Plastics having polar molecular groups for providing isolating coatings on stoppers for injections and infusion bottles, and coated stoppers for injection and infusion bottles

THE USE-eF PLASTICS HAVING POLAR MOLECULAR GROUPS FOR PROVIDING ' ISOLATING COATINGSON STOPPERS FOR INJECTION AND INFUSION BOTTLES, ' AND COATED STOPPERS FOR INJECTION AND INFUSION BOKLES '

משימוש <חומרים פלסטיים כעלי קבוצות פולריות לציפויים מבודדים על פקקים לבקבוקים של זריקות ושל אינפוסיות,>ופקקים לבקבוקים כאלה

HOECHST AKTIENGESELLSCHAFT

HOE 87/F 245

Dr .D/sch

Desc r ipt ion

T hcy.3 c I a s t i^r *= having polar oLecuLar groups for ^^providing isolating coatings on stoppers for injection 5 and infusion bottles, and coated stoppers for injection and infusion bottles

The stoppers required for closure of injection bottles and infusion bottles containing β-lactam antibiotics as 10 dry substances, such as cefotaxime, cefodizime, cefpirome or 1 -/?(6R,7R) -7-/2-.(2-amino-4-thiazolyl) -glyoxylamidoj-2-carboxy-8-oxo-5-thia-1-azabicyclof4.2.0_>7oct-2-en-3-yl7־ methyl7-5,6,7,8-tetra-hydroquinolinium hydroxide, inner salt, 7^-(Z) - (O-methyloxime) ( also called HOE 111), or their physio15 logically tolerated salts, where appropriate mixed with pH-regulating substances, are ones which are inert towards the product and protect it from damaging environmental effects, there being a particular need for an adequate action to seal against microbial and particulate 20 contamination as well as water and water vapor.

Stoppers for injection and infusion bottles are normally composed essentially of rubber. Although their puncture and reclosure properties are satisfactory, they cause 25 the solutions of the active substances to be deficient in clarity, which is a disadvantage which cannot be tolerated for injection solutions and infusion solutions.

The stoppers currently used for injection and infusion 30 bottles to avoid this disadvantage have their plugs coated with a fluorinated polymer (cf. German Offenlegungsschrift 3,346,351, corresponding to Derwent ref. 85-172 215/29). However, the disadvantage of stoppers coated with a fluorinated polymer is that, owing to their 35 rigid coated plugs, the closure of the bottles is less tight than that of uncoated stoppers, and thus there is, in particular, the risk of penetration of moisture. The coating with a fluorinated polymer also has an adverse effect on the puncture and reclosure propert רes.

Fluorinated polymer film is costly, and stoppers coated with a fluorinated polymer are considerably more costly than uncoated stoppers and, moreover, have serious disadvantages.

To date, no material which is suitable for stoppers for injection bottles and stoppers for infusion bottles for sterile cephalosporin derivatives such as, for example, cefotaxime, cefodizime, cefpirome and HOE 111 and their physiologically tolerated salts, where appropriate mixed with pH-regulating compounds, and which can be used as such, i.e. uncoated, without resulting in cloudy solutions, fragmentation and damaging environmental effects because of a deficient־ sealant action has yet been described.

It has been found, surprisingly, that stoppers which have coatings composed of plastics having polar molecular groups, such as, for example, cellophane _׳ polyamide, polyester, polyurethane or acetylcellulose, have an 5 adequate sealant action and do not cause solutions of substances which are cephalosporin derivatives to be cloudy. Plastics of this type should be less suitable as coating material, because of the polar groups, than the fluorinated polymer which is currently 0 used and regarded as inert.

Hence the invention relates to the use of plastics having polar molecular groups for coating stoppers for injection and infusion bottles, in particular for β-lactam anti5 biotics, and to stoppers coated with plastics having polar molecular groups for injection and infusion bottles, in particular for β-lactam antibiotics.

Particularly suitable plastics are cellophane (for example ® Cellophan׳) cellulose ,acetate, polyamide (־for example ®f»la-ster ו I), polyester and polyurethane, cellophane , polyamide and polyester are particularly preferred.

Particularly suitable β-lactam derivatives are cephalosporins, in particular cefotaxime, cefodizime, cefpirome and HOE 111, and their physiologically tolerated salts, where appropriate mixed with pH-regul ating compounds.

Examples of suitable pH-regulating substances are sodium carbonate, trisodium phosphate and basic amino acids.

Either the stoppers are entirely coated with the plastic, 5 or only the plug is coated. The coating or isolation is carried out, for example, by applying a film of plastic having polar molecular groups, preferably only to the plug. However, the coating material can also be applied by spray-coating.

The thickness of the coating can vary. It is merely necessary to ensure an adequate sealant action and an adequate mechanical stability.

It is possible, by coating stoppers or stopper plugs with soft films of plastics having polar molecular groups, to produce stoppers which seal well, are easy to puncture and close again after removal of the needle or of the infusion element, and which do not cause β-lactam 0 antibiotics as dry substances to give cloudy solutions.

Since films composed of the said materials are Less costly, stoppers having isolating coatings of plastics having polar molecular groups can be produced at Lower cost than those having a coating of a fluorinated polymer.

The sealant action of the stoppers coated entirely or partially according to the invention is very good. If, for example, bottles closed with such stoppers are placed in water, no gain in weight is found. The risk that the crimped seal is not sufficiently tight is extremely slight because the coating material has a certain etas ticity compared with the fluorinated polymer.

Stoppers entirely or partially coated with plastics haw ing polar molecular groups withstand sterilization, for example with gaseous formaldehyde, as well as sterilize tion in an autoclave, which is preferred.

The examples which follow show that a coating or isolation of the stoppers with films composed of the said plastics ensure the clear solutions required for pharma ceuticals, even under various types of stress, whereas a cloudiness of the solutions is perceptible with the naked eye when non-isolated stoppers are used.

Example I

Cefodizitne disodiun salt with various stoppers for injection bottles:

Stress

<td> Uncoated</td><td> Stoppers for</td><td> Stoppers for</td><td> Stoppers for</td>

<td> stoppers for</td><td> injection</td><td> injection</td><td> injection</td>

<td> injection</td><td> bottles, iso-</td><td> bottles, iso-</td><td> bottles, iso-</td>

<td> bottles</td><td> lated with</td><td> lated with</td><td> lated with</td>

<td></td><td> polyamide</td><td> cellophane</td><td> polyester</td>

<td> rolling for 7 days</td><td> cloudy</td><td> clear</td><td> clear</td><td> clear</td><td></td>

<td></td><td> solution</td><td> solution</td><td> solution</td><td> solution</td><td> I U1</td>

<td> storage upside down for 7 days at</td><td> cloudy</td><td> clear</td><td> clear</td><td> clear</td><td> 1</td>

<td> room temperature after rolling for</td><td> solution</td><td> solution</td><td> solution</td><td> solution</td><td></td>

storage upside down for 7 days at cloudy clear clear clear ₊40°C after rolling for 1 h solution solution solution solution

Example II .

Cefotaxime sodium salt with various stoppers for injection bottles:

<td> Stress</td><td> Uncoated stoppers for injection bottles</td><td> Stoppers for injection bottles, isolated with polyamide</td><td> Stoppers for injection bottles, isoLated with cellophane</td><td> Stoppers for injection bottles, iso־ Lated with polyester</td>

<td> rolling for 7 days</td><td> cloudy solution</td><td> clear solution</td><td> clear solution</td><td> clear solution</td>

<td> storage upside down for 7 days at room temperature after rolling for 1 h</td><td> cloudy solution</td><td> clear solution</td><td> clear solution</td><td> clear solution</td>

<td> storage upside down for 7 days at +40°C after rolling for 1 h</td><td> cloudy solution</td><td> clear solution</td><td> clear solution</td><td> clear solution</td>

Example III

Cefpirome sulfate/sodiurn carbonate mixture with various stoppers for injection bottles:

<td> Stress</td><td> Uncoated stoppers for injection bottles</td><td> Stoppers for injection bottles, isolated with polyamide</td><td> Stoppers for injection bottles, isolated with cellophane</td><td> Stoppers for injection bottles, iso׳ lated with polyester</td>

<td> rolling for 1 days</td><td> cloudy solution</td><td> clear solution</td><td> clear solution</td><td> clear solution</td>

<td> storage upside down for 7 days at room temperature after rolling for ו h</td><td> cloudy solution</td><td> clear solution</td><td> clear solution</td><td> clear solution</td>

<td> storage upside down for 7 days at +40°C after rolling for 1 h</td><td> cloudy solution</td><td> clear solution</td><td> clear solution</td><td> clear solution</td>

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