Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-04-26
2003-07-22
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S490000, C424S530000, 57, 57
Reexamination Certificate
active
06596318
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a suitable formulation of a stable, pulverulent, as free from dust as possible and hence very pourable, solid administration form of a fibrin tissue adhesive for use in haemostasis, wound care (wound healing), tissue adhesive and securing sutures for external and internal surgical operations on humans, wherein the formulation can be prepared by means of a fluidised bed or spray-drying process or by a suitable combination of both drying processes.
BACKGROUND OF THE INVENTION
Blood clotting in the healthy body of animals (mammals) and in the human being proceeds naturally in the form of a co-enzyme/enzyme controlled cascade reaction. The main step consists in the soluble (in water, physiological saline solution and also in blood) fibrinogen being converted to the insoluble fibrin. The proteolytic enzyme thrombin is necessary for this and is formed by the prothrombin activator, a mixture of Stuart Prower factor (factor X) and proaccelerin (factor V) in the presence of calcium ions from the inactive prothrombin (factor II). The thrombin cleaves the fibrinogen usually present as monomer (75%) having a molar mass of 340,000 Dalton, as dimer (15%) and as polymer (10%) into fibrin and thus forms long molecular chains. The latter are linked by the fibrin-stabilising factor XIII (and in the presence of calcium ions) to form a stable, cross-linking fibrin polymer. The smooth interplay of a series of factors (clotting factors) is necessary for this biochemical reaction. In the healthy organism the clotting factors required are present in adequate quantity in a labile equilibrium.
Disturbances to this equilibrium may be a danger to life. Disturbances of the equilibrium may be caused, apart from the hereditary lack of a clotting factor (for example haemophilia), during severe tissue bleeding, for large surface area, diffuse bleeds (soft tissue bleeds), which cannot be stopped by mechanical closure of arterial or venous vessels, or by therapeutically administered medicaments acting as an anti-coagulant for the prophylaxis of thromboembolism. These disturbances may be compensated by so-called fibrin tissue adhesives, a mixture of fibrinogen, factor MII, thrombin and human albumen as well as calcium chloride, resulting in local homeostasis. Fibrin tissue adhesives are therefore used in many different applications.
For surgical interventions on tumors, particularly in mouth-jaw-face surgery as well as the overall ENT field (for example tongue carcinoma resection) there are often diffuse bleeds which are difficult to control. Electrosurgical homeostasis by electrocoagulation which is often used conventionally leaves behind extensive thermal tissue scars after coagulation, which are extremely undesirable, particularly in these areas.
In plastic-aesthetic face and neck surgery (“face-lifting”), homeostasis using fibrin adhesive is indispensable, since electrocoagulation is a danger to the facial nerve because of the anatomical proximity of the treatment site to the path of the facial nerve and may damage the latter.
Furthermore, treatment with a fibrin tissue adhesive is indicated for non-stopping bleeds in emergency treatment for dental surgical interventions. This also applies to patients who are treated with anti-coagulant medicaments because of a certain underlying disease (for example treatment for prophylaxis of embolism with heparins) and have to be operated on in spite of the associated risk of inhibited blood clotting (extended blood clotting, inhibition of thrombocyte function). In this case measures which guarantee homeostasis and avoid post-operative bleeds, should therefore be taken by means of local application of a fibrin tissue adhesive. This may become necessary, for example even for operations on internal organs (for example liver, spleen). The tissue adhesive may thus be supplied externally by endoscope via a double catheter.
Furthermore, the use of a fibrin tissue adhesive is indicated in emergency care of large surface area wounds due to third degree burns as well as large surface area excoriation.
When administering and applying a fibrin tissue adhesive, care should be taken to ensure that fibrinogen and thrombin are only brought together directly at the site of the bleed (that is “in the wound”), since the onsetting clotting starts spontaneously in the presence of wound fluid. Neighbouring sites should thus be well covered. A precondition for clotting is the freedom to move of the individual participating molecules, for example in water. In practice this is realised in that, for example the four different components (fibrinogen-factor XIII concentrate, solution for fibrinogen, thrombin concentrate, calcium chloride solution for thrombin) are stored separately before application and are only brought into mutual contact directly at the wound. The components must be packed in sterile manner in each case and be stored in a suitable form and under defined conditions, so that the activity of the individual proteins or enzymes is not damaged by storage. This is usually achieved so that the protein concentrates are present in freeze-dried form in small containers. They are stable to storage in this form under refrigerator conditions (4 to 8° C.) for a certain time and for a shorter time even at room temperatures (20° C.). However, freeze-dried the concentrate is present in solid, compressed and thus immobile form, but as a soluble solid. Therefore the protein concentrates must be completely dissolved again before application in order to be able to start the required biochemical reaction (FIG.
1
). However, this may only be effected directly at the wound, so that each of the solutions has to be prepared separately from the other beforehand. Before application of the fibrin tissue adhesive the wound should then be as dry as possible, which in some cases can only be achieved with difficulty for large surface area, diffuse bleeding in order to facilitate good fixing of the tissue adhesive there and then. The two solutions may be added in each case via injection syringes, for example in the same volume ratio. Hence the fibrinogen solution should be applied initially to the wound and coated as soon as possible with the thrombin solution. The parts to be adhered should then be fixed until provisional solidification has taken place. Alternatively, there are mechanical aids, for example in the form of a double-chamber injection syringe, by means of which both solutions may be applied to the wound at the same time. Further technical auxiliaries are, for example spray tip systems for large surface area wounds, double-balloon catheters in urology or double catheters for endoscopic application. The concentration of the proteins in both solutions must be adjusted so that fibrinogen is present in significant excess with respect to thrombin. Suitable ratios are known according to the state of the art (for example 100:1).
This makes it clear that application requires on the one hand a qualified and concentrated preparation, which cannot always be ensured in some emergency situations. On the other hand application by the clumsy and manual handling of the 2-syringe system is likewise restricted.
A spray-dried tissue adhesive formulation is known from World application 97/44015. However, these microparticles have a defined size distribution up to 50 &mgr;m in diameter, reproducibly with 90% or more up to 20 &mgr;m in size. Hence this product is not pourable and is difficult to meter. It has been shown that this product not only forms dust when it is applied but also has poor solubility.
THE OBJECT OF THE INVENTION
The object of the present invention is therefore to indicate a fibrin tissue adhesive formulation which is simple to handle, meter and apply and can be stored without problems over a longer period, so that the possibilities for use of such a fibrin tissue adhesive formulation are significantly expanded with respect to the state of the art.
The object of the invention is likewise to indicate a corresponding process for producing such a fibrin t
Luy Bernhard
Prasch Armin
Glatt Process Technology GmbH
Witz Jean C.
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