The technical field of the present invention relates to method of improving the bioavailability of prodrug targeting absorption via lymphatic system The technical field also relates to self emulsifying drug delivery system of prodrug and process of preparation thereof
The dawn of novel drug developing and screening technologies has improved the potency of the molecules, but at the same time has induced greater physicochemical and biological obstacles, such as poor solubility and poor hpophihcity Drug administration through oral route is the most preferred one as it offers numerous advantages but the therapeutic efficacy of an orally administered drug is primarily dependent on the drug's potency and the systemic availability or bioavailability Drug potency is largely under the influence of its chemical or molecular structure and reclines to be an inherent property of an individual molecule Bioavailability is affected by multiple reasons like physicochemical, formulation, and patient related issues As the drug bioavailability is influenced by a number of factors, it can be improved by applying formulation strategies involving modification of its physicochemical and to some extent biological response, to obtain highest possible bioavailability and therapeutic benefit However, it is important to understand the behavior of a drug molecule during its (i) processing (11) storage and (in) post administration phase The drug after the oral administration has to successfully overcome a complex gastrointestinal tract (GIT) environment consisting of varying pH, digestive enzymes before it gets absorbed into systemic circulation
To improve the bioavailability of drugs having poor solubility and poor hpophihcity, number of approaches are documented in the prior art These approaches may be broadly classified into two categories including modifications in the chemical structure of the molecule and in the formulation Alteration of the structure of the molecule, preparation of prodrug and salt formation are amongst the chemical modifications of the drug molecule Use of solubility enhancing agents or absorption enhancers, formation of inclusion complexes and size reduction to micron or even nanometer levels, are amongst formulation development methods to enhance the bioavailability
Prodrug preparation is a well-known approach to improve the bioavailability A prodrug means any pharmaceutical^ acceptable ester, salt of an ester, or other derivative of an active moiety, which upon administration to a recipient, is capable of readily providing
the active moiety enzymatically or non-enzymatically Prodrugs are designed to improve the solubility and permeability of a molecule, and consist of very weak bonds in their structures These weak bonds help in easy reversal to active parent moiety in the intestinal epithelial cell or blood, but at the same time it makes them susceptible to the actions of digestive enzymes and pH of the gastrointestinal tract, leading to pre-absorption degradation, thus defeating the purpose for which the prodrug was designed The problem is further aggravated when prodrugs show rapid efflux from the intestinal wall, wherein the prodrug is absorbed well, but after entering into the intestinal cells is readily converted into the active moiety, and effluxed back into the intestine instead of entering into the blood circulation thereby reducing the effective bioavailability Cefpodoxime proxetil is a prototype example of such prodrugs, which has problems of extensive pre-absorption degradation and efflux mechanism The absolute bioavailability of commercially available cefpodoxime proxetil tablets is thereby reduced to only about 50% compared to that of cefpodoxime sodium intravenous infusion Judicious application of formulation technology is required, for achieving better results in such cases
The prior art teaches various formulation approaches targeted mainly to improvement of solubility, which is thereby expected to improve the bioavailability One such approach relates to the use of lipidic systems for poorly soluble drugs The formation of lipidic systems includes micro or nano emulsions, liposomes, self-emulsifying drug delivery systems, and solid lipid nanoparticles
Charman et al, 1992, Pharm Res, 9, 87-93 discloses a method of incorporating the drug into a self-emulsifying liquid, which emulsifies to form oil in water (O/W) emulsion spontaneously after mixing with water
US 5,965,160 discloses self-emulsifying oily formulation comprising an oil component and a surfactant, the formulation being characterized in that the oil component comprises an oily carrier and a cationic lipid and optionally, a lipophilic oily fatty alcohol The oil-in-water emulsion, which forms upon mixture with water, has oily droplets, which are positively charged
Pouton, 1985, Int J Pharm 27, 335-348, Pouton 1985b, Int J Pharm 37 1P, Pouton et al 1987 Proc Int Symp Control Rel Bioacta Mater, 14, 113-117, Wakerly et al
1986, ACS Symp Ser 311, 242-255, Wakerly et al, 1987, J Pharm Sci, 67, 1375-1377 discloses few other self-emulsifying drug delivery systems which use medium-chain triglyceride oils and nonionic surfactants
Self-emulsifying drug delivery systems may be easily and economically encapsulated in soft gelatin capsules or sealed in to hard gelatin capsules to yield precise and convenient unit dosage systems
The self-emulsifying systems are well known to improve the bioavailability of drugs having solubility related problems, however there is no such mention of use of self-emulsifying systems to improve the bioavailability of the prodrugs having problems due to pre-absorption degradation and/or efflux mechanism
We have now discovered that self-emulsifying drug delivery systems could be used to formulate prodrugs having problems of pre-absorption degradation (in the gastrointestinal lumen, or in the enterocytes or epithelial cells), and/or efflux mechanism, and consequently enhancing their bioavailability to surprising levels by targeting absorption via lymphatic system
Hence, in one general aspect there is provided, a method of improving the bioavailability of a prodrug by targeting absorption via lymphatic system
In another general aspect there is provided, a method of improving the bioavailability of prodrug by 1 25 times or more than from conventional oral dosage forms, using self-emulsifying drug delivery system
In another general aspect there is provided, a process for the preparation of self-emulsifying drug delivery system of prodrug comprising the steps of combining prodrug with lipophilic solvent, surfactant, and optionally co-solvent, to form a clear solution, and processing into a delivery system
In another general aspect there is provided, a stable self-emulsifying drug delivery system of prodrug comprising prodrug, lipophilic solvent, surfactant and stabilizer
In another general aspect there is provided, a stable self-emulsifying drug delivery system of cefpodoxime proxetil comprising cefpodoxime proxetil, lipophilic solvent, surfactant and stabilizer
In another general aspect there is provided, a stable self-emulsifying drug delivery system of cefpodoxime proxetil comprising cefpodoxime proxetil, lipophilic solvent, surfactant and an acidic stabilizer
The lymphatic system is a subsystem of the circulatory system Lymphatic system is like the blood circulatory system, wherein the lymph vessels branch through all parts of the body like the arteries and veins, except that the lymphatic system carries a colorless liquid called lymph instead of blood The anatomy and physiology of the lymphatic system varies in different regions of the body The lymphatics of the small intestine are characterized by the presence of a centrally located lacteal in each villi The lacteals join a plexus of lymphatic capillaries and drain, via the mesenteric lymph vessel, into the cisterna chyli Lymph from the cisterna chyli is drained by the thoracic duct, which empties directly into the general circulation at the junction of the left internal jugular and left subclavian veins Gut associated lymphoid tissues comprise tonsils, adenoids (Waldeyer's ring), Peyer's patches, lymphoid aggregates in the appendix and large intestine, lymphoid tissue accumulating with age in the stomach, small lymphoid aggregates in the oesophagus, diffusely distributed lymphoid cells and plasma cells in the lamina propria of the gut Peyer's patches are quite large aggregates of lymphoid tissue found in the small intestine The overlying 'dome' epithelium contains large numbers of intraepithelial lymphocytes Some of the epithelial cells have complex microfolds in their surfaces They are known as M cells and are believed to be important in the transfer of antigens from the gut lumen to Peyer's Patches
Hence, due to its unique anatomy and physiology, potential exists to exploit the lymphatic system as an alternative means of drug delivery Targeting drugs into the lymph has certain advantages These advantages include avoidance of first pass metabolism, direct delivery of drugs to particular regions of the lymphatic circulation e g in the treatment of disease states and the possibility of regulating the rate of drug delivery into the systemic circulation The major factors affecting apparent lymphatic transport include the route of administration, the design of the drug delivery system, and the physicochemical and metabolic properties of the drug Macromolecules and
colloidal particles such as chylomicrons are selectively taken up from the interstitial space via the lymphatics Nanoparticles enter into the lymphatic system through specialized processes called endocytosis Lymphotropic delivery systems, where the drug is complexed with a high molecular weight carrier, e g dextran sulphate, have been used in the presence of absorption enhancers to potentiate the selective lymphatic delivery of anticancer drugs
The drugs belonging to class II, III and IV of Biopharmaceutical classification, having solubility and/or permeability problems are the targets for preparing prodrugs Prodrugs are known to improve the bioavailability of poorly soluble drugs by improving their solubility and/or permeability Prodrugs are believed to be absorbed from the intestinal tract after oral administration and hydrolyzed to its parent moiety by enzymatic or non-enzymatic action in the intestinal wall/plasma But in some cases preparation of prodrugs alone does not solve the problem These prodrugs in spite of having improved solubility and permeability shows poor bioavailability because of preabsorption degradation and rapid efflux back into the lumen of intestine One of the approach to improve the bioavailability of such prodrugs is to target the lymphatic system in which the prodrug is directly entering into the lymph so that there is no preabsorption degradation and efflux mechanism The lymphatic system would also provide certain additional advantages so that the overall bioavailability is enhanced to surprising levels
Cefpodoxime proxetil is one of the prototype example of prodrugs, commercially available oral tablets of which show absolute bioavailability of only 50% compared to that of intravenous infusion Systematic studies were conducted to determine the potential reasons for the poor bioavailability of cefpodoxime proxetil
Solubility and stability studies were conducted at different pH conditions and it was found that cefpodoxime proxetil has pH dependent solubility and stability, both decreasing with increase in pH Though reduced, the solubility at intestinal pH is expected to be sufficient to achieve the desired absorption Therefore stability and not solubility, in the intestine could be one of the probable reasons for the reduced bioavailability
Further studies were conducted to determine the effective permeability coefficients of cefpodoxime and cefpodoxime proxetil using an in vitro rat intestinal "Everted Sac"
method Surprisingly the permeability coefficients for both cefpodoxime and cefpodoxime proxetil were found to be similar This was against expectation as cefpodoxime proxetil is supposed to be more lipophilic than cefpodoxime and was designed to improve permeability and absorption Hence, it appears that permeability coefficients obtained were under the influence of unknown factors like the presence of efflux mechanism, which would reduce the bioavailability further
The role of efflux mechanism in reducing the overall bioavailability was confirmed by the in vitro rat intestinal "Everted Sac" method in which stability of cefpodoxime proxetil in the presence of jejunal segment was studied It was observed that about 90% of the cefpodoxime proxetil present was converted to cefpodoxime acid within fifteen minutes, and within thirty minutes the conversion was nearly complete as represented in Figures 1 and 2 The reason for rapid conversion of cefpodoxime proxetil to cefpodoxime exposed to these epithelial cells was found to be post absorption metabolism of cefpodoxime proxetil to cefpodoxime within the enterocytes and its efflux, back into the intestinal lumen
Efflux mechanism was confirmed by intestinal tissue uptake studies using fresh everted jejunal rings The jejunal rings showed presence of high amounts of cefpodoxime proxetil inside the enterocyte in the initial stages as early as less than one minute But the concentrations inside the epithelial cells depleted fast and recurrence of cefpodoxime concentration was observed with time When cefpodoxime proxetil was studied for uptake, its traces were observed in tissue for five minutes only The point illuminated that cefpodoxime proxetil permeates quickly, but is rapidly converted into cefpodoxime, effluxed towards apical side rather than basal side leading to lowered absorption With time, the accumulated cefpodoxime is absorbed but slowly and to a lesser extent When similar study was performed with cefpodoxime, it exhibited a constant intake rate into the tissue giving an upward movement of concentration vs time profile The results of the study are represented in Figures 3 and 4 Such efflux mechanism further reduces the bioavailability in addition to preabsorption degradation
Conversion of prodrugs to active moieties, prior to absorption into the systemic circulation will remain a hurdle in all types of conventional oral dosage forms Hence, a formulation needs to be prepared for prodrugs such as cefpodoxime proxetil, which can bypass and provide sufficient protection to the prodrug from the intestinal contents as
well as from the enterocytic enzymes Self-emulsifying drug delivery systems, which undergo lymphatic absorption, would be a better choice in such cases The system produces an oil in water emulsion spontaneously as soon as after coming into contact with water after oral ingestion Lipase, bile salts and other metabolizing enzymes present in the gastrointestinal contents, act on the emulsion to form chylomicrons, which are absorbed through lymphatic circulatory system As the prodrug is not entering into the enterocytes in which it may be degraded, secondly as direct contact with gastrointestinal environment is avoided, there are less chances of preabsorption degradation Moreover when the prodrug is absorbed through lymphatic system, there would not be any first pass effect, if any, and hence bioavailability would additionally be enhanced
Self-emulsifying drug delivery system of prodrugs of the present invention may improve the bioavailability by 1 25 times or more, in particular 1 5 times or more than from conventional oral dosage forms Less amount of prodrug would be required to achieve the plasma levels of the drug compared to conventional dosage forms Hence self-emulsifying drug delivery systems would be cost-effective and have reduced chances of dose-dumping leading to toxicity problems
In its simplest version, self-emulsifying system of the present invention would comprise a prodrug, lipophilic solvent and a surfactant
Self-emulsifying drug delivery systems may be used for prodrugs having poor bioavailability due to problems of preabsorption degradation and/or efflux mechanism Examples of prodrugs include cefpodoxime proxetil, cefetamet pivoxil, cefditoren pivoxil, cefuroxime axetil, valacyclovir, valganciclovier, azidothymidine, capecitabme, famciclovir, nabumelone, pivampicillin, innotecan terfenadine, enalapnl, ramipril, dipivefnn, omeprazole, sulfasalazine, olsalazine, methanamie, bambuterol, allopunnol, gemcitabine, fludarabine, cladnbine, simvastatin, tegafur, fosphenytoin and viramidine The amount of prodrug may vary from about 5% to about 50% w/w of the self-emulsifying composition
Lipophilic solvent may be one or more of a long or medium chain triglyceride oils having different degrees of saturation Medium chain triglyceride oil is a triglyceride oil of average carbohydrate chain of about 8-12 carbon atoms Suitable examples include
those available commercially as TCM from Societe des Oleagineux, France (a mixture of triglycerides wherein about 95% of the fatty acid chains have either 8 or 10 carbon atoms), and MYGLYOL 812™ from Dynamit Nobel, Sweden (a mixture of triesters of glycerine and of caprylic and capnc acid), and the like Novel semi-synthetic medium chain triglycerides, which are amphiphihc compounds exhibiting surfactant properties, may also be used Long chain triglyceride oil is a triglyceride oil of average carbohydrate chain of above12 carbon atoms Suitable examples of long chain triglyceride oils include arachis oil, safflower oil, sesame oil, soybean oil, cotton seed oil, olive oil, sunflower oil, corn oil, kernel oil and the like Modified or hydrolyzed vegetable oils have contributed widely to the success of self-emulsifying drug delivery system owing to their formulation and physiological advantages such as captex, capmul, and the like Lipophilic solvent may also include various other oily ingredients including lipophilic fatty acids such as oleic acid, mynstic acid, or substituted lipophilic fatty acids, e g esters with alkyl alcohols, such as methyloleate, ethyl oleate, isopropyl mynstate, lecithin, and the like In addition, neutral or ionic lipids may also be included In particular, the lipophilic solvent having HLB value less than 8 may be used Lipophilic solvent may comprise from about 10% w/w to about 70% w/w, in particular from about 15% w/w to about 60% w/w of the self-emulsifying composition When the prodrug is cefpodoxime proxetil, lipophilic solvents particularly includes one or more of glyceryl monooleate (Maisine), mixture of mono and diglycendes of oleic acid (Peceol), polyethylene glycol -6- apricot kernel oil ester (Labrafil 1944CS), and polyethylene glycol -6- corn oil ester (Labrafil 2215CS)
Surfactant is an essential component of self-emulsifying system, which helps in the spontaneous formation of oil in water emulsion droplets as well as their rapid dispersion in the gastrointestinal environment, thereby playing an important role in the overall performance of self-emulsifying drug delivery systems Additionally, it helps to dissolve large quantities of prodrug in lipophilic solvent, as well as prevents precipitation in the gastrointestinal lumen Surfactants used in self-emulsifying drug delivery system include one or more non-ionic and ionic (cationic, anionic and zwittenonic) surfactants Examples of non-ionic surfactants include one or more of polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate, alcohol - oil transestenfication products, for example polyethylene glycol - 6 corn oil, polyglycenzed fatty acids, for example polyglyceryl - 6 pentaoleate,
propylene glycol fatty acid esters, for example propylene glycol monocaprylate, mono and diglycendes for example glyceryl ricinoleate, Sterol and sterol derivatives, for example sitosterol, sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate, polyethylene glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol, sugar esters, for example sucrose monopalmitate, polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer", ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyi carnitine, and the like The surfactant may have a HLB value of equal to or greater than 12, or equal to or less than 8, in particular, a combination thereof may be used The surfactant concentration may vary from about 10% w/w to about 70% w/w, in particular more than 20% w/w of the self-emulsifying composition When the prodrug is cefpodoxime proxetil, surfactants particularly includes one or more of polyethylene glycol -32- glyceryl laurate (Gelucire 44/14), polyoxyethylene monolauryl ether (Bnj 35), polyoxyl 35 castor oil (Cremophor EL), polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), polyethylene glycol -6- apricot kernel oil ester (Labrafil 1944CS), and polyethylene glycol -6- corn oil ester (Labrafil 2215CS)
Besides the above, self-emulsifying drug delivery system may further comprise one or more of other pharmaceutically acceptable additives such as co-solvents, stabilizers, and the like
Co-solvent helps in dissolving the prodrug and other components of the system to form a single phase composition Suitable examples of co-solvents include one or more of different grades of polyethylene glycol, propylene glycol, ethanol, transcutol, labrasol and the like Based on the need, the amount of co-solvent may vary in the range of about 2% w/w to about 20% w/w of the self-emulsifying composition
One or more stabilizers may be incorporated in the system, in small amounts, to improve the storage stability of the self-emulsifying system in terms of the prodrug content or of the composition itself, or both Suitable stabilizer includes pH adjusting agents, antimicrobial preservatives, antioxidants, and the like
Examples of pH adjusting agents include acids, bases and buffers Suitable acids may include any organic or inorganic acids such as hydrochloric acid, phosphoric acid, lactic acid, and the like, suitable bases may include any organic or inorganic base such as diethanolamine, triethanolamine, meglumine, trimethanolamine, diethanolamine ethylenediamine, L-lysine, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium oxide, magnesium hydroxide, ammonia, and the like, and suitable buffers include monobasic or dibasic sodium phosphate, lactates, sodium ascorbate, sodium citrate, and the like Examples of antimicrobial preservatives include benzyl alcohol, phenethyl alcohol, phenoxyethanol, sodium benzoate, methyl paraben, propyl paraben, butyl paraben, and the like Examples of antioxidants include propyl gallate demercaprol, butylhydroxyanisole, butylhydroxytoluene, palmityl ascorbate, sodium pyrosulfite, tocopherols e g alpha-tocopherol (vitamin E), and/or its esters, and the like
The amount of stabilizer may vary in the range of about 0 002% w/w to about 10% w/w of the self-emulsifying composition
When the prodrug is cefpodoxime proxetil, use of an acid such as hydrochloric acid or acetic acid, as a stabilizer in small amounts, from about 0 01% w/w to about 0 03% w/w of the self-emulsifying composition, improved the storage stability to surprising levels
In one of the embodiments, self-emulsifying system of prodrug may be prepared by mixing prodrug with lipophilic solvent and surfactant to form a clear solution
In another embodiment, self-emulsifying system of cefpodoxime proxetil may be prepared by mixing cefpodoxime proxetil with lipophilic solvent and surfactant to form a clear solution
In another embodiment, self-emulsifying system of cefpodoxime proxetil may be prepared by mixing cefpodoxime proxetil with lipophilic solvent, surfactant, and acid (stabilizer) to form a clear solution
The performance of self-emulsifying drug delivery systems may be analyzed by evaluating certain parameters listed below
(Table Removed)
Self-emulsifying solutions prepared in any of the embodiments above may be processed into self-emulsifying drug delivery systems suitable for oral administration, using conventional techniques known in the art In particular, self-emulsifying drug delivery systems may be in the form of sealed soft or hard gelatin capsules Optionally, the self-emulsifying drug delivery systems may be coated with a gastroresistant coating layer, if desired, to control the release of the emulsifying solution at specific regions of the gastrointestinal tract Gastroresistant coating helps to carry the delivery system unchanged to the small intestine, the primary site for lymphatic absorption
The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention any way
Examples (Table Removed)
Procedure
1 Cefpodoxime proxetil was added to the lipophilic solvent (ingredient 2, 3, or 4) and is stirred for 10-15 minutes at ambient temperature (up to 35°C) in a water bath, to form a uniform mixture
2 Surfactant (ingredient 5, 6, or 7) and stabilizer (ingredient 8 or 9) were added to the mixture of step 1 with continuous stirring, and stirred till a clear solution was formed
The clear solutions prepared above as per the compositions of Example 1-4, were tested for ease of dispersibility in water (1 250 v/v) or 0 1N HCI (1 250 v/v) on mild agitation All the solutions dispersed readily within 5 minutes, to form oil in water emulsion globules having an average globule size of less than 100nm (particularly 25-40 nm)
The clear solutions prepared above as per the compositions of Example 1-4, were filled in to closed glass vials and stored at 40°C, and cefpodoxime proxetil content was analyzed at regular intervals over a period of 4 weeks using a validated HPLC method Compositions of example 1 and 2 containing an acidic stabilizer were found to maintain at least 95% of drug content after 4 weeks
In vivo performance of self emulsifying drug delivery system (T) was evaluated with respect to the Cepodem™ 100 (Marketed By Ranbaxy Lab Ltd ) tablets (R) in male Sprague-Dawely rats (weight 250-275 gms) at a dose of 10 mg per kg (equivalent to cefpodoxime acid) body weight, under fasted conditions (with free access to water) All experiments and procedures on animals were conducted in accordance with protocols approved by the Animal Institutional Ethical Committee Each formulation at the specified dose was administered orally, with the help of oral gauge needle along with saline Blood samples (0 4-0 5 ml) were collected at 0 5, 1, 1 5, 2, 3, 4, 6, 8, 12, and 24 hours Samples were centrifuged to separate plasma and drug content analyzed using a validated HPLC method Pharmacokinetic parameters Cmax (Maximum plasma concentration), Tmax (Time to attain maximum plasma concentration), AUCot (Area under the plasma concentration vs time curve from 0 hours to the time of last sample collected) and AUCo« (Area under the plasma concentration vs time curve from 0 hours to infinity) were calculated from the data obtained The data was analyzed using both MS-Excel™ and using non-linear regression software- PC-NONLIN™ The results of the study are represented in the table below (Table Removed)
The above results clearly indicate the importance of self emulsifying drug delivery systems in improving the oral bioavailability of prodrugs

WE CLAIM:
1. A method of improving the bioavailability of prodrug by 1.25 times or more than from conventional oral dosage forms, using self-emulsifying drug delivery system.
2. The method of improving the bioavailability of prodrug according to claim 1 wherein poor bioavailability is due to preabsorption degradation and/or efflux mechanism.
3. A self-emulsifying drug delivery system of prodrug comprising prodrug, lipophilic solvent, and surfactant; and providing bioavailability of 1.25 times or more than from conventional oral dosage forms.
4. The self-emulsifying drug delivery system according to claims 1 to 3 wherein prodrug is selected from the group consisting of cefpodoxime proxetil, cefetamet pivoxil, cefditoren pivoxil, cefuroxime axetil, valacyclovir, valganciclovier, azidothymidine, capecitabine, famciclovir, nabumelone, pivampicillin, irinotecan, terfenadine, enalapril, ramipril, dipivefrin, omeprazole, sulfasalazine, olsalazine, methanamie, bambuterol, allopurinol, gemcitabine, fludarabine, cladribine, simvastatin, tegafur, fosphenytoin and viramidine.
5. The self-emulsifying drug delivery system according to claim 4 wherein prodrug comprises from about 5% w/w to about 50% w/w of the self-emulsifying composition.
6. The self-emulsifying drug delivery system according to claim 3 wherein lipophilic solvent is selected from the group consisting of one or more of a long or medium chain triglyceride oils, lipophilic fatty acids, substituted lipophilic fatty acids, and the like.
7. The self-emulsifying drug delivery system according to claim 6 wherein lipophilic solvent comprises from about 10% w/w to about 70% w/w of the self-emulsifying composition.
8. The self-emulsifying drug delivery system according to claim 3 wherein surfactant is selected from the group consisting of non-ionic, cationic, anionic and zwitterionic surfactants.
9. The self-emulsifying drug delivery system according to claim 8 wherein surfactant comprises from about 10% w/w to about 70% w/w of the self-emulsifying composition.
10. The self-emulsifying drug delivery system according to any of the preceding claims wherein self-emulsifying drug delivery system may further comprise one or more of co-solvents and stabilizers.
11.A stable self-emulsifying drug delivery system of prodrug comprising prodrug,
lipophilic solvent, surfactant and stabilizer. 12.The stable self-emulsifying drug delivery system according to claim 11 wherein
prodrug is cefpodoxime proxetii.
13. The self-emulsifying drug delivery system according to any of the preceding claims prepared by a process comprising the steps of combining prodrug with lipophilic solvent, surfactant, and optionally co-solvent, to form a clear solution; and processing into a delivery system.
14. The self-emulsifying drug delivery system according to claim 13 wherein the delivery system is a soft or hard gelatin capsule.
15. A method of improving the bioavailability of prodrug as described and illustrated in the examples herein.