Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
1999-03-02
2002-10-08
Casler, Brian L. (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C427S002100
Reexamination Certificate
active
06461334
ABSTRACT:
The present invention relates to a medical article for containing a pharmaceutical protein preparation comprising at least a first component and a second component, having at least one surface coated with a coating to reduce the friction between the two components and to reduce the protein adsorption to the coating.
The described coatings are particularly useful for coating containers for storage and administration of liquid protein solutions, such as insulin formulations.
BACKGROUND
Protein formulations are mostly dosed from relatively small containers, i.e. up to 5 ml, and many of the containers are designed for multiple dosages, each dosage often being in the range of 0.1 ml or even less.
Such containers equipped with stoppers require a smooth sliding movement of one component, e.g. a stopper, in contact with another component, e.g. a container wall, to provide reliable dosages with high precision. Often, surfaces of the components have been shown to develop an initial resistance to movement after being in contact for some time, and movement does not start until a certain applied force, hereafter called a static friction force, has been applied. The phenomenon causes a sudden, rapid relative movement of the two surfaces. Frequently, the movement stops and another resistance is built up. This kind of movement is generally known as the ‘slip-stick’ phenomenon and is caused by a degree of adhesion between the components. When the “slip-stick” phenomena occurs with coated components, most often it is due to migration of the coating, leaving two components in contact with each other. The “slip-stick” causes a problem in that it leads to irregular and imprecise dosages. The phenomenon is especially troublesome in dispensing devices where very small, drop-wise dosages of protein solutions, e.g. insulin formulations, are required. If the ‘slip-stick’ phenomenon does not occur when the surfaces start to slide after the static friction force has been applied, the surfaces slide at a smoother rate by application of a so-called dynamic friction force.
Today large amounts of insulin are sold in dispensing devices. The insulin is filled in glass containers, which are equipped with rubber stoppers, and these containers are then loaded into dispensing devices. Usually, both the glass containers and the rubber stoppers are coated with silicon oil, poly(dimethyl siloxane) (PDMS), to reduce the friction between the container wall and the stopper. One common method to coat glass containers with silicon oil is to apply a PDMS-in-water emulsion and subsequently evaporate the water in an oven.
For example U.S. Pat. No. 4,767,414 suggests a coating of a medical container having reduced friction between the components wherein a surface is plasma-treated as well as a lubricant at one of the components is plasma-treated to inhibit migration of the lubricant into the content of the container. The lubricant is disclosed to reduce the friction between a container wall and a stopper compared to untreated containers and stoppers. The reference does not discuss adherence of proteins.
Another reference U.S. Pat. No. 5,338,312 discloses an article having a coating with two or more layers of lubricant securing a low friction force at different movement velocities, in that one layer may secure low friction at low velocities and the other(s) at other velocities. The adherence of protein molecules to the coating is not disclosed.
An aspect, which should be considered, when dispensing protein formulations is the events occurring at the surface between the protein solution and the container material that play a crucial role for the overall performance of biological material. Especially if the drug is in contact with a packaging material for a long time during storage which is often the case with protein formulations that are filled into the containers immediately after molding of the containers, the stability and life-time of the drug will be affected. The primary reason for this is that protein may be adsorbed to the surfaces of the container, where it is deactivated or denaturated. In this way, layers of deactivated and inaccessible protein are built up at the container surface. This will lead to a loss in protein activity and an enhanced risk of incorrect dosage, due to lowering of the concentration of soluble protein.
In particular in respect of insulin, adsorbed insulin may desorb and some molecules will associate with other deactivated molecules and form aggregates. Aggregates, such as fibrils or gel-like particles, form as a result of lower degree of water solubility and aggregation after denaturation. Aggregation of insulin is thought to be an auto-catalyzed process, and leads to an overall destabilization of the insulin formulation. When these aggregates become large enough, they can be seen visually. By blocking the adsorption of insulin at the container surface, the propensity of the insulin molecule to change its conformation is removed. The result is a significant improvement of the drug stability. Furthermore, the presence of protein aggregates may lead to immunological reactions in the patient, which is unacceptable.
In the prior art, solutions to the adsorption problem have been attempts to increase the stability of different insulin formulations by adding to the protein formulation a stabiliser.
Addition of glycerol and certain polysaccarides are well known methods to improve the stability. Further, addition of zinc and calcium ions significantly stabilizes the insulin by promoting the formation of more stable species, i.e., dimers and hexamers. It is also known that low concentrations of lecithins or synthetic detergents has a markedly positive effect on the stability of insulin. This effect is thought to be coupled to their ability to cover hydrophobic domains exposed by the insulin molecules. These hydrophobic domains are thought to be involved in the destabilization of insulin.
In relation to insulin, different kinds of non-ionic surfactants have been used to stabilize insulin formulation, e.g., ethoxylated fatty acids and Pluronics®. Chawla et al. (Diabetes Vol 34, May 1985, pp 420-424) was able to stabilize insulin in PS and PP containers by adding Pluronic® F68, a non-ionic surfactant containing PEO. These types of molecules are however only loosely adsorbed to the surfaces, and are probably present in the insulin solution which results in injection of the polymer when the protein formulation is injected. It is therefore unclear whether the surfactants cover the hydrophobic domains of the insulin, or the hydrophobic plastic surface. Chawla et al. also found that other types of Pluronics®, 17R8 and 25R5, did not stabilize the insulin formulations.
As previously mentioned, also U.S. Pat. No. 4,767,414 and U.S. Pat. No. 5,338,312 (vide above) are both silent with respect to adsorption of the content to the coating and do not suggest any solution to that problem.
Accordingly, it is an object of the present invention to provide a medical article being coated with a coating whereby the exposed surface of the coating is hydrophilic thereby reducing the protein adsorption, in particular insulin, and said surface also exhibits a lubricity resulting in reduced friction at surfaces being in frictional engagement with each other.
Furthermore, it is of importance that the coating of the surfaces of the article will not migrate into the content of the article.
SUMMARY OF THE INVENTION
The object of the invention is obtained by a medical article for containing a pharmaceutical protein preparation comprising at least a first component and a second component, which is in frictional engagement with said first component, wherein at least one surface on either the first or the second component or both is coated independently with a hydrophilic coating whereby
the hydrophilicity of the surface of the coating as measured by the water contact angle is below 90°, and
the long term static friction forces between the first and the second component are below 14 N.
The coatings according to the present invention are
Buch-Rasmussen Thomas
Jannasch Patric
Johannesen Ib
Jørgensen Erling Bonne
Ndoni Sokol
Casler Brian L.
Novo Nordisk A S
Serke Catherine
Skadden, Arps, Slate, Meagher & Flom
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