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