CA1190475A

CA1190475A - Pharmaceutical composition for implantation

Info

Publication number: CA1190475A
Application number: CA000396693A
Authority: CA
Inventors: Desmond Mackey
Original assignee: Leo Pharmaceutical Products Ltd AS
Current assignee: Leo Pharma AS
Priority date: 1981-02-23
Filing date: 1982-02-22
Publication date: 1985-07-16
Also published as: FR2500307A1; BE892224A; GB2093348A; GB2093348B; FR2500307B1; NL8200722A; ZA821028B; DE3206044A1

Abstract

ABSTRACT OF THE DISCLOSURE

A noval pharmaceutical composition for implantation in a natural, pathological or artificial cavity in body tissue and which includes an antibiotic which is slowly released from the composition upon implantation, is provided herein. The pharmaceutical composition comprises CaSO4, e.g. Plaster of Paris or gypsum, and at least one antibiotic substance,e.g. fusidic acid or gentamycin or their respective pharmaceutical-ly-acceptable salts, selected for its ability to be slowly released from CaSO4 and to maintain antibiotically effective concentrations in fluid in the cavity for a period of up to several weeks. The preparation of the composition comprises forming a slurry of CaSO4,e.g. calcium sulphate hemihydrate, gypsum or Plaster of Paris, with the desired aforesaid anti-bacterial substance or substances and a suitable amount of sterile water, optionally adding specified auxiliary agent(s), and allowing the slurry obtained to set in moulds, or in situ.

Description

This invention relates to processes for the production of a pharmaceutical composition for implantation in a natural, pathological or artificial cavity in body tissue of animals, including humans, and to the composition so prepared.
It is known that when set, calcium sulphate, hereinafter referred to as gypsum or plaster of Paris, is an effective filler of bone cavities in cases of osteomyelitis and bone cysts, and that it is spontaneously absorbed over a period of some months, being replaced by bone of normal architecture.
In the absence of a filler, such cavities tend to be occupied by haematomata or blood clots, which likewise disappear slowly giving way to new bone tissue, but which during their residence in the cavities constitute a haven and a growth medium for microorganisms including pathogenic and pyogenic bacteria.
It is also known that gypsum fillers, without additives, have no particular effect in discouraging bacterial infection apart from the mechanical exclusion of clots.
It is likewise known to fill bone cavities with beads or the like composed of synthetic resin cement and impregnated with ae least one antibiotic substance which diffuses into the cavities over a prolonged period, this being an effective local antibiotic, therapeutic or prophylactic, method of treat-ment. These beads, which are conventionally strung together on an inert metal wire in the manner of a necklace or chapelet, ~re not however absorbed by the human body and it is generally thought proper to remove them, a few at a time, in subsequent surgical operations which have no other purpose.
These operations have the disadvantageous side-effect of reopening relatively fresh wounds, of disturbing replacement tissue which rnay have begun to surround some or all of the beads, and of involving a risk of re-infection, or re-activation of old infection sites. Removal of beads leaves dead spaces which it is customary to refill the autogenous cancellous bone graft;
this is a further complication of the method.
Among the ob~ects of aspects of this invention are the alleviation or removal of some or all oE the above recited disadvanta~es.
It has been found that certain antibiotic substances when present in admixture with small bodies of gypsym, and exposed to fluids9 e.g. water buffer solutions or body fluids, are released from those bodies to appear in the fluids, the rate of release being dependant on several conditions, e.g.
the choice of antibiotic, the preparation of said bodies and other factors.
This phenomenon permits a therapeutically or prophylactically effective concentration of antibiotic substances to be maintained for that period in an environment of which the volume is suitably limited as Eor example the volume of a cavity in a body tissue, e.g. bone is limited. The period in question normally extends to many days or several weeks.
It is, however, important that the release of the antibiotic sub-stance has an optimal rate being neither too fast or too slow, and it has now surprisingly been found that, in particular, the antibiotics fusidic acid and gentamycin and salts thereof each and together fulfill the desired releasing requirements giving rise to both a favourable prolonged and adequate antibiotic activity in the fluids of the cavities. For the easy reference it shall be emphasized that FUCIDINE is the trade name for fusidic acid or its salts.
The inven~ion therefore provides in one broad aspect a pharmaceutical composition adapted for implantation in a natural, pathological or artificial cavity in a body tissue, which composition comprises CaS04 at least one antibio~ic substance selected from the group consisting of -- 2 ~

~- . ,3 fusidic acid and gentamycln or pharmaceutically-acceptable salts thereof and a suitable amount of sterile water, that antiblotlc substance being selected for its ability to be slowly released from the composition on implantation and to malntain antibiotically effective concentrations in fluids in the cavity.
By one broad process aspect of this invention, a process is provided for the preparation of a pharmaceutical composition adaptecl for implantation in a natural, pathological or artificial cavity in a body tissue, which process comprising: forming a slurry of CaSO~, at least one of fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof and sterile water; and allowing the slurry obtained to sct in moulds of the desired form and size.
By another broad process aspect of this invention, a process is provided for the preparation of a pharmaceutical composition adapted for implantation in a natural pathological or artificial cavity in a body tissue, which process comprises: forming a mixture of CaS04, at least one fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof 1/2 to 2 mol sterile water; and allowing the slurry obtained to set in moulds of the desired form and size.
By yet another broad process aspect of this invention, a process is provided for the preparation of a pharmaceutical composition adapted for implantation in a natural, pathological or artifial cavity in a body tissue which process comprising: mixing calcium sulphate hemihydrate with at least one of fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof; reacting the mixture with from 1/2 to 2 mol sterile water for injection, thereby to form a slurry; and allowing the slurry obtained to set in moulds of the desired form and size.

~, ! - 3 -By still another broad process aspect of this invention, a process is provided for preparation of a pharmaceutical compostion adapted Eor implantation in a natural, pathological or artificial cavity in a body tissue which process comprises: mixing calcium sulphate hemi-hydrate wlth a sterile mixture of 1/2 to 2 mol of water and at least one of fusidic acid and gentamycin or pharmaceutically-acceptable salts there-of, thereby to form a slurry; and allowing the slurry obtained to set in moulds of the desired form and size.
By yet a further broad process aspect of this invention, a process is provided for the preparation of a pharmaceutical composition adapted for implantation in a natural, pathological or artificial cavity in a body tissue, which comprises mixing powdered gypsum or Plaster of Paris set with at least one of fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof and with from 1/2 to 2 mol sterile water; and subjecting the slurry to standard pharmaceutical techniques to compound and transform the slurry to the form of granules, flakes, pills, tablets, pellets or beads shaped units.
By a variant thereof, the process includes the step of in-corporating therein at least one known pharmaceutically-acceptable ingredient affecting the setting time of calcium sulphate hemihydrate, as well as the releasing tirne, of X-ray contrast media.
By variants thereof, either gypsum or Plaster of Paris is used as the calcium sulphate hemihydrate.
By anther variant, the antibiotic substance is fusidic acid or a pharmaceutically-acceptable salt thereof~ used together with gypsum or Plaster of Paris.

By a further varlants, the antibiotic substance is gentamycin or a pharmaceutically-acceptable salt thereof used together with gypsum or Plaster of Paris.
By a still further variants, a mixture of fusidic acid and gentamycin is used in a ratio of from 10:1 to 1:10, preferably from 3:1 to 1:3 with gypsum or Plaster of Paris.
By yet another variant, the total amount of antibiotic substance is used in an amount of from 50 - 1000 mg per 10 g of gypsum, the antibiotic being slowly released from the composition on implantation.
By a still further variants the antibiotic substance is fusidic acid or its pharmaceutically-acceptable salt, gypsum or Plaster of Paris used, and from 50 mg to 1000 mg, preferably 100 - 500 mg and most desirably 200 - 300 mg of fusidic acid or a pharmaceutically-acceptable salt are used per 10 g of gypsum or Plaster of Paris, the antibiotic thus being slowly released from the composition on implantation.

, , ~ ~i i - 5 i ~ y still further variant, the antibiotic substance is gentamycin or its pharmaceutically-acceptable salt, gypsum or Plaster of Paris used, and from 50 mg to 1000 mg preferably 100 - 500 mg of gentamycin or a pharmaceutically-acceptable salt thereof are used per 10 g gypsum, the antibiotic being slowly released from the composition on implantation.
By yet anther aspect, the process comprises using the Plaster of Paris or gypsum in any suitable form adapted for implantation, to provide a composition in the form of pellets, tablets, beads, pills or shaped units.
By a still further aspect, the process is carried out in a manner in which all the ingredients are sterile and in whicl- the procedure is aseptic.
By a further aspect, the process is first carried out and is then followed by sterilization of ~he resul~ing product.
By another aspect of this invention, a pharmaceutical composition is provided adapted for implantation in a natural, pathological, or artificial cavity in a body tissue, which composition comprises CaSO~, of fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof and sterile water, the antibiotic being slowly released from the composition on implantation.
By yet another aspect of this invention, a pharmaceutical composition is provided adapted for implantation in a natural, pathological, or artificial cavity in a body tissue, which composition comprises CaS04 at least one of fusidic acid and gentamycin or pharmaceutically-acceptale salts thereofand from 1/2 to 2 mol sterile water, the antibiotic being slowly - 5a -. .

released from the composition on implantation.
By still another aspect of thls invention, a pharmaceutical composition i5 provided adapted for implantation Ln a natural, pathological, or artificial cavity in a body tissue in the form of moulds of the desired size and form, which composition comprises CaS04, at least one of fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof and from 1/2 to 2 mol sterlle water, the antibiotic being slowly released from the composition on implantation.
By a further aspect of this invention, a pharmaceutical composition is provided adapted for implantacion in a natural, patholotical, or artificial cavi~y in a body tissue inthe form of moulds of the desired size and form, which composition comprises a sterile mixture of CaS04 with with from 1/2 to 2 mol sterile water and at least one of fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof, the antibiotic being slowly released from the composition on implantation.
By a still anther aspect of this invention, a pharmaceutical composition is provided adapted for implantation in a natural, pathological, or artificial cavity in a body tissue in the form of granules, flakes, pills, tablets, pellets or beads shaped units, the composition comprising gypsum or Plaster of Paris set with from 1/2 to 2 mol sterile water with at least one of fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof.
By variants of this composition aspect of the invention, the compositions provided by the processes described above of aspects and variants of the invention are also aspects and variants of the composition aspects.

- 5b -i According to experiments, fusidic acid and gentamycin or salts thereof have shown a surprising suitable degree of release from the gypsum.
In some cases they can with adv~ntage be s~lpplemented with another antibacterial substance which then are mixed together in a suitable ratio in the composition in order to obtain a broader antibacterial spectrum of the composition.
Such other antibacterial substances may be e.g. sulfonamides, or antibiotics, e.g. ~--lactam antibiotics such as ampicillin, cloxacillin, oxacillil-l, or pro-drugs thereof, optionally together with ~-lactamase inhibitors, or rifampicin, erythromycin, or cephalosporins. It is, in particular, be advantageous to mix fusidic acid or its salts with aminoglycoside, as e.g. gentamycin or salts thereof. In such cases the releasing rate of each of the components will have to be taken into consideration to secure that the concentration in the body fluids will be optimal. This can be achieved e.g. by addition of suitable auxiliary agents, which are able to influence the setting time, the structure of the gypsum and thereby the releasing rate of the antibiotics, or by coating the antibiotic in question in known manner in order to obtain substantially same releasing rate of the antibiotics used.
As a further advantage, fusidic acid is known for its ability to promote wound-healing and gentamycin is known for its particular - 5 c -suitability for treatment and prophylaxis in the management of bone conditions and so the combination provides a dual advantage.
It will be appreciated that the invention is not restricted to compositions for bone implantation. Cavities in tissues other than bone should respond well to implantation with the compositions of aspects of this invention.
The composition of aspects of this invention can be presented in several forms and sizes. It is, however, preferred that the composition be presented in the form of pellets, a plurality of such pellets being implanted so as substantially to fill a cavity in a tissue under treatment.
However other forms, e.g. beads or flakes, pills or tablets, or a powder for preparation of larger casting in situ designed to occupy a substantial part of all of the volume of a given cavity, comprise possible embodiments within the scope of broad aspects of the invention.
The pellets, beads, etc. are preferably cast from an aqueous slurry or unset gypsum, i.e. calcium sulphate hemihydrate9 also called plaster of Paris, a predetermined proportion of the selected antibiotic substance or sub-stances being mixed, either into the aqueous part or the gypsum part of the composition, if desired together with auxiliary agents capable of influencing the setting time. A pretreatment of the antibiotic, e.g. by microencapsulation in a suitable medium known in the pharmaceutical technique can control or sustain the release from the resulting composition during its presence in the cavity.

The slurry is filled into suitable moulds and allowed to set. The resul-ting pellets, beads or the li~ie are removed from the moulds, dried and packaged. ~lternatively, a dry mix of unset gypsum and antibiotic, containill~ conventional tabletting excipients~ may be compounded and formed into suitable bodies, granulates or powders by standard pharma~
ceutical techniques. Such compositions absorb water from body fluids after implantation, and set in situ. It shall, however, be noticed that this absorption gives rise 1;o evolution of heat, and certain precautions therefore have to be taken by this process, e.g- by addition of setting inhi-bitors such as colloids. A third process of manufacture starts from set gypsum (dihydrate) in powdered form, to w3lich anti-biotics and tabletting excipients are added, and the mixture compounded as before, and compressed into pellets, bead or the like. This product, consisting substantially of set gypsum, does not undergo the process of setting after implantation but behaves similarly to the cast pellets etc. pre~iously referred to.
By addition of auxiliary agents the setting time can either by retarded, e.g. by adding a colloid, e.g. dextran, or other blood-plasma substituents, or any sub~tance which will decrease the solubility of the gypsum, e.g. ethanol, or can be accelerated by e.g. adding sodium chloride, potas-sium sulphate or other salts, thereby also in~ encing the releasing rate in an ad~antageous manner.

Adjuvant substances ~or various purposes m~y be incor-porated in the composition of aspects of the invention, e.~. X-ray contrast media.
The antibacterial substances can be used either as such, or in the forrn of suitable salts depending on their different solubilities, pH-values, stabilities and other factors influencing the preparation of the pellets, beads etc.
Such salts can be alkali-metal salts or organis salts~
e.g. with diethanolamine, of fusidic acid and the hydrohalides, the sulphate etc~ of ~entamycin, The composition of aspects of the invention is preferably pre-sented in a clinically sterile form, and is advantageously presented in a sterile package for convenience in use. The beads, pellets, flakes or castings may be manufactured under sterile or aseptic conditions from sterile ingredients, or the finished, pac~ed product may be sterilised by exposure to ionizing radiation or other suitable kllown technique.
Since the composition of aspects of this invention i6 spontaneously absorbed by the body, the pellets or beads do not need to be threaded on an inert wire for accessibility~
The amount of antibiotic substance in the implantation units has to be of a ran~e which ~ives rise to a therapeu-tica~ly acceptable concentration of the antibiotic in the cavity ~luids during the treatment period. The number of -- o units used depend on the circumstances, e.g. the size of the cavity or the si~e of the units, many small pellets givirlg faster release of the antibiotic. ~or difrerent purposes therefore different amounts of antibiotic in the pellet will be used, but will for most purposes be within the range of frorn 50 mg to 1000 mg per 10 g gypsum, pre-ferably from 100 -to 500 mg per 10 g. In the case where two antibiotics are used they are advantageously mi~ed in a ratio of from 10:1 to 1:10, preferably of from 3:1 to 1:3.
~len fusidic acid or a salt thereof is used alone an amount of from 200 - 300 mg per 10 g gypsum is advan~
tageous.
Pellets prepared as described in Example 1 were tested to determine the rate at which they released the contained antibiotic in an environment roughly simulating the conditions to which they would be subject following implantation. Two batches of pellets ~ere chosen, prepared each time from 10 g plaster of Paris containing respectively 250 mg i`usidic acid an~ 500 mg gentamycin~ The batches~ label-led F and G comprised pellets containing respecti~ely 2.9 mg and 5.75 mg of the respective antibiotic per pellet.
For each test, 10 pellets were taken from a selected batch and placed in 20 ml buffer solution in a large test tube, which was then incubated at 37 C for 24 hours. The buffer solution was then carefully removed and stored at -20 C pending assay. The pellets were washed twice with fresh buffer solution which was discarded~ A second ~0 ml portion of buffer solution was added to the pellets in a _ g _ similar test tube which was incubated for a further 24 hours at 37 C, the buffer solution being then removcd as before and stored at -20 C to provide the second sample for assay.
This procedure was repeated daily, yielding a sample every day, until the series of tests was deemed complete (see below) or the pellets began to disintegrate~ Several *ests of this kind were performed simultaneously on e~ch of the two batches.
As a running check on the progress o~ the tests, each separated portion of buffer solution, followin~ its removal from the pellets, and prior to storing at -20 C, was checked for the presence of antibacterial activity by placing one drop thereof on a standard agar plate inoculated with a strain of Micrococcus pyogenes var. aureus (Staphylococcus aureus) which was sensitive to the respective antibioticO
The plate was then incubated at 37 C for 24 hours and inspec-ted for signs of a circle of inhibition indicating antibac-terial activity. ~en, in the course of each series of tests of a particular set of 10 pellets, activity was ~irst shown to be absent, the series wàs deemed complete and no further tests ~ere carried out.
The fro~en samples of buffer solutions, W21iCh samples had been carefully labelled as to batch, series number and date, were thawed out and assayed, each for its respective antibiotic substance. This was done by the ngnr diffusion test, as modified after Grove and Randell ( 19553, usin~ the paper disc method. For batch G, the test organism used was Bacillus subtilis ATCC 6633, on DIFC0 ~registered lrAde Mark) medium No. 1.

~or batch ~ the test organism was a local hospital strain of Staphylococcus a~reus, on DIFCO medium No. 5.
The results, which are set out in graphic form in the accompanying drawing, are calculated in terms of micro-grams of antibiotic released per gram of pellet material exposed to 20 ml of buff0r solution for 24 hours. They should be divided by 5 for micrograms per pellet released daily under the same conditions, and the latter figure divided by 20 to obtain the daily release rate in micro-grams per tablet per ml of fluid in a closed cavity with a volume of 20 ml.
The following observations are included to amplify the results summarized in the drawing.

~usidic acid (250 mg/10 g plaster) is slowly libe-rated at significant levels until the pellet finally dis-integrates. Initially 450-500 ~g/g pellet/day are released, a rate which finally falls to 50 ~g/g original pellet by day 50.

Gentamycin pellets (500 mg/10 g plaster) release 41 mg/g pellet (approximately 80% of the contained an*i-biotic) in the first 24 hours. By the fifth day, this high level has fallen to 50 ~g/g pellet/day, and thereafter there is a slow progressive decay until a final level of 12 ~g/g original pellet is reached at the time of disinte-gration of the pellet. Pellets containing 250 mg gentamycin~10 g plaster liberate 15.8 mg (approximately 60~ genta-mycin/g plaster in the first day, 25 ~g by day 15, and release thereafter rapidly falls to trace amounts~

Control pellets containing no antibiotic showed no antibacterial action.
The binding capacity of the pellets is obviously differellt for the two antibiotics. The plaster of Paris slurry used to make the pellets is slightly acid (pH 6).
The fact that fusidic acid crystallises at this pH might explain its slower release until final disintegration of the pelletsD ~entamycin is soluble at pH 6, and diffuse initially more rapidly, though release persists until final disintegration.

~ or the purpose of prot;racted release, fucidin and gentamycin are obviously excellent. The Minimal Inhibitory Concentration (M.I.C.) of fucidin for sensitive Staphylo-coccus aureus lies in the range 0.10-0.32 ~g/ml. The M.I.C.
for sensitive organisms with gentamycin, in ~g/ml, for Staphylococcus aureus is 0.5, for Escherichia coli 1-4, for Proteus 1-12, for Pseudomonas 1.5-12. Thus for fucidin and gentamycin, -the rate of release is such, that if the pelle$s are contained wi-thin a cavity and the organism is sensitive, the concentration of antibiotic should be well in excess of the M.I.C.
Theoretically, toxic levels of gentamyci~ could be reached in the first d~y if more than 20-30 gentamycin pellets of the strength here considered were implanted in an adult patien*. In vivo experiments indicate that the danger is more theoretical than real. However, it may proYe necessary, as part of the preparation of the gentamycin pellet for implantation 9 to place it in an eluant fluid for up to 24 hours. This simple measure would effectively reduce serum levels to trace amounts, as the pellets release only 300-/100 ~Ig gentamycin/g pellet on day 2.
By contrast, fucidin is liberated at a more steady rate, even from day 1, and thus toxicity should not prove a problem.
It is also within the scope of aspects of the invention that, if indicated~ fucidin pellets and pellets with ~entamycin or another antibiotic or antibacterial substance could be used simultaneously in the same implantation. The user is thereby free to choose and vary the amount and ratios of antibiotics in accordance with the character and degree of the infection of the patient.
Clinical reports show very successful results of the treatment with antibiotic loaded gypsum pellets (ALGP) accor-ding to the invention. Of 13 patients treated with A~GP
complete healing was seen in 11 cases without complications.
Even where a great number of pellets were implanted the serum calcium did not rise above normal, but rose in one case from abnormal low to normal in a few weeks.

The invention in its various aspects is set out in greater detail in the following example.

Yt~

Example 100 g commercial grade gypsum plaster, CaS04~ 2H20 was dried to constant weight in a hot air oven at 100 C
for 4 hours and allowed to cool. The cooled material was subdivided into portions each weighing 10 g, and these portions were sterilised in a hot air oven at 160 C for 4 hours.
Pellets were prepared under bacteriologically sterile conditions as set out hereunder. The temperature Or *he materials used was first lowered to 0 C to delay the setting time of the gypsum.
To each 10 g portion of gypsum a quantity of either 250 mg or 500 mg of the relevant antibiotic, or antibio-tics, corrected to give said amount of the pure substance by reference to the manufacturer's index of purity, was added and thoroughlymixed in. A measured volume Or sterile physiological saline (5-7 ml) was added to the mixture to give a slurry of optimum consistency for handling. The exact volume of saline was previously determined empi-rically. The slurry was taken up into a sterile syringe, dispensed therefrom in*o previously sterilised mo~lds7 and allowed to set. The resulting pellets were removed from the moulds, and stored at 0 C~
This procedure yielded, for each 10 g portion of gypsum~ about 80 flat cylindrical pellets weighing 0.18 to 0.20 g each being of diameter 6 mm and height 4 mmO The pellets were packaged under aseptic conditions in heat-- 14 ~

sealed sachets of transparent plastics material previously sterilised7 20 pellets to a sachet.
Each pellet accordingly contained 5.75 mg or 2.9 mg of pure antibiotic, according to whether 500 mg or 250 mg thereof had been added to the 10 g portion o~ gypsum. The product was now ready for use in surgical implantation.

_ 15 -

Claims

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

1. A process for the preparation of a pharmaceutical composition adapted for implantation in a natural, pathological or artifical cavity in a body tissue, which process comprising: forming a slurry of CaSO4, at least one of fusidic acid and gentamycin or pharmaceutically, acceptable salts thereof and sterile water; and allowing the slurry obtained to set in moulds of the desired form and size.

2. A process for the preparation of a pharmaceutical composition adapted for implantation in a natural pathological or artifical cavity in a body tissue, which process comprises: forming a slurry of CaSO4, and at least one of fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof and 1/2 to 2 mol sterile water; and allowing the slurry obtained to set in moulds of the desired form and size.

3. A process for the preparation of a pharmacutical composition adapted for implantation in a natural, pathological or artificial cavity in a body tissue which process comprising: mixing calcium sulphate hemihydrate with at least one of fusidic acid and gentamycin or pharma-ceutically-acceptable salts thereof; reacting the mixture with from 1/2 to 2 mol sterile water for injection, thereby to form a slurry; and allowing the slurry obtained to set in moulds of the desired form and size.

4. A process for the preparation of a pharmaceutical composi-tion adapted for implantation in a natural, pathological or artifical cavity in a body tissue which process comprises: mixing calcium sulphate hemihydrate with a sterile mixture of 1/2 to 2 mol of water and at least one of fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof, thereby to form a slurry; and allowing the slurry obtained to set in moulds of the desired form and size.

5. A process for the preparation of a pharmaceutical composi-tion adapted for implantation in a natural, pathological or artificial cavity in a body tissue, which comprises; mixing powdered gypsum or Plaster of Paris set with at least one of fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof, and, thereby to form a slurry with from 1/2 to 2 mol sterile water and subjecting said slurry to standard pharmaceutical techniques to compound and transform the slurry to the form of granules, flakes, pills, tablets, pellets or beads shaped units.

6. The process of claim 1, including the step of incorporating therein at least one known pharmaceutically-acceptable ingredient affecting the setting time of calcium sulphate hemihydrate, as well as the releasing time of X-ray contrast media.

7. The process of claims 1, 3 or 4 wherein gypsum or Plaster of paris is used.

8. The process of claims 1, 3 or 4 wherein the antibiotic substance is fusidic acid or a pharmaceutically-acceptable salt thereof, and wherein gypsum is used.

9. The process of claims 1, 3 or 4 wherein the antibiotic substance is fusidic acid or a pharmaceutically-acceptable salt thereof, and wherein Plaster of Paris is used.

10. The process of claims 1, 3 or 4 wherein the antibiotic substance is a mixture of fusidic acid or a pharmaceutically-acceptable salt thereof and gentamycin or a pharmaceutically-acceptable salt thereof, and wherein gypsum is used.

11. The process of claims 1, 3 or 4 wherein the antibiotic substance is a mixture of fusidic acid or a pharmaceutically-acceptable salt thereof and gentamycin or a pharmaceutically-acceptable salt thereof, and wherein Plaster of Paris is used.

12. The process of claims 1, 3 or 4 wherein a mixture of fusidic acid and gentamycin is used in a ratio of from 10:1 to 1:10, and wherein gypsum is used.

13. The process of claims 1, 3 or 4 wherein a mixture of fusidic acid and gentamycin is used in a ratio of from 10:1 to 1:10, and wherein Plaster of Paris is used.

14. The process of claims 1, 3 or 4 wherein a mixture of fusidic acid and gentamycin are used in ratio of from 3:1 to 1:3, and wherein gypsum is used.

15. The process of claims 1, 3 or 4 wherein fusidic acid and gentamycin are used in ratio of from 3:1 to 1:3, and wherein Plaster of Paris is used.

16. The process of claims 1, 3 or 4 wherein Plaster of Paris is used and wherein the total amount of antibiotic substance is from 50 -1000 mg per 10 of Plaster of Paris.

17. The process of claims 1, 3 or 4 wherein gypsum is used and wherein the total amount of antibiotic substance is from 50 - 1000 mg per 10 g of gypsum. I

18. The process of claims 1, 3 or 4 wherein the antibiotic substance is fusidic acid, or its pharmaceutically-acceptable salt, wherein gypsum is used and wherein from 50 mg to 1000 mg of fusidic acid or its pharmaceutically-acceptable salt are used per 10 g gypsum.

19. The process of claims 1, 3 or 4 wherein the antibiotic substance is fusidic acid, or its pharmaceutically-acceptable salt wherein gypsum is used, and wherein from 100 - 500 mg fusidic acid or its pharmaceutically-acceptable salt are used per 10 g gypsum.

20. The process of claims 1, 3 or 4 wherein the antibiotic substance is fusidic acid, or its pharmaceutically-acceptable salt wherein gypsum is used and wherein 200 - 300 mg of fusidic acid or a pharmaceutically-acceptable salt thereof are used per 10 g gypsum.

21. The process of claims 1, 3 or 4 wherein the antibiotic substance is fusidic acid, or its pharmaceutically-acceptable salt, wherein gypsum is used and wherein from 50 mg to 1000 mg of gentamycin or a pharmaceutically-acceptable salt thereof are used per 10 g gypsum.

22. The process of claims 1, 3 or 4 wherein the antibiotic substance is gentamycin or its pharmaceutically-acceptable salt wherein gypsum is used, and wherein 100 - 500 mg gentamycin or a pharmaceutically-acceptable salt thereof are used per 10 g gypsum.

23. The process of claim 1, comprising using the Plaster of Paris or gypsum in any suitable form adapted for implantation, to provide a composition in the form of pellets, tablets, beads, pills or shaped units.

24. The process of claims l, 3 or 4 carried out in a manner in which all the ingredients are sterile and in which the procedure is aspectic.

25. The process' of claims 1, 3 or 4 followed by sterilization of the resulting product.

26. A pharmaceutical composition adapted for implantation in a natural, pathological, or artificial cavity in a body tissue, which com-position comprises CaSO4, at least one of fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof, and sterile water said anti-biotic being slowly released from said composition on implantation, whenever prepared by the process of claim 1 or by its obvious chemical equivalent.

27. A pharmaceutical composition adapted for implantation in a natural, pathological, or artificial cavity in a body tissue, which composition comprises CaSO4, at least one of fusidic acid gentamycin or pharmaceutically acceptable salts thereof and from 1/2 to 2 mol sterile water, said antibiotic being slowly released from said composition on implantation, whenever prepared by the process of claim 2 or by its obvious chemical equivalent.

28. A pharmaceutical composition adapted for implantation in a natural, pathological, or artificial cavity in a body tissue, in the form of moulds of the desired form and size which composition comprises CaSO4 and at least one of fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof from 1/2 to 2 mol sterile water, said antibiotic being slowly released from said composition on implantation, whenever prepared by the process of claim 2, or by its obvious chemical equivalent.

29. A pharmaceutical composition adapted for implantation in a natural, pathological, or artificial cavity in a body tissue, in the form of moulds of the desired size and form which composition comprises a sterile mixture of CaSO4 with from 1/2 to 2 mol sterile water and at least one of fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof, said antibiotic being slowly released from said composition on implantation, whenever prepared by the process of claim 4, or by its obvious chemical equivalent.

30. A pharmaceutical composition adapted for implantation in a natural pathological or artificial cavity in a body tissue, in the form of granules, flakes, pills, tablets, pellets or beads shaped units, said composition comprising gypsum or Plaster of Paris set with from l/2 to 2 mol sterile water and with at least one fusidic acid and gentamycin or pharmaceutically-acceptable salts thereof, whenever prepared by the process of claim 5 or by its obvious chemical equivalent.

31. A pharmaceutical composition of claim 26, also including at least one known pharmaceutically-acceptable ingredient affecting the setting time of calcium sulphate hemihydrate, as well as the releasing time of X-ray contrast media, whenever prepared by the process of claim 6 or by its obvious chemical equivalent.

32. A pharmaceutical composition according to claim 26 and in which the antibiotic substance is gentamycin or a pharmaceutically-acceptable salt thereof, and in which gypsum or Plaster of Paris is used, whenever prepared by the process of claim I or by its obvious chemical equivalent.

33. A pharmaceutical composition according to claim 26 and in which the antibiotic substance is fusidic acid or a pharmaceutically-acceptable salt thereof, and in which gypsum or Plaster of Paris is used, whenever prepared by the process of claim 1 or by its obvious chemical equivalent.

34. A pharmaceutical composition according to claim 26 in which the antibiotic substance is a mixture of fusidic acid or a pharmaceutically-acceptable salt thereof and gentamycin or a pharmaceutically-acceptable salt thereof, and in which gypsum or Plaster of Paris is used, whenever prepared by the process of claim 1 or by its obvious chemical equivalent.

35. A pharmaceutical compostion according to claim 28 in which a mixture of fusidic acid and gentamycin is used in a ratio of 10:1 to 1:10, and in which gypsum or Plaster of Paris is used, whenever prepared by the process of claim 2 or by its obvious chemical equivalent.

36. A pharmaceutical composition according to claim 28 in which a mixture of fusidic acid and gentamycin are used and are present in a ratio of 3:1 to 1:3, and wherein gypsum or Plaster of Paris is used, whenever prepared by the process of claim 2 or by its obvious chemical equivalent.

37. A pharmaceutical composition according to claim 28 wherein gypsum or Plaster of Paris is used and in which the total amount of antibiotic substances is from 50 - 1000 mg per 10 g of gypsum or Plaster of Paris, whenever prepared by the process of claim 2 or by its obvious chemical equivalent.

38. A pharmaceutical composition according to claim 28 wherein gypsum or Plaster of Paris is used and containing from 50 mg to 1000 mg of fusidic acid or its pharmaceutically-acceptable salt per 10 g of gypsum or Plaster of Paris, whenever prepared by the process of claim 2 or by its obvious chemical equivalent.

39. A pharmaceutical composition according to claim 28 wherein gypsum or Plaster of Paris is used and containing from 100 - 500 mg fusidic acid or its pharmaceutically-acceptable salt per 10 g gypsum or Plaster of Paris, whenever prepared by the process of claim 2 or by its obvious chemical equivalent.

40. A pharmaceutical composition according to claim 28 wherein gypsum or Plaster of Paris is used and containing 200 - 300 mg of fusidic acid or a pharmaceutically-acceptable salt thereof per 10 g gypsum or Plaster of Paris whenever prepared by the process of claim 2 or by its obvious chemical equivalent.

41. A pharmaceutical compostion according to claim 28 wherein gypsum or Plaster of Paris is used and containing from 50 mg to 1000 mg of gentamycin or a pharmaceutically-acceptable salt thereof per 10 g gypsum or Plaster of Paris, whenever prepared by the process of claim 2 or by its obvious chemical equivalent.

42. A pharmaceutical composition according to claim 28 wherein gypsum or Plaster of Paris is used and containing 100 - 500 mg gentamycin or a pharmaceutically-acceptable salt thereof per 10 g of gypsum or Plaster of Paris, whenever prepared by the process of claim 2 or by its obvious chemical equivalent.

43. A composition according to claim 26 which contain at least one known pharmaceutically-acceptable ingredient affecting the setting time of calcium sulphate hemihydrate, as well as the releasing time, of X-ray contrast media, whenever prepared by the process of claim 6 or by its obvious chemical equivalent.

44. A composition according to claim 28 which contain at least one known pharmaceutically-acceptable ingredient affecting the setting time of calcium sulphate hemihydrate, as well as the releasing time of X-ray contrast media, whenever prepared by the process of claim 6 or by its obvious chemical equivalent.

45. A composition as claimed in claim 26 in form of pellets, tablets, beads, pills or shaped units, whenever prepared by the process of claim 23 or by it obvious chemical equivalent.