it has now been surprisingly found that the prior art drawbacks cab be effectively overcome by including into the external phases of double microemulsions suitable enzymes and / or permeation enhancers . the invention provides therefore water / oil / water or oil / water / oil double microemulsions as carriers of drugs having different solubility characteristics , said microemulsions being characterized in that they comprise agents improving the bioavailability of the drug , either by inhibiting enzymes responsible for the metabolic degradation of the drug at the site of action , by enhancing the permeation of the drug through the membranes and mucosae and / or by inhibiting enzymes responsible for the drug - efflux phenomenon . the invention also provides pharmaceutical compositions comprising said double microemulsions as carriers of medicaments to be administered oral , topical , transdermal , nasal , pulmonary , transmucosal , vaginal , ocular , rectal application . both scarcely water - soluble / hydrophobic drugs and highly polar , water - soluble drugs may be advantageously formulated according to the invention . the present invention provides pharmaceutical compositions comprising oil / water / oil ( o1 / w2 / o3 ) or a water / oil / water ( w1 / o2 / w3 ) double microemulsions wherein the external phases ( w2 and o3 for o1 / w2 / o3 , o2 and w3 for w1 / o2 / w3 ) contain mucosal / physiological environment enzymes - inhibitors and / or p - gp inhibitors and / or absorption permeation enhancers . examples of permeation enhancers contained in the external phases o2 and w3 of w1 / o2 / w3 double microemulsion or to external phases w2 and o3 of o1 / w2 / o3 double microemulsion include non - ionic surfactants such as polyoxyalkylene fatty ethers ( brij ®), ( tween ® 20 , tween ® 80 , etc . ); ionic surfactants such as sodium dodecylsulfate ; bile salts ( e . g ., sodium glycholate , sodium taurocholate , sodium deoxycholate , etc . ); fatty acids like oleic acid , palmitoleic acid , linoleic acid , sodium oleate , sorbitan trioleate , polyoxyethylene sorbitan trioleate , etc ; sodium salicylate , sodium caprate , diethylmaleate , laurylmaltopyranoside , etc . examples of metabolic degradation enzymes inhibitors contained in the external phase o2 and w3 of w1 / o2 / w3 double microemulsion or to the external phases w2 and o3 of o1 / w2 / o3 double microemulsion are cyp3a inhibitors , protease inhibitors like aprotinin , chymostatin , bacitracin , benzamidine , phosphoramidon , leupeptin , bestatin , leupeptin , cystatin , amastatin , pepstatin , potato carboxypeptidase , soybean trypsin inhibitor , diisopropylfluorophosphate , edta . examples of drug - efflux p - glycoprotein enzymes inhibitors contained in the external phase o2 and w3 of w1 / o2 / w3 double microemulsion or in the external phases of w2 and o3 of o1 / w2 / o3 double microemulsion are flavonoids contained in fruit juices such as naringenin , isoquercetin , quercetin , vitamin e tpgs ( tocopheryl glycolsuccinate ). the microemulsions of the invention may contain both a permeation enhancing agent and an enzyme inhibitor . preferred drugs which may be advantageously formulated in the double microemulsion o1 / w2 / o3 of the invention are scarcely water - soluble / hydrophobic drugs , with very low polarity and consequent poor solubility in the biological aqueous fluids such as gastro - intestinal content , pulmonary fluids or buccal fluids . examples of these drugs are anesthetics , anti - asthma agents , antidepressants , anti - diabetics , anti - epileptics , anti - fungals , anti - gout , anti - neoplastics , anti - obesity agents , anti - protozoals , anti - virals , anti - psychotics , calcium regulating agents , cardiovascular agents , corticosteroids , diuretics , dopaminergic agents , gastrointestinal agents , hormones ( peptide and non - peptide ), immunosuppressants , lipid regulating agents , phytoestrogens , prostaglandins , relaxants and stimulants , vitamins / nutritionals and xanthines . said therapeutic categories include well known compounds such as paclitaxel , docetaxel , etoposide , teniposide , fludarabine , doxorubicin , daunomycin , mitoxanthrone , emodin , 5 - fluorouracil , camptothecin , retinoic acids , ubidecarenone , verapamil , cyclosporine , tacrolimus , statins such as lovastatin , atorvastatin , simvastatin , piroxicam , nimesulide , naproxen , ibuprofen , indomethacin , phenyloin , fentanyl , desmopressin , angiotensin i , ii and iii , enkephalins and their analogs , acth , antiinflammatory peptides i , ii , iii , bradykinin , calcitonin , interferon , cholecystikinin ( cck ) fragments , luteinizing hormone releasing hormone ( lhrh ), neurokinins ( e . g . neurokinin a ), somatostatin , substance p , thyroid releasing hormone ( trh ), vasopressin , fibrinogen receptor antagonists growth hormone releasing peptides ( ghrp ), insulin , lh - rh releasers and inhibitors , immunosuppressive anti - tnf alpha - monoclonal antibodies ( e . g . rituximab , trastuzumab , infliximab , gemtuzumab , alemtuzumab , ibritumomab , tositumomab - iodine 131 , cetuximab , bevacizumab ) endothelins , atrial natriuretic factor , gastrin , msh modulators , cytokines , renin inhibitors , hiv protease inhibitors , fluconazole , itraconazole , nifedipine , carbamazepine , fluoxetine , griseofulvin , raloxifene , paroxetine , glimepiride , anagrelide , modafinil , losartan , valsartan , cabergoline , replaginide , glipizide , benzodiazepines , clofibrate , chlorpheniramine , digoxin , digitoxin , ergotamine tartate , estradiol , fenofibrate , hydrochlorothiazide , hydrocortisone , medrogeston , oxyphenbutazone , prednisolone , prednisone , polythiazide , progesterone , spironolactone , tolbutamide , 10 , 11 - dihydro - 5h - dibenzo [ a , d ] cyclo - heptene - 5 - carboxamide , 5h - dibenzo [ a , d ] cycloheptene - 5 - carboxamide . in the case of the double microemulsion w1 / o2 / w3 , the preferred drugs are very water - soluble , highly polar , in some case with ionic charges and / or high molecular weight , with consequent poor permeability of biological barriers such as gastro - intestinal or pulmonary or buccal mucosa . examples of these drugs are antibiotics , polypeptides , proteins ( insulin , erythropoietin , csf ), polynucleotides , acellular vaccines , bisphosphonates ( alendronate , ibandronate , clodronate , zoledronate , pamidronate , risedronate , etidronate etc . ), enalapril , acyclovir , enfuvirtide , polyphenols , bioflavones , hydrosoluble vitamins , choline , carnitine , carnosine and related peptides , platinum complexes , glycosamineglycans such as heparins or fraction thereof , hyaluronic acid , dermatans , glucosamine . the oil used for the internal / external phases of the double microemulsions of the invention can be natural , synthetic or semisynthetic . examples of natural oils include of olive , sunflower , safflower , peanut , corn , soybean , maize , coconut , sesame oils . examples of synthetic or semisynthetic oils are esters of short , medium or long chain fatty acids as isopropyl miristate , isopropylpalmitate , ethyl laurate , isopropyl caprilate , isopropyl caprinate , isopropyl laurate , isopropyl stearate , ethyl oleate , oleyl oleate or long chain alcohols or polyols such as hexadecylic alcohol , oleic alcohol , lauric alcohol , cetyl stearylic alcohol , benzyl alcohol , decanoic acid , butanoic acid , silicon oils , mono -, di - and tri - glycerides mixtures or poly - ethoxylated derivatives thereof , polyhydroxyethyl triglycerides , polyhydroxy triglycerides , capricocaprilic triglycerides . the surfactants can be of natural or synthetic origin ; examples of surfactants include sorbitan laurate , sorbitan palmitate , sorbitan stearate ( span 20 ®, span 40 ®, span 60 ® respectively ), polysorbates such as polyoxyethylene ( 20 ) sorbitan monostearate , polyoxyethylene ( 20 ) sorbitan monopalmitate , polyoxyethylene ( 20 ) sorbitan monolaurate , polyoxyethylene ( 20 ) sorbitan monooleate ( tween 60 ®, tween 40 ®, tween 20 ®, tween 80 ®), polyoxyethylene ethers of fatty acids , e . g . polyoxyethylene 2 cetyl ether , polyoxyethylene 20 cetyl ether ( brij 52 ®, brij 58 ®) and polyoxyethylene hydrogenated castor oil 40 ( hco - 40 ®). polyvinyl alcohol may also be used as amphiphylic surfactant . combinations of surfactants with different chemical characteristics can also be used . the cosurfactants can either be synthetic or natural . examples of synthetic cosurfactants include short chain alcohols such as ethanol , isopropanol , n - butanol , ethanediol , 1 , 2 - propanediol , 1 , 3 - propanediol , 1 , 3 - butane diol , 1 , 4 - butane diol , glycerine , polyethylene glycols ( e . g . peg 400 , peg 600 ) butyric acid , valerianic acid , capronic acid , benzyl acid , decanoic acid , lauric acid , lauryl alcohol . the external water ( w / o / w ) phase of the double microemulsions of the invention ( w1 / o / w3 ) consists of water as such or buffered at different ph &# 39 ; s and ionic strengths , of mixtures of water and polyethylenglycols , polyol glycerides , propylene glycol , tetra glycol , ethoxy glycol , mixtures of water and polyvinylpyrrolidone , polyacrylic acids and derivatives , polymethacrylic acids and derivatives , alginic acids and derivatives , polyvinylalcohol , chitosan and derivatives , xanthan and derivatives , guar gum , arabic gum , dextran , cellulose and derivatives , starch and derivatives . the internal aqueous phase of the double microemulsions of the invention ( w2 for o1 / w2 / o3 ) consists of water as such or buffered at different ph &# 39 ; s and ionic strengths or of mixtures of water and polyethyleneglycols , polyglycol glycerides , propylene glycol , tetra glycol , ethoxy glycol . the double microemulsions ( o1 / w2 / o3 or w1 / o2 / w3 ) of the invention have the following preferred compositions by weight percentage : b1 ) water or aqueous solution ( w1 , internal phase ) from 1 . 0 % to 5 . 0 %. b3 ) water or aqueous solution ( w3 , external phase ) from 60 % to 90 %. b4 ) metabolic enzymes inhibitor , p - gp - inhibitor , absorption enhancer from 0 . 05 % to 10 . 0 %. the compositions of the invention can be prepared by a process comprising : a . solubilization of the mucosal / physiological environment enzymes - inhibitor , p - gp - inhibitor , absorption permeation enhancer in the external phase / phases of the double microemulsion of choice ( w2 and o3 for o1 / w2 / o3 , o2 and w3 for w1 / o2 / w3 ); b . solubilization of the drug in the internal phase of the double microemulsion of choice ( o1 of the o1 / w2 / o3 in the case of hydrophobic , scarcely water soluble drug ; w1 of the w1 / o2 / w3 in the case of water soluble , poorly permeable drugs ); c . addition of the oil or water drug solution of stage b ) to the water or oil solution of stage a ); d . addition of surfactant / cosurfactant to the mixture of stage c and agitation with the formation of the o1 / w2 or w1 / o2 microemulsion ; e . addition of the microemulsion o1 / w2 or w1 / o2 of stage d ) to the oil ( o3 ) phase or water ( w3 ) phase containing surfactant / cosurfactant and agitation with the formation of the double microemulsion o1 / w2 / o3 or w1 / o2 / w3 with mucosal / physiological environment . enzymes - inhibitors and / or p - gp - inhibitors and / or absorption permeation enhancers in the w2 and o3 of the o1 / w2 / o3 or o2 and w3 of the w1 / o2 / w3 double microemulsion . possible variations to this process can be introduced in relation to specific experimental conditions . for example , in some cases , the mucosal / physiological environment enzymes - inhibitor / p - gp - inhibitor / absorption enhancer cannot be completely solubilized in the oil or water external phase of choice : in this case the substance will be dispersed in the suitable external phase . it is also possible that the drug is dispersed in the internal phase of choice when it is not completely soluble in the internal oil or water phase of choice . if desired , a viscosity - increasing substance can be added to the second external phase of the double microemulsions ( w3 for the w1 / o2 / w3 , o3 for the o1 / w2 / o3 ) such as polymers such as hydroxypropylcellulose , chitosan , polyvinylpyrrolidone , polymethylmethacrylate . said viscosity - increasing substances can also be added to the other phases of the double microemulsions . in some cases , these viscosity - increasing polymers may also have bioadhesive properties so to increase residence - time in the biological environment of action ( e . g ., stomach , eye sac , mouth cavity , etc .) or to guarantee more intimate contact with the biological barrier to be overcome , e . g ., gastro - intestinal tract mucosa , pulmonary tissues , etc . the compositions according to the invention may be formulated with the addition of conventional excipients as dosage forms for oral , topical , transdermal , nasal , pulmonary , transmucosal , vaginal , ocular , rectal application . the compositions according to the invention may also be formulated in dosage forms after the addition of said compositions onto solid adsorbent particles . the compositions of the present invention present unexpected improved properties both in terms of biopharmaceutical properties ( particle size of droplets in the nanometers range with consequent extremely high surface area , high solubility of hydrophobic drugs in the oil components , higher diffusion tendency through hydrophobic membranes of very polar drugs ) and in terms of a much lower metabolic degradation or p - glycoprotein efflux effects with consequent much higher biological membranes / barriers permeation tendency . the invention is disclosed in more detail in the following some examples . a w / o microemulsion was prepared by mixing using a paddle mixer at the speed of 250 rpm at 25 ° c . for 1 h an aqueous phase containing erythropoietin dissolved ( 300 μg / g ) to an oily phase lauroglycol fcc ®: labrasol ® ( 1 : 1 ) containing chymostatin ( 200 μg / g ) and the surfactant tween 20 ® ( 1 . 04 g ). the microemulsion a ) w / o was added to an aqueous phase ( 75 . 45 g ) under paddle stirring at the speed of 300 rpm for 0 . 75 h , tween 20 ® was then added ( 4 . 04 g ) under paddle stirring at the speed of 280 rpm for 0 . 5 h to obtain a double microemulsion w / o / w . the composition of the resulting w / o / w double microemulsion was the following : a w / o microemulsion was prepared by mixing using a paddle mixer at the speed of 240 rpm at 25 ° c . an aqueous phase containing sodium alendronate dissolved ( 0 . 5 g / g ) with an oily phase containing akoline ®: labrasol ®: taurumdeoxycholate in ratio 1 : 1 : 0 . 09 , and the surfactant tween 80 ® ( 0 . 653 g ). the microemulsion a ) w / o was added to an aqueous phase ( 33 . 39 g ) under paddle stirring at the speed of 300 rpm for 0 . 5 h , tween 80 ® was then added ( 2 . 50 g ) under paddle stirring at the speed of 280 rpm for 0 . 75 h to obtain a double microemulsion w / o / w . the composition of the resulting w / o / w double microemulsion was the following : a w / o microemulsion was prepared by mixing using a paddle mixer at the speed of 220 rpm at 25 c an aqueous phase containing somatostatin dissolved ( 0 . 4 g / g ), to an oily phase , labrafac cc ®: egg lecithin ( 1 : 0 . 005 ), containing cyp3a inhibitor as hesperidin ( 100 μg / g ), and the surfactant span 40 ® ( 2 . 04 g ). the microemulsion a ) w / o was added to an aqueous phase ( 72 . 78 g ) under paddle stirring at the speed of 310 rpm for 0 . 5 h , span 40 ® was then added ( 5 . 03 g ) under paddle stirring at the speed of 280 rpm for 0 . 5 h to obtain a double microemulsion w / o / w . the composition of the resulting w / o / w double microemulsion was the following : a o / w microemulsion was prepared by mixing using a paddle mixer at the speed of 220 rpm for 0 . 5 h at 25 ° c . an oily phase ( akoline ®: transcutol hp ® 7 : 3 ) containing simvastatin dissolved ( 0 . 34 g / g ), to a water phase , the surfactant tween 80 ® was subsequently added with a mixing rate of 250 rpm for 0 . 5 h ; the composition of the resulting microemulsion was : the o / w microemulsion a ) was added under stirring ( 300 rpm ) for 0 . 75 h to a an oily phase ( akoline ®), the surfactant tween 80 ® ( 3 . 01 g ) was added under paddle stirring at speed of 270 rpm for 0 . 5 h , obtaining a double microemulsion containing simvastatin . a o / w microemulsion was prepared by mixing using a paddle mixer at the speed of 220 rpm for 0 . 75 h at 25 ° c . an oily phase ( lauroglycol fcc ®) containing quercetin ( 0 . 05 g / g ) and dissolved itraconazole ( 0 . 44 g / g ) to a water phase , the surfactant tween 80 ® was subsequently added with a mixing rate of 250 rpm for 0 . 5 h ; the composition of the resulting microemulsion was : the o / w microemulsion a ) was added under stirring ( 300 rpm ) for 0 . 5 h to an oily phase ( lauroglycol ®: quercetin ) ( 55 . 90 ), the surfactant tween 80 ® ( 4 . 01 g ) was added under paddle stirring at speed of 270 rpm for 0 . 75 h , obtaining a double microemulsion containing itraconazole . a o / w microemulsion was prepared by mixing using a paddle mixer at the speed of 280 rpm for 0 . 50 h at 25 ° c . an oily phase ( plurol oleique cc497 ®) containing quercetin ( 0 . 02 g / g ) and dissolved danazole ( 0 . 40 g / g ) to a water phase , the surfactant tween 80 ® was subsequently added with a mixing rate of 240 rpm for 0 . 5 h ; the composition of the resulting microemulsion was : the o / w microemulsion a ) was added under stirring ( 300 rpm ) for 0 . 5 h to a an oily phase ( plurol oleique cc497 ®) ( 26 . 96 g ), the surfactant tween 80 ® ( 2 . 02 g ) was added under paddle stirring at speed of 280 rpm for 0 . 50 h , obtaining a double microemulsion containing itraconazole the double microemulsions of the invention were characterized by the following methods . the size of the droplets of the double microemulsions prepared as shown in the examples 1 - 6 was determined by laser light scattering ( coulter counter , mod . n4 plus ); data are reported in table 1 . the “ in vitro ” solubilization kinetics was determined in buffer solution ( ph 7 . 4 , 37 ° c . ); sample of the double microemulsion under testing is dispersed in tubes filled with 50 ml of buffer solution and placed over a thermostated shaking plate ; at predetermined time intervals samples of the solution were filtered and then ultra - centrifuged ; drug concentration was determined by hplc , data are reported in table 2 . the permeation test was carried out on anasthetized wistar rats ; the intestinal tract was isolated and incannulated starting form the treitz ligament ( entrance cannula ) to a point at 20 - 30 cm of distance ( exit cannula ); the experimental double microemulsion under analysis was dispersed in a ph 7 . 4 , 37 ° c . buffer solution and then perfused ; the drug concentration remaining in the perfusion liquid was analyzed by hplc at predetermined time intervals ; apparent permeability ( pa ) values are derived from the decrease over time of drug concentration in the perfusion liquid ( dc / dt = pa . cin - cfin ). data relative to alendronate in double microemulsion of invention are reported in table 3 .
pharmaceutical compositions comprising a water / oil / water or an oil / water / oil double microemulsion , with droplets size below one micron , with the drug included in the internal water phase w1 or internal oil phase 01 , whereas the external oil 02 and second water phase w3 or the external water phase w2 and second oil phase 03 contain substances able to inhibit the enzymes , present in the mucosa or biological barrier to be permeated or physiological environment of administration , capable to degrade the drug or to cause its efflux from the barrier ; alternatively the external oil and second water phase or external water phase and second oil phase contain permeation enhancing agents , i . e ., substances able to increase the diffusion of the drug through the biological barrier .