GB2168354A - Hemin compound - Google Patents

Hemin compound Download PDF

Info

Publication number
GB2168354A
GB2168354A GB08431398A GB8431398A GB2168354A GB 2168354 A GB2168354 A GB 2168354A GB 08431398 A GB08431398 A GB 08431398A GB 8431398 A GB8431398 A GB 8431398A GB 2168354 A GB2168354 A GB 2168354A
Authority
GB
United Kingdom
Prior art keywords
hemin
water
amino acid
compound
acetone
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.)
Granted
Application number
GB08431398A
Other versions
GB2168354B (en
GB8431398D0 (en
Inventor
Grels Daniel Ingberg
Ritva Laila Aneri Penttila
Reino Olavi Tokola
Raimo Antero Tenhunen
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.)
MEDICA PHARMA CO Ltd
Original Assignee
MEDICA PHARMA CO Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to SE8406263A priority Critical patent/SE457958B/en
Priority to AT0390784A priority patent/AT389308B/en
Application filed by MEDICA PHARMA CO Ltd filed Critical MEDICA PHARMA CO Ltd
Priority to GB08431398A priority patent/GB2168354B/en
Priority to NL8403782A priority patent/NL192682C/en
Priority to FR848419134A priority patent/FR2574662B1/en
Priority to BE0/214195A priority patent/BE901319A/en
Priority to DE3446887A priority patent/DE3446887C2/en
Priority to LU85716A priority patent/LU85716A1/en
Priority to CH45/85A priority patent/CH666273A5/en
Priority to SU3831925A priority patent/SU1384188A3/en
Priority to JP60009302A priority patent/JPH0647541B2/en
Publication of GB8431398D0 publication Critical patent/GB8431398D0/en
Priority to CA000473658A priority patent/CA1242713A/en
Publication of GB2168354A publication Critical patent/GB2168354A/en
Application granted granted Critical
Publication of GB2168354B publication Critical patent/GB2168354B/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • 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
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/02—Iron compounds
    • C07F15/025—Iron compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)

Abstract

A method for the preparation of a new, physiologically active, water-soluble complex compound of hemin arginate or hemin lysinate in which crystalline hemin and the amino acid L-arginine or L-lysine, in a molar proportion of 1:3, are allowed to react at room temperature under vigorous stirring for 10 to 15 hours in a solvent mixture of acetone and water 300:20 v/v. The hemin arginate or hemin lysinate thus formed is a powdery, stable compound suitable for use as raw material in tablets or capsules or as dry substance for preparation of injections for treatment of various types of anemia, particularly anemias associated with prophyria.

Description

SPECIFICATION Hemin compound The present invention relates to a method for the preparation of a physiologically active water-soluble hemin compound, such as hemin arginate or hemin lysinate suitable for use in tablets or capsules or as a dry substance for injection after reconstitution e.g. with sterile saline solution.
Hemin occurs in the organism as a prosthetic group of hemoglobin in most cytochromes and in certain enzymes. Hemoglobin is synthesized in the bone marrow. When hemin proteins decompose hemin is released, but only a minor part of it is used in the synthesis of new hemin proteins under normal physiological conditions. Hemin is split by the action of hemin oxygenase into biliverdin, which is further reduced to bilirubin. Native, intact hemoglobin does not, naturally, serve as a substrate for hemin oxygenase.
Defects in the hemoglobin synthesis may be due to disturbed synthesis of hemin or of globin chains.
The hemin synthesis may be disturbed because of a) lack of some component necessary for the synthesis, or b) dysfunction of an enzyme catalyzing the synthesis.
a) Iron deficiency is the limiting factor in the hemin synthesis. The organism gets its daily requirement of iron (1-2 mg) with the food. Iron deficiency may be due to a diet deficient in iron or possibly to the presence of iron-binding compounds in the food. Disturbances in the iron absorption mechanism may also lead to iron deficiency despite adequate iron content in the food. Regardless of the cause, iron deficiency sooner or later leads to anemia.
In the rarely occurring vitamin B6 deficiency the absoprtion of iron is normal, but its utilization by the cells is inhibited. As a consequence of this, a certain type of sideroblastic anemia develops.
Iron deficiency anemia is treated either with oral iron preparations (e.g. iron sulphate or iron gluconate) or, more rarely, with injections (iron sorbitol). When the iron absorption mechanism is disturbed, these conventional oral preparations are useless; the iron does not even penetrate into the cells of the intestinal mucosa. In contrast to inorganic iron, hemin iron, in which the iron is bound to hemin, is absorbed by these cells even in such cases of disturbed iron absoprtion which are resistant to conventional oral therapy. Thus, hemin iron is the only known, effective remedy for oral treatment of therapy-resistant cases. Hemin iron has been found to be four to five times better absorbed than inorganic iron even in quite healthy subjects (Seppanen H & Takkunen H: Suomen Laakarilehti 36 : 2071-2072, 1981).
b) The synthesis of hemin is enzymatically regulated. Impaired function of the enzymes catalyzing the hem in synthesis may be either hereditary or due to external factors. It invariably leads to decreased formation of hemin, manifested by the development of porphyria or certain kinds of sideroblastic anemia or other diseases.
Porphyria is the most important group of diseases resulting from impaired enzyme function. In porphyria patients there is an accumulation of porphyrins, intermediary products in the hemin synthesis, and an increased excretion of these into urine and feces. Most kinds of porphyria are manifested by acute attacks which are extremely difficult to master.
Sometimes, sideroblastic anemias of different kinds may develop instead of porphyria as a consequence of dysfunction of enzymes participating in the hemin synthesis. Sideroblastic anemias, too, may be either hereditary or acquired.
The treatment of porphyria has until now been based principally on the avoidance of certain drugs and the administration of large amounts of carbon hydrates during the acute attacks, but the effect has been poor. Since the etiology of porphyria became clarified, intravenous treatment with hemin compounds (hematin) has been continuously gaining ground. Hematin has proved effective in the treatment of porphyria attacks, but in more than 50% of the patients it has caused thrombophlebitis. Moreover, it is very unstable and therefore unsuitable for production on an industrial scale. There are thus very few possibilities for effective treatment of porphyria patients.
The aim of the present invention was to produce a water-soluble hemin iron compound suitable for treatment of anemia, with the iron ready at hand, so to speak, in the hemin molecule. The compound is intended in the first place for treatment of porphyria, where the normal production of hemoglobin is disturbed for some reason or other. The compound is intended for oral administration in tablets or capsules as well as for injection, and should be water-soluble.
Hemin, which is sparingly soluble in water, can be obtained in pure form from blood by extraction with a mixture of hydrochloric or acetic acid from a water solution of hemolyzing erythrocytes. Another method is based on the extraction of hem in with acetone in the presence of e.g. histidylhistidine, pilocarpine, or imidazole at pH 7.0 (Wakid N.W. & Helou K.Y.: Int. J.Biochem. 4 : 259-267, 1973).
The PCT patent application No. 813749 (PCT/F181/00026) described a method for the preparation of a water-soluble hemin concentrate in which about 40% wlw is hemin and the rest is a 'blood substance' of unknown nature. The product is intended for use in lyophilized form as an iron supplement in food or as an antianemic drug.
The drawback of this method is that the final product is a mixture of hemin and 'blood substance'. As the latter component is not uniform, the mixture is unsuitable for injection.
Porphyria has been treated in hospitals with a mixture prepared extempore by dissolving hem in in a sterile sodium carbonate solution (hematin). As this solution is unstable it cannot be manufactured as a commercial product on a large scale. Moreover, hematin causes thrombophlebitis at the site of injection in about 50% of the cases, probably because of the high pH of the solution. This is a serious drawback which reduces the usefulness of the product considerably.
According to one aspect of the invention, there is provided a method of preparation of a physiologi cally active, water-soluble hemin compound suitable for treatment of anemias, such as anemias associated with porphyria, in which crystalline hemin is allowed to react with a basic amino acid in a mixture of an organic solvent and water, at room temperature under agitation for 10 to 15 hours, whereby a complex compound of hemin and the basic amino acid is formed.
The basic amino acid may be L-arginine or L-lysine.
The solvent mixture may comprise acetone and water and the volume ratio of acetone and water is preferably from 300:10 to 300:25, for example 300:20. With such a volume ratio, of the order of 7% water, neither the hemin nor the basic amino acid are dissolved. The reaction takes place with agitation, such as by vigorous stirring, and it is desirable to control the pH value of the reaction medium during the reaction. The product formed during the reaction may be separated and dried; the product is soluble in water, which is important from both the medical and the pharmotechnical points of view.
The molar proportion of hemin to basic amino acid used is preferably from 1:1 to 1:4, for example 1:3.
The hemin molecule contains two carboxyl groups which, it is believed, react with the basic amino groups of L-lysine or L-arginine.
Hemin arginate and hemin lysinate prepared by the method of the invention were dissolved in water, and the pH of the solutions was measured and compared at different time points with the pH of a mechanical mixture of hemin and L-arginine dissolved in water. The results are seen in Table 1.
TABLE 1 pH 0 min. 60 min. 24h Hemin arginate 0.02937 9/25 ml 8.22 8.22 8.22 Hemin lysinate 0.02760 9/25 ml 8.10 7.97 8.13 Hemin + 0.01630 9/25 ml 10.13 9.81 9.33 L-arginine 0.01307 g/25 ml The results of the pH measurements show that the pH of the hemin arginate and hemin lysinate is stable (pH about 8) for up to 24 hours. The pH of the mechanical mixture, on the other hand, decreases very slowly, probably owing to the extremely slow reaction between the carboxyls in the hemin and the amino group in the L-amino acid. A therapeutically useful product cannot therefore be obtained by this method. Hemin arginate and hemin lysinate prepared according to the invention are believed to consist of a complex compound where the L-amino acid has reacted with the hemin carboxyls.
To determine, on the one hand, the optimal molar relation between the two reactants and, on the other, the most suitable composition of the solvent mixture, the following tests were performed with hemin and arginine: Crystalline hemin and L-arginine in molar proportions of 1:2 and 1:3 were allowed to react, under vigorous stirring, in a solvent mixture consisting of an organic solvent and water in varying proportions.
The precipitates formed were filtered off, washed and dried.
The solubility in water was determined by dissolving, under vigorous stirring for about one hour, about 1.0 g of the hemin arginate obtained in each test in 50 ml of distilled water.
The solutions were centrifuged (about 3500 r/min.) and the residue was washed with 10 ml of distilled water and 10 ml of acetone, after which it was dried and weighed. The insoluble residue consisted mainly of unreacted hemin. The test results are presented in Table 2.
TABLE 2 hemin : L-arginine weights molar temp. water (g) proportion solvent ml "C insoluble residue 6.52 : 3.48 1:2 methanol 300 20 tar 6.52 : 3.481:2 ethanol 300 20 =100% 6.52 : 5.22 1:3 ethanol 300 40 20.2% 6.52 : 3.48 1:2 isopropanol 300 20 =100% 6.52 : 3.48 1:2 isopropanol/water 300:20 20 21.2% 6.52 : 5.22 1:3 isopropanol/water 300:20 20 9.7% 6.52 : 3.48 1:2 acetone/water 300:15 20 16.8% 6.52 : 3.48 1:2 acetone/water 300:20 20 12.4% 6.52 : 5.221:3 acetone/water 300:10 20 =100% 6.52 : 5.221:3 acetone/water 300:10 40 11.4% 6.52 : 5.221:3 acetone/water 300:15 20 8.3% 6.52 : 5.22 1:3 acetone/water 300:20 20 0.3% 6.52 :: 5.22 1.3 acetone/water 300:30 20 tar 6.52 :5.221:3 acetone/water 150:10 20 4.2% 6.52 :5.221:3 acetone/water 150:12.5 20 tar The tarry substance formed in some of the tests could not be transferred into powder form.
The preferable molar proportion of hemin to arginine was found to be 1:3 and the most suitable solvent mixture 300 ml of acetone and 20 ml of water, because hemin needs a slight excess of L-arginine to react properly.
The local effect of intravenously infused hemin compounds on surrounding tissues was studied by means of infusing 5 mg/kg into the auricular vein of California White rabbits. A conventional hemin carbonate solution (hematin) was used as reference solution.
After infusion of hemin arginate solution the tissue surrounding the vein remained normal, i.e. no sterile inflammation (thrombophlebitis) occurred.
A similar result was seen after infusion of a corresponding hemin lysinate solution. Thus, it can be concluded that the compounds do not cause thrombophlebitis when infused intravenously.
When a hemin carbonate solution was administered in the same manner, the tissue surrounding the vein became red and irritated; i.e., a manifest sterile inflammation (thrombophlebitis) developed. Three days after the infusion of the hemin carbonate solution the thrombophlebitis was still manifest.
The physiological character of the different water-soluble hemin compounds was assessed by testing the ability of hemin oxygenase to split the compounds. The physiological substrate for hemin oxygenase, methemalbumin, is split by this into biliverdin, which is further reduced to bilirubin by biliverdin reductase.
Thus, the excess hemin which the organism cannot utilize is decomposed, in the first place, by hemin oxygenase into bilirubin and other, closely related substances, which are then normally excreted. The reaction rate limiting enzyme is thus hemin oxygenase.
In our enzymatic analyses, performed in order to find out, for one thing, the ability of hemin arginate and hem in lysinate to serve as substrates for hemin oxygenase, the activity of the reference substrate methemalbumin was expressed by 100. The corresponding value obtained for hemin arginate and hemin lysinate was 106. The activities of other hemin amine derivatives, where the amine component was diethanol amine, ethyl amine, cyclohexyl amine or piperidine, were found to be 13,21,31 and 78 respectively. The tests show that hemin arginate and hemin lysinate behave in the organism like normal physiological compounds with regard to hemin oxygenase.
Embodiments of the invention are described by the following examples given by way of illustration.
Example 1 6.52 g of crystalline hemin (0.01 M) and 3.48 g of crystalline L-arginine (0.02 M) in a beaker provided with a mechanical stirrer and containing a solvent mixture of 300 ml of acetone and 20 ml of water were vigorously stirred for 10 to 15 hours. The product formed was filtered off, washed with acetone, and dried.
Yield of hemin arginate: 9.5 g (95%). Insoluble residue, determined by the method mentioned above: 0.14 g (14%).
Example 2 6.52 g of crystalline hemin (0.01 M) and 4.36 g of crystalline L-arginine (0.025 M) were treated as described in Example 1.
Yield of hemin arginate: 11.1 g (about 100'or.
Insoluble residue: 0.042 g (4.2to).
Example 3 6.52 g of crystalline hemin (0.01 M) and 5.23 g of crystalline Larginine (0.03 M) were treated as described in Example 1.
Yield of hemin arginate: 12.0 g (about 102to).
Insoluble residue: 0.001 g (0.1to).
Example 4 6.52 g of crystallinehemin (0.01 M) and 6.10 g of crystalline L-arginine (0.035 M) were treated as described in Example 1.
Yield of hemin arginate: 12.0 g (9500).
Insoluble residue: 0.0005 g (0.05to).
Example 5 6.52 g of crystalline hemin (0.01 M) and 4.39 g of crystalline L-lysine (0.03 M) were treated as described in Example 1.
-Yield of hemin lysinate: 10.8 g (99to).
Insoluble residue: 0.020 g (2.8to).
It appears that the optimal molar proportion of hemin to arginate is 1:3 (Example 3), because this gave the highest yield of hemin arginate, while the amount of insoluble residue was minimal

Claims (11)

1. A method of preparation of a physiologically active, water-soluble hemin compound suitable for treatment of anemias, such as anemias associated with porphyria, in which crystalline hemin is allowed to react with a basic amino acid in a mixture of an organic solvent and water, at room temperature under agitation for 10 to 15 hours, whereby a complex compound of hemin and the basic amino acid is formed.
2. A method according to Claim 1, in which the basic amino acid is L-arginine or L-lysine.
3. A method according to Claim 2, in which the molar proportion of hemin to basic amino acid is from 1:1 to 1:4.
4. A method according to Claim 3, in which the molar proportion of hemin to basic amino acid is 1:3.
5. A method according to any one of the preceding claims in which the organic solvent comprises acetone.
6. A method according to Claim 5, in which the solvent mixture comprises acetone and water in a proportion of from 300:10 to 300:25 by volume.
7. A method according to Claim 6, in which the proportion of acetone to water is 300:20 by volume.
8. A method of making a hem in compound, substantially as hereinbefore described with reference to the foregoing examples.
9. A hemin compound, preparable by a method according to any preceding claim.
10. A composition comprising a compound according to Claim 9 and a pharmaceutically acceptable carrier.
11. A tablet, capsule or solution for medical use containing a hemin compound according to Claim 9.
GB08431398A 1984-12-12 1984-12-12 Hemin compound Expired GB2168354B (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
SE8406263A SE457958B (en) 1984-12-12 1984-12-10 WATER-SOLUBLE HEMIN ARGINATE OR HEMIN-LYSINATE SOCIETY, PROCEDURE FOR PREPARING THEREOF AND USING THEREOF FOR MANUFACTURE OF MEDICAL COMPOSITIONS
AT0390784A AT389308B (en) 1984-12-12 1984-12-10 METHOD FOR PRODUCING NEW HAEMINARGINATE OR HAEMINLYSINATE
GB08431398A GB2168354B (en) 1984-12-12 1984-12-12 Hemin compound
NL8403782A NL192682C (en) 1984-12-12 1984-12-13 Method for preparing a hemin complex, and drug.
FR848419134A FR2574662B1 (en) 1984-12-12 1984-12-14 PROCESS FOR THE PREPARATION OF A NEW HEMIN COMPLEX AND THE PRODUCT THUS OBTAINED AND MEDICAMENTS CONTAINING THE SAME
BE0/214195A BE901319A (en) 1984-12-12 1984-12-19 HEMIN COMPOUNDS, THEIR PREPARATION AND THEIR USE.
DE3446887A DE3446887C2 (en) 1984-12-12 1984-12-21 Process for the production of physiologically active, water-soluble hemin arginate or hemin lysinate
LU85716A LU85716A1 (en) 1984-12-12 1984-12-28 PROCESS FOR THE PREPARATION OF A NEW COMPLEX HEMINE COMPOUND WITH MEDICAL APPLICATIONS
CH45/85A CH666273A5 (en) 1984-12-12 1985-01-07 METHOD FOR PRODUCING A NEW HAEMIN COMPLEX COMPOUND AND THIS PHARMACEUTICAL PREPARATIONS CONTAINING AN ACTIVE SUBSTANCE.
SU3831925A SU1384188A3 (en) 1984-12-12 1985-01-09 Method of producing stable water-soluble hemin-arginate or hemin-lysate complex compound for treating porphyria
JP60009302A JPH0647541B2 (en) 1984-12-12 1985-01-23 Method for producing novel hemin complex compound for medical use
CA000473658A CA1242713A (en) 1984-12-12 1985-02-06 Process for preparation of a new hemin complex compound with medical applications

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB08431398A GB2168354B (en) 1984-12-12 1984-12-12 Hemin compound

Publications (3)

Publication Number Publication Date
GB8431398D0 GB8431398D0 (en) 1985-01-23
GB2168354A true GB2168354A (en) 1986-06-18
GB2168354B GB2168354B (en) 1988-12-07

Family

ID=10571084

Family Applications (1)

Application Number Title Priority Date Filing Date
GB08431398A Expired GB2168354B (en) 1984-12-12 1984-12-12 Hemin compound

Country Status (12)

Country Link
JP (1) JPH0647541B2 (en)
AT (1) AT389308B (en)
BE (1) BE901319A (en)
CA (1) CA1242713A (en)
CH (1) CH666273A5 (en)
DE (1) DE3446887C2 (en)
FR (1) FR2574662B1 (en)
GB (1) GB2168354B (en)
LU (1) LU85716A1 (en)
NL (1) NL192682C (en)
SE (1) SE457958B (en)
SU (1) SU1384188A3 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003092674A1 (en) * 2002-05-02 2003-11-13 Integrity Pharmaceutical Corporation Prenatal multivitamin/multimineral supplement
RU2611636C1 (en) * 2016-02-25 2017-02-28 Федеральное государственное бюджетное образовательное учреждение высшего образования Новосибирский государственный аграрный университет Hematogen
RU2671633C1 (en) * 2017-11-30 2018-11-06 Общество с ограниченной ответственностью "ОКТАВА ХОЛДИНГ" Highly effective hematogen

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0645681B2 (en) * 1986-02-05 1994-06-15 美浜 久春 Modified hem
IT1245890B (en) * 1991-04-12 1994-10-25 Alfa Wassermann Spa PHARMACEUTICAL FORMULATIONS FOR ORAL USE GASTRORESANTS CONTAINING BILE ACIDS.

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2912M (en) * 1963-07-24 1964-11-09 Rech S Pharma E R P H A R Soc Procaine hematoporphyrinate dihydrochloride.
JPS4930521A (en) * 1972-07-17 1974-03-19
JPS5144623A (en) * 1974-10-14 1976-04-16 Green Cross Corp CHUSHAYOASECHIRUSARICHIRUSANENNO SEIHO
DE2527158A1 (en) * 1975-06-18 1976-12-23 Herz Eberhard MEDICINAL PRODUCTS FOR THE TREATMENT OF INFECTIOUS DISEASES AND INFLAMMATION IN HUMAN AND VETERINAL MEDICINE THAT CANNOT BE DETECTED BY MICROORGANISMS
JPS6021570B2 (en) * 1978-07-04 1985-05-28 三共株式会社 Method for manufacturing high concentration preparations of DOPAs
JPS5780317A (en) * 1980-11-05 1982-05-19 Sumitomo Chem Co Ltd Preparation of pharmaceutical composition for injection
JPS57209211A (en) * 1981-06-18 1982-12-22 Shiseido Co Ltd Antimicrobial composition

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003092674A1 (en) * 2002-05-02 2003-11-13 Integrity Pharmaceutical Corporation Prenatal multivitamin/multimineral supplement
US7994217B2 (en) 2002-05-02 2011-08-09 Xanodyne Pharmaceuticals, Inc. Prenatal multivitamin/multimineral supplement
RU2611636C1 (en) * 2016-02-25 2017-02-28 Федеральное государственное бюджетное образовательное учреждение высшего образования Новосибирский государственный аграрный университет Hematogen
RU2671633C1 (en) * 2017-11-30 2018-11-06 Общество с ограниченной ответственностью "ОКТАВА ХОЛДИНГ" Highly effective hematogen

Also Published As

Publication number Publication date
NL192682C (en) 1997-12-02
CA1242713A (en) 1988-10-04
AT389308B (en) 1989-11-27
FR2574662B1 (en) 1990-03-02
NL8403782A (en) 1986-07-01
JPS61172821A (en) 1986-08-04
SE457958B (en) 1989-02-13
NL192682B (en) 1997-08-01
DE3446887A1 (en) 1986-07-03
GB2168354B (en) 1988-12-07
SE8406263D0 (en) 1984-12-10
JPH0647541B2 (en) 1994-06-22
FR2574662A1 (en) 1986-06-20
GB8431398D0 (en) 1985-01-23
BE901319A (en) 1985-04-16
DE3446887C2 (en) 1994-05-05
ATA390784A (en) 1989-04-15
CH666273A5 (en) 1988-07-15
SE8406263L (en) 1986-06-11
SU1384188A3 (en) 1988-03-23
LU85716A1 (en) 1985-07-24

Similar Documents

Publication Publication Date Title
US8686053B2 (en) Alginic acid with low molecular weight, its salts, uses, preparative methods, pharmaceutical compositions and foods
AU603574B2 (en) Formulations containing unsaturated fatty acids for the synthesis of prostaglandins and hydroxy-fatty acids in biological systems
US4258030A (en) Urokinase preparation for oral administration
US4760135A (en) Phloretin and phlorizin derivative containing compounds
TW201219370A (en) Agent for regulating the formation of nitrogen monoxide
US5008388A (en) Process for preparation of a new hemin complex
US20090247492A1 (en) Manganese based organometallic complexes, pharmaceutical compositions and dietetic products
US4110441A (en) Gamma-l-glutamyl cholamine phosphate
GB2168354A (en) Hemin compound
US4153710A (en) N-(4-[2-(pyrazole-1-carbonamide)-ethyl]-benzenesulphonyl)-urea
US3903285A (en) Method for treating parkinsonism
JPH0859485A (en) Maillard reaction inhibitor consisting mainly of 3-oxygermylpropionic acid compound
CS247187B2 (en) Method of new haemin complex production
JP3406334B2 (en) Tyrosine-specific kinase inhibitors and anticancer agents
US4599328A (en) Therapeutic and preventive agent containing dolichol
US3663700A (en) Therapeutic hypotensive compositions comprising calcium salts of 5-alkylpicolinic acids
US4959394A (en) Novel Guanidinium aspartates
EP0485232A1 (en) Neovascularisation inhibitors
JP2885261B2 (en) Infusion preparation comprising 3-hydroxybutyric acid oligomer and salt thereof
US4774232A (en) Bile-substituting method of treatment for the promotion of fat digestion
DD249028A5 (en) METHOD FOR PRODUCING A NEW HAEMIN COMPLEX COMPOUND WITH MEDICAL AVAILABILITY
DK172797B1 (en) Process for preparing a physiologically active, water- soluble haemin complex, and the use of this complex for producing a pharmaceutical preparation.
KR100344099B1 (en) Novel biphenyldicarboxylate derivative and method for manufacturing the same
PL144343B1 (en) Method of obtaining novel complex compound of hemine with l-arginin or l-lysine
US4239779A (en) Use of phenylglyoxylic acids and derivatives thereof in the treatment of ischemic heart disease

Legal Events

Date Code Title Description
732E Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977)
PCNP Patent ceased through non-payment of renewal fee

Effective date: 20031212