New Zealand No. 274901 International No. PCT/GB94/02380
Priority Date{3):
ComptoJe SpAoificfttion Fiiod:
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Pucrficatkiri Dart»:
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COMPLETE SPECIFICATION
NEW ZEALAND PATENTS ACT 1953
Title of Invention:
Gelatin capsule fill able to foam
2RW, United Kingdom , ck
PRODUCTS LIMITED, of One Burlinc • | c\ $"£>
Lane, London W4
274901
Gelatln capsule fill able to foam
This invention relates to pharmaceutical products and in particular to compositions for the treatment of reflux oesophagitis, gastritis or peptic ulceration.
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 inflamination 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 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
SUBSTITUTE SHEET (RULE 26)
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 reflusced 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 choles try amine 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 B1 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, ;SUBSTITUTE SHEET (RULE 26) ;WO 95/11668 PCT/GB94/02380 ;-3- ;pectin, xanthan, gellan, carageenan and mixtures thereof; (b) a carbonate or bicarbonate salt; (c) an oil-basea or hydrophilic based liquid vehicle; wherein on oral ingestion the gelatin capsule shell ruptures and the fill reacts with 5 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 10 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. ;He have shown that when the polymeric material is 15 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, 20 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 25 or aluminium sodium silicate. Conveniently the relative ;SUBSTITUTE SHEET (RULE 26) ;WO 95/11668 ;PCT/GB94/02380 ;-4- ;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 salts 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 CO32" 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. ;SUBSTITUTE SHEET (RULE 26) ;27 4 9 0 1 ;-5- ;/ ;Suitable hydrophilic based liquid vehicles are polyethylene glycols (PEG'S) particularly PEG 400 and PEG 600, glycofvirol, polyglycerols, propylene glycol, ;Transcutol, polysorbate and propylene carbonate and mixtures 5 thereof. ;Also described but not claimed herein is 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 10 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 15 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 20 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 ;WO 95/11668 ;PCT/GB94/02380 ;-6- ;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 of the fill in the liquid vehicle a surfactant 5 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 10 vegetable oils, glyceryl monostearate, glyceryl xnonopaImitate, 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." IS The capsules will be suitably shaped and sized so as to be readily ingestible by a person following chewing. ;Sodium Bicarbonate BP ;100 mg ;Calcium Carbonate ;30 mg ;25 ;Fractionated Coconut Oil BP ;600 mg ;SUBSTITUTE SHEET (RULE 26) ;WO 95/11668 ;PCT/GB94/02380 ;10 ;15 ;20 ;-7- ;Lecithin ;Colloidal Silicon Dioxide Sorbitan Fatty Acid Esters Polysorbate 80 BP Flavouring, colouring, sweetener ;12 mg 34 mg 34 mg 20 mg 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 following fill: ;Quantity/Capsule t ;Sodium Alginate 500 mg ;Xanthan Gum 100 mg ;Sodium Bicarbonate Calcium Carbonate Aerosil ;Flavour, Sweetener Soya Bean Oil ;100 mg 100 mg 35 mg qs qs ad ;1500 mg ;25 Example 4 ;SUBSTITUTE SHEET (RULE 26) ;WO 95/11668 PCT/GB94/02380 ;-8- ;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 Oil qs ad ;1500 mg ;Example ? ;15 Capsules were prepared as in Example l having the following fill: ;Quantity/Capsule ;Magnesium Alginate 500 mg ;Gellan Gum 50 mg ;20 Magaldrate 200 mg ;Sodium Bicarbonate 150 mg ;Glyceryl Mono-Stearate 100 mg ;Polysorbate 80 20 mg ;Flavour, Sweetener qs ;25 Fractionated Coconut Oil qs ad ;SUBSTITUTE SHEET (RULE 26) ;WO 95/11668 ;PCT/GB94/02380 ;9- ;1600 mg in Example l having the ;Quantity/Capsule 300 mg 300 mg 150 mg 150 mg 150 mg 15 mg qs 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 273801 C2. In this patent we used a metal cone assembly of weight 26.Og (cf a weight of 150.Og of ASTM D217-68) as shown in Fig 1. ;Preparation of raft samples ;Example 6 ;Capsules were prepared as following fill: ;Alginic Acid Pectin ;Calcium Carbonate Sodium Bicarbonate Hydrogenated Vegetable Oil Lecithin ;Flavour, Sweetener Arachis Oil ;SUBSTITUTE SHEET (RULE 26) ;WO 95/11668 PCT/GB94/02380 ;-10- ;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 lq of polymeric material) was weighed and added to 5 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 10 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 120ml of deionized water was added and the mixture homogenized for 5 minutes as before. ;IS After homogenization, a quantity of homogenized mixture equivalent to lg of polymeric material was added to 150mls 0.1M HCl in a 250ml low-form beaker (height 94mm & diameter 67nun) preheated to 37#C, using a 50ml Plastipak syringe with 60ml scale and lok tip. The raft was allowed to stand for 20 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 25 cone arrangement described above of weight 26.Og. The tip ;SUBSTITUTE SHEET (RULE 26) ;WO 95/11668 PCT/GB94/02380 ;-11- ;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 5 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 10 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 IS 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 10 ml and (b) Algicon 20 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. ;25 ;SUBSTITUTE SHEET (RULE 26) ;WO 95/11668 ;PCT/GB94/02380 ;-12-2&1LE ;Product ;Raft Depth (mm) ;Penetration Depth (mm) ;Penetration (*)
Example 1
34
33
34 31
Mean = 33
22.1
24.0
29.2
12.1 Mean = 22.08
65.00 75.45 85.88 39.03 Mean = 66.34
Example 2
34 34 30 33 33
Mean «■ 32.8
.5
7.7 9.3
9.8
.6 Mean =9.58
.88 22.65 31.00 29.70 32.12 Mean « 29.27
Liquid Gaviscon
37 40 42 40 40.5 Mean = 39.9
9.7 9.5 12.8 8.7 11.1 Mean = 10.36
26.22 23.75 30.48 21.75 27.41 Mean - 25.92
Algicon
34 36 32 34 36.5 Mean - 16.0
Complete
M If n
i«
Mean = Complete
100 100 100 100 100 Mean « 100
In the case of Algicon the cone of the penetrometer passed completely through the rafts.
SUBSTITUTE SHEET (RULE 26)
2.7 4 9 0 1