JPS6092212A - Pharmaceutical of doxorubicin salt - Google Patents

Abstract

PURPOSE:A pharmaceutical of doxorubicin salt, obtained by incorporating a dissolution assistant, e.g. a lower alkanoic acid or amino acid, in the doxorubicin salt which is ananthracycline based antitumor agent, and capable of dissolving even in a salt solution in a short time. CONSTITUTION:A least one of a lower alkanoic acid, lower alkanoic diacid, hydroxy lower alkanoic acid, amino acid, and urea-related substances as a dissolution assistant is incorporated in a doxorubicin salt expressed by the formula to give the titled pharmaceutical having improved solubility. A 2-4C hydroxy lower alkanoic acid, phenylalanine, serine, and urea etc. are preferred for the dissolution assistant, and the amount thereof to be used is preferably 1/10-3 times (W/W) of that of the doxorubicin salt. The dissolution time is remarkably reduced as compared with the case in the absence of the dissolution assistant.

Description

[Detailed description of the invention] The present invention relates to formulations of doxorubicin salts.

More specifically, the present invention relates to doxorubicin salts, lower alkanoic acids, lower alkaniic acids, hydroxy or mercapto lower alkanoic acids, amino acids, strong inorganic acids, urea-related substances, phenols, naphthols, and lower alkyl gallates and the general formula X is hydroxy or amino, R
No. 1 relates to a preparation of a doxorubicin salt containing at least one solubilizing agent selected from the group consisting of hydrogen or compounds represented by the formula R2 is hydrogen or lower alkyl.

Doxorubicin salt is an anitracycline-based antitumor agent and is commonly used as a conventional solution.

Doxorubicin salt has the property of gelling in the presence of salts in the case of a highly concentrated aqueous solution or even at low concentrations. Therefore, when dissolving in a saline solution such as physiological saline or Ringer's solution, the concentration becomes locally high at the time of dissolution, and that part becomes a gel. Since the gelled doxorubicin salt has a very slow dissolution rate, it takes a long time to dissolve the preparation, making it inconvenient to use.

Even when the doxorubicin salt preparation of the present invention is dissolved in a saline solution, dissolution is completed in a very short time.

Next, the present invention will be explained in more detail.

Doxorubicin salts used in the present invention include hydrochloride,
Hydrobromide, Hydroiodide, Nitrate.

sulfate, phosphate, acetate, benzoate 7maleate, fumarate, succinate, tartrate, citrate, oxalate, glyoxylate, aspartate, methanesulfonate, Ethanesulf (3) phonate, propane sulfonate, methanedisulfo: /
Examples include acid salts, α, β-ethane disulfonates, benzenesulfonates, and the like.

Among the solubilizing agents used in the present invention, lower alkanoic acids include those having 1 to 6 carbon atoms, such as formic acid, acetic acid, propionic acid, n-acetic acid, and caproic acid. As the lower alkaniic acid, those having 2 to 6 carbon atoms, such as oxalic acid, succinic acid, adipic acid, etc., are used. The hydroxy or mercapto lower alkanoic acid has 2 to 6 carbon atoms and hydroxyl or mercapto 1 or 2. Those containing 1 to 3 carboxyl acids, such as glycolic acid, lactic acid, glyceric acid, citric acid, malic acid, tartaric acid, thiomalic acid, etc., are used. As an amino acid, it is D-form.

Either the L-form or the DL-form may be used, but the L-form is preferable when considering in vivo utilization. A specific example is alanine.

N-acetylcysteine, inleucine, leucine, cysteine, cystine, serine, tyrosine.

Examples include drift fan, threonine, valine, histidine, phenylalanine, proline, and methionine. Hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc. are used as the inorganic strong acid. Urea, urethane, thiourea, guanidine, semicarbazide, thiosemicarbazide, etc. are used as urea-related substances. As the lower alkyl ester of gallic acid, a lower alkyl ester having 1 to 6 carbon atoms is used.

Lower alkyl has 1 to 6 carbon atoms.

Among the compounds represented by the above general formula, particularly preferred are P-
It is lower alkyl hydroxybenzoate.

Examples of the compounds represented by the general formula include methyl P-hydroxybenzoate, ethyl P-hydroxybenzoate, n-propyl P-hydroxybenzoate, n-butyl P-hydroxybenzoate, P-hydroxybenzoic acid, and P-hydroxybenzoate. Aminobenzoic acid, ethyl P-aminobenzoate, salicylic acid, 2-hydroxy-m-Fruyl acid, etc. are used. Among the above solubilizing agents, particularly preferred are hydroxy lower alkanoic acids having 2 to 4 carbon atoms, phenylalanine, serine, urea, thiourea, lower alkyl P-hydroxybenzoate, and the like.

The doxorubicin salt formulation of the present invention typically contains mannitol, lactose, and sorbitol as excipients.

Contains sugars such as dextran, albumin, etc.

The preparation of the present invention can be obtained by mixing doxorubicin salt, an excipient, and a solubilizing agent, or by dissolving these in water and freeze-drying in a conventional manner.Solubilizing agent for doxorubicin salt The amount of agent used is 1
/20 to 10 times the amount, especially 1/10 to 3 times the amount (W/W) is suitable.

Experimental Example Doxorubicin hydrochloride, excipients, and solubilizing agents were pulverized and mixed and filled into a vial, or dissolved in water, filled into a vial, and lyophilized, and the dissolution time was measured as follows. We compared the times.

Inject 5 ml of physiological saline (hereinafter abbreviated as normal saline) as a dissolution solution into a vial using a syringe equipped with a subcutaneous Z-needle for approximately 10 minutes.
Inject in seconds, shake 5 times at a rate of 1 time/1 second, leave to stand, and observe. Thereafter, the container was shaken 5 times every 30 seconds, and the time from the time when the solution was added until the contents were completely dissolved was measured.

The results are shown in Table 1.

10 mg of doxorubicin salt was used in each case.

As is clear from Table 1, in the formulation of the present invention, that is, the formulation to which the solubilizing agent was added, the control formulation, that is,
It can be seen that the dissolution time is significantly shortened compared to the formulation without additives, and the effect of the solubilizing agent is remarkable.

Therefore, it can be seen that the preparation prepared according to the formulation of the present invention is a preparation that dissolves quickly after addition of the dissolving solution.

Next, examples of the present invention will be shown.

Example 1 Doxorubicin hydrochloride 10 mg, lactose 50 mg.

1 mg of methyl p-hydroxybenzoate was dissolved in distilled water for injection to make 2 ml, and the solution was filled into a 5 ml vial and freeze-dried. When 5 ml of normal saline was added and dissolved, the dissolution time was 30 seconds.

Example 2 Doxorubicin hydrochloride 10 mg, lactose 1001+1
30 mg of gs urea was dissolved in distilled water for injection to make 2 ml, and the solution was filled into a 5 ml vial and freeze-dried. When 5ml of saline was added to this and dissolved, the dissolution time was 3
It was 0 seconds.

Example 3 Doxorubicin hydrochloride 10 mg, mannitol 50 mg,
15 mg of citric acid was dissolved in distilled water for injection to make 1 ml, and the solution was filled into a 5 ml vial and freeze-dried. When 5ml of saline was added to this and dissolved, the dissolution time was 3
It was 0 seconds.

Example 4 Doxorubicin hydrochloride 10 mg, mannitol 50 mg,
10 mg of L-phenylalanine was dissolved in distilled water for injection to make 2 ml, and the solution was filled into a 5 ml vial and freeze-dried. When 5 ml of normal saline was added and dissolved, the dissolution time was 30 seconds.

Example 5 Doxorubicin hydrochloride 10mg, lactose 200mg5
Dissolve 20mg of L-leucine in 2ml of distilled water for injection.
The mixture was filled into a 5 ml vial and freeze-dried. When 5 ml of normal saline was added and dissolved, the dissolution time was 30 seconds.

Example 6 Doxorubicin hydrochloride 10+ngs mannitol 50 mg
Dissolve p + (2,3
and further add distilled water for injection to make 2 ml.
The mixture was filled into ml vials and freeze-dried.

When 5ml of saline was added to this and dissolved, the dissolution time was 3
It was 0 seconds.

Example 7 Doxorubicin hydrochloride 10mg, lactose 100mgz
0.8 mg of methyl p-hydroxybenzoate and 0.1 mg of n-propyl p-hydroxybenzoate were dissolved in distilled water for injection to make 2 ml, and the solution was filled into a 5 ml vial and freeze-dried. When 5 ml of saline was added to this and dissolved, the dissolution time was 30 seconds.

Example 8 Doxorubicin hydrochloride 10 mg, lactose 50 mg.

30 mg of urea was ground, mixed, and filled into a 5 ml vial. When 5 ml of normal saline was added and dissolved, the dissolution time was 55 seconds.

Example 9 Doxorubicin hydrochloride 10+++g, lactose 1010
1 mg of methyl p-hydroxybenzoate was ground, mixed, and filled into a 5 ml vial. Add this to raw food 5
The dissolution time when ml was added and dissolved was 50 seconds.

Patent applicant (102) Kyowa Hakko Kogyo Co., Ltd. (11) Procedural amendment (method) 1.Display of the incident 1981 Patent Application No. 200379 2. Name of the invention Preparations of doxorubicin salts 3. Person who makes corrections Relationship to the incident: Patent applicant

Claims (4)

[Claims] (1) Doxorubicin salt, lower alkanoic acid, lower alkaniic acid, hydroxy lower alkanoic acid, amino acid,
Strong inorganic acids, urea-related substances, phenol, naphthol, gallic acid or lower alkyl esters thereof, and those represented by the general formula (wherein, X is hydroxy or amino, R1 is hydrogen or methyl, and R2 is hydrogen or lower alkyl) A doxorubicin salt preparation containing at least one solubilizing agent selected from compounds. (2) The doxorubicin salt preparation according to claim 1, which contains an excipient. (3) The doxorubicin salt preparation according to claim 1, which is a lyophilized product. (4) Doxorubicin according to claim 1.2 or 3, wherein the solubilizing agent is a hydroxy lower alkanoic acid having 2 to 4 carbon atoms, phenylalanine, serine, urea, thiourea, or lower alkyl p-hydroxybenzoate. Salt preparations.