CA1304686C - Pharmaceutical composition containing cimetidine - Google Patents

Abstract

A PHARMACEUTICAL COMPOSITION
CONTAINING CIMETIDINE

ABSTRACT

The invention provides a pharmaceutical granule comprising cimetidine and 2-20% (w/w) relative to the cimetidine of a co-polymer of dimethylaminoethyl-methacrylate and neutral methacrylic acid asters.
Compositions of this invention have good palatability and dissolution characeristics.

Description

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A PHARMACEUTICAL COMPOSI~l~ION CO~TAINING CIMETIDINE

This invention relates to granules of cimetidine which are u~eful in ~he preparation o~ tabl0ts and which have an improved flavour.

Cimetidine i8 a hi~tamine H2-antagonist. It has been de~sribed in U.K. Patent S~eci~ication 1,397,~36.
Cimetidine ha~ been ~hown to be useful in the treatment of duodenal, ga~tric, recurrant and stomal ulceration, and reflux oe~ophagitis and in the management o~ patients who are at high risk ~rom haemorrhage o~ tha up~er ga8tro-intestinal tract.

Cime~idine i~ know~ to have a pconouncsd bitter ta~te. Thi~ is ~ot u~ually a problam when the dosage Porm employed i8 a capsule or a tablet designad ~o be swallo~ed, thereafter to dis$ntegrate upon re~ching ~he stomach. Howeval, such dosage form6 can be impractical when it i8 desired to admini~ter a large amount of active ingrsdient, or to co-admini ter a relatively bulky second active ingredient such as an an~acid or alginate.
Moreover many individual~ have di~iculty in svallowing a solid do~age ~orm.
A convantional approach to administering ralatively large amounts o~ active ingrediant in a ~olid do~age form is by mean~ o~ a chewable tablet, i.e. a tablet which disintegrate~ in the mouth upon bein~ chewed. Such a tablet al80 circumven~s ths p~oblem of a solid dosaqe being di~icult to swallo~.

It will be appreciated ~hat a ma30r requirement o~
such a dosage form i6 that it must be palatableO since an unpalatable ~ormulation increase~ the ri~k of a patient neglecting to tako ~he tablet. Such non-com~lianca with ~' ~

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~2--the dosing regimen will in tu~n delay or prevent the pa~ient's recoveLy from the condition under treatment.

A further requirement of such a compo~ition is that once the disintegrated tablet reache~ the stomach, the individual particles shollld release the active ingredient rapidly and completely in order to ensure that sub~tantially all of the active ingredient is ab~orbed;
that is to say the formulation should be bioavailable.
In the case of cimetidine, because of its bitterness, the provision of such a dosage form represents a considerable problem.

Several solution to the problem of the bitterne~s of cimetidine have been proposed. One propo6al i6 disclosed in Jaeanese Patent Application No. 67375/80 wherein there are described granules of cimetidine containing ethylcellulo6e preferably in the range of 15 to 85% (w/w) and particularly 50% (w/w) relative to the cimetidine. Such granules are described as having good stability to light, good disfiolution characteristics and are stated not to have a bit~e~ taste. These properties are stated to be specific to granules containing ethylcellulose; it i~ disclosed that methylcellulose does not impart such proeerties.

Another eroposed solution is disclo~ed in Japanese Patent Application No. 86228/78 which 6imilarly describe6 cimetidine granule~ containing a specific polymeric substance: in this case eolyvinylacetal diethylamino-acetate. The paLticular granules exemplified in the specification of JP 8622~/78 are characteLi6ed by having a high ~ugar content (approximately 75% by weight of the granule~), and it is noteworthy that, of all those granule~ for which test Lesults are provided in the 4~

specification demonstrating acceptable solubility and palatability characteristics, all contain approximately 75~ by weight of granulated sugar ~i.e. presumably sucrose).

Although both JP 67375/80 and JP 86228/7B address the problem of the bitterness of cimetidine, in neither case is it sugges~ed that the granules described therein would be suitable for preparing chewable tablets. In the lOcase of the granules disclosed in JP 86228/78, the use of a high loading of sucrose would be expected to be disadvantageous in a chewable dosage form in view of the well known ability of sucrose to promote tooth decay, 15As far as we ace aware, up un~il the time of the making of the present invention, no chewable tablets containing cimetidine have been marketed, or marketed to any significant extent, even though cimetidine ~ se has been on the market for approximately ten years, and is a well established drug.

Thus it is clear that there remains a need for a cimetidine solid dosage form such as a chewable tablet which is both palatable and allows efficient eelea~e of the cimetidine in the stomach.

It has now surprisingly been found that by granulating cimetidine with a particular amount of a earticular polymethacrylate co-polymer, a granule is foemed which is palatable and which has good dissolution characteri~tics in the stomach, that is to say, it releases the cimetidine rapidly and completely. Such a granule is particularly useful in the preearation of chewable tablets.

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~4--In a first a6pect, therefora, the present invention provides a pharmaceutical gra~ule comprising cimetidi~e and 2-20~ (w/w) relative to the cimetidine of a co-polymer o~ dimethylaminoethylmethacrylate and neutral methacrylic acid esters.

It i8 preferred that the co-poly~er ~hould be pre6ent in an amount o~ approximately 5-15~ (w/w) relative to the cimetidine and most pre~ecably it is pre~ent in an amount of approximately 10% ~w/w).

A co-polymer o~ the type suitable for u8e in the pre6en~ invention i8 Eudragi~ ~ which i8 manu~actured and marketed by R~hm-Pharma of Darmstad~.
In addition to the good palatability and good dissolution characteris~ic6 of the granule~ of the present invention, a ~urthar adYantags ~8 that ~hey to not need to contain a hiqh loading oi sugar, and typiaally they con~ain no sugar at all. It i8 pre~erred that the granules consi~t essentially only o cimetidine and the co-polymeE.

The granules of the present inven~ion ty~ically are prepared by a wat-granulation method wherein a solution of the Eudragit E in a suitable 801vent, ~or exa~ple dichloromethane, i~ added to the cimetidine and the resulting mixturs i~ blended to fo!m granule~. The BOlVene i$ 108t through evaporation during the granulation sta~ and ths ~ubsequent dryiAg step. It ~ill be appreciated that ln uch a ~ethod, the Eudragit is acting as a granulating agent.

Alternatively, the polymethacrylate co-polymeE can be used as a coating agent rather than as a granulating agent. In such a case, the cimetidlne ca~ be granulated * Trade mark ", ~L3~46~3~

in conventional fashion, for example by using a conventional binding agent such as polyvinylpyrrolidone (PVP): the resulting granules then being coated with the polymethacrylate co-polymer according to known method~.
Such methods include tumbling the granules in a coating pan with a solution of the co-polymer or spraying a solution of the co-polymer onto the granules in a fluidised bed apparatus.

Preferably the granules are free of fine powder and aggregates: that i6, before compres~ion, the granules will pass through a 1.4 mm sieve and be retained by a 0.2 mm sieve.

The granules of the present invention are particularly suitable for use in chewable tablets and ~hus chewable tablets containing such granules represent a preferred aspect of the invention.

The tablets of this invention contain normally at least 75 mg of cimetidine. As a maximum the tablet will not normally contain more than 800 mg of cimetidine.
Preferably it contains 100 or 200 mg of cimetidine.

The tablets of the invention can also contain a hydroxide or carbonate antacid. Examples o~ suitable antacids include aluminium hydroxide, magnesium hydroxide, magnesium carbonate, calcium carbonate and co-dried gels for example aluminium hydroxide-magnesium carbonate co-dried gel. In practice the quantity of antacid is between 5 milliequivalents per tablet and 30 milli-equivalents, typically approximately 14 milliequivalents.

The tablets can also contain solid diluents such as sugars and sugar alcohols, for example lacto~e, xylitol, sorbitol and mannitol. Where desired additional 4~8~

119~0 6weeteners can be added, ~or example a~monium glycyrrhizinate, godium cyclamate and ~odium saccharinata a~ well a~ ~lavours and taste maskers, for exampla ~odium chlori~e and Contramarum, and tableting 8ta~ch, whiCh gives the tablets a palatable texture.

The tablets can also contain other standard tableting excipient~ ~or example a di~integrant uch a~ a cross-linked polymeric disinteg~ant; particular examples being c~o~-linked polyvinyl pyrrolidone and cross-linked carboxymethyl celluloses.

Where the tablet contain~ an antacid, pre~erably the antacid is pre-compreesed or granulatsd before it i8 mixed lS with the cimetidine granules, ~or example as degcribed in a co-pending Canadian application 566,093, and as de~cribed in the Example~ 4 and 5 of this ap~lication.
The granule~ caP be sieved to remove ~ine par~icles and larger ~artiales. Preerably the granulea pass throuqh a 1.4 ~m giQVe but are retained by a 0.2 mm sieve.

The antacld ca~ be pre-compre~ed or granulated by standard me~hods.

Tablets prepared according to the present invention can also contai~ alginate. The purpose of the alginate ~0 is to ~orm a ra~t of mucilage which ca~ ~loat on the gastric contents to prevent re~lux oesophagitls.

Typically the alginate i8 in the torm o~ alginic acid and ln such casas the tablet u8ually also contains a carbonate salt such as sodium bicarbonate to react with the alginic acid to form an alginate ~alt and liberatQ

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~3~4686 ~ -7-carbon dioxide. The liberated gas is dispersed and entrapped in the mucilage thus increasing the volume of the mucilaqe and decreasing the density.

Alginic acid is a polyuronic acid composed of residues of D-mannuronic and L-guluronic acids. It is a natural product extracted from selected seaweeds, and therefore is subject ~o some variation in composition and purity. Various grades of alginic acid are available which vary in the proeortions of mannuronic and guluronic acid monomers. It is preferred that high guluronic grades are used in the tablets of the present invention since they form a viscous gel in acid media, as opposed to high mannuronic grades which form very weak gels.
The following Example6 illu~trate the invention.

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-8- llg40 Cimetidine lOO mq Chewable Tablet Premix Gra_ules mq/tablet % w/w Cimetidine 100 90.g Eudragit E100* 10 9.1 *Added a6 a 40~ w/v 601ution in Dichloromethane Chewable Tablet mq/tablet Premix Granules 110.0 Direct Compression Grade Sorbitol790.0 Direct Compression Grade Lacto~es:
Crystalline 500.0 Spray dried 500.0 Croscarmellose Sodium Tyee A 60.0 Sodium Saccharin (Dried Fine Powder)2.0 Aspartame 2.0 Flavouring~ 16.0 Magnesium Stearate 45.0 TOTAL: 2,025.0 ~L30~68~i _g_ Cimetidine 200 mq Chewable Tablet PLemix Geanules mq/tablet % w/w Cimetidine 200 90.9 Eudragit ElOO* 20 9.1 *Added as a 40% w/v solution in Dichloromethane Chewable Tablet mq/tablet Premix Granules 220.0 Direct Compression Grade Sorbitol790.0 Direct Compressi~n Grade Lacto6es:
Crystalline 450.0 Spray dried 4so.0 Croscarmellose Sodium Type A 60.0 Sodium Saccharin (Dried Fine Powder) lO.G
Aspartame 1.0 Flavourings 17.5 Magnesium Stearate 45.0 TOTAL: 2,043.5 The formulation~ of Examples 1 and 2 were pLepared as follows:

The cimetidine was wet~granulated with a solution of the Eudragit E100 in dichloromethane and the resulting granules were dried in a suitable drier and then screened through a 1.4 mm mesh screen. The granules were then blended with the remaining ingredients and the resulting mixture was compressed to form tablets.

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Cimetidine/Alqinate Tablet Acti~e constituents mq/tablet Cimetidine 200.0 Alginic acid 500.0 Other cons~ituents Sodium Bicarbonate 170 Eudragit ~loO 20 Sorbitol 680 Pregelatinised Starch 30 Croscarmellose Sodium Type A 60 Lactose 330 A~partame 5 sOaium Saccharin 5 Magnesium Stearate 35 Flavourings 50 * A range of 15 to 35~g of magnesium stearate may be used.

The cimetidine was granulated with a 40% w/v 2S solution of Eudragit E100 in dichloromethane. The lactose was wet granulated with half the alginic acid, using pregelatinised starch as a binde After granu}ation, the granules were dried using either a fluid bed drier or a tray drier. The tablet b}end was prepared by mixing together the two component granulations with the remainder of the materials in a planetacy mixer or other suitable equipment, and the resulting blend was compressed using a rotary tablet machine.

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100 mq Chewable Tablet Inaredient mqttablet Cimetidine Premix G~anulss Cimetidine 100.0 Eudragit E100* 10.0 110.0 Extraaranular ~partame 3.0 lQ Peppermin~ 15.0 Tutti Frutti*** 5.0 Spearmint 5.0 Lacto6e 200.0 Croscarmsllose Sodium30.0 Type A
Magnesium S~earate lS.O 273.0 Antacid Granulatlon:
DiLect Co~p~ ion Sorbitol 590.0 Direct Compression Lactose Crystalline 325.0 Spray dried 325.0 Crosca~mello~e Sodium30.0 Type A
Dried Aluminium Hydroxide Gel~ 2SO.O
Magne6ium HydLoxide**200.0 Magne~ium Stearats 15.0 1735.0 ~ . ~
Z118.0 2118.0 * Added to the cimetidine by granulation as a 40~ w/v solution in methylene chloride. Solvent lost in processing .
~* Quantitie~ used ad3usted ~or the potencie~ of raw materials:
~Standard quantity o~ Dried Aluminium Hydroxide gel is equivalent to 117.5 my~tablet A1203 or 180 mg/tablet ~luminium HydLoxide (Al(OH~3~.
*** Tra~e-mark ~? '''~

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Process DescriPtion A 40% w/v solution of the Eudragit E100 in methylene chloride is added with mixing to the cimetidine and blended until granules are formed. The resulting granules are dried and then sieved through a 16 mesh screen .

The aluminium hydroxide, magnesium hydroxide and other ingredients for the antacid granules are sieved through a 12 mesh (1.4 mm) screen and mixed together.
The resulting mix is compressed on a rotary tablet press and the resulting compacts are milled using a 12 mesh screen.
The cimetidine granules; an~acid granules and extragranular excipients are pu~ into a cone blender and mixed thoroughly. The resulting mix is discharged from the blender and compressed on a suitable rotary tablet pre6s fitted with the appropriate punches.

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200 ma Chewable Tablet In~redient Cime~idine Premix ~ranules Cimetidine 200.0 90.9 ~udragit E100* 20.0 9.1 Antacid (Al/Mq) Granule~
ma/tablet %w/w Sorbitol: Direct Compre~sion Grade 295.0 34.01 Lactose: Direct Compre~sion Grade Spray dLied 162.5 18.73 Crys~alline 162.5 18.73 Dried Aluminium Hydroxide Gel 125.0 14.41 Magnesium Hydroxide lOo.o 11.53 Croscarmellose Sodium Type A 15.0 1.73 Magnesium Stearate 7.5 0.86 867.5 lOO.oo Tabletinq Mix for Compression ma~tablet Cimetidine Premix Granules 220.0 Antacid ~Al/Mg) Granules 867.5 Dried Aluminium ~ydroxide Gel 125.0 Magnesium Hydroxide loa.o Sorbitol: Direct Com~ression Grade 295.0 Lactose: Direct Compres6ion Grade S~ray dried 162.5 Crystalline 162.5 Croscarmellose Sodium Type A 45.0 Aspa~tame 3.0 Aniseed 20.0 Butterscotch 20.0 Magnesium Stearate22.5 or 37.5 TOTAL 2048.0 2063.0 * Added to the cimetidine by granulation as a 40% w/v solution in methylene chloride. Solvent lost in processing.

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s~o Process_DescriPtion The cimetidine premix granules and antacid granules we~e prepared according to the method described in Example 1. The cimetidine granules and antacid granules were then blended with the remaining ingredients and compressed on a rotary press fitted with ~he appropriate tablet punches and dies.

Claims (18)

1. A pharmaceutical granule comprising cimetidine and 2-20% (w/w) relative to the cimetidine of a co-polymer of dimethylaminoethylmethacrylate and neutral methacrylic acid esters.

2. A granule according to claim 1 wherein the co-polymer is present in an amount of approximately 5-15%
(w/w) relative to the cimetidine.

3. A granule according to claim 2 wherein the co-polymer is present in an amount of approximately 10%
(w/w).

4. A granule according to any one of claims 1-3 which consists essentially only of the cimetidine and the co-polymer.

5. A granule according to any one of claims 1-3 wherein the co-polymer functions as a granulating and binding agent and is in admixture with the cimetidine.

6. A solid pharmaceutical dosage form comprising a granule as defined in claim 4.

7. A dosage form according to claim 6 further containing an antacid.

8. A dosage form according to claim 6 further containing alginate.

9. A dosage form according to any one of claims 6 to 8 which is a chewable tablet.

10. A solid pharmaceutical dosage form comprising a granule as defined in claim 5.

11. A dosage form according to claim 10 further containing an antacid.

12. A dosage form according to claim 10 further containing alginate.

13. A dosage form according to any one of claims 10 to 12 which is a chewable tablet.

14. A granule according to claim 4 wherein the co-polymer functions as a granulating and binding agent and is in admixture with the cimetidine.

15. A solid pharmaceutical dosage form comprising a granule as defined in claim 14.

16. A dosage form according to claim 15 further containing an antacid.

17. A dosage form according to claim 15 further containing alginate.

18. A dosage form according to any one of claims 15-17 which is a chewable tablet.