DESC:
The following specification particularly describes the invention and the manner in which it is to be performed.
INTRODUCTION

The drug compound having the adopted name “Milvexian” has chemical name: (9R,13S)-13-{4-[5-chloro-2-(4-chloro- 1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.02,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one as below.

The compound Milvexian was first described in PCT publication WO2015116886A1 and its use thereof as selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein also disclosed.
Amorphous solid dispersion composition of Milvexian with PVP, PVP-VA, HPMCAS, and HPMC has been described in WO2020210629A1.
Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid-state forms of Milvexian, that can be used readily in pharmaceutical compositions suitable for use as therapeutics.
SUMMARY

In an aspect, the present application provides an amorphous solid dispersion of Milvexian.
In another aspect of present application provides a process for the preparation of amorphous solid dispersion of Milvexian.
In another aspect, the present application provides a pharmaceutical composition comprising an amorphous solid dispersion of Milvexian and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1: PXRD pattern of amorphous solid dispersion of Milvexian with PVAP(Poly vinyl acetate pthalate) (1:2 w/w)
Figure 2: PXRD pattern of amorphous solid dispersion of Milvexian with Eudragit L100 55 (1:2 w/w).
Figure 3: PXRD pattern of amorphous solid dispersion of Milvexian With (Eudragit L100 55: HPMC Pthalate HP50::1:1) (1:2 w/w)
Figure 4: PXRD pattern of amorphous solid dispersion of Milvexian with Eudragit L100 55: HPC SSL::3:1 (1:2 w/w).
Figure 5: PXRD pattern of amorphous solid dispersion of Milvexian with (Eudragit L100 55: TPGS::9:1) (1:2 w/w).
Figure 6: PXRD pattern of amorphous solid dispersion of Milvexian with Eudragit L100 55 (3:1 w/w)
Figure 7: PXRD pattern of amorphous solid dispersion of Milvexian with Eudragit L100 55: HPC SSL::3:1 (3:1 w/w)
Figure 8: PXRD pattern of amorphous solid dispersion of Milvexian with (Eudragit L100 55: TPGS::9:1) (3:1 w/w)
Figure 9: PXRD pattern of amorphous solid dispersion of Milvexian with Eudragit L100 55: HPC SSL::3:1 (4:1 w/w)

DETAILED DESCRIPTION

As used herein the term "amorphous" refers to solid forms that consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice.
As used herein "crystalline" refers to compounds or compositions where the structural units are arranged in fixed geometric patterns or lattices, so that crystalline solids have rigid long range order. The structural units that constitute the crystal structure can be atoms, molecules, or ions. Crystalline solids show definite melting points.
As used herein, a "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary considerably (e.g. colloidal particles of nanometer dimension, to multiple microns in size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase), or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase).
The term "amorphous solid dispersion" generally refers to a solid dispersion of two or more components, usually a drug and polymer, optionally containing other components such as surfactants or other pharmaceutical excipients, where drug is either amorphous, and the physical stability and/or dissolution and/or solubility of the amorphous drug is enhanced by the other components.
The term “polymer” used herein may comprise hydrophobic regions and hydrophilic regions. In some embodiments, the polymer is selected from cellulose esters; cellulose ethers; polyalkylene oxides; polyvinyl chlorides; polyvinyl alcohols; polyacrylates; polymethacrylates; homopolymers and copolymers of N-vinyl lactams, polyacrylamides, and vinyl acetates; graft copolymers of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate; oligosaccharides; polysaccharides; and mixtures thereof.
In some embodiments polymer from polyethylene glycol (PEG) glyceride include but not limited to PEG-6 caprylic/capric glyceride, palm glycerides and like.
In some embodiments polymer from polyethylene glycol (PEG) include but not limited to poly(ethylene glycol) methyl ether, poly-ethylene glycol vinyl acetate vinylcaprolactam (Soluplus), polyethylene glycol 6000 (PEG 6000), D?a?tocopheryl polyethylene glycol succinate (TPGS) and like.
In some embodiments polymer from Vinyl Acetate include but not limited to Polyvinyl Acetate phthalate, Soluplus and like.
In some embodiments polymer from cellulose esters, cellulose ethers include but not limited to Hydroxypropylcellulose (HPC), cellulose acetate phthalate (CAP), hypromellose (HPMC), hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS) and like.
In some embodiments polymer from methyl acrylic acid /ethyl acrylate copolymer is selected from Eudragit S 100, Eudragit RS 100, Eudragit L 100-55, EUDRAGIT L 30 D-55, Kollicoat, Acrycoat, MAE 100P, L100 and like.
In some embodiments, the polymer is selected from but not limited to methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, Hydroxypropylcellulose (HPC), cellulose acetate phthalate (CAP), hypromellose (HPMC), hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate (HPMCP), poly(ethylene glycol) methyl, poly-ethylene glycol vinyl acetate vinylcaprolactam (Soluplus), polyethylene glycol 6000 (PEG 6000), D?a?tocopheryl polyethylene glycol succinate (TPGS), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVP-VA), Polyvinyl acetate phthalate (PVAP), blended polyvinyl acetate phthalate (e.g., Sureteric), Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit RS 100), methyacrylic acid copolymer type B (e.g., Eudragit S 100), methacrylic acid-ethyl acrylate copolymer (1:1) (e.g. Eudragit L 100-55); methyacrylic acid copolymer type B, polyoxyethylene-polyoxypropylene block copolymer (e.g., Pluronic F-68) and polyoxyethylene (20) sorbitan monooleate (Tween 80) and like and mixture thereof.
As used herein, the term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
An aspect of the present application relates to solid form of Milvexian and the pharmaceutical compositions thereof. Specific aspect of present application relate to the amorphous solid dispersions (ASD) of Milvexian and their preparative processes.
Another aspect of the present application provides an amorphous solid dispersion of Milvexian with pharmaceutically acceptable polymers.
An embodiment of the present application provides an amorphous solid dispersion of Milvexian with pharmaceutically acceptable polymers selected from Methacrylic acid/ethyl acrylate copolymer, polyethylene glycol (PEG) glycerides, Polyethylene Glycols, Carbopol copolymers, Caprylocaproyl polyoxyl-8 glycerides and the like.
Another embodiment of the present application provides an amorphous solid dispersion of Milvexian with pharmaceutically acceptable polymers selected from but not limited to Gelucire, Poloxamer, Sodium Alginate, Labrasol ALF, Eudragit, Kollicoat MAE, Polyvinyl Acetate phthalate, Soluplus, HPMC phthalate, Ethyl cellulose, Methyl cellulose and the like; and mixture thereof.
One embodiment of the present application provides an amorphous solid dispersion of Milvexian with Methacrylic acid/ethyl acrylate copolymer optionally in presence of one or more polymer.
One specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit.
Another specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit, wherein the ratio of API: polymer is 1:2.
Yet another specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit, wherein the ratio of API: polymer is 3:1.
Another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit, optionally with one more pharmaceutically acceptable polymer.
Specifically, the optional polymer may be selected from a group of a cellulose ester polymer, cellulose ether polymer and polyethylene glycol polymer. More specifically, the optional polymer may be selected from a group of HPMC phthalate, HPC and TPGS.
Still another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and HPMC phthalate.
One specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and HPMC phthalate in a API: polymer ratio of 1:2, wherein the ratio of Eudragit and HPMC phthalate is 1:1.
Yet another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and HPC.
One specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and HPC in a API: polymer ratio of 1:2, wherein the ratio of Eudragit and HPC is 3:1.
Another specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and HPC in a API: polymer ratio of 3:1, wherein the ratio of Eudragit and HPC is 3:1.
Another specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and HPC in a API: polymer ratio of 4:1, wherein the ratio of Eudragit and HPC is 3:1.
Another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and TPGS.
One specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and TPGS in a API: polymer ratio of 1:2, wherein the ratio of Eudragit and TPGS is 9:1.
Another specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and TPGS in a API: polymer ratio of 3:1, wherein the ratio of Eudragit and TPGS is 9:1.
Yet another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Poly vinyl acetate pthalate, optionally with one more pharmaceutically acceptable polymer.
Yet another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Poly vinyl acetate phthalate (in a API: polymer ratio of 1:2), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 1.
Still another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit (in a API: polymer ratio of 1:2), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 2.
Yet another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit (in a API : polymer ratio of 3:1), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 6.
One embodiment of the present application provides ASD of Milvexian with Eudragit and hydroxypropyl methylcellulose phthalate (HPMC phthalate) (in a API: polymer ratio of 1:2 and Eudragit and HPMC phthalate in a ratio of 3:1), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 3.
Another embodiment of the present application provides amorphous solid dispersion of Milvexian with Eudragit and Hydroxypropylcellulose (HPC) (in a API: polymer ratio of 1:2 and Eudragit and HPC in a ratio of 3:1), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 4.
Another embodiment of the present application provides amorphous solid dispersion of Milvexian with Eudragit and Hydroxypropylcellulose (HPC) (in a API : polymer ratio of 3:1 and Eudragit and HPC in a ratio of 3:1), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 7.
Another embodiment of the present application provides amorphous solid dispersion of Milvexian with Eudragit and Hydroxypropylcellulose (HPC) (in a API : polymer ratio of 4:1 and Eudragit and HPC in a ratio of 3:1), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 9.
Yet another embodiment of the present application provides amorphous solid dispersion of Milvexian with Eudragit and D-a-Tocopherol polyethylene glycol succinate (TPGS) (in a API : polymer ratio of 1:2 and Eudragit and TPGS in a ratio of 1:9), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 5.
Yet another embodiment of the present application provides amorphous solid dispersion of Milvexian with Eudragit and D-a-Tocopherol polyethylene glycol succinate (TPGS) (in a API : polymer ratio of 3:1 and Eudragit and HPC in a ratio of 1:9), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 8.
One embodiment of the present application provides Milvexian in an amount from 1% to 90% by weight of the amorphous solid dispersion. One specific embodiment of the present application provides Milvexian in an amount from 10% to 85% by weight of the amorphous solid dispersion.
Another specific embodiment of the present application provides Milvexian in an amount from 20% to 80% by weight of the amorphous solid dispersion.
Yet another specific embodiment of the present application provides Milvexian in an amount of 33% by weight of the amorphous solid dispersion.
Yet another specific embodiment of the present application provides Milvexian in an amount of 75% by weight of the amorphous solid dispersion.
Yet another specific embodiment of the present application provides Milvexian in an amount of 80% by weight of the amorphous solid dispersion.
In another aspect, the present application provides a process for the preparation of amorphous solid dispersion of Milvexian comprising:
a) Dissolving Milvexian and one or more polymer in an organic solvent, and
b) Isolating the solid.

One embodiment of the present application provides isolation of amorphous solid dispersion by distillation, lyophilization or spray-drying. Another embodiment of the present application provides isolation of amorphous solid dispersion by melting technique, Co-precipitation process, simple physical mixing and like.
Another aspect of the present application provides a pharmaceutical composition comprising an amorphous solid dispersion of Milvexian and at least one pharmaceutically acceptable excipient.
Yet another aspect of the present application provides use of amorphous solid dispersion of Milvexian for treating a disease for which a selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein is indicated. Specifically, the disease may be selected from a group of Ischemic Stroke, Acute Coronary Syndrome and Atrial Fibrillation.
In all the embodiments, the isolated solid are optionally dried under suitable drying conditions such as aerial drying, drying under vacuum or inert gas at a suitable temperature of about 25°C or above.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

Examples
Example-1: Amorphous solid dispersion with PVAP (Poly vinyl acetate phthalate) (API : Polymer::1:2 w/w)
In a round bottomed flask, Milvexian (1.5 g) was dissolved together with PVAP (3 g; 1:2 w/w) in Methanol-Acetone(1:1) solvent mixture at ambient temperature and subjected to dry distillation over rotavapor under vacuum at 50°C.
The PXRD of the resultant solid material is given in Fig.1.

Example-2: Amorphous solid dispersion with Eudragit L100 55
(API : Polymer::1:2 w/w)
Dissolved Milvexian (1.5 g) and Eudragit L100 55 (3 g; 1:2 w/w) in Methanol-Acetone(1:1) solvent mixture at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.
The PXRD of the resultant solid material is given in Fig.2.

Example-3: Amorphous solid dispersion with Eudragit L100 55: HPMC phthalate HP50::1:1) (API : Polymer::1:2 w/w)
In a round bottomed flask, Milvexian (1 g) was dissolved together with polymer (Eudragit L100 55 (1 g): HPMC phthalate HP50 (1 g)::1:1) (1:2 w/w) in Methanol-Acetone(1:1) solvent mixture at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.
The PXRD of the resultant solid material is given in Fig.3.

Example-4: Amorphous solid dispersion with Eudragit L100 55: HPC SSL::3:1 (API : Polymer::1:2 w/w)
Dissolved Milvexian (1 g) and polymer (Eudragit L100 55 (750 mg): HPC SSL (250 mg) ::3:1) (1:2 w/w) in methanol at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.
The PXRD of the resultant solid material is given in Fig.4.

Example-5: Amorphous solid dispersion with (Eudragit L100 55: TPGS::9:1) (API : Polymer::1:2 w/w).
Milvexian (1 g) was dissolved in Polymer (Eudragit L100 55 (1.8 mg): TPGS (0.2 g) ::9:1) (1:2 w/w) in Methanol-Acetone(1:1) solvent mixture at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C
The PXRD of the resultant solid material is given in Fig.5.

Example-6: Amorphous solid dispersion with Eudragit L100 55 (API : Polymer::3:1 w/w)
Dissolved Milvexian (3 g) and polymer (Eudragit L100 55) (990 mg) (3:1 w/w) in methanol and acetone in a ratio of 1:1 (160 mL) at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.
The PXRD of the resultant solid material is given in Fig. 6.

Example-7: Amorphous solid dispersion with Eudragit L100 55: HPC SSL::3:1 (API : Polymer::3:1 w/w)
Dissolved Milvexian (3 g) and polymer (Eudragit L100 55 (742.5 mg): HPC SSL (247.5 mg) in methanol and acetone in a ratio of 1:1 (180 mL) at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.
The PXRD of the resultant solid material is given in Fig. 7.

Example-8: Amorphous solid dispersion with (Eudragit L100 55: TPGS::9:1) (API : Polymer::3:1 w/w).
Milvexian (1 g) was dissolved in Polymer (Eudragit L100 55 (297 mg): TPGS (33 mg) in Methanol-Acetone (1:1) (60 mL) solvent mixture at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.
The PXRD of the resultant solid material is given in Fig. 8.

Example-9: Amorphous solid dispersion with Eudragit L100 55: HPC SSL::3:1 (API : Polymer ::4:1 w/w)
Dissolved Milvexian (1 g) and polymer (Eudragit L100 55 (187.5 mg): HPC SSL (62.5 mg) in methanol and acetone in a ratio of 1:1 (60 mL) at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.
The PXRD of the resultant solid material is given in Fig. 9.

Example-10: Solubility Studies of Amorphous solid dispersions of the present application:
Kinetic solubility of the ASDs were compared with the Milvrexian ASD with HPMC-AS MG (As known in WO2020210629A1) in pH 1.2 chloride buffer, pH 4.5 acetate buffer and pH 6.8 phosphate buffer as shown in table-1. Approximately 2 mg of API or API equivalent ASD suspended in 1 mL of the above said buffers and maintained at 37?C and collected aliquots at stated intervals, centrifuged to collect the supernatant and analyzed by HPLC.

Table 1:
Name API: Polymer Solubility (µg/mL)
15 min 30 min 1 h 2 h 6 h 24 h
pH = 1.2
Milvexian:HPMC AS MG 3:1 16 20 26 29 40 53
Milvexian:Eudragit L100/55 3:1 5 7 10 12 22 14
Milvexian:(Eudragit L100/55:HPC SSL :: 3:1) 3:1 16 21 28 33 43 59
Milvexian:(Eudragit L100/55+TPGS 1000 :: 9:1) 3:1 11 17 23 28 39 40
Milvexian: (Eudragit L100/55 + HPC SSL :: 3:1) 4:1 17 27 35 43 62 77
pH = 4.5
Milvexian:HPMC AS MG 3:1 12 16 21 23 30 41
Milvexian:Eudragit L100/55 3:1 5 8 11 15 21 16
Milvexian:(Eudragit L100/55:HPC SSL :: 3:1) 3:1 10 15 21 28 35 51
Milvexian:(Eudragit L100/55+TPGS 1000 :: 9:1) 3:1 11 16 21 26 17 5
Milvexian: (Eudragit L100/55 + HPC SSL :: 3:1) 4:1 14 20 27 33 45 56
pH = 6.8
Milvexian:HPMC AS MG 3:1 39 47 53 55 61 64
Milvexian:Eudragit L100/55 3:1 49 60 61 65 65 63
Milvexian:(Eudragit L100/55:HPC SSL :: 3:1) 3:1 47 60 62 65 68 63
Milvexian:(Eudragit L100/55+TPGS 1000 :: 9:1) 3:1 43 58 61 61 57 52
Milvexian: (Eudragit L100/55 + HPC SSL :: 3:1) 4:1 50 53 57 60 63 57

Example-11: Stability Studies of Amorphous solid dispersions of the present application:
The ASDs were kept at 40°C/75%RH at open condition for 7 days and the chemical purities were checked by HPLC method and physical nature of the samples were checked by XRD. The results are tabulated in Table-2.

Table-2
Name API: Polymer Initial Purity
(HPLC) Chemical Purity -After Stress study
(HPLC) Physical Purity - After Stress study
(XRD)
Milvexian:(Eudragit L100/55:HPC SSL :: 3:1) 3:1 99.08 99.66 Amorphous
Milvexian:EudragitL100/55 3:1 98.66 99.14 Amorphous
Milvexian:(Eudragit L100/55+TPGS 1000 :: 9:1) 3:1 99.25 99.65 Amorphous
Milvexian:(Eudragit L100/55 + HPC SSL :: 3:1) 4:1 99.33 99.54 Amorphous

Dated: 4th Nov 2024 Signature: ________________
Dr. B. Dinesh Kumar
Dr. Reddy’s Laboratories Limited.
,CLAIMS:CLAIMS
1. An amorphous solid dispersion of Milvexian and at least one polymer, wherein the polymer is selected from the group comprising of Methacrylic acid/ethyl acrylate copolymer, polyethylene glycol (PEG) glycerides, Polyethylene Glycols, Carbopol copolymers, Caprylocaproyl polyoxyl-8 glycerides.

2. The amorphous solid dispersion of Milvexian, as claimed in claim 1, comprising a methyl acrylic acid /ethyl acrylate copolymer.

3. The amorphous solid dispersion of Milvexian, as claimed in claim 2, comprising Eudragit.

4. The amorphous solid dispersion of Milvexian, as claimed in claim 3, optionally with an additional polymer.

5. The amorphous solid dispersion, as claimed in claim 4, wherein the additional polymer is selected from polyethylene glycol (PEG) glyceride, Polyethylene Glycols, cellulose esters and cellulose ethers.

6. An amorphous solid dispersion of Milvexian comprising Eudragit.

7. The amorphous solid dispersion, as claimed in claim 6, optionally with an additional polymer.

8. The amorphous solid dispersion, as claimed in claim 7, wherein the additional polymer is selected from a group of HPC, HPMC and TPGS.

9. A process for the preparation of amorphous solid dispersion of Milvexian comprising:
a) Dissolving Milvexian and one or more polymer in an organic solvent, and
b) Isolating the solid.

10. A Pharmaceutical composition comprising amorphous solid dispersions as claimed in claim 1 to 8.