Chewable gelled emulsions

Abstract

An oral pharmaceutical composition in unit dose form, each unit dose comprising a lipophilic drug substance within a unitary carrier body, said body comprising a soft, chewable, gelled oil-in-water emulsion.

Claims

1. An oral pharmaceutical composition in dose unit form comprising a physiologically tolerable calcium compound within a unitary carrier body, said body comprising a soft, chewable, gelled oil-in-water emulsion, wherein the calcium compound is dispersed in one or both of the oil and aqueous phases of the emulsion, and wherein the calcium content per dose unit is at least 125 mg Ca, and further wherein the aqueous phase comprises gelatin as a gelling agent in an amount of 5 to 50% wt. of the aqueous phase, and the weight of said dose unit is 1,000 mg to 5,000 mg.

2. A composition as claimed in claim 1 containing particulate calcium carbonate.

3. A composition as claimed in claim 1 further containing xylitol.

4. A composition as claimed in claim 1 consisting of a said gelled emulsion containing said calcium compound.

5. A pharmaceutical package comprising a composition as claimed in claim 1, wherein said composition is foil-encased.

6. A package as claimed in claim 5 in the form of a blister pack.

Description

(1) Embodiments of the invention will now be described in the following non-limiting examples and the accompanying drawings, in which:

(2) FIGS. 1 and 2 are graphs showing the omega-3 fatty acid concentration and composition of EPA and DHA respectively in total plasma delivered by three different administration forms;

(3) FIGS. 3 and 4 are graphs showing the total amount of EPA and DHA taken up respectively, i.e. the area under the curve of the graphs in FIGS. 1 and 2 respectively.

EXAMPLE 1

(4) Drug-Free Composition

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

(6) TABLE-US-00001 Gelatin 7.5% wt Xylitol 36% wt Sorbitol 14% wt 50% Citric acid 1% wt Lemon flavour 0.15% wt Water ad 100% wt

(7) 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

(8) Drug-Containing Compositions

(9) The drugs listed in Table 1 below are dissolved or dispersed in the oil or water phases used in Example 1 (in the oil phase if lipophilic or in the aqueous phase if not) 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.

(10) 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. Where an omega-3 ester is used as the oil of the oil phase, the dose units are preferably at least 1000 mg.

(11) TABLE-US-00002 TABLE 1 Drug substance Dose per dose unit (mg) Ibuprofen 100-1500 (e.g. 200, 400, 600 and 800) Naproxen 250, 375 and 500 Ketoprofen 12.5-300 (e.g. 12.5, 50, 75, 100 and 200) Paracetamol 500-1000 Loratadine 10 Astemizole 10, 50 and 200 Dexochlorpheniramine 2-12 (e.g. 2, 4, 6 and 8) Chlorpheniramine 4 Clemastine 1 and 2 (as fumarate, 1.34 and 2.68) Diphenhydramine 25 and 50 Buspirone 5, 10, 15, and 30 Fluoxetine 5-90 (e.g. 10 and 20) Perphenazine 2, 4, 8 and 16 Chlorpromazine 10, 25, 50, 100 and 200 Prochlorperazine 5, 10 and 15 Mazindol 1, 2 and 3 Phentermine 8-40 (e.g. 8, 15 and 30) Dextroamphetamine 5, 10 and 15 Amitriptyline 10, 25, 50, 75, 100 and 150 Selegiline 1.25, 5 and 10 Apomorphine 5 and 10 Bromocryptine 2.5 to 40 (e.g. 2.5, 5, 10, 15) Phenylpropanolamine 25, 50, 75, 400 and 600 Pseudoephedrine 60 and 120 Dextromethorphan 30-600 (e.g. 30, 90, 400) Calcitonin 5, 30, 35, 75 and 150 Insulin Recommended daily dose Cyclosporine 25 and 100 Barbiturate (butabarbital) 30, 50 and 100 Benzodiazepine (e.g. temazepam, 0.25, 0.5, 1 and 2 triazolam and nitrazepam) Progesterone 100, 200 and 300 Estradiol (as estradiol valerinate) 0.5, 1 and 2 Testosterone (as testosterone 10 undecanoate) Nitrazepam 0.3, 1, 2.5, 5 and 10 Triazolam 0.125, 0.25 and 0.5 Zolpidem 5 and 10 Temazepam 7.5, 15, 22.5 and 30 Ergocalciferol 10-200 kIU (e.g. 30000 IU) Alphacalcidol 0.25, 0.5, 1 and 2 micrograms Calcitriol 0.25, 0.5, 1 and 2 micrograms

(12) The selegiline, apomorphine, insulin and calcitonin dose units are preferably dissolved in the mouth rather than chewed/swallowed.

EXAMPLE 3

(13) Gum Arabicum-Containing Compositions

(14) An aqueous phase is prepared using the following components:

(15) TABLE-US-00003 Gelatin 5.7% wt Xylitol 24.2% wt Sorbitol 10.4% wt 50% Citric acid 0.6% wt Lemon flavour 1.1% wt Gum arabicum 3.7% wt Water ad 100% wt

(16) Drug-free and drug-containing dose units are prepared using this aqueous phase analogously to Examples 1 and 2.

EXAMPLE 4

(17) Calcium Composition

(18) An aqueous phase is prepared according to Example 1 but with an additional 1% wt hydroxypropyl methyl cellulose. 1250 mg/mL calcium carbonate (Scoralite 1B from Scora SA, France) is dispersed in this aqueous phase whereafter an emulsion is formed with the addition of cod liver oil (1:1 by volume) containing dissolved vitamin D.sub.3. The emulsion is stirred until gelling begins whereafter it is dosed into moulds at a dose unit of 1250 mg CaCO.sub.3 and 400 IU vitamin D.sub.3 per dose unit. The dose units are sealed as in Example 1.

EXAMPLE 5

(19) Randomised, Controlled Trial

(20) The absorption of omega-3 fatty acids delivered by two different administration forms (two different formulations of omega-3 food supplements) is compared.

(21) 5 g omega-3 fatty acids (2.805 g eicosapentaenoic acid (EPA), 1.87 g docosahexaenoic acid (DHA)) in triglyceride form and 13 mg Vitamin E were administered to students of 18-28 years of age, in the form of either a soft gelled oil-in-water emulsion or as standard softgel capsules. Blood samples were collected after 0, 2, 3, 4, 6, 8 and 26 hours. The fatty acid concentration and composition in total plasma were measured.

(22) In FIGS. 1-4, A and D correspond to administration of the soft-gelled oil-in-water emulsion of the present invention containing EPA or DHA respectively, B and E correspond to the administration of a standard omega-3 soft gel capsules containing a liquid marine phospholipid core and C and F correspond to the administration of standard omega-3 soft gel capsules containing a liquid triglyceride core.

(23) From FIGS. 1 and 2, it can be seen that lipophilic compounds (e.g. the omega-3 fatty acids EPA and DHA) are absorbed more quickly when administered in a soft gelled oil-in-water emulsion than when administered in the form of a standard soft gel capsule containing a liquid core.

(24) From FIGS. 3 and 4, it can be seen that a higher total plasma concentration of lipophilic compounds (e.g. the omega-3 fatty acids EPA and DHA) is achieved when administered in a soft gelled oil-in-water emulsion than when administered in the form of a standard soft gel capsule containing a liquid core.

EXAMPLE 6

(25) Ibuprofen Composition (Double Emulsion)

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

(27) Ibuprofen solution (50 (w/v) %)* 71.6 wt %

(28) Flavouring 28.4 wt % *Solvent:

(29) 50 (v/v) % water 25 (v/v) % PEG (50 (w/v) %) 25 (v/v) % KOH (50 (w/v) %)

(30) Sorbitan sesquiolate (or another emulsifier) is mixed with the oil (e.g. an omega-3 ester (Omacor®)) in a weight ratio of 5:95. This oil phase is emulsified with the aqueous phase in a weight ratio of 69:31 using an ULTRA-TURRAX® high-performance disperser (available from IKA).

(31) A further aqueous phase is formed from the following ingredients:

(32) TABLE-US-00004 Gelatin 17.2 wt % Gum arabicum 4.2 wt % Sorbitol 15.9 wt % Xylitol 29.6 wt % Na-Saccharin 0.1 wt % Na-Cyclamate 0.9 wt % Citric acid 0.9 wt % Colouring 1.5 wt % Water ad 100 wt %

(33) The above water-in-oil emulsion is further emulsified with the further aqueous phase in a weight ratio of 69:31 using an ULTRA-TURRAX® high-performance disperser and the water-in-oil-in-water emulsion (double 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

(34) Hydrophilic Drug-Containing Compositions

(35) The drugs listed in Table 2 below are dissolved or dispersed in the oil or water phases used in Example 6 at the concentrations per dose unit set out in Table 2 before emulsions are produced, poured and allowed to set as in Example 6. The set-gel dosage units are packaged as in Example 6.

(36) TABLE-US-00005 TABLE 2 Drug substance Dose per dose unit (mg) Acetazolamide sodium 125 Acetyl salicylic acid 75 Aminophylline 100 Amiodarone hydrochloride 100 Ascorbic acid  25-100 Atenolol  25-100 Bendroflumethiazide  5-10 Calcium folinate  5-25 Captopril 12.5-100  Cetrizine hydrochlorid 2.5-10  Chloramphenicol sodium succinate 125 Chlorpheniramine maleate  2-12 Chlorpromazine hydrochloride  10-100 Cimetidine hydrochloride 100 Ciprofloxacin hydrochloride 100 Clindamycin hydrochloride  75-150 Clonidine hydrochloride 0.1-0.3 Codeine phosphate 15-60 Cyclizine hydrochloride  50-150 Cyclophosphamide 25-50 Dexamethasone sodium phosphate 0.25-6   Dicloxacillin sodium 125 Dicyclomide hydrochloride 20 Diltiazem hydrochloride  30-120 Diphenhydramine hydrochloride 12.5-50   Disopyramide phosphate 100 Doxepin hydrochloride  10-150 Enalapril maleate 2.5 Erythromycin ethylsuccinate 100 Flecanide acetate  50-150 Fluphenazine hydrochloride  1-10 Folic acid 0.4-1   Granisteron hydrochloride 1 Guafenesin 100 Haloperidol lactate 0.5-20  Hydralazin hydrochloride  10-100 Hydrochloroquine sulfate 200 Hydromorphone hydrochloride 1-8 Hydroxyzine hydrochloride  10-100 Indomethacin sodium 25-75 Isoniazid  50-100 Isoprenaline hydrochloride 10-15 Ketorolac trometamol 10 Labetalol hydrochloride 100 Lisinopril 2.5-40  Lithium sulfate 42-83 Mesoridazine bensylate  10-100 Methadone hydrochloride  5-40 Methylphenidate hydrochloride  5-20 Methylprednisolone sodium succinate  2-32 Metorprolol tartrate  50-100 Metronidazole hydrochloride 250 Metyldopa 125 Mexiletine hydrochloride 150 Molidone hydrochloride  5-100 Morphine sulfate  15-200 Naltrexone hydrochloride 50 Neomycin sulfate 125 Ondanstreon hydrochloride 4-8 Orciprenaline sulfate 10-20 Oxacillin sodium 250 Oxybutynin chloride 5 Oxycodone hydrochloride  5-80 Paracetamol  80-160 Penicillamine 125 Pentoxifylline 400 Petidine hydrochloride  50-100 Phenobarbital sodium  15-100 Phenoxymethylpenicillin potassium 125 Phenylephrine hydrochloride 10 Phenytoin sodium  50-100 Potassium iodide 130 Primaquine phosphate 15 Procainamide hydrochloride 250 Procarbazine hydrochloride 50 Prochlorperazine maleate  5-30 Promazine hydrochloride 25-50 Promethazine hydrochloride 12.5-50   Propranolol hydrochloride  10-160 Pseudoephedrine hydrochloride  30-120 Pyridostigmine bromide  60-180 Pyridoxine hydrochloride  10-200 Ranitidine hydrochloride  75-150 Salbutamol sulfate 2-8 Sodium ethacrynate 25-50 Sotalol hydrochloride  80-160 Sumatripan succinate 25-50 Terbinafine hydrochloride 250 Terbutaline sulfate 2.5-5   Tetracycline hydrochloride 125 Thioridazine hydrochloride  10-150 Thiothixene hydrochloride  1-20 Trifluoperazine hydrochloride  1-10 Triprolidine hydrochloride 2.5 Valproate sodium 125 Vancomycin hydrochloride 125 Verapamil hydrochloride  40-120 Warfarin sodium  1-10

EXAMPLE 8

(37) Vitamin B Composition (Double Emulsion)

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

(39) TABLE-US-00006 Premix vitamin powder 11.8 wt % UF29278368 * Water ad 100 wt % * Supplemix Multivit-Tab containing among others Vitamin B1 base, Vitamin B2, Vitamin B6 base, Vitamin B9 and Vitamin B12

(40) Sorbitan sesquiolate (or another emulsifier) is mixed with the oil (e.g. caprilic/capric triglyceride (fractionated coconut oil)) in a weight ratio of 5:95. This oil phase is emulsified with the aqueous phase in a weight ratio of 50:50 using an ULTRA-TURRAX® high-performance disperser.

(41) A further aqueous phase is formed from the following ingredients:

(42) TABLE-US-00007 Gelatin 17.2 wt % Gum arabicum 4.2 wt % Sorbitol 15.9 wt % Xylitol 29.6 wt % Na-Saccharin 0.1 wt % Na-Cyclamate 0.9 wt % Citric acid 0.9 wt % Colouring 1.5 wt % Water ad 100 wt %

(43) The above water-in-oil emulsion is further emulsified with the further aqueous phase in a weight ratio of 69:31 using an ULTRA-TURRAX® high-performance disperser and the water-in-oil-in-water emulsion (double 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

(44) Calcium and Vitamin D Composition

(45) An aqueous phase is prepared using the following components:

(46) TABLE-US-00008 Gelatin 9.1% wt Xylitol 38.7% wt Sorbitol 16.6% wt Citric acid 0.9% wt Gum arabicum 5.9% wt Water ad 100% wt

(47) An oil phase is prepared using the following components:

(48) TABLE-US-00009 Flavouring 25% wt Vitamin D 0.03% wt Colouring 5% wt Sunflower oil* ad 100% wt *or alternatively an omega-3 ester(Omacor ®)

(49) The oil phase is emulsified with the aqueous phase in a weight ratio of 7:93. The emulsion is mixed with calcium carbonate powder (Eskal 500 from Staubtechnik, particle size 4-14 μm, ca. 80% by volume<10 μm) in a weight ratio of 1:1 to form a homogeneous solution and 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.

(50) Analogous dose units, produced without Vitamin D, did not have the gritty or dustlike taste of other commercially available tablets. Instead, said dose units tasted like fizzy candy.