Non-deliquescent formulation comprising or consisting of sodium valproate and cyclodextrin having a molar ratio of sodium valproate to cyclodextrin within the range of from 1:0.01 to 1:0.09.

The present invention relates to solid pharmaceutical formulations of
 non-deliquescent compositions of sodium valproate with cyclodextrins.
 These formulations arc characterized by a high valproate content and by
 having improved technological properties like enhanced flowing, better
 tablettability and higher stability to moisture. The invention further
 describes improved granulation and tabletting processes.
 BACKGROUND OF THE INVENTION
 Valproate is a broad spectrum antiepileptic and anticonvulsive agent.
 Valproic acid is liquid at room temperature and thus not suitable for
 manufacturing of solid dosage forms, e.g., tablets for oral
 administration. Sodium valproate is solid, but an extremely hygroscopic,
 deliquescent substance. It absorbs water from the atmosphere already
 during tabletting, resulting in problems of tablet production, like
 sticking to the punches.
 A valproic cid-sodium valproate 1:1 complex (divalproex sodium) is
 described in U.S. Pat. No. 5,212,326 and WO 96/23491. It is a solid at
 room temperature and is described to be nonhygroscopic.
 To eliminate the extreme tendency to deliquescence, various methods have
 been recommended. One possibility is the hydrophobic coating of the
 tablets (Yamatogi, Yasuko; Yokhinaga, Harimi; Oka, Eiji; Ohtahara,
 Shunsuke; Yamashita, Syoichi; Furuno, Katsushi; Gomita, Yutaka, Psychiatry
 Clin. Neurosci. (1995), 49(3), S245-S247 (Chem. Abstr.:23:217657)).
 Another way is to use the prodrug of valproic acid, valpromide, a primary
 amide of valproic acid, which is a solid, neutral, non-hygroscopic
 material having several pharmaceutical advantages over valproic acid or
 sodium valproate (Bialer, Meir, Trends, Med. Chem. '90, Proc. Int. Symp.
 Med, Chem., 11.sup.th (1992), 337-81. Editor(s): Sarel, Shalom; Mechoulam,
 Raphael; Agranat, Israel. Publisher:Blackwell, Oxford, UK.)
 It has been found by the inventors that granulation of sodium valproate
 leads to a water content of more than 2%. This results in extreme
 technical problems of further processing the granules, e.g., in order to
 produce the compression mass and to tablet the mass. Problems are sticking
 to the punches and an increase of rejection force of the lower punch,
 stopping the tabletting machine. A too dry compression mass leads to
 capping of the tablets while sticking is reduced. That means when sodium
 valproate is granulated with, e.g.,. lactose, the absolute humidity of the
 compression mass should not be above 2% to be successfully tabletted after
 granulation. To enable production, usually high technical efforts have to
 be made and expensive equipment is necessary, like air conditioning to low
 relative moisture.
 It is further known that inclusion complex formation with cyclodextrins can
 suppress the deliquescence of sodium valproate (JP 56133236). The
 effective molar ratio of sodium valproate/cyclodextrin complex is claimed
 to be in the range of 1:0.1 to 1:2. This is, however, technically not
 feasible because the daily dose of valproate is 2 g, i.e., to this dose
 1.4 g to 28 g .beta.-cyclodextrin would be necessary, which--taking into
 account the further inevitable tablet ingredients, like binding, gliding,
 disintegrating additives would result in unacceptable large tablets.
 The object of the invention is to provide solid formulations of sodium
 valproate with increased stability to deliquescence, to pharmaceutical
 formulations with high sodium valproate content and to processes with
 improved technical handling features to prepare the same.
 According to the present invention, it has surprisingly been found that
 cyclodextrins are effective in decreasing the deliquescence of sodium
 valproate, by forming a composition of sodium valproate with cyclodextrin
 at a molar ratio of 1:0.01 to 1:0.09, preferably at a molar ratio of
 1:0.02 to 1:0.05. In this case, only one cyclodextlin molecule to about
 25-50 valproate molecules is necessary to prevent the deliquescence of the
 drug. This amount of cyclodextrin is not enough to clathrate the drug. The
 inclusion complex formation is practically not detectable, and the
 cyclodextrin behaves as an unusual antideliquescence carrier in the solid
 dispersion.
 According to the present invention, the first three members of cyclodextrin
 homologues, that is .alpha.-, .beta.-or y-cyclodextrin can be used.
 In the embodiments of the present invention, the solvent evaporation method
 is applied, preferably with water. The use of any other solvent of sodium
 valproate (e.g., ethanol, dimethyl sulfoxide) is limited because
 particular attention has to be devoted to the removal of the residual
 solvent that may be toxic and environmental polluting at the production.
 Generally, their presence is not tolerated in the finished product. As
 cyclodextrins form inclusion complexes with most of these solvents, the
 removal of last traces might be difficult.
 The solid dispersion according to the invention can be prepared by the
 following methods:
 Solution method:
 Sodium valproate and a water soluble cyclodextrin are dissolved in water.
 The solution is stirred thoroughly and water is removed by evaporation or
 freeze drying or spray drying to obtain the solid dispersion.
 Suspension method:
 Sodium valproate is dissolved in water and .beta.-cyclodextrin is suspended
 in the valproate solution. The solid dispersion is obtained by freeze
 drying or spray drying.
 Kneading method:
 The components are well mixed, then wetted with water, kneaded thoroughly
 at 0-80.degree. C. and dried in an oven at 40-110.degree. C. It has
 further been found that the solid dispersion of the invention has improved
 technological properties, showing enhanced flowability, tabletability and
 stability to moisture. Especially with respect to the stability to
 moisture, the solid dispersion shows features that enable a granulation
 and tabletting process with an absolute moisture content of about 3-5%.
 The advantage of the present invention is that using cyclodextrins, in far
 less than the stoichiometric ratio (i.e., without formation of inclusion
 complex) the obtained product is non-deliquescent and has improved
 handling and processing characteristics. Sodium valproate itself can only
 be tabletted, if air conditioning to low relative humidity and/or anti
 adhesive coating of the punches and other expensive and non standard
 measures during routine tablet production are applied, because of the poor
 flowing and high sticking to the tabletting machine of the tabletting
 masses with a high concentration of the active ingredient. Using as low as
 10-40 weight percent .beta.-cyclodextrin (equivalent to 1:0.01 to 1:0.09
 drug to cyclodextrin molar ratio) the product has improved flowing and
 ejection properties, even in the presence of 3-5% of loss drying of the
 compression mass.
 In contrast to complexes formed by equimolar amounts of sodium valproate
 and cyclodextrin dosage forms can be prepared having a sodium valproate
 content of 50 to 90% by weight. Usually single dose tablets contain 300 to
 600 mg sodium valproate. According to the invention, tablets having a
 total weight of 500 to 950 mg can be prepared. Moreover, the solid
 dispersion is also suitable for direct tabletting.
 The granulation process can be done by standard methods, e.g., fluid bed or
 wet granulation. The solid dispersion will granulate together with usual
 excipients like polyvinylpyrrolidone, silicon dioxide, cellulose esters,
 cyclodextrins, etc. The granulate will be further processed to tablets by
 employing usual techniques, and may also contain cyclodextrin as further
 excipient. The tablets may further be enteric coated.
 The solid dispersion can further be used for the preparation of sustained
 release compositions. The sustained release compositions can be obtained
 with hydrogel matrices like HPMC, alginic acid, and/or salts thereof,
 and/or polyacrylates such as Eudragit.RTM. and may, in addition, contain a
 pharmaceutically acceptable organic acid such as citric acid, tartaric
 acid or succinic acid or salts of these acids.
 The following examples are presented to further illustrate the present
 invention.

EXAMPLE 1
 166 g (1 mole) sodium valproate and 60 g (moisture content 14%, 0.045 mole)
 .beta.-cyclodextrin are blended and 30 mL water is added. The ingredients
 are thoroughly kneaded in a laboratory mortar. The cream-like product is
 dried at 60.degree. C. under vacuum. 202.3 g product is obtained by
 grinding. (The weight ratio of the drug to cyclodextrin is 1:0.31.) One
 gram of the dried product is placed into a Petri dish and stored for 24
 hours at 40.degree. C. under 75% relative humidity. The moisture
 absorption measured by the weight-increase was found to be 48%, compared
 to 70% of sodium valproate itself. After storage, the product looks wet
 but not liquified, while sodium valproate itself or the product obtained,
 in a similar way with lactose instead of .beta.-cyclodextrin, are
 liquified.
 EXAMPLE 2
 166 g (1 mole) sodium valproate and 120 g (moisture content 14%, 0.09 mole)
 .beta.-cyclodextrin are blended and 60 mL water is added. The ingredients
 are thoroughly kneaded and the product is obtained by drying and grinding
 as described in Example 1. (The weight ratio of the drug to cyclodextrin
 is 1:0.62) The moisture absorption after 24 hour storage at 40.degree. C.
 under 75% relative humidity was found to be 36%, compared to 70% and 47%
 of sodium valproate itself and of the product obtained in a similar way
 with lactose instead of .beta.-cyclodextrin, respectively. The latter two
 were liquified.
 EXAMPLE 3
 166 g (1 mole) sodium valproate and 90 g (moisture content&lt;5%, 0.09 mole) a
 .alpha.-cyclodextrin are blended and 20 mL water is added. The ingredients
 are thoroughly kneaded, and the product is obtained by drying and grinding
 as described in Example 1. The moisture absorption after 24 hour storage
 at 40.degree. C. under 75% relative humidity was found to be 43%, compared
 to 70% and 47% of sodium valproate itself and of the product obtained in a
 similar way with lactose instead of a .alpha.-cyclodextrin, respectively.
 The latter two were liquified.
 EXAMPLE 4
 166 g (1 mole) sodium valproate and 120 g (moisture content&lt;5%, 0.09 mole)
 .gamma.-cyclodextrin are blended and 20 mL water is added. The ingredients
 are thoroughly kneaded and the product is obtained by drying and grinding
 as described in Example 1. The moisture absorption after 24 hour storage
 at 40.degree. C. under 75% relative humidity was found to be 30%, compared
 to 70% and 47% of sodium valproate itself and of the product obtained in a
 similar way with lactose instead of .gamma.-cyclodextrin, respectively.
 EXAMPLE 5
 166 g (1 mole) sodium valproate and 60 g (moisture content 14%, 0.045 mole)
 .beta.-cyclodextrin are blended and 300 mL water is added. The ingredients
 are thoroughly mixed. The 212 g product is obtained by freeze drying. The
 moisture absorption after 24 hour storage at 40.degree. C. under 75%
 relative humidity was found to be 45%, compared to 70% and 56% of sodium
 valproate itself and of the product obtained in a similar way with lactose
 instead of .beta.-cyclodextrin, respectively.
 EXAMPLE 6
 Tablets of 10 mm diameter and 0.5 g weight are compressed from the products
 obtained by Example 1 by direct compression without further tabletting
 ingredients. The flowing properties as well as the compressibility of the
 product were much better than those of the physical mixture of sodium
 valproate and .beta.-cyclodextrin. The tablets were stored at 40.degree.
 C. under 75% relative humidity. The moisture absorption of tablets of
 sodium valproate/.beta.-cyclodextrin kneaded product, physical mixture and
 of the product obtained by kneading with lactose instead of
 .beta.-cyclodextrin after 24 hour storage was found to be 32.9, 36.3 and
 52%, respectively, the last one was liquified.
 EXAMPLE 7
 3 kg sodium valproate, 0.834 kg .beta.-cyclodextrin and 0.066 kg Kollidon
 were granulated in a fluid bed granulator. Further, the granulate was
 mixed with 0,32 kg microcrystalline cellulose, 0.65 kg lactose, 0.025 kg
 silicium dioxide and magnesium stearate and compressed to tablets. The
 tablets were enteric coated.
 EXAMPLE 8
 3 kg sodium valproate, 0.4 kg .beta.-cyclodextrin and 0.07 kg Kollidon were
 granulated as described above. The granulate was mixed with 0.32 kg
 microcrystalline cellulose, 0,3 kg lactose, 0.025 kg silicium dioxide, 0.5
 kg .beta.-cyclodextrin and magnesium stearate and compressed to tablets.
 The tablets were then enteric coated.
 EXAMPLE 9
 3 kg sodium valproate, 1 kg .beta.-cyclodextrin, 2 kg Metolose 90 SM
 100000, 1,15 kg anhydracitric acid and 0,4 kg Kollidon were granulated in
 a fluid bed granulator. The granulate will be compressed together with
 magnesium stearate and finally film coated.