WO2002053131A1 - Compositions pharmaceutiques colloïdales micellaires renfermant un principe actif lipophile - Google Patents
Compositions pharmaceutiques colloïdales micellaires renfermant un principe actif lipophile Download PDFInfo
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- WO2002053131A1 WO2002053131A1 PCT/FR2001/004212 FR0104212W WO02053131A1 WO 2002053131 A1 WO2002053131 A1 WO 2002053131A1 FR 0104212 W FR0104212 W FR 0104212W WO 02053131 A1 WO02053131 A1 WO 02053131A1
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- 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
- A61K9/127—Liposomes
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- 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
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
Definitions
- the present invention relates to new micellizable pharmaceutical compositions containing at least one lipophilic active principle, making it possible to increase the bioavailability of active principles insoluble in aqueous solvents, designated by the name MIDDS® (Micellar Improved Drug
- This new pharmaceutical form, micellisable is similar to forms known and described as Self Emulsifying Drug Delivery Systems (SEDDS) or self-emulsifying systems, comprising a lipid phase and large amounts of surfactants (TA) and / or solvents.
- SEDDS Self Emulsifying Drug Delivery Systems
- TA surfactants
- AP very lipophilic active ingredients
- lipophilic PAs and a fortiori that of very lipophilic PAs, poses real problems due mainly to their low solubility in aqueous liquid pharmaceutical excipients, to their propensity to precipitate or recrystallize in aqueous solution and to their low solubility in liquids. from the gastrointestinal tract from which they must be absorbed.
- the bioavailability of a PA is a function of its concentration in the gastrointestinal fluid; this itself depends on the release of the PA from the oily phase.
- the more lipophilic a PA the less it tends to migrate in the digestive fluids.
- the absorption of these oily solutions begins with hydrolysis at the oil-water interface, followed by solubilization in the micelles of bile salts which penetrate into the intestinal micro-villi, thus carrying the hydrophobic AP (NA Armstrong et al, Int. J. Pharm., 1980, 6, 195-204).
- French patent application FR-A-2 408 345 describes the preparation of micronized progesterone which is in the form of an oily suspension thereof, in particular based on vegetable oil (soy lecithin , peanut oil, etc.) in soft capsules. This specialty is marketed under the name of Utrogestan®.
- lipophilic PAs can be increased by their formulation using digestible oils and hydrophilic and lipophilic surfactants (KJ McGREGOR et al, Adv. Drug Deliv. Rev., 1997, 25, 33- 46 and international application WO95 / 24893).
- This type of formulation makes it possible to maintain the AP in solution during its passage in the digestive tract and this until its intestinal absorption.
- the digestion of the oily ingredients of this type of formulation often has the advantage of solubilizing the AP within mixed micelles made up of bile salts and products of the lipolysis of the triglycerides of the digestible oil used.
- SEDDS are mixtures of isotropic oils and surfactants, sometimes comprising co-solvents and which emulsify under gentle agitation, condition similar to the conditions encountered in the digestive tract (CW Pouton, Int. J. Pharm., 1985, 27, 335-348; MG Wakerly et al. Am. Chem. Soc. Symposium Séries, 1986, 311, 242-255 ; Charman et al., Pharm. Res., 1992, 9, 87-93; BJ Aungst, J. Pharm. Sci., 1993, 82, 979-987; P Constantinides, Pharm. Res., 1995, 12, 1561 - 1572).
- Microemulsions find numerous applications in various fields.
- the study of the formation of these transparent dispersions has enabled researchers interested in their physicochemical (HL Rosano et al., J. Colloid Interface Sci., 1979, 72, 233-244) or pharmaceutical (CW Pouton, supra; WA Ritschel et al, Meth. Find. Exp. Clin. Pharmacol, 1990, 12, 127-134 and WA itschel, Meth. Find. Exp. Clin. Pharmacol., 1991, 13, 205-220) to specify the relevant operating procedures and adequate methods of analysis of the performance of self-emulsifying systems called SEDDS.
- patent application EP-A-0 670 715 describes SMEDDS® (Self Micro-Emulsifying Drug Delivery System) which contain a lipophilic active principle such as indomethacin, diclofenac or hydrocortisone, a lipophilic phase representing preferably from 10 to 75% by weight of the total weight of the composition and consisting of a mixture of glycerides and fatty acid esters of C 8 -C
- X having a hydrophilic-lipophilic balance (HLB) less than 16 and preferably close to 14, a TA based on glycerides having an HLB less than 16, a co-surfactant (CoTA) chosen from the lauric esters of propylene glycol, the oleic esters of polyglycerol and ethyl diglycol, the TA / CoTA ratio being between 0.5 and 6.
- a hydrophilic phase constituted for example by physiological fluid from the intestinal medium, this composition spontaneously forms a microemulsion.
- microemulsifiable systems make it possible to dissolve certain hydrophobic PAs, however they do not systematically improve their bioavailability (Farah, self-microemulsifying drug delivery Systems for improving in-vitro dissolution of drugs: AAPS Annual meeting Orlando, Florida, 1993).
- the best SEDDS that is to say those which dissolve a large amount of PA and which form very fine micellar dispersions, are generally the most hydrophilic.
- these hydrophilic SEDDS comprising a hydrophilic TA and a CoTA of HLB high in general greater than 12
- the risks of recrystallization of the PA in vivo are the greatest (Pouton, Bulletin Technique Gattefossé, 1999, 92, 41 -49) and therefore the super-bioavailability of the AP is not necessarily reached.
- the lipophilicity of a PA can be determined according to its partition coefficient (P) between octanol and water which corresponds to the ratio concentration of PA in octanol (Co.t.) / concentration of PA in l 'water (C_ au ).
- the determination of the partition coefficient is a factor widely used in the various fields of application of therapeutic chemistry or pharmacochemistry, from the synthesis of chemical substances for medicinal purposes to the analysis of pharmaceutical products.
- octanol / water partition coefficient (P), generally expressed in log P, is a major element among the indicators of the structure-activity relationships of active pharmaceutical ingredients or toxic substances (C. Hansch et al, Exploring OSAR, (1995), Vol. I & II, Ed. American Chemical Society, USA; C. Hansch et ai, J. Pharm. Sci., 1987, 76, 663-687; V. Pli * ka et al., Lipophilicity in drug action an toxicology, Vol. 4 Verlagsgesellschaft mbH. Weinheim (1996); H.
- Inventors have developed what is the subject of the invention.
- the inventors have therefore set themselves the objective of providing a self-emulsifying pharmaceutical composition intended for oral administration, capable of forming a micellar solution or a microemulsion in contact with digestive liquids, thus allowing the formulation of very lipophilic active principles. , or even extremely lipophilic, while improving their bioavailability, said composition being stable in the liquid state as well as in the form of microemulsion and leads to a very fine and homogeneous micellar dispersion.
- the very lipophilic APs are those having a log P greater than 2, the extremely lipophilic APs having a log P greater than 4.
- the present invention therefore relates to a pharmaceutical composition for oral use, self-emulsifiable comprising:
- At least one surfactant having a hydrophilic-lipophilic balance of less than 16, - at least one co-surfactant,
- the lipophilic active ingredient (s) have a log E greater than 2, - that the surfactant (s) represent at least 50% by weight of the total weight of said composition,
- co-surfactant (s) are chosen from the good solvents of said active ingredient (s),
- the lipophilic phase is optionally teroioactive and represents from 0.5 to 4.5% of the total weight of said composition and has an HLB less than or equal to 6, and - that when the active principle is different from a retinoid, then said composition also comprises an oily non-surfactant phase representing from 1 to 12% of the total weight of said composition.
- the pharmaceutical composition in accordance with the invention differs essentially from those described by the prior art by the fact that the lipophilic phase and the oily phase have very low HLB values and are used in small quantities and also by the essential presence of 'a CoTA which acts as a good solvent for PA in the pharmaceutical form.
- composition allows the dissolution of very lipophilic PAs and leads, in the presence of a hydrophilic phase, to formulations forming fine, stable and homogeneous micellar colloidal dispersions, thus making it possible to improve the bioavailability of these PA in the gastrointestinal tract.
- the pharmaceutical composition in accordance with the invention makes it possible in particular to obtain microemulsions whose micelles have a size less than 500 nm and more particularly between 1 and 200 nra.
- compositions in accordance with the present invention in all cases form a microemulsion or a colloidal solution, of micellar type, in contact with an aqueous phase.
- PAs having a log P greater than 2, and more particularly greater than 4 can be used in accordance with the present invention.
- These very lipophilic or even extremely lipophilic active principles are generally molecules comprising long carbon chains and / or aromatic rings or rings carrying hydrophobic substituents, with very few hydrophilic groups or substituents.
- These very lipophilic active ingredients can in particular be chosen from retinoids, lipid-lowering agents, steroid hormones, steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDs), anti-retrovirals, protease inhibitors ("navirs") , antacids, inhibitors of proton pump, antiques, fat-soluble vitamins, cardiovascular system drugs, platelet aggregation inhibitors, anticancer drugs, certain plant extracts and their isolated or derived APs, immunosuppressants, central nervous system drugs, antimigraine drugs, antibiotics , antifungals and antiparasitics; provided of course that they have a log P greater than 2.
- Retinoids are compounds capable of binding and interacting with a retinoic acid receptor (RAR alpha, beta or gamma) or with an X retinoid receptor (RXR alpha, beta, gamma).
- RAR alpha, beta or gamma retinoic acid receptor
- RXR alpha, beta, gamma X retinoid receptor
- retinoids derived from vitamin A, such as tretinoin, also known under the name of all-trans retinoic acid or of all-trans vitamin A acid, isotretinoin which corresponds to the 13-cis isomer of tretinoin, and which, therefore, is also called 13-cis retinoic acid or 13-cis vitamin A acid, 9-cis retinoic acid or 9- acid cis vitamin A, acitretin, etretinate, but also acetylenic retinoids such as tazarotene, naphthalene-based reti
- lipid-lowering agents which are compounds capable of inhibiting the synthesis of cholesterol and triglycerides
- COX-2 inhibitors such as celecoxib, rofecoxib, parecoxib and valdecoxib.
- Antiretrovirals and protease inhibitors are very poorly water-soluble compounds, the partition coefficients of which can be calculated or determined analytically, including amprenavir
- pantoprazole pantoprazole
- rabeprazole pariprazole
- lansoprazole lansoprazole and timoprazole.
- granisetron granisetron and azasetron.
- the angiotensin II antagonists sartans
- valsartan losartan
- irbesartan candesartan
- tasosartan telmisartan
- telmisartan 4.8
- renin inhibitor peptides such as renin inhibitor peptides, oxazolidinone or glycol derivatives peptides substituted by amino residues and / or azole or thiazole heterocyclic rings (log E between 2 and 4).
- paclitaxel and docetaxel which are compounds which are insoluble in water
- desloratadine and cetirizine tricyclic and serotonergic antidepressants such as fluoxetine, paroxetine, sertraline and citalopram.
- anti-migraine drugs there may be mentioned the compounds of the group of serotonergic "triptans” such as oxitriptan, sumatriptan and almotriptan.
- cephalosporins such as cefixime trihydrate and cefpodoxime proxetil
- synergistins such as pristinamycin
- quinolones and quinoxalines including carbadox.
- griseofulvin 2.18
- azole antifungals conazoles
- itraconazole log P - 5.68
- fluconazole fluconazole
- the active principle or principles are preferably chosen from retinoids, lipid-lowering agents and steroid hormones.
- the active ingredient (s) having a log P greater than 2 preferably represent from 1 to 10% by weight relative to the total weight of the composition.
- this amount preferably varies between 1 and 2.5% by weight relative to the total weight of the composition.
- the pharmaceutical composition according to the invention contains a retinoid, then the presence of an oily phase, although possible, is however not necessary.
- this amount preferably varies between 5 and 10% by weight relative to the total weight of the composition.
- this amount preferably varies between 3 and 7% by weight relative to the total weight of the composition.
- surfactants having an HLB of less than 16 mention may in particular be made of surfactants behaving like good solvents of the PA to be formulated, among which are the glycerides polyglycolized at C 8 -C
- 8 such as lauric, oleic, palmitic, stearic, hydrogenated ricinoleic acids and their derivatives, sold under the brands Ablunol® (Taiwan Surf), Aldosperse® (Lonza), Arlacel® (ICI), Crillet® (Croda), Drewmulse® (Stepan Food Ingredients), Ethylan® (Akcros), Emulpharma® (Respharma), Eumulgin® (Flenkel), Montanox® (Seppic), Nikkol® (Nikko Chem Co), Nissan Nonion® (Nippon Oils & Fats), Sorbilene® (Auschem), Sorgen® TW (Dai-ichi Kogyo Seiyaku) and Tween®- (BASF); macrogol and propylene glycol
- Nikkol® Nikko Chem Co
- Tagat® Goldschmidt
- 8 isostearic, lauric, oleic or stearic
- Caprol® Abitec
- Drewpol® Steppan Food Ingredients
- Nikkol Decaglyn® Nikko Chem Co
- These surfactants represent at least 50% and preferably from 70 to
- a co-surfactant is considered to be a good solvent for the active principle or principles present in the pharmaceutical composition in accordance with the invention, when it allows, during dissolution tests, to sufficiently dissolve the the active ingredients while being compatible with the formulation of the finished product.
- isotretinoin is soluble at 3% in the monoethyl ether of diethylene glycol (marketed under the brand Transcutol® by Gattefossé; fenofibrate is soluble at 5% in the same solvent; progesterone is soluble at 5% in propylene glycol monocaprylate (sold under the brand Capryol® by Gattefossé.
- the TA and the CoTA are preferably nonionic compounds.
- CoTA behaving as good solvents for the PA to be formulated and among which mention may be made, for example, of the corresponding diethyl glycol monoethyl ether (EMDG) for example to the product sold under the Transcutol® brand by the company Gattefossé.
- EMDG diethyl glycol monoethyl ether
- CoTAs acting as solvent for the PA may also be made, such as N-methyl-2-pyrr ⁇ lidone or Pharmasolve® (ISP), the glycerol and acetic acid triester or Triacetin® (Aldrich), dimethyl -isosorbate (Aldrich), polyethylene glycols (PEG) such as PEG-400 and PEG-600 (otherwise called PEG-8 and PEG-12) and the products marketed for example under the names Carbowax® (Union Carbide), Lipoxol® (H ⁇ ls), Pluracol® (BASF), as well as the alcohols and glycols used as solvents or co-solvents, ethanol, isopropanol, glycerol, propylene glycol, butylene glycol, glycofurol and sorbitol; the mono- and diesters of propylene glycol and caprylic, capric, lauric fatty acids, sold under the brands Labrafac®
- the concentration of CoTA is more preferably between 10 and 15% by weight relative to the total weight of the composition .
- the concentration of CoTA is more preferably between 5 and 10% by weight relative to the total weight of the composition.
- the lipophilic phase preferably has an HLB of less than or equal to 4, is liquid at room temperature and is preferably chosen from fatty acid esters, in particular macrogol (or polyethylene glycol) glycerides.
- the pharmaceutical composition contains a lipophilic phase in a proportion preferably of between 3 and 4.5% by weight relative to the total weight of the composition.
- the oily phase can be chosen from oils of natural and synthetic origin.
- oils of natural origin mention may especially be made of almond, peanut, rapeseed, cottonseed, flaxseed, corn, olive, borage, evening primrose, fish, palm, palm kernel, grape seed, sesame, soy, sunflower or other.
- These oils can be first expression, refined or inter-esterified, such as the oils sold under the brands Akofine®, Akosoft®, Akosol® (Karlshamns), Myverol®, Myvacet® (Eastman) and Neobee® (Stepan Food Ingredients) .
- oils with a FILB value of less than or equal to 5, and even more particularly less than or equal to 3 are preferred, among which mention may be made of the products sold under the Captex® brands (Abitec) , Crodamol® (Croda), DUB 810 PG (Stéarineries Dubois), Neobee® (Stepan Food Ingredients) and Labrafac® (Gattefossé).
- the oily phase consists of a synthetic oil
- this can, according to the invention, have a very low HLB, of the order of 1 to 3, preferably chosen from the fatty acid esters sold under the denomination Labrafac®, such as Labrafac® PG, Labrafac® CC or Labrafac® lipophilic (Gattefossé), and their mixtures.
- Labrafac® such as Labrafac® PG, Labrafac® CC or Labrafac® lipophilic (Gattefossé)
- the pharmaceutical composition contains an oily phase in a proportion preferably between 2 and 12% by weight.
- composition requires it, it may prove useful to incorporate preservatives either in the lipid solution or in the shell of the capsule, for example: butyl-hydroxyanisole (BHA), butyl-hydroxytoluene (BHT). vitamins of group E or tocopherols, ethylene diamine tetracetic acid (EDTA) or its salts, methyl or propylparabens, salts of derivatives of para-hydroxybenzoic acid, etc.
- BHA butyl-hydroxyanisole
- BHT butyl-hydroxytoluene
- vitamins of group E or tocopherols ethylene diamine tetracetic acid (EDTA) or its salts, methyl or propylparabens, salts of derivatives of para-hydroxybenzoic acid, etc.
- EDTA ethylene diamine tetracetic acid
- salts of derivatives of para-hydroxybenzoic acid etc.
- the composition contains at least one vitamin from group E, preferably vitamin E.
- vitamin E is indeed advantageous insofar as, in addition to its antioxidant effect with respect to isotretinoin, it also makes it possible to avoid the formation of crystals during storage of the compositions in accordance with the invention at low temperature.
- the pharmaceutical composition in accordance with the invention may also contain one or more thickeners chosen from celluloses, waxes, acrylic polymers, gums.
- This thickening agent is preferably chosen from celluloses such as carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose and methylcellulose.
- the surfactants described above can also be used, in particular esters of fatty acids and of polyethylene glycol.
- the pharmaceutical composition when it contains a retinoid such as isotretinoin, then it also preferably contains at least one thickening agent.
- the pharmaceutical composition in accordance with the invention can be packaged in capsules or soft capsules, for example in gelatin which, after oral ingestion and disintegration, will release the composition pharmaceutical according to the invention which will spontaneously form a microemulsion on contact with physiological fluid.
- compositions in accordance with the invention can be prepared according to a process consisting in: - in a first step, dissolving the PA to be formulated in its appropriate solvent which is CoTA, optionally in the presence of a co-solvent or of a surfactant or of the lipophilic phase and optionally of the oily phase when it is present;
- the invention also comprises other provisions which will emerge from the description which follows, which refers to an example concerning a comparative study of the stability of a composition in accordance with the invention with respect to a composition as described in the prior art, to an example concerning a comparative study of the permeability of Caco-2 cells to isotretinoin in different formulations, to an example concerning the study of the bioavailability of isotretinoin formulated in accordance with the invention compared to the commercial presentation ROACCUTANE®, to an example of formulation based on fenofibrate, to an example concerning the study of the bioavailability of fenofibrate formulated in accordance with the invention compared to the commercial presentation LIPANTHYL® 67M, to a example of a progesterone-based formulation, as well as in the attached FIGS. 1 and 2 in which:
- FIG. 1 shows the bioavailability of isotretinoin formulated according to the invention compared to that of the commercial product ROACCUTANE®;
- FIG. 2 shows the bioavailability of fenofibrate formulated according to the invention compared to that of the commercial product LIPANTHYL® 67M.
- composition F2 is a propylene glycol monocaprylate containing 60% monoesters.
- composition FI according to the invention that is to say containing less than 5% of a lipophilic phase of weak HLB, was liquid at room temperature and led, in the presence of a hydrophilic phase, to the formation of a fine microemulsion (120 nm), stable at 25 ° C, which is a discriminating temperature with regard to the constituents of the self-emulsifying system, and homogeneous.
- composition F2 not forming part of the invention, of the
- composition F3 consisting of a solution of isotretinoin alone, at 1.4% in dimethyl sulfoxide (DMSO), as well as the commercial formulation of isotretinoin sold under the brand ROACCUTANE® containing isotretinoin in a mixture of excipients composed of yellow beeswax, hydrogenated soybean oils and not hydrogenated, and partially hydrogenated vegetable oil.
- DMSO dimethyl sulfoxide
- the permeability study was carried out on intestinal epithelial cells Caco-2, according to the methods described in the articles by IJ Hidalgo et al, "Characterization of the human colon carcinoma cell line (Caco-2) as a model System for intestinal epithelial permeability ", Gastroenterology, 1989, 96, 736-749 and de
- the intestinal cell line Caco-2 (derived from human colorectal carcinoma) develops the morphological characteristics of normal enterocytes (columnar epithelium of the wall of the small intestine). When grown on a polycarbonate membrane, Caco-2 cells form a single-cell layer of polarized enterocytes.
- the membrane integrity of Caco-2 cells has also been studied. This integrity was followed thanks to the incorporation into the working solution of a carbon 14-labeled mannitol solution.
- this tracer makes it possible to verify that the passage through the membrane and not outside has indeed occurred.
- the permeability to mannitol for all the solutions tested is comparable to the control permeability of mannitol.
- composition F3 containing isotretinoin alone is explained by the fact that this active principle has been completely dissolved in DMSO, however this excellent solvent for organic substances cannot be used as such in pharmaceutical preparations. for reasons of toxicity.
- composition F4 in accordance with the invention, was prepared: - Active ingredient: Isotretinoin 2%
- the bioavailability study was conducted according to a protocol for administering a single dose of each of the treatments: the test formula and the reference formula are administered in a cross-order and randomized order.
- the isotretinoin formulated according to the pharmaceutical composition F4 was compared with that of the commercial formulation of the isotretinoin sold under the brand ROACCUTANE® and as described above in Example 2.
- the two products were administered, during a meal, at the rate of the single intake of 3 soft capsules of composition F4 and two soft capsules of ROACCUTANE® 20 mg.
- composition F4 in accordance with the invention
- composition F4 in accordance with the invention
- the yet higher dose of 40 mg of isotretinoin of ROACCUTANE® in terms of absorption speed, these results also show that the composition F4 according to the invention is faster than the reference composition ROACCUTANE®, with an earlier peak plasma concentration, expressed by the parameter T max , which is one hour on average for the composition
- this composition spontaneously led to a stable and fine microemulsion in which the fenofibrate was perfectly dissolved.
- Composition F5 was packaged in capsules each containing 66 mg of fenofibrate. Composition F5 and LIPANTHYL® were administered during a meal, at the rate of 1 capsule.
- composition F5 is faster than LIPANTHYL®, with an earlier peak plasma concentration, expressed by the parameter T max , which is 2.5 hours on average for the composition
- composition F5 This bio-equivalence between the composition F5 and the dose of 67 mg of the formulation LIPANTHYL® is particularly interesting, insofar as the composition F5 is found to be bio-equivalent to the formulation LIPANTHYL®, which is itself super-bioavailable by compared to the non-micronized form previously marketed.
- the self-emulsifiable and icellisable composition F5 in accordance with the invention makes it possible to obtain the maximum bioavailability of fenofibrate while applying to this active principle a galenic preparation pathway totally different from micronization, while up to present, only the micronization of fenofibrate had improved its bioavailability.
- PROGESTERONE The following pharmaceutical composition F6, in accordance with the invention, was prepared:
- composition F2 of the prior art which is not stable after a few months, by the fact that it contains 4% of oily phase. It spontaneously leads, in the presence of an aqueous phase, to a stable and fine microemulsion in which the progesterone is perfectly dissolved.
- the lipophilicity of PA plays an important role on the balance of the system.
- the contribution of the oily phase makes it possible to better solubilize the progesterone and it is this oil which will be micellized and which makes it possible to improve stability significantly.
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Abstract
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01989667A EP1345590A1 (fr) | 2000-12-28 | 2001-12-27 | Compositions pharmaceutiques colloidales micellaires renfermant un principe actif lipophile |
US10/465,923 US20040052824A1 (en) | 2000-12-28 | 2001-12-27 | Micellar colloidal pharmaceutical composition containing a lipophilic active principle |
CA002432362A CA2432362A1 (fr) | 2000-12-28 | 2001-12-27 | Compositions pharmaceutiques colloidales micellaires renfermant un principe actif lipophile |
KR10-2003-7008830A KR20030066781A (ko) | 2000-12-28 | 2001-12-27 | 친지성 유효성분을 포함하는 미셀 콜로이드상의 약제학적조성물 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0017250A FR2818905A1 (fr) | 2000-12-28 | 2000-12-28 | Compositions pharmaceutiques colloidales micellaires renfermant un principe actif lipophile |
FR00/17250 | 2000-12-28 |
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WO2002053131A1 true WO2002053131A1 (fr) | 2002-07-11 |
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PCT/FR2001/004212 WO2002053131A1 (fr) | 2000-12-28 | 2001-12-27 | Compositions pharmaceutiques colloïdales micellaires renfermant un principe actif lipophile |
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US (1) | US20040052824A1 (fr) |
EP (1) | EP1345590A1 (fr) |
KR (1) | KR20030066781A (fr) |
CA (1) | CA2432362A1 (fr) |
FR (1) | FR2818905A1 (fr) |
WO (1) | WO2002053131A1 (fr) |
Cited By (22)
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WO2003011207A2 (fr) * | 2001-07-27 | 2003-02-13 | Gattefosse Holding | Composition pharmaceutique a usage oral comprenant un principe actif susceptible de subir un important effet de premier passage intestinal |
FR2873585A1 (fr) * | 2004-07-27 | 2006-02-03 | Aventis Pharma Sa | Nouvelles formulations galeniques de principes actifs |
WO2008049552A1 (fr) * | 2006-10-24 | 2008-05-02 | Helsinn Healthcare S.A. | Capsules molles comprenant du chlorhydrate de palonosétron ayant une stabilité et une biodisponibilité améliorées |
FR2925855A1 (fr) * | 2007-12-26 | 2009-07-03 | Virbac Sa Sa | Composition liquide autoemulsionnable de florfenicol destinee a etre incorporee a l'eau de boisson des animaux d'elevage. |
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Also Published As
Publication number | Publication date |
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EP1345590A1 (fr) | 2003-09-24 |
CA2432362A1 (fr) | 2002-07-11 |
KR20030066781A (ko) | 2003-08-09 |
US20040052824A1 (en) | 2004-03-18 |
FR2818905A1 (fr) | 2002-07-05 |
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