NZ199632A

NZ199632A - Preparation of a dosage unit from lyophilised penicillin derivative

Info

Publication number: NZ199632A
Application number: NZ199632A
Authority: NZ
Inventors: B E Haeger
Original assignee: American Cyanamid Co
Priority date: 1981-03-26
Filing date: 1982-02-02
Publication date: 1985-07-12
Also published as: DK157976C; AT395533B; AU549784B2; HK39189A; IT1147916B; LU84031A1; NL192664C; PL130564B1; DE19375106I2; IL64924A; ES8302455A1; JPH0219804B2; CA1209477A; HU186489B; DE3208505C2; PL235509A1; FR2502624A1; GB2095551B; BE892541A; IE52936B1

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 1 99632 199632 Priority Dc, Complete Spcoifscation Filed;7??-. Class* ^1 ^ h e Jl-j. v"UJO' ' v.. • • Publication Date- . ... HZ JUL .1985. P.O. Journal, Wo: ...... A-?,"7. ' NO DRAWINGS1 NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION COMPOSITION OF MATTER COMPRISING A LYOPHILIZED PREPARATION OF A PENICILLIN DERIVATIVE tyWe, AMERICAN CYANAMID COMPANY, a corporation organized and existing under the laws of the State of Maine, United States of America, and having its executive offices at Wayne, New Jersey, United States of America, hereby declare the invention for which}®?/ we pray that a patent may be granted to ?soe/us, and the method by which it is to be,performed, to be particularly described in and by the following statement:- - 1 - (followed by la) 199632 - la - COMPOSITION OF MATTER COMPRISING A LYOPHILIZED 10 PREPARATION OF A PENICILLIN DERIVATIVE BACKGROUND OF THE INVENTION This invention is concerned with a pharmaceutical composition of matter, in particular a dosage unit parenteral form of the penicillin derivative 6-[2-(4-ethyl-2,3-di-^ oxo-l-piperazinecarboxamido)-2-phenylacetamido]-3,3-dimethyl--7-oxo-4-thia-l-azabicyclo[3•2*0]heptane-2-carboxylie acid, sodium salt (hereinafter called Sodium Piperacillin), which is disclosed in U.S. Patent No. 4,112,090 (Toyama Chemical Co.) wherein its utility as an antibacterial agent is estab- 7Ci lished. This invention also concerns a method of making said parenteral dosage unit. The conventional procedure for preparing a lyophil-ized parenteral dosage form of a penicillin derivative involves preparing a 200 mg./ml. aqueous solution of the 25 derivative, filling the solution in a vial at 5 ml. per vial, and then lyophilizing the contents; the dried cake representing one 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 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 with a syringe and administers the appropriate dose to the patient. The difficulty with the above parenteral composition is that the physician must administer 4 mis. of solution 199632 - 2 - per 1 gram dose. Piperacillin, like many penicillin derivatives, is hypertonic and therefore inherently causes pain upon intramuscular injection. Furthermore, the dosage limit for injection into the arm is approximately 2 milliliters, as the musculature simply will not tolerate larger interstitial volumes. The 4 milliliter dosage of the prior art thus necessitates the less convenient procedure of giving injections in the buttocks. Even with injection in the buttocks, the large 4 milliliter dosage means that distribution time is increased. It is a purpose of this invention to provide a parenteral dosage unit form of Piperacillin and similar penicillin derivatives which decreases the injection volume from that known in the prior art by providing a more concentrated final product. The difficulty with preparing a concentrated reconstituted preparation of a lyophilized penicillin derivative is that as concentration of the final product increases, reconstitution time also increases. At a final product concentration of 400 mg./ml., the reconstitution time may be as long as several minutes with continuous shaking. The time required to reconstitute such products has led to a discouragement of their Use, with the result that more dilute preparations are used, with all their above-described disadvantages. It is therefore another goal of this invention to provide a lyophilized parenteral dosage unit form of Piperacillin and similar penicillin derivatives which provide a highly concentrated but easily reconstituted final product. DETAILED DESCRIPTION OF THE INVENTION 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-l-piperazinecarboxamido)-2-phenylacetamido]--3,3-dimethyl-7i-oxo-4-thia-l-azabicyclo[3'2-0]heptane-2--carboxylic acid, sodium salt defined above as Sodium 199632 - 3 - Piperacillin. The term "expanded cake" means a lyophilized cake which occupies a larger volume than that taken up 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 are then filled into a vial to a total of 1 gram of penicillin derivative per vial. The vials are chosen for their ability to withstand the lyophilization procedure and for their ability to accept a suitable stopper which will allow for syringe withdrawal of the contents. The penicillin derivative is then lyophilized in the vial according to standard procedures well known to those skilled in the art. During the lyophilization step, the freeze-dried cake maintains the volume of the liquid fill dose and forms a crystalline loosely textured mass sealed under negative pressure. Since the volume of the liquid fill is eight milliliters, the lyophilized cake is much larger and looser ("expanded cake") than the five-milliliter cake of the prior art. Following lyophilization the vials are sealed with appropriate septa for syringe compatability. When the physician is ready to administer a dose, he reconstitutes the lyophilized cake with 2.5 ml. of a suitable diluent. Examples of suitable diluents are, e.g., water or lidocaine hydrochloride, a local anesthetic which may be added to counteract the inherent pain of the injection due to the hypertonic nature of penicillin derivatives such as Piperacillin. The time necessary to reconstitute the 1 gram of lyophilized derivative is approximately 35 seconds with shaking. The final product provides 2.5 milliters of a 400 mg./ml. solution of the desired penicillin derivative, and an injection dose of 2.5 mis./gram as opposed to the 4 ml./gram dose of the prior art. The above-described process may be modified to provide a larger or smaller amount of final product by proportionately increasing or decreasing the amount of 125 mg./ml. of liquid fill introduced into the vials before 199632 - 4 - lyophilization, and by proportionately increasing or decreasing the amount of diluent needed to reconstitute the final product to provide a final concentration of 400 mg./ml. The above-described process may also be modified 5 to use a liquid fill concentration higher or lower than 125 mg./ml., although less successfully. At higher liquid fill concentrations the density of the lyophilized cake increases and the reconstitution time necessary to solubilize the penicillin derivative at a concentration of 400 mg./ml. 10 also increases, but at a greatly disproportionate rate. For example, increasing the liquid fill concentration by 157o increases the reconstitution time by over 100%. See Example 3. Alternatively, lower liquid fill concentrations may be used but the lower the liquid fill concentration, 15 the greater the liquid fill volume required to provide a given amount of lyophilized derivative and the larger the lyophilization vial required. If a more dilute liquid fill concentration is used and a very large vial is necessary to contain the proportionately larger fill volume required, 20 the final product after reconstitution to 400 mg./ml. will occupy only a relatively small fraction of the total vial volume. As a practical matter, the fill concentration should be within a range of 100-135 mg./ml., with a concentration of about 125 mg./ml. preferred. 25 A further understanding of the invention can be had from the following non-limiting examples. 30 199632 - 5 - Example 1 Determination of the Optimum Concentration of the Final Product - 2 gms/vial 6-[2-(4-ethyl-2,3-dioxo-l-piperazinecarboxamido]-5 2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo-[3*2'0]heptane-2-carboxylic acid, sodium salt, was dissolved in water to a final concentration of 200 mg./ml. 10 mis. of this solution were filled into each of five vials and lyophilized by standard methods. Each of these lyo-10 philized cakes was then reconstituted with a different amount of water to provide a series of final concentrations of Sodium Piperacillin with allowances made for the fact that each gram of Sodium Piperacillin displaces 0.7 ml. of water. These products were tested for pH, density, and vis-15 cosity by standard procedures. Solubilization time was measured by shaking the vials containing the lyophilized cake and the reconstitution water by hand and measuring the time necessary for the Sodium Piperacillin to go into solution. Syringeability was also estimated by measuring the 20 time necessary to withdraw 1 ml. from a vial of final product. The results are given as follows: 25 30 • • • I Sample mis. water to reconstitute Final* Volume Final conc. (mg./ml.) Avg. time to Sol-ubi-1 ize (mis) PH Density Viscosity (cps) Syringeability** 26 gauge 21 gauge 1 8.6 10 200 0.5 5.87 1.072 2.6 Good Good 2 6.6 8 200 0.5 5.95 1.090 3.8 Good Good 3 3.6 5 400 2.0 6.09 1.141 16.2 Fair Good 4 2.6 4 500 5.75 6.16 1.173 65 Poor Fair 5 1.93 3.33 600 25-30 6.27 1.206 314 Poor Poor * Each gram of Sodium Piperacillin displaces 0.7 ml. water ** Syringeability Test: Good = 5 15 sees to withdraw 1 ml. Fair = 20-30 sees to withdraw 1 ml. Poor = >1 min to withdraw 1 ml. 199632 Example 2 Determination of the Optimum Concentration of the Final Product - 1 g/vial Following the procedure of Example 1, each of 5 5 vials were filled with 5 mis. of a 200 mg/ml solution of Sodium Piperacillin and lyophilized to provide 1 gram/vial. The vials were then diluted as above and the same tests were run. The results are given as follows: 15 20 25 30 / • • • i Sample No. mis water to Reconstitute Final* volume (mis) Final conc. (mg./ml.) Avg. time to Sol-ubi-lize (min) PH Density Viscosity (cps) Syringeability** 26 gauge 21 gauge 1 4.3 5 200 0.75 5.83 1.073 i 2.6 Good Good 2 3.3 4 250 0.75 5.92 1.090 3.8 Good Good 3 1.8 2.5 400 2.75 6.07 1.141 16.2 Fair Good 4 1.3 2.0 500 8.5 6.16 1.175 65 Poor Fair 5 0.97 1.67 600 25-30 6.26 1.208 317 Poor Poor * Each ml. of Sodium Pipericillin displaces 0.7 ml. water. ** Syringeability Test: Good = 5-15 sees to withdraw 1 ml. Fair = 20-30 sees to withdraw 1 ml. Poor = >1 min to withdraw 1 ml. 199632 Based on the drastic increase in solubilization time and density and the drastic decrease in syringeability between the 400 and 500 mg/ml levels in Examples 1 and 2, it was concluded that 400 mg/ml is the uppermost practical 5 reconstituted concentration to be used. Example 3 Relationship of Fill Concentration to Reconstitution Time Sodium Piperacillin was prepared in four separate 10 concentrations of 200, 166.7, 142.9, and 125 mg./ml. by dilution with water. An appropriate amount of each liquid fill concentration to provide 1 gram of Sodium Pipericillin was filled into a series of 4 vials and lyophilized. After lyophilization, each 1 gram cake was reconstituted with 1.8 15 mis. of water to a final volume of 2.5 mis. at a concentration of 400 mg./ml. Reconstitution time was measured and the results are as follows: 20 25 30 Reconstitution Sample Fill conc. (mg./ml.) Ml Fill/vial Mis. Water* Final Conc. (mg/ml) Average Reconstitution Time 1 200 5 1.8 400 1 min 42 sec. 2 166.7 6 1.8 400 1 min 16 sec. 3 142.9 7 1.8 400 36 sec. 4 125 8 1.8 400 15 sec. * Each gram of Sodium Piperacillin displaces 0.7 ml. of water. vO NO & 04 N> </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 199632 - 11 - » Example 4 The following Table represents the amount of liquid fill of a 125 mg/ml solution necessary to. provide a lyophilized product which when reconstituted will provide a 400 mg/ml final concentration, with allowance for USP overage: Label claim per Vial (g) Mis. of 125 mg/ml solution Actual mg/vial Mis. to reconstitute to 400 mg/ml * Final Conc.** (mg/ml) / 1 8.64 1,080 2.0 "400 2 '17.28 2,160 4.0 400 3 25.92 3,240 6.0 400 4 34.24 4,280 7.8 404 50.56 6,320 11.6 400 * Each gram of Sodium Piperacillin displaces 0.7 grams of water^ 1 ** Final concentration allows for USP overage to compen sate for syringe clearance and product left in the vial. - 12 - 139632 WHAT WE CLAIM IS:

1. A process for the preparation of a pharmaceutical parenteral dosage unit comprising a lyophilized penicillin derivative, said process comprising : a) preparing a solution of said penicillin derivative in water at a concentration of from 100 mg/ml to 135 mg/mlJ b) filling said solution into a container to the desired amount; and c) lyophilizing said penicillin derivative in said container, thereby providing a light, fluffy lyophilized product which upon reconstitution to a concentration of 4 00 mg/ml with a pharmaceutically acceptable diluent will go into solution rapidly and completely.

2. The process of Claim 1 wherein the concentration of said penicillin derivative in water is 125 mg/ml.

3. The product of the process of Claim 1 or Claim 2.

4. The process of Claim 1 or Claim 2 wherein said penicillin derivative is 6-[2-(4-ethyl-2,3-dioxo-l-piperazine-.. carboxamido) -2-phenylacetamido] -3 , 3-dimethyl-7-oxo-4-thia--1-aza-bicyclo[3•2 *0]heptane-2-carboxylic acid, sodium salt.

5. The product of Claim 3, a lyophilized parenteral dosage unit comprising 6-[2-(4-ethyl-2,3-dioxo--1-piperazinecarboxamido) -2-phenylacetamido] -3 , 3-dimethyl--7-oxo-4-thia-l-azabicyclo [ 3•2•0]heptane-2-carboxylic acid, sodium salt^P^, OATED THIS DAY OF * .S A. J. PARK A SON X PER AGENTS FOR THE APfUCANTS </div>