WO2002067994A2 - Composes constitues d'une molecule analgesique liee a un vecteur - Google Patents
Composes constitues d'une molecule analgesique liee a un vecteur Download PDFInfo
- Publication number
- WO2002067994A2 WO2002067994A2 PCT/FR2002/000667 FR0200667W WO02067994A2 WO 2002067994 A2 WO2002067994 A2 WO 2002067994A2 FR 0200667 W FR0200667 W FR 0200667W WO 02067994 A2 WO02067994 A2 WO 02067994A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- vector
- compound according
- molecule
- analgesic
- bond
- Prior art date
Links
Classifications
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Definitions
- the present invention relates to compounds consisting of an analgesic molecule vectorized by its binding to a vector so that said analgesic molecule crosses the blood-brain barrier, as well as to the use of said compounds for the preparation of medicaments. useful for the treatment of pain.
- Morphine is one of the compounds most used in the treatment of pain of medium and high intensity.
- treatment with morphine is often accompanied by undesirable effects such as: euphoria or drowsiness, respiratory depression, inhibition of intestinal transit, nausea, vomiting, and above all dependence syndrome and induction of tolerance (Cherny et al, 1996).
- morphine undergoes a significant first pass liver effect, which results in low bioavailability which varies depending on the route of administration.
- Morphine mainly undergoes enantioselective glucuronidation catalyzed by the enzyme UDP-glucuronyltransferase (UGT) and the liver appears as the main site of its biotransformation.
- UDP-glucuronyltransferase UDP-glucuronyltransferase
- M6G morphine 6-glucuronide
- This metabolite also has analgesic activity.
- M6G binds to opioid receptors and is 3 to 5 times less refines for ⁇ receptors as morphine (Christensen & Jorgensen 1987; Frances et al, 1992).
- the ⁇ receptors are of two types: ⁇ l receptors of very high affinity and low capacity, and ⁇ 2 receptors of basic affinity and high capacity (Pasternak & Wood, 1986).
- Binding to ⁇ l receptors leads to a supraspinal type analgesic reaction and a decrease in turnover of acetylcholine, while binding to ⁇ 2 receptors leads to a spinal type analgesic reaction and is responsible for respiratory depression, inhibition of transit intestinal and several signs associated with addiction.
- Morphine and its active metabolite, M6G must cross the blood-brain barrier (BBB) before being distributed in the brain, the main place of action for their analgesic effects.
- BBB blood-brain barrier
- Morphine is a base whose pKa is between 8 and 9, therefore weakly ionized at blood pH, and whose cerebral penetration has been described as a simple diffusion.
- Its metabolite, M6G is an acid (pKa between 2 and 3), strongly ionized at blood pH. Because of its hydrophilicity, the penetration of M6G is very limited in the brain.
- Intracerebroventricular administration at equal doses, of morphine and M6G has produced an analgesic effect which is 50 to 100 times greater for M6G than for morphine (Pasternak et al 1987; Frances et al, 1982; Stain et al 1995).
- the two molecules have roughly the same analgesic activity.
- the blood-brain barrier is made up of endothelial cells that make obstacle, in various ways, to the molecules which try to cross them. They constitute a physical barrier represented by the tight junctions which bond between them and prevent any passage by the paracellular way and this, all the more since the endocytosis activity is weak there. All this greatly limits the passage of molecules from the plasma to the cerebral extracellular space.
- vectors such as linear peptides derived from natural peptides such as Protegrine and Tachyplesin transport active molecules through the BBB.
- Protegrine and Tachyplésine are natural peptides whose structure is of the hairpin type maintained by disulfide bridges. These bridges play an important role in the cytolytic activity observed on human cells. The irreversible reduction of these bridges makes it possible to obtain linear, non-cytotoxic peptides, having the capacity to rapidly cross the membranes of mammalian cells by a passive mechanism which does not call upon a membrane receptor.
- the present invention relates to compounds consisting of an analgesic molecule linked to a vector capable of vectorizing said analgesic molecule across the blood-brain barrier.
- the vector capable of vectorizing said analgesic molecule across the blood-brain barrier is a linear peptide derived from the family of Protegrin or of
- peptide derived from the Protegrin family means any peptide which corresponds to the following formula I:
- - groups B identical or different, represent an amino acid residue whose side chain carries a basic group
- - groups X identical or different, represent a residue of aliphatic or aromatic amino acid or said peptides of formulas (I) or (II), in retro form, consisting of amino acids of configuration D and / or L, or a fragment thereof consisting of a sequence of at least 5 and preferably at least 7 successive amino acids of the peptides of formulas (I) or (II) •
- B is chosen from arginine, lysine, diaminoacetic acid, diaminobutyric acid, diaminopropionic acid and ornithine.
- X is chosen from glycine, alanine, valine, norleucine, isoleucine, leucine, cysteine, , penicillamine, methionine, serine, threonine, asparagine, glutamine, phenyalanine, histidine, tryptophan, tyrosine, proline, 1 'Abu, amino-1- cyclohexane carboxylic acid, Aib, 2-aminotetralin carboxylic, 4-bromophenyalanine, tert-Leucine, 4-chlorophenylalanine, beta-cyclohexyalanine, 3,4-dichlorophenyalanine, 4 - fluorophenyalanine, 1 'homoleucine, beta-homoleu ,
- analgesic molecule contemplates compounds chosen from opioids, such as encephalin, morphine, non-steroidal anti-inflammatory compounds (NSAID), inhibitor compounds of Cox 2, NMDA receptor agonist compounds, calcium channel blocking compounds, neuropeptides and in particular morphine derivatives.
- opioids such as encephalin, morphine, non-steroidal anti-inflammatory compounds (NSAID), inhibitor compounds of Cox 2, NMDA receptor agonist compounds, calcium channel blocking compounds, neuropeptides and in particular morphine derivatives.
- NSAID non-steroidal anti-inflammatory compounds
- the analgesic molecule used in the context of the present invention is morphine, one of its derivatives or one of its metabolites. Most preferably, such a metabolite is M6G.
- the binding positions for the analgesic molecule can be at the N- ends terminal or C-terminal or else at the side chains of the vector peptide.
- Functional groups such as -OH, - SH, -COOH, -NH 2 can be naturally present or can be introduced, either on the vector, or on the analgesic molecule, or on both.
- connection between the vector and the analgesic molecule can be carried out by any acceptable means of connection taking into account the chemical nature and the bulk both of the vector and of the analgesic molecule.
- the bonds can be covalent, hydrophobic or ionic, cleavable or non-cleavable in physiological media or inside cells.
- linking agents which can be used in the context of the invention, mention may be made of bi- or multifunctional agents containing alkyl, aryl, aralkyl or peptide groups, esters, aldehydes or acids of alkyl, aryl or aralkyl, anhydride, sulfhydrile or carboxy groups such as derivatives of maleymil benzoic acid, maleymil propionic acid and succynimidyl derivatives, groups derived from bromide or cyanogen chloride, carbonyldiimidazole, esters succinimide or sulphonic halides.
- bonds involving at least one disulfide bridge are used, which are characterized by their stability in the plasma after injection of the compound, then once the compounds of the invention have crossed the blood-brain barrier, said disulfide bridge is reduced by releasing the active analgesic molecule.
- the binding can be performed at any site of the vector.
- the vectorized analgesic compound consists of a derivative of morphine coupled by its position 6 to the vector.
- the vector is fixed at the position 6 of said morphine molecule.
- the vector is fixed at the level of the carboxylic acid of the glucuronide residue of said morphine-6-glucuronide molecule.
- the present invention also relates to the use of said vectorized compounds of an analgesic molecule in a pharmaceutical composition for the preparation of a medicament useful for the treatment of pain.
- the pharmaceutical composition is in a form suitable for administration by the systemic route, by parenteral route, by oral route, by rectal route, by nasal route, by transdermal route, by pulmonary route.
- the subject of the invention is also a method of treating pain consisting in administering to a patient a pharmaceutical composition comprising at least one vectorized compound consisting of a analgesic molecule linked to a vector, said peptide being a derivative of the family of Protegrin or Tachyplesin.
- FIG. 1 schematically represents the chemical synthesis of a vectorized compound of morphine-6-glucuronide (M6G), metabolite of morphine.
- M6G morphine-6-glucuronide
- FIG. 2 illustrates the results of a comparative study of the analgesic efficacy between compound 1 (morphine) and compound 2 (vectorized M6G).
- FIG. 3 illustrates the results of a comparative study of the analgesic efficacy between compound 1 (morphine), compound 2 (vectorized M6G) and compound 3 (free M6G).
- FIG. 4 illustrates a comparative study of the penetration into the BBB of free M6G (compound 1) with that of vectorized M6G (compound 2).
- Figure 5 illustrates the results of a comparative study of the effect of morphine, vectorized M6G and free M6G on respiratory depression.
- the compounds were used at the ED50 dose (Figure 5, A), at the 5x ED50 dose ( Figure 5, B) and at the 10x ED50 dose (Figure 5, C).
- the peptide SynB3 of sequence RRLSYSRRRF (SEQ ID No. 1 in the sequence list in the appendix) (a molar equivalent) is incubated for 30 minutes with a molar equivalent of the reagent SPDP (S-pyridinium succinimidyl-mercaptopropionate) in the solvent DMF
- M6G is incubated with two molar equivalents of PyBOP, in the presence of four molar equivalents of DIEA in the solvent DMF.
- Test used hot plate test.
- Experimental conditions
- the hot plate test is carried out by following the experimental protocol described by Eddy NB et al. Synthetic analgesia. 1 - Methadone isomers and derivatives. J. Pharmacol. Exp. Ther. 1950 (98): 121-137.
- the reaction time is then noted.
- the compounds studied are administered intravenously into the tail vein of the mouse at a dose of 1 mg / kg.
- the reaction time is then measured after 5 to 90 minutes (results presented in Figure 2) and from 5 to 180 minutes (results presented in Figure 3).
- Tail flick test Tail flick test.
- tissue homogenates are prepared from calf brains (thalamus for ⁇ l and ⁇ 2 and frontal cortex for delta).
- [ 3 H] [D-Ala 2 , D-Leu 5 ] enkephalin (DADLE) (0.7 nM) is incubated with 3 ml of tissue homogenate (15 mg of tissue per ml) in the presence of 10 nM of [D- Pen 2 , D-Pen 5 ] enkephalin (DPDPE) and increasing concentrations of free or vectorized M6G. Under these conditions, a specific binding to the binding sites of ⁇ l is observed.
- enkephalin For the ⁇ 2 receptor, [D- Ala 2 , MePhe 4 , Gly (ol) 5 ] enkephalin (DAMGO) (1 nM) is incubated with 3 ml of tissue homogenate in the presence of 5 nM [D- Ser 2 , Leu 5 ] enkephalin-Thr 6 (DSLET) and increasing concentrations of free or vectorized M6G.
- DAMGO Gly (ol) 5 ] enkephalin
- DSLET enkephalin-Thr 6
- the tissue is incubated with [ 3 H] [D-Pen 2 , D-Pen 5 ] enkephalin in the presence of free or vectorized M6G.
- the non-specific binding is determined by the addition to the labeled ligands of 1 ⁇ M of levallorphan.
- M6G is an active metabolite of morphine which binds to the ⁇ receptors with very high affinity.
- affinity of free M6G (compound 1) to that of vectorized M6G (compound 2) at the ⁇ l, ⁇ 2 and delta receptors.
- mice (20-25 g, Iffa-Credo; l'Arbresle, France) are anesthetized.
- the right external carotid artery is linked to the level of bifurcation with the internal carotid artery and the common carotid artery is linked between the heart and the catheter implantation site (polyethylene catheter, ID: 0.76).
- This, previously filled with a heparin solution (100 units / ml) is inserted into the common carotid.
- mice are perfused with the perfusion buffer (128 mM NaCl, 24 mM NaHC0 3 , 4.2 mM KC1, 2.4 mM NaH 2 P0 4 , 1.5 mM CaCl 2 , 0.9 mM MgS0 4 , and 9 mM D-glucose).
- This buffer is filtered and then bubble by a mixture containing 95% 0 2 /5% C0 2 in order to maintain the pH. close to 7.4 and supplying the brain with oxygen during the infusion.
- mice are perfused with the buffer containing free M6G (compound 1; specific activity 84 mCi / mg) or vectorized M6G (compound 2; specific activity 14.3 mCi / mg).
- the heart is stopped by section of the ventricles, in order to avoid reflux of the perfusate during the infusion.
- the right hemisphere is then perfused at a speed of 10 ml / min for 60 seconds after which the mouse is decapitated. The amount of radioactivity in the right hemisphere is then measured and the cerebral penetration index (Kin) is calculated.
- Respiratory depression has been studied in rats.
- the product is injected into the animals subcutaneously and after a certain time, an aliquot of blood is drawn from the femoral artery via a catheter previously implanted. During the study, the animals are placed in a quiet place. After blood sampling, oxygen saturation (S0 2 ) and C0 2 pressure (PC0 2 ) are measured. The values of S0 2 are measured in% of 0 2 .
- the rats were injected with 3 doses of each product which correspond to ED50, 5xED50, 10xED50 (see Table 5). After times ranging from 0 to 150 min (30, 60, 90, 120, 150 min), the blood is drawn and the saturation in O 2 (S0 2 ) and the pressure of C0 2 are measured.
- morphine is the substance most used in the treatment of pain of medium and high intensity, its use induces respiratory depression in patients.
- results presented in FIG. 5 demonstrate that the vectorized M6G product not only has a better analgesic effect than free M6G or morphine but also makes it possible to significantly reduce the side effects associated with morphine.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Image Analysis (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002567359A JP2004529886A (ja) | 2001-02-23 | 2002-02-22 | 血液脳関門を通して鎮痛分子をベクター化することが可能なベクターに結合した前記鎮痛分子からなる化合物、及びそれらを含む医薬組成物 |
IL15721402A IL157214A0 (en) | 2001-02-23 | 2002-02-22 | Compounds comprising an analgesic molecule linked to a vector that can vectories said molecule through the hematoencephalic barrier and pharmaceutical compositions containing same |
EP02704883A EP1397161B1 (fr) | 2001-02-23 | 2002-02-22 | Composes constitues d'une molecule analgesique liee a un vecteur |
US10/468,412 US20040248806A1 (en) | 2001-02-23 | 2002-02-22 | Compounds comprising an analgesic molecule linked to a vector that can vectorise said molecule through the hematoencephalic barrier and pharmaceutical compositions containing same |
AU2002238687A AU2002238687B2 (en) | 2001-02-23 | 2002-02-22 | Compounds comprising an analgesic molecule linked to a vector that can vectorise said molecule through the hematoencephalic barrier and pharmaceutical compositions containing same |
CA002438824A CA2438824A1 (fr) | 2001-02-23 | 2002-02-22 | Composes constitues d'une molecule analgesique liee a un vecteur capable de vectoriser ladite molecule a travers la barriere hemato-encephalique et compositions pharmaceutiques les contenant |
DE60226319T DE60226319T2 (de) | 2001-02-23 | 2002-02-22 | Verbindungen die ein an einen vektor gebundenes analgetisches molekül enthalten |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR01/02504 | 2001-02-23 | ||
FR0102504A FR2821272B1 (fr) | 2001-02-23 | 2001-02-23 | Composes constitues d'une molecule analgesique liee a un vecteur capable de vectoriser ladite molecule a travers la barriere hematoencephalique et compositions pharmaceutiques les contenant |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2002067994A2 true WO2002067994A2 (fr) | 2002-09-06 |
WO2002067994A3 WO2002067994A3 (fr) | 2003-12-24 |
Family
ID=8860381
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2002/000667 WO2002067994A2 (fr) | 2001-02-23 | 2002-02-22 | Composes constitues d'une molecule analgesique liee a un vecteur |
Country Status (11)
Country | Link |
---|---|
US (1) | US20040248806A1 (fr) |
EP (1) | EP1397161B1 (fr) |
JP (1) | JP2004529886A (fr) |
AT (1) | ATE393633T1 (fr) |
AU (1) | AU2002238687B2 (fr) |
CA (1) | CA2438824A1 (fr) |
DE (1) | DE60226319T2 (fr) |
ES (1) | ES2305204T3 (fr) |
FR (1) | FR2821272B1 (fr) |
IL (1) | IL157214A0 (fr) |
WO (1) | WO2002067994A2 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012076824A1 (fr) | 2010-12-10 | 2012-06-14 | Institut Gustave Roussy | Nouveaux derives d'oxazaphosphorines pre-activees, utilisation et methode de preparation |
CN103012596A (zh) * | 2012-12-28 | 2013-04-03 | 兰州大学 | 具有血脑屏障通透性的内吗啡肽衍生肽及其合成和应用 |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2864082B1 (fr) | 2003-12-22 | 2006-03-10 | Synt Em | Nouveau derive de la morphine-6-glucuronide, composition pharmaceutique le contenant et son utilisation pour le traitement de la douleur |
FR2907121B1 (fr) * | 2006-10-12 | 2012-05-04 | Neorphys | Nouveaux derives morphiniques |
UY32099A (es) | 2008-09-11 | 2010-04-30 | Enanta Pharm Inc | Inhibidores macrocíclicos de serina proteasas de hepatitis c |
JP2014502620A (ja) | 2010-12-30 | 2014-02-03 | エナンタ ファーマシューティカルズ インコーポレイテッド | 大環状c型肝炎セリンプロテアーゼ阻害剤 |
CN103380132B (zh) | 2010-12-30 | 2016-08-31 | 益安药业 | 菲啶大环丙型肝炎丝氨酸蛋白酶抑制剂 |
US10201584B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
WO2015103490A1 (fr) | 2014-01-03 | 2015-07-09 | Abbvie, Inc. | Formes galéniques antivirales solides |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999007728A2 (fr) * | 1997-08-12 | 1999-02-18 | Synt:Em (S.A.) | Peptides lineaires derives de peptides antibiotiques, leur preparation et leur utilisation pour vectoriser des substances actives |
WO2000032237A1 (fr) * | 1998-11-30 | 2000-06-08 | Synt:Em (S.A.) | Composition pharmaceutique comprenant un agent anti-cancereux et au moins un peptide |
WO2000032236A1 (fr) * | 1998-11-30 | 2000-06-08 | Synt:Em (S.A.) | Vecteurs peptidiques de substances a travers la barriere hemato-encephalique |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6258774B1 (en) * | 1998-03-19 | 2001-07-10 | University Of Medicine And Dentistry Of New Jersey | Carrier for in vivo delivery of a therapeutic agent |
-
2001
- 2001-02-23 FR FR0102504A patent/FR2821272B1/fr not_active Expired - Fee Related
-
2002
- 2002-02-22 AU AU2002238687A patent/AU2002238687B2/en not_active Ceased
- 2002-02-22 CA CA002438824A patent/CA2438824A1/fr not_active Abandoned
- 2002-02-22 WO PCT/FR2002/000667 patent/WO2002067994A2/fr active IP Right Grant
- 2002-02-22 JP JP2002567359A patent/JP2004529886A/ja active Pending
- 2002-02-22 US US10/468,412 patent/US20040248806A1/en not_active Abandoned
- 2002-02-22 ES ES02704883T patent/ES2305204T3/es not_active Expired - Lifetime
- 2002-02-22 DE DE60226319T patent/DE60226319T2/de not_active Expired - Fee Related
- 2002-02-22 AT AT02704883T patent/ATE393633T1/de not_active IP Right Cessation
- 2002-02-22 EP EP02704883A patent/EP1397161B1/fr not_active Expired - Lifetime
- 2002-02-22 IL IL15721402A patent/IL157214A0/xx unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999007728A2 (fr) * | 1997-08-12 | 1999-02-18 | Synt:Em (S.A.) | Peptides lineaires derives de peptides antibiotiques, leur preparation et leur utilisation pour vectoriser des substances actives |
WO2000032237A1 (fr) * | 1998-11-30 | 2000-06-08 | Synt:Em (S.A.) | Composition pharmaceutique comprenant un agent anti-cancereux et au moins un peptide |
WO2000032236A1 (fr) * | 1998-11-30 | 2000-06-08 | Synt:Em (S.A.) | Vecteurs peptidiques de substances a travers la barriere hemato-encephalique |
Non-Patent Citations (7)
Title |
---|
DEROSSI D ET AL: "TROJAN PEPTIDES: THE PENETRATIN SYSTEM FOR INTRACELLULAR DELIVERY" TRENDS IN CELL BIOLOGY, ELSEVIER SCIENCE LTD, XX, vol. 8, février 1998 (1998-02), pages 84-87, XP002940006 ISSN: 0962-8924 * |
LOETSCH JOERN ET AL: "Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers." CLINICAL PHARMACOLOGY & THERAPEUTICS, vol. 60, no. 3, 1996, pages 316-325, XP001041619 ISSN: 0009-9236 * |
MIGNAT CHRISTIAN ET AL: "Plasma and Cerebrospinal Fluid Concentrations of Morphine and Morphine Glucuronides in Rabbits Receiving Single and Repeated doses of Morphine." JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 47, no. 2, 1995, pages 171-175, XP001041620 ISSN: 0022-3573 * |
NEGRI L ET AL: "Production of antinociception by peripheral administration of [Lys7]dermorphin, a naturally occurring peptide with high affinity for mu-opioid receptors." BRITISH JOURNAL OF PHARMACOLOGY, JAN 1995, VOL. 114, NO. 1, PAGE(S) 57-66, XP001041563 * |
ROQUES BP: "Peptidomimetics as receptors agonists or peptidase inhibitors: a structural approach in the field of enkephalins, ANP and CCK." BIOPOLYMERS, APR 1992, VOL. 32, NO. 4, PAGE(S) 407-10, XP001041605 * |
ROUSSELLE C ET AL: "NEW ADVANCES IN THE TRANSPORT OF DOXORUBICIN THROUGH THE BLOOD-BRAIN BARRIER BY A PEPTIDE VECTOR-MEDIATED STRATEGY" MOLECULAR PHARMACOLOGY, vol. 57, no. 4, avril 2000 (2000-04), pages 679-686, XP001004535 ISSN: 0026-895X * |
ROUSSELLE CHRISTOPHE ET AL: "Enhanced delivery of doxorubicin into the brain via a peptide-vector-mediated strategy: Saturation kinetics and specificity." JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 296, no. 1, janvier 2001 (2001-01), pages 124-131, XP001041627 ISSN: 0022-3565 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012076824A1 (fr) | 2010-12-10 | 2012-06-14 | Institut Gustave Roussy | Nouveaux derives d'oxazaphosphorines pre-activees, utilisation et methode de preparation |
CN103012596A (zh) * | 2012-12-28 | 2013-04-03 | 兰州大学 | 具有血脑屏障通透性的内吗啡肽衍生肽及其合成和应用 |
CN103012596B (zh) * | 2012-12-28 | 2014-12-03 | 兰州大学 | 具有血脑屏障通透性的内吗啡肽衍生肽及其合成和应用 |
Also Published As
Publication number | Publication date |
---|---|
FR2821272A1 (fr) | 2002-08-30 |
US20040248806A1 (en) | 2004-12-09 |
DE60226319D1 (de) | 2008-06-12 |
DE60226319T2 (de) | 2009-07-09 |
JP2004529886A (ja) | 2004-09-30 |
ATE393633T1 (de) | 2008-05-15 |
FR2821272B1 (fr) | 2004-12-17 |
EP1397161B1 (fr) | 2008-04-30 |
EP1397161A2 (fr) | 2004-03-17 |
IL157214A0 (en) | 2004-02-19 |
CA2438824A1 (fr) | 2002-09-06 |
ES2305204T3 (es) | 2008-11-01 |
AU2002238687B2 (en) | 2006-10-05 |
WO2002067994A3 (fr) | 2003-12-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1135168B1 (fr) | Vecteurs peptidiques de substances a travers la barriere hemato-encephalique | |
KR101170840B1 (ko) | 남용 방지성 암페타민 화합물 | |
US8440623B2 (en) | Polymer stabilized neuropeptides | |
ES2673219T3 (es) | Composición para la entrega transdérmica de agentes activos | |
NL8403618A (nl) | Werkwijze voor het percutaan toedienen van metoclopramide. | |
WO2011119953A1 (fr) | Procédés et compositions pour la perte de poids | |
WO2002067994A2 (fr) | Composes constitues d'une molecule analgesique liee a un vecteur | |
CN100358515C (zh) | 神经退行性及心血管疾病之治疗药物 | |
Salameh et al. | Prodrugs targeting the central nervous system (CNS) | |
CN111278452B (zh) | 以阿林肽为活性成分的尿毒症药物 | |
US7671029B2 (en) | Compositions and methods for enhanced pharmacological activity of compositions comprising peptide drug substances | |
FR2787029A1 (fr) | Utilisation dans une composition pharmaceutique pour l'administration par voie nasale de vitamine b12 pour la delivrance d'agents actifs au systeme nerveux central | |
WO2003105907A2 (fr) | Compositions pour le transport de molecules therapeutiques dans les poumons et leur utilisation pour le traitement des cancers du poumon et des maladies pulmonaires | |
Pardridge | Blood-Brain Barrier Peptide Transport und Peptide Drug | |
KR20000013593A (ko) | 피록시캄의 경피투여 조성물 | |
JP2005505492A (ja) | ポリペプチド・ドラッグ物質および他の難吸収性活性成分を含む組成物の経口および非経口投与後の薬理活性を強化させる組成物および方法 | |
EP2678024A1 (fr) | Compositions pharmaceutiques administrables par voie cutanée et destinées au traitement local de la dermatite atopique canine | |
AU2012206979A1 (en) | Opioid peptide esters and methods of use | |
WO2012175642A1 (fr) | Prodrogues peptidiques |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE 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 NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 157214 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002238687 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2438824 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002704883 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002567359 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10468412 Country of ref document: US |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 2002704883 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 2002704883 Country of ref document: EP |