WO2011128628A2 - Gelled oral pharmaceutical compositions - Google Patents

Gelled oral pharmaceutical compositions Download PDF

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Publication number
WO2011128628A2
WO2011128628A2 PCT/GB2011/000558 GB2011000558W WO2011128628A2 WO 2011128628 A2 WO2011128628 A2 WO 2011128628A2 GB 2011000558 W GB2011000558 W GB 2011000558W WO 2011128628 A2 WO2011128628 A2 WO 2011128628A2
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WO
WIPO (PCT)
Prior art keywords
drug substance
drugs
oil
leprosy
erectile dysfunction
Prior art date
Application number
PCT/GB2011/000558
Other languages
French (fr)
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WO2011128628A3 (en
Inventor
Kurt Ingar Drageet
Ingvild Johanne Haug
Steinar Johan Engelsen
Tore Seternes
Original Assignee
Probio Asa
Cockbain, Julian
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Application filed by Probio Asa, Cockbain, Julian filed Critical Probio Asa
Publication of WO2011128628A2 publication Critical patent/WO2011128628A2/en
Publication of WO2011128628A3 publication Critical patent/WO2011128628A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to pharmaceutical compositions in the form of gelled oil-in- water emulsions and to methods of treatment of a human subject therewith.
  • administration of drug substances is by oral administration of tablets or capsules. Unlike administration by injection, oral self administration is simple and does not require special equipment or skin-surface sterilization.
  • the invention provides an oral pharmaceutical composition
  • a drug substance contained in a physiologically tolerable gelled oil-in-water emulsion, wherein said drug substance is selected from the group consisting of anti-retrovirals, anti-tuberculosis drugs, anti-pneumonials, antimalarials, anti-leprosy drugs, and anti-erectile dysfunction agents.
  • Anti-retrovirals are drugs used in the treatment of HIV/AIDS, a disease which is particularly predominant in regions where a ready supply of clean water is frequently absent. For HIV it is extremely important to ensure patient compliance in order to avoid build up of viral resistance and thus there is a particular need for drug dosage forms which do not require water for ingestion, or in the case of child patients, for formulation at the required dosage. This is solved by the use of the gelled emulsion compositions of the invention.
  • Examples of anti-retrovirals include reverse transcriptase (RT) inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors. RT inhibitors fall into two classes: nucleoside and non- nucleoside RT inhibitors - NRTI and NNRTI.
  • Suitable NRTIs include emtricitabine, lamivudine, zidovudine, tenofovir, abazavir, didanosine and stavudine.
  • Suitable NNRTIs include efavirenz and nevirapine.
  • Suitable protease inhibitors include lopinavir, ritonavir, nelfinavir, fosamprenavir, darunavir and atazanavir.
  • Ritonavir will generally only be used as part of a cocktail of two or more anti-retrovirals. Examples of further anti-retrovirals suitable for oral administration are well known from the literature.
  • compositions of the invention will contain two or more anti HIV drugs of different classes, e.g. at least one RT inhibitor (preferably at least two) and at least one (preferably two) protease inhibitor.
  • RT inhibitor preferably at least two
  • protease inhibitor examples include: lopinavir, ritonavir and one or two NRTIs; fosamprenavir, ritonavir and one or two NRTIs; atazanavir, ritonavir and one or two NRTIs; efavirenz and one or two NRTIs; and nevirapine and one or two NRTIs, however the use of only one NRTI in these combinations is less preferred.
  • the preferred NRTIs are abacavir, tenofovir, zidovudine, lamuvidine and emtricitabine, particularly the combinations of abacavir, tenofovir, zidovudine and lamuvidine or emtricitabine.
  • compositions according to the invention containing orally administrable anti-TB agents, such as for example isoniazid, rifampicin, pyrazinamide, ethambutol, amikacin, kanamycin, capreomycin, viomycin, enviomycin, ciprofloxacin, levofloxacin, moxifloxacin, ethionamide, prothionamide, cycloserine, rifabutin, linezolid, thioacetazone and thoridazine, especially isoniazid, rifampicin, pyrazinamide and ethambutol and combinations of these four or of isoniazid and rifampicin.
  • orally administrable anti-TB agents such as for example isoniazid, rifampicin, pyrazinamide, ethambutol, amikacin, kanamycin, capreomycin, viomycin, enviomycin, cip
  • HIV patients likewise frequently need to be treated to control or prevent other opportunistic infections, in particular pneumonia, especially Pneumocystis pneumonia (PCP).
  • PCP Pneumocystis pneumonia
  • the anti-pneumonials used may also conveniently be presented as gelled oil-in-water emulsions according to the invention.
  • Anti-pneumonials useful in this regard include sulfametoxazole and trimethoprim and indeed these are preferably given in combination.
  • compositions of the invention are anti-malarial compositions containing an antimalarial agent, e.g. a drug selected from chloroquine, hydroxychloroquine, atovaquone, proguanil, mefloquine, primaquine, artemisin, tetracycline,
  • an antimalarial agent e.g. a drug selected from chloroquine, hydroxychloroquine, atovaquone, proguanil, mefloquine, primaquine, artemisin, tetracycline,
  • the anti-malarial agent is artemisin and the derivatives artemether and artesunate.
  • compositions of the invention contain at least one anti-leprosy drug.
  • Suitable anti-leprosy drugs include rifampicin, dapsone and clofazimine, and preferably two of these or all three are used together.
  • the compositions of the invention are to combat erectile dysfunction, particularly in men and contain an erection facilitating drug substance, e.g. a PDE5 inhibitor such as sildenafil, vardenafil or tadalafil, especially sildenafil.
  • the compositions of the invention are particularly suited to this use since the patient may consume the erection facilitating agent without drawing attention to his doing so and thus causing embarrassment.
  • 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
  • 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.
  • marking the dose unit e.g. with surface markings such as a scale of bodyweight, height or age
  • its packaging e.g. the blister or blister cover of a blister-packed gelled emulsion
  • 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 selected from the group consisting of anti-retrovirals, anti-tuberculosis drugs, anti-pneumonials, anti-malarials, anti- leprosy drugs and anti-erectile dysfunction agents, for use in medicine.
  • 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 selected from the group consisting of anti-retrovirals, anti-tuberculosis drugs, anti-pneumonials, anti-malarials, anti- leprosy drugs and anti-erectile dysfunction agents, for use in treatment to combat retroviral infection, tuberculosis, pneumonia, malaria, leprosy or erectile
  • the invention provides the use of a drug substance selected from the group consisting of anti-retrovirals, anti-tuberculosis drugs, anti-pneumonials, anti-malarials, anti-leprosy drugs and anti-erectile dysfunction agents for the manufacture of a medicament for use by oral administration in the treatment of a retroviral infection, tuberculosis, pneumonia, malaria, leprosy or erectile dysfunction.
  • the invention provides a method of treatment of a human subject to combat retroviral infection, tuberculosis, pneumonia, malaria, leprosy or erectile dysfunction, 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 selected from the group consisting of anti- retrovirals, anti-tuberculosis drugs, anti-pneumonials, anti-malarials, anti-leprosy drugs and anti-erectile dysfunction agents.
  • 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%.
  • 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.
  • 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 1500 mg, particularly 400 to 1000 mg.
  • the dose units of the gelled emulsion may be formed for example by moulding, extrusion or cutting or the like.
  • 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.
  • compositions 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.
  • 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.
  • physiologically tolerable lipid e.g. fatty acid esters such as triglycerides and phospholipids
  • 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.
  • omega-3, omega-6 or omega-9 essential fatty acids especially omega-3 essential fatty acids, more especially EPA and DHA.
  • omega-3 acids examples include a-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA),
  • ALA a-linolenic acid
  • SDA stearidonic acid
  • ETE eicosatrienoic acid
  • ETA eicosatetraenoic acid
  • EPA eicosapentaenoic acid
  • DPA docosapentaenoic acid
  • DHA docosahexaenoic acid
  • 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.
  • omega-9 acids include oleic acid, eicosenoic acid, mead acid, erucic acid and nervonic acid.
  • 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.
  • a citrus flavour e.g. orange or lemon oil
  • xylitol e.g. as 0.5 to 50% wt., preferably 1 to 40% wt., e.g. 15 to 40% wt.
  • 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.
  • 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.
  • solubilisers would be known to a person skilled in the art and include Chremophor ELTM, castor oil, Tween 80TM, SolutolTM HS15, LutrolTM and Olestra.
  • 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.
  • a physiologically tolerable gelling agent e.g. a hydrocolloid such as gelatin, alginate, carrageenan or a pectin.
  • a physiologically tolerable gelling agent e.g. a hydrocolloid such as gelatin, alginate, carrageenan or a pectin.
  • 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 GO and Williams PA (Eds.) Handbook of hydrocolloids, Woodhead Publishing, Cambridge (2000). The use of gelatin is especially preferred.
  • 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.
  • Emulsion formation may be effected by conventional techniques; however emulsification under a non-oxidising gas, e.g. nitrogen, is preferred.
  • a non-oxidising gas e.g. nitrogen
  • 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.
  • 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.
  • the gelled emulsions may if desired be more than biphasic.
  • 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.
  • the oil(s) and abazavir, lamivudine, lopinavir and ritonavir 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.
  • the oil(s), abazavir and lamivudine 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.
  • the oil(s) and abazavir, lamivudine and efavirenz 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.
  • the oil(s) and zidovudine, neifinavir and ritonavir 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.
  • the oil(s) and zidovudine, emtricitabine, neifinavir and ritonavir 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.
  • the oil(s) and zidovudine, lamivudine and nevirapine 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.
  • the oil(s) and tenofovir, emtricitabine and efivarenz 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.
  • PCP Anti-pneumonia Agent
  • 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.
  • the oil(s) and isoniazid and rifampicin 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.
  • the oil(s) and artemether and lumefantrine is 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.
  • the oil(s) and sildenafil is 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
  • the oil(s) and rifampicin, dapsone and clofazimine 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.

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Abstract

This 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 selected from the group consisting of anti- retrovirals, anti-tuberculosis drugs, anti-pneumonials, anti-malarials, anti-leprosy drugs and anti-erectile dysfunction agents.

Description

Gelled Oral Pharmaceutical Compositions
This invention relates to pharmaceutical compositions in the form of gelled oil-in- water emulsions and to methods of treatment of a human subject therewith.
For most human subjects in the developed world the preferred route of
administration of drug substances (pharmaceuticals) is by oral administration of tablets or capsules. Unlike administration by injection, oral self administration is simple and does not require special equipment or skin-surface sterilization.
However in order to swallow a tablet or capsule many patients also require to swallow a quantity of liquid, e.g. water, to ensure the tablet or capsule reaches the stomach and to avoid a gag reaction.
This need for water when taking an oral pharmaceutical is highly problematic when the patient is in a region where clean water is not readily available or when taking a drink of water to facilitate oral administration of the drug substance might draw attention to the fact that a drug is being administered and so embarrass the patient (e.g. where the drug is to combat erectile dysfunction).
For drugs which are administered in suspension form, clean water is also essential in order to keep the suspension stable and free from bacteria. Refrigeration of the suspension after adding water is important for stability, particularly in hot climates. In addition to be being cumbersome due to the water requirement and having limited stability, suspensions often taste bad, leading to poor patient compliance.
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.
Thus there is a need for pharmaceutical compositions which may be administered orally without the need for an accompanying draft of water. We have now found that this need is satisfactorily met by formulation of the drug substance in a physiologically tolerable gelled oil-in-water emulsion.
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 selected from the group consisting of anti-retrovirals, anti-tuberculosis drugs, anti-pneumonials, antimalarials, anti-leprosy drugs, and anti-erectile dysfunction agents.
Anti-retrovirals are drugs used in the treatment of HIV/AIDS, a disease which is particularly predominant in regions where a ready supply of clean water is frequently absent. For HIV it is extremely important to ensure patient compliance in order to avoid build up of viral resistance and thus there is a particular need for drug dosage forms which do not require water for ingestion, or in the case of child patients, for formulation at the required dosage. This is solved by the use of the gelled emulsion compositions of the invention. Examples of anti-retrovirals include reverse transcriptase (RT) inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors. RT inhibitors fall into two classes: nucleoside and non- nucleoside RT inhibitors - NRTI and NNRTI.
Suitable NRTIs include emtricitabine, lamivudine, zidovudine, tenofovir, abazavir, didanosine and stavudine. Suitable NNRTIs include efavirenz and nevirapine. Suitable protease inhibitors include lopinavir, ritonavir, nelfinavir, fosamprenavir, darunavir and atazanavir. Ritonavir will generally only be used as part of a cocktail of two or more anti-retrovirals. Examples of further anti-retrovirals suitable for oral administration are well known from the literature.
Particularly preferably the compositions of the invention will contain two or more anti HIV drugs of different classes, e.g. at least one RT inhibitor (preferably at least two) and at least one (preferably two) protease inhibitor. Examples of combinations include: lopinavir, ritonavir and one or two NRTIs; fosamprenavir, ritonavir and one or two NRTIs; atazanavir, ritonavir and one or two NRTIs; efavirenz and one or two NRTIs; and nevirapine and one or two NRTIs, however the use of only one NRTI in these combinations is less preferred. In these combinations, the preferred NRTIs are abacavir, tenofovir, zidovudine, lamuvidine and emtricitabine, particularly the combinations of abacavir, tenofovir, zidovudine and lamuvidine or emtricitabine.
Besides the primary infection by HIV, sufferers are especially susceptible to secondary infection, most worryingly by tuberculosis (TB). Thus such sufferers, especially those living in unsanitary conditions, will also particularly benefit from compositions according to the invention containing orally administrable anti-TB agents, such as for example isoniazid, rifampicin, pyrazinamide, ethambutol, amikacin, kanamycin, capreomycin, viomycin, enviomycin, ciprofloxacin, levofloxacin, moxifloxacin, ethionamide, prothionamide, cycloserine, rifabutin, linezolid, thioacetazone and thoridazine, especially isoniazid, rifampicin, pyrazinamide and ethambutol and combinations of these four or of isoniazid and rifampicin.
HIV patients likewise frequently need to be treated to control or prevent other opportunistic infections, in particular pneumonia, especially Pneumocystis pneumonia (PCP). The anti-pneumonials used may also conveniently be presented as gelled oil-in-water emulsions according to the invention. Anti-pneumonials useful in this regard include sulfametoxazole and trimethoprim and indeed these are preferably given in combination.
For inhabitants of or visitors to malarial regions, the problem of easy access to clean water is also particularly serious and in an alternative embodiment the compositions of the invention are anti-malarial compositions containing an antimalarial agent, e.g. a drug selected from chloroquine, hydroxychloroquine, atovaquone, proguanil, mefloquine, primaquine, artemisin, tetracycline,
clindamycin, doxycycline, and dapsone. Particularly preferably the anti-malarial agent is artemisin and the derivatives artemether and artesunate.
Leprosy also tends to be prevalent in areas where access to fresh clean water is difficult and in a further embodiment the compositions of the invention contain at least one anti-leprosy drug. Suitable anti-leprosy drugs include rifampicin, dapsone and clofazimine, and preferably two of these or all three are used together. ln another alternative embodiment, the compositions of the invention are to combat erectile dysfunction, particularly in men and contain an erection facilitating drug substance, e.g. a PDE5 inhibitor such as sildenafil, vardenafil or tadalafil, especially sildenafil. The compositions of the invention are particularly suited to this use since the patient may consume the erection facilitating agent without drawing attention to his doing so and thus causing embarrassment.
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.
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 1
Typical daily or one-off drug doses (in the adult unless indicated).
Drug/Drug combination Dosage
lopinavir 200 mg
ritonavir 50 mg
efavirenz 600 mg
tenofovir 300 mg
emtricitabine 200 mg
lopinavir 100 mg"1
ritonavir 25 mg emtricitabine 6 mg/kg'2
4 mg/kg'3
200 mg"4 lamivudine 4 mg/kg"5
75 mg/kg*6
150 mg/kg'7 zidovudine 12 mg/kg"8
9 mg/kg'9
300 mg'10 didanosine 120 mg/m2 '11
200-400 mg'12 stavudine 1 mg/kg"ia
30 mg"14
40 mg*15 efavirenz 200 mg"1B
300 mg'17 nelfinavir 45-55 mg/kg" B sulfametoxazole 25 mg/kg"13 trimethoprim 5 mg/kg sulfametoxazole 375 mg/m2"20 trimethoprim 75 mg/m2 chloroquine 300 mg proguanil 00 mg mefloquine 260 mg plaquenil 310 mg atouvaquone 250 mg atouvaquone 250 mg proguanil 100 mg
Children (20-30 kg)
atouvaquone 1500 mg proguanil 200 mg sildenafil 50 mg vardenafil 10 mg tadalafil 10 mg rifampicin 300 mg isoniazid 150 mg
dapsone 50 mg
clofazimine 150 mg
*1 Paediatric
*2 up to 240 mg/day
*3 Infants
*4 over 33 kg bodyweight
*5 Twice daily in children
*6 14-21 kg bodyweight
*7 Above 30 kg bodyweight in children
*8 Children 4-9 kg
*9 Children 9-30 kg
*10 Children above 30 kg
*11 Children less than 6 years
*12 Children above 6 years
*13 Children below 30 kg
*14 Children above 30 kg
*15 Above 60 kg bodyweight
*16 Children 10-15 kg
*17 Children 20-25 kg
*18 Children less than 2 years
*19 four times daily - therapy
*20 four times daily - prophylaxis
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 selected from the group consisting of anti-retrovirals, anti-tuberculosis drugs, anti-pneumonials, anti-malarials, anti- leprosy drugs and anti-erectile dysfunction agents, for use in medicine.
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 selected from the group consisting of anti-retrovirals, anti-tuberculosis drugs, anti-pneumonials, anti-malarials, anti- leprosy drugs and anti-erectile dysfunction agents, for use in treatment to combat retroviral infection, tuberculosis, pneumonia, malaria, leprosy or erectile
dysfunction.
Viewed from a still further aspect the invention provides the use of a drug substance selected from the group consisting of anti-retrovirals, anti-tuberculosis drugs, anti-pneumonials, anti-malarials, anti-leprosy drugs and anti-erectile dysfunction agents for the manufacture of a medicament for use by oral administration in the treatment of a retroviral infection, tuberculosis, pneumonia, malaria, leprosy or erectile dysfunction.
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 or erectile dysfunction, 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 selected from the group consisting of anti- retrovirals, anti-tuberculosis drugs, anti-pneumonials, anti-malarials, anti-leprosy drugs and anti-erectile dysfunction agents.
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%.
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..
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 1500 mg, particularly 400 to 1000 mg. 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.
The compositions 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.
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.
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.
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. 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.
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™, castor oil, Tween 80™, Solutol™ HS15, Lutrol™ and Olestra.
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 GO and Williams PA (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.
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.
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.
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. 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.
The invention will now be illustrated further with reference to the following non- limiting Examples.
Example 1
Anti-HIV Aaent Children - Protease Inhibitor Based
Components
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
Plant oil* 0 - 600 mg
Fish oil* 0 - 600 mg
Abazavir 150 mg
Lamivudine 75 mg
Lopinavir 200 mg
Ritonavir 50 mg
Water to 1500 mg
* Total no more than 600 mg
The oil(s) and abazavir, lamivudine, lopinavir and ritonavir 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 2
Anti-HIV Agent Children - NNRTI based - Morning Tablet
Components
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
Plant oil* 0 - 600 mg
Fish oil* 0 - 600 mg
Abazavir 150 mg
Lamivudine 75 mg
Water to 1500 mg
* Total no more than 600 mg
The oil(s), abazavir and lamivudine 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 3
Anti-HIV Agent CHILDREN - NNRTI based - Bedtime Tablet
Components
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
Plant oil* - 600 mg
Fish oil* - 600 mg
Abazavir 50 mg
Lamivudine 75 mg
Efavirenz 300 mg
Water to 1500 mg
* Total no more than 600 mg
The oil(s) and abazavir, lamivudine and efavirenz 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
Anti-HIV Agent Children - Protease Inhibitor (PI) based - Morning Tablet
Components
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
Plant oil* 0 - 600 mg
Fish oil* 0 - 600 mg
zidovudine 150 mg
Nelfinavir 500 mg
Ritonavir 25 mg
Water to 1500 mg * Total no more than 600 mg
The oil(s) and zidovudine, neifinavir and ritonavir 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
Anti-HIV Agent Children - PI based - Evening Tablet
Components
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
Plant oil* 0 - 600 mg
Fish oil* 0 - 600 mg
Zidovudine 150 mg
Emtricitabine 75 mg
Neifinavir 500 mg
Ritonavir 25 mg
Water to 1500 mg
* Total no more than 600 mg
The oil(s) and zidovudine, emtricitabine, neifinavir and ritonavir 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
Anti-HIV Agent Adults - NNRTI based Components
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
Plant oil* 0 - 600 mg
Fish oil* 0 - 600 mg
Zidovudine 150 mg
Lamivudine 75 mg
Nevirapine 100 mg
Water to 500 mg
* Total no more than 600 mg
The oil(s) and zidovudine, lamivudine and nevirapine 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
Anti-HIV Agent Adults - NNRTI based
Components
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
Plant oil* 0 - 600 mg Fish oil* 0 - 600 mg
Tenofovir 150 mg
Emtricitabine 100 mg
Efavirenz 300 mg
Water to 1500 mg
* Total no more than 600 mg
The oil(s) and tenofovir, emtricitabine and efivarenz 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
Anti-pneumonia Agent (PCP) Children Components
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
Plant oil* 0 - 600 mg
Fish oil* 0 - 600 mg
Sulfamethoxazole 200 mg
Trimethoprim 40 mg
Water to 1500 mg
* Total no more than 600 mg
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 9
Anti-Tuberculosis Agent
Components
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
Plant oil* 0 - 600 mg
Fish oil* 0 - 600 mg
Isoniazid 150 mg
Rifampicin 300 mg
Water to 1500 mg
* Total no more than 600 mg
The oil(s) and isoniazid and rifampicin 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 10
Anti-Malarial Agent
Components
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
Plant oil* 0 - 600 mg
Fish oil* 0 - 600 mg
Artemether 20 mg
Lumefantrine 120 mg
Water to 1500 mg
* Total no more than 600 mg
The oil(s) and artemether and lumefantrine is 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 11
Erectile Dysfunction Agent
Components
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
Plant oil* 0 - 600 mg
Fish oil* 0 - 600 mg
Sildenafil 50 mg
Water to 1500 mg
* Total no more than 600 mg B2011/000558
- 18 -
The oil(s) and sildenafil is 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 12
Anti-leprosy druq combination
Components
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
Plant oil* 0 - 600 mg
Fish oil* 0 - 600 mg
Rifampicin 150 mg
Dapsone 50 mg
Clofazimine 50 mg
Water to 1500 mg
* Total no more than 600 mg
The oil(s) and rifampicin, dapsone and clofazimine 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.

Claims

Claims:
1. An oral pharmaceutical composition comprising a drug substance contained in a physiologically tolerable gelled oil-in-water emulsion, wherein said drug substance is selected from the group consisting of anti-retrovirals, anti-tuberculosis drugs, anti-pneumonials, anti-malarials, anti-leprosy drugs and anti-erectile dysfunction agents.
2. A pharmaceutical composition, comprising a drug substance contained in a physiologically tolerable gelled oil-in-water emulsion, wherein said drug substance is selected from the group consisting of anti-retrovirals, anti-tuberculosis drugs, anti- pneumonials, anti-malarials, anti-leprosy drugs and anti-erectile dysfunction agents, for use in medicine.
3. A pharmaceutical composition, comprising a drug substance contained in a physiologically tolerable gelled oil-in-water emulsion, wherein said drug substance is selected from the group consisting of anti-retrovirals, anti-tuberculosis drugs, anti- pneumonials, anti-malarials, anti-leprosy drugs and anti-erectile dysfunction agents, for use treatment to combat retroviral infection, tuberculosis, pneumonia, malaria, leprosy or erectile dysfunction.
4. The use of a drug substance selected from the group consisting of anti- retrovirals, anti-tuberculosis drugs, anti-pneumonials, anti-malarials, anti-leprosy drugs and anti-erectile dysfunction agents for the manufacture of a medicament for use by oral administration in the treatment of a retroviral infection, tuberculosis, pneumonia, malaria, leprosy or erectile dysfunction.
5. A method of treatment of a human subject to combat retroviral infection, tuberculosis, pneumonia, malaria, leprosy or erectile dysfunction, which method comprises orally administering to said subject an effective amount of a provides a pharmaceutical composition, comprising a drug substance contained in a physiologically tolerable gelled oil-in-water emulsion, wherein said drug substance is selected from the group consisting of anti-retrovirals, anti-tuberculosis drugs, anti- pneumonials, anti-malarials, anti-leprosy drugs and anti-erectile dysfunction agents.
6. A composition, use or method as claimed in any of the preceding claims wherein said drug substance is an anti-retroviral.
7. A composition, use or method as claimed in any of the preceding claims wherein said drug substance is a combination of at least two anti-retrovirals.
8. A composition, use or method as claimed in any of claims 1 to 5 wherein said drug substance is a PDE5 inhibitor.
9. A composition, use or method as claimed in any of claims 1 to 5 wherein said drug substance is an anti-malarial.
10. A composition, use or method as claimed in any of claims 1 to 5 wherein said drug substance is an antibiotic.
PCT/GB2011/000558 2010-04-14 2011-04-11 Gelled oral pharmaceutical compositions WO2011128628A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1006175.2 2010-04-14
GBGB1006175.2A GB201006175D0 (en) 2010-04-14 2010-04-14 Composition

Publications (2)

Publication Number Publication Date
WO2011128628A2 true WO2011128628A2 (en) 2011-10-20
WO2011128628A3 WO2011128628A3 (en) 2012-11-08

Family

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Country Status (2)

Country Link
GB (1) GB201006175D0 (en)
WO (1) WO2011128628A2 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101795115B1 (en) 2014-02-03 2017-11-08 최원형 Anti-tuberculosis composition for treating or preventing tuberculosis comprising gamma-Linolenic acid
KR101798286B1 (en) 2015-07-08 2017-11-15 최원형 A composition for treating or preventing tuberculosis comprising Linolenic acid

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007085840A1 (en) 2006-01-25 2007-08-02 Probio Nutraceuticals As Emulsion

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GB9721746D0 (en) * 1997-10-15 1997-12-10 Panos Therapeutics Limited Compositions
US6692771B2 (en) * 2001-02-23 2004-02-17 Cima Labs Inc. Emulsions as solid dosage forms for oral administration

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WO2007085840A1 (en) 2006-01-25 2007-08-02 Probio Nutraceuticals As Emulsion
WO2007085835A1 (en) 2006-01-25 2007-08-02 Probio Nutraceuticals As Chewable capsules

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Handbook of hydrocolloids", 2000, WOODHEAD PUBLISHING

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101795115B1 (en) 2014-02-03 2017-11-08 최원형 Anti-tuberculosis composition for treating or preventing tuberculosis comprising gamma-Linolenic acid
KR101798286B1 (en) 2015-07-08 2017-11-15 최원형 A composition for treating or preventing tuberculosis comprising Linolenic acid

Also Published As

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WO2011128628A3 (en) 2012-11-08

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