HK1158514A - Pharmaceutical composition comprising a strontium salt, vitamin d and a cyclodextrin - Google Patents

Description

Pharmaceutical composition comprising strontium salt, vitamin D and cyclodextrin

Technical Field

The present invention relates to pharmaceutical compositions comprising strontium salts, vitamin D and cyclodextrins, and their use in the treatment of bone diseases and arthrosis.

Background

The use of strontium salts in therapy has been described, in particular in patent specifications EP 0415850, EP 0813869, EP 1534305 and EP 1845082.

Compositions comprising a strontium salt and vitamin D have been described in a general way in patent application WO 2004/098618.

A pharmaceutical composition comprising strontium ranelate (strontium ranlate) and vitamin D has been described in patent application CN 1823764.

Disclosure of Invention

The applicants have found that complexing vitamin D with cyclodextrin improves both the stability and content uniformity of vitamin D in the composition.

Vitamin D is understood to mean cholecalciferol (vitamin D)₃) Ergocalciferol (vitamin D)₂) Calcifediol (calcidiol) (25-hydroxyvitamin D)₃) Or calciferol triol (1, 25-dihydroxyvitamin D)₃)。

Vitamin D which is preferably used in the composition of the invention is vitamin D₃。

Among the cyclodextrins which can be used in the composition of the invention, mention may be made, without implying any limitation, of substituted or unsubstituted forms of α -cyclodextrin, β -cyclodextrin and γ -cyclodextrin.

Among the substituted cyclodextrins, mention may be made more particularly of α -cyclodextrins, β -cyclodextrins and γ -cyclodextrins substituted by one or more methyl, hydroxypropyl or sulfobutyl ether groups.

Preferred cyclodextrins are substituted beta-cyclodextrins.

Among the substituted β -cyclodextrins, mention may be made more particularly of HPBCD (hydroxypropyl- β -cyclodextrin), SBECD (sulfobutyl ether β -cyclodextrin) and methylated or partially methylated β -cyclodextrins, such as DIMEB (hepta (2, 6-di-O-methyl) - β -cyclodextrin), RAMEB (randomly methylated β -cyclodextrin) or TRIMEB (hepta (2, 3, 6-tri-O-methyl) - β -cyclodextrin).

Among the strontium salts, mention may be made more particularly of strontium ranelate, strontium malonate, strontium acetate, strontium L-ascorbate, strontium aspartate, strontium borate, strontium camphorate, strontium carbonate, strontium ketoglutarate, strontium citrate, strontium ethanesulfonate, strontium formate, strontium fumarate, strontium gluconate, strontium glutamate, strontium hydrogenphosphate, strontium lactate, strontium L-malate, strontium maleate, strontium methanesulfonate, strontium nitrate, strontium oxalate, strontium phosphate, strontium propanesulfonate, strontium succinate, strontium sulfate, strontium tartrate and their hydrates.

Among the pharmaceutical compositions of the invention, mention may be made more particularly of those suitable for oral administration, and in particular of swallowed tablets and lozenges, chewable tablets, effervescent tablets, dispersible tablets, sublingual tablets, capsules and granules of sachets.

In addition to the strontium salt, vitamin D and cyclodextrin, the pharmaceutical compositions of the present invention comprise one or more excipients or carriers, such as diluents, lubricants, binders, disintegrants, colorants, sweeteners, flavoring agents.

The following examples of excipients or carriers may be mentioned:

as diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,

as a lubricant: silicon dioxide, talcum powder, stearic acid and its magnesium salt and calcium salt, polyethylene glycol,

as a binder: aluminium and magnesium silicate, starch, gelatin, methyl cellulose, sodium carboxymethyl cellulose and polyvinylpyrrolidone, maltodextrin,

as a disintegrant: alginic acid and sodium salt thereof, effervescent mixture, carboxymethyl cellulose, croscarmellose sodium,

as a sweetener: aspartame, acesulfame, sucralose (sucralose).

The percentage of strontium salt in the pharmaceutical composition is preferably between 40% and 99.9% by weight, inclusive.

The amount of strontium salt in the pharmaceutical composition is preferably between 200mg and 2g, inclusive.

Vitamin D in pharmaceutical compositions₃The amount of (A) is preferably between 5. mu.g (200IU) and 175. mu.g (7000IU), inclusive.

The amount of cyclodextrin in the pharmaceutical composition is preferably between 200 μ g and 140mg, more preferably between 2mg and 70mg, inclusive.

The weight ratio between the amount of vitamin D and the amount of cyclodextrin is preferably between 1/40 and 1/800, inclusive.

The invention also relates to the use of the pharmaceutical composition according to the invention for the treatment of bone diseases, more particularly osteopenia and osteoporosis, and for the treatment of joint diseases.

Detailed Description

Abbreviation/abbreviation

DIMEB hepta (2, 6-di-O-methyl) -beta-cyclodextrin. The degree of substitution of DIMEB was 14 formazans

Base/cyclodextrin.

HPBCD hydroxypropyl-beta-cyclodextrin

Relative humidity of RH

Random MEthylated beta-cyclodextrin (random MEthylated) of RAMEB

Beta-cyclodextin). The average degree of substitution of the RAMEB is 12.6 methyl groups-

A cyclodextrin.

SBECD sulfobutyl ether beta-cyclodextrin

IU international units. 25 μ g of vitamin D in 1000 IU.

TRIMEB hepta (2, 3, 6-tri-O-methyl) - β -cyclodextrin. The degree of substitution of TRIMEB was 21

Methyl/cyclodextrin.

The following examples illustrate the invention.

Example 1: complex of vitamin D3 and RAMEB:

example 1A

Mixing 25 μ g cholecalciferol to 0.975mg RAMEB in water or tert-butanol; the solvent is then removed by spraying or freeze drying.

Example 1B

Mixing 25 μ g cholecalciferol to 9.975mg RAMEB in water or tert-butanol; the solvent is then removed by spraying or freeze drying.

Example 1C

Mixing 25 μ g cholecalciferol to 19.975mg RAMEB in water or tert-butanol; the solvent is then removed by spraying or freeze drying.

Example 2: sachet containing 2g strontium ranelate and 1000IU vitamin D₃Pharmaceutical composition of (1)

Example 2A

Vitamin D from example 1A₃And RAMEB complex to 4g containing 2g of anhydrous strontium ranelateIn the granules.

Anhydrous strontium ranelate 2g

Cholecalciferol 25 μ g

RAMEB 0.975mg

Aspartame 20mg

Maltodextrin 400mg

Mannitol 948mg

Example 2B

Vitamin D from example 1B₃And RAMEB complex to 4g containing 2g of anhydrous strontium ranelateIn the granules.

Anhydrous strontium ranelate 2g

Cholecalciferol 25 μ g

RAMEB 9.975mg

Aspartame 20mg

Maltodextrin 400mg

Mannitol 948mg

Example 2C

Vitamin D from example 1C₃And RAMEB complex to 4g containing 2g of anhydrous strontium ranelateIn the granules.

Anhydrous strontium ranelate 2g

Cholecalciferol 25 μ g

RAMEB 19.975mg

Aspartame 20mg

Maltodextrin 400mg

Mannitol 948mg

Example 3: comprises 600mg of strontium malonate and 500IU of vitamin D₃In the form of tablets

Example 3A

Anhydrous strontium malonate 600mg

Cholcidol 12.5 μ g

RAMEB 487.5μg

Microcrystalline cellulose 87mg

Povidone 24mg

Anhydrous colloidal silica 5mg

Magnesium stearate 5mg

Example 3B

Anhydrous strontium malonate 600mg

Cholcidol 12.5 μ g

RAMEB 9.9875mg

Microcrystalline cellulose 87mg

Povidone 24mg

Anhydrous colloidal silica 5mg

Magnesium stearate 5mg

Preparation of the tablet of example 3

For about 5000 tablets:

3000g of strontium malonate was carefully mixed with 170g of microcrystalline cellulose. The mixture was sieved and then 120g povidone and purified water (q.s.p. to obtain homogeneous granules-about 375g) were added. The granules were sieved, dried at 40 ℃ for 2.5 to 3 hours and then sieved again.

25g of anhydrous colloidal silicon dioxide and 265g of microcrystalline cellulose were carefully mixed and sieved and then added to the previously prepared granules and to the complex of example 1 (2.5 g of complex 1A when it was desired to prepare the tablet of example 3A; 50g of complex 1C when it was desired to prepare the tablet of example 3B).

300g of the resulting mixture was added to 25g of sieved magnesium stearate and then, when a homogeneous mixture was obtained, the remaining mixture was added.

The final mixture is pressed.

Example 4: contains 798mg strontium acid and 500IU vitamin D₃In the form of tablets

Example 4A

798mg of anhydrous strontium acetate

Cholcidol 12.5 μ g

RAMEB 487.5μg

Microcrystalline cellulose 116mg

Povidone 32mg

6.66mg of anhydrous colloidal silica

Magnesium stearate 6.66mg

Example 4B

798mg of anhydrous strontium acetate

Cholcidol 12.5 μ g

RAMEB 9.9875mg

Microcrystalline cellulose 116mg

Povidone 32mg

6.66mg of anhydrous colloidal silica

Magnesium stearate 6.66mg

Preparation of the tablet of example 4

For about 5000 tablets:

3990g of strontium acetate were carefully mixed with 227g of microcrystalline cellulose. The mixture was sieved and then 160g povidone and purified water (q.s.p. to obtain a homogeneous granulate-about 500g) were added. The granules were sieved, dried at 40 ℃ for 2.5 to 3 hours and then sieved again.

33.3g of anhydrous colloidal silicon dioxide and 353g of microcrystalline cellulose were carefully mixed and sieved and then added to the previously prepared granules and to the complex of example 1 (2.5 g of complex 1A when it was desired to prepare the tablet of example 4A; 50g of complex 1C when it was desired to prepare the tablet of example 4B).

400g of the resulting mixture was added to 33.3g of sieved magnesium stearate and then, when a homogeneous mixture was obtained, the remaining mixture was added.

The final mixture is pressed.

Example 5: contains 790mg strontium succinate and 500IU vitamin D₃In the form of tablets

Example 5A

Strontium succinate anhydrate 790mg

Cholcidol 12.5 μ g

RAMEB 487.5μg

Microcrystalline cellulose 114.5mg

Povidone 31.6mg

6.6mg of anhydrous colloidal silica

Magnesium stearate 6.6mg

Example 5B

Strontium succinate anhydrate 790mg

Cholcidol 12.5 μ g

RAMEB 9.9875mg

Microcrystalline cellulose 114.5mg

Povidone 31.6mg

6.6mg of anhydrous colloidal silica

Magnesium stearate 6.6mg

Preparation of the tablet of example 5

For about 5000 tablets:

3950g of strontium succinate were carefully mixed with 224g of microcrystalline cellulose. The mixture was sieved and then 158g povidone and purified water (q.s.p. to obtain a homogeneous granulate-about 500g) were added. The granules were sieved, dried at 40 ℃ for 2.5 to 3 hours and then sieved again.

33g of anhydrous colloidal silicon dioxide and 348g of microcrystalline cellulose were carefully mixed and sieved and then added to the previously prepared granules and the complex of example 1 (2.5 g of complex 1A when it was desired to prepare the tablet of example 5A; 50g of complex 1C when it was desired to prepare the tablet of example 5B).

400g of the resulting mixture was added to 33g of sieved magnesium stearate and then, when a homogeneous mixture was obtained, the remaining mixture was added.

The final mixture is pressed.

Example 6:contains 900mg strontium ketoglutarate and 500IU vitamin D₃In the form of tablets

Example 6A

Anhydrous strontium ketoglutarate 900mg

Cholcidol 12.5 μ g

RAMEB 487.5μg

Microcrystalline cellulose 130.5mg

Povidone 36mg

7.5mg of anhydrous colloidal silica

Magnesium stearate 7.5mg

Example 6B

Anhydrous strontium ketoglutarate 900mg

Cholcidol 12.5 μ g

RAMEB 9.9875mg

Microcrystalline cellulose 130.5mg

Povidone 36mg

7.5mg of anhydrous colloidal silica

Magnesium stearate 7.5mg

Preparation of the tablet of example 6

For about 5000 tablets:

4500g of strontium ketoglutarate were carefully mixed with 255g of microcrystalline cellulose. The mixture was sieved and then 180g povidone and purified water (q.s.p. to obtain homogeneous granules-about 560g) were added. The granules were sieved, dried at 40 ℃ for 2.5 to 3 hours and then sieved again.

37.5g of anhydrous colloidal silicon dioxide and 397g of microcrystalline cellulose were carefully mixed and sieved and then added to the previously prepared granules and the complex of example 1 (2.5 g of complex 1A when it was desired to prepare the tablet of example 6A; 50g of complex 1C when it was desired to prepare the tablet of example 6B).

525g of the resulting mixture was added to 37.5g of sieved magnesium stearate, and then when a homogeneous mixture was obtained, the remaining mixture was added.

The final mixture is pressed.

Example 7: vitamin D of example 1B₃Stability of + RAMEB complexes

Vitamin D was tested as in example 1B₃The stability of the + RAMEB complex at 40 ℃/75% RH was compared to the following: 1) pure vitamin D₃2) vitamin D in powder form₃The concentrate (DSM) of (1).

The study was carried out in sealed glass ampoules (pill) containers (stopper of antibiotic type, chlorinated butyl rubber, grey, D13-natural aluminium crown D20mm, tear open lid).

The above table shows vitamin D of the present invention₃And RAMEB are improved in stability.

Example 8: stability of the pharmaceutical composition of example 2B

The stability of the pharmaceutical composition of example 2B of the present invention in sachets was tested under various conditions of temperature and humidity.

The sachet contained a multilayer complex (paper/polyethylene/aluminium/polyethylene).

The above table shows that vitamin D contained in the sachet formulations of strontium ranelate, vitamin D and cyclodextrin of the present invention has excellent stability even under high temperature and humidity conditions (40 ℃/75% RH).

Example 9: example 2B pharmaceutical composition of (vitamin D)₃) Content uniformity

The test was performed on 10-part sachets.

The contents of each sachet were introduced into a conical flask and then 25mL of methanol was added. The mixture was stirred for 1 hour and then centrifuged at 4000 rpm for 10 minutes.

Simultaneous preparation of vitamin D in methanol₃Reference solution (concentration 1. mu.g/mL).

The test solutions were analyzed using reverse phase liquid chromatography techniques and detected by UV spectrophotometry.

Vitamin D from the ith sachet₃Content X_iIs calculated as follows:

X_i＝AT_i/AR

wherein AT_iIs vitamin D in the ith sachet₃The peak area of (a) is,

and AR is vitamin D in the chromatogram of the reference solution₃Peak area of (a).

Average content X_mAs follows:

X_m＝(∑X_i)/10

the Acceptance Value (AV) expressed as a percentage of the theoretical value is given by the following formula:

AV＝(M-X_m)+kxs

wherein:

X_mis the average content, expressed as a percentage of the theoretical value;

m is a reference value, expressed as a percentage of the theoretical value: if X is_mIf < 98.5, M is 98.5; if 98.5. ltoreq.X_mLess than or equal to 101.5, then M ═ X_m(ii) a If X is_mIf > 101.5, M is 101.5;

k is the acceptance constant (for 10 sachets, k is 2.4);

s is a content value X_iStandard deviation of (2).

As a result:

content uniformity parameter (vitamin D)3)	Batch L0027602 (sachet) of example 2B
		Average content	94.4％
Coefficient of variation	2.3％
		Acceptance Value (AV)	9.4

An acceptance value of less than 15 means that the content uniformity satisfies the requirements (grade L1) according to the european pharmacopoeia, item 2.9.40.

Thus, the above table shows that the sachet formulations of strontium ranelate, vitamin D and cyclodextrin of the present invention contain vitamin D with a content uniformity that meets regulatory requirements.

Claims (13)

1. A pharmaceutical composition comprising a strontium salt and vitamin D as active ingredients, and cyclodextrin as excipient, together with one or more other inert, non-toxic pharmaceutically acceptable excipients or carriers.

2. The pharmaceutical composition of claim 1, wherein vitamin D is cholecalciferol (vitamin D)₃)。

3. The pharmaceutical composition of claim 2, wherein the vitaminBiotin D₃The dosage is 1000 IU.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the cyclodextrin is a substituted β -cyclodextrin.

5. The pharmaceutical composition of claim 4, wherein the β -cyclodextrin is substituted with one or more methyl, hydroxypropyl, or sulfobutyl ether groups.

6. The pharmaceutical composition of claim 5, wherein the substituted β -cyclodextrin is selected from the group consisting of HPBCD (hydroxypropyl- β -cyclodextrin), SBECD (sulfobutylether β -cyclodextrin), and methylated or partially methylated β -cyclodextrin.

7. The pharmaceutical composition of claim 6, wherein the substituted β -cyclodextrin is RAMEB.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the weight ratio between the amount of vitamin D and the amount of cyclodextrin is between 1/40 and 1/800, inclusive.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the strontium salt is selected from the group consisting of strontium ranelate, strontium malonate, strontium acetate, strontium L-ascorbate, strontium aspartate, strontium borate, strontium camphorate, strontium carbonate, strontium ketoglutarate, strontium citrate, strontium ethanesulfonate, strontium formate, strontium fumarate, strontium gluconate, strontium glutamate, strontium hydrogen phosphate, strontium lactate, strontium L-malate, strontium maleate, strontium methanesulfonate, strontium nitrate, strontium oxalate, strontium phosphate, strontium propanesulfonate, strontium succinate, strontium sulfate, strontium tartrate and hydrates thereof.

10. The pharmaceutical composition of any one of claims 1 to 9, which is in the form of a granule of a swallowed tablet, a chewed tablet, an effervescent tablet, a dispersible tablet or a sachet.

11. The pharmaceutical composition of claim 9, wherein the strontium salt is strontium ranelate.

12. The pharmaceutical composition of claim 11, which is in the form of a particulate sachet.

13. The pharmaceutical composition according to any one of claims 1 to 12 for use in the treatment of bone diseases or joint diseases.