Title of Invention

A NOVEL PROCESS FOR TASTE MASKING OF FORMULATIONSCONTAINING BETTER BIO ACTIVE SUBSTANCES

Abstract

A process for taste masking of bitter drugs is disclosed. The process comprises the steps of [i] selecting a lipidic, hydrobhobic coating composition; [ii] selecting a bio compatible solvent, having a low boiling point, in which the said drugs are insoluble but in which the coating composition is soluble; [iii] dissolving hydrophobic coating composition in the solvent in a reaction vessel which is greater than 12% by weight of the drug; [iv] particulating the drug to obtain particles in the range of 5 to 1000 microns; [v] suspending particles of the drugs in the solvent having the coating composition dissolved therein by continuous agitative mixing; [iv] extracting the solvent from the said vessel by vacuum evaporation during the mixing process to enable the coating composition to precipitate on the suspended drug particles. A planetary mixer is modified to carry out the apparatus.

Full Text

FORM-2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE Specification (Section 10, rule 13) ORGN 316/MUM/2003 31.03.2003 A PROCESS FOR TASTE MASKING OF FORMULATIONS CONTAINING BITTER BIO ACTIVE SUBSTANCES ALKEM LABORATORIES LIMITED of 510 Shah Nahar Industrial Estates, Dr. E.Moses Road, Worli, Mumbai 400 018, Maharashtra, India, an Indian Company THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:- This invention relates to a process for taste masking of formulations containing bitter bio active substances. In particular this invention relates to a process of making formulations containing drugs which do not have a palatable taste and where it is difficult to ingest such drugs directly in solid state. Taste-masking is usually done by adding flavours. However, taste masking of certain classes of drugs which are unpalatable through the use of flavours is not found to be sufficient to make them palatable. Therefore, in the prior art certain physical procedures or methods were employed to encapsulate or place a chemical barrier to mask their undesirable taste characteristics. A convenient means of presenting any drug for oral administration is in the form of granules, which may be administered as a solution or a suspension or taken with a draught of water. Solutions or suspensions of granules as for example, a syrup are particularly convenient for oral administration for paediatric population. However certain drugs have an extremely bitter taste, which is long lasting and which cannot be adequately masked by addition of sweeteners and flavours to conventional granule preparations. Again, for making granules of the bio active material a first step is required to be done where the granules are formed with binding agents and other excipients and the granules are then formed by 2 binding together drug particles in a wet state and then drying these granules. Further while formulating a coated drug molecule, it is desirable that the drug should not be released in the liquid suspension which is used or even in mouth. This problem can be solved by coating the drug molecule with coating materials that has limited permeability to water. The coating however should be integral otherwise, the efficiency of the procedure will be reduced drastically. These coatings however should easily dissociate or dissipate to release the active drug on contact with GI fluid. OBJECTS OF THE INVENTION This invention also relates to a process for delivery of drugs which do not have a palatable taste and where it is difficult to ingest such drugs directly in solid state. This particular invention relates to the use of coating agents to coat the drug molecule in order to mask the bitter taste of the drug molecule. An object of this invention is to provide a coated drug molecule whose unpalatable taste is effectively masked.. 3 Another object of this invention, is to provide a process which uses a low concentration of the coating agent to coat the drug molecule. Yet another object of this invention is that the coated drug particles are used instead of granules and hence the use of binding agents and other excipients are avoided and at the same time the process of granulation is eliminated in the process steps. The present invention also envisages the use of a Modified Planetary Mixer in which the whole process of the coating of drug particles with the coating agent and drying the coated particles is done in a single stage. The advantage of using this equipment is that recovery of solvent is possible which can again be recycled. Another object of this invention is to improve the yield of the coated particles to above 95%. Yet another object of the invention is to provide coated particles that do not melt or release the active drug in mouth, but on contact with acidic medium they easily dissociate to release the drug for absorption. Yet another object of the invention is to provide coatings which are integral. 4 It is envisaged that these coated particles are used for formulating various pharmaceutical dosage forms, intended for oral administration. Solutions or suspensions of particles as for example, a syrup are particularly convenient for oral administration for pediatric population. STATEMENT OF INVENTION According to this invention there is provided a process for taste masking of bitter drugs, comprising [i] selecting a lipidic, hydrobhobic coating composition; [ii] selecting a bio compatible solvent, having a low boiling point, in which the said drugs are insoluble but in which the coating composition is soluble; [iii] dissolving hydrophobic lipidic coating composition in the solvent in a reaction vessel; [iv] particulating the drug to obtain particles in the range of 5 to 1000 microns; [v] suspending particles of the drugs in the solvent having the coating composition dissolved therein by continuous agitative mixing; [vi] extracting the solvent from the said vessel by vacuum evaporation during the mixing process to enable the coating composition to precipitate on the suspended drug particles. 5 The Lipid coated drug molecules are highly efficient in masking the bitter taste of the drug molecule which otherwise cannot be easily masked by using conventional flavours and sweeteners. The lipids, also known as lipins or lipoids are the fat like substances that occur in the plants and animals. The lipids may be classified into: 1. Fixed oils and fats, which are mixtures of glyceryl esters of high molecular weight fatty acids. 2. Waxes, which are esters of high molecular weight monohydric alcohol and high molecular weight fatty acids. 3. Sterols, which are alcohols containing the cyclopentanophenanthrene nucleus. 4. Phospholipids and glycolipids, which are esters consisting of glycerol in combination with fatty acids, phosphoric acid and certain nitrogenous compounds. The lipids used as coating agents have an advantage that they form a hydrophobic coating on the drug molecule which is insoluble in mouth but gets rapidly dissolved in acidic pH, thereby releasing the active drug for absorption. The lipids can be, for example - a high molecular weight (C10-C30) straight chain saturated or unsaturated aliphatic acid such as Stearic Acid or Palmitic Acid, 6 - A triglyceride for example a glyceryl ester of high molecular weight (C10-C30) aliphatic acid Glyceryl trilaurate, Glyceryl trimyristate, - A wax such as Bees Wax or Carnauba Wax - A high molecular weight (C10-C30) straight chain aliphatic alcohol such as Stearyl Alcohol or Cetostearyl Alcohol - Mixtures of high molecular weight fatty acids such as mixtures of Stearic Acid or Palmitic Acid. - Mixtures of high molecular weight straight chain aliphatic alcohols such as Cetostearyl alcohol, - Mixtures of partially hydrogenated oils such as Cottonseed and Soyabean oils, - Mixtures of high molecular weight aliphatic acid and glyceryl esters such as a mixture of Stearic Acid and Glyceryl trilaurate - Materials which are insoluble in salivary pH such as polymethamethacrylate salts commonly available in the trade name of Eudragit. The lipid coating material has to be dissolved in an organic solvent for coating the active drug molecule. An organic solvent that can be used for easy dissolution of the lipid coating material should have a low boiling point, so that the removal of organic solvent under vacuum is rapid. The solvent should also not be inflammable. Examples of organic solvents that can be used are Dichloromethane, Acetone, Isopropyl Alcohol etc. 7 Active ingredients on which the process of this invention can be used include drugs which have a bitter taste and are selected from a large group of therapeutic agents which include antibiotics, alkaloids, antacids, analgesics, antiallergics, antimalarials, antihistamines, anti-inflammatory drugs, antiemetics, antispasmodics, antipsychotics, antithyroid preparations, antipyretics, antinauseants, appetite stimulants, bronchodilators, cough suppressants, decongestants, diuretics, laxatives, expectorants, mucolytics, mineral supplement, sedatives, antidepressants, antifungals, vitamins, antidiabetics, like amoxicillin, amodiaquine ampicillin, alprazolam, ambroxol, acetylsalicylic acid, ascorbic acid, bromopheniramine, caffeine, calcium carbonate, cefaclor, cefpodoxime proxetil, clarithromycin, chlorpheniramine, cefalexin, cefuroxime axetil, cefadroxil, cefixime, chlorpromazine, cimetidine, citalopram, chloroquin, ciprofloxacin, cyproheptadine, dextromethorphan, diclofenac, diphenhydramine, doxycycline, ferrous fumarate, fluconazole, oxiconazole, erythromycin, famotidine, gentamicin, griseofulvin, guiafensin, hydrochlorthiazide, hydrocortisone, ibuprofen, indomethacin, iron, ketoprofen, loratadine, mefenamic acid, metoprolol, methylsalicylate, norfloxacin, omeprazole, ondansetron, phenytoin, propoxyphene, riboflavine, sucralfate, sulfasalazine, sumatriptan, tetracycline, niacinamide, triprolidine, vancomycin, etc. 8 EQUIPMENT USED The equipment used for manufacturing the lipid coated drug molecules is a Planetary mixer which in a preferred embodiment of this invention and in accordance with another aspect of this invention has been modified as needed to optimize the process as described in Figure 1 of the accompanying drawings. This equipment is basically a mixing assembly where the agitation is of the peripheral and homogenizing nature. The central beater or the agitation assembly rotates around a central axis as in the bowl thereby achieving intimate mixing leading to a higher heat transfer coefficient. The unit which is illustrated schematically in figure 1 of the accompanying drawings, consists of: A] A cylindrical bowl ,typically of 50 L capacity, to obtain appropriate temperature inside the bowl. The bowl is fitted with steam/hot fluid inlet, cold water inlet and outlet connections to the jacket. The bowl is also equipped with standard fittings like pressure gauge, vent cock, release valve and drain. Special connections for application of vacuum are also fitted with the bowl. B] A SS top dish for covering the bowl that is accompanied by a flange for fixing the sealing gasket. The dish also contains the necessary connections with serrated nozzles provided for 9 connecting flexible pipe [G] for vacuum application. The top dish also contains the openings for the addition of materials. C] The agitator assembly consists of Anchor type SS scrappers fitted with PTFE strip on both the sides of the two beaters. D] One additional chopper is also fitted in the agitator assembly. The modification is done mainly with side scrapper with increasing number of plates from 2 to 20. Modification is also done in beater by addition of a chopper which will chop the material to increase the surface area thereby helping in hastening the evaporation process. The scrappers will help in stirring the material continuously thereby leading to uniform mixing and increasing the evaporation. Results of both the modification is that it helped in reducing the distillation time by 50% and increasing the recovery of Solvent by 40%. E] The unit is also equipped with Hydraulic Power Pack Assembly F] Jacketed receiver, to collect the evaporated solvent. G] Serrated nozzles to connect flexible pipes. H] Hydraulic cylinder for lifting the top dish. I] A vacuum pump J] A heat exchanger unit. Modification in heat exchanger unit is that it is connected to VAM ( Vapour Absorption Machine) whereby temperature of circulating water was reduced from 15% to 7%. Due to this modification, rate of condensation of Solvent increased. 10 Recovery of solvent was increased from 40% to 80% due to its reduction in the rate of evaporation in the chilling apparatus. The increase in recovery of solvents like Methylene Chloride helped in protecting the environment. The following examples as in Table 1 Figure 2 of the accompanying drawings, illustrates the various aspects of the invention. They are not to be construed to limit the claims in any manner whatsoever. PROCEDURE All the steps are carried out under controlled humidity conditions (40% RH). Process for formulations using Lipid, Cellulose Esters, waxy Esters. MethacrvlicAcid Copolymer and Glyceryl Esters as the coating material: 1. The coating material is dissolved in the required amount of organic solvent, (which has a low boiling point and is nonflammable) under stirring. The solution of coating material is then filtered through muslin cloth. 2. To obtain the solution of coating material and drug, the bitter tasting drug molecule is charged slowly under stirring. 3. The dispersion of Drug and coating material mixture is stirred for a period of 15 - 20 minutes. 4. The solvent is then evaporated slowly under vacuum and is collected in another receiver. 5. The temperature of the reaction vessel containing the drug and coating material mixture is maintained below 28° C by 11 We Claim: 1. A process for taste masking of bitter drugs, comprising [i] selecting a lipidic, hydrobhobic coating composition; [ii] selecting a bio compatible solvent, having a low boiling point, in which the said drugs are insoluble but in which the coating composition is soluble; [iii] dissolving hydrophobic coating composition in the solvent in a reaction vessel, the hydrophobic coating composition being greater than 12% by weight of the drug to be coated, and is preferably 20% of the weight of the drug ; [iv] particulating the drug to obtain particles in the range of 5 to 1000 microns; fv] suspending particles of the drugs in the solvent having the coating composition dissolved therein by continuous agitative mixing; [vi] extracting the solvent from the said vessel by vacuum evaporation during the mixing process to enable the coating composition to precipitate on the suspended drug particles. 2. A process for taste masking of bitter drugs, as claimed in claim 1, in which the coating composition is a substance which includes one or more substances from a group containing the following : high molecular weight (C10-C30) straight chain saturated or unsaturated aliphatic acids such as Stearic Acid or Palmitic Acid; triglycerides for example a glyceryl ester of high molecular weight (C10-C30) aliphatic acid such as Glyceryl trilaurate,

Documents:

316-mum-2003-claims(granted)-(23-06-2004).doc

316-mum-2003-claims(granted)-(23-06-2004).pdf

316-mum-2003-correspondence(15-1-2007).pdf

316-mum-2003-correspondence(ipo)-(2-5-2008).pdf

316-mum-2003-form 1(31-03-2003).pdf

316-mum-2003-form 18(29-03-2006).pdf

316-mum-2003-form 2(granted)-(23-06-2004).pdf

316-mum-2003-form 3(19-03-2003).pdf

316-mum-2003-form 4(16-02-2004).pdf

316-mum-2003-form 5(23-06-2004).pdf

316-mum-2003-form-2-(granted)-(23-06-2004).doc

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316-mum-2003-power of authority(27-03-2003).pdf