WO2011132008A2

WO2011132008A2 - Controlled release pharmaceutical composition

Info

Publication number: WO2011132008A2
Application number: PCT/HU2011/000037
Authority: WO
Inventors: Tibor KORBÉLY; Zsolt Zsigmond; György UJFALUSSY; Zoltánné PÁLFI; Zoltán Horváth; Ádám ORBÁN; Krisztina ÁBRAHÁM; Zsolt Istavánné BOKOR
Original assignee: EGIS Gyűgyszergyár Nyilvánosan Múködő Részvény társaság
Priority date: 2010-04-22
Filing date: 2011-04-21
Publication date: 2011-10-27
Also published as: WO2011132008A3

Abstract

The present invention relates to a sustained release pharmaceutical composition. Particularly, a sustained release compressed tablet which contains coated compacted granules containing the active ingredient quetiapine and further excipients. If desired, one or more coatings are on the surface of the tablet.

Description

CONTROLLED RELEASE PHARMACEUTICAI COMPOSITION

Technical field of the invention

The present invention relates to a compressed sustained release tablet containing quetiapine or pharmaceutical acceptable salts thereof which contains coated granules containing active ingredient and further accessories. The surface of the tablet is coated with one or more coatings if necessary.

The technical background of the invention

Numerous processes are known from the literature for the preparation of so called retard compositions having sustained release. From therapeutical point of view the use of retard compositions in case of use of several active ingredients is more advantageous than immediate release compositions.

Retard compositions are used in all therapeutic fields as for example in the administration of compounds for the treatment of diseases of the central nervous system, gastrointestinal tract and cardiovascular system. Using retard compositions lower maximums of blood level can be achieved than using immediate release compositions and the effective dose level remains for a longer time. In case of using retard compositions the difference between the maximum and minimum blood levels is lower during the treatment.

In case of venlafaxine, which was developed for the treatment of the central nervous system, using immediate release compositions administered twice a day the change of the blood level causes nausea and vomiting in a considerable part of the patients, meanwhile these side effects rarely occur with patients treated with retard compositions according to the patent description No. EP 797991. From the active ingredients used for the treatment of cardiovascular diseases a sustained release composition of propanolol is described in the US patent No. 4138475.

For the preparation of compositions having retard effect several technical solutions are known.

Quetiapine, having the chemical name l l-[4-[2-(2- hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo-[b,fj [l,4]thiazepine of the formula

or the pharmaceutical active salt thereof is an antipsychotic agent having antidopaminerg effect which is used for treatment and prevention of acute and chronic psychosis, maniac phase of bipolar disorders.

The film tablet Seroquel^® being on the market is a sustained release pharmaceutical composition containing quetiapine-hemifumarate. Quetiapine-hemifumarate is a white crystalline material having a melting point of 172-173°C and dissolving in water at a moderate level depending on the pH value. So called matrix tablets are used as sustained release pharmaceutical compositions in case of use of numerous active ingredients. Several patents and patent applications relate to sustained release compositions, so called matrix compositions containing quetiapine as active ingredient. The essence of these compositions is that the matrix forming excipient forms a gel in the presence of moisture and the active ingredient diffuses through the gel layer to the surface of the composition, thus the dissolution gets slower.

The European Patent No. 907364 discloses a sustained release tablet, a so called matrix tablet, which contains quetiapine or a pharmaceutically accepted salt thereof and a gelling agent. The gelling agent is hydroxypropylmethylcellulose (HPMC) preferably. According to the patent description the active ingredient and the accessories of the inner phase are granulated with a wet granulation process, then the obtained granules are dried and mixed with the external phase and the obtained mixture is compressed into tablets.

The International Patent Application No. WO 2008/060228 discloses a matrix composition containing quetiapine or a pharmaceutically accepted salt thereof which, beside the quetiapine and gelling agent (hydroxypropylmethylcellulose), contains also sodium citrate dihydrate. The European patent application No. 1 689 367 discloses a matrix composition which, beside the quetiapine or salts thereof, contains a waxy compound. This document also discloses compositions in which quetiapine particles are coated and these coated particles are formed into a pharmaceutical composition. According to the description it can be realized only by using particles having suitable geometry. In case of the use of needle crystals or particles having sharp edges the coating layer is not uniform on the surface of particles which impairs the reproducibility. Thus, the retard effect of the individual tablets can show a large deviation. According to the application the taste covering effect of these compositions is also unacceptable. The International Patent Application No. WO 2008/090569 discloses a modified release pharmaceutical composition which contains an active ingredient having pH dependent dissolution properties, a dissolution controlling polymer and a dissolution controlling system which contains at least one in-situ gelling agent, at least one compound helping the gelling process and optionally contains at least one retardizer polymer having pH independent dissolution properties. The International Patent Application No. WO 2008/110337 discloses a pharmaceutical composition which contains quetiapine or a pharmaceutically acceptable salt thereof, a mixture of polyvinylacetate and polyvinylpyrrolidine in a ratio of 5:2-10:2 and optionally an organic acid.

In the description of the International Patent Application No. WO2009/113051 non-gelling agents are used for the preparation of sustained release pharmaceutical compositions. According to one embodiment the active ingredient and certain accessories are granulated with the solution of non-gelling polymer, thus the active ingredient is included in a matrix structure from which the active ingredient is dissolved in a regulated manner via the slow erosion of the matrix. According to the other embodiment, the immediate release tablet core is coated which a coating which decreases the dissolution rate. The third embodiment is the combination of the two principles.

There are some solutions known from the prior art for controlling the dissolution of active ingredients where gelling agents are used. These compounds tend to absorb the humidity during the shelf life and facilitate the degradation of the active ingredient.

This is indicated by the fact that the marketed tablet containing quetiapine hemifumarate is not only covered by a coating but a special waterproof finishing material, PVC+PCTFE/Alu blisterfoil also protects the tablet from the absorption of humidity. Contrary to this fact, the maximum storage temperature of the composition is 30°C. This implies that the composition can be sensitive for physical and chemical changes.

In case of using a non-gelling polymer as matrix forming agent, as it is disclosed for example in the International Patent Application No. WO2009/113051, the remained humidity of the composition resulted by the wet granulation process or the heat stress caused by the elimination of the solvent of the granulation mixture can facilitate the degradation of the active ingredient. Consequently, there is a need for a modified release system which provides an appropriate physical and chemical stability and also an optimal blood level in case of active ingredients or pharmaceutically accepted salts thereof having a strongly pH dependent solubility such as quetiapine, even in case of a once-a-day administration.

SUMMARY OF THE INVENTION

Our aim was the development of modified release pharmaceutical compositions complying with the required blood level of an active ingredient in case of a once-a-day administration and providing an appropriate physical and chemical stability until the expiry date of the composition. The once-a-day therapy compared with the twice-a- day therapy saves the patient the side effects caused by significant fluctuations of the blood level, improves the compliance of patients which is a very important point of view in case of psychotic patients. For providing the appropriate chemical and physical stability we avoid to use wet granulation processes. A further aim of our invention is to prepare such compositions which do not require an external coating providing the sustained release.

Accordingly, the difference of dissolution rates among tablets caused by the statistical difference of film-coatings thereof can not be developed

Our further aim was to prepare a tablet which can be dispensed without a significant change of the dissolution profile. DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is a controlled release tabletted pharmaceutical composition, which comprises granules coated with a non-gelling polymer having pH dependent solubility or with a mixture of a non-gelling polymer having pH dependent solubility and a non-gelling polymer having pH independent solubility, which modify the dissolution of active ingredient and comprise quetiapine or a pharmaceutically accepted salt . thereof and a mixture of pharmaceutically accepted excipients as the inner phase and further pharmaceutically accepted excipient(s) as the external phase. More particularly, the used granules of the composition of the present invention are so called dry granules. Using dry granulation process granules containing only the active ingredient can also be prepared. The dry granules according to the present invention are prepared by compaction or briquetting processes without using any solvent or water.

According to one embodiment of the present invention the coated granules comprise besides the active ingredient or pharmaceutically accepted salts thereof an osmotic compound, if necessary. The tablet according to the present invention comprises as the external phase such water soluble additives which control the dissolution of the active ingredient situated in the inner phase.

The pharmaceutical composition according to the present invention contains quetiapine or a pharmaceutically acceptable salt thereof, most preferably quetiapine hemifumarate. According to a preferable embodiment of the present invention the tablet does not have an external coating. According to an other embodiment of the present invention the tablet is coated with one or more coatings which do not sustain the release of the active ingredient. The tablets according to the present invention without coating or with coating(s) which do not sustain the release of the active ingredient can be applied incision(s) for dispensation of the tablets, preferably for bisection or quartation of the tablets.

We found surprisingly that the granules prepared by a compaction or briquetting process can be coated with the sustained release polymers according to the present invention, which results in a well reproducible active ingredient dissolution profile, even if these granules have an irregular shape and size. A further surprising recognition of the present invention is that the dissolution of the active ingredient can be modified if necessary with the proportion of the external phase and the solubility and osmotic properties thereof. A surprising nature of the composition according to the present invention is that it provides appropriate taste masking and stability properties without necessity of a coating layer on the surface of tablets.

The complex controlling system which provides an optimal dissolution of the active ingredient from the composition has an important role in the technical solution of the present invention. This controlling system comprises three parts: a) a dry granulated inner phase that has a pH controlling component if necessary, which provides an appropriate micro environment for the active ingredient dissolving at a progressively lower rate if the pH values are higher, both in the stomach at an acidic and in the intestinal tract at a softly basic pH, and in case of need it contains also an osmotic component;

b) a polymer or a polymer mixture coating on the surface of the granules which comprises a polymer having pH dependent solubility or a mixture of polymers of a polymer having pH dependent solubility and a polymer having pH independent solubility and controlled permeability and if desired a pore forming agent;

c) water soluble excipients in the external phase which are mixed to the coated dry granules.

In the course of our experiments we found surprisingly that the presence of organic or inorganic salts or acid salts in the external phase influences the dissolution significantly. In Figure 2 we show that by means of the partial change of non-ionic filling agents to ionic filling agents the dissolution can by modified significantly. Decreasing the water solubility of used ionic compounds the dissolution rate increases significantly. Even more surprising, as shown in Figure 2, that the appropriate change of the salts and acid salts can modify the slope of the dissolution curve. In this Figure the compound prepared according to Example 3.3 and containing 30% of lactose in its external phase is compared with the tablets according to Examples 3.4, 3.5 and 3.6 in which the lactose was partly changed with ionic compounds:

In addition to the above constituents the dissolution profile of the composition is controlled by the solubility of the excipients mentioned in point c.) above; the quantitative ratio of these agents compared with the inner phase and the used compressing force. The increase of the pressing force decreases the dissolution rate. The suitable pressing force depends also from the used apparatus. Optimizing the suitable pressing force is the duty of the person skilled in the art.

The decrease of the rate of the external phase also results in the decrease of the dissolution rate which is demonstrated in Figure 1. The external phase/tablet weight ratios of the Figure are shown in the following table:

Example The external phase/tablet weight

ratios [%]

2.3 Example 46%

2.4 Example 36%

2.5 Example 22,7%

We found surprisingly that if the tablet according to the present invention is bisected, the dissolution profile of the two half tablets remained similar. According to the literature two compositions have a similar dissolution profile if the similarity factor of compared tablets is (f₂) >50 (Shah, V.P. et al., Pharm. Res. 1998, 15, 889- 896.). On the Figure 4 we show that we examined as a whole and also in bisected form the dissolution of tablets prepared according to Example 7.3 containing 400 mg active ingredients (example 8). Comparing the two dissolution profiles the similarity factor is 50, which means that the bisection did not influence the dissolution significantly.

The excipients for the preparation of the composition of the present invention are as follows:

The dry granulated inner phase can contain besides the active ingredient or the pharmaceutically accepted salts thereof anti- adhesive and lubricant agents. Such agents can be the colloidal silica, magnesium stearate, potassium stearate, talcum, sodium stearyl fumarate and the like, preferably colloidal silica and magnesium stearate or a mixture thereof. The combined weight related to the weight of the composition is 0.1-5 %, preferably 0.5-3 % in the composition according to the present invention.

The inner phase can contain as filling agent non-gelling, compressible compounds capable of evolving binding forces, such as microcrystalline cellulose, lactose, potassium phosphate, sodium chloride etc.. The weight of excipients used in the inner phase is 0.5- 40 %, preferably 15-35 %, more preferably 20-30% in the composition according to the present invention.

Besides these compounds the dry-granulated inner phase can contain one or more pH controlling compounds. Such pH controlling compounds are for example the tri-sodium citrate and di-potassium hydrogen phosphate. The composition of the present invention contains preferably tri-sodium citrate. The weight of the pH controlling agents is 1-25 %, preferably 5-15 %, most preferably 8- 12 % in the composition according to the present invention.

The dry-granulated inner phase can contain an osmotic compound if necessary. Such osmotic compounds can be organic compounds, for example saccharides, mannitol, cyclodextrines etc., or inorganic compounds, such sodium chloride etc.

For the coating of the dry-granulated inner phase a permeability controlling film forming polymer having pH dependent solubility, or a mixture dissolution controlling polymers of polymers having pH dependent solubility and polymers having pH independent solubility are used. Such dissolution controlling polymers having pH dependent solubility can be hypromellose acetate succinate (HPMC- As), hypromellose phthalate (HPMC-phthalate), polyvinyl acetate phthalate (PV acetate phthalate), copolymers of methacrylic acid and methacrylic acid esters, preferably copolymers of methacrylic acid and methacrylic acid methylester, more preferably Eudragit L. The amount of these compounds is 1-25%, preferably 2-20%, most preferably 2-15% in the composition according to the present invention.

The permeability controlling film forming polymers having pH independent solubility can be polyvinyl acetate, ethyl cellulose, copolymers of acrylic acid and methacrylic acid esters, preferably copolymers of acrylic acid and methacrylic acid methylester, more preferably Eudragit RL. The amount of these compounds is 1-25%, preferably 2-20%, most preferably 2-15% in the composition according to the present invention.

These coating polymers are used in a form of aqueous dispersion, diluted with water or in a solution thereof with organic solvents. In case of the composition of the present invention a solution of these compounds in ethanol is used preferably. If appropriate, the above- mentioned coating can contain pore forming agent(s) too. The pore forming agents dissolve due to the effect of the gastro-intestinal juice from the polymer coating layer, thus increase the permeability of the coating. Such pore forming agents can be even Eudragit L, which dissolves at the pH of intestinal juice and leaves pores on the coating.

According to the present invention an external phase is mixed to the dry-granulated and coated granules, which plays an important role for providing the optimal dissolution of the active ingredient on the one hand and is necessary for the tablet pressing on the other.

For the regulation of the dissolution of the active ingredient excipients having different water solubility can be used in the external phase such as sugars, sugar derivatives, e.g. sugar alcohols, mono-, di- and tertiary alkali phosphates and citrates, alkali chlorides, preferably lactose monohydrate and tri-sodium citrate. The amount of these compounds based on the weight of the composition is 1-70 %, preferably 3-60 %, most preferably 3-40 % according to the present invention. The compounds of the external phase, which are necessary for the tablet compression process, can be binders capable of direct pressing processes, lubricants, gliding agents and anti-adhesives. The composition according to the present invention contains preferably microcrystalline cellulose, colloid silica and magnesium stearate in a ratio of 0.5-10 %, preferably 0.5-7 %, most preferably 0.5-3 % on the basis of the weight of the composition.

According to an advantageous embodiment of the present invention the tablet does not have an external coating. According to an other embodiment the tablet is coated with one or more coatings which do not sustain the dissolution. According to a further advantageous embodiment of the present invention the tablet has incisions for dispensation of tablets. Such incision(s) make(s) the bisection or quartation of tablets possible.

The tablet compositions of the present invention allow the preparation of proportional tablets having different strength. Furthermore, the dissolution of the tablets remains in the required ranges even if the tablets are dispensed.

The most advantageous pharmaceutical effect can be achieved if we prepare a tablet, from which 35-45% of the active ingredient is dissolved in the first two hours of the dissolution in an acidic medium, then the dissolution rate should decrease in such a way that 45-65 % of the active ingredient is dissolved after 6-hour dissolution and 70-85% of the active ingredient is dissolved until the 16th hour of the dissolution.

Such properties can be detected for example in the tablets according to the present invention which contain 65-84 % of coated granules and 1-3% of microcrystalline cellulose, 5-10% of lactose, 6.5-10% of tri-sodium citrate, 0.5-2% of colloidal silica and 0.5-2% of talc as external phase based on the weight of the tablet,

and in which the coated granules contain 60-70% of dry granules, and as coating 3.5-5.5% of Eudragit L-100 55, 3.5-4.5% of Eudragit RL-100 polymers, 1-2% of triethyl citrate and 3-6% of talc based on the weight of the tablet,

and in which the dry granules contain 5-45 % of quetiapine hemifumarate, 15-55% of microcrystalline cellulose, 5.5-8 % of tri- sodium citrate, 0.5-1% of colloid silica and 0.5-1 % of magnesium stearate based on the weight of the tablet.

For the preparation of the composition of the present invention the following methods can be used: the components of the inner phase are homogenized for dry granulation processes. For this purpose any apparatuses known by a person skilled in the art are suitable. The dry-granulation process can be carried out either by compaction or by briquetting process according to the general knowledge of the person skilled in the art. As a result of both processes large-scale compressed particles are formed, which have to be disintegrated and sieved. Apparatuses for these processes are known in large selection in the industrial practice.

An important step is the selection of the appropriate particle fraction of the dry granulated inner phase. According to the composition of the present invention the used particle size is between 0.2-1.6 mm, preferably 0.4-0.8 mm. For the selection of the appropriate particle fraction e.g. vibration sieves can be used.

For the coating of the inner phase numerous types of apparatuses can be used which are known for the person skilled in the art. These can be coating cauldrons having an unperforated wall, traditional fluidization equipments based on principles of Hiittlinger or Wurster, or roto-fluidization apparatuses.

For admixing the external phase to the inner phase such homogenizing equipments are suitable which gently move the mixture to avoid the degradation of granules or the injury of the coating. The homogenized mixture ready to compressing can be compressed into tablets in a high performance tablet pressing apparatus because the homogenized mixture prepared according to the present invention as described above has good compressibility.

The composition according to the present invention can be prepared that the active ingredient or a pharmaceutically active salt thereof is mixed with pharmaceutically acceptable excipients and formed into granules by a dry-granulation process, preferably by a compaction or briquetting process, then the obtained granules are coated with a dissolution controlling a non-gelling polymer having a pH dependent solubility, or a mixture of dissolution controlling, non-gelling polymers having pH dependent solubility and a polymer having pH independent solubility, then the obtained coated granules are mixed with the external phase containing further excipients and pressed into tablets.

In case of the preparation of the mixture of the inner phase of the composition of the present invention the active ingredient or a pharmaceutically accepted salt thereof is mixed with 5-55 %, preferably 15-55 %, most preferably 20-30 % of water-insoluble, compressible excipient; 1-25 %, preferably 5-15 %, most preferably 8-12 % of pH controlling agent based on the weight of the tablet, and, if necessary, with osmotic, anti-adhesive and gliding agents and granulated using any of the known method of dry-granulation.

The surface of the obtained granules is coated with

i.) 1 -25 %, preferably 2-20 %, most preferably 2-15 % of polymers having pH dependent solubility based on the weight of the composition,

or, ii.) 1-25 %, preferably 2-20 %, most preferably 2-1 % of dissolution modifying polymers having pH dependent solubility and dissolution permeability controlling film forming polymers having pH independent solubility with a method known from the prior art,

then the obtained granules are mixed with 1-70 %, preferably 3-60 %, most preferably 3-40 % of the compounds capable of controlling the dissolution rate of the active ingredient and, if necessary, with further excipients and compressed into tablets. The obtained tablets can be coated with one or more coatings, if necessary. The used coatings do not sustain the dissolution of the active ingredient. Such coatings can be chosen from the commercially available coating polymers but a sugar coating can be applied as well.

The tablet can be pressed with an apparatus which presses dispensing incisions into the tablet. The preparation of these incisions for dispensing is the part of the knowledge of the person skilled in the aft.

According to an advantageous embodiment of the present invention we can proceed that the coated granules are selected and the selected particle fractions between 0.2 and 1.6 mm, preferably between 0.4 and 0.8 mm are mixed with the compounds of the external phase and the mixture is compressed into tablets using a method known from the prior art. If necessary, tablets are coated with one or more coating layers, which do not alter the dissolution properties. In the course of the preparation of the composition macrocrystalline cellulose is preferably used as water insoluble, non-gelling compressible accessory agent for the preparation of the granules. As pH controlling agent preferably tri-sodium citrate, potassium di- hydrogen phosphate, most preferably tri-sodium citrate are used. As osmotic agent for example mono- oligo- and polysaccharides, mannitol, cyclodextrin, or inorganic compounds such as sodium chloride are used. As anti-adhesives colloidal silica, magnesium stearate, potassium stearate, talc, sodium stearyl fumarate, preferably 0.05-3%, more preferably 0.5-3 % colloid silica and/or magnesium stearate are used based on the weight of the tablet.

For coating of granules, polymers having pH dependent solubility are used, such as HPMC-As, HPMC-phthalate, PV acetate phthalate, copolymers of methacrylic acid and methacrylate esters, preferably copolymers of methacrylic acid and methyl methacrylate, most preferably Eudragit L or a mixture of dissolution controlling film forming polymers comprising polymer(s) having pH dependent and polymer(s) having pH independent solubility. The mixture can contain as a further component a pore forming agent, preferably Eudragit L.

In case of use of a mixture dissolution controlling polymers of polymer(s) having pH dependent and polymer(s) having pH independent solubility as coating, as dissolution controlling polymers having pH dependent solubility e.g. HPMC-As, HPMC-phthalate, PV acetate phthalate, copolymers of metharylic acid and methacrylate esters, preferably copolymers of methacrylic acid and W

20 methyl methacrylate, most preferably Eudragit L are used, while as a permeability controlling film forming polymer having pH independent solubility e.g. polyvinyl acetate, ethyl cellulose, copolymers of arylic acid and methacrylate esters, preferably copolymers of acrylic acid and methyl methacrylate, most preferably Eudragit RL are used.

In the external phase for the regulation of the dissolution of the active ingredient as water soluble compounds sugars, sugar derivatives, sugar alcohols, mono-, di- and tertiary alkali phosphates and citrates, preferably lactose monohydrate and tri-sodium citrate are used. To the external phase excipient(s), preferably colloid silica and magnesium stearate are mixed in an amount of 0.1-10%, preferably 0.25-7%, most preferably 0.5-3%, if necessary.

The tablet according to the present invention can be coated with coatings which do not alter the dissolution of the pharmaceutically active ingredient.

During the tablet pressing process incisions dispensing the tablet can be evolved by an appropriate tablet pressing apparatus. The preparation of such incisions is the part of the knowledge of the person skilled in the art.

According to a more advantageous embodiment of the present invention the composition also can be prepared that for making the mixture of the inner phase 5-45 % of quetiapine hemifumarate, 15- 55% of microcrystalline cellulose, 5.5-8 % tri-sodium citrate, 0.5-1% colloidal silica and 0,5-1% magnesium stearate based on the weight of the tablet are mixed and homogenized, then using any of the dry- granulation processes known from the prior art are pressed into granules. The surface of the obtained granules of particle fraction between 0.2-16 mm, preferably 0.4-0.8 mm is coated using with an alcoholic mixture of 3.5-5.5% of Eudragit L-100 55, 3.5-4.5% of Eudragit RL-100 polymers, 1-2% of triethyl citrate and 3-6% of talc based on the weight of the tablet, then dried according to any of the processes known from the prior art. The obtained coated granules are mixed with the compounds of external phase, with 1-3% of microcrystalline cellulose, 5-10% of lactose, 6.5-10% of tri-sodium citrate, 0.5-2% of colloidal silica and 0.5-2% of talc based on the weight of the tablet, then homogenized and pressed into tablets. The tablets thus obtained can be applied with dispensing incisions and coated with one or more coatings which do not decrease the dissolution of the active ingredient.

From the tablets thus prepared in the first two hours of dissolution - in acidic conditions - 35-45% of the active ingredient is dissolved, then the dissolution of active ingredient decreases in such a manner that at the end of 6 hours dissolution 45-65 % of the active ingredient dissolves and after 16 hours 70-85% of the active ingredient dissolves.

An advantage of the composition of the present invention - besides that the once-a-day therapy improves the compliance of patients - is that the composition saves the patients the side effects of the suddenly emerging high blood level, which characterizes the immediate release compositions. A further advantage is that it is not necessary to use a coating for the retard effect. It is not only a technological advantage but the statistical weight discrepancy of the coatings of the tablets which cause the dissolution rate differences among the tablets can not be developed. Furthermore, if the tablet is damaged, e.g. a patient bites it, the dissolution profile does not change therefore the tablet according to the present invention allows a safer treatment than a composition based on a coating having dissolution decreasing properties. The fact that the tablet is dispensable gives an opportunity to the physician to adjust the doses regime e.g. by bisection of the tablets in such a manner which could not be achieved with marketed tablets without dispensing of tablets. The dispensable tablet makes the adjustment of the lowest effective doses possible for the treatment, thus it is expected that the intensity of side effects decreases. It is very important in case of quetiapine because it has numerous side effects, which significantly decrease the life quality such as somnolence and dizziness.

Another advantage of the dispensable tablet that high-dose tablets can be administered by patients easier in bisected form.

The sustained release (retard) composition according to the present invention has several technological advantages in the pharmaceutical field. For example, the used composition and process allow the preparation of such compositions, in which the amounts of single ingredients change in proportion with the amount of the active ingredient. These so called proportional tablets can be prepared in the same way using the same equipments except for the tablet pressing tool and the packing material. The used dry granulation and the direct compression facilitate the chemical and physical stability of the active ingredient. The technical solution which is the base of the present invention is shown below by a composition containing quetiapine hemifumarate. In case of quetiapine hemifumarate it is surprising for the person skilled in the art that quetiapine hemifumarate can be compacted well together with a small amount of excipients. According to the solution of the present invention the quetiapine hemifumarate ratio can be as high as 95% in the dry granulated phase. This high concentration allows to evolve relatively small tablet weights and size. These granules having a high-dose active ingredient content can be coated with polymers without the necessity to smooth the surface of the granules or form shapes thereof to isodimension form.

The external phase of the tablets pressed from the coated granules thus prepared does not contain disintegrants, the dissolution of the active ingredient from the tablet is regulated according to requirements by the ratio of the external phase and the solubility of components thereof. The tablets according to the present inventions show a good chemical and physical stability.

The content of quetiapine or the pharmaceutically acceptable salts thereof is 5-70 %, preferably 8-65 %, most preferably 8-40 % of the composition according to the present invention.

The in-vitro dissolutions of the tablets prepared in the examples of the present invention were carried out and evaluated as follows:

In the course of development of the examination process of the in vitro dissolution we considered the physiological environments of passing over of the composition in the gastrointestinal tract. According to the present knowledge the pH of the gastric juice before eating is about 1.2 meanwhile the pH value of the intestinal tract is about 6.8. The tablets pass over from the stomach to the intestine tract in 2 hours the latest. The in vivo environments were modeled that the dissolution of the active ingredients of the present invention was measured from the beginning up to two hours in acidic conditions (pH=1.2) then the buffer solution was changed to a buffer having pH 6.8.

Dissolution apparatus:

Ph.Eur. I (basket) apparatus,

100/min. rpm,

37°C dissolution media:

0 - 2 hours 0.1 N HC1 ; 2 - 24 hours pH 6.8 phosphate buffer Measuring the active ingredient content: HPLC

Figures:

Figure 1 : In vitro dissolution curves of tablets according to examples 2.3, 2.4 and 2.5.

Figure 2: In vitro dissolution curves of tablets according to examples 3.3, 3.4, 3.5 and 3.6.

Figure 3 : In vitro dissolution curves of tablets according to examples 4.3, 5.2 and 5.4.

Figure 4: The comparison of in vitro dissolution curves of a tablet containing 400mg active ingredient (Example 7.3) as a whole and the dissolution curve of the bisected tablet containing 400mg active ingredient. Our invention is presented below in the examples in particulars without limiting our claims to these examples:

Example 1

1.1 Dry granulation:

The components of the inner phase, quetiapine hemifumarate, Aerosil 200 and a magnesium stearate are homogenized in a drum mixer for 10 minutes. The obtained homogenized mixture is granulated in a roller compactor. The obtained granules are sieved with a vibration sieve. The fraction between 0.4 and 1.0 mm is used for the next step.

1.2 Coating:

The dry granules were coated in a Glatt GPCG 3 equipment having a Wurster attachment with diluted dispersion of Surelease E- 7-19040 Clear. The coated pellets were dried in the equipment. 1.3 Tablet 1

The dried coated granules are mixed with spray dried lactose and magnesium stearate. The mixture is homogenized for 15 minutes then compressed into tablets of 600 mg weight with a high- performance tablet pressing machine. The active ingredient content of the tablet related to the quetiapine base is 300 mg.

1.4 Tablet 2

The dried coated granules are mixed with spray dried lactose and magnesium stearate The mixture is homogenized for 15 minutes then compressed into tablets of 498 mg weight with a tablet pressing machine. The active ingredient content of the tablet related to the quetiapine base is 300 mg.

Example 2 2.1 Dry granulation:

The components of the inner phase, quetiapine hemifumarate, spray dried lactose, tri-sodium citrate, Aerosil 200 and magnesium stearate are homogenized for 10 minutes. The obtained homogenized mixture is granulated in a roller compactor. The obtained granules are sieved with a vibration sieve. The fraction between 0.40 and 0.80 mm is used for the next step.

Caolin is suspended in water and poured under stirring into the premixed mixture of Eudragit NE30D and Eudragit L30D. The dry granules containing quetiapine hemifumarate are coated with the mixture thus obtained in a Glatt GPCG 3 equipment having a Wurster attachment.

2.3 Tablet 1

The dried coated granules are mixed with spray dried lactose and Aerosil 220. The mixture is homogenized for 10 minutes, then magnesium stearate is added and the mixture is homogenized for two additional minutes. The homogenized mixture is compressed into tablets of 1762 mg weight with a tablet pressing machine. The active ingredient content of the tablet related to the quetiapine base is 400 mg.

2.4 Tablet 2 Composition g

Coated granules containing

quetiapine hemifumarate according 951 63.2% to Example 2.2

Microcrystalline cellulose 75 5.0%

Spray dried lactose DC 21 450 30.0%

Aerosil 12 0.8%

Magnesium stearate 15 1.0%

Total: 1503 100.0%

The dried coated granules are mixed with spray dried lactose and Aerosil. The mixture is homogenized for 10 minutes then magnesium stearate is added and the mixture is homogenized for two additional minutes. The homogenized mixture is compressed into tablets of 1503 mg weight with a tablet pressing machine. The active ingredient content of the tablet related to the quetiapine base is 400 mg.

2.5 Tablet 3

The dried coated granules are mixed with spray dried lactose and Aerosil. The mixture is homogenized for 10 minutes, then magnesium stearate is added and the mixture is homogenized for two additional minutes. The homogenized mixture is compressed into tablets of 1231 mg weight with a tablet pressing machine. The active ingredient content of the tablet related to the quetiapine base is 400 mg.

Example 3

3.1 Dry granulation

The components of the inner phase, quetiapine hemifumarate, microcrystalline cellulose, Aerosil and a magnesium stearate are homogenized for 10 minutes. The obtained homogenized mixture is granulated in a roller compactor. The obtained granules are sieved with a vibration sieve. The fraction between 0.40 and 0.80 mm is used for the next step.

3.2 Coating Composition g Dry-matter Composition of content g dry granules %

Granules containing 400 400 83.9% quetiapine hemifumarate

according to Example 3.1

0.4- 0.8 mm

Eudragit L- 100 55 24 24 5.0%

Eudragit RL 100 24 24 5.0% triethyl-citrate 9.6 9.6 2.0%

Talc 19.2 19.2 4.0%

Ethanol (96%) 576 0 0.0%

Weight of dry granules: 476.8 100.0%

The talc is suspended under stirring in an alcoholic solution of Eudragit polymers and triethyl citrate. The granules containing quetiapine hemifumarate are coated with the suspension thus obtained in a Glatt GPCG 3 equipment having a Wurster attachment.

3.3 Tablet 1

Composition g

Coated granules containing

quetiapine fumarate according to 80.00 64.0%

Example 3.2

Microcrystalline cellulose 5.00 4.0%

Spray dried lactose DC 21 37.50 30.0%

Aerosil 1.25 1.0%

Magnesium stearate 1.25 1.0%

Total: 125.00 100.0% The dried coated granules are mixed with spray dried lactose, microcrystalline cellulose and Aerosil. The mixture is homogenized for 10 minutes, then magnesium stearate is added and the mixture is homogenized for two additional minutes. The homogenized mixture is compressed into tablets of 1250 mg weight with a tablet pressing machine.

3.4 Tablet 2

The dried coated granules are mixed with spray dried lactose and Aerosil. The mixture is homogenized for 10 minutes, then magnesium stearate is added and the mixture is homogenized for two additional minutes. The homogenized mixture is compressed into tablets of 1250 mg weight with a tablet pressing machine.

3.5 Tablet 3 Composition g

Coated granules containing

quetiapine fumarate according to 80.00 64.0% Example 3.2

Microcrystalline cellulose 5.00 4.0%

Spray dried lactose DC 21 17.50 14.0%

Tri-sodium citrate 20.00 16.0 %

Aerosil 1.25 1.0%

Magnesium stearate 1.25 1.0%

Total: 125.00 100.0%

3.6 Tablet 4

Composition g

Coated granules containing 80.00 64.0% quetiapine fumarate according to

Example 3.2

Microcrystalline cellulose 5.00 4.0%

Spray dried lactose DC 21 17.50 14.0%

Dipotassium hydrogen phosphate 20.00 16.0 %

Aerosil 1.25 1.0%

Magnesium stearate 1.25 1.0%

Total: 125.00 100.0% The dried coated granules are mixed with spray dried lactose and Aerosil, The mi ^ for 10 minutes, then magnesium stearate is added and the mixture is homogenized for two additional minutes. The homogenized mixture is compressed into tablets of 1250 mg weight with a tablet pressing machine

Example 4

4.1 Dry granulation:

The components of the inner phase, quetiapine hemifumarate, microcrystalline cellulose, tri-sodium citrate, Aerosil 200 and magnesium stearate are homogenized for 10 minutes. The obtained homogenized mixture is granulated in a roller compactor. The obtained granules are sieved with a vibration sieve. The fraction between 0.40 and 0.80 mm is used for the next step.

4.2 Coating:

Weight of dry granules: 1779.2 100.0%

The talc is suspended under stirring in an alcoholic solution of Eudragit L-100 55 and triethyl citrate. The granules containing quetiapine hemifumarate are coated with the suspension thus obtained in a Glatt GPCG 3 equipment having a Wurster attachment.

4.3 Tablet 1

Composition g

Coated granules containing

quetiapine hemifumarate according 826 76.84% to Example 4.2

Microcrystalline cellulose 26.5 2.47%

Spray dried lactose DC 21 106 9.86%

Tri-sodium citrate 95 8.84%

Aerosil 10.75 1.00%

Magnesium stearate 10.75 1.00%

Total: 1075 100.00% The dried coated granules are mixed with spray dried lactose and Aerosil. The mixture is homogenized for 10 minutes, then magnesium stearate is added and the mixture is homogenized for two additional minutes. The homogenized mixture is compressed into tablets of 806 mg weight with a tablet pressing machine. (300mg)

Example 5

5.1 Coating

The talc is suspended under stirring in an alcoholic solution of Eudragit L-100 55, Eudragit RL-100 and triethyl citrate. The granules containing quetiapine hemifumarate are coated with the suspension thus obtained in a Glatt GPCG 3 equipment having a Wurster attachment. 5.2 Tablet 1

The dried coated granules are mixed with spray dried lactose and Aerosil. The mixture is homogenized for 10 minutes, then magnesium stearate is added and the mixture is homogenized for two additional minutes. The homogenized mixture is compressed into tablets of 924 mg weight with a tablet pressing machine.

The talc is suspended under stirring in an alcoholic solution of Eudragit L-100 55, Eudragit RL-100 and triethyl citrate. The granules containing quetiapine hemifumarate were coated with the thus obtained suspension in a Glatt GPCG 3 equipment having a Wurster attachment.

5.4 Tablet 2

The dried coated granules are mixed with spray dried lactose, microcrystalline cellulose, tri-sodium citrate, Aerosil and magnesium stearate. The mixture is homogenized for 15 minutes, then compressed into tablets of 140 mg weight with a tablet pressing machine.

Example 6: Composition containing 50mg/tablet of active ingredient 6.1. Dry granulation:

6.2. Coating

The talc is suspended under stirring in an alcoholic solution of Eudragit L-100 55, Eudragit RL-100 and triethyl citrate. The granules containing quetiapine hemifumarate are coated with the suspension thus obtained in a Glatt GPCG 3 equipment having a Wurster attachment.

6.3 Tablet

The coated granules are mixed with microcrystalline cellulose, spray dried lactose, tri-sodium citrate and Aerosil. The mixture is homogenized for 15 minutes, then magnesium stearate is added and the mixture is homogenized for 3 additional minutes. The homogenized mixture is compressed into tablets of 628 mg weight with a tablet pressing machine.

Example 7: Process for the preparation of a composition containing 400mg/tablet of active ingredient

7.1. Dry granulation Composition g

Quetiapine hemifumarate 1860 61.96%

Microcrystalline cellulose 780 25.98%

Tri-sodium citrate 307.5 10.24%

Aerosil 200 32 1.07%

Magnesium stearate 22.5 0.75%

Total: 3002 100.00%

The components of the inner phase quetiapine hemifumarate, microcrystalline cellulose, tri-sodium citrate, Aerosil 200 and magnesium stearate are homogenized for 10 minutes. The obtained homogenized mixture is granulated in a roller compactor. The obtained granules are sieved with a vibration sieve. The fraction between 0.40 and 0.80 mm is used for the next step.

7.2. Coating:

7.3 Tablet

The coated granules are mixed with microcrystalline cellulose, spray dried lactose, tri-sodium citrate and Aerosil. The mixture is homogenized for 15 minutes, then magnesium stearate is added and the mixture is homogenized for 3 additional minutes. The homogenized mixture is compressed into tablets of 1248 mg weight with a tablet pressing machine.

Example 8

Comparative dissolution examination of tablet containing 400 mg active ingredient with a bisected tablet thereof. A tablet containing 400 mg of active ingredient prepared according to Example 7.3 was bisected by a knife and the dissolution profile of bisected tablet was compared with an intact tablet from the same charge.

Dissolutions were measured in an Ph.Eur. I (basket) apparatus, under circumstances as follows:

100/min. rpm,

37°C dissolution media:

The result of the experiment:

Similarity factor is f₂=50

Claims

Claims:

1. Controlled release tabletted pharmaceutical composition containing quetiapine comprising granules containing quetiapine or pharmaceutically acceptable salt thereof and a mixture of pharmaceutically accepted excipients and coated with a non-gelling, dissolution controlling polymer having pH dependent solubility, or with a mixture of a non-gelling, dissolution controlling polymer having pH dependent solubility and a non-gelling, dissolution controlling polymer having pH independent solubility in inner phase, and further excipient or excipients in external phase.

2. Pharmaceutical composition according to Claim 1 characterized in that the granules are dry-granules.

3. Pharmaceutical composition according to any of Claims 1 or 2 characterized in that the particle fraction of used granules is between 0.2 and 1.6 mm, preferably between 0.4 and 0.8 mm.

4. Pharmaceutical composition according to any of Claims 1-3 characterized in that the coated granules contain besides the active ingredient or pharmaceutically accepted salts thereof osmotic compound(s) if necessary.

5. Pharmaceutical composition according to any of Claims 1-4 characterized in that the external phase of the tablet contains one or more water soluble accessory agents which influence the dissolution of the active ingredient in the inner phase.

6. Pharmaceutical composition according to any of Claims 1-5 characterized in that the composition contains quetiapine hemifumarate.

7. Pharmaceutical composition according to any of Claims 1-6 characterized in that the granulated inner phase contains besides the active ingredient or pharmaceutically accepted salts thereof 0.1-5%, preferably 0.5-3% of anti-adhesive, gliding agents, preferably colloidal silica, magnesium stearate, talc, sodium stearyl fumarate, more preferably colloidal silica and magnesium stearate or a mixture thereof.

8. Pharmaceutical composition according to any of Claims 1-7 characterized in that the granulated inner phase contains besides the active ingredient or pharmaceutically accepted salts thereof 0.5-55%, preferably 15-55%, most preferably 20-30% of excipient which does not form gel in water, e.g. microcrystalline cellulose, lactose, calcium phosphate, calcium sulphate or sodium chloride.

9. Pharmaceutical composition according to any of Claims 1-8 characterized in that the granulated inner phase further contains 1- 25%, preferably 5-15%, most preferably 8-12% of pH controlling agent, e.g. tri-sodium citrate, potassium dihydrogen phosphate, preferably tri-sodium citrate.

10. Pharmaceutical composition according to any of Claims 1-9 characterized in that the granulated inner phase further contains osmotic compounds e.g. organic osmotic compounds as saccharides, mannitol, cyclodextrins etc. or inorganic osmotic compounds, as sodium chloride etc.

11. Pharmaceutical composition according to any of Claims 1-10 characterized in that the coating of the granules contains as coating agent having pH dependent solubility HPMC acetate succinate, HPMC phthalate, polyvinyl acetate phthalate, copolymers of methacrylic acid and methacrylic acid esters, preferably methacrylic acid and methacrylic acid esters, more preferably Eudragit L and, if appropriate, as film forming polymer having pH independent solubility polyvinyl acetate, ethyl cellulose, copolymers of acrylic acid and methacrylic acid esters, preferably copolymers of acrylic acid and methacrylic acid esters, more preferably Eudragit RL and the coating further comprises pore forming agents, if necessary.

12. Pharmaceutical composition according to any of Claims 1-1 1 characterized in that the weight of the coating related to the weight of the composition is 1-25%, preferably 2-20%, more preferably 2-15%.

13. Pharmaceutical composition according to any of Claims 5-12 characterized in that the weight of the external phase of the composition contain for controlling of the dissolution of active ingredient 1 -70%, preferably 3-60%, more preferably 3-40% of water soluble excipients, e.g. sugars, sugar derivatives, sugar alcohols, mono-, di- and tertiary . alkali phosphates and citrates, alkali chlorides, preferably lactose and tri-sodium citrate.

14. Pharmaceutical composition according to any of Claims 1-13 characterized in that the external phase comprises further excipients as lubricants, gliding agents, anti-adhesives or a mixture thereof in an amount of 0.5-10%, preferably 0.5-7%, more preferably 0.5-3% related to the weight of the composition.

15. Pharmaceutical composition according to any of Claims 1-14 characterized in that the tablet is coated with one or more coating layers which do not delay the dissolution of the active ingredient.

16. Pharmaceutical composition according to any of Claims 1-15 characterized in that the tablet is furnished with incision or incisions for dispensing.

17. Pharmaceutical composition according to any of Claims 1-15 characterized in that the tablet contains on the basis of the weight of the tablet 65-84% of coated granules and as external phase 1-3% of microcrystalline cellulose, 5-10% of lactose, 6.5-10 % of tri-sodium citrate, 0.5-2% of colloidal silica and 0.5-2% of talc,

and in which the granules, related to the weight of the tablet, contain 60-70% of dry granules, as coating 3.5-5.5 % of Eudragit L-100 55, 3.5-4.5% of Eudragit RL-100 polymers, 1-2% of triethyl citrate and 3-6 % of talc,

and in which the dry granules, related to the weight of the tablet, contain 5-45% of quetiapine hemifumarate, 15-55% of microcrystalline cellulose, 5.5-8% of tri-sodium citrate, 0.5-1% of colloidal silica and 0.5-1% of magnesium stearate.

18. Process for the preparation of pharmaceutical compositions of any of the Claims 1-17 characterized in that the quetiapine or pharmaceutically accepted salts thereof and a mixture of pharmaceutical excipients are mixed and pressed into granules by dry granulation processes, preferably with compaction or briquetting process, then these granules are coated with a non-gelling polymer having pH dependent solubility, or with a mixture of dissolution controlling, non-gelling polymer having pH dependent solubility and a dissolution controlling, non-gelling polymer having pH independent solubility, then the obtained coated granules are mixed with further excipients and pressed into tablets.

19. Process according to the Claim 18 characterized in that in the course of the preparation of the mixture for the granules quetiapine or pharmaceutically accepted salts thereof are mixed on the basis of the weight of the tablet with 5-55%, preferably 15-55%, more preferably 20-30% of compressible excipient, which is not swelling in water, 1-25%, preferably 5-15%, more preferably 8-12% of pH controlling agent and, if necessary, osmotic, anti-adhesive, and gliding agents, then the mixture is granulated by using any dry granulation methods of the prior art, then the surface of the obtained granules is coated

i.) with polymers having pH dependent solubility in an amount of 1 - 25%, preferably 2-20%, more preferably 2-15% related to the weight on the composition or

ii) with a mixture of dissolution controlling, non-gelling polymer having pH dependent solubility and a dissolution controlling, non-gelling polymer having pH independent solubility, in an amount of 1 -25%, preferably 2-20%, more preferably 2-15% related to the weight on the composition,

then the granules are mixed with excipients for controlling of the dissolution of active ingredient in an amount of 1-70%, preferably 3- 60%, more preferably 3-40% related to the weight on the tablet and further excipients, if necessary, and the obtained mixture is pressed into tablets.

20. Process according to the Claim 18 or 19 characterized in that the tablet is coated with one or more coatings, if necessary.

21. Process according to any of Claims 18-20 characterized in that the used coating or coatings do not delay the dissolution of the active ingredient.

22. Process according to any of Claims 18-21 characterized in that the incision or incisions for dispensing are prepared on the surface of the tablet during the tablet pressing process.

23. Process according to any of Claims 18-22 characterized in that in the course of the preparation of the mixture for the granules on the basis of the weight of the tablet 5-54% of quetiapine hemifumarate, 15-55 % of microcrystalline cellulose, 5.5-8% of tri-sodium citrate, 0.5-1% colloidal silica and 0.5-1% magnesium stearate are mixed, homogenized, then using one of the known dry granulating processes the mixture is granulated, the particle fraction between 0.2 and 1.6 mm, preferably between 0.4 and 0.8 mm is selected and coated with an alcoholic mixture of 3.5-5.5% of Eudragit L-100 55, 3.5-4.5% of Eudragit RL-100 polymers, 1-2% of triethyl-citrate and 3-6% talc based on the weight of the composition, then dried and the coated granules are mixed and homogenized with 1-3% of microcrystalline cellulose, 5-10% of lactose, 6.5-10% of tri-sodium citrate, 0.5-2% of colloidal silica and 0.5-2% talc based on the weight of the tablet and pressed into tablets.