Note: Descriptions are shown in the official language in which they were submitted.
~ WogS/11668 2 1 7 4 7 7 ~ PCT/GB94102380
Gelat~n capsule f~ll able to foam
This invention relates to pharmaceutical products and
in particular to compositions for the treatment of reflux
oesophagitis, gastritis or peptic ulceration.
S Reflux oesophagitis occurs when small amounts of
gastric juice, food and/or bile acids pass into the lower
part of the oesophagus and cause oesophageal inflammation
accompanied by pain which may manifest itself in the form of
heartburn.
One approach to the problem of reflux oesophagitis
comprises the administration of a preparation which on
contact with gastric acid generates a carbonated gelatinous
foam or raft which floats on the stomach contents. When
reflux occurs it is this raft which precedes the stomach
lS contents into the oesophagus thus protecting the mucosa from
further irritation. Known preparations of this type
included solid preparation in the form of powders or tablets
containing alginic acid, sodium bicarbonate and antacid
materials or liquid preparations containing sodium alginate,
sodium bicarbonate and calcium carbonate marketed under the
name GAVISCON (TM Reckitt & Colman Products Ltd). In our
British Patent No. 1524740 we describe such liquid
preparations. In our corresponding German Patent No
2738014 C2 we describe a penetration test used for
evaluating raft rigidity. The procedure described is based
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on ASTM D217-68 "Standard Method for Cone Penetration of
Lubricating Grease". In the method described in the patent
a lightweight cone assembly of a penetrometer is released
and allowed to penetrate into the raft, the depth of
penetration being measured.
In our US Patent No. 4172120 we describe a preparation
including cholestyramine which is retained in the stomach
for a prolonged period of time and is therefore more
effective in binding duodenally refluxed bile. This
preparation includes alginic acid and/or sodium alginate
together with sodium bicarbonate which on being swallowed
react with gastric acid to form a carbonated raft which
holds the cholestryamine sufficiently loosely that it is
able to absorb bile acid in the stomach.
The carbonated alginic acid raft type of product is
further exemplified by ALGICON (Rhone-Poulenc Rorer)
described in European Patent No. 0179858 Bl as containing
magnesium alginate, potassium bicarbonate, magnesium
carbonate and as antacid materials aluminium
hydroxide/magnesium carbonate co-dried gel.
According to the present invention there is provided a
pharmaceutical product for the treatment of reflux
oesophagitis, gastritis or peptic ulceration in the form of
a chewable soft gelatin capsule with a fill comprising (a)
polymeric material selected from alginic acid, alginates,
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pectin, xanthan, gellan, carageenan and mixtures thereof;
(b) a carbonate or bicarbonate salt; (c) an oil-based or
hydrophilic based liquid vehicle; wherein on oral ingestion
the gelatin rapsule shell ruptures and the fill reacts with
the acid contents of the stomach thereby producing a
carbonated floating gelatinous raft of such rigidity that in
the penetration test as hereinafter defined there is not
complete penetration.
By complete penetration we mean that the cone of the
penetrometer passes completely through the raft.
Preferably the polymeric material is the sodium,
potassium, ammonium, magnesium or calcium salt of alginic
acid or the propylene glycol esters or mixtures thereof.
We have shown that when the polymeric material is
alginic acid or a salt or ester thereof rafts of improved
strength are obtained if the composition includes a source
of divalent calcium or trivalent aluminium ion which act as
cross-linking agents. Suitable sources of calcium ions are
those derived from the carbonate, lactate, chloride,
gluconate, phosphate, hydrogen phosphate, sulphate, tartrate
or citrate salts. Suitable sources of aluminium ions are
those derived from the carbonate, lactate, glycinate or
phosphate salts or from aluminium magnesium carbonate
hydroxide, magaldrate, aluminium sodium carbonate hydroxide
or aluminium sodium silicate. Conveniently the relative
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quantities by weight of the calcium salt or aluminium
compound to the alginic acid or alginate calculated as ions
are 4 to 120 Ca2+ to 500 alginate~ or 2 to 80 Al3+ to 500
alginate~ respectively.
Suitable carbonate or bicarbonate 5alts are potassium
carbonate or bicarbonate, sodium carbonate or bicarbonate,
calcium carbonate, sodium glycine carbonate, magnesium
carbonate or aluminium carbonate. The carbonate or
bicarbonate salt is present in an amount so as to provide an
adequate volume of gas (carbon dioxide) to float the gel
produced when the polymeric material contacts the gastric
acid in the stomach. Preferably the relative quantities by
weight of polymeric material to the carbonate or bicarbonate
calculated as ions is 35 to 300 C032- or HCO3- to 500
polymeric material.
It will be understood that the rigidity and thickness
of the carbonated raft formed on contact with the gastric
acid will depend upon the ratio of carbonate or bicarbonate
to the polymeric material and upon the grade of the
polymeric material.
Suitable oil-based liquid vehicles are natural oils
such as soya bean oil, fractionated coconut oil, mineral
oils, triacetin, ethyl oleate, hydrogenated natural oil and
mixtures thereof.
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Suitable hydrophilic based liquid vehicles are
polyethylene glycols (PEG's) particularly PEG 400 and PEG
600, glycofurol, polyglycerols, propylene glycol,
Transcutol, polysorbate and propylene carbonate and mixtures
thereof.
The invention also includes a method of treating reflux
oesophagitis, gastritis or peptic ulceration which comprises
administration of an effective amount of a product which is
capable of forming a floating gelatinous raft when contacted
with the acid contents of the stomach said raft being of
such rigidity that in the penetration test as hereinafter
defined there is not complete penetration and said product
being in the form of a chewable soft gelatin capsule with a
fill comprising (a) polymeric material selected from alginic
acid, alginates, pectin, xanthan, gellan, carageenan and
mixtures thereof; (b) a carbonate or bicarbonate salt; (c)
an oil-based or hydrophilic based liquid vehicle.
The gelatin capsules may be simultaneously formed and
filled using conventional methods and apparatus such as
disclosed, for example, in an article by H. Seager in
Pharmaceutical Technology September 1985. Thus all the
ingredients of the fill material including the liquid
vehicle are mixed together, with heating if necessary, until
the desired consistency for filling and the desired
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uniformity is obtained. The encapsulation machine is
suitably an R P Scherer encapsulation machine.
In order to facilitate the even dispersion of the solid
components o~ the fill in the liquid vehicle a surfactant
S may be included in the fill.
In the fill the polymeric materials will have a
thickening effect upon the liquid fill. This thickening
effect may be further increased if so desired by the
inclusion of a thickening agent such as hydrogenated
vegetable oils, glyceryl monostearate, glyceryl
monopalmitate, beeswax (or other high melting point fat or
wax) or a dispersed thickener such as colloidal silicon
dioxide. For hydrophilic vehicles, a suitable thickening
agent may be one or more high molecular weight PEG's."
The capsules will be suitably shaped and sized so as to
be readily ingestible by a person following chewing.
The invention is illustrated by the following Examples:
Example l
Capsules in a standard gelatin shell were prepared
having the following fill:
Quantity/Capsule
Sodium Alginate (Protanal L~5/60) 500 mg
Sodium Bicarbonate BP l00 mg
Calcium Carbonate 30 mg
Fractionated Coconut Oil BP 600 mg
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Lecithin 12 mg
Colloidal Silicon Dioxide 34 mg
Sorbitan Fatty Acid Esters 34 mg
Polysorbate 80 BP 20 mg
S Flavouring, colouring, sweetener 80 mg
1410 mg
ExamPle 2
Capsules were prepared as in Example 1 except that the
amount of calcium carbonate in the fill materials was
increased to 100 mg.
Example 3
Capsules were prepared as in Example 1 having the
f ollowing f ill:
Quantity/Capsule
Sodium Alginate 500 mg
Xanthan Gum 100 mg
Sodium Bicarbonate 100 mg
Calcium Carbonate 100 mg
Aerosil 35 mg
Flavour, Sweetener qs
Soya Bean Oil qs ad
1500 mg
Example 4
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Capsules were prepared as in Example 1 having the
following fill:
Quantity/Capsule
Alginic Acid 500 mg
Carrageenan 100 mg
Sodium Carbonate 100 mg
Calcium Chloride 100 mg
Aerosil 35 mg
Polysorbate 80 20 mg
Flavour, Sweetener qs
Fractionated Coconut Oilqs ad
1500 mg
ExamPle 5
Capsules were prepared as in Example 1 having the
following fill:
Quantity/Capsule
Magnesium Alginate 500 mg
Gellan Gum 50 mg
Magaldrate 200 mg
Sodium Bicarbonate 150 mg
Glyceryl Mono-Stearate100 mg
Polysorbate 80 20 mg
Flavour, Sweetener gs
Fractionated Coconut Oilqs ad
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1600 mg
Example 6
Capsules were prepared as in Example l having the
5 following fill:
Quantity/Capsule
Alginic Acid 300 mg
Pectin 300 mg
Calcium Carbonate 150 mg
Sodium Bicarbonate l50 mg
Hydrogenated Vegetable Oil150 mg
Lecithin 15 mg
Flavour, Sweetener qs
Arachis Oil qs ad
1550 mg
Raft Penetration Test
The rigidity of the rafts produced by the products of
the invention are assessed by a cone penetration test
adapted from ASTM D217-68. This method had been previously
described for the determination of alginate raft rigidity in
our German Patent No DE 27380l C2. In this patent we used a
metal cone assembly of weight 26.0g (cf a weight of 150.0g
of ASTM D217-68) as shown in Fig l.
PreParation of raft samples
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The raft was prepared as follows: a bulk sample was
prepared sufficient for 6 rafts.
The appropriate amount of product (equivalent to 6
doses of lg of polymeric material) was weighed and added to
a 250ml tall-form beaker (height 120mm & diameter 60mm)
previously weighed. A volume of 120ml of deionised water
was added and the mixture homogenized for 5 minutes using
the Silverson Model L4R homogenizer with a Turbular Unit 1"
in diameter and a square hole high shear screen. The speed
of the homogenizer was set at speed 4 / 5000-5200 rpm. In
the case of Liquid Gaviscon and Algicon Mint, 120ml of the
product was taken and added to a 250ml tall-form beaker. A
volume of 12Oml of deionized water was added and the mixture
homogenized for 5 minutes as before.
After homogenization, a quantity of homogenized mixture
equivalent to lg of polymeric material was added to 150mls
o.lM HCl in a 250ml low-form beaker (height 94mm & diameter
67mm) preheated to 37C, using a 50ml Plastipak syringe with
60ml scale and lok tip. The raft was allowed to stand for
30 minutes. After that time, the raft depth was measured
and the cone penetration test carried out.
DescriPtion of the method
The Cone Penetration test was carried out using a
Penetrometer (Stanhope-Seta, Surrey England) fitted with the
cone arrangement described above of weight 26.0g. The tip
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of the cone was brought carefully into contact with the
upper surface of the raft, the dial micrometer arm was
brought into contact with the upper surface of the cone
assembly, and the dial micrometer was zeroed. The spring
loaded release button was depressed for approximately one
second, and the cone assembly was allowed to sink into the
raft. The centre knob on the dial micrometer was turned to
bring the micrometer arm again into full contact with the
upper surface of the cone assembly. The depth of
penetration was recorded, this being inversely proportional
to the rigidity of the raft. The mean of 5 raft evaluations
was calculated.
ExPerimental Results
The rigidity of the rafts produced by the products of
Examples 1 and 2 were assessed by the above method.
Tests were also carried out on two comparative Examples
(a) Liquid Gaviscon (Reckitt & Colman Products Ltd)
containing sodium alginate 500 mg, sodium bicarbonate 267
mg, calcium carbonate 160 mg per lo ml and (b) Algicon
suspension (Rhone-Poulenc Rorer) containing magnesium
alginate 250 mg, aluminium hydroxide/magnesium carbonate co-
dried gel 140 mg, magnesium carbonate 175 mg, potassium
bicarbonate 50 mg per 5 ml.
The results obtained are set out in the Table below.
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Product Raft Depth Penetration Depth Penetration
(mm) (mm)
34 22.1 65.00
Example 1 33 24.0 75.45
34 29.2 85.88
31 12.1 39.03
Mean = 33 Mean = Z2.08 Mean z 66.34
34 10.5 30.88
34 7.7 22.65
Example 2 30 9.3 31.00
33 9.8 29.70
33 10.6 32.12
Mean = 32.8 Mean = 9.58 Mean = 29.27
37 9.7 26.22
9.5 23.75
Liquid 42 12.8 30.48
Gaviscon 40 8.7 21.75
40.5 11.1 27.41
Mean = 39.9Mean = 10.36 Mean = 25.92
34 Complete 100
36 " 100
Algicon 32 " 100
34 " 100
36.5 " 100
Mean = 16.0Mean = Complete Mean = 100
In the case of Algicon the cone of the penetrometer passed
completely through the rafts.
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