Cimetidine granules coated with a partially hydrogenated vegetable oil

A non-aqueous, chewable composition for oral delivery of unpalatable drugs is provided. The composition contains the drug intimately dispersed or dissolved in a pharmaceutically acceptable lipid that is solid at room temperatures. The composition also has a matrix that contains a granulating agent for the total composition and a rapid dispersal agent and optionally additives such as buffering agents, flavoring agents, surfactants and the like.

This application is a 371 of PCT/EP93/03272 filed Nov. 22, 1993. 
This invention relates to granules of cimetidine which are useful in the 
preparation of pharmaceutical compositions having an improved flavour. 
Cimetidine is a histamine H.sub.2 -antagonist and has been described in UK. 
Patent Specification 1,397,436. Cimetidine has been shown to be useful in 
the treatment of duodenal, gastric, recurrent and stomal ulceration, and 
reflux oesophagitis and in the management of patients who are at high risk 
from haemorrhage of the upper gastrointestinal tract. 
Cimetidine is known to have a pronounced bitter taste. This is not usually 
a problem when the dosage form employed is a capsule or a tablet designed 
to be swallowed, thereafter to disintegrate upon reaching the stomach. 
However, such dosage toms can be impractical when it is desired to 
administer a large amount of active ingredient, or to co-administer a 
relatively bulky second active ingredient such as an antacid or alginate. 
Moreover many individuals have difficulty in swallowing a solid dosage 
form. 
A conventional approach to administering relatively large amounts of active 
ingredient is by means of a suspension or a chewable tablet, i.e. a tablet 
which disintegrates in the mouth upon being chewed. 
It will be appreciated that a major requirement of such dosage forms is 
that they must be palatable, since an unpalatable formulation increases 
the risk of a patient neglecting to take a medicament. Such non-compliance 
with the dosing regimen will in turn delay or prevent the patient's 
recovery from the condition under treatment. 
A further requirement of such compositions is that once the formulation 
reaches the stomach, the individual particles should release the active 
ingredient rapidly and completely in order to ensure that substantially 
all of the active ingredient is absorbed; that is to say the formulation 
should be bioavailable. 
In the case of cimetidine, because of its bitterness, the provision of such 
dosage forms represents a considerable problem. 
EP-A-257823 describes a stable aqueous suspension of cimetidine wherein at 
least 90% of the cimetidine is in the polymorphic B form. It is disclosed 
that the use of polymorph B overcomes the problem of polymorphic 
interconversion found in the case of polymorph A suspensions of relatively 
low viscosity which tend to result in lumpy and non homogeneous 
suspensions. 
EP-A-322048 describes a pharmaceutical granule composition comprising 
cimetidine and an ester of a polyhyctroxy compound, in particular a 
glycerol ester selected from: 
a) gylcerol esters having a hydroxyl value of greater than 120; 
b) glycerol esters having a hydroxyl value of greater than 60 and having a 
triglyceride content of less than 30% by weight, and 
c) gylcerol esters having a hydroxyl value of greater than 5 and a melting 
point of less than 40.degree. C. 
It is disclosed that such cimetidine containing granules are useful in the 
preparation of chewable tablets. 
Coated cimetidine granules have now been discovered which have improved 
flavour. They can be presented in a variety of pharmaceutical forms, e.g., 
as a chewable tablet, a constitutable powder, or as a sprinkle powder, 
i.e., a powder that can be sprinkled, for example, onto food before 
consumption. 
In a first aspect the present invention provides a pharmaceutical 
composition comprising cimetidine granules coated with a partially 
hydrogenated vegetable oil or a chemical equivalent thereof, in an amount 
corresponding to at least 20%, suitably from 25% to 200%, by weight 
relative to the cimetidine. 
More suitably the partially hydrogenated vegetable oil is present in an 
amount from 50% to 150%, preferably 75% to 125%, particularly 100% by 
weight relative to the cimetidine. 
The cimetidine can exist in any form, for example, polymorph A, B, C or Z 
or any mixture thereof, preferably polymorph A. 
Partially hydrogenated vegetable oils are derived from natural products and 
generally comprise a mixture of glycerides of C.sub.14-20 fatty acids, in 
particular palmitic and stearic acids, said raixmre suitably having an 
iodine value of less than 10 and a melting point greater than 40.degree. 
C. Preferably said mixture has an iodine value less than 5 and a melting 
point between 45.degree. and 75.degree. C. 
Suitable examples of partially hydrogenated vegetable oils include 
partially hydrogenated cottonseed oil, soybean oil, corn oil, peanut oil, 
palm oil, sunflower seed oil or mixtures thereof. Examples of commercially 
available oils are those sold by Van Den Burgh Foods Company, USA, and 
include Stearine 07 (partially hydrogenated cottonseed oil), Stearine 17 
(partially hydrogenated soybean oil), Stearine 27 (partially hydrogenated 
palm oil) and K.L.X. (a mixture of partially hydrogenated 
cottonseed/soybean oil). 
Chemical equivalents of partially hydrogenated vegetable oils include 
synthetically produced glycerides of C.sub.14-20 fatty acids having the 
same properties as the naturally derived products as hereinbefore 
described. 
The coated granules of the present invention can be prepared by adding a 
partially hydrogenated vegetable oil to cimetidine, warming the mixture 
until the vegetable oil just melts and mixing for a short period of time 
until the mixture just granulates. Alternatively, the granules can be 
prepared in a spray dryer according to conventional techniques. Preferably 
the granules are prepared in a hot-melt fluid bed coating process for 
example as described in J Pharmaceutical Research, Vol 7, No. 11, 1990, 
1119. 
In a second aspect the present invention provides a constitutable powder 
composition comprising coated cimetidine granules as hereinbefore defined 
and a suspending agent. Such constitutable powders can be mixed with water 
in order to prepare extemporaneously aqueous cimetidine suspensions. 
It has been found that such aqueous suspensions have the advantage that 
cimetidine polymorph A can be used in the coated granules of the present 
invention without suffering from the problem of polymorphic 
interconversion. 
Examples of suspending agents include xanthan gum, 
hydroxypropylmethylcellulose, methylcellulose, carageenan, sodium 
carboxymethyl cellulose, and sodium carboxymethyl 
cellulose/microcrystalline cellulose mixes, particularly sodium 
carboxymethyl cellulose/microcrystalline cellulose mixtures. Preferred 
suspending agents are thixotropic suspending agents such as xanthan gum, 
carageenan and sodium carboxymethyl cellulose/microcrystalline cellulose 
mixtures and mixtures thereof and particularly preferred suspending agents 
are Avicel RC591, Avicel RC581 and Avicel CL611. Avicel is a trademark of 
FMC Corporation, and RC591, RC581 and CL611 are mixtures of 
microcrystalline cellulose and sodium carboxymethyl cellulose. The mount 
of suspending agent present will vary according to the particular 
suspending agent used and the presence or absence of other ingredients 
which have an ability to act as a suspending agent or which contribute 
significantly to the viscosity of the composition. In general, however, 
the mount of suspending agent will lie in the range 1-50% w/w relative to 
the coated cimetidine granules. When the suspending agent is xanthan gum, 
it will usually be present in an mount corresponding to 1-20% w/w relative 
to the coated cimetidine granules whereas when Avicel is used, the amount 
typically will lie in the range 5-50% w/w, suitably 10-25% w/w. When 
carageenan or hydroxypropylmethylcellulose is used, typically this will 
constitute 5-50% w/w relative to the coated cimetidine granules. Suitably, 
the suspending agent is a mixture of xanthan gum and 
hyctroxypropylmethylcellulose or Avicel in mounts falling within the 
ranges noted above. 
Suitably, the constitutable powder composition also comprises a suffactant. 
The surfactant improves the wettability of the coated cimetidine granules. 
Examples of surfactants include co-block polymers such as poloxamer 188 
and partial esters of sorbitan and sorbitol and their polyoxyethylene 
derivatives, e.g. Tween and Span series of surfactants. 
A particularly preferred surfactant is Tween 80 which has been found to 
minimise the degradation of coated cimetidine granules when in aqueous 
suspension. 
The surfactant is generally present in an amount from 0.1-10%, suitably 
1-8%, preferably 2-6%, (w/w) relative to the coated cimetidine granules. 
The constitutable powder composition can contain ingredients which improve 
its taste, for example sweeteners, bitter-taste maskers such as sodium 
chloride and tastemasking flavours such as contramaxum, flavour enhancers 
such as monosodium glutamate, and flavouring agents. 
Examples of sweeteners include bulk sweeteners such as sucrose, 
hydrogenated glucose syrup, the sugar alcohols sorbitol and xylitol, and 
sweetening agents such as sodium cyclamate, sodium saccharin, aspme and 
ammonium glycyrrhizinate. 
A bulk sweetener will usually be present in an amount corresponding to 
about 50-1000% relative to the coated cimetidine granules, the amount 
depending in part upon whether other ingredients are present which have a 
thickening effect on the composition. For example, when sorbitol is used 
as the sole bulk sweetener and no thickener is present, typically the dry 
weight of sorbitol present is in the range 200-800% w/w relative to the 
coated cimetidine granules. 
When hydrogenated glucose syrup (solids content approximately 74%) is used 
as the sole bulk sweetener, typically it is present in an amount 400-1000% 
w/w relative to the coated cimetidine granules. It will be appreciated 
that combinations of bulk sweeteners can be used, for example combinations 
of sorbitol and hydrogenated glucose syrup, or sucrose and sorbitol. 
Other excipients which can be used include humectants such as propylene 
glycol and glycerol and colourants such as titanium dioxide. 
Typically the total quantity of humectant present is in the range 0-150% 
w/w relative to the coated cimetidine granules. Thus, for example, 
propylene glycol and glycerol can each be present in an amount 
approximating to 60% w/w. 
The constitutable powder composition can contain preservatives to prevent 
microbial contamination. Examples of preservatives are the alkylparabens, 
such as methylparaben, propylparaben and butylparaben. 
The constitutable powder composition can be prepared by blending the 
ingredients together to form a dry powder mix which can be packaged into 
suitable containers for example glass or plastic bottles. Such bottles are 
sufficiently large so that in use the requisite amount of water can be 
added whilst leaving sufficient head space to allow efficient shaking of 
the contents to aid constitution. If desired the coated cimetidine 
granules can initially be mixed with the surfactant in the presence of 
sufficient water or glycerol to aid mixing until the surfactant is 
uniformally adsorbed onto the cimetidine granules. After drying the 
mixture can be blended with the remaining ingredients. 
In a third aspect the present invention provides a chewable tablet 
comprising coated cimetidine granules as hereinbefore defined. 
Such tablets normally contain at least 75 mg of cimetidine. As a maximum 
the tablet will not normally contain more that 800 mg of cimetidine. 
Preferably it contains 100 to 200 mg of cimetidine. 
The tablets can also contain solid diluents such as sugars and sugar 
alcohols, for example lactose, xylitol, sorbitol and mannitol. Where 
desired additional sweeteners can be added, for example ammonium 
glycyrrhizinate, sodium cyclamate and sodium saccharinate as well as 
flavours and taste markers, for example sodium chloride and Contramature, 
and tableting starch, which gives the tablets a palatable texture. 
The tablets can also contain other standard tableting excipients for 
example a disintegrant such as a cross-linked polymeric disintegrant; 
particular examples being cross-linked polyvinyl pyrrolidone and 
cross-linked carboxymethyl celluloses. 
The compositions of this invention can optionally contain an antacid. An 
antacid is a pharmaceutically acceptable basic material of sufficient 
neutralising capacity to neutralise stomach acid. Examples of antacids are 
aluminium hydroxide, magnesium hydroxide, magnesium carbonate, calcium 
carbonate, sodium carbonate or bicarbonate and co-dried gels for example 
aluminium hydroxide-magnesium carbonate co-dried gel. Suitable antacids 
also include those disclosed in U.S. Pat. No. 5,169,640 and European 
Patent 294933. Preferably the amount of antacid is such that a unit dose 
contains 10-30 milliequivalents. 
The compositions of this invention can optionally contain an alginate 
including alginic acid. 
The purpose of the alginate is to form a raft of mucilage which floats on 
the contents of the stomach thereby preventing gastro-oesophageal reflux 
(GORD) or reducing its symptoms. Usually a carbonate salt such as 
potassium bicarbonate or sodium bicarbonate is added. Reaction of the 
carbonate with the acidic gastric juices generates carbon dioxide which 
aerates the alginate raft, reducing its density and thereby enabling it 
more easily to float on the stomach contents. 
In order to avoid too great an increase in the viscosity in the case of a 
suspension, a low viscosity grade of alginate is used. Low viscosity 
grades of alginate suitable for use in the compositions of the present 
invention will generally have a viscosity of 4-10 mPa.s in 1% aqueous 
solution at 20.degree. C. Alginates are polymers composed of mannuronic 
and guluronic acid monomer units. The ratio of mannuronic to guluronic 
acids determines the raft-forming properties of the alginate and, in 
general, alginates having a high guluronic:mannuronic ratio (e.g. 70% 
guluronic acid) form the strongest rafts. Alginates containing such high 
levels of guluronic acid are preferably used in the compositions of the 
present invention, and one such alginate is Protuna/LFR 5/60. 
If desired, the present compositions can contain further therapeutic 
agents, for example, a suitable chewable tablet comprises coated cimetidme 
granules as herein defined, an antacid, an alginate and simethicone. 
The preferred size for the coated cimetidine granules is dependent upon 
their use. For sprinkle powders and constitutable powders, generally the 
coated granules have an apparent diameter of less than 250 .mu.m, 
preferably less than 180 .mu.m. For chewable tablets the granules 
preferably pass through a 1 mm sieve but are retained by a 0.2 mm sieve.

The present invention is illustrated by the following Examples. 
EXAMPLE 1 
Cimetidine-partially hydrogenated cotton seed oil granules. 
Granules containing cimetidine (50%) and partially hydrogenated cotton seed 
off (stearine 07) (50%) (w/w) are prepared by spraying molten coating 
material onto a fluidised bed of cimetidine granules. 
EXAMPLE 2 
Cimetidine-partially hydrogenated soybean oil granules. 
In a similar manner to Example 1 granules are obtained containing 
cimetidine (50%), and partially hydrogenated soybean oil (stearine 17) 
(50%) (w/w). 
EXAMPLE 3 
Cimefidine Consfitutable Powder 
______________________________________ 
g per 100 
% w/w ml after 
Ingredients dry powder mix 
constitution 
______________________________________ 
Coated cimetidine granules (Ex. 1) 
19.56 8.0 
Xanthan Gum 0.98 0.4 
Hydroxypropylmethylcellulose 
7.82 3.2 
Tween 80 0.98 0.4 
Aspartame 0.98 0.4 
Colloidal Silicon Dioxide 
1.22 0.5 
Sorbitol 61.12 25.0 
Sodium Carbonate 3.67 1.5 
Flavours 3.67 1.5 
Total 100.00 40.9 
______________________________________ 
The coated cimetidine granules are blended with the remaining ingredients 
to form a constimtable dry powder mix which is packed into glass or 
plastic bottles each to contain 81 g of dry powder mix. Each bottle is 
sufficiently large so that in use the requisite amount of water can be 
added to the container to produce a final volume of 200 ml, whilst leaving 
sufficient head space in the bottle to allow efficient shaking of the 
contents to aid constitution. When constituted the suspension contains 200 
mg cimetidine per 5 ml. 
EXAMPLE 4 
Cimetidine 100 mg Chewable Tablet 
______________________________________ 
Ingredients mg/tablet 
______________________________________ 
Coated Cimetidine Granules (Example 1) 
200.0 
Direct Compression Grade Sorbitol 
790.0 
Direct Compression Grade Lactoses: 
Crystalline 500.0 
Spray dried 500.0 
Croscarmellose Sodium Type A 
60.0 
Sodium Saccharin (Dried Fine Powder) 
2.0 
Aspartame 2.0 
Flavourings 16.0 
Magnesium Stearate 45.0 
Total 2,115.0 
______________________________________ 
The coated cimetidine granules are blended with the remaining ingredients 
and the resulting mixture is compressed to form tablets. 
EXAMPLE 5 
Cimetidine 200 mg Chewable Tablet 
______________________________________ 
Ingredients mg/tablet 
______________________________________ 
Coated Cimetidine Granules (Example 1) 
400.0 
Direct Compression Grade Sorbitol 
790.0 
Direct Compression Grade Lactoses: 
Crystalline 450.0 
Spray dried 450.0 
Croscarmellose Sodium Type A 
60.0 
Sodium Saccharin (Dried Fine Powder) 
10.0 
Aspartame 1.0 
Flavourings 17.5 
Magnesium Stearate 45.0 
Total 2,223.5 
______________________________________ 
The coated cimetidine granules are blended with the remaining ingredients 
and the resulting mixture is compressed to form tablets. 
EXAMPLE 6 
Cimetidine 200 mg/Aiginate Chewable Tablet 
______________________________________ 
Ingredients mg/tablet 
______________________________________ 
Coated Cimetidine Granules (Example 2) 
400 
Alginic acid 500 
Sodium Bicarbonate 170 
Sorbitol 680 
Pregelatinised Starch 30 
Croscarmellose Sodium Type A 
60 
Lactose 330 
Aspartame 5 
Sodium Saccharin 5 
Magnesium Stearate 35 
Flavours 50 
Total 2265 
______________________________________ 
The coated cimetidine granules are blended with the remaining ingredients 
and the resulting mixture is compressed to form tablets. 
EXAMPLE 7 
Cimetidine 200 mg/Alginate/Antacid/Simethicone Chewable Tablet 
______________________________________ 
Ingredients mg/tablet 
______________________________________ 
Coated Cimetidine Granules (Example 1) 
400 
Aluminium Hydroxide Dried Gel 
225 
Magnesium Hydroxide 175 
Alginic Acid 300 
Simethicone 30 
Sorbitol (Direct Compression Grade) 
900 
Lactose (Direct Compression Grade) 
300 
Pregelatinised Starch 30 
Croscarmellose Sodium Type A 
60 
Aspartame 5 
Sodium Saccharin 5 
Flavours 40 
Magnesium Stearate 30 
Total 2500 
______________________________________ 
The coated cimetidine granules are blended with the remaining ingredients 
and the resulting mixture is compressed to form tablets.