WO2012097867A1

WO2012097867A1 - Cladribine particles and pharmaceutical compositions comprising them

Info

Publication number: WO2012097867A1
Application number: PCT/EP2011/050575
Authority: WO
Inventors: Asad Abukhalil; Borek ŽALUDEK
Original assignee: Synthon BV
Current assignee: Synthon BV
Priority date: 2011-01-18
Filing date: 2011-01-18
Publication date: 2012-07-26
Anticipated expiration: 2013-07-18

Abstract

The present invention relates to a population of cladribine particles having a particle size as expressed by d(0.9) value in the range from about 1μ to about 100μ. It further relates to pharmaceutical compositions comprising said population of particles and to processes of making the same.

Description

CLADRIBINE PARTICLES AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM

BACKGROUND OF THE INVENTION

Cladribine is a compound used since 1993 to treat hairy cell leukemia (leukemic reticuloendotheliosis). Its chemical name is 2-chlorodeoxyadenosine = (2R,3S,5R)-5-(6- amino-2-chloro-purin-9-yl)-2-hydroxymethyl-tetrahydro-furan-3-ol of formula (1).

In current pharmaceutical practice, i.e. in the treatment of leukemia, cladribine has been marketed as an intravenous or subcutaneous injection.

Since 1996, cladribine has been tested for treatment of multiple sclerosis. This might result in its future use as the first oral medication for multiple sclerosis patients. The Cladribine tablets for treatment of multiple sclerosis have been approved in 2010 in Russia and in Australia under brand name Movectro (Merck Serono).

Little is known about actual composition of the oral medicament which has been approved. Available data indicate that the pharmaceutical dose of cladribine within a tablet is lOmg. Other components in the Movectro tablets are hydroxypropyl beta cyclodextrin, sorbitol and magnesium stearate.

WO 2006/067141 and EP 2263678A of Merck Serono disclose a specific dose regimen useful for treatment of multiple sclerosis. In said applications, an example of a tablet composition qualitatively identical with the Movectro tablets is also described.

Formulation of cladribine to pharmaceutical compositions such as a tablet for oral administration with immediate release of the active in the stomach environment faces several problems to be solved. Inherently limited water solubility and, in particular, the hydrophobicity of the surface of cladribine particles, triggers a significant problem in formulating the drug into suitable dosage form for oral administration. In essence, compositions of cladribine with conventional excipients often show low and unpredictable dissolution rates. In a solution, the dissolution rate of cladribine from solid dosage form may be enhanced by using a complex of cladribine with a cyclodextrin, e.g. as suggested,e.g., in US 6, 194,395, WO 2004/087100 and

WO 2004/087101.

Important is also the fact that cladribine is inherently unstable in the acid medium of stomach (see, e.g., WO 00/25758). The cladribine/cyclodextrin complex might improve the stability of cladribine in the stomach medium.

The solid oral cladribine/cyclodextrin compositions of the prior art, while exhibiting enhanced stability and bioavailability, exhibit a problem in that making a well defined cladribine/cyclodextrin complex is difficult and , furthermore, the process needs an extra technological step using a lyophilization or a melt extrusion process, which is costly and of low capacity.

Thus, there exists a need of further improvement in the matter. In particular, there exists a need of making a solid oral composition comprising cladribine with improved stability and bioavailability, which does not need formulating cladribine into a complex with cyclodextrin.

SUMMARY OF THE INVENTION

Now, we have found that a population of cladribine particles having a particle size expressed by d(0.9)value in the range from about 1 μ to about 100μ provides the desired in vitro release profile from conventional solid oral pharmaceutical compositions, typically tablet compositions, without using cyclodextrin complexation, is sufficiently stable and does not suffer from pharmaco-technological problems such as bad flowability and/or

agglomeration during processing.

Hence, according to the first aspect, there is provided a population of cladribine particles for use in orally administrable pharmaceutical compositions, having a particle size expressed by d (0.9) value in the range from about 1μ to about 100μ, preferably from about 5μ to about 50μ. In a particular aspect, there is provided a population of the cladribine particles having a particle size distribution expressed by d(0.5) value in the range from about 1μ to about 50μ, preferably by d(0.5)value in the range from about 2μ to about 20μ.

In another aspect, there is provided a process of preparation of the cladribine particles defined above comprising a step of micronising coarser cladribine particles using milling and/or sieving to obtain cladribine particles having a particle size expressed by d(0.9) value from about 1μ to about 100μ, preferably from about 5μ to about 50μ and/or having a particle size distribution expressed by d(0.5) value in the range from about 1 μ to about 50μ, preferably by d(0.5)value in the range from about 2μ to about 20μ.

In another aspect, there is provided a solid pharmaceutical composition for oral administration of cladribine to a patient in need thereof comprising cladribine particles population having d(0.9) value from about 1 μ to about 100μ, preferably from about 5μ to about 50μ , and/or having d(0.5) value from about 1 μ to about 50μ , preferably from about 2μ to about 20μ, and at least one pharmaceutically acceptable excipient, wherein said solid carrier does not comprise cyclodextrin.

Preferably, the dissolution of cladribine from said composition, when measured in acetate buffer pH 4.5 by a Ph.Eur. paddle method at 70 rpm, is more than 80% in 15 minutes.

In another aspect, there is provided a process of preparing a solid pharmaceutical composition for oral administration of cladribine, comprising the steps of:

a] Providing a population of cladribine particles, wherein said cladribine particles have d(0.9) value from about 1μ to about 100μ, preferably from about 5μ to about 50μ and/or have d(0.5) value from about 1μ to about 50μ , preferably from about 2μ to about 20μ

b] dispersing the cladribine particles with one or more pharmaceutically acceptable excipients with the proviso that none of these excipients comprises cyclodextrin.

c] Processing the dispersion of step b) into suitable pharmaceutical composition

In a particular aspect, the pharmaceutical composition is formulated in a form of a tablet, preferably by direct compression.

In another aspect, there is provided a method of treatment comprising orally administering to a patient of need thereof a solid pharmaceutical composition comprising therapeutical amount of cladribine particles having d(0.9) value from about 1 μ to about 100μ and/or having d(0.5) value from about 1 μ to about 50μ. In other words, the present invention relates to use of cladribine particles having d(0.9) value from about 1 μ to about 100μ and/or having d(0.5) value from about 1 μ to about 50μ in making a medicament, in particular in making solid pharmaceutical composition for oral administration of cladribine to patients in need thereof.

BRIEF DESCRIPTION OF DRAWINGS

Fig. l. Dissolution profiles of cladribine lOmg tablets in acetate buffer pH 4.5.

Fig.2. Dissolution profiles of cladribine lOmg tablets in acetate buffer pH 4.5.

Fig.3. Decomposition of cladribine in simulated gastric fluid without pepsine (0.1 M hydrochloric acid) at 37°C

DETAILED DESCRIPTION OF THE INVENTION

The present invention is related to a population of cladribine particles for use in orally administrable pharmaceutical compositions, said particles being of a suitable particle size range, as defined by parameters d(0.9) and d(0.5), resp. Such population of particles may be typically formulated into solid pharmaceutical compositions for per oral administration, whereby such compositions exhibit bioavailability and stability comparable to similar compositions employing cladribine/cyclodextrin complex. The population of cladribine particles of the present invention also exhibits advantageous pharmaco-technological properties, particularly good flowability and low tendency to agglomeration during processing into solid oral pharmaceutical compositions.

"Cladribine" as employed herein is intended to include amorphous or crystalline form of the compound of the chemical formula (1). The crystalline form may include any

polymorphic form or a mixture thereof.

Cladribine is a known compound, which is commercially available and/or may be produced by processes well known in the art.

"For use in orally administrable pharmaceutical compositions" means that the cladribine particles exhibit physical and chemical properties that are approvable in pharmaceutical applications, e.g. properties, which meet requirements of a Pharmacopoeia, e.g. Ph.Eur. The term "d(0.9)value" in an association with a number means that the size of 90% of particles of the population were less than or equal to the size expressed by that number when measured by a light scattering method.

The term "d(0.5)value" in an association with a number means that the size of 50% of particles of the population were less than or equal to the size expressed by that number when measured by a light scattering method.

The population of cladribine particles of the present invention is characterized by having a particle size, expressed by the d(0.9) value, which is in the range from about 1 μ to about 100μ. Preferably, the population of cladribine particles of the present invention is characterized by the d(0.9) value in the range from about 5μ to about 50μ . Alternately and/or yet preferably, the population of cladribine particles of the present invention is characterized by the d(0.5) value from about 1μ to about 50μ and, simultaneously, by the d(0.5) value from about 2μ to about 20μ.

The known particle size analysis methods can be used for determining the particle size, for example particle size measurement using light, like light-scattering methods, in particular Malvern Mastersizer.

The population of cladribine particles of the present invention is preferably produced by micronising coarser cladribine particles, i.e. mechanically reducing the size of cladribine particles to a particle size expressed by the d(0.9) value , which is in the range from about 1 μ to about 100μ, more advantageously from about 5μ to about 50μ. Micronization to the desired particle size range may be carried out using dry milling technique, advantageously combined with sieving. Various conventional mills available for dry milling are ball mill, an attritor mill, a vibratory mill, air jet mill etc. The milling may be carried out using the cladribine alone or with a suitable diluent. Accordingly, the content of cladribine in the cladribine particles may be sometimes less than 100%, typically from 50 % to 100%. The milling process, whenever appropriate, may be accompanied by a step of sieving the milled product.

Also, supercritical fluid technique may be utilized for particle size reduction.

The desired particle size may also be obtained by modifying the reaction conditions during the manufacturing of cladribine. Apart of providing the desired particle size, step(s) of assuring quality for use in orally administrable pharmaceutical compositions, such as purification steps, must be performed whenever appropriate.

The population of cladribine particles according to the present invention is suitable for making pharmaceutical formulations, typically for solid pharmaceutical formulations for oral administration. In this respect, the cladribine particles population exhibits advantageous characteristics.

First, the release rate of cladribine from the solid pharmaceutical formulation may be significantly improved in comparison with a formulation comprising cladribine particles population of a particle size outside the ranges specified above, in particular a population having the particle size expressed by d(0.9) value higher than 100 μ and/or d(0.5)value higher than 50μ. In particular, such improved release rate may be comparable with that obtainable by employing cladribine/cyclodextrin complex of the prior art.

Second, the stability of the so formulated cladribine particles of the present invention in the stomach environment is also comparable with that of the cladribine/cyclodextrin complex. This is important for pharmaceutical use, as cladribin is absorbed to body fluids already in stomach. Proper concentration in plasma can be thus obtained without the need of a particular stabilization by formulating cladribine into a cyclodextrine complex.

Third, the population of cladribine particles of the present invention exhibits good flow properties, which fact is important for industrial manufacture of powder blends and, in particular, for compressing them into compressed dosage forms, e.g., tablets , by direct compression procedures. Such properties, whenever expressed e.g. by a measuring the flow rate through an orifice or by determination of compressibility index or Hausner ratio, are superior to a particle population having too low particle size, e.g. of d(0.9) below 1 μ ( which otherwise would exhibit good release rate from pharmaceutical composition) as such population of too low particle size may exhibit tendency to agglomeration (thus affecting content uniformity) and to sticking on the walls of equipment due to electrostatic forces. Nanonization (providing an active substance with the average particle size of less than 1 micron), which is a complex process and requires additional step during manufacturing, is therefore not necessary for improving the release rate of cladribine from pharmaceutical composition. The solid pharmaceutical composition comprising the cladribine particles population having a particle size expressed by the d(0.9) value in the range from about 1μ to about 100μ and preferably by the d(0.9) value in the range from about 5μ to about 50μ and/or by d(0.5) value in the range from about 1 μ to about 50μ , preferably by d(0.5)value in the range from about 2μ to about 20μ typically comprises at least one pharmaceutically acceptable excipient with the cladribine particles dispersed therein. In accordance with the above, the

pharmaceutical composition does not preferably comprise a cyclodextrin.

Thus, the term "pharmaceutically acceptable excipients" as used herein include binders, fillers/diluents, lubricants/glidants, disintegrating agents, surfactants, pH-adjustors , antioxidants and coloring agents. Typically, the excipients are so selected to allow an immediate release of cladribine in the stomach environment; however they are not strictly limited thereto.

Specific examples of "binders" include methyl cellulose, hydroxypropyl cellulose, hydroxylpropyl methycellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, carboxymethyl cellulose, sodium alginate, propylene glycol, microcrystalline cellulose or mixtures thereof.

The term "fillers/diluents" as used herein includes calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, sucrose and mixtures thereof.

Specific examples of "lubricants/glidants" include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, and mixtures thereof.

"Disintegrating agent" for purpose of the present invention may be selected from starches or crosslinked celluloses, polymers or starches, such as starch, modified starch, croscarmellose sodium, crospovidone and sodium starch glycolate.

The "surfactants" include any pharmaceutically acceptable surface active amphiphilic compound, which may comprise non-ionic or ionic hydrophilic part, for instance a sulphate, sulphonate, phosphate, quarternary ammonium compound, a fatty alcohol, a polyoxyethylene glycol, a glycerol ether etc.

The "pH-adjustors" may comprise one or more pharmaceutically acceptable acids, bases or salts. The composition may further comprise antioxidant, to protect the drug from oxidative degradation. Antioxidants may be selected from group consisting of ascorbic acid, sodium pyrosulphite, glutathion or sorbic acid, tocopherol and the like, in particular tocopherol E- acetate.

Coloring agent may be selected from approved colorants and the examples are Iron oxide, Opalux yellow, Lake of Tartrazine, Allura red, Lake of Quinoline yellow, Lake of Erythrosine.

Typically, the excipients are so selected for to allow immediate release of cladribine from the composition. Preferably, the composition of the present invention exhibits a dissolution rate, which is characterized by dissolution of more than 80% of cladribine in 15 minutes, when measured in acetate buffer pH 4.5 by a Ph.Eur. paddle method at 70 rpm. It was found that the release rate of cladribine from the composition may be specifically enhanced by using a surfactant, which apparently enhances wetting properties of hydrophobic surface of cladribine. Thus, in an advantageous mode, the composition of the present invention comprises a surfactant.

In certain embodiment, the immediate release composition comprising cladribine particles of the present invention advantageously comprises soluble and/or insoluble fillers/diluents, e.g., lactose, mannitol, sorbitol and/or microcrystalline cellulose , a disintegrant e.g., crospovidone, Na-croscarmellose or sodium starch glycolate, and optionally a surfactant , e.g. sodium lauryl sulfate, without any binder and/or a release-modifying excipient.

The composition of the present invention is made by a process comprising

a] Providing a population of cladribine particles, wherein said cladribine particles have d(0.9) value in the range of from about 1 μ to about 100μ, preferably from about 5μ to about 50μ and/or have d(0.5) value from about 1 μ to about 50μ , preferably from about 2μ to about 20μ,

b] dispersing the cladribine particles with one or more pharmaceutically acceptable excipients with the proviso that none of these excipients comprises cyclodextrin,

c] Processing the dispersion of step b) into suitable pharmaceutical composition.

The process step sub a] has been already disclosed above. The process step sub b] comprises thorough mixing cladribine with excipients, either direct in solid state, or in a granulator optionally using certain amount of a granulation liquid such as water, an alcohol or a mixture of both, followed by drying ; some extra-granular excipients may be added thereafter. Typically, such composition comprises from 1 to 10 % of cladribine.

The process step sub c] comprises adding lubricants and/or glidants to the formed composition, adjusting it to portions comprising therapeutical amount of the active substance and, optionally, formulating it into a pharmaceutically acceptable dosage form, which typically comprises compressing the dose of the composition into a tablet or filling it into a capsule. Typically, the dosage form such as a tablet or capsule comprises from 1 to 20 mg of cladribine, which includes 1,2,5, 10, 15 or 20 mg of cladribine.

An advantageous example of a process for making tablets comprising cladribine population of particles of the present invention is a direct compression of a powder mixture of the cladribine particle population with excipients, i.e. without a granulation step.

The tablet may be optionally further coated with a coating, e.g. with a film coating. The coating may be selected from amongst one or more of those suitable coating materials known in the art. Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution/suspension. Coating is done using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.

A process for making capsules comprises a simple step of filling the weighed amount of thoroughly mixed powder mixture of cladribine particles population and excipients.

The pharmaceutical compositions and dosage forms comprising the cladribine particles of the invention are useful in treating diseases and conditions known to be treated with cladribine. Typically these conditions include multiple sclerosis, but it is not limited thereto. Typically, once-a-day dosing should be possible.

Thus, in summary, the population of particles having d(0.9) value from about 1μ to about 100μ and/or having d(0.5) value from about 1 μ to about 50μ may be used in making a medicament, in particular in making solid pharmaceutical composition for oral administration of cladribine to patients in need thereof. Accordingly, the present invention provides a method of treatment, particularly that of multiple sclerosis, comprising orally administering to a patient of need thereof a solid pharmaceutical composition comprising therapeutical amount of cladribine particles having the d(0.9) value in the range from about 1 μ to about 100μ and/or d(0.5) value in the range from about 1μ to about 50μ.

The invention is further illustrated by the following examples but they should not be construed as limiting the scope of this invention in any way.

EXAMPLES

Example 1

Providing a population of cladribine particles with desired particle size

A. Milling of cladribine drug substance in the mortar.

Raw crystalline substance was manually grinded in the mortar by the pestle for 10 minutes.

B. Milling of cladribine drug substance in the ball mill.

Raw crystalline substance was milled in ball mill Pulverisette 6. About 10 g of native crystalline substance was transferred into 500 ml agate bowl thereafter 100 pieces of balls with diameter 10 mm were added. Milling process took 2 hours at 400 revs per minute.

C. Micronisation of cladribine drug substance by the jett mill.

Raw crystalline substance was micronized by laboratory jet mill with using of working pressure 2 bars.

Particle size determination

The particle size distribution of cladribine particles was determined by laser light scattering method. The representative sample of cladribine drug substance was dispersed in sunflower seed oil and delivered by a sample dispersion accessory to the optical unit equipped with the detector.

Particle analyser MasterSizer 2000 (Malvern) equipped with liquid sample dispersion unit Hydro 2000S (Malvern) was used for determination of distribution of of cladribine particles in the population. Examples of various populations of cladribine particles

Native crystalline substance: d(0.1)= 13.6μ, d(0.5)= 84.7μ, d(0.9)= 200.9μ

Milling process A: d(0.1)= 2.6μ, d(0.5)= 25.5μ, d(0.9)= 97.0μ

Milling process B: d(0.1)= 1.8 μ, d(0.5)= 1 1.1 μ, d(0.9)= 43. ^

Milling process C: d(0.1)= 1.2 μ, d(0.5)= 3.7 μ, d(0.9)= 1 1.3μ

Example 2

Pharmaceutical compositions

Composition A - without surfactant

Process:

Mix the cladribine particles with the required quantities of sorbitol and polyplasdone for min at 33 rpm.

Add magnesium stearate and mix for 2 min at 33 rpm.

Compress into 8 mm round tablets with thickness of 4.2mm ±0.1mm Composition B - with surfactant.

Process:

Mix the cladribine particles with sodium lauryl sulfate thoroughly for 10 minutes. Add required quantities of sorbitol and polyplasdone and mix for 15min at 33 rpm. Add magnesium stearate and mix for 2min at 33 rpm.

Compress into 8 mm round tablets with thickness of 4.2mm ±0.1mm

Example 3

Several tablets have been made by a process of Example 2, using different populations of cladribine particles:

a] d(0.5) = 85μ (non-micronized, outside of the scope of invention).

b] d(0.5) = 3.7μ and d(0.9) = 1 1.3μ

c] cladribine/cyclodextrin complex (comparative) ( prepared by a lyophilization of a mixture of cladribine and 2-hydroxypropyl-beta-cyclodextrin). Dissolution testing of prepared tablets was performed by Ph.Eur. method under following conditions:

Medium: Acetate buffer, pH 4.5, 500 mL

Paddle method, 70 r.p.m.

Temperature : 36 - 38 °C

Results are shown in Fig. 1 and in Fig. 2.

Example 4

Comparative stability of population of particles of cladribine drug substance and cladribine/cyclodextrin complex prepared by a lyophilization of a solution of a mixture of cladribine and 2-hydroxypropyl-beta-cyclodextrin

10 mg of cladribine drug substance particles was dissolved in 500 ml of simulated gastric fluid without pepsine (0.1 M hydrochloric acid) at 37 °C. Then after each 10 minutes sample was taken and analyzed on cladribine assay. Last sampling was performed after 2 hours.

In the same way an amount of cladribine /cyclodextrin complex corresponding to 10 mg of cladribine drug substance was also dissolved and tested.

Results are shown in Fig. 3.

The invention having been described, it will be readily apparent to those skilled in the art that further changes and modifications in actual implementation of the concepts and embodiments described herein can easily be made or may be learned by practice of the invention, without departing from the scope of the invention as defined by the following claims.

Claims

1. A population of cladribine particles for use in orally administrable pharmaceutical compositions, having a particle size expressed by the d(0.9) value in the range from about Ιμ ίο about 100μ.

2. The population according to claim 1 having a particle size expressed by the d(0.9) value in the range from about 5μ to about 50μ.

3. The population according to claim 1-2, having a particle size expressed by the d(0.5) value in the range from about 1μ to about 50μ, preferably by d(0.5)value in the range from about 2μ to about 20μ.

4. A process of making a population of cladribine particles according to claim 1-3,

comprising a step of micronising coarser cladribine particles using milling and/or sieving to obtain cladribine particles having the desired particle size.

5. A solid pharmaceutical composition for oral administration of cladribine to a patient in need thereof comprising cladribine particles according to claims 1-3 and at least one pharmaceutically acceptable excipient, wherein said solid carrier does not comprise cyclodextrin.

6. The composition according to claim 5, which comprises a surfactant.

7. The composition according to claims 5-6 which comprises at least one binder, at least one disintegrant and at least one lubricant/glidant.

8. The composition according to claims 5-7 comprising 1 to 10% of cladribine.

9. The composition according to claims 5-8 , wherein the dissolution of cladribine from said composition, when measured in acetate buffer pH 4.5 by a Ph.Eur. paddle method at 70 rpm, is more than 80% in 15 minutes.

10. The pharmaceutical composition of claim 5-9 wherein the composition is formulated in a solid dosage form, preferably a tablet dosage form.

1 1. The composition according to claim 10, wherein the dosage form comprises from 1 to 20 mg of cladribine.

12. A process of preparing a solid pharmaceutical composition for oral administration of cladribine, comprising the steps of:

a] Providing a population of cladribine particles having the d(0.9) value in the range from about 1 μ to about 100μ, preferably from about 5μ to about 50μ and/or having d(0.5) value from about 1 μ to about 50μ , preferably from about 2μ to about 20μ; b] Dispersing the cladribine particles with one or more pharmaceutically acceptable excipients with the proviso that none of these excipients comprises cyclodextrin; and

13. A process according to claim 12, wherein the process c) comprises compressing the pharmaceutical composition into a tablet.

14. The process according to claim 13, further comprising a step of coating the tablet with a coat.

15. Use of a population of cladribine particles having the d(0.9) value in the range from about 1μ to about 100μ in making a medicament, in particular in making solid pharmaceutical composition for oral administration of cladribine to patients in need thereof.