Modified Release Formulations of Emoxypine

(19) &

(11) EP 2 241 310 A2

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 20.10.2010 Bulletin 2010/42 A61K 9/20 (2006.01) A61K 31/44 (2006.01) A61K 9/28 (2006.01) A61K 9/28 (2006.01) (21) Application number: 10160217.5

(22) Date of filing: 16.04.2010

(84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Toksöz, Ahmet HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL 34398, Istanbul (TR) PT RO SE SI SK SM TR • Cifter, Ümit Designated Extension States: 34398, Istanbul (TR) AL BA ME RS • Türkyilmaz, Ali 34398, Istanbul (TR) (30) Priority: 17.04.2009 TR 200903013 28.05.2009 TR 200904159 (74) Representative: Sevinç, Erkan Istanbul Patent & Trademark Consultancy Ltd. (71) Applicant: Sanovel Ilac Sanayi ve Ticaret A.S. Plaza-33, Büyükdere cad. No: 33/16 34398 Istanbul (TR) Sisli 34381 Istanbul (TR)

(54) Modified release formulations of emoxypine

(57) The present invention is related to a modifed a rate controlling polymer, with at least one pharmaceu- release pharmaceutical formulations comprising emox- tically acceptable excipient. ypine or a pharmaceutically acceptable salt thereof and EP 2 241 310 A2

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 241 310 A2 2

Description ing intraocular hemorrhage, myopic chorioretinal dystrophies, congenital retinal dystrophies, retinal burns and Technical Aspect prevention of injury in lasercoagulation. [0007] A conventional tablet formulation of emoxypine [0001] The present invention is related to modifed re- 5 succinate (Mexidol ®) is described in PCT application WO lease pharmaceutical formulations comprising emox- 96/02238 A1, Aktsionernoe Obschestvo Zakrytogo Tipa ypine or a pharmaceutically acceptable salt thereof and ’Olvik’, 15.07.1994. The proposed neurotropic and sed- a rate controlling polymer, with at least one pharmaceu- ative formulation contains emoxypine and auxiliary tically acceptable excipient. agents in core and a coating layer. The auxiliary agents 10 in the core comprise kaolin, potato starch, calcium stea- Background of the Invention rate, stearic acid, talc and methyl cellulose. The coating layer contains titanium dioxide and serge 80. [0002] Emoxypine is a heteroaromatic antioxidant [0008] It is desirable in the treatment of a number of which has a membranoprotective, nootropic and seda- diseases, to provide the active pharmaceutical ingredient tive action. Its aromatic activity range is very wide such 15 ina modified release form. Desirably the modified release as increasing the stress resistance of organism. It acts provides a generally uniform and constant rate of release as the anxiolytic which doesn’t cause the sleepiness and over a modified period of time which achieves desired myorelaxant effect; its nootropic properties allow to pre- plasma level of the active ingredient without the need for vent and reduce learning and memory defects in patients frequent administration of the medicament. of old age under pathogenic factors. One of the activities 20 [0009] Accordingly, a need rises for modified release of emoxypine is its anticonvulsant action which shows formulations of emoxypine or pharmaceutically accept- antioxidant and antihypoxic properties. It increases the able salt, which overcomes the above described prob- attention concentration and capacity for work and de- lems and minimizes the adverse effects and provides a creases the alcohol toxic affect. It inhibits peroxide oxi- comperable drug plasma concentration which is equiva- dation of lipids, increases the superoxidoxidase activity 25 lent to or better than the immediate release tablet or in- and elevates the ratio of lipid-protein. Also, provides a jectable formulations currently used. The formulation of higher dopamine concentration in brain. this invention represents a novel modified release formu- [0003] Its chemical name is ethyl- 2- 6-methyl-3-hy- lation previously undisclosed in the prior art. droxypyridine and its chemical structure is shown in the [0010] The modified relase formulation of this inven- Formula I. 30 tion further provides the advantageous property of allow- ing the active medicament to be administered less frequently, e.g. once-a-day or twice-a- day, while achieving comparable plasma levels to immediate release forms.

35 Description of the invention

[0011] The main embodiment of the present invention is to provide a novel modified release formulation comprising emoxypine or a pharmaceutically acceptable salt 40 thereof and a rate controlling polymer, with at least one pharmaceutically acceptable excipient which overcomes the above described problems in prior art and have an additive advantages over them. [0004] Emoxypine is marketed under the brand name [0012] "Modified release dosage forms" are defined as MEXIDOL® and it is administered orally in a therapeutic 45 those whose drug release characteristics of time course dose from 125 mg to 250 mg, three times a day and it and/or location are chosen to accomplish therapeutic or has injectable formulations containing 50mg/ml in 2 ml convenience objectives not offered by conventional and 5ml ampules in IV/IM forms. forms. A modified release dosage form potentially pro- [0005] In prior art, emoxypine is widely used as inject- vides greater effectiveness in the treatment of chronic able preparations but it can not provide enough nootropic 50 conditions; greater convenience; reduces side effects activity over a prolonged period in enjectable prepara- and provides higher levels of patient compliance or ther- tions. It has to be used in higher dosage ranges and long- apeutic performance due to a simplified dosage sched- er time periods such as between 30 to 95 days which is ule, compared with those of immediate-release drugs. not very suitable for the patient compliance and for the Modified release pharmaceutical products are formulat- therapeutic activity ranges of emoxypine. 55 ed to release the drug’s active ingredient gradually and [0006] US patent no 4,486,440 in 17.08.1983, disclos- predictably over a 12-hour to 24-hour period. es injectable solutions and drops containing 1% of emox- [0013] The USP (United States Pharmacopeia) con- ypine HCl by weight. It is used as retinoprotector for treat- siders that the terms controlled release; prolonged re-

2 3 EP 2 241 310 A2 4 lease extended release and sustained release is inter- tion. Preferably, the amount of rate controlling polymer changeable with modified release. Accordingly, the is from about 5.0% to about 70.0% by weight of the for- terms "modified-release", controlled-release", "prolon- mulation. Most preferably, the amont of the rate control- ged-release", "extended-release", and "sustained-re- ling polymer is from about 10.0% to about 60.0% by lease" are used interchangeably herein. 5 weight of the formulation. [0014] One of the advantages of modified release for- [0020] According to another embodiment of this inven- mulation of this invention for the outpatient is reduced tion, the modified release formulation comprises emox- dosage regimens convenience and, more importantly, ypine or a pharmaceutically acceptable salt in an amount better assurance of compliance. For example, the reduc- of about 1.0% to 80.0% by weight of total formulation, tion of a dose regimen from four times a day to three10 preferably about 20.0% to 75.0% by wieght, the most times a day allows the patient to take the prescribed drug preferably about 45.0% to 70.0% by weight. Emoxypine during waking hours. Reduction of a dose regimen to is preferably in the form of succinate or HCl salt. twice a day allows the patient to take the prescribed drug [0021] In a further aspect, the present invention relates in the morning and in the evening, which provides greater to the modified release formulations comprising emox- convenience; e.g., the patient is not required to carry an 15 ypine or a pharmaceutically acceptable salt thereof, in additional one when away from home. Of course, the an amount of 1 mg to 1000mg. Preferably 50 mg to 800 most convenient dosage form is a once daily dose regi- mg, the most preferably 125 mg to 750 mg. men. This also reduces the risk of the omitted tablets. [0022] The modified release formulation of this present [0015] The other advantage of modified release for- invention is administered in the form of a once-a-day or mulations is to make the plasma concentration level sta- 20 twice-a-day dosage regimen. ble by maintaining the drug in the blood stream for a [0023] It has surprisingly found that in this modified longer time period. In this manner, the formulation of this release formulation having a weight ratio of emoxypine invention is designed as modified release to prevent the or a pharmaceutically acceptable salt to rate controlling changes in drug plasma concentration levels and can be polymer between the ranges of about 1:10 to 10: 1 (w/w) administered only once ortwice a day for drugs thatwould 25 has a synergistic effect over the dissolution rate. otherwise have to be taken more frequently to maintain [0024] Another advantageof this invention isto provide required blood levels. Also modified release oral dosage a modified release formulation with a rate controlling pol- forms may help to treat with reduced dosage regimens. ymer, wherein the maximum 30% of total amount of Using lower dosages of active ingredients provide great- emoxypine or a pharmaceutically acceptable salt is re- er convenience and reduced side effects and toxicity. 30 leased in 2 hours and 40-65% in 6 hours and at least [0016] Another advantage of this modified release for- 85% between in a period of 16 to 20 hours. mulations of this invention is to prevent dose dumping. [0025] Rate controlling polymers can be used to form Dose dumping is one of the most important disadvantag- a matrix in which an active substance is dispersed, the es of modified release dosage forms. Because of several properties of the polymer are then utilised control the rate different reasons it is difficult to develop modified release 35 at which the active is released from the formulation. The formulations of highly soluble pharmaceuticals although rate controlling polymers of this invention, are selected there are many modified release formulations formulated from the group comprising cellulosic polymers, polyvi- with rate controlling polymers. First of all, modified re- nylpyrrolidine, polyethylene oxide, glyceryl behenate, vi- lease formulations of highly soluble medicaments can be nyl acetate/crotonic acid copolymers, maleic anhydride/ prone to "dose dumping" in which the release of the active 40 methyl vinyl ether copolymers, copolymer of acrylic and ingredient is delayed but once the release begins the methacrylic acid esters, shellac, waxes, zein and the like medicament is released very fast. The most important and mixtures thereof and alginate salts and complex salt criteria of dose dumping under in-vitro conditions, is the of alginic acid. amount of the active substance released in early time [0026] According to this invention, the preferred cellu- point. 45 losic polymers are selected from the group comprising [0017] It is also hard to achieve the desired dissolution hydroxypropylmethyl cellulose, hydroxypropyl cellulose, profiles in other words the control of the release rate is low-substituted hydroxylpropyl cellulose, hydroxyethyl difficult. Therefore, fluctuation of the active ingredient cellulose, ethyl cellulose, methyl cellulose, sodium car- concentration in the plasma may occur which may lead boxy methyl cellulose, cellulose acetatebutyrate and the to toxicity. Also, diurnal variation of the active ingredient 50 like and mixtures thereof. in plasma is also possible. [0027] The cellulosic polymer is preferably hydroxy- [0018] As used here in, ’rate controlling polymer’ propyl methylcellulose. The amount of hydroxypropyl means an excipient in the final dosage form whose pri- methylcellulose is present about 1.0 to 80.0% by weight mary function is to modify the duration of release of the of total formulation, particularly about 10.0% to 60.0%, active drug substance from the dosage form. 55 more particularly about 20.0% to 50.0% by weight. [0019] In one of the embodiments, the amount of the [0028] The amount of rate controlling polymer, hydrox- rate controlling polymer in the formulation generally var- ypropyl methylcellulose is preferably adjusted to provide ies from about 1.0% to 80.0% by weight of the formula- a release of maximum 30% of the total amount of emox-

3 5 EP 2 241 310 A2 6 ypine or a pharmaceutically acceptable salt in 2 hours thereof; preferably sodium stearyl fumarate, magnesium and 40-65% in 6 hours and at least 85% between in a stearate and stearic acid. period of 16 to 20 hours. [0041] Suitable glidants may include but not limited to [0029] The cellulosic polymer is preferably ethyl cellu- colloidal silicon dioxide, talc, aluminium silicate and the lose. The amount of ethyl cellulose is present about 1.0 5 like and mixtures thereof; preferably colloidal silicon di- to 40.0 % by weight of total formulation, particularly about oxide. 1.0 to 20.0%. [0042] Suitable preservatives may include but not lim- [0030] The amount of rate controlling polymer, ethyl ited to methyl paraben, propyl paraben, sodium ben- cellulose is preferably selected to provide a release of zoate, citric acid and benzoic acid and the like and mix- maximum 30% of the total amount of emoxypine or a10 tures thereof; preferably citric acid. pharmaceutically acceptable salt in 2 hours and 40-65% [0043] These modified release pharmaceutical formu- in 6 hours and at least 85% between in a period of 16 to lations of this invention, are administrated by oral, 20 hours. parenteral, intramuscular or topical route. The modified [0031] The rate controlling polymer is preferably algi- release pharmaceutical formulations of this invention in- nate salt which is selected from the group comprising 15 clude tablet, capsule, sachet, microcapsules, minitablet, sodium alginate, calcium alginate, potassium alginate, multilayer and multicoated tablet, pellet, injectable prep- propylene glycol alginate, and the like and mixtures aration, suspension, syrup, gel, cream or ointment which thereof. can be formulated in accordance with methods that are [0032] The alginate salt is preferably sodium alginate. standard in the art. It is preferably in the form of tablets The amount of sodium alginate is about 1.0 to 20.0% by 20 or capsules. weight of total formulation. [0044] The formulations of the present invention may [0033] The amount of rate controlling polymer, sodium be prepared by conventional technology well known to alginate is preferably selected to provide a release of those skilled in the art such as wet granulation, direct maximum 30% of the total amount of emoxypine or a compression, dry granulation and the like. Thus, for in- pharmaceutically acceptable salt in 2 hours and 40-65% 25 stance, emoxypine, or a pharmaceutically acceptable in 6 hours and at least 85% between in a period of 16 to salt thereof, a rate controlling polymer and other excipi- 20 hours. ents are mixed together to form the modified release for- [0034] The rate controlling polymer is preferably the mulations. The prepared mixture is filled into capsules or complex salt of alginic acid which is sodium-calcium al- compressed to form tablets. ginate. The amount of sodium-calcium alginate is about 30 [0045] In another embodiment, the modified relase 1.0 to 10.0% by weight of total formulation. pharmaceutical dosage forms may comprise a coating [0035] The amount of rate controlling polymer, sodi- layer. The coating layer preferably comprises, for exam- um-calcium alginate is preferably selected to provide a ple, zein, hydroxyproply cellulose, hydroxypropyl meth- release of maximum 30% of the total amount of emox- ylcellulose, ethly cellulose, triacetin, dibutyl sebacate, ypine or a pharmaceutically acceptable salt in 2 hours 35 lactose, talc, polyethylene glycol, polyvinyl alcohol, and 40-65% in 6 hours and at least 85% between in a polysorbate, titanium dioxide, iron oxide, Food and Drug period of 16 to 20 hours. Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C [0036] The modified release formulations of this inven- green, FD&C red, FD&C yellow, FD&C lakes) and the tion further comprising at least one pharmaceutically ac- like and mixtures thereof. ceptable excipient selected from the group comprising 40 [0046] According to another embodiment of the mod- diluents, fillers, disintegrants, binders, lubricants, glid- ified relase formulations of this invention, core or coating ants and preservatives. may comprise enteric coating. [0037] Suitable diluents and fillers may include but not [0047] The enteric coating layer may comprise cellu- limited to lactose, microcrystalline cellulose, starch, talc, lose acetate phthalate, methyl acrylate-methacrylic acid mannitol, glucose, and the like and mixtures thereof; pref- 45 copolymers, cellulose acetate succinate, shellac, hy- erably lactose and starch. droxypropyl methylcellulose phthalate, hydroxypropyl [0038] Suitable disintegrants may include but not lim- methylcellulose acetate, hypromellose acetate succi- ited to microcrystalline cellulose, sodium starch glycol- nate, polyvinyl acetate phthalate, cellulose acetate late, croscarmellose sodium, crospovidone, starch and phthalate, polymethacrylates, methyl methacrylate- the like and mixtures thereof; preferably microcrystalline 50 methacrylic acid copolymers and the like and mixtures cellulose and croscarmellose sodium. thereof. [0039] Suitable binders may include but not limited to [0048] Another preferred embodiment of this invention polyvinylpyrrolidone, sucrose, polyethylene glycol and is a modified release formulation which is in the form of the like and mixtures thereof; preferably polyvinylpyrro- a tablet comprising: lidone. 55 [0040] Suitable lubricants may include but not limited (a) a core comprising the emoxypine or a pharma- to sodium stearyl fumarate, stearic acid, magnesium ceutically acceptable salt thereof and pharmaceuti- strearate, calcium stearate and the like and mixtures cally acceptable excipients,

4 7 EP 2 241 310 A2 8

(b) a coating layer comprising the rate controlling Example 1 polymer which provides slow release. [0056] The modified release formulation, comprises [0049] The manufacturing process is preferably per- about 1.0 to 80.0% by weight of emoxypine or a pharma- formed by mixing the components, wet granulating the 5 ceutically acceptable salt, about 1.0 to 80.0% by weight mixed components; the mixed components, drying the HPMC (hydroxypropyl methylcellulose), about 5.0 to mixture, milling the dried mixture, blending the mixture 60.0% by weight of lactose, about 0.50 to 20.0% by with a lubricant(s) and compressing the blended mixture weight of polyvinylpyrrolidone, about 5.0 to 60.0% by to form tablets or filling the blended mixture into capsules. weight of microcrystalline cellulose, about 0.10 to 5.0% [0050] A preferred process for preparing the modified 10 by weight of sodium stearyl fumarate, about 0.10 to 5.0% release formulations of the invention comprises the fol- by weight of colloidal silicon dioxide. lowing steps; Example 2 (a) mixing emoxypine or a pharmaceutically acceptable salt thereof and a rate controlling polymer and 15 [0057] The modified release formulation, comprises other excipients; about 1.0 to 80.0 % by weight of emoxypine or a phar- (b) wet granulating the mixed components; maceutically acceptable salt, about 1.0 to 40.0 % by (c) drying the mixture; weight ethyl cellulose, about 5.0 to 60.0% by weight of (d) milling the dried mixture; starch, about 0.50 to 20.0 % by weight of polyvinylpyrro- (e) blending the mixture with a lubricant; and 20 lidone, about 5.0 to 60.0 % by weight of crosscarmellose (f) compressing the blended mixture to form tablets, sodium, about 0.10 to 5.0 % by weight of sodium stearyl and optionally coating said tablets. fumarate, about 0.10 to 5.0 % by weight of colloidal silicon dioxide. [0051] Another embodiment of the present invention is to provide an orally administrable modified release25 Example 3 pharmaceutical dosage form comprising emoxypine and a rate controlling polymer with at least one pharmaceu- [0058] The modified release formulation, comprises tically acceptable excipient wich has a wide spectrum of about 1.0 to 80.0 % by weight of emoxypine or a phar- pharmacological activities such as membranoprotection, maceutically acceptable salt, about 1.0.to 20.0 % by neuroprotection, cardioprotection, antihypoxic, anxiolyt- 30 weight sodium alginate, about 5.0 to 60.0 % by weight ic, nootropic, antiamnestic, antiatherogenic, antistress of lactose about 0.50 to 20.0 % by weight of polyvinylpyr- and antialcoholic actions. rolidone, about 5.0 to 60.0 % by weight of microcrystalline [0052] Another action of emoxypine is seen on neuro- cellulose, about 0.10 to 5.0 % by weight of magnesium and the effective status in patients at early stages of di- stearate, about 0.10 to 5.0 % by weight of colloidal silicon abetic foot syndrome when it is used in combination with 35 dioxide and about 5.0 to 30.0 % by weight of citric acid. alpha-lipoic acid. Emoxypine also improves learning and [0059] The formulations of these examples are man- memory in hemorrhagic stroke and exerted influence on ufactured according to the process described above in the locomotor activity. the description and was tested for its dissolution profile [0053] It is also reported that emoxypine can be ad- using a USP paddle method. These tablet formulations ministered in combination with non-narcotic analgesics, 40 may comprise a coating layer and this coating layer may in particular with Pentalgin, for relieving painful syndrome comprise enteric coating. on the background of stress. Also it may be effective in combination with valproic acid (sodium valproate-Depa- kine®) for treatment of patients with generalized epilepsy Claims and as monotherapy in patients with first episode of fe- 45 brile seizures. 1. A modified release pharmaceutical formulation com- [0054] Another action of emoxypine is eliminating anx- prising emoxypine or a pharmaceutically acceptable iety and fear, recovering adequate reactions and the ori- salt thereof and a rate controlling polymer which is entative-trying behavior, and lessens aggressiveness. selected from the group comprising hydroxypropyl- [0055] This invention is further defined by reference to 50 methyl cellulose, low- substituted hydroxylpropyl cel- the following examples. Although the example is not in- lulose, ethyl cellulose, methyl cellulose, cellulose ac- tended tolimit the scopeof thepresent invention,it should etatebutyrate, polyethylene oxide, glyceryl behen- be considered in the light of the description detailed ate, vinyl acetate/crotonic acid copolymers, maleic above. It will be apparent to those skilled in the art that anhydride/methyl vinyl ether copolymers, copolymer many modifications, both to materials and methods, may 55 of acrylic and methacrylic acid esters, shellac, wax- be practiced without departing from the scope of the in- es, zein, alginate salts and complex salt of alginic vention. acid and the like and mixtures thereof with at least one pharmaceutically acceptable excipient.

5 9 EP 2 241 310 A2 10

2. The modified release pharmaceutical formulation 13. The modified release formulation according to any according to claim 1, wherein the amount of the rate preceding claims, further comprising at least one controlling polymer is from 1.0% to 80.0% by weight, pharmaceutically acceptable excipient selected preferabaly it is from 5.0 to 70.0% by weight, more from the group comprising diluents, fillers, disinte- preferably it is 10.0 to 60.0 % by weight of the for- 5 grants, binders, lubricants, glidants and preserva- mulation. tives.

3. The modified release pharmaceutical formulation 14. The modified release formulation according to any according to claim 1, wherein the rate controlling pol- preceding claims, comprising about 1.0 to 80.0% by ymer is hydroxypropyl methylcellulose. 10 weight of emoxypine or a pharmaceutically acceptable salt, about 1.0 to 80.0% by weight HPMC (hy- 4. The modified release pharmaceutical formulation droxypropyl methylcellulose), about 5.0 to 60.0% by according to claim 1, wherein the rate controlling pol- weight of lactose, about 0.50 to 20.0% by weight of ymer is ethyl cellulose. polyvinylpyrrolidone, about 5.0 to 60.0% by weight 15 of microcrystalline cellulose, about 0.10 to 5.0% by 5. The modified release pharmaceutical formulation weight of sodium stearyl fumarate, about 0.10 to according to claim 1, wherein the rate controlling pol- 5.0% by weight of colloidal silicon dioxide. ymer is alginate salts comprising sodium alginate, calcium alginate, potassium alginate, propylene gly- 15. The modified release formulation according to any col alginate and the like and mixtures thereof, pref- 20 preceding claims, comprising about 1.0 to 80.0% by erably the alginate salt is sodium alginate. weight of emoxypine or a pharmaceutically acceptable salt, about 1.0 to 40.0% by weight ethyl cellu- 6. The modified release pharmaceutical formulation lose, about 5.0 to 60.0% by weight of starch, about according to claim 1, wherein the rate controlling pol- 0.50 to 20.0% by weight of polyvinylpyrrolidone, ymer is complex salt of alginic acid, preferably the 25 about 5.0 to 60.0% by weight of crosscarmellose so- complex salt of alginic aicd is sodium-calcium algi- dium, about 0.10 to 5.0% by weight of sodium stearyl nate. fumarate, about 0.10 to 5.0% by weight of colloidal silicon dioxide 7. The modified release formulation according to claim 6, wherein the amount of sodium- calcium alginate is 30 16. The modified release formulation according to any from 1.0 to 10.0% by weight of total formulation. preceding claims, comprising about 1.0 to 80.0% by weight of emoxypine or a pharmaceutically accept- 8. The modified release formulation according to any able salt, about 1.0 to 20.0% by weight sodium algi- preceding claims, wherein the weight ratio of emox- nate, about 5.0 to 60.0% by weight of lactose about ypineto rate controlling polymer is about 1:10 to 10: 1. 35 0.50 to 20.0% by weight of polyvinylpyrrolidone, about 5.0 to 60.0 % by weight of microcrystalline 9. The modified release formulation according to cellulose, about 0.10 to 5.0% by weight of magnesi- claims 1 to 8, wherein emoxypine or a pharmaceu- um stearate, about 0.10 to 5.0 % by weight of colloi- tically acceptable salt is present in an amount of 1.0 dal silicon dioxide and about 5.0 to 30.0 % by weight to 80.0% by weight, preferably it is 20.0 to 75.0% by 40 of citric acid. weight, more preferably it is 45.0 to 70.0% by weight. 17. The modified release formulation according to 10. The modified release formulation according to claims 1 to 16, wherein emoxypine is in the form of claims 1 to 9, wherein emoxypine or a pharmaceu- a succinate salt. tically acceptable salt is in an amount of 1 mg to 1000 45 mg. 18. The modified release formulation according to claims 1 to 16, wherein emoxypine is in the form of 11. The modified release formulation according to a HCl salt. claims 1 to 10, wherein the formulation is in the form of a once-a-day or twice-a-day dosage regimen. 50 19. The modified release formulation according to any preceding claims, further comprising a coating layer. 12. The modified release formulation according to claims 1 to 11, wherein the maximum 30% of total 20. The modified release formulation according to claim amount of emoxypine or a pharmaceutically accept- 19, wherein the coating layer comprising zein, hy- able salt is released in 2 hours and 40-65% in 6 hours 55 droxyproply cellulose, hydroxypropyl methylcellu- and at least 85% between in a period of 16 to 20 lose, ethly cellulose, triacetin, dibutyl sebacate, lac- hours. tose, talc, polyethylene glycol, polyvinyl alcohol, polysorbate, titanium dioxide, iron oxide, Food and

6 11 EP 2 241 310 A2 12

Drug Cosmetic (FD&C) dyes and the like and mixtures thereof.

21. The modified release formulation according to claim 19, wherein the coating layer is preferably enteric 5 coating.

22. The modified release formulation according to claim 21, wherein the enteric coating layer comprising cellulose acetate phthalate, methyl acrylate-methacryl- 10 ic acid copolymers, cellulose acetate succinate, shellac, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, hypromellose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, polymethacrylates, me- 15 thyl methacrylate-methacrylic acid copolymers and the like and mixtures thereof.

23. The modified release formulation according to claims 19 to 22, in the form of a tablet comprising: 20

(a) a core comprising the emoxypine or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, (b) acoating layer comprising therate controlling 25 polymer which provides slow release.

24. The modified release formulation according to any preceding claim, wherein the formulation is to be administrated by orally. 30

25. The modified release formulation according to any preceding claim, wherein the formulaiton is in the form of a tablet, capsule, sachet, microcapsule, minitablet, pellet, multilayer and multicoated tablet. 35

26. A process for preparing modified release formulations according to claims 1 to 22 and 24 to 25 which comprises; 40 (a) mixing emoxypine or a pharmaceutically acceptable salt thereof and a rate controlling polymer and other excipients; (b) wet granulating the mixed components; (c) drying the mixture; 45 (d) milling the dried mixture; (e) blending the mixture with a lubricant; and (f) compressing the blended mixture to form tablets, and optionally coating said tablets. 50

7 EP 2 241 310 A2

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 4486440 A [0006] • WO 9602238 A1 [0007]