DK147727B - PROCEDURE FOR PREPARING A SOLUBILIZED AND STABILIZED SOLUTION CONTAINING 2-CHLOR-11- (4-METHYL-1-PIPERAZINYL) -DIBENZ (B, F) (1,4) OXAZEPINE OR PHARMACEUTICAL ACCEPTABLE - Google Patents

Description

χ 147727 d

The invention relates to a process for preparing a solubilized and stabilized solution containing 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz- (b, f) (1,4) oxazepine or a pharmaceutically acceptable salt thereof.

The compound 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz (bff) (1,4) oxazepine is a known compound with therapeutic effects on the central nervous system. In U.S. Patent No. 3,546,226 there is a direct description of 2-chloro-11- (4-methyl-1-piperazinyl) -di benz (b, f) (1,4) oxazepine, its non-toxic, pharmaceutically acceptable acid addition salts, the parenteral administration of these compounds, and their utility as agents for affecting the central nervous system. U.S. Patent No. 3,663,696 discloses a parenteral solution composed of 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine and certain acid addition salts thereof in a mixture of propylene glycol, water and ascorbic acid.

U.S. Patent No. 3,412,193 discloses the oral administration of 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz- (b, f) (1,4) oxazepine in propylene glycol with the purpose of testing the anti-fertility efficiency.

So far, problems have been associated with preparations containing 2-chloro-11- (4-methyl-1-piperazinyl) -25-dibenz (b, f) (1,4) oxazepine. Due to the low solubility of the compound in water, it is difficult to incorporate into conventional pharmaceutical forms such as parenteral and oral liquid preparations using e.g. water for injection. Another problem that makes it difficult to incorporate the compound into liquid dosage forms is its poor solubility in liquids having a basic pH or a pH close to the neutral point.

A further problem associated with the compound is that one of its hydrolysis products, namely 2-chloro-dibenz-35 (b, f) (1,4) oxazepin-11 (10H) -one, is highly insoluble in water. Aqueous solutions of 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine have been found to be unstable and unsuitable, primarily due to the precipitation thereof. the above hydrolysis product, 5 which appears in trace amounts long before the strength of the solution has fallen below an acceptable level. Of course, although the hydrolysis product is non-toxic, its precipitation is unacceptable in an injection solution of the active oxazepine. All the above-mentioned problems can be overcome by utilizing the method of the present invention.

The present oxazepine and its acid addition salts can be prepared as described in U.S. Patent No. 3,663,696.

The process according to the invention is characterized in that the said oxazepine or a salt thereof is dissolved in a 50-80% (vol / vol), preferably a 70% aqueous solution of propylene glycol, at which the pH is adjusted to from approx. 5.0 to approx. 7.0, preferably approx.

20, with dilute mineral acid, e.g. dilute salt or sulfuric acid, e.g. 10% and add water to the desired volume (water for injection in the case of parenteral preparations).

According to the invention, if desired, an additional step comprising addition of from 2% to 10%, preferably approx. 5% polyoxyethylene (20) sorbitan monooleate, cf. below. The process of the invention has the advantage of providing a stable, pharmaceutically acceptable solution of the active oxazepine, the solution being complete and remaining for a long period of time. Furthermore, the pH contributes to maintaining the solution and is incompatible with neither oral nor parenteral administration. The stability is good and trace amounts of the hydrolysis product mentioned remain in solution.

o 3 147727

The addition of polyoxyethylene (20) sorbitan monoleate in an amount of from 2% to 10%, although this addition is not absolutely necessary, has an additional advantage in connection with both the parenteral solution and the oral concentrate. Since 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) ox-azepine crystallizes from neutral or basic media, the oxazepine exhibits a tendency to crystallize by parenteral administration into body fluids ( pH value about 7.0).

The addition of polyoxyethylene (20) sorbitan monooleate raises the solubility rate of the oxazepine in the 70% aqueous propylene glycol and eliminates crystallization during intramuscular administration. The addition of polyoxyethylene (20) sorbitan monooleate to the oral concentrate is advantageous when it is desired to add the concentrate to non-acidic foods or beverages because the oxazepine is precipitated by dilution with such foods unless the sorbitan monooleate is present.

According to the already mentioned United States patent no.

No. 3,663,696, a parenteral solution of the subject active oxazepine is prepared by dissolving the compound in propylene glycol and water, then adding ascorbic acid in water and finally adding hydrochloric acid to adjust the pH of the solution to 5.5 . In contrast, the solution prepared by the process according to the invention contains no ascorbic acid, and it is clear from the comparative experiments referred to below that the solutions containing ascorbic acid are substantially inferior to solutions prepared according to the invention (due to of increased lactam formation, darkening of the solution and formation of precipitates).

o 4 147727

Sammenligningsforsøq

Solutions of 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine are prepared as follows:

5 Resolution No. X II III ΙΑ IIA IIIA

mg of active substance per day ml 20 20 20 50 50 50 2-Chloro-11-4-methyl-1- 2.1 2.1 2.1 5.25 5.25 5.25 -piperazinyl) - dibenz (b, f) -10 (1,4) oxazepine (% w / v)

Propylene Glycol 70.00 70.00 70.00 70.00 70.00 70.00 USP (% by volume)

Polyoxyethylene (20) - - 5.00 - - 5.00 - 15 sorbitan monooleate OSP (% w / v)

Hydrochloric acid q.s. q.s q.s q.s q.s q.s

(% w / v)

Ascorbic acid USP - - 0.250 - - 0.250 (% w / v) 20 Water for injection to (% w / v) 100.00 100.00 100.00 100.00 100.00 100.00

Each of the solutions is prepared as follows:

A portion of 21.5 g or 52.5 g of 2-chloro-11- (4-25-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine is dissolved in a solution of 700 ml of propylene glycol and 200 ml of water for injection under stirring at a pH of 5.5. After the solution is complete, a solution of 2.5 g of ascorbic acid in 20 ml of water is injected into solutions III and IIIA as described in Example 6 of U.S. Patent No. 3,663,696, and a portion of 5.0 g of polyoxyethylene (20) sorbitan monooleate USP is added to solutions II and IIA. Solutions I and IA containing only active substance and propylene glycol are used for control purposes. Make up all solutions with distilled water. The solutions are then filtered through a 0.45 µl sterile filter and filled under nitrogen on 2 ml vials, some of which are stored in a steam autoclave at 121 ° C under a pressure of about 1.05 kg / cm 2 for 30, 60 and 120 minutes. The stability data obtained in the evaluation of the solutions are shown in the following Table A: 6 147727

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The following Table B shows the physical appearance of the samples in the above stability tests:

Table B

f Time in minutes

Resolution No. Initial appearance 30 60 120 I Light yellow solution 1 1 1 II "111 III .... 12 3 IA .... 111 IIA .... 111 IIIA .... 12 3 15 _____ where: 1 no change 2 = · darker solution and 3 = darker solution with precipitate.

The results of physical stability experiments under less stringent storage conditions can be seen in the following Table D: 8 147727 ———— I — i ——— 'i υ o ·'

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o 9 147727

The compound 2-chloro-11- (4-methyl-1-piperazinyl) - dibenz (b, f) (1,4) oxazepine can be used in the solutions of this invention either in the form of the free base or in the form of the compound -toxic, pharmaceutically acceptable acid addition salts, preferably the succinate. Other nontoxic, pharmaceutically acceptable acid addition salts useful in addition to the succinate include the hydrochloride, sulfate, phosphate, citrate, tartrate, maleinate, fumarate, heptanoate and pamoate.

A parenteral solution prepared by the method of the invention can be obtained as follows:

The concentrations of the constituents are based on the final volume, unless otherwise stated. 2-Chloro-11 - (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine in an amount sufficient to achieve a final concentration of 3 volumes of 0.5-5% (5 mg / cm to 50 mg / cm) are dissolved in 50% to 80% (volume per volume) of propylene glycol USP. The pH of the solution is adjusted to 5.0 to 7.0 with a dilute mineral acid, diluted to 100% with 20 water for injection (USP) and then sterile filtered.

If desired, polyoxyethylene (20) sorbitan monooleate (USP) in an amount of 2-10% can be added to the propylene glycol solution before dilution to final volume with water for injection.

An oral concentrate prepared by the method according to the invention can be obtained in the same way as above, except that sterilization is not required and that distilled water can be used instead of water for injection purposes.

The oral concentrate may be added to foods for the purpose of producing a tasty form of the oxazepine or to obscure the presence of the compound, e.g. by administration to patients who may refuse to take drugs if they knew it was present in the administered formulation. Such patients include mentally disordered persons, children and senile persons. However, although a variety of foods can be used for this purpose, liquid foods are particularly suitable, especially fruit juices, e.g. orange juice and similar beverages. Oral concentrates containing approx. 10-50 mg of drug per day. ml of concentrate can be used, with approx. 25 mg per ml is preferred.

The oral concentrate can be added to foods in amounts up to approx. 0.07 ml concentrate per grams of food, from approx. 0.02 to approx. 0.04 ml per grams are preferred. Of course, the two-digit amount of concentrate will depend on the nature of the disease and on the patient, but in general per . per day is used from one half to six milliliters of concentrate containing e.g. 25 mg / ml, the preferred range being from 2 to 4 ml. Such amount can be given in one dose or divided into 2, 15 3 or 4 doses given at appropriate intervals.

The following examples serve to elucidate the method of the invention.

Example 1 Preparation of a parenteral solution of 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine base 63.0 g of 2-chloro-11- ( 4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine base is added to 2100 ml of USP grade propylene glycol and mixed. Add 800 ml of water for injection and mix. The pH is adjusted to 6.2 with 10% hydrochloric acid and mixed and heated to 60 ° C for 30 minutes. The pH is adjusted to 6.0 with 10% hydrochloric acid, giving the total volume of hydrochloric acid used is 51 ml. The mixture is diluted to 3000 ml with water for injection and sterile filtered through a 293 mm Selas filter or equivalent filter with a 0.22 µ membrane. The final solution has a strength of 2.0% active ingredient.

35 h 147727 o

The preparation is filled into vials or vials each containing 2.0 ml, corresponding to 40 mg of drug.

Example 2 Preparation of a parenteral solution of 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine base 105.63 g of 2-chloro-11 (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine base is added to a mixture of 10,400 ml of propylene glycol USP and 400 ml of water for injection and mixed. The pH is adjusted to 6.0 with 10% hydrochloric acid. 100 g of polyoxyethylene (20) sorbitan monooleate USP are added. The pH is reset to 6.0 with 10% hydrochloric acid and the solution is diluted to 2000 ml 15 with water for injection. The solution is filtered through a Millipore AP 20 pad and then through a Selas 0.2 µ silver membrane or equivalent. The final solution has a strength of 5.0% active ingredient.

The preparation is filled into vials or vials each containing 0.2 ml corresponding to 100 mg of the drug.

Example 3

Preparation of an Oral Concentrate of 2-Chloro-11- (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine base 12600 ml of propylene glycol USP is placed in a stainless steel container with a volume of 25 liters. 4 liters of water are added and mixed, then 474 g of 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) ox-30-azepine base are added and mixed again . The pH of the solution is adjusted to 6.0 with 10% hydrochloric acid. The solution is diluted to 18000 ml with water to be mixed, the pH is reset to 6.0 and then filtered through a Millipore AP 20 pad and a 0.45-1.2 µm solvent resistant 35 . The final solution has a strength of 2.5% active ingredient.

o 12 147727

Example 4

Use of an oral concentrate of 2-chloro-11- (4-methyl-1-piperazinyl) -dlbenz (b, f) (1,4) oxazepine base An oral concentrate containing 2.5% (w / v) - catch) 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz (b, f) - (1,4) oxazepine base in 70% aqueous propylene glycol prepared as described in Example 3 is added for grapefruit, orange or pineapple juice, adding 0.83 mg of 10 ml drink. The taste, appearance and pH of the beverages are acceptable and the stability is satisfactory for at least 24 hours in the types of juice mentioned.

Example 5 Typical compositions are as follows:

Parenteral% w / v 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine base 5.25

Polysorbate 80 USP (polyoxyethylene- (20) grade 20 sorbitan monoolea φ for food additive 5.0

Hydrochloric acid reagent q.s. pH 6.0 q.s.

Propylene Glycol USP 70.0 (Volume)

Water for injection USP

q, s. ad 100.0 (volume) Oral 2-chloro-11- (4-methyl-1-piperazinyl-dibenz (b, f) (1,4) oxazepine base 2.63

Hydrochloric acid reagent q.s. pH 6.0 q.s.

Propylene Glycol USP 70.0 (Volume) 30 Distilled Water 100.0 (Volume) o 13 147727

Other ingredients which do not adversely affect the parenteral solution or the concentrate may also be added, e.g. buffers, preservatives, flavors, dyes, sweeteners and suspending agents. Minor amounts of other active ingredients may also be added, provided these do not adversely affect the solution or concentrate.

The effectiveness of the solutions of 2-chloro-11 - (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine prepared by the process of the invention can be illustrated by a comparison of their strength with the encapsulated form of the connection. For this test, male rats of the Wistar strain are used. Capsule contents comprising 2-chloro-11- (4-methyl-1-piperazinyl) -di-benz (b, f) (1,4) oxazepine succinate and conventional fillers are suspended in a 2% starch carrier and administered to rats using a gastric probe at a rate of 0.5 ml per ml. 100 g body weight. Nine dose levels ranging from 0.06 to 12.0 mg per dose are used. kg with 20 10-15 rats per dosage. A parenteral solution containing end 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz (b, f) - (1,4) oxazepine base at a concentration of 20 mg / ml in 70% propylene glycol injected undiluted in rats, intramuscularly in microliter volumes. Eight dose levels from 0.12 to 12.0 mg / kg are used with 10-40 rats per day. dosage.

Each rat is tested for catalepsy, a measure of the neuroleptic activity of the drug, at different times up to 6 hours after drug administration. The criterion for catalepsy is maintaining the paw position on four cork-30 plugs for more than 10 seconds. The effective mean doses, ie. the doses at which 50% of the animals show catalepsy are calculated at different times after drug administration. The results are shown in the following Table I.

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The foregoing results show that there are no real differences in strength between the oral (capsule) form and the parenteral (intramuscular) form at any time up to 6 hours after administration.

The favorable stability of the oral and parenteral solutions prepared by the process of the invention has been demonstrated by numerous experiments, the criterion of stability being the failure to precipitate the hydrolysis product 2-chloro-dibenz (b, f) (1,4) oxazepine-11 -10 (ΙΟΗ) -οη. In general, no crystallization of this hydrolysis product occurs at concentrations below 500 mcg / ml in the novel solutions. In the following, three experimental series must be explained.

In the first test series, a number of 10 mg / ml solutions of 2-chloro-11- (4-methyl-1-pipe-razinyl) -dibenz (b, f) (1,4) oxazepine base are prepared. in 50%, 60% and 70% aqueous propylene glycol at a pH of 6.01.

For a stability test over 15 months, the results given in the following Table II were obtained: 16 1477 2 7 H 0) <U M Ό G Ό> i G -G (d to + i to tn 0) -H Λ H (1)

> 03 • H G • G -H Μ G

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All solutions maintain acceptable strength levels and none exhibit precipitation of the hydrolysis product.

In the second test series, a parenteral solution of 2-chloro-11- (4-methyl-1-piperazinyl) dibenz (b, f) (1,4) oxazepine at a concentration of 15 mg / ml is prepared. in 70% (vol / vol) propylene glycol in water for injection USP at a pH of 6.0. Stability tests are carried out at different temperatures and for different periods, as shown in Table III, to measure the retained strength of the active ingredient as well as the increase in the concentration of the hydrolysis product.

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ap +) 01 vo o O fe co ** in t "19 147727 o In the third test series, a parenteral solution of the active ingredient at a concentration of 20 mg / ml is prepared as described in connection with the second test series. results obtained are shown in the following 5 Table IV.

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As can be seen from the results of the second and third test series (stability tests), the solutions at issue here show excellent stability even under forced conditions.