US3219532A - Preparations having a protracted b12 effect and method of preparing same - Google Patents

Preparations having a protracted b12 effect and method of preparing same Download PDF

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Publication number
US3219532A
US3219532A US195395A US19539562A US3219532A US 3219532 A US3219532 A US 3219532A US 195395 A US195395 A US 195395A US 19539562 A US19539562 A US 19539562A US 3219532 A US3219532 A US 3219532A
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Prior art keywords
vitamin
tannin
suspension
injection
protracted
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US195395A
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English (en)
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Kristensen Knud Morten
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Xellia Pharmaceuticals ApS
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Dumex AS
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    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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 or vitamin B12

Definitions

  • cyanocobalamine and other cobalamines are effective in the treatment of pernicious anemia and some other diseases, when applied parenterally.
  • vitamin B forms a complex compound with tannin which is slightly soluble in water, but on trying to inject suspensions of the said compound, it has been found that no protracted effect of consequence is obtained. If zinc ions are also present at the precipitation of the B12 tal'l1'1ll'l complex, the said ions also form part of the complex, and a water-insoluble product is obtained, the injection of an aqueous suspension of which results in a lower blood serum level than in the case of an aqueous B -solution, and in a protracted effect which may last for as long as 3 weeks. The excretion with the urine is correspondingly lower.
  • injection of the said preparation produces serious pains at the site of injection, probably because the tannin acts upon the tissue protein, and even if this inconvenience may be reduced to some extent upon addition of a local anesthetic, it cannot be completely removed. Further, a still longer protraction would be desirable.
  • the present invention relates to preparations, which do not give any inconveniences upon injection, and by means of a single injection of which a satisfying blood serum level can be obtained and maintained for a considerably longer period than hitherto possible.
  • the said preparations comprise a complex compound of a vitamin B -active substance and tannin suspended in a pharmaceutically acceptable solution of aluminium monostearate in a solvent selected from the group consisting of vegetable oils and liquid fatty acid esters.
  • oils which may be used as a suspension medium
  • oils may be mentioned olive oil, sesame oil and peanut oil.
  • a usable ester of a fatty acid may be mentioned isopropyl myristate.
  • an antioxidant such as cysteine, should be added to the oil to counteract oxidative decomposition of the tannic acid moiety of the complex.
  • the present oil suspensions also show good results when zinc forms part of the complex, and in a preferred embodiment of the present method, therefore, a complex compound of vitamin B zinc and tannin is used according to the invention.
  • incorporation of a metal, for example zinc, in the complex does not result in a greater protraction as observed in aqueous suspensi-ons, so that the protracted effect of the present composition is due to other causes.
  • a complex compound is preferably used in which the tannin component is a fraction of the said kind produced from tannin, forming an article of commerce.
  • a particularly simple method of producing the present preparation consists in producing the complex compound by mixing aqueous solutions of the components, whereby the complex compound. forms a precipitate which is filtered off, dried and ground into the suspension medium.
  • the antioxidant such as cysteine
  • the antioxidant is preferably added to the solution of alu minium monostearate.
  • the ratio of B to tannin may be from 1:2 to 1:5, preferably 1:4, and the preferred suspension ratio is from 2501000 ,ug. per ml. of vegetable oil.
  • EXAMPL'E 1.-B -TANNATE SUSPENSION Under aseptic conditions and using sterile vessels, 500 mg. of B are dissolved in 100 ml. of sterile water, and the solution is sterile-filtered into a suction flask. The filter is washed with 3 x 5 ml. of sterile water, whereafter a solution of 2000 mg. of tannin and 200 mg. of cysteine in 50 ml. of sterile water is also sterile-filtered into the flask. The filter is then washed with 2 x 10 ml. of sterile 1% aqueous NaCl-solution. After standing in a refrigerator for 30 minutes, the precipitate is removed by filtration, and dried in vacuum over P According to a spectrophotometric determination, the resulting powder contains 0.40 mg. of B per mg.
  • EXAMPLE 3 .B -BISMUTHTANNATE SUSPENSION In the manner described in Example 2, solutions of 30 mg. of B in 5 ml. of Water, 80 mg. of tannin and 60 mg. of cysteine in 5 ml. of water, and 10 mg. of bismuthsodium tartrate in 5 ml. of water, respectively, are introduced in the said order into a flask through a glass filter and there is washed with 5 ml. of water after the addition of each of the solutions. The resulting precipitate is isolated by centrifuging. A spectrophotometric determination shows that the liquid, which is centrifuged 015?, contains 0.08 mg. of B per ml. or in all 8% of the initial amount of B After drying in vacuum over P 0 the precipitate is ground with 10 mg. of cysteine in 55 ml. of a 2% solution of aluminium monostearate in sesame oil to form the final suspension.
  • Table 1 the amount remaining on the injection site at different times after the injection is given in percent of the injected amount.
  • Table 2 gives the percentual amount which has been excreted with the urine during the 1', 2, and 3 day after the injection,
  • Intramuscular injection of the preparations F, G, H and J specified hereinafter has further been made in healthy human beings, and the B contents in the blood serum and urine have been followed by means of microbiological determinations with Lactobacillus leichmannz'i.
  • the injections, each of which contained 300 ,ug. of vitamin B were made in the manner that each test person got all 4 preparations successively and with suitable intervals, the injections being made in the order of G, F, H and I, and the results of the microbiological determination for a test person chosen at random appears from the following Tables 3 and 4 where the blood serum level of B is given in pg. per ml., and the excretion with ing to 500 g. of vitamin B The excretion with the urine during the first day was here 0.12 g. of B corresponding to 0.2 pro mille.
  • the determinations of B in the urine have been made microbiologically with Loctobacillus leichmannii, and in the same manner the blood serum levels of B were determined.
  • the values of the latter, which have been determined until now, is given in the following Table 5 in pg. per ml.
  • the blood serum level in healthy persons is between 150 and 800 the urine lS given in ,ug. of B per day. pg. per ml.
  • Patient No. 1 got an intramuscular injection of 540 g. of vitamin B in aqueous solution, of which 412 ,ug. or 77% were excreted with the urine during the first day.
  • Patient No. 2 got an injection of 1 ml., corresponding to 1000 ,ug. of vitamin B of a suspension of B -zinc tannate in oil suspension with aluminium monostearatc. During the first day after the injection 0.4 g. were excreted with the urine, corresponding to 0.4/ of the injected dose.
  • Patient No. 3 got 1 ml. of a suspension of B -zinc tannate in oil with aluminium monostcarate correspond- It appears from the table that the blood serum level for patient No. 1 having a very high value immediately after the injection, has decreased to under the allowable level in the course of 16 days, whereas patient No. 2 after 19 days and patient No. 3 after 34 days still show blood levels above the average value of above 400 pg. per ml. for normal persons.
  • Patient No. 3 whose blood serum level at present has been followed for 54 days, has still a blood serum level of twice the minimum value for healthy human beings.
  • a preparation having a protracted vitamin B effect comprising a complex compound of a vitamin B -active substance and tannin suspended in a pharmaceutically acceptable solution of aluminium monostearate in a solvent selected from the group consisting of vegetable oils and isopropyl myristate.
  • a preparation having a protracted vitamin B ei iect comprising a complex compound of a vitamin B -active substance, zinc and tannin suspended in a pharmaceutically acceptable solution of aluminium monostearate in a solvent selected from the group consisting of vegetable oils and isopropyl myristate.
  • An injectable composition comprising a suspension of a complex compound of a vitamin B -active substance, zinc and tannin, in a solution of aluminium monostearate in a pharmaceutically acceptable vegetable oil.
  • An injectable preparation having protracted vitamin B efiect, consisting essentially of particles of a complex compound of vitamin B -active substance and tannin suspended in a pharmaceutically acceptable suspension of aluminium monostearate in a liquid selected from the group consisting of vegetable oils and isopropyl myristate, the ratio of vitamin B -active substance to tannin being that resulting from precipitating 1 part by weight of the former with 2 to 5 parts by weight of the latter.
  • An injectable composition comprising a suspension of a complex compound of a vitamin B -active substance and tannin, in a solution of aluminium monostearate in a pharmaceutically acceptable vegetable oil.
  • An injectable composition having protracted vitamin B eifect, consisting essentially of particles of cyanocobalamine and tannin, the ratio of the cyanocobalamine to tannin being that obtained by precipitating 1 part by weight of the former with 4 parts by weight of the latter, in a pharmaceutically acceptable suspension of aluminum monostearate in sesame oil, the ratio of aluminum monostearate to oil forming a gel, the ratio of cyanocobalamine and tannin to gel being about 1 to 720 by weight, and the particle size of suspended particles being less than 10 microns.
  • a preparation according to claim 5 in which the ratio of B -active substance to tannin is that resulting from precipitating 1 part by weight of the former to 4 parts by weight of the latter and the oil is sesame oil.
  • a preparation according to claim 5 in which the complex compound is of a vitamin B -active substance, bismuth and tannin.
  • the method comprising preparing a composition having protracted vitamin B effect wherein a vitamin B -active substance and tannin are reacted by admixture in aqueous solution to form a B -active substance con- 8 taining precipitate, separating the precipitate containing active product, and drying the same, and suspending the dry precipitate in a pharmaceutically acceptable solution of aluminum monostearate in a solvent selected from the group consisting of vegetable oils and isopropyl myristate.
  • compositions having protracted vitamin B elfect which consists essentially in heating aluminium monostearate in benzene until a limpid gel is formed, mixing into the gel a vitamin B tannin complex compound, evaporating off the benzene, grinding the residue to a powder to form a pharmaceutically acceptable suspension in a solvent selected from the group consisting of vegetable oils and isopropyl myristate.
  • compositions having protracted vitamin B effect which consist essentially in heating aluminium monostearate in benzene until a limpid gel is formed, mixing into the gel a vitamin B zinc tannin complex compound, evaporating ofi the henzene, grinding the residue to a powder to form a pharmaceutically acceptable suspension in a solvent selected from the group consisting of vegetable oils and isopropyl myristate.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Dermatology (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Compounds Of Unknown Constitution (AREA)
  • Medicines Containing Plant Substances (AREA)
US195395A 1961-05-23 1962-05-17 Preparations having a protracted b12 effect and method of preparing same Expired - Lifetime US3219532A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DK209861AA DK100792C (da) 1961-05-23 1961-05-23 Fremgangsmåde til fremstilling af et præparat med protraheret vitamin B12-virkning.

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US (1) US3219532A (fr)
DE (1) DE1467743A1 (fr)
DK (1) DK100792C (fr)
FR (1) FR1974M (fr)
GB (1) GB960030A (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060280761A1 (en) * 2002-03-11 2006-12-14 Health Plus International, Inc. Nanofluidized B-12 composition and process for treating pernicious anemia

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL79681A (en) * 1985-08-12 1991-06-10 Int Minerals & Chem Corp Transition metal complexes of growth hormones and their prolonged release compositions
JPH0296532A (ja) * 1988-10-03 1990-04-09 Akiomi Yamaguchi トベラ科植物からの水溶性抽出物より成る肝臓疾患治療剤
US6787527B1 (en) * 1994-11-10 2004-09-07 Duke University Methods of preventing and treating HIV infection

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2768112A (en) * 1953-10-21 1956-10-23 Bristol Lab Inc Repository vitamin compositions
US2920015A (en) * 1957-08-27 1960-01-05 Armour & Co Long-acting vitamin b12

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2768112A (en) * 1953-10-21 1956-10-23 Bristol Lab Inc Repository vitamin compositions
US2920015A (en) * 1957-08-27 1960-01-05 Armour & Co Long-acting vitamin b12

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060280761A1 (en) * 2002-03-11 2006-12-14 Health Plus International, Inc. Nanofluidized B-12 composition and process for treating pernicious anemia

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DE1467743A1 (de) 1968-12-12
DK100792C (da) 1965-01-18
GB960030A (en) 1964-06-10
FR1974M (fr) 1963-08-19

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