FR2502624A1 - COMPOSITION COMPRISING A LYOPHILIZED PREPARATION OF A PENICILLIN DERIVATIVE AND PREPARATION METHOD THEREOF - Google Patents

Abstract

THE INVENTION CONCERNS A COMPOSITION COMPRISING A LYOPHILIZED PREPARATION OF A PENICILLIN DERIVATIVE AND ITS PREPARATION METHOD; IT PARTICULARLY CONCERNS A UNIT DOSE FORM FOR PARENTERAL ADMINISTRATION OF SODIUM SALT OF ACID 6-2- (4-ETHYL-2-DIOXO-1-PIPERAZINECARBOXAMIDO) -2-PHENYLACETAMIDO-3,3-DIMETHYL- 7-OXO-THIA-1-AZABICYCLO3.2.0HEPTANE-2-CARBOXYLIQUE.

Description

The present invention relates to a composition

  comprising a lyophilized preparation of a penile derivative

  cillin and its preparation process. More particularly the invention relates to a

  pharmaceutical composition, especially a single dose form

  shut up for parenteral, from the penicillin derivative that is

  the sodium salt of 6- [2- (4-ethyl-2,3-dioxo-1-pipé-) acid

  razinecarboxamido) -2-phenylacetamido7-3,3-dimethyl-7-oxo-4-

  thia-l-azabicyclof3.2.O] heptane-2-carboxylic (called here-

  after piperacillin sodium) which is described in US Pat. No. 4,112,090 (Toyama Chemical Co.) where its usefulness as an antibacterial agent is established. The invention also relates to a method for preparing this unit dose for administration.

parenterally.

  The classic form preparation process

  lyophilized administration for parenteral administration of a

  riveted penicillin includes the preparation of an aqueous solution of the derivative at 200 mg / ml, the introduction of the solution

  in vials at a rate of 5 ml per vial then lyophi-

  content reading; the dry cake being made up of one gram of the derivative. When the practitioner prepares to administer the drug, he reconstitutes the contents of the vial with 3.3 ml of water or another suitable parenteral diluent. The derivative

  penicillin replaces 0.7 ml of diluent per gram of de-

  bank. The final product therefore consists of 4.0 ml of the derivative

  v reconstituted at a concentration of 250 mg / ml. The practitioner then draws the appropriate amount of solution from the vial with a syringe and administers the appropriate dose

to the patient.

  The difficulties of parenting

  rale above is that the practitioner should administer 4 ml of solution per dose of 1 gram. Piperacillin, like many penicillin derivatives, is hypertonic and causes

  therefore naturally pain during intramuscular injection-

  cular. In addition, the administration limit for the injection

  tion in the arm is about 2 ml simply because the

  musculature does not tolerate larger interstitial volumes

  load-bearing. The 4 ml dose of the prior art required

  site therefore to perform the injections in a less practical way in the buttock. Even in the case of an injection, in the

  buttock, the large dose of 4 ml increases the repair time

tition.

  One of the objects of the invention is to provide a form

  unit dose for parenteral administration

  rale of piperacillin and analog penicillin derivatives

  which reduces the volume of the injection compared to the prior art by providing a more concentrated final product.

  The difficulty of preparing a pre-

  concentrated, reconstituted paration of a lyophilized derivative of

  penicillin is that when the concentration of the product fi-

  nal increases, the duration of reconstitution also increases.

  For a final product concentration of 400 mg / ml, the

  reconstitution may take several minutes with shaking

  tion continues. The time required to reconstitute

  these products dissuaded from using them so much that one used

  read more diluted preparations that have all of the

  disadvantages previously described.

  Another object of the invention is to provide a lyophilized unit dose form for administration by

  parenteral of piperacillin and penile derivatives

  analogs cillin which provides a concentrated end product but

easy to reconstitute.

  The unit dose for parenteral administration of the invention comprises a loose and light expanded cake of a lyophilized derivative of penicillin, in particular salt of

  6- / 2- acid sodium (4-ethyl-2,3-dioxo-1-piperazinecarbo-

  xamido) -2-phenylacetamido7-3,3-dimethyl-7-oxo-4-thia-1-aza-

  bicyclo / 3.2.0lheptane-2-carboxylic acid, defined above as piperacillin sodium. The term "expanded cake" denotes a lyophilized cake which occupies a volume greater than that

  of 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 introduced into a bottle, each bottle

  con containing a total of one gram of penicillin derivative.

  We choose bottles capable of withstanding the freeze-drying operation and capable of receiving an appropriate stopper

  allowing the contents to be withdrawn with a syringe.

  The penicillin derivative is then frozen and lyophilized in the vial according to conventional techniques

  well known to the specialist. During the stage of lyophilisa-

  tion, the lyophilized cake retains the volume of the liquid

  produces and forms a crystalline mass with a loose texture, sealed

  Negative pressure. As the volume of the content li-

  which is 8 ml, the freeze-dried cake is much larger

  thinner and looser ("expanded cake") than the 5 ml cake

  of the prior art. After lyophilization,

  me the bottles with appropriate caps allowing the

syringe sample.

  When the practitioner 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 which is a local anesthetic which can be added to control

  the pain caused by the injection by the hyper-

  tonic of penicillin derivatives, such as piperacilli-

  born. The time required to reconstitute the gram of drift

  ly freeze-dried is approximately 35 seconds with agitation. The final product provides 2.5 ml of a 400 mg / ml solution of the desired penicillin derivative and an injection dose of 2.5 ml / gram which contrasts with the 4 ml / gram dose of the

prior art.

  The previously described process can be modified to provide a greater or lesser quantity of the final product by proportional increase or decrease in the quantity of liquid of 125 mg / ml which is introduced into the vials before lyophilization and by increase

  or proportional decrease in the amount of diluent ne-

  stop to reconstitute the final product by obtaining a final concentration of 400 mg / ml. The method described above can also be modified to use a concentration of the filling liquid greater than or less than 125 mg / ml although such concentrations are of less interest. For increased concentrations of the liquid content, the density of the lyophilized cake increases and the reconstitution time necessary to dissolve the penicillin derivative at the concentration of 400 mg / ml also increases, but very disproportionately. For example, a 15% increase in the concentration of the liquid content increases the reconstitution time by more than 100%; see example 3. Otherwise you can use lower concentrations of the liquid content but the higher the concentration of the liquid content

  the lower the volume of liquid content required to

  hold a given amount of the lyophilized derivative increases and the more the lyophilization vial must be voluminous. If a more diluted liquid content is used and a very large bottle is necessary to contain the volume of

  proportionally higher liquid content required

  re, the final product after reconstitution at 400 mg / ml does not

  only a relatively small fraction of the total volume of the

  bottle. In practice, the concentration of the filling liquid

  sage should be in the range of 100 to 135 mg / ml and

  a concentration of about 125 mg / ml is preferred.

  The invention will be better understood on reading the

following non-limiting examples.

EXAMPLE 1

  Determination of the optimal concentration of the final product:

2 g / bottle.

  The sodium salt of the acid is dissolved in water

  6-f2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenyl-

  acetamidc7-3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo / 3.2.0 / hep-

  tane-2-carboxylic to obtain a final concentration

  200 mg / ml. 10 ml of this solution are introduced into each

  one of five vials and lyophilized according to conventional techniques. Each of the freeze-dried cakes is then reconstituted with a different quantity of water to obtain a series of final concentrations of piperacillin sodium,

  taking into account that each gram of Piperacillin is

  dique replaces 0.7 ml of water. The pH1 is then determined, according to conventional techniques, the density and viscosity of these products. To measure the solubilization time, the bottles containing the lyophilized cake and the reconstitution water are shaken by hand and the time required is measured.

  for the Piperacillin Sodium to dissolve. We also assess

  the ease of withdrawal with a syringe by measuring the time required to withdraw 1 ml of final product from

  a flask. The following results are obtained.

  Echan- Number of Volume Concentration Time Viscosity Sample test-

  till ml of final water * average final of 10-3 ment a No for the (ml) (mg / ml) solubili- (10P syringe ** reconstitution tution (min) pH Density 0 0.45mm 0 0, 8mm 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 Fairly good good 4 2.6 4,500 5.75 6.16 1.173 65 Bad Fairly good 1.93 3.33 600 25-30 6.27 1.206 314 Bad Bad s * Each gram of Piperacillin Sodium replaces 0, 7 ml of water ** Syringe sampling test: Good = 5-15 seconds to withdraw 1 ml; Fairly good = 20-30 seconds to withdraw 1 ml; Bad = '7 1 min

to withdraw 1 ml.

ri> Un o '4'>

EXAMPLE 2

  Determination of the optimal concentration of the final product: 1 g / bottle

  According to the procedure of Example 1, we replace

  fold each of five 5 ml vials of a 200mg / ml solution of Piperacillin sodium and lyophilize to obtain lg /

  bottle. Then dilute the contents of the vials as below

  above and the same tests are carried out. The results are as follows: Echan- Number of Volume Concentration Time Viscosi- Sample test til- ml of final water * final final of tee & syringe ** lon for the (ml) (mg / ml) solubili- (10 -3P1) reconstruction tution (min): pH Density 0 0.45mm 0 0.8mm 1 4.3 5 200 0.75 5.83 1.073 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 Fairly good Good 4 1, 3 2.0 500 8.5 6.16 1.175 65 Poor Fairly good 0.97 1.67 600 25-30 6.26 1208 317 Bad Bad * Each gram of piperacillin sodium replaces 0.7 ml of water ** Syringe sample test: Good m 5-15 seconds to withdraw 1 ml; Fairly good = 20-30 seconds to withdraw 1 ml;

  Bad => 1 min to take 1 ml.

  Nv na 01% Due to the considerable increase in

  solubilization time and density, and the decrease-

  considerable ease of collection with the serin-

  gue between the concentrations of 400 and 500 mg / ml of examples 1 and 2, it is concluded that the maximum practical concentration

  after reconstitution which can be used is 400 mg / ml.

EXAMPLE 3

  Relationship between the concentration of the filling liquid

and the reconstitution time.

  Four concentrations are prepared by dilution in water.

  separate portions of piperacillin sodium: 200, 166.7, 142.9 and 125 mg / ml. A suitable quantity of each of the liquids is introduced into a series of four bottles.

  filling with different concentrations to obtain

  1 gram of piperacillin sodium and freeze-dried. After lyophilization, each 1 gram cake is reconstituted with 1.8 ml of water to obtain a final volume of 2.5 ml at

  a concentration of 400 mg / ml. We measure the time of recons-

  titution; the results are as follows.

o

  * Each gram of Piperacillin sodium replaces 0.7 ml of water.

  Q V.I 0% 4r w Sample Concentration Volume of liquid Reconstitution Average time of filling liquid per Concen- reconstitution N filling filling bottle (mg / mli (m) ml of water * final (mg / ml)

1,200 5 1.8 400 1 min 42 s.

2,166.7 6 1.8,400 1 min 16 s.

3,142.9 7 1.8,400 36 s.

4,125 8 1.8,400 15 s.

EXAMPLE 4

  The following table shows the amount of liquid

  filling consisting of a 125 mg / ml solution required

  to obtain a lyophilized product which, after reconstitution, provides a final concentration of 400 mgiml, taking into account the surplus provided by The United States Pharmacopeia. * Each gram of piperacillin sodium replaces 0.7 g of water '** The final concentration takes into account the surplus provided by The United States Pharmacopeia to compensate for the play of the syringe and the amount of product remaining

in the bottle.

  Weight ml of solution Actual weight M1 for Concen-

  indicated by reconstituting tration ** on the label vial (mg) (g) 125 mg.ml 400mg / ml * (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 4.280 798 404

6 50.56 6.320 11.6 400

REV E N D I C A T I 0 N S

  1 - Process for preparing a pharmaceu-

  unit tick for parenteral administration

  taking a lyophilized derivative of penicillin, characterized in that:

  a) a solution in water of said derivative is prepared

  v of penicillin at a concentration of 125 mg / ml;

  b) a container is filled with the desired quantity

of said solution; and

  c) the penile derivative is frozen and lyophilized

  cillin in the container; thus obtaining a light and loose lyophilized product which, after reconstitution at a concentration of 400 mg / ml with

  a pharmaceutically acceptable diluent, dissolves quickly-

completely.

  2 -_Process according to claim 1, character-

  se in that the penicillin derivative is the sodium salt

  1 t acid --6-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -

  2-phenylacetamido7-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo

/n.2.Q7heptane-2-carboxylic.

  3 - Product obtained by the process according to the resale

dication 1.

  4 - Product according to claim 2 which is a

  lyophilized unit dose for parenteral administration

  teral comprising the sodium salt of 6-12- (4-ethyl-

  2.3-dioxo-l-pip erazine-carboxamido) -2-phenylacetamidQ7-3,3-

  dimethyl-7-oxo-4-thia-1-azabicyclo (3.2.0Jheptane-2-carboxy-

lique.