharmacodynamics of the drug over each dosing interval.
  • ketobemidone has a short duration of action and is inefficient- ly and variably absorbed orally due to first-pass metabolism in the intestine and liver (Bondesson et al.-Eur.J.CIin. Pharmacol. 17 (1980) 45-50).
  • Transdermal administration may be a promising approach to overcome many of the drawbacks associated with the parenteral, rectal or oral route of administration.
  • a prerequisite for the development of a transdermal delivery system of ketobemidone is, however, that the drug is capable of penetrating the skin at a sufficiently high rate and is not metabolized during the percutaneous absorption.
  • Ketobemidone shows, unfortunately, a limited skin permeability which makes it unsuited for transdermal delivery.
  • ketobemidone O-ethoxycarbonyl derivative of ketobemidone is known. Said derivative was prepared for use in a method for determination of the concentration of ketobemidone and norketobemidone in plasma (Bondesson et al., Biomedical Mass Spectrometry,1983, 10 , 283-286). No mention or indication of pharmacologi ⁇ cal activity of said derivative is given.
  • R1 is a group
  • R2 is C1-20 alkyl, C2-20 alkenyl, aryl, cycloalkyl, adamantyl, cycloalkenyl, arylalkyl or -alkenyl, cycloalkylalkyl or -alkenyl, adamantyl, or cycloalkenylalkyl or - alkenyl;
  • R3, R4 and R 5 are each independently hydrogen or as R2; or a non-toxic pharmaceutically acceptable acid addition salt thereof.
  • Any alkyl or alkenyl group present may be substituted or unsubstituted, and straight- chain or branched.
  • Cycloalkyl, and cycloalkenyl may be substituted or unsubstituted and comprise 3-8 carbon atoms in the ring and cycloalkyl- and cycloalkenylalkyl and -alkenyl groups designate alkyl or alkenyl substituted with such groups and containing until 20 carbon atoms.
  • Aryl means optionally substituted phenyl or a heteroaromatic group containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and arylalkyi or -alkenyl designate alkyl or alkenyl substituted with such aryl group and containing 4-13 carbonatoms.
  • Suitable straight-chain alkyl groups in Formula I include methyl, ethyl propyl, butyl, hexyl, heptyl, octyl, dodecyl, palmityl and the like groups.
  • Suitable branched-chain alkyl groups include isopropyl, sec-butyl, t- butyl, 2-methylbutyl, 2-pentyl, 3-pentyl and the like groups.
  • Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • alkenyl groups examples include vinyl (ethenyl), 1 -propenyl, i-butenyl, pentenyl, hexenyl, n-decenyl and c-pentenyl and the like groups.
  • the groups may be substituted, generally with 1 or 2 substituents, wherein the substituents are independently selected from halogen, hydroxy, alkoxy, amino, mono-and dialkylamino, nitro, carboxyl, alkoxycarbonyl and cyano groups.
  • substituents are independently selected from halogen, hydroxy, alkoxy, amino, mono-and dialkylamino, nitro, carboxyl, alkoxycarbonyl and cyano groups.
  • suitable aryl groups comprise phenyl and heteroaromatic groups such as pyridinyl, thienyl and imidazolyl.
  • arylalkyi groups are benzyl, phenethyl and phenylpropyl groups wherein the phenyl moiety may be substituted.
  • the aryl group or the aryl moiety of the arylalkyi group may contain independently, from 1 to 3 alkyl, hydroxy, alkoxy, halogen, amino, mono- and dialkylamino, nitro, carboxyl, alkoxycar-. bonyl and cyano groups.
  • halogen is meant in the conventional sense to include F, Cl, Br, and I.
  • non-toxic pharmaceutically acceptable acid addition salts generally includes the non-toxic addition salts of compounds of Formula I, formed with non-toxic inorganic or organic acids.
  • the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, nitric, phosphoric and the like; and the salts with organic acids such as acetic, propionic, succinic, fumaric, maleic, tartaric, citric, glycolic, lactic, stearic, malic, pamoic, ascorbic, phenylacetic, benzoic, glutamic, salicylic, sulfanilic, methanesul- fonic, and the like.
  • the composition of the invention is a topical composition for transdermal delivery comprising a compound of formula I in association with a topical pharma- ceutical carrier which gives a solution, suspension, oinment, lotion, cream, gel, paste, jellie, spray or aerosol.
  • a topical pharma- ceutical carrier which gives a solution, suspension, oinment, lotion, cream, gel, paste, jellie, spray or aerosol.
  • the composition may be incorporated in a medical device for transdermal administering .
  • composition of the invention may also contain a non-toxic additive acting as a skin penetration enhancer.
  • composition is a topical dosage form consisting af a matrix type or reservoir type patch system containing a compound as defined in Formula I and optionally in combination with a penetration enhancing delivery device/process such as iontophoresis.
  • a penetration enhancing delivery device/process such as iontophoresis.
  • Reservoir type patch system and iontophoresis are both well known systems for transdermal delivery.
  • composition according to the invention may also be combined with an additio ⁇ nal drug delivery device such as patches, gauze or compresses.
  • the absorption enhancers used may be of any type such as fatty acids, fatty acid esters and fatty alcohols as well as any type of pharmaceutical additive commonly used for topical or dermal preparations and/or delivery systems such as trans ⁇ dermal patches.
  • the invention relates to the use of the prodrugs of Formula I for the manufacture of a topical medicament for transdermal delivery and useful in relieving pain or tranquilizing a mammal.
  • the present invention provides the novel ketobemidone prodrugs having the general formula I as defined above with the proviso that Ri may not be an ethoxycarbonyl group.
  • the composition according to the present invention When applied to mammalian skin, the composition according to the present invention induces and maintains analgesia by administering through an area of intact skin a ketobemidone prodrug of the Formula I at an analgetically effective rate and continuing the administration of said material at said rate for an extended period of time at least sufficient to induce analgesia.
  • the present invention provide an improved method of treating and controlling acute and/or chronic pain.
  • the fluxes of the compounds and compositions through mammalian skin tissue are established as being sufficient in magnitude to be practical for direct transdermal applications, producing time-sustained dosage rates consistent for pain suppression and tranquilizing effects over prolonged periods of time.
  • ketobemidone prodrug derivatives of the present invention show a higher lipid solubility or lipophilicity and a lower melting point than the active parent drug while still having a proper water affinity and have been found to be more able to pene ⁇ trate the skin of a human or non-human animal and surprisingly they are capable of reverting to the active ketobemidone during or following the transport through the skin. These characteristics make the derivatives useful for transdermal delivery of ketobemidone.
  • preferred compounds are those wherein Ri is one of the following groups: formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, isobutyryl, octanoyl, methoxyacetyl, ethoxyacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxy- carbonyl, iso-butoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, and imidazo- lylcarbonyl.
  • Ri is one of the following groups: formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, isobutyryl, octanoyl, methoxyacetyl, ethoxyacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxy-
  • the compounds of Formula I can be prepared by a variety of synthetic routes commonly used for the preparation of esters, and carbamates.
  • One method comprises reacting ketobemidone or a ketobemidone salt, e.g. ketobemidone- hydrochloride, with an acylating agent selected from
  • reaction can conve- niently be carried out in the absence of a solvent or in an inert solvent such as acetonitrile, toluene, dichloromethane, dioxane or the like, or in a mixture of solvents such as water and methylene chloride, at a temperature of from 0°C to reflux, for about 1/2 to about 100 hours.
  • An acid acceptor like triethylamine or pyridine may be added to the reaction mixture.
  • acid chlorides including chloroformates acid anhydrides or mixed anhydrides may be used.
  • Pivaloyl chloride ( 2.46 ml, 20 mmol) was added to a stirred mixture of ketobemi ⁇ done hydrochloride (1.4 g, 5 mmol), 40 ml of a 1 M aqueous solution of sodium bicarbonate (pH adjusted to 9.5) and 40 ml of methylene chloride. The mixture was stirred at room temperature (20-25°C) for 3 h whereupon the layers were sepa ⁇ rated. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title compound as an oil.
  • the hydrochloric acid salt of O-pivaioyl ketobemidone was prepared as follows: The oil obtained as described above was dissolved in ether (50 ml) and a 2.5 M metha- nolic hydrochloric acid solution (2.5 ml, 6.3 mmol) was added. After standing overnight at -18°C the precipitated hydrochloric acid salt of the title compound was filtered off and recrystallized from acetone-ether. The yield was 68%. Mp 214- 2 5°C.
  • the compound was prepared by reacting 3,3-dimethylbutyryl chloride (2.79 ml, 20 mmol) with ketobemidone hydrochloride (1.4 g, 5 mmol) by a method analogous to that descibed in Example 1.
  • the title compound was isolated as an oil in a yield of 76%.
  • the fumarate salt of 0-3,3-dimethylbutyryl ketobemidone was prepared as follows: The ketobemidone ester (3 mmol) was dissolved in ether (50 ml) and a solution of fumaric acid (383 mg, 3.3 mmol) in 2-propanol (5 ml) was added. After standing for 5 h at 5°C the crystalline 0-3,3-dimethylbutyryl ketobemidone fumarate was isolated by filtration. The compound was washed with ether and recrystallized from ethanol- ether (82% yield). Mp 172-173°C.
  • the compound was prepared by reacting ethyl chloroformate (1.9 ml, 20 mmol) with ketobemidone hydrochloride (1 .4 g, 5 mmol) by a method analogous to that described in Example 1.
  • the title compound was isolated as an oil in a yield of 67%.
  • the hydro-chloric acid salt of the title compound was prepared essentially as described in Example 1. Mp 85-86°C.
  • ketobemidone and various ketobemidone esters in isopropyl myristate and ethanol and their partition coefficients between octanol and pH 7.4 aqueous buffer (P) are shown in Table 1.
  • Ketobemidone O-Acetyl ketobemidone O-Pivaloyl ketobemidone 0-3,3-Dimethylbutyryl ketobemidone O-Benzoyl ketobemidone O-Methoxycarbonyl ketobemidone O-Ethoxycarbonyl ketobemidone O-lsopropoxycarbonyl ketobemidone O-lsobutoxycarbonyl ketobemidone O-Butoxycarbonyl ketobemidone 0-Hexyloxycarbonyl ketobemidone
  • b- IPM Isopropyl myristate.
  • the apparent partition coefficients (P) of ketobemidone and the various prodrugs were determined at 21 °C in an octanol-0.02 M phosphate buffer (pH 7.4) system.
  • concentration of the compounds in the aqueous phase before and after partitioning was determined by HPLC analysis, and the partition coefficients determined.
  • ketobemidone prodrugs are more lipophilic than the parent drug in terms of octanol-aqueous buffer partition coefficients. It is also apparent that ketobemidone prodrugs with increased solubility in a polar solvent like ethanol and an apolar solvent like isopropyl myristate relative to ketobemidone can be obtained. This solubility and lipophilicity may be characteristics favourable for skin penetration.
  • a reversed-phase HPLC procedure was used for the quantitative determination of the ketobemidone prodrugs and the parent drug.
  • a reversed-phase Supelcosil LC- 8DB column (33 x 4.6 mm) was eluted with a mixture of methanol-acetonitrile-0.1% phosphoric acid containing triethylamine (10-3 M) in order to improve peak shape.
  • the composition of the mixture was 5:15:80 (v/v) whereas for the prodrugs the amount of methanol was 5% v/v and that of acetoni- trile between 15 and 40% v/v in order to provide an appropriate retention time.
  • the flow rate was 1-2 ml min-1 and the column effluent was monitored at 215 nm. Quantitation of the compounds was done by measurement of peak heights in relation to those of standards chromatographed under the same conditions.
  • the excised skin was mounted in open Franz diffusion cells. They had an available diffusion area of 0.70 cm2.
  • the dermal side of the skin was exposed to the receptor medium (7.5 ml of 0.05 M isotonic phosphate buffer of pH 7.2) which was stirred magnetically and kept at a constant temperature of 37°C with a circulating water bath.
  • the receptor medium 7.5 ml of 0.05 M isotonic phosphate buffer of pH 7.2
  • the compounds studied were applied as solutions or suspensions (200 ⁇ l) in isopropyl myristate (IPM), ethanol or ethanol-water (3:1 v/v).
  • IPM isopropyl myristate
  • ethanol ethanol-water
  • 3:1 v/v ethanol-water
  • ketobemidone Only ketobemidone was found in the receptor phase after application of the ketobe ⁇ midone prodrugs on the skin, indicating complete enzymatic conversion of the . prodrugs to the parent drug during diffusion through the skin.
  • the cumulative amounts of ketobemidone in the receptor phase divided by the surface area of the diffusion cell were plotted against the time of sampling. The steady-state fluxes were obtained from the slopes of the linear portions of these plots.
  • the values obtained for ketobemidone and some prodrugs are given in Table 3.
  • ketobemidone via the prodrug approach of the present invention
  • the feasibility of obtaining transdermal delivery of ketobemidone via the prodrug approach of the present invention can be assessed by comparing the doses of ketobemidone usually used in parenteral administration with those obtainable by transdermal delivery of the present invention. If the area of the patch, for example, for transdermal delivery is 25 cnr ⁇ 2 and if a flux of 50 ⁇ g/cm ⁇ /h is used, it would be 5 possible to deliver 1.25 mg ketobemidone/h or 30 mg over 24 hours. This amount is in the range as that usually given (20-40 mg) parenterally during 24 hours.
  • the active ketobemidone prodrug of Formula I may be used in association with any pharmaceutical dosage form such as, but not limited to, any solution, ointment, lotion, paste, jelly, gel, cream, spray or aerosol as generally known in the art.
  • the narcotic analgetic prodrug form in associa ⁇ tion with the pharmaceutical dosage form can be used directly as a topical composi- tion or used in combination with an additional drug delivery device, for example, but not limited to, patches, gauzes, compresses, or the like, again, as generally known in the art.
  • the dosage forms may contain any type of absorption enhancers such as fatty acids, fatty acid esters and fatty alcohols or any other non-toxic compound which is known to increase skin permeability.
  • the transdermal analge- sic compositions can be administered in the form of a patch wherein the ketobemi ⁇ done prodrug is present, in a polymeric matrix or in a reservoir system combined with a polymeric rate controlling membrane.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à une composition destinée à la libération topique de cétobémidone. La composition comprend une quantité efficace d'un médicament précurseur à base de cétobémidone en association avec un véhicule pharmaceutique topique qui permet d'obtenir des solutions, des suspensions, des pommades, des laits, des crèmes, des gels, des pâtes, des atomiseurs et des aérosols, et/ou avec un dispositif médical. L'invention se rapporte aussi à l'utilisation des médicaments précurseurs à base de cétobémidone pour la préparation d'un médicament topique permettant de soulager des douleurs ou agissant comme tranquillisant chez un mammifère.
PCT/DK1992/000184 1991-06-13 1992-06-12 Medicaments precurseurs a base de cetobemidone WO1992022530A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK1130/91 1991-06-13
DK113091A DK113091D0 (da) 1991-06-13 1991-06-13 Ketobemidone prodrugs

Publications (1)

Publication Number Publication Date
WO1992022530A1 true WO1992022530A1 (fr) 1992-12-23

Family

ID=8101358

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1992/000184 WO1992022530A1 (fr) 1991-06-13 1992-06-12 Medicaments precurseurs a base de cetobemidone

Country Status (4)

Country Link
AU (1) AU1984992A (fr)
DK (1) DK113091D0 (fr)
IE (1) IE921890A1 (fr)
WO (1) WO1992022530A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5607691A (en) * 1992-06-12 1997-03-04 Affymax Technologies N.V. Compositions and methods for enhanced drug delivery
WO2004043396A2 (fr) * 2002-11-09 2004-05-27 Nobex Corporation Promedicaments contenant du carbamate modifie et methodes de synthese de ces derniers
US20150087674A1 (en) * 2012-05-10 2015-03-26 Mahesh Kandula Compositions and methods for the treatment of severe pain

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ACTA PHARM. NORD., Vol. 3, No. 2, 1991 LAILA BACH HANSEN et al., "Ketobemidone Prodrugs for Buccal Delivery", see page 77 - page 82. *
ACTA PHARMACEUTICA SUECICA, Vol. 17, No. 1, 1980, ULF BONDESSON et al., "Synthesis and Mass Spectra of Deuterium-Labelled Ketobemidone and of some Potential Ketobemidone Metabolites", see page 1 - page 11. *
BIOMEDICAL MASS SPECTOMETRY, Vol. 10, No. 4, 1983, ULF BONDESSON et al., "Simultaneous Determination of Ketobemidone and its N-Demethylated Metabolite in Patient Plasma Samples by Gas Chromatography Mass Spectometry with Selected Ion Monitoring", see page 283 - page 286. *
FRESENIUS Z ANAL. CHEM., Vol. 317, 1984, H. MAURER et al., "Screening Procedure for the Detection of Opiods, other Potent Analgesics and their Metabolites in Urine using a Computerized Gas Chromatographic-mass Spectrometric Technique", see page 42 - page 52. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5607691A (en) * 1992-06-12 1997-03-04 Affymax Technologies N.V. Compositions and methods for enhanced drug delivery
WO2004043396A2 (fr) * 2002-11-09 2004-05-27 Nobex Corporation Promedicaments contenant du carbamate modifie et methodes de synthese de ces derniers
WO2004043396A3 (fr) * 2002-11-09 2004-08-12 Nobex Corp Promedicaments contenant du carbamate modifie et methodes de synthese de ces derniers
US20150087674A1 (en) * 2012-05-10 2015-03-26 Mahesh Kandula Compositions and methods for the treatment of severe pain

Also Published As

Publication number Publication date
DK113091D0 (da) 1991-06-13
AU1984992A (en) 1993-01-12
IE921890A1 (en) 1992-12-16

Similar Documents

Publication Publication Date Title
AU655612B2 (en) Topical compositions for transdermal delivery of produg derivatives of morphine
US6569449B1 (en) Transdermal delivery of opioid antagonist prodrugs
JP2587034B2 (ja) 脳への特異的薬剤供給化合物
US20070224253A1 (en) Transdermal Delivery of Meptazinol
Bodor et al. Improved delivery through biological membranes. 13. Brain-specific delivery of dopamine with a dihydropyridine. dblharw. pyridinium salt type redox delivery system
US7759358B2 (en) Oral bioavailable prodrugs
US8653271B2 (en) Enhancing transdermal delivery of opioid antagonists and agonists using codrugs linked to bupropion or hydroxybupropion
DE3382795T2 (de) Gehirnspezifische arzneimittelabgabe.
US8492422B2 (en) Ester pro-drugs of [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl] methanol for treating skin diseases and conditions
EP0375689A1 (fr) Composition pharmaceutique adaptee a l administration transdermique d'un medicament opioid.
US5750534A (en) Nalbuphine esters having long acting analgesic action and method of use
EP0615756B1 (fr) Esters de nalbuphine, et compositions pharmaceutiques à action prolongée les contenant
US5895660A (en) Deuterated active substances in transdermal application
CZ102797A3 (cs) Sloučeniny na bázi omega-aminokyselin, způsob jejich přípravy jejich použití jako akcelerantů transdermální penetrace a akceleranty transdermální penetrace těmito sloučeninami tvořené
WO1992022530A1 (fr) Medicaments precurseurs a base de cetobemidone
Klimentová et al. Synthesis and transdermal penetration-enhancing activity of carbonic and carbamic acid esters—Comparison with transkarbam 12
US4880816A (en) Brain-specific delivery of dopamine utilizing dihydropyridine/pyridinium salt-type redox carriers
WO2008059224A1 (fr) Utilisation de buprénorphine ou de dérivés n-alkylés de celle-ci dans la guérison des plaies
US5610160A (en) Topical 5-fluorouracil prodrug composition and method
EP2991682B1 (fr) Promédicaments de naproxène et de diclofénac
KR100555884B1 (ko) 모르핀 알칼로이드의 산부가염 및 이의 용도
Jackman et al. Synthesis, β-adrenoceptor pharmacology and toxicology of S-(−)-1-(4-(2-ethoxyethoxy) phenoxy)-2-hydroxy-3-(2-(3, 4-dimethoxyphenyl) ethylamino) propane hydrochloride, a short acting β1-specific antagonist
CZ20001048A3 (cs) Adiční soli morfinových alkaloidů s kyselinami a jejich použití
US20050032893A1 (en) New biodegradable penetration enhancers with multiple hydrophilic moieties
US4167636A (en) 7,8-Dihydroisomorphine derivative, namely azidoethylmorphine

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA CS FI JP KR NO RU US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA