CA2485268A1 - Resorbable pharmaceutical formulation for the continuous release of thrombin - Google Patents
Resorbable pharmaceutical formulation for the continuous release of thrombin Download PDFInfo
- Publication number
- CA2485268A1 CA2485268A1 CA002485268A CA2485268A CA2485268A1 CA 2485268 A1 CA2485268 A1 CA 2485268A1 CA 002485268 A CA002485268 A CA 002485268A CA 2485268 A CA2485268 A CA 2485268A CA 2485268 A1 CA2485268 A1 CA 2485268A1
- Authority
- CA
- Canada
- Prior art keywords
- resorbable
- pharmaceutical formulation
- thrombin
- formulation according
- collagen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- XLDIAUNLPWGNHO-UHFFFAOYSA-N topostatin Natural products CCCCCCCC(C)CC=C(C)C=CC(=O)C(C)CCC1OC(=O)C(CC(OS(O)(=O)=O)C(N)=O)NC(=O)C(C)CNC(=O)C(=C)NC(=O)C1C XLDIAUNLPWGNHO-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/425—Porous materials, e.g. foams or sponges
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4833—Thrombin (3.4.21.5)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
- A61L15/325—Collagen
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Materials Engineering (AREA)
- Dispersion Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to resorbable pharmaceutical formulations for the continuous local release of thrombin. The thrombin is embedded in resorbable polymer spheres which are incorporated in a collagen sponge. The inventive formulation provides a resorbable haemostatic for using in surgery, especially dental surgery, in dentoalveolar operations.
Description
w ~ CA 02485268 2004-11-08 ' VOSSIUS 8z PARTNER
Patentanwalte SIEBERTSTRASSE 3 ~ 81675 M~7NCHEN
TEL.: +49-89-41 30 40 ~ FAX:+49-89-41 30 41 11 ~ FAX (Marken-Trademarks): +49-E-MAIL: infoQvossiusa~~ru~:.oornn-HOMEPAGE: www.vassiusandpatu~a:oom RHEINISCH-WESTFALISCHE TECHNISCHE HOCHSCHULE AACHEN
Our Ref.: H 1722 PCT
English translation of the PCT-application as originally filed on 3 June 2003 Resorbable Pharmaceutical Formulation The present invention relates to a resorbable pharmaceutical formulation for continuous local release of thrombin comprising thrombin embedded in resorbable spheres of polymers, the spheres being incorporated in a collagen sponge. The formulation according to the invention provides a resorbable hemostyptic for use in surgery, particularly in dental surgery/dento-alveolar operations.
Due to most varied diseases, there is an increased number of patients in need of therapeutic treatment of blood clotting inhibition (anticoagulation). These include, for example, patients with artificial prosthetic valves or patients who suffered a stroke or a vein thrombosis.
In nearly all cases, therapeutically-induced anticoagulation is achieved by daily administration of vitamin K-antagonists (coumarin derivatives such as e.g.
phenprocoumon in the form of Marcumar~ or Falithrom~ or coumadin derivatives in the form of Warfarin~). Due to inhibition of blood clotting, even small surgical operations such as e.g. tooth extractions are linked with a high risk of haemorrhage.
For this reason, the patients concerned are usually hospitalised for treatment, which is cost-intensive. In this case, permanent oral anti-coagulation is replaced by administering heparin intravenously, which also results in an inhibition of blood clotting. However, heparin has a significantly shorter half-life, which allows a better control of the anti-coagulation in the case of bleeding complications whilst not having to dispense with the necessary thrombosis protection. Apart from these forms of therapeutically-induced blood clotting inhibition, post-operative secondary bleeding is also due to the plasmin system. On a systemic level, the plasmin system, the physiological antagonist of the blood clotting system, provides a dissolution of blood clots. This function, however, is not desired in the case of an increased risk of post-operative haemorrhage.
Patentanwalte SIEBERTSTRASSE 3 ~ 81675 M~7NCHEN
TEL.: +49-89-41 30 40 ~ FAX:+49-89-41 30 41 11 ~ FAX (Marken-Trademarks): +49-E-MAIL: infoQvossiusa~~ru~:.oornn-HOMEPAGE: www.vassiusandpatu~a:oom RHEINISCH-WESTFALISCHE TECHNISCHE HOCHSCHULE AACHEN
Our Ref.: H 1722 PCT
English translation of the PCT-application as originally filed on 3 June 2003 Resorbable Pharmaceutical Formulation The present invention relates to a resorbable pharmaceutical formulation for continuous local release of thrombin comprising thrombin embedded in resorbable spheres of polymers, the spheres being incorporated in a collagen sponge. The formulation according to the invention provides a resorbable hemostyptic for use in surgery, particularly in dental surgery/dento-alveolar operations.
Due to most varied diseases, there is an increased number of patients in need of therapeutic treatment of blood clotting inhibition (anticoagulation). These include, for example, patients with artificial prosthetic valves or patients who suffered a stroke or a vein thrombosis.
In nearly all cases, therapeutically-induced anticoagulation is achieved by daily administration of vitamin K-antagonists (coumarin derivatives such as e.g.
phenprocoumon in the form of Marcumar~ or Falithrom~ or coumadin derivatives in the form of Warfarin~). Due to inhibition of blood clotting, even small surgical operations such as e.g. tooth extractions are linked with a high risk of haemorrhage.
For this reason, the patients concerned are usually hospitalised for treatment, which is cost-intensive. In this case, permanent oral anti-coagulation is replaced by administering heparin intravenously, which also results in an inhibition of blood clotting. However, heparin has a significantly shorter half-life, which allows a better control of the anti-coagulation in the case of bleeding complications whilst not having to dispense with the necessary thrombosis protection. Apart from these forms of therapeutically-induced blood clotting inhibition, post-operative secondary bleeding is also due to the plasmin system. On a systemic level, the plasmin system, the physiological antagonist of the blood clotting system, provides a dissolution of blood clots. This function, however, is not desired in the case of an increased risk of post-operative haemorrhage.
VOSSIUS & PARTNER
Apart from the indications mentioned above, there are further groups of patients who, due to an innate disorder of the blood clotting system such as e.g. lack of protein C, protein S or antithrombin, need therapeutic anticoagulation with vitamin K
antagonists, but also an innate tack of factors such as e.g. haemophilia A or B or von Willebrand's syndrome or an isolated lack of factors within the prothrombin complex can, even in the case of small, local surgeries, lead to considerable post-operative secondary bleedings. In order to avoid post-operative secondary bleedings after tooth extractions or dento-surgical operations without risk of losing the necessary protection against thrombosis, the following procedures according to the state of the art have become established. However, even with these two therapy regimens it is not possible to avoid possible secondary bleedings:
L) Changing the oral permanent anticoagulation by vitamin K-antagonists to an intravenous permanent heparinisation in the so-called therapeutic range (PTT
twice or three times the norm). Due to the relatively short duration/half-life of heparin, secondary bleedings which are partly caused by the heparin anticoagulation (PTT over 80 sec) are to be controlled by reduction of the heparin dosage. In this case, however, a therapeutic heparinisation as protection against thrombembolic complications does not exist any more (PTT
< twice the norm). In addition, this procedure involves considerable costs for the insurers due to the temporary hospitalisation of the patients.
II.) Continuing the oral permanent medication by vitamin K antagonists and carrying out small dento-surgical operations in the upper limit of the oral anticoagulation (Quick value of 25% to 35%). In this case, however, the problem arises that patients who need strict anticoagulation (Quick maximum 25% with an artificial prosthetic valve in mitralis position) cannot be treated by this concept. Furthermore, the physiological, perioperative use of the residual blood clotting factors present in the circulation leads to a further reduction of the supply of endogenous factors, since these are reproduced only to an insufficient extent during the continued administration of vitamin K-antagonists.
Thus, the PTT decreases further and post-operative haemorrhage complications occur. At times, the frequency of secondary bleedings increases to a tenfold high.
Apart from the indications mentioned above, there are further groups of patients who, due to an innate disorder of the blood clotting system such as e.g. lack of protein C, protein S or antithrombin, need therapeutic anticoagulation with vitamin K
antagonists, but also an innate tack of factors such as e.g. haemophilia A or B or von Willebrand's syndrome or an isolated lack of factors within the prothrombin complex can, even in the case of small, local surgeries, lead to considerable post-operative secondary bleedings. In order to avoid post-operative secondary bleedings after tooth extractions or dento-surgical operations without risk of losing the necessary protection against thrombosis, the following procedures according to the state of the art have become established. However, even with these two therapy regimens it is not possible to avoid possible secondary bleedings:
L) Changing the oral permanent anticoagulation by vitamin K-antagonists to an intravenous permanent heparinisation in the so-called therapeutic range (PTT
twice or three times the norm). Due to the relatively short duration/half-life of heparin, secondary bleedings which are partly caused by the heparin anticoagulation (PTT over 80 sec) are to be controlled by reduction of the heparin dosage. In this case, however, a therapeutic heparinisation as protection against thrombembolic complications does not exist any more (PTT
< twice the norm). In addition, this procedure involves considerable costs for the insurers due to the temporary hospitalisation of the patients.
II.) Continuing the oral permanent medication by vitamin K antagonists and carrying out small dento-surgical operations in the upper limit of the oral anticoagulation (Quick value of 25% to 35%). In this case, however, the problem arises that patients who need strict anticoagulation (Quick maximum 25% with an artificial prosthetic valve in mitralis position) cannot be treated by this concept. Furthermore, the physiological, perioperative use of the residual blood clotting factors present in the circulation leads to a further reduction of the supply of endogenous factors, since these are reproduced only to an insufficient extent during the continued administration of vitamin K-antagonists.
Thus, the PTT decreases further and post-operative haemorrhage complications occur. At times, the frequency of secondary bleedings increases to a tenfold high.
VOSrSIUS & PARTNER
The optimal local wound care is carried out identically in both concepts:
after the extraction of the teeth or after a smaller dental surgery was carried out the bone wound was tamponed with a collagen fleece (e.g. Lyostypt) or a gelatine sponge (e.g. Topostatin). The mechanical compression of the bone wound thus achieved can lead to an initial arrest of bleeding. If a stronger bleeding from the site of the tooth occurs intra-operatively, a local hemostyptic on a thrombin base or a fibrin glue preparation can additionally be applied onto the bone wound.
In order to reduce the fibrinolytic influence of the sputum, the mucosal wound is subsequently closed sputum-tight with atraumatic sutures. It is for the same reason that a plastic plate protecting the wound is fastened onto the patient's remaining teeth.
The result of an own, prospective study by the inventors could identify the following reasons for post-operative bleeding in dental surgery with ongoing marcumarisation (Gerhards et al., Gerhards F., Wagner W.: "Zum Blutungsrisiko nach zahnartzlich-chirurgischen Eingriffen unter fortgefuhrter Marcumarisierung". Dtsch.
Zahnarztl. Z.
(1997) 52:53-56):
1. Consumption of the residual coagulation factors circulating in the blood circulation system and 2. their additional inactivation by the intravenous administration of heparin (inactivation of the complete prothrombin complex).
Thus, the problem underlying the present invention is to provide a pharmaceutical formulation with which it is possible to provide the end product of the blood coagulation cascade, thrombin, over a limited period of time. Thus, the phase until a stable intra-oral wound healing is achieved is considered the required period of time. This corresponds to 7 to 10 days. After this period of time, a stable wound healing has occurred. As a result external mechanical influences on the wound can no longer have an effect.
In order to achieve this, thrombin is embedded in resorbable spheres, preferably from commercially available polymers which are already used for other medicinal products (e.g. surgical suture material) (cf. figure 1).
The optimal local wound care is carried out identically in both concepts:
after the extraction of the teeth or after a smaller dental surgery was carried out the bone wound was tamponed with a collagen fleece (e.g. Lyostypt) or a gelatine sponge (e.g. Topostatin). The mechanical compression of the bone wound thus achieved can lead to an initial arrest of bleeding. If a stronger bleeding from the site of the tooth occurs intra-operatively, a local hemostyptic on a thrombin base or a fibrin glue preparation can additionally be applied onto the bone wound.
In order to reduce the fibrinolytic influence of the sputum, the mucosal wound is subsequently closed sputum-tight with atraumatic sutures. It is for the same reason that a plastic plate protecting the wound is fastened onto the patient's remaining teeth.
The result of an own, prospective study by the inventors could identify the following reasons for post-operative bleeding in dental surgery with ongoing marcumarisation (Gerhards et al., Gerhards F., Wagner W.: "Zum Blutungsrisiko nach zahnartzlich-chirurgischen Eingriffen unter fortgefuhrter Marcumarisierung". Dtsch.
Zahnarztl. Z.
(1997) 52:53-56):
1. Consumption of the residual coagulation factors circulating in the blood circulation system and 2. their additional inactivation by the intravenous administration of heparin (inactivation of the complete prothrombin complex).
Thus, the problem underlying the present invention is to provide a pharmaceutical formulation with which it is possible to provide the end product of the blood coagulation cascade, thrombin, over a limited period of time. Thus, the phase until a stable intra-oral wound healing is achieved is considered the required period of time. This corresponds to 7 to 10 days. After this period of time, a stable wound healing has occurred. As a result external mechanical influences on the wound can no longer have an effect.
In order to achieve this, thrombin is embedded in resorbable spheres, preferably from commercially available polymers which are already used for other medicinal products (e.g. surgical suture material) (cf. figure 1).
VOS'SIUS & PARTNER
According to the invention, the term "spheres" includes particles, capsules or liposomes in which the active ingredient is embedded, enclosed, dispersed or - dissolved, such as described in Voigt, Pharmazeutische Technologie, Deutscher Apothekerverlag Stuttgart, 2000, pages 467-471.
- Under the term "spheresu according to the present invention, particularly micro or nano particles are understood which contain an active ingredient embedded in a polymer matrix without the formation of a separate capsule skin.
Here, spheres having a size of 0.1 to 1,000 Vim, more particularly having a size of to 150 wm are preferred.
The loading of the spheres can, depending on the corresponding thrombin preparation, be 0.1 to 20% wherein the loading of the collagen sponge can be 0.1 to 50%. The overall dosage should be 1 I.U. to 2,000 I.U., preferably 250 I.U. to 1,000 I.U. thrombin per implant.
The spheres can be prepared with the help of known methods, in this respect particularly emulsion techniques (w/o; o/w; w/o/w-emulsion-evaporation or extraction method) or spray drying have to be mentioned. The methods are described in the prior art. Thus, EP 0 330 180 describes micro spheres of the polylactic acid type containing physiologically active substances and methods for their preparation. Other methods for preparation are inter alia disclosed in Muller.
R.H. and Hildebrand G.E., Pharmazeutische Technologies Moderne Arzneiformen, Wissenschaftliche Verlagsgesellschaft Stuttgart, 1998, p. 243-258 and S. 339-355, Eldrige J. et al., J. Controlled Release 1990, 11, 205-214; Jeffrey J. et al.
Pharm.
Res. 1993, 10, 362-368 and Pavanetto et al., Int. J. of Pharmaceutics 1992, 84, 152-159.
Resorbable polymers used according to the invention for the production of the resorbable spheres include polysugars and their derivatives, polyvinyl alcohol (PVA), polyvinyl pyrrolidine (PVP), polylactic acid (PLA), polylactides, polyhydroxybutyrate (PHB), poly-L-lysine, their homologues and co-condensates, lactic acid glycol acid co-polymer (PLG), particularly Resomer RG 504 and 505 by Boehringer Ingelheim.
Other usable polymers are amongst others disclosed in Muller R.H. and Hildebrand G.E., Pharmazeutische Technologies Moderne Arzneiformen, Wissenschaftliche Verlagsgesellschaft Stuttgart, 1998, p. 243-258 and p. 339 to 355.
VOSSIUS & PARTNER
The spheres thus obtained are, in turn, incorporated into resorbable sponges, particularly collagen sponges. This is, e.g., carried out by freeze drying of an aqueous collagen or an aqueous collagen suspension or gelatine solution in which the spheres are uniformly dispersed. The production of collagen sponges is, e.g., described in US 4,5'15,637, EP 562862 or by Chvapil, J. Biomed. Mater. Res.
11, 721-74i (1977).
Collagen The collagen used according to the present invention should preferably be soluble in vivo by enzymatic degradation or by other biological processes. Native collagen in its potentially soluble form or natural insoluble collagen which is inherently cross-linked and which is either soluble in an acidic or alkaline medium such as e.g.
described in US 4,515,637 are preferred.
The collagen used is preferably type 1 collagen.
The origin of the collagen for use according to the present invention is not subject to any special limitation. In general, collagen is used which is derived from the skin, bone, cartilage, tendons, inner organs etc. of a mammal such as e.g. a human, horse, cow, pig, sheep, rabbit, mouse. Collagen-like protein derived from birds, fish and the like can also be used. Moreover, collagen prepared by genetic engineering can also be used, the production of which by means of genetic engineering is at present worked at (e.g. ZymoGenetics, WA, U.S.A.).
Thrombin The thrombin of the invention can be derived from a great number of sources such as pooled human or animal plasma. Bovine thrombin is e.g. available from a great number of commercial sources. Moreover, according to the invention, recombinant thrombin can also be used (e.g. ZymoGenetics, WA, U.S.A.).
This can be obtained from a great number of recombinant sources such as e.g.
transformed host cells (bacteria, yeasts or mammalian cells). Moreover, thrombin-iike compounds such as proteolytic snake venoms and thrombin precursors such as prothrombin can be used as sources for thrombin.
Thus, the term "thrombin" as used herein also comprises thrombin precursors and thrombin-like compounds and refers to all proteins and amino acid polymers of natural and synthetic origin which are capable of catalysing the formation of fibrin clots from fibrinogen and/or of activating the blood platelets.
V~S,SIUS &, PARTNER
Moreover, other coagulation factors such as e.g. factor VIII can also be used.
- This formulation of the invention has various advantages as, on the one hand, the existing therapy concept is only slightly changed due to the use of collagen sponges - for the mechanical wound compression and the collagen-induced aggregation of the thrombocytes, and, on the other hand, the wound healing is supported over a period of time of 7 to 10 days by means of the thrombin released. The aggregation of the thrombocytes caused by the collagen leads to the activation of the plasmatic blood coagulation via the release of mediators.
To sum up, it can be stated that the combination of the invention of collagen with its thrombocyte aggregation-supporting properties and a temporary - for the period of time sufficient for wound healing - local release of the coagulation factor Ila (thrombin), makes a local hemostatis which is independent of systemic influences possible over a longer period of time. The release is carried out 0 to 14 days, particularly preferred 7 to 10 days.
Moreover, the preparation can be supplemented by adding further therapy-supporting antifibrinolytics which are incorporated into the resorbable spheres, such as e.g. tranexamic acid, E-aminocaprinic acid, 4-(aminomethyl)benzoic acid, aprotinine, EPO, acetaminonaphtone, thromboplastin, menadione sodium bisulphate, adrenochrome monoaminoguanidine methanesulfonate and carbazochromosodium sulphate. By this means, it is possible to balance additional thrombolytic influences by the plasmin system and the fibrinolytic effect of the sputum until the wound healing is completed. Moreover, the spheres of the invention can contain further active ingredients such as antibiotics, anti-infectants or local anaesthetics.
The release of active thrombin from resorbable polylactic acid co-glycolid spheres has been examined and detected in vitro by means of a chromogenic substrate.
Figure 2 shows the release profile of thrombin from poly(DL-lactic-co-glycolid) 50:50 (Boehringer Ingelheim RG 504) at 37°C in PBS buffer. The time-dependent cumulative thrombin release is shown, determined by means of the Bradford test in vitro measured over the release period of 28 days.
VOSSIUS 8r. PARTNER
Figure 3 shows a release profile of thrombin from poly (DL-lactid-co-glycolid) 50:50 (Boehringer Ingelheim RG 504) at 37°C in PBS buffer. The time-dependent cumulative thrombin release is shown which is measured in vitro by means of the cleavage of p-nitroaniline from the chromogenic substrate over the release period of 28 days. 1 NIH thrombin corresponds to 0.324+/- 0.073 pg thrombin. The amount of p-nitrolanilin released is proportional to the active thrombin, the thrombin used had an activity of 50 NIH/mg.
The present invention moreover provides the use of the pharmaceutical formulation of the invention as local hemostyptic, particularly for local hemostasis in patients where the coagulation is inhibited or who have impaired coagulation. The cause for the inhibition of the coagulation can in this respect be iatrogenic, i.e. due to an inhibition of the coagulation due to the administration of vitamin K
antagonists such as phenoprocoumon or coumadin, inhibitors of thrombocyte aggregation such as acetylsalicylic acid, tirofibran, dipyramidol, ticlopidine or eptifibatid or is endogenous such as in the case of patients with a mild form of an innate defect in blood coagulation, e.g. hemophilia A/B, von Willebrand syndrome and an isolated lack in factors within the prothrombin complex.
As is known from the literature and as has already been discussed above, the frequency of the postoperative secondary bleeding in patients who have impaired coagulation is approximately 30% and the duration of the hospitalisation amounts to several days (on the average 5 days). The clinical use of the pharmaceutical formulation of the invention considerably decreases the frequency of secondary bleeding and thus shortens the duration of hospitalisation. Moreover, it makes it possible to carry out certain operations on an out-patient basis. Apart from a markedly reduced risk for the patients, this also means a considerable saving of costs in the health sector.
According to the invention, the term "spheres" includes particles, capsules or liposomes in which the active ingredient is embedded, enclosed, dispersed or - dissolved, such as described in Voigt, Pharmazeutische Technologie, Deutscher Apothekerverlag Stuttgart, 2000, pages 467-471.
- Under the term "spheresu according to the present invention, particularly micro or nano particles are understood which contain an active ingredient embedded in a polymer matrix without the formation of a separate capsule skin.
Here, spheres having a size of 0.1 to 1,000 Vim, more particularly having a size of to 150 wm are preferred.
The loading of the spheres can, depending on the corresponding thrombin preparation, be 0.1 to 20% wherein the loading of the collagen sponge can be 0.1 to 50%. The overall dosage should be 1 I.U. to 2,000 I.U., preferably 250 I.U. to 1,000 I.U. thrombin per implant.
The spheres can be prepared with the help of known methods, in this respect particularly emulsion techniques (w/o; o/w; w/o/w-emulsion-evaporation or extraction method) or spray drying have to be mentioned. The methods are described in the prior art. Thus, EP 0 330 180 describes micro spheres of the polylactic acid type containing physiologically active substances and methods for their preparation. Other methods for preparation are inter alia disclosed in Muller.
R.H. and Hildebrand G.E., Pharmazeutische Technologies Moderne Arzneiformen, Wissenschaftliche Verlagsgesellschaft Stuttgart, 1998, p. 243-258 and S. 339-355, Eldrige J. et al., J. Controlled Release 1990, 11, 205-214; Jeffrey J. et al.
Pharm.
Res. 1993, 10, 362-368 and Pavanetto et al., Int. J. of Pharmaceutics 1992, 84, 152-159.
Resorbable polymers used according to the invention for the production of the resorbable spheres include polysugars and their derivatives, polyvinyl alcohol (PVA), polyvinyl pyrrolidine (PVP), polylactic acid (PLA), polylactides, polyhydroxybutyrate (PHB), poly-L-lysine, their homologues and co-condensates, lactic acid glycol acid co-polymer (PLG), particularly Resomer RG 504 and 505 by Boehringer Ingelheim.
Other usable polymers are amongst others disclosed in Muller R.H. and Hildebrand G.E., Pharmazeutische Technologies Moderne Arzneiformen, Wissenschaftliche Verlagsgesellschaft Stuttgart, 1998, p. 243-258 and p. 339 to 355.
VOSSIUS & PARTNER
The spheres thus obtained are, in turn, incorporated into resorbable sponges, particularly collagen sponges. This is, e.g., carried out by freeze drying of an aqueous collagen or an aqueous collagen suspension or gelatine solution in which the spheres are uniformly dispersed. The production of collagen sponges is, e.g., described in US 4,5'15,637, EP 562862 or by Chvapil, J. Biomed. Mater. Res.
11, 721-74i (1977).
Collagen The collagen used according to the present invention should preferably be soluble in vivo by enzymatic degradation or by other biological processes. Native collagen in its potentially soluble form or natural insoluble collagen which is inherently cross-linked and which is either soluble in an acidic or alkaline medium such as e.g.
described in US 4,515,637 are preferred.
The collagen used is preferably type 1 collagen.
The origin of the collagen for use according to the present invention is not subject to any special limitation. In general, collagen is used which is derived from the skin, bone, cartilage, tendons, inner organs etc. of a mammal such as e.g. a human, horse, cow, pig, sheep, rabbit, mouse. Collagen-like protein derived from birds, fish and the like can also be used. Moreover, collagen prepared by genetic engineering can also be used, the production of which by means of genetic engineering is at present worked at (e.g. ZymoGenetics, WA, U.S.A.).
Thrombin The thrombin of the invention can be derived from a great number of sources such as pooled human or animal plasma. Bovine thrombin is e.g. available from a great number of commercial sources. Moreover, according to the invention, recombinant thrombin can also be used (e.g. ZymoGenetics, WA, U.S.A.).
This can be obtained from a great number of recombinant sources such as e.g.
transformed host cells (bacteria, yeasts or mammalian cells). Moreover, thrombin-iike compounds such as proteolytic snake venoms and thrombin precursors such as prothrombin can be used as sources for thrombin.
Thus, the term "thrombin" as used herein also comprises thrombin precursors and thrombin-like compounds and refers to all proteins and amino acid polymers of natural and synthetic origin which are capable of catalysing the formation of fibrin clots from fibrinogen and/or of activating the blood platelets.
V~S,SIUS &, PARTNER
Moreover, other coagulation factors such as e.g. factor VIII can also be used.
- This formulation of the invention has various advantages as, on the one hand, the existing therapy concept is only slightly changed due to the use of collagen sponges - for the mechanical wound compression and the collagen-induced aggregation of the thrombocytes, and, on the other hand, the wound healing is supported over a period of time of 7 to 10 days by means of the thrombin released. The aggregation of the thrombocytes caused by the collagen leads to the activation of the plasmatic blood coagulation via the release of mediators.
To sum up, it can be stated that the combination of the invention of collagen with its thrombocyte aggregation-supporting properties and a temporary - for the period of time sufficient for wound healing - local release of the coagulation factor Ila (thrombin), makes a local hemostatis which is independent of systemic influences possible over a longer period of time. The release is carried out 0 to 14 days, particularly preferred 7 to 10 days.
Moreover, the preparation can be supplemented by adding further therapy-supporting antifibrinolytics which are incorporated into the resorbable spheres, such as e.g. tranexamic acid, E-aminocaprinic acid, 4-(aminomethyl)benzoic acid, aprotinine, EPO, acetaminonaphtone, thromboplastin, menadione sodium bisulphate, adrenochrome monoaminoguanidine methanesulfonate and carbazochromosodium sulphate. By this means, it is possible to balance additional thrombolytic influences by the plasmin system and the fibrinolytic effect of the sputum until the wound healing is completed. Moreover, the spheres of the invention can contain further active ingredients such as antibiotics, anti-infectants or local anaesthetics.
The release of active thrombin from resorbable polylactic acid co-glycolid spheres has been examined and detected in vitro by means of a chromogenic substrate.
Figure 2 shows the release profile of thrombin from poly(DL-lactic-co-glycolid) 50:50 (Boehringer Ingelheim RG 504) at 37°C in PBS buffer. The time-dependent cumulative thrombin release is shown, determined by means of the Bradford test in vitro measured over the release period of 28 days.
VOSSIUS 8r. PARTNER
Figure 3 shows a release profile of thrombin from poly (DL-lactid-co-glycolid) 50:50 (Boehringer Ingelheim RG 504) at 37°C in PBS buffer. The time-dependent cumulative thrombin release is shown which is measured in vitro by means of the cleavage of p-nitroaniline from the chromogenic substrate over the release period of 28 days. 1 NIH thrombin corresponds to 0.324+/- 0.073 pg thrombin. The amount of p-nitrolanilin released is proportional to the active thrombin, the thrombin used had an activity of 50 NIH/mg.
The present invention moreover provides the use of the pharmaceutical formulation of the invention as local hemostyptic, particularly for local hemostasis in patients where the coagulation is inhibited or who have impaired coagulation. The cause for the inhibition of the coagulation can in this respect be iatrogenic, i.e. due to an inhibition of the coagulation due to the administration of vitamin K
antagonists such as phenoprocoumon or coumadin, inhibitors of thrombocyte aggregation such as acetylsalicylic acid, tirofibran, dipyramidol, ticlopidine or eptifibatid or is endogenous such as in the case of patients with a mild form of an innate defect in blood coagulation, e.g. hemophilia A/B, von Willebrand syndrome and an isolated lack in factors within the prothrombin complex.
As is known from the literature and as has already been discussed above, the frequency of the postoperative secondary bleeding in patients who have impaired coagulation is approximately 30% and the duration of the hospitalisation amounts to several days (on the average 5 days). The clinical use of the pharmaceutical formulation of the invention considerably decreases the frequency of secondary bleeding and thus shortens the duration of hospitalisation. Moreover, it makes it possible to carry out certain operations on an out-patient basis. Apart from a markedly reduced risk for the patients, this also means a considerable saving of costs in the health sector.
Claims (15)
1. A resorbable pharmaceutical formulation for the continuous local release of thrombin (coagulation factor IIa) comprising thrombin which is embedded in resorbable polymer spheres wherein the spheres are incorporated into collagen sponges and wherein the resorbable spheres can optionally in addition contain one or more antifibrinolytics.
2. The resorbable pharmaceutical formulation according to claim 1 wherein the polymer is selected from polysugars and their derivatives, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polymethylmethacrylate (PPMA).
polyalkylcyanoacrylate (PACA), arylcopolymeres, polyethylene vinylacetate, polyhydroxypropyl cellulose, polyorthoesters, poly-.epsilon.-caprolactone, polyamino acids, polyurethane, polyethylene glycol, polylactic acid (PLA), polylactides, polyhydroxybutyrate (PHB), poly-L-lysine and their homologues and co-®
and Resomer RG 505®.
polyalkylcyanoacrylate (PACA), arylcopolymeres, polyethylene vinylacetate, polyhydroxypropyl cellulose, polyorthoesters, poly-.epsilon.-caprolactone, polyamino acids, polyurethane, polyethylene glycol, polylactic acid (PLA), polylactides, polyhydroxybutyrate (PHB), poly-L-lysine and their homologues and co-®
and Resomer RG 505®.
3. The resorbable pharmaceutical formulation according to claim 1 or 2 wherein the diameter of the spheres is 0.1 to 1,000 µm, preferably 10 to 150 µm.
4. The resorbable pharmaceutical formulation according to any one of claims 1 to 3 wherein the collagen sponge (collagen Type 1) is prepared from collagen from human, bovine, swine, equine source or from collagen produced by means of genetic engineering.
5. The resorbable pharmaceutical formulation according to any one of claims 1 to 4 wherein thrombin is selected from bovine, swine, equine or human origin or is produced by means of genetic engineering.
6. The resorbable pharmaceutical formulation according to any one of claims 1 to 5 wherein thrombin is present in amount of 1 I.U. to 2,000 I.U., preferably 250 I.U. to 1,000 I.U. per implant.
7. The resorbable pharmaceutical formulation according to any one of claims 1 to 6 wherein the antifibrinolytics are selected from tranexamic acid, .epsilon.-aminocaprinic acid, 4-(aminomethyl)benzoic acid, aprotinine, EPO, acetaminonaphtone, thromboplastin, menadione sodium bisulphate, adrenochrome monoaminoguanidine methanesulfonate and carbazochromosodium sulphate.
8. The resorbable pharmaceutical formulation according to any one of claims 1 to 7 wherein the release takes place over a period of time of 0 to 14 days, preferably 7 to 10 days.
9. The resorbable pharmaceutical formulation according to any one of claims 1 to 8 moreover containing an antibiotic, an anti-infectant or a local anaesthetic.
10. Use of a formulation according to any of the preceding claims as a hemostyptic.
11. Use according to claim 10 in patients who have impaired coagulation.
12. Use according to claim 10 or 11 wherein the patients have therapeutically induced anti-coagulation or suffer from a mild form of innate defects in coagulation.
13. Use according to any one of claims 10 to 12 in patients with venous thromboses, pulmonary embolism, stroke, cardiac infarction, atria!
fibrillation or artificial prosthetic valves or in the case of therapeutic anticoagulation due to innate lack of protein C, protein S or antithrombin.
fibrillation or artificial prosthetic valves or in the case of therapeutic anticoagulation due to innate lack of protein C, protein S or antithrombin.
14. Use according to any one of claims 10 to 12 in patients with hemophilia A/B, von Willebrand syndrome or isolated lack of factors within the prothrombin complex.
15. Use according to any one of claims 9 to 14 in surgery or dental surgery.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10220030.0 | 2002-05-08 | ||
| DE10220030 | 2002-05-08 | ||
| PCT/EP2003/004680 WO2003094983A1 (en) | 2002-05-08 | 2003-05-05 | Resorbable pharmaceutical formulation for the continuous release of thrombin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2485268A1 true CA2485268A1 (en) | 2003-11-20 |
Family
ID=29413701
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002485268A Abandoned CA2485268A1 (en) | 2002-05-08 | 2003-05-05 | Resorbable pharmaceutical formulation for the continuous release of thrombin |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1501558A1 (en) |
| AU (1) | AU2003232257A1 (en) |
| CA (1) | CA2485268A1 (en) |
| WO (1) | WO2003094983A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104163779A (en) * | 2014-06-06 | 2014-11-26 | 浙江工业大学 | Method for preparing menadione sodium bisulfite continuously in tubular type reactor |
| US9283187B2 (en) | 2011-04-27 | 2016-03-15 | Biom'up | Hemostatic compositions |
| CN111053944A (en) * | 2019-11-28 | 2020-04-24 | 中国科学院大学温州研究院(温州生物材料与工程研究所) | Thrombin-carrying microsphere-expanded sponge composite hemostatic material and preparation method and application thereof |
| US11052172B2 (en) | 2016-08-12 | 2021-07-06 | Biom'up France SAS | Hemostatic flowable |
| US12171900B2 (en) | 2018-02-15 | 2024-12-24 | Dilon Technologies Inc. | Multi-dimensional hemostatic product and method for producing the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2259803B2 (en) | 2008-02-29 | 2019-03-13 | Ferrosan Medical Devices A/S | Device for promotion of hemostasis and/or wound healing |
| CN104159527B (en) | 2012-03-06 | 2017-04-12 | 弗罗桑医疗设备公司 | Pressurized container containing haemostatic paste |
| EP2977066A3 (en) | 2012-06-12 | 2016-07-27 | Ferrosan Medical Devices A/S | Dry haemostatic composition |
| JP6390873B2 (en) | 2013-06-21 | 2018-09-19 | フェッローサン メディカル ディバイス エー／エス | Dry composition expanded under reduced pressure and syringe for holding the same |
| CA2928963C (en) | 2013-12-11 | 2020-10-27 | Ferrosan Medical Devices A/S | Dry composition comprising an extrusion enhancer |
| CA2960309A1 (en) | 2014-10-13 | 2016-04-21 | Ferrosan Medical Devices A/S | Dry composition for use in haemostasis and wound healing |
| RU2705905C2 (en) | 2014-12-24 | 2019-11-12 | Ферросан Медикал Дивайсиз А/С | Syringe for holding and mixing first and second substances |
| CA2986981A1 (en) | 2015-07-03 | 2017-01-12 | Ferrosan Medical Devices A/S | Syringe for mixing two components and for retaining a vacuum in a storage condition |
| EP3790600B1 (en) | 2018-05-09 | 2023-12-27 | Ferrosan Medical Devices A/S | Method for preparing a haemostatic composition |
| CN114159623B (en) * | 2020-12-12 | 2022-11-08 | 复旦大学 | A kind of self-anti-coagulation elastomer material and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4515637A (en) * | 1983-11-16 | 1985-05-07 | Seton Company | Collagen-thrombin compositions |
| DE69724243T2 (en) * | 1996-04-04 | 2004-06-17 | Baxter Ag | Hemostatic sponge based on collagen |
| EP1053753A1 (en) * | 1999-05-19 | 2000-11-22 | Resorba Chirurgisches Nahtmaterial Franz Hiltner GmbH & Co. | Drug carrier for local use |
-
2003
- 2003-05-05 CA CA002485268A patent/CA2485268A1/en not_active Abandoned
- 2003-05-05 EP EP03749866A patent/EP1501558A1/en not_active Withdrawn
- 2003-05-05 WO PCT/EP2003/004680 patent/WO2003094983A1/en not_active Application Discontinuation
- 2003-05-05 AU AU2003232257A patent/AU2003232257A1/en not_active Abandoned
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9283187B2 (en) | 2011-04-27 | 2016-03-15 | Biom'up | Hemostatic compositions |
| US9662374B2 (en) | 2011-04-27 | 2017-05-30 | Biom'up | Hemostatic compositions |
| US10046034B2 (en) | 2011-04-27 | 2018-08-14 | Biom'up | Hemostatic compositions |
| US10342856B2 (en) | 2011-04-27 | 2019-07-09 | Biom'up | Hemostatic compostions |
| CN104163779A (en) * | 2014-06-06 | 2014-11-26 | 浙江工业大学 | Method for preparing menadione sodium bisulfite continuously in tubular type reactor |
| CN104163779B (en) * | 2014-06-06 | 2016-04-13 | 浙江工业大学 | A kind of pipe type continuously prepares the method for sodium menadione sulfate |
| US11052172B2 (en) | 2016-08-12 | 2021-07-06 | Biom'up France SAS | Hemostatic flowable |
| US12171900B2 (en) | 2018-02-15 | 2024-12-24 | Dilon Technologies Inc. | Multi-dimensional hemostatic product and method for producing the same |
| CN111053944A (en) * | 2019-11-28 | 2020-04-24 | 中国科学院大学温州研究院(温州生物材料与工程研究所) | Thrombin-carrying microsphere-expanded sponge composite hemostatic material and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003094983A1 (en) | 2003-11-20 |
| AU2003232257A1 (en) | 2003-11-11 |
| EP1501558A1 (en) | 2005-02-02 |
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| Date | Code | Title | Description |
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