US 20140296.191A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0296.191 A1 PATEL et al. (43) Pub. Date: Oct. 2, 2014

(54) COMPOSITIONS OF PHARMACEUTICAL (52) U.S. Cl. ACTIVES CONTAINING DETHYLENE CPC ...... A61K 47/10 (2013.01); A61 K9/0019 GLYCOL MONOETHYLETHER OR OTHER (2013.01); A61 K9/0048 (2013.01); A61 K ALKYL DERVATIVES 45/06 (2013.01) USPC ...... 514/167: 514/177; 514/178: 514/450; (71) Applicant: THEMIS MEDICARE LIMITED, 514/334: 514/226.5: 514/449; 514/338; Mumbai (IN) 514/256; 514/570; 514/179; 514/174: 514/533; (72) Inventors: Dinesh Shantilal PATEL, Mumbai (IN); 514/629; 514/619 Sachin Dinesh PATEL, Mumbai (IN); Shashikant Prabhudas KURANI, Mumbai (IN); Madhavlal Govindlal (57) ABSTRACT PATEL, Mumbai (IN) (73) Assignee: THEMIS MEDICARE LIMITED, The present invention relates to pharmaceutical compositions Mumbai (IN) of various pharmaceutical actives, especially lyophilic and hydrophilic actives containing Diethylene glycol monoethyl (21) Appl. No.: 14/242,973 ether or other alkyl derivatives thereofas a primary vehicle and/or to pharmaceutical compositions utilizing Diethylene (22) Filed: Apr. 2, 2014 glycol monoethyl ether or other alkyl derivatives thereofas a primary vehicle or as a solvent system in preparation of Such (30) Foreign Application Priority Data pharmaceutical compositions. The pharmaceutical composi Apr. 2, 2013 (IN) ...... 1287/MUMA2013 tions of the present invention are safe, non-toxic, exhibits enhanced physical stability compared to conventional formu Publication Classification lations containing such pharmaceutical actives and are Suit able for use as injectables for intravenous and intramuscular (51) Int. Cl. administration, as well as for use as a preformed solution/ A647/ (2006.01) liquid for filling in and preparation of capsules, tablets, nasal A6 IK 45/06 (2006.01) sprays, gargles, dermal applications, gels, topicals, liquid oral A6 IK9/00 (2006.01) dosage forms and other dosage forms. Patent Application Publication Oct. 2, 2014 US 2014/0296.191 A1

Figure l: Sensor application and method at injection site US 2014/0296.191 A1 Oct. 2, 2014

COMPOSITIONS OF PHARMACEUTICAL XI) Antibiotics; ACTIVES CONTAINING DETHYLENE GLYCOL MONOETHYLETHER OR OTHER XII) Aldosterone Receptor Antagonists; ALKYL DERVATIVES XIII) Cardiovascular Agents; FIELD OF THE INVENTION XIV) Calcium Channel Blockers; 0001. The present invention relates to pharmaceutical compositions of various pharmaceutical actives containing XV) Anti-arrhythmic Agents: Diethylene glycol monoethyl ether or other alkyl derivatives 0005 XVI) Cardiac Glycosides and other Drugs related to thereof as a primary vehicle and/or to pharmaceutical com CVS; positions utilizing Diethylene glycol monoethyl ether or other alkyl derivatives thereof as a primary vehicle or as a XVII) Antipsychotic Agents: Solvent system in preparation of Such pharmaceutical com XVIII) Anticonvulsants: positions. The present invention especially relates to pharma ceutical compositions of lipophilic and hydrophilic actives XIX) Diuretics; containing Diethylene glycol monoethyl ether or other alkyl XX) Anticancer Agents; derivatives thereofas a primary vehicle and/or to pharmaceu tical compositions utilizing Diethylene glycol monoethyl XXI) Immunosuppressants; ether or other alkyl derivatives thereofas a primary vehicle or XXII) Vitamins and Minerals; and as a solvent system in preparation of Such pharmaceutical compositions. The pharmaceutical compositions of the XXIII) Peptides present invention are safe, non-toxic, exhibits enhanced 0006. In the past, numerous agents have been used to physical stability compared to conventional formulations solubilize various categories of drugs. The use of organic containing Such pharmaceutical actives and are Suitable for solvents like Acetone, Methanol, Ethyl acetate, Tetrahydro use as injectables for intravenous and intramuscular admin furan, Chloroform, Hexane, etc., for their Subsequent use istration, as well as for use as a preformed solution/liquid for either as oral or injectable (intramuscularly or intravenously) filling in and preparation of capsules, tablets, nasal sprays, is prohibited. gargles, dermal applications, gels, topicals, liquid oral dosage 0007 Use of oil and its derivatives has its limitations as forms and other dosage forms. these are derived from plant origin like sesame oil, cottonseed oil etc., which poses stability problems because their quality BACKGROUND OF THE INVENTION changes with season, may get unstable/rancid as well as their 0002 Formulation of various pharmaceutical actives, bulky viscous nature result in pain and further complication especially lipophilic actives is a problem because many Such during application at the injecting site. actives are difficult to solubilize, by virtue of their poor solu 0008. Manufacture of injectables using oil and its deriva bility; because many formulations containing Such actives tive also leads to problems from a quality control point of have poor stability and hence are difficult to manufacture and view. The tendencies of seasonal changes in oil quality (ran in many instances require Such formulations to be lyophilized cidity) and color change were problems encountered by or freeze dried; and because many formulations containing manufacturing chemists. The pesticide residue from oil of Such actives are required to be formulated as emulsions and natural origin is a potential risk factor for injectable forms. hence difficult to manufacture. This is especially true for Further sterilization and difficulties during filtration are the formulations of Such actives in the form of injectables, cap added secondary problems. Sules, gargles, solutions etc and other dosage forms. Prepa 0009 Use of emulsions for solubilizing various drugs was ration of various lipophilic drugs that are poorly soluble or also attempted. But the stability of emulsions, its particle size insoluble in water/other solvents in soluble pellucid has been and sterility resulted in high cost of production. Moreover, a continuing problem in the art. various technologies are developed for administration in the 0003. Examples of such pharmaceutical actives, useful in injectable form and also pose the problems of pain at the site various physiological conditions to alleviate the pathology of the injection. caused due to various disease conditions are the following, 0010. The abovementioned factors limit the use of oil as which are not restrictive and a person of skill in the art may well as oil/water emulsions as solubilizing agents for the select other compounds which fall into the aforementioned preparation of various categories of active drugs. Moreover, categories: Some of the derivatives of oil cause anaphylactic shocks and I) Steroids and Hormones: histamine release, thus reducing their usage. 0011. The use offatty acids and its derivative also requires 0004 II) Antimalarial agents; special quality control and their therapeutic use in oral and III) Proton Pump Inhibitors: injectable forms are therefore limited. Use of polyethylene IV) Analgesic Agents (NSAIDs and Narcotic Analgesics): glycol derivatives are quite high but there are limitations to their use as they can be administered up to certain levels only V) COX 2 Inhibitors; and are toxic at higher levels. Thus they become specific VI) Hypnotic Agents: either for oral or local applications and their use is limited in injectables. VII) Antifungal Agents; 0012. Further, the problems associated with oil-based VIII) Oxicams; injections are many, Such as for instance a small test dose prior to actual administration is usually required to confirm IX) ACE Inhibitors: tolerability of both active and oily vehicle; it causes pain, X) Muscle Relaxants; erythema and Swelling at the site of injection; it leads to US 2014/0296.191 A1 Oct. 2, 2014

nodule formation at the site of injection; it is associated with 0019. Thus the formulation of a clear solution of drugs for a risk of damage to nerves, arteries or veins if improperly therapy has always been challenge with the need of a solubi given or administered; if side effects occur they would be lizer to give clear Solution. prolonged until plasma levels fall—hence the necessity for a test dose; it can take several weeks for plasma levels to reach 0020. It is known that ethanol is often used in varying steady state; injection technique competency, assessment and amounts upto 50-60% for solubilization of many drugs dur training are required; there are logistical difficulties for ing their preparation. However, if it is used for therapeutic administering to a patient who is employed; there is a need for application in the concentration through intravenous, intra stabilizers and preservatives in larger amounts in Such formu muscular or for oral delivery, then it may lead to intoxication lations for maintaining stability of the oily injections; some leading to its restrictions. people have dislike orphobia of pain from the needles of such 0021. The use of Propylene Glycol is also limited. The injectables; there could be staffing and medicine storage safety regarding its parenteral application is only up to 40%, issues; it is viewed by Some as Stigmatizing and coercive, etc. that too also through Intramuscular route and is considered as hemolytic and toxic at higher concentration to the central 0013. It is also found that there are some drugs available in nervous system. The formulation containing 30% Propylene the lyophilized form and the doctor/physician requires other Glycol which has been used is known to cause hemolysis in pack of solvents to reconstitute before an administration. The humans. Hemolysis, CNS depression, hyperosmolality, and technique of lyophilization is a costly process and unviable, lactic acidosis have been reported after I.V. administration of leading many of Such drugs uneconomical to patients. Propylene glycol (NTP-CERHRMonograph on the Potential 0014. Many drugs that are oil soluble have limited appli Human Reproductive and Developmental Effects of Propy cation as only to be administered intramuscularly and not lene Glycol (March 2004) NIH Pub. No. 04-4482 Page II-30 used for ocular or intravenous purpose. Propylene glycol is viscous with a viscosity of 58.1 cps, thus 0015 Complications associated with intramuscular injec limiting their use in IM/IV formulation and is not known for tions are also many, Such as they cause skin and tissue trauma; the Intravenous administration. (Handbook of Pharmaceuti muscle fibrosis and contracture; nerve palsies, paralysis; ana cal Excipients, 3" Edition by Dr. Arthur H. Kibbe, Page No. phylactic shock; formation of thrombosis in veins; thrombo 443) phlebitis; can involve infectious processes and cause 0022 Cyclodextrins and its advanced derivatives are used abscesses organgrene. in the formulation for solubilizing by the process of complex 0016. The formulation of drugs used for application as ation of lipophilic compounds. Because of its toxicity, their “Eye drops” in form of suspension/emulsions is limited use is limited. When administered, it is un-metabolized and because of their limited solubility in the aqueous media. accumulates in kidney as the insoluble cholesterol complexes Quality control attributes like stability, particulate matter, resulting in severe nephrotoxicity and hence it has been used particle size etc., for Such emulsions and Suspensions, are the primarily for oral purpose. Questions always arise on safety problems that are encountered by chemists during their when Cyclodextrin derivatives are administered parenterally preparation and application as "Eye drops”. (Handbook of Pharmaceutical Excipients, 3" Edition by Dr. Arthur H. Kibbe, Page No. 165). Also the molecular weight of 0017. The problems associated with parenteral suspension B-cyclodextrin is more than 1000 and hence after administra formulations are also many, such as typically they limit the tion it could lead to problems of excretion with or without formulator in selecting the ingredients, which are parenter causing damages to kidney or any functions of the organ in the ally acceptable as Suspending agents, viscosity inducing body. agents, wetting agents and preservatives; they are difficult to 0023 Glycofurol is cyclic glycol derivative used nowa manufacture—special facilities are required to maintain days as Solubiliser solvent in parenteral products for intrave aseptic conditions for manufacturing Such as crystallization, nous or intramuscular injection in concentration up to 50% particle size reduction, wetting, Sterilization etc.; stability of V/v. It has viscosity of 8-18 Cps which may also attribute to the formulations during the period between manufacture and cloudiness when miscible in water. It is irritant when used use resulting in many occasions in settlement of Solids, cak undiluted; its tolerability is approximately the same as pro ing, causing difficulty in redispersion etc.; difficulty in main pylene glycol. Glycofurol has found to have effect on liver tenance of physical stability; non-uniformity of dose at the function. (Handbook of Pharmaceutical Excipients, Ray time of administration; vials to be shaken for uniformity prior mond C. Rowe, 5th Edition Page. No. 313). Central nervous to use; necessity of ensuring or ruling out of clumping or system toxicity was also observed when given by intravenous granular appearance of the Suspension before withdrawing (I.V.) injection. Necrosis of tissue was even observed when it into Syringes; after withdrawal, the injections are to be was given intramuscularly (I.M.) Chremophor E1R (Trade applied as soon as possible before its starts settling in the mark for a polyoxy-ethylene castor oil derivative), a Surfac syringe, with the result that the entire problems can be an tant was also used to solubilize poorly soluble drugs, which issue for the doctor/physician. was found to have acute anaphylactoid reaction after initia 0018 Many drugs for solubilization require milling or tion of intravenous fusion. It was a result due to improper micronization to enhance the solubility in the Solubilising mixing of this vehicle in parenterals and hence different mix agents. For instance, steroids require micronisation to Solu ing techniques were used to assess their effect on the distri bilise in oil or its derivatives or in a co-solvent. The use of bution of Chremophor EL in the solution. This led to problem co-solvents or other additives in oil type product adds up in parenteral formulation of various actives with this solubi difficulty in administration due to viscosity and may also lizer and time is required for developing a proper technique cause hemolysis if not used in appropriate acceptable con for mixing of this solubilizer which limits its use in parenter centration in the body particularly for the parenteral prepara als with non-safe toxic profile. Due to safety issues, it is used tion. carefully as exceptional use and last resort as drug solubilis US 2014/0296.191 A1 Oct. 2, 2014 ing agent (eg. Paclitaxel injection, where balance of conve 0033. The structure of Diethylene glycol monoethylether nience Suggests its use for terminal therapy of cancer verses is as given below: anaphylaxis). 0024. Ethyl oleate/Oleic acid ethyl ester is used nowadays for lipophilic compounds and for steroids as vehicle in certain N-N-11--" parenteral preparations intended for intramuscular and Sub cutaneous administration. It is an oily liquid with Viscosity of 3.9 Cps at 25°C., less viscous than fixed oils. It is found that 0034. It is less viscous and safe. It has inherent viscosity of it remains clear at 5°C., but darkens in color on standing, so about 3.11 cps. It is soluble in water. The density of Diethyl antioxidants are to be added frequently to extend shelf life. ene glycol monoethyl ether is 0.985 to 0.991. Diethylene Thus addition of group of antioxidants as well as use of amber glycol monoethyl ether is less dense than water thereby mak bottle is required to protect it from light. This increases the ing it easily flowable. As the compound has less viscosity it cost of formulation by taking control on above factor of can be used for preparations of compositions which are hav packing, stability (Handbook of Pharmaceutical Excipients, ing an easy Syringability and thus advantageous to withdraw from vials or ampoules by the healthworkers. Further the Raymond C. Rowe, 5th Edition Page. No. 274). same advantage offers doctors with its less painful impact and 0025 U.S. Pat. No. 4,628,053 relates to stabilized injec also less volume of liquid could be administered for the drug tion solutions of PiroXicam in which propylene glycol, etha products in the therapeutic concentration through parenteral nol and water as the solvent for parenteral administration, rOuteS. which might be viscous and painful at the site of injection. 0035 U.S. Pat. No. 5,837,714 discloses solid pharmaceu 0026 U.S. Pat. No. 4,824,841 relates to a process for the tical dispersions comprising a poorly soluble drug Substance, transformation of Piroxicam into an hydrated form suitable as SR48692 or Naproxen, Xylitol and Diethylene glycol for Oral, topic or parenteral administration. monoethyl ether, and a method of preparing Such dispersions comprising the steps of dissolving the poorly soluble drug 0027 U.S. Pat. No. 4.942,167 discloses aqueous pharma Substance in Diethylene glycol monoethyl ether and adding ceutical formulation containing lyophilized Piroxicam in the solution to Xylitol. The dispersions exhibit good pharma Glycine as vehicle which is not transparent solution and sta ceutical properties and reduced levels of impurities and deg bility can be issue. radation products. 0028 U.S. Pat. No. 5,420,124A relates to an injectable 0036 U.S. Patent Application No. 2010.0056982A1 Piroxicam potassium composition which contains triethyl teaches the photodynamic treatment of acne Vulgaris. The eneglycol as a solvent and stabilizer. method involves the topical administration of a photosensi 0029 WO/1996/041646 disclose a pharmaceutical com tizer composition comprising hydrophobic green porphyrins position in the form of an aqueous Solution or in the form of Such as Lemuteporfin, Polyethylene glycol and skin penetra a product for reconstitution as an aqueous solution, for tion enhancers such as Oleyl alcohol and TranscutolTM to parenteral administration or ophthalmic administration, com acne-affected skin and Subsequent exposure of that skin to prising Lornoxicam or a pharmaceutically acceptable salt energy of a wavelength of activating the photosensitizer. thereof and a cyclodextrin selected from the group consisting 0037 U.S. Patent Application No. 20100010059A1 of hydroxypropylated or sulphoalkylated derivatives of teaches partially based on a discovery that an oral formulation alpha, beta or gamma cyclodextrin. containing N-(3-methylisothiazol-5-yl)-2-1-(3-methylisox azol-5-ylmethyl)-1H-indol-3-yl)-2-oxoacetamide unexpect 0030 Chinese Patent No. CN 101327.193 relates to Lor edly enhances the oral bioavailability of the compound. In noxicam freeze-dried powder injection and a preparation one aspect, this invention features an anticancer formulation, method thereof. The freeze-dried powder injection comprises which contains d-alpha-Tocopheryl Polyethylene glycol Lornoxicam, mannite, tromethamine, EDTA and pH regula 1000 succinate (“TPGS), 2-(2-ethoxyethoxy)ethanol tOr. (“Transcutol’); and an effective amount of a compound of 0031. From all the above limitations, it is apparent that formula there is need for a solvent, which is safe and non-toxic, which 0038 WO97/03698 teaches for Transdermal therapeutic can be employed as a vehicle for preparation of pharmaceu system (TTS) having a backing film, having an acrylate tical compositions in an efficient way through an economical based pressure sensitive adhesive having a hormone content process and being beneficial in treating mammals. and a content of absorption accelerators and having a protec 0032. The present inventors have surprisingly found that tive film, wherein the hormone content is provided by a con most, if not all of the limitations/problems/concerns associ tent of an oestrogen and/or gestagen and/or androgen, and ated with the conventional formulations of various pharma wherein the absorption accelerators are the two Substances ceutical actives, especially lipophilic actives can be overcome Oleic acid and 2-(2-ethoxyethoxy)-ethanol. by employing Diethylene glycol monoethyl ether or other 0039 U.S. Pat. No. 5,552,153 teaches a pharmaceutical alkyl derivatives thereofas a primary vehicle or as a solvent in composition for transdermal delivery comprising an effective formulation of pharmaceutical compositions containing Such amount of an active ingredient selected from a BenZodiaz pharmaceutical actives. Diethylene glycol monoethyl ether or epine and a BenZodiazepine antagonist; Ethanol; Caprylic other alkyl derivatives thereof are versatile enough to be acid; and Oleic acid. Additionally, the composition may con accepted as vehicles for use in various drug delivery systems. tain Silicon fluid, Benzyl alcohol, and Diethylene glycol It has been tested for its safety and toxicity and is reported to monoethyl ether or Dimethylsulfoxide. be safe for its therapeutic use through various routes of 0040 U.S. Pat. No. 5,998.392 teaches about the improved administration. Presently the ethyl derivative is in vogue, but compositions of Benzoyl peroxide and methods of processing use of methyl or any other alkyl derivatives may also be used. Benzoyl peroxide. More particularly, the invention relates to US 2014/0296.191 A1 Oct. 2, 2014

the use of a composition such as Transcutol R. Diethylene 0051 Still another object of the present invention is to glycol monoethyl ether as a processing aid for making a new utilize Diethylene glycol monoethyl ether or other alkyl benzoyl peroxide premixture which can be admixed with an derivatives thereofas a primary vehicle or solvent for formu aqueous medium to make a new benzoyl peroxide flocculent lation of lipophilic and hydrophilic actives which are difficult composition. to Solubilize in physiologically acceptable solvents and 0041 U.S. Pat. No. 5,741,512 teaches with the Pharma require to be formulated as oily injections. ceutical compositions comprising Cyclosporin, e.g. 0.052 Another object of the present invention is to utilize Cyclosporin as “microemulsion pre-concentrate' and micro Diethylene glycol monoethyl ether or other alkyl derivatives emulsion form. The compositions typically comprise a C. Sub. thereof as a primary vehicle or solvent for formulation of 1-5 alkyl or tetrahydrofurfuryl di- or partial-ether of a low pharmaceutical actives which are difficult to solubilize in molecular weight mono- or poly-oxy-alkane diol, e.g. Tran physiologically acceptable solvents and require to be formu Scutol or Glycofurol, as hydrophilic component. Composi lated as emulsions. tions are also provided comprising a cyclosporin and, Suit 0053. Yet another object of the present invention is to ably, also a saccharide monoester, e.g. raffinose or saccharose utilize Diethylene glycol monoethyl ether or other alkyl monolaurate. Dosage forms include topical formulations and, derivatives thereofas a primary vehicle or solvent for formu in particular, oral dosage forms. lation of lipophilic and hydrophilic actives which are difficult to Solubilize in physiologically acceptable solvents and Objects of the Invention require to be formulated as emulsions. 0054 Still another object of the present invention is to 0042. An object of the present invention is to provide utilize Diethylene glycol monoethyl ether or other alkyl pharmaceutical compositions of various pharmaceutical derivatives thereofas a primary vehicle or solvent for formu actives containing Diethylene glycol monoethyl ether or lation of pharmaceutical actives which are free from oil and other alkyl derivatives thereofas a primary vehicle or solvent. related matters. 0043. Another object of the present invention is to provide 0055 Another object of the present invention is to utilize pharmaceutical compositions of various lipophilic and Diethylene glycol monoethyl ether or other alkyl derivatives hydrophilic actives containing Diethylene glycol monoethyl thereof as a primary vehicle or solvent for formulation of ether or other alkyl derivatives thereofas a primary vehicle or lipophilic and hydrophilic actives which are free from oil and solvent. related matters. 0044. Yet another object of the present invention is to 0056. Yet another object of the present invention is to provide use of Diethylene glycol monoethyl ether or other utilize Diethylene glycol monoethyl ether or other alkyl alkyl derivatives thereofas a primary vehicle or as a solvent in derivatives thereofas a primary vehicle or solvent for formu preparation of pharmaceutical compositions containing Vari lation of pharmaceutical actives which are less viscous, less ous pharmaceutical actives. dense and more transparent than oily injections containing 0045 Still another object of the present invention is to Such pharmaceutical actives. provide use of Diethylene glycol monoethyl ether or other 0057 Still another object of the present invention is to alkyl derivatives thereofas a primary vehicle or as a solvent in utilize Diethylene glycol monoethyl ether or other alkyl preparation of pharmaceutical compositions containing Vari derivatives thereofas a primary vehicle or solvent for formu ous lipophilic and hydrophilic actives. lation of lipophilic and hydrophilic actives which are less 0046. Another object of the present invention is to utilize Viscous, less dense and more transparent than oily injections Diethylene glycol monoethyl ether or other alkyl derivatives containing Such lipophilic actives. thereof as a primary vehicle or solvent for formulation of 0.058 Another object of the present invention is to utilize pharmaceutical actives which are difficult to solubilize in Diethylene glycol monoethyl ether or other alkyl derivatives physiologically acceptable solvents. thereof as a primary vehicle or solvent for formulation of 0047 Yet another object of the present invention is to pharmaceutical actives which results in less pain when utilize Diethylene glycol monoethyl ether or other alkyl injected compared to that caused by administration of oily derivatives thereofas a primary vehicle or solvent for formu injections containing Such pharmaceutical actives. lation of lipophilic and hydrophilic actives which are difficult 0059 Yet another object of the present invention is to to solubilize in physiologically acceptable solvents. utilize Diethylene glycol monoethyl ether or other alkyl 0048 Still another object of the present invention is to derivatives thereofas a primary vehicle or solvent for formu utilize Diethylene glycol monoethyl ether or other alkyl lation of lipophilic and hydrophilic actives which results in derivatives thereofas a primary vehicle or solvent for formu less pain when injected compared to that caused by adminis lation of pharmaceutical actives which exhibit instability tration of oily injections containing Such lipophilic actives. when compounded with an aqueous phase. 0060 Still another object of the present invention is to 0049. Another object of the present invention is to utilize utilize Diethylene glycol monoethyl ether or other alkyl Diethylene glycol monoethyl ether or other alkyl derivatives derivatives thereofas a primary vehicle or solvent for formu thereof as a primary vehicle or solvent for formulation of lation of pharmaceutical actives which can be easily admin lipophilic and hydrophilic actives which exhibit instability istered by doctors/physicians/nurses. when compounded with an aqueous phase. 0061 Another object of the present invention is to utilize 0050 Yet another object of the present invention is to Diethylene glycol monoethyl ether or other alkyl derivatives utilize Diethylene glycol monoethyl ether or other alkyl thereof as a primary vehicle or solvent for formulation of derivatives thereofas a primary vehicle or solvent for formu lipophilic and hydrophilic actives which can be easily admin lation of pharmaceutical actives which are difficult to solubi istered by doctors/physicians/nurses. lize in physiologically acceptable solvents and require to be 0062 Yet another object of the present invention is to formulated as oily injections. provide pharmaceutical compositions of pharmaceutical US 2014/0296.191 A1 Oct. 2, 2014

actives containing or utilizing Diethylene glycol monoethyl which do not cause skin and tissue trauma; muscle fibrosis ether or other alkyl derivatives thereofas a primary vehicle or and contracture; nerve palsies; paralysis; anaphylactic shock; Solvent, which are easy to manufacture, do not involve any formation of thrombosis in veins; thrombo phlebitis; and lengthy and tedious manufacturing steps, which are viable abscesses or gangrene, when administered intramuscularly. and economical. 0071. Yet another object of the present invention is to 0063 Still another object of the present invention is to provide pharmaceutical compositions of lipophilic and provide pharmaceutical compositions of lipophilic and hydrophilic actives containing or utilizing Diethylene glycol hydrophilic actives containing or utilizing Diethylene glycol monoethyl ether or other alkyl derivatives thereof as a pri monoethyl ether or other alkyl derivatives thereof as a pri mary vehicle or solvent, which do not cause skin and tissue mary vehicle or solvent, which are easy to manufacture, do trauma; muscle fibrosis and contracture; nerve palsies; not involve any lengthy and tedious manufacturing steps, paralysis; anaphylactic shock; formation of thrombosis in which are viable and economical. veins; thrombo phlebitis; and abscesses or gangrene, when 0064. Another object of the present invention is to provide administered intramuscularly. pharmaceutical compositions of pharmaceutical actives con 0072 Still another object of the present invention is to taining or utilizing Diethylene glycol monoethyl ether or provide pharmaceutical compositions of pharmaceutical other alkyl derivatives thereofas a primary vehicle or solvent, actives containing or utilizing Diethylene glycol monoethyl which do not cause side effects; which do not cause pain, ether or other alkyl derivatives thereofas a primary vehicle or erythema, Swelling at the site of injection; which do not cause Solvent, which does not require special facilities to maintain damage to nerves, arteries or veins; and which does not aseptic conditions for manufacturing Such as crystallization, require a test dose to be given to the patient prior to actual particle size reduction, wetting, sterilization etc. administration. 0073. Another object of the present invention is to provide 0065. Yet another object of the present invention is to pharmaceutical compositions of lipophilic and hydrophilic provide pharmaceutical compositions of lipophilic and actives containing or utilizing Diethylene glycol monoethyl hydrophilic actives containing or utilizing Diethylene glycol ether or other alkyl derivatives thereofas a primary vehicle or monoethyl ether or other alkyl derivatives thereof as a pri Solvent, which does not require special facilities to maintain mary vehicle or solvent, which do not cause side effects: aseptic conditions for manufacturing Such as crystallization, which do not cause pain, erythema, Swelling at the site of particle size reduction, wetting, sterilization etc. injection; which do not cause damage to nerves, arteries or 0074 Yet another object of the present invention is to veins; and which does not require a test dose to be given to the provide pharmaceutical compositions of pharmaceutical patient prior to actual administration. actives containing or utilizing Diethylene glycol monoethyl 0066 Still another object of the present invention is to ether or other alkyl derivatives thereofas a primary vehicle or provide pharmaceutical compositions of pharmaceutical solvent, wherein the stability of the compositions during the actives containing or utilizing Diethylene glycol monoethyl period between manufacture and use does not result in settle ether or other alkyl derivatives thereofas a primary vehicle or ment of Solids, caking, difficulty in redispersion etc. solvent, which do not cause logistical difficulties when 0075 Still another object of the present invention is to administered to a patient who is in employment; which does provide pharmaceutical compositions of lipophilic and not have staffing and medicine storage issues; and which is hydrophilic actives containing or utilizing Diethylene glycol not stigmatizing or coercive to a patient. monoethyl ether or other alkyl derivatives thereof as a pri 0067. Another object of the present invention is to provide mary vehicle or solvent, wherein the stability of the compo pharmaceutical compositions of lipophilic and hydrophilic sitions during the period between manufacture and use does actives containing or utilizing Diethylene glycol monoethyl not result in settlement of Solids, caking, difficulty in redis ether or other alkyl derivatives thereofas a primary vehicle or persion etc. solvent, which do not cause logistical difficulties when 0076 Another object of the present invention is to provide administered to a patient who is in employment; which does pharmaceutical compositions of pharmaceutical actives con not have staffing and medicine storage issues; and which is taining or utilizing Diethylene glycol monoethyl ether or not stigmatizing or coercive to a patient. other alkyl derivatives thereofas a primary vehicle or solvent, 0068. Yet another object of the present invention is to wherein there is uniformity of dose at the time of administra provide pharmaceutical compositions of pharmaceutical tion and vials need not be shaken for uniformity prior to use. actives containing or utilizing Diethylene glycol monoethyl 0077 Yet another object of the present invention is to ether or other alkyl derivatives thereofas a primary vehicle or provide pharmaceutical compositions of lipophilic and solvent, which do not contain stabilizers or preservatives in hydrophilic actives containing or utilizing Diethylene glycol large amounts for maintaining the stability of the composi monoethyl ether or other alkyl derivatives thereof as a pri tions. mary vehicle or solvent, wherein there is uniformity of dose at 0069. Still another object of the present invention is to the time of administration and vials need not be shaken for provide pharmaceutical compositions of lipophilic and uniformity prior to use. hydrophilic actives containing or utilizing Diethylene glycol 0078 Still another object of the present invention is to monoethyl ether or other alkyl derivatives thereof as a pri provide pharmaceutical compositions of pharmaceutical mary vehicle or solvent, which do not contain stabilizers or actives containing or utilizing Diethylene glycol monoethyl preservatives in large amounts for maintaining the stability of ether or other alkyl derivatives thereofas a primary vehicle or the compositions. Solvent, which need not be applied as soon as possible to 0070 Another object of the present invention is to provide avoid settling in the Syringe and do not cause an issue for the pharmaceutical compositions of pharmaceutical actives con doctor/physician/nurse. taining or utilizing Diethylene glycol monoethyl ether or 0079 Another object of the present invention is to provide other alkyl derivatives thereofas a primary vehicle or solvent, pharmaceutical compositions of lipophilic and hydrophilic US 2014/0296.191 A1 Oct. 2, 2014 actives containing or utilizing Diethylene glycol monoethyl monoethyl ether or other alkyl derivatives thereof as a pri ether or other alkyl derivatives thereofas a primary vehicle or mary vehicle or solvent, for use of administration via I.M Solvent, which need not be applied as soon as possible to and/or I.V route, oral, dermal, nasal, optic, and other routes of avoid settling in the Syringe and do not cause an issue for the administration. doctor/physician/nurse. 0090 Still another object of the present invention is to 0080 Yet another object of the present invention is to provide pharmaceutical compositions of pharmaceutical provide pharmaceutical compositions of pharmaceutical actives containing or utilizing Diethylene glycol monoethyl actives containing or utilizing Diethylene glycol monoethyl ether or other alkyl derivatives thereofas a primary vehicle or ether or other alkyl derivatives thereofas a primary vehicle or Solvent, which also provides the function of a permeation solvent, which exhibit enhanced physical stability in com enhancing agent. parison to conventional compositions containing such phar 0091 Another object of the present invention is to provide maceutical actives. pharmaceutical compositions of lipophilic and hydrophilic 0081. Still another object of the present invention is to actives containing or utilizing Diethylene glycol monoethyl provide pharmaceutical compositions of lipophilic and ether or other alkyl derivatives thereofas a primary vehicle or hydrophilic actives containing or utilizing Diethylene glycol Solvent, which also provides the function of a permeation monoethyl ether or other alkyl derivatives thereof as a pri enhancing agent. mary vehicle or solvent, which exhibit enhanced physical 0092. Yet another object of the present invention is to stability in comparison to conventional compositions con provide pharmaceutical compositions of pharmaceutical taining Such lipophilic and hydrophilic actives. actives containing or utilizing Diethylene glycol monoethyl 0082 Another object of the present invention is to provide ether or other alkyl derivatives thereofas a primary vehicle or pharmaceutical compositions of pharmaceutical actives con Solvent, which provides ease of application of the said phar taining or utilizing Diethylene glycol monoethyl ether or maceutical actives comparatively reduced pain at the site of other alkyl derivatives thereofas a primary vehicle or solvent, injection via I.M and I.V route. which are versatile enough to be accepted as vehicles for use 0093 Still another object of the present invention is to in various drug delivery systems. provide pharmaceutical compositions of lipophilic and 0083. Yet another object of the present invention is to hydrophilic actives containing or utilizing Diethylene glycol provide pharmaceutical compositions of lipophilic and monoethyl ether or other alkyl derivatives thereof as a pri hydrophilic actives containing or utilizing Diethylene glycol mary vehicle or solvent, which provides ease of application of monoethyl ether or other alkyl derivatives thereofas a pri the said lipophilic and hydrophilic actives comparatively mary vehicle or solvent, which are versatile enough to be reduced pain at the site of injection via I.M and I.V route. accepted as vehicles for use in various drug delivery systems. 0094. Another object of the present invention is to provide 0084. Still another object of the present invention is to pharmaceutical compositions of pharmaceutical actives con provide pharmaceutical compositions of pharmaceutical taining or utilizing Diethylene glycol monoethyl ether or actives containing or utilizing Diethylene glycol monoethyl other alkyl derivatives thereofas a primary vehicle or solvent, ether or other alkyl derivatives thereofas a primary vehicle or which exist in different dosage forms with desired quality Solvent, which are safe and non-toxic for various routes of control and are especially free from toxicity problems administration. encountered due to solvents. 0085. Another object of the present invention is to provide (0095 Yet another object of the present invention is to pharmaceutical compositions of lipophilic and hydrophilic provide pharmaceutical compositions of lipophilic and actives containing or utilizing Diethylene glycol monoethyl hydrophilic actives containing or utilizing Diethylene glycol ether or other alkyl derivatives thereofas a primary vehicle or monoethyl ether or other alkyl derivatives thereof as a pri Solvent, which are safe and non-toxic for various routes of mary vehicle or solvent, which existin different dosage forms administration. with desired quality control and are especially free from I0086 Yet another object of the present invention is to toxicity problems in the therapeutic dose of drugs and provide pharmaceutical compositions of pharmaceutical encountered due to solvents. actives containing or utilizing Diethylene glycol monoethyl 0096. Still another object of the present invention is to ether or other alkyl derivatives thereofas a primary vehicle or provide pharmaceutical compositions of pharmaceutical Solvent, for use in parenteral, oral, dermal, nasal, and other actives containing or utilizing Diethylene glycol monoethyl dosage forms. ether or other alkyl derivatives thereofas a primary vehicle or 0087 Still another object of the present invention is to solvent, which can be formulated into different dosage forms provide pharmaceutical compositions of lipophilic and Such as capsules, nasal sprays, gargles, dermal gels, and oth hydrophilic actives containing or utilizing Diethylene glycol ers, which, moreover, can be made into a soluble pellucid monoethyl ether or other alkyl derivatives thereof as a pri Solution. mary vehicle or solvent, for use in parenteral, oral, dermal, 0097 Another object of the present invention is to provide nasal, and other dosage forms. pharmaceutical compositions of lipophilic and hydrophilic 0088 Another object of the present invention is to provide actives containing or utilizing Diethylene glycol monoethyl pharmaceutical compositions of pharmaceutical actives con ether or other alkyl derivatives thereofas a primary vehicle or taining or utilizing Diethylene glycol monoethyl ether or solvent, which can be formulated into different dosage forms other alkyl derivatives thereofas a primary vehicle or solvent, Such as capsules, nasal sprays, gargles, dermal gels, and oth for use of administration via I.M and/or I.V route, oral, der ers, which, moreover, can be made into a soluble pellucid mal, nasal, optic, and other routes of administration. Solution. 0089. Yet another object of the present invention is to 0098. Yet another object of the present invention is to provide pharmaceutical compositions of lipophilic and provide pharmaceutical compositions of pharmaceutical hydrophilic actives containing or utilizing Diethylene glycol actives containing or utilizing Diethylene glycol monoethyl US 2014/0296.191 A1 Oct. 2, 2014

ether or other alkyl derivatives thereofas a primary vehicle or SUMMARY OF THE INVENTION Solvent, which are comparatively less toxic and at the same 0108. In accordance with the need for a vehicle or solvent, time would be excreted out easily without causing damage to which is safe and non-toxic for formulation and preparation any organ, especially kidney, as well as would not get accu of pharmaceutical compositions, containing pharmaceutical mulated in any part of the body. actives, especially lipophilic and hydrophilic actives belong 0099 Still another object of the present invention is to ing to diverse pharmacological and therapeutic classes and provide pharmaceutical compositions of lipophilic and which, moreover, can be manufactured in an efficient way hydrophilic actives containing or utilizing Diethylene glycol through an economical process and being beneficial in treat monoethyl ether or other alkyl derivatives thereof as a pri ing mammals and, which, further, is free from most, if not all mary vehicle or solvent, which are non-toxic and at the same of the limitations/problems/concerns associated with the con time would be excreted out easily without causing damage to ventional formulations of Such pharmaceutical actives the any organ, especially kidney, as well as would not get accu present inventors have found that Diethylene glycol monoet mulated in any part of the body. hyl ether or other alkyl derivatives thereof, especially the 0100 Another object of the present invention is to provide former, is the vehicle or solvent of choice. pharmaceutical compositions of pharmaceutical actives con 0109 The present inventors have found Diethylene glycol taining or utilizing Diethylene glycol monoethyl ether or monoethyl ether, otherwise known as 2-(2-Ethoxyethoxy) other alkyl derivatives thereofas a primary vehicle or solvent, ethanol, CARBITOLTM, DE Solvent, Diethylene glycol ethyl which provides transparent and less Viscous parenteral solu ether, Ethyldiglycol or Transcutol and having the structure tions. shown below, 0101. Yet another object of the present invention is to provide pharmaceutical compositions of lipophilic and hydrophilic actives containing or utilizing Diethylene glycol monoethyl ether or other alkyl derivatives thereof as a pri N-'N-1-1--" mary vehicle or solvent, which provides transparent and less Viscous parenteral Solutions. is versatile enough to be accepted as a vehicle for use in 0102 Still another object of the present invention is to various drug delivery systems. It has been tested for its safety provide pharmaceutical compositions of pharmaceutical and toxicity and is reported to be safe for its therapeutic use actives containing or utilizing Diethylene glycol monoethyl through various routes of administration. Presently the ethyl ether or other alkyl derivatives thereofas a primary vehicle or derivative is in Vogue, but use of methyl or any other alkyl solvent, which exhibit better bioavailability in comparison to derivatives after its safety evaluation may be used. conventional compositions containing Such pharmaceutical 0110. The use of Diethylene glycol monoethyl ether or actives. other alkyl derivatives thereof informulation or manufacture 0103) Another object of the present invention is to provide of pharmaceutical compositions of pharmaceutical actives, pharmaceutical compositions of lipophilic and hydrophilic especially lipophilic actives belonging to diverse pharmaco actives containing or utilizing Diethylene glycol monoethyl logical and therapeutic categories results in many advantages, ether or other alkyl derivatives thereofas a primary vehicle or Such as: solvent, which exhibit better bioavailability in comparison to 0111 (a) It has great Solubilizing power and can easily conventional compositions containing Such lipophilic and solubilize various pharmaceutical actives, belonging to hydrophilic actives. diverse pharmacological and therapeutic classes as listed in Categories (I) to (XXII) described in the BACKGROUND 0104 Yet another object of the present invention is to OF THE INVENTION section of this Application, which provide pharmaceutical compositions of pharmaceutical other solvents/vehicles known in the art are not completely actives containing or utilizing Diethylene glycol monoethyl capable of ether or other alkyl derivatives thereofas a primary vehicle or 0112 (b) It is versatile enough to be accepted as a vehicle Solvent, wherein the said pharmaceutical actives are not or solvent for use in various drug delivery systems for use milled or micronized. in parenteral (both intramuscular and intravenous), oral, 0105 Still another object of the present invention is to dermal, nasal, optic, ocular and otic other routes of admin provide pharmaceutical compositions of lipophilic and istration, especially as injectables, capsules, nasal sprays, hydrophilic actives containing or utilizing Diethylene glycol gargles, dermal gels etc.; monoethyl ether or other alkyl derivatives thereof as a pri 0113 (c) It is a highly versatile vehicle or solvent for mary vehicle or solvent, wherein the said lipophilic and formulation of pharmaceutical actives, especially lipo hydrophilic actives are not milled or micronized. philic actives, which are difficult to solubilize and require 0106 A further object of the present invention is to pro to be formulated as oily injections or as emulsions, or vide pharmaceutical compositions of pharmaceutical actives which exhibit instability when compounded with an aque containing or utilizing Diethylene glycol monoethyl ether or ous phase; other alkyl derivatives thereofas a primary vehicle or solvent, 0114 (d) It is safe for various routes of administration and which preferably contains preservatives and buffers to main is less toxic from toxicity and quality control problems tain its pH. encountered with other solvents known in the art; 0107 Yet further object of the present invention is to pro 0115 (e) The pharmaceutical compositions of various vide pharmaceutical compositions of lipophilic and hydro pharmaceutical actives containing it as a vehicle or solvent philic actives containing or utilizing Diethylene glycol mono exhibit enhanced physical stability in comparison to con ethyl ether or other alkyl derivatives thereof as a primary vention compositions of Such pharmaceutical actives; vehicle or solvent, which preferably contains preservatives 0116 (f) Its use as a vehicle or solvent results in formula and buffers to maintain its pH. tion of pharmaceutical compositions of pharmaceutical US 2014/0296.191 A1 Oct. 2, 2014

actives, which are easy to manufacture; do not involve and should be construed as non-limiting can be classified into the lengthy and tedious manufacturing steps; which are viable following three categories, viz. and economical; and which do not require special facilities 0129. 1) Those which are difficult to solubilize and often to maintain aseptic conditions for manufacturing such as require toxic vehicles for solubilization and may further crystallization, particle size reduction, wetting, steriliza require unwanted excipients for formulation into suitable tion etc.; dosage forms: 0117 (g) Its use as a vehicle or solvent results in formu I0130 2) Those which have stability issues and often lation of pharmaceutical compositions of pharmaceutical require complex and expensive technology for formulation actives, which will have a better bioavailability; of such actives into suitable stable dosage forms; and 0118 (h) Its use as a vehicle or solvent results in formu I0131 3) Those which are available in the form of suspen lation of pharmaceutical compositions of pharmaceutical sions and are very difficult to be solubilized into a solution actives, which are more transparent, less viscous, and less form. dense than oily injections containing such pharmaceutical (0132). By utilizing the vehicle or solvent of the present actives and can be made into a soluble pellucid solution; invention solvent, Diethylene glycol monoethyl ether or other 0119 (i) The pharmaceutical compositions of various alkyl derivatives, a transparent, non hazy as well as less vis pharmaceutical actives containing it as a vehicle or solvent cous solution is obtained, which can be useful as I.M as well are free from oil and objectionable/problematic matters as I.V. injections for rapid onset of action when required to and hence more stable; provide earliest result into the patient as well as can be used 0120) (j) The pharmaceutical compositions of various for formulation of different dosage forms like capsules, nasal pharmaceutical actives containing it as a vehicle or solvent sprays, gargles, gels, topical, ocular, otic, oral dosage forms cause less pain when injected compared to that caused by etc. The solution may additionally contain preservatives and injection of oily injections containing such pharmaceutical buffers for maintenance of pH. The solutions exhibit actives; enhanced stability compared and are less toxic. 0121 (k) The pharmaceutical compositions of various In accordance with the above: pharmaceutical actives containing it as a vehicle or solvent 0133. In one embodiment the present invention provides are easy to administer and thereby useful for doctors/phy pharmaceutical compositions of various pharmaceutical sicians/nurses; actives containing Diethylene glycol monoethyl ether or I0122 (1) The pharmaceutical compositions of various other alkyl derivatives thereofas a primary vehicle or solvent. pharmaceutical actives containing it as a Vehicle or solvent 10134. In another embodiment the present invention pro are free of side effects associated with conventional formu vides pharmaceutical compositions of various lipophilic and lations and most importantly do not require a test dose to be hydrophilic actives containing Diethylene glycol monoethyl given to the patient prior to actual administration; ether or other alkyl derivatives thereofas a primary vehicle or (0123 (m) The pharmaceutical compositions of various solvent. pharmaceutical actives containing it as a vehicle or solvent I0135) In yet another embodiment the present invention do not cause pain, erythema, Swelling at the site of injec relates to use of Diethylene glycol monoethyl ether or other tions; do not cause damage to nerves, arteries or veins: do alkyl derivatives thereofas a primary vehicle oras a solvent in not cause skin and tissue trauma; muscle fibrosis and con preparation of pharmaceutical compositions containing Vari tracture; nerve palsies; paralysis; anaphylactic shock; for ous pharmaceutical actives. mation of thrombosis in veins; thrombo phlebitis; 0.136. In still another embodiment the present invention abscesses or gangrene; do not have staffing and medicine relates to use of Diethylene glycol monoethyl ether or other storage issues; is not stigmatizing or coercive to a patient; alkyl derivatives thereofas a primary vehicle oras a solvent in and do not cause logistical difficulties when administered preparation of pharmaceutical compositions containing vari to a patient who is in employment; ous lipophilic and hydrophilic actives. 0124 (n) The pharmaceutical compositions of various 0.137 In another embodiment the present invention relates pharmaceutical actives containing it as a vehicle or solvent to utilization of Diethylene glycol monoethyl ether or other which do not exhibit instability during the period between alkyl derivatives thereofas a primary vehicle or solvent for manufacture and use; do not result in settlement of solids, formulation of pharmaceutical actives which are difficult to caking, difficulty in redispersion etc.; do not result in non solubilize in physiologically acceptable solvents. uniformity of dose at the time of administration and vials (0.138. In yet another embodiment the present invention need not be shaken for uniformity prior to use; relates to utilization of Diethylene glycol monoethyl ether or 0.125 (o) It also functions as a permeation enhancing other alkyl derivatives thereofas a primary vehicle or solvent agent, for formulation of lipophilic and hydrophilic actives which 0126 (p) The pharmaceutical compositions of various are difficult to solubilize in physiologically acceptable sol pharmaceutical actives containing it as a vehicle or solvent VentS. do not require stabilizers or preservatives in large amounts 0.139. In still another embodiment the present invention for maintaining the stability of the compositions; and relates to utilization of Diethylene glycol monoethyl ether or 0127 (q) It is excreted easily without causing damage to other alkyl derivatives thereofas a primary vehicle or solvent any organ, especially kidney, as well as would not get for formulation of pharmaceutical actives which exhibit accumulated in any part of the body; and instability when compounded with an aqueous phase. I0128 (r) Its use obviates the need for the pharmaceutical 0140. In another embodiment the present invention relates actives or lipophilic actives to be milled or micronized to utilization of Diethylene glycol monoethyl ether or other prior to use. alkyl derivatives thereofas a primary vehicle or solvent for Typically, the pharmaceutical or lipophilic actives, embraced formulation of lipophilic and hydrophilic actives which within the scope of the present invention, which however, exhibit instability when compounded with an aqueous phase. US 2014/0296.191 A1 Oct. 2, 2014

0141. In yet another embodiment the present invention 0152. In still another embodiment the present invention relates to utilization of Diethylene glycol monoethyl ether or relates to utilization of Diethylene glycol monoethyl ether or other alkyl derivatives thereofas a primary vehicle or solvent other alkyl derivatives thereofas a primary vehicle or solvent for formulation of pharmaceutical actives which are difficult for formulation of pharmaceutical actives which can be easily to Solubilize in physiologically acceptable solvents and administered by doctors/physicians/nurses. require to be formulated as oily injections. 0153. In another embodiment the present invention relates 0142. In still another embodiment the present invention to utilization of Diethylene glycol monoethyl ether or other relates to utilization of Diethylene glycol monoethyl ether or alkyl derivatives thereof as a primary vehicle or solvent for other alkyl derivatives thereofas a primary vehicle or solvent formulation of lipophilic and hydrophilic actives which can for formulation of lipophilic and hydrophilic actives which be easily administered by doctorS/physicians/nurses. are difficult to solubilize in physiologically acceptable sol 0154) In yet another embodiment the present invention vents and require to be formulated as oily injections. provides pharmaceutical compositions of pharmaceutical 0143. In another embodiment the present invention relates actives containing or utilizing Diethylene glycol monoethyl to utilization of Diethylene glycol monoethyl ether or other ether or other alkyl derivatives thereofas a primary vehicle or alkyl derivatives thereof as a primary vehicle or solvent for Solvent, which are easy to manufacture, do not involve any formulation of pharmaceutical actives which are difficult to lengthy and tedious manufacturing steps, which are viable solubilize in physiologically acceptable solvents and require and economical. to be formulated as emulsions. 0.155. In still another embodiment the present invention 0144. In still another embodiment the present invention provides pharmaceutical compositions of lipophilic and relates to utilization of Diethylene glycol monoethyl ether or hydrophilic actives containing or utilizing Diethylene glycol other alkyl derivatives thereof is employed in an amount of monoethyl ether or other alkyl derivatives thereof as a pri 1% to 100% by volume of the pharmaceutical active. mary vehicle or solvent, which are easy to manufacture, do 0145. In yet another embodiment the present invention not involve any lengthy and tedious manufacturing steps, relates to utilization of Diethylene glycol monoethyl ether or which are viable and economical. other alkyl derivatives thereofas a primary vehicle or solvent 0156. In another embodiment the present invention pro for formulation of lipophilic and hydrophilic actives which vides pharmaceutical compositions of pharmaceutical actives are difficult to solubilize in physiologically acceptable sol containing or utilizing Diethylene glycol monoethyl ether or vents and require to be formulated as emulsions. other alkyl derivatives thereofas a primary vehicle or solvent, 0146 In still another embodiment the present invention which do not cause side effects; which do not cause pain, relates to utilization of Diethylene glycol monoethyl ether or erythema, Swelling at the site of injection; which do not cause other alkyl derivatives thereofas a primary vehicle or solvent damage to nerves, arteries or veins; and which does not for formulation of pharmaceutical actives which are free from require a test dose to be given to the patient prior to actual oil and related matters. administration. 0147 In another embodiment the present invention relates to utilization of Diethylene glycol monoethyl ether or other 0157. In yet another embodiment the present invention alkyl derivatives thereof as a primary vehicle or solvent for provides pharmaceutical compositions of lipophilic and formulation of lipophilic and hydrophilic actives which are hydrophilic actives containing or utilizing Diethylene glycol free from oil and related matters. monoethyl ether or other alkyl derivatives thereof as a pri 0148. In yet another embodiment the present invention mary vehicle or solvent, which do not cause side effects: relates to utilization of Diethylene glycol monoethyl ether or which do not cause pain, erythema, Swelling at the site of other alkyl derivatives thereofas a primary vehicle or solvent injection; which do not cause damage to nerves, arteries or for formulation of pharmaceutical actives which are less vis veins; and which does not require a test dose to be given to the cous, less dense and more transparent than oily injections patient prior to actual administration. containing Such pharmaceutical actives. 0158. In still another embodiment the present invention 0149. In still another embodiment the present invention provides pharmaceutical compositions of pharmaceutical relates to utilization of Diethylene glycol monoethyl ether or actives containing or utilizing Diethylene glycol monoethyl other alkyl derivatives thereofas a primary vehicle or solvent ether or other alkyl derivatives thereofas a primary vehicle or for formulation of lipophilic and hydrophilic actives which solvent, which do not cause logistical difficulties when are less Viscous, less dense and more transparent than oily administered to a patient who is in employment; which does injections containing Such lipophilic and hydrophilic actives. not have staffing and medicine storage issues; and which is 0150. In another embodiment the present invention relates not stigmatizing or coercive to a patient. to utilization of Diethylene glycol monoethyl ether or other 0159. In another embodiment the present invention pro alkyl derivatives thereof as a primary vehicle or solvent for vides pharmaceutical compositions of lipophilic and hydro formulation of pharmaceutical actives which results in less philic actives containing or utilizing Diethylene glycol mono pain when injected compared to that caused by administration ethyl ether or other alkyl derivatives thereof as a primary of oily injections containing Such pharmaceutical actives. vehicle or solvent, which do not cause logistical difficulties 0151. In yet another embodiment the present invention when administered to a patient who is in employment; which relates to utilization of Diethylene glycol monoethyl ether or does not have staffing and medicine storage issues; and which other alkyl derivatives thereofas a primary vehicle or solvent is not stigmatizing or coercive to a patient. for formulation of lipophilic and hydrophilic actives which 0160. In yet another embodiment the present invention results in less pain when injected compared to that caused by provides pharmaceutical compositions of pharmaceutical administration of oily injections containing Such lipophilic actives containing or utilizing Diethylene glycol monoethyl and hydrophilic actives. ether or other alkyl derivatives thereofas a primary vehicle or US 2014/0296.191 A1 Oct. 2, 2014

solvent, which do not contain stabilizers or preservatives in monoethyl ether or other alkyl derivatives thereof as a pri large amounts for maintaining the stability of the composi mary vehicle or solvent, wherein there is uniformity of dose at tions. the time of administration and vials need not be shaken for 0161 In still another embodiment the present invention uniformity prior to use. provides pharmaceutical compositions of lipophilic and 0170 In still another embodiment the present invention hydrophilic actives containing or utilizing Diethylene glycol provides pharmaceutical compositions of pharmaceutical monoethyl ether or other alkyl derivatives thereof as a pri actives containing or utilizing Diethylene glycol monoethyl mary vehicle or solvent, which do not contain stabilizers or ether or other alkyl derivatives thereofas a primary vehicle or preservatives in large amounts for maintaining the stability of Solvent, which need not be applied as soon as possible to the compositions. avoid settling in the Syringe and do not cause an issue for the 0162. In another embodiment the present invention pro doctor/physician/nurse. vides pharmaceutical compositions of pharmaceutical actives 0171 In another embodiment the present invention pro containing or utilizing Diethylene glycol monoethyl ether or vides pharmaceutical compositions of lipophilic and hydro other alkyl derivatives thereofas a primary vehicle or solvent, philic actives containing or utilizing Diethylene glycol mono which do not cause skin and tissue trauma; muscle fibrosis ethyl ether or other alkyl derivatives thereof as a primary and contracture; nerve palsies; paralysis; anaphylactic shock; vehicle or solvent, which need not be applied as soon as formation of thrombosis in veins; thrombo phlebitis; and possible to avoid settling in the Syringe and do not cause an abscesses or gangrene, when administered intramuscularly. issue for the doctor/physician/nurse. 0163. In yet another embodiment the present invention 0172. In yet another embodiment the present invention provides pharmaceutical compositions of lipophilic and provides pharmaceutical compositions of pharmaceutical hydrophilic actives containing or utilizing Diethylene glycol actives containing or utilizing Diethylene glycol monoethyl monoethyl ether or other alkyl derivatives thereof as a pri ether or other alkyl derivatives thereofas a primary vehicle or mary vehicle or solvent, which do not cause skin and tissue solvent, which exhibit enhanced physical stability in com trauma; muscle fibrosis and contracture; nerve palsies; parison to conventional compositions containing Such phar paralysis; anaphylactic shock; formation of thrombosis in maceutical actives. veins; thrombo phlebitis; and abscesses or gangrene, when 0173. In still another embodiment the present invention administered intramuscularly. provides pharmaceutical compositions of lipophilic and 0164. In still another embodiment the present invention hydrophilic actives containing or utilizing Diethylene glycol provides pharmaceutical compositions of pharmaceutical monoethyl ether or other alkyl derivatives thereofas a pri actives containing or utilizing Diethylene glycol monoethyl mary vehicle or solvent, which exhibit enhanced physical ether or other alkyl derivatives thereofas a primary vehicle or stability in comparison to conventional compositions con Solvent, which does not require special facilities to maintain taining Such lipophilic and hydrophilic actives. aseptic conditions for manufacturing Such as crystallization, 0.174. In another embodiment the present invention pro particle size reduction, wetting, sterilization etc. vides pharmaceutical compositions of pharmaceutical actives 0.165. In another embodiment the present invention pro containing or utilizing Diethylene glycol monoethyl ether or vides pharmaceutical compositions of lipophilic and hydro other alkyl derivatives thereofas a primary vehicle or solvent, philic actives containing or utilizing Diethylene glycol mono which are versatile enough to be accepted as vehicles for use ethyl ether or other alkyl derivatives thereof as a primary in various drug delivery systems. vehicle or solvent, which does not require special facilities to 0.175. In yet another embodiment the present invention maintain aseptic conditions for manufacturing Such as crys provides pharmaceutical compositions of lipophilic and tallization, particle size reduction, wetting, sterilization etc. hydrophilic actives containing or utilizing Diethylene glycol 0166 In yet another embodiment the present invention monoethyl ether or other alkyl derivatives thereof as a pri provides pharmaceutical compositions of pharmaceutical mary vehicle or solvent, which are versatile enough to be actives containing or utilizing Diethylene glycol monoethyl accepted as vehicles for use in various drug delivery systems. ether or other alkyl derivatives thereofas a primary vehicle or 0176). In still another embodiment the present invention solvent, wherein the stability of the compositions during the provides pharmaceutical compositions of pharmaceutical period between manufacture and use does not result in settle actives containing or utilizing Diethylene glycol monoethyl ment of Solids, caking, difficulty in redispersion etc. ether or other alkyl derivatives thereofas a primary vehicle or 0167. In still another the present invention provides phar solvent, which are safe and less toxic for various routes of maceutical compositions of lipophilic and hydrophilic administration. actives containing or utilizing Diethylene glycol monoethyl 0177. In another embodiment the present invention pro ether or other alkyl derivatives thereofas a primary vehicle or vides pharmaceutical compositions of lipophilic and hydro solvent, wherein the stability of the compositions during the philic actives containing or utilizing Diethylene glycol mono period between manufacture and use does not result in settle ethyl ether or other alkyl derivatives thereof as a primary ment of Solids, caking, difficulty in redispersion etc. vehicle or solvent, which are safe and non-toxic in the desired 0.168. In another embodiment the present invention pro dose for various routes of administration. vides pharmaceutical compositions of pharmaceutical actives 0178. In yet another embodiment the present invention containing or utilizing Diethylene glycol monoethyl ether or provides pharmaceutical compositions of pharmaceutical other alkyl derivatives thereofas a primary vehicle or solvent, actives containing or utilizing Diethylene glycol monoethyl wherein there is uniformity of dose at the time of administra ether or other alkyl derivatives thereofas a primary vehicle or tion and vials need not be shaken for uniformity prior to use. Solvent, for use in parenteral, oral, dermal, nasal, and other 0169. In yet another embodiment the present invention dosage forms. provides pharmaceutical compositions of lipophilic and 0179. In still another embodiment the present invention hydrophilic actives containing or utilizing Diethylene glycol provides pharmaceutical compositions of lipophilic and US 2014/0296.191 A1 Oct. 2, 2014 hydrophilic actives containing or utilizing Diethylene glycol Such as capsules, nasal sprays, gargles, dermal gels, and oth monoethyl ether or other alkyl derivatives thereof as a pri ers, which, moreover, can be made into a soluble pellucid mary vehicle or solvent, for use in parenteral, oral, dermal, Solution. nasal, and other dosage forms. 0189 In Another embodiment the present invention pro 0180. In another embodiment the present invention pro vides pharmaceutical compositions of lipophilic and hydro vides pharmaceutical compositions of pharmaceutical actives philic actives containing or utilizing Diethylene glycol mono containing or utilizing Diethylene glycol monoethyl ether or ethyl ether or other alkyl derivatives thereof as a primary other alkyl derivatives thereofas a primary vehicle or solvent, vehicle or solvent, which can be formulated into different for use of administration via I.M and/or I.V route, oral, der dosage forms such as capsules, nasal ocular, otic deliveries, mal, nasal, optic, and other routes of administration. gargles, dermal gels, and others, which, moreover, can be 0181. In yet another embodiment the present invention made into a soluble pellucid solution. provides pharmaceutical compositions of lipophilic and 0190. In yet another embodiment the present invention hydrophilic actives containing or utilizing Diethylene glycol provides pharmaceutical compositions of pharmaceutical monoethyl ether or other alkyl derivatives thereof as a pri actives containing or utilizing Diethylene glycol monoethyl mary vehicle or solvent, for use of administration via I.M ether or other alkyl derivatives thereofas a primary vehicle or and/or I.V route, oral, dermal, nasal, optic, and other routes of Solvent, which are comparatively less toxic and at the same administration. time would be excreted out easily without causing damage to 0182. In still another embodiment the present invention any organ, especially kidney, as well as would not get accu provides pharmaceutical compositions of pharmaceutical mulated in any part of the body. actives containing or utilizing Diethylene glycol monoethyl 0191 In still another embodiment the present invention ether or other alkyl derivatives thereofas a primary vehicle or provides pharmaceutical compositions of lipophilic and Solvent, which also provides the function of a permeation hydrophilic actives containing or utilizing Diethylene glycol enhancing agent. monoethyl ether or other alkyl derivatives thereof as a pri 0183 In another embodiment the present invention pro mary vehicle or solvent, which are non-toxic and at the same vides pharmaceutical compositions of lipophilic and hydro time would be excreted out easily without causing damage to philic actives containing or utilizing Diethylene glycol mono any organ, especially kidney, as well as would not get accu ethyl ether or other alkyl derivatives thereof as a primary mulated in any part of the body. vehicle or solvent, which also provides the function of a permeation enhancing agent. (0192 In another embodiment the present invention pro vides pharmaceutical compositions of pharmaceutical actives 0184. In yet another embodiment the present invention containing or utilizing Diethylene glycol monoethyl ether or provides pharmaceutical compositions of pharmaceutical other alkyl derivatives thereofas a primary vehicle or solvent, actives containing or utilizing Diethylene glycol monoethyl which provides transparent and less Viscous parenteral solu ether or other alkyl derivatives thereofas a primary vehicle or Solvent, which provides ease of application of the said phar tions. maceutical actives comparatively reduced pain at the site of 0193 In yet another embodiment the present invention injection via I.M and I.V route. provides pharmaceutical compositions of lipophilic and 0185. In still another embodiment the present invention hydrophilic actives containing or utilizing Diethylene glycol provides pharmaceutical compositions of lipophilic and monoethyl ether or other alkyl derivatives thereof as a pri hydrophilic actives containing or utilizing Diethylene glycol mary vehicle or solvent, which provides transparent and less monoethyl ether or other alkyl derivatives thereof as a pri Viscous parenteral Solutions. mary vehicle or solvent, which provides ease of application of 0194 In still another embodiment the present invention the said lipophilic and hydrophilic actives comparatively provides pharmaceutical compositions of pharmaceutical reduced pain at the site of injection via I.M and I.V route. actives containing or utilizing Diethylene glycol monoethyl 0186. In Another embodiment the present invention pro ether or other alkyl derivatives thereofas a primary vehicle or vides pharmaceutical compositions of pharmaceutical actives solvent, which exhibit better bioavailability in comparison to containing or utilizing Diethylene glycol monoethyl ether or conventional compositions containing Such pharmaceutical other alkyl derivatives thereofas a primary vehicle or solvent, actives. which exist in different dosage forms with desired quality 0.195. In another embodiment the present invention pro control and are especially free from toxicity problems vides pharmaceutical compositions of lipophilic and hydro encountered due to solvents. philic actives containing or utilizing Diethylene glycol mono 0187. In yet another embodiment the present invention ethyl ether or other alkyl derivatives thereof as a primary provides pharmaceutical compositions of lipophilic and vehicle or solvent, which exhibit better bioavailability in hydrophilic actives containing or utilizing Diethylene glycol comparison to conventional compositions containing Such monoethyl ether or other alkyl derivatives thereof as a pri lipophilic and hydrophilic actives. mary vehicle or solvent, which existin different dosage forms 0196. In yet another embodiment the present invention with desired quality control and are especially free from provides pharmaceutical compositions of pharmaceutical toxicity problems in the therapeutic dose of drugs and actives containing or utilizing Diethylene glycol monoethyl encountered due to solvents. ether or other alkyl derivatives thereofas a primary vehicle or 0188 In still another embodiment the present invention Solvent, wherein the said pharmaceutical actives are not provides pharmaceutical compositions of pharmaceutical milled or micronized. In still another embodiment the present actives containing or utilizing Diethylene glycol monoethyl invention provides pharmaceutical compositions of lipo ether or other alkyl derivatives thereofas a primary vehicle or philic and hydrophilic actives containing or utilizing Dieth solvent, which can be formulated into different dosage forms ylene glycol monoethyl ether or other alkyl derivatives US 2014/0296.191 A1 Oct. 2, 2014

thereof as a primary vehicle or solvent, wherein the said tives, Purgatives, Digestives, Cholagogues, lipophilic and hydrophilic actives are not milled or micron Cholelitholytics, Hepatic Protectors. Anorectal Prepara ized. tions, Antiemetics and other Gastrointestinal Drugs. 0197) In another embodiment the present invention pro 0204 2. Cardiovascular and Hematopoietic System vides pharmaceutical compositions of pharmaceutical actives Drugs: containing or utilizing Diethylene glycol monoethyl ether or 0205 This can include Cardiac Drugs, Anti-anginal other alkyl derivatives thereofas a primary vehicle or solvent, Drugs, ACE Inhibitors/Direct Renin Inhibitors, Beta which preferably contains preservatives and buffers to main Blockers, Calcium Antagonists, Angiotensin II Antago tain its pH. In yet another embodiment the present invention nists, Diuretics, Antidiuretic, Peripheral Vasodilators provides pharmaceutical compositions of lipophilic and and Cerebral Activators, Vasoconstrictors, Dyslipi hydrophilic actives containing or utilizing Diethylene glycol daemic Agents, Haemostatics, Anticoagulants. Other monoethyl ether or other alkyl derivatives thereof as a pri Antihypertensives and other Cardiovascular Drugs. mary vehicle or solvent, which preferably contains preserva 0206 3. Respiratory System Drugs: tives and buffers to maintain its pH. 0207. This can include Antiasthmatic and COPD Prepa rations, Cough and Cold Preparations, Nasal Deconges BRIEF DESCRIPTION OF THE FIGURE tants and other Respiratory System Drugs 0198 FIG. 1 shows the operator simply wears a special (0208 4. Central Nervous System (CNS) Drugs: force sensor on thumb and measures the force whichelicit the 0209. This can include Anxiolytics, Hypnotics and animal response. Sedatives, Antidepressants, Antipsychotics, Anticon Vulsants, Antiparkinsonian Drugs, Analgesics (Opioid DETAILED DESCRIPTION OF THE INVENTION & Non-Opioid) and Antipyretics, Non Steroidal Anti 0199 As mentioned hereinbefore, the primary object and Inflammatory Drugs (NSAIDs) and other CNS Drugs. embodiment of the present invention lies in providing phar 0210 5. Musculo-skeletal System Drugs maceutical compositions of pharmaceutical or lipophilic/hy 0211 6. Hormones, Steroids and Contraceptive Agents drophilic actives in desired pellucid clear solution form for 0212 7. Anti-infective Drugs: their use in formulation of various dosage forms, which 0213. This can include Systemic Antibiotics, Antifun includes parenteral/injectable form for use as intramuscular gals, Antivirals, Antimalarials, Antiamoebics, Antipro and/or intravenous administration, as well as for use as a toZoal agents, Anti-tuberculars, Antibacterial Combina preformed solution/liquid for filling in and preparation of tions, Macrollides and other anti-infectives capsules, tablets, nasal sprays, gargles, ocular delivery, otic 0214 8. Oncology Drugs delivery applications and other dosage forms. 0215 9. Genito-urinary Drugs 0200 Further, as mentioned hereinbefore, the primary object and embodiment of the present invention is realized 0216 10. Endocrine and Metabolic System Drugs through utilization of Diethylene glycol monoethyl ether or 0217 11. Vitamins and Minerals other alkyl derivatives thereofas a primary vehicle or solvent 0218 12. Nutritional Drugs in the formulation of pharmaceutical compositions compris 0219 13. Ophthalmic (Eye) Drugs ing Such pharmaceutical or lipophilic actives. By definition, a pharmaceutical active, referred to herein in the specification 0220 14. Drugs for Ear, Nose, Mouth/Throat is a Substance that is biologically active. It is also commonly 0221 15. Dermatological Drugs referred to as a Pharmaceutically Active Ingredient (API), a 0222 16. Anesthetics—Local and General Drug Substance or a Bulk Active. It is the active ingredient 0223) 17. Allergy and Immune System Drugs which is utilized in formulation of pharmaceutical composi tions or Drug Products of such actives. By definition, a lipo 0224, 18. Antidotes, Detoxifying agents and Drugs used in philic active, referred to herein in the specification are com Substance Dependence pounds which exhibit “Lipophilicity', meaning the ability of 0225, 19. Intravenous and other Sterile Solutions Such compounds to dissolve in fats, oils, lipids, and non-polar 0226, 20. Miscellaneous Drugs and Compounds Solvents such as hexane or toluene. Such compounds gener 0227. As per the embodiments of the present invention, the ally are poorly soluble or insoluble in water and therefore “Hydrophobic”. Barring a few exceptions the terms "Lipo following pharmaceutical and/or lipophilic actives or drugs philic' and “Hydrophobic' are synonymous. or compounds, which, however, is non-limiting and should 0201 By definition, a hydrophilic active, referred to not be construed as limiting the Scope of the invention, herein in the specification are compounds which exhibit belonging to various pharmacological or therapeutic classes “hydrophilicity', meaning the ability of such compounds to can be solubilised in Diethylene glycol monoethyl ether or dissolve in water and polar solvents. other alkyl derivatives thereof to provide pharmaceutical The pharmaceutical and/or lipophilic/hydrophilic actives of compositions, which exhibit good physical stability. the present invention are drug Substances belonging to Vari 0228 1. Gastrointestinal and Hepatobiliary System ous pharmacological or therapeutic classes. By way of illus Drugs: tration, which, however, is non-limiting and should not be 0229 a) Antacids, Antireflux agents and Antiulcerants: construed as limiting the scope of the invention, such phar Famotidine, Misoprostol, Pantoprazole, Rabeprazole, macological or therapeutic classes can be selected from: Domperidone, Omeprazole, Lansoprazole Dexlanso 0202 1. Gastrointestinal and Hepatobiliary System prazole etc. Drugs: 0230 b) GIT Regulators, Antiflatulents and Anti-in 0203 This can include Antacids, Antireflux Agents, flammatories: Mesalazine, Metoclopromide, Mosapride Antiulcerants. GIT Regulators, Antiflatulents, Anti-in etc. flammatories, Antispasmodics, Antidiarrheals, Laxa 0231 c) Antispasmodics: Drotaverine US 2014/0296.191 A1 Oct. 2, 2014

0232 d) Antidiarrheals: Loperamide 0261 6. Hormones, Steroids and Contraceptive Agents: 0233 e) Laxatives and Purgatives: Bisacodyl Testosterone, Estradiol, Ethinyl estradiol, Mesterolone, 0234 f) Cholagogues, Cholelitholytics and Hepatic Allylestrenol, Estraliol, Hydroxy-Progesterone Caproate, Protectors: Metadoxine Medroxy-Progesterone, Norethisterone, Progesterone, 0235 g) Antiemetics: Domperidone Betamethasone, Hydrocortisone, Methyl Prednisolone, 0236 h) Other Gastrointestinal Drugs: Trifluoperazine Prednisolone, Triamcinolone, Clomifene, Octreotide, 0237 2. Cardiovascular and Hematopoietic System Nandrolone, Levonorgestrel etc. Drugs: 0262 7. Anti-infective Drugs: 0238 a) Cardiac Drugs: Adenosine, Digoxin, 0263 Systemic Antibiotics, Antifungals, Antivirals, Lidocaine, Propafenone etc. Antimalarials, Antiamoebics, Antiprotozoal agents, 0239 b) Anti-anginal Drugs: Diltiazem HCl, Nic Anti-tuberculars, Antibacterial Combinations, Mac orandil, Nifedipine etc. rolides and otheranti-infectives: Fluconazole, Voricona 0240 c) ACE Inhibitors/Direct Renin Inhibitors: Cap Zole Tobramycin, CefoperaZone, Cefotaxime, Cef topril, Enalapril, Fosinopril, Lisinopril, Losartan, Rami prozil, Erthyromycin, Ciprofloxacin, Ofloxacin, pril etc. Tetracycline, Metronidazole, Ornidazole, Rifampicin, 0241 d) Beta Blockers: Labetelol, Sotalol, Nebivolol, Vancomycin, Cycloserine, Protionamide, Isoniazide, Amplodipine etc. Clotrimazole, Fluconazole, Itraconazole, Griseofulvin, 0242 e) Calcium Antagonists: Amplodipine Besylate, Ketoconazole, Terbinafine, Ketoconazole, Acyclovir, Lacidipine Ganciclovir, Levamisole, Mebendazole, Artemether, 0243 f) Diuretics: Acetazolamide, Spironolactone, Artesunate, Hydroxy-chloroquine, Mefloquine, Met Torasemide etc. ronidazole, Furazolidine, Artesunate, Arteether, Arte 0244 g) Peripheral Vasodilators and Cerebral Activa mether etc. tors: ISOXSuprine, Nimodipine etc. 0264 8. Oncology Drugs: Dacarbazine, Doxorubicin, 0245 h) Dyslipidaemic Agents: Bezafibrate, Atorvasta Vinblastine Sulphate, Bleomycin, Etoposide, Melphalan, tin, Bezafibrate, Rosuvastatin, Lovastatin, Simvastatin, Paclitaxel, Vincristine sulfate, Amifostine, Anastrazole, Somatostatin etc. Leuprolide etc. 0246 i) Anticoagulants: Cilostazol 0265 9. Genito-urinary Drugs: Miconazole, Methylergo 0247 j). Other Antihypertensives and other Cardiovas metrine, Tadalafil, Tamsulosin, Calcitriol etc. cular Drugs: Doxazocin, Prazocin, Reserpine etc. 0266 10. Endocrine and Metabolic System Drugs: Orl 0248 3. Respiratory System Drugs: istat, Alfacalcidol etc. 0249 a) Antiasthmatic and COPD Preparations: 0267 11. Vitamins and Minerals: Vitamin K. Cholecalcif Beclomethazone, Beclonetasone, Budesonide, Flutica erol, Retinol, Other Vitamins A, D & E. Zone, Ipratomium Bromide etc. 0268 12. Miscellaneous Drugs and Compounds: Aldos 0250 b) Cough and Cold Preparations: Codeine, Dex terone receptor Antagonists—Eplerenone, Spironolactone tromethorphan, Mesna etc. etc 0251 c) Nasal Decongestants and other Respiratory 0269. As mentioned hereinbefore, the aforementioned System Drugs: Oxymetazoline pharmaceutical or lipophilic actives can be solubilised into Diethylene glycol monoethyl ether or other alkyl derivatives 0252) 4. Central Nervous System (CNS) Drugs: thereof to provide a clear and transparent stable liquid solu 0253 a) Anxiolytics: Alprazolam, Buspirone, Chlor tion, which can be used as such directly for formulation of diazepoxide, ClobaZem, Clonazepam, Diazepam, injectable solutions for parenteral delivery; or which can be Lorazepam, Hydroxy Zine, Pregabalin etc. matrixed with pharmaceutically acceptable adjuvants into a 0254 b) Hypnotics and Sedatives: Midazolam, tablet form for oral administration; or else which can be use as Nitrazepam etc. a preformed solution/liquid for filling in and preparation of 0255 c) Antidepressants: Bupropion Hydrochloride, capsules, tablets, nasal sprays, gargles, dermal applications Clomipramine, Doxepin, Fluoxetine, Mianserin etc. ocular, otic and other dosage forms. In such cases, the clear 0256 d) Antipsychotics: Clozapine, Lamotrigine, and transparent stable liquid solution can be either used as a Olanzapine, Quetiapine, Valproic acid etc. single drug preparation or can be given in combination with 0257 e) Anticonvulsants: Carbamazepine, Clon other Suitable drugs for the requisite pharmacological azepam, Clobazam, Diazepam, Lamotrigine, Levetirac actions. etam Phenyloin, Pregabalin, Dimenhydrinate etc. (0270. While the invention is primarily illustrated with 0258 f) Analgesics (Opioid & Non-Opioid) and Anti respect to Diethylene glycol monoethyl ether, otherwise pyretics: Buprenorphine, Pentazocin etc. known also as 2-(2-Ethoxyethoxy)ethanol, CARBITOLTM, 0259 g) Non Steroidal Anti Inflammatory Drugs DE Solvent, Diethylene glycol ethyl ether, Ethyldiglycol or (NSAIDs): Buprenorphine, Pentazocine, Aceclofenac, Transcutol and having the structure shown below, Indometacin, Ibuprofen, Ketorolac, Lornoxicam, Mefe namic acid, NimeSulide, PiroXicam, Tenoxicam, Fluna rizine, Citicoline, Mecobalamin, Pyritinol, Piracetam, Leflunomide, Celecoxib, Eterocoxib, Tilmacoxib, N-N-1-1--" Acetaminophen, LevoSulpiride etc. 0260 5. Musculo-skeletal System Drugs: Chloroquine, however, other alkyl derivatives can also be equally utilized in Allopurinol, Baclofen, Glycopyrronium Bromide. Thio the present invention and a person skilled in the art would colchicoside Tizanidine, Neostigmine, Diacerein, Tolp have no difficulty in embracing the other alkyl derivatives for erisone, Eperisone etc. working of the invention. Typical examples of other alkyl US 2014/0296.191 A1 Oct. 2, 2014 derivatives are Diethylene glycol monomethyl ether, Dieth solubilisation activity of Diethylene glycol monoethyl ether ylene glycol mono-n-propyl ether, Diethylene glycol mono is very effective when such pharmaceutical compositions are iso-propyl ether, Diethylene glycol mono-n-butyl ether, used for their therapeutic use. The pharmaceutical composi Diethylene glycol mono-iso-butul ether, and Diethylene gly tions comprising Diethylene glycol monoethyl ether or other col mono-n-hexyl ether. lakyl derivatives are found to provide better chemical and 0271 Diethylene glycol monoethyl ether is less viscous biological stability to the said compositions. and safe. It has inherent viscosity of about 3.11 cps. It is 0275. The pharmaceutical compositions containing the soluble in water. The density of Diethylene glycol monoethyl aforementioned pharmaceutical or lipophilic actives may in ether is 0.985 to 0.991. Diethylene glycol monoethyl ether is addition to Diethylene glycol monoethyl ether or other alkyl less dense than water thereby making it easily flowable. As derivatives contain buffers, for maintenance of pH. Examples the compound has less Viscosity it can be used for prepara of suitable buffers that can be employed are 0.1 N Sodium tions of compositions which are having an easy Syringability hydroxide, Acetic acid, Sodium citrate, Potassium chloride, and thus advantageous to withdraw from vials or ampoules by Sodium chloride, Citric acid, Sodium bicarbonate, L-Argin the healthworkers. Further the same advantage offers doctors ine, Tris buffers, Cholic acid Derivatives, Amino acid Deriva with its less painful impact and also less Volume of liquid tives etc. could be administered for the drug products in the therapeutic concentration through parenteral routes. 0276. The pharmaceutical compositions containing the aforementioned pharmaceutical or lipophilic actives may in 0272. Of the various vehicles known in the art including addition to Diethylene glycol monoethyl ether or other alkyl various organic solvents, oils and oil-water mixtures for solu derivatives contain preservatives, which are typically bilizing the aforementioned pharmaceutical actives including employed in an amount of 0.001% to 2% by weight of the lipophilic actives and poorly water Soluble drugs and steroids, composition. Examples of preservatives that can be used are Diethyleneglycol monoethyl ether provides an efficient solu Benzyl alcohol, Methyl paraben, Propyl paraben, Thiomero bilizing activity and drug permeation activity which can avoid sol, Phenyl mercuric salts (acetate, borate, nitrate), Chlorobu most, if not all the limitations/problems/concerns associated tanol, Meta-cresol etc. Typically Benzyl alcohol is employed with utilization of the said vehicles known in the art for in an amount of 0.01% to 2% by weight of the composition, formulation of pharmaceutical compositions. Methyl paraben is employed in an amount of 0.18% to 0.2% 0273. The wide range of pharmaceutical or lipophilic by weight of the composition, Propyl paraben is employed in actives, described hereinbefore, namely the following Ant an amount of 0.01 to 0.02% by weight of the composition, and acids, Antireflux agents and Antiulcerants. GIT Regulators, Thiomerosol is employed in an amount of 0.001% to 0.01% Antiflatulents, Anti-inflammatories, Antispasmodics, Antidi by weight of the composition. The preservatives also help in arrheals, Laxatives, Purgatives, Cholagogues, Cholelitholyt maintenance of the stability of the compositions. ics, Hepatic Protectors, Anorectal Preparations, Antiemetics, and Other Gastrointestinal Drugs; Cardiac Drugs, Anti-angi 0277. The pharmaceutical compositions containing the nal Drugs, ACE Inhibitors/Direct Renin Inhibitors, Beta aforementioned pharmaceutical or lipophilic actives may in Blockers, Calcium Antagonists, Angiotensin II Antagonists, addition to Diethylene glycol monoethyl ether or other alkyl Other Antihypertensives, Diuretics, Antidiuretics, Peripheral derivatives contain antioxidants or chelating agents or stabi Vasodilators and Cerebral Activators, Vasoconstrictors, Dys lizers. Examples of antioxidants that can be employed are lipidaemic Agents, Haemostatics, Anticoagulants and Other Ascorbic acid, Ascorbyl palmitate. Thioglycerol and its Cardiovascular Drugs; Antiasthmatic and COPD Prepara derivatives, Sodium bisulphate, Sodium metabisulphite, tions, Cough and Cold Preparations, Nasal Decongestants Sodium formaldehyde sulphoxylate. Thiourea, Ascorbic acid and other Respiratory System Drugs; Anxiolytics, Hypnotics ester, BHT (Butylated hydroxyl toluene), Tocopherols etc. and Sedatives, Antidepressants, Antipsychotics, Anticonvul Typically Ascorbic acid is employed in an amount of 0.02% to sants, Antiparkinsonian Drugs, Analgesics (Opioid & Non 0.1% by weight of the composition, Ascorbyl palmitate is Opioid) and Antipyretics, NSAIDs and Other CNS Agents, employed in an amount of 0.5% to 2% by weight of the Musculo-skeletal System Drugs, Hormones, Steroids and composition, Sodium bisulphate is employed in an amount of Contraceptive Agents, Antibiotics, Antifungals, Antivirals, 0.1% to 0.15% by weight of the composition, Sodium met Antimalarials, Antiamoebics, Antiprotozoal agents, Anti-tu abisulphite is employed in an amount of 0.1% to 0.15% by berculars, Antibacterial Combinations, Macrollides and other weight of the composition, Sodium formaldehyde Sulphoxy Anti infectives. Oncology Drugs, Drugs related to Genito late is employed in an amount of 0.1% to 0.15% by weight of urinary, Endocrine & Metabolic System Drugs, Vitamins and the composition, Thiourea is employed in an amount of Minerals, Nutrition Drugs belonging to Eye, Nose, Ear & 0.004% to 0.005% by weight of the composition, Ascorbic Mouth/Throat, Dermatologicals, Anesthetics—Local and acid ester is employed in an amount of 0.1% to 0.15% by General, Drugs belonging to Allergy and Immune System, weight of the composition, BHT is employed in an amount of Antidotes, Detoxifying Agents & Drugs used in Substance 0.005% to 0.02% by weight of the composition, and Toco Dependence, Intravenous and other Sterile Solutions and pherols are employed in an amount of 0.05% to 0.075% by various Miscellaneous Therapeutic Category Drugs— weight of the composition. Chelating agents like Ethylene showed highly selective solubility in the vehicle or solvent, diamine tetraacetic acid in an amount of 0.01% to 0.075% by Diethyleneglycol monoethyl ether or other alkyl derivatives weight of the composition are typically employed and Stabi thereof. lizers like Maleic acid or Malate salts may be employed. 0274 The selective vehicle or solvent, Diethylene glycol 0278. The pharmaceutical compositions containing the monoethyl ether or other alkyl derivatives thereof is typically aforementioned pharmaceutical or lipophilic actives may in employed in an amount of 25% to 30% by weight of the addition to Diethylene glycol monoethyl ether or other alkyl pharmaceutical composition containing the aforementioned derivatives contain other appropriate adjuvants or excepients, pharmaceutical or lipophilic actives. The penetrating cum based on the dosage forms. US 2014/0296.191 A1 Oct. 2, 2014

0279. The pharmaceutical compositions containing the a class of hormones called progestogens, and is the major aforementioned pharmaceutical or lipophilic actives may in naturally occurring human progestogen. The molecular struc addition to Diethylene glycol monoethyl ether or other alkyl ture of progesterone is as: derivatives contain other pharmaceutically acceptable co-sol vents. Water can also be added in minimal quantity to make the compositions more fluidic. (I.1) 0280. The versatility of the selective solubilizing agent diethylene glycol monoethyl ether and alike solvent enables formulation for lipophilic actives which could be used as injectable both intravenously and intramuscularly use as well as for application in various pharmaceutical dosage compo sitions thereby providing for its diverse application of this drugs for treating diverse diseases and for alleviating the sickness of mammals effectively. 0281. The wide range of the drugs that can be effectively solubilized by Diethylene glycol monoethyl ether or other alkyl derivatives and formulated into suitable pharmaceutical 0288. It is white crystalline powder insoluble in water. The compositions or dosage forms are the following, which, how solubility profile of Progesterone in water is <0.1 g/100 ml at ever, is non-limiting as far as the scope of the invention, is 19°C. It is freely soluble in dehydrated alcohol, sparingly concerned. soluble in vegetable oils and acetone. It is available in micron Class I: Pharmaceutical Actives or Drugs which are Difficult ized form as an oily intramuscular injection prepared in to Solubilize sesame oil according to USP which is viscous in nature and can be painful at the site of injection. It differs from other 0282. As mentioned hereinbefore, there are certain phar commonly used steroids in that it is irritating at the place of maceutical actives or drugs, which are difficult to solubilize injection. and often require toxic vehicles for solubilization and may 0289. By utilizing the vehicle or solvent of the present further require unwanted excipients for formulation into Suit invention solvent, Diethylene glycol monoethyl ether or other able dosage forms. alkyl derivatives, a transparent, non hazy as well as less vis 0283 Such pharmaceutical actives or drugs can be effec cous solution is obtained, which can be useful as I.M as well tively solubilised by utilization of Diethylene glycol mono as I.V. injections for rapid onset of action when required to ethyl ether or other alkyl derivatives as a primary vehicle or provide earliest result into the patient as well as can be used Solvent, to provide clear, transparent, non hazy Solutions of for formulation of different dosage forms like capsules, gels, the said pharmaceutical actives or drugs in the said vehicle or topical gels, vaginal Suppository, liquid oral dosage forms etc. solvent, which are further less viscous and are ready to use The solution may additionally contain preservatives and buff for parenteral administration through I.V., I.M. or other routes ers for maintenance of pH. of injection or can be used for formulation of various other 0290 I.2) Nandrolone Decanoate (Steroids & Hor dosage forms of the pharmaceutical actives or drugs, such as mones) for example, capsules, tablets, nasal sprays, gargles, dermal 0291 Nandrolone (19-nortestosterone, I.2) is an anabolic applications, gels, ocular, otic, liquid oral dosage forms and steroid that may be present naturally in the human body. other dosage forms. Further, when administered parenterally, Nandrolone is most commonly sold commercially as its the solutions are easily flowable, easily Syringable, easy to decanoate ester and as a phenyl propionate ester. inject and cause less pain at the site of the injection and are 0292 Nandrolone decanoate (D1) is synthetic derivative therefore, beneficial not only to the patients bit also to the of testosterone indicated for the management of the anemia of doctors/physicians/nurses. Furthermore, the pharmaceutical renal insufficiency and has been shown to increase hemoglo compositions are safe and less toxic, when administered bin and red cell mass. The chemical formula of Nandrolone through various routes, especially if administered parenter decanoate is as Estr-4-en-3-one, 17-(1-oxodecyl)oxy-, ally. In addition, utilization of Diethylene glycol monoethyl (17b)-17b-Hydroxyestr-4-en-3-one decanoate The molecu ether or other alkyl derivatives enhances the chemical and biological stability of the pharmaceutical actives or drugs and lar formula of decanoate esteris CHO and the molecular also offers a better permeation of such actives or drugs. structure is given as: 0284 Diethylene glycol monoethyl ether or other alkyl derivatives offers comparatively less viscosity (of less than (I.2) 7-8 cps if used alone in the composition and less than 15 cps OOCCH2(CH2)6CH2CH3 if used as co solvents in few examples) if administered CH through parenteral routes. H 0285. The various pharmaceutical actives or drugs, H belonging to this class, to name a few are the following, which again to reiterate is non-limiting as far as the scope of the H invention, is concerned. 0286 I.1) Progesterone (Steroids & Hormones) O 0287 Progesterone also known as P4 (pregn-4-ene-320 dione) is a C-21 steroid hormone involved in the female 0293 Nandrolone decanoate (CHO) occurs as a fine, menstrual cycle, pregnancy (Supports gestation) and embryo white to creamy white, crystalline powder. It is odorless, or genesis of humans and other species. Progesterone belongs to may have a slight odor. Nandrolone decanoate is soluble in US 2014/0296.191 A1 Oct. 2, 2014

chloroform, in alcohol, in acetone, and in vegetable oils. It is 0299 I.3, I.3, I.3) Testosterone and its Salt Forms i.e. practically insoluble in water. As Nandrolone decanoate, it is Testosterone Enanthate and Testosterone Cypionate (Steroids available as a sterile oleaginous solution in which sesame oil & Hormones) is administered. It is available in dose of 100 mg/ml in which 0300 Testosterone is an anabolic steroid hormone which upto 10% of benzyl alcohol is used as solubilizer as well as is also used in prevention of Osteoporosis. Its molecular preservative. While, benzyl alcohol can be used in 2% to 4% formula is CHO, (M.W-288.4) with the following struc as preservative in parenterals but at 10% of concentration it ture as: shows anesthetics effect. While sesame oil makes the injec tion more Viscous, this can be painful at the site of injection.

0294 By utilizing the vehicle or solvent of the present (I.3) invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis cous solution is obtained, which can be useful as I.V. bolus injection or Depot I.M. injection for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, nasal sprays, gargles, gels, topical, liquid oral dos age forms etc. The Solution may additionally contain preser vatives and buffers for maintenance of pH. 0295 I:2) Nandrolone Phenyl Propionate (Steroids & 0301. It is white crystalline or yellowish white crystals, Hormones) practically insoluble in water, and fatty oils. It has low bio 0296 Nandrolone phenyl propionate is an I.M. injectable availability with half-life of 2 to 4hrs and metabolism occurs form of the anabolic steroid Nandrolone. It is chemically in liver, testis and prostate. It is useful intestosterone replace designated as 17b-hydroxyestr-4-en-3-one 17-(3-phenylpro ment therapy in male hypogonadal disorders, and also pionate) and the chemical structure is given as: improves type 2 diabetes. 0302 Testosterone enanthate is a derivative of the primary endogenous androgen testosterone, for intramuscular admin (I.2p) istration. In their active form, androgens have a 17-beta hydroxy group. Esterification of the 17-beta-hydroxy group increases the duration of action of testosterone; hydrolysis to free testosterone occurs in vivo.

(I.3) (?) (2) OCO(CH) CH CH (2) (2) (2) H CH

0297. It is a white to creamy white, crystalline powder, H practically insoluble in water. Nandrolone phenylpropionate is active for about a week. Esterified steroids are less polar O than free steroids, and are absorbed more slowly from the area C26H40O3 of injection. Once in the bloodstream, the ester is removed to MW: 400.6 yield free (active) 37aphtha37ol. Esterified steroids are designed to prolong the window of therapeutic effect follow (2) indicates text missing or illegible when filed ing administration, allowing for a less frequent injection schedule compared to injections of free (unesterified) steroid. (0303 Testosterone enanthate (CHO) (M.W. 400.60) Nandrolone is not C-17 alpha alkylated, and not known to is a white or creamy white, crystalline powder. It is odorless have hepatotoxic effects in healthy subjects. Nandrolone Phe or has a faint odor characteristic of heptanoic acid. It is nyl Proprionate is available in select human human drug insoluble in water, very soluble in ether and soluble in veg markets in compositions and dosage containing 25 mg/mL or etable oils. Testosterone Enanthate Injection is a clear, color 50 mg/ML of the steroid dissolved in oil. less to pale yellow sterile oleaginous solution of testosterone 0298 By utilizing the vehicle or solvent of the present enanthate for intramuscular use. Each mL contains: Test invention solvent, Diethylene glycol monoethyl ether or other osterone Enanthate 200 mg. Chlorobutanol (Chloral deriva alkyl derivatives, a transparent, non hazy as well as less vis tive) 0.5% in Sesame Oil qs. cous solution is obtained, which can be useful as I.M as well 0304 Testosterone cypionate is the lipophilic active as I.V. injections for rapid onset of action when required to 17(beta)-cyclopentylpropionate ester of the androgenic hor provide earliest result into the patient as well as can be used mone testosterone. It is a white or creamy white crystalline for formulation of different dosage forms like capsules, nasal powder freely soluble in ether with the chemical formula is sprays, gargles, gels, topical, liquid oral dosage forms etc. androst-4-en-3-one, 17-(3-cyclopentyl-1-oxopropoxy)-. The solution may additionally contain preservatives and buff (17B)-. Its molecular formula is CHO with the molecular ers for maintenance of pH. weight 412.61. US 2014/0296.191 A1 Oct. 2, 2014 17

0305 The structural formula is represented below: methanol, dehydrated ethanol, dioxane and ether, slightly (I.3B) soluble in light petroleum. According to U.S. Pat. No. 7,025, 979, the invention shows a formulation for male contracep tion comprising a progestin possessing both estrogenic and for 1) androgenic properties is remarkably effective for spermato genesis Suppression in males. The progestin Norethisterone (NET), particularly its derivatives Norethisterone acetate and Norethisterone enanthate in Sufficient doses induce oligoZo ospermia or azoospermia in males. 0313 By utilizing the vehicle or solvent of the present O invention solvent, Diethylene glycol monoethyl ether or other 0306. It is available in parenteral form in two strengths, alkyl derivatives, a transparent, non hazy as well as less vis 100 mg/ml and 200 mg/ml. It is recommended to inject the cous solution is obtained, which can be useful as I.V. injection drug in the buttocks after every 7-12 days for maximum for rapid onset of action when required to provide earliest results. At a time, whole of testosterone will remain bound to result into the patient as well as can be used for formulation of the protein while only 2% will be available and is secreted in different dosage forms like capsules, nasal sprays, gargles, to the blood. It is indicated for replacement therapy in the gels, topicals, liquid oral dosage forms etc. The solution may male in conditions associated with symptoms of deficiency or additionally contain preservatives and buffers for mainte absence of endogenous testosterone. nance of pH. 0307 The ester forms are available as oil based depot type 0314 I.5) 17B Estradiol (Steroids & Hormones) parenteral preparation in which sesame oil or cottonseed oil is 0315 Estradiol (E2 or 17? 3-estradiol) is a sex hormone used, which might cause pain as well as allergic reaction This which is abbreviated E2 as it has two hydroxyl groups in its may lead to abscess formation, Sores and some skin infec tions. Moreover, a single site cannot be used for injection molecular structure. The chemical name of this lipophilic every time. Due to their bulkiness/viscous nature it may be active is (17B)-estra-1,3,5(10)-triene-3,17-diol with molecu difficult to syringe it. lar formula and molecular structure is as: 0308) By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis (I.5) cous solution is obtained, which can be useful as I.M as well as I.V. injection for rapid onset of action when required to provide earliest result into the patient. The solution may addi tionally contain preservatives and buffers for maintenance of pH. 0309. I.4) Norethisterone Enantate (Steroids & Hor mones) HO 0310 Norethisterone enantate is a synthetic progestin, contraceptive usually given through intragluteal route as a single injection in strength of 200 mg/ml. It continuously 0316. It is used, either as an injection or topically, in the releases its progestin into the bloodstream over a period of treatment of inflammation, allergy, collagen diseases, eight weeks (2 months). A second and final injection may be asthma, adrenocortical deficiency, shock, and Some neoplas given eight weeks after the first injection if necessary. Nore tic conditions. This hormone is available as salt form like thisterone enantate is only used as a short-term method of Estradiol Benzoate, Estradiol Cypionate, Estradiol Valerate in contraception in certain circumstances. parenteral forms which are used in treatment of female 0311. It is chemically designated as 17alpha-Ethynyl-19 hypogandism. These salts are sparingly soluble in oil like nortestosterone 17-heptanoate and the molecular structure is sesame oil so it may be chances of stability problem. given as: 0317. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis (I.4) cous solution is obtained, which can be useful as I.V. injection for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, nasal sprays, gargles, gels, topicals, transdermal discs, intravaginal rings, liquid oral dosage forms etc. The solution may additionally contain preservatives and buffers for maintenance of pH. 0318 I.6) Fulvestrant (Steroids & Hormones) 0319 Fulvestrant is an estrogen receptor antagonist as a drug for treatment of hormone receptor-positive metastatic O breast cancer in postmenopausal women with disease pro (2) indicates text missing or illegible when filed gression following anti-estrogen therapy. 0320. The chemical name is 7-alpha-9-(4.4.5.5.5-penta fluoropentylsulphinyl)nonylestra-1,3,5-(10)-triene-3, 0312. It is a white to creamy white, crystalline powder; 17beta-diol. The molecular formula is CHFOS and its practically insoluble in water; freely soluble in acetone, structural formula is: US 2014/0296.191 A1 Oct. 2, 2014 18

0327. It is a white crystalline powder with a bitter taste; (I.6) practically insoluble in water, soluble in chloroform, acetone, OH and alcohols. It is a relatively lipophilic and unstable drug. Artemether is highly effective against the blood schizonts of both malarial parasites Pfalciparum and P. vivax. Its unique features are: 0328. Unlike most other antimalarial, it lacks a nitrogen containing heterocyclic ring system; 0329 Is equally as effective as quinine in the treatment of severe malaria; and 0330 Is as effective as quinine in the treatment of cerebral malaria. 0321 Fulvestrant is a white powder with a molecular 0331. It is available as I.M injection form at dose of 80 weight of 606.77. It is available as injection for intramuscular mg/ml. for adult and accepted as 20 mg/ml for pediatric administration. The solution for injection is a clear, colorless patients by WHO. The product available in the market is to yellow, viscous liquid. Fulvestrant is soluble in ethanol, prepared in miglycol, Medium chain triglyceride oils which DSMO, Dimethyl formamide and practically insoluble in may below viscous but are irritant at the site of injection. Water. 0332 By utilizing the vehicle or solvent of the present 0322 This injection contains upto 10% of benzyl alcohol invention solvent, Diethylene glycol monoethyl ether or other which might act as anaesthetic level while castor oil USP is alkyl derivatives, a transparent, non hazy Solution is obtained, used as release rate modifier which can be viscous that can be which can be useful as I.M as well as I.V. injections for rapid painful at the time of injection and the solution might be onset of action when required to provide earliest result into appear yellowish color too. According to FDA drug approval the patient. The solution may additionally contain preserva Summaries, injection site reaction and hot flashes were tives and buffers for maintenance of pH. The solution can also observed. be used for formulation of other dosage forms, such as cap 0323 By utilizing the vehicle or solvent of the present Sules, gel, patches, liquid dosage forms etc. invention solvent, Diethylene glycol monoethyl ether or other 0333 I.8) Arteether (Antimalarial) alkyl derivatives, a transparent, non hazy as well as less vis 0334 Arteether is the ethyl ether derivative of artemisinin, cous solution is obtained, which can be useful as I.V. injection a natural product of the Chinese plant Artemisia annua. It is for rapid onset of action when required to provide earliest currently only used as a second line drug in severe cases of result into the patient. The Solution may additionally contain malaria as fast acting blood Schizontocidal agent for Pfalci preservatives and buffers for maintenance of pH. parum malaria at the erythrocytic stage. The molecular for 0324. In a similar way, Anabolic steroids like Boldenone mula is C7H8Os and molecular weight is 312.4. The Undecylanate, Drostanolone propionate, Trenbolone molecular formula of Arteether is 10-Ethoxydecahydro-3,6, Acetate, Trenbolone Enanthate, Methenolone Enanthate, 9-trimethyl-3,12-epoxy-12H-pyrano.4.3-i-1,2-benzodiox Methyl Testosterone can also be prepared as I.M and I.V. epin with molecular structure is given as: injectable forms by utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether (I.8) or other alkyl derivatives to give a transparent, non hazy as well as less Viscous solution. 0325 I.7) Artemether (Antimalarial) 0326. It is a methyl ether derivative of artemisinin, which is a peroxide lactone isolated from the Chinese antimalarial plant, Artemisia annua. It is also known as dihydroartemisi nin methyl ether, but its correct chemical nomenclature is (+)-(3-alpha.5a-beta,6-beta.8a-beta, 9-alpha,12-beta, 12aR)- decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12H pyrano (4.3-)-1,2-benzodioxepin with the molecular struc 0335. It is quite water insoluble, but very soluble in a ture as variety of organic solvents. It is available in injection form in market as intramuscular application at the dose of 150 mg/2 ml.

(I.7) 0336. In one of the parenteral formulation available in the market, it is manufactured by incorporation of ethyl oleate which is yellow color liquid, addition of alcohols ethyl alco hol, benzyl alcohol and group of preservatives which leads to high cost product as well as Viscous formulation which can be irritant at site of injection. This problem can be solved by using the selected Solvent in the present invention to prepare I.V. parenteral. 0337. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis cous solution is obtained, which can be useful as I.V. injection for rapid onset of action when required to provide earliest US 2014/0296.191 A1 Oct. 2, 2014

result into the patient. The Solutions can be prepared in con 0344. By utilizing the vehicle or solvent of the present centrations of 150 mg/ml or 75 mg/ml. The solution may invention solvent, Diethylene glycol monoethyl ether or other additionally contain preservatives and buffers for mainte alkyl derivatives, a transparent, non hazy as well as less vis nance of pH. The solution can also be used for formulation of cous solution is obtained, which can be useful as I.M. injec other dosage forms, such as capsules. tion of 6,00,000 IU per ml and optionally containing pre 0338 I.9) Haloperidol (Antipsychotic) servatives and antioxidants for rapid onset of action when 0339 Haloperidol is the first of the butyrophenone series required to provide earliest result into the patient. The solu of major antipsychotics. The chemical designation is 4-4-(p- tion can preventissue damage and pain at the site of injection, chlorophenyl)-4-hydroxypiperidino-4'-fluorobutyrophe caused by oily injections currently available in the market. none and it has the following structural formula: I.V. infusion is also possible, since the safety of the same has (I.9) been established. The solution is easily syringable and can be combined with calcium salts using water or mixed with co OH solvents for combined therapy after homogenization. The solution can also be used for formulation of different dosage forms like capsules, tablets, nasal sprays, gargles, gels, topi ()--inchO cals, liquid oral dosage forms etc. The solution may addition ally contain preservatives and buffers for maintenance of pH. 0345 A2) Medroxy Progesterone Acetate C 0346 Medroxyprogesterone acetate, also known as 17C.- (2) indicates text missing or illegible when filed hydroxy-6C.-methylprogesterone acetate, and commonly abbreviated as MPA, is a steroidal progestin, a synthetic vari 0340. The product has very low solubility in water (1.4 ant of the human hormone progesterone. It is used as a con mg/100 ml), but it is freely soluble in chloroform, benzene, traceptive, in hormone replacement therapy and for the treat methanol, acetone, and dilute acids. It is soluble in 0.1 N ment of endometriosis as well as several other indications. It hydrochloric acid (3 mg/ml) with heating. is chemically designated as 17O-hydroxy-6C.-methylpregn 0341 Haloperidol is available as a sterile parenteral form 4-ene-3,20-dione acetate and molecular structure is: for intramuscular injection. The injection provides 5 mghalo peridol (as the lactate) and lactic acid for pH adjustment between 3.0-3.6. Haloperidol Injection is recommended for (A2) intramuscular administration only. Skin rash and injection site reaction has been found by use of this parenteral. 0342. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, not only a transparent, non hazy as well as less viscous solution is obtained, which can be useful as I.V. or I.M. injections for rapid onset of action when required to provide earliest result into the patient, but also the rashes at the site of injection is prevented. The solution can also be used for formulation of different dosage forms like capsules, tab lets, nasal sprays, gargles, gels, topicals, liquid oral dosage forms etc. The Solution may additionally contain preserva tives and buffers for maintenance of pH. 0347 MPA is a more potent derivative of its parent com (0343 I.10) Vitamin D. (Vitamins & Minerals) pound medroxyprogesterone. It is a white to off-white, odor Presently Cholecalciferol (Vitamin D.) is available as oily less crystalline powder, stable in air, melting between 200° Viscous injectable which is painful when administered and and 210°C. It is freely soluble in chloroform, soluble in needs to be modified into less viscous and painless injection. acetone and in dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether and insoluble in water. It is (I.10) available as Aqueous Suspension active by the parenteral and CH oral routes of administration. It is available as intramuscular injection in which each ml consists of 400 mg/ml MPA. The vehicle used as parenteral solvent is PEG 3350. (0348. The viscosity of PEG 3350 is about 83 to 130 cps, which is more viscous and may be painful to patient at the time of injection. As it is available in Suspension form, sta bility, particle size, and storage of the product are critical factors for handling 0349. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis cous solution is obtained, which can be useful as I.M as well as I.V. injections for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, nasal US 2014/0296.191 A1 Oct. 2, 2014 20 sprays, gargles, gels, topical, liquid oral dosage forms etc. preferably in the parenteral form for the treatment of pain & The solution may additionally contain preservatives and buff inflammatory. In this invention, solvent Dimethyl Isosorbide ers for maintenance of pH. (DMI) is used which was found to be irritant at site of appli 0350. I.11) Allyoestrenol (Steroids & Hormones) cation as well as during long term storage, there was possible 0351. It is a synthetic progestogen with progestational crystal formation of the drug in the liquid. activity used to prevent threatened miscarriage, recurrent 0357 By utilizing the vehicle or solvent of the present pregnancy loss and premature labor. In men, it has also been invention solvent, Diethylene glycol monoethyl ether or other studied as a treatment for benign prostatic hyperplasia, with alkyl derivatives, a transparent, non hazy as well as less vis encouraging results. It is chemically denoted as (17B)-17 cous solution is obtained, which can be useful as I.V. injection (prop-2-en-1-yl)estr-4-en-17-ol and the molecular structure for rapid onset of action when required to provide earliest is given as: result into the patient as well as can be used for formulation of different dosage forms like capsules, gels, patches, liquid oral dosage forms etc. The Solution may additionally contain pre

(I.11) servatives and buffers for maintenance of pH. 0358 Other drugs under this category like Firocoxib, Mavacoxib, Robenacoxib, Cimicoxib that are used for veteri nary can be also be compounded into parenteral preparation by utilization the vehicle or solvent of the present invention, Diethylene glycol monoethyl ether or other alkyl derivatives. 0359 Newer drugs of this category like Tilmacoxib (I.12) which was found to be an effective chemo-preventive agent against rat experimental liver fibrosis can also be pre pared as parenteral dosage form by using diethyleneglycol 0352. It is practically insoluble in water. According to U.S. mono ethyl ether. The chemical name of Tilmacoxib is 4-(4- Pat. No. 6,696,433, this sex steroid was prepared in injectable cyclohexyl-2-methyl-1,3-oxazol-5-yl)-2 fluorobenzene form by improving its solubility using beta cyclodextrin. Sulfonamide with molecular structure as: 0353. It is available in injectable form at dose of 250 mg/ml and as oral dosage format dose of 5 mg per tablet in the market. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other (I.12A) alkyl derivatives, a transparent, non hazy as well as less vis cous solution is obtained, which can be useful as I.M as well as I.V. injection for rapid onset of action when required to stS provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, nasal (2) sprays, gargles, gels, topicals, liquid oral dosage forms etc. 21 The solution may additionally contain preservatives and buff (2) ers for maintenance of pH. S 0354 I. 12, 1.12.) Etoricoxib and Tilmacoxib (Cox-2 Inhibitors) 2N. (2) 0355 Like any other COX-2 selective inhibitor, Etero coxib selectively inhibits isoform 2 of the enzyme cyclooxy genase (COX-2). This reduces the generation of prostaglan () dins (PGs) from arachidonic acid. The chemical name of Etoricoxib is 5-chloro-6'-methyl-3-4-(methylsulfonyl)phe (2) indicates text missing or illegible when filed nyl-2,3'-bipyridine with molecular structure as: 0360 Tilmacoxib is still new active without any dosage preparation available in the market. O. O (I.12) 0361 Here also, by utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether \/ HC1 or other alkyl derivatives, a transparent, non hazy as well as less viscous solution is obtained, which can be useful as I.V. injection for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, gels, patches, liquid oral dosage forms etc. The solution may addi tionally contain preservatives and buffers for maintenance of pH. 0362. I.13) Cyclosporine (Immunosuppressant) 0363 Cyclosporine is an immunosuppressant drug widely 0356. It is very low soluble in water about 3.3 mg/L. used in organ transplantation to prevent rejection. It reduces According to Indian Patent No. 146674, the invention was the activity of the immune system by interfering with the related to a clear, stable novel pharmaceutical preparation of activity and growth of T cells. Cyclosporine is a cyclic selective cyclooxygenase II inhibitors (COX 2) inhibitors polypeptide immunosuppressant agent consisting of 11 US 2014/0296.191 A1 Oct. 2, 2014

amino acids. It is chemically designated as (E)-14, 17.26.32 cancer, and advanced forms of Kaposi's sarcoma. Paclitaxel tetrabutyl-5-ethyl-8-(1-hydroxy-2-methylhex-4-enyl)-1,3,9. is also used for the prevention of restenosis. 12,15, 18.20.23.27-nonamethyl-11,29-dipropyl-1,3,6,9,12, 0368 Paclitaxel is chemically designated as (2C.4C,5B, 15, 18.21,24,27.30-undecaazacyclodotriacontan-2,4,7,10,13, 7 B, 10B, 13c.)-4,10-bis(acetyloxy)-13-(2R.3S)-3-(benzoy 16, 19.22.25.28,31-undecaoneand molecular structure is: lamino)-2-hydroxy-3-phenylpropanoyloxy)-1,7-dihy droxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate and the molecular structure is given as: (I.13) O (?) (I.14) On Na1n ----- O

(2) (2) -SO )- O OH (2) -9- (2) (2) OHS () O (o O -N (3) N (2) O (2) (2)

() indicates text missing or illegible when filed 0369. The nomenclature for Paclitaxel is structured on a tetracyclic 17-carbon (heptadecane) skeleton. Paclitaxel is a white to off-white crystalline powder with the empirical for 0364 The drug exhibits very poor solubility in water, and, mula C7H5NO and a molecular weight of 853.9. It is as a consequence, Suspension and emulsion forms of the drug highly lipophilic, insoluble in water, and melts at around have been developed for oral administration and for injection. 216-217o C. cyclosporine injection, USP, is available in a 5 mL sterile 0370 Paclitaxel Injection is a slightly yellow viscous solu ampoule for I.V. administration in which Each mL contains: tion. It is Supplied as a nonaqueous Solution intended for cyclosporine, USP 50 mg. Cremophor R EL (polyoxyethy dilution with a suitable parenteral fluid prior to intravenous lated castor oil) 650 mg, alcohol about 32.9% by volume infusion. It is available in 30 mg (5 mL), 100 mg (16.7 mL), which must be diluted further with 0.9% Sodium Chloride and 300 mg (50 mL) multidose vials. Each mL of sterile Injection or 5% Dextrose Injection before use. As discussed nonpyrogenic Solution contains 6 mg paclitaxel, 527 mg of earlier, Cremophor R EL was found to have acute anaphylac purified Cremophor R EL (polyoxyethylated castor oil) and toid reaction and requires administration of antihistamines 49.7% (v/v) dehydrated alcohol, USP. From the above for prior to the injection and thus the double injections cause mulation, it is easily to guess that how much painful would be discomfort to the patients. the injection when given to the cancerous patient. It might be 0365. By utilizing the vehicle or solvent of the present Surprisingly advantage to prepare the injection of this highly invention solvent, Diethylene glycol monoethyl ether or other lipophilic active by its solubilizing in the present permeating alkyl derivatives, not only a transparent, non hazy as well as enhancer without any reaction that might be possible to occur less viscous solution is obtained, which can be useful as I.V. by Cremophor R. E.L. or I.M. injections for rapid onset of action when required to provide earliest result into the patient, but also does not have 0371. It is now available and marketed as conjugation as a the safety and toxicity issues associated with Cremophor(R) albumin complex.The technique to prepare the same is costly EL. The solutions can be prepared in concentrations of 25 and is uneconomic and does not cater the need of the poor. mg/ml to 100 mg/ml. The solution can also be used for for Cancer is prevalent is various countries in vast majority of mulation of different dosage forms like capsules, tablets, global population. liquid oral dosage forms etc. The Solution may additionally 0372. By utilizing the vehicle or solvent of the present contain preservatives and buffers for maintenance of pH. invention solvent, Diethylene glycol monoethyl ether or other 0366 I.14) Paclitaxel (Anticancer Agent) alkyl derivatives, not only a transparent, non hazy as well as 0367 Paclitaxel is a mitotic inhibitor used in cancer che less viscous solution is obtained, which can be useful as I.V. motherapy. When it was developed commercially by Bristol injections for rapid onset of action when required to provide Myers Squibb (BMS), the generic name was changed to earliest result into the patient, but also does not have the safety Paclitaxel and the BMS compound is sold under the brand and toxicity issues associated with Cremophor R EL as well name Taxol. R. In this formulation, Paclitaxel is dissolved in as does not involve the complex and expensive technology Cremophor EL and ethanol, as a delivery agent. Another involved for making albumin based complexes. The Solution formulation, in which paclitaxel is bound to albumin, is sold can also be used for formulation of different dosage forms under the brand name Abraxane R, which is prepared using like capsules, tablets, liquid oral dosage forms etc. The solu Nanotechnology and hence a costly technique. Paclitaxel is tion may additionally contain preservatives and buffers for used to treat patients with lung, ovarian, breast, head and neck maintenance of pH. US 2014/0296.191 A1 Oct. 2, 2014 22

0373). I.15) Piroxicam (Antirhuematic Actives for Mus culo Skeletal System Oxicams) (I.16) O 0374. Oxicams are members of a class of NSAIDs that bind closelytoplasma proteins. Most oxicams are unselective inhibitors of the cyclooxygenase (COX) enzymes, which N7–4. includes PiroXicam. Its anti-inflammatory potency is similar to Indomethacin and analgesic action is greater than Aspirin. It has useful antipyretic property. PiroXicam is chemically designated as (8E)-8-hydroxy-(pyridin-2-ylamino)meth ylidene-9-methyl-10,10-dioxo-10.6-thia-9-azabicyclo4.4. Odeca-1,3,5-trien-7-one with molecular structure as: C

0384. It is a light yellow crystalline powder insoluble in (I.15) water, sparingly soluble in acetone and chloroform and 21 O OH slightly soluble in alcohol. It has a molecular weight of 315. 72. Clonazepam was approved in the United States as a N N 21 generic drug in 1997 and is now manufactured and marketed H by several companies. Clonazepam is available as tablets and orally disintegrating tablets (wafers), oral Solution (drops), as 1ns well as solution for injection or intravenous infusion. This / \, injection is appearing as lightly greenish yellow solution. 0385 For panic disorder, the initial recommended dose is 0.25 mg twice daily. This dose can be increased every three 0375. It is a white crystalline solid; sparingly soluble in days in increments of 0.125-0.25 mg twice daily. The target water (23 mg/L at 22°C.), dilute acid and organic Solvents; dose for panic disorder is 1.0 mg per day, although some people benefit from doses up to a maximum of 4 mg per day. slightly soluble in alcohols and in aqueous alkalines. It is When a person stops taking Clonazepam, the drug should be available as injection in dose of 20 mg/2 ml. gradually discontinued by decreasing the dose by 0.125 mg 0376. In U.S. Pat. No. 4,628,053: Invention relates to sta twice daily every three days. bilized injection solutions of Piroxicam in which propylene 0386 Although, clonazepam is not FDA-approved for the glycol, ethanol and water as the solvent for parenteral admin treatment of post-traumatic stress disorder, doses in the range istration which might be viscous and painful at the site of of 0.25-3 mg daily appears to help treat symptoms of this injection. disorder. Daily dosages for the treatment of social phobia range from 1.0-2.5 mg, while the dosage to control mania 0377. In U.S. Pat. No. 4,824.841, Invention relates to a may be as high as 10 mg daily. process for the transformation of Piroxicam into anhydrated 0387 By utilizing the vehicle or solvent of the present form suitable for Oral, topic or parenteral administration. invention solvent, Diethylene glycol monoethyl ether or other 0378. In U.S. Pat. No. 4,942,167, Aqueous pharmaceuti alkyl derivatives, a transparent, non hazy as well as less vis cal formulation containing lyophilized Piroxicam in Glycine cous solution is obtained, which can be useful as I.V. injec as vehicle which is not transparent Solution and stability can tions for rapid onset of action when required to provide ear be issue. liest result into the patient. The solution can also be used for 0379. In U.S. Pat. No. 5,420,124A, Invention relates to an formulation of different dosage forms like capsules, tablets, injectable PiroXicam potassium composition which contains liquid oral dosage forms etc. The Solution may additionally triethyleneglycol as a solvent and stabilizer. contain preservatives and buffers for maintenance of pH. 0388. I.17) Diazepam (Anticonvulsant) 0380. By utilizing the vehicle or solvent of the present 0389 Diazepam is a benzodiazepine derivative chemi invention solvent, Diethylene glycol monoethyl ether or other cally designated as 7-chloro-1,3-dihydro-1-methyl-5-phe alkyl derivatives, a transparent, non hazy as well as less vis nyl-2H-1,4-benzodiazepin-2-one. It is a colorless crystalline cous solution is obtained, which can be useful as I.V. injection compound, insoluble in water, with the following molecular for rapid onset of action when required to provide earliest Structure: result into the patient as well as can be used for formulation of different dosage forms like capsules, nasal sprays, gargles, gels, topical, liquid oral dosage (I.17) 0381 I.16) Clonazepam (Anticonvulsant) 0382 Clonazepam is a benzodiazepine drug having anxi olytic, anticonvulsant, muscle relaxant, sedative, and hyp notic properties. 0383 Clonazepam is classified as a high potency benzo diazepine. Clonazepam is a chlorinated derivative of nitrazepam. It is a light yellow crystalline powder. It has a molecular weight of 315.72 It is chemically designated as 5-(2-chlorophenyl)-7-nitro-2,3-dihydro-1,4-benzodiazepin 2-one and the molecular structure is given as: US 2014/0296.191 A1 Oct. 2, 2014

0390 Diazepam Injection, USP is a sterile, nonpyrogenic tions are easily flowable, easily Syringable, easy to inject and Solution intended for intramuscular or intravenous adminis cause less pain at the site of the injection and are therefore, tration. Each milliliter (mL) contains 5 mg diazepam; 40% beneficial not only to the patients bit also to the doctors/ propylene glycol; 10% alcohol; 5% sodium benzoate and physicians/nurses. Furthermore, the pharmaceutical compo benzoic acid added as buffers; and 1.5% benzyl alcohol added sitions are safe and less toxic, when administered as a preservative. pH 6.6 (6.2 to 6.9). Solution may appear light yellow. Diazepam Injection is classified by the Drug 0396 The various pharmaceutical actives or drugs, Enforcement Administration as a schedule IV controlled sub belonging to this class, to name a few are the following, which stance. The usual recommended dose in older children and again to reiterate is non-limiting as far as the scope of the adults ranges from 2 mg to 20 mg IM or IV, depending on the invention, is concerned. indication and its severity. Diazepam Injection is injected deeply into the muscle while given through I.M. and through 0397 II.1) Hydrocortisone Acetate (Steroids & Hor I.V., the Solution may be injected slowly, taking at least one mones) minute for each 5 mg (1 mL) given. This might be due to its 0398 Hydrocortisone is the main glucocorticoid secreted Viscosity. by the adrenal cortex. Its synthetic counterpart, Hydrocorti 0391 Thus it is possible to produce less viscous, clear Sone acetate is a hormone used to treat local pain and Swelling viable injectable with Diethylene glycol monoethyl ether. (inflammation) due to joint problems (e.g., arthritis, bursitis) 0392 By utilizing the vehicle or solvent of the present or certain skin conditions (e.g., keloids, psoriasis). The invention solvent, Diethylene glycol monoethyl ether or other chemical name for cortisone acetate is pregn-4-ene-3,11.20 alkyl derivatives, a transparent, non hazy as well as less vis trione, 21-(acetyloxy)-17-hydroxy and the molecular weight cous solution is obtained, which can be useful as I.V. or I.M. is 402.49. The structural formula is represented below: injections for rapid onset of action when required to provide earliest result into the patient. Since the solution is less vis cous, it can be easily filtered aseptically and is easily Syring (II.1) able. The solution can also be used for formulation of differ CHOOCCH ent dosage forms like capsules, tablets, liquid oral dosage (2) forms etc. The Solution may additionally contain preserva tives and buffers for maintenance of pH. Class II: Pharmaceutical Actives or Drugs which have Stabil ity Issues 0393 As mentioned hereinbefore, there are certain phar maceutical actives or drugs, which have inherent stability issues i.e. instability and often require complex and expensive technology for formulation of such actives into suitable stable dosage forms. (?) indicates text missing or illegible when filed 0394 Typical example is that of pharmaceutical actives or drugs that are marketed as Lyophilized Powders or as a Dry Fill Powder and which requires reconstitution while injecting to the patient. The process of reconstitution in clinical prac tice is many times cumbersome due to fact that doctor and 0399. A white or almost white, crystalline powder, odour health workers are always conscious for injecting the clear less, practically insoluble in water; slightly soluble in ethanol liquid without leaving the trace of particles remaining as (-750 g/l). It is mostly available as tablet of strength 5 mg or unsolubilized. Further, if the reconstituted clear liquid is kept 10 mg and as powderfor solution in the market for I.M as well over a shelf, commonly the drug decomposes due to instabil as I.V. injections as it is an insoluble molecule in water. ity or may increase the bioburden during storage. Further, compositions containing Such pharmaceutical actives or 0400. By utilizing the vehicle or solvent of the present drugs are costly to manufacture, as the processes involve invention solvent, Diethylene glycol monoethyl ether or other lengthy and tedious technology. Due to the same, it is cost alkyl derivatives, a transparent, non hazy as well as less vis prohibitive and not beneficial to patients. cous solution is obtained, which can be useful as I.V. injection 0395. Such pharmaceutical actives or drugs can be effec for rapid onset of action when required to provide earliest tively stabilized by utilization of Diethylene glycol monoet result into the patient as well as can be used for formulation of hyl ether or other alkyl derivatives as a primary vehicle or different dosage forms like capsules, gels, creams patches, Solvent, to provide clear, transparent, non hazy Solutions of liquid oral dosage forms etc. The Solution may additionally the said pharmaceutical actives or drugs in the said vehicle or contain preservatives and buffers for maintenance of pH. solvent, which are further less viscous and are ready to use for parenteral administration through I.V., I.M. or other routes 04.01 II.2) 15-me-PGF: Carboprost (Steroids & Hor of injection or can be used for formulation of various other mones) dosage forms of the pharmaceutical actives or drugs, such as 04.02 15-me-PGF2alpha is as effective as natural for example, capsules, tablets, nasal sprays, gargles, dermal PGF2alpha in inducing abortions during very early preg applications, gels, topicals, liquid oral dosage forms and other nancy. Carboprost induces contractions and can trigger abor dosage forms. The Solutions are easy to manufacture, do not tion in early pregnancy. It also reduces postpartum bleeding. involve lengthy and tedious manufacturing processes and are Chemically it is designated (Z)-7-(3R,5S)-3,5-dihydroxy-2- therefore, economical, viable and hence beneficial to (E.3S)-3-hydroxy-3-methyloct-1-enylcyclopentylhept-5- patients. Further, when administered parenterally, the solu enoic acid and chemical structure is given as: US 2014/0296.191 A1 Oct. 2, 2014 24

0410. To overcome the poor solubility of Artesunate in (II.2) water a number of dosage forms and routes have been tried. 0411 Several potent derivatives with more suitable phar

maceutical properties have been developed in which, the Sodium salt of the hemisuccinate ester i.e., Sodium Artesunate which is soluble in water but have poor stability in aqueous Solutions. 0412 Artesunate is available in form of oral formulation, intramuscular formulation, intravenous formulation and Sup positories. It is available as dry free powder to be reconsti tuted using Sodium bicarbonate and water to prepare 6 mg/ml of liquid. This can cause problem of adverse reactions if not 0403. It is an Off-White Solid. Carboprost is a synthetic properly constitured with sodium bicarbonate as it leaves prostaglandin analogue of PGF2C (specifically, it is 15-me particulate matter and slight opalescence if the pharmaceuti thyl-PGF2C.) with oxytocic properties. cal active or drug is not highly pure. 0413 A Systemic review has suggested that intravenous 04.04. It is available in market inform of the tromethamine Artesunate should be the drug of choice in adults with severe salt of the (15S)-15 methyl analogue of naturally occurring malaria, particularly in Asia. prostaglandin F2C. in a solution Suitable for intramuscular injection. It contains Sodium chloride and benzyl alcohol as 0414 Sodium Artesunate was also found to be used in Solvent, which can cause hypersensitivity. Further, anaphy control of schistosomaniasis. It is soluble in water but has lactic reaction, anaphylactic shock, anaphylactoid reaction poor stability in aqueous solution. The limitation of present and angiodema have been reported in patients. Furthermore, products its instability when composition is prepared using the use of benzyl alcohol in maximum amount in this sterile alkalinser like sodium bi carbonate solution is associated with fatal “Gasping Syndrome' in pre 0415 By utilizing the vehicle or solvent of the present mature patients. invention solvent, Diethylene glycol monoethyl ether or other 0405. By utilizing the vehicle or solvent of the present alkyl derivatives, a transparent, non hazy as well as less vis invention solvent, Diethylene glycol monoethyl ether or other cous solution is obtained, which can be useful as I.V. injection alkyl derivatives, a transparent, non hazy as well as less vis for rapid onset of action when required to provide earliest cous solution is obtained, which can be useful as I.V. injection result into the patient. The solution may additionally contain for rapid onset of action when required to provide earliest preservatives and buffers for maintenance of pH. The solution result into the patient as well as can be used for formulation of can also be used for formulation of other dosage forms. Such different dosage forms like capsules, vaginal delivery like as capsules. sponge bars, Suppositories, liquid oral dosage forms etc. The 0416) II.4) Ergotamine Maleate (Oxytoxic) Solution may additionally contain preservatives and buffers 0417. Ergometrine maleate is a medicine which is used in for maintenance of pH. bleeding after labour and inducing or enhancing labour. It is available as Ergometrine 500 micrograms/1 ml solution for 0406 II.3) Artesunate (Antimalarial) injection ampoules when used in inducing labour. It is lipo 0407 Artesunate is an Artemisinin derivative with the philic in nature. The formulation is insoluble and often leads antimalarial activity having molecular structure (CoHsOs, to coloration of liquid with the observed reduction in potency. M.W 384.4): It needs to be stabilized with antioxidants. 0418. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other (II.3) alkyl derivatives, a transparent, non hazy as well as less vis cous solution is obtained, which can be useful as I.V. or I.M. injections for rapid onset of action when required to provide earliest result into the patient. The solution can also be used for formulation of different dosage forms like capsules, tab lets, liquid oral dosage forms etc. The Solution may addition ally contain preservatives and buffers for maintenance of pH. 0419 II.5, II.5.) Lansoprazole and Dexlansoprazole (Pro ton Pump Inhibitors) 0420 Lansoprazole (II.5) is a Proton Pump Inhibitor (PPI) in the same pharmacologic class as Omeprazole. It is avail 0408. The IUPAC name of the drug is as: (3R,5aS,6R,8aS, able as 30 mg administered nasogastrically, effectively con 9R,10S,-12R,12aR)-Decahydro-3,6,9-trimethyl-3,12-ep trols intragastric pH and is an alternative to I.V. Pantoprazole oxy-12H-pyrano-4.3-i-1,2-benzodioxepin-10-ol hydrogen in patients who are unable to Swallow solid dosage formula Succinate. It is a white crystalline powder, slightly soluble in tions. Lansoprazole is a racemate 1:1-mixture of the enanti Water. omers Dexlansoprazole and Levolansoprazole. 04.09. According to WHO recommendation, Artesunate is 0421 Dexlansoprazole (II.5) is an enantiomerically pure the first option for the parenteral treatment of severe falci active ingredient of a commercial drug as a result of the parum malaria, with the dose of 2.4 mg/kg intravenously or enantiomeric shift. Dexlansoprazole was approved by the intramuscularly, repeated after 12 and 24 hours and then once U.S. Food and Drug Administration (FDA) on Jan. 30, 2009. daily thereafter. It’s chemical name is (R)-(+)2-(3-methyl-4-(2.2.2-trifluoro US 2014/0296.191 A1 Oct. 2, 2014 25 ethoxy)pyridin-2-yl)methylsulfinyl)-1H-benzodimidazole with molecular structure of given as: (II.6)

(II.5) N / - N O (3 F F F 0428. In a bulk powder form, it appears as a white crystal 0422 Dexlansoprazole is a white to nearly white crystal line powder, and it is very slightly soluble in water and soluble line powder which melts with decomposition at 140°C. Dex in alcohol. lansoprazole is freely soluble in dimethylformamide, metha 0429 Fluconazole injection, USP in 0.9% NaCl adminis nol, dichloromethane, ethanol, and ethyl acetate; and soluble tered as intravenous infusion, is an iso osmotic solution con in acetonitrile; slightly soluble in ether; and very slightly taining 2 mg/ml of Fluconazole. It is initially administered soluble in water; and practically insoluble in hexane. double dose as loading dose to get earlier plasma steady state. Thus by the present art, this can be solved by making the 0423 Dexlansoprazole is stable when exposed to light. formulation as I.V. bolus injection which may provide earlier Dexlansoprazole is more stable in neutral and alkaline con plasma steady state concentration without increasing the ditions than acidic conditions. loading dose. There are also chances of precipitation or 0424. According to US Patent Application No. US 2011/ cloudy solution formation in I.V. infusion as it is free from 0028518 A1, Processes for the preparation of Dexlansopra preservative can also be prevented by new formulation using Zole, an amorphous form of Dexlansoprazole, a solid disper suitable preservative and buffer maintaining stability of the sion of amorphous Dexlansoprazole and a pharmaceutically product. Chances of air embolism or moisture may occur as acceptable carrier, and processes for their preparation is I.V. infusion is packed in plastic container which might be due made. Dexlansoprazole is available as solid dosage form as to plastic leaching. capsule of 30 mg and 60 mg. 0430 By utilizing the vehicle or solvent of the present 0425 The solution of the sodium salt for ready-to-use invention solvent, Diethylene glycol monoethyl ether or other administration is unstable in nature. This has been overcome alkyl derivatives, not only all the abovementioned problems by acidifying the solution to convert into a free acid form and are solves, but also a transparent, non hazy as well as less then solubilizing the same in Diethylene glycol monoethyl viscous solution is obtained, which can be useful as I.V. bolus ether or other alkyl derivatives to provide a transparent, non injection or Depot I.M. injection for rapid onset of action hazy solution is obtained, which can be useful as I.V. injection when required to provide earliest result into the patient as well for rapid onset of action when required to provide earliest as can be used for formulation of different dosage forms like result into the patient. The Solution may additionally contain capsules, nasal sprays, gargles, gels, topical, liquid oral dos preservatives and buffers for maintenance of pH. The solution age forms, otic delivery systems etc. The solution may addi shows good stability and can be used directly for parenteral tionally contain preservatives and buffers for maintenance of use, obviating the need for lyophilization when metal salts are pH. used. The solution can also be used for formulation of other 0431 II.7) Enalapril (ACE Inhibitor) dosage forms, such as capsules, tablets etc. 0432. It is a prodrug that belongs to the angiotensin-con verting enzyme (ACE) inhibitor class of medications. It is 0426 II.6) Fluconazole (Antifungal Agent) chemically designated as (2S)-1-(2S)-2-(2S)-1-ethoxy-1- 0427 Fluconazole also known as Diflucan R, is a triazole OXO-4-phenylbutan-2-yl)aminopropanoylpyrrolidine-2- antifungal agent first described in UK Patent Application No. carboxylic acid with chemical formula CoHNOs and 2099818 (Pfizer Limited). It is used worldwide for the treat molecular structure: ment of infections due to Candida, Cryptococcus, and other opportunistic yeasts or fungi. The drug is available as a tablet (50, 100, or 200 mg), as an oral Suspension, and as an intra (II.7) venous formulation (200 or 400 mg). When used in the treat HOOC ment of invasive candidiasis, e.g., bloodstream infections, CH3 deep tissue sites, or other normally sterile site infections, Fluconazole is administered as an initial loading dose of 800 mg (oral or intravenous) followed by a daily maintenance N dose of 400 mg (oral or intravenous). Fluconazole is desig nated chemically 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4- triazol-1-yl)propan-2-ol with an empirical formula CHFNO and molecular weight 306.3 The structural 0433. It is available as Enalaprilat (Enalapril Maleate) formula is given as: Injection, 1.25 mg per mL as I.V bolus or infusion. US 2014/0296.191 A1 Oct. 2, 2014 26

HeartFailure 0442. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other Adults alkyl derivatives, not only the abovementioned stability issues are solved, but also a transparent, non hazy as well as 0434 PO Initial dosage is 2.5 mg twice daily. Usual dos less viscous solution is obtained, but also the nephrotoxicity age is 2.5 to 20 mg/day in 2 divided doses (max, 40 mg/day). associated with the prior art composition is avoided. The Titrate doses upward as tolerated over a period of a few days Solutions remain clear without any precipitation even under or weeks. The max daily dose is 40 mg in divided doses. refrigerated conditions. The solutions can be useful as I.V. Hypertension injection for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, nasal Adults sprays, gargles, gels, topical, liquid oral dosage forms, otic 0435 POInitial dosage is 2.5 mg (patients on diuretics) to delivery systems etc. The solution may additionally contain 5 mg (patients not on diuretics) per day. Titrate to desired BP preservatives and buffers for maintenance of pH. control. Usual maintenance dosage is 10 to 40 mg/day in a 0443 II.9) Lignocaine (Anti-Arrhythmic Drug) single dose or 2 divided doses. 0444 Lignocaine Injection belongs to two groups of 0436 IV 1.25 mg over a 5-min period every 6 h. For medicines known as local anesthetics and antiarrhythmic patients at high risk of excessive hypotension, the starting drugs. It is injected as a dental anesthetic or as a local anes dose should be 0.625 mg or less administered IV overa period thetic for minor Surgery and it is used intravenously for the of 5 minor more and preferably longer (up to 1 h). treatment of ventricular arrhythmias 0437. By utilizing the vehicle or solvent of the present 0445 Lignocaine is white crystalline powder, practically invention solvent, Diethylene glycol monoethyl ether or other insoluble in water and freely soluble in ether. Lignocaine is alkyl derivatives, a transparent, non hazy as well as less vis chemically known as 2-(diethylamino)-N-(2,6-dimethylphe cous solution is obtained, which can be useful as I.V. bolus nyl)acetamide and the molecular structure is given as: injection for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, tablets, (II.9) liquid oral dosage forms etc. The Solution may additionally contain preservatives and buffers for maintenance of pH. 0438 II. 8) Methocarbamol (CNS Depressant) 0439 Methocarbamol is a carbamate derivative of guaifenesin, is a central nervous system (CNS) depressant r with sedative and musculoskeletal relaxant properties. Methocarbamol is a white powder, sparingly soluble in water 0446. One of the injections available in the market con and chloroform, soluble in alcohol (only with heating) and tains Lignocaine Hydrochloride 1% or 2% as the active ingre propylene glycol, and insolubleinbenzene and n-hexane. The dient and Sodium Chloride and Water for Injections as the available dose approved for human dose is Methocarbamol excipients. It does not contain a preservative. Lidocaine for Tablets 500 mg, 750 mg. Methocarbamol Injection 100 infusion packed in PVC container has found to behaving less mg/ml in 10 ml vials. It is a sterile, pyrogen-free Solution content of lidocaine as result from ph dependent sorption onto intended for intramuscular or intravenous administration. the plastic. 0440 Each mL contains: Methocarbamol, USP 100 mg. 0447 Lidocaine is injected in form of HCl form, and by polyethylene glycol 300, NF 0.5 mL, Water for Injection, utilization the vehicle or solvent of the present invention, USP q.s. The pH is adjusted, when necessary, with hydro Diethylene glycol monoethyl ether or other alkyl derivatives, chloric acid and/or sodium hydroxide. The chemical name of it is possible to use Lidocaine free base as such. Methocarbamol is 3-(2-methoxyphenoxy)-1,2-propanediol 0448. By utilizing the vehicle or solvent of the present 1-carbamate and has the empirical formula of C11H15NO5. invention solvent, Diethylene glycol monoethyl ether or other Its molecular weight is 241.24. The structural formula is alkyl derivatives, a transparent, non hazy as well as less vis shown below: cous Solution is obtained, which can be useful as injections for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of (II.8) O different dosage forms like capsules, tablets, nasal sprays, M gargles, gels, topicals, liquid oral dosage forms etc. The solu O-CH-CH(OH)-CHO-C-NH tion may additionally contain preservatives and buffers for maintenance of pH. 0449 II.10) Azithromycin (Antibiotic) OCH 0450 Azithromycin is an azalide, a subclass of macrollide antibiotics. Azithromycin is one of the world’s best-selling 0441 This injection consists of polyethylene glycol 300 as antibiotics. It is derived from erythromycin, with a methyl solvent. Polyethylene glycol 300 has been noted to increase Substituted nitrogen atom incorporated into the lactone ring, preexisting acidosis and urea retention in humans with renal thus making the lactone ring 15-membered. This lipophilic impairment. Solutions prepared for IV infusion should not be active is chemically designated (3R,4S,5S,6R,7R,9R, 11S, refrigerated as a precipitate may form. Because a haze or 12R,13S, 14S)-6-(2S,3R.4S,6R)-4-(dimethylamino)-3-hy precipitate may form, all diluted intravenous solutions should droxy-6-methyloxan-2-yl)oxy-14-ethyl-12,13-dihydroxy be physically inspected before administration. 4-(2R,4S,5S,6S)-5-hydroxy-4-methoxy-4,6- US 2014/0296.191 A1 Oct. 2, 2014 27 dimethyloxan-2-yl)oxy-7-methoxy-3,5,7,9,11,13 available as sterile free dried powder (500 mg) for reconsti hexamethyl-1-oxacyclotetradecane-2,10-dione and tution with sterile water for injection. molecular structure is given as: 0452. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis (II.10) cous solution is obtained, which can be useful as I.V. or I.M. O injections for rapid onset of action when required to provide H3C (2) CH3 earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, tablets, HO OCH H3C liquid oral dosage forms etc. The Solution may additionally OH CH \-CH contain preservatives and buffers for maintenance of pH. H3C (2) 0453 II.11) Cardiac Glycoside: Digoxin (Anti-Arrhyth H3C HO mic Drug) Ho1 No1 ... Zia-ul 0454 Digoxin is a purified cardiac glycoside extracted from the foxglove plant, Digitalis lanata. Its corresponding O O (3) aglycone is digoxigenin, and its acetyl derivative is acetyl (2) digoxin. Digoxin is widely used in the treatment of various CH3 CH3 heart conditions, namely atrial fibrillation, atrial flutter and O OH sometimes heart failure that cannot be controlled by other CH medication. It is available as tablet form and also available as () indicates text missing or illegible when filed a 0.05 mg/ml oral solution and 0.25 mg/ml or 0.5 mg/ml injectable solution. Digoxin is described chemically as (3,3, 5 B, 12B)-3-(O-2,6-dideoxy-3-D-ribo-hexopyranosyl 0451. It is practically insoluble in water, freely soluble in (1->4)-O-2,6-dideoxy-B-D-ribo-hexopyranosyl-(1->4)-2,6- methylene chloride and ethanol. It is available in Oral (cap dideoxy-3-D-ribo-hexopyranosyl)oxy-12, 14-dihydroxy Sule or Suspension), intravenous, ophthalmic dosage form. card-20(22)-enolide. Its molecular formula is CHO, its For parenteral administration, Azithromycin (anhydrous) is molecular weight is 780.95, and its structural formula is:

(II.11)

OH

HO HO OH Ho

0455 It is practically insoluble in water, freely soluble in equal amount of methylene chloride and methanol, slightly soluble in ethanol. 0456 I.V. therapy may be better tolerated (less nausea); Digoxin has a very long distribution half-life into the cardiac tissue, which will delay its onset of action by a number of hours. The half-life is about 36 hours; digoxin is given once daily, usually in 125-lug or 250-lug doses. Digoxin is usually given by mouth, but can also be given by I.V. injection in urgent situations. It is available as a sterile solution of digoxin for intravenous or intramuscular injection. The vehicle con tains 40% propylene glycol and 10% alcohol. The injection is buffered to a pH of 6.8 to 7.2 with 0.17% dibasic sodium phosphate and 0.08% anhydrous citric acid. Each 2-mL ampoule contains 500mcg (0.5 mg) Digoxin (250 mcg 0.25 mg per mL). Dilution is not required. 0457 Intramuscular injection of Digoxin is extremely painful and offers no advantages unless other routes of administration are contraindicated. Thus this pain can be US 2014/0296.191 A1 Oct. 2, 2014 28 prevented by preparing parenteral for I.M/I.V by using the p-aminophenol. The full chemical name is N-acetyl-p-ami present selected solvent which will also increase onset of nophenol. It is stable at a pH between 4 and 7 at 25°C. It is action as it will also act as permeation enhancer. available in injection as i.V bolus, i.V infusion, tablet, syrup, 0458. By utilizing the vehicle or solvent of the present Suppository and as oral Suspension. invention solvent, Diethylene glycol monoethyl ether or other 0467. According to U.S. Patent Application No. 2004/ alkyl derivatives, not only a transparent, non hazy as well as 0247627 A1, this invention refers to ready-to-use highly less viscous solution is obtained, which can be useful as I.V. stable paracetamol injectable solutions, prepared by mixing or I.M. injections for rapid onset of action when required to paracetamol, water, propylene glycol, and a citrate buffer (pH provide earliest result into the patient, but also the pain at the 4.5 to 6.5), and by heating said solution under preset condi site of injection is prevented. The solution can also be used for tions. This injection consists of about 20% of propylene gly formulation of different dosage forms like capsules, tablets, col only co-solvent that shows the high viscous nature of the nasal sprays, gargles, gels, topicals, liquid oral dosage forms injection which may be painful for use. At long time period etc. The Solution may additionally contain preservatives and storage, there is formation of paracetamol polymers or ben buffers for maintenance of pH. Zoquinoneimines providing color to the solution which is 0459 II.12) Dicyclomine (Gastrointestinal) unsafe for use due to decomposition. 0460 Dicyclomine is used to treat intestinal hypermotility 0468. In U.S. Application No. 20090215903, aqueous and the symptoms of irritable bowel syndrome Solution of paracetamol is prepared for its use by perfusion (II.12) with a pH between 4.5 to 6.0. In this formulation, byproducts of sulfate, gluconate or fufural ions can be found in Solution even in presence of antioxidant into the same formulation. 0469. There is reported death of neonate due to use of 1 preservative like benzyl alcohol used in Paracetamol injec 1S-N-1 tion. 0470 Thus above problems can be obviated by using Diethylene glycol monethyl ether to provide an alternate stable injection preventing the development of unwanted 0461 Dicyclomine hydrochloride occurs as a fine, white, color of solution overtime and preventing formation of any of crystalline, practically odorless powder with a bitter taste. It is byproducts as cited above. soluble in water, freely soluble in alcohol and chloroform, 0471. It is possible to add other excipients while com and very slightly soluble in ether. pounding in combination with other vehicles which are cur 0462. The solubility of dicyclomine in the present inven rently used in Paracetamol as infusion liquid to prevent vari tion vehicle is observed in range of 1 to 20 mg/ml. ous problems of high viscosity, stability, and impurity related 0463. By utilizing the vehicle or solvent of the present matterS. invention solvent, Diethylene glycol monoethyl ether or other 0472. By utilizing the vehicle or solvent of the present alkyl derivatives, not only a transparent, non hazy as well as invention solvent, Diethylene glycol monoethyl ether or other less viscous solution is obtained, which can be useful as I.V. alkyl derivatives, not only a transparent, non hazy as well as injections for rapid onset of action when required to provide less viscous solution is obtained, which can be useful as I.V. earliest result into the patient, but also the pain at the site of and I.M. injections for rapid onset of action when required to injection is prevented. The solution can also be used for provide earliest result into the patient, but also the pain at the formulation of different dosage forms like capsules, tablets, site of injection is prevented. The solution can also be used for liquid oral dosage forms etc. The Solution may additionally formulation of different dosage forms like capsules, tablets, contain preservatives and buffers for maintenance of pH. It liquid oral dosage forms, oral Suspensions, Suppositories, can be also prepared and administered in combination with buccal delivery systems, sprays etc. The solution may addi other drugs. Similarly, different drug combination of drug tionally contain preservatives and buffers for maintenance of like Diclofenac with Dicyclomine can also be prepared in pH. It can be also prepared and administered in combination Solution form for therapeutic use in required dose. with other drugs. 0464 II.13) Paracetamol/Acetaminophen (Analgesic & 0473. The concentration range and fill volumes can be Antipyrretic) 0474 50 mg/0.5 ml, 100 mg/0.5 ml, 200 mg/ml, 400 mg/2 0465 Paracetamol or Acetaminophen has analgesic and ml. 600 mg/3 ml, 1000 mg/5 ml filled as ampoules similarly, antipyretic properties and weak anti-inflammatory activity vials of 5 ml containing 200 mg/ml, 10 ml vial containing 100 and is used in the symptomatic management of moderate pain mg/ml, 20 ml vial containing 50 mg/ml, 50 ml vial containing and fever. It belongs to class 3 BCS drug. The structural 20 mg/ml, 100 ml vial containing 10 mg/ml dose of Parac formula of Paracetamol is given as: etamol may be filled for convenient use of the medical prac titioner. This ampoule and vial form can offer flexibility to medical professional for use as this can provide flexibility of (II.13) dose as per patients need. These forms can be diluted online H with Saline solution and can be administered as a drip. A low N CH dose of 50 mg/0.5 ml can be useful for use in neonates for reduction and monitoring of temperature in case of fever. O Thus, this invention solubiliser can provide oil free painless HO low viscosity injectables of Paracetamol filled in ampoules, vials, blow fill ampoules, Prefilled Syringes for Intravenous 0466 It is a white, crystalline powder. Acetaminophen is a and Intramuscular use for the use in Neonatal, Pediatric and synthetic, non-opiate, centrally acting analgesic derived from Adult Patients. US 2014/0296.191 A1 Oct. 2, 2014 29

0475 II.14) Pentazocine (Analgesic Agent) Fentanyl Citrate is a potent narcotic analgesic which is 0476 Pentazocine is a synthetically prepared prototypical administered only by the intravenous or intramuscular routes mixed agonist-antagonist narcotic (opioid analgesic) drug of of injection. Each milliliter contains fentanyl (as the citrate) the benzomorphan class of opioids used to treat moderate to 50 mcg (0.05 mg). It may contain sodium hydroxide and/or moderately severe pain. Pentazocine is sparingly soluble in hydrochloric acid for pH adjustment. pH 4.7 (4.0 to 7.5). It is water. Its salt form Pentazocine HCl as well as Pentazocine intended only for use as a single-dose injection. Lactate are also sparingly soluble in water. While lactate salt 0483 Fentanyl Citrate, a white powder which is sparingly is prepared as injectable according USP and BP. Chemically, soluble in water, is chemically designated N-(1-phenethyl-4- Pentazocine lactate is 1,2,3,4,5,6-hexahydro-6,11-dimethyl piperidyl)propionanilide citrate (1:1). The molecular formula 3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ollac is CHNO.CHO, and the molecular weight is 528.60. tate, a white, crystalline Substance soluble in acidic aqueous Fentanyl Citrate has the following structural formula: solutions. The molecular structure of Pentazocine is (II.14) H (II.15) N CH3

CHCOOH

(n\-( CH circle-O-clich-O-to-co CHCOOH oH, HO 0477. It is white powder practically insoluble in water; 0484. By utilizing the vehicle or solvent of the present freely soluble in methylene chloride and soluble in ethanol invention solvent, Diethylene glycol monoethyl ether or other (almost 96%). alkyl derivatives, a transparent, non hazy as well as less vis 0478. The recommended single parenteral dose is 30 mg cous solution is obtained, which can be useful as I.V. injection by intramuscular, Subcutaneous, or intravenous route. This for rapid onset of action when required to provide earliest may be repeated every 3 to 4 hours. Total daily dosage should result into the patient as well as can be used for formulation of not exceed 360 mg. A single, intramuscular 30 mg dose has different dosage forms like capsules, gels, patches, liquid oral been most commonly administered. Severe injection site dosage forms etc. The Solution may additionally contain pre necrosis and sepsis has occurred with multiple injection of servatives and buffers for maintenance of pH. Pentazocine lactate. 0485 II.16) Prostaglandin E1/Alprostadil (Steroids & 0479. By utilizing the vehicle or solvent of the present Hormones) invention solvent, Diethylene glycol monoethyl ether or other 0486 Alprostadil as the naturally occurring form of pros alkyl derivatives, a transparent, non hazy as well as less vis taglandin E1 (PGE1) and is designated chemically as (11C. cous solution is obtained, which can be useful as I.V. injection for rapid onset of action when required to provide earliest 13E,15S)-11, 15-dihydroxy-9-oxoprost-13-en-1-oic acid. result into the patient as well as can be used for formulation of The molecular weight is 354.49. different dosage forms like capsules, gels, patches, liquid oral 0487. Alprostadil is a white to off-white crystalline pow dosage forms etc. The solution may additionally contain pre der with a melting point between 115° and 116°C. Its solu servatives and buffers for maintenance of pH. bility at 35° C. is 8000 micrograms per 100 milliliter double 0480 II.15. II.15) Fentanyl & Fenatyl Citrate (Analgesic distilled water. Agents) 0488. The structural formula of alprostadil is represented 0481 Fentanyl is a potent, synthetic narcotic analgesic aS with a rapid onset and short duration of action. It is a strong agonist at the u-opioid receptors. Fentanyl is approximately 100 times more potent than morphine. Intravenous fentanyl is (Ii.16) extensively used for anesthesia and analgesia, most often in operating rooms and intensive care units. It is chemically C-OH designated as N-(1-(2-phenylethyl)-4-piperidinyl)-N-phe nylpropanamide and molecular structure is given as:

HO OH (II.15) 0489. It is available in market as a sterile freeze-dried powder for intracavernosal use in four sizes: 5, 10, 20 and 40 micro-grams per vial When reconstituted as directed with 1 C milliliter of bacteriostatic water for injection or sterile water, both preserved with benzyl alcohol, gives 1.13 milliliters of reconstituted solution. Each milliliter of this injection con tains 5.4, 10.5, 20.5 or 41.1 micrograms of Alprostadil depending on vial strength, lactose, Sodium citrate and benzyl 0482 Fentanyl Citrate Injection, USP is a sterile, nonpy alcohol. The deliverable amount of Alprostadil is 5, 10, 20 or rogenic Solution of Fentanyl citrate in water for injection. 40 micrograms per milliliter because approximately 0.4 US 2014/0296.191 A1 Oct. 2, 2014 30 microgram for the 5 microgram strength, 0.5 microgram for 0498. According to Patent No. KP 1019930009791, an the 10 and 20 microgram strengths and 1.1 microgram for the Omeprazole injection is made by (a) dissolving Omeprazole 40 microgram strength is lost due to adsorption to the vial and or non-oral administrating omeprazole salt and other addi syringe. When necessary, the pH of Alprostadil for injection tives into distilled water; (b) adjusting pH 8.5-9.5 with N-me is adjusted with hydrochloric acid and/or sodium hydroxide thylglucamine or Such buffer Solution as 2-amino-2-hy before lyophilization. droxymethyl-1,3-propanediol or the mixture of 0490 By utilizing the vehicle or solvent of the present N-methylglucamine and potassium hydrogen phosphate in invention solvent, Diethylene glycol monoethyl ether or other order to make it stable. alkyl derivatives, a transparent, non hazy Solution is obtained, 0499. By utilizing the vehicle or solvent of the present which can be useful as I.M as well as I.V. injection for rapid invention solvent, Diethylene glycol monoethyl ether or other onset of action when required to provide earliest result into alkyl derivatives, a transparent, non hazy Solution is obtained, the patient. The solution may additionally contain preserva which can be useful as I.V. injection for rapid onset of action tives and buffers for maintenance of pH. The solution can be when required to provide earliest result into the patient. The filled in FFS or glass disposable syringes as well as there Solution may additionally contain preservatives and buffers would be no loss of drug from the vial and Syringe. for maintenance of pH. The solution shows good stability and 0491 Proton Pump Inhibitors (PPIs) can be used directly for parenteral use, obviating the need for 0492 Generally all the PPIs are manufactured as metal lyophilization when metal salts are used. The solution can salts, the reason being for formation of suitable crystalline also be used for formulation of other dosage forms, such as forms, ready to be formulated as lyophilized metal salts or by capsules, tablets etc. complexing with Suitable stabilizing agents to avoid their degradation. The present inventors have found that if the acid (0500 II.18) Rabeprazole (Proton Pump Inhibitor) form of the PPIs is isolated during manufacture the same acid 0501 Rabeprazole is an anti-ulcer agent used for Short form can be solublised in Diethylene glycol monoethyl ether term treatment in healing and symptomatic relief of duodenal or other alkyl derivatives, to yield a clear and stable solution, ulcers and erosive or ulcerative gastroesophageal reflux dis which can be used directly as injectables or used for prepa ease (GERD). The chemical name of this lipophilic active is ration of other dosage forms, Suitable for oral administration. (RS)-2-(4-(3-methoxypropoxy)-3-methylpyridin-2-yl)me 0493. The following examples illustrate the abovemen thylsulfinyl)-1H-benzodimidazole with the following com tioned findings, which should be construed as non-limiting plex molecular structure that makes it insoluble in water: and construed as also applicable for other drugs or com pounds belonging to the same or different class, having simi lar stability limitations. (II.18) 0494 II. 17) Omeprazole (Proton Pump Inhibitor) 0495 Omeprazole is one of the most widely prescribed / drugs internationally as Proton pump inhibitor in the treat S N ment of dyspepsia, peptic ulcer disease (PUD), gastro esoph ageal reflux disease (GORD/GERD), laryngopharyngeal reflux (LPR) and Zollinger-Ellison syndrome. The chemical name of this drug is (RS)-2-(3-methyl-4-(2.2.2-trifluoroet hoxy)pyridin-2-yfmethylsulfinyl)-1H-benzodimidazole and molecular structure is as:

(II. 17) 0502. In market, it is mostly available in enteric coated OCH tablet dosage form in 20 mg and 10 mg dose. The bioavail HC N CH N OCH ability is only 51% which can be increased by preparing its parenteral preparation in I.V formulation. While available I.V preparation consist of Rabeprazole sodium in freeze dried N2 S l N powder for reconstitute in 5 ml of sterile water. This available H product may be time consuming and costly by process. So it O may be possible to make easier I.V. parenteral preparation by dissolving this salt in our selected solvent Diethylene glycol 0496 Omeprazole is a white to off-white crystalline pow mono ethyl ether and alike solvents with preferable preserva der that melts with decomposition at about 155°C. It is a weak tives and tris buffers to maintain its pH near alkaline nature to base, freely soluble in ethanol and methanol, and slightly maintain its stability in Solution. soluble in acetone and isopropanol and very slightly soluble 0503. By utilizing the vehicle or solvent of the present in water. The stability of Omeprazole is a function of pH; it is invention solvent, Diethylene glycol monoethyl ether or other rapidly degraded in acid media, but has acceptable stability alkyl derivatives, a transparent, non hazy Solution is obtained, under alkaline conditions. which can be useful as I.V. injection for rapid onset of action 0497. It is available for use in injectable form (I.V.) in when required to provide earliest result into the patient. The Europe, but not in the U.S. The injection pack is a combina Solution may additionally contain preservatives and buffers tion pack consisting of a vial and a separate ampule of recon for maintenance of pH. The solution shows good stability and stituting solution. Each 10 ml clear glass vial contains a white can be used directly for parenteral use, obviating the need for to off-white lyophilized powder consisting of Omeprazole lyophilization when metal salts are used. The solution can Sodium 42.6 mg equivalent to 40 mg of Omeprazole. also be used for formulation of other dosage forms, such as US 2014/0296.191 A1 Oct. 2, 2014

capsules—soft and hard gelating types, tablets, ready to use 0512 PCT Application No. WO/1996/041646, discloses a drops, syrups, buccal delivery systems, oral liquids etc. pharmaceutical composition in the form of an aqueous solu 0504 II.19) Pantoprazole (Proton Pump Inhibitor) tion or in the form of a product for reconstitution as an aqueous solution, for parenteral administration or ophthalmic 0505 Pantoprazole is a PPI with the actions and uses administration, comprising lornoxicamora pharmaceutically similar to those of Omeprazole. acceptable salt thereof and a cyclodextrin selected from the 0506. It is given as the sodium salt but doses a expressed in group consisting of hydroxypropylated or Sulphoalkylated terms of base. The molecular name of this drug is derivatives of alpha, beta or gamma cyclodextrin. CHFNNaOS with the molecular structure is as: 0513. In Chinese Patent No. CN 101327.193 A, the inven (II.19) tion relates to Lornoxicam freeze-dried powder injection and OCH a preparation method thereof. The freeze-dried powder injec tion comprises lornoxicam, mannite, tromethamine, EDTA HCO and pH regulator. "N4 0514. The marketed one vial compositions contains 8 mg Lornoxicam, which provides 4 mg Lornoxicam per ml when 1.F MX s reconstituted as recommended in water. It contains Mannitol, F O N trometamol, disodium edentate. The manufacturing of the powder filling is costly process and reconstitution is tedious 0507 Pantoprazole sodium 11.28 mg is equivalent to and not friendly process to the doctors. about 10 mg of Pantoprazole. It is given intravenously as the 0515 Freeze dried product needs special care of storage Sodium salt, over 2 to 15 minutes, either as a slow injection or for the stability of the product for reconstitute into parenteral a short term infusion. For peptic ulceration or gastro-esoph solution. While inclusion of Lornaxicam into cyclodextrin ageal reflux disease, the recommended dose is 40 mg daily. can be costly in sense of process and may be nephrotoxic. This sodium salt form is available in form of lyophilized 0516 By utilizing the vehicle or solvent of the present parenteral which is mostly off white in color. invention solvent, Diethylene glycol monoethyl ether or other 0508. The solution of the sodium salt for ready-to-use alkyl derivatives, not only all the abovementioned problems administration is unstable in nature. This has been overcome by acidifying the solution to convert into a free acid form and are solves, but also a transparent, non hazy as well as less then solubilizing the same in Diethylene glycol monoethyl viscous solution is obtained, which can be useful as I.V. bolus ether or other alkyl derivatives to provide a transparent, non injection or Depot I.M. injection for rapid onset of action hazy solution is obtained, which can be useful as I.V. injection when required to provide earliest result into the patient as well for rapid onset of action when required to provide earliest as can be used for formulation of different dosage forms like result into the patient. The Solution may additionally contain capsules, nasal sprays, gargles, gels, topical, liquid oral dos preservatives and buffers for maintenance of pH. The solution age forms, otic delivery systems etc. The solution may addi shows good stability and can be used directly for parenteral tionally contain preservatives and buffers for maintenance of use, obviating the need for lyophilization when metal salts are pH. used. The solution can also be used for formulation of other 0517 II.21) Etoposide (Anticancer Agent) dosage forms, such as capsules capsules—soft and hardgelat 0518 Etoposide is a semisynthetic derivative of podo ing types, tablets, ready to use drops, syrups, buccal delivery phyllotoxin used in the treatment of certain neoplastic dis systems, oral liquids etc. eases. It is 4'-demethylepipodophyllotoxin 9-4,6-O-(R)-eth 0509 II.20) Lornoxicam (Antirhuematic Actives for Mus ylidene-B-D-glucopyranoside. It is very soluble in methanol culoskeletal System—Oxicams) and chloroform, slightly soluble in ethanol and sparingly 0510. It is a Non-steroidal Anti-inflammatory Drug soluble in water and ether. It is made more miscible with (NSAID of the Oxicam) class with analgesic (pain relieving), water by means of organic solvents. It has a molecular weight anti-inflammatory and antipyretic (fever reducing) proper of 588.58 and a molecular formula of CHO and the ties. It is available in oral and parenteral formulations. It is molecular structure is given as: chemically designated as (3E)-6-chloro-3-hydroxy(pyridin 2-ylamino)methylene-2-methyl-2,3-dihydro-4H-thieno 2. (II.21) 3-e12thiazin-4-one 1,1-dioxide with molecular structure aS

(II.20) Cl O OH s -N-N/ C / \,

0511. It is slight yellow crystalline powder hardly soluble in water, slightly soluble in chloroform and methanol, very lightly soluble in methanol and Acetonitrile, soluble in DMSO. US 2014/0296.191 A1 Oct. 2, 2014 32

0519 Etoposide Injection USP is available for intravenous 0526 Docetaxel is a white powder and is the active ingre use as 20 mg/mL solution in 100 mg (5 mL), 500 mg (25 mL), dient available in 20 mg and 80 mg Taxotere single-dose vials and 1 g (50 mL) sterile, multiple-dose vials. The pH of the of concentrated anhydrous docetaxel in polysorbate 80. It is clear, nearly colorless to yellow liquid is 3 to 4. Each mL pale yellow to brownish-yellow solution at 20 mg/mL con contains 20 mg Etoposide USP, 2 mg citric acid, 30 mg benzyl centration. Each mL contains 20 mg docetaxel (anhydrous) in alcohol, and 80 mg modified polysorbate 80/tween 80, 650 0.54 grams polysorbate 80 and 0.395 grams dehydrated alco mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol. hol solution. Etoposide Injection available in market is been diluted prior 0527. Another formulation made available consist of one to use with either 5%. Dextrose Injection, or 0.9% Sodium vial preparation in which all the composition of the above Chloride Injection, to give a final concentration of 0.2 to 0.4 remains the same except the quantity of ethanol is decreased. mg/mL If solutions are prepared at concentrations above 0.4 0528. From the above marketed formulations, it is seen mg/mL, precipitation may occur. The injection is viscous and that it still contains high concentration of alcohol and gaives pain at the site of injection. Further, it uses a cocktail of Polysorbate 80. To obviate the use of above toxic vehicles, a excipients, like PEG and Polysorbate 80, which are toxic. Solution prepared using Diethylene glycol monoethyl ether 0520. By utilizing the vehicle or solvent of the present can be prepared in the Suitable concentration and may be invention solvent, Diethylene glycol monoethyl ether or other diluted to the desired concentration while performing infu alkyl derivatives, not only a transparent, non hazy as well as sion therapy. less viscous solution is obtained, which can be useful as I.V. 0529. By utilizing the vehicle or solvent of the present injections for rapid onset of action when required to provide invention solvent, Diethylene glycol monoethyl ether or other earliest result into the patient, but also does not result in pain alkyl derivatives, a transparent, non hazy as well as less vis at the site of injection. The solution can also be used for cous solution is obtained, which can be useful as I.V. injec formulation of different dosage forms like capsules, tablets, tions for rapid onset of action when required to provide ear liquid oral dosage forms etc. The Solution may additionally liest result into the patient. The solution can also be used for contain preservatives and buffers for maintenance of pH. formulation of different dosage forms like capsules, tablets, 0521 II.22) Docetaxel (Anticancer Agent) liquid oral dosage forms etc. The Solution may additionally 0522. It is a semi-synthetic analogue of Paclitaxel (Taxol), contain preservatives and buffers for maintenance of pH. an extract from the bark of the rare Pacific yew tree Taxus 0530 II.23) Leuprolide (Anticancer Agent) brevifolia. Docetaxel is a clinically well-established anti-mi 0531 Leuprorelin or Leuprolide acetate is a GnRH ana totic chemotherapy medication. It is used mainly for the treat log. Leuprolide acts as an agonist at pituitary GnRH recep ment of breast, ovarian, prostate, and non-Small cell lung tors. Leuprolide may be used in the treatment of hormone CaCC. responsive cancers such as prostate cancer or breast cancer, 0523 Docetaxel is chemically designated as 1,7f8, 10B estrogen-dependent conditions, to treat precocious puberty, trihydroxy-9-oxo-5? 3.20-epoxytax-11-ene-2C.4.13C-triy14 and to control ovarian stimulation in In Vitro Fertilization acetate2-benzoate13-(2R.3S)-3-(tert-butoxycarbonyl) (IVF). 0532. The chemical name is 5oxo-L-prolyl-L-histidyl-L- amino]-2-hydroxy-3-phenylpropanoate) and the molecular tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl structure is given as: N-ethyl-L-prolinamide acetate (salt) and the molecular struc ture is given as: (II.22) (II.23) X HO O OH (2) O (2) indicates text missing or illegible when filed

0533. It is available as a slow-release implant or subcuta 3 NO neous/intramuscular injection. It is available in a prefilled (2) H. a O dual-chamber Syringe containing sterile lyophilized micro OH spheres which, when mixed with diluent, become a Suspen O sion intended as a monthly intramuscular injection. Leupro O lide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LH (2) indicates text missing or illegible when filed RH). 0534. This suspension may have stability issue concern with Viscousness that may painful too. 0524. According to a 2005 article in the Journal, Drugs, 0535. By utilizing the vehicle or solvent of the present Docetaxel is administered as a one-hour infusion every three invention solvent, Diethylene glycol monoethyl ether or other weeks generally over a ten cycle course and Docetaxel is alkyl derivatives, a transparent, non hazy as well as less vis considered as more effective than Doxorubicin, Paclitaxel cous solution is obtained, which can be useful as I.V. or I.M. and Fluorouracil as a cytotoxic antimicrotubule agent. injections for rapid onset of action when required to provide 0525 Docetaxel is a white to almost-white powder with an earliest result into the patient. The solution can also be used empirical formula of CHNO3H2O and a molecular for formulation of different dosage forms like capsules, tab weight of 861.9. It is highly lipophilic and practically lets, liquid oral dosage forms etc. The Solution may addition insoluble in water. ally contain preservatives and buffers for maintenance of pH. US 2014/0296.191 A1 Oct. 2, 2014

0536 II.24) Clarithromycin (Antibiotic) 0537. It is effective against a broad spectrum of gram (II.25) positive and gram-negative bacteria. It is used to treat respi ratory tract infections and soft tissue infections. It is used to treat duodenal ulcer associated with Helicobacter pylori infections in combination with omeprazole. One common feature of clarithromycin appears to be the stability against acids. It is absorbed and diffused easily into tissues and phagocytes without being protected from gastric acids. It is more effective against certain gram-negative bacteria, such as Legionella pneumophilae than Erythromycin. 0538. This lipophilic active is chemically designated as (3R,4S,5S,6R,7R,9R,11R,12R,13S, 14R)-4-(2,6-Dideoxy 3-C-methyl-3-O-methyl-a-L-ribo-hexopyranosyl)oxy-14 0543. It is available as a lyophilized powder for solution ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexam for intravenous infusion, film-coated tablets for oral admin ethyl-6-3,4,6-trideoxy-3-(dimethylamino)-b-D-xylo istration, and as a powder for oral Suspension. It is available as hexopyranosylloxyloxacyclotetradecane-2,10-dione(6-O- I.V. parenteral containing a white lyophilized powder con methylerythromycin A) and molecular structure is given as: taining nominally 200 mg Voriconazole and sulfobutyl ether beta-cyclodextrin sodium in a 30 mL. Type I clear glass vial. 0544 The beta-cyclodextrin derivatives are nephrotoxic. (II.24) Thus there is a limitation of present formulation. The formu O lation requires costly technique of manufacturing for lyo H3C (2) CH3 phillisation and requires reconstitution. The practice to recon stitute is cumbersome to the health professional. Further (2) OCH stability of solution is an issue. HO on/ (2) \ 1-13CH 0545. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis cous solution is obtained, which can be useful as I.V. injection for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, nasal sprays, gargles, gels, topical, liquid oral dosage forms etc. The Solution may additionally contain preservatives and buffers for mainte nance of pH. 0546 II.26) Neuromuscular Blocking Agents () indicates text missing or illegible when filed 0547 Various Neuromuscular agents like Vecuronium, Atracurium isomers like Cisatracurium, Doxacurium, Tub ocurarine, Pipecuronium, Rocuronium, Pancuronium etc. are available in market as lyophilized product as well as ready to 0539 Clarithromycin is a white to off-white crystalline use injectables. powder, insoluble in water, soluble in acetone, slightly 0548. By utilizing the vehicle or solvent of the present soluble in alcohol and acetonitrile; administered orally. invention solvent, Diethylene glycol monoethyl ether or other 0540. By utilizing the vehicle or solvent of the present alkyl derivatives, a transparent, non hazy as well as less vis invention solvent, Diethylene glycol monoethyl ether or other cous solution is obtained, which can be useful as I.V. injection alkyl derivatives, a transparent, non hazy as well as less vis for rapid onset of action when required to provide earliest cous Solution is obtained, which can be useful as injections result into the patient as well as can be used for formulation of for rapid onset of action when required to provide earliest different dosage forms like capsules, nasal sprays, gargles, result into the patient as well as can be used for formulation of gels, topical, liquid oral dosage forms etc. The Solution may different dosage forms like capsules, tablets, liquid oral dos additionally contain preservatives and buffers for mainte age forms etc. The Solution may additionally contain preser nance of pH. vatives and buffers for maintenance of pH. (0549 II.27) Ibuprofen (Anti-Inflammatory) 0550 Presently Ibuprofen injections are available as drug 0541 II.25) Voriconazole (Antifungal Agent) with arginine comlexation. as 200 mg/2 ml and 400 mg/4 ml 0542. Voriconazole is a triazole antifungal medication that 0551. The use of arginine is very high and the drug to is generally used to treat serious, invasive fungal infections arginine ratio is 1:1 which adds up the cost and close moni and it has become the new standard of care in the treatment of toring of manufacturing and its therapeutic effect. invasive aspergillosis, which may occur in immune-compro 0552. Often the muscular phlebitis is observed after its use mised patients, including allogeneic BMT, other hematologic in the clinical trials. cancers, and solid organ transplants. The systemic name of 0553. By utilizing the vehicle or solvent of the present this drug is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyri invention solvent, Diethylene glycol monoethyl ether or other midin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol with the alkyl derivatives, a transparent, non hazy as well as less vis molecular structure as: cous solution is obtained, which can be useful as I.V. injection US 2014/0296.191 A1 Oct. 2, 2014 34 for rapid onset of action when required to provide earliest physicians/nurses. Furthermore, the pharmaceutical compo result into the patient as well as can be used for formulation of sitions are safe and less toxic, when administered different dosage forms like capsules, nasal sprays, gargles, 0561. The various pharmaceutical actives or drugs, gels, topical, liquid oral dosage forms etc. The injections can belonging to this class, to name a few are the following, which be prepared in the desired strengths of 200 mg and 400 again to reiterate is non-limiting as far as the scope of the mg/ml. The solution may additionally contain preservatives invention, is concerned. and buffers for maintenance of pH. 0562 III.1, III.1) Prednisolone & Prednisolone Acetate Class III: Pharmaceutical Actives of Drugs which are Avail (Steroids & Hormones) able in the Form of Suspensions and are Very Difficult to be 0563 Prednisolone is a synthetic glucocorticoid, a deriva Solubilized into a Solution Form tive of cortisol. It is used to treat a variety of inflammatory and 0554. As mentioned hereinbefore, there are certain phar auto-immune conditions. It is the active metabolite of the maceutical actives or drugs, which are very difficult to solu drug prednisone. bilize into a solution form and have further stability issues i.e. instability and often require complex and expensive technol 0564. It is a white, hygroscopic, crystalline powder and it ogy for formulation of such actives into Suitable stable dosage shows polymorphism. It is very slightly soluble in water, forms, especially suspension forms. soluble in alcohol and sparingly soluble in acetone. The 0555 Drugs that are present in oily or aqueous liquid form IUPAC name of this drug is (11B)-11, 17.21-trihydroxypre have solubility problems as well as various physical as well as gna-1,4-diene-320-dione and the chemical structure is given chemical issues when incorporated in the formulation. They aS are also prepared using difficult manufacturing process. Such formulations are found to cake on Standing in addition to phase separation which is common problems of Suspension (III.1) form. Stabilization of the emulsion formulation is a consistent problem and challenge to pharmaceutical Scientists. Cur rently available formulations in the market are associated with multitude of problems as cited below. 1) Costly Technology: 0556. The process involved in their preparation uses com plex technologies to maintain it as Suspension form. Hence, there are difficulties in their manufacturing and maintaining of consistency of the formulation. 0565. It is available in various salt forms as Prednisolone 0557. The suspensions during the manufacturing requires acetate, Prednisolone sodium Succinate, Prednisolone diso process controls and checks to maintain uniformity of the dium phosphate, Prednisolone Tebutate. In market, Predniso particle size in the preparations and for their stability for the lone acetate is available as an injectable Suspension. intended forms during the end use. 0566 Prednisolone acetate is a white crystalline powder. It is practically insoluble in water and slightly soluble in alco 2) Manufacturing Problems: Difficulties in Stabilizing the hol. The chemical name of this salt is 11B, 17.21-Trihydrox Suspensions. ypregna-1,4-diene-320-dione 21-acetate and the chemical 0558. The suspension should remain homogenous on stor structure is given as: age. The Suspension often causes agglomeration and thus becomes nonhomogenious.

(III.1A) 0559 The emulsions are not user friendly to the Doctors. Health professionals always prefer clear solution for the parenteral administration. 0560 Such pharmaceutical actives or drugs can be effec tively stabilized by utilization of Diethylene glycol monoet hyl ether or other alkyl derivatives as a primary vehicle or Solvent, to provide clear, transparent, non hazy Solutions of the said pharmaceutical actives or drugs in the said vehicle or solvent, which are further less viscous and are ready to use for parenteral administration through I.V., I.M. or other routes of injection or can be used for formulation of various other dosage forms of the pharmaceutical actives or drugs, such as for example, capsules, tablets, nasal sprays, gargles, dermal applications, gels, topicals, liquid oral dosage forms and other 0567. In the market, Prednisolone acetate is available as 25 dosage forms. The Solutions are easy to manufacture, do not mg/mlaqueous white suspension for injection which contains involve lengthy and tedious manufacturing processes and are water for injection, Sodium chloride for injection, benzyl therefore, economical, viable and hence beneficial to alcohol, sodium carboxymethylcellulose, Polysorbate 80, patients. Further, when administered parenterally, the solu with sodium hydroxide or hydrochloric acid as pH adjuster. tions are easily flowable, easily Syringable, easy to inject and 0568. This suspension requires good micronisation of the cause less pain at the site of the injection and are therefore, drug (thus maintaining the particle size) and thus in all pos beneficial not only to the patients bit also to the doctors/ sibility of caking on storage particularly at low temperatures. US 2014/0296.191 A1 Oct. 2, 2014

Further phase separation on long storage can also occur. It is also prepared using costly methods. (III.2A) CHOCOCH

0569. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy Solution is obtained, which can be useful as I.V. injection for rapid onset of action when required to provide earliest result into the patient. The Solution may additionally contain preservatives and buffers for maintenance of pH. The solution shows good stability and can be used directly for parenteral use, obviating the need for lyophilization when metal salts are used. The Solution can also be used for formulation of other dosage forms, such as capsules, tablets, eye drops, ear drops etc. 0570 III.2) Methyl Prednisolone (Steroids & Hormones) 0576. It is available as sterile aqueous suspension so the stability of Such product may be issue for long time storage. 0571 Methylprednisolone is a synthetic glucocorticoid or Polyethylene glycol used in the product increases the Viscos corticosteroid drug. It is a variant of prednisolone, methylated ity of the formulation (Gibaldi’s Drug Delivery System in at carbon 6 of the B ring. The molecular structure of this Pharmaceutical Care, Page No. 117) which may be also an lipophilic active is as: issue concern with the painto patient at the site of application. 0577 As it is available in suspension form, stability, par ticle size, and storage of the product are critical factors for (III.2) handling. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis cous solution is obtained, which can be useful to use as I.M as well as I.V. injection for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, nasal sprays, gargles, gels, topical, liquid oral dosage forms etc. The solution may additionally contain preservatives and buff ers for maintenance of pH. (0578 III.3) Medroxy Progesterone Acetate (Steroids & Hormones) 0579 Medroxyprogesterone acetate, also known as 17C.- 0572 Methylprednisolone is typically used for its anti hydroxy-6C.-methylprogesterone acetate, and commonly inflammatory effects. Methylprednisolone occurs as a white abbreviated as MPA, is a steroidal progestin, a synthetic vari to practically white, odorless, crystalline powder. It is spar ant of the human hormone progesterone. It is used as a con ingly soluble in alcohol, in dioxane, and in methanol, slightly traceptive, in hormone replacement therapy and for the treat soluble in acetone, and in chloroform, and very slightly ment of endometriosis as well as several other indications. It soluble in ether. It is practically insoluble in water. is chemically designated as 17O-hydroxy-6C.-methylpregn 4-ene-3,20-dione acetate and molecular structure is: 0573 By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other

alkyl derivatives, a transparent, non hazy as well as less vis (III.3) cous solution is obtained, which can be useful as I.M as well as I.V. injection for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, nasal sprays, gargles, gels, topicals, liquid oral dosage forms etc. The solution may additionally contain preservatives and buff ers for maintenance of pH. 0574 III.2) Methyl Prednisolone Acetate (Steroids & Hormones) 0575 Methyl Prednisolone acetate is an anti-inflamma tory glucocorticoid available as intramuscular, intra-articular, soft tissue or intralesional injection. It is available in three 0580 MPA is a more potent derivative of its parent com strengths: 20 mg/Ml; 40 mg/ml; 80 mg/ml. The chemical pound Medroxyprogesterone. It is a white to off-white, odor name for methylprednisolone acetate is pregna-1,4-diene-3, less crystalline powder, stable in air, melting between 200° 20-dione, 21 (acetyloxy)-1,1,17-dihydroxy-6-methyl-, (6C. and 210°C. It is freely soluble in chloroform, soluble in 11 B)— and the molecular weight is 416.51. The structural acetone and in dioxane, sparingly soluble in alcohol and formula is represented below: methanol, slightly soluble in ether and insoluble in water. It is US 2014/0296.191 A1 Oct. 2, 2014 36 available as Aqueous Suspension active by the parenteral and 0587 III.5) Stanozolol (Steroids & Hormones) oral routes of administration. It is available as intramuscular 0588 Stanozolol is a synthetic anabolic steroid derived injection in which each ml consists of 400 mg/ml MPA. The from dihydrotestosterone. It has been approved by the FDA vehicle used as parenteral solvent is PEG 3350. for human use. Unlike most injectable anabolic steroids, 28aphtha28ol is not esterified and is sold as an aqueous Sus 0581. The viscosity of PEG 3350 is about 83 to 130 cps pension, or in oral tablet form. Thus this aqueous Suspension which is more viscous and is painful to a patient at the time of can be prepared as clear viable I.M injectable preparation by injection. As it is available in Suspension form, stability, par using present art solvent. It is chemically designated as ticle size, storage of the product are required to be monitored. 1S,3AS.3Br.5As, 10As, 10Bs, 12AS)-1,10a, 12a-trimethyl-1,2, 0582. By utilizing the vehicle or solvent of the present 3.3a,3b.4.5.5a,6,7,10,10a, 10b,11,12,12a-hexadecahydrocy invention solvent, Diethylene glycol monoethyl ether or other clopenta5,679aphtha 1.2-findazol-1-ol with chemical alkyl derivatives, a transparent, non hazy as well as less vis Structure as: cous solution is obtained, which can be useful to use as I.M as well as I.V. injection for rapid onset of action when required to provide earliest result into the patient as well as can be used (III.5) for formulation of different dosage forms like capsules, nasal sprays, gargles, gels, topical, liquid oral dosage forms etc. The solution may additionally contain preservatives and buff ers for maintenance of pH. 0583 III.4) Triamcinolone Acetonide (Steroids & Hor mones) 0584 Triamcinolone acetonide is ester form of triamcino lone, a synthetic glucocorticoid corticosteroid with marked anti-inflammatory action. The chemical name for triamcino lone acetonide is 9-Fluoro-113,16C, 17.21-tetrahydroxypre 0589. It is white crystal practically insoluble in water; gna-1,4-diene-320-dione cyclic 16,17acetal with acetone. Its soluble 1 in 41 of alcohol, 1 in 74 of chloroform, and 1 in 370 structural formula is: of ether; soluble in dimethylformamide: slightly soluble in acetone and ethyl acetate. 0590. It is available as suspension. It is presented most (III.4) commonly as a 50 mg/mL injection or a 5 mg tablet. However, recently 100 mg/mL versions have become available. A com mon dosage can be 10-25 mg/day orally and 25-50 mg daily injected. The suspension might have stability related problem on long Storage; it is also required to maintain the particle S17C. 0591. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis cous solution is obtained, which can be useful as I.M as well as I.V. injection for rapid onset of action when required to provide earliest result into the patient. The solution may addi tionally contain preservatives and buffers for maintenance of 0585. It is white to off-white crystalline powder, practi pH. The same solution may be employed for other dosage cally insoluble in water but soluble in alcohol and chloro forms for example, like capsule form. form. It is available in a sterile aqueous Suspension form in 40 0592. III.6) Propofol (Hypnotic Agent) mg dose in the market for intramuscular application. During 0593 Propofol is a short-acting, intravenously adminis administration of this product, many precautions have to be tered hypnotic agent. Its uses include the induction and main taken. Before using the vial is to be shaken to ensure a uni tenance of general anesthesia, sedation for mechanically ven form Suspension. During Syringability, ruling out of clumping tilated adults, and procedural sedation. The chemical name of or granular appearance of the Suspension before withdrawing Propofol is 2,6-diisopropylphenol with molecular structure into Syringe is necessary. After withdrawal, injection is to be given as: applied as soon as possible before it starts settling in the Syringe. The entire problems are always an issue for a physi (III.6) C1a. OH 0586 By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis cous solution is obtained, which can be useful as I.V. injection for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, nasal sprays, gargles, 0594. It is light yellow liquid, very slightly soluble in gels, topical, liquid oral dosage forms etc. The Solution may water, miscible with hexane and with methanol. additionally contain preservatives and buffers for mainte 0595 Propofol has been referred to as “milk of amnesia s nance of pH. because of the milk-like appearance of its intravenous prepa US 2014/0296.191 A1 Oct. 2, 2014 37 ration. The currently available preparation is 1% propofol, 0602 Clevidipine is practically insoluble in water and is 10% soybean oil, and 1.2% purified egg phospholipid (like generally formulated in an oil-in-water emulsion. Clevidipine LIPOVA-E120) as an emulsifier, with 2.25% of glycerol as a butyrate is rapidly distributed and metabolized, resulting in tonicity-adjusting agent, and Sodium hydroxide to adjust the an ultra-short half-life. So it is prepared in form of I.V injec pH. It also contains EDTA, a common chelation agent, that tion. But the available marketed product is a sterile, milky also acts alone (bacteriostatically against Some bacteria) and white opaque emulsion in a vial containing 0.5 mg/mL of synergistically with Some other antimicrobial agents. Newer Clevidipine butyrate for intravenous use as an infusion cen generic formulations contain Sodium metabisulfite or benzyl trally or peripherally. The maximum recommended dose is 32 alcohol as antimicrobial agents. Propofol emulsion is a highly mg/h. It is a single-use parenteral product that contains phos opaque white fluid due to the scattering of light from the tiny pholipids and can Support the growth of micro organisms. (~150 nm) oil droplets that it contains. Thus from the above Thus there are chances of contamination as well as Stability problem, milk of amnesia might be removed by using the problem of such emulsion when stored for a long time. Con present invention solvent using preferable preservatives and stant quality check on particle size, microbial load, caking buffer with efficient process without any lyophilization for and phase separation are required. the drug and making cost effective product. 0603. By utilizing the vehicle or solvent of the present 0596 Doctors always prefer to use clear liquid to avoid invention solvent, Diethylene glycol monoethyl ether or other any extraneous material directly injected into veins. The pres alkyl derivatives, a transparent, non hazy as well as less vis ently available injection has a difficulty in maintaining the cous solution is obtained, which can be useful as I.V. injec particle size and also prohibitive for multiple uses because of tions for rapid onset of action when required to provide ear the composition is rich in nitrogen to Support microbial liest result into the patient as well as can be used for growth. formulation of different dosage forms like capsules, tablets, 0597. The cited problems in emulsion formulations can be liquid oral dosage forms etc. The Solution may additionally overcome by formulating the drug using Diethylene glycol contain preservatives and buffers for maintenance of pH. monoethyl ether in strength of 1 mg to 500 mg/ml and can administered with suitable adjuvants to directly infused in the 0604 III.8) Vitamin K (Vitamins & Minerals) infusion bag after modifying Suitably and modified drug 0605. It belongs to a group of structurally similar, fat delivery system can be developed. soluble vitamins that the human body needs for posttransla 0598 Viscosity of propofol is less than 5 cps. tional modification of certain proteins required for blood coagulation, and in metabolic pathways in bone and other 0599. By utilizing the vehicle or solvent of the present tissue. They are 2-methyl-1,4-naphthoduinone (3-) deriva invention solvent, Diethylene glycol monoethyl ether or other tives. This group of vitamins includes two natural Vitamins: alkyl derivatives, a transparent, non hazy as well as less vis Vitamin K (Phytomenadione) and Vitamin K cous solution is obtained, which can be useful as I.V. bolus injection or Depot I.M. injection for rapid onset of action (Menaquinone). Vitamin K is available as injectable emul when required to provide earliest result into the patient as well sion through I.V.I.M. and S.C. (Subcutaneous) in the market, as can be used for formulation of different dosage forms like while Vitamin K (MK) type is made orally available to mam capsules, nasal sprays, gargles, gels, topical, liquid oral dos mals by natural dietary source. age forms etc. The Solution may additionally contain preser 0606 Vitamin K: Phytomenadione is a Vitamin, which is vatives and buffers for maintenance of pH. a clear, yellow to amber, Viscous, odorless or nearly odorless 0600 III.7) Clevidipine Butyrate (Calcium Channel liquid. It is insoluble in water, soluble in chloroform and Blocker) slightly soluble in ethanol. It has a molecular weight of 450. 70. 0601. It is a dihydropyridine L-type calcium channel blocker. It is used to achieve the desired reduction in blood 0607 Phytomenadione is 2-methyl-3-phytyl-1,4-naph pressure. It is chemically designated as O3-(butanoyloxym thoquinone. Its empirical formula is CHO and its struc ethyl) O5-methyl (4R)-4-(2,3-dichlorophenyl)-2,6-dim tural formula is: ethyl-1,4-dihydropyridine-3,5dicarboxylate and molecular structure is given as (III.8) (III.7)

O (2) indicates text missing or illegible when filed US 2014/0296.191 A1 Oct. 2, 2014

0608 Vitamin K1 Injection (Phytomenadione Injectable Emulsion, USP) is a yellow, sterile, nonpyrogenic aqueous (III.9) dispersion available for injection by the intravenous, intra muscular and Subcutaneous routes. Each milliliter contains C phytomenadione 2 or 10 mg, polyoxyethylated fatty acid derivative, dextrose, hydrous in water for injection; benzyl alcohol added as preservative. It may contain hydrochloric NH O acid for pH adjustment. pH is 6.3 (range of 5.0 to 7.0). 0609. This is an available emulsion which is yellow in C sus OH color while it might be high cost process to provide desired particle size dispersion, thus stability can be issue. Thus a clear pellucid parenteral Solution can be prepared by using the present invention solvent diethylene glycol monoethyl ether with addition of suitable preservatives and antioxidant as 0617. It is white crystalline powder practically insoluble Phytomenadione is oxygen sensitive. in water, freely soluble in acetone, soluble in alcohol. 0610. By utilizing the vehicle or solvent of the present 0618 Aceclofenac is present as I.V bolus in market as invention solvent, Diethylene glycol monoethyl ether or other dose of 150 mg per ml in which vehicles like Polyethylene alkyl derivatives, a transparent, non hazy as well as less vis glycol, TCLS01 solvent, Arginine solution for lyophilized cous solution is obtained, which can be useful as I.V. or I.M. injections for rapid onset of action when required to provide Active are used. earliest result into the patient. The solution can also be used 0619. In WO 2006054315 B1, the invention relates to for formulation of different dosage forms like capsules, tab nonaqueous liquid parenteral aceclofenac formulation in lets, liquid oral dosage forms etc. The Solution may addition which propylene glycol was used as injectable vehicle which ally contain preservatives and buffers for maintenance of pH. is viscous in nature (58.1 cps) that can be painful at the site of injection. Analgesic Agents: (NSAIDs as Well as Narcotic Analgesics) 0620. In Indian Patent Application No. 67/BOM/99, use of 0611. The Non-steroidal anti-inflammatory drugs dimethyl isosorbide as a parenteral solvent in Aceclofenac (NSAIDs) has a wide range and they are available both in injection was found to be irritant and pain full at site of non-prescription and prescription mode. The major groups of injection. NSAIDs which can be used to prepare parenteral I.V bolus as 0621. By utilizing the vehicle or solvent of the present well as I.M preparations utilizing the vehicle or solvent of the invention solvent, Diethylene glycol monoethyl ether or other present invention, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis alkyl derivatives are given below: cous solution is obtained, which can be useful as I.V. injection 0612 Salicylic acid group: Aspirin (acetyl salicylic acid); for rapid onset of action when required to provide earliest Choline magnesium trisalicylate. Diflunisal and Salsalate; result into the patient as well as can be used for formulation of Propionic acid group: Fenoprofen, Flurbiprofen, Ibuprofen, different dosage forms like capsules, nasal sprays, gels, topi Ketoprofen, Naproxen, and Oxaprozin, Acetic and acid cals, liquid oral dosage forms etc. The solution may addition group: Aceclofenac, Indomethacin, Sulindac, and Tolimetin: ally contain preservatives and buffers for maintenance of pH. Fenamic acid group: Meclofenamate and Mefenamic acid; Napthylalkenone group: Nabumetone; Pyarnocarboxylic 0622 III.10) Ethinylestradiol (Steroids & Hormones) acid group: Etodalac, Pyrrole group: Keterolac. 0623 Ethinyl estradiol is a derivative of 17 B-estradiol 0613. The injections of NSAIDs can be prepared alone or (E2), the major endogenous estrogen in humans. It is an orally in combination with other drugs for therapeutic purpose i.e. bioactive estrogen used in many formulations of combined presently approved drugs can be made available in combina oral contraceptive pills. It is one of the most commonly used tion with other drugs combined to produce a clear injectables medications for this purpose. wherein wholly Diethylene glycol monoethyl ether up to 0624. It is chemically denoted as 19-nor-17C.-pregna-1,3, 100% by volume can be used in varying concentration with 5(10)-trien-20-yne-3,17-diol with molecular structure as: other co-solvents without causing any physical changes like color change, crystal formation, etc. 0614 Injection form is more advantageous over oral form (III.10) of the compound as serum concentration of oral NSAID is lesser because of intestinal metabolism of the drug. Dry pow der injectable NSAID needs to be lyophilized and then recon stituted before use. The process is costly and cumbersome. So, the present art is helpful to provide clear parenterals obviating above difficulties. 0615 III.9) Aceclofenac (NSAID) 0616 Aceclofenac is a non-steroidal anti-inflammatory drug (NSAID) used for the relief of pain and inflammation in rheumatoid arthritis, osteoarthritis and ankylosing spondyli tis. Aceclofenac is the glycolic acid ester of diclofenac. The 0625. It is a white to slightly yellowish white, crystalline systemic name of this NSAID is 2-2-[2-(2,6-dichlorophe powder, odourless, practically insoluble in water; freely nyl)aminophenyl)acetyloxyacetic acid with the molecular soluble in ethanol (-750 g/l) TS; soluble in acetone and Structure aS dioxan. US 2014/0296.191 A1 Oct. 2, 2014 39

0626. It is available in the market as 0.5 mg and 1 mg of dimethyloxan-2-yl)oxy-10-(2- Ethinyl estradioloral tablet. Most combination birth control methoxyethoxymethoxyimino)-3,5,7,9,11,13-hexamethyl pills today contain between 20 mcg (low dose pills) to 30/35 1-oxacyclotetradecan-2-one and molecular structure is given mcg of Ethinyl estradiol. aS 0627 By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis (III.12) cous solution is obtained, which can be useful as I.V. injection for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, liquid oral dosage forms etc. The Solution may additionally contain preservatives and buffers for maintenance of pH. 0628 III.11) Terbinafine (Antifungal Agent) 0629 Terbinafine hydrochloride is a syntheticallylamine antifungal. It is highly lipophilic in nature. It prevents con version of squalene to lanosterol, ergosterol cannot be syn thesized. This is thought to change cell membrane permeabil ity; causing fungal cell lysis. Terbinafine hydrochloride is a white fine crystalline powder that is freely soluble in metha nol and dichloromethane, Soluble in ethanol, and slightly soluble in water. It is chemically designated as (2E)-6,6- dimethylhept-2-en-4-yn-1-yl(methyl)(naphthalen-1-ylm ethyl)amine with the molecular structure given as: (2) indicates text missing or illegible when filed

(III.11) 0635. It is soluble in ethanol and acetone, methanol and ethyl ether dissolved, almost insoluble in water; 2, the water CH solubility: 0.1 g dissolved in 30 ml water. 0636. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis cous solution is obtained, which can be useful as I.V. or I.M. injections for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, tablets, liquid oral dosage forms etc. The Solution may additionally contain preservatives and buffers for maintenance of pH. 0630. As a 1% cream or powder it is used for superficial 0637 III.13) Spironolactone (Aldosterone Receptor skin infections. Oral 250 mg tablets are often prescribed for Antagonist) the treatment of onychomycosis of the toenail or fingernail 0638 Spironolactone is a potassium-sparing diuretic (wa due to the dermatophyte Tinea unguium. It is also available as terpill) that prevents your body from absorbing too much salt gel. The drug accumulates in the skin tissues and in nails after and keeps your potassium levels from getting too low. It is ingestion or dermal application to have localized effect. It practically insoluble in water about 22 mg/L at 25°C. It is might be possible to formulate parenteral I.V. Bolus for rapid used to diagnose or treat a condition in which you have too onset of action by the present art. much aldosterone in your body. It is chemically designated as 0631 By utilizing the vehicle or solvent of the present 17-hydroxy-7.C.-mercapto-3-oxo-17C-pregn-4-ene-21-car invention solvent, Diethylene glycol monoethyl ether or other boxylic acid, Y-lactone acetate and the molecular structure is: alkyl derivatives, a transparent, non hazy as well as less vis cous solution is obtained, which can be useful as I.V. bolus injection for rapid onset of action when required to provide (III.13) earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, nasal sprays, gargles, gels, topical, liquid oral dosage forms etc. The solution may additionally contain preservatives and buff ers for maintenance of pH. 0632 III.12) Roxithromycin (Antibiotic) 0633 Roxithromycin is a semi-synthetic macrollide anti biotic. It is used to treat respiratory tract, urinary and soft tissue infections. 0634. This lipophilic active is chemically designated as (3R,4S,5S,6R,7R,9R,11S, 12R,13S, 14R)-6-(2S,3R,4S,6R)- 4-d-3-hydroxy-6-methyloxan-2-yl)oxy-14-ethyl-7,12,13 trihydroxy-4-(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6- US 2014/0296.191 A1 Oct. 2, 2014 40

0639. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other (III.15) alkyl derivatives, a transparent, non hazy as well as less vis cous Solution is obtained, which can be useful as injections for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, tablets, liquid oral dos age forms etc. The Solution may additionally contain preser vatives and buffers for maintenance of pH. 0640 III.14) Eplerenone (Aldosterone Receptor Antago nist) 0641 Eplerenone is an aldosterone antagonist used as an adjunct in the management of chronic heart failure. It is similar to the diuretic spironolactone, though it is much more selective for the mineralocorticoid receptor in comparison (i.e., does not possess any antiandrogen, progestogen, or (2) indicates text missing or illegible when filed estrogenic effects), and is specifically marketed for reducing cardiovascular risk in patients following myocardial infarc 0646. It is slightly soluble in water. It is available as oral tion. It is chemically designated as pregn-4-ene-7,21-dicar tablet in dose of 2.5, 5 and 10 mg and as capsule as per USP. boxylic acid, 9,11-epoxy-17-hydroxy-3-oxo, E-lactone, According to 14 reports from FDA, it was found to have methyl ester (7C.11C. 17C.) and molecular structure is Swelling at site of injection might be due to use of Viscous Solvents. 0647. By utilizing the vehicle or solvent of the present

(III.14) invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis cous Solution is obtained, which can be useful as injections for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, tablets, liquid oral dos age forms etc. The solution further avoids swelling at the site of injection. The solution may additionally contain preserva tives and buffers for maintenance of pH. 0648. III.16) Barnidipine Hydrochloride (Calcium Chan nel Blocker) 0649. It is found to be safer antihypertensive agent used to provide hypotension effect in patient. It is chemically desig 0642 Eplerenone is an odorless, white to off-white crys nated as 3-(3R)-1-benzylpyrrolidin-3-yl 5-methyl 2,6-dim talline powder. It is very slightly soluble in water, with its ethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxy solubility essentially pH-independent. The octanol/waterpar late and molecular structure is tition coefficient of eplerenone is approximately 7.1 at pH 7.0. These drugs are mostly available in market as oral tablet. This both actives are possible to be formulated as a parenteral (III.16) for unconscious patient. 0643. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis cous solution is obtained, which can be useful as I.V. or I.M. injections for rapid onset of action when required to provide earliest result into the patient as well as can be used for HCI formulation of different dosage forms like capsules, tablets, liquid oral dosage forms etc. The Solution may additionally contain preservatives and buffers for maintenance of pH. 0644 III.15) Amlodipine Besylate (Calcium Channel Blocker) 0650. It is a light yellow crystalline powder which is 0645. It is a long-acting calcium channel blocker. Amlo insolubleinwater while soluble in DMSO and methanol. This dipine besylate, USP is chemically described as 3-Ethyl-5- product is available in capsule form in dose strength of 5, 10, methyl(t)-2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)- 15 mg. 1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, OO 0651. By utilizing the vehicle or solvent of the present benzene Sulphonate. Its molecular formula is invention solvent, Diethylene glycol monoethyl ether or other CoHCINOs .CHOS and its structural formula is: alkyl derivatives, a transparent, non hazy as well as less vis US 2014/0296.191 A1 Oct. 2, 2014

cous Solution is obtained, which can be useful as injections Soft gelatin capsules for oral administration, each containing for rapid onset of action when required to provide earliest 10 mg Nifedipine, in which glycerin and PEG is used as inert result into the patient as well as can be used for formulation of excipients. different dosage forms like capsules, tablets, liquid oral dos 0659 According to Chinese Patent No. 941 10139, this age forms etc. The Solution may additionally contain preser invention refers to a Nifedipine injection belonged to calcium vatives and buffers for maintenance of pH. antagonist. It is prepared, by involving Nifedipine, polyvinyl 0652) III.17) Benidipine Hydrochloride (Calcium Chan pyrrolidone, alcohol for injection at ratio of formulation nel Blocker) required to obtain the product. 0653. It is a new hypertensive agent i.e., dihydropyridine 0660. By utilizing the vehicle or solvent of the present calcium channel blocker for the treatment of high blood pres invention solvent, Diethylene glycol monoethyl ether or other Sure, licensed in Japan for oral administration. It is chemi alkyl derivatives, a transparent, non hazy as well as less vis cally known as O5-methyl O3-(3R)-1-(phenyl methyl)pip cous Solution is obtained, which can be useful as injections eridin-3-yl)2,6-dimethyl-4-(3-nitrophenyl)-1,4- for rapid onset of action when required to provide earliest dihydropyridine-3,5-dicarboxylate and its molecular result into the patient as well as can be used for formulation of structure is given as: different dosage forms like capsules, tablets, liquid oral dos age forms etc. The solution may additionally contain preser vatives and buffers for maintenance of pH. (III.17) 0661 III.19) Cilnidipine (Calcium Channel Blocker) 0662 Cilnidipine is the novel calcium antagonist accom panied with L-type and N-type calcium channel blocking function. Due to its N-type calcium-channel blocking prop erties, it has more advantages compared to conventional cal cium-channel blockers. It has lower incidence of Pedal edema, one of the major adverse effects of other calcium channel blockers. Cilnidipine has similar blood pressure low ering efficacy as compared to Amlodipine. The chemical name of this active is O3-(2-methoxyethyl) O5-(E)-3-phe nylprop-2-enyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihy dropyridine-3,5-dicarboxylate and the molecular structure is given as: 0654. It is occurs as a yellow crystalline powder. It is very soluble informic acid, soluble in methanol, sparingly soluble in ethanol and practically insoluble in water. (III.19) 0655 By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives, a transparent, non hazy as well as less vis cous Solution is obtained, which can be useful as injections for rapid onset of action when required to provide earliest result into the patient as well as can be used for formulation of different dosage forms like capsules, tablets, liquid oral dos age forms etc. The Solution may additionally contain preser vatives and buffers for maintenance of pH. O N O 0656 III.18) Nifedipine (Calcium Channel Blocker) (2) 0657 Nifedipine is a dihydropyridine calcium channel O blocker. Its main uses are as an anti-anginal and antihyper (2) indicates text missing or illegible when filed tensive. It is chemically designated as Dimethyl 2,6-dim ethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxy 0663. It is available in marketed as oral tablet in dose of 5 late and molecular structure is. mg, 10 mg, and 40 mg. This medication works by inhibiting the action of angiotensin receptors, thereby helping to control hypertension. (III.18) OCH 0664. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other O CH3 alkyl derivatives, a transparent, non hazy as well as less vis cous Solution is obtained, which can be useful as injections for rapid onset of action when required to provide earliest NH result into the patient as well as can be used for formulation of different dosage forms like capsules, tablets, liquid oral dos ON O CH3 age forms etc. The solution may additionally contain preser vatives and buffers for maintenance of pH. OCH 0665 Other Calcium Channel Blockers like Darodipine, Nimodipine, Nisoldipine, Nitrendipine, Felodipine, Nicar 0658. It has a molecular weight of 346.3, practically dipine, and Isradipine can also be formulated into clear pel insoluble in water. It is available as capsules are formulated as lucid solutions for I.V. or I.M. injections utilizing the vehicle US 2014/0296.191 A1 Oct. 2, 2014 42 or solvent of the present invention, Diethylene glycol mono ethyl ether or other alkyl derivatives. (III.21) 0666 III.20) Captopril 0667. It is an angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first ACE inhibitor developed. It is chemically designated as (2S)-1- (2S)-2-methyl-3-sulfanylpropanoylpyrrolidine-2-carboxy lic acid and molecular structure is:

(III.20)

HS O 0673. It is soluble in DMSO at 200 mg/mL: soluble in O ethanol at 100 mg/mL: very poorly soluble in water; Cele coxib is available by prescription in capsule form and as I.V Nils bolus parenteral in market. ( ) OH 0674. The pain relief offered by celecoxib is similar to that offered by paracetamol. 0675. The prior art indicates that such injections are pre pared and marketed using Dimethyl Isosorbide which is pain 0668. It is easily soluble in water but might get converted ful at the site. into salt form so I.V form might be not developed yet till now. 0676 Celecoxib is soluble in Diethylenglycol monoether Small intravenous bolus injections of captopril may appear to ether and with other cosolvents like diemthyl isosrbide in be effective rapidly and can be well tolerated in moderate to minimum quantity severe essential hypertension. Short-term intravenous admin 0677 To overcome the problem of pain and irritancy at site istration seems to predict the response to chronic oral capto of injections the I.V/I.M Injection of Etoricoxib and Cele pril therapy. Thus by the present art, I.V bolus parenteral can coxib is prepared by dissolving 60, 90, 120 mg/ml solution be prepared by first converting this active into acid form and 100 mg/ml/200 mg/ml in Diethylene glycol monoethyl ether with antioxidant and preservative respectively. which is then solubilize in diethylene glycol monoethyl ether. 0678. It offers an advantage of less painful, less viscous 0669. By utilizing the vehicle or solvent of the present free flowing easily Syringable liquid. It offers a quick onset of invention solvent, Diethylene glycol monoethyl ether or other action. alkyl derivatives, a transparent, non hazy as well as less vis 0679. By utilizing the vehicle or solvent of the present invention solvent, Diethylene glycol monoethyl ether or other cous solution is obtained, which can be useful as I.V. bolus alkyl derivatives, a transparent, non hazy as well as less vis injection or Depot I.M. injection for rapid onset of action cous solution is obtained, which can be useful as I.V. injection when required to provide earliest result into the patient as well for rapid onset of action when required to provide earliest as can be used for formulation of different dosage forms like result into the patient as well as can be used for formulation of capsules, nasal sprays, gargles, gels, topical, liquid oral dos different dosage forms like capsules, gels, patches, liquid oral age forms, otic delivery systems etc. The solution may addi dosage forms etc. The Solution may additionally contain pre tionally contain preservatives and buffers for maintenance of servatives and buffers for maintenance of pH. pH. 0680 III.22) Isoxsuprine Hydrochloride (Anti-Arrhyth mic Drug) 0670. Other commercially available ACE inhibitors like 0681. It is beta-adrenergicagonist that causes direct relax Ramipril, Fosinopril, Zofenopril, Perindopril, Quinapril, ation of uterine and vascular Smooth muscle. Its vasodilating Lisinopril etc., which are lipophilic in nature can also be actions are greater on the arteries Supplying skeletal muscle formulated by utilizing the vehicle or solvent of the present than on those Supplying skin. It is used in the treatment of invention solvent, Diethylene glycol monoethyl ether or other peripheral vascular disease and in premature labor. The chemical name of this lipophilic active is 4-1-hydroxy-2-(1- alkyl derivatives, a transparent, non hazy as well as less vis phenoxypropan-2-ylamino)propylphenol hydrochloride. cous solution is obtained, which can be useful as I.V. bolus lsoXSuprine hydrochloride occurs as a white odorless, crys injection or Depot I.M. injection for rapid onset of action talline powder, having a bitter taste. It has a following struc when required to provide earliest result into the patient as well tural formula: as can be used for formulation of different dosage forms like capsules, nasal sprays, gargles, gels, topical, liquid oral dos age forms, otic delivery systems etc. The solution may addi (III.22) tionally contain preservatives and buffers for maintenance of pH. 0671 III.21) Celecoxib i-O--- Y - 0672 Celecoxib is a sulfonamide NSAID and selective OH NH -cio-O) COX-2 inhibitor used in the treatment of osteoarthritis, rheu CH3 matoid arthritis, acute pain. The chemical name of celecoxib is with molecular structure as: US 2014/0296.191 A1 Oct. 2, 2014 43

0682. It is marketed as Tablet form of dose strength 20 mg 0684 III.23) Drugs Related to Ophthalmic Suspension and as parenteral infusion as well as I.M parenteral of 5 (Ocular) and Otic Suspension 0685. Drugs that are prepared for ophthalmic as well as mg/ml. An intravenous infusion is prepared by dilution of the otic Suspensions can also be formulated as clear pellucic injection in an appropriate quantity of 5% dextrose injection, Solutions, which are further transparent, non hazy and less 5% dextrose in 0.45% sodium chloride injection, or 5% dex viscous by utilization of the vehicle or solvent of the present trose in 0.23% sodium chloride injection. Dilution in 0.9% invention solvent, Diethylene glycol monoethyl ether or other Sodium chloride injection is not recommended because of the alkyl derivatives. 0686. In the prior art formulations the particles in the risk of pulmonary edema. Because of the risk of hypotension Suspension have a tendency of sedimentation and aggrega and tachycardia, single intramuscular doses greater than 10 tion. If administered in to the tissues, often lead to irritation mg are not recommended. and embolism (e.g. Eye drops having Suspended particles can cause irritation to mucosal membrane of eyes causing pain 0683. By utilizing the vehicle or solvent of the present and discomfort to the patients, embolism which is caused due invention solvent, Diethylene glycol monoethyl ether or other to particles infused as I.V. alkyl derivatives, a transparent, non hazy as well as less vis 0687. The preparations using Diethylene glycol monethyl cous Solution is obtained, which can be useful as injections ether or other alkyl derivatives are clear limpid, free from for rapid onset of action when required to provide earliest particulate matter and devoid of particle agglomeration. 0688 Table-I provides Drugs belonging to different phar result into the patient as well as can be used for formulation of macological or therapeutic classes which can also be formu different dosage forms like capsules, tablets, nasal sprays, lated as clear pellucic Solutions, which are further transpar gargles, gels, topicals, liquid oral dosage forms etc. The solu ent, non hazy and less viscous by utilization of the vehicle or tion may additionally contain preservatives and buffers for solvent of the present invention solvent, Diethylene glycol maintenance of pH. monoethyl ether or other alkyl derivatives. TABLE I

Drugs Available as Opthalmic Suspensions and Otic Suspensions

Drug & Therapeutic Chemical Structure & Chemical Solubility Formulations Available in the Code Category Name Profile Market & their Problems Ophthalmic Suspensions

III.23 Brinzolamide /N Insoluble in As a Sterile, Aqueous Carbonic HN water, very Suspension of Brinzolamide Anhydrase soluble in which has been formulated to Inhibitor methanol and be readily Suspended and slow (R) soluble in settling, following shaking. It W \ N O ethanol. has a pH of approximately 7.5 HN / nu1N1 N Solubility in and an osmolality of 300 2'N, S S \ Diethylene mOsm/kg. M V I O glycol 1% (10 mg/ml) opthalmic O O O monoethyl ether Suspension is 55.55 mg/ml. Settling Problem of Suspension III.23 Difluprednate CHOCOCH Very low Sterile Preserved Opthalmic Anti- solubility in Emulsion for the Treatment of inflammatory CO Water Inflammation and Pain Corticosteroid HC associated with Ocular Surgery. HO OCOCH2CH2CH 0.05% is a Sterile, Topical Anti inflammatory Corticosteroid for Ophthalmic use. Diflupredinate 0.5 mg (0.05%); INACTIVE: Boric acid, Castor oil, Glycerin, Polysorbate 80, Water for injection, Sodium acetate, Sodium EDTA, Sodium hydroxide (to adjust the pH to 5.2 to 5.8). The emulsion is essentially isotonic with a tonicity of 304 to 411 mosm/kg. PRESERVATIVE: Sorbic acid 0.1%. Settling Problems and Unwanted Chemicals like Castor Oil being used US 2014/0296.191 A1 Oct. 2, 2014 44

TABLE I-continued

Drugs Available as Opthalmic Suspensions and Otic Suspensions

Drug & Therapeutic Chemical Structure & Chemical Solubility Formulations Available in the Code Category Name Profile Market & their Problems

III.23 Flurometholone Freely soluble in Opthalmic Suspension (not for Acetate chloroform and injection) Anti acetone, soluble Flarex inflammatory in ethanol, very (Fluorometholone Acetate Corticosteroid ---OCCH slightly soluble Ophthalmic Suspension) in water Sterile O Each mL contains: Active: Fluorometholone acetate 1 mg (0.1%). Preservative: Benzalkonium chloride 0.01%. Inactives: Sodium chloride, Monobasic sodium phosphate, Edetate disodium, Hydroxyethyl cellulose, Tyloxapol, Hydrochloric acid and/or Sodium hydroxide (to adjust pH), and purified water. The pH of the Suspension is approximately 7.3, with an Osmolality of approximately 300 mCSm/kg. Partile Size Control and Irritation if Agglomeration OCCS.

III.23 Loteprednol Soluble in Sterile, Topical Anti Anti DMSO 34%, in inflammatory Corticosteroid inflammatory 0.83% ethanol, The active ingredient is Corticosteroid O.224.1% Loteprednol Etabonate. Each propylene ml contains 5 mg (0.5%) glycol, Loteprednol Etabonate. 8 Jug per 1t in The other ingredients are Water. Disodium Edeta e, Glycerol, Povidone, Purified Water and Tyloxapol. Benzalkonium Chloride (0.01%) is added as a preservative. Sodium Hydroxide and/or Hydrochloric Aci are added to adjust the pH. Suspension and Particle Size Controls.

III.23 Besifloxacin Sparingly 0.6% Suspension : Opthalmic Antibacterial soluble in Suspension formulated with COOH methanol, DuraSite Technology Sparingly 6.63 mg Besi floxacin soluble in water Hydrochloride equivalent to 6 oHCI (1 mg/mL), mg Besifloxacin Base (6 mg/ml) N DMSO Suspension and Control on (<1 mg/mL) Particles C

H US 2014/0296.191 A1 Oct. 2, 2014 45

TABLE I-continued

Drugs Available as Opthalmic Suspensions and Otic Suspensions

Drug & Therapeutic Chemical Structure & Chemical Solubility Formulations Available in the Code Category Name Profile Market & their Problems

III.23 Loteprednol CH-NH2 NH2 Solubility of Ocular Steroid Suspension Etabonate + Tobramycin: Each mL contains: Actives: Tobramycin O NH2 Soluble in Loteprednol Etabonate 5 mg Anti- water; very (0.5%) and Tobramycin 3 mg inflammatory slightly soluble (0.3%). Inactives: Edetate Corticosteroid + O in 100% Disodium, Glycerin, Povidone, Antibiotic HO ethanol. Purified Water, Tyloxapol, and Solubility in Benzalkonium Chloride 0.01% NH2 CHOH Diethylene (preservative). Sulfric Acid glycol and/or Sodium Hydroxide may O monoethyl be added to adjust the ether: 25 mg/ml pH to 5.7-5.9. The Suspension NH2 Solubility in is essentially isotonic with a O Diethylene tonicity of 260 to 320 HO glycol mOsm/kg. monoethyl The control on particle size is a OH ether: 3 mg/ml consistent problem for both the Tobramycin drugs

III.23. Brimonidine + NHCH2CH3 Brinzolamide: Opthalmic Suspension Brinzolamide insoluble in (1%/0.2%) Carbonic O water, very 10 mg/ml Brinzolamide Anhydrase | / soluble in 2 mg/ml Brimonidine Tartarate Inhibitor + H.N- methanol and Particle Size Control is Antiglaucoma N-1- soluble in essential Agent O S S 1. N ethanol. M V Brimonidine O O tartarate: Brinzolamide soluble in water (34 mg/mL) at pH 6.5 Br | N N N n e OH 2 N N H1 Brimonidine tartarate

III.23 Rimexolone O Very slightly 1% Opthalmic Suspension Glucocorticoid soluble in water; Control on Particle Size is Steroid freely soluble in essential HO chloroform: soluble in ethyl

... I III acetate and in methanol

III.23 Sulfacetamide + O H Sulfacetamide: Opthalmic Suspension Prednisolone \ -N Water-soluble 10%. Sulfacetamide Acetate S <0.01 g/100 mL 0.2% Prednisolone Acetate Antibacterial + \, at 16° C. Control on Particle Size Corticosteroid O HN Sulphactamide US 2014/0296.191 A1 Oct. 2, 2014 46

TABLE I-continued

Drugs Available as Opthalmic Suspensions and Otic Suspensions

Drug & Therapeutic Chemical Structure & Chemical Solubility Formulations Available in the Code Category Name Profile Market & their Problems

III.23, Tobramycin + OH 3 mg/ml Opthalmic Suspension Dexamethasone Tobramycin (0.3%/0.1%) Antibiotic + 1 mg/ml Control on Particle Size Steroid Dexamethasone aOH

Dexamethasone

III.23 Neomycin NH2 Each gram As an anti-infective Steroid Sulphate + contains: combination as Sterile Topical Polymixin B O Neomycin Ointment Sulphate + OH Sulphate: 3.5 mg (3.5 g Sterile Ointment in an Dexamethasone O H Polymixin B aluminium tube) Antibiotic + NH2 HN Sulphate: Control on Particle Size Glucocorticoid 10.000 unit O O NH Dexamethasone: HO O 0.1% (1 mg) OH

OH HN O O

OH NH 2 Neomycin

III.23 Nepafenac O NH2 Soluble in Each mL contains: Active: NSAID DMSO and Nepafenac 0.1% NH2 Methanol Inactives: Mannitol, Carbomer Solubility in 974P, Sodium chloride, diethyleneglycol Tyloxapol, Edetate disodium, O mono ethyl Benzalkonium chloride 0.005% ether is found (Preservative), Sodium upto 2 mg/ml hydroxide and/or Hydrochloric acid to adjust pH and purified water, USP Control on Particle Size

III.23A Betaxolol OH Freely soluble in Opthalmic Solution/Drops Hydrochloride water, ethanol, Betaxolol Hydrochloride 0.5% Beta Receptor chloroform, and Opthalmic Solution/Drops Blocker methanol. Falcon Pharmaceuticals Each 5.6 mg Betaxolol Hydrochloride equivalent to rou Betaxolol base 5 mg try Control on Particle Size

Otic Suspensions US 2014/0296.191 A1 Oct. 2, 2014 47

TABLE I-continued Drugs Available as Opthalmic Suspensions and Otic Suspensions Drug & Therapeutic Chemical Structure & Chemical Solubility Formulations Available in the Code Category Name Profile Market & their Problems III.23 Ciprofloxacin Ciprofloxacin: Sterile Otic Suspension & HN Soluble in (Ciprofloxacin 0.3% and Dexamethasone water; slightly Dexamethasone 0.1%) Antibacterial + soluble in Ciprofloxacin Hydrochloride Glucocorticoid N- N () HCI (2) HO methanol R: (equivalent to 3 mg very slightly Ciprofloxacin Base), 1 mg soluble in Dexamethasone ethanol Control on Particle Size F CO2H (-750 g/l) TS: O practically insoluble in Ciprofloxacin HCI acetone Rand dichloromethane R.

(2) indicates text missing or illegible when filed

Class IV: Drugs Belonging to Other Therapeutic Categories be useful as I.V. or I.M. injections for rapid onset of action 0689 Table-II provides Drugs belonging to different phar when required to provide earliest result into the patient, but macological or therapeutic classes which can also be formu also does not have the safety and toxicity issues associated lated as clear pellucic Solutions, which are further transpar with Cremophor R EL. The solution can also be used for ent, non hazy and less viscous by utilization of the vehicle or formulation of different dosage forms like capsules, tablets, solvent of the present invention solvent, Diethylene glycol liquid oral dosage forms etc. The solution may additionally monoethyl ether or other alkyl derivatives. The solutions can contain preservatives and buffers for maintenance of pH. TABLE II

Drugs Belonging to Different Pharmacological or Therapeutic Classes

Form Drug & Available Therapeutic Chemical Structure & Chemical In The Code Category Name Solubility Profile Market

IV.1 Vinpocetine Soluble in DMSO, As an Oral, An inhibitor of DMF, ethanol, acetic I.V. as Ca2+/CaM-PDE acid, acetone, and Supplement with chloroform. Neuroprotective Insoluble in water. properties

(3C,16C)-Eburnamenine-14-carboxylic acid ethyl ester

IV.2 Itraconazole () (2) (2) Soluble in organic Available as Triazole Solvents such as Capsules or Antifungal Agent DMSO and dimethyl as an Oral (2R4S)-rel-1-(butan-2-yl)-4-(4-4-(4- formamide. Solution {(2R-4S)-2-(2,4-dichlorophenyl)-2- (1H-1,2,4-triazol-1-ylmethyl)-1,3- Insoluble in water. dioxolan 4-yl)methoxyphenyl)piperazin-1- yl)phenyl-4,5-dihydro-1H-1,2,4- triazol-5-one US 2014/0296.191 A1 Oct. 2, 2014 48

TABLE II-continued

Drugs Belonging to Different Pharmacological or Therapeutic Classes

Form Drug & Available Therapeutic Chemical Structure & Chemical In The Code Category Name Solubility Profile Market

IV.3 Nimodipine Soluble in methanol. As Film Potent L-type Insoluble in water Coated Ca2+ Channel in beta Tablet, Antagonist cyclodextrin Intravenous Injection

CH3 O O

NO 3-(2-methoxyethyl) 5-propan-2-yl 2,6- dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate

IV.4 Ezetimibe Freely to very As Tablet of Anti OH Soluble in ethanol, 10 mg. hyperlipidemic methanol, and acetone and practically insoluble in water.

(3R,4S)-1-(4-fluorophenyl)-3-((3S)-3- (4-fluorophenyl)-3-hydroxypropyl-4- (4-hydroxyphenyl)aZetidin-2-one

IV.5 Valproic acid A colorless liquid As 250 mg Anticonvulsant with a characteristic of So 1 and Mood odor. It is slightly Elastic stabilizing Agent HO soluble in water (1.3 Capsu mg/mL) and very Enteri soluble in organic Coated Solvents. Capsu e Syrup Solution, 2-Propylpentanoic acid I.V. Injectable Form.

IV.6 Bexaroteine CH3 CH Insoluble in water As 75 mg of Antineoplastic and slightly soluble Soft Ge atin Agent in vegetable oils and Capsu ethanol, USP Topical So Gel.

CH3 COOH CH 4-1-(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)ethenyl benzoic acid US 2014/0296.191 A1 Oct. 2, 2014 49

TABLE II-continued Drugs Belonging to Different Pharmacological or Therapeutic Classes

Form Drug & Available Therapeutic Chemical Structure & Chemical In The Code Category Name Solubility Profile Market IV.7 Tretinoin H3C CH3 CH3 CH3 Insoluble in water As Cream Anti-acne Drug or Gel of COOH 30, 45, 60 N1 N1 N1 N. mg, 30 ml Liquid Solution: CH3 Soft Capsule of Retinoic acid 10, 20, 30, 40 mg, Tablet IV.8 Loperamide N Yellow powder A Tablet, Anti-diarrheal insoluble in water Capsule, and Liquid 2 to be taken / \ by mouth OH N O N e \

4-4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)- N,N-dimethyl-2,2-diphenylbutanamide IV.9 Melphalan <0.1 g/100 mL at 22°C., SOMG Alkylating Agent C 95% ethanol and 1 Injectable drop 6 NHCl: 0.05 Vial, N O OH g/mL 2 mg C Tablet.

NH2 3-(p-(bis(2-chloroethyl)amino)phenyl)-1- alanine; 3(p-(bis(2-chloroethyl)amino)phenyl)-1- alanine

IV.10 Tadalafil Insoluble in water As almond PDES Inhibitor and very slightly shaped soluble in ethanol Tablet.

b-/ IV.11 Loxapine / \ Sparingly soluble in Available as (Loxapine N N-CH H2O, freely soluble Capsule 3 AntipsychoticSuccinate) N \ / in DMS

O 2-Chloro-11-(4-methyl-1- piperazinyl)dibenzb.f14 oxazepine US 2014/0296.191 A1 Oct. 2, 2014 50

TABLE II-continued

Drugs Belonging to Different Pharmacological or Therapeutic Classes

Form Drug & Available Therapeutic Chemical Structure & Chemical In The Code Category Name Solubility Profile Market

IV.12 Amilsulpride Practically insoluble Available as Antipshycotic in water, sparingly Tablet and Soluble in ethanol, 100 mg/ml soluble in methanol Solution and freely soluble in Form. N HN O dichloromethane O NH2

(RS)-4-amino-N-(1-ethylpyrrollidin-2- yl)methyl 5-ethylsulfonyl-2-methoxy-benzamide

IV.13 Tacrolimus Insoluble in water, Available as Antibiotic freely soluble in Capsule & ethanol, and very 5 mg/ml soluble in methanol Injection. and chloroform.

H H w

IV.14 Doxorubicin O OH O Soluble in DMSO at Available as Anticancer Agent 100 mg/mL; very 2 mg/ml CCH2OH poorly soluble in Multidose ethanol; soluble in Vials & as water at 10 mg/mL. Lyophilized with slight warming. Powder.

H OCH O OH oHC O Q CH HO NH2 (8S, 10S)-10-(3-Amino-2,3,6- trideoxy-a-L-lyxo-hexopyranosyl)- oxy-8-glycoloyl-7,8,9,10-tetrahydro 6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedione hydrochloride Oct. 2, 2014

TABLE II-continued Drugs Belonging to Different Pharmacological or Therapeutic Classes

Form Drug & Available Therapeutic Chemical Structure & Chemical In The Code Category Name Solubility Profile Market IV.15 Olanazapine \ Olanzapine is AS Yellow Antipsycotic N soluble in organic Lyophilized Solvents such as Powder for ethanol, DMSO, and Injection. dimethyl formamide, which should be purged with an inert gas. The solubility of olanzapine in these Solvents is approx. 1, 16, and 20 mg/ml, respectively. 2-methyl-4-(4-methyl-1-piperazinyl)- 10H-thieno.2,3-b1,5benzodiazepine

IV.16 Fluticasone It is practically Available as Propionate insoluble in water, 50 mcg Corticosteroid freely soluble in Nasal spray. dimethylsulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. Solubility in Diethylene glycol monoethyl ether is 14.7 mg/ml.

S-(fluoromethyl)6C,9-difluoro-11B-17 dihydroxy-16C.-methyl-3-oxoandrosta 1,4-diene-17B-carbothioate, 17-propionate

(2) indicates text missing or illegible when filed

0690. In addition to the above, various other drugs for TABLE III treating AIDS, Rare Diseases, Neglected diseases such as Tuberculosis, Malaria etc. can also be made into clear, trans The Solubility of various Pharmaceutical Actives parent and non hazy Solutions by utilizing the vehicle or in Diethylene Glycol Monoethyl Ether solvent of the present invention solvent, Diethylene glycol monoethyl ether or other alkyl derivatives. Such solutions can Solubility in Diethylene be useful as injections for rapid onset of action when required Code Pharmaceutical Active Glycol Monoethyl Ether to provide earliest result into the patient. The solution can also be used for formulation of different dosage forms like cap Class I: Drugs which are Difficult to Solubilize Sules, tablets, nasal sprays, gels, topics, liquid oral dosage forms etc. The solutions can also be used for preparation of .1 Progesterone 50 mg/m nano Solutions. 24 Nandrolone Decoanate 100 mg/ml 100 mg/m 2B Nandrolone Phenyl Propionate 71.42 mg/m EXAMPLES .34 Testosterone Enanthate 55.50 mg/m 0691. The following Examples illustrate the invention in .3B Testosterone Cypionate 45.45 mg/m detail, which should not be construed as limiting the scope of .6 Fulvestrant 58.80 mg/m the invention. 7 Artemether 100 mg/m 8 Arteether 80 mg/m Example 1 9 Haloperidol 8.30 mg/m 10 Vitamin D3 30 mg/m Solubility .12 Etoricoxib 200 mg/m 0692. The solubility of various pharmaceutical actives, 13 Cyclosporine 50 mg/m belonging to the three classes, referred to hereinbefore in .14 Paclitaxel 23.80 mg/m Diethylene glycol monoethyl ether are summarized in Table 1S Piroxicam 15 mg/m III. US 2014/0296.191 A1 Oct. 2, 2014

TABLE III-continued TABLE III-continued The Solubility of various Pharmaceutical Actives The Solubility of various Pharmaceutical Actives in Diethylene Glycol Monoethyl Ether in Diethylene Glycol Monoethyl Ether Solubility in Diethylene Code Pharmaceutical Active Glycol Monoethyl Ether Solubility in Diethylene IV.15 Olanazapine 45 mg/ml Code Pharmaceutical Active Glycol Monoethyl Ether IV.16 FluticasOne Propionate 14.70 mg/ml

Class II: Drugs which have Stability Issues Example 2 Progesterone (I.1) 3 Artesunate 100 mg/m .9 Lignocaine 200 mg/m 0693 1O Azithromycin 83 mg/m .12 Dicyclomine Hydrocloride 20 mg/m Sr. No Ingredients Quantity/ml 13 Paracetamol 66.66 mg/m 1 Progesterone 100 mg 16 Prostaglandin E (Alprostadil) 50 mg/m 2 Benzyl Alcohol 20% 3 Diethylene Glycol Monoethyl Ether q.S. up to 1 ml 19 Pantoprazole 80 mg/m .21 Etoposidep 30 mgm.g 0694. The maximum solubility- 0 of Progesterone in Dieth 22 Docetaxel 55 mg/m ylene glycol monoethyl ether was found to between 0.1 to 50 25 Voricanozole 83 mg/m mg/ml while its solubility in Benzyl alcohol was found up to 27 Ibuprofen 400 mg/m 100 mg/ml. Progesterone is dissolved in solution of 20% Class III: Those which are Available in the Form of Benzyl alcohol g1V1ng a clear Solution and add Diethylene glycol monoethyl ether with constant stirring and make the Suspensions and are very Difficult to be volume up to 100 ml with Diethylene glycol monoethyl ether. Solubilized into a Solution Form The clear colourless liquid has viscosity of 3.86 cps. This solution is filled in 3 ml clear glass vial. 0695) Similarly, 2 g to 12 g of drug is dissolved in 100 ml II.1 Prednisolone 11.11 mg/m Diethylene glycol monoethyl ether to give a clear solution for II.2 Methyl Prednisolone 30 mg/m use in therapeutic concentration as a parenteral form. The II.4 Triamcinolone Acetonide 15 mg/m same may be filled in vial or ampoules, PFS. II.9 Aceclofenac 150 mg/m 0696 Optionally, it can be mixed with preservative like II.11 Terbinafine 16.66 mg/m benzyl alcohol in the range of about 2%O to 4%O for filling in multi dose container or the Liquid prepared can be used for II.2.1 Celecoxib 71.42 mg/m the preparation of pessaries for vaginal delivery by Success II.23 Brinzolamide 55.55 mg/m fully matrixing with Suitable excipients. II.23. Loteprednol 25 mg/m 0697. Other adjuvant may be used optionally with water in II.23. Nepafenac 2 mg/m sufficient quantity to keep the solution pellucid as well as II.23A Betaxolol Hydrochloride 27.77 mg/m physically and chemically stable. 0698. The nonaqueous solution can be filled in capsule or W.1 Vinpocetine 12 mg/m aqueous or nonaqueous liquid can be employed for their use W.11 Loxapine Succinate 31.25 mg/m in other oral delivery system. W.12 Amilsulpride 25 mg/m (0699 Stability Study Data for Progesterone Injection 100 mg/ml.

40° C.; 40°C., 25o C. 30° C. 40° C. 25 C. 30° C. 40° C., 25° C. 30° C. Sr. 75% 75% 60% 65% 75% 60% 65% 75% 60% 65% No. Tests Specification Initial RH/1M RH/2M RH/3M RH/3M RH/3M RH/6M RH/6M RHA6M RHA9M RHA9M

1 Description Clear Colourless Solution Yellowish Clear Colourless Colour Solution Clear Solution 2 Assay 92.5 103.OO 103.OO 103.50 101.06 99.90 102.10 102.50 99.30 96.20 1OO.12 99.37 UV to (%) 107.5 US 2014/0296.191 A1 Oct. 2, 2014

0700. The stability study of this formulation containing 0710. The preservative like benzyl alcohol, solubilisers 100 mg/ml Progesterone and tested by the validated method and antioxidants added keeps the solution pellucid, physi was found to be satisfactory. cally and chemically stable. 0711 Stability Study Data for Nandrolone Decanoate 0701. The viscosity of the comparator brand is 4.9 cps Injection 100 mg/ml:

40° C., 40° C. 25° C. 30° C., 40° C.? 25°C. 30° C., 40° C. Sr. Specifi- 75% 75% RHS 60% 65% RHS 75% 60% 65% 75% No. Tests cation Initial 2M RHA3M 3M RHA3M RHA6M RHA6M RHA6M 1 Description Clear Colourless Solution Slight Pale Yellowish Clear Liquid 2 Assay (%) 90-110 100.71 102.81 102.83 102.81 101.22 101.OO 99.14 99.25 98.29

Example 3 0712 Stability Study Data for Nandrolone Decanoate Injection 25 mg/ml: Nandralone Decanoate (I.2) (0702. The solubility profile of Nandrolol decanoate with 40° C. 25 C. 30° C. 40° C. Diethylene glycol monoethylether is about 1 to 100 mg/ml. 75% 60% 65% 75% Sr. Specifi- RHS RHA RHS RHA No. Tests cation Initial 1M 3M 3M 3M Sr. No. Name of Ingredients Qty/ml Qty/ml Qty/ml 1 Nandrolone 100 mg 25 mg 25 mg 1 Descrip- Clear Colourless Solution Decanoate tion 2 Benzyl Alcohol 296 2% 296 3 BHA 1 mg 1 mg 0.3 mg 2 Assay 90-110 101.95 101.69 103.21 102.79 101.59 4 BHT 1 mg 1 mg 0.3 mg (%) 5 Vitamin E. Acetate 1 mg 1 mg 1 mg 6 Diethylene Glycol C.S C.S C.S Monoethyl Ether 0713 The stability study of Nandrolone Decanoate injec tion of both dose strength 25 mg/ml and 100 mg/ml are found 0703 Weigh accurately Nandrolone Decanoate under to be in the acceptable range. cool & dark place & take clean vessel. Add Diethylene glycol monoethyl ether into this and stir vigorously to dissolve Nan drolone Decanoate until a clear solution is obtained. Add Example 4 BHA, BHT & Vit. E. acetate, stir vigorously to dissolve it in Diethylene glycol monoethyl ether. Testosterone Cypionate (I.3) 0704. Make up the volume up to 100 ml. using Diethylene glycol monoethyl ether. Solution is filtered by 0.45 micron filter 0.22L & filled in 1 ml clear glass ampoules with nitrogen 0714. The solubility of testosterone cypionate in Diethyl flushing & stability. ene glycol monoethyl ether was found to be 50 mg/ml with 0705 The resultant solution gives a concentration of Nan Viscosity less than 7 cps. drolone Decanoate. 0715 2.5g to 5g of drug is dissolved in 100 ml Diethylene 0706 The stable solution of Nandrolone Decanoate in the glycol monoethyl ether to give a clear Solution. concentration of 25 mg and 100 mg/ml can be prepared which has viscosity of 3.485 cps. as compared to only injection 0716. The stable injections are filled in ampoules or vials which has more than 19 cps. The new compsotion Solution is or PFS for ready use. painless while administering in the tissues. 0717 The final concentration can be given to the doctors 0707 Clear solution of Nandrolone decanoate 100 mg/ml after filling in ampoules and vials for it therapeutic applica injection or 25 mg/ml injection is obtained. The viscosity of tion to the doctors, for the parenteral application. this final solution was found about 3.485 cps. 0718 The solution may be optionally filled in the desired 0708. The dispensing & manufacturing process should be concentration in caps for oral delivery or for preparing the completed into cool & dark place because Nandrolone composition for applying as gel. Decoanate is a hormonal drug and sensitive to light, moisture, 0719. The liquid may optionally have preservative like & Temperature. benzyl alcohol in concentration of about 2% to 6% antioxi 0709 Thus, 1 mg to 100 mg of drug injection can be dants in butylated hydroxyl anisole or butylated hydroxy prepared using Diethylene glycol monoethyl ether and may toluene may be added, which keeps the Solution pellucid as be filled in ampoules or vials. well as physically and chemically stable. US 2014/0296.191 A1 Oct. 2, 2014 54

Example 5 0728. The Injections can be Administered Through I.M. or I.V. Route Artemether ((I.7) 0729. The stability data of Artemether injection prepared using Dietheylene glycol monoethyl ether solvent was found 0720 in the accepted range.

Example No. Example 6 Sr. 1 2 3 Arteether (I.8) No. Name of Ingredients Qty/ml Qty/ml Qty/ml 0730. The solubility range for C.B-Arteether in Diethylene 1 Artemether 80 mg 80 mg 80 mg glycol monoethyl ether was observed about 1 to 76.74 mg/ml. 2 Benzyl alcohol 296 wiv 296 2% 3 BHA 1 mg 0.2 mg 4 BHT 1 mg 0.2 mg 5 Vitamin E Acetate 0.25 mg 1 mg 1 mg Sr. 6 Diethylene Glycol Monoethyl Ether Q.S Q.S Q.S No Name of Ingredient Qty/ml 7 Molecular Sieve for Drying 25 mg 1 C, B Arteether 75 mg 2 Benzyl alcohol 4% 0721 The viscosity of the final solution of Artemether 3 Vitamin E. Acetate 1 mg Injection 80 mg/ml was found about 3.322 cps. 4 Diethylene Glycol Monoethyl Ether C.S 0722 4g to 10g of drug is dissolved in 100 ml Diethylene glycol monoethyl ether to give a clear Solution. 0731 7.5g of drug is taken in a flask to dissolve in 100 ml 0723. The necessary antioxidants and preservatives like Diethylene glycol monoethyl ether to give therapeutically Butylated hydroxyl anisole. Butylated hydroxyl toluene, Suitable preservative and antioxidants are added to give clear Tocopherolacetate and Benzyl alcohol is added. The solution Solution ready to be used as a composition after filtering is found to be stable and can be easily administered by I.M. or aseptically in an ampoule or vial for use as injection which I.V. route for desired therapeutic purpose. can be administered through I.M. and I.V. The viscosity of the 0724. The achieved concentration may be filled in liquid is found to be 2.85 cps as compared to oily injection ampoules, PFS or vials to be used by the doctors. which has more than 39 cps. 0725 Suitable preservatives like benzyl alcohol and anti (0732 Optionally, preservatives like Benzyl alcohol in the oxidants like, thioglycerol and ascorbyl palmitate may be concentration from 1% to 10% may be added with adding anti optionally added, which keeps the Solution pellucid physi oxidants like Vitamin E acetate, BHA, BHT and other avail cally and chemically stable. able antioxidants in the acceptable range. 0726. The final clear solution is filled into clear glass vial 0733. Additionally, adjuvants may be added in pharma of 5 ml volume as well as can be filled into ampoules or ceutically acceptable concentration to stabilize the liquid for prefilled Syringes. its use directly or by matrixing in the Suitable excepients to 0727 Stability Study Data of Artemether Injection 80 give Suitable oral delivery composition. mg/ml. 0734 The final solution of C.B Arteether 75 mg/ml injec tion have viscosity of about 2.85 cps. It can be packed into vials or 2 ml ampoule or prefilled Syringes in therapeutic Sir No. Test Initial 1M40° C. 2MA40° C. concentrations and in desired Volumes. 1 Descrpition Clear Colourless Solution 0735. As the viscosity is less, same can be administered 2 Assay, Limit 104.84 100.35 98 safely without any pain as compared to presently available 90 to 11.0% oily injection which has viscosity of more than 35 cps (0736. Stability Study Data for C. B Arteether 75 mg/ml Injection:

40° C.; 40°C., 25° C. 30° C. 40° C., 25° C. 30° C. 40° C. 250 C.? 30° C. Sr. Specifi- 75% 75% 60% 65% 75% 60% 65% 75% 60% 65% No. Tests cation Initial

1 Descrip Clear colourless solution tion 2 Assay 90-110 101.10 100.84 100.24 101.62 100.91 98.42 98.7S 101.13 101.SO 99.63 99.86 (%) US 2014/0296.191 A1 Oct. 2, 2014 55

(0737 Stability study of C. B Arteether 75 mg/ml injection Composition of Etoricoxib Gel 10 mg prepared in Diethylene glycol monoethyl ether was per formed according to ICH guidelines and all the test were 0747 found in acceptable criteria. Example 7 Sr. No Ingredients Qty/ml 1 EtOricoxib IH 10 mg Etoricoxib (I.12) Propylene Glycol IP 250 mg 0738 Etoricoxib was found to be soluble in Diethylene 3 St. E. 100 mg glycol monoethyl ether in range of 1 to 200 mg/ml. 4 Ethanol IP 200 mg 5 Tocopheryl Phosphate 10 mg Hydrolysate (TPM) IH 6 Sepineo P600 IH 50 mg Sr. No Name of Ingredient Qty/ml 7 Purified Water IP Qs up to 1.0gm 1 Etoricoxib 90 mg 2 Benzyl Alcohol 4% 3 Diethylene Glycol Monoethyl C.S 0748 Stability Study Data of Etoricoxib Gel 10 mg: Ether

0739 The same is novel delivery otherwise is not available Sr. No Test Initial After 1M40° C. After 3M 40°C. in market as 1njections. - 1 Description White to off White to off white White to off 0740 1 g to 20g of drug is dissolved in 100 ml Diethylene white colour, colour, semisolid, white colour, glycol monoethyl ether to give a clear solution. Preservative semisolid, homogeneous semisolid, like Benzyl alcohol in varying concentration can be added. homogeneous viscous Gel. homogeneous 10741. Herein,in, thet eunerapeutic th ti concentrauonoiarugtrati fd is pre- 2 pH viscous4.09 Gel. Not done viscousNot Done Gel. pared in concentration of 90 mg/ml in Diethylene glycol 3 Viscosity 48.614 cps Not done Not Done monoethyl ether. It has viscosity 3.70 cps. The injection being 4 Assay, 99.83 101.06 97.33 less viscous easily Syringable and can be easily administered O 0. in the tissues through I.M or I.V. route. 5 Impurity Not Detected Single: 0.38% Not Detected 0742 The achieved concentration may be useful for its NMT 20% Total: 0.38% application as injections filled in ampoules, PFS and or filled inhard filled caps/softgel or suitably compounded as Roll On composition or for dermal delivery to give stable formulation. Other additives may be added to incorporate the same as Example 8 tablets or for oral liquid with combining in aq liquid with buffering agents and pH adjusting buffers like Tris buffer, Piroxicam (I.15) acids or alkali. 0743 Stability Study Data of Etoricoxib Injection 90 0749. The solubility of Piroxicam in Diethylene glycol mg/ml. monoethyl ether was found to be about 0.1 to 35 mg/ml.

40°C., 25° C. 30° C. 40° C. 25o C. 25o C. 75% 40°C., 60%. 65% 75%. 25°C., 30° C., 40°C., 60%. 30° C., 60%. 30° C., Sr. Specifi- RH 75% RHA RHA RHS 60%. 65% 75% RHS 65% RHA1 65% No. Tests cation Initial (2) RH2M (2) () (2) RH/6M RH/6M RH/6M (2) RH/9M (2) RH/12M 1 Descrip- Clear Yellow Coloured Solution tion 2 ASSaw 90-110 100.23 99.0 100.60 101.94 102.20 102.80 100.54 99.52 100.23 100.24 100.63 100.63 100.55 3 Impurity Single: Not Determined Single: Single: Single: Single: (%) O.S O.29 O.298 0.299 O.326 Tot Total Total: Total: Total: () () 0.7 (2) O.724

(2) indicates text missing or illegible when filed

0744. The stability study was carried out for Etoricoxib injection 90 mg/ml and was found to be satisfactory with Sr. No. Ingredient Qty/ml acceptable. Assay range and no impurities were detected. A) Thus, the trial of new formulation of Etoricoxib injection 90 mg/ml in Diethvlene glvcol monoethvil ether indicate the 1 Piroxicam 20 mg 9. - y gly y Dimethyl Isosorbide 15% wiv Solution stability and ready to use for therapy. 3 Diethylene Glycol Monoethyl Ether C.S 0745. The viscosity of the liquid prepared in Diethyelene pH of solution B) 4.2 glycol monoethyl ether is found to be 3.70 cps. 1 Piroxicam 20 mg 0746 Etoricoxib gel is prepared with composition as 2 Tris Buffer 2.5 mg below for dermal application. US 2014/0296.191 A1 Oct. 2, 2014 56

-continued Example 9 Sr. No. Ingredient Qty/ml Vitamin D. (I.10) 3 Diethylene Glycol Monoethyl Ether C.S pH of solution 5.71 (0756. The solubility of Vitamin D, was found upto 0.1 to 33.33 mg/ml in Diethylene glycol monoethyl ether. (0750 1 g to 5g of drug is dissolved in 100 ml Diethylene glycol monoethyl ether to give a clear Solution to give 10 mg/ml to 50 mg of Piroxicam per ml with the viscosity 3.365 cpS. Sr. No. Ingredient Qty/ml Qty/ml 0751. Further pH of the solution can be brought to alkaline side using alkaliser. 1 Vitamin D. 15 mg 15 mg 0752. The same may be used as injection after aseptic 2 BHA 1 mg 1 mg filtration using 0.22 Lufilter and filled in ampoules or vials as 3 Vitamin E. Acetate 1 mg 1 mg per therapeutic requirements. 4 BHT 1 mg 0753. The hard filled or soft gelatin caps can be filled in a 5 Diethylene Glycol Monoethyl Ether Q.S Q.S suitable concentration for the oral delivery or suitable formu lated for the dermal delivery in form of gels or for use as SprayS. (0754 Stability Study Data of Piroxicam Injection 20 (0757. Weigh accurately 15 mg of Vitamin D3 and add into mg/ml. clean 100 ml glass vessel. Dissolve the drug into Diethylene glycol with addition of Vitamin E acetate. BHA and BHT optionally. 40° C., 40°C., 75% RHS 75% RHS Sr. 1M 1M 0758 Mix the solution till drug get dissolve to produce No. Test Initial A. B final solution. The same is filled aspecticvally through 0.22L 1 Description Greenish Yellow Colour Liquid filter and filled aseptically in syringe, PFS or vials for thera 2 Assay, 98.78 97.52 96.28 Limit 90% to peutic use through I.M. or I.V. route. 1.10% 3 Related Not Detected Not Detected Single: 0.53% Substances, Limit Total: 0.72% 0759. The solution thus prepared can be made available as NMT 290 injectables as well as can be used for preparing other dosage forms like filled into capsule when matrixed with other excipients and adjuvants (0755 Stability study was performed for new injectable solution of Piroxicam of dose strength 20 mg/ml. It was found to be in acceptable range and the formulation was stable at 0760 Stability Study Data of Vitamin D. Injection 15 studied accelerated conditions. mg/ml.

Sr. No Test Initial 25°C. 40° C. 25° C. 40° C. 25° C. 40° C.

1 Description Clear Colourless Solution 2 Assay, 12062 108.48 110.33 105.46 101.26 105.90 105.90 Limit 90% to 11.0% US 2014/0296.191 A1 Oct. 2, 2014 57

0761 Vitamin D3 Injection 15 mg/ml prepared in Dieth 0770. The injection can be administered as slow infusion ylene glycol monoethylether was kept for stability study. The or as bolus for safe, for I.V. use for therapeutic action. viscosity of it in Diethylene glycol monoethyl ether is 3.13 0771. The solution of Artesunate in therapeutic dose of 60 cps. The results were found to be satisfactory. mg/ml is prepared using Diethylene glycol monethyl ether by mixing with 2% Benzyl alcohol. This solution of 60 mg/ml Example 10 prepared is having the Viscosity of about 3.466 cps. (0772 Stability Study Data of Artesunate Injection 60 Paclitaxel (I.14) mg/ml. 0762 1MF 2M 3M Sr. 40° C.; 40°C., 40°C., Trial 1 Trial 2 Trial 3 No Test Initial 75% RH. 75% RH. 75% Sr. No. Ingredients Qty (ml) Qty (ml) Qty (ml) 1 Description Clear Colourless Solution 1 Paclitaxel 6 mg 6 mg 6 mg 2 Assay, Limit 100.23 98.02 99.65 99.58 2 Polysorbate 80 0.15 ml 0.1 ml 0.1 ml 90 to 11.0% 3 PEG 400 0.15 ml 0.3 ml 0.2 ml 4 Ethanol 0.4 ml 0.3 ml 0.3 ml 5 Diethylene Glycol 0.3 ml 0.1 ml 0.2 ml Monoethyl Ether 0773. The stability data of marketed injection and Artesu pH of final solution 6.85 6.17 6.26 nate injection 60 mg/ml were compared and it was found that adjusted with acetic acid the new formulation prepared in Diethylene glycol monoet hyl ether were stable. 0763. 300 mg to 1200 mg of paclitaxel is dissolved in 100 ml Diethylene glycol monoethyl ether to give a clear Solution. Example 12 0764. The solution is stable and can be administered directly for its therapeutic purpose as injectable form by Paracetamol (II.13) filling in ampoule or vials. 0774 The solubility of Paracetamol was found to be about 0765. The same can also be prepared in the concentration 1 to 66.6 mg per ml of Diethylene glycol monoethyl ether of 6 mg/ml which is therapeutically recommended concen solvent and when mixed with co-solvent, same is increased to trations using above compostions. The Solution is clear and 200 mg/ml for preparation of therapeutic dosage of Paraceta limpid. It is further process under nitrogen to filter it asepti mol injection for 1 mg and 225 mg/ml of Paracetamol Injec cally through 0.22L membraneandfilled Suitably inampoules tion or vials, PFS for multidose applications for use in infusions. 0766. The same can be administered as bolus or slow infusion. Sr. Packing Details 0767 The trial of Paclitaxel injection prepared in Dieth No. of Product ngredients Qty/ml ylene glycol monoethyl ether was kept for stability study and 1 Paracetamol 10 mg/ml Paracetamo 10 mg (5 ml clear glass vial) Sodium Chloride 9 mg the formulation was found to be stable. Viscosity of it in For 100 ml infusion Diethylene Glycol S.0% wiv Diethylene glycol monoethyl ether was found to be 2.967 cps. Monoethyl Ether Water for injection C.S Example 11 2 Paracetamol 20 mg/ml Paracetamo 20 mg (10 ml clear glass vial) Sodium Chloride 9 mg For 50 ml infusion Diethylene Glycol 7.5% wiv Artesunate (II.3) Monoethyl Ether Water for injection C.S 0768. The solubility of Artesunate in Diethylene glycol 3 Paracetamol 200 mg/ml Paracetamo 200 mg PEG 400 15% monoethyl ether was found to be from 1 to 100 mg/ml. Tris Buffer 2.5 mg Diethylene Glycol C.S Monethyl Ether Sr. 4 Paracetamol 150 mg/ml Paracetamo 150 mg No. Name of Ingredient Qty/ml Benzyl Alcohol 2% Diethylene Glycol C.S 1 Artesunate 60 mg Monoethyl Ether Benzyl Alcohol 2% 5 Paracetamol 100 mg/ml Paracetamo 100 mg 3 Diethylene Glycol Monoethyl ether C.S Benzyl Alcohol 2% Diethylene Glycol C.S Monoethyl Ether 0769 5 g to 8 g in acid form of the drug is dissolved in 100 ml Diethylene glycol monoethyl ether to give a clear, thera peutically acceptable concentration solution. Preservative For Sr. No. 1 & 2: like benzyl alcohol can be added along with antioxidants like 0775. In a suitable vessel, Paracetamol in required quan Vit E derivatives, thioglycerol or ascorbyl palmitate can be tity is dissolved in Diethylene glycol monoethyl ether with optionally added which keeps the solution pellucid, physi stirring simultaneously. In another beaker, Sodium chloride is cally and chemically stable. Same is filtered aseptically under added in water for injection. Then, both the solution are nitrogen through 0.22L filter and filled in ampoules, PFS or mixed together and final volume is make up with water for vials as per therapeutic need and further use. injection to give final Solution of 10 mg/ml and 20 mg/ml US 2014/0296.191 A1 Oct. 2, 2014 respectively. The pH of final Solution containing dose 0785. Following example is cited to study combination of strength 10 mg/ml is 5.78 and same for 20 mg/ml is 5.67 20 mg Dicyclomine HCl with 50 mg Diclofenac Sodium respectively. using the inventive process which is giving stable injections. 0776. As the viscosity is very less, the solution can be Same is easily Syringeable and administered in the tissues infused slowly without causing pain. Viscosity of the solution in Diethylene 0777 1 g to 20 g of paracetamol is dissolved in 100 ml glycol monoethyl ether is 5.022 cps. Diethylene glycol monoethyl ether to give a clear Solution with addition of suitable preservative like Benzyl alcohol and adjusting pH with suitable buffering agent like Tris buffer. Example No. For Sr. No. 3: Sr. 1 2 3 0778 Diethylene glycol monoethyl ether is heated upto No. Ingredients Qty/ml Qty/ml Qty/ml 80°C. in suitable vessel and Tris buffer is added with stirring 1 Dicyclomine Hydrochloride 20 mg 20 mg 20 mg till a clear solution is obtained. Then, PEG 400 is added into 2 Diclofenac Sodium 50 mg 50 mg 50 mg the solution while dissolving the drug Paracetamol. Maintain 3 Diethylene Glycol Monoethyl Ether Q.S 60% 60% the temperature 80-85°C., a clear solution is obtained. Then 4 O.1MNaOH Q.S Q.S solution is cooled and final volume is make up with Diethyl 5 Sodium Metabisulphite 1 mg 1 mg ene glycol monoethyl ether in Sufficient quantity to give final 6 WFI Q.S Q.S solution of drug. 200 mg/ml. Filter the solution in 0.22L filter 7 Benzyl alcohol 296 2% and fill in 2 ml clear ampoule, 5 ml clear ampoule, 5 ml clear vial as well can be filled in prefilled syringes or multi dose 0786. The Stability study data given below for Diclofenac vials. (50 mg)+Dicyclomine HCl (20 mg) injection is of optimized (0779. Similarly, final solution of 100 mg/ml & 150 mg/ml can also be prepared as given above. example Nos. 2 & 3. 0780. The final solutions of Paracetamol containing 150 mg/ml have viscosity about 7.34 cps. This solution can be 40° C., 40° C., 40° C., filled into 2 ml clear ampoule, PFS or in multidose vials. Sr. 75% RHS 75% RHS 75% RHA 0781. The solution may be used for parenteral as i.v bolus No Tests Initial 1M 2M 3M or infusion or oral purpose after filling in ampoule, vial or in 1 Description Clear Clear Clear Clear caps forms. Transparent Transparent Transparent Transparent 0782 Stability Study Data of Paracetamol Injection 150 Liquid Liquid Liquid Liquid mg/ml.

40° C., 30° C. 25° C. 30° C. 40° C. 75% 40° C. 25° C. 65% 40° C., 60% 65% 75% 25° C. 30° C. S. Speci- RHS1 75% 60% RHS3 75% RHS6 RHA6 RHA6 60% 65% No Tests fication Initial (2) RH/2M RH/3M (2) RH/3M (2) () (2) RH/9M RH/9M 1 Descrip- Clear Colourless Solution tion 2 Assay 90-110 103.24 105.09 100.76 100.87 100.37 99.16 101.94 99.30 98.99 101.18 99.75 (%) 3 Impur- 4 4 4 4 4 4 4 4 4 4 4 ities Amino- Amino- Amino- Amino- Amino- Amino- Amino- Amino- Amino- Amino- Amino- Amino phenol- phenol- phenol- phenol- phenol- phenol- phenol- phenol- phenol- phenol- phenol- phenol NMT ND ND ND ND ND ND ND ND ND ND O.S9/o Total Total Total Total Total Total Total Total Total Total Total Total impur- impur- impur- impur- impur- impur- impur- impur- impur- impur- impur impur- ity- ity- ity-ND ity- ity - ity- ity- ity- ity-ND ity-ND ity- ND ND O.28% 0.34% 0.1.28% 0.023% 0.023% 0.57% NMT 2.0%

(2) indicates text missing or illegible when filed

0783 The stability study for Paracetamol Injection 150 -continued mg/ml was performed and was found to be in acceptable range and is satisfactory when compared with the available 40° C., 40° C., 40° C., marketed product of the same dose strength. Sr. 75% RHS 75% RHS 75% RHA No Tests Initial 1M 2M 3M Example 13 2 Assay of 99.4 99.1 98.7 100.6 Diclofenac, Limit 90 to Dicyclomine Hydrochloride (II.12)+Diclofenac 1.10% Sodium Injection 3 Assay of 101.2 100.7 99.9 98.6 Dicyclomine 0784 The solubility of Dicyclomine was about 0.1 to 20 hydrochloride mg/ml and of Diclofenac upto 0.1 to 133 mg/ml in Diethylene Limit 90 to glycol monoethyl ether. US 2014/0296.191 A1 Oct. 2, 2014

-continued 0791 Similarly, 1 g to 10 g of drug in acid form (Pantap razole Sodium) is dissolved in 100 ml Diethylene glycol 40°C., 40° C., 40° C., monoethyl ether to give a clear Solution and compounded as above. Sr. 75% RHS 75% RHS 75% RHS 0792. The therapeutic concentration is suitably filled in No Tests Initial 1M 2M 3M ampoules, PFS or vials for its direct use after, filling asepti cally through 0.22L and filling Suitable antioxidants and pre 1.10% servatives are added to the liquid. Limit HCL 0793 Alternatively, Water for injection qs and preserva 4 Impurity, Not O.O1 O.O1 O.O1 tive like Benzyl alcohol 2 to 4%, buffer agents may be option NMT 290 detected ally added to maintain pH more than 8 i.e. 9.5 to 11.5 which keeps the solution pellucid, physically and chemically stable. 0794 Stability Study Data of Pantaprazole Sodium Injec tion 40 mg/ml:

1M 3M Sr. No Test Initial 40° C.;75% RH 25 C.60% RH 3M40° C.;75% RH 1 Description Slight Yellow Colour Solution Assay, 101.36% 95.12% 98.43% 95.94% Limit 90 to 1.10% 3 Impurities, Single: 0.03% Single: 0.42% Single: 0.04% Single: 0.62% single NMT Total: 0.05% Total: 0.55% Total: 0.08% Total: 0.81% 196 Total NMT 296

0787. The combination of Diclofenac (50 mg) and Dicy 0795. The stability study of Pantaprazole Sodium injec clomine HCl (20 mg) injection were kept for stability study as tion 40 mg/ml was found to be satisfactory. Viscosity of the per ICH guidelines and were found to be stable with all the solution in Diethylene glycol monoethyl ether is 3.816 cps. tests in acceptable criteria. Example 14 Example 15 Pantoprazole Sodium Injection (II.19) Voriconazole (II.25) 0788 Pantoprazole Sodium is soluble in Diethylene gly 0796. The solubility profile of Voriconazole is found to be col monoethyl ether from 1 to 80 mg/ml. from 0.1 to 83 mg/ml in Diethylene glycol monoethyl ether.

Examples Sr. No. Ingredient Qty/ml Sr. 1 2 3 1 Voriconazole 10 mg No. Name of Ingredients Qty/ml Qty/ml Qty/ml 2 Diethylene Glycol Monoethyl Ether 0.5 ml 3 Water For Injection Q.S 1 Pantoprazole Sodium 40 mg 40 mg 40 mg 2 BHA 1 mg 1 mg 0.3 mg 3 Benzyl Alcohol 296 296 2% 4 BHT 1 mg 0.3 mg 0797] 1 g to 10g of drug is dissolved in 100 ml Diethylene 5 Diethylene Glycol Monoethyl Ether C.S C.S C.S glycol monoethyl ether to give a physically clear Solution. Viscosity of the solution in Diethylene glycol monoethyl 0789. In the current example, 40 mg/ml of Pantoprazole ether is 2.977 cps. Sodium stable injection are prepared by dissolving preferably 0798. The finally achieved therapeutic concentration may Sodium or its acid salts by taking 4 g of the drug in mixture of be employed for parenteral use as slow infusion or Solution So Diethylene glycol monoethyl ether and Benzyl alcohol in 100 preferred can be used to prepare oral delivery suitably formu ml vessel. BHA i.e. Butylated Hydroxy Anisole (in Example lated with adjuvants, additives and preservatives for treating 1) or in combination of BHA and BHT i.e. Butylated Hydroxy the mammals for therapeutic purpose. Toulene (can be added as antioxidant/preservative in Example 2 & 3) or Thioglycerol is added into this mixture Finally, the total volume is make up with Diethylene glycol Example 16 monoethyl ether in Sufficient quantity to give clear colorless solution which is filtered and filled in vials, PFS or ampoules. Ibuprofen (II.27) 0790. It is preferred to bubble the liquid with nitrogen and filled under nitrogen. The viscosity of Pantoprazole Sodium 0799. The solubility of Ibuprofen in Diethylene glycol injection 40 mg/ml was found to be 3.816 cps. monoethyl ether was found to be about 500 mg/ml. US 2014/0296.191 A1 Oct. 2, 2014 60

0800 The following formulation can be prepared using Example 1 Diethylene glycol monoethyl ether: 0803. In mixture of Diethylene glycol monoethyl ether, benzyl alcohol and Dimethyl isosorbide in a vessel, Methyl Sr. No. Ingredient Qty/ml Qty/ml prednisolone is dissolved and stirs well to get a clear colorless 1 Ibuprofen 400 mg 200 mg solution. Make up the final volume with Diethylene glycol 2 Diethylene Glycol Monoethyl Ether q.s to 1 ml qs to 1 ml monoethyl ether

0801) 10 g to 50 g of Ibuprofen is taken in a vessel and Example 2/3 dissolved in Diethylene glycol monoethyl ether to give final solution. The therapeutically available and marketed 400 0804 A mixture of Diethylene glycol monoethyl ether, mg/ml and 200 mg/ml of Ibuprofen injectable solution were Benzyl alcohol and Dimethyl isosorbide is prepared in a prepared using the invention solvent which was found to be vessel. Methyl prednisolone is dissolved and stirs well to get colorless and physically stable in nature and the viscosity in Diethylene glycol monoethyl ether is 6.76 cps and 4.51 cps a clear colorless solution. Then Vitamin E in example 2 and respectively. BHA (butylated hydroxyanisole) in example 3 is added into the solution respectively and make up the final Volume using Example 17 Diethylene glycol monoethyl ether. Methyl Prednisolone (III.2) (0805. The viscosity of Methyl Prednisolone Injection 40 mg/ml was measured about 3.70 cps which is lesser than the (0802. The solubility of Methyl Prednisolone was found to available marketed products. be about 1 to 30 mg/ml in Diethylene glycol monoethyl ether and about 130 mg/ml in benzyl alcohol. Hence, formulations 0806. Similarly, 2 g to 10 g of drug is dissolved in 100 ml were prepared using co-solvents. Diethylene glycol monoethyl ether to give a clear solution for therapeutic use as injectable. Preservative like benzyl alcohol at 2 to 10% may be added with antioxidants like Thioglycerol, Sr. No Ingredients Qty/ml Qty/100 ml Sodium Ascorbate, Tocopherols are added in the desired con Example 1: centration to give clear, pellucid liquid which is physically and chemically stable. 1 Methyl Prednisolone 40 mg 4g 2 Benzyl Alcohol 10% wiv 10 ml 0807. After making of volume for the desired strength the 3 Dimethyl Isosorbide 296 wiv 2 ml 4 Diethylene Glycol Monoethyl Ether C.S C.S liquid is filtered aseptically through 0.22L filter and filled in Example 2: ampoules, PFS, vials with nitrogen bubbling. 1 Methyl Prednisolone 40 mg 4g 0808. Above solutions are found to be stable and yields a 2 Benzyl Alcohol 10% wiv 10 ml comfortably syringable, low viscosity solution which can be 3 Dimethyl Isosorbide 296 wiv 2 ml easily administered in the tissues without causing pain. 4 Vitamin E 1 mg 100 mg 5 Diethylene Glycol Monoethyl Ether C.S C.S (0809 Stability Study Data of Methyl Prednisolone Injec tion 40 mg/ml:

Sr. Specifica No Test tion Initial 1M40° C. 3M 40° C. 3M 250 C. 6M25 C. 6M 40° C. 1 Descrip Clear Colourless Solution tion 2 Assay 90-110 99.08 101.49 98.40% 98.39 99.68 98.53 IH (HPLC) 3 RS Single = 1.0% Single = 0.09% Single = 0.33% Single = 0.935% Single = 0.444% Single = 0.38% Single = 0.56% Total = 2.0% Total = 0.09% Total = 0.52% Total = 1.67% Total = 0.78% Total = 0.63% Total = 0.85%

-continued 0810 Stability study of Methyl Prednisolone Injection 40 mg/ml was performed and result was obtained in the accept Sr. No Ingredients Qty/ml Qty/100 ml able range. Example 3: Example 18 1 Methyl Prednisolone 40 mg 4g 2 Benzyl Alcohol 10% wiv 10 ml 3 Dimethyl Isosorbide 296 wiv 2 ml Triamcinolone Acetonide (III.4) 4 BHA (Butylated Hydroanisole) 1 mg 100 mg 5 Diethylene Glycol Monoethyl Ether C.S C.S 0811. The solubility of Triamcinolone Acetonide was found upto 1 to 15 mg/ml in Diethylene glycol monoethyl ether. US 2014/0296.191 A1 Oct. 2, 2014

Sr. No Ingredients Qty/ml Qty/ml Example 1: Example 2: 1 Triamcinolone Acetonide 10 mg 20 mg Sir Sir 2 Benzyl Alcohol O.8% O.8% O. Ingredient Qty/ml no. Ingredient Qty/ml 3 Diethylene Glycol Monoethyl Ether C.S C.S 1 Aceclofenac 150 mg 1 Aceclofenac 150 mg 2 Trisodium citrate C.S 2 Benzyl alcohol 2% 0812. While preparation of injection, Diethylene glycol aqeous solution 3 Triss Buffer 30% O.O26 monoethyl ether & Benzyl alcohol are mixed well in a suit- 30% (pH = 4.57) ageous solution ml able vessel. Triamcinolone acetonide is added in required 3 DiethyleneMonoethyl GlycolEther C.S 4 MonoethylDiethylene GlycolEther C.S dose strength (i.e 1 gm to 5gm) and stirred till a clear Solution is obtained. Final volume of this solution is made up with Example 3: Example 4: Diethylene glycol monoethyl ether. The solution is filtered S S aseptically through 0.22L filter and filled in ampoules, PFS No.. Ingredient Qty/ml No.. Ingredient Qty/ml and vials. Optionally, benzyl alcohol can be added which keeps the solution pellucid as well as physically and chemi- 1 Aceclofenac 150 mg 1 Aceclofenac 150 mg cally stable. 2 Benzyl Alcohol 296 2 Dimethyl Isosorbide 59% 3 Tris buffer 8 mg 3 Diethylene Glycol C.S 0813 The viscosity of Triamcinolone injection 20 mg/ml 4 Diethylene Glycol C.S Monoethyl Ether was measured about 3.036 cps. Monoethyl Ether 0814 Stability Study Data of Triamcinolone Acetonide Injection 20 mg/ml:

40° C., 25o C. 30° C. 40° C., 25o C. 30° C. 40° C., Sr. 75% 60% 65% 75% 60% 65% 75% No. Tests Initial RHS1M RHA3M RHA3M RHA3M RHA6M RHA6M RHA6M 1 Description Clear Complies Complies Complies Complies Complies Complies Complies colourless Solution 2 Assay 103.97% 98.52% 99.93% 99.79% 99.83% 99.96% 98.45% 98.87% (90%- 11.0%) 3 Impurities; Single = Single = Single = Single = Single = Single = Single = Single = single O.12% O.29% O.62% O.S2% O.42% O.32% O.28% O.19% NMT1% Total = Total = Total = Total = Total = Total = Total = Total = Total O.12% O.S2% O.84% O.80% O.71% O.64% O.63% O.S.4% impurities NMT 290

0815 Stability Study Data of Triamcinolone Acetonide Injection 10 mg/ml:

40° C., 40° C., 25o C. 40° C., 25o C. 40° C., 25o C. Sr. 75% 75% 60% 75% 60% 75% 60% No. Tests Initial RH1M RHA2M RHA3M RHA3M RHA6M RHA6M RHA9M 1 Description Clear Complies Complies Complies Complies Complies Complies Complies colorless solution 2 Assay 101.30%. 101.88%. 101.58%. 101.40% 98.53% 98.34% 96.77% 97.97% (90%- 11.0%) 3 Impurities; ND Single = Single = Single = Single Single Single = Single = single O.29.1% O.07% O.24% O.40% O.12% O.33% O.16% NMT1% Total = Total = Total = Total Total = Total = Total = Total O.S92% O.21% O.37% O.S6% O.22% O.76% O.40% impurities NMT 290

0816. The stability study of both the dose strength 10 0818 5 g to 16 g of drug is dissolved in 100 ml Diethylene mg/ml and 20 mg/ml of Triamcinolone acetonide injection glycol monoethyl ether with other excipients as above to give was found to be satisfactory as per ICH guidelines. therapeutically acceptable stable clear Solution liquid. Example 19 0819. The same may be used therapeutically after asepti cally filtering and filling in ampoule, PFS or vials with use of Aceclofenac (III.9) suitable preservative and antioxidants like benzyl alcohol, 0817. The solubility profile of aceclofenac in Diethylene other alcohols and butylated hydroxyl anisole, sodium met glycol monoethyl ether was observed upto 1 to 160 mg/ml. abisulphite, thioacetamide. US 2014/0296.191 A1 Oct. 2, 2014 62

0820. Alternatively for an aqueous injection, preservative like benzyl alcohol 2 to 4%, buffer agents and pH adjusting Sr. No. Ingredient Qty/ml agents like NaOH or HCl may be added which keeps the Solution pellucid, physically and chemically stable. 1 Nepafenac O.1% The viscosity of final solution containing Aceclofenac 150 2 Sodium Chloride O.8% mg/ml was found about 5.11 cps. 3 Benzyl Alkonium Chloride O.05% 0821 Stability Study Data of Aceclofenac 150 mg/ml 4 Diethylene Glycol Monoethyl Ether SO% Injection:

1W 3W 3W 40° C., 25o C. 40. 40. 25o C. 25o C. 25o C. Sr. Para- Speci- 75% 60% 75% 75% 60% 60% 60% No leter fication Initial RH RH RH 1 Descrip- Light Complies Complies Complies Complies Complies Complies Complies Complies tion yellow coloured, clear liquid fill in amber coloured 1 ml glass ampoules. 2 Assay (90%- 103.25%. 102.15%. 102.90% 1.02% 101.8% 102.8% 102.41% 98.25% (By 11.0%) UV) Aceclofenac 3 Related Diclofenac ND O.26% O.23% 0.57% 1.25% 0.57% O.70% O.70% Substance impurity NMTS.0% Single ND ND ND ND ND ND ND ND KOW impurity NMT 1.0% Total ND ND ND ND ND ND ND ND KOW impurity NMT 2.0%

0822. The stability study of Aceclofenac Injection 150 -continued mg/ml was found to be in acceptable criteria. The injectable formulation of Aceclofenac in dose strength 150 mg/ml was Sr. No. Ingredient Qty/ml found to be stable. As the viscosity of the liquid is less it is easily Syringable and administered in the tissues without causing pain. 5 Water for Injection Q.S 6 Sodium Hydroxide (1N) To adjust pH 7.37 Example 20 0824. The viscosity of Nepafenac eye drop prepared by Nepafenac Eye Drops 0.1% (III.23) using Diethylene glycol monoethyl ether was found to be 0823. The solubility of Nepafenac in Diethylene glycol 4.137 cps. It was kept for stability study at 40°C. monoethyl ether was found to be upto 2 mg/ml. 0825 Stability Study Data of Nepafenac Eye Drops 0.1%:

Sr. Specifica- 40° C.75%, 25 C.60% 30° C.f659, 40° C.75% No. Tests tion Initial RHS1M RHA3M RHA3M RHA3M 1 Description Yellow Coloured Clear Solution 2 Assay 90-110%, 102.18% 103.29% 103.58% 102.21% 98.64% (Glass vial) 3 Impurity Single: Single: Single: Single: Single: Single: (Glass vial) NMT 1.0% O.11% O.39% O.39% O.39% O.39% Total Total: Total: Total: Total: Total: impurity: O.17% O.39% O.39% O.39% O.39%

(2) indicates text missing or illegible when filed US 2014/0296.191 A1 Oct. 2, 2014

0826. The formulation examples described herein and Acute Eye Irritation/Corrosion Test for Diethylene Glycol which is containing Diethylene glycol mono ethyl ether as Monoethyl Ether (Transcutol HP) in Rabbits solvent can also be used for prepare other drug delivery like preparing oral delivery systems, dermal, delivery systems by Test Item Transcutol HP filling in as roll on gels or creams and for otic delivery systems like drops or filling in capsules for rectal delivery or other 0838. Diluted with: Water for injection delivery systems as stated in the description. Test System Rabbits (New Zealand White) 0827 Oral delivery like filing the liquid directly into Hard fill capsule with band sealing. Eg 30 mg to 120 mg of Etori 0839 Total No. of Animals: 6 animals for initial test coxib filled in HFC. 0840 12 animals for confirmatory test 0828. It can also be mixed with PEGs and oils or it deriva No. of groups: 6 tives to fill in Soft gelatin capsules. Study Design: 0829 Paracetamol liquid, Dilcofeneac liquid, Acel cofenac liquid prepared in Dietheyne glycol monoethyl ether 0841 can be employed for filling in Soft gelatin capsules for rectal deliveries. 0830. The Liquid gels of antifungal agents like Azole Total No. of Animals derivatives, Flucanzole, Ticonazole can be prepared for vagi Volume Concen- For nal deliveries. Sr. (ml/ tration For Initial confirmatory 0831 Drugs like Lignocaine, Prilocaine can be prepared No Group animal) Route (%) test test in Diethyleneglycol monoethyl ether can be incorporated in 1 1 O.1 Intra Occular 2% 1 2 2 2 O.1 Intra Occular 20% 1 2 spray delivery systems for treating erectile dysfunction. 3 3 O.1 Intra Occular 40% 1 2 0832 Drugs like Amlodipine, Nifedipine can be solubi 4 4 O.1 Intra Occular 60% 1 2 lised in Diethyleneglycol monoethyl ether and sprayed in the 5 5 O.1 Intra Occular 80% 1 2 granulation of tablet matrix containing starch, lactose, Stear 6 6 O.1 Intra Occular 100% 1 2 ates and compressed in to tablets. 0833 Dermal delivery of gels like Etoricoxib is prepared with other gel matrices to prepare Gels for dermal application Summary: for faster onset of pharmacological action. Initial Test: 0834 Drug solutions like Aceclofenac solution prepared in Diethylene glycol monoethyl ether can also be prepared for 0842) Initial test is carried out by using one animal per preparing the Roll on for dermal delivery. group. After dosing animals were observed for irritation at 1, 0835. The solution can further be used for preparing Tulles 24, 48, and 72 hours by appropriately mixing the drug solution with various PEGS 0843. There is no test item related effects were observed sprayed on waxes like wool fat, PEG 4000, 6000 etc for during first hour in all the animals of first three groups. Mild dermal application in pain managements.(ex Aceclofenac, irritation was observed in group 4 and 5 animals. Group 6 animal showed moderate irritation and more severity when NSAIDs, Cox 2 inhibitors etc) compared to the group 4 and group 5 animals. Tioconazole Gel 6.5% 0844 Irrigation was carried out after 24hrs from the treat ment and the animals are again observed for symptoms of 0836 toxicity. 0845 During 24 hr observation, all the animals are appeared normal except group 6 animal which was showed Qty mild irritation including Chemosis and Lacrimation. Mild Sr. No Ingredients Spec Rationale Gming conjunctivitis was also observed. 1 Tioconazole BP Active 6S.O 0846. Depending up on the observations made from the 2 Carbomer-940 (Acrypol-940) USP Gelling agent 11 initial test and there was no corrosion effect was observed, 3 Propylene Glycol IP Gelbase 804 hence we proceeded for the confirmatory test. 4 Diethylene glycol mono ethyl BP Solubilser 120 ether Confirmatory Test: 0847 Confirmatory test is carried out by using two ani Spray: mals per group. After dosing animals were observed at 1, 24. 48, and 72 hours for toxicity. 0837 0848. The dosing methodology and irrigation procedure was same as mentioned in the initial test and the observations were found as follows: Lignocaine ... 8.82% 0849. During 1 hr observations, there is no test item Prilocaine... 2.94% related effects were observed in all the animals of first three Propellent HFA. .. 58.83% Diethyleneglycol monoethyl ether... 29.41% groups. 0850 Mild irritation was observed in group 4 and group 5 animals. US 2014/0296.191 A1 Oct. 2, 2014 64

0851. One animal from the group 6 was showed severe Protocol: irritation when observed after 1 hr from the dosing and the Pain Assessment Model Study: other animal also showed irritation but the severity was less when compared with the previous animal. Measurement of Pain Sensitivity (Threshold) at Injection Site in Wistar Rats by Intravenous Route & Intramuscular Route 0852. During 24 hr observation, animals from group 1 to 0857. The pain assessment model study was carried out on group 3 were normal and there is no irritation was observed in two representative drugs from each class prepared as per all the animals. application. This study was performed to prove that the injectables prepared by this solvent are painless and less 0853 Animals from group 4 and group 5 were showed Viscous when compared to the respective marketed products mild irritation including Chemosis, lacrimation and mild as a reference. pupillary constriction. 0858. The following procedure was carried out to check pain assessment of new formulation against the marketed 0854 Group 6 animals were suffered with severe irritation products: and the symptoms includes Chemosis, lacrimation, conjunc tivitis, pupillary constriction. The corneal reflex and Iris were Objective: normal in all the animals. 0859. To evaluate pain sensitivity (threshold) at injection site by Pressure application measurement method and com 0855. The above mentioned observations were lasts for 48 parison with control. hrs. Test Injections Different injectable formulations (2 drugs from each group of class I, II and III) Summary: Reference Injections Marketed formulations w.r.teach group of class I, II, and III. 0856. In summary, all the above mentioned observations, Species used for the study: Wistar rats the test itemTranscutol is not showing any occular toxicity up No of animals used during different route I.M & I.V individu to 80% of concentration. But, the test item Transcutol, may ally: irritant but not corrosive, at the concentration of 100% when The total number of 18 animals will be divided in to 3 groups administered intra occularly. containing 6 animals (3M+3F) per group. Further, when performing Intramuscular, Intravenous and Study Design: Intraocular studies, Diethyelene glycol monoethyl ether was 0860. The following table are given as study design as pain found to be safe and non toxic. assessment study through I.V as well I.M. route TABLE A

Dosage schedule

Dose Dose Duration of No. of Sr. No Group (in mg/kg) (in mL/kg) Route treatment animals

1 Negative control N1- N2- IV Single 6 (3M + 3F) (Water for dose Injection) 2 Reference Injection R1- R2- IV Single 6 (3M + 3F) dose 3 Test Injection T1- T2- IV Single 6 (3M + 3F) dose

TABLE B Dosage schedule

Duration Dose Dose of No. of Sr. No Group (in mg/kg) (in mL/kg) Route treatment animals 1 Negative control N1A, N2ta. IM Single dose 6 (3M + 3F) (Water for Injection) 2 Reference Injection R1 R2Af IM Single dose 6 (3M + 3F) 3 Test Injection T1FM T21M IM Single dose 6 (3M + 3F) US 2014/0296.191 A1 Oct. 2, 2014

Rationale of the Study: human tissues and thus the injections prepared using 0861. The Pressure Application Measurement (PAM) Diethyelene glycol monoethyl ether will be beneficial device is a novel, easy-to-use tool for measuring mechanical for the parenteral purpose. pain threshold in experimental pain hyperSensitivity models Summary: in rodents. 0862 The PAM applies a quantifiable force for direct 0876 From the studies of viscosity for various formula stimulation of the injection site and automatic readout of the tions prepared in diethyele glycol mono ethyl ether, it is animal response. imminent that the formulations are easily drawable in the 0863. The operator simply wears a special force sensor on Syringe and can be easily administered in the tissues in the thumb and measures the force which elicits the animal required Volume without causing pain at the site of injection. response (normally, limb withdrawal) as shown in FIG. 1. 0877. Following injections are tested against the marketed formulation: Experimental Procedure: 0878 1. Paracetamol injection prepared in Diethyelene 0864. After administration of Negative control, Reference glycol monoethyl ether against Fabrinil item and test item by intravenous route/intramuscular route 0879 2. Triamcinolone Acetonide injection in diethye mark will be made at injection site so that every time the pain lene glycol monoethyl ether against Kenacort. sensitivity will be measure same site by using transducer/ 0880. 3. Methyl Prednisolone Acetate injection in applicator. Diethyele glycol monoethyl ether against Depo Medrol. 0865 Transducer placed at injected site and gradually 0881. 4. Nandrolone Decanoate injection in Diethyele increases the pressure at peak force elicit the animal response glycol monoethyl ether against Deca Durabolin. and the Transducer/applicator measures the force which elic 0882 5. Progesterone injection in Diethyele glycol its the animal response (normally, limb withdrawal). monoethyl ether against Susten 100. 0866 Force sensor pass the signals of application force, 0883 6. Pantaprazole Sodium injection Diethyele gly withdrawal force and duration of highest peak force applied at col monoethyl ether against Pentodec. injected site will be record in compact PAM controller. 0867 Pain sensitivity will be measure in control, reference Measurement of Pain Sensitivity (Threshold) at and test groups Immediately (within one minute after injec Triamcinolone Acetonide Injection Site in Wistar Rats by tion), 5 min, 10 min, 20 min, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr and 24 Intramuscular Route hrs after injection. 0868 Pain sensitivity will be measure in control, reference 0884 The aim of the study is to evaluate pain sensitivity at and treated groups will be compared and difference calcu Triamcinolone acetonide injection site and comparison with lated by using SAS System 8.2. reference 0869. Results: The following parameters are observed to evaluate the pain assessment value for the test items. VS. Details of Test System: reference item:— 0870 body weights; Species Rat (Wistar) Animal age 6-8 weeks 0871 Nature. Severity and Duration of pain sensitivity Number of The total number of 8 animals divided into 2 (whether reversible or not); Animals groups containing 4 animals (2M + 2F) per group. 0872 Pain sensitivity potentials of control, reference and test item statistical treatment of results, where appropriate. as below Study Design: 0873. Alternatively other models are also adopted to assess the pain in Suitable animal model. 0885

Duration S. No Group Dose (in g/kg) Dose (in L/KG) Route of treatment No. of animals 1 Reference item 7.2 O.1 IM Single dose 4 (2M + 2F) (Kenacort) 2 Test item 7.2 O.1 IM Single dose 4(2M +2F) (Triamcinolone acetonide injection)

0874. The results indicated that though not very signifi Experimental Procedure: cant reductions in pain in the animals, the prepared injection using diethyleneglycol monoethylether exhib 0886. After administration of test and reference item by its comparatively less pain against following reference intramuscular routemark will be made at injection site so that injections. every time the pain sensitivity will be observed same site. 0875. It may be concluded logically with prudent sci entific judgements that with a large body Surface in Results: human as compared animals, the perception of pain will 0887. There were no significant pain sensitivity observed be much lesser when similar injections are injected in at Triamcinolone acetonide injected site compared with US 2014/0296.191 A1 Oct. 2, 2014 66

Kenacort at 15, 30 Min, 1, 2, 4 hrs. Kenacort injected animals 15, 30 Min, 1, 2, 4 hrs. SUSTEN100 injected animals observed with slightly higher pain compared with Triamci observed with slightly higher pain compared with Progester nolone acetonide injection. one injection. Measurement of Pain Sensitivity (Threshold) at Progesterone Measurement of Pain Sensitivity (Threshold) at Nandrolone Injection Site in Wistar Rats by Intramuscular Route Decanoate Injection Site in Wistar Rats by Intramuscular Route 0888. The amin of the study is to evaluate pain sensitivity 0892. The aim of the study is to evaluate pain sensitivity at at Progesterone injection site and comparison with reference Nandrolone Decanoate injection site and comparison with reference Details of Test System: Details of Test System: Species Rat (Wistar) Species Rat (Wistar) Animal age 6-8 weeks Animal age 6-8 weeks Number of The total number of 8 animals divided into 2 Number of The total number of 8 animals divided into 2 Animals groups containing 4 animals (2M + 2F) per group. Animals groups containing 4 animals (2M + 2F) per group.

Study Design: 0893

Dose (in Dose (in Duration of No. of S. No. Group mg/kg) mL/kg) Route treatment animals

1 Reference item (DECA-18 O.18 IM Single dose 4 (2M + 2F) DURABOLIN) 2 Test item 18 O.18 IM Single dose 4 (2M + 2F) (NandroloneDecanoate injection)

Study Design: Experimental Procedure: 0889 0894. After administration of test and reference item by intramuscular route mark will be made at injection site so that every time the pain sensitivity will be observed same site. Dose Dose Duration S. (in (in of No. of Results: No Group g/kg) L/KG) Route treatment animals 0895. There were no significant pain sensitivity observed at Nandrolone Decanoate injected site compared with 1 (SUSTEN100)Reference item 0.9 O.OO9 IM Single9. dose 4 (2MM" + 2F DECADURABOf Nails, 36 Min. 24Es ECA 2 Test item 0.9 0.009 IM Single dose 4 (2M + 2F) DURABOLIN injected animals observed with slightly higher (Progesterone pain compared with Progesterone injection. injection) Measurement of Pain Sensitivity (Threshold) at Methyl Prednisolone Injection Site in Wistar Rats by Intramuscular Route Experimental Procedure: 0896. The aim of the study I to evaluate pain sensitivity at 0890. After administration of test and reference item by Methyl Prednisolone injection site and comparison with ref intramuscular route mark will be made at injection site so that CC every time the pain sensitivity will be observed same site.

Results: Details of Test System: Species Rat (Wistar) 0891. There were no significant pain sensitivity observed Animal age 6-8 weeks at Progesterone injected site compared with SUSTEN 100 at US 2014/0296.191 A1 Oct. 2, 2014 67

-continued Details of Test System: Number of The total number of 8 animals divided into Animals 2 groups containing 4 animals (2M + 2F) per group.

Study Design: 0897

Dose Dose Duration No. S. No. Group (in mg/kg) (in mL/kg) Route of treatment of animals 1 Reference item (DEPO- 7.2 O.17 IM Single dose 4 MEDROL) (2M + 2F) 2 Test item 7.2 O.17 IM Single dose 4 (Methyl Prednisolone (2M + 2F) injection)

Experimental Procedure: Experimental Procedure: 0898. After administration of test and reference item by intramuscular route mark will be made at injection site so that 0902. After administration of test and reference item by every time the pain sensitivity will be observed same site. intramuscular route mark all be made at injection site so that Results: every time the pain sensitivity will be observed same site 0899. There were no significant pain sensitivity observed at Methyl Prednisolone injected site compared with DEPO Results: MEDROL at 15, 30 Min. 1, 2, 4 hrs. DEPO-MEDROL injected animals observed with slightly higher pain compared with Methyl Prednisolone injection. 0903. There were no significant pain sensitivity observed a paracetamol injection 150 mg/ml injected site compared Measurement of Pain Sensitivity at Paracetamol Injection with Febrinil at 15.30 Min 1, 2, 4 hrs, Febrinil injected animal Site in Wistar Rats by Intramuscular Route observed with slightly higher pain compared with paraceta 0900. The aim of the study is to evaluate pain sensitivity at mol injection 150 mg/mL injection. paracetamol injection site and comparison within reference Study Design: y 9. Measurement of Pain Sensitivity (Threshold) at Pantoprazole 0901) Injection Site in Wistar Rats by Intravenous Route

Details of Test system

Species Rat (Wistar) Animal age 6-8 weeks Number The total number of 8 animals divided in to 2 of animals group containing 4 animals (2M + 2F) per group

S. Dose (in Dose (in Duration of No. Group mg/kg) mL/kg) Route treatment No. of animal

1 Reference item 27 O.18 IM Single dose 4(2m+2F) (febtinil) 2 Test item 27 O.18 IM Single dose 4(2m+2F) (Paracetamol injection 150 g/ml) US 2014/0296.191 A1 Oct. 2, 2014

Study Design: 0904

Details of Test system Species Rat (Wistar) Animal age 6-8 weeks Number The total number of 8 animals divided in to 2 group of animals containing 4 animals (2M + 2F) per group S. Dose (in Dose (in Duration of No. Group mg/kg) mL/kg) Route treatment No. of animal 1 Reference item 3.6 O.9 IV Single dose 4(2m+2F) (Pantrodac i.v.) 2 Test item 3.6 O.9 IV Single dose 4(2m+2F) (Pantoprazole injection)

Experimental Procedure: (Opioid & Non-Opioid) and Antipyretic; a NSAID; a Mus culo-skeletal System Drug; a Hormone; a Steroids and Con 0905. After administration of test and reference item by traceptive Agent; an Antibiotic; an Antifungal Agent; an Anti intravenous route mark all be made at injection site so that viral Agent; an Antimalarial Agent, an Antiamoebic; an every time the pain sensitivity will be observed same site Antiprotozoal Agent; an Anti-tubercular, an Antibacterial Combination; a Macrollides; an Anticancer Agent; a Genito Results: urinary Drug: An Endocrine & Metabolic System Drug; a Vitamin and Mineral; a Nutrition Drug belonging to Eye, 0906. There were no significant pain sensitivity observed Nose, Ear & Mouth/Throat; a Dermatological; an Anes at Pantoprazole Injected site compared with Pantodac i.v at thetic—Local and General; a Drug belonging to Allergy and 15.30 Min 1, 2, 4 hrs, Pantodac i.v injected animals observed Immune System; an Antidote; and a Detoxifying Agent & with slightly higher pain compared with Pantoprazole injec Drug used in Substance Dependence. tion. 7. A pharmaceutical composition according to claim 6. We claim: wherein the pharmaceutical active is selected from the group 1. A stable clear liquid pharmaceutical composition com consisting of Progesterone, Nandrolone, Nandrolone prising a pharmaceutical active and Diethylene glycol mono Decanoate, Nandrolone Phenyl Propionate, Testosterone, ethyl ether or an other alkyl derivative thereof. Testosterone Enanthate, Testesterone Cypionate, Norethis 2. The pharmaceutical composition according to claim 1, terone Enanthate, 17B Estradiol, Fulvestrant, Artemether, wherein the pharmaceutical active is a lipophilic active or a Arteether, Haloperidol, Vitamin D, Allylestrenol, Etori hydrophilic active. coxib, Firocoxib, Mavacoxib, Robernacoxib, Cimicoxib, Til 3. The pharmaceutical composition according to claim 1, macoxib, Celecoxib, Boldenone Undecylanate, Drostanolone Propionate, Trenbolone Acetate, Trenbolone for parenteral administration. Enanthate, Methenolone Enanthate, Methyl Testesterone, 4. The pharmaceutical composition according to claim 3, Cyclosporine, Paclitaxel, Piroxicam, Clonazepam, Diaz wherein the administration is intravenous, intramuscular, epam, Hydrocortisone, Hydrocortisone Acetate, Carboprost, Subcutaneous or ocular. Artesunate, Sodium Artesunate, Ergotamine Maleate, Lanso 5. The pharmaceutical composition according to claim 1, prazole, Dexlansoprazole, Fluconazole, Enalapril, Methocar further comprising a preservative, a buffering agent, an anti bamol, Lignocaine, Azithromycin, Digoxin, Dicyclomine, oxidant, a chelating agent, a stabilizer or a co-solvent. Dicyclomine & Diclofenac combination, Paracetamol, Pen 6. The pharmaceutical composition according to claim 1, tazocine, Fenatyl, Fenatyl Citrate, Prostaglandin E, Omepra wherein the pharmaceutical active is selected from the group Zole and its metallic salts, Rabeprazole and its metallic salts, consisting of an Antacid; an Antireflux Agent and Antiulcer Pantaprazole and its metallic salts, Lornoxicam, Etoposide, ant; a GIT Regulator, an Antiflatulent; an Anti-inflammatory Docetaxel, Leuprolide, Clarithromycin, Voriconazole, Vecu Agent; an Antispasmodic Agent; an Antidiarrheal Agent; a ronium, Atracurium, Cisatracurium, Doxacurium, Tub Laxative; a Purgative; a Cholagogue; a Cholelitholytic; a ocurarine, Pipecuronium, Rocuronium, Pancuronium, Atra Hepatic Protector; an Anorectal Preparation; an Antiemetic curium Besylate, Cisatracurium Besylate, Ibuprofen, Agent; a Gastrointestinal Drug; a Cardiac Drug; an Anti Prednisolone, Methyl Prednisolone, Methyl Prednisolone anginal Drug; an ACE Inhibitor/Direct Renin Inhibitor; a Acetate, Medroxy Progesterone Acetate, Triamcinolone Beta Blocker; a Calcium Channel Blocker; an Angiotensin II Acetonide, Stanozolol, Propofol, Clevidipine Butyrate, Vita Antagonist; an Antihypertensive; a Diuretic; an Antidiuretic min K. Vitamin K. Vitamin K, Aspirin, Choline Magnesium Agent; a Peripheral Vasodilator and Cerebral Activator; a Trisalicylate. Diflunisal and Salsalate, Fenoprofen, Fluripro Vasoconstrictor; a Dyslipidaemic Agent; a Haemostatic; an fen, Ketoprofen, Naproxen, Oxaprozin, Aceclofenac, Anticoagulant; an Antiasthmatic and COPD Preparation; a Indomethacin, Sulindac, Tolimetin, Meclofenamate, Mefe Cough and Cold Preparation; a Nasal Decongestant; a Res namic Acid, Nabumetone, Etodolac, Ketorolac, Ethinylestra piratory System Drug, an Anxiolytic Agent; a Hypnotic and diol, Terbinafine, Roxythromycin, Spironolactone, Sedative; an Antidepressant; an Antipsychotic Agent; an Eplerenone, Amlodipine Besylate, Barnidipine Hydrochlo Anticonvulsant; an Antiparkinsonian Drug; an Analgesic ride, Benidipine Hydrochloride, Nifedipine, Clinidipine, US 2014/0296.191 A1 Oct. 2, 2014 69

Darodipine, Nimodipine, Nisoldipine, Nitrendipine, Fello 16. The pharmaceutical composition according to claim 5. dipine, Nicardipine, Isradipine, Captopril, Ramipril, Fosino wherein the chelating agent is Ethylene diamine tetraacetic pril, Zofenopril, Perindopril, Quinapril, Lisinopril, Isoxsu acid, in an amount of 0.01% to 0.075% by weight of the prine Hydrochloride, Brinzolamide. Difuprednate, composition. Fluorometholone Acetate, Loteprednol, Besifloxacin, 17. The pharmaceutical composition according to claim 5. Loteprednol and Tobramycin Combination, Brimonidine and wherein the stabilizer is Maleic acid or a Malate salt. Brinzolamide Combination, Rimexolone, Sulfacetamide, Sulfacetamide and Prednisolone Acetate Combination, 18. The pharmaceutical composition according to claim 1, Tobramycin and Dexamethasone Combination, Neomycin for preparation of a capsule, a tablet, a nasal spray, a gargle, a Sulphate and Dexamethasone Combination, Nepafenac, gel, a cream, an ointment, an eye drop, a topical or a liquid Betaxolol Hydrochloride, Ciprofloxacin, Ciprofloxacin and oral dosage form. Dexamethasone Combination, Tadalafil. Vinpocetine, Itra 19. A stable clear liquid pharmaceutical composition com conazole, Nimodipine, EZetimibe, Valproic Acid, Bexaro prising a steroidal pharmaceutical active and Diethylene gly tene, Tretinoin, Loperamide, Melphalan, Loxapine, Amilsul col monoethyl ether. pride, Tacrolimus, Doxorubicin, Olanzapine, Fluticasone 20. The pharmaceutical composition according to claim Propionate, Prilocaine, and Tioconazole. 19, wherein the steroidal pharmaceutical active is selected 8. The pharmaceutical composition according to claim 1, from the group consisting of Progesterone, Nandrolone, Nan wherein the pharmaceutical active is not milled or micronized drolone Decanoate, Nandrolone Phenyl Propionate, Test prior to use. osterone, Testosterone Enanthate, Testesterone Cypionate, 9. The pharmaceutical composition according to claim 1, Norethisterone Enanthate, 17B Estradiol, Fulvestrant, Bold wherein the alkyl derivative of Diethylene glycol monoethyl enone Undecylanate, Drostanolone Propionate, Trenbolone ether is methyl, n-propyl, iso-propyl. n-butyl, iso-butyl or Acetate, Trenbolone Enanthate, Methenolone Enanthate, hexyl ether. Methyl Testesterone, Hydrocortisone, Hydrocortisone 10. The pharmaceutical composition according to claim 1, Acetate, Prostaglandin E, Prednisolone, Methyl Predniso wherein said Diethylene glycol monoethyl ether or an other lone, Methyl Prednisolone Acetate, Medroxy Progesterone alkyl derivative thereof is present in an amount of 1% to 100% Acetate, Triamcinolone Acetonide, Stanozolol, Ethinylestra by volume of the pharmaceutical active. diol. Difuprednate, Fluorometholone Acetate, Loteprednol, 11. The pharmaceutical composition according to claim 5. Rimexolone, Spironolactone, Eplerenone and FluticaSone wherein the buffering agent is selected from the group con Propionate. sisting of 0.1 N Sodium hydroxide, Acetic acid, Sodium citrate, Potassium chloride, Sodium chloride, Citric acid, 21. The composition of claim 1, wherein said pharmaceu Sodium bicarbonate, L-Arginine, Tris buffers, Cholic acid tical active is a non-steroidal drug. Derivatives, and Amino acid Derivatives. 22. The pharmaceutical composition according to claim 12. The pharmaceutical composition according to claim 5. 21, wherein the non-steroidal drug is selected from the group wherein the preservative is Benzyl alcohol, Methyl paraben, consisting of an analgesic, an antipyretic and an anti-inflam Propyl paraben, Thiomerosol, a Phenyl mercuric salt (acetate, matory agent. borate, nitrate), Chlorobutanol or Meta-cresol, 13. The pharmaceutical composition according to claim 23. The pharmaceutical composition according to claim 12, wherein the preservative is present in an amount of 22, wherein the analgesic, antipyretic or a anti-inflammatory 0.001% to 2% by weight of the composition. agent is selected from the group consisting of Etoricoxib, 14. The pharmaceutical composition according to claim 5. Firocoxib, Mavacoxib, Robernacoxib, Cimicoxib, Tilma wherein the antioxidant is selected from the group consisting coxib, Celecoxib, Piroxicam, Paracetamol, Pentazocine, of Ascorbic acid, Ascorbyl palmitate. Thioglycerol and its Fenatyl, Fenatyl Citrate, Lornoxicam, Aspirin, Choline Mag derivatives, Sodium bisulphate, Sodium metabisulphite, nesium Trisalicylate. Diflunisal and Salsalate, Ibuprofen, Sodium formaldehyde sulphoxylate. Thiourea, Ascorbic acid Fenoprofen, Fluriprofen, Ketoprofen, Naproxen, Oxaprozin, ester, Butylated hydroxyl toluene or Tocopherols. Aceclofenac, Indomethacin, Sulindac, Tolimetin, Meclofe 15. The pharmaceutical composition according to claim namate, Mefenamic Acid, Nabumetone, Etodolac, Ketorolac 14, wherein the antioxidant is present in an amount of 0.004% and Nepafenac. to 2% by weight of the composition.