WO2012131722A1

WO2012131722A1 - Controlled release composition of betahistine

Info

Publication number: WO2012131722A1
Application number: PCT/IN2012/000218
Authority: WO
Inventors: Nitin Bhalachandra Dharmadhikari; Yashoraj Rupsinh Zala; Sunil Beharilal Jaiswal
Original assignee: Sun Pharma Advanced Research Company Ltd.
Priority date: 2011-03-30
Filing date: 2012-03-29
Publication date: 2012-10-04

Abstract

The present invention provides a controlled release dosage form comprising a mixture of betahistine or its pharmaceutically acceptable salt complexed with ion exchange resin with one or more gel forming polymer. Further, in preferred aspect, the present invention provides a controlled release solid dosage form comprising " a controlled release composition comprising betahistine or its pharmaceutically acceptable salt, one or more gel forming polymers and pharmaceutically acceptable excipients; " an immediate release composition comprising betahistine or its pharmaceutically acceptable salt wherein the solid dosage form is suitable for once a day administration.

Description

CONTROLLED RELEASE SOLID DOSAGE FORM OF BETAHISTINE

FIELD OF INVENTION

The present invention relates to a controlled release dosage form comprising betahistine or its pharmaceutically acceptable salt.

BACKGROUND OF THE INVENTION

Betahistine, or N-methyl-2-pyridineethanamine or 2-[2-(methylamino) ethyl] pyridine or [2-(2- pyridyl)ethyl]methylamine, and the respective salts: hydrochloride, dihydrochloride, methanesulfonate, and fumarate, is a vasodilator active through the oral route used in the therapy of vertigo. It is commercially available only in the form of prompt release tablets or drops. At present the posology of betahistine comprises two to four times daily administrations, depending on the dosage of the concerned pharmaceutical form, and the total amount of active ingredient per dose is of 16 to 64 mg. A pharmaceutical composition with reduced frequency of daily administrations, while maintaining the plasma levels of the drug for prolonged period is always desirable. It is always a challenge to design and formulate controlled release compositions of highly water-soluble drugs such as betahistine. It is a further challenge to ensure that the drug release occurs at a predetermined rate in order to maintain desired plasma levels for twenty four hours round-the-clock to enable once daily dosage regimen. Moreover, for hygroscopic and moisture ensitive drug like betahistine, one has to develop a dosage form that not only confers controlled drug release characteristics but is also stable on storage during its shelf life period.

Various attempts have been made to make controlled release pharmaceutical form of Betahistine or its salts. For example, European Patent EP1493435 (hereinafter referred to as EP'435 patent) describes a core comprising granulates of betahistine, an organic or inorganic acid and hydrophilic polymer. These cores may be optionally coated further with hydrophilic polymers. The EP'435 patent mentions that the release from the compositions could be sustained for about 10 hours to 12 hours. Further, the patent does not provide any information regarding the constant plasma levels for 24 hours duration that is suitable for once a day administration.

Another prior art, namely Shamma et al (International Journal of Pharmaceutics Vol. 405, Issues 1-2, 28 February 201 1, Pages 102-1 12) discloses betahistine resinate beads which are encapsulated by emulsification, solvent evaporation techniques with pH independent polymers such as Eudragit RS. Shamma et al illustrates effect of change in coating and formulation parameters to obtain multiparticulates system that gives in vitro drug release for about 24 hours suitable for once daily administration. It is however to be noted that this article demonstrated the release profile only in vitro in various dissolution medias. No in vivo study was shown to indicate its suitability for once a day administration. However when we complexed betahistine with ion exchange resins and coated such complex with a coating of a polymer capable of controlling the diffusion or release of betahistine, we found that the rate of release from the composition exhibited significant and undesirable change upon storage.

Another patent publication, namely, European Patent Number EP 1158963 provided a controlled release tablet comprising betahistine incorporated in a carrier mainly composed of fatty compounds and hydrophilic polymers. However, the compositions showed controlled release of betahistine only upto eight hours.

Another patent publication, European Patent Publication Number EP0502642 disclosed a sustained release composition of drug comprising cores having diameter not greater than 5 mm that are coated with a mixture of a film forming agent and an anionic surfactant in various ratios. The use of an anionic surfactant helps to modulate release properties of the film-forming polymer and enables prolonged release. Although drug release shows retarding effect, no in vivo results have been provided to show suitability for once a day administration.

The inventors of the present invention were encountered with hygroscopicity and instability problem during the development of once daily betahistine preparation. Surprisingly and unexpectedly, it was found that that dosage form of the present invention was stable on storage in terms of chemical and physical stability but also in terms of a dissolution profile was able to achieve desirable plasma levels. Also, it was found that the dosage form was suitable for once a day administration in human volunteers. SUMMARY ON THE INVENTION

The present invention provides a controlled release dosage form comprising a mixture of betahistine or its pharmaceutically acceptable salt complexed with ion exchange resin with one or more gel forming polymer.

Further, in preferred aspect, the present invention provides a controlled release solid dosage form comprising

• a controlled release composition comprising betahistine or its pharmaceutically acceptable salt, one or more gel forming polymers and pharmaceutically acceptable excipients;

• an immediate release composition comprising betahistine or its pharmaceutically acceptable salt

wherein the solid dosage form is suitable for once a day administration. DESCRIPTION OF FIGURES

Figure 1 is a graph showing the plasma concentration time profiles of 2-pyridylacetic acid in healthy volunteers following oral administration of the solid dosage form of 24 mg of betahistine dihydrochloride (example 1) and following oral administration of 8 mg betahistine immediate release tablets three times a day, under fasting condition.

Figure 2 is a graph showing the plasma concentration time profiles of 2-pyridylaeetic acid in healthy volunteers following oral administration of the solid dosage form of 24 mg of betahistine dihydrochloride (example 2) and following oral administration of 8 mg betahistine immediate release tablets three times a day, under semi fed condition.

Figure 3 is a graph showing the plasma concentration time profiles of 2-pyridylacetic acid in healthy volunteers following oral administration of the solid dosage form of 48 mg of betahistine dihydrochloride (example 3) and following oral administration of 16 mg betahistine immediate release tablets three times a day, under fed condition.

DETAILED DESCRIPTION OF THE INVENTION

The term "controlled release" implies that the dosage form of the present invention is capable of retarding release for prolonged periods, and provides desired plasma levels of drug, for prolonged duration such as more than 12 hours, preferably 24 hours and is therefore, suitable for once daily administration.

The term 'immediate release' as used herein means that the drug is almost 100 % of the drug is released. For instance, when the immediate release composition contains 25 % of the total dose of the active ingredient, then the composition is said to be immediate release when 25 % of the drug is released from the solid dosage form.

The term "tablet" means that the dosage form is either compressed or a compacted mass, such as tablets or mini tablets, slugs that maybe administered, individually or maybe filled in capsule. It is clear that the multiparticulates like pellets, microencapsulated particles of size less than 5mm in diameter are not compressed dosage form according to the present invention. In fact, the inventors of the present invention have found that when the betahistine was prepared in the form of particles of size less than 5mm, it suffered from the problem of dose dumping on storage under accelerated conditions. This observation clearly indicated that the release retarding effect was not maintained when the dosage form was stored under stability conditions. This was particularly interesting and unexpected problem associated with betahistine. The controlled release dosage form of the present invention has solved this problem by forming a complex of betahistine with a suitable ion exchange resin. The term 'enteric' means any material that exhibits a pH dependent solubility such that it is insoluble in acidic pH and soluble in alkaline pH. It is apparent that the polymers that exhibit pH independent solubility are not the enteric material of the present invention. The term 'suitable for once a day administration' as used herein means that the solid dosage form of the present invention when administered to healthy human subjects, a mean plasma concentration of betahistine at the end of 24 hours, was above the minimum effective concentration analyzed as 2- pyridylacetic acid. Betahistine is known to be very hygroscopic and under the influence of various stress conditions such as heat, moisture, acid-base, and ultra-violet (UV) light, may undergo a catalytic degradation by various reactions like oxidation, hydrolysis to generate various degradation products and by-products. Some of the degradation products identified for betahistine include 2-vinyl pyridine also known by the nomenclature of Impurity A, and 2₇(pyridin-2-yl) ethanol [Impurity B], and N-methyl-2-(pyridin- 2-yl)-N-[2-(pyridin-2-yl)ethyl]ethanamine [Impurity C]. In case of betahistine mesylate, the primary degradation product is 2-ethenylpyridine. The degradation impurities can be determined by methods well known in literature, such as those described in standard literature or the standard official compendia or may be developed in-house. The stability is, as is well known to a person skilled in the art, often expressed in terms of the assay or potency of drug in the dosage form and the related substances as defined by the known and unknown impurities. It is further desired that the desirable attributes of good stability and low degradation of drug that are obtained initially for the dosage form should be preserved throughout its shelf life or storage period. Surprisingly and unexpectedly, the solid dosage form of the present invention apart from providing a controlled release of betahistine through-out the shelf life of the product, was found to provide a very stable tablet composition. Particularly, levels of 2-vinyl pyridine (impurity A) were found to be always less than the standard limit of 0.2% during its shelf life. Another characteristic degradation product of betahistine, N- methyl-2-(pyridin-2-yl)-N-[2-(pyridin-2-yl)ethyl]ethanolamine [impurity C] is also always less than 2.0% and most preferably less than 1.0% during its shelf life. Further, unexpectedly it was found that a composition of betahistine without any immediate release betahistine fraction in combination with a controlled release betahistine fraction, when subjected to pharmacokinetic study, showed a very low plasma concentration of 37.1 l ng/ml at the end of 20 hours. Also, the A/B ratio of the C_maji was found to be 106.7 indicating a high C_max and an early T_max of 5.00 hours. Without wishing to be bound by any theory, the inventors believed that such composition without the immediate release fraction of the dose, may provide sub-therapeutic level of betahistine at the end of 20 hours and also early T_max may make the composition unsuitable for once daily administration. Betahistine or its pharmaceutically acceptable salt may be selected from a group consisting of hydrochloride, dihydrochloride, methanesulfonate, mesylate, fumarate, or any other commercially available form of betahistine. In one preferred embodiment, the betahistine hydrochloride is used at a dose of 24 mg to 48 mg. The tablet may be preferably taken with meals. One preferred embodiment of the present invention includes betahistine dihydrochloride and is present in an amount ranging from about 0.5% by weight to 90% by weight of the compressed dosage form, preferably 1% by weight to 50 % by weight of the dosage form and most preferably 1% by weight to 10% by weight of the dosage form. Since the immediate release fraction of betahistine was considered to be essential for making the dosage form suitable for once a day administration, the total dose of betahistine in the controlled release dosage form is equal to the total dose of betahistine that is intended to be taken during 24 hour duration was provided in two fractions- one as immediate release and the other as controlled release fraction. Alternately, the dosage form may comprise one or more immediate release fractions or one or more controlled release fractions. The immediate release fraction is designed to provide an effective plasma level at early time points. The controlled release fraction of the dosage form is designed to maintain the effective blood level throughout a 24 hour period, thus making the solid dosage form suitable for once a day administration. According to one embodiment, the immediate release fraction may range from 15% by weight to 35% by weight of the total dose of betahistine and the sustained release fraction may vary from 65% by weight is 85% of the total dose of betahistine. In one embodiment, the ratio of immediate release fraction to controlled release fraction is 25:75. In one embodiment, the controlled release dosage form comprises about 60% by weight to 80% by weight of the total dose of betahistine or its pharmaceutically acceptable salt and 20% by weight to 40% by weight of betahistine or its pharmaceutically acceptable salt is in the form of immediate release composition. In one of the embodiment, the controlled release dosage form comprises a controlled release composition comprising about 60% by weight to 80% by weight of the total dose of betahistine or its pharmaceutically acceptable salt and an immediate release composition comprising about 20% by weight to 40% by weight of the total dose of betahistine or its pharmaceutically acceptable salt. In one most preferred embodiment, the solid dosage form of the present invention comprised a controlled release composition comprising about 75% by weight of the total dose of betahistine or its pharmaceutically acceptable salt, one or more gel forming polymer and pharmaceutically acceptable excipients an immediate release fraction comprising about 25% by weight of the total dose of the betahistine or its pharmaceutically acceptable salt. According to the present invention, the ion-exchange resins used in the dosage form of the present invention, have versatile properties as drug delivery vehicles and have been extensively studied in the development of novel drug delivery systems. Many grades of ion-exchange resins, varying in acid or base strength, cross-linkage and particle size, are commercially available and make it possible to control the rate of drug release over a wide range of pH. The ion exchange resins of the present invention are cation exchange resins either in the form of acidic hydronium ion or a weakly acidic potassium form or a strongly acidic sodium form and maybe selected from the group consisting of Amberlite IRP69, Amberlite IRP64, Amberlite IRP88, Dowex® 50WX series, polystyrene sulfonate, the acidic resins known by the brand name of Indion® such as Indion 204, Indion 264, Indion 254 and so on. In one embodiment, the ion exchange resin is Amberlite IRP69. Amberlite is a strongly acidic, cation exchange resin available as dry powder. It is insoluble in water and used in pharmaceutical field as a carrier for basic (cationic) drugs. It can be used for sustained release applications with compatible coating technologies. It is official in the United . States Pharmacopeias as sodium polystyrene sulfonate USP. Amberlite IRP69 resin is derived from a sulfonated copolymer of styrene and divinylbenzene. The mobile or exchangeable cation is sodium this can be exchanged for, or replaced by, many cationic (basic) species. Since Amberlite IRP69 resin is an insoluble salt of a strong acid and a strong base, its ability to exchange ions is virtually independent of pH. Usual particle size of a grade of Amberlite IRP69 is more than 0.075 mm. In one embodiment, a cation exchange resin available under the brand name of Amberlite IRP69 is used. The ratio of the ion exchange resin to betahistine ranges from about 1 :1 to 1 :3, preferably about 1 :2.3. The drug to resin ratio was optimized on the basis of target in vitro release profile. According to the present invention, it was found that the resinate complex of betahistine coated with an enteric polymer in a matrix of gel forming polymer, was found to protect the resinate from dissociating in the buffer at an alkaline pH (See comparative example 1 where at a change of dissolution medium from acidic to alkaline, a dose dumping occurred i.e. at 3 hours almost 76% of the drug was released. Without wishing to be bound by any theory, the inventors believed that the presence of gel forming polymers that could protect betahistine-resinate from getting dissociated into free betahistine, would be able to overcome the problem of dose dumping. This finding was indeed surprising since the solution to the problem is to simply protect betahistine-resinate with a strong matrix of polymers that prevent the contact of the betahistine-resinate with the alkaline aqueous environment. Thus, not only the dose dumping problem is said to be solved, but also the solution further provides a solid controlled release dosage form that is stable and suitable for once a day administration.

Thus, the controlled release solid dosage form of the present invention comprises one or more gel forming polymers. In one embodiment, the gel forming polymers are high viscosity grades of hydrophilic polymers that are capable of protecting the betahistine-resinate from the alkaline aqueous medium. It may be noted that the polymers exist in variety of grades and only those grades that provide high viscosity and can provide protection to the betahistine resinate, are considered to be suitable gel forming polymer, according to the present invention. For instance, although, Hydroxypropylmethylcellulose can exist in grades that provide viscosity as low as 5 cps and such grades of polymers are not under the scope of the gel forming polymers of the present invention. Examples of such hydrophilic polymers include, but are not limited to, poly (ethylene oxide), polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid, alginates, carrageenan, cellulose derivatives such as carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl methylcellulose, polycarbophil, carbomer, hydroxypropylmethyl cellulose phthalate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, starch and its derivatives such as hydroxyethyl starch, sodium starch glycolate, dextrin, chitosan and its derivatives, albumin, zein, gelatin, collagen, xanthan gum, guar gum, etc. The cellulose ethers are commercially available in various grades under several trade names. The grades available under a given trade name represent differences in composition and molecular weight. Thus, water-soluble methylcellulose (Methocel A, previously designated as Methocel MC, from The Dow Chemical Co., U.S.A. and Metolose SM from Shin-Etsu, Ltd., Japan) has a methoxyl content of 27.5% by weight to 31.5% by weight and is available in various viscosity grades. Hydroxypropylmethylcellulose is actually a series of compounds (Methocel E, F, J and K, all previously designated as versions of Methocel HG, from The Dow Chemical Co., U.S.A., and Metolose SH from Shin-Etsu, Ltd., Japan), each of which has a different chemical composition with a methoxyl content within the range of 16.5% by weight to 30% by Weight, a hydroxypropyl content within the range of 4% by weight to 32% by weight and each of which is available in various viscosity grades. The viscosities range from 50 cps to 100,000 cps and represent number average molecular weights ranging from 15,000 to over 150,000, as calculated from the data in "Handbook of Methocel Cellulose Ether Products" (The Dow Chemical Co., 1974). In a preferred embodiment, the hydrophilic polymer used according to the present invention is hydroxypropyl methylcellulose of a particular viscosity alone or in combination with other viscosity grades to control the release. A preferable grade of hydroxypropyl methylcellulose is the one, which provides a viscosity greater than 50 cps, such as, for example, K100 LV, and more preferable are those, which provide a viscosity greater than 4000 cps, such as HPMC K4M, or can be greater than 100,000 cps, such as hydroxypropyl methylcellulose K100M that may be suitable for the purpose of conferring controlled or. retarded release characteristics for prolonged periods of time. The amount of gel forming polymer when present in the dosage form may range from 5% by weight to about 50% by weight of the mixture, preferably, 10% by weight to 30% by weight of the mixture. In a preferred embodiment, the gel forming polymer comprises a mixture of two or more grades of cellulose ethers. In another aspect of the present invention, the rate controlling excipients are a blend of gel forming polymers and hydrophobic polymers. Hydrophobic polymers that may be used in such embodiments of the present invention are usually not water-soluble and are independent of pH. The hydrophobic polymers, when used in certain embodiments, are selected from the group consisting, of ethyicellulose known by the name of Aquacoat, propyl cellulose, or those commonly known by the trade name of Eudragit RS and Eudragit RL. Hydrophobic waxes such as free fatty acids, glyceryl esters of fatty acids, fatty alcohols, microcrystalline wax, beeswax, carnauba wax, etc. may also be used as matrix materials. The amount of hydrophobic material when present in the tablet may range from 0 to about 80% by weight of the tablet, preferably, 5 to 50% by weight of the tablet.

In one embodiment, the present invention provides a controlled release solid dosage form comprising,

• a controlled release dosage form comprising 18 mg of betahistine or its pharmaceutically acceptable salt, one or more rate controlling excipients such as gel forming polymers and pharmaceutically acceptable excipients;

• an immediate release composition comprising 6 mg of betahistine or its pharmaceutically acceptable salt,

wherein the solid dosage form is orally administered by humans, the mean plasma concentration of 2- pyridylacetic acid was found in the range of about 50-70 ng/ml at 24 hours.

In one embodiment, the present invention provides a solid dosage form comprising,

• a controlled release composition comprising 36 mg of betahistine or its pharmaceutically acceptable salt, one or more cationic ion exchange resins, one or more rate controlling excipients and pharmaceutically acceptable excipients;

· an immediate release composition comprising 12 mg of betahistine or its pharmaceutically acceptable salt,

wherein when the solid dosage form is orally administered by humans, the mean plasma concentration of 2-pyridylacetic acid was found in the range of about 140- 160 ng/ml at 24 hours. In one embodiment, the present invention provided a dosage form comprising

• a core comprising betahistine or its pharmaceutically acceptable salt, one or more ion exchange resin and other pharmaceutically acceptable excipients;

• coating comprising one or more enteric polymer;

wherein the dosage form when subjected to in vitro dissolution testing in USP type I apparatus rotating at 100 rpm with sinkers, it provides about 25% of betahistine after 2 hours, provides about 40% betahistine after 4 hours, about 60% betahistine after 8 hours and more than 75% of betahistine released after 16 hours, wherein the dosage form is suitable for once a day administration.

Thus, the present invention also relates to a method of providing betahistine to person in need thereof, wherein the method comprises orally administering, once daily, a controlled release solid dosage form comprising a • a controlled release composition comprising fraction of total dose of betahistine or its pharmaceutically acceptable salt, one or more cationic ion exchange resins, one or more rate controlling excipients and pharmaceutically acceptable excipients and

• an immediate release composition comprising remaining fraction of betahistine or its pharmaceutically acceptable salt.

Thus, the present invention also relates to a method of providing betahistine to person in need thereof, wherein the method comprises orally administering, once daily, a controlled release solid dosage form comprising a

· a controlled release composition comprising 75 % by weight of the total dose of betahistine or its pharmaceutically acceptable salt, one or more cationic ion exchange resins, one or more rate controlling excipients and pharmaceutically acceptable excipients and

• an immediate release composition comprising 25 % by weight of the total dose of betahistine or its pharmaceutically acceptable salt.

In another aspect, the present invention also describes a controlled release tablet comprising a core comprising at least two layers

• one layer comprising betahistine or its pharmaceutically acceptable salt, one or more ion exchange resins, one or more enteric polymers and other pharmaceutically acceptable excipients;

• another layer comprising one more excipients that upon contact with water swell quickly and expand and thereby exert pressure on the coating.

water insoluble polymeric coating surrounding the core;

wherein the dosage form when subjected to in vitro dissolution testing in USP type I apparatus rotating at 100 rpm with sinkers provides the following release profile it provides the about 25% of betahistine after 2 hours, provides about 40% betahistine after 4 hours, about 60% betahistine after 8 hours and more than 75% of betahistine released after 16 hours, wherein the dosage form is suitable for once a day administration.

In one embodiment, the solid dosage form of the present invention in the controlled release composition further comprises one or more ion exchange resins. Ion-exchange resins are solid and suitably high molecular weight polyelectrolyte that can exchange their mobile ions of equal charge with surrounding medium reversibly and stoichiometrically. In one embodiment, the controlled release composition comprises cationic ion exchange resin that may be present in the range of 1% by weight to about 35 % by weight and generally 3% by weight to about 15% by weight of the dosage form. In a preferred embodiment, the ion exchange resin may be present in the core of the compressed unit dosage form.

In one embodiment the solid dosage form of the present invention further comprises an enteric material. The enteric material may be a polymer or a substance with pH dependent solubility that can confer delayed release properties to the compressed unit dosage form, particularly, the polymer is soluble in alkaline pH and insoluble in acidic pH. The enteric material may be present in admixture with betahistine or its pharmaceutically acceptable salt or maybe present as a coating over a compressed core comprising betahistine or its pharmaceutically acceptable salt. The ratio between the immediate release fraction and the controlled release fraction can be used to adjust the in vitro drug release profile and in vivo blood concentration profile. Moreover, the profile can be manipulated by the properties of the immediate release and controlled release fractions. Suitable enteric polymers used in the dosage form of the present invention, either in the coating or in admixture with betahistine, include, but not limited to, enteric coating polymers such as acrylic polymers such as acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethpxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamine copolymer, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), polyacrylamide, poly (methacrylic acid anhydride), and glycidyl methacrylate copolymers. Some acrylate based polymers that are commonly used in the pharmaceutical industry known by the trade name of Eudragit L-100, Eudragit LI 00-55 and Eudragit S or by the trade name of Kollicoat® MAE series, which preferentially dissolve in the more alkaline pH of the intestine. ollicoat® MAE 30DP and Kollicoat® MAE 100P are copolymers derived from methacrylic acid/ethyl acrylate and are used as film-formers in the pharmaceutical industry or the production of enteric coatings for solid dosage forms. The enteric polymer may vary from 0.1% by weight to 95% by weight of the compressed core, preferably 1% by weight to 50% by weight and most preferably 5% by weight to 20% by weight of the compressed core. Other enteric polymers such hypromellose phthalate, hypromellose acetate succinate, cellulose acetate phthalate, polyvinyl acetate phthalate, shellac, etc. may also be used. In one embodiment, the dosage form is coated with an enteric polymer. In another embodiment, the tablet comprises betahistine and enteric polymer in homogeneous admixture with other excipient. In the embodiment wherein the enteric polymers in admixture with betahistine and other excipient such as hydrophilic polymers, the compressed unit dosage form is coated swellable composition layer. In one embodiment, controlled release dosage form comprises a controlled release composition in the form of compressed tablet where the core is coated with an enteric polymer to a weight gain of about 5% by weight to 20% by weight of the compressed core and the immediate release composition is a compressed tablet, and the two compositions are filled into a hard gelatin capsule. In another embodiment, the solid dosage form may comprise of coated or uncoated pellets that may be compressed to form a tablet. Alternately, the dosage form may comprise a single tablet comprising one laminar layer of a controlled release fraction of betahistine and an immediate release fraction of betahistine in another layer. In a particular embodiment, controlled release dosage form comprise a controlled release composition in the form of compressed core coated with an enteric coating to a weight gain of about 5% by weight to 20% by weight of the compressed core and an immediate release composition is coated on the compressed core.

The size of the tablet is greater than 5 mm and generally ranges from about 5 mm to about 12 mm. In yet another embodiment, the compressed dosage form maybe in the form of a layered tablet such as a laminar bilayer or laminar trilayer tablet. The layered compressed dosage form of the present invention may be in the form of layered tablet, the details of the technology are disclosed in corresponding patent publication number WO2005039481, which is incorporated herein by reference. The following examples do not limit the scope of the invention and are presented as illustrations.

Comparative Examples 1

Table 1(a): Composition details

Specified amount of betahistine dihydrochloride was complexed with Amberlite IRP69 (sodium polystyrene sulfonate) dried and sifted through 60 mesh. Resinate was further impregnated with polyethylene glycol 3350 and dried. The impregnated resin was further sifted through 60 mesh and the particles were coated with mixture of ethylcellulose and castor oil. The coated particles were filled into hard gelatin capsules. The filled capsules were subjected to dissolution for in vitro release profile. Dissolution testing was done using 900 ml of 0.1 N HC1 (0-2 hour) followed by 6.8 pH phosphate buffer, in USP Type I apparatus (basket) at 100 RPM with sinkers. Table 1(b): Dissolution profile

The dissolution profile achieved at the initial condition was satisfactory, however after at 40°C/70% RH for 1 month (i.e. on accelerated storage condition) the dissolution profile was significantly altered. The dose dumping effect may have occurred because of hygroscopic nature of betahistine and absence of any protection of gelling polymer.

Example 1

Table 2(a): Composition details

Specified amount of betahistine dihydrochloride was complexed with Amberlite IRP69 (sodium polystyrene sulfonate) and granulated with microcrystalline cellulose using polyvinylpyrrolidone K 90 as the binder. The wet mass was dried in fluid bed dryer at an inlet temperature of 60°C. The dried granules were blended with hydroxypropyl methylcellulose 4M, hydroxypropyl methylcellulose K100M, citric acid anhydrous, colloidal silicon dioxide, talc and magnesium stearate. The granules were compressed into tablets. Three controlled release tablets of 8 mg each were then filled in the hard gelatin capsule and subjected to dissolution to check in vitro release profile. Dissolution testing was done using 900 ml of 0.1 N HC1 (0-2 hour) followed by 6.8 pH phosphate buffer, in USP Type II apparatus (paddle) at 50 RPM with sinkers. The dissolution results are given in table 2(b). Dissolution data indicates a considerable release over a dissolution period of time.

Table 2(b): Dissolution profile

The stability data in Table 2 (b) indicates that the dissolution profile achieved at the initial condition does not change substantially on stability at 40°C/70% RH and 30°C/65% RH for upto 6 months. It may be concluded that inclusion of gel forming polymer may be protecting the resinate complex of betahistine form getting dissociated when the table is exposed to alkaline media. Thus, the controlled release dosage form of the present invention can be said to solve the problem of dose dumping which the inventors faced during the development of the controlled release dosage form.

EXAMPLE 2

The solid dosage form of the present invention was in the form of a hard gelatin capsule filled with two compressed controlled release tablets of 9 mg each of betahistine dihydrochloride and one compressed immediate release tablet of 6 mg of betahistine dihydrochloride. The controlled release fraction was prepared according to the formula described in Table 3(a) and the immediate release fraction was prepared according to the formula described in Table 3(b). The total dose of the drug was divided into an immediate release fraction (6 mg) and controlled release fraction (18 mg) for a 24 mg once a day betahistine solid dosage form of the present invention. Table 3(a): Controlled release fraction of betahistine

Specified amount of betahistine dihydrochloride was complexed with Amberlite IRP69 (sodium polystyrene sulfonate) (1 :2.3 drug to resin ratio) by methods well known in the art. The drug-resin complex obtained as an aqueous dispersion was used to granulate mixture of microcrystalline cellulose and polyvinylpyrrolidone K 90. The wet mass was dried in fluid bed dryer at an inlet temperature of 50°C to 60^°C. The dried granules were blended with other excipients. The blend was further lubricated with colloidal silicon dioxide and magnesium stearate. The tablets were then compressed on a tablet compression machine. The tablets were then enteric coated with Kollicoat MAE 30 DP to a weight gain of 10% by weight of the controlled release fraction. The Kollicoat MAE 30 DP is a ready to use dispersion that contains 72.32% by weight of methacrylic acid-ethyl acrylate copolymer 1 : 1, triethyl citrate 14.47% by weight, talc and purified water.

To prepare the immediate release fraction, the ingredients are tabulated in Table 3(b). Betahistine was granulated with microcrystalline cellulose using polyvinylpyrrolidone K 90 as the binder. The wet granules obtained were dried and lubricated with citric acid anhydrous, talc, colloidal silicon dioxide and magnesium stearate and then compressed to form tablets. Table 3(b): Immediate release fraction of betahistine

Two controlled release tablets of 9 mg each [(Table 3(a)] and one immediate release tablet of 6 mg [(Table 3(b)] were filled into hard gelatin capsule. The capsules were subjected to in vitro dissolution testing at initial condition and on storage, using USP type II apparatus.

The dissolution medium was 900 ml of 0.1 N HCl for first 2 hours followed by phosphate buffer pH 6.8 for the remaining hours, at a rotating speed of 50 RPM. The results of the in vitro dissolution are recorded below in Table 3(c). Further, the solid dosage form of example 2 was subjected to accelerated stability studies at 40^°C/75% RH for a period of three months. The assay of betahistine dihydrochloride was determined at specified intervals. The dissolution profile at initial condition and after storage under the accelerated conditions was analyzed. The results of the stability studied are recorded below in Table 3(d). This is because betahistine is known to be hygroscopic and water soluble and it is important that the dosage form maintains its release retarding effect during the shelf life of the product.

Table 3(c): Dissolution profile recorded at initial condition and on storage at 40^°C/75% RH

Table 3(d): Results of the stability studies

' reiers ιο loiai ot Known ana un«

* below quantitative limit (BQL)

It was found that the solid dosage form of Example 2 was a stable composition. The composition provided a control over the release of betahistine on storage in accelerated stability conditions, inspite of the hygroscopic nature of betahistine. Thus, the present invention can be said to have successfully provided a physically and chemically stable composition.

EXAMPLE 3

The solid dosage form is a controlled release core which is coated with immediate release fraction of betahistine. The total dose of betahistine was 48 mg in which the immediate release fraction contained 12 mg of betahistine dihydrochloride and the controlled release fraction contained 36 mg of betahistine dihydrochloride. The controlled release core fraction is a compressed tablet which is coated with enteric coating. These enteric coated tablets were further coated with betahistine dihydrochloride containing immediate release composition of 12 mg. Table 4(a): Composition of the controlled release fraction

The betahistine-resin complex was prepared using water as the dispersion medium. The aqueous slurry of betahistine-resin complex was used as the granulating aid for mixture of microcrystalline cellulose and polyvinylpyrrolidone K 90. The granulated mass was dried, sifted and blended with hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose 100M, colloidal silicon dioxide, talc and magnesium stearate. The lubricated granules were compressed into controlled release tablets containing 75% by weight betahistine hydrochloride which is 36 mg. The controlled release core tablets were enteric coated with Kollicoat MAE 30 DP. The enteric coated tablets were further coated with a drug layer comprising betahistine hydrochloride (25% by weight portion for immediate release) which is 12 mg. The tablets were subjected to dissolution to check in vitro release profile. Dissolution testing was done using USP Type II apparatus with 900 ml of 0.1 N HC1 for first two hours followed by 6.8 pH phosphate buffer for remaining hours at 50 RPM.

The solid dosage form of example 3 was subjected to accelerated stability studies at 40^°C/75% RH for a peri od of three months. The solid dosage form was analyzed for assay of betahistine dihydrochloride at specified intervals. The dissolution profile at initial time point and after storage under the accelerated conditions was analyzed. This is because betahistine is known to be hygroscopic and water-soluble and it is important that the dosage form maintains its release retarding effect during the shelf life of the product.

Table 4(b): Assay, dissolution profile and related substances of betahistine controlled release tablet at initial condition and on storage under stability conditions

*refers to total of known and unknown impurities

* below quantitative limit (BQL)

It was found that the solid dosage form of Example 3 was a stable composition. The composition provided a control over the release of betahistine on storage in accelerated stability conditions, inspite of the hygroscopic nature of betahistine. Thus, the present invention can be said to have successfully provided a physically and chemically stable composition.

EXAMPLE 4

In this example, the solid dosage form is in the form of a bilayer tablet core which is coated with a functional coat. The controlled release fraction of betahistine dihydrochloride was prepared according to table 5(a) and swellable composition layer was prepared according to table 5(b) and further both the layers were compressed to form a controlled release bilayer tablet of the' present invention.

Table 5(a): Composition of controlled release betahistine

Amberlite I P69 added to vortex of purified water and stir for 30 min then added betahistine dihydrochloride stirred for 3 hours and finally added polyvinylpyrrolidone K 30 and stirred for 30 min to get uniform dispersion. In a separate step, a blend of previously sifted hydroxypropyl methylcellulose 4M and mannitol is prepared and transferred to fluid bed processor. The dry powder blend is then granulated by top spraying with drug resin coating dispersion. The wet granules are dried and sifted through suitable screen. The dried granules are then mixed with enteric polymer Eudragit LI 00-55 and the remaining ingredients to form the ready -to- compress controlled release portion.

In a separate step, weighed quantities of silicified microcrystalline cellulose and hydrophobic colloidal silica were sifted and mixed with crospovidone, lubricants and colorants. The above powder mixture is blended and the powder blend obtained is subjected to slugging process. The slugs are milled and then lubricated with stearic acid. The controlled release drug layer powder blend and the swellable composition layer are then compressed into bilayer tablets with suitable tooling. The tablets were further coated with 16% by weight of aqueous dispersion of ethyl cellulose with mannitol in a ratio of 70:30 to a weight gain of 8% by weight of the tablet .The tablets are further top coated with Opadry clear 12% by weight dispersion to a weight gain of 4.5% by weight of the tablet. The tablets were subjected to dissolution studies using USP Type I apparatus using 900 ml of 6.8 pH phosphate buffer as dissolution media at 100 rpm.

Table 5(c): Dissolution profile

EXAMPLE 5

The composition of example 1 of the present inventidn was evaluated in healthy human subjects. Study design involved single vs multiple dose, open label, randomized, comparative relative bioavailability and 2-way crossover. Twelve healthy human adult volunteers who were made to fast for at least 10 hours prior to dosing and 4 hours after dosing, were given the tablets of example 1.

Latter meals or snacks were served 4 hours after dosing and at appropriate times thereafter.

Volunteers were advised to consume the complete meal and the same is recorded. Meal plans were identical for all two periods. Water was permitted ad-lib until 1 hour before dosing and again 1 hour after dosing. Test product i.e. single oral dose (lx 24 mg capsule) of the comparative example 3 was given with 240 ml (±2 ml) of water at ambient temperature in the morning according to the randomization. Blood samples were collected before dosing at 0.00 hours (pre-dose) and at different time points after dosing and analysed for 2-pyridylacetic acid, a major metabolite of betahistine.

Reference product was administered three times a day. The first oral, dose of Sere® 8 (Betahistine d (hydrochloride) was given with 240 ml of water at ambient temperature in the morning and second dose of one tablet 8 mg after 8 hours of the first dose and the third dose of one tablet of the 8 mg was given 8 hours after the second dose (i.e., 16 hours after the first dose) according to the randomization. Blood samples were collected before dosing at 0.00 hours (pre-dose) and at different time points after dosing and analysed for 2-pyridylacetic acid, a major metabolite of betahistine. The plasma levels have been mentioned in Table 6.

Table 6: Mean plasma concentration 2-pyridylacetic acid-time profile after oral administration of tablets of comparative Example 3 (OD) vs immediate release tablets ( i.d)

The table 6 provides the mean plasma concentrations achieved for a period of 24 hours. It was found that at the end of 14-20 hours, the mean plasma concentration dropped down to low levels of about 67ng/ml to 37ng/ml. These values have been also been presented by a graph, in figure 1. Also, the A/B ratio of the C_max was found to be 106.7 indicating a high C_max and an early T_max of 5.00 hours, AUCo of 92.80 which makes the composition unsuitable for once a day administration. Thus the sub-therapeutic level at the end of 20 hours and early T_max< the reasons that the composition without immediate release fraction of betahistine, was considered to be not be suitable once daily administration EXAMPLE 6

The composition of example 2 of the present invention is evaluated in healthy human subjects. Study design involves single vs multiple dose, open label, randomized, comparative relative bioavailability and 2-way crossover. Twelve healthy human adult volunteers who were fasted overnight and then administered a low fat breakfast (650+50 Kcal) meal 30 minutes prior to administration of the drug product, were given the capsule of example 2. Latter meals or snacks were served 4 hours after dosing. Test product i.e. single oral dose (1x24 mg capsule) of the example 2 was given with 240 ml of water at ambient temperature in the morning 30 minutes after administration of low-fat breakfast (650±50 Kcal) according to the randomization. Blood samples were collected before dosing at 0.00 hours (pre-dose) and at different time points after dosing and analysed for 2-pyridylacetic acid, a major metabolite of betahistine. Reference product i.e. single oral dose (1x8 mg tablet) of the Sere® 8 (Betahistine dihydrochloride) was given with 240 ml of water at ambient temperature in the morning and second dose of one tablet 8 mg after 8 hours of first dose and the third dose of one tablet of 8 mg was given 8 hours after the second dose (i.e., 16 hours after the first dose) according to the randomization. Blood samples were collected before dosing at 0.00 hours (pre-dose) and at different time points after dosing and analysed for 2-pyridylacetic acid, a major metabolite of betahistine. The plasma levels have been mentioned in table 6.

Table 7: Mean plasma levels of 2-pyridylacetic acid from composition of example 2 of the present invention vs reference product of betahistine immediate release tablets available under the brand name Sere ^® 8

The table 7 provides the mean plasma concentrations achieved for a period of 24 hours. The results provide confirmation that the controlled release formulation of the present invention (example 2) provides maintained plasma levels of drug for 24 hours. The prepared controlled release formulation of the present invention is thus suitable for once daily administration. The mean plasma time profile curve has been plotted and depicted in figure 2. At the end of 20 to 24 hours, the composition of example 2 were found to give therapeutic levels of betahistine and thus, the composition having an immediate release composition along with controlled release composition, was considered to be suitable for once a day administration. The results of the biostudy of example 1 subjected to pharmacokinetic study indeed proved this conclusion, that it is very critical and crucial to have an immediate release fraction of betahistine so that the composition provides plasma levels that are sustained for 24 hours period of time. This finding was indeed surprising, as there are no reports of pharmacokinetic or pharmacodynamic studies' for betahistine, so far reported in the literature.

EXAMPLE 7

The composition of example 3 of the present invention is evaluated in healthy human subjects. Study design involves single vs multiple dose, open label, randomized, comparative relative bioavailability and 2-way crossover. Twelve healthy human adult volunteers who were fasted for at least 10 hours before breakfast, subjects were given the high caloric high-fat breakfast, 30 minutes prior to administration of the drug product. Volunteers were advised to eat the complete meal in 30 minutes or less, were given the tablet of example 3. Latter lunch, snacks and dinner was served at 5.0, 8.0 and 12.0 hours after dosing and at appropriate times thereafter. Test product i.e. single oral dose (1x48 mg tablet) of the Example 3 was given with 240 ml (±2 ml) of water at ambient temperature in the morning according to the randomization. Blood samples were collected before dosing at 0.00 hours (pre-dose) and at different time points after dosing and analysed for 2-pyridylacetic acid, a major metabolite of betahistine. Reference product i.e. single oral dose (1x16 mg tablet) of the Sere® 16 (Betahistine dihydrochloride) was given with 240 ml (±2 ml) of water at ambient temperature in the morning and second dose of one tablet 16 mg after 8 hours of first dose and the third dose of one tablet of 16 mg was given 8 hours after the second dose (i.e., 16 hours after the first dose) according to the randomization. Blood samples were collected before dosing at 0.00 hours (pre-dose) and at different time points after dosing and analysed for 2-pyridylacetic acid, a major metabolite of betahistine. The mean plasma time profile cruves have been provided in figure 3. Table 8: Mean plasma levels of 2-pyridylacetic acid from composition of example 3 of the present invention vs reference product of betahistine immediate release tablets available under the brand name

The table 8 provides the mean plasma concentrations achieved for a period of 24 hours. The results confirmed that the solid dosage form having a fraction of dose in the immediate release form and a fraction of dose in the controlled release form provided sustained plasma levels of betahistine at the tapering end of 24 hours, making the composition suitable for once a day administration.

Claims

Claims:

1. A controlled release dosage form comprising a mixture of betahistine or its pharmaceutically acceptable salt complexed with ion exchange resin and one or more gel forming polymer.

2. A controlled release dosage form as claimed in claim 1, wherein the dosage form is coated with enteric polymer.

3. A controlled release dosage form as claimed in claim 1, wherein the dosage form comprises a controlled release composition comprising about 60% by weight to 80% by weight of the total dose of betahistine or its pharmaceutically acceptable salt and an immediate release composition comprising about 20% by weight to 40% by weight of the total dose of betahistine or its pharmaceutically acceptable salt.

4. A controlled release dosage form as claimed in claim 1, wherein the gel forming polymer is selected from the group consisting of hyaluronic acid, alginates, carrageenan, carboxymethyl cellulose sodium, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl starch, chitosan, xanthan gum, gaur gum and mixtures thereof.

5. A controlled release dosage form as claimed in claim 1, wherein the gel forming polymer is present in an amount of about 10% by weight to 30% by weight of mixture.

6. A controlled release dosage form as claimed in claim 1, wherein the ratio of ion exchange resin to betahistine dihydrochloride ranges from 1 :1 to 1 :3.

7. A controlled release dosage form as claimed in claim 1, wherein the dosage form is a compressed unit dosage form.

8. A controlled release dosage form as claimed in claim 3, wherein the controlled release composition is in the form of compressed tablet and the immediate release composition is a compressed tablet, wherein the compositions are filled into a hard gelatin capsule.

9. A controlled release dosage form as claimed in claim 3, wherein the controlled release composition is a compressed core and immediate release composition is a coated on the compressed core.

10. A controlled release dosage form as claimed in claim 9, wherein the compressed core is coated with an enteric coating to a weight gain of about 5% by weight to 20% by weight of the compressed core.