Oral pharmaceutical dispersion compositions

Abstract

The invention provides an oral pharmaceutical composition, optionally in dose unit form, comprising a lipophilic drug substance in dispersion in a physiologically tolerable aqueous carrier, preferably an aqueous gel, wherein said drug substance contains a functional electrostatic group having a pKa value of from 2 to 10, characterised in that said aqueous carrier has a pH at least 0.3 below or above said pKa value, said pH being below said pKa where said group is acidic and above said pKa where said group is basic.

Claims

1. An oral pharmaceutical composition which is set and in uncoated dose unit form, wherein said composition is a physiologically tolerable continuous aqueous gel which is not an oil-in-water emulsion, said continuous aqueous gel comprising water, gelatin as a gelling agent, and a pH modifier, and having dispersed therein uncoated crystalline ibuprofen, and said continuous aqueous gel having a pH in the range of 4 to 4.5.

2. The composition as claimed in claim 1 wherein the gelatin in the physiologically tolerable continuous aqueous gel comprises a type B gelatin.

3. The composition as claimed in claim 1 wherein the gelatin in the physiologically tolerable continuous aqueous gel comprises a type A gelatin.

4. The composition as claimed in claim 2 wherein the gelatin in the physiologically tolerable continuous aqueous gel further comprises a type A gelatin.

5. A method of treatment of a human or non-human animal subject comprising the step of orally administering an effective amount of an oral pharmaceutical composition according to claim 1.

Description

(1) The invention will now be illustrated further with reference to the following non-limiting Examples and the accompanying drawings, in which:

(2) FIG. 1 shows the release profile of ibuprofen from the aqueous compositions of the invention compared to the release profile of standard Nurofen™ tablets (Reckitt Benkieser).

(3) FIG. 2 shows the release profile of paracetamol from the aqueous compositions of the invention.

EXAMPLE 1

Drug-Free Composition

(4) An aqueous phase is formed from the following ingredients:

(5) TABLE-US-00003 Gelatin 7.5% wt Xylitol 36% wt Sorbitol 14% wt 50% Citric acid 1% wt Lemon flavour 0.15% wt Water ad 100% wt

(6) Sunflower oil (or alternatively an omega-3 ester (Omacor®)) is emulsified with the aqueous phase in a weight ratio of 45:55 and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.

EXAMPLE 2

Drug-Containing Compositions

(7) The drugs listed in Table 1 above are dissolved in the aqueous phase and dispersed in the oil phase used in Example 1 at the concentrations per dose unit set out in Table 1 before emulsions are produced, poured and allowed to set as in Example 1. The set-gel dosage units are packaged as in Example 1.

(8) For drug concentrations below 100 mg per dose unit, the dose units are conveniently 250, 500 or 750 mg. For concentrations above 100 mg per dose unit, the dose units are conveniently 500, 1000, 1500, 2000, 2500 or 3000 mg.

EXAMPLE 3

Components

(9) TABLE-US-00004 Gelatin 84 mg Gum arabicum 55.5 mg Sorbitol 155 mg Xylitol 360 mg Citric acid 9 mg Flavour 18 mg Colour 10.5 mg oil 0-600 mg Sulfamethoxazole 200 mg Trimethoprim 40 mg Water to 1500 mg

(10) The oil(s) and sulfamethoxazole and trimethoprim are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.

EXAMPLE 4

Components

(11) TABLE-US-00005 Gelatin 84 mg Gum arabicum 55.5 mg Sorbitol 155 mg Xylitol 360 mg Citric acid 9 mg Flavour 18 mg Colour 10.5 mg Oil 0-600 mg Naltrexone 50 mg Water to 1500 mg

(12) The oil(s) and naltrexone are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.

EXAMPLE 5

Components

(13) TABLE-US-00006 Gelatin 84 mg Gum arabicum 55.5 mg Sorbitol 155 mg Xylitol 360 mg Citric acid 9 mg Flavour 18 mg Colour 10.5 mg Oil 0-600 mg Promethazine 12.5 mg Water to 1500 mg

(14) The oil(s) and promethazine are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.

EXAMPLE 6

Components

(15) TABLE-US-00007 Gelatin 84 mg Gum arabicum 55.5 mg Sorbitol 155 mg Xylitol 360 mg Citric acid 9 mg Flavour 18 mg Colour 10.5 mg Oil 0-600 mg leucovorin 10 mg Water to 1500 mg

(16) The oil(s) and leucovorin are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.

EXAMPLE 7

Components

(17) TABLE-US-00008 Gelatin 84 mg Gum arabicum 55.5 mg Sorbitol 155 mg Xylitol 360 mg Citric acid 9 mg Flavour 18 mg Colour 10.5 mg Oil 0-600 mg Atenolol 50 mg Water to 1500 mg

(18) The oil(s) and atenolol are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.

EXAMPLE 8

Components

(19) TABLE-US-00009 Gelatin 84 mg Gum arabicum 55.5 mg Sorbitol 155 mg Xylitol 360 mg Citric acid 9 mg Flavour 18 mg Colour 10.5 mg Oil 0-600 mg Sumatriptan 25 mg Water to 1500 mg

(20) The oil(s) and sumatriptan are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.

EXAMPLE 9

Gelled Ibuprofen Dispersions

(21) Crystalline ibuprofen is dispersed at 10% wt concentration in an aqueous solution comprising the ingredients listed below and the dispersion is poured into elongate molds as described in the previous example, allowed to set and sealed.

(22) Contents:

(23) TABLE-US-00010 Ingredient Content (% wt) Water 27.45 Gelatin 11.49 Sorbitol 18.50 Xylitol 30.85 Sodium saccharin 0.0158 Sodium cyclamate 0.1573 Citric acid 0.53 Ibuprofen 90 10.00 Total 100.00

EXAMPLE 10

Gelled Ibuprofen Dispersions

(24) Crystalline ibuprofen was dispersed at 6.7% wt concentration in an aqueous solution comprising the ingredients listed below and the dispersion was poured into rounded molds as described in the previous examples, allowed to set and sealed.

(25) Contents:

(26) TABLE-US-00011 Ingredient Content (% wt) Water 28.46 Gelatin (Type B, 226 Bloom, DGF Stoess) 11.92 Sorbitol 19.18 Xylitol 31.99 Sucralose 0.310 Orange flavour 0.900 Citric acid 0.544 Ibuprofen (Grade 90, BASF) 6.70 Total 100.00 Total 100.00

EXAMPLE 11

Comparison of Ibuprofen Release Profiles

(27) Gelled dispersions according to Example 9 (but set in rounded rather than elongate molds) were compared for their ibuprofen release profiles with Nurofen™ tablets (Reckitt Benkieser), i.e. ibuprofen-containing test units having a conventional sugar coating covering the drug and carrier. Both the dispersions and tablets contained 200 mg ibuprofen.

(28) The dispersions and test units were exposed to simulated intestinal juice (Phosphate buffered saline, pH 7.2, Sigma) at 37° C. and with 75 rpm stirring (according to the European Pharmacopoeia) in order to study the release of ibuprofen. The release profiles are shown in FIG. 1 (the square symbols represent the data points for the dispersions and the diamond symbols represent the data points for the Nurofen™ tablets). This Figure surprisingly shows that the gelled dispersions according to Example 9 result in 100% of the ibuprofen being released within 75 minutes, i.e. 10-15 minutes faster than the Nurofen™ tablets.

EXAMPLE 12

Gelled Paracetamol Dispersions

(29) Paracetamol was dispersed at 7.5% wt concentration in an aqueous solution comprising the ingredients listed below and the dispersion was poured into rounded molds as described in the previous examples, allowed to set and sealed.

(30) Contents:

(31) TABLE-US-00012 Ingredient Content (% wt) Water 30.09 Gelatin (Type B, 226 Bloom, DGF Stoess) 18.86 Sorbitol 12.77 Xylitol 29.82 Sucralose 0.135 Peppermint 0.475 Citric acid 0.338 Paracetamol (acetaminophen, Sigma) 7.50 Total 100.0

EXAMPLE 13

Paracetamol Release Profile

(32) Gelled dispersions according to Example 12 were tested for their paracetamol release profiles.

(33) The dispersions were exposed to simulated gastric juice (0.1 M HCl) at 37° C. and with 75 rpm stirring (according to the European Pharmacopoeia) in order to study the release of paracetamol. The release profile is shown in FIG. 2. It is clear from this Figure that the total release of the paracetamol (100% release) occurs within 20 minutes.

EXAMPLE 14

Gelled Ketoprofen Dispersions

(34) Ketoprofen is dispersed at 2.5% wt concentration in an aqueous solution comprising the ingredients listed below and the dispersion is poured into elongate molds as described in the previous example, allowed to set and sealed.

(35) Contents:

(36) TABLE-US-00013 Ingredient Content (% wt) Water 29.95 Gelatin 12.52 Sorbitol 20.14 Xylitol 33.60 Sodium saccharin 0.0172 Sodium cyclamate 0.1713 Citric acid 0.5794 Apple flavour 0.5667 Ketoprofen 2.50 Total 100.0

EXAMPLE 15

Gelled Paracetamol and Diphenylhydramine Dispersions

(37) Paracetamol and diphenylhydramine HCl are dispersed in an aqueous solution comprising the ingredients listed below at 7.5 and 0.38% wt concentration, respectively and the dispersion is poured into elongate molds as described in the previous example, allowed to set and sealed.

(38) Contents:

(39) TABLE-US-00014 Ingredient Content (% wt) Water 30.09 Gelatin 18.86 Sorbitol 12.77 Xylitol 29.45 Sucralose 0.135 Citric acid 0.338 Peppermint 0.475 Paracetamol 7.50 Diphenylhydramine HCl 0.38 Total 100.0

EXAMPLE 16

Gelled Paracetamol, Dextrometorphan and Phenylephrine Dispersions

(40) Paracetamol, dextrometorphan HBr and phenylephrine HCl are dispersed in an aqueous solution comprising the ingredients listed below at 7.5, 0.23 and 0.12% wt concentration, respectively and the dispersion is poured into elongate molds as described in the previous example, allowed to set and sealed.

(41) Contents:

(42) TABLE-US-00015 Ingredient Content (% wt) Water 30.09 Gelatin 18.86 Sorbitol 12.77 Xylitol 29.47 Sucralose 0.135 Citric acid 0.338 Peppermint 0.475 Paracetamol 7.50 Dextrometorphan HBr 0.23 Phenylephrine HCl 0.12 Total 100.0

EXAMPLE 17

Gelled Paracetamol, Chlorpheniramine Maleate and Phenylephrine Dispersions

(43) Paracetamol, chlorpheniramine maleate and phenylephrine HCl are dispersed in an aqueous solution comprising the ingredients listed below at 7.5, 0.046 and 0.12% wt concentration, respectively and the dispersion is poured into elongate molds as described in the previous example, allowed to set and sealed.

(44) Contents:

(45) TABLE-US-00016 Ingredient Content (% wt) Water 30.09 Gelatin 18.86 Sorbitol 12.77 Xylitol 29.65 Sucralose 0.135 Citric acid 0.338 Peppermint 0.475 Paracetamol 7.50 Chlorpheniramine maleate 0.46 Phenylephrine HCl 0.12 Total 100.0