EP0456113A2 - 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 vial 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 type of freezing with the respective temperature gradient 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 materials to be dried are just as crucial for production-based production Solution into the container without solution reaching the ampoule neck or the vial rim, as well as avoiding all circumstances which can lead to product residues in the spit or shoulder of the ampoules or between the contact and sealing surface between the vial and stopper. 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.

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

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

It is known that siliconized glass surfaces are used under the designation "glass grade II" (Hartke, Mutschler, editor, DAB 9 commentary, volume I, page 353, Scientific publishing company 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 particularly important 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); U.S. P 2,504,482; GB patent 702,292. Another application serves to increase the hydrolytic resistance, an application which is, however, 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 ingredients adsorbing on glasses, for example from the substance classes peptides and proteins, siliconization serves to reduce glass adsorption; Franz et al. U.S.-P 3,717,498.

Due to 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 undesirable 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 the product rejection of lyophilisates by placing the product to be lyophilized in glass primary packaging material coated on the inside with a silicone layer and lyophilizing to form a compact product template.

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-sodium and therefore in contact with aqueous solutions, the glass does not change its pH, Classification according to valid pharmacopoeias, e.g. Ph. Eur. Or USP XII) approx. 10% product scrap obtained during the freeze-drying of 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 approx. 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 had been surface-tempered by siliconization exceeded the abovementioned. Product defects eliminated.

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

Embodiment

Glass ampoules of glass quality I were sprayed on a Bausch & Ströbel washing siliconizing machine using a 1% silicone emulsion by adding 550 ml of Baysilon H®, which was dissolved in 55 liters of denatured water, siliconized. Baysilon H® is an aqueous emulsion made of polydimethylsiloxane from Bayer AG, Leverkusen, Germany.

The silicone is dried or stoved in a continuous oven, the throughput time being 40 minutes at a temperature of 300 ° C. The siliconized ampoules are subjected to a three-time washing process with bi-distilled water at 50 ° C and a subsequent sterilization phase of 3 minutes at 300 ° C without damaging the silicone film.

A solution with a composition per ampoule of 20 µg PGE₁ as an approximately 3% inclusion complex of α-cyclodextrin and 50 mg lactose · H₂O in 400 µl water was prepared for injections. This solution was metered in volume in alternatively 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, as described above.

The glass ampoules containing PGE 1 solution were then subjected to a standard lyophilization process and the same process, but with variations in freeze-drying time, temperature and drying time.

• 1. Die Gefrierkammer wird mit den PGE₁-enthaltenden Ampullen unter Stickstoffbelüftung beladen.
• 2. Einfrieren
  Die Anfangstemperatur beträgt + 25°C bis + 30°C. Innerhalb 8 Std. wird dann unter Stickstoffatmosphäre auf -40°C eingefroren. Weitere 30 Std. wird die Einfriertemperatur bei -40°C gehalten.
• 3. Haupttrocknung
  8 Std. erfolgt bei -40°C die Haupttrocknung unter Stickstoffatmosphäre. Danach wird in 5 Std. auf +25°C erwärmt. Anschließend wird die Temperatur mindestens 6 weitere Stunden bei +25°C konstant gehalten.
  Das Vakuum beträgt 5 x 10⁻² mbar. Die Heizleistung beträgt 12 KW.
• 4. Nachtrocknung
  Mindestens weitere 7 Std. wird bei +25°C unter Stickstoffatmosphäre getrocknet. Das Vakuum beträgt hierbei 10⁻³ mbar.

The standard lyophilization procedure is described as follows:

• 1. The freezer is loaded with the PGE₁-containing ampoules under nitrogen aeration.
• 2. Freeze
  The initial temperature is + 25 ° C to + 30 ° C. The mixture is then frozen to -40 ° C. in a nitrogen atmosphere within 8 hours. The freezing temperature is kept at -40 ° C. for a further 30 hours.
• 3. Main drying
  Main drying takes place at -40 ° C for 8 hours under a nitrogen atmosphere. The mixture is then heated to + 25 ° C in 5 hours. The temperature is then kept constant at + 25 ° C for at least 6 more hours.
  The vacuum is 5 x 10⁻² mbar. The heating power is 12 KW.
• 4. Post-drying
  At least a further 7 hours are dried at + 25 ° C under a nitrogen atmosphere. The vacuum is 10⁻³ mbar.

The ampoules are finally removed from the chamber and sealed by melting the ampoule ends.

The results of the lyophilization process and their variations are summarized in Table 1.

Claims (3)

Glass primary packaging for lyophilisates, characterized in that the inner glass surface has a silicone coating. Process for preventing the rejection of lyophilized products, characterized in that the product to be lyophilized is placed in glass primary packaging material coated on the inside with a silicone layer and is lyophilized to form a compact product template. Use of glass primary packaging with a silicone coating on the inner glass surface for the production of lyophilisates.