NL8201251A - MATERIAL COMPOSITION COMPRISING A LYOPHILIZED PREPARATION OF A PENICILLIN DERIVATIVE. - Google Patents

Description

if i VO 3065

Material composition comprising a lyophilized preparation of a penicillin derivative.

The invention relates to a pharmaceutical material composition / in particular a dosage unit in parenteral form of the penicillin derivative 6- (2- (4-ethyl-2,3-dioxo-1-piperazine-carboxamido) -2-phenylacetamidol-3,3 dimethyl-7-oxo-4-thia-1-azabicyclo 5 [3 * 2 Ό] heptane-2-carboxylic acid, sodium salt (hereinafter referred to as sodium piperacillin), which is described in U.S. Patent 4,112,090 (Toyama Chemical Co.) which establishes its utility as an antibacterial agent The invention also relates to a method of making this parenteral dosage unit.

The conventional procedure for preparing a lyophilized parenteral dosage form of a penicillin derivative comprises preparing a 200 mg / ml aqueous solution of the derivative, placing the solution in a vial at 5 ml per vial, and lyophilizing the content thereafter; wherein the dried cake represents 1 gram of the derivative. When the physician is ready to administer the drug, he reconstitutes the vial with 3.3 ml of water or other suitable parenteral diluent. The penicillin derivative displaces 0.7 ml of diluent per gram of the derivative. The final product is therefore 4.0 ml of reconstituted derivative at a concentration of 250 mg / ml. The physician then withdraws the appropriate amount of solution from the vial using a syringe and administers the appropriate dose to the patient.

The difficulty with the above parenteral composition is that the physician must administer 4 ml of solution per 1 gram dose. Pipera-25 cillin, like many penicillin derivatives, is hypertonic and therefore inherently causes pain upon intramuscular injection. Furthermore, the dose limit for injection into the arm is about 2 ml, because the muscular system will simply not tolerate larger volumes of intervention.

The prior art 4 ml dosage therefore necessitates the use of the less suitable procedure of giving buttocks injections. Even with injection into the buttocks, the large 4 ml dose means that the distribution time is increased.

The object of the invention is to provide a parenteral dosage unit form of piperacillin and similar penicillin derivatives whereby the injection volume is reduced from the known volume by providing a more concentrated final product.

The difficulty in preparing a concentrated reconstituted preparation of a lyophilized penicillin derivative is that the reconstitution time increases with an increase in the concentration of the final product. At a final product concentration of 400 mg / ml, the reconstitution time may be several minutes with continuous shaking. The time required to reconstitute such products has led to a discouragement of use, with the result that more dilute preparations are used, with all of the drawbacks described above.

Accordingly, another object of the invention is to provide a lyophilized parenteral dosage unit form of piperacillin and similar penicillin derivatives which gives a highly concentrated but easily reconstituted end product.

The parenteral dosage unit of the present invention comprises a loose, fluffy expanded cake of a lyophilized penicillin derivative, in particular the derivative 6- [2- (4-ethyl-2,3-dioxo-1-piperazine carboxamido) -2-phenylacetamido ] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3 * 2 * 0] heptane-2-carboxylic acid, sodium salt defined above as sodium piperacillin. The term "expanded cake" means a lyophilized cake that occupies a larger volume than the volume covered by the "standard cake" of the prior art.

The penicillin derivative is dissolved in water at a concentration of 125 mg / ml. Eight milliliters of this solution is then placed in a vial to a total amount of 1 gram of penicillin derivative per vial. The vials are selected for their ability to withstand the lyophilization procedure and for their ability to accept an appropriate stopper which allows for syringe removal.

The penicillin derivative is then frozen and lyophilized in the vial according to standard procedures well known to those skilled in the art. During the lyophilization step, the lyophilized cake retains the volume of the dose of liquid introduced and forms a crystalline mass of loose structure which is sealed under negative pressure. Since the volume of the liquid filling is 8 ml, the lyophilized cake is much larger and looser ("expanded cake") than the 5 ml of the prior art cake. After lyophilization, the vials are closed with 8201251. * * - * -3- Suitable dividers with compatibility for syringes.

When the physician is ready to administer a dose, he reconstitutes the lyophilized cake with 2.5 ml of an appropriate diluent. Examples of suitable diluents are, for example, water or lidocaine hydrochloride, a local anesthetic that can be added to counteract the inherent pain of the injection due to the hypertonic nature of penicillin derivatives such as piperacil line. The time to reconstitute 1 gram of lyophilized derivative with shaking is about 35 seconds.

The final product gives 2.5 ml of which a 400 mg / ml solution of the desired penicillin derivative, and an injection dose of 2.5 ml / gram as compared to a 4 ml / gram dose according to the prior art.

The above-described method can be modified to obtain a greater or smaller amount of final product by proportionally increasing or decreasing the amount of 125 mg / ml liquid filling introduced into the vials for lyophilization, and by the amount of diluent needed is to reconstitute the final product proportionally to increase or decrease a final concentration of 400 mg / ml.

The method described above can also be modified to use a liquid fill concentration of more or less than 125 mg / ml, although this is less successful. At higher liquid fill concentrations, the density of the lyophilized cake increases, and the reconstitution time required to dissolve the penicillin-25 derivative increases at a concentration of 400 mg / ml, but at a relatively different rate. For example, when the liquid fill concentration is increased by 15%, the reconstitution time increases by more than 100%. See example III. On the other hand, lower liquid fill concentrations can be used, but the lower the liquid fill concentration, the greater the liquid fill volume required to provide a given amount of lyophilized derivative and the larger the lyophilization vial. When a more dilute liquid fill concentration is used and a very large vial is required to contain the proportionally larger required fill volume, the final product will only occupy a relatively small proportion of the total volume of the vial after reconstitution to 400 mg / ml . For practical reasons, the fill concentration should be in a range of 100 - 135 mg / ml, with a concentration of about 125 mg / ml being preferred. The invention is illustrated by the non-limiting examples further explained.

Example I.

5 Determination of the optimal concentration of the final product - 2 g / vial.

6- [2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido] -2-phenylacetamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo- [3'2) was dissolved ♦ Olheptane-2-carboxylic acid, sodium salt in water to a final concentration of 200 mg / ml 10 ml of this solution was added to each of five vials of 10 and lyophilized by standard methods Each of these lyophilized cakes was then reconstituted with a different amount water to obtain a series of final concentrations of sodium piperacillin taking into account that each gram of sodium piperacillin displaces 0.7 ml of water These products were tested for pH, density and viscosity according to standard procedures.

The dissolution time was measured by shaking the vials containing the lyophilized cake and the reconstitution water by hand and measuring the time it took for the sodium pipacillin to dissolve. The usability of a syringe was also assessed by measuring the time it took to remove 1 ml of finished product from a bottle. The results were as follows: 8201251 -5- X xs X o 3 cn cd ui ifc w μ h to OH rr CX * 2

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8201251 -6-

Example II.

Determination of the optimal concentration of the final product - 1 g / bottle.

According to the procedure of Example I, each of 5 vials was filled with 5 ml of a 200 mg / ml solution of sodium piperacillin 5 and lyophilized to obtain 1 gram / vial. The vials were then diluted as above and the same tests were performed.

The results were as follows: 8 2 0 1 2 5 1 -7- £

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Based on the drastic increase in dissolution time and density and the drastic decrease in spray usability between the 400 and 500 mg / ml levels in Examples 1 and 2, it was concluded that 400 mg / ml is the most practical reconstitution concentration for use.

Example III.

Relationship between filling concentration and reconstitution time.

Sodium piperacillin was prepared in four separate concentrations of 200, 166.7, 142.9, and 125 mg / ml by dilution with water. An appropriate amount of each liquid fill concentration to obtain Igram sodium pipacillin was placed in a series of 4 vials and lyophilized. After lyophilization, each 1 gram of cake was reconstituted with 1.8 ml of water to a final volume of 2.5 ml at a concentration of 400 mg / ml. The reconstitution time was measured 15 and the results were as follows:

Sample fill quantity Reconstitution average concentration per ml of water x final reconstitution vial in ml of concentration time (mg / ml) tration 20 (mg / ml) 1 200 5 1.3 400 1 min. 42 sec.

2 - 166.7 6 1.8 400 1 min.16 sec.

3 142.9 7 1.8 400 36 sec.

25 4 125 8 1.8 400 15 sec.

x each gram of sodium piperacillin displaces 0.7 ml of water.

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Example IV.

30 The following table gives the amount of liquid filling of a 125 mg / ml solution required to give a lyophilized product that after reconstitution has a 400 mg / ml final concentration, with room for ÜSP excess: 82 0 1 2 5 1 ... .....

9- I yy amount of amount actual number of ml for final concentration per vial of solution (amount of reconstitution according to the from 125 jper vial to 400 mg / ml (mg / ml) label (g) in ml j in mg x 5 1 8.64 i 1,080 I 2.0 400 i 2 17.28 2,160 {4.0 400 3 25.92 3,240 6.0 400 4 34.24 4,280 7.8 400 6 50.56 6,320 11.6 400 10 x each gram of displaced sodium piperacillin 0 .7 grams of water xx final concentration provides space for USP excess to compensate for syringe clearance and product left in the bottle 82 0 1 2 5 1

Claims (4)

A method of preparing a pharmaceutical parenteral dosage unit comprising a lyophilized penicillin derivative, characterized in that a) a solution of the penicillin derivative in water is prepared at a concentration of about 125 mg / ml; b). the solution is placed in a container until the desired amount? and c) the penicillin derivative is frozen and lyophilized in the container to yield a light, fluffy lyophilized product which will rapidly and completely dissolve with a pharmaceutically acceptable diluent upon reconstitution to a concentration of about 400 mg / ml. 2. Product obtained using the method according to claim 1. Process according to claim 1, characterized in that the penicilin derivative 6- [2- (4-ethyl-2,3-dioxo-1-piperazine carboxamido) -2-phenyl-acetamido] -3,3-dimethyl-7 -oxo-4-thia-1-azabicyclo [3 * 2 * 0] heptane-2-carboxylic acid, sodium salt. The product of claim 2, which is a lyophilized parenteral dosage unit containing 6- [2- (4-ethyl-2,3-dioxo-1-piperazine-carboxamido) -2-phenylacetamldo] -3,3-dimethyl-1 7-oxo-4-thia-1-azabicyclo [3 * 2 * 0] heptane-2-carboxylic acid, sodium salt. 8201251