Title of Invention	PROCESS FOR PREPARATION OF SELF MICRO/NANO EMULSIFYING SYSTEMS AND COMPOSITIONS THEREOF
Abstract	A processing technique for the formulation of SMETs /SNETs which enhances the bioavailability of poor water soluble drug substance and eliminates the fluctuation in bioavailability due to the fed and non fed condition is disclosed. A composition of pharmaceutical interest in the present invention comprises of lipid based drug delivery system, utilizing anhydrous microemulsion, a SMEDDS/SNEDDS, and further adsorbed on to solid adsorbent particles and formulated into tablet dosage form is also disclosed. The composition and dosage forms of the present invention have capacity to improve the bioavailability of a wide range of drugs including drugs that are known or suspected to have poor bioavailability.

Title of Invention

PROCESS FOR PREPARATION OF SELF MICRO/NANO EMULSIFYING SYSTEMS AND COMPOSITIONS THEREOF

Abstract

A processing technique for the formulation of SMETs /SNETs which enhances the bioavailability of poor water soluble drug substance and eliminates the fluctuation in bioavailability due to the fed and non fed condition is disclosed. A composition of pharmaceutical interest in the present invention comprises of lipid based drug delivery system, utilizing anhydrous microemulsion, a SMEDDS/SNEDDS, and further adsorbed on to solid adsorbent particles and formulated into tablet dosage form is also disclosed. The composition and dosage forms of the present invention have capacity to improve the bioavailability of a wide range of drugs including drugs that are known or suspected to have poor bioavailability.

Full Text	THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFIC A TION [See section 10; rule 13] PROCESS FOR PREPARATION OF SELF MICRO/NANO EMULSIFYING SYSTEMS AND COMPOSITIONS THEREOF" (a) PATRAVALE VANDANA BHARAT (b) University Institute of Chemical Technology, Nathalal Parikh Marg, Matunga, Mumbai-400 019. India (c) Indian National (a) KHAN IMRAN AHMAD (b) University Institute of Chemical Technology, Nathalal Parikh Marg, Matunga, Mumbai-400 019. India (c) Indian National The following specification describes the nature of this invention and the manner in which it is to be performed 1 O92lSt,l2004 1 I OCT 2Q0A FIELD OF INVENTION This invention relates to process for preparation of self emulsifying drug delivery systems for active ingredients including drugs and nutritional supplements, cosmeceuticals, and diagnostic agents. In particular, the present invention provides compositions and dosage forms comprising self emulsifying drug delivery system (SEDDS), self micro emulsifying drug delivery system (SMEDDS) having globule size less than 1000 nm, self nano emulsifying drug delivery system (SNEDDS) having globule size less than 100 nm and micro emulsions incorporated with the active(s) in solid dosage forms to enhance bioavailability and minimize the fluctuation in bioavailability due to type of food, for poorly soluble (drug showing dissolution rate limited bioavailability) as well as highly water soluble (drug showing permeation rate limited bioavailability) drugs. This invention also relates to self emulsifying tablets (SETs), self micro emulsifying tablets (SMETs®) and self nano emulsifying tablets (SNETs) with a good hardness. Background of the invention Hydrophobic active ingredients such as progesterone, cyclosporine, itraconazole and glyburide present delivery challenges due to their poor aqueous solubility and slow dissolution rate and thus poor bioavailability, whilst other drug have good bioavailability but their solubility varies depending on the nature of the food e.g. in presence of fatty meal their dissolution rate get increased resulting in improved bioavailability and under influence of normal meal they remains insoluble resulting in poor bioavailability. These types of fluctuations in bioavailability can be well handled by giving the drug in solublized form either as microemulsions or as SEDDS, SMEDDS and SNEDDS. Several commercial products of these hydrophobic drugs are available based on different technologies so as to enhance their in vivo performance. One approach is size reduction by micronization such as in Prometrium (micronized progesterone) and Micronase (micronized glyburide). Other approaches include size reduction in emulsion formulations such as in Sandimmune (cyclosporine emulsion) and Neoral (cyclosporine microemulsion). These approaches suffer from several disadvantages. Micronization/ nanonization present processing and stability challenges as well as dissolution limitations, since the micronized/ nanosized drug still possesses a high degree of crystallinity. Liquid formulations present drug precipitation and packaging challenges mainly due to solvent evaporation. Moreover, non-solid formulations are more prone to chemical instability and capsule-shell incompatibility leading to the possibility of leakage upon storage and even during handling. For hydrophilic active ingredients, the formulation challenges are different. Although these compounds are readily soluble in the aqueous gastrointestinal environment, they are poorly absorbed due to poor membrane permeability and/or enzymatic degradation. Surfactants and lipophilic additives have been reported to improve membrane permeability; e.g., Y.V. Rama Prasad et.al.in "Evaluation of Oral Formulations of Gentamicin Containing Labrasol in Beagle Dogs" International Journal of Pharmaceutics 268 (2003) 13-21; indicated that bioavailability of such highly hydrophilic drugs can be improved by using some^jo-enhancejrs^Labrasol in this case. These may be given as microemulsions or SMEDDS. Most solid dosage forms of hydrophilic active ingredients exhibit poor or no absorption of the active. Moreover, these non-solid formulations suffer from the disadvantages of chemical instability, leakage and capsule shell incompatibility as discussed above. In order to eliminate or reduce these problems associated with liquid formulation the present invention is focused on development of SEDDS, SMEDDS or SNEDDS as tablets referred as Self Emulsifying, Micro-Emulsifying, Nano Emulsifying Tablets (SETs, SMETs®, SNETs). These tablets (SETs, SMETs®, SNETs) possess following advantages- they are convenient and easy to handle and more robust, stable dosage; better compliance for patients having allergy to capsule shells or who do not prefer to take capsules. Furthermore, oral administration of peptides is feasible. Also these tablets (SETs, SMETs®, SNETs) have capacity to reduce/ eliminate the localized release of drug and surfactant in the intestinal mucosa which may cause the gastrointestinal mucosal damage and may have capacity to release drug faster as compared to its capsule counterpart i.e. SMEDDS. Tablets are uncoated solid dosage forms that are produced by compression of solid tabletting ingredients between upper and lower punches in definite boundary of die cavity or by molding. Tablets contain not only medicaments but also other excipients (inert) which act as filler, binder, disintegerants, glidants, coloring agents and flavoring agents. These inactive substances do not affect the dosage form therapeutically but affect the mechanical and aesthetic properties which are the most important requirement in the success of dosage form along with its therapeutic value. Design of tablet dosage form needs powder or granules which have to be compacted in the form of tablet, the resulting tablet should have sufficient strength to maintain its shape during post formulation steps till it is being ingested. This led us to process self emulsifying tablets, self micro emulsifying tablets and self nano emulsifying tablets with a good hardness which consists of lipid based drug delivery system utilizing anhydrous micro emulsion (SEDDS, SMEDDS & SNEDDS) system and further adsorbed on to solid particulate adsorbent and formulated into solid dosage form. The compositions and dosage forms of the present invention have capacity to improve the bioavailability of a wide range of drugs including drugs that are known or suspected of having poor bioavailability. Micro emulsions are clear, thermodynamically stable solutions that generally contain water, surfactant, and oil. Micro emulsions differ from emulsions in that the dispersed phase consists of globules less than 100 nm and more particularly about 30-60 nm in diameter. The difference between coarse (macro) emulsions and micro emulsions is not only the size of the globules but also the ease of dispersion. Micro emulsions do not separate on standing where as emulsions will separate. SMEDDS are a novel system developed by.-.Gattefosse, based upon specific blends of excipients. SMEDDS comprises of a surfactant, a co surfactant, a_ lipid phase and an active _compound. These systems are custom designed for each active molecule. On dilution, SMEDDS spontaneously convert into optically clear, thermodynamically stable micro emulsions which contain the drug in molecular dispersion. SMEDDS can be filled into hard gelatin capsule and delivered orally. I US patent 5993858 discloses the method and formulation for increasing the bio availability of poorly water soluble drugs which comprises an emulsion and includes oil or other lipid material, a surfactant, and a hydrophilic co surfactant. ) WOOO 16744 discloses pharmaceutical solution preparation containing prostaglandin El for the treatment of erectile dysfunction, which is prepared into a form of microemulsion preconcentrate (SEDDS formulation). This preparation is prepared by dispersing or dissolving a drug into a liquid mixture of oil, surfactant and co surfactant. Eutectic-self-nanoemulsified drug delivery systems formulated from polyoxyl 35 castor oil (cremphor), medium chain mono and diglycerides (capmul), essensial oils, and a pharmacologically effective drug was disclosed in US2003147927. WO03017986 describes the SMEDDS compositions containing Itraconazole with a greatly increased bioavailability and their preparation methods. ^ The nearest prior art to our invention is US patent 6,280,770 entitled "Microemulsions as Solid Dosage Forms for Oral Administration" which discusses the development of tablet from the liquid microemulsion to improve the rate and/ or extent of absorption. The patent further describes in their invention figure- 1 wherein tablet contains core containing emulsion concentrate adsorbed on the powder and an optional compression coated effervescent layer and an enteric coating layer. In figure-2 of the same patent, schematic preparation of a soft tablet consisting of agglomerates of adsorbent containing adsorbed microemulsion which are coated with an enteric material is shown. Whilst in 5 detailed description of the invention, the inventors had mentioned in granulation procedure that dry__granulation may be achieved through slugging or chilsonation. But neither have they claimed this point nor they have mentioned at what step the slugging is required. On our trials, the direct compression of mixture of adsorbate and tabletting ^excpients failed to yield structurally strong tablets. Slugging of adsorbate-inert excipients mixture followed by direct compression also fails to yield structurally strong tablets. Slugging at an intermediate stage was the most critical part governing structurally strong tablets. During description of hardness, inventors of the US patent no 6,280,770 have mentioned that tablet hardness is preferably between about 5N and about 5 ON and more preferably between about 5N and 35N. The tablet having hardness up to 50 N which is the upper limit of this range is really a soft tablet and may break during the packaging or even during the shipping. Thus, an easy and suitable method circumventing coating was developed for tabletting which was able to give sufficiently hard tablets having capacity) to withstand the stress during packing and shipping. Direct compression of adsorbate-inert excipients mixture does not give structurally strong tablets. Slugging at an intermediate stage is the most critical part to yield structurally strong tablets. Our invention starts from the draw back of the earlier prior art which yields tablets with poor hardness utilizing complicated procedures as indicated in figure 1. Our invention relates to adsorbates of SMEDDS with or without disintegerants, made into slugs using slugging and then tabletted through direct compression technique mixed with additives especially hardening agents. This process results in sufficiently hard tablets. The present invention also relates to pharmaceutical dosage forms of particularly insoluble/ soluble drugs that display poor bioavailability and slow absorption in the gastro intestinal system. The drugs incorporated with SMEDDS adsorbed on the solid particulate adsorbent may further be formulated in to dosage forms either before or after chilsonation. 6 Objective of the Invention It is an object of the present invention to provide a process for preparation of the self emulsifying systems. It is another object of the invention is to provide solid pharmaceutical compositions having active ingredients in a rapid dissolvable and more solubilized state therein. A further object of the invention is to provide solid pharmaceutical compositions having more rapid dissolution upon administration to a patient. Yet another object of the invention is to provide solid pharmaceutical compositions capable of delivering a wide variety of pharmaceutical active ingredients. It is another object of the invention, to provide solid pharmaceutical compositions capable of improving the absorption and/or bioavailability of a pharmaceutical active ingredient. Yet another object of the invention is to provide solid pharmaceutical compositions capable of reducing the fluctuation absorption and/or bioavailability of a pharmaceutical active ingredient. A further object of the invention is to provide solid pharmaceutical compositions having better protection of the upper gastrointestinal tract from untoward effects of the active ingredient. Another object of the present invention is to prepare SMEDDS/SNEDDS composition in the form of free flowing compressible powder. Further object of the present invention is granulation by slugging of the free flowing adsorbate or by wet granulation technique and the compression into tablet after mixing with other directly compressible tabletting excipients, resulting in harder tablets. In accordance with these and other objects, the present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients contained therein or separately administered and will become more fully apparent from the following description and appended claims, or may be learned by the practice of the invention as set forth herein after. Summary of the invention This invention discloses a process for preparation of self emulsifying drug delivery systems for active ingredients including drugs and nutritional supplements, cosmeceuticals, and diagnostic agents. More particularly the present invention discloses compositions and dosage form comprising self emulsifying drug delivery systems, which comprise a lipid based drug delivery system, utilizing anhydrous micro emulsion and further adsorbed on to solid adsorbent particles, made slugs, mixing with other tabletting excipients and formulated into solid dosage form under direct compression technique. The compositions and dosage forms of the present invention have capacity to improve the bio availability of a wide range of drugs, including drugs that are known or suspected of having poor bioavailability. 'The process for preparation of self micro emulsifying tablet (SMETs) composition in the form of a free flowing compressible powder wherein the said process comprises, j preparing self micro emulsifying drug delivery system (SMEDDS or SNEDDS) of active moiety by using defined proportion of oils surfactants, and co-surfactants; adsorbing the SMEDDS/SNEDDS on a selected adsorbent to give free flowing powder; slugging of free flowing absorbate; mixing with other tabletting excipients and compressing on I tabletting machine. The drug containing system on dilution with water forms oil-in-water, water-in-oil or bicontinuous-phase microemulsion in vivo. The solid particle adsorbent is selected from the group consisting of but not limited to aluminum hydroxide, bentonite, hectorite, colloidal magnesium-aluminum silicate, kaolin, magnesium tri silicate, magnesium hydroxide, magnesium oxide, silicon dioxide talc and hydrophobic starch. The SMEDDS/SNEDDS adsorbate is compacted on heavy duty tablet machines or passed through roller compactor / chilsonator either alone or intimately mixed with disintegerants to form the slug which is ground to a uniform size and compressed into the finished tablet after mixing with tabletting excipients. The SMETs/SNETs can be prepared by direct compression method or wet granulation method using a solution of polymer, starch paste or pre-gelatinized starch or any other binding agent. The tabletting excipients refer to mixing with conventional excipients. Drug containing system is a microemulsion, Self Micro Emulsifying Drug Delivery Systems or self nano emulsifying drug delivery system (SNEDDS). The compressible vehicle is blended with the slugged and powdered SMEDDS/SNEDDS adsorbate, and if necessary (optionally), with a lubricant and a disintegrant, and then the blend is compressed into a tablet. The compressible vehicle belongs to conventional tabletting agents and here acts as hardening agents for SMETs/SNETs. The compressible vehicle is selected from microcrystalline cellulose, calcium phosphate, lactose, dextrose and mannitol. The composition or dosage form is self emulsifying tablets (SETs), self micro emulsifying tablets (SMETs) and self nano emulsifying tablets (SNETs). 9 The dosage forms may be a conventional tablet, dispersible tablet, multi-particulate tablet, a suppository or a pessary. The dosage form comprises the amount of diluents is about 10% to 90% of the tablet weight, more preferably 40 to 60% of the tablet weight. The dosage form comprises the amount of binder is about 1% to 25% of tablet, more preferably 4% to 10% of the tablet weight. The dosage form comprises the amount of lubricants is about 0.25% to 10% of the tablet weight, more preferably 0.5 to about 3%. The dosage form comprises the amount of disintigrants is about 2 to 20%) of the tablet weight, more preferably 5 to 15% of the tablet weight. The drug containing microemulsion is a drug that displays poor bioavailability in the gastrointestinal tract of a mammal or shows fluctuation in bioavailability with fed and non-fed condition, when said drug is administered in a form other than said microemulsion. The composition contains the active ingredient may belongs to group consisting of biological molecules; drugs and nutritional supplements; nifedipine, nimodipine, amlodipine, flucanazole, ketoconazole, itraconazole, celecoxib, loratadine, desloratadine, cetrizine, valdecoxib, ritonavire, acyclovir, auranofin, bretylium, cytarabine, doxepin, doxorubicin, hydrolazine, ketamine, labetalol, mercaptopur, methyldopa, nalbuphine, nalozone, pentoxifylline, pridostigm, terbutaline, verapamil, buserlin, calcitonin, cyclosporine, and oxytocin; any drug of synthetic origin, natural origin, protein, peptide and oligonucleotide, or any drug suspected to have poor bioavailability; and any drug of synthetic origin, natural origin, protein, peptide and oligonucleotide, the bioavailability of which fluctuates on fed and non fed condition. The solid dosage forms for the oral administration with a therapeutically effective amount of a drug may be a tablet; coated tablet; dispersible tablet; Modified extended/controlled release tablet; Pellet; Multi-particulate tablet; Minitablet; Suppository/ Pessary; Dry free flowing powder; and Dry syrup. The solid dosage form may further comprises of a mucoadhesive agent; release retardant polymer which ultimately led to releasing the drug in pulsatile or controlled manner in the form of microemulsion; enteric polymer which over coats the dosage form, wherein said drug does not release until it reaches the GI tract; pH adjusting substance; effervescent agent; low density material for buoyant tablet; high density materials for high density tablet; disintegrating agent, wherein said disintegrating agent causes rapid dispersion of said drug- containing microemulsion to a target area following oral administration; and sweetener and flavor to give palatable form. The SMETs (self micro emulsifying tablets) may also be SETs (self emulsifying tablets) or SNETs (self nano emulsifying tablets). One aspect of the invention is administration of the homogenous micro emulsion solution that can be directly filled into soft/ hard gelatin capsule. In another aspect of the invention, the SMEDDS/SNEDDS adsorbed on solid particle adsorbent in the form of free flowing powder can be administered even after or before slugging/chilsonation and can be filled in to hard gelatin capsule/ sachet as powder. In another aspect of invention, the adsorbed SMEDDS/SNEDDS in the free flowing powder can be converted into pellets using extrusion spherunization. In another aspect of invention, the spherunized pellets can be mixed with cushioning agent and compressed into multiparticulate tablet. In a further aspect of invention, the administration of the drug can be a suppository/ pessary containing SMEDDS/SNEDDS prepared using special shaped punches on tabletting machine. In a further aspect of invention, the administration of the drug can be a solid dosage form of tablet containing SMEDDS with hardness of 20 to 200 N, more preferably 100 to 125 N, which inside gastrointestinal tract give microemulsion on disintegration of tablet. In other aspect of invention, the drug can be administered as a dispersible tablet form which contains SMEDDS with a hardness of 20 to 200 N, more preferably 75 to 100 N, which on disintegration gives microemulsion. In other aspect of invention, the administration of the drug can be controlled release/ modified release/ extended release tablet containing SMEDDS, which inside gastrointestinal tract releases the drug in controlled manner and give microemulsion. Detailed description According to the present invention a process is provided to prepare self micro emulsifying tablet dosage forms (SMETs®) which comprise of lipid based drug delivery system utilizing anhydrous micro emulsion and further adsorbed on to solid adsorbent particles mixed with or without disintegerants, made into slugs, mixing with other directly compressible tabletting excipients and formulated into solid dosage form using direct compression technique. The compositions and dosage forms of the present invention have capacity to improve the bio availability of a wide range of drugs, including drugs that are known or suspected of having poor bioavailability. Any drug of synthetic origin, natural origin, protein, peptide and oligonucleotide, the bioavailability of which fluctuates on fed and non fed condition. Active ingredients are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti¬migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, .beta.-Blockers, cardiac inotropic agents, corticosteroids, diuretics, antiparkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2 inhibitors, leucotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non¬essential fatty acids, and mixtures thereof. In one embodiment, the active ingredient is hydrophobic. Hydrophobic active ingredients are compounds with little or no water solubility. Intrinsic water solubilities (i.e., water solubility of the unionized form) for hydrophobic active ingredients are less than about 1% by weight, and typically less than about 0.1% or 0.01% by weight. In a particular aspect of this embodiment, the active ingredient is a hydrophobic drug. In other particular aspects, the active ingredient is a nutrient, a cosmeceutical, a diagnostic agent or a nutritional agent. Specific, non-limiting examples of suitable hydrophobic active ingredients are: acutretin, albendazole, albuterol, aminogluthemide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethsone, benezepril, benzonatate, betamethasone, bicalutanide, budesonide, bupropion, busulphan, butenafme, calcifediol, calciprotiene, calcitriol, camptothecan, candesartan, capsaicin, carbamezepine, carotenes, celecoxib, cerivistatin, cetrizine, chlorpheniramine, cholecalciferol, cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene, clomipramine, clopidrogel, codeine, coenzyme Q10, cyclobenzaprine, cyclosporine, danazol, dantrolene, dexchlopheniramine, diclofenac, dicoumarol, digoxin, dihydro epiandrosterone, dihydroergotamine, dihydrotachysterol, dirithromycin, donepezil, efavirenz, eposartan, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, flucanazole, flurbiprofen, fluvastatin, fosphenytion, frovatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, glymepride, griseofulvin, halofantrine, ibuprofen, irbesartan, irinotecan, isosorbide dinitrate isotreinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lanosprazole, leflunomide, lisinopril, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone, mefepristone, mefloquine, megesterol acetate, methadone, methoxsalen, metronidazole, metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone, montelukast, nabumetone, nalbuphine, naratiptan, nelfmavir, nifedipine, nilsolidipine, nilutanide, nitrofurantoin, nizatidine, omeprazole, oprevelkin, osteradiol, oxaprozin, paclitaxel, paricalcitol, paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone, probucol, progesterone, pseudo-ephedrine, pyridostigmine, rabeprazole, raloxifene, refocoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosigiltazone, saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine, terzosin, tetrahydrocannabinol, tiagabine, ticlidopine, tirofibran, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine, vertoporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, Zolpidem, and zopiclone. Of course, salts, isomers and derivatives of the above-listed hydrophobic active ingredients may also be used, as well as mixtures. In another embodiment, the active ingredient is hydrophilic. Amphiphilic compounds are also included within the class of hydrophilic active ingredients. Apparent water solubilities for hydrophilic active ingredients are greater than about 0.1% by weight, and typically greater than about 1% by weight. In a particular aspect of this embodiment, the hydrophilic active ingredient is a hydrophilic drug. In other particular aspects, the hydrophilic active ingredient is a cosmeceutical, a diagnostic agent, or a nutritional agent. Specific, non-limiting examples of suitable hydrophilic active ingredients include: acarbose; acyclovir; acetyl cysteine; acetylcholine chloride; alatrofloxacin; alendronate; alglucerase; amantadine hydrochloride; ambenomium; amifostine; amiloride hydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor (human); antihemophilic factor (porcine); antihemophilic factor (recombinant); aprotinin; asparaginase; atenolol; atracurium besylate; atropine; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladona; bepridil hydrochloride; bleomycin sulfate; calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate; cefamandole nafate; cefazolin sodium; cefepime hydrochloride; cefixime; cefonicid sodium; cefoperazone; cefotetan disodium; cefotoxime; cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin; cephapirin sodium; cholera vaccine; chrionic gonadotropin; cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin and clindamycin derivatives; ciprofloxacin; clondronate; colistimethate sodium; colistin sulfate; cortocotropin; cosyntropin; cromalyn sodium; cytarabine; daltaperin sodium; danaproid; deferoxamine; denileukin diftitox; desmopressin; diatrizoate megluamine and diatrizoate sodium; dicyclomine; didanosine; dirithromycin; dopamine hydrochloride; domase alpha; doxacurium chloride; doxorubicin; editronate disodium; elanaprilat; enkephalin; enoxacin; enoxaprin sodium; ephedrine; epinephrine; epoetin alpha; erythromycin; esmol hydrochloride; factor IX; famiciclovir; fludarabine; fluoxetine; foscarnet sodium; ganciclovir; granulocyte colony stimulating factor; granulocyte-macrophage stimulating factor; growth hormones- recombinant human; growth hormone-bovine; gentamycin; glucagon; glycopyrolate; gonadotropin releasing hormone and synthetic analogs thereof; GnRH; gonadorelin; grepafloxacin; hemophilus B conjugate vaccine; Hepatitis A virus vaccine inactivated; Hepatitis B virus vaccine inactivated; heparin sodium; indinavir sulfate; influenza virus vaccine; interleukin-2; interleukin-3; insulin-human; insulin lispro; insulin procine; insulin NPH; insulin aspart; insulin glargine; insulin detemir; interferon alpha; interferon beta; ipratropium bromide isofosfamide; Japanese encephalitis virus vaccine; lamivudine; leucovorin calcium; leuprolide acetate; levofloxacin; lincomycin and lincomycin derivatives; lobucavir; lomefloxacin; loracarbef; mannitol; measles virus vaccine; meningococcal vaccine; menotropins; mephenzolate bromide; mesalmine; methanamine; methotrexate; methscopolamine; metformin hydrochloride; metroprolol; mezocillin sodium; mivacurium chloride; mumps viral vaccine; nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate; neutontin; norfloxacin; octreotide acetate; ofloxacin; olpadronate; oxytocin; pamidronate disodium; pancuronium bromide; paroxetine; pefloxacin; pentamindine isethionate; pentostatin; pentoxifylline; periciclovir; pentagastrin; phentolamine mesylate; phenylalanine; physostigmine salicylate; plague vaccine; piperacillin sodium; platelet derived growth factor-human; pneumococcal vaccine polyvalent; poliovirus vaccine inactivated; poliovirus vaccine live (OPV); polymixin B sulfate; pralidoxine chloride; pramlintide; pregabalin; propofenone; propenthaline bromide; pyridostigmine bromide; rabies vaccine; residronate; ribavarin; rimantadine hydrochloride; rotavirus vaccine; salmetrol xinafoate; sincalide; small pox vaccine; solatol; somatostatin; sparfloxacin; spectinomycin; stavudine; streptokinase; streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutaline sulfate; thiopeta; ticarcillin; tiludronate; timolol; tissue type plasminogen activator; TNFR:Fc; TNK-tPA; trandolapril; trimetrexate gluconate; trospectinomycin; trovafloxacin; tubocurarine chloride; tumor necrosis factor; typhoid vaccine live; urea; urokinase; vancomycin; valaciclovir; valsartan; varicella virus vaccine live; vasopressin and vasopressin derivatives; vecoronium bromide; vinblastin; vincristine; vinorelbine; vitamin B12; warfarin sodium; yellow fever vaccine; zalcitabine; zanamavir; zolandronate; zidovudine; pharmaceutically acceptable salts, isomers and derivatives thereof; and mixtures thereof. A solid dosage for the oral administration of a therapeutically effective amount of a drug may be a tablet, multiparticulate tablet, dispersable tablet, controlled/ modified release / sustained release tablet, minitablet, dry syrup, pellet, suppository, pessary, dry free flowing powder, powder filled capsule. The main features of the process include, preparation of SMEDDS/SNEDDS by using defined proportions of oil(s), surfactant(s), and co-surfactant(s), adsorbing the SMEDDS/SNEDDS on the selected solid particle adsorbent to give free flowing powder, mixing with or without disintegerants, slugging of free flowing adsorbate, mixing with other tabletting excipients and compressing on tabletting machine. In order to illustrate the manner in which the above-recited and other advantages and objects of the invention are obtained, a more particular description of the invention briefly described above will be rendered by reference to specific embodiments thereof which are illustrated in the appended flow chart. Understanding that this flow chart depict only typical embodiments of the invention and are not therefore to be considered to be limiting of its scope. The invention will be described and explained with additional specificity and detail through the use of the accompanying flow chart. The flow chart for SMETs® processing is shown below. The SMEDDS/SNEDDS of the present invention forms oil in water micro emulsion when it is taken internally in which the oil is in the internal phase. Even though the present invention also relates to microemulsion system which may be oil in water micro emulsion in which the oil is in the internal phase, water in oil micro emulsion in which water is in the internal phase or bi continuous phase where the entire micro emulsion is designated as either w/o, or o/w or the multiple emulsion. Any non- toxic oils which can be used in the SMEDDS/SNEDDS including, but not limited to, mono-, di- and triglycerides, fatty acids and their esters and esters of propylene glycol or other polyols. The fatty acids and esters used as such or where they form part of a glyceride may be short chain, medium chain or long chain. The ingredients may be of vegetable or animal origin, synthetic or semi synthetic. The oils include, but are not limited to Aceituno oil, Almond oil Super Refined Almond Oil (Croda), Arachis oil, Babassu oil, Blackcurrant seed oil, Borage oil, Buffalo ground oil, Candlenut oil, Canola oil Lipex 108 (Abitec), Castor oil, Chinese vegetable tallow oil, Cocoa butter, Coconut oil Pureco 76 (Abitec), Coffee seed oil, Corn oil, Super Refined Corn Oil (Croda), Cottonseed oil, Super Refined Cottonseed Oil (Croda), Crambe oil, Cuphea species oil, Evening primrose oil, Grapeseed oil, Groundnut oil, Hemp seed oil, Illipe butter, Kapok seed oil, Linseed oil, Menhaden oil, Super Refined Menhaden Oil (Croda), Mowrah butter, Mustard seed oil, Oiticica oil, Olive oil, Super Refined Olive Oil (Croda), Palm oil, Palm kernel oil, Peanut oil, Super Refined Peanut Oil (Croda), Poppy seed oil, Rapeseed oil, Rice bran oil, Safflower oil, Super Refined Safflower Oil (Croda), Sal fat, Sesame oil, Super Refined Sesame Oil (Croda), Shark liver oil, Super Refined Shark Liver Oil (Croda), Shea nut oil, Soybean oil, Stillingia oil, Sunflower oil, Tall oil, Tea seed oil, Tobacco seed oil, Tung oil (China wood oil), Vernonia oil, Wheat germ oil, Super Refined Wheat Germ Oil (Croda), Hydrogenated castor oil, Hydrogenated coconut oil Pureco 100 (Abitec), Hydrogenated cottonseed oil Dritex C (Abitec), Hydrogenated palm oil Dritex PST (Abitec); Softisan 154 (Huls), Hydrogenated soybean oil Sterotex HM NF (Abitec), Dritex S (Abitec), Hydrogenated vegetable oil Sterotex NF (Abitec), Hydrokote M (Abitec), Hydrogenated cottonseed and castor oil Sterotex K (Abitec), Partially hydrogenated soybean oil Hydrokote AP5 (Abitec), Partially hydrogenated soy and cottonseed oil Apex B (Abitec), Glyceryl mono-, di-, tri-behenate, Compritol 888, Glyceryl tributyrate (Sigma), Glyceryl tricaproate (Sigma), Glyceryl tricaprylate (Sigma), Glyceryl tricaprate Captex 1000 (Abitec), Glyceryl triundecanoate Captex 8227 (Abitec), Glyceryl trilaurate (Sigma), Glyceryl trimyristate Dynasan 114 (Huls), Glyceryl tripalmitate Dynasan 116 (Huls), Glyceryl tristearate Dynasan 118 (Huls), Glyceryl triarchidate (Sigma), Glyceryl trimyristoleate (Sigma), Glyceryl tripalmitoleate (Sigma), Glyceryl trioleate (Sigma), Glyceryl trilinoleate (Sigma), Glyceryl trilinolenate (Sigma), Glyceryl tricaprylate/caprate Captex 300 (Abitec), Captex 355 (Abitec), Miglyol 810 (Huls), Miglyol 812 (Huls), Glyceryl tricaprylate/caprate/laurate Captex 350 (Abitec), Glyceryl tricaprylate/caprate/linoleate Captex 810 (Abitec), Miglyol 818 (Huls), Glyceryl tricaprylatekaprate/stearate Softisan 378 (Huls), (Larodan), Glyceryl tricaprylate/laurate/stearate (Larodan), Glyceryl 1,2-caprylate-3-linoleate (Larodan), Glyceryl l,2-caprate-3-stearate (Larodan), Glyceryl 1,2-laurate-3-myristate (Larodan), Glyceryl l,2-myristate-3-laurate (Larodan), Glyceryl 1,3-palmitate-2-butyrate (Larodan), Glyceryl l,3-stearate-2-caprate (Larodan), Glyceryl 1,2-linoleate-3-caprylate (Larodan), Fractionated triglycerides, modified triglycerides, synthetic triglycerides, and mixtures of triglycerides are also within the scope of the invention. Non toxic surfactants can be used in the SMEDDS/SNEDDS including, but not limited to alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof. 20 esp@cenet claims view \ ^ ^Q Page 1 of 3 Claims of US6280770 We claim: 1. A microemulsion composition iivthe\form bf a free-flowing, compressible powder, comprising: an admixture of a drug-containing microemulsion and a solid particle adsorbent; wherein said microemulsion is adsorbed on said solid particle adsorbent and forms a free-flowing, compressible powder. 2. The microemulsion composition of claim 1, wherein said drug-containing microemulsion is an oil-in-water microemulsion. 3. The microemulsion composition of claim 1 wherein said drug-containing microemulsion is a water-in-oil microemulsion. 4. The microemulsion composition of claim 1, wherein said drug-containing microemulsion is a bicontinuous phase microemulsion. 5. The microemulsion composition of claim 1, wherein said drug-containing microemulsion is a self-microemulsifying drug delivery system which converts to an oil-in-water microemulsion in vivo. 6. The microemulsion composition of claim 1, wherein said solid particle adsorbent is selected from the group consisting of kaolin, bentonite, hectorite, colloidal magnesium-aluminum silicate, silicon dioxide, magnesium trisilicate, aluminum hydroxide, magnesium hydroxide, magnesium oxide and talc. 7. The microemulsion composition of claim 1, wherein the drug-containing microemulsion is a drug that displays poor bioavailability in the gastrointestinal tract of a mammal, when said drug is administered in a form other than said microemulsion. 8. The microemulsion composition of claim 1, wherein the drug in said drug-containing microemulsion includes a drug selected from the group consisting of biological molecules. 9. The microemulsion composition of claim 1, wherein said drug-containing microemulsion includes a drug selected from the group consisting of drugs and nutritional supplements. 10. The microemulsion composition of claim 1, wherein said drug-containing microemulsion includes a drug selected from the group consisting of acyclovir; auranofin; bretylium; cytarabine; doxepin; doxorubicin; hydralazine; ketamine; labetalol; mercaptopur; methyldopa; nalbuphine; nalozone; pentoxifyll; pridostigm; terbutaline; verapamil; buserelin; calcitonin; cyclosporin; and oxytocin. esp@cenet claims view Page 2 of 3 11. A microemulsion composition in the form of a free-flowing, compressible powder, comprising: an admixture of a drug-containing self-microemulsifying drug delivery system and a solid particle adsorbent; wherein said drug-containing self-microemulsifying drug delivery system is adsorbed on said solid particle adsorbent and forms a free-flowing, compressible powder. 12. A solid dosage for the oral administration of a therapeutically effective amount of a drug, comprising: an admixture of a drug-containing microemulsion and a solid particle adsorbent; wherein said microemulsion is adsorbed on said solid particle adsorbent and forms a free-flowing, compressible powder. 13. The solid dosage form of claim 12, wherein said solid dosage form is a tablet. 14. The solid dosage form of claim 12, wherein said solid dosage form is a pellet. 15. The solid dosage form of claim 12, wherein said solid dosage form is a multiparticulate. 16. The solid dosage form of claim 12, wherein said solid dosage form is a minitablet. 17. The solid dosage form of claim 12, wherein said solid dosage form further comprises a bioadhesive. 18. The solid dosage form of claim 12, wherein said solid dosage form further comprises an enteric coating maintained over said dosage form; wherein said enteric coating prevents the release of said drug-containing microemulsion until a time at which said dosage form reaches a target area following oral administration. 19. The solid dosage form of claim 12, wherein said solid dosage form further comprises at least one effervescent agent. 20. The solid dosage form of claim 12, further comprising at least one disintegration agent; wherein said disintegration agent causes rapid dispersion of said drug-containing microemulsion to a target area following oral administration. 21. The solid dosage form of claim 12, further comprising a Ph adjusting substance. 22. A method for preparing a microemulsion, comprising the steps of: preparing a drug-containing microemulsion; converting said drug-containing microemulsion into a free-flowing, compressible powder by admixing said drug-containing microemulsion with a esp@cenet claims view Page 3 of 3 solid particle adsorbent. 23. A method for preparing a solid dosage for the oral administration of a therapeutically effective amount of a drug, comprising the steps of: preparing a drug-containing microemulsion; converting said drug-containing microemulsion into a free flowing compressible powder by admixing said drug-containing microemulsion with a solid particle adsorbent; compressing said free-flowing, compressible powder into a solid dosage form. 24. A stable microemulsion composition which is the product of the process of: preparing a drug-containing microemulsion; converting said drug-containing microemulsion into a free-flowing, compressible powder by admixing said drug-containing microemulsion with a solid particulate adsorbent. 25. A method for delivering a drug to a mammal comprising the steps of: preparing a drug-containing microemulsion; converting said drug-containing microemulsion into a free-flowing, compressible powder by admixing said drug-containing microemulsion with a solid particle adsorbent; orally administering said free, flowing compressible powder to a mammal. 26. The microemulsion composition of claim 8, wherein the biological molecules comprise peptides, proteins and oligonucleotides.

Full Text

THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFIC A TION
[See section 10; rule 13]
PROCESS FOR PREPARATION OF SELF MICRO/NANO EMULSIFYING SYSTEMS AND COMPOSITIONS THEREOF"

(a) PATRAVALE VANDANA BHARAT
(b) University Institute of Chemical Technology, Nathalal Parikh Marg, Matunga, Mumbai-400 019. India
(c) Indian National

(a) KHAN IMRAN AHMAD
(b) University Institute of Chemical Technology, Nathalal Parikh Marg, Matunga, Mumbai-400 019. India
(c) Indian National
The following specification describes the nature of this invention and the manner in which it is to be performed

1 O92lSt,l2004
1 I OCT 2Q0A

FIELD OF INVENTION
This invention relates to process for preparation of self emulsifying drug delivery systems for active ingredients including drugs and nutritional supplements, cosmeceuticals, and diagnostic agents. In particular, the present invention provides compositions and dosage forms comprising self emulsifying drug delivery system (SEDDS), self micro emulsifying drug delivery system (SMEDDS) having globule size less than 1000 nm, self nano emulsifying drug delivery system (SNEDDS) having globule size less than 100 nm and micro emulsions incorporated with the active(s) in solid dosage forms to enhance bioavailability and minimize the fluctuation in bioavailability due to type of food, for poorly soluble (drug showing dissolution rate limited bioavailability) as well as highly water soluble (drug showing permeation rate limited bioavailability) drugs. This invention also relates to self emulsifying tablets (SETs), self micro emulsifying tablets (SMETs®) and self nano emulsifying tablets (SNETs) with a good hardness.
Background of the invention
Hydrophobic active ingredients such as progesterone, cyclosporine, itraconazole and glyburide present delivery challenges due to their poor aqueous solubility and slow dissolution rate and thus poor bioavailability, whilst other drug have good bioavailability but their solubility varies depending on the nature of the food e.g. in presence of fatty meal their dissolution rate get increased resulting in improved bioavailability and under influence of normal meal they remains insoluble resulting in poor bioavailability. These types of fluctuations in bioavailability can be well handled by giving the drug in solublized form either as microemulsions or as SEDDS, SMEDDS and SNEDDS.
Several commercial products of these hydrophobic drugs are available based on different technologies so as to enhance their in vivo performance. One approach is size reduction by micronization such as in Prometrium (micronized progesterone) and Micronase (micronized glyburide). Other approaches include size reduction in emulsion formulations such as in Sandimmune (cyclosporine emulsion) and Neoral (cyclosporine

microemulsion). These approaches suffer from several disadvantages. Micronization/ nanonization present processing and stability challenges as well as dissolution limitations, since the micronized/ nanosized drug still possesses a high degree of crystallinity. Liquid formulations present drug precipitation and packaging challenges mainly due to solvent evaporation. Moreover, non-solid formulations are more prone to chemical instability and capsule-shell incompatibility leading to the possibility of leakage upon storage and even during handling.
For hydrophilic active ingredients, the formulation challenges are different. Although these compounds are readily soluble in the aqueous gastrointestinal environment, they are poorly absorbed due to poor membrane permeability and/or enzymatic degradation. Surfactants and lipophilic additives have been reported to improve membrane permeability; e.g., Y.V. Rama Prasad et.al.in "Evaluation of Oral Formulations of Gentamicin Containing Labrasol in Beagle Dogs" International Journal of Pharmaceutics 268 (2003) 13-21; indicated that bioavailability of such highly hydrophilic drugs can be improved by using some^jo-enhancejrs^Labrasol in this case. These may be given as microemulsions or SMEDDS. Most solid dosage forms of hydrophilic active ingredients exhibit poor or no absorption of the active. Moreover, these non-solid formulations suffer from the disadvantages of chemical instability, leakage and capsule shell incompatibility as discussed above.
In order to eliminate or reduce these problems associated with liquid formulation the present invention is focused on development of SEDDS, SMEDDS or SNEDDS as tablets referred as Self Emulsifying, Micro-Emulsifying, Nano Emulsifying Tablets (SETs, SMETs®, SNETs). These tablets (SETs, SMETs®, SNETs) possess following advantages- they are convenient and easy to handle and more robust, stable dosage; better compliance for patients having allergy to capsule shells or who do not prefer to take capsules. Furthermore, oral administration of peptides is feasible. Also these tablets (SETs, SMETs®, SNETs) have capacity to reduce/ eliminate the localized release of drug and surfactant in the intestinal mucosa which may cause the gastrointestinal mucosal

damage and may have capacity to release drug faster as compared to its capsule counterpart i.e. SMEDDS.
Tablets are uncoated solid dosage forms that are produced by compression of solid tabletting ingredients between upper and lower punches in definite boundary of die cavity or by molding. Tablets contain not only medicaments but also other excipients (inert) which act as filler, binder, disintegerants, glidants, coloring agents and flavoring agents. These inactive substances do not affect the dosage form therapeutically but affect the mechanical and aesthetic properties which are the most important requirement in the success of dosage form along with its therapeutic value.
Design of tablet dosage form needs powder or granules which have to be compacted in the form of tablet, the resulting tablet should have sufficient strength to maintain its shape during post formulation steps till it is being ingested.
This led us to process self emulsifying tablets, self micro emulsifying tablets and self nano emulsifying tablets with a good hardness which consists of lipid based drug delivery system utilizing anhydrous micro emulsion (SEDDS, SMEDDS & SNEDDS) system and further adsorbed on to solid particulate adsorbent and formulated into solid dosage form. The compositions and dosage forms of the present invention have capacity to improve the bioavailability of a wide range of drugs including drugs that are known or suspected of having poor bioavailability.
Micro emulsions are clear, thermodynamically stable solutions that generally contain water, surfactant, and oil. Micro emulsions differ from emulsions in that the dispersed phase consists of globules less than 100 nm and more particularly about 30-60 nm in diameter. The difference between coarse (macro) emulsions and micro emulsions is not only the size of the globules but also the ease of dispersion. Micro emulsions do not separate on standing where as emulsions will separate.

SMEDDS are a novel system developed by.-.Gattefosse, based upon specific blends of excipients. SMEDDS comprises of a surfactant, a co surfactant, a_ lipid phase and an active _compound. These systems are custom designed for each active molecule. On dilution, SMEDDS spontaneously convert into optically clear, thermodynamically stable micro emulsions which contain the drug in molecular dispersion. SMEDDS can be filled into hard gelatin capsule and delivered orally.
I US patent 5993858 discloses the method and formulation for increasing the bio availability of poorly water soluble drugs which comprises an emulsion and includes oil or other lipid material, a surfactant, and a hydrophilic co surfactant.
) WOOO 16744 discloses pharmaceutical solution preparation containing prostaglandin El for the treatment of erectile dysfunction, which is prepared into a form of microemulsion preconcentrate (SEDDS formulation). This preparation is prepared by dispersing or dissolving a drug into a liquid mixture of oil, surfactant and co surfactant.
Eutectic-self-nanoemulsified drug delivery systems formulated from polyoxyl 35 castor oil (cremphor), medium chain mono and diglycerides (capmul), essensial oils, and a pharmacologically effective drug was disclosed in US2003147927.
WO03017986 describes the SMEDDS compositions containing Itraconazole with a greatly increased bioavailability and their preparation methods.
^ The nearest prior art to our invention is US patent 6,280,770 entitled "Microemulsions as Solid Dosage Forms for Oral Administration" which discusses the development of tablet from the liquid microemulsion to improve the rate and/ or extent of absorption. The patent further describes in their invention figure- 1 wherein tablet contains core containing emulsion concentrate adsorbed on the powder and an optional compression coated effervescent layer and an enteric coating layer. In figure-2 of the same patent, schematic preparation of a soft tablet consisting of agglomerates of adsorbent containing adsorbed microemulsion which are coated with an enteric material is shown. Whilst in
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detailed description of the invention, the inventors had mentioned in granulation procedure that dry__granulation may be achieved through slugging or chilsonation. But neither have they claimed this point nor they have mentioned at what step the slugging is required. On our trials, the direct compression of mixture of adsorbate and tabletting ^excpients failed to yield structurally strong tablets. Slugging of adsorbate-inert excipients mixture followed by direct compression also fails to yield structurally strong tablets. Slugging at an intermediate stage was the most critical part governing structurally strong tablets. During description of hardness, inventors of the US patent no 6,280,770 have mentioned that tablet hardness is preferably between about 5N and about 5 ON and more preferably between about 5N and 35N. The tablet having hardness up to 50 N which is the upper limit of this range is really a soft tablet and may break during the packaging or even during the shipping. Thus, an easy and suitable method circumventing coating was developed for tabletting which was able to give sufficiently hard tablets having capacity) to withstand the stress during packing and shipping.
Direct compression of adsorbate-inert excipients mixture does not give structurally strong tablets. Slugging at an intermediate stage is the most critical part to yield structurally strong tablets. Our invention starts from the draw back of the earlier prior art which yields tablets with poor hardness utilizing complicated procedures as indicated in figure 1. Our invention relates to adsorbates of SMEDDS with or without disintegerants, made into slugs using slugging and then tabletted through direct compression technique mixed with additives especially hardening agents. This process results in sufficiently hard tablets.
The present invention also relates to pharmaceutical dosage forms of particularly insoluble/ soluble drugs that display poor bioavailability and slow absorption in the gastro intestinal system. The drugs incorporated with SMEDDS adsorbed on the solid particulate adsorbent may further be formulated in to dosage forms either before or after chilsonation.
6

Objective of the Invention
It is an object of the present invention to provide a process for preparation of the self emulsifying systems.
It is another object of the invention is to provide solid pharmaceutical compositions having active ingredients in a rapid dissolvable and more solubilized state therein.
A further object of the invention is to provide solid pharmaceutical compositions having more rapid dissolution upon administration to a patient.
Yet another object of the invention is to provide solid pharmaceutical compositions capable of delivering a wide variety of pharmaceutical active ingredients.
It is another object of the invention, to provide solid pharmaceutical compositions capable of improving the absorption and/or bioavailability of a pharmaceutical active ingredient.
Yet another object of the invention is to provide solid pharmaceutical compositions capable of reducing the fluctuation absorption and/or bioavailability of a pharmaceutical active ingredient.
A further object of the invention is to provide solid pharmaceutical compositions having better protection of the upper gastrointestinal tract from untoward effects of the active ingredient.
Another object of the present invention is to prepare SMEDDS/SNEDDS composition in the form of free flowing compressible powder.
Further object of the present invention is granulation by slugging of the free flowing adsorbate or by wet granulation technique and the compression into tablet after mixing with other directly compressible tabletting excipients, resulting in harder tablets.

In accordance with these and other objects, the present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients contained therein or separately administered and will become more fully apparent from the following description and appended claims, or may be learned by the practice of the invention as set forth herein after.
Summary of the invention
This invention discloses a process for preparation of self emulsifying drug delivery systems for active ingredients including drugs and nutritional supplements, cosmeceuticals, and diagnostic agents. More particularly the present invention discloses compositions and dosage form comprising self emulsifying drug delivery systems, which comprise a lipid based drug delivery system, utilizing anhydrous micro emulsion and further adsorbed on to solid adsorbent particles, made slugs, mixing with other tabletting excipients and formulated into solid dosage form under direct compression technique. The compositions and dosage forms of the present invention have capacity to improve the bio availability of a wide range of drugs, including drugs that are known or suspected of having poor bioavailability.
'The process for preparation of self micro emulsifying tablet (SMETs) composition in the form of a free flowing compressible powder wherein the said process comprises,
j preparing self micro emulsifying drug delivery system (SMEDDS or SNEDDS) of active
moiety by using defined proportion of oils surfactants, and co-surfactants; adsorbing the
SMEDDS/SNEDDS on a selected adsorbent to give free flowing powder; slugging of
free flowing absorbate; mixing with other tabletting excipients and compressing on
I
tabletting machine.
The drug containing system on dilution with water forms oil-in-water, water-in-oil or bicontinuous-phase microemulsion in vivo.

The solid particle adsorbent is selected from the group consisting of but not limited to aluminum hydroxide, bentonite, hectorite, colloidal magnesium-aluminum silicate, kaolin, magnesium tri silicate, magnesium hydroxide, magnesium oxide, silicon dioxide talc and hydrophobic starch.
The SMEDDS/SNEDDS adsorbate is compacted on heavy duty tablet machines or passed through roller compactor / chilsonator either alone or intimately mixed with disintegerants to form the slug which is ground to a uniform size and compressed into the finished tablet after mixing with tabletting excipients.
The SMETs/SNETs can be prepared by direct compression method or wet granulation method using a solution of polymer, starch paste or pre-gelatinized starch or any other binding agent.
The tabletting excipients refer to mixing with conventional excipients.
Drug containing system is a microemulsion, Self Micro Emulsifying Drug Delivery
Systems or self nano emulsifying drug delivery system (SNEDDS).
The compressible vehicle is blended with the slugged and powdered SMEDDS/SNEDDS adsorbate, and if necessary (optionally), with a lubricant and a disintegrant, and then the blend is compressed into a tablet.
The compressible vehicle belongs to conventional tabletting agents and here acts as hardening agents for SMETs/SNETs.
The compressible vehicle is selected from microcrystalline cellulose, calcium phosphate, lactose, dextrose and mannitol.
The composition or dosage form is self emulsifying tablets (SETs), self micro emulsifying tablets (SMETs) and self nano emulsifying tablets (SNETs).
9

The dosage forms may be a conventional tablet, dispersible tablet, multi-particulate tablet, a suppository or a pessary.
The dosage form comprises the amount of diluents is about 10% to 90% of the tablet weight, more preferably 40 to 60% of the tablet weight.
The dosage form comprises the amount of binder is about 1% to 25% of tablet, more preferably 4% to 10% of the tablet weight.
The dosage form comprises the amount of lubricants is about 0.25% to 10% of the tablet weight, more preferably 0.5 to about 3%.
The dosage form comprises the amount of disintigrants is about 2 to 20%) of the tablet weight, more preferably 5 to 15% of the tablet weight.
The drug containing microemulsion is a drug that displays poor bioavailability in the gastrointestinal tract of a mammal or shows fluctuation in bioavailability with fed and non-fed condition, when said drug is administered in a form other than said microemulsion.
The composition contains the active ingredient may belongs to group consisting of biological molecules; drugs and nutritional supplements; nifedipine, nimodipine, amlodipine, flucanazole, ketoconazole, itraconazole, celecoxib, loratadine, desloratadine, cetrizine, valdecoxib, ritonavire, acyclovir, auranofin, bretylium, cytarabine, doxepin, doxorubicin, hydrolazine, ketamine, labetalol, mercaptopur, methyldopa, nalbuphine, nalozone, pentoxifylline, pridostigm, terbutaline, verapamil, buserlin, calcitonin, cyclosporine, and oxytocin; any drug of synthetic origin, natural origin, protein, peptide and oligonucleotide, or any drug suspected to have poor bioavailability; and any drug of synthetic origin, natural origin, protein, peptide and oligonucleotide, the bioavailability of which fluctuates on fed and non fed condition.

The solid dosage forms for the oral administration with a therapeutically effective amount of a drug may be a tablet; coated tablet; dispersible tablet; Modified extended/controlled release tablet; Pellet; Multi-particulate tablet; Minitablet; Suppository/ Pessary; Dry free flowing powder; and Dry syrup.
The solid dosage form may further comprises of a mucoadhesive agent; release retardant polymer which ultimately led to releasing the drug in pulsatile or controlled manner in the form of microemulsion; enteric polymer which over coats the dosage form, wherein said drug does not release until it reaches the GI tract; pH adjusting substance; effervescent agent; low density material for buoyant tablet; high density materials for high density tablet; disintegrating agent, wherein said disintegrating agent causes rapid dispersion of said drug- containing microemulsion to a target area following oral administration; and sweetener and flavor to give palatable form.
The SMETs (self micro emulsifying tablets) may also be SETs (self emulsifying tablets) or SNETs (self nano emulsifying tablets).
One aspect of the invention is administration of the homogenous micro emulsion solution that can be directly filled into soft/ hard gelatin capsule.
In another aspect of the invention, the SMEDDS/SNEDDS adsorbed on solid particle adsorbent in the form of free flowing powder can be administered even after or before slugging/chilsonation and can be filled in to hard gelatin capsule/ sachet as powder.
In another aspect of invention, the adsorbed SMEDDS/SNEDDS in the free flowing powder can be converted into pellets using extrusion spherunization.
In another aspect of invention, the spherunized pellets can be mixed with cushioning agent and compressed into multiparticulate tablet.

In a further aspect of invention, the administration of the drug can be a suppository/ pessary containing SMEDDS/SNEDDS prepared using special shaped punches on tabletting machine.
In a further aspect of invention, the administration of the drug can be a solid dosage form of tablet containing SMEDDS with hardness of 20 to 200 N, more preferably 100 to 125 N, which inside gastrointestinal tract give microemulsion on disintegration of tablet.
In other aspect of invention, the drug can be administered as a dispersible tablet form which contains SMEDDS with a hardness of 20 to 200 N, more preferably 75 to 100 N, which on disintegration gives microemulsion.
In other aspect of invention, the administration of the drug can be controlled release/ modified release/ extended release tablet containing SMEDDS, which inside gastrointestinal tract releases the drug in controlled manner and give microemulsion.
Detailed description
According to the present invention a process is provided to prepare self micro emulsifying tablet dosage forms (SMETs®) which comprise of lipid based drug delivery system utilizing anhydrous micro emulsion and further adsorbed on to solid adsorbent particles mixed with or without disintegerants, made into slugs, mixing with other directly compressible tabletting excipients and formulated into solid dosage form using direct compression technique. The compositions and dosage forms of the present invention have capacity to improve the bio availability of a wide range of drugs, including drugs that are known or suspected of having poor bioavailability. Any drug of synthetic origin, natural origin, protein, peptide and oligonucleotide, the bioavailability of which fluctuates on fed and non fed condition.
Active ingredients are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial

agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti¬migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, .beta.-Blockers, cardiac inotropic agents, corticosteroids, diuretics, antiparkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2 inhibitors, leucotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non¬essential fatty acids, and mixtures thereof.
In one embodiment, the active ingredient is hydrophobic. Hydrophobic active ingredients are compounds with little or no water solubility. Intrinsic water solubilities (i.e., water solubility of the unionized form) for hydrophobic active ingredients are less than about 1% by weight, and typically less than about 0.1% or 0.01% by weight. In a particular aspect of this embodiment, the active ingredient is a hydrophobic drug. In other particular aspects, the active ingredient is a nutrient, a cosmeceutical, a diagnostic agent or a nutritional agent.
Specific, non-limiting examples of suitable hydrophobic active ingredients are: acutretin, albendazole, albuterol, aminogluthemide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethsone, benezepril, benzonatate, betamethasone, bicalutanide, budesonide, bupropion, busulphan, butenafme, calcifediol, calciprotiene, calcitriol, camptothecan, candesartan, capsaicin, carbamezepine, carotenes, celecoxib, cerivistatin, cetrizine, chlorpheniramine, cholecalciferol, cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene, clomipramine, clopidrogel, codeine, coenzyme Q10, cyclobenzaprine, cyclosporine, danazol, dantrolene, dexchlopheniramine, diclofenac, dicoumarol, digoxin, dihydro epiandrosterone, dihydroergotamine,

dihydrotachysterol, dirithromycin, donepezil, efavirenz, eposartan, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, flucanazole, flurbiprofen, fluvastatin, fosphenytion, frovatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, glymepride, griseofulvin, halofantrine, ibuprofen, irbesartan, irinotecan, isosorbide dinitrate isotreinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lanosprazole, leflunomide, lisinopril, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone, mefepristone, mefloquine, megesterol acetate, methadone, methoxsalen, metronidazole, metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone, montelukast, nabumetone, nalbuphine, naratiptan, nelfmavir, nifedipine, nilsolidipine, nilutanide, nitrofurantoin, nizatidine, omeprazole, oprevelkin, osteradiol, oxaprozin, paclitaxel, paricalcitol, paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone, probucol, progesterone, pseudo-ephedrine, pyridostigmine, rabeprazole, raloxifene, refocoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosigiltazone, saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine, terzosin, tetrahydrocannabinol, tiagabine, ticlidopine, tirofibran, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine, vertoporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, Zolpidem, and zopiclone. Of course, salts, isomers and derivatives of the above-listed hydrophobic active ingredients may also be used, as well as mixtures.
In another embodiment, the active ingredient is hydrophilic. Amphiphilic compounds are also included within the class of hydrophilic active ingredients. Apparent water solubilities for hydrophilic active ingredients are greater than about 0.1% by weight, and typically greater than about 1% by weight. In a particular aspect of this embodiment, the hydrophilic active ingredient is a hydrophilic drug. In other particular aspects, the hydrophilic active ingredient is a cosmeceutical, a diagnostic agent, or a nutritional agent.

Specific, non-limiting examples of suitable hydrophilic active ingredients include: acarbose; acyclovir; acetyl cysteine; acetylcholine chloride; alatrofloxacin; alendronate; alglucerase; amantadine hydrochloride; ambenomium; amifostine; amiloride hydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor (human); antihemophilic factor (porcine); antihemophilic factor (recombinant); aprotinin; asparaginase; atenolol; atracurium besylate; atropine; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladona; bepridil hydrochloride; bleomycin sulfate; calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate; cefamandole nafate; cefazolin sodium; cefepime hydrochloride; cefixime; cefonicid sodium; cefoperazone; cefotetan disodium; cefotoxime; cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin; cephapirin sodium; cholera vaccine; chrionic gonadotropin; cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin and clindamycin derivatives; ciprofloxacin; clondronate; colistimethate sodium; colistin sulfate; cortocotropin; cosyntropin; cromalyn sodium; cytarabine; daltaperin sodium; danaproid; deferoxamine; denileukin diftitox; desmopressin; diatrizoate megluamine and diatrizoate sodium; dicyclomine; didanosine; dirithromycin; dopamine hydrochloride; domase alpha; doxacurium chloride; doxorubicin; editronate disodium; elanaprilat; enkephalin; enoxacin; enoxaprin sodium; ephedrine; epinephrine; epoetin alpha; erythromycin; esmol hydrochloride; factor IX; famiciclovir; fludarabine; fluoxetine; foscarnet sodium; ganciclovir; granulocyte colony stimulating factor; granulocyte-macrophage stimulating factor; growth hormones- recombinant human; growth hormone-bovine; gentamycin; glucagon; glycopyrolate; gonadotropin releasing hormone and synthetic analogs thereof; GnRH; gonadorelin; grepafloxacin; hemophilus B conjugate vaccine; Hepatitis A virus vaccine inactivated; Hepatitis B virus vaccine inactivated; heparin sodium; indinavir sulfate; influenza virus vaccine; interleukin-2; interleukin-3; insulin-human; insulin lispro; insulin procine; insulin NPH; insulin aspart; insulin glargine; insulin detemir; interferon alpha; interferon beta; ipratropium bromide isofosfamide; Japanese encephalitis virus vaccine; lamivudine; leucovorin calcium; leuprolide acetate; levofloxacin; lincomycin and lincomycin derivatives; lobucavir; lomefloxacin; loracarbef; mannitol; measles virus vaccine; meningococcal vaccine; menotropins; mephenzolate bromide; mesalmine; methanamine; methotrexate;

methscopolamine; metformin hydrochloride; metroprolol; mezocillin sodium; mivacurium chloride; mumps viral vaccine; nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate; neutontin; norfloxacin; octreotide acetate; ofloxacin; olpadronate; oxytocin; pamidronate disodium; pancuronium bromide; paroxetine; pefloxacin; pentamindine isethionate; pentostatin; pentoxifylline; periciclovir; pentagastrin; phentolamine mesylate; phenylalanine; physostigmine salicylate; plague vaccine; piperacillin sodium; platelet derived growth factor-human; pneumococcal vaccine polyvalent; poliovirus vaccine inactivated; poliovirus vaccine live (OPV); polymixin B sulfate; pralidoxine chloride; pramlintide; pregabalin; propofenone; propenthaline bromide; pyridostigmine bromide; rabies vaccine; residronate; ribavarin; rimantadine hydrochloride; rotavirus vaccine; salmetrol xinafoate; sincalide; small pox vaccine; solatol; somatostatin; sparfloxacin; spectinomycin; stavudine; streptokinase; streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutaline sulfate; thiopeta; ticarcillin; tiludronate; timolol; tissue type plasminogen activator; TNFR:Fc; TNK-tPA; trandolapril; trimetrexate gluconate; trospectinomycin; trovafloxacin; tubocurarine chloride; tumor necrosis factor; typhoid vaccine live; urea; urokinase; vancomycin; valaciclovir; valsartan; varicella virus vaccine live; vasopressin and vasopressin derivatives; vecoronium bromide; vinblastin; vincristine; vinorelbine; vitamin B12; warfarin sodium; yellow fever vaccine; zalcitabine; zanamavir; zolandronate; zidovudine; pharmaceutically acceptable salts, isomers and derivatives thereof; and mixtures thereof.
A solid dosage for the oral administration of a therapeutically effective amount of a drug may be a tablet, multiparticulate tablet, dispersable tablet, controlled/ modified release / sustained release tablet, minitablet, dry syrup, pellet, suppository, pessary, dry free flowing powder, powder filled capsule.
The main features of the process include, preparation of SMEDDS/SNEDDS by using defined proportions of oil(s), surfactant(s), and co-surfactant(s), adsorbing the SMEDDS/SNEDDS on the selected solid particle adsorbent to give free flowing powder,

mixing with or without disintegerants, slugging of free flowing adsorbate, mixing with other tabletting excipients and compressing on tabletting machine.
In order to illustrate the manner in which the above-recited and other advantages and objects of the invention are obtained, a more particular description of the invention briefly described above will be rendered by reference to specific embodiments thereof which are illustrated in the appended flow chart. Understanding that this flow chart depict only typical embodiments of the invention and are not therefore to be considered to be limiting of its scope. The invention will be described and explained with additional specificity and detail through the use of the accompanying flow chart.
The flow chart for SMETs® processing is shown below.

The SMEDDS/SNEDDS of the present invention forms oil in water micro emulsion when it is taken internally in which the oil is in the internal phase. Even though the present invention also relates to microemulsion system which may be oil in water micro emulsion in which the oil is in the internal phase, water in oil micro emulsion in which water is in the internal phase or bi continuous phase where the entire micro emulsion is designated as either w/o, or o/w or the multiple emulsion.
Any non- toxic oils which can be used in the SMEDDS/SNEDDS including, but not limited to, mono-, di- and triglycerides, fatty acids and their esters and esters of propylene glycol or other polyols. The fatty acids and esters used as such or where they form part of a glyceride may be short chain, medium chain or long chain. The ingredients may be of vegetable or animal origin, synthetic or semi synthetic. The oils include, but are not limited to Aceituno oil, Almond oil Super Refined Almond Oil (Croda), Arachis oil, Babassu oil, Blackcurrant seed oil, Borage oil, Buffalo ground oil, Candlenut oil, Canola oil Lipex 108 (Abitec), Castor oil, Chinese vegetable tallow oil, Cocoa butter, Coconut oil Pureco 76 (Abitec), Coffee seed oil, Corn oil, Super Refined Corn Oil (Croda), Cottonseed oil, Super Refined Cottonseed Oil (Croda), Crambe oil, Cuphea species oil, Evening primrose oil, Grapeseed oil, Groundnut oil, Hemp seed oil, Illipe butter, Kapok seed oil, Linseed oil, Menhaden oil, Super Refined Menhaden Oil (Croda), Mowrah butter, Mustard seed oil, Oiticica oil, Olive oil, Super Refined Olive Oil (Croda), Palm oil, Palm kernel oil, Peanut oil, Super Refined Peanut Oil (Croda), Poppy seed oil, Rapeseed oil, Rice bran oil, Safflower oil, Super Refined Safflower Oil (Croda), Sal fat, Sesame oil, Super Refined Sesame Oil (Croda), Shark liver oil, Super Refined Shark Liver Oil (Croda), Shea nut oil, Soybean oil, Stillingia oil, Sunflower oil, Tall oil, Tea seed oil, Tobacco seed oil, Tung oil (China wood oil), Vernonia oil, Wheat germ oil, Super Refined Wheat Germ Oil (Croda), Hydrogenated castor oil, Hydrogenated coconut oil Pureco 100 (Abitec), Hydrogenated cottonseed oil Dritex C (Abitec), Hydrogenated palm oil Dritex PST (Abitec); Softisan 154 (Huls), Hydrogenated soybean oil Sterotex HM NF (Abitec), Dritex S (Abitec), Hydrogenated vegetable oil Sterotex NF (Abitec), Hydrokote M (Abitec), Hydrogenated cottonseed and castor oil Sterotex K (Abitec), Partially hydrogenated soybean oil Hydrokote AP5 (Abitec),

Partially hydrogenated soy and cottonseed oil Apex B (Abitec), Glyceryl mono-, di-, tri-behenate, Compritol 888, Glyceryl tributyrate (Sigma), Glyceryl tricaproate (Sigma), Glyceryl tricaprylate (Sigma), Glyceryl tricaprate Captex 1000 (Abitec), Glyceryl triundecanoate Captex 8227 (Abitec), Glyceryl trilaurate (Sigma), Glyceryl trimyristate Dynasan 114 (Huls), Glyceryl tripalmitate Dynasan 116 (Huls), Glyceryl tristearate Dynasan 118 (Huls), Glyceryl triarchidate (Sigma), Glyceryl trimyristoleate (Sigma), Glyceryl tripalmitoleate (Sigma), Glyceryl trioleate (Sigma), Glyceryl trilinoleate (Sigma), Glyceryl trilinolenate (Sigma), Glyceryl tricaprylate/caprate Captex 300 (Abitec), Captex 355 (Abitec), Miglyol 810 (Huls), Miglyol 812 (Huls), Glyceryl tricaprylate/caprate/laurate Captex 350 (Abitec), Glyceryl tricaprylate/caprate/linoleate Captex 810 (Abitec), Miglyol 818 (Huls), Glyceryl tricaprylatekaprate/stearate Softisan 378 (Huls), (Larodan), Glyceryl tricaprylate/laurate/stearate (Larodan), Glyceryl 1,2-caprylate-3-linoleate (Larodan), Glyceryl l,2-caprate-3-stearate (Larodan), Glyceryl 1,2-laurate-3-myristate (Larodan), Glyceryl l,2-myristate-3-laurate (Larodan), Glyceryl 1,3-palmitate-2-butyrate (Larodan), Glyceryl l,3-stearate-2-caprate (Larodan), Glyceryl 1,2-linoleate-3-caprylate (Larodan), Fractionated triglycerides, modified triglycerides, synthetic triglycerides, and mixtures of triglycerides are also within the scope of the invention.
Non toxic surfactants can be used in the SMEDDS/SNEDDS including, but not limited to alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof.
20

esp@cenet claims view \ ^ ^Q Page 1 of 3
Claims of US6280770
We claim:
1. A microemulsion composition iivthe\form bf a free-flowing, compressible powder, comprising: an admixture of a drug-containing microemulsion and a solid particle adsorbent; wherein said microemulsion is adsorbed on said solid particle adsorbent and forms a free-flowing, compressible powder.
2. The microemulsion composition of claim 1, wherein said drug-containing microemulsion is an oil-in-water microemulsion.
3. The microemulsion composition of claim 1 wherein said drug-containing microemulsion is a water-in-oil microemulsion.
4. The microemulsion composition of claim 1, wherein said drug-containing microemulsion is a bicontinuous phase microemulsion.
5. The microemulsion composition of claim 1, wherein said drug-containing microemulsion is a self-microemulsifying drug delivery system which converts to an oil-in-water microemulsion in vivo.
6. The microemulsion composition of claim 1, wherein said solid particle adsorbent is selected from the group consisting of kaolin, bentonite, hectorite, colloidal magnesium-aluminum silicate, silicon dioxide, magnesium trisilicate, aluminum hydroxide, magnesium hydroxide, magnesium oxide and talc.
7. The microemulsion composition of claim 1, wherein the drug-containing microemulsion is a drug that displays poor bioavailability in the gastrointestinal tract of a mammal, when said drug is administered in a form other than said microemulsion.
8. The microemulsion composition of claim 1, wherein the drug in said drug-containing microemulsion includes a drug selected from the group consisting of biological molecules.
9. The microemulsion composition of claim 1, wherein said drug-containing microemulsion includes a drug selected from the group consisting of drugs and nutritional supplements.
10. The microemulsion composition of claim 1, wherein said drug-containing
microemulsion includes a drug selected from the group consisting of
acyclovir; auranofin; bretylium; cytarabine; doxepin; doxorubicin; hydralazine;
ketamine; labetalol; mercaptopur; methyldopa; nalbuphine; nalozone;
pentoxifyll; pridostigm; terbutaline; verapamil; buserelin; calcitonin;
cyclosporin; and oxytocin.

esp@cenet claims view Page 2 of 3
11. A microemulsion composition in the form of a free-flowing, compressible
powder, comprising:
an admixture of a drug-containing self-microemulsifying drug delivery system and a solid particle adsorbent; wherein said drug-containing self-microemulsifying drug delivery system is adsorbed on said solid particle adsorbent and forms a free-flowing, compressible powder.
12. A solid dosage for the oral administration of a therapeutically effective
amount of a drug, comprising:
an admixture of a drug-containing microemulsion and a solid particle adsorbent; wherein said microemulsion is adsorbed on said solid particle adsorbent and forms a free-flowing, compressible powder.
13. The solid dosage form of claim 12, wherein said solid dosage form is a tablet.
14. The solid dosage form of claim 12, wherein said solid dosage form is a pellet.
15. The solid dosage form of claim 12, wherein said solid dosage form is a multiparticulate.
16. The solid dosage form of claim 12, wherein said solid dosage form is a minitablet.
17. The solid dosage form of claim 12, wherein said solid dosage form further comprises a bioadhesive.
18. The solid dosage form of claim 12, wherein said solid dosage form further comprises an enteric coating maintained over said dosage form; wherein said enteric coating prevents the release of said drug-containing microemulsion until a time at which said dosage form reaches a target area following oral administration.
19. The solid dosage form of claim 12, wherein said solid dosage form further comprises at least one effervescent agent.
20. The solid dosage form of claim 12, further comprising at least one disintegration agent; wherein said disintegration agent causes rapid dispersion of said drug-containing microemulsion to a target area following oral administration.
21. The solid dosage form of claim 12, further comprising a Ph adjusting substance.
22. A method for preparing a microemulsion, comprising the steps of: preparing a drug-containing microemulsion;
converting said drug-containing microemulsion into a free-flowing, compressible powder by admixing said drug-containing microemulsion with a

esp@cenet claims view Page 3 of 3
solid particle adsorbent.
23. A method for preparing a solid dosage for the oral administration of a
therapeutically effective amount of a drug, comprising the steps of:
preparing a drug-containing microemulsion;
converting said drug-containing microemulsion into a free flowing compressible powder by admixing said drug-containing microemulsion with a solid particle adsorbent; compressing said free-flowing, compressible powder into a solid dosage form.
24. A stable microemulsion composition which is the product of the process
of:
preparing a drug-containing microemulsion; converting said drug-containing microemulsion into a free-flowing, compressible powder by admixing said drug-containing microemulsion with a solid particulate adsorbent.
25. A method for delivering a drug to a mammal comprising the steps of:
preparing a drug-containing microemulsion;
converting said drug-containing microemulsion into a free-flowing, compressible powder by admixing said drug-containing microemulsion with a solid particle adsorbent; orally administering said free, flowing compressible powder to a mammal.
26. The microemulsion composition of claim 8, wherein the biological
molecules comprise peptides, proteins and oligonucleotides.

Documents:

1092-mum-2004 claims(superceded).pdf

1092-mum-2004 claims.pdf

1092-mum-2004 correspondence.pdf

1092-mum-2004 description(granted).pdf

1092-mum-2004 drawing.pdf

1092-mum-2004 form 1.pdf

1092-mum-2004 form 2(granted).pdf

1092-mum-2004 form 18.pdf

1092-mum-2004 form 2 (title page).pdf

1092-mum-2004 form 26.pdf

1092-mum-2004 form 3.pdf

1092-mum-2004 form 9.pdf

1092-mum-2004 patent certificate.pdf

1092-mum-2004-abstract(12-10-2004).doc

1092-mum-2004-abstract(12-10-2004).pdf

1092-mum-2004-abstract.doc

1092-mum-2004-abstract.pdf

1092-mum-2004-claims(granted)-(12-10-2004).doc

1092-mum-2004-claims(granted)-(12-10-2004).pdf

1092-mum-2004-claims.doc

1092-mum-2004-correspondence(5-11-2007).pdf

1092-mum-2004-correspondence(ipo)-(2-8-2007).pdf

1092-mum-2004-description (granted).doc

1092-mum-2004-drawing(12-10-2004).pdf

1092-mum-2004-form 1(12-10-2004).pdf

1092-mum-2004-form 18(28-9-2005).pdf

1092-mum-2004-form 2 (granted).doc

1092-mum-2004-form 2(granted)-(12-10-2004).doc

1092-mum-2004-form 2(granted)-(12-10-2004).pdf

1092-mum-2004-form 26(17-9-2004).pdf

1092-mum-2004-form 3(12-10-2004).pdf

1092-mum-2004-form 9(11-7-2005).pdf

1094-mum-2004 u.s.patent.pdf

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Patent Number

208589

Indian Patent Application Number

1092/MUM/2004

PG Journal Number

30/2008

Publication Date

25-Jul-2008

Grant Date

02-Aug-2007

Date of Filing

12-Oct-2004

Name of Patentee

1)PATRAVALE VANDANA BHARAT 2)KHAN IMRAN AHMAD

Applicant Address

UNIVERSITY INSTITUTE OF CHEMICAL TECHNOLOGY, NATHALAL PARIKH MARG, MATUNGA, MUMBAI - 400 019

Inventors:

#	Inventor's Name	Inventor's Address
1	PATRAVALE VANDANA BHARAT	UNIVERSITY INSTITUTE OF CHEMICAL TECHNOLOGY, NATHALAL PARIKH MARG, MATUNGA, MUMBAI - 400 019

PCT International Classification Number

A61K 9/20

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA