WO1995011668A1

WO1995011668A1 - Gelatin capsule fill able to foam

Info

Publication number: WO1995011668A1
Application number: PCT/GB1994/002380
Authority: WO
Inventors: Keith Sugden; Keith Graeme Hutchison
Original assignee: Reckitt & Colman Products Limited
Priority date: 1993-10-29
Filing date: 1994-10-28
Publication date: 1995-05-04
Also published as: NZ274901A; JPH09504286A; NO961638L; BR9407916A; CA2174777A1; CN1133558A; AU8000494A; NO961638D0; EP0725626A1

Abstract

A pharmaceutical product for the treatment of reflux oesophagitis, gastritis or peptic ulceration in the form of a chewable soft gelatine 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; wherein on oral ingestion by a patient the gelatine capsule shell ruptures and the fill reacts with the acid contents of the stomach to produce a carbonated floating gelatinous raft of specified rigidity.

Description

Gelat.π 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 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 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 St 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 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, 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 capsule 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 penetro eter 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, agaldrate, aluminium sodium carbonate hydroxide or aluminium sodium silicate. Conveniently the relative 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 CO₃ ²" or HC0₃~ 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. 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 unifor ity 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 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 1

Capsules in a standard gelatin shell were prepared having the following fill:

Quantity/Capsule

Sodium Alginate (Protanal LF5/60) 500 mg

Sodium Bicarbonate BP 100 mg

Calcium Carbonate 30 mg Fractionated Coconut Oil BP 600 mg -1-

Lecithin 12 mg

Colloidal Silicon Dioxide 34 mg

Sorbitan Fatty Acid Esters 34 mg

Polysorbate 80 BP 20 mg

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 following fill: 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 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 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-Stearate 100 mg

Polysorbate 80 20 mg

Flavour, Sweetener qs Fractionated Coconut Oil qs ad 1600 mg Example 6

Capsules were prepared as in Example l having the following fill:

Quantity/Capsule Alginic Acid 300 mg

Pectin 300 mg

Calcium Carbonate 150 mg Sodium Bicarbonate 150 mg

Hydrogenated Vegetable Oil 150 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 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 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 ho ogenizer 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 120ml 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 0.1M HC1 in a 250ml low-form beaker (height 94mm & diameter 67mm) preheated to 37°C, 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.Og. The tip 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 & Col an Products Ltd) containing sodium alginate 500 mg, sodium bicarbonate 267 mg, calcium carbonate 160 mg per 10 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.

TABLE

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 = 22.08 Mean = 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 40 9.5 23.75

Liquid 42 12.8 30.48 Gaviscon 40 8.7 21.75 40.5 11.1 27.41 Mean = 39.9 Mean = 10.36 Mean = 25.92

34 Complete 100 36 II 100

Algicon 32 II 100 34 II 100 36.5 II 100 Mean = 16.0 | Mean = Complete Mean = 100

In the case of Algicon the cone of the penetrometer passed completely through the rafts.

Claims

1. 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, 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 capsule 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 hereinbefore defined there is not complete penetration.

2. A pharmaceutical product according to Claim 1 wherein the polymeric material is alginic acid or the alginates, are the sodium, potassium, ammonium, magnesium or calcium salts or the propylene glycol esters or mixtures thereof.

3. A pharmaceutical product according to Claim 2 which includes a calcium or aluminium cross-linking ion.

4. A pharmaceutical product according to Claim 3 wherein the calcium ion is derived from the carbonate, lactate. chloride, gluconate, phosphate, hydrogen phosphate, sulphate, tartrate or citrate salt.

5. A pharmaceutical product according to Claim 3 wherein the aluminium ion is derived from the carbonate, lactate, glycinate or phosphate salt or from, aluminium magnesium carbonate hydroxide, magaldrate, aluminium sodium carbonate hydroxide or aluminium sodium silicate.

6. A pharmaceutical product according to Claim 4 wherein the relative quantities by weight of the calcium salt to the alginic acid or alginate calculated as ions is 4 to 120 Ca²⁺ to 500 alginate".

7. A pharmaceutical product according to Claim 5 wherein the relative quantities by weight of the aluminium compound to the alginic acid or alginate calculated as ions is 2 to 80 Al³⁺ to 500 alginate".

8. A pharmaceutical product according to any of the preceding Claims wherein the carbonate or bicarbonate salt is potassium carbonate or bicarbonate, sodium carbonate or bicarbonate, calcium carbonate, sodium glycine carbonate, magnesium carbonate or aluminium carbonate.

9. A pharmaceutical product according to any of the preceding Claims wherein the relative quantities by weight of carbonate or bicarbonate to the polymeric material calculated as ions is 35 to 300 C0₃ ²" or HC0₃" to 500 polymeric material.

10. A pharmaceutical product according to any of the preceding Claims wherein the oil-based liquid vehicle is a natural oil such as soya bean oil, fractionated coconut oil, mineral oil, triacetin, ethyl oleate, a hydrogenated natural oil or mixture thereof.

11. A pharmaceutical product according to any one of Claims 1 to 9 wherein the hydrophilic based liquid vehicle is a polyethylene glycol (PEG'S) particularly PEG 400 and PEG 600, glycofurol, polyglycerols, propylene glycol, transcutol, polysorbate, propylene carbonate or mixtures thereof.

12. A pharmaceutical product according to any of the preceding Claims wherein the fill includes a thickening agent.

13. A pharmaceutical product according to any of the preceding Claims wherein the fill includes a surfactant.

14. 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 hereinbefore 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.

15. A method according to Claim 14 wherein the polymeric material is alginic acid or the alginates, are the sodium, potassium, ammonium, magnesium or calcium salts or the propylene glycol esters or mixtures thereof.