JPS632926A - Stable injectable antiemetic composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Summary of the Invention The present invention provides methods for reducing the polarity of solutions of 4-amino-5-chloro-N-(2-(diedylamino)ethyl)-2-((substituted)alkoxy]benzamide antiemetics. Stable, water-miscible hydroxyl organic solvents or water-soluble polyhydric alcohols or sugars as stabilizers that are acceptable for use in formulations
Relating to injectable aqueous solutions.

Background and Description of the Prior Art Methods for stabilizing drugs vary widely depending on the type of drug. The addition of reducing agents to oxidizable drugs is a well-known example. Ascorbic acid was stabilized against oxidation by the use of mixed solvents with low dissolved oxygen content. Decomposition (hydrolysis) of some narcotic esters was inhibited by the addition of caffeine, which has been shown to complex with the esters.

-A series of "paraben" preservatives such as methylparaben, ethylparaben, propylparaben and butylparaben are well-known stabilizers used in many pharmaceutical compositions. Ecker (V.) et al. 1982
U.S. Patent No. 4,328,213, issued May 4,
For example, their use in stabilizing injectable formulations of Laheclol is described and claimed in the US Pat.

The antiemetics used in the stable formulations described and claimed herein are known compounds, e.g.
UK Patent Application No. 2.160,871 published on 2nd May
No. A, the disclosure of which is incorporated herein by reference.

Metoclopramide is a well-known antiemetic drug with the structure of the antiemetic drug class utilized here, but it is
Contains a methoxy group at the - position. Physicians' Desk Reference
erence), 36th edition, 1982.1565~
Page 6 shows that the injectable form of metoclopramide sold at the time was stabilized with sodium metabisulfite.

British patent 1t19 published on November 20, 1985
7I No. 2.158.714 No. A Niha Injectable J Tora 0
It has been shown that the Furamide formulation was then stabilized with sodium metabisulfite. It subsequently notes that metoclopramide was used in combination with cisplatinum chemotherapy for cancer, and that cisplatinum was found to be incompatible with sodium metabisulfite. It states that it has surprisingly been found that sodium metabisulfite can be excluded from injectable metoclopramide formulations without unduly affecting their stability.

Chemical and Pharmaceutical Bulletin (Chem, Pharm, Bull), 8.
504 (1960), Ikeda, K., showed the high stability of certain barbitrates in water-ethanol or water-methanol solutions with lower dielectric constants compared to aqueous solutions of barbitrates. The results of the research are reported.

Chemical and Pharmaceutical Bulletin (Chem, Pharm, Bull,), 8,
(1960), L Ikeda reported that the same barbiturate salts had increased stability in aqueous solutions of ethylene glycol, propylene glycol, glycerin, glucose, mannitol, and sucrose. However, his research shows that this cannot be reduced solely to changes in the dielectric constant of the medium. In addition, he developed Amis (E, S, Am1s) by alkaline decomposition of bromothymol blue.
Other Journal of the American Chemical
Society - (J, 8m, Chem, Soc,)
, 63, 2621 (1940). Amis et al. reported that the reaction between a negative divalent dye ion and a hydroxyl ion was
We followed the theory in water and ethanol-water, but recognized that in the glycerin-water mixture the activation energy was opposite to the theory for dielectric constant.

Journal of the American Pharma'/,z
- Technical Association (J, 8m, Pharm
.

^5soc, ), 4 B, 77 (1959) Marcus, D. et al. [Information on the widespread use of mixed solvents in formulations and the effect of such solvent systems on the stability of active ingredients] ``Relatively few people.'' They argue that any assumption that the replacement of part of the water by non-aqueous solvents is a strategy is incorrect, and that non-aqueous solvents, especially hydroxyl It has been pointed out that this is due to a lack of evaluation of the solvent's ability to be used as a solvent. In their study of hydrogen ions catalyzing the solvolysis of chloramphenicol in water-propylene glycol solutions, they observed that the addition of propylene glycol to the aqueous solution increased the rate of solvolysis of chloramphenicol. There is.

full disclosure The present invention relates to formula I, N.H.

(wherein R1, R2 and R1 are each independently hydrogen or methyl, R4 is hydrogen, a straight or branched chain alkyl group containing 1 to 4 carbon atoms, or
R4 can be phenyl when R3 is hydrogen) or its non-toxic acid addition salts are acceptable for formulations that reduce the polarity of the solution (specific inductivity). The present invention relates to stable, injectable aqueous solutions containing water-miscible hydroxylic organic solvents or water-soluble polyhydric alcohols or sugars as stabilizers. Preferred organic hydroxyl stabilizers include ethanol, propylene glycol, glycerin and mannitol, with glycerin being most preferred. A particularly preferred formulation-acceptable acid addition salt of a compound of formula I is the hydrochloride. Most preferred compounds of formula I are those in which R1, R3 and R4 are hydrogen;
A compound in which R2 is methyl, which is 4-amino-
It is named 2-(2-butanon-3-yl)-oxy-5-chloro-N-(2-(diethylamino)edyl)henzamide (Ia).

Aqueous isotonic (isotonicity adjusted with sodium chloride and/or dextrose) and buffered (0,1M citrate and phosphate buffer, pl+5.7 and 6,5)
It was found that the compound of formula (■) in the formulation was not suitable for long shelf life. Typical isotonic and buffered formulations at 56°C
33% and 4 of its potency, respectively, after 8 weeks of storage at
Lost 0%. For example, a compound of formula Ia was observed to degrade by an intramolecular cyclization reaction resulting in the formation of a compound of formula (1), which was isolated and identified as Ta. Tables 1 and 2 show the results of stability studies for compounds of formula Ta in water and isotonic saline, and citrate buffer, respectively.

Pig-''-others in filtrate and isotonic saline at 56°C 1a
(Stability time of 5 mg/n7 Residual % (a
l Residual %fa)] Week A water 1 (isotonic saline) Initial 100.0 100. O L 97.4 96
．． 02 95, 5 9
1.64 90, 8
83.58 B 0.5
66.9 (al) Values shown are average values of duplicate samples.

Moat-1 4 p) 15.7 and 6.5 at 56°C 0. OI
M ku y U 11 j L yoshi fat Φ kobari 1 U AE i ■ / col)
"Die (Sex Time Residual % (81 Residual % (a) - Ω
Pull-1 Starvation 1) (■6.5) Initial 100.0 100.0 1 94.8 93.62
87, 8 87.94 77, 2
77.58 58, 9
60.3 ta + Values shown are average values of duplicate samples.

According to the present invention, the formula
It has been found that stable, injectable aqueous formulations of compounds of the invention can be obtained. Preferred hydroxyl stabilizers include ethanol, propylene glycol, glycerin and mannitol, with glycerin being most preferred.

The amount of hydroxyl stabilizer added can vary from about 5% to about 75% depending on the actual compound used. However, it is preferred to use from about 5% to about 30%, and from about 10% to about 2%.
0% is most preferred. For example, a composition containing 75% ethanol was found to be one of the most stable; however, due to the possible undesirable side effects of intravenous administration of moderate amounts of ethanol, the use of smaller amounts of ethanol,
Or even the use of different hydroxyl solvents such as glycerin is preferred. Even high doses of glycerin can cause undesirable side effects, so it is most preferred to use stabilizers at concentrations of about 10%.

1 ml of stable formulation! The amount of Compound 1 per compound can vary from 1 to about 50 mg or more depending on the particular compound. Approximately 40 rem/mp with at least 1 mg/nu,
It is preferable to use up to

The pI of the final composition should be in the range of about 4 to about 7, preferably about 5.0 to about 6.7. Most preferably, ρ11 is about 6.0 to about 6.5. is within the range of

Optionally, about 9 mg/mA of the preservative benzyl alcohol can be added to the formulation. This is particularly preferred if the formulation is packaged in multi-dose form.

Pharmaceutically acceptable acid addition salts of compounds of Formula I can be derived from any acids commonly used in the art of formulation.

Preferred salts are sulfate, maleate, tartrate, citrate and hydrochloride, with hydrochloride being most preferred.

The hydroxyl stabilizing compounds used e.g. ethanol,
Propylene glycol, glycerin and mannitol all lower the dielectric constant of the formulation. Although it is believed that the stabilizing effect is due, at least in part, to the low dielectric constant of the formulation, we do not intend to be limited to any particular theory.

The dosage of the compound of formula I is within the discretion of the physician, depending on the individual active ingredient, the age, weight and general health of the patient, and the extent of the disease. For the prevention of nausea and vomiting associated with emetogenic cancer chemotherapeutic agents, compounds 2) are generally administered at dosages of about 1 to about 50 mg/kg given several times a day.

Example 1 --" C --- Kasiya-1 -- Amount/ml -- Compound Ia hydrochloride 5.51 mg glycerol
200mg thorium hydroxide (0
,0IN) 65μl water for injection appropriate amount, total amount 1. OOmj! Compounding Procedure Place excess batch volume of Water for Injection into a suitable compounding container. Heat to boil and boil water for 10 minutes. Cover the container while cooling and pass nitrogen through the water to maintain a jet of nitrogen at the top.

Drain some of the water, leaving approximately 70% water in the blending container. Glycerin is added quantitatively with continuous stirring to achieve thorough mixing. Add active ingredient and sodium hydroxide solution. Bring the solution to final volume, filter it through a sterile membrane, and fill with a nitrogen top layer into a sterile container.

Example 2 7ml- Compound Ia hydrochloride s, stmg Propylene glycol 200mg Sodium hydroxide (0.0IN) 70μl Water for injection Appropriate amount, total amount 1. OOmj! Compounding Procedure Place an excess of water for injection into a suitable compounding container. Heat to boil and boil water for 10 minutes. Cover the container while cooling and pass nitrogen through the water to maintain a jet of nitrogen at the top. Drain some of the water, leaving approximately 70% of the batch volume of water in the □compounding vessel. Add propylene glycol quantitatively with continuous stirring to achieve thorough mixing.

Add active ingredient and sodium hydroxide solution. Bring the solution to final volume, filter it through a sterile membrane, and fill with a nitrogen overlayer into a sterile container.

Example 3 1 Ingredient: Hydrochloride of compound Ta 5.51 mg Ethyl alcohol 200□8 Sodium hydroxide (0.0 IN) 55 pH Water for injection Appropriate amount, total amount 1.00 m6 Mixing procedure In a suitable mixing container Add excess batch volume of Water for Injection to . Heat to boil and boil water for 10 minutes. Cover the container while cooling and pass nitrogen through the water to maintain a jet of nitrogen at the top.

Drain some of the water and add approximately 70 ml of batch volume into the blending container.
Leave % water behind. Ethyl alcohol is added quantitatively with continuous stirring to achieve complete mixing. Add active ingredient and sodium hydroxide solution. The solution is brought to final volume, filtered through a sterile membrane, and filled into a sterile container under a blanket of nitrogen.

Example 4 1-amount/'Ny Compound 1a hydrochloride 44.1 mg Glycerin 200 mg Sodium hydroxide (0.0 IN) Water for injection up to pl+6.0-6.2 Appropriate amount, total amount 1. OOmj! Formulation Procedure Place an excess batch of Water for Injection into a suitable compounding container.

Heat to boil and boil water for 10 minutes.

Cover the container while cooling and pass nitrogen through the water to maintain a jet of nitrogen at the top. Drain some of the water, leaving about 70% of the batch volume water in the compounding vessel. Add the glycerin quantitatively while stirring continuously to achieve thorough mixing. Add the active ingredient and the sodium hydroxide solution. Bring the solution to final volume and filter it through a sterile membrane; Fill into a sterile container with a nitrogen top layer.

Example 5 1 minute of goo component/ml - Compound 1a hydrochloride 11.0 mg Glycerin 350 mg Sodium hydroxide (0.01N) Water for injection to pH 6.0 to 6.2 Appropriate amount, total amount 1. OOmn Compounding Procedure Place excess punch amount of Water for Injection into a suitable compounding container.

Heat to boil and boil water for 10 minutes.

Cover the container while cooling and pass nitrogen through the water to maintain a jet of nitrogen at the top. Drain some of the water, leaving approximately 70% of the hatch volume of water in the blending container. Glycerin is added quantitatively with continuous stirring to achieve complete mixing. Add active ingredient and sodium hydroxide solution. The solution is brought to final volume, filtered through a sterile membrane, and filled into a sterile container under a blanket of nitrogen.

Example 6 ゝ -Amount/'l- Compound Ta hydrochloride 1.1025mg Glycerin 100.0mg Benzyl alcohol 9.0mg Sodium hydroxide (1
, ON) p) Up to 16.3 ± 0.2 Water for injection Appropriate amount, total amount 1. OOmj! Example 7 - - - Min - Amount / l light - Compound 1a
hydrochloride 11.025mg glycerin
100. ．． 0mg benzyl alcohol
9.0mg sodium hydroxide (1,ON)
Appropriate amount of water for injection up to pl+6.3±0.2, total amount
1. OOm#Example 8 Formation ゝ -Weighed 6'' No Compound 1a Hydrochloride 27.56Mg Glycerin
100.0mg benzyl alcohol
9.0 mg sodium hydroxide (1, ON
) Water for injection (appropriate amount, total amount up to pH 6, 3 ± 0.2)
1. OOmI! Formulation Procedure for Examples 6.7 and 8 Take 80% of the required volume of water for injection into a suitable container and cover with nitrogen. Glycerin, benzyl alcohol and Compound 1a are added and dissolved with stirring. Stir to coat evenly and continuously cover with nitrogen or NF. solution p
u to 6.3±0 by addition of IN sodium hydroxide solution
．． Adjust to 2. The solution is made up to the desired batch volume with water for injection and stirred to completely dissolve. The solution is sterile filtered using a sterile membrane filter and the filtrate is collected into a sterile receiver. Fill the solution into a sterile ampoule, cover with nitrogen, and seal the ampoule.

Tables 3 and 4 provide stability data for some of the stable injectable formulations of the present invention.

Human Ta in ethanol-water mixture at 56°C
(5m/nu) ′″′-1′-1 ethanol/
Water permittivity Residual % Residual % (V/V) Calculated value (4 weeks) (8 weeks) 0/100 78
．． 5 94.9.89゜425/75 64
．． 9 98.7 97.550150 5
1.4 9'9.5 99.175/25
37.8 99.6 99.6 Table 4 Propylene glycol at 56°C - Water and Gribunbi l Ni Athlete's athlete's foot p decoy scheme unimg/mA and p Hiroshi set - Solvent Relative permittivity Residual % Residual % meter Value (4',) (8 weeks) Wednesday 7B, 5 94.
9 88.125χ(W/V)
67.3 97.7 96.8 Propylene glycol 5χ (V/V) Glycerin 76.3 95
．． 1 90.915z (enemy/V) glycerin
71.8 96.5 94.225χGloss) Glycerin 71.4 96.8 95.3”
e: piIiLE *<-ha> 62.7. ie
Date: Month, Day, 1949 To the Director-General of the I Licensing Agency: Indication of Case 1. 1988 Patent Application No. 85602. 2. Title of Invention.
Relationship to the Stable, Injectable Antiemetic Composition 3 Amended Person Case Applicant Name: Fristroom Myers Company 4 Agent

Claims (12)

[Claims] (1) Formula, ▲Mathematical formula, chemical formula, table, etc.▼ (In the formula, R^1, R^2 and R^3 are each independently hydrogen or methyl, R^4 is hydrogen, 1 to 4 straight or branched chain alkyl group containing carbon atoms or R^4 can be phenyl when R^3 is hydrogen) is acceptable for antiemetics or non-toxic preparations thereof. A stable, injectable aqueous solution of an acid addition salt containing an acceptable water-miscible hydroxylic organic solvent or a water-soluble polyhydric alcohol or sugar as a stabilizer in the formulation to lower the dielectric constant of the solution. A composition comprising. (2) the stabilizer is selected from ethanol, propylene glycol, glycerin and mannitol, and has a concentration of about 5 to about 30%;
% (W/V).
Compositions as described in Section. (3) The composition of claim (2), wherein the compound of formula I is present in an amount of about 0.1 to about 4% (W/V). (4) The composition according to claim (3), having a pH within the range of about 5.0 to about 6.7. (5) Claim No. 4, wherein the compound of formula I is 4-amino-2-(2-butanon-3-yl)oxy-5-chloro-N-[2-(diethylamino)ethyl]benzamide. ). (6) Claim No. 1, wherein the stabilizer is ethanol (
5) The composition described in item 5). (7) The composition according to claim (5), wherein the stabilizer is propylene glycol. (8) Claim No. 1, wherein the stabilizer is glycerin (
5) The composition described in item 5). (9) The compound of formula I is present as a hydrochloride salt and has a pH within the range of about 6.0 to about 6.5.
The composition described in item 8). (10) The composition of claim (9), wherein glycerin is present in an amount of about 10% (W/V). (11) The composition according to claim (4), further comprising benzyl alcohol as a preservative. (12) The composition according to claim (10), further comprising about 9 mg/ml of benzyl alcohol as a preservative.