Title of Invention

A PROCESS FOR THE PRODUCING PHARMACEUTICAL FORMULATIONS OF LIPOPHILIC COMPOUNDS IN LIMPID FORM

Abstract

A process for producing pharmaceutical formulations involving wide range of actives selected from anaesthetic agents, neuromuscular blocking agents, antibiotics, antifungals, anti- tuberculostic, anti-inflammatory, anti-malarials, steroids, lipid regulating drugs and anti- hypertension drugs including lipophilic compounds in limpid form comprising : the step of providing atleast one selective active drug in a selective solubilizing agent comprising 2,5-di-0-methyl-l-4, 3-6-dianhydro-D-glucitol

Full Text

FORM - 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION ( See Section 10) 1. TITLE OF INVENTION A PROCESS FOR THE PRODUCING PHARMACEUTICAL FORMULATIONS OF LIPOPHILIC COMPOUNDS IN LIMPID FORM 2. (a) PATEL Dinesh Shantilal, (b) 11/12 Udyognagar, S. V. Road, Goregaon (West), Mumbai - 400 104, State of Maharashtra, India, (c) an Indian national, and, (a) KURANI Shashikant Prabhudas, (b) 11/12 Udyognagar, S. V. Road, Goregaon (West), Mumbai - 400 104, State of Maharashtra, India, (c) an Indian national. The following specification particularly describes the nature of the invention and the manner in which it is to be performed. GRANTED This application has been divided out of parent application No. 67/BOM/99 dated 28 ' January 1999. Field of the Invention The present invention relates to a process for the manufacture of pharmaceutical formulations involving various actives such as lipophilic compounds in the form of limpid solutions and a selective solubilizing agent which would be non-toxic and a good carrier for permeation of the active drugs thereby favouring for wide and user-friendly application of the drug for various end uses especially as intravenous, intramuscular, oral and external agents. Background Art Preparation of various drugs in a soluble, limpid form - having therapeutic value, which are otherwise poorly soluble or insoluble in water media or other solvents of therapeutic use has been a continuing problem in the art. Importantly, drugs of lipophilic character, with limited water solubility, are difficult to formulate resulting in limitations in its end use/applications whether as injectable/oral formulations or for external applications or for multiple applications in various formulations. In the past, various agents have been tried which could solubilize and formulate various categories of drugs for their therapeutic purpose. The use of organic solvents like Acetone, Methanol, Ethanol, Ethylacetate, Tetrahydrofurane, Chloroform, Hexane etc., for solubilization have no therapeutic considerations, however, oil and oil-water mixtures are useful for their solubilization and their subsequent use either as oral or injectable (intramuscularly or intravenously) or for external application. Use of oil or its derivatives again has limitations. Oils are derived from plant origin hence their use and application in therapy of injectables are always problematic and hence debatable. Further the quality of oil changes seasonally which also complicates and limits its use. Manufacture of injectables using oil and its derivatives further lead to problems of strict quality control. The tendency of seasonal changes - in oil quality and its colour are often the problems encountered by manufacturing chemists. The pesticide residue from oil of natural origin is a potential risk factor for injectable forms. Further sterilization and difficulties during filtration are added secondary problems. Use of emulsions for solublizing various categories of drugs has also been attempted. However, if emulsion is prepared for the injections, then the matter of stabilizing the emulsion, its particle size and sterility require special consideration which, in a way involve increase in the cost of manufacture. Moreover, special technology is required for administration in.the injectable form and also post-therapy, problems of pain at the site of the injection. All the above factors limit the use of oil/oil-water emulsions as solubilizing agents for the preparation of various categories of active drugs. Moreover, some of the derivatives of oils are known to cause anaphylactic shocks and histamine release, thus reducing their usage. The use of fatty acids and its derivatives often requires special quality checks and their therapeutic use in oral and injectable forms are limited. The use of polyethylene glycol derivatives are quite high but there are limitations to their use as they can be administered up to certain levels only and are toxic at higher levels. Thus they become specific either for oral or local applications and their use is limited in injectable preparations. It is also found that some of the drugs of various categories, though water soluble, are unstable and require modifications during their use. In the form of oral formulations, the use of buffering agents, antioxidants and stabilizers, are required or lyophilization techniquies are often utilized for injectable forms for their utility during administration. This also increases the cost of formulations. Drugs which are oil soluble have limitations in their application namely they can be given only intramuscularly and are not used for intravenous purpose. The formulations of drugs used for application as 'Eye-drops' are often in the form of suspensions or emulsions, however their use in the form of suspension or emulsion is limited because of their limited solubility in the aqueous media. Quality control checks like -particulate matter, stability etc., for such suspensions and emulsions, are often the problems encountered by formulators during their preparation and application as "Eye-drops". Thus the formulation of a clear solution of various categories of drugs for therapy, has always been the "need of the time" for formulators besides which there is also the need that the solubilizing agent should be non-toxic as well as a good carrier for permeation of drugs. Drugs in the categories of 'Anti-fungal' and 'Antibiotics' require micronized material for solubilization as well as for uniform dispensation thus causing difficulties during formulation. A potent drug for oral formulations often requires some solubilizing agents which are non¬toxic and which improve taste and palatability. Dispersion in oral formulation and its stability, often pose problems to formulators during manufacture. Further drugs, which are used for external application viz., as lotions or emulsions on the skin and in the ear, nose and nasal cavity should not cause irritation or friction to unbroken skin. Hence there is always the need for a suitable vehicle for treatment of skin diseases or as antiseptics, astringents etc., or as protective or anti-parastitic medications. The solubility of such drugs are often problematic and if given in the emulsion form require checks on particle size. Thus a vehicle which can solubilize these drugs is always useful. It is known to use Ethyl alcohol in a very small amount for solubilization. However, it is used for therapeutic application in the concentration through Intravenous, Intramuscular or oral, used in a very small fractions which is about 1%. The use of Propylene Glycol is also limited. The safety regarding its parenteral application is only upto 40% that too also through Intramuscular route and is considered as toxic at higher concentration to the central nervous system. The formulation containing 30% Propylene Glycol which have been used is known to cause hemolysis in humans. The use of oral application is limited to 25 mg/kg. Propylene Glycol is viscous with viscosity of 58.1 cps, thus limiting the use in IM/TV formulation and is not known for the Intravenous administration. (Hand book of Pharmaceutical Excipients, 3rd Edition by Dr. Arthur H. Kibbe, page no. 443). The Cyclodextrin is used in the formulation for solubilizing by way of forming the inner complexes and because of its toxicity the use is limited. When administered it is unmetabolised and accumulates in kidney as the insoluble cholesterol complexes resulting in severe nephrotoxicity and hence, it has been used primarily for oral purpose. Questions always arise for safety when Cyclodextrin derivative is administered parenterally, (Hand book of Pharmaceutical Excipients, 3rd Edition by Dr. Arthur H. Kibbe, page no. 165). Also, the Molecular weight of 3-cyclodextrin is more than 1000 and hence after administration it could lead to problems of excertion with or without causing also damages to the kidney or any functions of the body. The above clearly reveal the existing problem in the art to identify solubilizing agents specific for a given active which would be non-toxic and safe which in term limited the application and/or use of the active for various end use/applications. Also in case of lipophilic compounds obtaining a limpid solution suitable for various applications/administrations including oral, topical and in injectable form is more difficult. This in turn affected the possible use/application and desired efficacy of such compounds. Objects of the Invention It is thus the basic object of the present invention to meet the need in the art for a stable solubilizing agent which would be capable of solubilizing various categories of drugs in limpid form having therapeutic value which would be__safe and non-toxic and meet the desired demands of the active in such limpid form as injectable, oral or topical use/administration. Another object of the present invention is directed to meet the demands in the art to.provide safe limpid forms of various active drugs at cost effective rates which would avoid the problems and limitations in the use of oils and derivatives of emulsions in providing such soluble forms of various actives/drugs. Further object of the present invention is directed to providing stable and cost-effective formulations of active drugs which have problems of solubility in a limpid form which can be administered intramuscularly and/or through intravenous route. Another object of the present invention to provide a process for the manufacture of wide range of pharmaceutical formulations involving actives and a selective solubilizing agent which would be non-toxic and at the same time would be a good carrier for permeation of the active drug thereby providing for wide and user-friendly application of the drug for various end uses/applications. Yet another object of the present invention is directed to a simple and cost-effective manner of manufacture of various categories of drugs in the form of injectables which would enable maintaining the desired quality control, free of problems of toxicity of the solvent. Yet further object is to provide for a versatile fluid solution having desired therapeutic value, which can be safely administered through the intramuscular and intravenous routes and avoid problems of the solubility and consequential therapy of various drugs through such routes to thereby increase efficacy and wide scale application of such drugs/actives and at the same time maintaining cost benefits. Yet further object of the present invention is directed to providing pharmaceutical composition of various categories of drugs in soluble limpid form which would be non-toxic and at the same time would be excreted out easily without causing any damage to any organ especially the kidney. Summary of the Invention Thus according to the basic aspect of the present invention there is provided a process for the producing pharmaceutical formulations involving wide range of actives including of lipophilic compounds in limpid form comprising: - the step of providing atleast one selective active drug in a selective solubilizing agent comprising 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. It is found by way of the present invention that out of the various known vehicles including various organic solvents, oils and oil-water mixtures for solubilizing actives including lipohilic and poorly water soluble drugs for their various therapeutic uses and purposes, 2,5-di-0-methyl-l-4;3-6-dianhydro-D-glucitol shows surprising and unexpected solubilizing activity which can avoid the above discussed limitations/problems of solubilizing and formulating various categories of drugs including lipophilic compounds in various forms such as for oral, rectal, injectable on topical administration. ' The wide range of actives/drugs which showed surprising and unexpected solubility in the selective solubilizing agent 2,5-di-O-methyl-l 4;3.6-dianhydro-D-glucitol include anesthetic agents such as Propofol, neuromuscular blocking agents such as Pipecuronium Bromide, Vecuronium Bromide, antibiotics such as Rifampin, Rifamycin-S, Rifamycin-SV, Roxythromycin, antifungals such as Itraconazole, Tolnaftate, anti-tuberculostic, anti¬inflammatory anti-malarials steroids, lipid regulating drugs and also anti-hypertension drugs. Detailed Description of the Invention The selective solubilising agent 2,5-di-O-methyl-l-4; 3-6-dianhydro-D-glucitol is used in an amount of 1% to 99 % by wt. in the above composition. Importantly, also it is identified that in amounts of less than 1%. The solubilizing activity of 2,5-di-O-methyl-1-4; 3-6-dianhydro-D-glucitol is not very effective. In accordance with an aspect of the present invention the pharmaceutical compositions involving 2,5-di-O-methyl-l-4; 3-6-dianhydro-D-glucitol are found to be storage stable and assist in avoiding decomposition of actives such as Propofol in solution. The formulation also achieves good pharmacokineties. Moreover, apart from solubilizing such wide range of actives, surprisingly, 2,5-di-O-methyl-l-4, 3-6-dianhydro-D-glucitol achieved good chemical and biological stability. The versatility of the selective solubilizing agent enables providing for formulation which would be injectable both intravenously and intramuscularly thereby providing for vast and diverse applications of the actives/drugs thus dissolved for treating diverse and varied symptoms effectively. The wide range of actives/drugs that can be surprisingly but effectively solubilized by 2,5-di-O-methyl-l-4, 3-6-dianhydro-D-glucitol include : (i) For Anaesthetics - A clear solution of Propofol can be prepared which is safe, non-toxic, economically beneficial and suitable for anaesthetists for their use and is also available in a single or multiple dose container. The additional advantage of this solvent is its synergistic effect in muscle relaxation. (ii) For Anti-Tuberculostic agents - A stable solution can be obtained for injectable/oral purpose by making the necessary formulation involving actives and the solubilizing agent. (iii) For Neuromuscular Blocking agents : A ready stable preparation can be produced as a single/multiple dose preparation without loss of activity. It is cost beneficial as no lyophilisation is required, which otherwise would add up cost to the ultimate consumer, (iv) For Anti-malarials - Anti-malarial formulation can be effectively provided in limpid form whereby the Iipophilicity of drugs and rapidly penetrating effect of this carrier solvent together effectually eradicates deadly 'P-falciparum' parasites. Presently the actives are only available as intramuscular injections or lyophilizing injections which are to be mixed with weak alkali to solubilize. The elegant and versatile solvent/formulation of the invention removes the deficiency of previous formulations by offering ready to use preparations which are effective and cost beneficial - being available in multi-dose form. Its further advantage is in its suitability to be administered intravenously. (v) For Anti-fungal - So far no preparation of Itraconazole could be provided as a clear solution, for its external or internal use. The Itraconazole formulation involving 2.5-di-O-methyl-1-4; 3-6-dianhydro-D-glucitol selectively provides a limpid solution, which can be utilized for its multiple therapeutic use. (vi) For Analgesics, Anti-inflammatory, Anti-pyretics - The preparations of Nimesulide which are presently available and marketed in tablet and syrup form, only when prepared involving the versatile selective solvent can be utilized for internal use as a injectables or for external use as lotions/gels/creams/ointments. This, therefore, provides for widening the effective areas of application and use of the active Nimesulide at cost-effective rates, (vii) For Antibiotics - As certain macrolide antibiotics of low solubility are used as oral formulations and even in oral preparations, the drug availaibility is sometimes different. However, the limpid form of even such actives in 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol resolve the difficulties of formulators. Following the invention it is thus possible to formulate a clear solution, ready-to-use preparation, for internal purposes, (viii) For Anti-hypertensives -There are limitations in terms of solubility and Iipophilicity of drugs like Nifedipine, as they are only available in oral form. The formulations of such actives in 2,5-di-0-methyl-l-4, 3-6-dianhydro-D-glucitol in accordance with the invention as the 'carrier solvent' provides an excellent formulation for internal use and can be life-saving. The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations discussed hereunder: Examples The surprising findings of the present invention that 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol acts synergistically with wide range of actives to provide limpid solution is further illustrated by way of the following examples. EXAMPLE : I ANAESTHETIC AGENTS Diisopropyl ether : Propofol 2.806 mmol to 280.6 mmol of drugs is dissolved in 100 ml. 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-gl^&kol to give a clear solution. Water and PEG 300 (15%) upto 20% can be added which keeps the solution limpid as well as physically and chemically stable. EXAMPLE : 11 NEUROMUSCULAR BLOCKING AGENTS a. Pipecuronium Bromide:- 0.262 mmol to 0.393 mmol of Pipecuronium bromide in 100 ml. of 2,5-di-O-methyl-1-4; 3-6-dianhydro-D-glucitol gave limpid stable solution. Water up to 4% to 5% v/v could be added without loss of activity. b. Vecuronium Bromide:- 0.3136 mmol to 0.4704 mmol of Vecuronium bromide is dissolved in 100 ml. of 2,5-di-O-methyl-1-4; 3-6-dianhydro-D-glucitol which gives a limpid stable solution. The presence of water up to 5% does not affect stability of the drug. EXAMPLE : III ANTIBIOTICS a. Rifampin: 1.215 mmol to 2.4301 mmol of Rifampin per 100 ml. of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol gave a limpid solution which was stable without loss of activity and remained chemically as well as physically stable. b. Rifamycin-S:- 2.5 mmol to 28 mmol of Rifamycin-S per 100 ml. of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol gave a limpid stable preparation having physical and chemical stability. c. Rifamycin-SV :- 3.5827 mmol of Rifamycin-SV per 100 ml of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol results in a limpid physically and chemical stable liquid. d. 3 Formyl Rifamycin S.V. 10 gms. Of 3 Formyl Rifamycin S.V. 100 ml. of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol results in a limpid physically and chemical stable liquid. Similarly derivatives Rifamycins also can be prepared in this versatile 2,5-di-0-methyl-l-4, 3-6-dianhydro-D-glucitol that to obtain stabilized liquid preparations. e. Clarithromycin:- 2.6739 mmol to 3.3424 mmol of Clarithromycin per 100 ml of 2,5-di-0-methyl-1-4; 3-6-dianhydro-D-glucitol gave a limpid physically and chemically stable solution. Water upto 10-20% can be added without loss of physical and chemical activity in the solution. f Azithromycin:- 4.005 mmol to 5.34 of Azithromycin per 100 ml. of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol gave a limpid physically and chemically stable solution. Addition of 10% v/v to 20% v/v/ was found not to affect the stability. g. Roxythromycin:- 2.389 mmol to 3.587 of Roxythromycin per 100 ml of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol gave a limpid physically and chemically stable solution. Drugs of various 'macrolides' can then be prepared in the form of solutions by way of its synergistic interaction with the selective versatile 2,5-di-0-methyl-l-4, 3-6-dianhydro-D-glucitol. EXAMPLE : IV ANTI-FUNGAL a. Itraconazole:- 1.417 mmol to 2.834 mmol Itraconazole per 100 ml. 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol gave a limpid physically and chemically stable solution. b. Tolnaftate;- 3.2528 mmol to 16.264 mmol of Tolnaftate per 100 ml. of 2,5-di-0-methyl-l-4, 3-6-dianhydro-D-glucitol gave a limpid physically and chemically stable solution. Various other Antifungal of these and other types can be prepared in 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. EXAMPLE : V ANTl-TUBERCULOSTIC a. Pvrazinamide: 8.122 mmol to 20.30 mmol of Pyrazinamide per 100 ml. 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol yields very limpid, physically and chemically stable solution. Water upto 10% to 20% does not alter the stability. b. Prothionamide:- 11.09 mmol to 27.736 mmol of Prothionamide per 100 ml. of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol gave a yellow limpid physically and chemically stable solution. c. Ethionamide:- 15.0375 mmol to 36.083 Ethionamide per 100 ml. of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol gave a yellow limpid physically and chemically stable solution. Various other categories of Anti-TB drugs may be prepared 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. EXAMPLE : VI ANTI-INFLAMMATORY, ANTIPYRETIC & ANALGESIC a. Nimesulide;- The compound Nimesulide is a powerful analgesic, anti-inflammatory and anti¬pyretic agents. 16.21 mmol to 48.652 mmol of Nimesulide per 100 ml. of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol gave a limpid stable solution. Water addition and PEG 300 up to 25% may be added to keep the solution with no loss of stability. b. Piroxicam:- 3.0179 mmol to 30.179 mmol of Piroxicam per 100 ml. of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol yields a limpid, physically and chemically stable solution. Co-solvents like water and PEG 300 up to 20% may be added without altering stability. EXAMPLE : VII ANTIMALARIALS The compound Artemisinin and its derivatives are powerful anti-malarials. The following derivatives also gave a limpid very stable solution: a. Artemisinin:- 53.12 mmol to 70.83 mmol of Artemisinin and its isomers per 100 ml. of 2,5-di- O-methyl-1-4; 3-6-dianhydro-D-glucitol gave a limpid, physically and chemically stable solution. b. Artesunate:- 7.8 mmol to 15.6 mmol of Artesunate and its isomers is taken in 100 ml. of 2,5-di-O-methyl-l-4; 3-6-dianhydro-D-glucitol gave a limpid, physically and chemically stable solution. c. Arteether:- 48.01 mmol to 80.02 mmol of Arteether and its isomers are taken in 100 ml. of 2,5-di-O-methyl-1-4; 3-6-dianhydro-D-glucitol to gave a limpid, physically and chemically stable solution. d. Artemether:- 26.81 mmol to 107.245 mmol of Artemether and its isomers is taken in 100 ml. of 2,5-di-0-methyl-l-4, 3-6-dianhydro-D-glucitol yielding a very stable solution. EXAMPLE : VIII STEROIDS Nandralone Phenyl Propionate:- An anabolic steroid solution prepared in the range of 24.594 mmol to 122.97 mmol per 100 ml. of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol to give a limpid, physically and chemically stable solution. The derivatives of Nandralone and other steroids can also be prepared. EXAMPLE : IX LIPID REGULATING DRUGS a. Lovastatin:- 12.34 mmol to 37.07 mmol of Lovastatin solution in 100 ml 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol is chemically and physically stable gave a limpid solution. b. Simvastatin:- 11.94 mmol to 23.89 mmol of Simvastatin in 100 ml. of 2,5-di-0-methyl-l-4, 3-6-dianhydro-D-glucitol yields a limpid stable solution. Other lipid lower drugs can also gave a limpid solution in this versatile solvent. EXAMPLE : X ANTI-HYPERTENSIVE Nifedipine:- 2.89 mmol to 14.44 mmol of Nifedipine per 100 ml. of 2,5-di-0-methyl-l-4, 3-6- dianhydro-D:glucitol gave a limpid, physically and chemically stable solution. Water and PEG up to 25% v/v does not alter the physical and chemical stability. Other drugs of anti-hypertensive category can also be prepared in this solvent and gave a limpid solution. The above clearly reveal that various limpid, stable solutions, can be obtained of 2,5-di-0-methyl-I-4; 3-6-dianhydro-D-giucitol whereby various lipophilic drugs/actives which were otherwise not soluble and had problems of solubility could be provides in a stable limpid form and suitable for oral, injectable and topical applications. Further stability studies of formulations in accordance with the invention incorporating 2,5-di-O-methyl-1-4, 3-6-dianhydro-D-glucitol vis-a-vis the same active dissolved in other solvent was studied as detailed hereunder : EXAMPLE : XI The stability of the propofol solution of the invention (Example I) was studied vis-a-vis the conventional propofol solution obtained of mixture of Egg lecithin, soya proteins/oils and glycerin. The results are provided in Table - I as per accompanying Figure 1. The result in Table I indicates that there is a clear advantage of using 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol as an excipient for the stability of the formulation containing Propofol. Propofol has a tendency to decompose when kept at 25°C if not properly formulated. The conventional formulation which is rich in carbon, hydrogen and nitrogen increases the bioload and cannot be used once opened and causes chemical decomposition of the formulation. Further Pharmacokinetic studies of Propofol formulation of Example I vis-a-vis the conventional propofol emulsion was carried out and the results are illustrated in Table 11 as per accompanying Figure 2. It would be apparent from the results in Table II that Pharmacokinetics indicate that formulation of the invention prepared by simple technology, has equivalent or slightly better Pharmacokinetic parameters when tested in the Rabbit model. This demonstrates the utility of the formulations involving 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol offers beneficial simple technology for the preparation of such injections over the available conventional emulsion formulations of Propofol which has a complicated technology of preparation. EXAMPLE : XII The stability of the Vecuronium and Pipecuronium clear solution involving the selective 2,5-di-O-methyl-1-4; 3-6-dianhydro-D-glucitol of the invention (Example II) was studied vis-a¬vis conventional Vecuronium / Pipecuronium formulations. The results are illustrated in Table III as per accompanying Figure 3. As would be apparent from Table III the Biological Assay based on acetyl choline induced contraction of Frog, Rectus abdominal muscle preparation. The result indicates that Biological activity, remains even at the end of 6 months as against the conventional preparation available of Vecuronium injection. The result indicated shows the clear advantage of formulation prepared in accordance with the invention using 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol exhibiting the chemical and biological stability even after 12 months when kept at R.T. whereas Lyophilised marketed preparation after 12 months loses the chemical and biological activity. EXAMPLE : XIII Further stability studies were carried out involving Rifampicin solution in accordance with the present invention (Example III) vis-a-vis the conventional formulation of Rifampicin. The results are represented in Table IV as per accompanying Figure 4. RIFAMPICIN : The results under Table IV clearly show the desired stability achieved by the formulations of the invention. EXAMPLE : XIV Under this Example stability studies of the antifungal formulation Itraconazole obtained in accordance with the present invention (Example IV) was tested vis-a-vis a conventional Itraconazole formulation. The results are provided in Table V as per accompanying Figure 5. ANTIFUNGAL : ITRACONAZOLE : Itraconazole is given orally for the fungal infections and is not available for the parenteral purpose. The inventive solution has a versatility of administering through Parenteral route and the solution has a very good physical and chemical stability which can be shown by stability indicating HPLC method as illustrated in Table V. EXAMPLE : XV The storage stability of the Nimesulide formulation in accordance with the present invention (Example VI) was studied vis-a-vis a conventional Nimesulide formulation. The results are illustrated in Table VI as per accompanying Figure 6. Since presently injectable formulations are not available the stability was compared against oral tablets. The injection formulation of Nimesulide in accordance with the present invention involving 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol shows comparative stability at the end of shelf life and the advantage of such injectable is quick onset of action when administered through Intramuscular/Intravenous route for antipyretic/analgesic effect. The above, therefore, clearly and sufficiently demonstrate the superior, surprising and unexpected results achieved involving the selective 2.5-di-0-methyl-l-4, 3-6-dianhydro-D-glucitol in accordance with the present invention. As illustrated the invention would provide for effective and wider application of various categories of drugs and avoid the limitations of providing formulations of various forms suitable for oral, topical and injectable forms even for lipophilic compounds/drugs. WE CLAIM : 1. A process for producing pharmaceutical formulations involving wide range of actives selected from anaesthetic agents, neuromuscular blocking agents, antibiotics, antifungals, anti- tuberculostic, anti-inflammatory, anti-malarials, steroids, lipid regulating drugs and anti- hypertension drugs including lipophilic compounds in limpid form comprising : the step of providing atleast one selective active drug in a selective solubilizing agent comprising 2,5-di-0-methyl-l-4, 3-6-dianhydro-D-glucitol 2. A process as claimed in claim 1 wherein the actives/drugs used is selected from anesthetic agents, neuromuscular blocking agents, antibiotics, antifungals, anti-tuberculostic, anti-inflammatory, anti¬malarials ,steroids, lipid regulating drugs and anti-hypertension drugs. 3. A process as claimed in anyone of claims 1 or 2 wherein the selective solubilising agent 2,5-di-O-methyl-1-4; 3-6-dianhydro-D-glucitol is used in an amount of 1% to 99% by wt. in the above composition. 4. A process as claimed in anyone of claims 1 to 3 wherein said active used is an anesthetic agent preferably Propofol and an amount of 0.5 to50 % is dissolved is said . 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol to obtain a clear solution. 5. A process as claimed in claim 4 comprising adding water and PEG 300 (15%) upto 20% to thereby obtain a physically and chemically stable formulation. 6. A process as claimed in anyone of claims 1 to 3 wherein the active drug is neuromuscularblockmg agent preferably selected from Pipecuronium Bromide,_Vecuronium BromideRocuranium Bromide, Pancuronium Bromide, Rapecuronium Bromide. 7. A process as claimed in claim 6 wherein the active is Pipecuronium Bromide used in amounts of 0.2% to 0.4 % by wt. in 90% to 95 % of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol as the solvent. 8. A process as claimed in anyone of claims 6 or 7 comprising adding water up to 4% to 5% v/v . 9. A process as claimed in claim 6 wherein the active used is Vecuronium Bromide in amounts of 0.2% to 0.4% by wt. in 90% to 95% of 2.5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol as the solvent. 10. A process as claimed in claim 9 comprising adding water upto 5 %. 11. A process as claimed in anyone of claims 1 to 3 wherein the active drug used is an antibiotic preferably selected from Rifampin , Rifamycin-S, Rifamycin-SV, 3 Formyl Rifamycin S.V, Clarithromycin, Azithromycin, Roxythromycin and other microlides. 12. A process as claimed in claim I I wherein the active rifampin is used in amounts of 1% to 2% in said 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. 13. A process as claimed in claim 11 wherein the active Rifamycin-S is used in amounts of 1% to 2% in said 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol . 14. A process as claimed in claim 1 1 wherein the active Rifamycin-SV is used in amounts of 1% to 2.5% in said 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol . 15. A process as claimed in claim 11 wherein the active 3 Formyl Rifamycin is used in amounts of 1% to 10% in said 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol . 16. A process as claimed in claim 1 1 wherein the active Clarithromycin is used in amounts of 2% to 2.5% in said 2,5-di-0-methyI-i-4; 3-6-dianhydro-D-glucitol . 17. A process as claimed in claim 11 wherein the active Azithromycin is used in amounts of 1% to3 % in said 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. 18. A process as claimed in claim 11 wherein the active Roxythromycin is used in amounts of 1% to 3% in said 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol . 19. A process as claimed in claim anyone of claims 16 or 17 wherein water upto 10-20% can be added without loss of physical and chemical activity in the solution. 20. A process as claimed in anyone of claims 1 to 3 wherein the active drug used is an anti¬fungal preferably selected from Itraconazole, Tolnaftate, Flucanazole, Diazole, Triazole. 21. A process as claimed in claim 20 wherein said Itraconazole is used in an amount of 1% to 2% in said 98% to 99% of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol as the solvent. 22. A process as claimed in claim 20 wherein said Tolnaftate is used in an amount of 1% to 5% in said 95% to 99% of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol as the solvent. 23. A process as claimed in anyone of claims 1 to 3 wherein the active drug used is an anti-tuberculostic preferably selected from Pyrazinamide, Prothionamide, Ethionamide, Cycloserine. 24. A process as claimed in claim 23 wherein said Pyrazinamide is used in amounts of 1% to 2.5% in 80% to 90% of said.2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. 25. A process as claimed in claim 23 wherein said Prothionamide is used in amounts of 2% to 5% in 80% to 90% of said 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. 26. A process as claimed in claim 23 wherein said Ethionamide is used in amounts of 2.5% to 6% in 80% to 90% of said 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. 27. A process as claimed in claim 24 comprising adding water upto 10% to 20%. 28. A process as claimed in anyone of claims 1 to 3 wherein the active drug used is an ANTI-INFLAMMATORY, ANTIPYRETIC & ANALGESIC preferably selected from. Nimesulide , Piroxicam, Meloxicam, COX-! & COX-2 Inhibitors and Mesanemic Acid derivative. 29. A process as claimed in claim 28 wherein said active drug used is Nimesulide in amounts of 5% to 15% in said 85% to 95% of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. 30. A process as claimed in claim 28 wherein said active drug used is Piroxicam in amounts of 1% to 10% in said 75% to 99% of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. 31. A process as claimed in claim 29 comprising adding water addition and PEG 300 up to 25%. 32. A process as claimed in claim 30 comprising adding co-solvents like water and PEG 300 up to 20%. . 33. A process as claimed in anyone of claims 1 to 3 wherein the active drug used is an ANTI-MALARIALS preferably selected from Artemisinin, Artesunate, Arteether, Artemether and Artemisinin derivatives. 34. A process as claimed in claim 33 wherein said active drug used is Artemisinin in amounts of 1.5% to 2% in said 98% to 98.5% of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. 35. A process as claimed in claim 33 wherein said active drug used is Artesunate in amounts of 3% to 6% in said 94% to 97% of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. 36. A process as claimed in claim 33 wherein said active drug used is Arteether in amounts of 15% to 25% in said 75% to 85% of 2,5-di-O-methyl-1-4; 3-6-dianhydro-D-glucitol. 37. A process as claimed in claim 33 wherein said active drug used is Artemether in amounts of 8% to 16% in said 84% to 92% of 2,5-di-0-methyl-U4; 3-6-dianhydro-D-glucitol. 38. A process as claimed in anyone of claims I to 3 wherein the active drug used is an steroid preferably selected from Nandralone or its derivatives, Nandralone Phenyl Propionate, Benzoate, Cyclohexanecarboxylate, Cyclohexanepropionate, Decanoate, Dodecanoate, Furylpropionate, p-Hexaneoxyphenylpropionate, Phenopropionate, Propionate. 39. A process as claimed in claim 38 wherein said active drug used is Nandralone Phenyl Propionate in amounts of 10% to 50% in said 50% to 99% of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. 40. A process as claimed in anyone of claims 1 to 3 wherein the active drug used is a lipid regulating drug preferably selected from Lovastatin , Simvastatin, Rosuvastatin, Pravastatin, Atorvastatin. 41. A process as claimed in claim 40 wherein said active drug used is Lovastatin in amounts of 1% to 15% in said 85% to 99% of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. 42. A process as claimed in claim 40 wherein said active drug used is Simvastatin in amounts of 1% to 15% in said 85% to 99% of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. 43. A process as claimed in anyone of claims 1 to 3 wherein the active drug used is an ANTI-HYPERTENSIVE drug preferably selected from Nifedipine, Nimodioine, Amlodipine and derivatives alike. 44. A process as claimed in claim 43 wherein said active drug used is Nifedipine in amounts of 1% to5 % in said 75% to 99 % of 2,5-di-0-methyl-l-4; 3-6-dianhydro-D-glucitol. 45. A process as claimed in claim 44 comprising adding water and PEG up to 25% v/v. 46. A process for the producing pharmaceutical formulations involving wide range of actives including of lipophilic compounds in limpid form substantially as herein described and illustrated in relation to the accompanying examples. Dated this 20th day of May 2003 AN]AN SEN Of S. MAJUMDAR & CO. Applicants' Agent

Documents:

546-mum-2003-abstract(28-5-2003).pdf

546-mum-2003-cancelled pages(13-01-2005).pdf

546-mum-2003-claims(28-5-2003).pdf

546-mum-2003-claims(amended)-(13-1-2005).pdf

546-mum-2003-claims(granted)-(13-01-2005).doc

546-mum-2003-claims(granted)-(13-01-2005).pdf

546-mum-2003-claims(granted)-(24-4-2007).pdf

546-mum-2003-correspondence(02-11-2006).pdf

546-mum-2003-correspondence(25-5-2010).pdf

546-mum-2003-correspondence(ipo)-(2-7-2007).pdf

546-mum-2003-correspondence(ipo)-(29-12-2004).pdf

546-mum-2003-description(complete)-(28-5-2003).pdf

546-mum-2003-description(granted)-(24-4-2007).pdf

546-mum-2003-drawing(13-01-2005).pdf

546-mum-2003-drawing(28-5-2003).pdf

546-mum-2003-drawing(granted)-(24-4-2007).pdf

546-mum-2003-form 1(19-06-2003).pdf

546-mum-2003-form 1(28-05-2003).pdf

546-mum-2003-form 19(08-08-2003).pdf

546-mum-2003-form 2(complete)-(28-5-2003).pdf

546-mum-2003-form 2(granted)-(13-01-2005).pdf

546-mum-2003-form 2(granted)-(24-4-2007).pdf

546-mum-2003-form 2(title page)-(28-5-2003).pdf

546-mum-2003-form 2(title page)-(granted)-(24-4-2007).pdf

546-mum-2003-form 3(28-05-2003).pdf

546-mum-2003-form-2-(granted)-(13-01-2005).doc

546-mum-2003-power of attorney(10-07-2003).pdf

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