FR2492259A1 - Heparin for oral admin. - coated with a phospholipid to enable it to be absorbed from the digestive tract - Google Patents

Abstract

Heparin formulations (I) for oral admin. comprise heparin coated with a phospholipid. The phospholipid may be lecithin, derived from eggs, soya or human placentas, or it may be a sphingomyelin, phosphatidyl-ethanolamine, phosphatidyl- serine, phosphatidyl inositol, phosphatidyl glycerol, L-alpha-distearoyl lecithin, or L-alpha dipalmitoyl lecithin. Heparin is a known anticoagulant for human and animal use. Conventional heparin formulations must be given parenterally, since heparin does not pass through the digestive tract into the blood stream. To prepare (I) an aq. soln. of a heparin salt is stirred in a vessel, the inside surfaces of which are coated with a film of phospholipid. The resultant flocculant mass is sepd. from the liq. medium.

Description

HEPARIN FORMULATION
The subject of the invention is a heparin formulation allowing its resorption through the mucosa of the human or animal digestive system.

 Heparin is used in human and veterinary medicine as an anti-coagulant with direct action and iw diate.

It is administered only parenterally, since it is not absorbed from the digestive tract.

 In order to remedy this drawback and to allow oral heparin administration, the heparin formulation according to the invention is characterized in that heparin or a heparin salt is coated in a phospholipid.

 The invention also relates to a process for the preparation of the above-mentioned heparin formulation, characterized in that an aqueous solution of heparin salt is poured with stirring into a container, the internal faces of which are coated with a film of phospholipid and thus fix the phospholipid to heparin in the form of a supernatant flaky mass which is separated from the liquid medium.

 The following example illustrates the implementation of the method.

 A solution of lecithin, for example of egg, containing 1 to 3% of phosphorus, is obtained by dissolving 1 g of the product in 20 ml of ethanol at 950. This solution is evaporated at low pressure in a flask driven in rotation, so as to cover the internal face of its wall with a thin layer of well-dried lecithin.

 A solution of 50,000 IU of heparin sodium in 10 ml of water is then introduced into the flask thus coated internally with lecithin, as well as a few glass beads of a diameter proportional to the volume of the flask. the whole is then stirred at a medium rate until a homogeneous suspension is obtained, the lecithin, detached from the wall of the balloon, then having coated the heparin. This suspension is then centrifuged at an acceleration of 245,250 m / s2 and at a determined temperature, in order to separate the combined supernatant into a fluffy mass. This use is then separated from the aqueous phase which is introduced into a second covered flask on the inner side of its wall with a thin layer of lecithin, as before. The contents of the flask are stirred until the internal layer of lecithin disappears and a new supernatant is obtained which, separated by centrifugation of the residual aqueous phase under the aforementioned conditions, is combined with the first supernatant obtained in the first operation, in a third balloon without internal lecithin coating. The total fluffy mass is then washed with an isotonic sodium chloride solution at low temperature and this twice. By centrifugation for the time necessary at 441,450 m / s2, and a heparin-coated mass is obtained. phospholipid, in this case lecithin.

 Analysis of the residual aqueous phase shows that only very weak traces of heparin are still present there and that thus almost all of the 50,000 IU of heparin used have been coated with the phospholipid in the flaky mass. thus prepared.

 In order to control the anti-coagulant activity of the mass obtained, it is weighed and it is divided into five equal fractions each corresponding to approximately 10,000 UT of heparin. Each fraction is suspended in 5 ml of isotonic sodium chloride solution in order to be able to administer it by gastric probing to rabbits.

 The anal used weighing between 2.2 and 2.4 kg, the amount of heparin thus administered is therefore about 5,000 IU of heparin per kg.

Bes coagulation times according to LEE and iSITE and HOVELL, determined at the time of administration, after 30 minutes, 1 h, 2 h, 3 h and 4 h, demonstrate a clear hypocoagulability. The figures obtained can be superimposed on those recorded in rabbits of the same weight after subcutaneous injection of 0.4 ml of heparin calcium at 25,000
IU / ml, i.e. a dose of 5,000 IU / kg.

 By way of example, HOWELL times of 2 minutes 30 seconds, 2 minutes 45 seconds and 3 minutes before the administration of the product increased to 3 minutes 45 seconds, 4 minutes and 5 minutes respectively at the first hour.

Starting coagulation times, according to LEE and WHITE, of 13 minutes 30 seconds, 10 minutes 30 seconds and 12 minutes 30 seconds, increased respectively to 45 minutes, 40 minutes and 45 minutes two hours after the administration of the product.

Comparable results were obtained in four human volunteers
Acute and subacute toxicity tests have been carried out in rabbits receiving either a single dose of 5,000 IU per kg orally, or daily doses of 1,000 IU per kg for 30 consecutive days. In both cases, macroscopic or microscopic hemorrhagic lesions have never been observed in the digestive tract, liver, heart, lungs, kidneys, gonads and encephalon. Blood cytology was normal and none of the treated animals showed hematuria or meloena. The digestive and general tolerance of the preparation is therefore very good.

 Soy lecithin, a composition significantly different from that obtained from the egg, seems to give equally interesting results according to the preparation method described.

 Lecithin of human placental origin can also be used for the proposed purpose, as well as other phospholipids such as sphingomyelins, phosphatidylethanolamine, phosphatidyl-serine, phosphatidyl-inositol, diphosphatidyl-glycerol or any mixture of these products in various proportions, including other phospholipids of animal and vegetable origin suitable for the application described above, as well as synthetic derivatives such as L - alpha -distearoyl - lecithin and I alpha dipalmitoyl - lecithin.

 It is also possible to use other heparin salts than its sodium derivative, namely the calcium, magnesium and potassium salts and all natural or synthetic derivatives designated under the name of heparinoSdes and having an anticoagulant activity, or alternatively following the case, an activating action on lipoprotein - lipase and, consequently, a corrective therapeutic activity vis-à-vis certain lipid abnormalities suspected of intervening in the pathogenesis of atherosclerosis and in that of coagulability disorders blood at the stage of primary hemostasis.

 For its oral administration, the flaky mass of heparin coated with phospholipid obtained according to the process described, can be put into pharmaceutical form by various galenical processes leading to the preparation of tablets, capsules or capsules, of micro-encapsulated preparations , enteric deliquescence forms where appropriate, as well as liquid forms such as drinkable ampoules, solutes, drops.

Claims (4)

R E V E N D I C A T I 0 N S  1. Heparin formulation allowing its resorption through the mucosa of the human or animal digestive system, characterized in that the heparin is coated in a phospholipid.  2. Formulation according to claim 1, characterized in that the heparin is coated in lecithin containing 1 to 3% of phosphorus.  3.. Process for the preparation of the heparin formulation according to claim 1, characterized in that an aqueous solution of heparin salt is poured, with stirring, into a container the internal faces of which are coated with a phospholipid film. and that the phospholipid is thus fixed to heparin in the form of a supernatant flaky mass, which is separated from the liquid medium.  4. Use of the formulation according to claim 1, for the preparation of drugs, for human or veterinary use, which can be administered orally.