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WO1992004368A1 - Substance pharmacologiquement active dite bpc, son procede de preparation et ses applications therapeutiques - Google Patents

Substance pharmacologiquement active dite bpc, son procede de preparation et ses applications therapeutiques Download PDF

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Publication number
WO1992004368A1
WO1992004368A1 PCT/EP1990/001896 EP9001896W WO9204368A1 WO 1992004368 A1 WO1992004368 A1 WO 1992004368A1 EP 9001896 W EP9001896 W EP 9001896W WO 9204368 A1 WO9204368 A1 WO 9204368A1
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bpc
disorders
animals
substance
diseases
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Inventor
Predrag SIKIRIC^´
Marijan Petek
Ivo ROTKVIC^´
Stjepan Mise
Simun Krizanac
Ivan UDOVICIC^´
Ernest Suchanek
Marko Duvnjak
Jerka JUKIC^´
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Priority claimed from EP90119376A external-priority patent/EP0432400B1/fr
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Priority to RO92-200639A priority Critical patent/RO112728B1/ro
Priority to SU5052246A priority patent/RU2104704C1/ru
Publication of WO1992004368A1 publication Critical patent/WO1992004368A1/fr
Priority to BG96324A priority patent/BG61191B1/bg
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to new substance BPC, the process for its preparation from human or animal gastric juice and its use in the therapy.
  • Gastric juice considered as a secretion of the parietal as well as other cells, contains a number of electrolyte components, hydrochloric acid, a number of enzymes, namely, pepsin, other proteinases, rennin, lipase, urease and lysozyme.
  • enzymes namely, pepsin, other proteinases, rennin, lipase, urease and lysozyme.
  • There are present many peptides and peptide fragments e. g. peptide hormons gastrins, a highly potent gastric secretion stimulants, first discovered by J.S.Edkins, Proc.Roy.Soc.L. , 76B, 376 (1905) .
  • glycoproteins In normal gastric juice are present glycoproteins (mucins) , desribed by F.Hanrowitz, Chem. and Biology of Proteins, 1950, p.199., and Intrinsic Factor (IF) , which is a thermolabile mucoprotein with .W. about 60.000. This factor promotes vitamin B 12 absorption, Castle et al, Am.J.Med Sci. 178, 748 (1929).
  • agent BPC was prepared from human or animal gastric juice. This juice was first homogenized, centrifuged, the supernatant was purified by dialysis, ion-exchange chromatography, again by dialysis and lyophilisation and finally the agent BPC was obtained using gel-chromatography, dialysis and lyophilisation.
  • agent BPC was investigated in vitro and in vivo (rat, mouse, rabbit and guinea-pig) and following pharmacological properties were found:
  • mice (18-25 gb.w.) (sacrifice after 30 days of experimental period) of both sexes, BPC was administered i.p., i.v. and i.g..
  • the lethal dose could't be obtained even with high dose such as 100 mg/kg b.w., which is at least 10 3 -10 5 fold higher than minimal effective doses.
  • B. C was injected i.p., i.v., i.g. (30 mg/kg) once a day subsequently over 30 days. No pathological signs (morphological or physiological) were registered.
  • the mean effective doses are from 0.01 to 50 ug/kg by i.p. administration and TI at least 1000.
  • mice Male rats (180-240 g) of istar strain were used. Animals were put in cold water (26°C) for 3 hours or restrainted for 48 hours. After the end of experimental periods the stomach was investigated for the presence of a lesions ("stress ulcers") .
  • the BPC was injected i.p. and intragastrically (0.1 to 10 ug/kg) one hour or 24 hours before of injury induction. A strong protective action of BPC was demonstrated on gastric lesions.
  • the ligation-experi ents were carried out on male rats (160-250g) of Wistar strain. The ligation of the bile duct and the hepatic artery was performed. This procedure induced besides severe ischemic necrotic lesions of liver tissues, also ulcers of the stomach and duodenum in the intervals from 6-24 hours.
  • cysteamine 400 mg/kg s.c. was applied for duodenal ulcer induction in female rats in 24 hours period.
  • BPC was administered i.p. in doses from 0.1-10 ug/kg.
  • the large ulcers induced by described ligation in stomach and duodenum were strongly prevented in BPC treated animals.
  • the cystea ' mine-induced ulcers were also abolished by BPC pretreatment.
  • Isoprenaline (30 mg/kg i.p.) was applied at zero time and 24 hours later.
  • BPC 50 ⁇ g/kg, i.p. was applied one hour before isoprenaline application.
  • the animals were sacrified 24 hours after second isoprenaline administration and investigated.
  • mice Male rats (180-220 g) anaesthetized by urethane were used. The artery carotis was canulated and the blood pressure was recorded on a dynograph. BPC was administered i.v. into v. jugularis in doses of 10 ⁇ g to 5mg/kg. The results showed no changes of arterial tension in animals in a group of rats prepared by above mentioned procedure. A short lasting changes of arterial tension were produced by i.v. administration of noradrenaline, adrenaline, 5-HT, acetylcholine or isoprenaline. The animals pretreated with BPC in doses of 10 ug to 5 mg/kg i.v. did no modified the change of arterial tension induced by used vasoactive substances.
  • BPC was administered i.p. in doses from 0.1 to 10 ⁇ g/kg. It strongly prevented (e.g. given 1 hour before ligation) or completely removed the injury (e.g. injected soon after ligation) .
  • the liver protective action of BPC administered i.p. in doses of 10 ug/kg of body weight one hour before intoxication of rats with carbon tetrachloride given in doses from 0.1-10 ml/kg i.g. or i.p. was demonstrated.
  • BPC (0.01-10 ug/kg i.p./i.g.) prevented also the fatty liver changes induced by 48 hours restraint stress.
  • Antipyretic activity of BPC was investigated in male rats (180-220g) of Wistar strain, using injection of the brewer's yeast.
  • the pretreatment with BP" applied in single doses (5-20 ⁇ g/kg i.p.) one hour before injection of yeast significantly reduced the temperature increase calculated at 30 minute intervals for 3 hours at least.
  • mice Male mice (18-24 g) of both sexes by injections of carrageenin in the hind paws.
  • the BPC was effective in doses of 10 ⁇ g/kg i.p. when injected one hour before of experimental procedure reducing of the volume of edemas induced by mentioned agent.
  • BPC in the same doses was inactive in the (53.5°C) hot plate test in mice unlike opioid agonists.
  • Wistar rats of both sexes were exposed to vapour of 10% formaldehyde one hour daily during 15 days.
  • BPC was administered in doses of 10 ⁇ g/kg i.p. on each day one hour before exposition.
  • the animals were sacrified after 13-15 days of treatment.
  • edemas of the nouse mucosa were significantly smaller and epithelium was preserved in comparison with control group. Secretion was catarrhal and not purulent.
  • mice (20-25 g) .
  • control group treated with saline
  • a purulent secretion was not observed and increased healing rate was consistently noted in all BPC pretreated (10 ⁇ g/kg, i.p., one hour before experimental procedure) animals.
  • the experimental procedure was carried out on rats (170-210 g) of Wistar strain.
  • the skin wounds were produced by a large incision of skin.
  • BPC was administered i.p. in single dosis of 10 ⁇ g/kg before incision.
  • lack of suppuration and edema, poor granulation formation and increased healing rate were consistently found in treated groups.
  • mice (18-22 g) of both sexes BPC was instilled in left eye.
  • the pupil size was measured by means of monocular lens.
  • one group of animals was treated with BPC administered i.p.
  • the results showed that BPC instilled topically did produce miosis.
  • BPC injected i.p. provoked a pupil constriction of about 20%. This effect lasted at least 30 minutes.
  • mice The contact hypersensitivity in mice was induced with application of DNFB (2,4- dinitrofluorobenzene) .
  • Mice was given two sensitizing doses of 25 ⁇ l of 0.5% DNFB (in 4:1 acetone: olive oil) on the previously shaved skin of the abdominal wall in two subsequent days.
  • 72 hours after the last sensitizing dose mice were given challenge of 20 ul of 0.2% DNFB, transrectally in aether anaesthesia. Animals were sacrified 24 hours later and the colon has been examined. Pathological changes in colon were characterized with severe hae orrhagies and ulcerations. These lesion occupied in some animals all parts of colon wall so that perforations can also occur.
  • SUBSTITUTESHEET 20 Effects on the tumor cells a) Two cell lines L-924 and melanoma B-16 were cultivated in vitro under standard conditions. BPC was tested in vitro on its activity on growing of mentioned cell cultures. Two days following the initiation of cell cultures BPC was added in 3% and 0.3% concentration (0.1 ml). Three days later the numbers of cells per culture were determined by cell counter. The results showed that BPC has an inhibition effect on both cell lines e.g. L-924 and melanoma B-16. b) Ehrlich's ascites tumor (EAT) is the tumor which can grow in all strains of mice. It can grow in ascitic or in solid form which depends upon a way of administration of tumor cells. We have tried to determine whether the incubation of EAT cells in BPC solution would change the survival time of mice after s.c. or i.p. injection of such treated EAT cells.
  • EAT Ehrlich's ascites tumor
  • mice received the same dose of tumor cells in the same volume, but these tumor cells were previously incubated in BPC solution (2 ⁇ g/1 ml) . Only 2/15 mice died during the observed period (45 days) , the others survived more than 45 days. Difference between the control and the experimental group was significantly different (p ⁇ 0.01).
  • mice (64) of both sexes, NMR-Y strain (22-28) g) .
  • mice pretreated with saline (0.2 ml) was irradiated with supralethal doses of 9 Gy (Co-60) .
  • Both experimental group (16+16) were irradiated with the same supralethal doses 9 Gy.
  • One hour after irradiation to the first group BPC was administered in doses of 20 ⁇ g/kg b.w.
  • the second group was treated with the same dosis of BPC one hour before irradiation.
  • BPC administered before irradiation increases survival rate after 12 days for 68,75% compared with other test group.
  • mice On albino mice were applied cytostatics (Endoxan, Vincristin, Adriablastin, Cytosin-arabinosid) in LD 50 dosis i.p.
  • BPC was apllied 1 hour before cytostatics in dosis 10 ug/kg, in control group only saline was injected.
  • the group of animals were sacrified on 3, 5, 7 and 11th day of experiment. Investigated were: blood (E,Hb,Htc,L,Tb, abs. number of neutrophiles) , bone marrow, citology and hystology of liver and spleen.
  • L,E,Tb and neutrophile values On the 3 st day of experiment there is no difference between experimental group regarding L,E,Tb and neutrophile values in comparison to control group. But in bone marrow of BPC treated animals were haemopoetic cells still intact, in control animals
  • SUBSTITUTESHEET aplasia is still present. In the 5th day of experiment significantly increases the number of neutrophiles and L until normalisation on 7th day of experiment. In control group the normalisation occurs newer before 11th.
  • the research was performed on ten men, in age from 30 to 40 ears with diagnosis oligoasthenospermis. From these patients there was taken ejaculate after 3 to 4 days of abstinence. After liquefaction (30 min.) to the 0.5 ml of ejaculate is added layer of 0.5 ml of medium.
  • the control medium consisted of HAM-
  • Experimental medium contained additionally 2 ⁇ g/ml or 4 ⁇ g/ml of BPC.
  • Experimental medium contained additionally 2 ⁇ g/ml or 4 ⁇ g/ml of BPC.
  • After traveling time for 90 minutes at 37"C in atmosphere containing 5% of C0 2 in the Horwell Fertility Chamber was determined the number of progressive movable, movable on place and immovable spermatozoa in 1 ml of ejaculate. Preliminary results show no effect on motility of spermatozoa in lower concentration of BPC. In concentration of 4 ⁇ g BPC/ml was found significantly higher % of motility in comparison with control group.
  • BPC The effect of BPC on reproduction was investigated in mice with previous history of three pregnancies. 20 days after cessation of the last lactation, the animals were subjected to copulation. BPC was applied in a dose 10 ⁇ g/kg i.p. once daily each day during all period of pregnancy (19-21 days) and lactation (next three weeks) . Control group received simultaneously an equivolume of saline, the number of offsprings per female and the weight of offspring were daily recorded.
  • SUBSTITUTESHEET A careful statistical analysis revealed consistently a significantly increased number of offsprings per female, as well as surprisingly no difference between their body weight at each studied time interval.
  • the aim of this research was to investigate the effect of BPC on the root resorption of the periodontal soft tissues induced by mechanical injury of the first molar of the albino rats.
  • Experimental group was treated after mechanical injury with solution of BPC (0.02 ml/200 g) .
  • the rats divided in 12 groups were sacrified at interval of 1,3,5,6,14 or 21 days after the final treatment.
  • the right maxillae of all control and experimental rats were removed, fixed in 10% neutral buffered formaline, demineralized with formic acid, embedded in paraffin and sectoned serially at 6 ⁇ in a mesiodistal plane.
  • the sections were stained with haematoxylin and eosin and examined with the light microscope.
  • Histologic findings in the first molar of the rats from the control groups were: the presence of high number inflammatory cells was registered. A small resorption lacuna was observed between 1-3 days in part of the root surface at the alveolar crest level. At 5th day, the resorption lacuna extended in a coronal direction. The lacuna contained many odontoclasts. At 7th day, the resorption lacuna with many odontoclasts extended further coronally. At 14th and 21st day, the resorption lacuna still extended coronally, approaching part of the lacuna close to the cementoenamel junction.
  • Dementia of the Alzheimer type is characterized by an acquired global impairment of higher cortical functions which affect memory and cognition.
  • Postmortem studies in patients with DAT have demonstrated that the nucleus basalis (NB) neurons undergo a profound and selective degeneration. These neurons are the major source of extrinsic cholinergic innervation to the cerebral cortex.
  • the purpose of the present study was to investigate the influence of BPC on the passive avoidance behaviour in the rat with bilateral electrolytic lesions of the NB. Namely, rats with lesions of the NB may represent an experimental model of DAT.
  • the NB lesioned animals received saline solution (control group) or BPC solution 10 ⁇ g/kg i.p. (test group) .
  • Tested substances were injected: a) only once, immediately after the NB lesions were made, or b) once a day in the course of four consecutive days after the NB lesions were made.
  • BPC was also administered once per day in the course of four training days, one hour before the passive avoidance experiment started.
  • Statistical significance was calculated according to the analysis of variance combined with Duncan's test for multiple comparisons (p ⁇ 0.05). The resuls of investigation showed that:
  • Animals were receiving saline in control group and BPC in doses of 10 ⁇ g/kg i.v. once per day during nine postsurgery days.
  • BPC can be a promising drug in the treatment of damaged neuron function (brain or spinal cord trauma) and that BPC should be given as early as possible after neurons damage.
  • BPC 1419 healthy pigs (from total 4306 pigs) received BPC (10 ⁇ g/kg b.w., i.m.) immediately after birth, other 1440 at 13 th day of life, 1 day before castration, whereas remaining 1477 received only conventional Fe-therapy. Contusion, culling, mortality, body weight and food consumption were assessed after 4 weeks. BPC, applied only once significantly decreases culling rate (in the group treated with BPC immediately after birth) and contusion rate (in both groups treated with BPC) . Same body weight was obtained in BPC treated animals with markedly lower consumption of food.
  • Antiviral activity was investigated in vitro and in vivo (mice).
  • BPC was used in dose of 10 ⁇ g/kg b.w., i.p. or T.e.v.
  • Remarkable activity was found against entero-viruses (Echo type: 6, 9, 11 and 16; Coxsackie type: A9, B3 and B4) , CNS viruses (Ixode encephalities, LCM choriomeningitis) and ARBO viruses (Tahyna, Bhanja, and Calovo) .
  • Prolonged survival 72 hours to absolute survival was noted in infected mice.
  • liver cirrhosis liver cirrhosis
  • SUBSTITUTESHEET 8. therapy before as well as after surgery also in other surgical liver operations (e.g. con ⁇ genital malformations, benigne and malignant bile duct stenosis) ;
  • shock (regardless ethiol ⁇ gy) ;
  • osteoarthrosis 33 .
  • glaukoma decrease of the intraocular pressure - dopamin and pilokarpin like activity
  • diabetes mellitus 45. diabetes mellitus; XV
  • Substance BPC was called according to the abrevitation of the statement: "Body Protecting Compound”.
  • a tibial fracture was induced by digital pressure using hipomochlion.
  • the animals were sacrificed at days 5, 8, 9, 12 and 30 after fracture induction.
  • the nasal mucosa was burned bilaterally by glowing thermocauter during 5 seconds. The animals were sacrificed at day 5, 9, 30 after lesions induction.
  • Carageenin (1%) was applied (0.05 ml s.c.) in the paw, as inflammatory agent; volume of the paw was measured 3 hours latter using the standard procedure.
  • the siccoferment was used (2,5 g/kg, i.p.). The temperature was thereafter measured rectally during 3 hours.
  • the animals were immobilized during 24 hours. Indomethacin was applied at the start of immobilization (0 hour) , and 12 hours latter. After the end of 24 hours period, the animals were sacrificed.
  • the investigated solution was applied: locally or intraperitoneally.
  • the pupille diameter was measured in the suitable time intervals (5, 10, 15, 30, 60, 90 and 120 minutes) according to standard procedures.
  • SUBSTITUTESHEET significantly decreased the myocardial damages, and lowered the values of CPK.
  • Pathohistological examination confirmed the macroscopically observed differences and changes.
  • the effects of the supstance on the CNS were investigated by observing the behaviour of animals (mice) .
  • BPC shows no effect on gutt smoot muscle in vitro (guinea pig) .
  • BPC like other egzogenous proteins
  • the action of BPC is a sequella of one of the following mechanism: direct interaction of the protein,or its fragments, with cell receptors; stimulation or inhibition of release of biologically active (stimulatory or inhibitory) proteins or non-proteins, through receptor or non-
  • liver cirrhosis liver cirrhosis
  • extraarticular rheumatic diseiase bursitis, tendinitis, sinovitis, humeroscapular periarthritis
  • diabetes mellitus XV diabetes mellitus XV
  • the application of the substance will be per os or parenterally, in the form of pills, capsules, dragees, lingualets, suppositories, vaginalets, injection sollutions, nasal spray, unguents, creams, gels, spray, eye drops, ear drops, nasal drops.
  • technique :
  • the material was stored at 2°-8°C.
  • the material is homogenised. Than it is centrifugated (12000 G ⁇ /30 min.). After that the supernatant is colected. 200 ml of supernatant is dialysed in water (+4°C), 1:125, meaning until a conductibility of lOO ⁇ S is achiewed. After that the dyalisate is lyophilised.
  • the dry rest is dissolved in 10ml of redestilled water and applied onta chromatographic column with a modiffied DEAE ion-exchange gel (40-80 um) . The column is 25x250 mm.
  • a buffer Na acetate 0,01 M, pH 5,2 was used for dilution. Fraction detection was by an UV detector in the range of 2800 nm. The f. actions of 40 - 120 ml were collected. The eluate was first concentrated by AQUACIDE - 3 (Calbiochem, USA) and than lyophilized.
  • the dry substance is dissolwed in 10 ml 0,2 M phosphate buffer, ph 7,4 and than put on 2 chromatograph collumn with SEPHACRYL-S-200, (2,5x450mm) with a flow of l,2ml/min. The fractions of 80 - 200 ml were collected.
  • the BPC substance is characterized by IR an UV spectrum (Fig. 1 and 2) .
  • the substance BPC can be used in the treatment of several diseasesand disorders particularly when normal formation of this agent in organism is insufficient or even absent.
  • Traumatism pre- and post-traumatic treatment
  • grafting wounds, burns, fracture, post-surgery complications.
  • Substance BPC will be used as a drug for enteral, local, rectal and parenteral administration.
  • the pharmaceutical compositions are formulated by adding inorganic and organic adjuvants. For tablets and dragees there are added e.g. talc, lactose, starch, stearates etc. for solutions and suspensions there are added e.g. water, alcohols, glycerine etc. For suppositories there are added e.g. natural oils, hardened oils, waxes or polyethylene glycols.
  • the formulations can generally contain suitable preservatives, buffers, stabilizers, surfactants, dissolving intermediaries sweetening agents and dye stuffs.
  • a suitable daily doses for the substance BPC are from 5 to 50 ⁇ g/kg of body weight and can be administered in single dosis or divided in parts.
  • the raw material used for the preparation of the substance BPC was obtained reproducible from stomach juice of 542 patients.
  • the collected material must be stored between +2 and 8°C. It was homogenized before use.
  • Flow was 1.2 ml/ in. Collected were fractions from the 80 th to 200 th ml, dialysed against distilled water, concentrated using Aquacid-3 and then lyophilized. It was obtained 2 mg of white substance.
  • the prepared substance - BPC - is very soluble in water. It decomposes between 180 and 200"C. Molecular weight, determined by gel chromatography is estimated as 40.000 + 5.000 Daltons.
  • the ultraviolet spectrum in water shows absorption in regions as indicated in Fig. 1.
  • the infrared spectrum (in KBr) shows absorption bands in regions as indicated in Fig. 2.
  • Composition mg/supposit.
  • Composition mg/vaginal mg/vaginal
  • substance BPC 0.3 polyethylene glycol 300 150.0 polyethylene glycol 1500 1290.0 polyethylene glycol 6000 700.0 propylen glycol 200.0 tween -40 59.7 lactose 100.0

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Abstract

Nouvelle substance dite BPC et procédé de préparation de celle-ci à partir du suc gastrique de l'homme ou d'un animal, lequel procédé comporte les étapes d'épuration suivantes: la centrifugation, la dialyse, la chromatographie sur échangeur d'ions, la chromatographie sur gel, et la lyophilisation; médicament à usage humain ou vétérinaire et procédé de traitement des maladies et troubles dus au stress, de l'inflammation et des oedèmes, des maladies et troubles à étiologie dopaminergique, du diabète sucré, des maladies et troubles du tube digestif, du coeur, des reins, du pancréas, du foie, des testicules, du système hématopoïétique, du système squelettique, et du sytème nerveux, des démences, des blessures, des brûlures, des fractures, des maladies virales, et de la malignité, ainsi que de certains troubles de la fécondité et du système immunitaire. Ladite substance assure une protection contre les rayonnements ionisants et présente également des applications vétérinaires pour l'élevage à des fins commerciales.
PCT/EP1990/001896 1990-09-11 1990-11-13 Substance pharmacologiquement active dite bpc, son procede de preparation et ses applications therapeutiques Ceased WO1992004368A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
RO92-200639A RO112728B1 (ro) 1990-09-11 1990-11-13 COMPUS DE PROTECȚIE A CORPULUI - BPC Șl PROCEDEU DE PREPARARE A ACESTUIA
SU5052246A RU2104704C1 (ru) 1990-09-11 1990-11-13 Фармакологически активная субстанция защитного соединения организма 3со, способ ее получения и терапевтическое применение
BG96324A BG61191B1 (bg) 1990-09-11 1992-05-11 Методът за получаване на телесно защитно вещество ВРС от човешки или животински стомашен сок, се характеризира със следните етапи на производство: събраният и хомогенизиран животински или човешки стомашен сок се разделя на твърди части и течна супернатанта чрез центрофугиране; течната супернатанта се диализира и лиофилизира; сухият остатък се пречиства през хроматографска колона, напълнена със слабо алкална, модифицирана йонообменна смола или гел; концентратът отново се диализира и лиофилизира; сухият остатък се пречиства чрез гел- хроматография; веществото ВРС се получава накрая от концентрата при използване на диализа и лиофилизация.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP9001533 1990-09-11
EP90119376A EP0432400B1 (fr) 1989-09-12 1990-09-11 Substance BPC pharmacologiquement active, sa préparation et utilisation
EP90119376.3 1990-09-11
USPCT/EP90/01533 1990-09-11

Publications (1)

Publication Number Publication Date
WO1992004368A1 true WO1992004368A1 (fr) 1992-03-19

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PCT/EP1990/001896 Ceased WO1992004368A1 (fr) 1990-09-11 1990-11-13 Substance pharmacologiquement active dite bpc, son procede de preparation et ses applications therapeutiques

Country Status (6)

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JP (1) JP2591875B2 (fr)
AU (1) AU6901191A (fr)
BG (1) BG61191B1 (fr)
HU (1) HU217541B (fr)
RU (1) RU2104704C1 (fr)
WO (1) WO1992004368A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU731317B2 (en) * 1997-05-23 2001-03-29 Marko Duvnjak New BPC peptide salts with organo-protective activity, the process for their preparation and their use in therapy
KR20030067435A (ko) * 2002-02-06 2003-08-14 유지고하라 에너지변환극판과 그 제법
KR20030076007A (ko) * 2002-03-22 2003-09-26 유지고하라 복수자계에 의한 열에너지의 변환장치
WO2018037020A1 (fr) * 2016-08-23 2018-03-01 Pharmacotherapia d.o.o. Compositions et méthodes de traitement des symptômes associés à la sclérose en plaques
CN114632092A (zh) * 2022-05-17 2022-06-17 北京第一生物化学药业有限公司 睾丸片在制备具有降糖活性的药物中的应用

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2179858C1 (ru) * 2001-02-28 2002-02-27 Цыпин Анатолий Борисович Эндоскопическая спленотерапия гастродуоденальных язв
RU2207149C2 (ru) * 2001-04-04 2003-06-27 Закрытое Акционерное Общество Производственное Предприятие "Эндо-Фарм-А" Способ профилактики и лечения желчекаменной болезни
RU2189830C1 (ru) * 2001-05-21 2002-09-27 Общество с ограниченной ответственностью Фирма "ЭЙКОСЪ" Биологически активная добавка "лактогон"

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1963816A1 (de) * 1968-12-26 1970-07-23 Nissui Seiyaku Co Mucoprotein,seine Herstellung und Verwendung

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1963816A1 (de) * 1968-12-26 1970-07-23 Nissui Seiyaku Co Mucoprotein,seine Herstellung und Verwendung

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU731317B2 (en) * 1997-05-23 2001-03-29 Marko Duvnjak New BPC peptide salts with organo-protective activity, the process for their preparation and their use in therapy
KR20030067435A (ko) * 2002-02-06 2003-08-14 유지고하라 에너지변환극판과 그 제법
KR20030076007A (ko) * 2002-03-22 2003-09-26 유지고하라 복수자계에 의한 열에너지의 변환장치
WO2018037020A1 (fr) * 2016-08-23 2018-03-01 Pharmacotherapia d.o.o. Compositions et méthodes de traitement des symptômes associés à la sclérose en plaques
US10350293B2 (en) 2016-08-23 2019-07-16 Pharmacotherapia d.o.o. Compositions and methods for treating symptoms associated with multiple sclerosis
AU2017315091B2 (en) * 2016-08-23 2020-01-23 Pharmacotherapia d.o.o. Compositions and methods for treating symptoms associated with multiple sclerosis
CN114632092A (zh) * 2022-05-17 2022-06-17 北京第一生物化学药业有限公司 睾丸片在制备具有降糖活性的药物中的应用

Also Published As

Publication number Publication date
AU6901191A (en) 1992-03-30
BG61191B1 (bg) 1997-02-28
JPH05503089A (ja) 1993-05-27
JP2591875B2 (ja) 1997-03-19
BG96324A (bg) 1993-12-24
RU2104704C1 (ru) 1998-02-20
HUT61320A (en) 1992-12-28
HU9201941D0 (en) 1992-09-28
HU217541B (hu) 2000-02-28

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