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WO2002064167A2 - Agents actifs au niveau biologique - Google Patents

Agents actifs au niveau biologique Download PDF

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Publication number
WO2002064167A2
WO2002064167A2 PCT/GB2002/000575 GB0200575W WO02064167A2 WO 2002064167 A2 WO2002064167 A2 WO 2002064167A2 GB 0200575 W GB0200575 W GB 0200575W WO 02064167 A2 WO02064167 A2 WO 02064167A2
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WO
WIPO (PCT)
Prior art keywords
prostaglandin
proteinaceous
complex
agent
chemotactic
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PCT/GB2002/000575
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English (en)
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WO2002064167A3 (fr
Inventor
Rodney William Kelly
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Medical Research Council
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Publication date
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Publication of WO2002064167A2 publication Critical patent/WO2002064167A2/fr
Publication of WO2002064167A3 publication Critical patent/WO2002064167A3/fr

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    • 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
    • A61K47/54—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 an organic compound
    • A61K47/55—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 an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds

Definitions

  • the present invention relates to biologically active agents and, in particular, cervical ripening agents.
  • the cervix acts as a barrier to the ingress of infection as well as a rigid barrier at the neck of the womb.
  • This organ has relatively little muscle with the majority of the strength of the organ derived from collagen.
  • the cervix has to soften and stretch (eface) to allow the baby's head to pass through, if this can be achieved with little uterine contractility then subsequent contractions can deliver the baby with minimal trauma for mother and child.
  • Biologically active agents such as prostaglandins and chemokines are delivered to the cervix or vaginal fornix to aid cervical ripening for a number of reasons including (a) the induction of labour, (b) to soften an unfavourable cervix during labour, (c) to assist medical termination of pregnancy, (d) to assist uterine surgery and (e) to accelerate normal parturition and to reduce the accompanying risks and discomforts.
  • prostaglandin gels used to ripen the cervix by administration to the vaginal fornix can stimulate the myometrium to contract excessively and, in extreme circumstances, an uterine rapture can occur (Maymon et al (1991) Am J. Obstet. Gynecol. 165, 368-270).
  • the present inventor has now found that it is possible to make complexes between proteinaceous agents which are chemotactic for monocytes and/or neutrophils, for example those used to induce cervical ripening, and prostaglandins, some of which are also used to induce cervical ripening.
  • the complexes allow for stoichiometric amounts of prostaglandin to be intimately associated with the proteinaceous chemotactic agent and this has the advantage that reasonably controlled ratios of prostaglandins and proteinaceous chemotactic agent can be formulated in the same complex. Furthermore, the presence of the prostaglandin in the complex with the proteinaceous agent provides lipophilic nature to the proteinaceous agent and may allow for better diffusion through lipid membranes.
  • a first aspect of the invention provides a complex comprising a proteinaceous agent which is chemotactic for monocytes and/or neutrophils and a prostaglandin.
  • proteinaceous agent which is chemotactic for monocytes and/or neutrophils we include any protein or polypeptide or oligopeptide or peptide which is able to encourage monocytes and/or neutrophils into a tissue where the agent is present.
  • the agent is a proteinaceous cervical ripening agent.
  • proteinaceous cervical ripening agent we include any protein or polypeptide or oligopeptide or peptide which has the ability to induce ripening of the cervix when suitably administered to the female.
  • the proteinaceous agent is one which contains peptide bonds and has amino acid side chain residues.
  • the proteinaceous agent which is chemotactic for monocytes and/or neutrophils is one with a pi value of 7.5 or above, preferably 8 or above and more preferably 8.5 or above.
  • >5% of the amino acid residues are ly sines.
  • the prostaglandin may be any suitable prostaglandin.
  • prostaglandin is included prostaglandin receptor agonists and prostacyclin, provided that they are able to form a complex with the proteinaceous agent which is chemotactic for monocytes and/or neutrophils as defined herein.
  • the prostaglandin agonist need not be a prostanoid.
  • the prostaglandin or agonist is one which binds to the EP2 or EP4 receptor. It is preferred that the prostaglandin is one which is able to induce cervical ripening when suitably administered to the female.
  • the prostaglandin is a PGE or PGI such as PGE 2 or a synthetic analogue thereof with a free acid under appropriate pH. Synthetic analogues include those modified at position 15 by the addition of a methyl group. It is preferred if the prostaglandin is not a PGF or agonist thereof.
  • prostaglandin examples include Butaprost (an EP2 receptor agonist) and 11-deoxy PGE 1 (an EP4 receptor agonist).
  • prostaglandin includes naturally- occurring prostaglandins as well as synthetic prostaglandin analogues.
  • the prostaglandin is one which has an acidic group such as a carboxylate group.
  • the acidic group is one which, under low pH conditions, gives a free acid.
  • the free acid form is used (ie without the alcohol esterified to the acid). Such free acid forms are also prostaglandins within the meaning of the invention.
  • Suitable prostaglandins or agonists thereof include, dinoprostone (sold as Propess by Ferring in Europe and Forest in the USA; sold as Prostin E2 by Pharmacia), the free acid form of gemeprost (sold by Farillon), the free acid form of misoprostol (which is sold as Cytotec by Searle and Pharmacia), alprostadil (which is sold as Caverject by Pharmacia and Niridal by Schwarz and MUSE by AstraZeneca) and limaprost.
  • Misoprostol is a PGE analogue which has EP2 and EP3 agonist effects. Its chemical structure if ( ⁇ ) methyl l l , 16-dihydroxy-16-methyl-9-oxoprost- 13-enoate. The free acid form (ie ( ⁇ l l ⁇ , 16-dihydroxy-16-methyl-9- oxoprost-13-enoic acid) is preferred.
  • Non-prostanoid compound which acts as a prostaglandin agonist is AH23848, an EP4 receptor agonist.
  • EP2 agonists which may be useful in the practice of the invention include 19-hydroxy PGE 2 , 19-hydroxy PGE1 and AH13205.
  • Prostaglandins including PGE 2
  • PGE 2 are commercially available, for example from Pharmacia and Upjohn as Prostin E2.
  • Particularly preferred proteinaceous cervical ripening agents include monocyte chemotactic peptide-1 (MCP-1) or interleukin-8 (IL-8) or variants thereof which retain the ability to induce cervical ripening.
  • MCP-1 monocyte chemotactic peptide-1
  • IL-8 interleukin-8
  • Human MCP-1 has a pi of about 9.7
  • mouse MCP-1 has a higher pi
  • Human IL-8 has a pi of about 8.6.
  • a “variant” refers to a protein wherein at one or more positions there have been amino acid insertions, deletions, or substitutions, either conservative or non-conservative, provided that such changes result in a protein whose basic properties, for example chemotactic activity against for monocytes and/or neutrophils or cervical ripening-inducing activity, thermostability, activity in a certain pH-range (pH-stability) have not significantly been changed.
  • “Significantly” in this context means that one skilled in the art would say that the properties of the variant may still be different but would not be unobvious over the ones of the original protein.
  • substitutions is intended combinations such as Gly, Ala; Nal, He, Leu; Asp, Glu; Asn, Gin; Ser, Thr; Lys, Arg; and Phe, Tyr.
  • variants may be made using the methods of protein engineering and site- directed mutagenesis.
  • the "variants” also includes the variants, functional derivatives and chemical derivatives of MCP-1 as described in US Patent No 5,908,829, incorporated herein by reference, specifically those listed in columns 2 and 3.
  • the “variants” includes the functional derivatives of IL-8 described in US Patent No 5,624,670, incorporated herein by reference, specifically those listed in columns 3 and 4.
  • the proteinaceous chemotactic agent such as cervical ripening agent, may be of any mammalian species, but it is preferred that it is of the species to which it is administered. Thus, for example, it is preferred if any proteinaceous chemotactic agent administered to a human female is human proteinaceous chemotactic agent.
  • the proteinaceous chemotactic agent of any particular species may be chemically synthesised or produced by recombinant means.
  • human IL-8 and human MCP-1 we include IL-8 and MCP-1 which has the same amino acid sequence as native human IL-8 or MCP-1 but which has been made synthetically.
  • IL-8 and MCP-1 and variants thereof may be made by chemical synthetic means and by recombinant DNA techniques as is well known in the art.
  • a complex we include that the proteinaceous chemotactic agent and the prostaglandin are, preferably, at least bound ionically.
  • the complex is between the proteinaceous chemotactic agent and the prostaglandin.
  • the term complex means that there is a close chemical or physical association between the proteinaceous chemotactic agent and the prostaglandin, and that there is intimate contact is at a molecular level.
  • the complex includes conjugates (including salts) of the proteinaceous chemotactic agent and the prostaglandin.
  • the complex consists of the proteinaceous chemotactic agent and the prostaglandin.
  • the complex exists as a single entity at a physiological salt concentration and pH; thus, typically, when at a physiological salt concentration and pH the complex behaves as though it has a higher molecular mass than the proteinaceous agent alone when passed through a size exclusion column.
  • the complex may have more than one type of proteinaceous chemotactic agent and it may have more than one type of prostaglandin.
  • the complex has one type of proteinaceous chemotactic agent and one type of prostaglandin.
  • Preferred complexes are those which contain IL-8 or MCP-1 and PGE 2 .
  • the complex is a conjugate or salt of IL-8 and PGE 2 or is a conjugate or salt of MCP-1 and PGE 2 .
  • the molar ratio (stoichiometry) of proteinaceous chemotactic agent and prostaglandin may vary.
  • the molar ratio of prostaglandin to proteinaceous chemotactic agent is between 1:1 and 20:1, preferably between 1:1 and 12:1 or 1:1 and 10:1 and typically about 6:1. It will be appreciated that the ratios given are the average within the overall complex and that a range of individual proteinaceous chemotactic agent-prostaglandin molecules with varying ratio may exist within the overall complex.
  • the prostaglandin residues interact with positively charged residues in the proteinaceous chemotactic agent, such as lysine residues, arginine residues and the N-terminal amino group.
  • lysine residues such as lysine residues, arginine residues and the N-terminal amino group.
  • MCP-1 proteinaceous chemotactic agent in MCP-1
  • a ratio of 8:1 of prostaglandin:MCP-l may represent nearly all lysines occupied with prostaglandin. Higher ratios may represent participation of the N-terminal amino group and then the arginine residues, of which there are 4.
  • Human MCP-1 has nine lysine residues.
  • a second aspect of the invention provides a pharmaceutical composition comprising a complex of the first aspect of the invention and a pharmaceutically acceptable carrier.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the compound of the invention and not deleterious to the recipients thereof.
  • the carriers will be water or saline which will be sterile and pyrogen free.
  • compositions or formulations are ones wherein the complex retains its integrity.
  • the composition or formulation is one where the solvent is a non-aqueous solvent or, if an aqueous solvent, it is at low ionic strength and about neutral pH.
  • the formulation may be a gel, cream and the like or an aqueous or non-aqueous solution.
  • the complex may be incorporated into liposomes wherein the integrity of the complex is maintained within the internal milieu of the liposome.
  • the solution within the liposome is a concentrated solution of the complex in water.
  • a third aspect of the invention provides a complex of the first aspect of the invention for use in medicine, that is to say packaged and presented for use in medicine.
  • the complex may be used in human or veterinary medicine; preferably it is used in human medicine.
  • the packaging and presentation typically includes details of the dose and method of administration.
  • a fourth aspect of the invention provides a method of inducing ripening of the cervix in a female in need of cervical ripening, the method comprising administering to the female a complex according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention.
  • the complex or pharmaceutical composition of the invention may be administered to induce or aid cervical ripening for a number of reasons including (a) the induction of labour, (b) to soften an unfavourable cervix during labour, (c) to assist medical termination of pregnancy, (d) to assist uterine surgery and (e) to accelerate normal parturition and to reduce accompanying risks and discomforts.
  • the method can be used for the induction of labour at term (ie time of ordinary birth), but it may also be used for the induction of pre-term labour, and induction of labour in connection with a pathological pregnancy, or in connection with intrauterine fetal death. It may be used to ripen dysfunctional cervices, ie when dilation stops before completion.
  • the method may also be used for preliminary cervical ripening prior to induction of abortion (eg in the first or second trimester abortion), and for induction of cervical ripening of a non-pregnant or pregnant female to assist surgical or diagnostic procedure such as D&C. Cervical ripening may also be induced in the female for the purposes of treatment by in vitro fertilisation.
  • the dose of the complex or pharmaceutical formulation thereof administered to the female is a suitable amount to give the desirable effect.
  • the dose of complex is one which contains between 0.1 and 500 ⁇ g of the proteinaceous chemotactic agent and/or between 0.01 and 50 ⁇ g of prostaglandin.
  • the dose of complex is one which contains between 0.1 and 100 ⁇ g of proteinaceous chemotactic agent and/or between 0.01 and 10 ⁇ g prostaglandin.
  • the complex or pharmaceutical composition thereof is administered to the cervix by any suitable means.
  • the proteinaceous chemotactic agent is delivered using a needleless injector.
  • the delivery may be directly to the cervix or may be via the vaginal fornix, which is a fold in the vagina where the cervix is located.
  • the end of the needleless injector may occupy the vaginal fornix and delivery may be at or through the vaginal fornix into the cervix.
  • injections will aim at the cervix but may be aimed from different angles.
  • the site of injection is "off-centre" into the cervical lumen or into any part of the externally presenting area of the cervix.
  • the needleless injector may be any suitable man-made needleless injector and, conveniently, may be a liquid injector or a powder injector as described above.
  • suitable needleless liquid injectors include those manufactured by Weston Medical Limited, Peterborough, UK and those described in WO 93/03779, WO 95/03844, WO 96/28202, WO 97/37705 and WO 00/10630, all of which are incorporated herein by reference.
  • Suitable needleless powder injectors include those manufactured by Powderject Research Limited, Oxford, UK and those described in WO 94/24263, WO 96/12513, WO 96/20022, WO 96/25190, WO 97/34652, WO 98/13470, WO 99/01168, WO 99/01169, WO 00/54827 and WO 00/62846, all of which are incorporated herein by reference.
  • the biologically active agent may be loaded into the injector by means known in the art.
  • the needleless injector may be adapted for this purpose, and the geometry of the device arranged such that there is easy passage through the vagina but that the exit from the injector (ie outlet orifice) is angled such that the biologically active agent is delivered efficiently to the desired site on the cervix.
  • the type of injectors described in WO 96/25190 may be particularly suitable; however, rather than the internal angle of approximately 90° shown in Figures 1 to 4 of WO 96/25190, it may be more appropriate if the internal angle of the head to the shaft is between 20° to 90°; preferably between 35° and 85°, for example 65°.
  • the arrangement of the head containing the outlet orifice shown in Figure 16B of WO 00/54827 may also be particularly suited for use in the present invention.
  • the arrangement shown in Figure 5 of WO 00/62846, where the exit plane is not perpendicular to the longitudinal axis of the nozzle, but angled, may be particularly suited for use with the invention.
  • Particles which are suitable for use with a powder injector may be prepared by coating a suitable particle with the complex of the invention by dissolving the complex in a suitable solvent (such as hexafluoroisopropanol) and evaporating in the presence of the particle.
  • a suitable solvent such as hexafluoroisopropanol
  • the female to which the complex or pharmaceutical composition thereof is administered is preferably a human female although the female may be any mammal such as a cat, dog, horse, cow, sheep, horse, pig and so on.
  • the method may be especially useful for sheep where in vitro fertilization and embryo transfer procedures currently involve laparoscopy which brings up ethical and animal husbandry considerations, the problem being that the cervix is impenetrable. It is believed that a diffuse injection of cervical ripening agent would give a very rapid response, allowing a wider use of in vitro fertilization.
  • a fifth aspect of the invention provides the use of a complex of the first aspect of the invention in the manufacture of a medicament for inducing ripening of the cervix in a female in need of cervical ripening.
  • the invention also provides a method of making a complex comprising a proteinaceous agent which is chemotactic for monocytes and/or neutrophils agent and a prostaglandin, the method comprising the steps of admixing the proteinaceous chemotactic agent and the prostaglandin under conditions in which they come into intimate contact and form a complex.
  • the method may be any suitable method and is typically one which leads to a complex wherein there is a close chemical or physical association between the proteinaceous chemotactic agent and the prostaglandin and that the intimate contact is at a molecular level.
  • the method includes the production of conjugates (including salts) of the proteinaceous chemotactic agent and the prostaglandin.
  • the steps include (1) providing the prostaglandin under acidic conditions so that it is substantially in the free acid form; (2) providing the proteinaceous chemotactic agent under basic conditions so that its amino groups are substantially in the free base form; and (3) admixing the prostaglandin from step (1) and the proteinaceous chemotactic agent from step (2) under conditions where the complex is formed.
  • >70% of the prostaglandin in step (1) is in the free acid form, preferably >75% or >80%.
  • >70% of the free amino groups are in the free base form, preferably >75% or >80%.
  • step (1) the prostaglandin is dissolved in a suitable water- miscible organic solvent such as ethanol, methanol, acetone and the like to which water is added and the pH adjusted to between 1 and 4, typically and preferably between pH3 and pH4.
  • the pH may be adjusted using any suitable strong acid such as HC1.
  • 50% to 95% of the prostaglandin may be in the free acid form.
  • step (2) the proteinaceous chemotactic agent is dissolved in a suitable solvent such as water or, for example, hexafluoroisopropanol, and the pH is adjusted to between 8 and 13, such as pH 10.5 or 13, using any suitable strong inorganic base such as potassium hydroxide or sodium hydroxide.
  • a suitable solvent such as water or, for example, hexafluoroisopropanol
  • the pH is adjusted to between 8 and 13, such as pH 10.5 or 13, using any suitable strong inorganic base such as potassium hydroxide or sodium hydroxide.
  • the proteinaceous chemotactic agent has its amino acid groups in the free base form, preferably around 80%.
  • step (3) typically, the prostaglandin from step (1) is admixed with the proteinaceous chemotactic agent from step (2) so that a complex is formed.
  • the prostaglandin is present in molar excess to the proteinaceous chemotactic agent and any prostaglandin which does not form part of the complex may be removed by any suitable means such as by extraction with a suitable solvent such as diethyl ether or mixtures of ethylacetate and hexane.
  • the complex may be purified using techniques known in the art such as size separation chromatography and HPLC.
  • the prostaglandin in step (1) may have been purified under appropriate conditions.
  • the prostaglandin may have been passed through a hydrophobic affinity column, such as a C18 column, primed with a suitable solvent such as ethanol.
  • the free acid form of the prostaglandin binds to the hydrophobic column and unbound material is washed away with water.
  • the proteinaceous chemotactic agent in step (2) may have been purified under appropriate conditions.
  • the proteinaceous chemotactic agent may have been passed through a size exclusion chromatography column, at the relevant pH to retain the free amine in the agent, such as a Sephadex G25 column. Elution of the high molecular fraction gives the free amine form of the proteinaceous chemotactic agent.
  • the proteinaceous chemotactic agent may also have been purified by HPLC.
  • the molar ratios of prostaglandin to proteinaceous chemotactic agent used in the synthesis may be varied according to the desired ratio in the resultant complex. Typically, a ratio of between 50:1 to 2:1 is used. Other ratios may be used such as 40:1, 30:1, 20:1, 10:1, 5:1, 4:1, 3:1 and 1 :1.
  • the molar ratio of the final complex may be controlled by regulating the proportion of free base in the proteinaceous chemotactic agent.
  • the proteinaceous chemotactic agent and the prostaglandin may be admixed in any suitable solvent, including hexafluoroisopropanol.
  • the complex may be separated from unreacted or unbound components by size separation chromatography or HPLC or other methods known in the art.
  • the proteinaceous cervical ripening agent is MCP-1 or IL- 8. It is also preferred that the prostaglandin is PGE 2 .
  • the complex of the first aspect of the invention includes a complex comprising a proteinaceous chemotactic agent, such as a proteinaceous cervical ripening agent, and a prostaglandin obtainable by the above- mentioned synthetic methods.
  • a proteinaceous chemotactic agent such as a proteinaceous cervical ripening agent
  • a prostaglandin obtainable by the above- mentioned synthetic methods.
  • Such a complex may be used in the medical methods and uses of the invention, and in the pharmaceutical formulations and in the kits of parts.
  • the invention further provides a kit of parts comprising (a) a complex according to the first aspect of the invention and (b) a solvent for the complex.
  • the complex and the solvent are sterile and pyrogen free.
  • Suitable solvents include non-aqueous solvents and aqueous solvents wherein the ionic strength and pH are ones which retain the integrity of the complex.
  • Suitable aqueous solvents are those with physiological pH and physiological salt concentration or lower salt concentration.
  • a suitable aqueous solvent has around 9 g/1 NaCl and pH -7.2.
  • the solvent may be water.
  • the kit may be used to prepare a pharmaceutical formulation of the prostaglandin and the proteinaceous chemotactic agent.
  • a further kit of parts of the invention comprises (a) a complex according to the first aspect of the invention or a pharmaceutical composition of the second aspect of the invention and (b) means to deliver the proteinaceous chemotactic agent/prostaglandin to the cervix or vaginal fornix.
  • Such means include needleless injectors as described above.
  • the complex may also be administered in combination with a dispersion agent or an agent which allows for or increases transdermal or transmucosal transfer or penetration, such as dimethyl sulphoxide (DMSO) and the like.
  • DMSO dimethyl sulphoxide
  • DMSO is a non-ionic permeability enhancer.
  • solvents are suitably those that maintain the integrity of the complex.
  • the complex is a complex between a proteinaceous cervical ripening agent, such as MCP-1 or IL-8, and prostaglandin.
  • a proteinaceous cervical ripening agent such as MCP-1 or IL-8
  • prostaglandin a proteinaceous cervical ripening agent
  • MCP-1 (Albachem, Edinburgh) was dissolved in 100 ⁇ l buffered saline and 40 ⁇ l 1.0N NaOH was added to bring the pH to 13. This was added to the top of a Sephadex G25 column (PD10) equilibrated with water and a further 2.36 ml of water was added. MCP-1 was then eluted with 3.5 ml water and 100 ⁇ l of 10 mg/ml PDE in ethanol was added. Salt was freeze dried and the residue was dissolved in 500 ⁇ l water and 200 ⁇ l ethanol. This was added to a Sephadex G25 column equilibrated with water and a further 1.8 ml of water was added.
  • MCP-1 was then eluted with 3.0 ml water.
  • the PGE content of the eluate was determined by ELISA (Amersham). 25 ⁇ l of the product was added to 1 ml of 0.5% Acetic acid in water to cleave ionic bonds and this was neutralised with 1 ml assay buffer from the Amersham kit. This diluted sample was further diluted 176 fold and the assayed concentration was 3.04 ng/ml. This gives a PGE equivalent of 172 ⁇ g in the eluate, equivalent to 10.6 PGE residues per molecule of MCP-1.1/4 of the above eluate in 1 ml water was separated on G25 as above in water. The number of residues of PGE per molecule of MCP-1 was found to be 8.7.
  • the stability of the conjugate in water will allow its use in an emulsion, either water in oil or oil in water.
  • a non-ionic detergent is indicated in such an application.
  • the emulsion can be applied to the cervix to elicit ripening.
  • the complex in the emulsion can be mixed with a non-ionic permeability enhancer such as dimethyl sulphoxide (DMSO).
  • DMSO dimethyl sulphoxide
  • Example 6 Administration of PGE-IL-8 complex to a human female using a needleless syringe
  • the patient is a human female in need of cervical ripening 200 ⁇ l of a solution of IL-8-PGE complex (100 ⁇ g/ml) prepared as in Example 2 is loaded into a helium-loaded injection device and the end of the device is placed either in the vaginal fornix against the cervical mass or against the exposed cervix.
  • the injector is fired at one or two locations.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention concerne un complexe comprenant un agent protéique qui est chimiotactique pour des monocytes et/ou des neutrophiles, et une prostaglandine. L'invention concerne également un procédé de fabrication d'un complexe comprenant un agent protéique qui est chimiotactique pour des monocytes et/ou des neutrophiles, et une prostaglandine. Ce procédé comprend l'étape consistant à mélanger l'agent protéique de maturation du col et la prostaglandine dans des conditions dans lesquelles ils entrent en contact intime. De préférence, l'agent protéique de maturation du col est MCP-1 ou IL-8 ou un dérivé de ceux-ci. De préférence, la prostaglandine est PGE2. Ce complexe ou des compositions pharmaceutiques de celui-ci sont utiles pour la maturation du col utérin chez une femme qui en a besoin.
PCT/GB2002/000575 2001-02-10 2002-02-11 Agents actifs au niveau biologique WO2002064167A2 (fr)

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GBGB0103354.7A GB0103354D0 (en) 2001-02-10 2001-02-10 Biologically active agents
GB0103354.7 2001-02-10

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016111992A1 (fr) 2015-01-05 2016-07-14 Cornell University Compositions et procédés utilisant de l'il-8 pour améliorer la production de lait et la santé reproductive chez les mammifères
US11464831B2 (en) 2015-01-05 2022-10-11 Cornell University Compositions and methods using IL-8 for improving health of mammals

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL92937A0 (en) * 1989-01-31 1990-09-17 Us Health Human derived monocyte attracting protein,pharmaceutical compositions comprising it and dna encoding it
GB9124775D0 (en) * 1991-11-21 1992-01-15 Medical Res Council Cervical ripening
GB9406463D0 (en) * 1994-03-31 1994-05-25 Medical Res Council Cervical ripening

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016111992A1 (fr) 2015-01-05 2016-07-14 Cornell University Compositions et procédés utilisant de l'il-8 pour améliorer la production de lait et la santé reproductive chez les mammifères
AU2016205456B2 (en) * 2015-01-05 2021-10-07 Cornell University Compositions and methods using IL-8 to improve milk production and reproductive health in mammals
US11406689B2 (en) 2015-01-05 2022-08-09 Cornell University Compositions and methods using IL-8 to improve milk production and reproductive health in mammals
US11464831B2 (en) 2015-01-05 2022-10-11 Cornell University Compositions and methods using IL-8 for improving health of mammals

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GB0103354D0 (en) 2001-03-28

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