EP0456113B1 - Glass containers internally coated with a silicone and having an in situ freeze-dried solid product - Google Patents

Abstract

The present invention relates to glass containers, surface-coated with a silicone, in primary packaging means for freeze-dried solid products and their use in the production of freeze-dried solid products. By virtue of the extreme improvement in the coherence, compactness and geometry of the dried product, its undesired distribution within the container, for example in the shoulder, neck or onto the stopper contact surface of the container is avoided and, as a result, wastage is avoided in the case of freeze-dried solid products.

Description

The invention relates to surface-coated glasses in primary packaging of lyophilisates and their use in the production of lyophilisates.

Drugs sensitive to moisture that are to be used parenterally by infusion or injection must be stabilized for storage. A common method is to dry the drug solution using lyophilization. For this purpose, aqueous solutions of the medicinal substances are filled into glass ampoules, vials or sting-cap bottles, frozen and freeze-dried under reduced pressure. Once the drying process has ended, glass ampoules are sealed outside the freeze dryer; vials and sting cap bottles can be sealed in the freeze dryer with the freeze dry stoppers already in place.

Of primary importance for the pharmaceutical quality of the product are the composition and concentration of the active ingredient solution containing excipients, the manner in which the temperature gradient freezes, and the final temperature. Furthermore, the temperature and pressure curve as well as the time of freeze drying, the layer thickness of the solution to be freeze-dried, the container geometry with regard to the contact surface with the coolable and heatable shelf, and the moisture in the product closure influence the pharmaceutical quality.

The reliable exact volume metering of the solution to be dried into the container without the solution reaching the ampoule neck or the vial rim, as well as the avoidance of all circumstances leading to product residues in the spit or shoulder of the ampoules or between, are just as crucial for production-related production the contact and sealing surface between the vial and the plug. The latter contributes decisively to ensuring the removability of the declared dose as well as risks to product stability that occur in the event of product buildup on the sealing surface of the vial rim with the help of ensuring the content homogeneity in the individual ampoules or vials of a batch and the content conformity from batch to batch Avoid plug caused by insufficient sealing.

The product residues in the neck of ampoules can be seen in the visual inspection of the bulk goods (these are the already closed product containers) and must be sorted out. The lack of consistency and shape of the product cake leads to a loss of production or yield in the case of ampoules, which increases the cost of production depending on the raw material and manufacturing costs. The product adhesion between the sealing surface of vials with their plugs is not easily recognizable in the visual inspection of the bulk goods; after the protective caps have been applied, it is completely hidden. This leakage leads to the uncontrolled penetration of air humidity into the vials during storage and thus harbors the risk of hydrolytic decomposition of the active substances.

From document WORLD PATENT INDEX, week 7937, Derwent Publications Ltd., London, GB; AN 79-668848 B & JP-A-54 097 617 dated August 1, 1979 discloses that the surfaces of glass containers can be treated with certain silicone solutions.

Methyltrimethoxysilane is described as being particularly preferred. The treatment with the silane solutions described there produces a surface film on the glass which is intended to generally reduce powder particle adherence to the glass walls, and to impart increased heat resistance and chemical resistance.

From this document, however, there is no indication that pharmaceutical preparations can be lyophilized without loss of the lyophilisate obtained by using siliconized glasses with inner walls.

The object of the present invention is to avoid the disadvantages described above.

This object was achieved in that surface-coated glasses are used in the production of lyophilisates and in primary packaging for lyophilisates by means of siliconization.

According to one embodiment of the invention, the aforementioned surface-coated glasses are used for the production of lyophilisates which contain the active ingredient PGE 1.

It is known that siliconized glass surfaces are used under the designation "glass quality II" (Hartke, Mutschler, editor, DAB 9 commentary, volume I, page 353, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, Govi Verlag GmbH, Frankfurt 1987). According to the prior art, siliconization is used in injection bottles and ampoules in order to "facilitate the drainage of liquid residues when emptying, which is of particular importance in the case of expensive filling goods such as antibiotics" (H.Sucker, P.Fuchs, P.Speiser, ed Pharmaceutical technology page 762, Georg Thieme Verlag Stuttgart 1978). Another application serves to increase the hydrolytic resistance, an application which, however, is controversial in specialist circles (Hagers Handbook of Pharmaceutical Practice, 4th Edition, Volume 7, Part A, page 373, Springer Verlag Berlin, Heidelberg, New York 1971). Siliconization can also be used on syringes to reduce the friction of the plunger or the stopper (in the case of a two-chamber syringe) with the syringe barrel. In the case of active substances adsorbing on glasses, for example from the substance classes peptides and proteins, siliconization serves to reduce the glass adsorption.

Because of the previous uses of siliconized glasses, it was not foreseeable that their use would improve the compactness and coherence of the lyophilisate in such a way that an error-free lyophilization of the product is made possible. As a result of the extreme improvement in the coherence, compactness and geometry of the dried product, its undesired distribution within the container in the shoulder, skewer or on the stopper contact surface of the vessel is avoided.

Accordingly, a further embodiment of the invention relates to a method for preventing product rejection of lyophilisates by placing the product to be lyophilized in glass primary packaging coated with a silicone layer on the inside and lyophilizing to form a compact product template.

The method is advantageously used for products to be lyophilized which contain the active ingredient PGE 1.

When freezing, a maximally dense and optimally shaped ice body is formed, which is much more uniformly lyophilized than an ice body containing different layer thicknesses.

In the case of the lyophilization of a prostaglandin E 1 product, which in addition to PGE 1 also contains α-cyclodextrin and lactose, when using the state-of-the-art primary packaging material of glass quality I (ie particularly low in sodium and thus in contact with aqueous solutions whose glass does not change pH, classification according to valid pharmacopoeia, e.g. Ph. Eur. or USP XII) receive about 10% product scrap when freeze-drying the product in ampoules. This product committee is caused by a product cake with insufficient coherence and insufficient mechanical stability, which leads to the distribution of lyophilisate in the entire container in approximately 10% of the ampoules of each batch. This loss of product increases the production costs if ampoules are used, and storage stability can be unpredictably reduced in the case of vials or sting-cap bottles. Attempts to reduce the product scrap by modifying the freeze-drying conditions have been unsuccessful.

Surprisingly, however, it was found that the use of glass which has been surface-tempered by siliconization has Product defects eliminated.

The exemplary embodiment, without being limited thereto, explains the invention.

example

A solution was prepared with a composition per ampoule of 20 »g PGE₁ as an approximately 3% inclusion complex of α-cyclodextrin and 50 mg lactose · H₂O in 400» l water for injections. This solution was metered in volume into 5 ml glass ampoules, glass grade I, or 5 ml glass ampoules, glass grade I with additional baked-on siliconization, which had been applied with a commercially available aqueous silicone oil emulsion. The lyophilization parameters mentioned in Table 1 below were varied and led to the result listed in each case:

Claims (4)

1. The use of glass containers as primary packaging means having its inside surface coated with a silicone material for manufacturing Lyophilizates.
2. The use of glass containers as primary packaging means according claim 1 for the manufacturing of freeze-dried products which contain the active substance PGE₁.
3. Process for preventing the loss of lyophilized products, characterized in that the product to be lyophilized is transferred to primary packaging means made of glass which are coated on the inside surface with a silicone layer after which it is lyophilized to form a compact product.
4. Process according claim 3 characterized in that the product to be lyophilized contains the active substance PGE₁.