EP2908840A1 - Nouvelle utilisation d'une composition comprenant de l'oxytocine - Google Patents

Nouvelle utilisation d'une composition comprenant de l'oxytocine

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Publication number
EP2908840A1
EP2908840A1 EP13777020.2A EP13777020A EP2908840A1 EP 2908840 A1 EP2908840 A1 EP 2908840A1 EP 13777020 A EP13777020 A EP 13777020A EP 2908840 A1 EP2908840 A1 EP 2908840A1
Authority
EP
European Patent Office
Prior art keywords
composition
oxytocin
use according
administered
variant
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP13777020.2A
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German (de)
English (en)
Inventor
Kerstin Uvnäs-Moberg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Peptonic Medical AB
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Peptonic Medical AB
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Filing date
Publication date
Application filed by Peptonic Medical AB filed Critical Peptonic Medical AB
Publication of EP2908840A1 publication Critical patent/EP2908840A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina

Definitions

  • the present document relates to the field of pharmaceuticals. More specifically the present document relates to new uses of pharmaceutical compositions comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof.
  • Oxytocin was one of the first peptide hormones to be isolated and sequenced. It is a nonapeptide with two cysteine residues that form a disulfide bridge between positions 1 and 6 and corresponds to the formula
  • Oxytocin SEQ ID NO: 1
  • oxytocin exerts a wide spectrum of effects within the central nervous system, CNS. It has been suggested that oxytocin participates in the control of memory and learning processes and of various types of behaviour such as feeding, locomotion, as well as maternal and sexual behaviour. Oxytocin is also suggested to participate in the control of cardiovascular functions, thermoregulation, and pain threshold and fluid balance. There is also evidence that oxytocin is involved in the control of various immunological processes. These findings have been confirmed in studies by administration of oxytocin to male subjects by the use of an oxytocin containing nasal spray.
  • Oxytocin injections cause a lowering of blood pressure and increased weight gain with long lasting effects after repetitive administration.
  • oxytocin plays an important role in the interaction between mother and progeny in mammals.
  • Oxytocin may also be used as prophylactics in young human beings e.g. already in new born babies or young children to prevent the development of diseases later on in life, which diseases are dependent on stress conditions during the fetal life. Such conditions may be heart/vessel diseases such as stroke, heart infarction, hypertension, and diabetes type 2.
  • oxytocin is produced in the paraventricular nucleus, PVN, and the supraoptic nucleus, SON, of the hypothalamus.
  • the magnocellular oxytocinergic neurones of the SON and PVN send axons to the posterior pituitary from which oxytocin is released into the circulation. Parvocellular oxytocinergic neurones that originate in the PVN project into multiple areas within CNS. The oxytocin-producing cells are innervated by cholinergic, catecholaminergic, serotonergic, dopaminergic as well as peptidergic neurones.
  • oxytocin in different tissues outside the brain, such as the uterus, ovaries, testis, thymus, adrenal medulla and pancreas has been demonstrated and oxytocin is suggested to be produced in and to exert local effects in these organs.
  • oxytocin has been shown to have a positive effect on many medical conditions, such as wound healing, cancer in situ and cervicitis, inflammation etc., in the context of a local effect.
  • carbetocin has also been mentioned as a therapeutic as an oxytocin analogue.
  • carbetocin it is not appropriate to compare oxytocin and carbetocin when it comes to pharmacokinetics and the ability to cross natural membranes, as the half-life of oxytocin is about 30 min, while the half-life of carbetocin is about three times longer in addition to several structural differences. Therefore, the use of oxytocin is a challenge.
  • Jonas et al. (Breastfeeding medicine, 2009, Vol.4, No:2) described the effects of intrapartum oxytocin administration and epidural analgesia on the concentration of plasma oxytocin and prolactin in response to suckling during the second day postpartum.
  • oxytocin was administered intravenously and intramuscularly to investigate the effect on endogenous production of oxytocin in a dose-dependent manner.
  • the intravenous administration of oxytocin was shown to provide an inhibiting effect on the endogenous oxytocin production. Accordingly, intravenously administrated oxytocin into the blood circulation in the doses of Jonas et al. can cause negative effects on the endogenous production of oxytocin.
  • a pharmaceutical composition comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof, for use in the treatment and/or prevention of a disorder which is responsive to modulation of the endogenous oxytocin production.
  • the treatment and/or prevention may further comprise the healing of a wound, and/or treating and/or preventing an atrophic condition in the skin or mucosa, such as treating and/or preventing vaginal atrophy.
  • the composition may be administered topically, such as epicutaneously, sublingually, buccally, vaginally and/or anally.
  • the composition may be administered once daily.
  • the present document is also directed to provide a method for the treatment and/or prevention of a disorder which is responsive to modulation of the endogenous oxytocin production in a subject comprising administrating a therapeutically effective amount of a composition comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof to said subject in need thereof.
  • the composition in such a method may be administered topically, such as epicutaneously, sublingually, buccally, vaginally and/or anally.
  • the composition may be administered once daily.
  • Such a method may further comprise the healing of a wound, and/or treating and/or preventing an atrophic condition in the skin or mucosa, such as treating and/or preventing vaginal atrophy.
  • the present document is also directed to the use of oxytocin and/or one or more fragment(s) and/or variant(s) thereof, in the manufacture of a composition for the treatment and/or prevention of a disorder which is responsive to modulation of the endogenous oxytocin production.
  • a use may further comprise the healing of a wound, and/or treating and/or preventing an atrophic condition in the skin or mucosa, such as treating and/or preventing vaginal atrophy.
  • the composition may be administered topically, such as epicutaneously, sublingually, buccally, vaginally and/or anally.
  • the composition may be administered once daily.
  • the disorder may be selected from the group consisting of: oxytocin deficiency, low social ability, anxiety, low energy level, stress sensitivity, mental climacteric symptoms, obsessive-compulsive disorder (OCD), borderline, attachment disorders, depression, autism and other forms of mental fragility or illness, pain, inflammation, an abusive disorder and/or disturbances of cardiovascular and gastrointestinal function of central origin, in particular an oxytocin deficiency.
  • OCD obsessive-compulsive disorder
  • the present document is also directed to a kit of parts comprising: a composition comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof, a container for said composition, and optionally instructions for use and/or means for applying said composition to a subject.
  • the oxytocin and/or one or more fragment(s) and/or variant(s) thereof in the composition may be administered in a dose of about 10-10 000 IU.
  • Exemplary doses are about 100-6 000 IU, about 1 000-6 000 IU or about 2 000-4 000 IU, such a dose being particularly suitable for epicutaneous, sublingual or buccal administration.
  • Other exemplary doses are about 10-600 IU, about 100-600 IU or about 200-400 IU, such doses being particularly suitable for vaginal or anal administration.
  • the composition may be a topical composition, such as an epicutaneous, sublingual, buccal, vaginal, or anal composition.
  • the composition may be administered once a day.
  • the one or more fragment(s) and/or variant(s) of oxytocin may correspond to;
  • X is selected from the group consisting of Cys and nothing
  • X 2 is selected from the group consisting of Tyr, Phe, and nothing;
  • X 3 is selected from the group consisting of lie, Val, Hoph, Phe, Cha, and nothing;
  • X4 is selected from the group consisting of Gin, Ser, Thr, Cit, Arg, and Daba;
  • X 5 is selected from the group consisting of Pro and nothing;
  • e is selected from the group consisting of lie, Leu, nothing, Val, Hos, Daba, Thr, Arg, and
  • X 7 is selected from the group consisting of Gly, nothing, and Ala;
  • X 8 is selected from the group consisting of Gly and nothing.
  • the one or more fragment(s) and/or variant(s) of oxytocin is/are selected from the group consisting of the peptides corresponding to SEQ ID NO:3-24.
  • the composition may have a pH from about 3 to about 5, such as from about 3 to about 4.
  • the composition may further comprise an epithelium penetration enhancer.
  • the epithelium penetration enhancer may e.g. be propylene glycol (PG), SDS, isopropyl myristate, ethanol, diethylene glycol ethyl ether and/or cineole.
  • the composition may further comprise at least one non-ionic cellulose ether, such as a non-ionic cellulosic ether selected from the group consisting of methyl cellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
  • HPMC hydroxypropylmethylcellulose
  • HEEC hydroxyethylethylcellulose
  • HEMC hydroxyethylmethyl cellulose
  • HPMC hydroxypropylmethylcellulose
  • composition may e.g. comprise oxytocin (SEQ ID NO:1 ) and
  • HPMC hydroxypropylmethylcellulose
  • An exemplary composition comprises:
  • oxytocin i) about 0.1 to 2 mg/ml, 0.17-1 mg/ml, 0.17-0.68 mg/ml, or 0.34-0.68 mg/ml oxytocin and/or one or more fragment(s) and/or variant(s) of oxytocin;
  • a non-ionic cellulose ether such as hydroxypropylmethylcellulose (HPMC);
  • composition having a pH of about 3-5, such as about 3-4.
  • Another exemplary composition comprises:
  • HPMC hydroxypropylmethylcellulose
  • composition having a pH of about 3-5, such as about 3-4.
  • the composition may further comprise an epithelium penetration enhancer, such as propylene glycol (PG), SDS, isopropyl myristate, ethanol, diethylene glycol ethyl ether and/or cineole.
  • PG propylene glycol
  • SDS isopropyl myristate
  • ethanol diethylene glycol ethyl ether
  • cineole such as ethanol, diethylene glycol ethyl ether and/or cineole.
  • oxytocin oxytocin peptide
  • oxytocin molecule this encompasses oxytocin (SEQ ID NO:1 ) and/or one or more fragment(s) and/or variant(s) thereof as defined herein according to the general formula of SEQ ID NO:2, or any other variant and/or fragment as mentioned herein, as well as homologues thereof, as well as pharmaceutically acceptable salts thereof.
  • a fragment, variant or homologue of an oxytocin molecule/peptide is envisaged it is to be understood that such a variant, fragment or homologue encompasses a biological activity comparable to the oxytocin molecule itself (SEQ ID NO:1 ).
  • SEQ ID NO:1 biological activity comparable to the oxytocin molecule itself
  • a substance has oxytocin activity by performing tests showing the activity of the actual substance, e.g. by performing a double blind cross-over randomised protocol as described in Example 1 of WO0178758.
  • a "variant" of oxytocin as referred to herein refers to a peptide which has been varied in its amino acid structure as compared to the oxytocin molecule in that some amino acid positions may have been altered by introducing other amino acids in such positions, such as natural or unnatural amino acids as exemplified herein, or it may have been extended by adding one or more natural or unnatural amino acid(s) to either ends of the peptide.
  • other structural variations may also have been performed to the present peptides as referred to herein, such as synthetic modifications. Said "variant” still maintains a biological activity similar to oxytocin and said oxytocin variant is also stabilized by being present in a topical composition according to the present disclosure.
  • a "fragment" of oxytocin is a peptide which comprises a part of the amino acid sequence of oxytocin, but wherein one or more amino acids may have been removed from one or both of the amino acid terminal end(s).
  • This term also refers to a fragment of a oxytocin variant as defined in SEQ ID NO:2, hence meaning that also encompassed by the present disclosure is any fragment of a peptide as presented by SEQ ID NO:2.
  • endogenous oxytocin production refers to the endogenous production in a subject, such as a mammal, e.g. a human, of oxytocin.
  • Oxytocin is produced in neurons in the supraoptical nucleus (SON) and the paraventricular nucleus (PVN), in the
  • Oxytocin originates from the magnocellular cells in PVN and SON. Oxytocin is also released into important regulatory sites of the the brain from axoncollaterals originating from the PVN and from oxytocinergic nerves originating from parvocellular nerons.
  • an “imbalance” in oxytocin production refers to a condition in a subject, such as a mammal, where the endogenous production of oxytocin is somewhat disturbed, low, insufficient and/or deficient in any manner as e.g. due to the presence of less efficient variants of oxytocin receptors so that the subject may experience a disharmony in life, e.g. depression, mental illness etc., and as further explained herein. Further, such a condition/imbalance may for example be evaluated as explained in the experimental section.
  • a “topical composition” as defined herein, refers to a pharmaceutical composition which is formulated to be administered topically, e.g.
  • topical composition also comprises a composition to be administered anally, then e.g. being referred to as an anal composition or a composition which is to be administered anally.
  • topical composition also comprises a composition to be administered epicutaneously, then e.g. being referred to as an epicutaneous composition or a composition which is to be administered epicutaneously.
  • Said topical composition may also be administered e.g. to the skin (epicutaneously), anally e.g. by suppositories etc.
  • composition may also be administered sublingually or buccally, then being referred to as a sublingual or buccal composition.
  • This may also be referred to as a pharmaceutical composition for epicutaneous, sublingual, buccal, vaginal or anal administration.
  • a topical composition may comprise in addition to oxytocin and/or a fragment or a variant thereof as defined herein, a suitable carrier and/or stabilizer, such as a gel, which is exemplified herein, making it suitable for topical administration, pH regulating entities, such as a buffer, preservatives, such as benzoic acid, and/or water producing an aqueous composition.
  • a “pH regulating agent” is any agent, such as a liquid agent, such as an aqueous liquid, which is able to regulate and/or maintain the pH of said pharmaceutical composition, wherein said pH is kept approximately in a selected range, which selected range is exemplified herein.
  • a pH regulating agent can for example be a buffer, such as a citrate, lactate or phosphate buffer.
  • a “buffer” is an ionic compound, usually a salt of a weak acid or base, added to a solution to resist changes in its acidity or alkalinity and thus stabilize its pH.
  • a buffer solution is a solution containing such a compound.
  • Other examples of a pH regulating agents are organic and inorganic acids and bases, such as acetic acid, citric acid, phosphoric acid, hydrochloric acid and sodium hydroxide.
  • disorder which is responsive to modulation of the endogenous oxytocin production is in the present context intended a disorder (pathological condition) which may be positively affected by modulation of the endogenous oxytocin production, i.e. by an increase and/or normalization in the amount of endogenously produced oxytocin.
  • pathological condition a disorder (pathological condition) which may be positively affected by modulation of the endogenous oxytocin production, i.e. by an increase and/or normalization in the amount of endogenously produced oxytocin.
  • disorders include, but are not limited to oxytocin deficiency, low social ability, anxiety, low energy level, stress sensitivity, mental climacteric symptoms, obsessive-compulsive disorder (OCD), borderline, attachment disorders, depression, autism and other forms of mental fragility or illness, pain, inflammation, an abusive disorder and/or disturbances of cardiovascular and gastrointestinal function of central origin.
  • the disorder may benefit from an increase in endogenous oxytoc
  • abusive disorders is in the context of the present document intended disorders involving an abuse of an activity or an abuse by ingestion e.g. such as alcoholism, drug abuse, smoking, sex abuse, an eating disorder.
  • eating disorder is in the context of the present document intended anorexia or bulimia.
  • oxytocin deficiency is in the context of the present document a deficiency which is due to either a too low amount of endogenous oxytocin being produced or due to a deficient function of the oxytocin receptor. In the latter case, the amount of oxytocin that is produced may be normal but due to a defect in the oxytocin receptor, the sensitivity of the oxytocin receptor to oxytocin is reduced.
  • a defect in the oxytocin receptor causing a lowered oxytocin sensitivity may be due to an innate deficiency of the function of the oxytocin receptor or by a down-regulation of the oxytocin receptor function as a consequence of hormonal changes with age, such as by a lowering of oestrogen levels during menopause.
  • IU international unit of oxytocin is the equivalent of about 1 .7 ⁇ g (about 1.67 ⁇ g) of pure oxytocin peptide.
  • Figure 1 shows the reduction of the scores of vaginal atrophy as measured by histological analysis of vaginal biopsies in response to a 7 week long treatment with placebo and 100 and 400 IU of oxytocin. The difference between values obtained at 1 and 7 weeks of treatment after administration of 100 and 400 IU was statistically significant, but not that for placebo.
  • Figure 2 shows increase plasma levels in response to placebo, 100 and 400 IU administered intravaginally. The first value is taken before the treatment of intravaginal oxytocin has started. The following values show that oxytocin levels at 15, 30, 60 and 90 minutes after administration of oxytocin are elevated in a pulse like fashion. Note that the value obtained 10 hours after treatment are higher than those observed before treatment was started. The y-axis displays the oxytocin levels in pg/ml plasma.
  • Figure 3 illustrates the women's evaluation of their most bothersome symptom.
  • the women were asked to name which symptom that bothered them the most (dyspareunia, dysuria, vaginal dryness and itching or irritation) when they were included in the study. At the subsequent visits at 2 and 7 weeks, they were asked whether this symptom was still present or not.
  • the size of the bars indicate the percentage of women experiencing the symptom identified as the most bothersome at the start of the study at the different time points.
  • Figure 4 illustrates how much oxytocin in a citrate buffered water solution containing 4000 lU/g oxytocin has penetrated the test skin membrane into the recipient solution.
  • Figure 5 shows a chromatogram of the content of oxytocin in the recipient solution that has penetrated the test skin membrane, from a buffered water solution containing 4000 I U/g oxytocin, after 48 h.
  • the present document is based on the surprising finding that administration of oxytocin resulting in a specific blood level of oxytocin may be used for the treatment and/or prevention of a disorder which is responsive to modulation of the endogenous oxytocin production.
  • administration of oxytocin resulting in a specific blood level of oxytocin may be used for the treatment and/or prevention of a disorder which is responsive to modulation of the endogenous oxytocin production.
  • means for treating and/or preventing different disorders which are responsive to and benefit from modulation of the endogenous oxytocin production by administrating oxytocin The amount of oxytocin produced in a healthy object is regulated by a feed-back mechanism regulating the amount oxytocin produced.
  • Exogenously administered oxytocin may affect this feed-back mechanism, leading to a lower amount of endogenous oxytocin being produced, which is of course disadvantageous.
  • Administration of oxytocin in accordance with the present disclosure appears to avoid such negative feedback inhibition of the endogenous oxytocin system. Without wishing to be bound by theory, this may be due to a stimulating effect on the endogenous oxytocin production when oxytocin is administered to a subject in accordance with the present document, without a concomitant negative feed-back inhibition on such production.
  • oxytocin when administered in accordance with the present disclosure therefore appears to occur due to a stimulating effect on endogenous oxytocin production, rather than a direct effect on a disorder by the exogenously administered oxytocin.
  • these effects are not produced by oxytocin from the blood entering into the brain, as the blood brain barrier comes in between, but instead that oxytocin in the circulation affects and increases the activity of certain sensory nerves which in turn leads to a stimulation of the release of oxytocin from the neurons in the SON and PVN in the hypothalamus.
  • oxytocin in the blood and also an enhanced release of oxytocin from the oxytocin containing neurons in the brain, which in turn creates positive effects of a disorder which is responsive to modulation of the endogenous oxytocin production. Accordingly, again without being bound by theory, this may be a bidirectional connection between peripheral and central nervous oxytocin release.
  • circulating oxytocin may via activation of the sensory nervous system make it possible to increase the central release of endogenous oxytocin via the blood. This may be done by small, short increases of the level of oxytocin in the blood according to a breast feeding model, or alternatively by a small sustained increase of oxytocin.
  • oxytocin in accordance with the present document leads to an increase in the endogenous production of oxytocin.
  • This increase may lead to endogenous oxytocin levels approaching normal endogenous oxytocin levels or a level above normal endogenous oxytocin levels.
  • the latter is particularly beneficial in the case the disorder is caused by a defect in the oxytocin receptor, which defect leads to a lowered oxytocin sensitivity, thus demanding higher oxytocin concentrations in order for the receptor to become activated.
  • Such disorders may therefore benefit from a higher than normal level of endogenous oxytocin.
  • administration of oxytocin in accordance with the present document allows a significantly lower dose of oxytocin to be administered by still allowing the provision of the same or substantially the same effect as the dose based on passing two barriers. While not wishing to be bound by any specific theory, administration of oxytocin in accordance with the present disclosure is believed to achieve the desired effect by activation of nerves via the blood and/or through a communication between the peripheral or central nerves via the blood. Disorders
  • Disorders which may be treated and/or prevented in accordance with the present document include conditions which are responsive to modulation of endogenous oxytocin production.
  • Objects to be treated with oxytocin in accordance with the present document are in particular objects which have a deficiency the production of endogenous oxytocin, leading to an oxytocin deficiency.
  • Such objects benefit from administration of oxytocin as disclosed herein as this results in an increase in the blood concentration of oxytocin by an increased endogenous production of oxytocin, without a concomitant inhibition of the endogenous oxytocin production.
  • one problem with previous methods involving an attempt to increase the blood concentration of oxytocin is that such an increase is often followed by a negative feed-back mechanism which causes a decrease in the endogenous oxytocin production.
  • Objects benefiting from administration of oxytocin in accordance with the present disclosure are also objects which may have a normal or close to normal endogenous production of oxytocin, but which have a defect in the oxytocin receptor which leads to a lower oxytocin sensitivity. Such objects also benefit from an increase in oxytocin production as more circulating oxytocin is required to get a proper response from the oxytocin receptor.
  • disorders which benefit from administration of oxytocin in accordance are selected from the group consisting of oxytocin deficiency, low social ability, anxiety, low energy level, stress sensitivity, mental climacteric symptoms, obsessive-compulsive disorder (OCD), borderline, attachment disorders, depression, autism and other forms of mental fragility or illness, pain, inflammation, an abusive disorder and/or disturbances of cardiovascular and gastrointestinal function of central origin.
  • a disorder which in particular may be treated and/or prevented in accordance with the present document is an oxytocin deficiency.
  • Such an oxytocin deficiency may in turn result in a disorder selected from the group consisting of low social ability, anxiety, low energy level, stress sensitivity, mental climacteric symptoms, obsessive-compulsive disorder (OCD), borderline, attachment disorders, depression, autism and other forms of mental fragility or illness, pain, inflammation, an abusive disorderand/or disturbances of cardiovascular and gastrointestinal function of central origin which may then be prevented and/or treated by the administration of oxytocin in accordance with the present document.
  • abusive disorders is in the context of the present document intended disorders involving an abuse of an activity or an abuse by ingestion e.g. such as alcoholism, drug abuse, smoking, sex abuse, an eating disorder.
  • treating disorder is in the context of the present document intended anorexia or bulimia.
  • administration of oxytocin in accordance with the present document may also be used for effecting a local effect of oxytocin, such as wound healing, and/or treating and/or preventing an atrophic condition in the skin or mucosa, such as vaginal atrophy, depending on the site where the oxytocin is administered such as in a combination treatment with one or more of the other disorders disclosed herein.
  • the present document is also directed to a method for the treatment and/or prevention of a disorder which is responsive to modulation of the endogenous oxytocin production in a subject comprising administrating a therapeutically effective amount of a composition comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof to said subject in need thereof. Further, the present document is directed to a
  • compositions comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof, for use in the treatment and/or prevention of a disorder which is responsive to modulation of the endogenous oxytocin production.
  • present document is also directed to the use of oxytocin and/or one or more fragment(s) and/or variant(s) thereof, in the manufacture of a composition for the treatment and/or prevention of a disorder which is responsive to modulation of the endogenous oxytocin production.
  • Further disorders/conditions which may be treated and/or prevented by the administration of oxytocin in accordance with the present document are disclosed elsewhere herein.
  • the subjects which may benefit from an administration of oxytocin in accordance with the present document are, for instance, subjects that have a too low endogenous production of oxytocin, subjects which have a normal endogenous production of oxytocin but are affected or in risk of being affected by the herein disclosed disorders, or subjects which have a defect in the oxytocin receptor causing a lowered oxytocin sensitivity.
  • a defect in the oxytocin receptor causing a lowered oxytocin sensitivity may be due to an innate deficiency of the function of the oxytocin receptor or by a down-regulation of the oxytocin receptor function as a consequence of hormonal changes with age, such as by a lowering of oestrogen levels during menopause.
  • Administration of the compositions may be due to an innate deficiency of the function of the oxytocin receptor or by a down-regulation of the oxytocin receptor function as a consequence of hormonal changes with age, such as by a lowering of oestrogen levels during menopause.
  • Administration of oxytocin in accordance with the present document may take place by topical administration, such as by epicutaneous, sublingual, buccal (e.g. intrabuccal), vaginal, or anal administration.
  • topical administration such as by epicutaneous, sublingual, buccal (e.g. intrabuccal), vaginal, or anal administration.
  • administration takes place so that the oxytocin penetrates the epithelial membrane.
  • the oxytocin by such administration enters the blood circulation and therefore does not enter the CNS (central nervous system) as is the case when a nasal spray is used for administering oxytocin.
  • the positive effects of the oxytocin when administered in accordance with the present document are not produced by oxytocin from the blood entering into the brain, as the blood brain barrier comes in between, but instead that oxytocin in the circulation affects and increases the activity of certain sensory nerves which in turn leads to a stimulation of the release of oxytocin from the neurons in the SON and PVN in the hypothalamus.
  • the exogenously administered oxytocin exerts its effects by the direct effect of increasing the blood level of exogenous oxytocin, but rather that the exogenous oxytocin causes an indirect increase of the level of the endogenously produced circulating amount of oxytocin by affecting the production of oxytocin.
  • the oxytocin may be administered once daily, even if other administration intervals, such as twice a day, every second day, 2-3 times a week or once weekly also may be used.
  • vaginal or anal administration of oxytocin in accordance with the present document, it can be expected that about 10 % of the exogenously administered oxytocin is expected to be taken up (i.e. passes the vaginal or anal epithelial membrane) and enter the blood.
  • oxytocin is administered epicutaneously, sublingually or buccally, about 1 % of the amount of exogenously administered oxytocin is expected to be taken up and enter the blood.
  • doses of about 10-10 000 IU of oxytocin may be administered when topical administration is used.
  • oxytocin When oxytocin is administered epicutaneously, sublingually or buccally, a dose of about 100-6 000 IU, such as about 1 000-6 000 IU or about 2 000-4 000 IU, is typical.
  • a composition comprising about 1 -15 mg/ml of oxytocin, such as about 1.7-10 mg/ml, about 1.7-6.8 mg/ml or about 3.4-6.8 mg/ml oxytocin, may be suitable for such epicutaneous, sublingual or buccal administration.
  • oxytocin When oxytocin is administered vaginally or anally, a dose of about 10-600 IU, such as about 100-600 IU or about 200-400 IU, is typical due to a higher expected uptake of oxytocin when vaginally/anally administered as compared to when epicutaneously administered.
  • a composition comprising about 0.1 -2 mg/ml of oxytocin, such as about 0.17-1 mg/ml, about 0.17-0.68 mg/ml or about 0.34-0.68 mg/ml oxytocin, may be suitable for such vaginal/anal administration.
  • 1 IU oxytocin corresponds to about 1 .7 ⁇ g oxytocin.
  • oxytocin when oxytocin is administered epicutaneously, sublingually or buccally in accordance with the present document, about 1 % of the administered dose of oxytocin is expected to penetrate the epithelium and enter the blood.
  • An epicutaneously, sublingually or buccally administered dose of 10-10 000 IU oxytocin is thus expected to result in about 0.1-100 IU (corresponding to about 0.17-170 ⁇ g) oxytocin entering the blood.
  • oxytocin when oxytocin is administered vaginally or anally in accordance with the present document, about 10 % of the administered dose of oxytocin is expected to penetrate the epithelium and enter the blood. A vaginally or anally administered dose of 10-10 000 IU oxytocin is thus expected to result in about 1 -1 000 IU (corresponding to about 1.7-1700 ⁇ g) oxytocin entering the blood.
  • an oxytocin may in certain aspects be facilitated by applying touch, pressure, massage, heat, or infrared light on the skin, which leads to enhanced skin permeability.
  • Hirvonen, J., Kalia, Y N, and Gay, R H. Transdermal delivery of peptides by iontophoresis. Nat Biotechnol December 1996; 14(13): 1710-1713 describes how to enhance the transport of a drug via the skin using the driving force of an applied electric field. Iontophoresis may be effected at a slightly basic pH.
  • the subject to which the oxytocin is administered to may be a mammal, such as a human being.
  • compositions comprising oxytocin
  • composition comprising oxytocin which is used in the context of the present document for the treatment and/or prevention of a disorder which is responsive to modulation of the endogenous oxytocin production is a (pharmaceutical) composition comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof, as well as pharmaceutically acceptable salts thereof.
  • the fragment(s) and/or variant(s) of oxytocin may correspond to the peptide of;
  • X-i is selected from the group consisting of Cys and nothing;
  • X2 is selected from the group consisting of Tyr, Phe, and nothing;
  • X3 IS selected from the group consisting of lie, Val, Hoph, Phe, Cha, and nothing;
  • X4 is selected from the group consisting of Gin, Ser, Thr, Cit, Arg, and Daba;
  • X 5 is selected from the group consisting of Pro and nothing;
  • ⁇ is selected from the group consisting of lie, Leu, nothing, Val, Hos, Daba,
  • X 7 is selected from the group consisting of Gly, nothing, and Ala;
  • Xs is selected from the group consisting of Gly and nothing.
  • fragment(s) and/or variant(s) of oxytocin may be selected from the group consisting of the peptides corresponding to SEQ ID NO:3-24.
  • X- in formula (I) is cysteine (Cys)
  • the thiol group of Xi may form a disulfide with the thiol group of the cystein that is located between the asparagine (Asn) and X 5 thereby forming a cyclic structure of formula (la): Cys-X :r X 3 -X 4 -Asii-C ⁇ S-X s -X 6 -X 7 -X 8 -NH 2
  • said topical composition may comprise oxytocin, i.e. when is Cys, X 2 is Tyr, X 3 is lie, X 4 is Gin, X 5 is Pro, X 6 is Leu, X 7 is Gly, and X 8 is nothing in SEQ ID NO:2, (Cys- Tyr-lle-Gln-Asn-Cys-Pro-Leu-Gly-NH 2 ) (SEQ ID NO:1).
  • the one or more variant(s) and/or fragment(s) of oxytocin of said topical composition may also be selected from the group consisting of the following compounds, as well as pharmaceutically acceptable salts thereof:
  • Xi is Cys, X 2 is Tyr, X 3 is lie, X 4 is Gin, X 5 is Pro, X 6 is lie, X 7 is Gly, and X 8 is nothing;
  • Xi is Cys
  • X 2 is Tyr
  • X 3 is lie
  • X 4 is Ser
  • X 5 is Pro
  • Xe is lie
  • X 7 is Gly
  • Xs is nothing
  • Xi Cys
  • X 2 is Phe
  • X 3 Val
  • X 4 is Arg
  • X 5 is Pro
  • ⁇ Thr
  • X 7 is Gly
  • Xs is nothing
  • Vasotocin Cys-Tyr-lle-Gln-Asn-Cys-Pro-Arg-Gly-NH 2 (SEQ ID NO:6)
  • Xi is Cys, X 2 is Tyr, X 3 is lie, X 4 is Gin, X 5 is Pro, X 6 is Arg, X 7 is Gly, and X 8 is nothing;
  • Vasopressin Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH 2 (SEQ ID NO:7)
  • Xi is Cys
  • X 2 is Tyr
  • X 3 is Phe
  • X 4 is Gin
  • X 5 is Pro
  • X 6 is Arg
  • X 7 is Gly
  • X 8 is nothing
  • Xi is Cys, X 2 is Tyr, X 3 is lie, X 4 is Gin, and X 5 -X 8 is nothing;
  • Xi is Cys, X 2 is Tyr, X 3 is lie, X 4 is Gin, X 5 is Pro, and X 6 -X 8 is nothing;
  • Xi is Cys
  • X 2 is Tyr
  • X 3 is lie
  • X 4 is Gin
  • X 5 is Pro
  • X 6 is Leu
  • X 7-8 is nothing
  • Tyr-lle-Gln-Asn-Cys-Pro-Leu-Gly-NH 2 SEQ ID NO:1 1
  • Xi is nothing, X 2 is Tyr, X 3 is lie, X 4 is Gin, X 5 is Pro, Xe is Leu, X 7 is Gly, and Xs is nothing; lle-Gln-Asn-Cys-Pro-Leu-Gly-NH 2 (SEQ ID NO:12)
  • X- i-X 2 is nothing, X 3 is lie, X 4 is Gin, X 5 is Pro, X 6 is Leu, X 7 is Gly, and X 8 is nothing;
  • X I - X3 is nothing, X 4 is Gin, X 5 is Pro, X 6 is Leu, X 7 is Gly, and X 8 is nothing;
  • X X 2 is nothing, X 3 is lie, X 4 is Gin, X 5 is Pro, and X 6 -Xs is nothing;
  • Xi is Cys, X 2 is Tyr, X 3 is lie, X 4 is Gin, X 5 is Pro, X 6 is Leu, X 7 is Gly, and X 8 is Gly;
  • X1-X3 is nothing, X 4 is Gin, X 5 is Pro, X 6 is Leu, X 7 is Leu, and X 8 is nothing;
  • Xi is Cys, X 2 is Tyr, X 3 is Val, X 4 is Thr, X 5 is Pro, X 6 is Leu, X 7 is Gly, and X 8 is nothing;
  • Xi is Cys
  • X 2 is Tyr
  • X 3 is Hoph
  • X 4 is Thr
  • X 5 is Pro
  • X is Val
  • X is Gly
  • Xs is nothing
  • Xi is Cys
  • X 2 is Tyr
  • X 3 is Phe
  • X 4 is Cit
  • X 5 is Pro
  • Xe is Leu
  • X 7 is Gly
  • X 8 is nothing
  • Xi is Cys, X 2 is Tyr, X 3 is Cha, X 4 is Arg, X 5 is Pro, Xe is Hos, X 7 is Ala, and X 8 is nothing;
  • Xi is Cys, X 2 is Tyr, X 3 is Val, X 4 is Daba, X 5 is Pro, Xe is Cit, X 7 is Ala, and Xs is nothing; Cys-Tyr-Hoph-Daba-Asn-Cys-Pro-Cit-Ala-NH 2 (SEQ ID NO:22)
  • Xi is Cys, X 2 is Tyr, X 3 is Hoph, X4 is Daba, X 5 is Pro, X 6 is Cit, X 7 is Ala, and X 8 is nothing; Cys-Tyr-Phe-Arg-Asn-Cys-Pro-Val-Ala-NH 2 (SEQ ID NO:23)
  • Xi is Cys
  • X2 is Tyr
  • X 3 is Phe
  • X4 is Arg
  • X 5 is Pro
  • Xe is Val
  • X 7 is Ala
  • Xs is nothing
  • Xi is Cys, X 2 is Tyr, X 3 is Cha, X4 is Cit, X 5 is Pro, X 6 is Arg, X 7 is Gly, X 8 is nothing; Accordingly, there is provided herein a topical composition, wherein said one or more fragment(s) and/or variant(s) of oxytocin is/are selected from the group consisting of the peptides corresponding to SEQ ID NO:3-SEQ ID NO:24.
  • the unnatural amino acids in said substances have the following structures:
  • Hoph Homophenylalanine
  • Citrulline herein referred to as Cit
  • Diaminobutyric acid herein referred to as Daba
  • Hos Homoserine, herein referred to as Hos
  • oxytocin When a position in SEQ ID NO:2 is stated as being “nothing” it means that it represents a single bond between the items (letter, atom or group).
  • Other variants of oxytocin could also be used in compositions as provided herein, such as naturally occurring or artificially modified variants, analogues, and/or derivatives of oxytocin, mesotocin, isotocin, and/or annetocin. Such variants could be obtained by addition, insertion, elimination, or substitution of at least one amino acid in these hormones.
  • Other substances include precursors, metabolites such as metabolic derivatives e.g. metabolic degradation products of the substances mentioned herein displaying the same properties.
  • Metabolic derivatives or metabolic degradation products may be oxytocin like peptides, e.g. with nine amino acids such as oxytocin, mesotocin, isotocin, and annetocin from which one or more amino acids has been deleted from either the carboxyl terminal end or the amino terminal end or both the carboxyl terminal and the amino terminal end, such as 1-3 amino acids from each terminal.
  • one, two or three amino acids may have been deleted from the carboxy terminal end i. e. Gly only, Gly and Leu, or Gly, Leu, and Pro.
  • one, two or three amino may have been deleted from the amino terminal i. e. Cys only, Cys and Tyr, or Cys, Tyr, and lie.
  • one, two or three amino acids may have been deleted both from carboxy terminal end i. e. Gly only, Gly and Leu, or Gly, Leu, and Pro, and one, two or three amino acids may have been deleted from the amino end i. e. Cys only, Cys and Tyr, or Cys, Tyr, and lie. It could be ascertained that these variants are analogues of oxytocin, mesotocin, isotocin or annetocin by immunological methods, e.g. RIA
  • oxytocin having at least 50, 60, 70, 80, 90, 95, 96, 97, 98, or 99 % sequence identity to oxytocin, said variants showing an oxytocin activity, as defined herein.
  • Annetocin has been isolated from the earthworm, as described in Oumi T.
  • a topical composition comprising oxytocin and/or a variant thereof in both D- and L-form, as well as racemates thereof.
  • the disclosure relates to the L-form.
  • the D-form could be converted to the L-form.
  • pharmaceutically acceptable salts of the compounds are also provided herein. Examples of salts of the compounds are pharmaceutically acceptable acid and base addition salts. Further, examples of salts of the compounds forming the topical compositions of the present disclosure are pharmaceutically acceptable acid and base addition salts.
  • pharmaceutically acceptable acid addition salts are intended to be any non-toxic organic or inorganic acid addition salt of the compounds of SEQ ID NO: 2, and/or any other variants and/or fragments of oxytocin as described herein.
  • examples of illustrative inorganic acids that form suitable salts are hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and acid metal salts such as sodium monohydrogen ortophosphate and potassium hydrogensulphate.
  • illustrative organic acids that form suitable salts are mono-, di-and tricarboxylic acids.
  • acids examples include acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2- phenoxybenzoic acid, and sulphonic acids such as p-toluenesulphonic acid, metha- nesulphonic acid and 2-hydroxyethanesulphonic acid.
  • Such salts could either be in hydrated or anhydrous form.
  • the acid addition salts of these compounds are generally water soluble and different hydrophilic organic solvents and, that compared to the free base forms thereof, generally display higher melting points.
  • pharmaceutically acceptable base addition salts are intended to be any non-toxic organic or inorganic base addition salt of the compounds of SEQ ID NO: 2, and/or any other variants and/or fragments of oxytocin as described herein.
  • illustrative inorganic bases that form suitable salts are alkali and earth alkali metal hydroxides and carbonates such as sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, calcium hydroxide, calcium carbonate, magnesium hydroxide, magnesium carbonate and ammonia.
  • illustrative organic bases that form suitable salts are methylamine, dimethylamine, trimethylamine and picoline. Either mono- or dibasic salts could be formed with such compounds.
  • the base addition salts of these compounds are generally water soluble and different hydrophilic organic solvents and, that compared to the free base forms thereof, generally display higher melting points.
  • the composition comprising oxytocin may be a topical composition, such as an epicutaneous, sublingal, buccal, vaginal or anal composition. Such topical compositions enable an uptake of oxytocin over the epithelial membrane.
  • the pH of the composition comprising oxytocin is typically between about 3 and 5, such as between about 3 and 4, such as between about 3 and 3.5.
  • the pH may thus be in the range of between about 3 and 4.5, such as between about 3.5 and about 4.5, between about 3.5 and 4, between about 3 and 4, between about 3 and 3.5, between about 3 and 3.1 , between about 3 and 3.2, between about 3 and 3.3, between about 3 and 3.4, between about 3 and 3.6, between about 3 and 3.7, between about 3 and 3.8, between about 3 and 3.9, between about 3.1 and 3.2, between about 3.1 and 3.3, between about 3.1 and 3.4, between about 3.1 and 3.5, between about 3.1 and 3.6, between about 3.1 and 3.7, between about 3.1 and 3.8, between about 3.1 and 3.9, between about 3.2 and 3.3, between about 3.2 and 3.4, between about 3.2 and 3.5, between about 3.2 and 3.6, between about 3.2 and 3.7, between about 3.2 and 3.8, between about
  • the pH the composition comprising oxytocin may be regulated by adding a pH regulating agent to said composition, such as a buffer.
  • a buffer may be a lactate buffer, a citrate buffer, a phosphate buffer, or a mixture thereof, but is not limited thereto.
  • concentration of a buffer to be added to the composition comprising oxytocin may be between about 20 and 100 mM, such as between about 25 mM and 100 mM, or about 25 to 50 mM, about 25 mM to 75 mM, or about 50 to 70 mM in an aqueous solution, but is not limited thereto. It should be noted that these values are not exact, meaning that they can vary slightly around the values provided.
  • the concentration of the buffer may vary in accordance with the above.
  • the composition comprising oxytocin may further comprise one or more epithelium penetration enhancer(s).
  • Such an epithelium penetration enhancer may increase the amount of oxytocin which penetrates the epithelium, such as the epicutaneous, sublingual, buccal, vaginal or anal epithelium.
  • Examples of such epithelium penetration enhancers include, but are not limited to propylene glycol (PG), SDS, isopropyl myristate, ethanol, diethylene glycol ethyl ether and/or cineole.
  • composition comprising oxytocin may further comprise a carrier e.g. in the form of a non-ionic cellulose ether.
  • a carrier e.g. in the form of a non-ionic cellulose ether.
  • Cellulose ethers are named after, and based on, cellulose which is a renewable material and the most common chemical compound in organic nature. There is a broad range of cellulose ethers available on the market, both ionic and non- ionic, for example sodium carboxymethylcellulose, hydroxyethylethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose and hydroxypropylmethycellulose.
  • Cellulose ethers are used as additives in such diverse applications as food, paint, oil recovery, paper, cosmetics, pharmaceuticals, adhesives, printing, agriculture, ceramics, textiles, detergents and building materials. Cellulose ethers improve the product quality in these applications and act as thickeners, water retention agents, suspending aids, protecting colloids, film formers or thermoplastics in such different products as dispersion paints, drilling muds, ice cream, tablet coatings, wallpaper paste and tile adhesive.
  • the cellulose ethers may be non-ionic, wherein alkyl and/or hydroxyalkyl groups are attached to the anhydroglucose units by ether linkages, which form
  • hydroxyalkylalkylcelluloses wherein the alkyl groups have from 1 to 4 carbon atoms.
  • a non-ionic cellulose ether is based on cellulose, which has been chemically modified in order to attain solubility in water by substitution of various groups onto the cellulose backbone. The substituents are characterised to have no electric charge when dissolved in water at a neutral pH.
  • Non-ionic cellulose ethers such as methylcellulose,
  • hydroxypropylmethylcellulose also referred to as hypromellose
  • methylhydroxyethylcellulose are widely used in the pharmaceutical industry due to their ability to thicken, bind and retain water, as well as to emulsify and suspend particles and form films. Further information regarding non-ionic cellulose ethers can be found e.g. in
  • the properties of the non-ionic cellulose ethers are determined by the molecular weight, (e.g. the degree of polymerisation), the type of substituents and also by the number and distribution of the substituents along the molecule. Hence, depending on the oxytocin and/or fragment and/or variant thereof which is present in the composition, the non-ionic cellulose ether can have varying properties and will be determined according to the prevailing circumstances.
  • cellulose ethers which may be used in a topical composition hereom are methyl cellulose (MC), hydroxyethylmethyl cellulose (HEMC),
  • HPMC hydroxypropylmethylcellulose
  • HEEC hydroxyethylethylcellulose
  • HPC hydroxypropylmethylcellulose
  • HPC hydroxyethylethylcellulose
  • HPC hydroxypropylmethylcellulose
  • HPC hydroxyethylethylcellulose
  • HPC hydroxypropylmethylcellulose
  • HPC hydroxyethylethylcellulose
  • HPC hydroxypropylmethylcellulose
  • HPMC hydroxyethylethylcellulose
  • HPC hydroxypropylcellulose
  • composition comprising oxytocin may thus further comprise at least one non-ionic cellulose ether, such as methyl cellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC),
  • non-ionic cellulose ether such as methyl cellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC)
  • composition comprising oxytocin may contain the non-ionic cellulose ether hydroxypropylmethylcellulose (HPMC).
  • the composition comprising oxytocin may thus e.g. be a composition comprising oxytocin (SEQ ID NO:1 ) and
  • HPMC hydroxypropylmethylcellulose
  • An exemplary composition comprising oxytocin is a composition comprising about 0.1 to 2 mg/ml, such as about 0.17-1 mg/ml, about 0.17-0.68 mg/ml or about 0.34-0.68 mg/ml, oxytocin and/or one or more fragment(s) and/or variant(s) of oxytocin and a non-ionic cellulose ether, such as hydroxypropylmethyl cellulose, said composition having a pH of about 3-5, such as about 3-4.
  • the concentration of hydroxypropylmethyl cellulose may be about 1-5 wt%, such as about 2-4 wt% or about 3 wt%.
  • Such a composition may further comprise an epithelium penetration enhancer, such as propylene glycol (PG), SDS, isopropyl myristate, ethanol, diethylene glycol ethyl ether and/or cineole.
  • an epithelium penetration enhancer such as propylene glycol (PG), SDS, isopropyl myristate, ethanol, diethylene glycol ethyl ether and/or cineole.
  • PG propylene glycol
  • SDS isopropyl myristate
  • ethanol diethylene glycol ethyl ether
  • cineole such as vaginal or anal administration.
  • Another exemplary composition comprising oxytocin is a composition comprising about 1 to 15 mg/ml, such as about 1.7-10 mg/ml, about 1.7-6.8 mg/ml or about 3.4-6.8 mg/ml oxytocin and a non-ionic cellulose ether, such as hydroxypropylmethyl cellulose, said
  • the concentration of hydroxypropylmethyl cellulose may be about 1 -5 wt%, such as about 2-4 wt% or about 3 wt%.
  • Such a composition may further comprise an epithelium penetration enhancer, such as propylene glycol (PG), SDS, isopropyl myristate, ethanol, diethylene glycol ethyl ether and/or cineole.
  • PG propylene glycol
  • SDS isopropyl myristate
  • ethanol ethanol
  • diethylene glycol ethyl ether diethylene glycol ethyl ether and/or cineole.
  • Such a composition is particularly suitable for epicutaneous, sublingual or buccal administration.
  • the composition comprising oxytocin should be administered to a subject in a dose which modulates the endogenous oxytocin production.
  • exemplary suitable doses include a dose of about 10-10 000 IU.
  • the dose may also be about 100-6 000 IU, about 1 000-6 000 IU or about 2 000-4 000 IU.
  • Such doses are particularly suitable for epicutaneous, sublingual or buccal administration.
  • the dose may also be about 10-600 IU, about 100-600 IU or about 200-400 IU.
  • Such a dose is particularly suitable for vaginal or anal administration.
  • compositions comprising oxytocin.
  • composition comprising oxytocin may be in the form of a gel, a suppository, a creme, a liquid suspension, a lozenge, a patch, a film etc.
  • compositions comprising oxytocin which may be used in the context of the present document is the Vagitocin® gel, the contents of which is disclosed elsewhere herein. Further exemplary compositions comprising oxytocin for use in accordance with the present document are disclosed elsewhere herein.
  • the present document is also directed to a kit of parts comprising a composition comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof as defined elsewhere herein, a container, such as a tube, a container for a stick, an ampoule etc., for said composition, and optionally instructions for use and/or means for applying said composition to a subject.
  • a container such as a tube, a container for a stick, an ampoule etc.
  • the container may be made of any suitable materials, such as plastics, metal or glass.
  • Exemplary means for applying the composition include, but are not limited to a spatula, a syringe for exact dosing, a wipe, a device for inserting the composition (e.g. when in the form of a pill or a suppository) in the vagina or anus.
  • a container or dispenser may e.g. be a plastic tube or box, or a type of vessel, or a foil container etc.
  • a kit may also comprise one or more containers each comprising one or more of a pharmaceutically acceptable carrier, adjuvant and/or excipient.
  • compositions such as a topical composition, comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof for use in treating and/or preventing an imbalance in the endogenous production and/or function of oxytocin.
  • Said prevention and/or treatment of the endogenous production and/or function of oxytocin comprise increasing the endogenous oxytocin production to a suitable degree as described herein.
  • a topical composition comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof for use in treating and/or preventing vaginal atrophy and an imbalance in the endogenous production and/or function of oxytocin.
  • Such a topical composition provides a combination treatment and/or prevention of both vaginal atrophy and an imbalance in the endogenous production and/or function of oxytocin. It is an object to provide uses of compositions comprising oxytocin which makes it possible to generate positive effects on the endogenous production of oxytocin. Further, there is also an objective art to identify compositions comprising oxytocin which are capable of providing both a local effect on an epithelial membrane, such as on a mucosal membrane, as well as a systemic effect thereby affecting the endogenous production and/or function of oxytocin. Such a composition could then be suitable for combination treatments for subjects suffering both from a physical and a mental disorder or discomfort, which is often experienced during menopause.
  • the present disclosure concerns a novel use of oxytocin in a topical composition, said topical composition comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof as defined herein, for use in treating and/or preventing an imbalance in the endogenous production and/or function of oxytocin.
  • a topical composition comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof as defined herein, for use in treating and/or preventing an imbalance in the endogenous production and/or function of oxytocin.
  • such as use may also be defined as a use in treating and/or preventing a disorder caused by and/or related to a deficiency in endogenous oxytocin production and/or for use in increasing the blood plasma level of oxytocin.
  • a topical composition comprising exogenous oxytocin and/or one or more fragment(s) and/or variant(s) thereof, wherein administration thereof results in an increase of circulating exogenously provided oxytocin thereby stimulating the endogenous production and release of oxytocin into the blood and/or to the brain.
  • an imbalance such as an underproduction of endogenous oxytocin and/or decreased function may be treated and/or prevented by raising the blood plasma concentration of oxytocin through topical administration of exogenous oxytocin and/or a fragment and/or a variant thereof as described herein.
  • a topical composition comprising oxytocin and/or a fragment or variant thereof for use in treating and/or preventing an imbalance in the endogenous production and/or function of oxytocin, wherein said imbalance results in a disorder, such as oxytocin deficiency, low social ability, anxiety, low energy level, stress sensitivity, mental climacteric disorders, obsessive-compulsive disorder (OCD), borderline, attachment disorders, depression autism and other forms of mental fragility or illness, as well as pain, inflammation, an abusive disorder and/or disturbances of cardiovascular and gastrointestinal function of central origin, in particular when these are due to an imbalance in the endogenous production and/or function of oxytocin.
  • a composition may be administered topically, such as by vaginal administration.
  • a topical composition comprising oxytocin as provided herein is capable of entering the blood plasma e.g. by virtue of being administered vaginally, which absorption surprisingly occurs via the epithelial membrane, in a dosage making it suitable for efficiently regulating the endogenous production of oxytocin in an individual, such as a human being.
  • the present disclosure also relates to a topical composition which allows for oxytocin to pass through an epithelial membrane, e.g. through the vaginal membrane, making it possible to achieve sustained pulse-like increases of the plasma level of oxytocin, preferably over a long period of time.
  • the topical mode of administration of oxytocin appears to avoid negative feedback inhibition of the endogenous oxytocin system.
  • a topical composition as provided also herein allows for treating both a local and a systemic disorder as disclosed herein.
  • the present disclosure also relates to a method for treating and/or preventing an imbalance in the endogenous production and/or function of oxytocin in a subject comprising topically administrating a therapeutically effective amount of a topical composition comprising oxytocin and/or a fragment or variant thereof, as described herein, to said subject in need thereof.
  • the present disclosure also relates to a method for treating and/or preventing vaginal atrophy and an imbalance in the endogenous production and/or function of oxytocin in a subject comprising topically administrating a therapeutically effective amount of a topical composition comprising oxytocin and/or a fragment or variant thereof, as described herein, to said subject in need thereof.
  • a topical formulation comprising oxytocin of the present disclosure is capable of being absorbed through the epithelial membrane, e.g. through the vaginal membrane. Further, surprisingly, such an administration mode is believed to provide additional advantages in the form of positive effects on the endogenous production of oxytocin, which was not possible through intravenous administration of oxytocin.
  • oxytocin by providing accurate doses of oxytocin by a topical administration, and through the epithelial membrane, it is believed that it is possible to generate a stimulating and/or increasing effect on the endogenous production of oxytocin further providing unexpected positive effects on the central nervous system via the body's own oxytocin production and/or release providing a more sustainable prevention and/or treatment of conditions where this production/release is not in balance.
  • topical compositions especially useful for treating and/or preventing disorder(s) and/or condition(s) which is/are the result of and/or the cause of an imbalance of oxytocin production and/or function, and/or when the oxytocin secretion from the brain is low.
  • disorder(s) and/or condition(s) which is/are the result of and/or the cause of an imbalance of oxytocin production and/or function, and/or when the oxytocin secretion from the brain is low.
  • administration e.g. by vaginal administration, to raise the blood plasma level of oxytocin and thereby possibly increase the activity of the oxytocin producing nerves in the brain.
  • the activity in these neurons is increased, there is an increased activity and release of endogenously produced oxytocin both to the blood and to the brain.
  • the increased levels in the blood may be seen as a mirror of the activities in the brain which creates the positive effects of a normal balance of oxytocin in the brain.
  • a topical composition comprising oxytocin for use in regulating and/or stimulating the levels, i.e. the amount and/or concentration of oxytocin in blood plasma, brain and/or the circulation as a whole, through topical, e.g. vaginal administration thereof.
  • a topical composition comprising oxytocin, i.e. a composition that is to be administered topically and which is absorbed via the epithelial membrane, achieves a positive effect, via the circulation, on the endogenous production of oxytocin without activating the negative feed-back systems.
  • the administration of oxytocin via such a route may stimulate the production of endogenous oxytocin as further explained herein.
  • oxytocin was taken up into blood plasma by being vaginally administered.
  • a topical composition as presented herein it appears possible to create a positive effect of externally administered oxytocin with no or little effect on the negative feedback mechanism of the endogenous oxytocin production in a subject.
  • Such a topical composition provides an advantageous mode of administration by allowing epithelial uptake and facilitating the uptake of oxytocin into the blood plasma to thereby, as a secondary effect, possibly positively regulate the endogenous production of oxytocin by stimulation of the production thereof.
  • a topical composition as described herein without wishing to be bound by theory, appropriate doses of oxytocin may be administered to a subject in need thereof to effectively regulate a positive feedback system of oxytocin.
  • a topical composition as described herein, for epithelial uptake, such as epicutaneous, sublingual, buccal, vaginal or anal uptake, has the ability to provide suitable concentrations of oxytocin to the circulation, affording advantageous effects on the state of mind.
  • the present disclosure relates to a topical composition
  • a topical composition comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof, for use in treating and/or preventing an imbalance in the endogenous production and/or function of oxytocin.
  • Such a use may also be described as a use in treating and/or preventing a deficiency in endogenous oxytocin production and/or for use in increasing the blood plasma level of oxytocin.
  • Such a composition may further be for use for treating and/or preventing vaginal atrophy.
  • Said imbalance/deficiency may be related to the endogenous release of oxytocin from the brain or alternatively to less functional oxytocin receptors, thus demanding higher oxytocin concentrations in order to become activated.
  • the present disclosure also provides a topical composition comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof, for use in treating and/or preventing vaginal atrophy and/or an imbalance in the endogenous production and/or function of oxytocin.
  • a topical composition is hence envisaged for a combination therapy for vaginal atrophy and an imbalance in the production and/or function of oxytocin.
  • a topical composition comprising oxytocin and/or one or more fragment(s) and/or variant(s) thereof, for use as a combination treatment and/or prevention of vaginal atrophy and an imbalance in the endogenous production and/or function of oxytocin.
  • a topical composition for use in treating and/or preventing an imbalance in the endogenous production and/or function of oxytocin, wherein said imbalance results in a disorder, such as a disorder selected from the following disorders: oxytocin deficiency anxiety, low energy level, stress sensitivity, mental climacteric disorders, decreased social ability, obsessive-compulsive disorder (OCD), borderline, autism, depression, an abusive disorder and/orother forms of mental fragility or illness.
  • oxytocin deficiency anxiety low energy level
  • stress sensitivity mental climacteric disorders
  • OCD obsessive-compulsive disorder
  • borderline autism, depression, an abusive disorder and/orother forms of mental fragility or illness.
  • a topical composition may be used for such a purpose, which has not previously been shown.
  • Said deficiency may be treated and/or prevented by stimulating the production of oxytocin into the circulation, resulting in the use in the treatment and/or prevention of disorders which are caused by and/or related to a deficiency/imbalance in the endogenous oxytocin production.
  • a topical composition such as a vaginal composition for use in the treatment and/or prevention of a disorder selected from oxytocin deficiency, low social ability, anxiety, low energy level, stress sensitivity, mental climacteric symptoms, obsessive-compulsive disorder (OCD), borderline, attachment disorders, depression, autism and other forms of mental fragility or illness, as well as pain, inflammation, an abusive disorder and/or disturbances of cardiovascular and gastrointestinal function of central origin.
  • Said disorder may be caused by and/or related to an imbalance in the endogenous production and/or function of oxytocin.
  • Such a composition may further be for use for treating and/or preventing vaginal atrophy.
  • oxytocin and/or one or more fragment(s) and/or variant(s) thereof in the manufacture of a topical composition for use in treating and/or preventing an imbalance in the endogenous production and/or function of oxytocin, wherein said imbalance results in a disorder selected from the group consisting of: oxytocin deficiency, low social ability, anxiety, low energy level, stress sensitivity, mental climacteric disorders, obsessive-compulsive disorder (OCD), borderline, attachment disorders, depression autism, an abusive disorder and other forms of mental fragility or illness.
  • a topical composition for use in treating and/or preventing an imbalance in the endogenous production and/or function of oxytocin, wherein said imbalance results in a disorder selected from the group consisting of oxytocin deficiency, low social ability, anxiety, low energy level, stress sensitivity, mental climacteric disorders, obsessive-compulsive disorder (OCD), borderline, attachment disorders, depression autism, an abusive disorder and other forms of mental fragility or illness.
  • oxytocin and/or one or more fragment(s) and/or variant(s) thereof in the manufacture of a topical composition for use in treating and/or preventing an imbalance in the endogenous production and/or function of oxytocin and/or in the treatment and/or prevention of vaginal atrophy, wherein said imbalance results in a disorder selected from the group consisting of: oxytocin deficiency, low social ability, anxiety, low energy level, stress sensitivity, mental climacteric disorders, obsessive- compulsive disorder (OCD), borderline, attachment disorders, depression autism, an abusive disorder and/or other forms of mental fragility or illness.
  • OCD obsessive- compulsive disorder
  • borderline attachment disorders
  • depression autism an abusive disorder and/or other forms of mental fragility or illness.
  • the present composition provides the local effects on vaginal atrophy, expanding the use also to physical disorders, e.g. the vaginal dryness experienced during menopause.
  • a topical composition of oxytocin comprising a non-ionic cellulose ether is absorbed via the epithelial membrane and further into the blood stream therein resulting in rise of plasma oxytocin levels which can be characterized as a particular area under the curve (see Figure 2).
  • This particular type of rise of oxytocin levels was linked to an increase of endogenous oxytocin release as reflected by a sustained increase of oxytocin levels in the plasma long after the oxytocin administered by intravaginal oxytocin was eliminated.
  • this sustained increase of peripheral oxytocin levels was paralleled by an increase of the release of neurons in the brain resulting in positive mental effects on the patient.
  • Intravenous administration has previously been shown to cause a negative effect on the endogenous production of oxytocin, which may be avoided by utilizing a topical administration mode instead. This opens up for additional uses of topical compositions of oxytocin to treat and/or prevent any disorders which are related to an imbalance and/or insufficiency in the endogenous oxytocin production and/or function.
  • a topical composition of oxytocin by administering a topical composition of oxytocin to a subject in need thereof, for instance on a daily basis for as long as desired, it is shown herein to be possible to generate an appropriate secretion of oxytocin in the circulation to effectively regulate the endogenous feed-back mechanism of oxytocin production, i.e. to stimulate the endogenous production.
  • This will make it possible to prevent and/or a treat disorder and/or a condition which is dependent on the endogenous level of oxytocin, and it may, as 5 described herein, be performed by the usage of a topical composition of oxytocin instead of e.g. an intravenous administration form which is not as convenient as described herein.
  • such a regulation and/or stimulation of the endogenous oxytocin production in a subject is performed by a composition which may be topically administered to the
  • said amount passing through an epithelial membrane is a dosage of about 15 and about 70 ⁇ g, such as between about 15 and 30 ⁇ g, 20-30 ⁇ g or between 15 and 40 ⁇ g, such as about 20 ⁇ g (about 1 1.8 Ul).
  • a topical composition comprising a dosage of oxytocin and/or a fragment or a variant thereof between about 50 and 600 IU of oxytocin, such as between
  • a topical composition for use as defined herein may be administered vaginally, i.e. it is also provided herein a topical composition for use in treating and/or preventing an imbalance in the endogenous production and/or function
  • composition is to be administered vaginally. It is provided herein a topical composition comprising oxytocin and hydroxypropylmethylcellulose for use in the treatment and/or prevention of an imbalance in the endogenous production and/or function of oxytocin, wherein said composition is to be administered vaginally in a dosage of between about 50
  • the concentration of oxytocin and/or a fragment and/or a variant thereof as defined herein may also be between about 0.1 to 1.5 mg/ml, such as about 0.5 to about 1.5 mg/ml, about 35 0.5 to about 1 mg/ml, about 0.5 to about 1.2 mg/ml, about 0.2 to about 0.5 mg/ml, about 0.1 to about 0.8 mg/ml, or about 0.2 to about 1 .2 mg/ml of the total pharmaceutical composition as defined herein.
  • I U One international unit (I U) of oxytocin is the equivalent of about 1 .67 micrograms of pure peptide. Accordingly, a composition of 1 g of oxytocin gel, 400 IU, is equivalent to about 0.67 mg/g (Ph Eur). This is also sometimes referred to as IE.
  • a topical composition for use as described herein may comprise about: 1 mg/g oxytocin, about 2 wt% hydroxypropylmethylcellulose in about 25 mM citrate or lactate buffer, and optionally about 1 mg/g benzoic acid.
  • a topical composition for use as described herein may comprise about 0.9 mg/g oxytocin, about 1 .1 mg/g benzoic acid, and about 2 wt%
  • HPMC hydroxypropylmethylcellulose
  • oxytocin, and/or said one or more fragment(s) and/or variant(s) thereof may be present in an amount of about 0.1 to 1 .5 mg/g, such as 0.5 to about 1.5 mg/g, about 0.5 to about 1 mg/g, about 0.5 to about 1 .2 mg/g, about 0.2 to about 0.5 mg/g, about 0.1 to about 0.8 mg/g, or about 0.2 to about 1 .2 mg/g of the total composition, and said at least one non-ionic cellulose ether may be present in an amount of about 1 -3 wt%, such as about 2 wt% or 3 wt% in a pH regulating agent, such as a buffer, said buffer having a concentration of about 25 mM to about 100 mM.
  • a pH regulating agent such as a buffer
  • said at least one non- ionic cellulose ether is hydroxypropyl methylcellulose.
  • a topical composition for use as described herein may comprise about 1 mg/g oxytocin, about 2 wt% hydroxypropylmethylcellulose (HPMC) in about 25 mM citrate or lactate buffer and optionally about 1 mg/g benzoic acid and wherein the pH of said composition is about 3.
  • a topical composition for use as described herein may comprise about 1 mg/g oxytocin, about 2 wt% hydroxypropylmethylcellulose (HPMC) in about 25 mM lactate buffer and wherein the pH of said composition is about 3.8.
  • a topical composition for use as described herein may comprise about 0.9 mg/g oxytocin, about 1 .1 mg/g benzoic acid, about 2 wt% hydroxypropylmethylcellulose (HPMC) in about 25 mM Iactate buffer and wherein the pH of said composition is about pH 3.8.
  • a topical composition for use as described herein may comprise hydroxypropylmethylcellulose, a citrate or a Iactate buffer, and optionally benzoic acid.
  • said pharmaceutical composition comprises about: 1 mg/g oxytocin, about 2 wt% hydroxypropylmethylcellulose in about 25 mM citrate or Iactate buffer, and optionally about 1 mg/g benzoic acid.
  • a topical composition for use as described herein may comprise: 1 mg/g oxytocin, 2 wt% hydroxypropylmethylcellulose in a 25 mM Iactate buffer, and optionally 1 mg/g benzoic acid.
  • a topical composition for use as described herein may comprise: 0.8 mg/g oxytocin, 3 wt% hydroxypropylmethylcellulose in a 22 mM Iactate buffer, and optionally 1 mg/g benzoic acid.
  • a topical composition for use as described herein may comprise 0.4 mg/g oxytocin, 3 wt% hydroxypropylmethylcellulose in a 22 mM Iactate buffer, and optionally 1 mg/g benzoic acid.
  • a topical composition for use as described herein may comprise 0.2 mg/g oxytocin, 3 wt% hydroxypropylmethylcellulose in a 22 mM Iactate buffer, and optionally 1 mg/g benzoic acid.
  • a topical composition for use as defined herein may be hydroxypropylmethylcellulose (HPMC), also referred to as hypromellose. It is also related to herein, a topical composition for use in the prevention and/or treatment of a deficiency in endogenous oxytocin production, wherein said topical composition comprises oxytocin (SEQ ID NO:1 ) and hydroxypropylmethylcellulose (HPMC). Said topical composition may be for vaginal use.
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • a non-ionic cellulose ether When a non-ionic cellulose ether is used herein, the concentration of a non-ionic cellulose ether, such as hydroxypropylmethylcellulose (HPMC) is provided in relation to a pH regulating agent of a topical composition, such as a buffer, as presented herein, e.g. 2 wt% or 3 wt% non-ionic cellulose ether in 25 mM buffer provides a certain viscosity due to the amount of the at least one non-ionic cellulose ether present in said buffer.
  • a buffer as presented herein, e.g. 2 wt% or 3 wt% non-ionic cellulose ether in 25 mM buffer provides a certain viscosity due to the amount of the at least one non-ionic cellulose ether present in said buffer.
  • the concentration of the non-ionic cellulose ether is presented in weight % (wt%) in said buffer, or other pH regulating agent.
  • the amount of non-ionic cellulose ether is somewhat less due to the addition of the therapeutic substance (oxytocin and/or one or more fragment(s) and/or variant(s) thereof as disclosed herein) to said composition.
  • the concentration of oxytocin and/or one or more fragment(s) and/or variant(s) thereof as defined herein is provided in relation to the total composition, e.g. for example in a buffer and a gel such as a non-ionic cellulose ether, if applicable, and optionally other additives such as a preservative.
  • a buffer and a gel such as a non-ionic cellulose ether, if applicable, and optionally other additives such as a preservative.
  • 1 mg/g oxytocin means that 1 mg oxytocin is present in 1 g of total composition.
  • 1 mg/ml means that 1 mg of oxytocin is present in 1 ml of total topical composition.
  • a further object of the present disclosure relates to a method for treating and/or preventing an imbalance in the endogenous production and/or function of oxytocin in a subject, and optionally vaginal atrophy, comprising administrating a therapeutically effective amount of a topical composition comprising oxytocin as defined herein to said subject in need thereof.
  • Said topical composition may be administered to the peripheral blood stream of said subject in a final dosage of between about 15 pg and about 70 ⁇ g, such as between about 15 and 30 g.
  • Such a composition may comprise between about 50 and 400 IU of oxytocin, such as between about 100 and 200 IU.
  • said disorder may be selected from the group consisting of oxytocin deficiency, low social ability, anxiety, low energy level, stress sensitivity, mental climacteric disorders, obsessive-compulsive disorder (OCD), borderline, attachment disorders, depression autism and other forms of mental fragility or illness, pain, inflammation, an abusive disorder and/or disturbances of cardiovascular and
  • Said subject may be a mammal, such as a human being.
  • the topical compositions as provided herein may in certain circumstances contain substances that extend or strengthen the effects of oxytocin. Such substances could increase the release of oxytocin and/or the member or affinity of oxytocin receptors, such as oestrogen, or drugs having an [alpha]2-agonistic effect, such as clonidine.
  • the topical compositions as defined herein are may be encompassed for topical use, such as for vaginal use.
  • the present disclosure relates to a topical composition
  • oxytocin SEQ ID NO:1
  • HPMC hydroxypropylmethylcellulose
  • buffers other pH regulating agents or additional components as exemplified herein, such as benzoic acid for vaginal use, for use in the treatment and/or prevention of a dysfunction in the endogenous release of oxytocin.
  • compositions as defined herein can optionally comprise other components, such as inert components or components having a physical or biological function.
  • an antibiotic or an analgesic is additionally present in a composition as provided herein.
  • the study comprised of 64 patients who received daily intravaginal treatment with an oxytocin containing gel or a placebo gel. 24 patients received 400 IU oxytocin, 24 patients received 100 IU oxytocin and 16 received placebo gel.
  • the vagitocin gel comprises of 1 mg of oxytocin per ml hypromellose (HPMC). Benzoic acid is used as preservative and lactic acid to adjust the pH to between about 3 and 4.
  • Karolinska Scales of personality or Swedish Scales of personality is a validated inventory which has been used to demonstrate oxytocin linked changes in personality during e.g. breastfeeding.
  • Oxytocin levels observed in response to breastfeeding correlates strongly with lower levels of anxiety and increased levels of social skills as determined by KSP.
  • Uvnas-Moberg K et al. Acta Obstet Gynecol Scand 69, 301 -6
  • Uvnas-Moberg K et al. J Psychosom Obstet Gynaecol 1990, 1 1 261 -273, Nissen E, J Psychosom Obstet Gyneaecol 1998, 19, 49-58).
  • the amount of oxytocin which is absorbed following intravaginal administration of oxytocin expressed as area under the curve (AUC) can be calculated using the trapezoid method according to standardized pharmacokinetic procedures as the clearance rat for oxytocin (CL) is known (70L/H).
  • a water solution of oxytocin was prepared in a concentration of 4000 lU/g, which corresponds to ca 6.8 mg/g.
  • the solution was pH adjusted with a 50 mM citrate buffer to 4.0 in order to achieve reasonable chemical stability.
  • the oxytocin solutions were added in excess, ca 1 g, on the donor side of the skin and covered to prevent evaporation.
  • the objective of the present analysis was to estimate the bioavailability of oxytocin following vaginal administration of 100 (170 ⁇ g) or 400 IU (680 ⁇ g) oxytocin vaginal gel using data from study OXYPEP002 (Clinical trial protocol OXYPEP002).
  • the oxytocin vaginal gel is Vagitocin® gel.
  • Vagitocin® is a clear gel in the strength 400 lU/g. Vagitocin gel is provided in single dose glass syringes containing 1 g. The pH of the gel is adjusted to 3.75 and benzoic acid is used as preservative.
  • Hypromellose (Benecel) 30 3.0 Viscosity agent Ph Eur
  • Study OXYPEP002 Data from study OXYPEP002 was used for the analysis. Study OXYPEP002 was conducted with the primary objective to investigate the dose-relationship of topical Vagitocin on the vaginal mucosal membrane (Clinical trial protocol OXYPEP002).
  • OXYPEP002 was a double-blind, randomized, placebo controlled trial, with a parallel group design.
  • Vagitocin oxytocin gel
  • a placebo gel was administered topically once daily during 7 weeks.
  • a placebo gel with the same
  • composition was used as comparator. In total 64 patients were to be included in the study. At the baseline visit (visit 1 ), blood sampling for oxytocin analysis were drawn for the first
  • the systemic oxytocin exposure following vaginally administered oxytocin was assessed 30 by calculating the area under the blood concentration versus time curve (AUC) according to the trapezoidal rule.
  • AUC blood concentration versus time curve
  • the blood concentration of oxytocin had not returned to the baseline observation at the lasts sampling time point (120 min post-dose).
  • Two approaches to calculate the oxytocin exposure after the 120 min post-dose sampling e.g. the residual area
  • the endogenous oxytocin level (AUC ba seiine) was calculated and subtracted from the total AUC to achieve the oxytocin exposure following the vaginally administered dose
  • the bioavailability was calculated according to equation 1. As no intravenous dose was administered in study OXYPEP002, AUC,v was calculated according to available information in the literature (De Groot AN et al. 1995, Amico JA ei a . 1987, Dawood MY et al. 1980) according to equation 2. An assumed intravenous dose of 1 ⁇ g and a CL of 70 L/h would result in an AUCi V of 14.3 pg/ml-h. According to this the bioavailability was calculated to be in the range of 0.064 - 0.16 (Table 4). Equation 1
  • the calculation of the bioavailability was not one of the objectives of study OXYPEP002 and due to limitations in the study design the results here should be regarded as a rough estimate rather than the true value.
  • the blood sampling in OXYPEP002 was sparse and limited to a 2 h sampling period. Since the oxytocin concentration at the latest sample was higher than the baseline observation assumptions were needed regarding the residual oxytocin exposure. Further, when comparing the decline in oxytocin concentration between the last two samples to the reported elimination rate of oxytocin it was indicated that the absorption process might not have been completed at the latest sampling time point. Two alternative calculations were thus made. In the first alternative, the oxytocin level were assumed to continue to decline with a rate according the decline in
  • C is the concentration and x is the space coordinate.
  • Clinical trial protocol OXYPEP002. A double-blind, placebo controlled single centre trial to evaluate the dose- relationship of the effects of vaginally administered oxytocin on the vaginal mucosal membrane in postmenopausal women with vaginal atrophy.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant de l'oxytocine et/ou un ou plusieurs fragment(s) et/ou variant(s) de celle-ci, pour son utilisation dans le traitement et/ou la prévention d'un trouble qui réagit à la modulation de la production endogène d'oxytocine.
EP13777020.2A 2012-10-12 2013-10-11 Nouvelle utilisation d'une composition comprenant de l'oxytocine Withdrawn EP2908840A1 (fr)

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