U.S. patent application number 13/641088 was filed with the patent office on 2014-01-02 for oral pharmaceutical dispersion compositions.
This patent application is currently assigned to AYANDA GROUP AS. The applicant listed for this patent is Kurt Ingar Draget, Steinar Johan Engelsen, Magnus N. Hattrem, Ingvild Haug, Tore Seternes. Invention is credited to Kurt Ingar Draget, Steinar Johan Engelsen, Magnus N. Hattrem, Ingvild Haug, Tore Seternes.
Application Number | 20140005179 13/641088 |
Document ID | / |
Family ID | 42245193 |
Filed Date | 2014-01-02 |
United States Patent
Application |
20140005179 |
Kind Code |
A1 |
Draget; Kurt Ingar ; et
al. |
January 2, 2014 |
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.
Inventors: |
Draget; Kurt Ingar; (Tromso,
NO) ; Haug; Ingvild; (Tromso, NO) ; Hattrem;
Magnus N.; (Tromso, NO) ; Seternes; Tore;
(Tromso, NO) ; Engelsen; Steinar Johan; (Stabekk,
NO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Draget; Kurt Ingar
Haug; Ingvild
Hattrem; Magnus N.
Seternes; Tore
Engelsen; Steinar Johan |
Tromso
Tromso
Tromso
Tromso
Stabekk |
|
NO
NO
NO
NO
NO |
|
|
Assignee: |
AYANDA GROUP AS
Tromso
NO
|
Family ID: |
42245193 |
Appl. No.: |
13/641088 |
Filed: |
April 11, 2011 |
PCT Filed: |
April 11, 2011 |
PCT NO: |
PCT/GB2011/000563 |
371 Date: |
June 4, 2013 |
Current U.S.
Class: |
514/226.2 ;
514/249; 514/282; 514/380; 514/415; 514/570; 514/620 |
Current CPC
Class: |
A61K 31/192 20130101;
A61K 9/06 20130101; A61P 31/04 20180101; A61K 31/485 20130101; A61P
3/02 20180101; A61K 9/10 20130101; A61P 29/00 20180101; A61P 15/10
20180101; A61P 31/06 20180101; A61K 31/4985 20130101; Y02A 50/411
20180101; Y02A 50/30 20180101; A61K 9/107 20130101; A61K 31/165
20130101; A61K 31/5415 20130101; A61P 31/12 20180101; A61P 11/00
20180101; A61P 31/08 20180101; A61P 9/00 20180101; A61P 35/00
20180101; A61P 9/12 20180101; A61P 33/06 20180101; A61K 31/42
20130101; A61K 31/4045 20130101 |
Class at
Publication: |
514/226.2 ;
514/380; 514/282; 514/249; 514/620; 514/415; 514/570 |
International
Class: |
A61K 9/107 20060101
A61K009/107; A61K 31/485 20060101 A61K031/485; A61K 31/192 20060101
A61K031/192; A61K 31/4985 20060101 A61K031/4985; A61K 31/165
20060101 A61K031/165; A61K 31/4045 20060101 A61K031/4045; A61K
31/42 20060101 A61K031/42; A61K 31/5415 20060101 A61K031/5415 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 14, 2010 |
GB |
1006218.0 |
Claims
1. 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.
2. A composition as claimed in claim 1 wherein said carrier is an
aqueous gel.
3. A composition as claimed in either of claims 1 and 2 wherein
said drug substance is an NSAID.
4. A composition as claimed in claim 3 wherein said drug substance
is ibuprofen.
5. A composition as claimed in claim 4 wherein the pH of said
carrier is in the range 4 to 4.5.
6. An oral pharmaceutical composition comprising a drug substance
contained in a physiologically tolerable gelled oil-in-water
emulsion, wherein said drug substance is a hydrophilic drug
dispersed in the lipid phase or a lipophilic drug substance
dispersed in a, preferably continuous, aqueous phase of the
emulsion.
7. A pharmaceutical composition, comprising a drug substance
contained in a physiologically tolerable gelled oil-in-water
emulsion, wherein said drug substance is a hydrophilic drug
dispersed in an oil phase and/or a lipophilic drug dispersed in a,
preferably continuous, aqueous phase of the emulsion for use in
medicine.
8. A pharmaceutical composition, comprising a drug substance
contained in a physiologically tolerable gelled oil-in-water
emulsion, wherein said drug substance is a hydrophilic drug
dispersed in an oil phase and/or a lipophilic drug dispersed in a,
preferably continuous, aqueous phase of the emulsion, for use
treatment of retroviral infection, tuberculosis, pneumonia,
malaria, leprosy, erectile dysfunction, cancer, cardiovascular
diseases, hypertension, pain, bacterial infection, vitamin
deficiency or inflammation.
9. A lipophilic drug substance having a functional electrostatic
group having a pKa of 2 to 10 for use in a method of treatment of a
human or non human animal subject to combat a condition responsive
thereto, which method comprises orally administering to said
subject an oral pharmaceutical composition comprising said drug
substance dispersed in an aqueous carrier having 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.
10. The use of a lipophilic drug substance having a functional
electrostatic group having a pKa of 2 to 10 for the manufacture of
an oral pharmaceutical composition for use by oral administration
in a method of treatment of a human or nonhuman animal subject to
combat a condition responsive to said drug substance, said
composition comprising said drug substance in dispersion in a
physiologically tolerable aqueous carrier, preferably an aqueous
gel, 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.
11. A method of treatment of a human or nonhuman animal subject by
oral administration thereto of an effective amount of an oral
pharmaceutical composition comprising a lipophilic drug substance
having a functional electrostatic group having a pKa of 2 to 10 to
combat a condition responsive to said drug substance, said
composition comprising said drug substance in dispersion in a
physiologically tolerable aqueous carrier, preferably an aqueous
gel, 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.
12. Use of a drug substance contained in a physiologically
tolerable gelled oil-in-water emulsion for the manufacture of a
medicament for use by oral administration in the treatment of
retroviral infection, tuberculosis, pneumonia, malaria, leprosy,
erectile dysfunction, cancer, cardiovascular diseases,
hypertension, pain, bacterial infection, vitamin deficiency or
inflammation, wherein said drug substance is a hydrophilic drug
dispersed in an oil phase and/or a lipophilic drug dispersed in a,
preferably continuous, aqueous phase of the emulsion.
13. A method of treatment of a human subject to combat retroviral
infection, tuberculosis, pneumonia, malaria, leprosy, erectile
dysfunction, cancer, cardiovascular diseases, hypertension, pain,
bacterial infection, vitamin deficiency or inflammation, which
method comprises orally administering to said subject an effective
amount of a pharmaceutical composition, comprising a drug substance
contained in a physiologically tolerable gelled oil-in-water
emulsion, wherein said drug substance is a hydrophilic drug
dispersed in an oil phase and/or a lipophilic drug dispersed in a,
preferably continuous, aqueous phase of the emulsion.
Description
[0001] This invention relates to oral pharmaceutical compositions
in the form of dispersions, preferably gelled aqueous emulsions,
particularly gelled oil-in-water emulsions, preferably comprising a
hydrophilic drug substance, but optionally a lipophilic or
amphiphilic drug substance and to methods of treatment of a human
subject therewith.
[0002] Many drug substances, i.e. the physiologically active
components of pharmaceutical compositions, have an unpleasant taste
and/or odour. Accordingly, any therapeutic or prophylactic dosage
regime which involves the consumption of unpleasant tasting or
nasty smelling dose units is inherently at risk of patient
non-compliance.
[0003] Moreover, when the unit dose of a drug substance is large,
the oral unit dosage forms, e.g. tablets or capsules, may likewise
be large and so difficult for elderly or young patients to swallow
and moreover may cause a gagging reaction even with healthy adults.
Accordingly, any therapeutic or prophylactic dosage regime which
involves the consumption of large numbers of dose units or numbers
of large, difficult to swallow, dose units is inherently at risk of
patient non-compliance.
[0004] For some drug substances it is possible to use a chewable
tablet, a suckable lozenge, or a film that dissolves in the mouth
as the vehicle for the drug substance. Nevertheless, this is not
feasible where the drug substance has a bitter or unpleasant taste
or where it is primarily intended to be taken up lower down the
gastrointestinal tract.
[0005] We have previously found that drug substances may be
administered without these problems when contained within a piece
of soft, chewable, gelled oil-in-water emulsion. Lipophilic drugs
may be dissolved in the lipid phase. Where the drug substance is a
hydrophilic drug, this may be dissolved in an aqueous phase within
said oil-in-water emulsion, i.e. as a gelled water-in-oil-in water
emulsion (a "double emulsion").
[0006] We have now surprisingly found that, rather than, or in
addition to, dissolving the drug in the innermost phase of the
emulsion (i.e. the lipophilic drug in the oil phase of an
oil-in-water emulsion or the hydrophilic drug in the aqueous phase
of a water-in-oil-in water emulsion) the drug substance may be
dispersed as a solid, e.g. in particulate form, in whatever phase
is most convenient. In this way a particularly high drug loading of
the emulsion may be achieved thus reducing the need for the patient
to consume multiple or oversized dosage units. Particularly
preferably, the invention comprises dispersion of a hydrophilic
drug in the lipid phase of a gelled oil-in-water emulsion, and more
particularly a lipophilic drug dispersed in the continuous aqueous
phase of a gelled oil-in-water emulsion.
[0007] This is especially useful when the drug substances to be
administrated have a strong, unpleasant taste.
[0008] Thus viewed from one aspect the invention provides an oral
pharmaceutical composition comprising a drug substance contained in
a physiologically tolerable gelled oil-in-water emulsion, wherein
said drug substance is a hydrophilic drug dispersed in the lipid
phase or a lipophilic drug substance dispersed in a, preferably
continuous, aqueous phase of the emulsion.
[0009] The gelled emulsions of the invention are preferably in
soft, chewable form.
[0010] Hydrophilic drugs, i.e. those which may be dispersed in, but
not fully dissolved in, the lipid phase include those characterised
by their physicochemical properties in that they carry
electrostatic charges (e.g. salts) and/or a substantial amount of
polar functions such as hydroxyl, keto, phosphate, amino and/or
sulphydryl groups. Examples of particular hydrophilic drug
substances for use according to the invention include: pyroxidine,
sulfamethoxazole, guanethidine monosulphate, leocovorin, lithium
salt, naproxen sodium, bismuth subsalicylate, sodium acetazolamide,
acetyl salicylic acid, aminophylline, amiodarone hydrochloride,
ascorbic acid, atenolol, bendroflumethiazide, calcium folinate,
captopril, cetrizine hydrochloride, chloramphenicol sodium
succinate, chlorpheniramine maleate, chlorpromazine hydrochloride,
cimetidine hydrochloride, ciprofloxacin hydrochloride, clindamycin
hydrochloride, clonidine hydrochloride, codeine phosphate,
cyclizine hydrochloride, cyclophosphamide, sodium dexamethasone
phosphate, sodium dicloxacillin, dicyclomide hydrochloride,
diltiazem hydrochloride, diphenhydramine hydrochloride,
disopyramide phosphate, doxepin hydrochloride, enalapril maleate,
erythromycin ethylsuccinate, flecanide acetate, fluphenazine
hydrochloride, folic acid, granisteron hydrochloride, guaifenesin,
haloperidol lactate, hydralazin hydrochloride, hydrochloroquine
sulfate, hydromorphone hydrochloride, hydroxyzine hydrochloride,
sodium indomethacin, isoniazid, isoprenaline hydrochloride,
ketorolac trometamol, labetalol hydrochloride, lisinopril, lithium
sulfate, mesoridazine benzylate, methadone hydrochloride,
methylphenidate hydrochloride, methylprednisolone sodium succinate,
metorprolol tartrate, metronidazole hydrochloride, metyldopa,
mexiletine hydrochloride, molidone hydrochloride, morphine sulfate,
naltrexone hydrochloride, neomycin sulfate, ondanstreon
hydrochloride, orciprenaline sulfate, sodium oxacillin, oxybutynin
chloride, oxycodone hydrochloride, paracetamol, penicillamine,
pentoxifylline, petidine hydrochloride, sodium phenobarbital,
potassium phenoxymethylpenicillin, phenylephrine hydrochloride,
sodium phenytoin, potassium iodide, primaquine phosphate,
procainamide hydrochloride, procarbazine hydrochloride,
prochlorperazine maleate, promazine hydrochloride, promethazine
hydrochloride, propranolol hydrochloride, pseudoephedrine
hydrochloride, pyridostigmine bromide, pyridoxine hydrochloride,
ranitidine hydrochloride, salbutamol sulfate, sodium ethacrynate,
sotalol hydrochloride, sumatripan succinate, terbinafine
hydrochloride, terbutaline sulfate, tetracycline hydrochloride,
thioridazine hydrochloride, thiothixene hydrochloride,
trifluoperazine hydrochloride, triprolidine hydrochloride, sodium
valproate, vancomycin hydrochloride, vancomycin hydrochloride,
verapamil hydrochloride, sodium warfarin.
[0011] Suitable doses for selected drugs are: sulfamethoxazole (200
mg), guanethidine monosulphate (10 mg), leucovorin (5 mg), lithium
salt (300 mg), naproxen sodium (250 mg), bismuth subsalicylate (250
mg), guaifenesin, (200 mg), ketorolac trometamol (10 mg),
cyclophosphamide (25 mg), phenoxymethylpenicillin (125 mg),
Metronidazol (250 mg). Further suitable doses are given in the
tables below.
[0012] In a further aspect the invention involves the dispersion of
a lipophilic drug in the aqueous phase of an oil in water emulsion
(i.e. the continuous phase) or a water-in-oil-in-water emulsion
(i.e. the continuous aqueous phase and/or the discontinuous aqueous
phase).
[0013] Thus viewed from a further aspect, the present invention
provides an oral pharmaceutical composition comprising a drug
substance contained in a physiologically tolerable gelled
oil-in-water emulsion, wherein said drug substance is a lipophilic
drug dispersed in an aqueous phase.
[0014] Suitable lipophilic drugs are well documented and include
temazepam; diphenhydramine; zolpidem; triazolam; nitrazepam;
testosterone; estradiol; progesterone; benzodiazepines;
barbiturates; cyclosporine; insulin; calcitonin; dextromethorphan;
pseudoephedrine; phenylpropanolamine; bromocryptine; apomorphine;
selegiline; amitriptyline; dextroamphetamine; phentermine;
mazindol; compazine; chlorpromazine; perphenazine; fluoxetine,
buspirone; clemastine; chlorpheniramine; dexochlorpheniramine;
astemizole; loratadine; paracetamol; ketoprofen; naproxen; and,
particularly, ibuprofen.
[0015] The present invention involves the dispersion of a drug in a
phase of an emulsion in which it is not fully soluble. The drug
substance therefore remains in solid, e.g. crystalline form to some
extent in the compositions, methods and uses of the invention.
[0016] In addition to a hydrophilic drug being dispersed in a lipid
phase and/or a lipophilic drug being dispersed in an aqueous phase
in the gelled compositions comprising oil-in-water emulsions of the
invention, further drug/phase combinations may be present in the
gelled compositions, whether by dispersion and/or dissolution. For
example, the following compositions are envisaged: [0017]
Hydrophilic drug dispersed in lipid phase and hydrophilic drug
dissolved in aqueous phase. [0018] Hydrophilic drug dispersed in
lipid phase and lipophilic drug dissolved in lipid phase. [0019]
Hydrophilic drug dispersed in lipid phase and lipophilic drug
dissolved in lipid phase and hydrophilic drug dissolved in aqueous
phase. [0020] Hydrophilic drug dispersed in oil phase and
lipophilic drug dispersed in aqueous phase. [0021] Lipophilic drug
dispersed in aqueous phase and lipophilic drug dissolved in lipid
phase. [0022] Lipophilic drug dispersed in aqueous phase and
hydrophilic drug dissolved in aqueous phase. [0023] Lipophilic drug
dispersed in aqueous phase and hydrophilic drug dissolved in
aqueous phase and lipophilic drug dissolved in lipid phase.
[0024] In each case the hydrophilic drugs in the phases may be the
same or different and the lipophilic drugs in the phases may be the
same or different. Amphiphilic drugs may also be present.
[0025] In one aspect of the invention the compositions of the
invention comprise a lipophilic drug dispersed in the continuous
aqueous phase of an oil in water emulsion in the gelled emulsions
of the invention.
[0026] In order to facilitate even dispersion throughout the phase
containing it, the drug substance is preferably in particulate
form. The optimal particle size for good dispersion and good
mouthfeel of the resulting gelled emulsion varies depending on the
nature of the drug and the composition of the phase in which it is
dissolved, however suitable particle sizes (e.g. mode maximum
particle dimension) are 0.5-25 .mu.m, preferably 1-20 .mu.m,
particularly 2-15 .mu.m.
[0027] Particularly preferably the compositions of the invention
will contain two or more drugs, or even one or more lipophilic
drugs in combination with one or more hydrophilic drugs, where the
drugs are dispersed in the aqueous and oil phases of an emulsion
respectively.
[0028] The compositions of the invention are preferably in dose
unit form, and each dose until will typically contain 10% to 100%,
preferably 50% to 100% of the recommended daily (or one-off) dose
of the particular drug substance. Examples of recommended daily or
one-off doses for some of the drug substances mentioned herein are
set out in Table 1 below.
[0029] Where the human recipient is a child, the compositions
according to the invention are especially suitable since they can
readily and accurately be divided, for example by cutting with a
blade, to provide the dosage required for the child's particular
age or bodyweight/size. For this reason it is preferred to mark the
dose unit (e.g. with surface markings such as a scale of
bodyweight, height or age) or its packaging (e.g. the blister or
blister cover of a blister-packed gelled emulsion) with indications
showing where the gelled emulsion dose unit may be divided to yield
a fragment containing the desired dosage.
TABLE-US-00001 TABLE 1 Typical daily or one-off drug doses 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 The selegiline, apomorphine, insulin and calcitonin dose
units are preferably dissolved in the mouth rather than
chewed/swallowed.
TABLE-US-00002 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 sulphate 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 sulphate 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 sulphate
15-200 Naltrexone hydrochloride 50 Neomycin sulphate 125
Ondanstreon hydrochloride 4-8 Orciprenaline sulphate 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 sulphate 2-8 Sodium
ethacrynate 25-50 Sotalol hydrochloride 80-160 Sumatripan succinate
25-50 Terbinafine hydrochloride 250 Terbutaline sulphate 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
[0030] By dispersing the drug substance in an emulsion phase, a
greater loading of the drug can be obtained than if it had to be
dissolved. In particular, the present invention can dramatically
increase the loading capacity of hydrophilic drugs and/or
lipophilic drugs in gelled oil-in-water emulsion. Moreover, by
administering drugs in the gelled emulsions of the invention, the
unpleasant taste of many drug substances can be masked, thus
improving patient compliance. The gelled emulsion dosage form also
protects the gastrointestinal tract from the irritation which may
be experienced from administration of certain drugs, e.g.
NSAIDs.
[0031] By drug substance is meant a substance having a desirable
therapeutic or prophylactic effect other than as a nutrient, i.e.
substances of the type for which regulatory approval as a drug is
required in for example the US or the European Union. Less
preferably, the drug substance may be a vitamin which classifies as
a drug substance for regulatory purposes, e.g. vitamin A, K or D
(e.g. ergocalciferol, alphacalcidol and calcitriol). Vitamins,
including these, as well as mineral and/or herbs may of course be
included in the compositions in addition to non-vitamin drug
substances.
[0032] By amphiphilic drug substance is meant a drug substance that
will distribute at the oil droplet surface. In the single emulsion
of the present invention the amphiphilic drug substance is mixed
with the oil phase and in the double emulsion of the present
invention the amphiphilic drug substance is mixed either with the
oil or with the discontinuous aqueous phase of the double
emulsion.
[0033] Examples of categories of suitable drug substances for use
according to the invention include: analgesics;
anti-inflammatories; anticancer agents; cardiovascular agents;
biological agents; antiallergy agents (e.g. antihistamines);
decongestants; antinausea agents, drugs affecting gastrointestinal
function, drugs acting on the blood and blood-forming organs, drugs
affecting renal and cardiovascular function, antifungal agents,
urological agents, hormones, antimicrobial agents, antiepileptical
agents, psycholeptical agents, antipsychotic agents,
psychoanaleptical agents, anticholinesterase agents, drugs acting
on the respiration organs and drugs acting on the eye.
[0034] Viewed from a further aspect the invention provides a
pharmaceutical composition, comprising a drug substance contained
in a physiologically tolerable gelled oil-in-water emulsion,
wherein said drug substance is a hydrophilic drug dispersed in an
oil phase and/or a lipophilic drug dispersed in a, preferably
continuous, aqueous phase of the emulsion for use in medicine.
[0035] Viewed from a further aspect the invention provides a
pharmaceutical composition, comprising a drug substance contained
in a physiologically tolerable gelled oil-in-water emulsion,
wherein said drug substance is a hydrophilic drug dispersed in an
oil phase and/or a lipophilic drug dispersed in a, preferably
continuous, aqueous phase of the emulsion for use in the treatment
of retroviral infection, tuberculosis, pneumonia, malaria, leprosy,
erectile dysfunction, cancer, cardiovascular diseases,
hypertension, pain, bacterial infection, vitamin deficiency or
inflammation.
[0036] Viewed from a still further aspect the invention provides
the use of a drug substance for the manufacture of a medicament for
use by oral administration in the treatment of retroviral
infection, tuberculosis, pneumonia, malaria, leprosy, erectile
dysfunction, cancer, cardiovascular diseases, hypertension, pain,
bacterial infection, vitamin deficiency or inflammation, wherein
said drug substance is contained in a physiologically tolerable
gelled oil-in-water emulsion and is a hydrophilic drug dispersed in
an oil phase and/or a lipophilic drug dispersed in a, preferably
continuous, aqueous phase of the emulsion.
[0037] Viewed from a still further aspect the invention provides a
method of treatment of a human subject to combat retroviral
infection, tuberculosis, pneumonia, malaria, leprosy, erectile
dysfunction, cancer, cardiovascular diseases, hypertension, pain,
bacterial infection, vitamin deficiency or inflammation, which
method comprises orally administering to said subject an effective
amount of a pharmaceutical composition comprising a drug substance
contained in a physiologically tolerable gelled oil-in-water
emulsion, wherein said drug substance is a hydrophilic drug
dispersed in an oil phase and/or a lipophilic drug dispersed in a,
preferably continuous, aqueous phase of the emulsion.
[0038] The drug substance may typically be included in the
compositions of the invention at 10% to 100% of its normal oral
daily dose, especially 50% to 100%.
[0039] Besides the drug substance, the compositions of the
invention may contain further components such as nutrients, e.g.
lipids, (especially triglycerides and phospholipids, typically of
plant or marine animal origin), vitamins, minerals, and folic acid,
pH modifiers, viscosity modifiers, flavours, aromas, sweeteners,
colorants, antioxidants, etc.
[0040] The gelled emulsion compositions of the invention will
preferably be in dose unit form, with each dose unit having a
weight of 50 to 3000 mg, especially 100 to 2000 mg, particularly
100 to 1500 mg, more particularly 400 to 1500 mg, more especially
400 to 1000 mg.
[0041] The composition of the invention will preferably be
uncoated, i.e. not within a capsule or shell-coating. Accordingly,
to avoid water loss during storage, the dose units will
conveniently be individually packaged, e.g. in foil wrappers or in
the blisters of a blister pack.
[0042] The dose units of the gelled emulsion may be formed for
example by moulding, extrusion or cutting or the like. For adult
use, the dose units are preferably in tablet or lozenge form;
however for child use they may conveniently be presented in
child-friendly form, e.g. geometric shapes such as rods, strips and
tubes, or animal, doll, or vehicle shapes, for example the shape of
a popular cartoon character.
[0043] The oil phase of the oil-in-water emulsion may be any
physiologically tolerable lipid, e.g. fatty acid esters such as
triglycerides and phospholipids, for example plant or animal oils,
especially plant and marine animal oils. Particularly preferably an
oil is used which is high in omega-3, omega-6 or omega-9 essential
fatty acids, especially omega-3 essential fatty acids, more
especially EPA and DHA. In this way the oil phase itself is a
highly bioavailable source of nutrient lipids.
[0044] Examples of omega-3 acids include a-linolenic acid (ALA),
stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic
acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid
(DPA), docosahexaenoic acid (DHA), tetracosapentaenoic acid and
tetracosahexaenoic acid. Examples of omega-6 acids include linoleic
acid, gamma-linolenic acid, eicosadienoic acid,
dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA),
docosadienoic acid, adrenic acid, docosapentaenoic acid, and
calendic acid. Examples of omega-9 acids include oleic acid,
eicosenoic acid, mead acid, erucic acid and nervonic acid.
[0045] It is particularly preferred that the compositions according
to the invention contain a citrus flavour (e.g. orange or lemon
oil) in order to mask any remaining oil taste on chewing. It is
also particularly preferred that the compositions according to the
invention contain xylitol, e.g. as 0.5 to 50% wt., preferably 1 to
40% wt., e.g. 15 to 40% wt., in order to mask both taste and mouth
feel. These may be in the aqueous phase or the oil phase (e.g. as a
water-in-oil-in water emulsion), or both; however inclusion in the
aqueous phase will generally be sufficient.
[0046] Other than the drug substance, the essential fatty acids may
form part or the whole of the oil phase in the gelled emulsion,
preferably at least 10% wt, more especially at least 50% wt,
particularly at least 80% wt. of that phase. They may be used as
single compounds or as compound mixtures, e.g. plant or marine
oils.
[0047] The oil phase of the oil-in-water emulsion may also contain
solubilisers in order to increase the solubility of the drug
substance in the oil phase. Suitable solubilisers would be known to
a person skilled in the art and include Chremophor EL.TM., castor
oil, Tween 80.TM., Solutol.TM. HS15, Lutrol.TM. and Olestra.
[0048] The aqueous phase of the gelled emulsion will contain water
and a physiologically tolerable gelling agent, e.g. a hydrocolloid
such as gelatin, alginate, carrageenan or a pectin. Such gelling
agents and their gel-forming properties are well known. See for
example Phillips G O and Williams P A (Eds.) Handbook of
hydrocolloids, Woodhead Publishing, Cambridge (2000). The use of
gelatin is especially preferred. Besides water and the gelling
agent, the aqueous phase of the gelled emulsion may contain other
water-soluble components, e.g. vitamins, minerals, pH modifiers,
viscosity modifiers, antioxidants, colorants, flavours,
water-soluble drug substances, etc. as desired.
[0049] The weight ratio of the lipid phase to the aqueous phase in
the gelled emulsions is preferably 1:19 to 3:1, especially 35:65 to
1:1, particularly 2:3 to 1:1.
[0050] Emulsion formation may be effected by conventional
techniques; however emulsification under a non-oxidising gas, e.g.
nitrogen, is preferred. Likewise, the components of the emulsion
are preferably degassed before emulsification and handling and
packaging of the set emulsion is preferably performed under such a
gas.
[0051] The gelled emulsions of and used according to the invention
may be produced as described in WO 2007/085835 and WO 2007/085840
and PCT/GB2009/002404 and PCT/GB2009/002406 (copies of which are
annexed to the description of this application as Annexes A and B)
the contents of which are hereby incorporated by reference.
[0052] The gelled emulsions may if desired be more than biphasic.
Thus a water-in-oil emulsion may be emulsified with an aqueous
gelling agent phase to produce a water-in-oil-in-water double
emulsion, or two oil-in-water emulsions with different oil phases
may be combined and intimately mixed before gelling onset.
[0053] We have also found that in the case of lipophilic drug
substances carrying a functional electrostatic group having a pKa
value of 2 to 10, more especially 4 to 10, particularly 4.5 to 9,
the composition may be presented in the form of an aqueous
dispersion of the drug substance and having an aqueous phase pH
which is at least 0.3, preferably at least 0.5, more preferably at
least 1, for example up to 2.5, preferably up to more preferably up
to 1.8, below or above the pKa value of the electrostatic group,
the pH being below the pKa value where the electrostatic group is
acidic (e.g. a carboxyl group) and above the pKa value where the
electrostatic group is basic (e.g. an amine group). Where the drug
substance contains two or more functional electrostatic groups, the
pH is preferably below or above the lowest acid group pKa or above
the highest basic group pKa by these values. In this way, not only
is it possible to achieve a high loading of the lipophilic drug
compound into the oral pharmaceutical composition but also the
unpleasant mouthfeel that otherwise arises with aqueous dispersions
of such drugs is masked. If desired, a strong flavouring agent may
also be included to further mask mouthfeel, e.g. a citrus fruit
flavour such as grapefruit for acidic drugs.
[0054] Thus viewed from a further aspect 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, preferably
4 to 9, especially 4.5 to 8.5, characterised in that said aqueous
carrier has a pH at least 0.3, preferably at least 0.5, more
preferably at least 1 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.
[0055] pH and pKa values as referred to herein are preferably as
measured at ambient temperature, typically and preferably
21.degree. C.
[0056] The aqueous dispersions of the invention may be in any
suitable form, e.g. gels, suspensions, viscous liquids (e.g.
syrups) or simple dispersions.
[0057] Preferably however they are aqueous gels. The gelling agents
used may be any physiologically tolerable agents, preferably
gelling agents as described elsewhere herein.
[0058] The lipophilic drug substance used in the dispersions of the
invention may be any lipophilic drug substances having a functional
group with a pKa in the appropriate range; preferably however it is
an NSAID, particularly ibuprofen.
[0059] Where ibuprofen is used, the pH of the aqueous carrier is
preferably about 4-4.5 as the pKa of the said group in ibuprofen is
about 5. Using an aqueous carrier with a pH of 4-4.5 allows the
extremely astringent mouthfeel of ibuprofen to be masked and
reduces the solubility of ibuprofen in the aqueous carrier.
[0060] The desired pH of the aqueous carrier may be achieved by the
use of well known physiologically tolerable acids, bases and
buffers, e.g. using fruit acids such as citric acid.
[0061] Viewed from a further aspect the invention provides a
lipophilic drug substance having a functional electrostatic group
having a pKa of 2 to 10 for use in a method of treatment of a human
or non human animal (especially a mammal) subject to combat a
condition responsive thereto, which method comprises orally
administering to said subject an oral pharmaceutical composition
comprising said drug substance dispersed in an aqueous carrier
having a pH at least 0.3, preferably at least 0.5, more preferably
at least 1 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.
[0062] Viewed from a further aspect the invention provides the use
of a lipophilic drug substance having a functional electrostatic
group having a pKa of 2 to 10 for the manufacture of an oral
pharmaceutical composition for use by oral administration in a
method of treatment of a human or nonhuman animal subject to combat
a condition responsive to said drug substance, said composition
comprising said drug substance in dispersion in a physiologically
tolerable aqueous carrier, preferably an aqueous gel, characterised
in that said aqueous carrier has a pH at least 0.3, preferably at
least 0.5, more preferably at least 1 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.
[0063] Viewed from a still further aspect the invention provides a
method of treatment of a human or nonhuman animal subject by oral
administration thereto of an effective amount of an oral
pharmaceutical composition comprising a lipophilic drug substance
having a functional electrostatic group having a pKa of 2 to 10 to
combat a condition responsive to said drug substance, said
composition comprising said drug substance in dispersion in a
physiologically tolerable aqueous carrier, preferably an aqueous
gel, characterised in that said aqueous carrier has a pH at least
0.3, preferably at least 0.5, more preferably at least 1 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.
[0064] The invention will now be illustrated further with reference
to the following non-limiting Examples.
EXAMPLE 1
Drug-Free Composition
[0065] An aqueous phase is formed from the following
ingredients:
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
[0066] Sunflower oil (or alternatively an omega-3 ester
(Omacor.RTM.)) 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
[0067] 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.
[0068] 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
TABLE-US-00004 [0069] 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
[0070] 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
TABLE-US-00005 [0071] 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
[0072] 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
TABLE-US-00006 [0073] 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
[0074] 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
TABLE-US-00007 [0075] 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
[0076] 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
TABLE-US-00008 [0077] 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
[0078] 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
TABLE-US-00009 [0079] 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
[0080] 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
[0081] 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.
Contents:
TABLE-US-00010 [0082] 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
* * * * *