JPH0818990B2 - Stable aqueous liquid preparation of activated vitamin D3 - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION TECHNICAL FIELD The present invention relates to a stable aqueous liquid preparation of active vitamin _D3 .

More specifically, the present invention relates to an aqueous liquid preparation of activated vitamin D3, which is solubilized in water with a nonionic surfactant and stabilized with one or _more chelating agents selected from the group consisting of citric acid, tartaric acid, and metal salts thereof, and an antioxidant.

BACKGROUND ART 1α-hydroxycholecalciferol, 1α-25-
Active vitamin _D3s , such as dihydroxycholecalciferol and 1α,24-dihydroxycholecalciferol, are absorbed into the body and distributed to the intestines, kidneys, parathyroid glands, and bone tissues, where they bind to receptors, and have been shown to exert pharmacological effects such as promoting calcium absorption from the intestines, increasing blood calcium, inhibiting parathyroid hormone secretion, and promoting bone formation. Clinically, they are used to improve symptoms (hypocalcemia, tetany, bone pain, bone lesions, etc.) associated with vitamin D metabolic disorders in chronic renal failure, hypoparathyroidism, vitamin D-resistant rickets, and osteomalacia, as well as to treat osteoporosis.

These active forms of vitamin _D3 are chemically unstable, so they must be stable for clinical use, and many stabilization methods have been proposed.

For example, oral preparations include those disclosed in Japanese Patent Publication Nos. 57-45415, 61-41351, 62-48667, and 63-48667.
Stabilization methods have been disclosed in, for example, Japanese Patent Application Laid-Open No. 62-51948, Japanese Patent Application Laid-Open No. 58-206533, and U.S. Pat. No. 4,729,895 (Japanese Patent Application Laid-Open No. 59-155309), and soft capsules and tablets of 1α-hydroxycholecalciferol, 1α,25-dihydroxycholecalciferol, 1α,24-dihydroxycholecalciferol, etc. utilizing these methods are actually used in clinical settings.

However, all of these relate to methods for stabilizing non-aqueous liquid or solid preparations.

On the other hand, when intravenous administration of activated vitamin _D3 is required for chronic renal failure, or when it is administered continuously to premature babies and infants, for the convenience of administration and to reduce side effects,
Aqueous formulations, particularly stable aqueous liquid formulations, are highly desired in clinical practice.

As a method for stabilizing such an aqueous liquid formulation, U.S. Pat.
JP-A-61-44845 discloses a method for stabilizing 1α,25-dihydroxycholecalciferol in an injection or oral liquid preparation. JP-A-61-17 discloses a method for stabilizing active vitamin _D3 in an aqueous solution by adding certain amino acids.
A variety of stabilization methods have been described.

However, in the course of research into the preparation of aqueous liquid formulations of active vitamin _D3 , the present inventors have found that these conventional techniques have serious practical problems.

That is, the method of the above-mentioned US Pat. No. 4,308,264 has the following two problems.

First, although the method described in U.S. Pat. No. 43,082,641 is certainly effective as a method for stabilizing 1,25-dihydroxycholecalciferol, as described in the specification, the stabilizing effect can only be obtained in the presence of an inert atmosphere.

However, in actual clinical practice, active vitamin _D3
It should be recognized that the administration conditions for aqueous preparations of this type are not necessarily limited to situations where preparations based on the method prepared under an inert atmosphere can be administered under conditions under an inert atmosphere, such as bolus intravenous administration or oral administration, where the entire dosage unit of a preparation prepared under an inert atmosphere is administered at once. For example, even when administered intravenously, when administered simultaneously with other preparations, it is often administered as an intravenous drip infusion rather than as a bolus administration as described above. In such cases, the active vitamin _D3 prepared under an inert atmosphere is often administered as an intravenous drip infusion rather than as a bolus administration.
Such preparations are often mixed with large amounts of other aqueous liquid preparations that are not under an inert atmosphere. For example, when administering oral aqueous liquid preparations to children, it is more convenient and economical to administer a large amount of aqueous liquid preparation in portions rather than using a unit preparation prepared under an inert atmosphere for each administration. In this case, it is impossible to maintain an inert atmosphere once the preparation is used.

The present inventors have found that, in reality, this method has a major problem when the inert atmosphere is violated or when the inert atmosphere is not taken into consideration from the beginning.
Specifically, they found that when the method is not performed in an inert atmosphere, i.e., when oxygen is present, decomposition of active vitamin _D3 occurs, and the decomposition rate is so high that it could be a practical problem.

Therefore, it is an active vitamin that is stable even in the presence of oxygen.
_D3 aqueous liquid formulations are desired.

Secondly, an aqueous pharmaceutical composition of 1α,25-dihydroxycholecalciferol insolubilized in water with a nonionic surfactant at pH 6.4-7.8 under an inert atmosphere and stabilized with a combination of metal ascorbate and disodium edetate (EDTA 2Na) was prepared by this method, and placed in an ampule for storage testing. It was found that the composition was prone to yellowing upon heating, and the degree of discoloration was small enough to occur even during the normal distribution process of pharmaceuticals. Therefore, there is a need for an aqueous solution of 1α,25-dihydroxycholecalciferol that is resistant to discoloration, or an aqueous solution of activated vitamin _D3 that is resistant to discoloration.

As a result of intensive research to solve the above problems, the present inventors discovered that an aqueous liquid preparation of activated vitamin _D3 that is resistant to discoloration and that is stable even in the presence of oxygen can be produced by solubilizing activated vitamin _D3 in water with a nonionic surfactant and adding one or more chelating agents selected from the group consisting of citric acid, tartaric acid, and metal salts _thereof , and an antioxidant, which led to the completion of the present invention.

A commonly known method for producing stable aqueous liquid preparations of fat-soluble vitamins, such as vitamins A, D, E, and K, is to solubilize the fat-soluble vitamins with a surfactant, add an antioxidant and a chelating agent, and, if necessary, add an isotonic agent, a preservative, a buffer, etc. These techniques are described in E. DeRitter, J. Pharm. Sci., 71, 1074 (1982),
(See, e.g., USP 3,070,499 and USP 3,384,545).

Examples of conventionally known chelating agents include EDTA·2Na, citric acid or its metal salts, tartaric acid or its metal salts, various amino acids, phosphoric acid, etc. ("Chemical Stability of Pharmaceuticals" J
(Published by Wiley & Sons in 1986, edited by K.A. Conners et al.) In fact, the specification of the above-mentioned U.S. Pat. No. 4,308,264 uses EDTA·2Na as a chelating agent, and JP-A-62-17
Although the specification of the publication does not mention a chelating agent,
However, there is no known general ranking of the drug stabilizing effects of these previously known chelating agents, and no comparison of their stabilizing effects on aqueous solutions of activated vitamin _D3 has ever been made.

In addition, in the specification of U.S. Pat. No. 4,308,264, the specific effectiveness of EDTA as a chelating agent is confirmed.
- It should also be noted that only 2Na is mentioned, and no other chelating agents are mentioned at all.

Therefore, the present inventors have found (these results will be specifically described in the Examples) that aqueous solutions of active vitamin _D3 containing EDTA.2Na as a chelating agent tend to turn yellow when heated, but
The fact that yellowing is significantly suppressed by using one or more compounds selected from the group consisting of citric acid, tartaric acid and their metal salts instead of EDTA·2Na, and that active vitamin D ₃ in aqueous solution under an inert atmosphere
EDTA-2Na, which is effective in stabilizing vitamin D3, not only loses its stabilizing effect in the presence of _oxygen , but also has the opposite effect.
Among chelating agents other than TA・2Na, hydroxycarboxylic acids such as citric acid and tartaric acid and their metal salts are effective in forming active vitamins in an inert atmosphere or in the presence of oxygen.
It will be understood that the fact that this method is effective in stabilizing vitamin _D3 compounds is completely unexpected based on the accumulated knowledge about methods for stabilizing unstable compounds in aqueous solutions, particularly the known facts about the methods for stabilizing active vitamin _D3 in aqueous solutions described in U.S. Pat. No. 4,308,264 and Japanese Patent Application Laid-Open No. 62-17.

Furthermore, in the specification of U.S. Pat. No. 4,308,264, 1α,25-dihydroxycholecalciferol is stabilized using a metal ascorbate, but the present invention is characterized in that the antioxidant does not have to be limited to a metal ascorbate, and other effective antioxidants can also be used.

That is, in the specification of U.S. Pat. No. 4,308,264, EDT
In order to use EDTA·2Na, it is necessary to significantly reduce the amount of oxygen present (the coexistence of EDTA·2Na and _O2 will have an adverse effect due to the presence of active vitamin _D3 ), and it is thought that sodium ascorbate, which has a high dissolved oxygen absorption capacity, must be used.However, in the present invention, it is not necessary to significantly reduce the amount of dissolved oxygen, so the agent is not necessarily limited to sodium ascorbate.Antioxidant agents such as tocopherol, butylhydroxytoluene, butylhydroxyanthol, propyl gallate, and noridihydroguaiaretic acid may also be solubilized with a nonionic surfactant.

Disclosure of the Invention The present invention relates to an aqueous liquid preparation of activated vitamin D3 that is solubilized in water with a nonionic surfactant and stabilized with one or _more chelating agents selected from the group consisting of citric acid, tartaric acid, and metal salts thereof, and an antioxidant.

BEST MODE FOR CARRYING OUT THE INVENTION The nonionic surfactants used in the present invention include:
Polyoxyethylene sorbitan fatty acid esters, poly
Oxyethylene hydrogenated castor oil derivatives, sorbitan fat
Acid esters, glycerin fatty acid esters, propylene
Glycol fatty acid esters, polyethylene glycol
fatty acid esters, polyoxyethylene alkyl esters
esters, sucrose fatty acid esters, etc.
Among them, polyoxyethylene hydrogenated castor oil derivatives, and
Polyoxyethylene sorbitan fatty acid esters are preferred
One of the polyoxyethylene hydrogenated castor oil derivatives
For example, HCO−60 (manufactured by Nikko Chemicals)
In addition, polyoxyethylene sorbitan fatty acid esters
An example of a terephthalate is polyoxyethylene (20) sol.
Vitamin monooleate (Tween 80 ) are examples.

The chelating agent used in the present invention is one or more chelating agents selected from the group consisting of citric acid, tartaric acid, and metal salts thereof. Citric acid may be anhydrous or monohydrate. Tartaric acid may be any of D-, L-, and DL-isomers. Examples of metal salts of citric acid and tartaric acid include sodium salts and potassium salts, with sodium salts being preferred.

The antioxidants used in the present invention include metal ascorbic acid salts as water-soluble antioxidants and tocopherol, butylhydroxytoluene, butylhydroxyanisole, propyl gallate, and nordihydroguaiaretic acid as fat-soluble antioxidants. In the aqueous preparation, the water-soluble antioxidants are dissolved as they are, while the fat-soluble antioxidants are solubilized with a nonionic surfactant before use. Sodium ascorbate is preferred as the metal ascorbic acid salt.

The active vitamin _D3 used in the present invention is 1α
-hydroxycholecalciferol (1α-OH- _D3 ),
1α,25-dihydroxycholecalciferol (1α,25
-(OH) ₂ - _D3 ), 1α,24-dihydroxycholecalciferol (1α,24-(OH) ₂ - _D3 ), 1α,24,25-
Trihydroxycholecalciferol (1α,24,25-
Active vitamin D3s having a hydroxyl group at the 1α position, such as 25-hydroxycholecalciferol (25-OH- _D3 ), 24-hydroxycholecalciferol (24-OH- _D3 ), 24-oxocholecalciferol, 24,25-dihydroxycholecalciferol (24,25-OH) 2 -D3), 1α-hydroxy-24-oxocholecalciferol, 1α,25-dihydroxy-24-oxocholecalciferol, 1α,25-dihydroxycholecalciferol, 1α, ₂₅ -dihydroxycholecalciferol-26,23-lactone, 1α,25-dihydroxycholecalciferol-26,23-peroxylactone, and 26,26,26,27,27,27-hexafluoro-1α,25-dihydroxycholecalciferol; or 25-hydroxycholecalciferol (25-OH- _D3 ), 24-hydroxycholecalciferol (24-OH- _D3 ), 24-oxocholecalciferol, 24,25-dihydroxycholecalciferol (24,25-OH) _{2 -D3} ), 25-hydroxy-24
Examples of such vitamin _D3 compounds include active vitamin D3 compounds that do not have a hydroxyl group at the 1α-position, such as 25-oxocholecalciferol, 25-hydroxycholecalciferol-26,23-lactone, and 25-hydroxycholecalciferol-26,23-peroxylactone.

These active forms of vitamin D3 _include 1α-OH- _D3 , 1
α,25−(OH) ₂ −D ₃ ,1α,24−(OH) ₂ −D ₃ ,1α,25
-Dihydroxycholecalciferol-26,23-lactone is preferred.

The chelating agent used in the present invention is usually an active vitamin
The amount of the hydroxybenzoate used is 100 to 10,000 parts by weight, preferably 500 to 2,000 parts by weight, per part by weight of D ₃ .

The antioxidant used in the present invention is usually active vitamin D3 _.
The amount of the hydroxybenzoate used is 500 to 20,000 parts by weight per 1 part by weight of the hydroxybenzoate, and more preferably 1,000 to 15,000 parts by weight.

The nonionic surfactant used in the present invention is generally used in an amount of 300 to 500,000 parts by weight per part by weight of active vitamin _D3 , with 1,000 to 10,000 parts by weight being preferred.

The present invention provides an active vitamin _D3 that is stable even in the presence of oxygen.
The present invention provides aqueous liquid preparations of the above type. It is clear from the gist of the present invention that the administration and dosage form of the preparation according to the present invention do not necessarily require the exclusion of oxygen, but the exclusion of oxygen is not prohibited. When oxygen is to be excluded, it is preferable to exclude oxygen dissolved in the liquid, and also to exclude oxygen from the container. For this purpose, it is preferable to pass an inert gas, such as nitrogen or argon, through the liquid and then replace the gas in the container with the inert gas when sealing it in a container.

The present invention provides a stable aqueous solution of active vitamin _D3 , which can be further formulated as an oral or parenteral preparation.

For oral use, it is formulated as a liquid or syrup.
In this case, flavoring agents, seasonings, etc. may also be added.
On the other hand, parenteral preparations include intravenous injections, intramuscular injections,
It is formulated into aqueous liquid preparations such as eye drops. In these preparations, isotonicity agents, preservatives, buffers, soothing agents, etc. can be added. Preservatives include parabens, chlorobutanol, benzalkonium chloride, thimerosal, etc. Buffers include sodium salts of acetic acid, phosphate, etc. Soothing agents include benzyl alcohol, xylocaine, etc.

The method for producing the aqueous injection is described in detail below.

First, activated vitamin _D3 is dissolved in a nonionic surfactant. This is preferably done under an inert gas atmosphere. In the case of a nonionic surfactant that is solid at room temperature, it is necessary to heat it until it becomes liquid. In the case of a liquid nonionic surfactant, activated vitamin _D3 is added to it and dissolved by stirring. Alternatively, activated vitamin _D3 can be dissolved in a small amount of ethanol.
The solution may be added to a nonionic surfactant solution and stirred. The nonionic surfactant solution of activated vitamin _D3 is then added to pre-boiled and cooled distilled water for injection, and simultaneously added with chelating agents, antioxidants, and any desired isotonicity agents, preservatives, buffers, soothing agents, etc., and stirred under an inert gas atmosphere to dissolve. After adjusting and confirming the final volume of the distilled water for injection, the solution is sterilized under an inert gas atmosphere, and the desired amount is poured into sterile, dry ampoules. Before sealing, the gas in the head space of the ampoules is replaced with a permeating inert gas. Thus, an aqueous injectable solution of activated vitamin _D3 can be prepared.

Next, the present invention will be explained in more detail with reference to examples.

EXAMPLE 1 Sterile ampoules having a nominal fill of 1.25 ml/unit were filled with a sterile, stable aqueous solution of 1α,24-dihydroxycholecalciferol having the following composition:

Ingredients Amount/mL 1α,24-Dihydroxycholecalciferol 10 μg Tween 20 4.0 mg Sodium Chloride 1.5 mg Sodium Ascorbate 10.0 mg Disodium Hydrogen Phosphate, Anhydrous 7.6 mg Sodium Dihydrogen Phosphate Dihydrate 2.0 mg Trisodium Citrate Dihydrate 1.0 mg Nitrogen (as needed) Distilled Water for Injection (as needed) This aqueous formulation is manufactured as follows:

40 g of Tween 20 (manufactured by Nikko Chemicals) was taken and heated to 50°C under a nitrogen atmosphere. When the Tween 20 became a solution, 105 mg of 1α,24-dihydroxycholecalciferol was added.
The mixture was stirred under a nitrogen atmosphere until a homogeneous solution was obtained, after which it was cooled to room temperature.

Separately, approximately 11 g of distilled water for injection was heated to 100°C, boiled for 20 minutes, and then cooled to room temperature under a nitrogen gas atmosphere. 10 g of cooled distilled water for injection was mixed with 15 g of sodium chloride, 100 g of sodium ascorbate, and 76 g of anhydrous disodium hydrogen phosphate.
20 g of sodium dihydrogen phosphate dihydrate, 10 g of trisodium citrate dihydrate, and 40 g of the 1α,24-dihydroxycholecalciferol Tween 20 solution were added and slowly stirred under a nitrogen gas atmosphere to obtain a homogeneous solution. The solution was then sterilized under a nitrogen gas atmosphere and filled into a sterile ampoule. The gas in the head space of the ampoule was replaced with nitrogen permeation gas, and the ampoule was then sealed to obtain an aqueous preparation for intravenous injection in an ampoule.

The aqueous injection of 1α,24-dihydroxycholecalciferol (Example 1) was stored under the conditions shown in Table 1.
The stability of 1α,24-dihydroxycholecalciferol and the presence or absence of discoloration of the injection were examined (hereinafter referred to as Experiment A). Separately, an ampoule of this aqueous injection was opened, 1 ml of the injection content was taken, and added to 200 ml of physiological saline. The stability of 1α,24-dihydroxycholecalciferol after 1 hour, 2 hours, and 1 day and the presence or absence of discoloration after 1 day were examined (hereinafter referred to as Experiment B).

Meanwhile, the same experiments A and B as above were carried out on an aqueous injection preparation (Control Example 1) prepared in the same manner as in Example 1 except that EDTA 2Na was used instead of trisodium citrate dihydrate, and an aqueous injection preparation (Control Example 2) prepared in the same manner as in Example 1 except that trisodium citrate dihydrate was not used.

The results of Experiments A and B are shown in Tables 1 and 2.

As shown in Tables 1 and 2, the present invention in Example 1
The aqueous injection of α,24-dihydroxycholecalciferol is stable under both oxygen-free and oxygen-containing conditions and does not discolor.
Control Example 1, which used TA·2Na, showed the same stability as Example 1 under oxygen-excluded conditions, but was significantly discolored and was significantly unstable compared to Example 1 in the presence of oxygen, and was even more unstable than Control Example 2, which did not contain any chelating agent.

Experiments (Experiments A and B) described in Example 1 were also carried out on an aqueous injection of 1α,24-dihydroxycholecalciferol (Example 2) using disodium D-tartrate instead of trisodium citrate dihydrate in Example 1, and on the same aqueous injection using glycine (Control Example 3). The results are shown in Tables 3 and 4.

Examples 3 to 5 Oral aqueous solutions of 1α-hydroxycholecalciferol having the following compositions were prepared.

Ingredients/ml 1α,24-dihydroxycholecalciferol 1.0 μg HCO/6 10.0 mg Sodium chloride 1.5 mg Tocopherol 10.0 μg Disodium hydrogen phosphate, anhydrous 7.6 mg Sodium dihydrogen phosphate dihydrate 2.0 mg Trisodium citrate dihydrate 1.0 mg Purified water (as needed) This aqueous formulation is manufactured as follows.

HCO−60 (manufactured by Nikko Chemicals) and heated to 60°C.
When HCO-60 becomes a solution,
Add 10.5 mg of roxycholecalciferol and stir to mix evenly.
After the solution became homogeneous, it was cooled to room temperature.
Add 15g of sodium chloride and 7g of anhydrous disodium hydrogen phosphate to the water.
6g, sodium dihydrogen phosphate dihydrate 20g, citric acid
10 g of trisodium chloride dihydrate was dissolved in the solution.
−60 60g of HCO-60 was heated to 60℃. is the solution
Once the mixture has reached the desired consistency, add 0.1g of tocopherol and stir until uniform.
After the solution was cooled to room temperature,
O-60 Add the two solutions to the aqueous solution one by one and stir slowly.
This solution was placed in a brown glass bottle.
It is sealed and used as an oral 1α-hydroxycholecalciferol
An aqueous solution of the compound was prepared (Example 3).

At the same time, an oral aqueous liquid preparation (Example 4) was prepared using disodium D-tartrate instead of trisodium citrate dihydrate in Example 3, and an oral aqueous liquid preparation (Example 5) was prepared using butylhydroxytoluene instead of tocopherol in Example 3.

At the same time, as control examples, an oral aqueous liquid preparation (Control Example 4) using EDTA 2Na instead of the trisodium citrate dihydrate of Example 3, and an oral aqueous liquid preparation (Control Example 5) using lysine instead of the trisodium citrate dihydrate of Example 3 were also produced.

These oral aqueous liquid preparations (Examples 3 to 5 and Control Examples 4 to 5) were stored at room temperature and the remaining rate of the active ingredient 1α-hydroxycholecalciferol was examined. The results are shown in Table 5.

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Claims (9)

[Claims] Claim 1: A composition solubilized in water with a nonionic surfactant,
An aqueous liquid preparation of activated vitamin _D3 stabilized with one or more chelating agents selected from the group consisting of citric acid, tartaric acid and metal salts thereof, and an antioxidant. 2. The aqueous liquid preparation according to claim 1, wherein the chelating agent is sodium citrate or sodium tartrate. 3. The aqueous liquid preparation according to claim 2, wherein the amount of the chelating agent is 100 to 10,000 parts by weight per part by weight of active vitamin D ₃ . 4. The aqueous liquid preparation according to claim 1, wherein the antioxidant is one or more antioxidants selected from the group consisting of metal ascorbic acid salts, tocopherol, butylhydroxytoluene, butylhydroxyanisole, propyl gallate, and nordihydroguaiaretic acid. 5. The aqueous liquid preparation according to claim 4, wherein the amount of the antioxidant is 500 to 20,000 parts by weight per part by weight of the active vitamin _D3 . 6. The aqueous liquid preparation according to claim 1, wherein the nonionic surfactant is a polyoxyethylene hydrogenated castor oil derivative or a polyoxyethylene sorbitan fatty acid ester. 7. The aqueous liquid preparation according to claim 6, wherein the amount of the nonionic surfactant is 300 to 500,000 parts by weight per part by weight of the active vitamin _D3 . 8. The aqueous liquid preparation according to claim 1, wherein the activated vitamin D3 is one or _more activated vitamin _D3 selected from the group consisting of 1α,24-dihydroxycholecalciferol, 1α-hydroxycholecalciferol, 1α,25-dihydroxycholecalciferol, and 1α,25-dihydroxycholecalciferol-26,23-lactone. [Claim 9] A method for producing a stabilized aqueous liquid preparation of activated vitamin D3, which comprises preparing a concentrated solution of activated vitamin _D3 and a nonionic surfactant, and then adding the concentrated solution, while stirring, to an aqueous solution containing one or _more chelating agents selected from the group consisting of citric acid, tartaric acid and metal salts thereof, and an antioxidant.