Title of Invention	"SUSTAINED RELEASE SYRUP COMPOSITION AND PROCESS THEREOF"
Abstract	The present invention relates to a novel sustained release syrup composition comprising a bronchodilator analgesic drug and a syrup base system and process thereof. The present compositions are capable of releasing the bronchodilator drug in a prolonged and sustained manner over a period of 24 hours.

Full Text

FIELD OF INVENTION: The present invention relates to a novel sustained release liquid composition comprising an anti-asthmatic drug. In particular, the invention provides a novel sustained release syrup composition comprising an anti-asthmatic drug such as salbutamol and etophylline, as active ingredients and process thereof. The syrup capable of releasing the active ingredient over a prolonged period to provide an extended duration of bronchodilator effect. BACKGROUND OF THE INVENTION: Various bronchodilators are in use since the 1950s. Some of these are available as tablets and some as syrups. Two bromchodilators of interest are salbutamol and etophylline. Salbutamol is a selective P2-adrenoceptor agonist. At therapeutic doses it acts on the ß2-adrenoceptors of bronchial muscle providing short acting (4-6 hour) bronchodilatation with a fast onset (within 5 minutes) in reversible airways obstruction. Etofylline is a theophylline derivative. It is used as a bronchodilator. Its plasma half life is 4.1 hrs. Both salbutamol and etofylline are water-soluble and are administered in low dose. These drugs are available as monophasic liquid dosage form (syrup). The marketed formulation requires 3 to 4 times administration in one day. This results in higher dose intake and patient inconvenience. Thus, the prior art provides bronchodilators but only as tablet or syrup which require frequent administration, which interferes with a patient's regular activities in addition to causing inconvenience during the intervals of administration. Noticeably absent from the art is a preparation that is capable of releasing a bronchodilator over a prolonged period to provide an extended duration of relief to a patient. One possible reason is that general view that for sustained or prolonged release preparations, certain special vehicles are required. And the view that bronchodilator are easy to formulate as tablets; however, these vehicles are unsuitable for liquid preparations such as to provide sustained relief. On account of such views, the art does not yet provide a sustained release preparation of a bronchodilator. The present invention goes against these views and provides a novel prolonged and sustained release preparation comprising a bronchodilator. OBJECTS OF THE INVENTION: The main object of the invention is to provide a preparation capable of releasing a bronchodilator in a prolonged and sustained manner over a period of 24 hours. DESCRIPTION OF THE INVENTION: Accordingly, in one aspect, the invention provides a liquid preparation comprising: a) a drug selected from salbutamol sulphate and etophylline; and b) a liquid vehicle comprising at least two components selected from any of sodium carboxy-methyl cellulose, xanthan gum, guar gum, tragacanth, sodium alginate and micro-crystalline cellulose, the components being capable of forming a gel in situ; the preparation capable of releasing the drug for a period of about 23-26 hours. The drug employed in the preparation may be about 2 to 10% by wt. The amount of the liquid is about 5 to 10 ml. The amount of each individual component in the vehicle may be about 1 to 5% by wt. The liquid preparation may further comprise water, sweetening agents, coloring agents and flavouring agents. As mentioned in the foregoing sections, noticeably absent from the prior art is a liquid dosage form essentially in the form of a syrup which is capable of releasing a bronchodilator drug for a prolonged manner for a period of over 24 hours. Syrup, as is known is usually a monophasic liquid, and the drug is dispersed in the said medium. A suspension is a biphasic liquid dosage form wherein any drug in soluble form is dispersed in the viscous base. The viscous base may be composed of two or more components capable of forming gel in situ. In the present case, the components may be polymers. The art provides sustained release aqueous preparations such as sustained release injections; however, so far it has been assumed in the art that a sustained release syrup or a liquid dosage form is difficult to prepare essentially in case of bronchodilator analgesic drug since the vehicle currently available are not suited for such purpose. The art has continued with such assumptions and hence today there are no sustained release syrups for bronchodilator drugs. Going against the current thinking, the Applicant has developed a novel liquid dosage form comprising a liquid vehicle and a drug, wherein the drug is dispersed in the liquid vehicle. The liquid vehicle is a combination of at least two polymeric substances. The polymers are chosen such that they trap the drug moiety and are also complementary to each other. In fact, the Applicant was surprised to note that when such a liquid dosage form is prepared, the composition provides a sustained and prolonged effect of bronchodilation. The novel dosage form of the invention is so designed that optimal amount of bronchodilator drug which is required to be present in the blood plasma to provide relief to a patient is maintained over a period of 24 hours, even upon a single administration of the drug. One of the main benefits of the composition is that a single dosage is sufficient for a day, thereby obviating the need to consume several doses of drugs. Further, liquid formulation facilitates dosage adjustment. This is achieved and is possible on account of the unique combination of ingredients such as present in the system of the invention which controls the release rate of the drug and delivers it at a constant rate for a prolonged period. The syrup system releases the drug at the rate of 5 to 15% per hour for 24 hours. Another benefit of the invention is that the syrup system is so designed when the drug is admixed with it, no foam, froth or lumps are formed and the drug gets mixed uniformly. Yet another benefit of the invention is that upon formation, the final product (which is in the form of a syrup) has an extended shelf life of more than 2 years. Yet another advantage of the invention is that since the current dosage form is in liquid form, it gives a physician and the patient the liberty of freedom to adjust the dosage form to the extent required so that the patient need not consume any more drug than what is required. DESCRIPTION OF THE ACCOMPANYING DRAWINGS: Figure 1 is a graphical representation of the release profile of a composition comprising sodium CMC and guar gum (100 + 100), and drug. Figure 2 is a graphical representation of the release profile of a composition comprising sodium CMC and guar gum (150 + 50), and drug. Figure 3 is a graphical representation of the release profile of a composition comprising sodium CMC and guar gum (150 + 75), and drug. Figure 4 is a graphical representation of the release profiles of compositions comprising different ratio of sodium CMC and guar gum, and drug. Figure 5 is a graphic representation of the release profile of a composition comprising drug, gelatin and guar gum. Figure 6 is a graphic representation of the release profile of a composition comprising gelatin, drug and xanthan gum. Figure 7 is a graphic representation of the release profile of a composition comprising carbopol, drug and guar gum. Figure 8 is a graphic representation of the release profile of a composition comprising HEC, drug and guar gum. Figure 9 is a graphic representation of the release profile of a composition comprising chitosan and drug. Figure 10 is a graphic representation of the release profile of a composition comprising CMC, drug and guar gum. Figure 11 is a graphical representation comparing the release profiles of SS5 and control. The invention is now illustrated by the following examples, which should not be construed as limitations on the inventive concept. Variations that may be arrived at by a skilled person are within the scope of this invention. EXAMPLES: Example 1: Preparation of liquid preparation The syrups of salbutamol sulphate were prepared by solubilising the drug in sustained release flavoured syrup base. The syrup base contains the different polymers combinations keeping the total polymer concentration constant that is 2% of final solution. The different polymer combination were (polymer l+polymer2) gelatin+xanthum gum (7:1,175+25), gelatin+guar gum (7:1,175+25), carbopol+guar gum (7:1,175+25), HEC+ guar gum (7:1,175+25), Sodium CMC +Guar gum(7:1,175+25), Chitosan(200mg), Chitosan + guar gum(l: 1,100+100), Chitosan +HPMC(1:1,100+100), per 10 ml of syrup base & the formulations prepared were coded as SS1,SS2,SS3,SS4,SS5, SS6,SS7&SS8 respectively. The drug load was kept constant that is 6mg/10ml of the base. The best polymer combination, which was giving the maximum sustaining effect was selected for further work. The two polymers in various proportions were taken keeping the total concentration of two polymers constant that is 2% of the final solution. The four different concentrations of the polymers were (7:1,175+25), (3:1,150+50),(5:3,125+75) &( 1:1,100+100) per 10 ml of syrup base & the formulation codes corresponds to SS41,SS42,SS43&SS44,respectively. The drug load was kept constant that is 6mg/10ml of the base. Preparation of syrup base: Composition of syrup base is shown in the table given below: Formula per 10 ml of syrup (Table Removed) All the solid ingredients of the syrup base were weighed accurately in a single pan digital balance. Polymerl (Sodium CMC) was added to 70% of the final volume of water in a beaker & stirred for 20 minutes using a magnetic stirrer to form a uniform solution. To this solution, polymer2 (guar gum) was added & stirred till a uniform clear, uniform viscous solution was formed. In a separate beaker, accurately weighed methyl paraben and propyl paraben aspartame were dissolved in sufficient volume of water, this was then mixed with above solution & stirred for another 10 minutes. Finally the color and flavor were added & stirred for another 5 minutes. The volume was make up using water and stirred until uniform syrup base was formed. Preparation of syrup: Accurately weighed amount of Salbutamol sulphate was dissolved in sufficient quantity of syrup base and stirred. Final volume was adjusted using the syrup base with constant stirring. The syrups of Etofylline were prepared by solubilising the drug in sustained release flavoured syrup base. The two polymers in various proportions were taken keeping the total concentration of two polymers constant that is 2% of the final solution. The four different concentrations of the polymers were (7:l,175+25mg), (3:l,150+50mg),(5:3,125+75mg) &(l:l,100+100mg) per 10 ml of syrup base & the formulation codes corresponds to ET1,ET2,ET3 & ET4,respectively. The drug load was kept constant that is 372mg/10ml of the base. Preparation of syrup base: Composition of syrup base is shown in the table given below: Formula per 10 ml of syrup (Table Removed) All the solid ingredients of the syrup base were weighed accurately in a single pan digital balance. Polymer 1 (Sodium CMC) was added to 70% of the final volume of water in a beaker & stirred for 20 minutes using a magnetic stirrer to form a uniform solution. To this solution, polymer2 (guar gum) was added & stirred till a uniform clear, uniform viscous solution was formed. In a separate beaker, accurately weighed methyl paraben and propyl paraben aspartame were dissolved in sufficient volume of water, this was then mixed with above solution & stirred for another 10 minutes. Finally the color and flavor were added & stirred for another 5 minutes. The volume was make up using water and stirred until uniform syrup base was formed. Preparation of syrup: Accurately weighed amount of Salbutamol sulphate was dissolved in sufficient quantity of syrup base and stirred. Final volume was adjusted using the syrup base with constant stirring. Physico-Chemical Evaluation of formulations : In vitro release studies: The in-vitro dissolution studies were performed on a Lab India dissolution apparatus (DISSO 2000). The formulations were evaluated for their release profile using USP type II apparatus. Dissolution Studies Specifications: Dissolution Medium: SGF For the First Two hours and SIF for the rest of the time. Sample Volume: 10 ml Replacement Volume: 10 ml Temperature: 37±0.5°C RPM: 50 Paddle Depth: 25 mm Dissolution Medium Volume: 900 ml Sampling Bottles: Amber Colored. The sample was analyzed using a double beam spectrometer (Shimadzu 1601). Plots were drawn between the amount of drug released and time for all the formulations. Fig. 1 to 10 shows in-vitro release profiles of salbutamol from different formulations prepared. As shown in figures 1 to 10 the percentage cumulative release of the drug by the system is plotted against the time taken for release of drug by the system. In such studies, it is expected that the graph should be devoid of excessive peaks and trough since such peaks and troughs depict spurts of drug release, which is highly undesirable. Similarly, it is not desirable that the composition provide an initial burst followed by no release. Such a composition is one wherein the entire dosage form is released in the beginning itself and no sustained effect is observed. For sustained release effect, the graph is expected to be more or less a straight line. From Figures 1 to 10, it may be observed that in case of compositions prepared using Chitosan, sodium carboxymethyl cellulose, gelatin, xanthan gum, HEC, carbopol etc., the drug is released within the first 3 hours, and there is nothing left to be released later. Whereas, when a composition comprising sodium carboxymethyl cellulose, drug and guar gum, the release is slow and sustained. The said effect is shown in figures 1 and 10. Figure 11 shows a comparison of the release profiles of the drug as compared to a control. Example 2: Analysis of drug FTIR Analysis: FTIR was done on a shimadazu model. Five milligram of the drug substance was taken on an agate pestle. It was thoroughly triturated with 100 mg of Potassium bromide. A pellet was made out of the mix and introduced into the instrument. The spectrum was recorded between 500-4000 cm-1 The Salbutamol Sulphate sample exhibited absorption at wave numbers at 085.8,1029.91,1244.0,1205.4,881.4. Etophylline exhibited peaks at 1651.0,1548.77,1188.1,981.7,748.3. DSC Analysis: A TA instruments Differential Scanning colorimeter Q10 DSC was used. Four mg of the sample was weighed on an electronic balance. The sample was placed on the aluminium Pans and then sealed. The instrument was calibrated using indium. On one side the sample pan was placed and on the other side an empty aluminium pan was placed. The sample was heated between 50- 300°C at the rate of 10°C/Minute.N2 gas was introduced at a pressure of 2 bars and a flow rate of 20 ml/minute maintained. Salbutamol sulphate and etophylline in solution was estimated using Ultraviolet Spectrophotometer for in vitro studies of formulations. For this purpose maax (Absorption maxima) was determined and subsequently standard curve in 0.1 N HC1 (pH 1.2) and USP Phosphate Buffer (pH 6.8) was prepared. Example 3: Estimation of drug Standard curve for both the drugs was plotted on HPTLC equipment (Camag). Blood (0.5ml) was withdrawn from tail vein of healthy albino rats weighing 150-200 Gms and added to 0.5ml of ethyl acetate and 0.5ml of drug solution ( a known amount of drug was added to methanol). This was then centrifuged for 40minutes at 3000rpm. The supernatant (plasma) was then collected and freezed until further analysis. This solution was then withdrawn in the HPTLC syringe & 6 spots of 2,4,6,8,10,12 and 20ul were applied on 10*10 silica gel plated by the syringe automatically. The whole Standard operation was monitored by a program that was fed into the HPTLC software. (Table Removed) Example 4: In vitro evaluation In Vivo Evaluation: Based on in vitro performance, the selected formulations were evaluated in Rats to compare the blood level profiles of the formulations with profiles obtained after oral administered of an aqueous solution of the drug in Rats. Rats weighing 175 -200 g of either sex were kept in normal housing conditions and were fed with commercially available diet, sprouted grams and cabbage. Rats were starved for 24 hours before the administration of the sample. Two groups were formed each containing six animals. First group was given the test formulation ; Second group was given the aqueous drug solution. Blood samples were withdrawn from the tail ear vein at given intervals in a syringe having 0.4 ml of Sodium Citrate and then transferred to apphindroff s tubes, 0.5 ml of Ethyl Acetate was added. The samples were centrifuged at 3000 rpm for 40 minutes at 4°C .The plasma obtained was separated and kept frozen until analyzed by HPTLC. The pharmacokinetic profile of the formulation was compared to that of the drug solution administered orally. ADVANTAGES: 1.1 Monophasic liquid formulation for water soluble drugs like salbutamol or etophiline can be prepared using a syrup base composing Sodium CMC, Gelatin, Guar Gum, Carbopol, Chitosan, HPMC, HEC & Xanthan Gum. 1.2 This formulation resembles the properties of syrup, (i.e. viscosity / consistency, sweetness, appearance etc.) 1.3 In-vitro this formulation releases the drug in a sustained manner. 1.4 This formulation when administered, delivers drugs at a sustained rate. The t max Cmax for salbutamol and etofylline were observed to be 12 hrs &0.04293 mg/ml and 8 hrs &0.12448 mg/ml resp. 1.5 The amount of drug release is directly proportional to the amount of syrup administered, which suggests that dose of the formulation can easily be adjusted, if needed, which is not possible with solid sustained release formulation. 1.6 The formulation is easy to swallow and more acceptable for children and elder people. 1.7 Easiest method (cost / equipment requirement and time required is least) for formulating a sustained release formulation WE CLAIM: 1. A sustained release syrup composition comprising: a) a bronchodilator analgesic drug in an amount of 2% to 10% by weight selected from salbutamol and etophylline; and b) a syrup base system comprising at least two or more polymers in ratio of 1:1 to 7: 1, selected from sodium carboxymethyl cellulose, micro-crystalline cellulose, xanthan gum, guar gum, tragacanth, sodium alginate and gelatin, wherein the ratio of syrup base system and the drug is 10:1 and the said drug is released at a constant rate of 5 to 15% per hour for the period of 23-26 hours. 2. A sustained release liquid composition as claimed in claim 1, wherein the polymers in syrup base system are sodium carboxymethyl cellulose and guar gum. 3. A sustained release liquid composition as claimed in claim 1, wherein the drug is salbutamol. 4. A sustained release liquid composition as claimed in claim 1, wherein the drug is etophylline. 5. A process for preparation of the sustained release syrup composition as claimed in claim 1 comprising the step of: a) preparing a syrup base system comprising at least two polymers selected from sodium carboxymethyl cellulose, micro-crystalline cellulose, xanthan gum, guar gum, tragacanth, sodium alginate, gelatin, wherein the ratio of two polymers are 1:1 to 7: 1; b) solublising the drug selected from salbutamol and etophylline in sustained release syrup base prepared in step (a); c) stirring the syrup mixture of step (b) and adjusting the final volume with syrup base of step (a), wherein the ratio of the syrup base to the drug is 10:1; d) to obtain sustained release syrup composition capable of releasing the drug at a constant rate of 5 to 15% per hour for the period of 23-26 hours.

Documents:

2448-DEL-2005-Abstract-(18-04-2012).pdf

2448-DEL-2005-Abstract-(29-06-2011).pdf

2448-del-2005-abstract.pdf

2448-DEL-2005-Claims-(18-04-2012).pdf

2448-DEL-2005-Claims-(29-06-2011).pdf

2448-del-2005-claims.pdf

2448-DEL-2005-Correspondence Others-(18-04-2012).pdf

2448-DEL-2005-Correspondence Others-(29-06-2011).pdf

2448-del-2005-correspondence-others.pdf

2448-del-2005-corrospondens other-.pdf

2448-DEL-2005-Description (Complete)-(18-04-2012).pdf

2448-DEL-2005-Description (Complete)-(29-06-2011).pdf

2448-del-2005-description (complete).pdf

2448-DEL-2005-Drawings-(29-06-2011).pdf

2448-del-2005-drawings.pdf

2448-DEL-2005-Form-1-(18-04-2012).pdf

2448-DEL-2005-Form-1-(29-06-2011).pdf

2448-del-2005-form-1.pdf

2448-DEL-2005-Form-13-(18-04-2012).pdf

2448-del-2005-form-18.pdf

2448-DEL-2005-Form-2-(18-04-2012).pdf

2448-DEL-2005-Form-2-(29-06-2011).pdf

2448-del-2005-form-2.pdf

2448-del-2005-form-3.pdf

2448-del-2005-form-5.pdf

2448-del-2005-form-9.pdf

2448-DEL-2005-GPA-(29-06-2011).pdf