PHARMACEUTICAL COMPOSITION FOR THE NASAL ADMINISTRATION OF HEPARIN AND METHOD FOR TREATMENT OF PATIENTS

Abstract: A pharmaceutical composition for the nasal administration of heparin to patients in need of treatment, comprising (a) as the active ingredient, a low molecular weight heparin (LMW-heparin), and (b) a specific enhancer for the nasal absorption. The component (b) preferably is sodium tauro-24, 25-dihydrofusidate.

Description: Pharmaceutical composition for the nasal administration of heparin and method for treatment of patients 1. The present invention relates to a new pharmaceu ical composition, more particularly a composition containing heparin, in particular heparin of low molecular weight (LMW heparin), and especially such composition for the nasal administration of LMW-heparin to a patient in need of treatment . In order to obtain the desired biological response in the patient to a treatment, it is necessary that the drug used must be made available at its site of action in an effective concentration. The concentration of the drug at its site of action is dependent upon the amount administered, the absorption and/or distribution of the drug from the site of administration, its binding to the tissues, its biotransformation and its rate of excretion. Apart from the amount administered of the above factors, it is further possible to influence the route of admini¬ stration. Intravenous drug administration is advantageous when a very rapid increase in blood levels is necessary, but it often requires continuous monitoring and in any event skilled medical personnel. Other parenteral routes are fre¬ quently painful or inconvenient for the patients, whereas enteral administration, being more convenient and acceptabl for the patients, may be inefficient due to poor absorption of the drug, stability problems with the drug, or lack of patients compliance. Nasal administration has also been proposed as a suitable means for systemic administration, but it has its restrictions because its application has up till now been limited to compounds of limited molecular weight. Smaller peptides such as oxytocin and vasopressin represent the extremes with respect to size of compounds given sys- temically by nasal administration when no penetration en¬ hancer is used, see : "Transnasal Systemic Medications" by Yie W. Chien (ed), Elsevier, Amsterdam, 1985. Recently, in EP 0 128 831, it has been indicated that the addition of carriers with a steroid nucleus, such as ionized or partially ionized alkali salts of fusidic acid, 24 , 25-dihydrofusidic acid, cephalosporin P, and C_, conjugates of these; and tauro-24 , 25-dihydro- fusidate and glyco-24, 25-dihydrαfusidate, and 17,20-24,25- -tetrahydrofusidic acid, 3-acetoxyl-fusidic acid, cephalo¬ sporin P_-P-., and C„, conjugates of these; and tauro-17,20- -24,25-tetrahydrofusidiate, tauro-16α-0H-24 , 25-dihydro- fusidate, tauro-16α-0H-17 ,20-24,25-tetrahydrofusidate, tauro-16-0-methyl-ether-24,25-dihydrofusidiate, tauro-16- 0-methyl-ether-17,20-2 ,25-tetrahydrofusidate to a compo¬ sition containing proteins with a molecular weight up to 300,000 dalton increases the bioavailability of the protein by nasal administration significantly. We have been looking for a reproducible, reliable and non-invasive way of administering heparin to patients in need of treatment, and therefore tried to apply the method of EP 0 128 831 to standard heparin having a mean molecular weight of about 15,000 dalton. It has, however, turned out that the increase in bioavailability of standard heparin following addition of sodium tauro-2 ,25-dihydrofusidate (STDF) to a nasal preparation is completely insignificant and of no practical value. From the experience with standard heparin it would seem of no interest to use nasal administration with STDF in connection with the LMW-heparin which is similar to standard heparin in structure and polarity. By LMW-heparin is understood heparin with a mean molecular weight in the range of 2,000 to 10,000, preferably about 3,000 to 7,000. As the reduction in molecular weight from 300,000 (which is the upper limit according to EP 0 128 831) to about 15,000 dalton (mean molecular weight of standard heparin) did not present significant results, a further reduction could not be foreseen to increase dramatically the uptake and thereby the bioavailability. However, it has surprisingly turned out that when STDF was added to such LMW-heparin composition, an unex¬ pected and surprising, significant increase in bioavaila¬ bility was obtained. Thus, the bioavailability of LMW-heparin was increased to no less than approximately 20. which is of a magnitude permitting practical use of this form of application. Addi¬ tion to standard heparin gave only rise to a change in bio¬ availability still too insignificant to be used in practice. Furthermore, it has surprisingly been shown that the ratio between anti Xa and anti IIa activity is enhanced in the heparin which reaches the circulation when administered as described in the present application. Such a high ratio between anti Xa and anti IIa activity is considered to be therapeutically benificial as it leads to a good anti- thrombotic effect with minimal risk of bleeding complica¬ tions. (Kakkar, V . V . et al, British Medical Journal 284 (1982), p. 375). The ratio of LMW-heparin to STDF may vary. Generally, STDF is provided in an aqueous physiological buffer solution which is then mixed with the LMW-heparin. The solution usually contains about 5 to 50_ w/v, preferably from 10 to 40?ό w/v of LMW-heparin, and about 0.1. to about 2.5?ό w/v, preferably from about 0.5 to about 1.5.0 w/v, STDF in a phys¬ iologically acceptable carrier, e.g. phosphate buffered sodium chloride, pH 5-8. The therapeutic composition may contain further active ingredients and/or auxiliary agents, such as pre¬ servatives and stabilizing agents. The dosage given at any one time depends on a number of factors, e.g. the frequence of administration and the condition of the patient. In the above description, STDF has been used as an example of a suitable enhancer for nasal absorption of LMW- heparin, but the invention is not limited to the use of this compound alone as also a number of other enhancers are applicable. These are characterized by the general for¬ mula I or II : in which X (in the - or 0-position) stands for hydrogen, -OH, -0-alkyl, -0-acyl, -S-alkyl, -S-acyl or halogen; Y (in the - or 0-position) stands for -OH, -0-alkyl, -0-acyl, halogen, -O-alkylsulfonyl , or -O-arylsulfony1 ; R stands for -OH or -NHZ, and in which the dotted lines indicate the possibility of double bond(s). When R represents -NHZ, then Z stands for alkyl or aryl, substituted with carboxyl, sulf- onic acid groups, and/or quaternary ammonium groups. wherein R. , R„ , and R, (in the - or 0-position), which can be the same or different, each stands for hydrogen or -OH, and in which R has the above meanings, provided that not all R,, R„, and R-, can be hydrogen at the same time. The compounds of formula I and II form pharmaceu¬ tically acceptable salts. Such salts preferably form part of the compositions of the invention. The following Example shall illustrate the invention, but not limit the scope. Example 1 Nasal absorption of heparin in rabbits The nasal absorption of standard heparin (SH) and of low molecular weight heparin (LMW-heparin) in rabbits was evaluated after administration of the heparins in pre¬ parations with and without STDF. Heparin used: SH: batch 184081 _ w (peak): 15,000 dalton LMW-heparin: batch KBJ 2031 _W (peak): 6,600 dalton Basic Heparin (SH or LMW-heparin) 7.5?ό (w/v) Formulation: Phosphate buffer, pH 7.4 43 M Sodium chloride 130 mM Ethanol 15__ (w/v) Preparations: I: basic formulation with 1% (w/v) sodium dihydro-taurofusidate The heparin is LMW-heparin. II: Basic formulation. The heparin is LMW-heparin. Ill: Basic formulation with 1% (w/v) sodium dihydro-taurofusidate. The heparin is SH. IV: Basic formulation. The heparin is SH. Animals: Rabbits. Himalayan strain (Chbb:HM) Experiments: The preparation in test was placed as a drop in the nasal cavity of the rabbit. Before administration and at 5, 15, 30, 60 and 120 minutes after the administratio a blood sample was taken from the marginal ear vein. The blood-sample was stabilized with EDTA, plasma isolated by centrifugati and the antifactor Xa activity was measure in the plasma by an amidolyti,c assay. Table I Anti-factor X 3-activities in plasma measured in U/ml after nasal administration of preparation I-IV. Table II Area under the activity/time curves calculated using the trapezoidal rule. Analogous areas from experiments with i.v. administration of 1.5 mg/kg LMW-heparin and SH are listed. From the areas the bioavailability of the nasal administration of preparation I-IV have been calculated. * ) Mean - standard deviation with the number of experiments in brackets. From Table II it can be seen that the addition of STDF to the preparation of SH increases the bioavailability after nasal administration from 0.02% to 1.4%. However, the resulting bioavailability is still too small to be of any practical value. The addition of STDF to the preparation of LMW-heparin increases the bioavailability after nasal administration from 2.0% to 8.8%, resulting in a bioavailability of prac¬ tical importance. Example 2 In the present study in dogs the bioavailability of different preparations of LMWH was evaluated after intra- nasal administration. Materials and methods The low molecular weight heparin fragment KJ 1001 was prepared by nitrous acid depolymerization, and the products showed the following characteristics: Batch KBJ 2031 KBJ 2250 M (peak) : 5100 dalton 3400 dalton anti Xa activity } : 63 u/mg 70 u/mg anti IIa activity J : 59 u/mg 60 u/mg The composition of the test preparations are given belo : Table III LMWH = Low molecular weight heparin; STDF = sodium tauro- dihydrofusidate; ETOH = Ethanol For the intranasal administration the dose adminis¬ tered was 10 mg/kg (LMWH) resulting in a dosage volume of 130 μl/kg of test preparations I and II (7.5%) and 100 μl/kg of test preparations J and K (10%). For the i.v. adminis¬ tration test preparation K (10%) or II (7.5%) was given in a dose of 1 mg/kg (LMWH) with an injection volume of 0.10 - 0.13 ml and 0.13 - 0.16 ml, respectively. Ex vivo Assays Anti X 3 activities were assayed *^e~x•——v——i—vo by the ehromogenic anti X assay described by Teien et al. (Thromb. Res. 10 , 399, 1977). Anti II activities were assayed ex vivo by the ehromogenic anti II assay essentially as described by Witt et al. in H.U. Bergmeyer (ed.): Methods of enzymatic analyses, Vol. V, 477-486, Verlag Chemie, Weinheim, 1984. Animal Studies The test preparations were administered to the nasal cavity of Beagle dogs by a nasal spray device. Blood samples were taken before and at 7, 15, 30, 60, 120, 180 and 240 minutes after drug administration. The dose was divided and approximately half of the dose was delivered in either nostril. After delivery the spray device was control-weighed. Intravenous Administration Test preparation II or K was administered intravenously to the same dogs and blood samples were collected from the cephalic vein at 0, 7, 15, 30, 60, 120 and 180 minutes. Results and Discussion In Fig 3 ures 1 and 2 the anti Xa and anti IIa activities in plasma are shown as a function of time, Abscissa: time after administration (hours); Ordinates: activities in plasma (u/ml); Symbols: : preparation II, intravenous; : preparation J , nasal; and : preparation I , nasal Table IV shows the corresponding bioavailabilities. It is characteristic that the absorption of anti Xa activity is much more efficient than the absorption of anti IIa activity '. The explanation could be that there is a preference for low molecular weight components to be ab¬ sorbed and as only components with a relative high molecular weight have an anti II activity while both high and low molecular weight components have an anti Xs activity a more efficient absor r ption of anti Xa activity would result. Plasma levels of anti Xa and anti IIa activities fol- lowing intranasal administration of LMWH preparations withou sodium tauro-dihydrofusidate (STDF) (preparations K and II) were found to result in activities below detection limit. Consequently the nasal bioavailabilities could not be eval¬ uated (Table IV). When STDF was present in the preparations (preparations J and I) a nasal absorption was found with corresp r onding * bioavailabilities of 17-19% (anti Xa). Ethanol (ETOH) per se could not promote the absorption of LMWH from the nasal cavity. Table IV Bioavailabilities in dogs after nasal administration of the preparations in test. The bioavailabilities were calculated from the areas under the activity time-curves as estimated by the trapezoidal route.

Claims: WHAT WE CLAIM IS: 1. A composition for the nasal administration of heparin to patients in need of treatment, comprising (a) as the active ingredient, a low molecular weight heparin (LMW-heparin), and (b) as an enhancer for the nasal absorption, a compound of the formula I in which X (in the a- or 0-position) stands for hydrogen, -OH, -0-alkyl, -0-acyl, -S-alkyl, -S-acyl or halogen; Y (in the - or 0-position) stands for -OH, -0-alkyl, -0-acyl, halogen, -O-alkylsulfonyl , or -0-arylsulfonyl ; R stands for -OH or -NHZ, Z being alkyl or aryl, substituted with carb¬ oxyl, sulfonic acid groups, and/or quaternary ammonium groups; and in which the dotted lines indicate the possi¬ bility of double bond(s); or a compound of the formula II: (ID wherein R, , R„, and R, (in the - or 0-position), which can be the same or different, each stands for hydrogen or -OH, and in which R has the above meanings, provided that not all R, , R«, and R, can be hydrogen at the same time; or a pharmaceutically acceptable salt of such compound of formula I or II. 2. A composition according to claim 1, in which the ingre¬ dient (a) is an LMW-heparin with a mean molecular weight in the range of 2,000 to 10,000, preferably about 3,000 to 7,000. 3. A composition according to claim 1, in which the ingre¬ dient (b) is sodium tauro-24,25-dihydrofusidate (STDF). 4. A composition according to any one of claims 1-3, in which the ingredient (a) is present in an amount of from 5 to 50 (w/v) %, preferably from 10 to 40 (w/v) %, and the ingredient (b) is present in an amount of from 0.1 to 2.5 (w/v) %, preferably from 0,5 to 1,5 (w/v) %, in a suitable, physiologically acceptable carrier at a pH of 5 to 8. 5. A method for the treatment of patients in risk of or suffering from thrombotic disorders, in which an effective amount of a composition according to any one of claims 1 to 4 is administered to such patients in need of treatment.

Inventors: JOHANSEN KRISTIAN BETTON, JOHANSEN, KRISTIAN, BETTON
Applicants: LEO PHARM PROD LTD, LEO PHARMACEUTICAL PRODUCTS LTD. A/S (LVENS KEMIS
Application year: 1987
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K47