WO1997039770A1

WO1997039770A1 - New pharmaceutical formulation of a thrombin inhibitor for parenteral use

Info

Publication number: WO1997039770A1
Application number: PCT/SE1997/000676
Authority: WO
Inventors: Anna Lundgren; Ulla Stjernfelt
Original assignee: Astra Aktiebolag
Priority date: 1996-04-24
Filing date: 1997-04-22
Publication date: 1997-10-30
Also published as: AR006664A1; AU2719597A; ZA973062B; SE9601556D0; ID17334A

Abstract

A pharmaceutical formulation of a trombin inhibitor for parenteral use having an extended release effect.

Description

NEW PHARMACEUTICAL FORMULATION OF A THROMBIN INHIBITOR FOR PARENTERAL USE

Field of invention

The present invention relates to a new pharmaceutical formulation of thrombin inhibitors

for parenteral use, which is an extended release formulation. The invention also relates to a process for the manufacture of such a formulation and, the use of the new formulation in medicine.

Background of the invention

Thrombin inhibitors are effective for treatment of a number of diseases characterized by hypercoagulation.

The compounds melagatran and inogatran are low- molecular weight, water-soluble

thrombin inhibitors which are rapidly cleared from the body. To permit administration with

a low dosing frequence an extended release formulation is desirable, especially when the administration is parenteral.

Parenteral extended release formulations allow a drug to be delivered in a dose resulting in

a suitable plasma concentration for an extended period of time, with less frequent

administration and avoiding high peak concentrations. An extended release effect may be a prerequisite for subcutaneous or intramuscular treatment, particularly for low molecular weight, water soluble drugs with short half-life.

A wide range of means have been used to achieve parenteral extended release.

One approach has been to retard the diffusion of the drug out of the formulation. Retardation can be obtained by using viscous vehicles, or by means of reversible complex formation to a constituent of the formulation.

Cyclodextrins are enzymatically modified starches made of glucopyranose units. In this

process, three different cyclodextrines are formed, α-, β-, and γ-cyclodextrin with six, seven

and eight glucopyranose units, respectively. The outer surface of the cyclodextrin is

hydrophilic and the internal cavity is hydrophobic. Cyclodextrins are known to form

inclusion complexes with compounds or parts of compounds that fit into the ring cavity and

are attracted to the hydrophobic environment. Cyclodextrins, and in particular β-

cyclodextrins, have been used in many pharmaceutical formulations, e.g. to increase solubility and stability.In EP 149 197 the combination of a medicinal substance sparingly

soluble in water and a partially etherified β-cyclodextrin is disclosed with the object of

providing better solubility and stability.

The object of achieving extended release of various water-soluble drugs from oral and oily

parenteral formulations by cyclodextrin derivatives is disclosed in K. Uekama et al., Release

control of water-soluble drugs by β-cyclodextrin derivatives. Minutes Int. Symp. Cyclodextrines, 5th Ed. Sante, Paris, France 1990, pages 418-423, Conference Proceedings.

In WO 95/05197 the use of a cyclodextrin derivative for preparing an opioid analgesic

preparation for intramuscular or subcutaneous administration is described. However, the

problem of achieving extended release of parenteral formulations of water-soluble low

molecular weight compounds from low viscosity cyclodextrin solutions has not been

previously described.

Disclosure of the invention

It has now surprisingly been found that a formulation of a water solution of a thrombin

inhibitor comprising a thrombin inhibitor which is melagatran, inogatran or a physiologically

acceptable water-soluble salt thereof, and a cyclodextrin additive can be used for extending

the release of the thrombin inhibitor in vivo after parenteral administration.

Melagatran is the compound HOOC-CH₂-(R)-Cgl-Aze-Pab (disclosed in EP 701 568) and

inogatran is the compound HOOC-CH₂-(R)-Cha-Pic-Nag (disclosed in EP 618 926),

wherein

Aze is (S)-azetidine-2-carboxylic acid

Cgl is (S)-cyclohexylglycine

Cha is (S)-β-cyclohexyl alanine

Nag is noragmatine

Pab is l-amidino-4-aminomethyl benzene Pic is (S)-pipecolinic acid.

Water solubility in this context is defined as a solubility of more than 3.5 g / 100 g of water, in accordance with the solubility definition of Martindale (Martindale, The Extra

Pharmacopea, The Pharmaceutical press, London 1993).

Physiologically acceptable salts, are such as for instance but not restricted to salts from inorganic and organic acids, e.g. hydrobromide, hydrochloride, sulphate, nitrate; salts of

sulphonic acids, e.g. methane sulphonate, ethane sulphonate, benzene sulphonate, toluene sulphonate, 'naphthalene-2-sulphonate, salts of carboxylic acids, e.g. maleate, benzoate, salicylate, salts of hydroxy acids, e.g. acetate, malate, succinate, gluconate, glycollate,

lactate, tartrate, citrate, ascorbate, salts of fatty acids, e.g. hexanoate, octanoate, decanoate, undecylenate, dodecylsulphate, oleate, stearate.

The additive is a cyclodextrin which may be either unsubstituted α-cyclodextrin, β- cyclodextrin, or γ-cyclodextrin or substituted derivatives thereof.

Preferred unsubstituted cyclodextrin is the γ-cyclodextrin.

The preferred substituted cyclodextrins according to the present invention are alkylated cyclodextrins.

The preferred alkylated cyclodextrins are O-alkylated cyclodextrins having alkyl (1-5C) groups. The alkyl groups may be linear or branched, preferably linear with 1 to 4 carbon atoms. The alkyl groups may be substituted by one or more hydroxy groups at position 2-5, preferably by a hydroxy group at the 2-position and/or the 3-position. The most preferred alkyl group is the 2-hydroxypropyl.

The preferred of the hydroxypropyl substituted cyclodextrins are the hydroxypropyl- β- cyclodextrins and the hydroxypropyl-γ-cyclodextrins. The most preferred are the hydroxypropyl- β-cyclodextrins.

The alkylated cyclodextrin is usually not a homogenous product but a mixture of alkylated cyclodextrin molecules with a various number of hydroxyl groups substituted.

The degree of substitution of the hydroxypropyl-β-cyclodextrins may theoretically vary

from 1 to 21 hydroxypropyl groups per β-cyclodextrin molecule, with a preferred average

degree of substitution in the range of 1 to 7. The most preferred average degree of

substitution is in the range of 2 to 4 hydroxypropyl groups per β-cyclodextrin molecule.

The concentration of the thrombin inhibitor is usually in the range 0.01 to 50% (w/w),

preferably 0.1 to 25% (w/w) of the ready to use formulation.

The concentration of cyclodextrin is 10 to 70 % (w/w) of the ready to use formulation.

The amount of thrombin inhibitor relative to the amount of cyclodextrin in the formulation according to the invention varies in the range 1 :7000 to 1 : 1 calculated by weight. Due to physiological considerations the pH of the formulation is preferably adjusted to

between 3 and 10. For pH adjustment an acid is used, such as but not restricted to acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, or an alkali, such as sodium hydroxide or any other physiologically suitable alkalising agent.

The formulation may contain antimicrobial preservatives, tonicity modifiers and/or antioxidants.

The formulation may be prepared by dissolving the solid components in water, adjusting the pH and sterilizing the resulting solution. The order in which the components are dissolved and at which stage the pH adjustment or sterilization is performed is not critical, however,

normally the sterilization is performed in the last step.

Suitable daily parenteral doses for the trombin inhibitor in the therapeutical treatment of

humans are 0.001 to 50 mg/kg body weight, preferably 0.005 to 5 mg/kg.

The pharmaceutical formulation is suitable for prophylaxis and/or treatment in arterial as well as venous thromboembolism.

The formulation is to be used parenterally including intracutaneous, subcutaneous, intra lipomateus, intramuscular and intraperitoneal administration. Working examples

Example 1 [1.8% w/w (20 mg/ml) melagatran in 40% w/w of hydroxypropyl-β-cyclodextrin (HPβCD)]

Melagatran 7.97 g

HPβCD 183.2 g

HCI to adjust pH to 5 qs

Adjust with water for inj. to 450.2 g

The cyclodextrin is weighed and dissolved during stirring in the main part of the water. The

weighed amount of melagatran is then added to the cyclodextrin solution and dissolved

during stirring. The pH of the dissolved solution is adjusted to 5 with 2 M HCI. The rest of the water is added to the final weight The solution is sterilized by filtration through 0.22

μm sterile filters and filled into sterile injection vials.

In a similar way the following formulations were prepared:

Example 2 [1.9% w/w (22 mg/ml) inogatran in 40% w/w of hydroxypropyl-γ-cyclodextrin

(HPγCD)]

Inogatran 0.329 g

HPγCD 6.88 g

HCI to adjust pH to 7.4 qs

Adjust with water for inj. to 17.52 g Example 3 [1.7% w/w (20 mg/ml) melagatran in 50% w/w of HPβCD)

Melagatran 0.518 g

HPβCD 15.0 g

HCI to adjust pH to 5 qs

Adjust with water for inj. to 30.0 g

Extended release

A dose of 5 mg of melagatran was administered subcutaneously to humans in a) the

cyclodextrin formulation of Example 1, and b) in a physiological saline solution.

The data in the Table shows a 3-fold decrease in absorption rate and a reduced peak plasma concentration for the cyclodextrin formulation as compared to the physiological saline

solution.

TABLE

Human data l

a) Cyclodextrin vehicle b) Physiological sali

Time Mean plasma concentration Time M Meeaann plasma concentration

N = 6 N = 6

(minutes) (μmole/litre) (minutes) (μmol

5 . ** 5 0.084

10 . * 10 0.23

15 . * 15 0.43

20 0.24 20 . *

30 . * 30 0.59

40 0.37 40 . *

45 . * 45 0.55

60 0.39 60 0.49

90 0.38 90 0.37

120 0.32 120 0.28

150 0.28 150 0.22

180 0.23 180 0.19

210 . * 210 0.15

240 0.15 240 0.12

300 0.10 300 0.085

360 0.063 360 . *

480 0.031 480 0.024

600 0.015 600 . *

720 0.010 720 . *

The total area under the plasma concentration versus time curves are equal for the two

-1 formulations (AUC=88.3 μmole L • min.)

*) not determined **) below limit of quantitation

Claims

1. An extended release formulation for parenteral administration of a water-soluble

thrombin inhibitor comprising a thrombin inhibitor which is melagatran, inogatran or a

physiologically accepatble water-soluble salt thereof and a water soluble cyclodextrin

additive for extending the release of the thrombin inhibitor.

2. A formulation according to claim 1 , wherein the cyclodextrin is a substituted cyclodextrin having alkyl-, or hydroxyalkyl groups.

3. A formulation according to claim 1 , wherein the cyclodextrin is hydroxypropyl

cyclodextrin.

4. A formulation according to any one of the preceding claims, wherein the cyclodextrin is

hydroxypropyl- β-cyclodextrin or hydroxypropyl-γ-cyclodextrin.

5. A formulation according to any one of the preceding claims, wherein the cyclodextrin is

2-hydroxypropyl-β-cyclodextrin.

6. A formulation according to any one of the preceding claims, wherein the thrombin

inhibitor is melagatran.

7. A formulation according to any one of the preceding claims, wherein the concentration of the thrombin inhibitor is in the range 0.01 to 50% (w/w) of the ready to use formulation.

8. A formulation according to any one of the preceding claims, wherein the concentration of cyclodextrin is 10 to 70% (w/w) of the ready to use formulation.

9. A formulation according to any one of the preceding claims for use in the prophylaxis

and/or treatment in arterial and/or venous thromboembolism in mammals including man.

10. A process for the preparation of a formulation according to any one of the preceding claims wherein the thrombin inhibitor and the cyclodextrin are dissolved in water, the pH is

adjusted and the resulting solution is sterilized or the separate steps are performed in any other order.

1 1. A method for the prophylaxis and/or treatment of arterial and/or venous

thromboembolism in mammals including man by administering to a host in need thereof of a formulation as defined in any of claims 1 to 9.

12. Use of a water-soluble thrombin inhibitor which is melagatran, inogatran or a

physiologically acceptable water-soluble salt thereof and a cyclodextrin additive for extending the release of the thrombin inhibitor as defined in any one of claims 1 to 9 for the

manufacture of an extended release medicament for prophylaxis and/or treatment of arterial and/or venous thromboembolism.