EP1680095A2

EP1680095A2 - Valsartan containing formulation

Info

Publication number: EP1680095A2
Application number: EP04797393A
Authority: EP
Inventors: Beáta VLADOVICOVA; Mikulás LEHOCK; Viera Kormanova; Viera Hubinova
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2003-11-03
Filing date: 2004-11-02
Publication date: 2006-07-19
Also published as: WO2005041941A3; SK50472005A3; WO2005041941A2; EA008063B1; EA200500973A1; PL382044A1

Abstract

A pharmaceutical containing valsartan, optionally a combination of valsartan with hydrochlorothiazide, obtainable by direct tabletting, comprises a filler having a particle size of 10 to 1000 µm, preferably 50 to 400 mm, in amounts of 20 to 60, preferably 40 to 60% by weight, based on the total weight of the formulation.

Description

Valsartan containing formulation

Technical Field

The invention relates to a tablet containing the active substance valsartan, optionally valsartan in combination with hydrochlorothiazide, prepared via direct tabletting.

Background Art

Valsartan, a compound having the chemical name N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5- yl)[l,l'-biphenyl]-4-yl]methyl]-L-valine, of formula I

of blood pressure. They are used to treat hypertension and chronic heart failure.

v ΛibΛiic i mm reiaieα compounds, wnicn snow affinity to receptors ot angiotensm 11, were described in US patent 5,399,578. The dosage form described in the patent contains:

■ A mixture of the active substance, lactose and parts of corn starch was granulated via wet ' granulation and after drying mixed with the rest of the starch and calcium stearate and talc and subsequently compressed into tablets.

In the ^'international patent application WO 95/24901, in example 1, a dosage capsule form is described of the following composition:

The first two components are granulated via wet granulation with a solution of the third and i . ^{• ■} i l . ^• fourth components in water. Components 5 and 6 are added to the dry granulate and the mixture, is filled into capsules.

However, as noted in application WO 97/49394, these earlier-published methods were not well reproducible, especially in their compression into the tablet form. This application applies a method of dry granulation for production of tablets of valsartan. The known composition from application WO 95/24901 has been slightly modified:

The first to fifth components are mixed and compacted at pressures 25 to 65 kN. The compacted material is further forced through a sieve. Granulate produced in this way is mixed with magnesium stearate and the mixture is compressed into tablets.

What is considered an extraordinary advantage of the production method of the cited application is the fact that for each specific formulation it is possible to find a minimal necessary compacting pressure within the range of compacting pressures from 25 up to 65 kN, which results in obtaining a tablet having about six times faster disintegration rate than that obtained via usual compacting (i.e. using higher pressure).

The faster disintegration of the tablet prepared via this method results in faster release of the active substance, its faster absorption in the organism, and, eventually, improvement of bioavailability of the formulation. This fact was verified in patent application WO 01/97805, in which bioavailability of the tablets prepared via this method was compared with that of capsules having analogous composition.

However, it has now been surprisingly found out that a small change in compόsitiδri of a valsartan based formulation allows avoiding compacting at all. This not only lowers labour expenditure of the dosage form, but appropriate disintegration rate of the tablet is better guaranteed without having to seek the optimum pressure.

Disclosure of Invention ^; "-^'-'^",

The p e'sent invention consists in a pharmaceutical formulation in the fόrai of tablets, ^' ' '^{! :}"- - '^> containing valsartan, the'active substance used for treating hypertension, όptiόnal Vaisartan in combination with hydrochlorothiazide, which is obtainable by direct tabletting. Hydrochlorothiazide is a thiazide diuretic, having diuretic and anti-hypertensive actions, and when combined with valsartan, the anti-hypertensive effect is enhanced. ^• ' '¹ -^''^{Λ n "}' ^u*

^■, ' , ^{' •}, »^{" •} . : ^• . ■ ; .^{• ■} • ! < •^■ . ^■ ! ^•. ! π \\ .. 'S i^'' i'i ^': > ; ! .^' The essence of dry tabletting consists in preparing the tablet material by dry mixing-i'The tablet material prepared in this way can be used for compressing cores and/or tablets without further treatment. Preparation of the tablet material is technologically simple; it is limited only iσ technological steps that are not demanding in terms of energy and time. The preparation of the tablet material does hot include stress-involving processes such as introducing a humidifier into the mixture of the active substance and additives, and dry granulation via compacting of the mixture of the active substance and additives for preparing the tablet material.

Compressing of the tablet material prepared via dry mixing allows a preparation of cores and/or tablets of satisfactory parameters and the mentioned method of preparation and selection of additives according to the invention also secure good stability of the formulation and desired physical properties of the dosage form.

TheWclmϊqu'e of dϊfect abletting is not only simple, b t, above mildest ^ήe¹ of ⁵allthe^! methods: Therefore, it represents a further progress cόriipared to tKB e'Mieridfesέribe '- ^;' ^ ^'■"^■ '^■ techniques¹ of dry "granulation, which are associated with compaetihg'arid'^thefHfo !, with ^:' necessity of using' high pressures, that can later cause problems wim^rrelέasιn^'g; me'hifedicament into the'patϊent's organism. Because of such problems, it may happen that a significant portion of the medicament is not utilized at all.

However, for applying direct tabletting, it is necessary to find such a mixture of the active substance and additives, which could be tabletted without any modification, producing a tablet complying with all requirements. A tablet of a pharmaceutical formulation has to be sufficiently hard to withstand various types of stress during transportation. However, it has to disintegrate fast enough in contact with water, in order to be ^"able to release ^"the ^'active substance into the solution before it passes through the upper¹ part of patient's digestive tract. The values of hardness of the tablet and of release (dissolution) of the active substance are, therefore, two factors that are more or less antagonistic and conditions have always to be optimized.

For the technique of direct tabletting, such additives are selected that have especially good tabletting properties. These include, above all, lactose granulate or microcrystalline cellulose.

Such a. substance is subsequently mixed with the active substance in a multiple excess so that its positive tabletting properties may prevail in the mixture. Such an excess can, however, not be ensured in every case. In a case such as valsartan, where the highest dose is 160 mg, such procedure would result in large, hard-to-swallow tablets weighing more than 1 g.

Patent application WO 9749394 points out the fact that it is possible to produce 300-mg tablets containing 160 mg valsartan by compacting as a surprising possibility. However, it would be a remarkably greater success if such a tablet could be produced without using any granulation.

Accordingly, a mixture capable to be directly tabletted, or a tablet produced via such technique, preferably contains 30 to 60% of valsartan.

The tablet material described in this invention includes, apart from the valsartan active substance, optionally valsartan in combination with hydrochlorothiazide, other additives, of which the most important one is suitably selected filler, which has a decisive importance for quality of the produced tablets. For ensuring the function of direct tabletting it is necessary to select a filler having a defined particle size and in defined amount.

Specifically, for valsartan, optionally its mixture with hydrochlorothiazide, it has turned out that it is necessary to choose particle sizes of the filler in the range of 10 to 1000 μm, preferably 50 to 400 μm, and its contents of 20 to 60% by weight, preferably 40 to 60% by weight.

The filler can be selected from the group including microcrystalline cellulose, lactose, the polyalcohols mannitol or sorbitol, calcium hydrogen phosphate and combinations of microcrystalline cellulose with a mono- or oligo-saccharide or polyalcohol.

A preferable composition of the filler according to this invention is microcrystalline cellulose having a particle size of 10 to 1000 μm, preferably 50 to 190 μm, especially preferably 90 μm, in amounts above 40 to 60% by weight, spray-dried anhydrous lactose having a particle size of 10 to 250 μm, preferably 150 to 250 μm, in amounts of 30 to 60%, compact lactose hydrate having a particle size of 10 to 250 μm, in amounts 40 to 60% by weight, a polyalcohol selected from mannitol or sorbitol, which is compacted and has a particle size of 100 to 850 μm, preferably 200 to 400 μm, in amounts of 40 to 60% by weight, calcium hydrogen phosphate having a particle size of 10 to 200 μm in amounts of 40 to 60 % by weight, a combination^' of microcrystalline cellulose with lactose, preferably spray-dried anhydrous lactose,^{' "}in a weight ratio' of 1:2 to 2:1 in amounts of 20 to 55%, and a combination of microcrystaliihe cellulose and a polyalcohol, preferably a compacted polyalcohol, in a ratio of 1:2, in amounts of 20 to 5 55%i'based on the total weight of the formulation. • _; ^■•- ^.»».«.^!. ^• .^•...••

; ..; ^• .. . . . ^• ; ^■ _^' '.-• ^'JK; : ^■ :^'•.^{• ■■}>

Microcrystalline cellulose, optionally its mixture with another filler, is an especially referred filler. With a suitable combination of fillers, by combining advantageous properties of both the components, it is possible to achieve a composition with minimal size of the tablet.

10 Microcrystalline cellulose with lactose or ■ polyalcohols like mannitol is a preferable combination.

[^•(living a panicle i/c of 10.• ■'■'■ ;n>, v ,f r. ,'-, .-;^'-i^,: :- % by wei ht a combination of prbρ'e eV^: ^he tablet¹ Material'; anti-adhesive agents¹ facilitating ^■ltBfeⁱ^aBieffi-^ⁱβfo'ee&^liaήd 15 age sraidϊhg itfdisiή'tegratiόn of the tablets. .->^] " ^•>'- ^:'^' -' -^ui'^; °^ri;^ «' aiu^'υu ^{ls <}S2^ ^l<:

L⁷^- ;>, bi>:- •«'.^'• ι»- iii i!^''^!.i^; '^■• '.'. .■ ^• ι ^' .• ^• . ^{■ ' ■ ' • '}

In another embodiment of the invention, the tablet contains 3 to 10% of a disintegrating agent, of which¹ the¹ sodium salt of carboxymethyl starch appears to b the 'preferable^''' one: -This substance will further improve disintegration rate of the tablet and allow fόr^: achieving an 20 excellent release rate of the active substance.

In a 'further embodiment, the tabletting mixture includes substances that improve its flow properties. Colloidal silica (silica colloidalis anhydrica) is the most advantageous substance for the described mixture, preferably in amounts from 0.1 to 10% by weight, ^■■'mos⁵i^eerabiy^'i0'.5 25 to 2% by weight. Theses^' substances are important for avoiding fluctuations- oτ 'the tablet weight, caused by inappropriate flow of the solid mixture through^' the ^"hopper into the high- performance tabletting machine.

The mixture can also contain an antiadhesive, preferably magnesium stearate, in amounts of 30 0.1 to 10% by weight, preferably 0.5 to 4% by weight.

It is possible to prepare a tablet material, or tablets, resp., from the above mixtures via dry ^■.,-_■. route, by dry mixing and direct tabletting. Tablets prepared according to the invention ensure reproducibility of the production process.

The preparation of the tablet material has the advantages of not being demanding in terms of energy and time.

The above process of production of valsartan containing tablet material and solid dosage forms via direct tabletting by dry mixing and selection of additives according to the invention allow for preparing a tablet material and solid dosage forms with excellent physical parameters.

Examples

Example 1

Valsartan 160 mg coated tablets

The description of technology of preparation of the tablet material (dry route, direct tabletting):

1. Mixing I: active substance, microcrystalline cellulose and carboxymethylamylum natricum are mixed in a homogenizing device for 15 minutes. 2. Mixing II: final treatment - silicii dioxidum colloidale and magnesii stearas - are added and mixed in a homogenizing device for 15 minutes.

3. Tabletting.

Two important factors were determined for thus prepared tablets: Fracture resistance, which is necessary for maintaining the integrity of tablets during transport, and rate of release of the active substance into the dissolution medium, the value of which indicates the availability of the drug for the patient's organism. Both values were measured using standard procedures. 0 The tablets prepared via the procedure had fracture resistance of at least 70N, which indicates that they will not be damaged during usual transport.

2 Mixing II: final ircαiii 'n ^{• ■•} lioi iαvduru colloidale vind magnesii stearas - are ad ed and

Durmg^te ng ϊhWrateδf -release of trie'atiVe' 'substance, at least 75% of the total content of the active' ^lsu^°i_ft^,ance was released within 45 minutes. Such a result is in very good agreement with 5 the already registered and sold preparation Diovan of Novartis.

5 1 wo important taαo"": -. _*.: V'< _;n>ικ- ! r . ^■!, . <._:v,v;-.<^{! '}.;i^''!ci: Frjoitn'e reistance_s is tablets produced' via this hew meth d'ha e' ϊ3eni aϊ δ & ^]as prό'duc!s^; cqιied^svia known, standard procedures. ^{■ •} "^{;; ■}'^■ rⁱJ'-^'^-s th avaιlal_;ιhiy OJ

I Ό diuu for !¹..; :.,Ή. •ι^"ι^'u ■ ^• • ^{' ' •'}: ■ • ■-. . :>^'■ • '<^■'■ "-: ..->'< ?i^: i^'d proccdui^'vs 0 Example 2

^■') !^'!.». ;al>i v , Γ- ^■■..^•>: ^■• ,., \,. ^■ _ . . c i M k'-;st 70 , which ,dicait:s cellulose filler

^•.!!'

25 The tablet core was coated as in Example 1.

Valsartan 80 mg coated tablets

The tablet core was coated as in Example 1.

Valsartan 160 mg coated tablets

The tablet core was coated as in Example 1.

Valsartan 320 mg coated tablets

The tablet core was coated as in Example 1.

Description of technology of preparation of the tablet material (dry route, direct tabletting):

4. Mixing I: active substance, microcrystalline cellulose and carboxymethylamylum natricum are. mixed in a homogenizing device for 15 minutes.

5- Mixing-I-I÷-final-treatment - silicii dioxidum colloidale and-magnesii- stearas — are-added and

! mixed in a homogenizing device for 15 minutes. 0 fab eMrig:^r

Two important factors were determined for thus prepared tablets: Fracture resistance, which is necessary for maintaining the integrity of tablets during transport, and rate of release of the active substance into the dissolution medium, the value of which indicates the availability of 5 the 'drug' for trie patient' s organism. Both values were measUred using standard ^!p'roc^!edures.

The' tablets prepared via the procedure had fracture resistance of at least 70ΪSF,^riwh indicates that^rt e^will' rib tb^'e '-^"damaged during Usual'transport.' 0 iDuririjg te'stihg the rate of release of the active substance, at least 75% of the total content of the ' active-'έubs'tance was released within 45 minutes. Such a result is in very good agreement with the already registered arid sold preparation Diovan of Novartis.

It turn^'s out- therefore, that tablets produced via this new method ⁱhave deⁱtitical' fb'pbrtϊes *as5 prόdUcts¹ acquired via known, standard procedures. Example 3

Combination of microcrystalline cellulose and mannitol

Valsartan 80 mg coated tablets

The tablet was produced by the procedure of Example 2. The tablet core was coated as in Example 1.

Example 4

Combination of microcrystalline cellulose and anhydrous lactose

Valsartan 80 mg coated tablets

Treatment conducted as in Example 2. The tablet core was coated as in Example 1.

Example 5

Mannitol used as the filler.

Valsartan 80 mg coated tablets

The tablet core was coated as in Example 1.

Example 6 iC.oiiip sitipri having less than 35% valsartan

^'.(^'- rnpwfti. f.-i -

Claims

C L A I M S

1. A pharmaceutical formulation containing valsartan, optionally a combination of valsartan with hydrochlorothiazide, obtainable by direct tabletting, characterized in that it comprises a filler having a particle size of 10 to 1000 μm, preferably 50 to 400 μm, in amounts of 20 to 60, preferably 40 to 60% by weight, based on the total weight of the formulation.

2. The pharmaceutical formulation according to claim 1, characterized in that it comprises a filler selected from the group including microcrystalline cellulose, lactose, the polyalcohol mannitol or sorbitol, calcium hydrogen phosphate and a combination of microcrystalline cellulose with a mono- or oligo-saccharide or polyalcohol.

3. The pharmaceutical formulation according to claim 2, characterized in that it comprises 30 to 60% by weight of valsartan, optionally 3 to 12% by weight of hydrochlorothiazide, and a filler selected from the group including microcrystalline cellulose having a particle size of 10 to 1000 μm, preferably 50 to 190 μm, in amounts above 40 to 60% by weight, spray- dried anhydrous lactose having a particle size of 10 to 250 μm in amounts of 30 to 60% by weight, lactose hydrate having a particle size of 10 to 200 μm in amounts of 40 to 60% by weight, a polyalcohol selected from mannitol or sorbitol, which is compacted and has a particle size of 100 to 850 μm, in amounts of 40 to 60% by weight, calcium hydrogen phosphate having a particle size of 10 to 200 μm in amounts of 40 to 60 % by weight, a combination of microcrystalline cellulose with lactose, preferably anhydrous spray-dried lactose, in a weight ratio of 1 :2 to 2: 1 in amounts of 20 to 55 % by weight and a combination of microcrystalline cellulose and a polyalcohol, preferably compacted polyalcohol, in a ratio of 1:2 in amounts of 20 to 55 % by weight, based on the total weight of the formulation.

4. The pharmaceutical formulation according to any of the preceding claims, characterized, in that it further comprises a disintegrating agent, a substance modifying the flow properties of the tablet material and an antiadhesive.

5. The pharmaceutical formulation according to any of the preceding claims, characterized in that it comprises 3 to 10% by weight of the disintegrating agent, preferably the_^sodium salt of carboxymethylstarch.

6. The pharmaceutical formulation according to any of the preceding claims, characterized in that it comprises 0.1 to 10% by weight, preferably 0.5 to 2% by weight of the substance modifying the flow properties of the tablet material, preferably colloidal silicon dioxide.

7. The pharmaceutical formulation according to any of the preceding claims, characterized in that it comprises 0.1 to 10 % by weight, preferably 0.5 to 4 % by weight of the antiadhesive, preferably magnesium stearate^"

8. The pharmaceutical formulation according to any of the preceding claims, .characterised hi that it comprises 160 mg of valsartan, 80 to 200 mg of the filler aηdil0[to<2Q-.mg^f,tlιe .;:,.] < sodium )S,altι of .carboxymethylstarch. ,

9. The pharmaceutical formulation according to any of claims.1-7, characterized n;that it ;_r: comprises; 80 mg of valsartan, 40 to 100 mg of the filler and 5 to 10 mg qf the Sp ium salt of carboxymethylstarch. . ,. . ..' ^■ , ..,; f. _r ^< .. i d-._;\ .:•

). The pharmaceutical formulation according to any of claims 1-7, characterized _;in_: that it . comprises 40 mg of valsartan, 20 to 50 mg of the filler and 2.5 to 5 mg of the sodium salt of carboxymethylstarch.