NZ517119A - Use of low-molecular-weight heparins for preventing and treating central nervous system (CNS) trauma - Google Patents

Abstract

Use of a low molecular weight heparin for the treatment and or prevention of trauma of the central nervous system, excluding craniospinal trauma. The low molecular weight heparin may consist of: - oligosaccharides having a 2-0-sulpho-4-enopyranosuronic acid at one of their ends, - a low molecular weight heparin obtained by depolymerisation of a heparin ester by means of a base, or - a low molecular weight heparin selected from enoxaparin, nadroparin, parnaparin, reviparin, dalteparin, tinzaparin, danaparin, ardepari n, certoparin, CY222 and SR90107/ORG31540.

Description

New Zealand Paient Spedficaiion for Paient Number 517119 1 7 1 ig INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 1 FEB 2002 RECEIVED NEW ZEALAND PATENTS ACT, 1953 No: Divided out of No. 501365 Date: Dated 25 May 1998 COMPLETE SPECIFICATION USE OF LOW-MOLECULAR-WEIGHT HEPARINS FOR PREVENTING AND TREATING CENTRAL NERVOUS SYSTEM TRAUMA We, RHONE-POULENC RORER S.A., a French body corporate, of 20, avenue Raymond Aron, F-92160 Antony, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page la) 517119 la USE OF LOW-MOLECULAR-WEIGHT HEPARINS FOR THE PREVENTION AND TREATMENT OF TRAUMA OF THE CENTRAL NERVOUS SYSTEM This application is divided out of New 5 Zealand Patent Application No. 501365 dated 25 May 1998.

The present invention relates to the use of particular low-molecular-weight heparins for the preparation of a medicament for the prevention and/or 10 treatment of trauma of the central nervous system, in particular of spinal or cranial trauma.

Standard heparin is a sulphated polysaccharide having, an average molecular weight of 12,000-15,000 daltons which is isolated from bovine, 15 ovine and porcine intestinal mucous membranes. Heparin is clinically used for the prevention and treatment of thromboembolic disorders but sometimes causes haemorrhages.

Over the past ten years, heparin has been 20 gradually replaced by low-molecular-weight heparins which no longer exhibit or which exhibit to a lesser degree the disadvantage of causing bleeding and which now require only one injection per day instead of 2 to 3 injections per day for standard heparin. These low-25 molecular-weight heparins are prepared in particular by fractionation, controlled depolymerization of heparin or by chemical synthesis. They have an anti-Xa activity/anti-IIa activity ratio greater than 2.

INTELLECTUAL PROPERTY OFFICE OF N.Z JUN 2003 received 2 It has now been found that certain low-molecular-weight heparins reduce the size of the trauma of the central nervous system and in particular of spinal and cranial trauma. Accordingly the present 5 invention provides the use, in the preparation of a medicament for the prevention and/or treatment of trauma of the central nervous system, excluding craniospinal trauma, of a low-molecular-weight heparin which is a low-molecular-weight heparin consisting of 10 oligosaccharides having a 2-0-sulpho-4-enopyranosuronic acid at one of their ends, a low-molecular-weight heparin obtained by depolymerization of a heparin ester by means of a base, or a low-molecular-weight heparin selected from enoxaparin, nadroparin, parnaparin, 15 reviparin, dalteparin, tinzaparin, danaparoid, ardeparin, certoparin, CY222 and SR90107/ORG31540.

Traumas of the central nervous system (SNC trauma or neurotrauma) relate to trauma of the brain (cerebral trauma) and traumas of the spinal cord 20 (medullary trauma). They are the consequence of a shock at the level of the central nervous system (car, motorbike, skiing or swimming-pool accident and the like) which is often but not always accompanied by fractures. The consequences of these traumas are 25 neurological disorders such as epilepsy, impairment of consciousness, motor problems, amnesia, aggressiveness and psychoaffective deficiency.

INTELLECTUAL PROPERTY OFFICE OF N.Z 17 SEP 2003 received INTELLECTUAL PROPERTY OFFICE OF NI.Z 5171 19 1 o jun 2003 received The low-molecular-weight heparins used in the present invention can be prepared by various processes from heparin: - fractionation by means of solvents (FR 2,440,376, US 5 4,692,435), - fractionation on an anionic resin (FR 2,453,875), - gel filtration (BARROWCLIFFE, Thromb. Res. 12, 27-36 (1977), - affinity chromatography (US 4,401,758), - depolymerization controlled by means of a chemical agent: nitrous acid (EP 14184, EP 37319, EP 76279, EP 623629, FR 2,503,714, US 4,804,652; WO 813276), p-elimination from a heparin ester (EP 4014 4, US 5,389,618), periodate (EP 287477), sodium borohydride 15 (EP 347588, EP 380943), ascorbic acid (US 4,533,549); hydrogen peroxide (US 4,629,699, US 4,791,195), quaternary ammonium hydroxide from a quaternary ammonium salt of heparin (US 4,981,955), alkali metal hydroxide (EP 380943, EP 347588) or by an enzymatic 20 route (EP 64452, US 4,396,762, EP 244235, EP 244236; US 4,826,827; US 3,766,167); by means of irradiation (EP 269981).

Some can also be prepared by chemical synthesis (US 4,801,583, US 4,818,816, EP 165134, 25 EP 84999, FR 2,535,306).

The preferred low-molecular-weight heparins are enoxaparin (INN) marketed by RHONE-POULENC RORER, nadroparin (INN) marketed by SANOFI, parnaparin (INN) marketed by OPOCRIN-ALFA, reviparin (INN) marketed by 517119 KNOLL, dalteparin (INN) marketed by.KABI PHARMACIA, tinzaparin (INN) marketed by NOVO NORDISK, danaparoid (INN) marketed by ORGANON, ardeparin (INN) developed by WYETH AYERST, certoparin (INN) marketed by SANDOZ, 5 SR9Q107/ORG31540 from SANOFI-ORGANON (Thrombosis and Haemostasis, 74, 1468-1473 (1995)), The effect of low-molecular-weight heparins on trauma of the central nervous system is demonstrated in rats on trauma induced according to the following 10 technique: male Sprague-Dawley rats (Charles River France) weighing 280-300 g (13 for the control group and 13 for the treated group) are anaesthetized with halothane (1.5%) in an N2O/O2 (70/30) mixture and placed in a stereotaxic frame. The epicranium is incised and 15 a hole is made by means of a toothed drill at the level of the right parietal cortex (coordinates: 3.5 mm before, 6 mm above the interaural line). A polyethylene tube with an internal diameter of 3 mm is placed on the dura mater, fixed in the cranial cavity with dental 20 cement and connected to a solenoid valve (Danfoss Evsi 24V, 15W). The dura mater is kept intact. The valve is connected to a HPLC pump (Walters 590). The system is filled with sterile water and when the pump has reached JUN 2003 a pressure of 3.8 to 4 bar, the fluid impact of moderate severity (1.6-1.8 bar) is induced by a brief opening (20 ms) of the valve. The tube is then withdrawn, the incision sutured and the animals are 5 returned to their cage in a room heated to 26-28°C.

The low-molecular-weight heparins dissolved in a saline solution (0.9% NaCl) are administered in the following manner: 2 hours after the lesion: 0.5 mg/kg/5 ml IV bolus, 10 2 hours 15 minutes after the lesion: 1 mg/kg/5 ml SC, 6 hours after the lesion: 1 mg/kg/5 ml SC, 24 hours after the lesion: 1 mg/kg/5 ml SC and 30 hours after the lesion: 1 mg/kg/5 ml SC. ml/kg of a saline solution (0.9% NaCl) are 15 administered to the control group under the same conditions.

The animals are sacrificed one week after the trauma and the size of the trauma is evaluated histologically. Coronal sections are stained with a 20 haematoxylin/eosin mixture and the surface areas of the trauma are measured with an image analyser.

In this test, the low-molecular-weight heparins reduce the size of the cerebral trauma by at least 40%. ~~ Enoxaparin (LOVENOX®) reduces the size of the cerebral trauma by 50%.

The medicaments consist of a salt (preferably sodium or calcium) of a low-molecular- 6 weight heparin in the form of a composition in which it is combined with any other pharmaceutically compatible product which may be inert or physiologically active. The medicaments according to the invention may be used 5 by the intravenous, subcutaneous, oral, rectal, topical or pulmonary (inhalation) route.

Sterile compositions for intravenous or subcutaneous administration are generally aqueous solutions. These compositions may also contain 10 adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. The sterilization can be carried out in several ways, for example by aseptisizing filtration, by incorporating sterilizing agents into the composition, by 15 irradiation. They may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or any other injectable sterile medium.

As solid compositions for oral 20 administration, there may be used tablets, pills, powders (gelatine capsules, cachets) or granules. In these compositions, the active ingredient is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica, under an argon stream. 25 These compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, an agent promoting oral 7 absorption, a colorant, a coating (sugar-coated tablets) or a glaze.

As liquid compositions for oral administration, there may be used pharmaceutically 5 acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil.

These compositions may comprise substances other than diluents, for example wetting, sweetening, thickening, 10 flavouring or stabilizing products.

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active ingredient, excipients such as cocoa butter, semisynthetic glycerides or polyethylene 15 glycols.

The compositions for topical administration may be, for example, creams, lotions, collyria, collutoria, nasal drops or aerosols.

The doses depend on the desired effect, the 2 0 duration of treatment and the route of administration used; they are generally between 0.2 mg and 4 mg per kg per day by the subcutaneous route, that is to say 14 to 280 mg per day for an adult.

In general, the doctor will determine the 2 5 appropriate dosage according to the age, weight and any other factors specific to the subject to be treated.

The present invention also relates to the method for the prevention or treatment of trauma of the

Claims (5)

8 central nervous system and in particular of spinal, cranial or craniospinal trauma in humans comprising the administration of an effective quantity of a low-molecular-weight heparin. 9 CLAIMS

1. Use, in the preparation of a medicament for the prevention and/or treatment of trauma of the central nervous system, excluding craniospinal trauma, 5 of a low-molecular-weight heparin which is a low- molecular-weight heparin consisting of oligosaccharides having a 2-0-sulpho-4-enopyranosuronic acid at one of their ends, a low-molecular-weight heparin obtained by depolymerization of a heparin ester by means of a base, 10 or a low-molecular-weight heparin selected from enoxaparin, nadroparin, parnaparin, reviparin, dalteparin, tinzaparin, danaparoid, ardeparin, certoparin, CY222 and SR90107/ORG31540. 15

2. Use according to claim 1, wherein the medicament is for the prevention and/or treatment of spinal trauma.

3. Use according to claim 1, wherein the 20 medicament is for the prevention and/or treatment of cranial trauma.

4. Use according to any one of the preceding claims wherein the heparin is enoxaparin. 25 INTELLECTUAL PROPERTY OFFICE OF ls|.Z 17 SEP 2003 received 517119 10

5. Use according to any.one of the preceding claims and substantially as hereinbefore described. INTELLECTUAL PROPERTY OFFICE OF N.Z 10 jun 2003 received