Title of Invention

A PROCESS FOR THE PREPARATION OF NATURAL PIGMENT BASED PARACETAMOL SYRUP"

Abstract

A process for the preparation of natural pigment based paracetamol syrup by mixing 50-60 weight% propylene glycol, 40-43 weight% glycerol, and 0.0002-0.0016 weight% anthocyanin pigment, adding the above said mixture to the standard paracetamol syrup in the ratio of 0.01:10-0.1:10, adjusting the pH by adding conventional buffer solution in the range of 5.0-6.0 to obtain natural pigment based paracetamol syrup.

Full Text

The present invention relates to a process for the preparation of natural pigment based paracetamol syrup formulation. The present invention particularly relates to an improved formulation with natural pigment -anthocyanin, for paracetamol syrup. This formulation has use as an antipyretic analgesic, particularly for children. Commercial syrup samples are pale-pink in color imparted due to synthetic dyes (carmine). The market for paracetamol in India is estimated to be Rs. 2.7 billion, and is growing at 7-8% each year. Around 44% of the market has been for oral preparations, wherein sales have been increasing 2-3% per annum. In recent years the use of natural colorants is preferred in food and pharmaceutical products because of the consumer preference towards more natural products, which are known to exhibit specific functional attributes. Certain natural colorants, particularly anthocyanins, are known to possess functional properties such as anti-oxidants, hence having health promoting effects (Igarashi et al (1989) Nippon Shokuhin Kogyo Gakkaishi 36: 852-856 and Kamei et al (1993) J. Clinical Expt. Med. 164:829-832). Reference may be made to Psczozola, (1998, Food Technology 52:70-82) where in among the natural red colourants from plant sources, red pigments such as anthocyanin from fruits and vegetables have been suggested for food applications. Reference may be made to Harborne JB et al, (1975, The Flavonoids, Chapman & Hall, London) where in anthocyanin is chemically grouped as "flavonoid", which is synthesized in a vast number of higher plants. Reference may be made to Shrikhande AJ (1986, Anthocyanins in foods, CRC Crit. Rev. Food Sci & Nutrition, 7: 193-213) where in several edible fruits are good sources of anthocyanin. Apart from imparting attractive red color, reference may be made to Stahl W & Sies H (1993, Annals of the New York Academy of Sciences 691: 10-19) and Narayan et al.(1999, Prostagland. Leuk. Essent. Fatty Acid 60:1-4) wherein it has high anti-oxidant activity and thus impart health-promoting effect to higher animals and human beings. Reference may be made to Timberlake CF & Henry BS (1986, Plant pigments as natural food colours, Endeavor NS 10: 31 - 36 ) where in the red grapes serve as an excellent source of anthocyanin and thus imparting attractive red color to red wines. Reference may be made to Diplock AT et al (1998, British Jour. Nutrition, Suppl. 1, S77-S112) where in anthocyanin extracts prepared from vegetables and edible fruits are used as edible colours throughout the world. Reference may be made to von-Elbe JH (1986, Chemical changes in plant and animal pigments during food processing. In. Role of Chemistry in the Quality of Processed Food. Ed. Owen R. Fennema et al, Food and Nutrition Press 41-64, Westport, Connecticut) where in anthocyanins are known to undergo chemical changes when incorporated in food products. The stability of natural red pigments, anthocyanins, from plant sources is strongly affected by light, pH, temperature, oxygen and water activity. In the present invention, the anthocyanins obtained from red edible grapes have been used to develop a syrup formulation with paracetamol as the active ingredient, and the formulation can be scaled up to commercial level. In the present invention, the synthetic dye is replaced with several levels of anthocyanin extracted from red grapes to match the hue of synthetic dye in syrup. The levels of components such as propylene glycol and glycerol in the syrup were varied to obtain good stability of anthocyanin for shelf life of over 100 days under varied light and temperature conditions. Reference may be made to Ames and Hoffmann (2001, Chemistry and Physiology of Selected Food Colorants, American Chemical Society Series 775, Washington, DC), wherein it has been quoted as FDA permits anthocyanin from grape skin as a food additive. The World Health Organization (1982), recommended an average daily intake of 2.5 mg anthocyanin/Kg body weight/day from grape skin extract. Production of anthocyanin concentrates from various plant parts and their use in food products has been studied for many years and there are many research articles and patents concerning it. The advantages of incorporating natural anthocyanin in food formulations are many. Reference may be made to Gorcia-Viguera et al (1999, J. Food Sci.64: 243-247, and Food Science and Technology International 1999, 4: 99-105) where in influence of different factors on anthocyanin concentration and color in several food products such as jams, pomegranate juice during storage were studied. The use of anthocyanins in pharmaceutical products such as syrup formulated with paracetamol is not known. Certain commercial formulation of syrups containing the active ingredient, paracetamol, has pale pink hue caused due to the addition of synthetic dye (carmine). Such synthetic dyes are known to cause harmful effects in human beings. While tablet formulations without any added color are available for adults and for children below 8 years, syrups are proposed which invariably contain synthetic dye. Since there is a worldwide preference for natural colourants in food and Pharmaceuticals, the replacement of synthetic colours with natural ones such as anthocyanin will be advantageous due to health considerations. The improvement in syrup formulation by incorporation of natural colourant, anthocyanin, is two-fold. Firstly it will replace the undesirable synthetic dye while imparting a similar color effect to the formulation. Secondly, the levels of incorporation act as nutraceutical owing to their anti-oxidant effect in human systems. The main objective of the present invention is to provide a process for the preparation of natural pigment based paracetamol syrup formulation Another objective of the present invention is to explore the possibility of developing paracetamol syrup formulation with natural red color with a hue value comparable to the commercial formulation. Still yet another objective of the present invention is to experiment and find out the level of pigment that may be needed to obtain a stable hue of the natural colour under expected fluctuations in light and temperature conditions during a known time period. Still yet another objective of the present invention is to explore the stability of the natural color, in the final formulation, under various light and temperature conditions. Still yet another objective of the present invention is to explore the effect of the natural color on the active ingredient i.e., paracetamol. Accordingly, the present invention relates to a process for the preparation of natural pigment based paracetamol syrup formulation which comprises a) mixing 50-60 weight% Propylene glycol, 40-43 weight% Glycerol, and 0.0002-0.0016 weight% Anthocyanin pigment, b) adding the above said mixture to the standard Paracetamol syrup in the ratio of 0.01:10-0.1:10, c) adjusting the pH by adding conventional buffer solution in the range of 5.0-6.0 to obtain a desired formulation. In an embodiment of the present invention, the standard paracetamol syrup used comprises Paracetamol 2.5% (w/v) Sodium benzoate 0.11 %(w/v) Methyl paraban sodiate 0.11%(w/v) Propyl paraban sodiate 0.11 %(w/v) Sucrose 20-60%(wt) Citric acid 0.02-0.06% Disodium EDTA 0.013% Water to make up 500 millilitre In an embodiment of the present invention, the stability of anthocyanin in formulation may be achieved in a period ranging from 150-180 days in transparent bottle in diffused light ranging from 1000-2000 lux and for a period of more than two years in dark bottle In another embodiment of the present invention, the prefered pH of the mixture obtained in the above step may be 5.5. The following examples are given by way of illustration of the present invention and therefore should not be considered to limit the scope of invention. Example 1 One Kg of uniformly ripened red grapes were washed with tap water followed by washing with distilled water to remove surface dust, insect debris, pesticides and other contaminants if any. Surface water was gently removed by blotting with clean blotters. Fruit skins were collected, homogenized in a blender with a known volume of acidified water (with 0.01 to 0.001% ascorbic acid) of pH 5.0, passed through nylon filter, the filtrate was centrifuged at 10000 x gravity at 5°C, supernatant was collected, passed through ion-exchange column (Dowex 1 and Dowex 50), concentrated the elute under vacuum at 30°C. The concentrated solution was collected and estimated the pigment, anthocyanin content by spectrophotometer following the method described by Garcia-Viguera et al 1999. J. Food Sci: 64 PP 243-247. Example 2 Five hundred ml of syrup containing standard paracetamol [containing paracetamol (2.5% w/v), sodium benzoate (0.11% w/v), methyl paraban sodiate (0.11% w/v), propyl paraban sodiate (0.011% w/v), sugar (20-60% w/v), citric acid (0.02-0.06%w/v), and disodium ethylenediaminetetraacetic acid (0.013% w/v)] was prepared was prepared to which 135 grams of propylene glycol and 75 miHiliter of glycerol was added, 3.75 milligram of anthocyanin extract (prepared as described in Example 1) was added, pH adjusted to 5.5, uniformly mixed by vortexing the content, dispensed to 50 tubes each holding 10 ml of syrup. The coloured syrup formulation was divided into batches and tested for colour stability as well as paracetamol stability at temperatures of 25, 30, 35 40 and 45°C light regimes of 1000 lux, 2000 lux and dark for 150 days. Colour stability was tested by using spectrophotometer and by using colour-measuring system. The colour of anthocyanin was stable till the end of 150th day with a no loss of red hue in samples stored in light however, the final hue after storage at all conditions was similar to that required for commercial sample. There was no change in the paracetamol content. Example 3 Five hundred ml of syrup containing standard paracetamol was prepared was prepared to which 125 grams of propylene glycol and 75 miHiliter of glycerol was added, 3.75 milligram of anthocyanin extract (prepared as described in Example 1) was added, pH adjusted to 5.5, uniformly mixed by vortexing the content, dispensed to 50 tubes each holding 10 ml of syrup. The coloured syrup formulation was divided into batches and tested for colour stability as well as paracetamol stability at temperatures of 25, 30, 35 40 and 45°C light regimes of 1000 lux, 2000 lux and dark for 150 days. Colour stability was tested by using spectrophotometer and by using colour-measuring system. The colour of anthocyanin was stable till the end of 150th day with a negligible loss of red hue in samples stored in light however, the final hue after storage at all conditions was similar to that required for commercial sample. There was no change in the paracetamol content. Example 4 Five hundred ml of syrup containing standard paracetamol was prepared was prepared to which 100 grams of propylene glycol and 75 milliliter of glycerol was added, 3.75 milligram of anthocyanin extract (prepared as described in Example 1) was added, pH adjusted to 5.5, uniformly mixed by vortexing the content, dispensed to 50 tubes each holding 10 ml of syrup. The coloured syrup formulation was divided into batches and tested for colour stability as well as paracetamol stability at temperatures of 25, 30, 35 40 and 45°C light regimes of 1000 lux, 2000 lux and dark for 150 days. Colour stability was tested by using spectrophotometer and by using colour-measuring system. The colour of anthocyanin was stable for 150 days with a partial loss of red hue in samples stored in light however, the final hue after storage at all conditions was similar to that required for commercial sample. There was no change in the paracetamol content. Example 5 Five hundred ml of syrup containing standard paracetamol was prepared was prepared to which 100 grams of propylene glycol and 75 milliliter of glycerol were added, 2.5 milligram of anthocyanin extract (prepared as described in Example 1) was added, pH adjusted to 5.5, uniformly mixed by vortexing the content, dispensed to 50 tubes each holding 10 ml of syrup. The coloured syrup formulation was divided into batches and tested for colour stability as well as paracetamol stability at temperatures of 25, 30, 35 40 and 45°C light regimes of 1000 lux, 2000 lux and dark for 150 days. Colour stability was tested by using spectrophotometer and by using colour-measuring system. The colour of anthocyanin was stable till the end of 150th day with a negligible loss of red hue in samples stored in light resulting in slight loss of red hue in the syrup. There was no change in the paracetamol content. Example 6 Five hundred ml of syrup containing standard paracetamol was prepared (based on the formulation of Kohli DPS, 1998, Drug Formulation Manual, Eastern Publishers, New Delhi, p. 272) to which 100 grams of propylene glycol and 60 mjlliliter of glycerol were added, 1.25 milligram of anthocyanin extract (prepared as described in Example 1) was added, pH adjusted to 5.5, uniformly mixed by vortexing the content, dispensed to 50 tubes each holding 10 ml of syrup. The coloured syrup formulation was divided into batches and tested for colour stability as well as paracetamol stability at temperatures of 25, 30, 35 40 and 45°C light regimes of 1000 lux, 2000 lux and dark for 150 days. Colour stability was tested by using spectrophotometer and by using colour-measuring system. The colour of anthocyanin was stable till the end of 150th day with a partial loss of red hue in samples stored in light resulting in slight loss of red hue in the syrup. The paracetamol was separated by TLC on a silica gel GF 254, using chloroform : acetone : toluene : acetic acid ( 65 : 25 : 10 : 0.5 ) and estimated as per Indian Pharmacopoeia Vol 2, Page 555-556 (1996) by spectrophotometer at 254nm.. There was no change in the paracetamol content. The Main Advantages of the present Invention are: 1. The new formulation developed in the present study replaces undesirable synthetic dye in paracetamol syrup targeted for treatment of infants and children as an anti-pyretic and analgesic. 2. Anthocyanin being a potent antioxidant, the new syrup developed here is expected to impart health benefit effect in human beings. 3. The formulation is expected impart better sensory properties to the product. 4. The natural color does not involve change in the standard procedure of syrup preparation. 5. The color is stable at different light and temperature conditions, for which the syrup is expected to be exposed to. 6. The active component i.e., paracetamol does not get affected by change in the formulation and the use of anthocyanin as a coloring agent. 7. The process described here can be easily scaled up to industrial level. We Claim, 1. A process for the preparation of natural pigment based paracetamol syrup formulation which comprises: a) mixing 50-60 weight% Propylene glycol, 40-43 weight% Glycerol, and 0.0002-0.0016 weight% Anthocyanin pigment, b) adding the above said mixture to the standard Paracetamol syrup in the ratio of 0.01:10-0.1:10, c) adjusting the pH by adding conventional buffer solution in the range of 5.0-6.0 to obtain a desired formulation. 2. A process as claimed in 1 where in the standard paracetamol syrup used comprises Paracetamol 2.5% (w/v) Sodium benzoate 0.11 %(w/v) Methyl paraban sodiate 0.11%(w/v) Propyl paraban sodiate 0.11 %(w/v) Sucrose 20-60%(wt) Citric acid 0.02-0.06% Disodium EDTA 0.013% Water to make up 500 millilitre 3. A process as claimed in claims 1&2, wherein the stability of anthocyanin in formulation is ranging from 150-180 days in transparent bottle in diffused light in the range of 1000-2000 lux and more than two years in dark bottle. 3. A process as claimed in claims 1 & 2, wherein the preferred pH of the mixture obtained in step (c) is 5.5. 4. A process for the preparation of natural pigment based paracetamol syrup formulation substantially as herein described with reference to examples.

Documents:

328-del-2002-abstract.pdf

328-del-2002-claims.pdf

328-del-2002-correspondence-others.pdf

328-del-2002-correspondence-po.pdf

328-del-2002-description (complete).pdf

328-del-2002-form-1.pdf

328-del-2002-form-2.pdf

328-del-2002-form-3.pdf

328-del-2002-form-4.pdf