WO2007009382A1 - Utilisation de rhgm-csf pour la fabrication d'un medicament a usage externe pour le traitement de cervicite et/ou de l'erosion cervicale - Google Patents

Utilisation de rhgm-csf pour la fabrication d'un medicament a usage externe pour le traitement de cervicite et/ou de l'erosion cervicale Download PDF

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Publication number
WO2007009382A1
WO2007009382A1 PCT/CN2006/001754 CN2006001754W WO2007009382A1 WO 2007009382 A1 WO2007009382 A1 WO 2007009382A1 CN 2006001754 W CN2006001754 W CN 2006001754W WO 2007009382 A1 WO2007009382 A1 WO 2007009382A1
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WO
WIPO (PCT)
Prior art keywords
csf
rhgm
use according
sodium
vaginal
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PCT/CN2006/001754
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English (en)
Chinese (zh)
Inventor
Lei Jin
Jin Pei
Lixin Zhao
Minghua Duan
Ban Wang
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Genescience Pharmaceuticals Co. Ltd
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Application filed by Genescience Pharmaceuticals Co. Ltd filed Critical Genescience Pharmaceuticals Co. Ltd
Publication of WO2007009382A1 publication Critical patent/WO2007009382A1/fr

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Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/08—Solutions
    • 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
    • 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

  • rhGM-CSF in preparation of external preparation for treating cervicitis and/or cervical erosion
  • the present invention relates to the use of recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF), and more particularly to the use of rhGM-CSF in the preparation of a topical preparation for treating cervicitis and/or cervical erosion.
  • rhGM-CSF granulocyte macrophage colony stimulating factor
  • GM-CSF is an acidic protein produced and secreted by activated T cells, B cells, macrophages, mast cells, endothelial cells and fibroblasts.
  • the mature rhGM-CSF consists of 127 amino acids, which is a protein of 144 amino acid protein precursors with a 17 amino acid signal peptide.
  • the relative molecular weight is 147000 Da, and the biological activity is not affected by glycosylation.
  • rhGM-CSF in large quantities, which promotes the research and expands its clinical application of rhGM-CSF. It is familiar to most clinical researchers among many cytokines and is officially launched. A product of the field. The most basic function of GM-CSF is to stimulate the proliferation and differentiation of granulocyte-producing progenitor cells into granulocytes and macrophages, and gradually mature into cells with phagocytic function.
  • GM-CSF is to stimulate the proliferation and differentiation of granulocyte-producing progenitor cells into granulocytes and macrophages, and gradually mature into cells with phagocytic function.
  • its clinical application is not so single, but it is very extensive and involves many fields.
  • the clinical application status of rhGM-CSF mainly includes the following aspects:
  • GM-CSF can promote the leukocyte progenitor cells to enter the cell cycle more, shorten the duration of neutropenia in chemotherapy patients, increase the killing effect of chemotherapy drugs on leukemia cells, reduce fever and Complications of infection.
  • Aplastic anemia GM-CSF is used in the treatment of aplastic anemia, but the patient's infection rate is reduced by about 50%.
  • GM-CSF can accelerate the recovery of hematopoietic function, significantly accelerate the recovery of WBC and PMN, reduce the infection rate, reduce the number of antibiotic infusions and shorten the length of hospital stay. At the same time, it can also regulate and promote normal hematopoietic stem cells by applying cytokines such as rhGM-CSF. Growth.
  • GM-CSF stimulates the proliferation and differentiation of granulocyte-producing progenitor cells into granulocytes and macrophages, and gradually matures into a function of phagocytic cells, it can be synergistically treated for infectious diseases in clinical practice.
  • bacteria in AIDS patients During the spread of blood and infection (mycobacteria invade into monocyte macrophages), GM-CS can activate infected macrophages, thereby inhibiting or killing intracellular fractions.
  • Phytobacteria can be combined with antibiotics to treat the effect.
  • Cervicitis and cervical erosion are common to women of childbearing age, and about 20% or more of women suffer from the disease.
  • the causes and pathological process of cervical erosion are more complicated. Its onset is often associated with its own estrogen metabolism levels, pregnancy and post-pregnancy, childbirth, miscarriage, taking birth control pills, psychotropic factors, bacteria (streptococcus, staphylococcus and enterococci) and viral infections, sexual life is too frequent, mechanical Damage is closely related.
  • Pathological changes are common non-specific inflammation of the cervix, lymphocytes, plasma cells and monocytes infiltration under the cervix endometrial epithelium, cervical columnar epithelium and glandular epithelium with varying degrees of squamous metaplasia.
  • cervicitis and cervical erosion are mainly based on local treatment after the exclusion of early cervical cancer.
  • topical application of corrosive drugs (silver nitrate, potassium chromate and traditional Chinese medicine) may be applied; in cases with large erosion area or deep inflammatory infiltration, cryotherapy, laser, or electric ironing may be used;
  • oral broad-spectrum antibiotics (such as cephalosporin antibiotics plus metronidazole) are generally used.
  • the pathological repair process is to expose the squamous epithelium to the columnar epithelial necrosis, crusting, and shedding.
  • the limitation of the above clinical treatment methods is that the drugs cannot reach the inflammatory tissue below the erosion surface, so the long-term effects of the patients are not satisfactory, and even if there is a short-term effect, they may relapse soon.
  • GM-CSF has not been used as a topical preparation for the treatment of cervicitis and cervical erosion and related literature and patent reports.
  • the object of the present invention is to provide a novel use of recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) for the preparation of an external preparation for treating cervicitis and/or cervical erosion.
  • rhGM-CSF human granulocyte macrophage colony stimulating factor
  • GM-CSF can chemot mononuclear cells in the blood circulation into tissues into macrophages, and at the same time activate macrophages and neutrophils that are locally aggregated in inflammation.
  • Activated macrophages and neutrophils can produce and secrete collagenase, elastase, plasmin activator, etc., and remove various necrotic tissues, cell debris, bacterial lysates, etc.; in addition, endothelial cells and epithelial cell surfaces contain
  • the GM-CSF receptor, GM-CSF directly promotes endothelial cell migration, proliferation and activation, allowing new squamous epithelium to cover the wound.
  • the present invention has developed a new use of rhGM-CSF in the preparation of a topical preparation for treating cervicitis and/or cervical erosion.
  • the external preparation contains 0.0001 to 0.1% by weight of rhGM-CSF. Preferably, it contains 0.0005 to 0.05% of rhGM-CSF.
  • the external preparation of the present invention includes a vaginal solution, a vaginal ointment, a vaginal gel, and a vaginal suppository.
  • the vaginal solution, the vaginal ointment, the vaginal gel and the vaginal suppository further comprise the following components in terms of weight percentage: pH regulator 0.5 ⁇ 5 %, stabilizer 0.1 ⁇ 5 %, bacteriostatic agent 0.025 ⁇ 5 %, Antioxidant 0.01 ⁇ 2%, humectant 0 ⁇ 30%, and absorbent absorbing agent 0.01 ⁇ 3%.
  • the vaginal solution further comprises 60-98% by weight of a solution, and the solution comprises sterile water for injection, physiological saline, physiological environment buffer.
  • the vaginal ointment further comprises 20 to 90% by weight of the ointment base.
  • the ointment base is selected from any one or more of the following materials: porpoise, vegetable oil, hydrogenated vegetable oil, hydrogenated hydrogenated castor oil, petrolatum, paraffin, ozokerite, liquid paraffin, lanolin, lanolin, beeswax, white Beeswax, cetyl, cholesterol, monovalent soap, cetyl alcohol, stearyl alcohol, sodium lauryl sulfate, sodium stearyl sulfate, glyceryl monostearate, polyglyceryl stearate, Tween - (20, 21, 40, 60, 61, 65, 80, 81, 85) Polyoxyethylene (40) stearate, glycerin gelatin, starch glycerin, sodium alginate, polyethylene glycol, methyl cellulose, Sodium hydroxymethylcellulose, vinyl pirone iodine.
  • the vaginal gel comprises 1 to 90% by weight of the gel matrix.
  • the gel matrix is selected from any one or more of the following: water soluble matrix: glycerin, propylene glycol, carbomer, alginate, gelatin, tragacanth, sodium hyaluronate, povidone, Poloxamer, chitosan, polyvinyl alcohol, povidone, methylcellulose, hypromellose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, xanthan gum, shell poly Sugar, phospholipids, liquid paraffin, polyoxyethylene, fat, colloidal silicon, aluminum soap, zinc soap.
  • the vaginal suppository further comprises 40 to 90% by weight of the suppository base.
  • the suppository base is selected from any one or more of the following: cocoa butter, fragrant fruit fat, semi-synthetic cocoate, mixed fatty acid glyceride, semi-synthetic fatty acid ester, propylene glycol stearate, glycerin gelatin, Polyethylene glycol, polyoxyethylene (40) stearate, Tween 61, Tween 60, carbomer.
  • the stabilizer is any one or more of the following: mannitol, glycerin, sucrose, trehalose, dextran, human serum albumin, cyclodextrin.
  • the pro-acceptor is any one or more of the following substances: azone, formyldimethylamine, dimethyl sulfoxide, ethyl nicotinate, propylene glycol, urea, aspartame, strontium Phenoxyl ether, trapolone, vitamin E succinate, neo-hesperidin dihydrochalcone, hesperidin, eucalyptol, N-methyl-2-pyrrolidone, isopropyl myristate .
  • the humectant is glycerin, propylene glycol or a mixture thereof.
  • the antioxidant is selected from one or more of the following: sodium hydrogen sulfite, sodium sulfite, sodium metabisulfite, sodium thiosulfate, sodium formaldehyde sulfoxylate.
  • the bacteriostatic agent is selected from any one or more of the following: sorbic acid, phenol, cresol, chlorocresol, propionic acid, benzoic acid, dehydroacetic acid, methylparaben, paraben Ester, propylparaben, vinylpyrrolidone.
  • the pH adjusting agent is selected from any one or more of the following: hydrochloric acid, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, citric acid, acetic acid, sodium acetate, maleic acid, sodium maleate, cesium Sodium citrate, boric acid, sodium borate, citric acid, sodium citrate, histidine.
  • the preparation method of the vaginal ointment of the present invention is to use 20 to 70% of the mooring percentage by weight. Mol is melted at 65 ⁇ 75 °C, 0.025 ⁇ 2% sorbic acid, 10 ⁇ 30% glycerol, etc. are added to the molten kabom matrix, and mixed evenly. When the temperature drops to 38 ⁇ 42 °C, 0.01 ⁇ 3 % human albumin and 0.0001 ⁇ 0.1 % rhGM-CSF solution, cooled, canned.
  • the vaginal gel preparation method of the invention is prepared by melting 1 ⁇ 10% of the carbomer by weight at 65 ⁇ 75 °C, 0.025 ⁇ 2 % sorbic acid, 10 ⁇ 30% glycerol, etc. respectively In the molten kabom matrix, mix well. When the temperature drops to 38 ⁇ 42 °C, add 0.01 ⁇ 3 % human albumin and 0.0001 ⁇ 0.1% rhGM-CSF solution, cool and canned.
  • the vaginal suppository of the invention is prepared by melting 60-90% glycerin gelatin at 65-75 ° C by weight percentage, adding 0.025-2% sorbic acid to the molten glycerin gelatin matrix, and mixing uniformly. When the temperature drops to 38 ⁇ 42 °C, add 0.01 ⁇ 3 % human albumin and 0.000:! ⁇ 0.1% rhGM-CSF solution is added to the above matrix, finally filled, cooled, shaped, demolded, packaged.
  • the rhGM-CSF external preparation of the present invention has a remarkable effect on cervicitis and cervical erosion, and has a high cure rate and is not easy to relapse.
  • Figure 1 is a histopathological chart of normal animals
  • Figure 2 is a histopathological map of the cervicitis animal model group
  • Figure 3 is a histopathological chart of normal animals
  • Figure 4 is a histopathological map of the cervicitis animal model group
  • Figure 5 is a histopathological diagram of the animal neck of the rhGM-CSF solution group
  • Figure 6 is a histopathological histogram of the rhGM-CS F ointment group
  • Figure 7 is a histopathological histogram of the rhGM-CSF gel group
  • Figure 8 is a histopathological histogram of the rhGM-CSF suppository gel group
  • Figure 9 is a histopathological map of the cervix of the positive drug group.
  • Example 3 rhGM-CSF solution 0.01 g of confrontation gold methyl ester and 0.015 g of sorbic acid were dissolved at 70 ° C, and 1 g of human albumin was added to rhGM-CSF 50 (g, and the volume of sterile water for injection was adjusted to 100 g. Filling.
  • Example 11 rhGM-CSF ointment 1 gram of Carbomer 941 melted at 74 ° C, adding 1 gram of sodium dodecyl sulfate (SDS), 25 grams of hydrogenated castor oil, 2 grams of triethanolamine, 10 grams of glycerin, swell overnight, the next day to make up Water volume (40 g), 115 ° C, sterilization for 20 minutes, reduce the temperature to 40 ° C, add 1 g of human albumin and rhGM-CSF ⁇ plus sterile water to 100 g, stir well, canned, Let cool, seal.
  • SDS sodium dodecyl sulfate
  • octadecyl alcohol 80 g was melted at 70 ° C, and Tween-80 2 g, 15 g of glycerin, and 0.016 g of paraben were added. The mixture was swollen overnight, and the next day was made up of water (40 g), 115 ° C, For 20 minutes, reduce the temperature to 40 ° C, add 3 grams of human albumin and rhGM-CSF 20 ( ⁇ g, add sterile water to 100 grams, stir well, then canned, let cool, seal.
  • fatty acid glyceride 90 g was melted at 70 ° C, 0.026 g of sorbic acid and 1 g of glycerol were added to the molten matrix, uniformly mixed, 115, sterilized for 20 minutes, and added to human blood when the temperature was lowered to 40 ° C.
  • Positive control drug Aibo therapy vaginal suppository (polycresol sulfonaldehyde vaginal suppository, Germany Baikedun Pharmaceutical Factory)
  • mice Female Kunming mice (18-20 g) were purchased from the Animal Department of Bethune Medical School of Jilin University. Animal model
  • test drug rhGM-CSF solution, ointment, gel and suppository were administered vaginally by O.lg (containing rhGM-CSF1.6 g) in 20g rats, and the rats were sacrificed after 4 weeks of administration. Animals, animals were removed, immediately placed in formalin fixative, paraffin sections, HE stained, and histopathological examination under a microscope.
  • Table 2 Changes in body weight after vaginal administration for two weeks. Number of animals Positive 3 ⁇ 4 blank rhGM-CSF rhGM-CSF rhGM-CSF rhGM-CSF positive drug control group solution group solution group soft sputum group gel group suppository group control group
  • Table 3 Changes in body weight after vaginal administration for three weeks. Number of animals Normal blank rhGM-CSF rhGM-CSF rhGM-CSF rhGM-CSF rhGM-CSF positive drug control group Solvent group Solution group Soft agent group; Gel group Suppository group Control group
  • the squamous epithelium and columnar epithelium are generally normal, and the interstitial and glandular membranes are normal. The results are shown in Figure 1.
  • the inflammatory reaction is obvious, the inflammatory cells infiltrate more, some columnar epithelial loss is missing, the structure is unclear, the interstitial blood vessels are congested, the inflammatory cells are infiltrated, the gland is dilated, and a small amount of inflammatory cells infiltrate, and there are more glandular secretions. Histopathological findings showed inflammation and erosion-like changes in the cervix. The results are shown in Figure 2.
  • the squamous epithelium and columnar epithelium are generally normal, with squamous epithelial aging, interstitial and glandular membranes normal. The results are shown in Figure 3.
  • Rhodo-CSF gel group animal cervical histopathology results
  • the positive drug (polycresol sulfone vaginal suppository) has a certain effect on cervicitis and cervical erosion in animals.
  • GM-CSF solution has significant effects on cervicitis and cervical erosion in animals.
  • GM-CSF ointment has a significant effect on cervicitis and cervical erosion in animals.
  • GM-CSF gel has a significant effect on cervicitis and cervical erosion in animals.
  • GM-CSF suppository has significant effects on cervicitis and cervical erosion in animals.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne nouvelle utilisation du rhGM-CSF pour la fabrication d'un médicament à usage externe pour le traitement de la cervicite et/ou de l'érosion cervicale. Le RhGM-CSF peut être utilisé dans la préparation de médicaments à usage externe tel que des solutions, onguents, gels et suppositoires appliqués par voie vaginale. Les médicaments sont efficaces contre la cervicite et/ou l'érosion cervicale, et il y a peu de probabilité de rechute.
PCT/CN2006/001754 2005-07-19 2006-07-19 Utilisation de rhgm-csf pour la fabrication d'un medicament a usage externe pour le traitement de cervicite et/ou de l'erosion cervicale WO2007009382A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNA2005100858615A CN1899605A (zh) 2005-07-19 2005-07-19 粒细胞巨噬细胞刺激因子治疗宫颈炎及宫颈糜烂的新用途
CN200510085861.5 2005-07-19

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3395355A4 (fr) * 2015-12-18 2019-06-12 Talengen International Limited Méthode destinée à prévenir et traiter une érosion cervicale
US11007253B2 (en) 2015-12-18 2021-05-18 Talengen International Limited Method for preventing or treating radiation and chemical damage
CN114272205A (zh) * 2021-12-30 2022-04-05 广州朗圣药业有限公司 一种具有宫颈表面保护作用的凝胶
CN117180492A (zh) * 2023-09-26 2023-12-08 吉林省七维生物科技有限公司 一种含丝素蛋白的凝胶敷料组合物、制备方法及应用

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CN104983671B (zh) * 2015-06-30 2018-11-02 哈尔滨欧替药业有限公司 重组人粒细胞巨噬细胞刺激因子阴道膨胀栓及其制备方法和检测方法
CN105709213A (zh) * 2016-01-29 2016-06-29 上海市同仁医院 一种重组人粒细胞巨噬细胞刺激因子喷雾剂及其制备方法
CN105859869B (zh) * 2016-03-24 2017-06-20 长春金赛药业有限责任公司 粒细胞巨噬细胞刺激因子及其制剂和应用

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HANG L. ET AL.: "GM-CSF Transgene-Based Adjuvant Allows the Establishment of Protective Mucosal Immunity Following Vaccination with Inactivated Chlamydia trachomatis", THE JOURNAL OF IMMUNOLOGY, vol. 169, 2002, pages 6234 - 6331, XP002399132 *
LIN D. ET AL.: "Purification of Secretory Recombinant Human Granulocyte-Macrophage Colony Stimulating Factor", CHINESE JOURNAL OF BIOLOGICAL PRODUCTS, vol. 10, no. 3, 1997, pages 132 - 135 *
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3395355A4 (fr) * 2015-12-18 2019-06-12 Talengen International Limited Méthode destinée à prévenir et traiter une érosion cervicale
US10874721B2 (en) 2015-12-18 2020-12-29 Talengen International Limited Method for preventing and treating cervical erosion
US11007253B2 (en) 2015-12-18 2021-05-18 Talengen International Limited Method for preventing or treating radiation and chemical damage
CN114272205A (zh) * 2021-12-30 2022-04-05 广州朗圣药业有限公司 一种具有宫颈表面保护作用的凝胶
CN114272205B (zh) * 2021-12-30 2023-09-08 广州朗圣药业有限公司 一种具有宫颈表面保护作用的凝胶
CN117180492A (zh) * 2023-09-26 2023-12-08 吉林省七维生物科技有限公司 一种含丝素蛋白的凝胶敷料组合物、制备方法及应用
CN117180492B (zh) * 2023-09-26 2024-04-26 吉林省七维生物科技有限公司 一种含丝素蛋白的凝胶敷料组合物、制备方法及应用

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