JPH04154724A - Fatty emulsion containing activation-type vitamin d3 compound - Google Patents

Abstract

PURPOSE:To obtain the subject formulation, having improved stability and persistency in vivo as well as affinity with bone marrow, enabling intravenous injection, and concentrated to tissue, comprising fatty emulsion containing said activation-type vitamin D3 compound. CONSTITUTION:A small amount, e.g. 0.01-100mug/ml of activation-type vitamin D3 compound such as 1alpha.25-dihydroxycholecalciferol, 1alpha.24- dihydroxycholecalciferol or 1alpha-hydroxycholecalciferol is contained in a fatty emulsion to afford the objective formulation, effective for chronic renal failure, reduction of parathyroidal function, vitamin D-resistant chachitis, osteomalacia or osteoporosis induced by bone metabolic disorder, etc., enabling intravenous injection, efficiently penetrating said compound into tissue and simultaneously exhibiting sufficient pharmacological effect with a small amount of daily dose of about 0.01-10mug in adults due to improved characteristics thereof by emulsifying with fat.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a fat emulsion containing active vitamin D, a compound.

[Prior art/problems to be solved by the invention] Active vitamin D compounds include vitamin D, such as lα,25-dihydroxycholecalciferol, lα,24-dihydroxycholecalciferol, lα-hydroxycholecalciferol, etc. cholecalciferol) hydroxide. Vitamin D3 is the active form of vitamin D in the liver and kidneys.
These active vitamin D compounds have physiological effects such as promoting the absorption of calcium and phosphorus in the small intestine, promoting the reabsorption of phosphorus and calcium in the back pressure tubules, and regulating bone resorption and bone formation in the bones. is known to have. Therefore, diseases such as chronic renal failure, hypoparathyroidism, vitamin D-resistant rickets, osteomalacia, and osteoporosis due to abnormal bone metabolism, where calcium absorption is decreased due to a lack of active vitamin D. For this purpose, administration of active vitamin D compounds is effective.

However, these active vitamin D compounds are unstable to light and air oxidation, and there is a need for stable pharmaceutical preparations of active vitamin D compounds.

Conventionally, active vitamin D and compound preparations, especially injections thereof, have been prepared by using aqueous injections (JP-A-57-1999) in which active vitamin D and compounds are solubilized with nonionic surfactants along with antioxidants, chelating agents, etc. No. 144218), an injectable preparation in which active vitamin D and the compound are lyophilized together with excipients such as amino acids, monosaccharides, and trisaccharides (Japanese Patent Application Laid-open No.
2-149619) and the like are known.

However, these water-based injections do not contain active vitamin D.
However, it cannot be said that the stability of the compound, its persistence in the body, and its absorptive properties are sufficient.

It is an object of the present invention to provide active vitamin D, a pharmaceutical formulation that is stable and capable of intravenous injection.

Another object of the present invention is to provide a pharmaceutical preparation of an active vitamin D compound that has sustained activity and excellent tissue concentration.

[Means to solve the problem]

As a result of various studies to solve the above problems, the present inventors have developed a lipid emulsion containing active vitamin D, a compound that improves the stability of active vitamin D2 compounds, and improves the stability of active vitamin D2 compounds. The present inventors have discovered that an active vitamin D compound preparation that has a long shelf life, has excellent affinity with the bone marrow, and can be injected intravenously, has led to the completion of the present invention.

That is, the present invention is a fat emulsion containing an active vitamin D compound.

The fat emulsion containing the active vitamin D compound of the present invention may be made of, for example, vegetable oil (e.g., soybean oil, sesame oil, castor oil, cottonseed oil, olive oil, etc., preferably soybean oil), for example, 5 to 5
0% (w/v), 1 to 50 parts by weight, preferably 5 to 30 parts by weight of phospholipids, an appropriate amount of water, and active vitamin D and compounds based on 100 parts by weight of vegetable oil.

The fat emulsion may further contain an emulsification adjuvant [for example,
up to 0.3% (w/v) of a fatty acid having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms, or a pharmacologically acceptable salt thereof], a stabilizer [e.g. %(w/v
), preferably 0.1% (w/v) or less of cholesterol or 5% (w/v), preferably 1% (w/v)
) phosphatidic acid, etc. in the following amounts], polymeric substances [e.g., active vitamin D, 0.1 part by weight of the compound]
~5 parts by weight, preferably 0.5 to 1 part by weight of albumin, dextran, vinyl polymer, nonionic surfactant, gelatin, hydroxyethyl starch, etc.], isotonic agent (e.g., glycerin, glucose, etc.) etc. can also be added.

Examples of active vitamin D compounds used in the present invention include lα-hydroxycholecalciferol, 1
α, 25-dihydroxycholecalciferol, 1α,
24(R)-dihydroxycholecalciferol, ]α
, 24.25-trihydroxycholecalciferol,
1α-Hydroquine-24-oxocholecalciferol, 1α,25-dihydroxy-24-oxocholecalciferol, Iα,25-dihydroxycholecalciferol-26,23-lactone, 1α,25-dihydroxycholecalciferol-26 , 23-peroxylactone, 26.26°26, 27.27.27-hexafluoro-1α, 25-dihydroxycholecalciferol, active vitamin D, compounds, or 25-hydroxycholecalciferol. force luciferol,
24-hydroxycholecalciferol, 24-oxocholecalciferol, 24.25-dihydroxycholecalciferol, 25-hydroxy-24-oxocholecalciferol, 25-hydroxycholecalciferol-26,23-lactone, 25-hydroxy Active vitamin D that does not have a 1α-hydroxyl group, such as cholecalciferol-26,23-peroxylactone.

Examples include compounds.

Among these active vitamin D2 compounds, particularly preferred are 1α-hydroxycholecalciferol,
25-hydroxycholecalciferol, 1α, 25-
Dihydroxycholecalciferol, 1α, 24(R
)-dihydroxycholecalciferol, 25-hydroxycholecalciferol-26,23-lactone, 1
α,25-dihydromushroomlecalciferol-26,
Examples include 23-lactone.

The content of active vitamin D and compounds in a fat emulsion can be adjusted as appropriate depending on the form of the emulsion, the form of administration, etc., but generally a trace amount, for example 0.01
It is sufficient to contain ~100 Jig/rd.

In the above fat emulsion, it is preferable to use high-purity refined soybean oil as the vegetable oil, and more preferably high-purity refined soybean oil (purity nitriglyceride, diglyceride, and 99.9% or more monoglyceride content) is used.

Examples of the phospholipid include purified phospholipids such as egg yolk lecithin and soybean lecithin, which can be prepared by a conventional fractionation method using an organic solvent. That is, for example, crude egg yolk phospholipid is dissolved in cold n-hexane-acetone, acetone is gradually added under stirring, insoluble matter is collected by filtration, and this operation is repeated one more time, and then the solvent is distilled off. Purified phospholipids can be obtained by removing the phospholipids. It mainly consists of phosphatidylcholine and phosphatidylethanolamine, and also contains other phospholipids such as phosphatidylinositol, phosphatidylserine, and sphingomyelin.

This purified phospholipid can also be purified to a higher degree to increase the purity of phosphatidylcholine (Japanese Patent Application Laid-open No. 149524/1983).

Any fatty acid having 6 to 22 carbon atoms can be used as an emulsification auxiliary agent as long as it can be added to pharmaceuticals. The fatty acid may be linear or branched, and it is preferable to use linear myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linuric acid, or the like. As these salts, pharmacologically acceptable salts such as alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, etc.), etc. can be used.

Any cholesterol or phosphatidic acid that can be used as a pharmaceutical stabilizer can be used.

As the albumin, vinyl polymer, and nonionic surfactant used as the polymeric substance, the following are preferable.

That is, as albumin, human-derived albumin is used due to antigenicity issues. Examples of vinyl polymers include polyvinylpyrrolidone and the like. Examples of nonionic surfactants include polyalkylene glycols (e.g. polyethylene glycol with an average molecular weight of 1.000 to 10.000, preferably 4.000 to 6,000), polyoxyalkylene copolymers (e.g. , average molecular weight i, oo.

~20.000, preferably 6.000-10.000
polyoxyethylene-polyoxybrobylene copolymer, etc.), hydrogenated castor oil polyoxyalkylene derivatives [e.g., hydrogenated castor oil polyoxyethylene-(40)-ether, same (20)-ether, same (100)- ether, etc.], castor oil polyoxyalkylene derivatives [e.g., castor oil polyoxyethylene (20)-ether,
the same (40)-ether, the same (100)-ether, etc.] can be used.

Any glycerin or glucose that can be used as a tonicity agent can be used as long as it is medicinally usable.

The fat emulsion used in the present invention can be prepared by various methods, for example, by the following method.

That is, a predetermined amount of vegetable oil (preferably soybean oil), phospholipids, active vitamin D, compounds, and other additives mentioned above are mixed and heated to form a solution, and the solution is prepared using a commonly used homogenizer (for example, a pressure injection type homogenizer). , an ultrasonic homogenizer, etc.) to prepare a water-in-oil dispersion, then add the necessary amount of water to this, and homogenize again with the homogenizer to convert it into an oil-in-water emulsion. By this, fat emulsions can be produced.

Depending on the manufacturing convenience, additives such as stabilizers and tonicity agents may be added after the production of the fat emulsion (Japanese Patent Laid-Open No. 58-2
22014).

The average particle diameter of the active vitamin D3 compound-containing fat emulsion thus produced is preferably 1.0 μm or less.

The active vitamin D compound-containing fat emulsion of the present invention is preferably administered parenterally, particularly by intravenous injection. The dosage varies depending on the administration route, patient's weight, sex, and symptoms, but is generally about 0.01 to 10 μg per adult dose. The frequency of administration is about once to several times a day.

〔Example〕

EXAMPLES In order to explain the present invention in more detail, Examples and Experimental Examples will be given and explained, but the present invention is not limited thereto.

Example 1 30 g of purified soybean oil, 3.6 g of purified egg yolk phospholipid, 900 μg of active vitamin I (lα, 25-dihydroxynilecalciferol), and 0.9 g of valmitinlu sodium.
15 g and 0.155 g of phosphatidic acid were added and dissolved by heating. 200 a of distilled water was added thereto, and then 7.5 g of Japanese Pharmacopoeia glycerin was added, the total amount was mixed with 300 n/g of distilled water for injection, and the mixture was emulsified under high pressure using a Manton-Gallalin type homogenizer. An example in which a homogenized extremely fine fat emulsion containing active vitamin D3 (1α, 25-dihydroxycholecalciferol) was obtained, and the average particle size of this emulsion was 0.2 to 0.4 μm. 2 Sodium palmitate used in Example 1 0, 15
A fat emulsion was prepared in the same manner as in Example 1 except that 0.15 g of sodium oleate was used in place of 0.15 g of phosphatidic acid and 0.15 g of phosphatidic acid.

〔Effect of the invention〕

The active vitamin D compound-containing fat emulsion of the present invention can be injected intravenously and can efficiently transfer the active vitamin D compound to tissues. The drug's stability is improved, its persistence in the body is extended, and its affinity for the bone marrow is increased, so it has the effect that even a small dose can exert its pharmacological effects. Such activity [casting vitamin D,
Compound-containing fat emulsions are effective in treating diseases such as chronic renal failure, hypoparathyroidism, vitamin D-resistant rickets, osteomalacia, and osteoporosis due to abnormal bone metabolism. In addition, active vitamin D, like vitamin D, is hydroxylated in the body. There is no need for it to become active. For this reason, the following. It also has effects. (1) The blood concentration rises quickly and is expected to be fast-acting. Therefore, it is also useful in pulse therapy for secondary hyperparathyroidism in dialysis patients. (2) It is also useful in cases where vitamin D is not effective in patients with disorders in organs related to the metabolic pathway of vitamin D2.

Procedural Dispute Letter (Voluntary) April 2, 1991

Claims (1)

[Claims] Fat emulsion containing active vitamin D_3 compounds.