WO2000027807A1 - Polymorphic forms of an amyloidosis inhibitor and methods of preparation - Google Patents

Abstract

This invention discloses novel polymorphic forms of 1,3 propanedisulfonic acid, disodium salt. The invention can be used to treat conditions such as peripheral amyloidosis.

Description

POLYMORPHIC FORMS OF AN AMYLOIDOSIS INHIBITOR AND METHODS OF PREPARATION

BACKGROUND OF THE INVENTION Nmyloidosis refers to a pathological condition characterized by the presence of amyloid. Amyloid is a generic term referring to a group of diverse but specific extracellular protein deposits, or plaques, which are seen in a number of different diseases. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, stain with specific dyes (e.g., Congo red), and have a characteristic red-green birefringent appearance in polarized light after staining. They also share common ultrastructural features and common x-ray diffraction and infrared spectra.

Nmyloidosis can be classified clinically as primary, secondary, familial and/or isolated. Primary amyloidosis appears de novo without any preceding disorder. Secondary amyloidosis is that form which appears as a complication of a previously existing disorder. Familial amyloidosis is a genetically inherited form found in particular geographic populations. Isolated forms of amyloidosis are those that tend to involve a single organ system. Different amyloids are also characterized by the type of protein present in the deposit. For example, neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeldt- Jakob disease and the like are characterized by the appearance and accumulation of a protease-resistant form of a prion protein (referred to as AScr or PrP-27) in the central nervous system. Similarly, Alzheimer's disease, another neurodegenerative disorder, is characterized by congophilic angiopathy, neuritic plaques and neurofibrillary tangles, all of which have the characteristics of amyloids. In this case, the plaques and blood vessel amyloid is formed by the beta protein. Other systemic diseases such as adult-onset diabetes, complications of long-term hemodialysis and sequelae of long-standing inflammation or plasma cell dyscrasias are characterized by the accumulation of amyloids systematically. In each of these cases, a different amyloidogenic protein is involved in amyloid deposition. Recently, researchers have identified compounds which may lead to a method of treatment for amyloidosis. Lower alkane sulfonates, such as 1,3- propanedisulfonic acid, disodium salt, have been found to reduce the amount of peripheral amyloid deposition in vivo (U.S. Patent No. 5,643,562, the disclosure of which is incorporated herein by reference).

SUMMARY OF THE INVENTION

The present disclosure relates to novel polymorphic forms of 1,3- propanedisulfonic acid salts.

In one aspect, the invention features a polymorphic form of 1,3- propanedisulfonic acid, disodium salt, designated Form I, characterized by powder X-ray diffraction peaks at approximately 8.5°, 9.0°, 15.5°, 18°, 19.5°, 21.5°, and 26.5°. The invention also features a polymorphic form of 1,3 propanedisulfonic acid salt (Form I) having a moisture content of 1% or less, and an apparent density of 0.64 g/ml. The salt is preferably a dialkaline salt, e.g. disodium. In another aspect the invention features a polymorphic form of 1,3- propanedisulfonic acid, disodium salt, designated Form II, which is characterized by powder X-ray diffraction peaks at approximately 7.0°, 9.0°, 10.0°, 10.5°, 14.5°, 16°, 16.5°, 19.5°, 20°, 21°, 21.5°, 26.5°, and 32.5°. The invention also features a polymorphic form of 1 ,3 propanedisulfonic acid salt (Form II) having a moisture content of about 7% or less, and an apparent density of 0.46 g/ml. The salt is preferably a dialkaline salt, e.g. disodium.

In yet another aspect, the invention features a method of preparing polymorphic forms I and II of 1,3 -propanedisulfonic acid salts as disclosed herein by preparing a solution of 1 ,3-propanedisulfonate in a solvent comprising ethanol and water in at least a 16: 1 ratio (v/v) and 8:1 ratio (v/v), respectively, and precipitating the compound from the solution.

In addition, the invention features a pharmaceutical preparation comprising an effective amount for treating amyloidosis of a polymorphic form of 1,3- propanedisulfonic acid salt, as disclosed herein in a pharmaceutically acceptable carrier. In another aspect, the invention features a method for treating a condition in vivo comprising administration of an effective amount of a polymorphic form 1,3- propanedisulfonic acid salt, as disclosed herein. In particular, amyloid deposition in a subject, e.g., a human with systemic amyloidosis-related disorders, may be modulated by administering an effective amount of a polymorphic form of 1,3- propanedisulfonic acid salt.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 depicts the powder X-ray diffraction pattern of Form I of 1,3 propanedisulfonic acid, disodium salt. Figure 2 depicts the powder X-ray diffraction pattern of Form II of 1,3 propanedisulfonic acid, disodium salt.

Figure 3 shows the variation of water content and sample weight loss as a function of drying for Form II of 1,3 propanedisulfonic acid, disodium salt.

Figure 4 shows the X-ray powder diffraction patterns of Form I of 1 ,3 propanedisulfonic acid, disodium salt as well as the X-ray powder diffraction pattern of a commercially available mixture of polymorphs.

Figure 5 depicts the X-ray powder diffraction patterns of the (redried) Form I of 1,3 propanedisulfonic acid, disodium salt.

DETAILED DESCRIPTION OF THE INVENTION The features and other details of the invention will now be more particularly described with reference to the accompanying drawings and pointed out in the claims. It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations ofthe invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. All parts and percentages are by weight unless otherwise specified.

The present invention relates to novel polymorphic forms of 1,3- propanedisulfonic acid salt. The invention also relates to the process for the preparation of these polymorphic forms as well as their pharmaceutical uses for the treatment of conditions characterized by amyloid deposition.

The term "polymorphic" relates to the ability of a compound of crystallizing in more that one type of crystal lattice, depending on temperature, pressure and the incorporation of solvent molecules into the crystal structure. Each crystalline form or polymorph has a specific thermodynamic stability at a given temperature and pressure. Under the normal manufacturing conditions in which the rate of phase transformation of a metastable polymorph to a stable one is relatively slow, it is common to find several polymorphs of crystalline compounds. Controlling polymorphism in pharmaceutical manufacturing is critical as different polymorphs and or solvates show varying dissolution rates and can lead to bioinequivalence of different forms ofthe drug substance.

Powder X-ray diffraction has shown that 1,3-propanedisulfonic acid, disodium salt exists in mono-hydrated and non-hydrated polymorphic forms, as shown in Figures 1 and 2. The term "Form I" refers to the non-hydrated polymorph of 1,3-propanedisulfonic acid, disodium salt. It is characterized by powder X-ray diffraction peaks at approximately 8.5°, 9.0°, 15.5°, 18°, 19.5°, 21.5°, and 26.5°. The term "Form II" refers to the mono-hydrated form of 1,3- propanedisulfonic acid, disodium salt which characteristically has powder X-ray diffraction peaks at approximately 7.0°, 9.0°, 10.0°, 10.5°, 14.5°, 16°, 16.5°, 19.5°, 20°, 21°, 21.5°, 26.5°, and 32.5°.

Form I can be prepared by direct recrystallization of a commercially available 1 ,3-propanedisulfonic acid, disodium salt. First, the compound is precipitated from solution with 16:1 ethanol: water (v/v). The recrystallized product is recovered as a fine white powder which is then dried at 65°C for 16 hours at 4 mm Hg or lower. The resulting non-hydrated polymorph has a moisture content of 0.2% and an apparent density of 0.64 g/ml.

Form I can be also be prepared from the Form II polymorph by prolonged heating at reduced pressures. First, the Form II polymorph (water content 6.8%) is dried at 65°C for 16 hours in a vacuum at 4 mm Hg or lower. This initial drying reduces the water content of the formerly hydrated polymorph to 2.3%. After another 24 hours at 65 °C, the moisture content ofthe formerly hydrated polymorph is reduced to 1 %. The compound is entirely converted to Form I polymorph only after an additional 48 hours of drying at 77°C. Figure 3 depicts the weight loss of the hydrated polymorph graphically as a function of drying time.

Form II can be prepared by direct recrystallization of a commercially available 1,3-propanedisulfonic acid, disodium salt in a fashion similar to Form I. The compound is precipitated from solution with 8:1 ethanohwater (v/v). The recrystallized product is recovered as a white solid which is then dried at 20-25°C for 16 hours at 4 mm Hg or lower. The resulting mono-hydrated polymorph has a moisture content of about 7% w/w and an apparent density of 0.46 g/ml.

Various compounds have been screened for the ability to reduce the amount of amyloid deposition. In animal trials, sodium salts of sulfonated lower alkanes have been recognized as being particularly effective. However, the effective doses of these compounds are fairly high, which could potentially cause detrimental side effects. One of these compounds, 1,3-propanedisulfonic acid, disodium salt has been shown to have a more thermodynamically stable non-hydrated polymorphic form, Form I. Form I also has a high apparent density, making it more suitable for manufacturing purposes, e.g., packing into capsules for oral administration. The forms I and II are useful for treating amyloidosis associated with any disease in which amyloid deposition occurs, particularly peripheral amyloid deposition. Clinically, amyloidosis can be primary, secondary, familial or isolated. Amyloids have been categorized by the type of amyloidogenic protein contained within the amyloid. Non-limiting examples of amyloids which may be modulated, as identified by their amyloidogenic protein, include (with the associated disease in parentheses after the amyloidogenic protein): β-amyloid (Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage amyloidosis (Dutch)); amyloid A (reactive (secondary) amyloidosis, familial Mediterranean Fever, familial amyloid nephropathy with urticaria and deafness (Muckle-Wells syndrome)); amyloid K L-chain or amyloid λ L-chain (idiopathic (primary), myeloma or macroglobulinemia-associated); Aβ2M (chronic hemodialysis); ATTR (familial amyloid polyneuropathy (Portuguese, Japanese, Swedish), familial amyloid cardiomyopathy (Danish), isolated cardiac amyloid, systemic senile amyloidosis); NIAPP or amylin (adult onset diabetes, insulinoma); atrial naturetic factor (isolated atrial amyloid); procalcitonin (medullary carcinoma of the thyroid); gelsolin (familial amyloidosis (Finnish)); cystatin C (hereditary cerebral hemorrhage with amyloidosis (Icelandic)); ANpoA-I (familial amyloidotic polyneuropathy (Iowa)); ANpoA-II (accelerated senescence in mice); fibrinogen-associated amyloid; lysozyme-associated amyloid; and NScr or PrP-27 (Scrapie, Creutzfeldt-Jacob disease, Gerstmann-Straussler-Scheinker syndrome, bovine spongiform encephalitis).

In the methods of the invention, amyloid deposition (e.g., deposition of β- amyloid) in a subject is modulated by administering a therapeutic compound ofthe invention, i.e., Form I and/or Form II to the subject. The term "subject" is intended to include living organisms in which amyloidosis can occur. Examples of subjects include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. Administration of the compositions of the present invention to a subject to be treated can be carried out using known procedures, at dosages and for periods of time effective to modulate amyloid deposition in the subject. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the amount of amyloid already deposited at the clinical site in the subject, the age, sex, and weight of the subject, and the ability of the therapeutic compound to modulate amyloid deposition in the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies ofthe therapeutic situation.

To administer the therapeutic compound by other than parenteral administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. For example, the therapeutic compound may be administered to a subject in an appropriate carrier, for example, liposomes. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al., (1984) J. Neuroimmunol. 7:27).

The therapeutic compound may also be administered parenterally or intraperitoneally, intraspinally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

Pharmaceutical compositions suitable for injectable use include dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the therapeutic compound into a sterile carrier which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a previously sterile- filtered solution thereof.

The therapeutic compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier. The therapeutic compound and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the therapeutic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The percentage of the therapeutic compound in the compositions and preparations may, of course, be varied. The amount ofthe therapeutic compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.

It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms ofthe invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a condition in a subject.

As an example of a formulation of the polymorphs of the invention which may be administered internally in capsule form, the following procedure for making such capsules is described. 400mg capsules of Form I or Form II are made by passing 302.4g of lactose hydrous fast flo and 3200g of Form I or Form II through a #30 mesh screen and adding to an 8 qt. Blendmaster mixer. The contents are mixed for 15 minutes at approximately 27 rpm. Thereafter 17.6g of magnesium stearate powder is added to the mixer and the contents are mixed for another 2 minutes at 27 rpm. After blend reconciliation and yield determination, the mixture is added to a capsule filler and the appropriate mass of the contents are filled into gelatin capsules to yield 400mg capsules.

The invention is further illustrated by the following non-limiting examples.

EXAMPLES

Preparation of Form I of 1,3-propanedisulfonic acid, disodium salt Two grams of 1,3-propanedisulfonic acid, disodium salt was dissolved in water (2 ml, Millipore 18.2 MΩ). A portion of this solution (1 ml) was added to a stirring solution of absolute ethanol (16 ml, 1% toluene as denaturant, Fluka lot #366907/1). The mixture was stirred for 30 minutes at room temperature. A white solid was recovered by filtration and dried in a vacuum oven at 65°C at .2 mm Hg for 16 hours. A fine white powder (587.9 mg) was obtained. The water content was determined to be 0.2% w/w by Karl Fisher titration. The apparent density was found to be 0.64 g/ml.

Preparation of Form II of 1,3-propanedisulfonic acid, disodium salt

22.6g of 1,3-propanedisulfonic acid, disodium salt was dissolved in water (42 ml, Millipore 18.2 MΩ). This solution was poured into a stirring solution of absolute ethanol (350 ml, 1% toluene as denaturant, Fluka lot # 366907/1). The mixture was stirred for 45 minutes at room temperature. N white solid was recovered by filtration and washed with absolute ethanol (2 x 50 ml). The solid was dried in air for 15 minutes. The solid was transferred to a crystallizing dish and dried in a vacuum oven at ambient temperature (20-25 °C) at 0.2 mm Hg for 16 hours. The initial pressure was 1.2 mm Hg (5 minutes after placing the oven under vacuum) and the final pressure was 0.2 mm Hg. A fine white powder, 22.84 g was obtained. The water content, determined by Karl Fisher titration, was 6.9 % w/w. The apparent density was found to be 0.46 g/ml. Conversion of Form II of 1,3-propanedisulfonic acid, disodium salt to Form I

The Form II polymorph was dried at 65°C for 16 hours in a vacuum at 4 mm Hg or lower, followed by drying periods of 24 hours at 65°C at 4 mm Hg or lower, and 48 hours of drying at 77°C at 4 mm Hg or lower to convert the Form II polymorph to the Form I polymorph.

Powder X-ray Diffraction (PXRD) analysis

The PXRD analysis was performed and the spectra were recorded on a Siemens D5000 Diffractometer system, operating at 50 kV/35 mA on a Cu Kα- target at the Department of Chemistry, University of Toronto. A step scan mode (0.02 1.2s) was used for data collection within a range of 4°-35° 2Θ.

The PXRD analysis of the (non-hydrated) Form I polymorph, prepared above showed a characteristic pattern for the non-hydrated polymorph (Figure 4) which is different from the hydrated polymorph and the commercially available 1,3-propanedisulfonic acid, disodium salt (Sigma, lot # 094H0497). The crystal structure of the redried material was found to be identical to that of the non-hydrated polymorph by PXRD analysis based on the appearance and the intensity of observed reflections. The redried sample (Figure 5) showed a slightly larger unit cell compared to that of the non-hydrated polymorph was measured to be 0.105° (20), while that of the redried sample was measured to be 0.155°. The observed difference in the degree of crystallinity between the manufactured non-hydrated polymorph vs. the converted is expected as a result of phase transformation due to perturbation of the crystal lattice of the hydrated polymorph upon loss of water as a result of heating under reduced pressure.

EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the following claims. The contents of all references, issued patents, and published patent applications cited throughout this application are hereby incorporated by reference. The appropriate components, processes, and methods of those patents, applications and other documents may be selected for the present invention and embodiments thereof.

Claims

WHAT IS CLAIMED IS:

1. A polymorphic form of 1 ,3-propanedisulfonic acid, disodium salt (Form I), characterized by X-ray powder diffraction pattern data (2Θ): reflections at approximately 8.5°, 9.0°, 15.5°, 18°, 19.5°, 21.5°, and 26.5°.

2. The polymorphic form of 1,3-propanedisulfonic acid salt, disodium salt (Form I) of claim 1, having a moisture content of less than 1%.

3. A method of preparing Form I of 1,3-propanedisulfonic acid salt comprising the steps of: a) preparing a solution of 1,3-propanedisulfonic acid salt in a solvent comprising ethanol and water in at least a 16:1 ratio (v/v); and b) precipitating the compound from the solution.

4. A polymorphic form of 1,3-propanedisulfonic acid, disodium salt (Form II), characterized by X-ray powder diffraction pattern data (2Θ): reflections at approximately 7.0°, 9.0°, 10.0°, 14.5°, 16°, 16.5°, 19.5°, 20°, 21°, 21.5°, 26.5°, and 32.5°.

5. The polymorphic form of Claim 4, wherein the moisture content is between 1% and about 7%.

6. A method of preparing Form II of 1,3-propanedisulfonic acid salt comprising the steps of: a) preparing a solution of 1,3-propanedisulfonic acid salt in a solvent comprising ethanol and water in at least a 8:1 ratio (v/v); and b) precipitating the compound from the solution.

7. A pharmaceutical preparation comprising a pharmaceutically acceptable carrier and an effective amount of Form I of a 1,3-propanedisulfonic acid salt.

8. The pharmaceutical preparation of Claim 7, where said effective amount is sufficient to treat systemic amyloidosis.

9. A pharmaceutical preparation comprising a pharmaceutically acceptable carrier and an effective amount of Form II of a 1,3-propanedisulfonic acid salt.

10. The pharmaceutical preparation of Claim 9, where said effective amount is sufficient to treat amyloidosis.

11. A method of modulating amyloid deposition in a subject comprising administering an effective amount of Form I of 1,3-propanedisulfonic acid salt.

12. The method of claim 11, where the subject is a human.

13. A method of modulating amyloid deposition in a subject comprising administering an effective amount of Form II of 1,3-propanedisulfonic acid salt.

14. The method of claim 13, where the subject is a human.

15. A method for treating a condition comprising administering an effective amount of Form I.

16. The method of claim 15, wherein said condition is systemic amyloidosis.

17. A method for treating a condition comprising administering an effective amount of Form II.

18. The method of claim 17, wherein said condition is systemic amyloidosis.

19. The use of Form I of 1 ,3-propanedisulfonic acid salt in the prepartion of a medicament for modulating amyloid deposition in a subject.

20. The use of claim 19, where the subject is a human.

21. The use of Form II of 1 ,3-propanedisulfonic acid salt in the prepartion of a medicament for modulating amyloid deposition in a subject.

22. The use of claim 21 , where the subject is a human.

23. The use of Form I in the prepartion of a medicament for treating a condition.

24. The use of claim 23, wherein said condition is systemic amyloidosis.

25. The use of Form II in the prepartion of a medicament for treating a condition.

26. The use of claim 25, wherein said condition is systemic amyloidosis.