CA1051780A - Stable chelocardin composition - Google Patents

Abstract

A B S T R A C T

A dry chelocardin salt composition which is stable to extended storage periods comprises a mixture of mono-sodium chelocardin and between 0.2 and 2.0 parts of sodium citrate.

Description

Chelocard7n is the antibiotic described in U.S.
3155582; i~ was originally idanti:Eied by M-319, but since that ~ime it:5 chemical structure has been determined; it is a tetra-. cyclic compc)ulld carrying specific functional groups in various positions:

,1 ~, , ' l H3 ~F~2 3'~ ~ ~ " : .
H H[ O OH o The prirnary use for this antibiotic lies in its form as a pa-renteral sol11tion; it shows outstanding activity against nu-merous bacteria not affected by other antibacterial drugsO
Unfortunately, howevP.r, chelocardin as a base or in the form o~ an acid addition s~lt is insoluble in water. This means that ch~locardin base or, for instance its hydrochloride salt, cannot be used for making injectable solutions. On the other hand, alkaline salts of chelocar~in are so highly unstable that they are of no practical value in the dxug ~ield; they degrade promptly and lose their antibacterial activity even when storad in the cold and under a nitrogen atmosphere.
It is therefore an objcct of the present invention to make a reconstitutable, water soluble solid product contailting chelocardin activity; it is a particular object of this in-vention to produce a solid composition that can readily be COTI-verted into an injectable ~olution and, at the same tlmeJ is s table to ~ torage .
These and other object~ are accompli.shed by providlng a compo~itiOn, in dry, solid form of a lyopholi~ed mlxture con-sis ting essentially of 1 part of the monosodiuro salt of chelo-cardin and between 0.2 and 2 parts by weight of socli~un citrate A freeze-dried composition of f.his nature can be stored almost indefinitely under proper storag2 conditions. All reference to sodium citrate herein is intended to indicate the dry sodium salt of ci~ric acid.
The findings covered by the present invention are very unusual and unexpected, particularly because a) chelocardin base or its salts with organic or inorganic acids are water insoluble and unsuitable for the in situ reconstitution into an injectable _ _ form, and b) alkaline metal salts of chelocardin are completely unstable and thus totally unsuitable for use as a drug component for the preparation o~ injectable solutionsO For instancQ, the sodium salt of chelocardin referred to above is so unstable that even under most cautious storage conditions it loses its potency and antibiotic activity to a great extent within a short period o t~me. It is also surprising to find that among all pos~ible additives ordinarily used in preparations of this type, only sodium citrate has the unique property of stabilizing the so-dium chelocardin to the point of making it a recons~itutable powder or a composition that can be stored under ordinary, pre-cautionary storage conditions. The new composition is well suited for the preparation of an injectable solution by the s~nple addition of water or a buffered aqueous mediumO
In order to illustrate the results obtained wlth the presen~ invention, reference is madP to the followillg example which, however, is not meant to limit the invention in any r~spect .

Exa_ple To a solution of 5 g~ of sodium citrate dihydrate in 200 ml. of water is added 5 g~ of chelocardin hydrochloride and the mixture is stirred to disperse the latter in a solution.
The dispersion is then cooled to 5 C. and neutralized by the addition of the stoichiometric quantity of sodium hydroxide (223 ml. of 0.1 N sodium hydroxide)O The resulting amber colored solution has a pH of between 8O0 and 8.7; it is diluted by the addition of water to make a total volume of 500 ~1~ The solution is then distribut~d in vials, 10 ml. per vial, and freeze dried in an ordinary freeze dry apparatus which allows ~he closure of each vial wi~hout removing the vials from ~he apparatus. Upon termination of the free~e drying cycleJ the vacuum in the ap-para~us is partially replaced by nitrogen to a pr~ssure of about 1/2 atmO The vials are then sealed and ready for storage or use at any time.
When in the above example the sodium citrate is varied be~ween 1 g. and 10 g~ per 5 g. of chelocardin hydrochloride, the stability of the p~ duct is essentially the same as that of the above described composition.
The stability of the product of the above example as well as some comparative products are carried out by g tandard, accelerated stability test methods, through detenmination of the first order degradation rate constant~ and the results are given in the following table~

~5~L~7~

Degradation Rate Constants k (expressed in 105/hr.) 1) No-chelocardin 44~6 167~3595.1

2 Na-chelocardin +
Na~citrate (1:1 by wt.) 5.6 21~6 57.0 All of the above deg.radation constants were determined on 3 to 4 lots prepared and stored in identical ~ashion to the lyopholized product of the above exampleO Ea~h of the above degradation rate constants is the average value of at least

3 lots each of which was based on at least 18 individual assays3 taken continuously over a time period of at least 2 weeks.
From the above table, the projected rate constant at 250 was calculated by standard kinetic procedures. The product of line 1 shows a first order degradation ra~e cons~ant of 2.6 x 105 per hour while the product according to the current invention (line 2) shows a constant of 0,47 x 105 per hour.
By conversion in standard fashion, the constants just given can be expressed as a 10% degradation time at 2SC. shawing that th~
product of line 1 is reduced to 90% of initial activity in 0.47 years while the product of line 2 degrades to this level only after 2,5 years. The result shown and calculated above clearl.y shows the unexpected improvement obtained by the addition of sodium citrat~.. This resul~c is particularly surprising in view o~ the fact that other commonly used stabilizers such as sodium ascorbate, sodi~m hydrosulfite, sodium formaldehyde-sulfoxylate and others do not produce the above improvement and in many in-stancesJ they are de~rimental to the cheloeardin stability.
The ~indings shown above and the calculation o:E de-gradation rate through s tandard kinetic formulas was cor.firmed by th~ values obtained by a 3-months stability 9 tudy carried out ~ 7~
under the above described condi.tions at 40C.
~ hile it has been pointed out above that sodium citrateamounts are flexible within a range of 20-200% by weight of the hydrochloride salt of chelocarclin, it should be noted that these amounts are based on crystalline sodium citrate dihydrate, i.e., the most conYenient form of that salt 3 Of course, other forms or hydrates thereof can be used as long as the equimolar amount is chosen to be within the desrribed range, In the simplest and often preferred embodiment~ equal weight parts of the two components are used where chelocardin is used in the form of the stable but water-insoluble chelocardin hydrochloride and sodium citrate dihydrata. Other aeid addition salts of chelo cardin can be used in place of the hydrochloride since that salt is neutralized by the addition of tha necessary amount of sodium hydroxide. Since the hydrochloride salt used above and khe monosodium s~lt of chelocardin differ in molecular weight by less than 3%, a stable composition c~n be made according tD the present invention by basing the ratio of components on either form of chelocardin mentioned aboveO
The ~tableg reconstitut~ble mixture of the present in-vention readily dissolves in water~ The preferred concentration for making ~u~h a solution is one that contains between 1 and 6 mg/ml. o~ t:he above solids. It is o:Eten pxeferred to add a suitableg pharmaceutically acceptable buffer to such a solution in ord r to achieve and maîntaiIl a pH of between 7.6 and 8.0 in order to prevent the chelocardin from precipitating and to main-tain its stabi.lity from the time the solution is prepared until it i~ injectecl into ~he patien~c ~ 5~
It will be obvious to those skilled in the art that thenew composition may contain optional additives frequently used in the preparation of injectable solutions, e.g. pre-servatives, buffers and the like~ ln many instances, suitable pharmaceutically acceptable ingredients of this nature may be added to the above aqueous starting ma~erial before freeze-dry-ing.

Claims (5)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A solid, pharmaceutical composition consisting essentially of a freeze-dried mixture of monosodium chelocardin and sodium citrate dihydrate in a weight ratio of between 1:0.2 and 1:2.

2. The composition of claim 1 wherein said ratio is essentially 1:1.

3. The process of preparing a pharmaceutical com-position according to claim 1 wherein an homogeneous dispersion of a pharmaceutically acceptable salt of chelocardin is con-verted to the monosodium salt of chelocardin by the addition of the stoichiometric amount of sodium hydroxide, adding between 0.2 and 2 parts by weight of sodium citrate dihydrate per part of chelocardin and freeze-drying said mixture to a dry solid.

4. The process of claim 3 wherein said chelocardin salt is the hydrochloride salt.

5. The process of claim 4 wherein sodium citrate is added in equal weight parts.