CA2049374A1 - Use of mixed micelles - Google Patents
Use of mixed micellesInfo
- Publication number
- CA2049374A1 CA2049374A1 CA002049374A CA2049374A CA2049374A1 CA 2049374 A1 CA2049374 A1 CA 2049374A1 CA 002049374 A CA002049374 A CA 002049374A CA 2049374 A CA2049374 A CA 2049374A CA 2049374 A1 CA2049374 A1 CA 2049374A1
- Authority
- CA
- Canada
- Prior art keywords
- vitamin
- solution
- acid
- mixed micelles
- cholanic acid
- 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.)
- Abandoned
Links
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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- 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
- A61P3/02—Nutrients, e.g. vitamins, minerals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Hematology (AREA)
- Biophysics (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract Vitamin K preparations for oral administration, especially in neonatology, are manufactured using cholanic acid/lecithin mixed micelles.
Description
Vitamin K-deficiency haemorrhages in neonates (3-5 days old) 5 have in recent years been diagnosed more and more frequently thanks to new diagnos~ic possibilities. At the same time, since 1980 late vitamin K-deficiency haemorrhages have been observed more and more frequently in infants (3-8 weeks old) who have hitherto appeared healthy.
An effective treatment of this disorder has, in the absence of suitable administration forms, been possible only with great risk for the neonates.
Hitherto, vitamin Kl for administration to neonates has been solubilized with the aid of synthetic solubilizers such as e.g.
C}emophor EL, Tween and Pluronics. When administered parenterally these synthetic micelle formers can occasionally cause various side effects such as e.g. allergic reactions, anaphylactic shock or 20 haemolysis.
In the scope of the present invention it has surprisingly been found that a safe and effective treatment with vitamin Kl by the oral route can be achieved in the form of aqueous mixed micelle solutions.
2s The invention is accordingly concerned with the use of mixed micelles for the manufacture of peroral administration forms of vitamin Kl, especially for use in neonatology.
As the mixed micelles there can be used aqueous solutions of cholanic acid salts and phospholipids which are known, for example, from DE-OS 2 730 570.
As cholanic acids there come into consideration for the solutions 3 s in accordance with the invention trihydroxycholanic acids such as cholic acid, glycocholic acid and taurocholic acid, and di-hydroxycholanic acids such as deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxy acid, glycochenodeoxycholic acid and taurochenodeoxycholic acid. Glycocholic acid is preferred. As Grn/4.7 .9 1 . .
An effective treatment of this disorder has, in the absence of suitable administration forms, been possible only with great risk for the neonates.
Hitherto, vitamin Kl for administration to neonates has been solubilized with the aid of synthetic solubilizers such as e.g.
C}emophor EL, Tween and Pluronics. When administered parenterally these synthetic micelle formers can occasionally cause various side effects such as e.g. allergic reactions, anaphylactic shock or 20 haemolysis.
In the scope of the present invention it has surprisingly been found that a safe and effective treatment with vitamin Kl by the oral route can be achieved in the form of aqueous mixed micelle solutions.
2s The invention is accordingly concerned with the use of mixed micelles for the manufacture of peroral administration forms of vitamin Kl, especially for use in neonatology.
As the mixed micelles there can be used aqueous solutions of cholanic acid salts and phospholipids which are known, for example, from DE-OS 2 730 570.
As cholanic acids there come into consideration for the solutions 3 s in accordance with the invention trihydroxycholanic acids such as cholic acid, glycocholic acid and taurocholic acid, and di-hydroxycholanic acids such as deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxy acid, glycochenodeoxycholic acid and taurochenodeoxycholic acid. Glycocholic acid is preferred. As Grn/4.7 .9 1 . .
2 ~ r ~r~ ~ r~
~ 2 ~
cholanic acid salts there come into consideration especially alkali salts such as the sodium salt.
J
Example of phospholipids are phosphatides such as phos-s phatidylcholines, glycerol ether phosphatides, phosphatidyl-ethanolamine, phosphatidylinositol, phosphatidylserine, plasmol-ogens or sphingomyelins. Phosphtatidylcholines such as soya lecithin and egg lecithin are preferred.
û The molar ratio of lipid to cholanic acid salt conveniently lies between 0.8:1 and 1.5:1.
The amount of lipid plus cholanic acid salt in the solution can vary over wide limits and can be e.g. 50-150 mg/ml.
The amount of vitamin Kl in the mixed micelle solutions can also vary over wide limits and can be e.g. 1-100 mg/ml of solution.
The mixed micelle solutions can be manufactured by simply 20 dissolving and mixing the individual ingredients.
In a special embodiment an aqueous mixed micelle solution of a lipid and a cholanic acid salt is firstly prepared and then the vitamin Kl is added.
2s For example, glycocholic acid is dissolved in purified water Ph.Eur. with the aid of sodium hydroxide and the pH is adjusted to a value of 5.5 with hydrochloric acid. The lecithin is dissolved in the sodium glycocholate solution while stirring and the vitamin Kl is 30 added while stirring.
Purified water Ph.Eur. is added to the thus-obtained vitamin K
mixed micelle solution, the pH is adjusted to a value of 6.0 with hydrochloric acid and the solution is made up to the final volume with 3 5 purified water Ph.Eur.
The solution obtained is conveniently filtered through a suitable filter and filled into suitable containers.
- , - . ...
~ 3 ~ 3 The following Example illustrates in more detail the manu-facture of oral vitamin Kl preparations in accordance with the invention .
Example Composition of a vitamin Kl preparation for oral admini-stration:
Ingredient Per ml Vitamin Kl 10.0 mg Glycocholic acid 54.6 mg Lecithin 75.6 mg NaOH (purest) q s Hydrochloric acid (analytical) q s Water for injection ad 1.0 ml k~nufacture:
a) 1.5 kg of sodium hydroxide are dissolved in 7.0 kg of purified water Ph.Eur. while gassing with N2 and cooling.
1s b ) 21.84 kg of glycocholic acid are suspended in solution a) and brought into solution by the addition of sodium hydroxide (10%) at pH
5.5-6.5. After the glycocholic acid has dissolved completely the pH is adjusted to a value of 5.5 with lN hydrochloric acid.
c) 30.240kg of comminuted lecithin are dissolved while stirring vigorously in the glycocholate solution b) which is heated to 600C.
d) 4.0kg of vitamin Kl are poured slowly into the mixed micelle 2s solution c) and the mixture is stirred until an almost clear solution is obtained .
e) The vitamin Kl mixed micelle solution d) is treated with 265 kg of purified water Ph.Eur. while stirring and cooled to 25C.
~ 2 ~
cholanic acid salts there come into consideration especially alkali salts such as the sodium salt.
J
Example of phospholipids are phosphatides such as phos-s phatidylcholines, glycerol ether phosphatides, phosphatidyl-ethanolamine, phosphatidylinositol, phosphatidylserine, plasmol-ogens or sphingomyelins. Phosphtatidylcholines such as soya lecithin and egg lecithin are preferred.
û The molar ratio of lipid to cholanic acid salt conveniently lies between 0.8:1 and 1.5:1.
The amount of lipid plus cholanic acid salt in the solution can vary over wide limits and can be e.g. 50-150 mg/ml.
The amount of vitamin Kl in the mixed micelle solutions can also vary over wide limits and can be e.g. 1-100 mg/ml of solution.
The mixed micelle solutions can be manufactured by simply 20 dissolving and mixing the individual ingredients.
In a special embodiment an aqueous mixed micelle solution of a lipid and a cholanic acid salt is firstly prepared and then the vitamin Kl is added.
2s For example, glycocholic acid is dissolved in purified water Ph.Eur. with the aid of sodium hydroxide and the pH is adjusted to a value of 5.5 with hydrochloric acid. The lecithin is dissolved in the sodium glycocholate solution while stirring and the vitamin Kl is 30 added while stirring.
Purified water Ph.Eur. is added to the thus-obtained vitamin K
mixed micelle solution, the pH is adjusted to a value of 6.0 with hydrochloric acid and the solution is made up to the final volume with 3 5 purified water Ph.Eur.
The solution obtained is conveniently filtered through a suitable filter and filled into suitable containers.
- , - . ...
~ 3 ~ 3 The following Example illustrates in more detail the manu-facture of oral vitamin Kl preparations in accordance with the invention .
Example Composition of a vitamin Kl preparation for oral admini-stration:
Ingredient Per ml Vitamin Kl 10.0 mg Glycocholic acid 54.6 mg Lecithin 75.6 mg NaOH (purest) q s Hydrochloric acid (analytical) q s Water for injection ad 1.0 ml k~nufacture:
a) 1.5 kg of sodium hydroxide are dissolved in 7.0 kg of purified water Ph.Eur. while gassing with N2 and cooling.
1s b ) 21.84 kg of glycocholic acid are suspended in solution a) and brought into solution by the addition of sodium hydroxide (10%) at pH
5.5-6.5. After the glycocholic acid has dissolved completely the pH is adjusted to a value of 5.5 with lN hydrochloric acid.
c) 30.240kg of comminuted lecithin are dissolved while stirring vigorously in the glycocholate solution b) which is heated to 600C.
d) 4.0kg of vitamin Kl are poured slowly into the mixed micelle 2s solution c) and the mixture is stirred until an almost clear solution is obtained .
e) The vitamin Kl mixed micelle solution d) is treated with 265 kg of purified water Ph.Eur. while stirring and cooled to 25C.
f) The solution e) obtained is adjusted to pH 6.0 with lN hydro-chloric acid and made up to the final volume of 4001 with purified water Ph.Eur.
s g) The solution f) is filtered through a suitable filter candle (e.g 0.2-1.2 mm~ and filled into containers under a N2 atmosphere.
The unexpectedly good activity of the preparations obtainable in accordance with the invention is evident when they are compared o with conventional vitamin K1 preparations.
Figure 1 shows the bioavailability of a conventional solution (rnanufactured with "Cremophor EL") and of the mixed micelle solution in accordance with the invention. The bioavailability which is 5 achieved by intramuscular administration of corresponding solutions serves as the reference (100%).
In the case of oral administration of a solution with a synthetic solubilizer (Cremophor EL) the bioavailability of vitamin K1 was only 20 5% of the comparable i.m. administered preparation (100%).
On the other hand, with a mixed micelle solution an oral bio-availability of vitamin Kl of 115% of that of the comparable i.m.
administered preparation was achieved.
Figure 2 shows the Quick value obtained in the blood of neo-nates 24 hours after the i.în. injection of a mixed micelle solution of vitamin K1 and after the oral administration of the Kl mixed micelle solution in accordance with the present invention, in each case in 30 comparison to the initial value.
The i.m. form of vitamin K1 was not able to increase the initial Quick value within 24 hours after administration (the most important phase of the activity), on the other hand with the oral administration 35 form the Quick value could be raised within 24 hours from about 55%
to 75%, i.e. in the normal range (min. normal range = 70%).
.
, '
s g) The solution f) is filtered through a suitable filter candle (e.g 0.2-1.2 mm~ and filled into containers under a N2 atmosphere.
The unexpectedly good activity of the preparations obtainable in accordance with the invention is evident when they are compared o with conventional vitamin K1 preparations.
Figure 1 shows the bioavailability of a conventional solution (rnanufactured with "Cremophor EL") and of the mixed micelle solution in accordance with the invention. The bioavailability which is 5 achieved by intramuscular administration of corresponding solutions serves as the reference (100%).
In the case of oral administration of a solution with a synthetic solubilizer (Cremophor EL) the bioavailability of vitamin K1 was only 20 5% of the comparable i.m. administered preparation (100%).
On the other hand, with a mixed micelle solution an oral bio-availability of vitamin Kl of 115% of that of the comparable i.m.
administered preparation was achieved.
Figure 2 shows the Quick value obtained in the blood of neo-nates 24 hours after the i.în. injection of a mixed micelle solution of vitamin K1 and after the oral administration of the Kl mixed micelle solution in accordance with the present invention, in each case in 30 comparison to the initial value.
The i.m. form of vitamin K1 was not able to increase the initial Quick value within 24 hours after administration (the most important phase of the activity), on the other hand with the oral administration 35 form the Quick value could be raised within 24 hours from about 55%
to 75%, i.e. in the normal range (min. normal range = 70%).
.
, '
Claims (9)
1. The use of mixed micelles for the manufacture of peroral administration forms of vitamin K1.
2. The use according to claim 1, in which mixed micelles from cholanic acid salts and phospholipids are used.
3. The use according to claim 2, in which the cholanic acid salt is a glycocholate and the phospholipid is lecithin.
4. The use according to claims 1-3 in neonatology.
5. A commercial pack containing a mixed micelle solution of vitamin K1 together with instructions for the oral administration to neonates.
6. A method of treating vitamin K1 deficiencies in humans wherein mixed micelle solution of vitamin K1 are administered perorally.
7. A method as in claim 6 wherein said mixed micelles are formed from cholanic acid salts and phospolipids.
8. A method as in claim 7 wherein the cholanic acid salt is a glycocholate and the phospholipid is lecithin.
9. A method as in claim 6 wherein human neonates are treated.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH267890 | 1990-08-17 | ||
| CH2678/90 | 1990-08-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2049374A1 true CA2049374A1 (en) | 1992-02-18 |
Family
ID=4239125
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002049374A Abandoned CA2049374A1 (en) | 1990-08-17 | 1991-08-16 | Use of mixed micelles |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0471309A1 (en) |
| JP (1) | JPH04244021A (en) |
| AU (1) | AU8178791A (en) |
| CA (1) | CA2049374A1 (en) |
| IE (1) | IE912918A1 (en) |
| ZA (1) | ZA916314B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3391909A1 (en) * | 2017-04-19 | 2018-10-24 | Tiofarma B.V. | Aqueous suspension comprising mixed micelles loaded with a lipophilic physiologically active substance |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2740153B2 (en) * | 1995-03-07 | 1998-04-15 | エフ・ホフマン−ラ ロシユ アーゲー | Mixed micelle |
| CN105997869A (en) * | 2016-06-17 | 2016-10-12 | 合肥华方医药科技有限公司 | Vitamin K1 micelle injection and preparation method thereof |
| CN110876719B (en) * | 2018-09-06 | 2022-08-09 | 中国人民解放军军事科学院军事医学研究院 | Vitamin K1 injection and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1202370B (en) * | 1976-07-12 | 1989-02-09 | Hoffmann La Roche | INJECTABLE SOLUTIONS IN WHICH THE EMOLITHIC LIFE OF NATURAL MICELLES TRAINING AGENTS IS AVOIDED BY THE ADDITION OF LIPOIDS AND RELATED PRODUCTS |
| DE3903753A1 (en) * | 1989-02-06 | 1990-08-23 | Schering Ag | METHOD FOR PRODUCING AQUEOUS MIXED MICRO SOLUTIONS |
-
1991
- 1991-08-09 EP EP91113420A patent/EP0471309A1/en not_active Withdrawn
- 1991-08-09 ZA ZA916314A patent/ZA916314B/en unknown
- 1991-08-12 AU AU81787/91A patent/AU8178791A/en not_active Abandoned
- 1991-08-13 JP JP3226335A patent/JPH04244021A/en active Pending
- 1991-08-16 CA CA002049374A patent/CA2049374A1/en not_active Abandoned
- 1991-08-16 IE IE291891A patent/IE912918A1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3391909A1 (en) * | 2017-04-19 | 2018-10-24 | Tiofarma B.V. | Aqueous suspension comprising mixed micelles loaded with a lipophilic physiologically active substance |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA916314B (en) | 1992-05-27 |
| IE912918A1 (en) | 1992-02-26 |
| JPH04244021A (en) | 1992-09-01 |
| EP0471309A1 (en) | 1992-02-19 |
| AU8178791A (en) | 1992-02-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |