CA2152615C - Atovaquone pharmaceutical compositions - Google Patents
Atovaquone pharmaceutical compositions Download PDFInfo
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- CA2152615C CA2152615C CA002152615A CA2152615A CA2152615C CA 2152615 C CA2152615 C CA 2152615C CA 002152615 A CA002152615 A CA 002152615A CA 2152615 A CA2152615 A CA 2152615A CA 2152615 C CA2152615 C CA 2152615C
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- Prior art keywords
- particles
- atovaquone
- pharmaceutical composition
- mixture
- microfluidised
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- KUCQYCKVKVOKAY-CTYIDZIISA-N atovaquone Chemical compound C1([C@H]2CC[C@@H](CC2)C2=C(C(C3=CC=CC=C3C2=O)=O)O)=CC=C(Cl)C=C1 KUCQYCKVKVOKAY-CTYIDZIISA-N 0.000 title claims abstract description 36
- 229960003159 atovaquone Drugs 0.000 title claims abstract description 36
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- 239000002245 particle Substances 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000000725 suspension Substances 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 239000000375 suspending agent Substances 0.000 claims description 7
- 239000003981 vehicle Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 5
- 239000000230 xanthan gum Substances 0.000 claims description 5
- 229920001285 xanthan gum Polymers 0.000 claims description 5
- 229940082509 xanthan gum Drugs 0.000 claims description 5
- 235000010493 xanthan gum Nutrition 0.000 claims description 5
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical group CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 3
- 229920001993 poloxamer 188 Polymers 0.000 claims description 3
- 229940044519 poloxamer 188 Drugs 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 238000011282 treatment Methods 0.000 claims description 2
- 208000030852 Parasitic disease Diseases 0.000 claims 1
- 241000233872 Pneumocystis carinii Species 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- BSJMWHQBCZFXBR-UHFFFAOYSA-N 3-[4-(p-chlorophenyl)cyclohexyl]-4-hydroxy-1,2-naphthoquinone Chemical compound O=C1C(=O)C2=CC=CC=C2C(O)=C1C(CC1)CCC1C1=CC=C(Cl)C=C1 BSJMWHQBCZFXBR-UHFFFAOYSA-N 0.000 description 1
- 241001312218 Arisaema triphyllum Species 0.000 description 1
- 208000003495 Coccidiosis Diseases 0.000 description 1
- 235000006481 Colocasia esculenta Nutrition 0.000 description 1
- 241000223924 Eimeria Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010023076 Isosporiasis Diseases 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 description 1
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 description 1
- 241000223777 Theileria Species 0.000 description 1
- 241000223778 Theileria annulata Species 0.000 description 1
- 201000005485 Toxoplasmosis Diseases 0.000 description 1
- 230000000842 anti-protozoal effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- YLGXILFCIXHCMC-JHGZEJCSSA-N methyl cellulose Chemical compound COC1C(OC)C(OC)C(COC)O[C@H]1O[C@H]1C(OC)C(OC)C(OC)OC1COC YLGXILFCIXHCMC-JHGZEJCSSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 1
- 229950000034 teneligliptin Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
Classifications
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K31/12—Ketones
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/08—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis for Pneumocystis carinii
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Plant Substances (AREA)
- Fertilizers (AREA)
- Food Preservation Except Freezing, Refrigeration, And Drying (AREA)
Abstract
The invention relates to microfluidised particles of atovaqnone and to a method of preparing them. More particularly, the invention is coned with a pharmaceutical composition containing microfluidised particles of atovaquone which has improved bioavailability and its use in therapy.
Description
ATOVAQUONE PHARMACEUTICAL COMPOSITIONS
The present invention relates to microfluidised particles of 2-[4-{=-c:~lorophenyl) cycIohexyl]-3-hydroxy-1,4-naphthoquinone and to a method for preparing them.
More particularly the invention is conce:ned with a pharmaceutical composition containing microffuidised particles of 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphtho-quinone ("atovaquone") and its use in therapy.
Atovaquone has previously been disclosed, for example in European Patent No.
0123238 and US Patent No. 506432 which relates to 2-substitutec~3-hydroxy-1,4-naphthoquinones of formula (I):
RZ
(CY2)n OH
wherein either RI is hydrogen and R2 is selected from C 1-6alkoxy, aralkoxy, C
alkyl-C1-6alkoxy, phenyl substituted by one oriwo gr 2 ps selected from halogen and C1-6alkyl, halogen and perhalo-C1-6alkyl or R and R are both C1-6aLkyl or phenyl, and n is zero or 1, and physiologically acceptable salts thereof. T'ne compounas are said to have antiprotozoal activity. Specifically, compounds of formula (Z) wherein n is zero are said to be active against the human malaria parasite Plasmodium falci~arum and also against Eimeria species such as E.tenelIa and E.acervuIina. which are causative organisms of coccidiosis and compounds of formula (1] where n is 1 are said to be active against protozoa of the genus Theileria, in particular T.annulata or T.parva_ Amongst the compounds specifically named and exemplified is the compound of formula (I) wherein n is zero, R is hydrogen and R is 4-chlorophenyl, i.e.
atovaquone.
EP 0362996 discloses the use of atovaquone in the treatment and/or prophylaxis of Pneumocystis carinii pneumonia.
The present invention relates to microfluidised particles of 2-[4-{=-c:~lorophenyl) cycIohexyl]-3-hydroxy-1,4-naphthoquinone and to a method for preparing them.
More particularly the invention is conce:ned with a pharmaceutical composition containing microffuidised particles of 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphtho-quinone ("atovaquone") and its use in therapy.
Atovaquone has previously been disclosed, for example in European Patent No.
0123238 and US Patent No. 506432 which relates to 2-substitutec~3-hydroxy-1,4-naphthoquinones of formula (I):
RZ
(CY2)n OH
wherein either RI is hydrogen and R2 is selected from C 1-6alkoxy, aralkoxy, C
alkyl-C1-6alkoxy, phenyl substituted by one oriwo gr 2 ps selected from halogen and C1-6alkyl, halogen and perhalo-C1-6alkyl or R and R are both C1-6aLkyl or phenyl, and n is zero or 1, and physiologically acceptable salts thereof. T'ne compounas are said to have antiprotozoal activity. Specifically, compounds of formula (Z) wherein n is zero are said to be active against the human malaria parasite Plasmodium falci~arum and also against Eimeria species such as E.tenelIa and E.acervuIina. which are causative organisms of coccidiosis and compounds of formula (1] where n is 1 are said to be active against protozoa of the genus Theileria, in particular T.annulata or T.parva_ Amongst the compounds specifically named and exemplified is the compound of formula (I) wherein n is zero, R is hydrogen and R is 4-chlorophenyl, i.e.
atovaquone.
EP 0362996 discloses the use of atovaquone in the treatment and/or prophylaxis of Pneumocystis carinii pneumonia.
Further uses of atovaquone agailzst Toxoplasmosis and Cryptospondiosis are disclosed in European patent application nos. 0445141 and 0496729 respec~~ively.
The efncacy of atovaquone as a therapeutic agent is limited by its bioavailability.
Accordingly it is an object of the present invention to provide atovaquone in a more bioavailable form.
It has now been found that the bioavailability of atovaquone can be increased by ensuring that the particle size is within a certain denned range of small particles.
However, conventional methods of reducing the particle size of atovaquone were found to be ursuccessful in producing particles of the size required to improve bioavailability.
The Microfluidiser (Trade-mark) has been marketed by the Microfluidics Corporation since 1985. The principle of its operation is based on a submerged jet technology. It was designed, primarily, as a homogenizing device for use in the food and pharmaceutical industries, for the preparation of e.g. emulsion and liposomal systems and has subsequently been used for cell-rupture purposes in biotechnology applications.
It has now surprisingly been found that microffuidised particles of atovaquone produced using a Microfluidiser have improved bioavailability of the compound.
It is believed that this is due to the small size and narrow range of sizes of the microffuidised atovaquone particles.
During operatioh of the Microfluiaiser, the feed stream is pumped into a specially designed chamber, in which fluid streams interact at very high velocities and pressures.
Fixed microchannels within the interaction chamber provide an extremely focussed interaction zone of intense turbulence, causing the release of energy amid cavitation and shear forces. Without wishing to be bound by theory it is believed that since all product passes through a dimensionally fixed area of energy release, greater size uniformity and smaller sizes are achieved by using the Microfluidiser rather than conventional methods for producing fine particles.
Thus, in a first aspect, the present invention provides small particles of atovaquone.
Preferably the particles are microffuidised particles. Suitably at least 90%
of the particles have a volume diameter in the range of 0.1-3pm. Preferably at least 95% of the particles have a volume diameter in the range of 0.1-2p.m In a second aspect, the present invention provides a pharmaceutical composition comprising particles of atovaquone and one or more pharmaceutically acceptable Garners therefor wherein at least 90% of the particles have a volume diameter in the range of 0.1-Sum, preferably at least 95% of the particles have a volume diameter in the range of 0.1-2p.m. Preferably the particles are microfluidised particles.
The Garners must be acceptable in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof.
According to a third aspect, the present invention provides a method for the preparation of microfluidised particles of atovaquone which comprises mixing atovaquone with a liquid vehicle to provide a mixture wherein the concentration of atovaquone is less than 450mg/mL and subjecting said mixture to at least 3 passes through a Microfluidiser in order to provide the atovaquone in the form of particles wherein at least 90% of the particles have a volume diameter in the range of 0.1-3~.m.
Preferably at least 95% of the particles have a volume diameter in the range 0.1-2~m.
In a further aspect the present invention provides a method for the preparation of a pharmaceutical composition comprising the steps of:
a) mixing atovaquone with a liquid vehicle to provide a mixture wherein the concentration of atovaquone is less than 450mg/mL.
3a b) subjecting the mixture to at least 3 passes through a Microfluidiser to provide a microfluidised preparation wherein the atovaquone is in the form of particles and at least 90% of those particles have a volume diameter in the range of 0.1-3p.m, and preferably at least 95% of the particles have a volume diameter in the range of 0.1-2 p,m.
c) mixing the microfluidised preparation with one or more pharmaceutically acceptable carriers therefor.
Suitably, the mixture is subjected to 10-50 passes through the Microfluidiser, e.g. 25-30 passes. Preferably the mixture is subjected to 15-25 passes through the Micro-fluidiser.
In one embodiment, the liquid vehicle is a surfactant. Preferably, the liquid vehicle is a surfactant solution. In a particularly preferred embodiment the surfactant is Poloxamer 188 solution. In another preferred embodiment the pharmaceutically acceptable carriers include a suspending agent. Suitable suspending agents include methyl cellulose and xanthan gum. Preferably the suspending agent is xanthan gum.
Pharmaceutical formulations include those suitable for oral and parenteral (including subcutaneous, intradermal, intramuscular and intravenous) administration as well as administration by naso-gastric tube. Suitable formulations within the scope of the present invention include, for example, solid dosage forms such as tablets and liquid dosage forms, such as suspensions, which are preferred formulations. The formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared from the microfluidised particles using methods known in the art of pharmacy.
' ~ CA 02152615 1999-02-08 -The invention will now be further illustrated by the following non-limiting examples:-Example 1 Preparation of Microfluidised particles of atovaquone Atovaquone was prepared by methods according to the prior art, e.g. US Patent No.
5053432. 600 mL of a mixture consisting of 2.5% w/v atovaquone in 0.25% w/v aqueous Celacol M2500 (Trade-mark) was prepared and 100 mL were retained in a glass jar as a control. A laboratory scale model 120B Microfluidiser was connected to a 90 psi pneumatic supply and adjusted to produce a fluid pressure of 15000 psi. The machine base, interaction chamber and pipework of the Microfluidiser were immersed in a bath of cold water. SOOmL of the mixture were loaded into the Microfluidiser's bulk vessel and passed through the Microfluidiser interaction chamber before being returned to the top, and side, of the bulk chamber. The mixture was recirculated continuously through the interaction chamber, and samples were taken at 10, 20, 30, 45 and 60 minutes. The number of passes to vsihich each of these samples had been subjected was calculated and is shown in Table 1 below.
S, am~le_ Nficrofluidisation Sample Volume Number of passes t~
(minutes) (ml) Control 0 100 0 1V>icroscopic observations of the control and samples at 40x magnification were made and the results were as follows:-Control Varied shapes, plates, rods and spheroids, around SxS~m generally and up to 7.Sx10p,m, loosely aggregated.
Sample 1 - More rounded smaller shapes, some "large" crystals, lots of small fragments 2.Sx2.5p,m, more dispersed.
Sample 2 - More rounded, smaller shapes, more fragments.
Sample 3 - Still more rounded, smaller shapes, more fragments.
Sample 4 - Yet more rounded, smaller shapes, more fragments.
WO 94E,344 .~ ~ ~ 2 ~ ~ PCT/GB93/02646 - 6 ...., ' Sample S - Very small particles, all under 2.S~m, all rounded, monodisperse.
Example 2 Pharmaceutical Formulation An oral suspension formulation was prepared by mixing the following ingredients:-Microfluidised particles of atovaquone150.Omg Poloxamer 188 S.Omg Benzyl alcohol lO.Omg Xanthan gum 7.Smg Purified water to make l.OmL
Exam,~le 3 Biological Test Nine healthy fasted male volunteers received single doses of Smg/mL
suspensions containing 250mg atovaquone as a 3N,m mean particle size suspension and lgm Microfluidised suspension in a randomised crossover study. Plasma. samples were taken at intervals up to two weeks after the last dose and assayed by HPLC.
The results are given in table 2 below:
WO 94/14426 ' PCT/GB93102646 3~,m suspension 1 ~,m suspension .. mean(SD)AUC 95 (62)p,g/mL.h 247(85)p,g/mL.h mean(SD)C 1.2(0.7)p,g/mL 5.0(1.6)~,g/mL
max median T 5 hours 1 hour max The mean (95% Cn increase for the AUC of the 1 p,m suspension relative to the 3 N.m suspension was 2.6-fold (1.9-3.5) and for C was 4.1-fold (2.5-6.6).
max
The efncacy of atovaquone as a therapeutic agent is limited by its bioavailability.
Accordingly it is an object of the present invention to provide atovaquone in a more bioavailable form.
It has now been found that the bioavailability of atovaquone can be increased by ensuring that the particle size is within a certain denned range of small particles.
However, conventional methods of reducing the particle size of atovaquone were found to be ursuccessful in producing particles of the size required to improve bioavailability.
The Microfluidiser (Trade-mark) has been marketed by the Microfluidics Corporation since 1985. The principle of its operation is based on a submerged jet technology. It was designed, primarily, as a homogenizing device for use in the food and pharmaceutical industries, for the preparation of e.g. emulsion and liposomal systems and has subsequently been used for cell-rupture purposes in biotechnology applications.
It has now surprisingly been found that microffuidised particles of atovaquone produced using a Microfluidiser have improved bioavailability of the compound.
It is believed that this is due to the small size and narrow range of sizes of the microffuidised atovaquone particles.
During operatioh of the Microfluiaiser, the feed stream is pumped into a specially designed chamber, in which fluid streams interact at very high velocities and pressures.
Fixed microchannels within the interaction chamber provide an extremely focussed interaction zone of intense turbulence, causing the release of energy amid cavitation and shear forces. Without wishing to be bound by theory it is believed that since all product passes through a dimensionally fixed area of energy release, greater size uniformity and smaller sizes are achieved by using the Microfluidiser rather than conventional methods for producing fine particles.
Thus, in a first aspect, the present invention provides small particles of atovaquone.
Preferably the particles are microffuidised particles. Suitably at least 90%
of the particles have a volume diameter in the range of 0.1-3pm. Preferably at least 95% of the particles have a volume diameter in the range of 0.1-2p.m In a second aspect, the present invention provides a pharmaceutical composition comprising particles of atovaquone and one or more pharmaceutically acceptable Garners therefor wherein at least 90% of the particles have a volume diameter in the range of 0.1-Sum, preferably at least 95% of the particles have a volume diameter in the range of 0.1-2p.m. Preferably the particles are microfluidised particles.
The Garners must be acceptable in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof.
According to a third aspect, the present invention provides a method for the preparation of microfluidised particles of atovaquone which comprises mixing atovaquone with a liquid vehicle to provide a mixture wherein the concentration of atovaquone is less than 450mg/mL and subjecting said mixture to at least 3 passes through a Microfluidiser in order to provide the atovaquone in the form of particles wherein at least 90% of the particles have a volume diameter in the range of 0.1-3~.m.
Preferably at least 95% of the particles have a volume diameter in the range 0.1-2~m.
In a further aspect the present invention provides a method for the preparation of a pharmaceutical composition comprising the steps of:
a) mixing atovaquone with a liquid vehicle to provide a mixture wherein the concentration of atovaquone is less than 450mg/mL.
3a b) subjecting the mixture to at least 3 passes through a Microfluidiser to provide a microfluidised preparation wherein the atovaquone is in the form of particles and at least 90% of those particles have a volume diameter in the range of 0.1-3p.m, and preferably at least 95% of the particles have a volume diameter in the range of 0.1-2 p,m.
c) mixing the microfluidised preparation with one or more pharmaceutically acceptable carriers therefor.
Suitably, the mixture is subjected to 10-50 passes through the Microfluidiser, e.g. 25-30 passes. Preferably the mixture is subjected to 15-25 passes through the Micro-fluidiser.
In one embodiment, the liquid vehicle is a surfactant. Preferably, the liquid vehicle is a surfactant solution. In a particularly preferred embodiment the surfactant is Poloxamer 188 solution. In another preferred embodiment the pharmaceutically acceptable carriers include a suspending agent. Suitable suspending agents include methyl cellulose and xanthan gum. Preferably the suspending agent is xanthan gum.
Pharmaceutical formulations include those suitable for oral and parenteral (including subcutaneous, intradermal, intramuscular and intravenous) administration as well as administration by naso-gastric tube. Suitable formulations within the scope of the present invention include, for example, solid dosage forms such as tablets and liquid dosage forms, such as suspensions, which are preferred formulations. The formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared from the microfluidised particles using methods known in the art of pharmacy.
' ~ CA 02152615 1999-02-08 -The invention will now be further illustrated by the following non-limiting examples:-Example 1 Preparation of Microfluidised particles of atovaquone Atovaquone was prepared by methods according to the prior art, e.g. US Patent No.
5053432. 600 mL of a mixture consisting of 2.5% w/v atovaquone in 0.25% w/v aqueous Celacol M2500 (Trade-mark) was prepared and 100 mL were retained in a glass jar as a control. A laboratory scale model 120B Microfluidiser was connected to a 90 psi pneumatic supply and adjusted to produce a fluid pressure of 15000 psi. The machine base, interaction chamber and pipework of the Microfluidiser were immersed in a bath of cold water. SOOmL of the mixture were loaded into the Microfluidiser's bulk vessel and passed through the Microfluidiser interaction chamber before being returned to the top, and side, of the bulk chamber. The mixture was recirculated continuously through the interaction chamber, and samples were taken at 10, 20, 30, 45 and 60 minutes. The number of passes to vsihich each of these samples had been subjected was calculated and is shown in Table 1 below.
S, am~le_ Nficrofluidisation Sample Volume Number of passes t~
(minutes) (ml) Control 0 100 0 1V>icroscopic observations of the control and samples at 40x magnification were made and the results were as follows:-Control Varied shapes, plates, rods and spheroids, around SxS~m generally and up to 7.Sx10p,m, loosely aggregated.
Sample 1 - More rounded smaller shapes, some "large" crystals, lots of small fragments 2.Sx2.5p,m, more dispersed.
Sample 2 - More rounded, smaller shapes, more fragments.
Sample 3 - Still more rounded, smaller shapes, more fragments.
Sample 4 - Yet more rounded, smaller shapes, more fragments.
WO 94E,344 .~ ~ ~ 2 ~ ~ PCT/GB93/02646 - 6 ...., ' Sample S - Very small particles, all under 2.S~m, all rounded, monodisperse.
Example 2 Pharmaceutical Formulation An oral suspension formulation was prepared by mixing the following ingredients:-Microfluidised particles of atovaquone150.Omg Poloxamer 188 S.Omg Benzyl alcohol lO.Omg Xanthan gum 7.Smg Purified water to make l.OmL
Exam,~le 3 Biological Test Nine healthy fasted male volunteers received single doses of Smg/mL
suspensions containing 250mg atovaquone as a 3N,m mean particle size suspension and lgm Microfluidised suspension in a randomised crossover study. Plasma. samples were taken at intervals up to two weeks after the last dose and assayed by HPLC.
The results are given in table 2 below:
WO 94/14426 ' PCT/GB93102646 3~,m suspension 1 ~,m suspension .. mean(SD)AUC 95 (62)p,g/mL.h 247(85)p,g/mL.h mean(SD)C 1.2(0.7)p,g/mL 5.0(1.6)~,g/mL
max median T 5 hours 1 hour max The mean (95% Cn increase for the AUC of the 1 p,m suspension relative to the 3 N.m suspension was 2.6-fold (1.9-3.5) and for C was 4.1-fold (2.5-6.6).
max
Claims (18)
1. Atovaquone in the form of particles wherein at least 90% of the particles have a volume diameter in the range 0.1-3 µm.
2. Microfluidised particles of atovaquone wherein at least 90% of the particles have a volume diameter in the range 0.1-3µm.
3. A pharmaceutical composition comprising particles of atovaquone and one or more pharmaceutically acceptable carriers therefor wherein at least 90% of the particles have a volume diameter in the range 0.1-3µm.
4. A pharmaceutical composition according to claim 3, wherein the particles are microfluidised particles.
5. A pharmaceutical composition according to claim 3 or 4, in suspension form.
6. A pharmaceutical composition according to any one of claims 3 to 5, wherein the pharmaceutically acceptable carriers include a suspending agent.
7. A pharmaceutical composition according to claim 6, wherein the suspending agent is xanthan gum.
8. A pharmaceutical composition according to any one of claims 3 to 7, for use in therapy.
9. A pharmaceutical composition according to any one of claims 3 to 7, for use in the treatment and/or prophylaxis of protozoal parasitic infections caused by P.carinii.
10. A method for the preparation of microfluidised particles of atovaquone according to claim 2, which comprises mixing atovaquone with a liquid vehicle to provide a mixture wherein the concentration of atovaquone is less that 450 mg/mL and subjecting said mixture to at least 3 passes through a Microfluidiser (Trade-mark).
11. A method for the preparation of a pharmaceutical composition which method comprises the steps of:
(a) mixing atovaquone with a liquid vehicle to provide a mixture wherein the concentration of atovaquone is less than 450 mg/mL, (b) subjecting the mixture to at least 3 passes through a Microfluidiser (Trade-mark) to provide a microfluidised preparation wherein the atovaquone is in the form of particles and at least 90% of those particles have a volume diameter in the range of 0.1-3µm;
(c) mixing the microfluidised preparation with one or more pharmaceutically acceptable carriers therefor.
(a) mixing atovaquone with a liquid vehicle to provide a mixture wherein the concentration of atovaquone is less than 450 mg/mL, (b) subjecting the mixture to at least 3 passes through a Microfluidiser (Trade-mark) to provide a microfluidised preparation wherein the atovaquone is in the form of particles and at least 90% of those particles have a volume diameter in the range of 0.1-3µm;
(c) mixing the microfluidised preparation with one or more pharmaceutically acceptable carriers therefor.
12. A method according to claim 10 or 11, wherein the mixture is subjected to 10 to 50 passes through the Microfluidiser (Trace-mark).
13. A method according to claim 12, wherein the mixture is subjected to 15 - 25 passes through the Microfluidiser (Trade-mark).
14. A method according to any one of claims 10 to 13, wherein the liquid vehicle is a surfactant solution.
15. A method according to claim 14, wherein the surfactant is Poloxamer 188 solution.
16. A method according to claim 13, wherein the pharmaceutically acceptable carriers include a suspending agent.
17. A method according to claim 16, wherein the suspending agent is xanthan gum.
18. A pharmaceutical composition produced by a process according to any one of claims 11 to 17.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929226905A GB9226905D0 (en) | 1992-12-24 | 1992-12-24 | Pharmaceutical preparation |
| GB9226905.9 | 1992-12-24 | ||
| PCT/GB1993/002646 WO1994014426A1 (en) | 1992-12-24 | 1993-12-23 | Atovaquone pharmaceutical compositions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2152615A1 CA2152615A1 (en) | 1994-07-07 |
| CA2152615C true CA2152615C (en) | 2001-10-16 |
Family
ID=10727175
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002152615A Expired - Lifetime CA2152615C (en) | 1992-12-24 | 1993-12-23 | Atovaquone pharmaceutical compositions |
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| AT (1) | ATE169215T1 (en) |
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| BR (1) | BR9307719A (en) |
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| CZ (1) | CZ289701B6 (en) |
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| FI (1) | FI114007B (en) |
| GB (1) | GB9226905D0 (en) |
| GE (1) | GEP19991515B (en) |
| HR (1) | HRP931516B1 (en) |
| HU (1) | HU220215B (en) |
| IL (1) | IL108154A (en) |
| MY (1) | MY109990A (en) |
| NO (1) | NO316745B1 (en) |
| NZ (1) | NZ258995A (en) |
| PL (1) | PL175374B1 (en) |
| RO (1) | RO119686B1 (en) |
| RU (1) | RU2127585C1 (en) |
| SA (1) | SA94140644B1 (en) |
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| SI (1) | SI9300678A (en) |
| SK (1) | SK281924B6 (en) |
| TW (2) | TW514531B (en) |
| UA (1) | UA39879C2 (en) |
| WO (1) | WO1994014426A1 (en) |
| YU (1) | YU48919B (en) |
| ZA (1) | ZA939673B (en) |
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| WO1996013254A1 (en) * | 1994-10-26 | 1996-05-09 | Glaxo Wellcome House | Pharmaceutical composition comprising atovaquone |
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-
1992
- 1992-12-24 GB GB929226905A patent/GB9226905D0/en active Pending
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1993
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- 1993-12-23 HR HR9226905.9A patent/HRP931516B1/en not_active IP Right Cessation
- 1993-12-23 CZ CZ19951451A patent/CZ289701B6/en not_active IP Right Cessation
- 1993-12-23 CA CA002152615A patent/CA2152615C/en not_active Expired - Lifetime
- 1993-12-23 SK SK828-95A patent/SK281924B6/en not_active IP Right Cessation
- 1993-12-23 TW TW088101847A patent/TW514531B/en not_active IP Right Cessation
- 1993-12-23 AT AT94902952T patent/ATE169215T1/en active
- 1993-12-23 MY MYPI93002823A patent/MY109990A/en unknown
- 1993-12-23 EP EP94902952A patent/EP0675711B1/en not_active Expired - Lifetime
- 1993-12-23 DE DE69320208T patent/DE69320208T2/en not_active Expired - Lifetime
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- 1993-12-23 IL IL10815493A patent/IL108154A/en not_active IP Right Cessation
- 1993-12-23 PL PL93309629A patent/PL175374B1/en unknown
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- 1993-12-23 RU RU95122758A patent/RU2127585C1/en active
- 1993-12-23 WO PCT/GB1993/002646 patent/WO1994014426A1/en not_active Ceased
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- 1993-12-23 SI SI9300678A patent/SI9300678A/en unknown
- 1993-12-23 RO RO95-01191A patent/RO119686B1/en unknown
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1994
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1995
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- 1995-06-22 FI FI953139A patent/FI114007B/en not_active IP Right Cessation
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