HUE033257T2 - Többfunkciós gél vaginális szárazságra közvetlen és késleltetett hatással - Google Patents

Description

(12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 36131 <200601> A61K 361886 <200β01> 15.02.2017 Bulletin 2017/07 A61K 31I164<200601> A61K 38I17<200601> A61K 311355 <2006 01> A61K 311205<2006 01> (21) Application number: 11799655.3 A61P 15102 <200601> (22) Date of filing: 02.12.2011 (86) International application number: PCT/EP2011/071612 (87) International publication number: WO 2012/076409 (14.06.2012 Gazette 2012/24)

(54) MULTIPURPOSE GEL FOR VAGINAL DRYNESS WITH DIRECT AND DELAYED EFFECT

MULTIFUNKTIONSGEL FUR VAGINALE TROCKENHEIT MIT DIREKTER UND VERZOGERTER WIRKUNG

GEL A BUTS MULTIPLES CONTRE LA SECHERESSE VAGINALE PRESENTANT UN EFFET DIRECT ET PROLONGE (84) Designated Contracting States: WO-A2-2004/089278 WO-A2-2007/039124 ALATBEBGCHCYCZDEDKEEESFIFRGB WO-A2-2010/060886 US-A1-2003 215 506

GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR · CHOWDARY K P R ET AL: "Mucoadhesive

Designated Extension States: microspheres for controlled drug delivery",

BA ME BIOLOGICAL AND PHARMACEUTICAL BULLETIN 200411 JP LNKD- (30) Priority: 09.12.2010 IT M120102260 DOI:10.1248/BPB.27.1717, vol. 27, no. 11,

November 2004 (2004-11), pages 1717-1724, (43) Date of publication of application: XP002654468, ISSN: 0918-6158 16.10.2013 Bulletin 2013/42 · PATIL SANJAY B ET AL: "Mucoadhesive microspheres: a promising tool in drug (73) Proprietor: Zambon S.p.A. delivery.", CURRENT DRUG DELIVERY OCT2008 20091 Bresso Ml (IT) LNKD- PUBMED:18855602, vol. 5, no. 4, October 2008 (2008-10), pages 312-318, XP002654469, (72) Inventors: ISSN: 1567-2018 • BARTORELLI, Alberto · ALBERTINI B ET AL: "Polymer-lipid based CH-3963 Crans sur Sierre (CH) mucoadhesive microspheres prepared by • GOBBI, Maria Rosa spray-congealing for the vaginal delivery of

I-22073 FINO MORNASCO (CO) (IT) econazole nitrate", EUROPEAN JOURNAL OF

PHARMACEUTICAL SCIENCES 20090302 NL (74) Representative: Minoja, Fabrizio LNKD- D0l:10.1016/J.EJPS.2008.12.009, vol. 36,

Bianchetti Bracco Minoja S.r.l. no.4-5,2March2009(2009-03-02),pages591-601,

Via Plinio, 63 XP002654470, ISSN: 0928-0987 20129 Milano (IT) · BOJKOVSKI J ET AL: "Colostrum composition before and after calving in Holstein-Friesian

(56) References cited: cows", VETERINARY RECORD, BRITISH WO-A1-2008/003688 WO-A1-2009/113065 VETERINARY ASSOCIATION, LONDON, GB, vol. 156, no. 23, 4 June 2005 (2005-06-04), pages 744-745, XP009157091, ISSN: 0042-4900

Description [0001] The present invention relates to topical vaginal compositions in gel form containing immune mediators, growth factors, chemotactic factors and antibacterial/antiviral factors extracted from bovine colostrum, and optionally other ingredients with complementary activity.

Prior art [0002] Under physiological conditions, the vaginal ecosystem is a dynamic balance of microbial flora modulated by the hormone balance, the pH and the immune response, which are closely interdependent factors. The cells of the vaginal wall play an important role in maintaining said balance, especially the surface and intermediate layers of the epithelium, whose proliferation and maturity is hormone-related.

[0003] The vaginal mucosa is normally moistened by fluid, visible on inspection as a clear secretion consisting of plasma transudate, cervical mucus and vestibular gland secretions. Said fluid also contains antimicrobial substances which give it the function of a protective interface. 5% of the vaginal secretion consists of vaginal transudate, and 95% of cervical mucus and the secretions that flow into it. The mucus prevents microbial colonisation by means of mechanical action, through its properties of viscosity and elution, and because it contains antibodies (IgG and IgA), cytokines and antibacterial factors.

[0004] "Vaginal dryness" is a frequent condition at menopausal age; it is less common but equally unpleasant when it affects patients of childbearing age.

[0005] While menopausal hypoestrogenism and urinary habits are the prevalent factors in elderly women, in women of childbearing age the causes can also be represented by the use of low-dose combined oestrogen-progestogen contraceptives, tampons, stress, etc..

[0006] The symptoms consist of pain, stinging and itching, particularly during sexual intercourse, and tend to persist. Bartolini’s and Skene’s glands should produce mucus; this is essential as a "lubricating fluid", which is useful for normal performance of sexual intercourse. However, when the disorder is present, this production does not take place, thus causing discomfort for the patient. Poor vaginal and vulvar lubrication often causes a series of disorders in women, such as stinging, itching and dyspareunia. There is also greater sensitivity to even modest irritant stimuli, and more frequent episodes of vaginosis and vaginitis. The disorder is quite frequently associated with urination disorders, in the form of urinary stinging. A frequent colposcopy finding is irregular iodine uptake on the Schiller Test.

[0007] Numerous hormone-based medicaments have been proposed for the treatment of these disorders. Unfortunately, there is a suspicion of increased incidence of breast tumours, especially comedocarcinoma, for all these products. Many products based on phytoestrogens have been proposed, but scientific evidence of a breast cancer risk also exists in these cases: soya isoflavones induce 97% proliferation of the murine MCF-7 tumour line compared with the controls.

[0008] There is consequently a need for a product based on natural substances which: do not alter the vaginal ecosystem but help to restore and maintain the balance, and boost its defences; are presented in a gel formulation similar to the physiological vaginal secretion and give immediate relief, at the same time promoting the reconstruction and maintaining the integrity of the mucosa; release part of the active ingredients quickly and part on a slow-release basis so as to produce a long-lasting therapeutic effect covering the period between successive administrations.

[0009] Compositions comprising colostrum or extracts or components thereof for administration to the vaginal mucosa are known from WO 2007/039124, WO 2009/113065, WO 2004/089278. Mucoadhesive microspheres for delivery to the buccal or vaginal mucosa are disclosed in WO 2010/060886 and in the papers by: CHOWDARY K P R ET AL: "Mucoadhesive microspheres for controlled drug delivery", BIOLOGICAL AND PHARMACEUTICAL BULLETIN, vol. 27, no. 11, November 2004 pages 1717-1724; PATIL SANJAY B ET AL: "Mucoadhesive microspheres: a promising tool in drug delivery." CURRENT DRUG DELIVERY, vol. 5, no. 4, October 2008, pages 312-318; ALBERTINI B ET AL: "Polymer-lipid based mucoadhesive microspheres prepared by spray- congealing for the vaginal delivery of econazole nitrate", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 36, no. 4-5, 2 March 2009, pages 591-601.

[0010] US 2003/215506 discloses a microencapsulated IgG-enriched colostrum fraction for delivery of creatine. Vaginal delivery is also envisaged but the main goal is oral delivery and the encapsulation is aimed at protecting from gastric hydrolysis.

Description of the invention [0011] It has now been discovered that these aims are achieved by a formulation containing, as active ingredient, a colostrum fraction enriched with immunoglobulins, growth factors, chemotactic factors and antibacterial/antiviral factors, partly in free, prompt-release form and partly in controlled-release form, preferably encapsulated in mucoadhesive microbeads.

[0012] Mucoadhesive microspheres are commercially available under the name SPHERULITE®, or can be prepared according to WO 2010060886.

[0013] The compositions according to the invention preferably contain other ingredients, especially panthenol, betaine, sericin, vitamin E, Lepidium mehenii (Maca) extract, and Aloe vera.

[0014] The compositions according to the invention are advantageously used to treat premenopausal, menopausal and hysterectomised women, teenage girls, postpartum or breast-feeding women, women suffering from stress-related dryness and women who make excessive use of imbalanced local treatments.

[0015] The colostrum fraction usable in the gel according to the invention is obtainable from bovine colostrum, in particular from Holstein (Friesian) and Guernsey cows. It has been demonstrated that these cows produce the colostrum with the highest concentration of growth factors, immune modulators, chemotactic factors and antibacterial/antiviral factors. The cows are preferably calving for the second or third time. The colostrum is preferably collected between the 5th and 6th hour after calving (colostrum 5H), because the highest concentration of active substances is found during that period. The colostrum collected in the first hour contains a lower concentration of active substances, while from the sixth hour onwards the active factors decline rapidly (only 15% are present 24 hours after calving).

[0016] The colostrum 5H collected is tested for tuberculosis, cytoxocity on cell cultures, mycoplasma, prions and human and bovine viruses.

[0017] The colostrum in the udder cistern is practically sterile, but once milked, despite all precautions, due to the high concentration of growth factors, its bacteria count rises very rapidly during freezing and thawing, which are rather slow processes in view of the high density of colostrum in the first few hours (Fig. 1).

[0018] The concentration of preservatives allowed for dietary use and those allowed for parenteral and/or intravenous use is not sufficient to stop the bacteria count. The use of y rays only produces sterile colostrum if radiation exceeding 10 Kgy is used, but this destroys a large part of the active factors, and in any event this method does not prevent the formation of pyrogens, the intravenous and/or topical use of which is prohibited in areas in contact with the blood and lymph nodes. An innovative collection system has therefore been devised to obtain a sterile, allergen-free compound, without preservatives or pyrogens.

[0019] Antiseptic agents in sufficient quantities to guarantee sterility and absence of pyrogens are added to the colostrum collected in sterile tanks (which are sterilised empty at 25 Kgy) (Figure 2). Potassium sorbate and sodium benzoate are preferably used, each at the concentration of 12.5% (a much higher concentration than normally used, namely 0.2%), or alternatively, phenoxyethanol at the concentration of 2.5% or diazolidinyl urea at the concentration of 1% (Figure 3).

[0020] The colostrum thus treated does not need to be stored frozen before the active factor extraction processes, which leads to an obvious saving of industrial costs.

[0021] The colostrum is then diluted with saline solution: this dilution not only gives better filtration without clogging the filter pores, but above all allows the release of active factors bonded to fats and casein. The colostrum thus diluted undergoes tangential microfiltration (ceramic membranes with a cut-off between 2 and 6 μίτι, temperature 5/20°C, transmembrane pressure between 0.2 and 2 bars), which may be repeated, to obtain an opalescent solution free of casein, fat matrix and milk proteins. All these substances constitute over 90% of the allergic content of colostrum and cow’s milk. The solution is then passed through membranes, or alternatively a molecular sieve with a cut-off at 300,000 daltons, for further purification of the active factors, all weighing less than 200,000 daltons.

[0022] The solution is then dialysed by ultrafiltration (cut-off 1000/2000 daltons) at high pressure to totally eliminate the preservatives (molecular weight under 150 daltons), and then immediately freeze-dried (Fig. 4). The result is a sterile, pyrogen-free, preservative-free, anallergic powder (casein and lactoalbumin are responsible for over 95% of allergies to cow’s milk) of very high solubility, with the maximum possible concentration of active factors.

[0023] This fraction, hereinafter called LIFEINSIDE™ Mucosa, contains the following factors:

IMMUNE MEDIATORS

[0024] Immunoglobulins of class lgG2 and IgA (a/mg), in the proportion of approx. 60% of the Lifeinside™ Mucosa content (approx. 50% lgG2 and approx. 10% IgA), with natural specificity against many bacteria and viruses, some of which are responsible for superimposed NEC infection.

[0025] COMPLEMENT C3/C4: The complement consists of circulating proteins able to interact with the biological membranes and with specific receptors situated on the surface of various cell types, which induce inflammatory reactions that help combat infection.

ANTIBACTERIAL/ANTIVIRAL FACTORS

[0026]

Transferrin;

Lactoferrin;

Lysozyme;

Lactoperoxidase.

GROWTH FACTORS

[0027] TGF-βΙ-TRANSFORMING GROWTH FACTOR: stimulates the production of Class A immunoglobulins, which are responsible for immune defences in the mucosa. Modulates cell proliferation and stimulates the deposit of extracellular matrix.

[0028] EGF - EPIDERMAL GROWTH FACTOR: regulates the development of the mucosa. Promotes the formation of epithelial cells.

[0029] IGF 1 - INSULIN-LIKE GROWTH FACTOR: modulates cell proliferation, adhesion and migration and induces maturity of the mucosa.

[0030] VEGF - VASCULAR ENDOTHELIAL GROWTH FACTOR: stimulates blood vessel production. Presents mitogenic activity and activation of vascular permeability.

[0031] FGF-b - FIBROBLAST GROWTH FACTOR BASIC: stimulates proliferation of cells of mesenchymal origin such as fibroblasts, endothelial cells, astrocytes and keratinocytes. Acts as a chemotactic and phytogenetic factor.

[0032] GH - GROWTH HORMONE: general growth factor of all tissues.

[0033] GHRF - GROWTH HORMONE RELEASING FACTOR.

[0034] NGF - NERVE GROWTH FACTOR: stimulates activity and regulates growth and differentiation of the sympathetic system.

[0035] PRP- Proline Rich Protein: Stimulates maturity of the T cells and has a regenerating effect on the nervous system, the bone system and the mucosa.

CHEMOTACTIC FACTORS

[0036] EOTAXIN: binds to the chemokine receptors to recruit eosinophils to inflamed tissues.

[0037] IP-10-Chemochin ligand 10: induced by interferon gamma, and aggregates inflammatory cells.

[0038] MCP-1 Monocyte chemotactic factor-1: promotes aggregation of monocytes to inflamed tissues.

CYTOKINES

[0039] IL-2: induces proliferation of T lymphocytes. IL-4: possesses anti-inflammatory activity. IL-6: stimulates innate and adaptive immunity. IL-9: regulator of haemopoietic cells, stimulates cell proliferation and prevents apoptosis. IL-17: regulates the activities of NF-KB and boosts nitric oxide (NO) production. IL-10: presents pleiotropic effects in immunoregulation and inflammation. Improves B cell survival, and therefore antibody production. Studies conducted on Knockout mice demonstrate that this protein is essential in immunoregulation of the mucosa. Interferon-gamma: presents known antiviral, antitumoral and immunoregulatory activities. Is a powerful macrophage activator, and activates cell-mediated activity against bacteria and viruses.

[0040] TNF -a - Tumour necrosis factor: stimulates the migration of neutrophils and monocytes to the site of infection.

[0041] The fraction containing the substances listed above can be advantageously associated with other compounds with complementary or otherwise useful activity. The following substances are preferred:

Betaine: Betaine (trimethylglycine) is a substance of plant origin extracted from sugarbeet. It is involved in transmethylation, the biochemical process essential for cell metabolism via which methyl groups (CH3) are transferred from one molecule to another. In the body, betaine loses a methyl group and is converted to dimethylglycine (vitamin B15); during this process, energy is produced, which is believed to be responsible for the beneficial effects of this compound: disappearance of inexplicable tiredness and favourable effect on the circulatory system, heart, allergies and cell respiration. Betaine is an ideal ingredientfor products designed forthe skin and mucosa, which are particularly sensitive and delicate, in view of its moisturising and wetting properties, which are useful to promote immediate moisturising of the vaginal mucosa.

[0042] Panthenol: Pantothenic acid and the corresponding reduced form, panthenol, is one of the vitamins most widely used in topical applications. It has proved effective as a softener, moisturiserand conditioner. It performs a number of essential functions: • after penetration into the mucosa it acts as an internally active moisturiser because it has an excellent ability to retain moisture, thus making the skin soft and elastic; • it stimulates cell proliferation and aids tissue repair; • it promotes normal keratinisation; • it promotes the healing of minor wounds, slight abrasions and small burns due to its soothing properties.

[0043] Vitamin E or tocopherol, a fat-soluble vitamin with marked antioxidant activity able to prevent the breakdown of vitamin A and fatty acids, with consequent formation of toxic catabolites and formation of free radicals and peroxides. Vitamin E enters the cellular respiration processes, fortifies the walls of the blood vessels, and has important favourable effects on the reproductive apparatus.

[0044] Sericin (MW 400,000): moisturising, film-forming, with acidity buffering ability. Reduces the aggressiveness of surfactants. Has a considerable affinity for hydrophobic proteins and excellent ability to retain water, both of which characteristics increase with molecular weight. Unlike hyaluronic acid, which is often used in vaginal moisturising products, the film-forming effect is not occlusive. In the case of intact sericin, the pleasant, therapeutic film-forming effect does not prevent the other factors from being absorbed by the vaginal mucosa.

[0045] Maca {Lepidium meyenii extract): is a little-known plant remedy and high-energy food. Its popularity is increasing due to its energy-giving, fertility-promoting and aphrodisiac effects. Maca extract contains glucosinolates and isothiocyanates with chemopreventive activity. In women, Maca extract promotes fertility, stimulates the libido, alleviates the symptoms associated with the menopause, attenuates menstrual pain and has an energising effect.

[0046] The constituents of Maca have no oestrogenic activity, as demonstrated in oestrogen-dependent breast cancer (MCF-7 tumour cells).

[0047] Aloe vera has useful regenerating, proteolytic, wound-healing, anti-inflammatory, antipyretic, analgesic, wetting, bacteriostatic, virustatic, fungicidal and anti-itching properties.

[0048] The gel formulations according to the invention are prepared according to known techniques, using conventional excipients. The concentration of colostrum fraction in free form can vary between 1 and 10%, while that in encapsulated controlled-release form varies between 0.1 and 5%.

[0049] The approximate concentration intervals for the other constituents, when present, are set out below:

Sericin: 0.5-5%

Panthenol: 0.1-1%

Betaine: 1-10%

Aloe vera extract: 1-5%

Vitamin E: 0.1-2%

Lepidium meyenii extract: 1-5% [0050] The invention is described in greater detail in the following experimental part, given by way of example.

Example 1 - Qualitative and quantitative composition of a vaginal gel with rapid and slow release of active factors

(continued)

Example 2 - Clinical trials [0051] The vaginal gel described in Example 1 was used on 30 fertile, premenopausal and menopausal women suffering from vaginal dryness due to hormonal or mechanical reasons, stress, unbalanced local treatments, breastfeeding, contraceptives, etc.

[0052] Table 1 shows the results of colposcopy with the Schiller Test on a group of 30 treated patients and 28 controls. The difference between the two groups at the end of the study was statistically significant (p < 0.05).

Table 1

DISTRIBUTION OF SUBJECTS STUDIED ACCORDING TO COLPOSCOPY RESULTS AND TREATMENT ARM

[0053] Table 2 shows the results for the presence and severity of vaginal dryness in the same groups. Once again, the difference was statistically significant (p < 0.05, treatment with a single daily administration for 20 days).

Table 2

[0054] Use of the combined prompt- and delayed-release vaginal gel led to a definite improvement in the clinical picture and the symptoms associated with vaginal dryness. In the control group, only 16.7% of cases had improved after 20 days, whereas 86.7% of cases in the treatment group had improved/were cured.

[0055] The cytological test after treatment (Figures 4-7) demonstrates: • increased cellularity • a relative increase in mature squamous cells • a relative reduction in basal and para-basal cells. • presence of inflammation and multinuclear histiocytes indicating increased tropism.

Claims 1. Topical vaginal compositions in gel form comprising a colostrum fraction enriched with immunoglobulins, growth factors, chemotactic factors and antimicrobial/antiviral factors, partly in free form and partly encapsulated in mu-coadhesive microbeads. 2. Compositions as claimed in claim 1 comprising immunoglobulins of class lgG2 and IgA, complement c3/c4, transferrin, lactoferrin, lysozyme, lactoperoxidase, TGF-ß1 - transforming growth factor, EGF - epidermal growth factor, IGF 1 - insulin-like growth factor, VEGF - vascular endothelial growth factor, FGF-b - fibroblast growth factor basic, GH - growth hormone, GHRF - growth hormone releasing factor, NGF - nerve growth factor, proline-rich proteins, eotaxin, IP-10-chemokine ligand 10, MCP-1 monocyte chemotactic factor-1, IL-2, IL- 4, IL-6, IL-9, IL-17, IL-10, interferon-gamma, and TNF-a - tumour necrosis factor. 3. Compositions as claimed in claim 1 or 2 wherein the colostrum fraction is obtainable from bovine colostrum milked between the 5th and 6th hours after calving and treated with a process which comprises: - addition of antiseptic agents to the colostrum in sufficient concentrations to ensure sterility and apyrogenicity; - dilution with saline solution; - one or more tangential microfiltration steps through ceramic membranes with cut-off ranging between 2 and 6 μπι; - passage through membranes or molecular sieves with cut-off of 300,000 Daltons; - dialysis by high-pressure ultrafiltration until complete removal of the antiseptic agents and final freeze-drying. 4. Compositions as claimed in claim 3 wherein the colostrum is obtained from Guernsey or Holstein cows. 5. Compositions as claimed in any one of claims 1 to 4 also containing one or more of the following ingredients: a) Sericin; b) Panthenol; c) Betaine; d) Aloe vera extract; e) Vitamin E; f) Lepldlum meyenii extract. 6. Compositions as claimed in claim 1 for the use in the treatment of vaginal dryness.

Patentansprüche 1. Topische vaginale Zusammensetzungen in Gelform, umfassend eine Kolostrumfraktion, die mit Immunglobulinen, Wachstumsfaktoren, chemotaktischen Faktoren und antimikrobiellen/antiviralen Faktoren angereichert ist, zum Teil in freier Form und zum Teil in mukoadhäsiven Mikrokügelchen eingekapselt. 2. Zusammensetzungen gemäß Anspruch 1, umfassend Immunglobulineder Klasse lgG2und IgA, Komplement c3/c4, Transferrin, Lactoferrin, Lysozym, Lactoperoxidase, transformierenden Wachstumsfaktor TGF-ß1, Epidermis-Wachstumsfaktor EGF, insulinartigen Wachstumsfaktor IGF 1, Gefäßendothel-Wachstumsfaktor VEGF, basischen Fibroblasten-Wachstumsfaktor FGF-b, Wachstumshormon GH, Wachstumshormon-freisetzenden Faktor GHRF, Nervenwachstumsfaktor NGF, prolinreiche Proteine, Eotaxin, Chemokin-Ligand 10 IP-10, Monocyten-Chemotaxis-Faktor-1 MCP-1, IL-2, IL-4, IL-6, IL-9, IL-17, IL-10, Interferon-gamma und Tumornekrosefaktor TNF-a. 3. Zusammensetzungen gemäß Anspruch 1 oder 2, wobei die Kolostrumfraktion aus bovinem Kolostrum erhältlich ist, das zwischen der fünften und sechsten Stunde nach dem Kalben gemolken und nach einem Verfahren behandelt wurde, das Folgendes umfasst: - Zugabe von antiseptischen Mitteln zu dem Kolostrum in ausreichenden Konzentrationen, um Sterilität und Pyrogenfreiheit zu gewährleisten; - Verdünnung mit Kochsalzlösung; - einen oder mehrere tangentiale Mikrofiltrationsschritte über keramische Membranen mit einer Ausschlussgrenze im Bereich zwischen 2 und 6 μΓη; - Passieren durch Membranen oder Molekularsiebe mit einer Ausschlussgrenze von 300 000 Dalton; - Dialyse durch Hochdruck-Ultrafiltration bis zur vollständigen Entfernung der antiseptischen Mittel und abschließendes Gefriertrocknen. 4. Zusammensetzungen gemäß Anspruch 3, wobei das Kolostrum von Guernsey-oder Holstein-Kühen erhalten wurde. 5. Zusammensetzungen gemäß einem der Ansprüche 1 bis 4, die auch einen oder mehrere derfolgenden Bestandteile enthalten: a) Sericin; b) Panthenol; c) Betain; d) Aloe-vera- Extrakt; e) Vitamin E; f) Lepidium-meyenii-Extrakt. 6. Zusammensetzungen gemäß Anspruch 1 zur Verwendung bei der Behandlung von Scheidentrockenheit.

Revendications 1. Compositions vaginales topiques sous forme de gel comprenant une fraction de colostrum enrichie avec des immunoglobulines, des facteurs de croissance, des facteurs chimiotactiques et des facteurs antimicrobiens/antiviraux, partiellement sous forme libre et partiellement encapsulées dans des microbilles mucoadhésives. 2. Compositions selon la revendication 1 comprenant des immunoglobulines de classe lgG2 et IgA, le complément c3/c4, latransferrine, la lactoferrine, le lysozyme, la lactoperoxydase, leTGF-ß1 -facteur de croissance transformant, l’EGF - facteur de croissance épidermique, l’IGF-1 - facteur de croissance de type insuline, le VEGF - facteur de croissance endothéliale vasculaire, le FGF-b - facteur basique de croissance fibroblastique, la GH - hormone de croissance, le GHRF - facteur libérant l’hormone de croissance, le NGF - facteur de croissance nerveuse, des protéines riches en proline, l’éotaxine, le ligand 10 de chimiokine IP-10, le MCP-1 facteur-1 chimiotactique de monocyte, l’IL-2, l’IL-4, l’IL-6, l’IL-9, l’IL-17, l’IL-10, l’interféron gamma et le TNFa - facteur de nécrose tumorale. 3. Compositions selon la revendication 1 ou 2 dans lesquelles la fraction de colostrum peut être obtenue à partir de colostrum bovin trait entre les 5ème et 6ème heures de vêlage et traitées avec un procédé comprenant : - l’addition d’agents antiseptiques au colostrum en concentrations suffisantes pour assurer la stérilité et l’apyrogénicité ; - une dilution avec une solution saline ; - une ou plusieurs étapes de microfiltration tangentielle à travers des membranes en céramique avec un seuil se situant dans la plage allant de 2 à 6 μσι ; - le passage à travers des membranes ou des tamis moléculaires avec un seuil de 300000 daltons ; - une dialyse par ultrafiltration à haute pression jusqu’à l’élimination complète des agents anti-septiques et une lyophilisation finale. 4. Compositions selon la revendication 3 dans lesquelles le colostrum est obtenu à partir de vaches Guernsey ou Holstein. 5. Compositions selon l’une quelconque des revendications 1 à 4 contenant de plus un ou plusieurs des ingrédients suivants : a) séricine ; b) panthénol ; c) bétaïne ; d) extrait d’Aloe vera ;

e) vitamine E f) extrait de Lepidium meyenii. 6. Compositions selon la revendication 1 pour une utilisation dans le traitement de la sécheresse vaginale.

RELATIONSHIP BETWEEN MICROBIAL CONTAMINATION AND CONCENTRATION OF PRESERVATIVES

TAMC: total aerobic microbial count TYMC: total yeast and mould count

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description • WO 2007039124 A [0009] · WO 2010060886 A [0009] [0012] • WO 2009113065 A [0009] · US 2003215506 A [0010] • WO 2004089278 A [0009]

Non-patent literature cited in the description • CHOWDARY K P R et al. Mucoadhesive micro- · ALBERTINI B et al. Polymer-lipid based mucoadhe- spheres for controlled drug delivery. BIOLOGICAL sive microspheres prepared by spray-congealing for AND PHARMACEUTICAL BULLETIN, November the vaginal delivery of econazole nitrate. EUROPE- 2004, vol. 27 (11), 1717-1724 [0009] AN JOURNAL OF PHARMACEUTICAL SCIENCES, • PATIL SANJAY B et al. Mucoadhesive micro- 02 March 2009, vol. 36 (4-5), 591-601 [0009]

spheres: a promising tool in drug delivery. CURRENT DRUG DELIVERY, October 2008, vol. 5 (4), 312-318 [0009]

Claims (2)

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2. 2. Az í igeiig pont szerinti készítmények. amelyek tartalmazzál·: pífeö vétkezőket:: Ii;ö:fí itnc'tunoglobulinok. eted komplement, transzferrin, laktnferrm, lizozbo, ktkmpuos J<v, K*F*{M transzformáló növekedési faktor, i tik - eptderatabs növekedést fa Mór, Kid ! mmbn zc-e műk v^i kktsu VΓ; iΓ- vasz.M.íSán:·: gíiööfiéiaije^ faktor., ív*F tr · nbtobitisz; növekedés: faktor alap. üH · növekedési Isormon. fi I SRI ·- !|ófe:|pÓS||:ka:xi#íÍ felszabadÍK) : aktot. NGF - elem növekedési faktor, pórimban gazdag:, fehérjék. eoSavto. iP· N.ivkemokiu ópíkf ijii, MO’· i monoéba kemotakoku:; faktor·· í , li..--§yÍj:pjí:iÍP, II. -A ti -H..- ii), inteoferori-gatmrut Cs fNF-α - tumor nekrözis faktor, t Azt sags 2 muvvooní szennu készítmények ahol a kotos-'tmm frakció az ebes m-mt 5 es m nta :löpti fejt s/m vavtnarba köiös zizííip;ÖPő jít jt Abéitl kön átkozó lépéseket taitammzo gl jjjássaI ke/dS: ·· amis/eptikus szerek iM^íiiiiiíisi^^usííhö-K elegendő koncentrációban a sterítiás és na apirogenieitás hi/toMtásihiv. - hígítás sónldabai; - egy vagy több kereszt irányú mikroszárési tépés 2 μνη es '·> a rn közönt tartom. m\ba esó vágási éttéko kerámia membránokon keresztül. - ίυοΟΟί! Dasutn v,m,·,·<: z'-jcku menti omekot vagy íooicktöaszoahoh kete-emu tnueao ith.uta , * dialízis nagynyomású niírasztiréssel az tmhszeptiktis szarok teljes «Itávolitasáig. és végső fagyasztva szárítás. I k t pz'sp't! Ν/,ϋ'ίι kev'fi'iases Ί e t ztt t mm to.,!ns,\ sa <\ Hőst,»· >et>f't z\ho nyerjük. * k' l-ö 'eenvpMütok háfotcsike szétmo koszomnyék, tme’vsk kni-dma/nak továbbá a kővetkező Összetevők közül egyet \at;> többet: 3j szenein; íbj panteao;: c) bétáit;: dt/i/oe v ;:·/·« kivonat:, e) |svipí:tít| :f> kepó/öm? ||jyöosí j t·. keszantenyek a? I Oeiupotn - -ént i vagmatts -z«naz,*ag ke/ek-r-eben íoovno tbkaínta/ahta.