NZ234872A - Preparation of parenterally administrable solutions from strongly acidic or basic salts of pharmaceuticals; kit therefor - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £34872 Ci C\ f3'i- if Priority Date{s):.X Cowav-* Sr-.cH:-ra-;.or Fited: .J.LV.^S ;P'jsKcation Date: .2.B..AUS..832.. ;i P.O. Journal, No: - A5.S?. ......r.L. ;23 4 8 7? ;NO DRAWINGS ;No.: Date: ;NEW ZEALAND ;PATENTS ACT, 1953 ;NEW ZEALAND | ;PATENT OFFICE ! ;' ;13 AUG 1990 ;RECEIVED ;COMPLETE SPECIFICATION ;PROCESS FOR THE MANUFACTURE OF PARENTERAL APPLICATION ;FORMULATIONS ;Jc/Wc, F. HOFFMANN-LA ROCHE AG 124 Grenzacherstrasse, CH-4002 Basle, Switzerland, a Swiss Company y=s ;1 ;hereby declare the invention for which Z I we pray that a patent may be granted to xbhe/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - ;- 1 - ;(followed by page la) ;V ;234 8 72 ;ta- ;RAN 4602/26 ;~"S ;10 ;15 ;20 ;25 ;30 ;35 ;The preparation of parenterally administerable solutions of pharmaceutical^ active substances is frequently associated with technical difficulties. Such difficulties occur, for example, when the solutions which are prepared are not sufficiently stable to guarantee a lengthy storage, if necessary below normal room temperatures (precipitation of the active substance) or above normal room temperatures (decomposition of the active substance). Attempts have been made to circumvent such difficulties by preparing the solutions in situ. i.e. immediately prior to use. The dissolution rate of the active substance is, however, often unsatisfactory, especially when the concentration of the active substance in the desired solvent volumes is close to the saturation limit. The problem is even greater when the active substance to be dissolved is not lyophilizable and must be present as a sterile powder. One remedy can be found in the case of ionizable active substances by preparing a salt which is sufficiently soluble and which is stable in the dry state. Salts of very weak bases or very weak acids with strong acids or, respectively, strong bases give, however, such acidic (pH < 3) or. respectively, strongly basic solutions (pH > 9.5) that their parenteral use is not possible or is possible only after neutralization to physiological pH values. Thus, for the preparation of parenteral solutions of metronidazole, the hydrochloride of which dissolves in water with a strong acidic reaction, a commercial preparation, two operations are required for the preparation of the finished solution. Firstly, the hydrochloride is dissolved in water, whereupon in a second operation the aqueous solution obtained in neutralized to a physiological pH value. This procedure is not only very ;Grn/12.6.90 ;234 872 ;10 ;15 ;20 ;- 2 - ;laborious and susceptible to contamination, but also holds the danger of the neutralization of the strongly acidic solution being inadvertently omitted. ;It has now surprisingly been found that the preparation of physiologically compatible parenterally administerable solutions from such strongly acidic or strongly basic salts of pharmaceutically active substances can be realized directly, i.e. in only one single step. In accordance with the invention there is provided a process for the direct preparation of physiologically compatible parenterally administerable solutions from strongly acidic or strongly basic salts of pharmaceutically active substances, which comprises bringing a sufficiently soluble salt of such an active substance into contact with a sufficient volume of a neutralizing solvent and. if necessary, bringing resulting and transiently--precipitating active substance base or active substance acid as the case may be into solution by slight shaking. ;The term "strongly acidic or strongly basic salts of pharmaceutically active substances" used here is intended to denote salts of pharmaceutically active substances which have a pKs of < 4 (very weak bases) or. ;25 respectively. > 8-9 (very weak acids). The solutions of these salts have pH values of < 2.5 and. respectively. > 9.5. which are far removed from the physiologically acceptable pH range of 4 to 8. 5-Fluorocytosine and metronidazole are examples of very weak bases. Flurazepam. ;30 levodopa. flunitrazepam, bromazepam and the like are further examples. 5-Fluorouracil. allobarbital. acetaminophen, butabarbital. hexobarbital. paracetamol, pentobarbital, phenobarbital, phenytoin and the like are examples of very weakly acidic active substances. ;35 ;23487i ;- 3 - ;All pharmaceutically usable bases come into consideration as bases for the neutralization of strongly 5 acidic solutions. There are preferably used bases with which, during the neutralization, an optimal iso--osmotizing effect is obtained, such as e.g. disodium monohydrogen phosphate. tris(hydroxymethyl)-aminomethane, L-arginine or L-lysine. preferably in admixture with 10 sodium hydrogen carbonate, which liberates C02 in the neutralization reaction and thereby substantially accelerates the process for the dissolution of the active substance base or acid which may result and precipitate. ;15 ;20 ;All pharmaceutically usable acids can come into consideration as acids for the neutralization of strongly basic solutions of such active substance salts. There are preferably used acids with which, during the neutralization, an optimal iso-osmotizing effect is obtained, such as e.g. citric acid, acetic acid, monosodium dihydrogen phosphate, lactic acid and the like. The sodium hydrogen carbonate, which is preferably used for accelerating the dissolution process, can be admixed with the active substance salt in this case. ;25 The solutions obtainable in accordance with the invention can also contain usual pharmaceutical adjuvants such as agents for isoosmotization or pH-adjustment. as well as buffers and/or stabilizers. These adjuvants can be admixed with the active substance salt or can be present dissolved in the solvent. ;In a preferred embodiment the invention is concerned with the preparation of parenteral solutions of 5-fluoro-cytosine. whereby 5-fluorocytosine monohydrochloride is 35 used as the salt. ;30 ;23487: ;4 ;10 ;15 ;20 25 ;W ;30 ;5-Fluorocytosine monohydrochloride has hitherto nowhere been described. The compound can be produced as described below in more detail by adding ethanol to an aqueous solution of the 5-fluorocytosine salt prepared in situ with hydrochloric acid. ;The parenteral solutions which can be prepared in a single step in accordance with the invention are conveniently prepared immediately prior to use. The invention is therefore also concerned with a kit, i.e. an article consisting of individual units, comprising: ;a) a container in which is located a strongly acidic or strongly basic salt of a pharmaceutically active substance which is sufficiently soluble and which is stable in the dry state; ~ " ;b) a container in which is located a sufficient volume of a neutralizing solvent which can dissolve the resulting active substance base or active substance acid; and c) a connecting piece which is suitable for transferring the active substance salt into the neutralizing solvent. ;For such an article there can be used e.g. the infusion system which is commercialized under the name "ADD-Vantage" (Abbot Laboratories. North Chicago. 111. ;USA). ;The invention is illustrated by the following Examples. ;234 8 72 ;5 ;10 ;15 ;- 5 -Example 1 ;A. Active substance ;5-Fluorocytosine monohydrochloride 3.21 g ;The active substance is introduced into a 20 ml glass vial which is closed with a rubber stopper. ;B. Solvent ;Sodium hydrogen carbonate 1.375 g Disodium monohydrogen phosphate dodecahydrate 3.275 g ;HC1 IN ad pH 8.0 q.s. ;Water for injection q.s. ad 250.0 ml ;The solvent is filled under a vacuum into a 500 ml infusion bag. e.g. an infusion bag of the ADD-Vantage infusion system. ;For the preparation of the finished infusion solution, the active substance salt is transferred into the neutralizing solvent in which the 5-fluorocytosine base which results therein can be dissolved to give a clear solution in less than 1 minute by slight shaking. The solution obtained contains 2.5 g of 5-fluorocytosine in ;."""s ;W 250 ml and has a pH value of about 5.9-6.0. The non- ;30 -neutralized solution of 5-fluorocytosine monohydrochloride would have a pH value of about 1.5. ;The complete dissolution of micronized 5-fluoro-cytosine base in 250 ml of a commercial infusion solution 35 would require a vigorous shaking for considerably more than 8 minutes, which obviously does not come into consideration for practical use. ;20 ;25 ;^ J ;10 ;15 ;20 ;25 ;O ;30 ;234872 ;35 ;- 6 -Example 2 ;A. Active substance ;Misonidazole hydrochloride 590.6 mg ;(corr. to 500 mg of misonidazole) ;B. Solvent ;Sodium hydrogen carbonate 0.55 g Disodium monohydrogen phosphate dodecahydrate 1.31 g ;HC1 IN ad pH 7.5 q.s. ;Water for injection q.s. ad 100.0 ml ;The solvent is filled under a vacuum into a commercial PVC infusion bag. ;For the preparation of the finished infusion solution, the misonidazole hydrochloride is firstly suspended in a portion of the solvent with the aid of a suitable connecting piece (e.g. a so-called transfer needle). The suspension obtained is then introduced into the infusion bag where finally the resulting misonidazole dissolves. The pH value of the solution, which contains 100 mg of misonidazole in 100 ml, amounts to about 6.9. The non--neutralized solution would have a pH value of < 2. ;Example 3 ;A. Active substance ;Flurazepam dihydrochloride 17.82 mg ;(corresponding to 15 mg of flurazepam) ;The active substance salt is introduced into a 10 ml glass vial which is closed with a rubber stopper. ;234 872 ;- 7 - ;B. Solvent ;L-Arginine 6.5 mg ;Sodium chloride 85.0 mg ;Water for injection q.s. ad 10.0 ml ;The solvent is filled into a sterilized 10 ml PE vial. ;For the preparation of the finished injection 1q solution, the partially neutralizing solvent is transferred with aid of a transfer needle into the active substance vial where the flurazepam is dissolved in the form of the resulting monohydrochloride by slight shaking. The pH value of the solution obtained, which contains 15 15 mg of flurazepam in the form of the monohydrochloride in 10 ml, amounts to 7.4. The non-neutralized solution of the corresponding dihydrochloride would have a pH value of about 2.4. ;20 ;25 ;Example 4 ;A. Active substance ;5-Fluorouracil 250.0 mg ;NaOH IN 1.923 ml ;Water for injection q.s. ad 5.0 ml ;This sodium salt solution prepared in situ is filled into a 20 ml glass vial and lyophilized as usual. ;30 ;B. Solvent ;Citric acid monohydrate 40.0 mg ;Water for injection 5.0 ml ;35 ;The solvent is filled into a sterilized 10 ml PE vial. * 234 8 72 For the preparation of the finished injection solution, the solvent is transferred with the aid of a ^ 5 transfer needle into the active substance vial where the -fluorouracil which results to some extent is dissolved by slight shaking.

The pH value of the solution obtained, which contains /""s 20 250 mg of 5-f luorouracil (only to some extent in the form of the sodium salt), amounts to 8.4. The non-neutralized solution would have a pH value of more than 10.

Example 5 The 5-fluorocytosine monohydrochloride can be prepared as follows: 200 g of 5-fluorocytosine are dissolved in 720 ml of 25% hydrochloric acid at 70°C. Subsequently, 8 1 of ethanol are added dropwise to the solution while cooling in an ice bath and stirring. Thereafter, the crystallizing mixture is stirred at 5°C for a further hour. The crystals are filtered off under suction, washed with ethanol and dried at 80°C. 234872

Claims (11)

WHAT WE CLAIM IS: 10 15

1. A process for the preparation of physiologically compatible parenterally administerable solutions from strongly acidic or strongly basic salts of pharmaceutically active substances, which process comprises bringing a sufficiently soluble salt of such an active substance into contact with a sufficient volume of a neutralizing solvent and. if necessary, bringing resulting and transiently-precipitating active substance base or active substance acid as the case may be into solution by slight shaking.

2. A process according to claim 1. wherein the pharmaceutically active substances are very weak bases (pKs < 4) or very weak acids (pKs > 8-9). 20

3. A process according to claim 1 or 2, wherein the active substance is 5-fluorocytosine. 25 30

4. A process according to any one of claims 1-3, wherein the active substance salt is 5-fluorocytosine monohydrochloride -

5. A process according to any one of claims 1-4, wherein the solvent for the neutralization of the strongly acidic or strongly basic salt contains one or more pharmaceutically usable bases or, respectively, acids.

6. A process according to claim 5. wherein the pharmaceutically usable base is disodium hydrogen phosphate. L-arginine or tris(hydroxymethyl)aminomethane. =|5

7. a process according to claim 5. wherein the f-7JUL1992 pharmaceutically usable acid is citric acid, acetic acid ✓ o\ •1 aor sodium dihydrogen phosphate. *» ev 234872 10

8. A process according to any one of claims 1-7, wherein additional pharmaceutically usable adjuvants for isoosmotization. pH-adjustment. buffering and stabilizing the active substance, mixed with the active substance salt and/or dissolved in the solvent, are used.

9. A process according to claim 8, wherein sodium hydrogen carbonate is used as the adjuvant.

10. A kit for the preparation of parenterally administerable solutions, comprising: a) a container in which is located a strongly acidic or strongly basic salt of a pharmaceutically active substance which is sufficiently soluble and which is stable in the dry state; b) a container in which is located a sufficient volume of a neutralizing solvent which can dissolve the resulting active substance base or active substance acid; and c) a connecting piece which is suitable for transferring the active substance salt into the neutralizing solvent.

11. A process according to claim 1, substantially as described hereinbefore, especially with reference to any one of the Examples 1 to 4.