KR860000512B1 - Method of preparing a dosage unit of a lyophilized penicillin derivatives - Google Patents

Abstract

Dosage unit of a sodium piperacillin for parenteral administration was prepd. by dissolving it in H2O and lyophilizing the soln. Thus, Na salt of b-[2-(4-ethyl-2,3-dioxo-1-piperazine carboxamido)-2- phenylacetamido -3,3-dimethyl-7-oxo-4-thio-1azabicyclo[3,2,0!heptane- 2-carboxylic acid was dissolved in H2O at 200 mg/ml, and 10 ml of the soln. was bottled in vial, and lyophilized to give stable, sol. Cake with average disintegration time 0.5 min, pH 5,87, density 1.072, and viscosity 2.6 cps.

Description

Method for preparing injectable unit of freeze-dried product of penicillin derivative

The present invention relates to a pharmaceutical composition, especially 6- [2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido], which is a penicillin derivative in unit dosage form. 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3,2,0] heptane-2-carboxylic acid sodium salt (hereinafter referred to as sodium piperacillin), which is described in US Pat. No. 4,112,090 As detailed above, the use is known as an antibiotic. The invention also relates to the preparation of injection dosage units.

Conventional methods for preparing penicillin derivatives in the form of lyophilized injectable dosages have been made of the derivatives in an aqueous solution of 200 mg / ml to freeze-dry the contents, with the dried cake corresponding to 1 g of the derivative. When penicillin is to be administered as a medicament, it is regenerated with 3.3 ml of water or other suitable injectable diluent. Penicillin derivatives are replaced with 0.7 ml of diluent per gram of derivative. Thus the final product is 4.0 ml of the regenerated derivative at a concentration of 250 mg / ml.

The problem with the above injectable compositions is that the doctor must administer 4 ml of solution per gram of dose. Like many penicillin derivatives, piperacillin is highly hypertonic and therefore painful during muscle injection. Moreover, the dose limit for injection into the arm is about 2 ml because the muscular system simply cannot tolerate large crevice volumes. Therefore, the conventional 4ml dose was much more uncomfortable when injected into the buttocks.

When injected into the buttock to 4ml amount is a longer dispersion time.

It is an object of the present invention to provide a piperacillin and similar penicillin derivatives thereof in an injectable unit which make a more concentrated final product and require less injection volume than conventional ones.

The difficulty in producing a concentrated regenerated product of the lyophilized penicillin derivative is that the longer the concentration of the final product, the longer the regeneration time. At the final product concentration of 400 mg / ml, the regeneration time takes a few minutes even with continuous shaking.

The time it takes to regenerate this product is inconvenient in use and results in a more diluted formulation. It is therefore another object of the present invention to present piperacillin and similar penicillin derivatives thereof in lyophilized injectable dosage units which give a highly concentrated but easily regenerated final product.

Injectable dosage units of the invention are lyophilized penicillin derivatives, in particular 6- [2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido]- 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] Sodium salt derivative of heptane-2-carboxylic acid, ie disintegrating sodium piperacillin as defined above This is made in the shape of an inflated cake. By "expanded cake" is meant a lyophilized cake that occupies a larger volume than the conventional "standard cake" occupies.

Penicillin derivatives are dissolved in water at a concentration of 125 mg / ml. When 8 ml of this solution is filled into a glass jar, 1 g of penicillin derivative is added to the glass jar. The vial shall be capable of withstanding freeze-drying conditions and be fitted with a suitable stopper for the contents to be withdrawn by a syringe.

The penicillin derivative thus filled is lyophilized in a bottle according to a standard method known in the art.

The freeze-dried cake during the freeze-drying step maintains the volume of the liquid fill volume and becomes a loose object with crystalline tissue sealed under negative pressure.

Since the volume of the liquid filling is 8 ml, the lyophilized cake is much larger and expanded than the conventional 5 ml cake. After freeze drying, the bottle is capped with a suitable stopper to allow the syringe to be used. When the physician wishes to administer the dose, the cake is lyophilized with 2.5 ml of a suitable diluent. Suitable diluents include water or lidocaine hydrochloride, which is a topical anesthetic that is added to counteract the specific pain seen during injection because penicillin derivatives such as piperacillin are hypertonic. The time required to regenerate 1 g of the lyophilized derivative is about 35 seconds with shaking. The final product accounts for 2.5 ml of the 400 mg / ml solution of the required penicillin derivative, which is an injection dose of 2.5 ml / gr compared to the conventional 4 ml / gr dose.

In improving the method described above to make the final product larger or smaller, the method requires a proportional increase or decrease in the amount of 125 mg / ml of the liquid charge introduced into the bottle prior to freeze-drying and the amount of diluent required to regenerate the final product. Proportionally increase or decrease the final concentration to 400mg / ml.

Although not successful, the above method can be supplemented by using a liquid filler concentration greater than or less than 125 mg / ml. The higher the liquid filler concentration, the higher the density of the lyophilized cake and the regeneration time required to dissolve the penicillin derivative to a concentration of 400 mg / ml. However, the ratio is inversely proportional. For example, if the concentration of the liquid filler is increased by 15%, the regeneration time is increased by 100% or more (see Example 3). In addition, since the concentration of the liquid filler can be used to be small, the smaller the concentration of the liquid filler, the larger the volume of the liquid filler and the size of the glass bottle required for lyophilization. Using a thinner liquid filler concentration and using a large glass bottle to fill a proportionately larger fill volume, the final product after regeneration at 400 mg / ml occupies only a relatively small portion of the total glass bottle.

The present invention is described in detail according to the embodiment.

Example 1

6- [2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -3,3-dimethyl-7-oxo-4-thia-1 The sodium salt of azabicyclo [3.2.0] heptane-2-carboxylic acid was dissolved in water to give a final concentration of 200 mg / ml. 10 ml of this solution was filled in each of the five vials and lyophilized by standard methods. Each lyophilized cake was regenerated with different amounts of water to make sodium piperacillin with a series of final concentrations, taking into account the fact that 1 gram of sodium piperacillin was replaced with 0.7 ml of water. They were tested for pH, density and viscosity by standard methods. The dissolution time was determined by shaking the freeze-dried cake and the glass bottle to which regeneration water was added by hand and measuring the time it takes for sodium piperacillin to dissolve into the solution. Injection characteristics were evaluated by measuring the time required to extract 1 ml from the vial containing the final product.

the results are as follow.

* 1 g of sodium piperacillin is replaced with 0.7 ml of water

** Scanning characteristic test: Good 1-15 seconds to extract 1ml

20-30 seconds to pull out 1 ml

1 minute or more

Example 2

Following the method of Example 1, each of the five glass bottles was filled with 5 ml of a 200 mg / ml solution of sodium piperacillin, and then lyophilized to make a 1 g / glass bottle.

These bottles were diluted with the same test as above and the results were as follows.

* Each ml of sodium piperacillin is replaced with 0.7 ml of water

** Scanning characteristic: Good 1-15 seconds to extract 1ml

Approx. 20-30 seconds to extract 1 ml

1 minute or more

It can be concluded that the injection properties are greatly reduced and the dissolution time and density are greatly increased between Examples 1 and 2, with 400 mg / ml being the best practical regeneration concentration before use.

Example 3

Dilute with water to make sodium piperacillin at four concentrations: 200, 166.7, 142.9 and 125 mg / ml.

To make 1 g of sodium piperacillin, an appropriate amount of each liquid filler concentration was filled into four glass bottles, respectively, and lyophilized. After freeze-drying, each 1 g cake was regenerated using 1.8 ml of water to give a final volume of 2.5 ml with a concentration of 400 mg / ml. The result of measuring the play time is as follows.

* 1 g of sodium piperacillin is replaced with 0.7 ml of water

Example 4

The following table shows the amount of 125 mg / ml liquid filler required to bring the final concentration of the lyophilized product to 400 mg / ml when regenerated, taking into account USP tolerance limits.

* 0.7 g of water per 1 g of sodium piperacillin

** Final concentrations are allowed by the US Pharmacy and take into account the product remaining in syringe washes and vials.

Claims (1)

An aqueous solution of a penicillin derivative having a concentration of 100-135 mg / ml is prepared, the solution is filled in the container as required, and the penicillin derivative is freeze-dried in the container, and the concentration is 400 mg / ml using a pharmaceutically acceptable diluent. Lyophilized penicillin derivative 6- [2- (4-ethyl-2,3-dioxo-, consisting of making a light, disintegratable lyophilized product that dissolves quickly and completely into solution when regenerated with 1-piperazincarboxamido) -2-phenylacetamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3,2,0] with heptane-2-carboxylate Method of preparation of the made dosage unit.