Title of Invention

"A SUSTAINED RELEASE MULTILAYERED TABLET COMPOSITION FOR UNSTABLE DRUG"

Abstract The present invention discloses a novel drug delivery system in form of multi-layered tablet composition having top and bottom layer made up of higher alcohol selected from cetyl alcohol, stearyl alcohol and middle layer or core layer comprising an unstable drug selected from nicorandil or venlafaxine HC1 in combination with an agent selected from xanthum gum, guar gum, karaya gum, tragacanth gum, pectin gum, cellulose derivatives or combination thereof.
Full Text FIELD OF INVENTION:
The present invention relates to a novel sustained release composition comprising an unstable drug. Particularly, the invention provides a novel sustained release composition comprising a drug such as nicorandil or venlafaxine HC1.
BACKGROUND OF THE INVENTION:
Nicorandil, first introduced in 1979, as a coronary vasodilator for angina pectoris is currently being used for prevention and long-term treatment of unstable angina. Tiara et al. (1979) Pharmacological profile of a new coronary vasodilator drug, 2-nicotinamidoethyl nitrate (SG-75) Clin Exp Pharmacol Physiol. 6; 301-306 and Uchida et al. (1978) Effect of 2-nicotinamidethyl nitrate (SG-75) on coronary circulation. Japan Heart J. 19: 112-124. Nicorandil which belongs to the class of potassium channel activators is used for disorders such as heart failure, cerebral ischaemia and erectile dysfunction. Kukowetz et al. (1991) Dual mechanism of relaxing effect of Nicorandil by stimulation of cyclic GMP formation and by Hyperpolarization. J Cardiovasc Pharmacol. 17: 627-633.
Nicorandil can be administered both orally and intravenously. It is rapidly absorbed from the GIT exhibiting oral bioavailability of 100%.It is not subject to hepatic first pass or oresystemic metabolism and reaches maximum plasma concentrations in 0.5-1.0 hr. It has a plasma ti/2 of approximately 1 hr. unlike nitrates; tolerance does not develop even on repeated dosing. The recommended dose is 10-20 mg twice daily, which in long-term therapy may lead to patient compliance problems.
Nicorandil preparations are relatively stable in the in the dry state; however, in humid conditions, in the presence of moisture they tend to disintegrate and hence, must be prepared, stored and handled with great care so as to avoid contact with moisture.
One solution to this problem is provided by JP 145659/1982 wherein a nicorandil crystal is used for tablet preparation by coating the crystal with one or more fatty or waxy
substances. While the method may be useful in achieving stability, it would be commercially quite expensive and time-consuming to coat crystals.
US 4,822,808 proposes mixing of nicorandil with a higher aliphatic acid or a satuated higher alcohol that was solid at ordinary temperatures and optionally with an organic acid. According to this Patent, the nicorandil preparation thus obtained is stable.
Similarly, US 5,580,576 and US 4,803,213 teach storage-stable preparations of nicorandil.
While all the above teachings are useful as propositions, they seem to be very unsatisfactory when it comes to production on a commercial scale. Some of these turn out as expensive processes and time consuming. Hence, there is a need to provide a composition wherein nicorandil is stable and easy to manufacture on commercial scale.
Another drug that is difficult to formulate is venlafaxine HC1. It is also a drug that is unstable in moist conditions. So far, in the art, there are no storage stable preparations (suited for commercial preparation) for these drugs. Further, these drugs need to administered frequently; hence a single dose formulation which is also storage stable is desirable in respect of both drugs.
DESCRIPTION OF THE INVENTION
Accordingly, in one aspect, the invention provides a novel composition comprising:
a) a top layer comprising a higher alcohol selected from a stearyl alcohol and cetyl alcohol;
b) a middle or core layer comprising an unstable drug selected from nicorandil or venlafaxine HC1 in combination with an agent selected from xanthum gum, guar gum karaya gum, tragacanth gum, pectin gum and cellulose derivative; and
c) a bottom layer comprising a higher alcohol selected from cetyl alcohol and stearyl alcohol.
The above composition is capable of releasing the drug at a rate of 5-15% per hour for 24 hours, making it a single dose composition and obviating the need to administer it in divided doses for 24 hours. The above composition also ensures stability of the drug and easy administration to a patient.
The inventors after intensive studies with unstable drugs such as nicorandil and verlafaxine HC1 found that several factors apart from stability of drug influence formulation preparation. These include effect of pressure exerted when compressing granules into tablets, granule aggregation, physical properties of the granules (such as area, shape, size, hardness as these can significantly affect the rate of dissolution of a drug); flow property of granule, granule density and porosity, presence of uniform drug content, friction between molecules etc. The inventors also found that moisture conditions greatly affect the stability of the drugs venlafaxine and nicorandil and that the conventional methods of preparing sustained release compositions are not suitable or appropriate for these drugs. They require special preparation such that they are not only protected from the hostile environment, but also released into the blood stream at a constant rate.
Towards this end, the inventors conducted intensive studies. It was found during the studies the entire structure of the tablet and the ingredients must be changed if a storage stable composition is to be developed having a sustained release effect. Further, the excipients of the prior art are unsuited. Surprisingly, when the said drugs were mixed with a gum such as xanthum gum, it was found to make the composition stable. It was also found that the active ingredient must be protected from the top and bottom in order to achieve the desired effect. Hence, the invention provides a multi-layered composition wherein the top and bottom layers are composed of a higher saturated alcohol and the middle layer is composed of the drug as active ingredient in combination with a gum. A schematic diagram depicting the said tablet combination is shown in figure 1.
Thus, it was surprisingly found that in order to obtain a composition which is storage stable and which provides a constant therapeutic dosage over a 24-hour period, it is
necessary to formulate the ingredient with a gum and cover the top and bottom portions with alcohols such that a waxy housing is formed around the active ingredient, protecting the drug from the outside environment.
The drug employed in the tablet may a water-soluble drug such as nicorandil or venlafaxine HC1. The amount of the drug in the composition may vary from 15 to 75 mg. The ratio of drug to the gum in the composition is 1:5 to 1:10. The amount of gum in the composition may be 100 to 300 mg, preferably 50 mg to 250 mg.
One of the main advantages of the invention is that the composition disclosed ensures complete stability of the drug as active ingredient. The composition of the invention may be kept under harsh conditions of high temperature, exposed to moisture or cold; yet the composition tends to remain stable and integral. The average shelf life of the composition is about 2 to 214 years.
Yet another advantage of the invention is that the composition releases the drug (active ingredient) at a constant rate such that the drug in the blood plasma levels are maintained within the optimal therapeutic range but below toxic levels over a period of 24 hours or longer. The amount of nicorandil released by the composition is 5-15% per hour for 24 hours, preferably at the rate of 5-15% per hour for 24 hours, preferably, 20% at 2 hrs-6 min, 50% in 5 hrs-21 min, 80% in 18 hrs-16 min, and 85% in 20 hrs-12 min.
As opposed to this, the compositions of the prior art are "rapid release compositions", wherein the active ingredient (drug) upon administration is released into the blood plasma immediately and the optimal/desired therapeutic range is maintained in the blood plasma for not more than 2-3 hours, owing to which, it is necessary for the patient to consume several doses of the drug. However, in case of the composition of the present invention, single dose is capable of maintaining the desired therapeutic range in the blood plasma for a prolonged period of over 24 hours.
A further advantage derived from the type of composition disclosed in this invention is that the materials are carefully chosen as to avoid any possibly interaction between the
drug and the agents with which it is combined. Some agents such as carbopol are found to make the composition so hard that the drug cannot escape to the outside and some other agent such as lactose and mannitol exhibit physical or chemical interaction with the drug. Hence, all materials / agents cannot be employed as such.
It has also been found chat only a combination as disclosed in the present invention is capable of providing a sustained release effect and that such effect is the result of the synergy between the drug and the agents / materials surrounding it. The combinatory effect of the composition is far greater than what a skilled person would expect and predict based on the ingredients separately. The examples provided below (example 1 to 5) illustrate this position. It has been found that only the composition of the invention achieves the desired sustained / prolonged release effect as opposed to the rapid release compositions of the prior art.
In another aspect, the invention provides a method for preparation of the composition, comprising the steps of:
a) mixing a drug selected from nicorandil or venlafaxine HC1 with at least 100 mg (by weight of composition) of xanthum gum and preparing granules thereof;
b) preparing a first top layer and a bottom layer comprising at least 50 mg (by weight of composition) of a saturated alcohol selected from stearyl alcohol or cetyl alcohol;
c) pouring the top layer into a die followed by the granules of step (a) and the bottom layer; and
d) compressing the layers to obtain a three-layered tablet.
The invention is now illustrated by the following examples and drawings.
Example 1: Preparation of nicorandil containing tablets:
Nicorandil and Guar gum were accurately weighed and dry mixed. To this mixture ethanol was added drop wise and dough was prepared. This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
Then Stearyl alcohol was accurately weighed and kept in oven to form its semisolid mass. This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
First of all, Stearyl alcohol granules were poured in dye then granules of Nicorandil and Guar gum were poured then again granules of Stearyl alcohol were added to dye in order to form triple layer matrix tablet of Nicorandil. Compression was performed on a single station tabletting machine with 8 mm round punches to prepare tablets of weight 150 mg.
Example 2: Preparation of nicorandil tablets with guar gum:
Nicorandil and Xanthum Gum were accurately weighed and dry mixed. To this mixture ethanol was added drop wise and dough was prepared. This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
Then Stearyl alcohol was accurately weighed and kept in oven to form its semisolid mass This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
First of all, Stearyl alcohol granules were poured in dye then granules of Nicorandil and Xanthum Gum, were poured then again granules of Stearyl alcohol, were added to dye in order to form triple layer matrix tablet of Nicorandil. Compression was performed on a single station tabletting machine with 8 mm round punches to prepare tablets of weight 150 mg.
Example 3: Combination of Stearyl Alcohol with Carbopol:
Nicorandil and Carbopol were accurately weighed and dry mixed. To this mixture ethanol was added drop wise and dough was prepared. This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
Then Stearyl alcohol was accurately weighed and kept in oven to form its semisolid mass This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
First of all, Stearyl alcohol granules were poured in dye then granules of Nicorandil and Carbopol were poured then again granules of Stearyl alcohol were added to dye in order to form triple layer matrix tablet of Nicorandil. Compression was performed on a single station tabletting machine with 8 mm round punches to prepare tablets of weight 150 mg.
Example 4: Preparation of venlafaxine tablet:
Venlafaxine and Guar gum were accurately weighed and dry mixed. To this mixture dichloromethane was added drop wise and dough was prepared. This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
Then Cetyl alcohol was accurately weighed and kept in oven to form its semisolid mass. This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
First of all, Cetyl alcohol granules were poured in dye then granules of Venlafaxine and Guar gum were poured then again granules of Cetyl alcohol were added to dye in order to form triple layer matrix tablet of Venlafaxine . Compression was performed on a single station tabletting machine with 8 mm round punches to prepare tablets of weight 350 mg.
Example 5: Preparation of venlafaxine tablet with xanthum gum:
Venlafaxine and Xanthum Gum were accurately weighed and dry mixed. To this mixture dichloromethane was added drop wise and dough was prepared. This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
Then Cetyl alcohol was accurately weighed and kept in oven to form its semisolid mass This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
First of all, Cetyl alcohol granules were poured in dye then granules of Venlafaxine and Xanthum Gum, were poured then again granules of Cetyl alcohol, were added to dye in order to form triple layer matrix tablet of Venlafaxine. Compression was performed on a single station tabletting machine with 8 mm round punches to prepare tablets of weight 350 mg.
Example 6: Other preparations of venlafaxine and nicorandil:
a) Venlafaxine and Xanthum Gum and Micro crystalline cellulose were accurately
weighed and dry mixed. To this mixture dichloromethane was added drop wise
and dough was prepared. This mass was passed through sieve No. 16 followed by
sieve of mesh no. 20 to get the granules of desired size.
Then Cetyl alcohol was accurately weighed and kept in oven to form its semisolid mass This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
First of all, Cetyl alcohol granules were poured in dye then granules of Venlafaxine and Xanthum Gum and Micro crystalline cellulose were poured then again granules of Cetyl alcohol were added to dye in order to form triple layer matrix tablet of Venlafaxine. Compression was performed on a single station tabletting machine with 8 mm round punches to prepare tablets of weight 350 mg.
b) Nicorandil + HPMC:
Nicorandil and Hydroxy Ethyl Cellulose were accurately weighed and dry mixed. To this mixture ethanol was added drop wise and dough was prepared. This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
Then Stearyl alcohol was accurately weighed and kept in oven to form its semisolid mass This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
First of all Stearyl alcohol granules were poured in dye then Granules of Nicorandil and Hydroxy Ethyl Cellulose poured then again granules of Stearyl alcohol were added to dye in order to form triple layer matrix tablet of Nicorandil. Compression was performed on a single station tabletting machine with 8 mm round punches to prepare tablets of weight 150 mg.
c) Nicorandil + HPMC:
Nicorandil and HPMC K100M Guar gum were accurately weighed and dry mixed. To this mixture ethanol was added drop wise and dough was prepared. This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
Then Stearyl alcohol was accurately weighed and kept in oven to melt the Stearyl alcohol in order to form semisolid mass This mass was passed through sieve No. 16 followed by sieve of mesh no. 20 to get the granules of desired size.
First of all, Stearyl alcohol granules were poured in dye then granules of Nicorandil and HPMC K100M were poured then again Stearyl alcohol granules were added to dye in order to form triple layer matrix tablet of Nicorandil. Compression was performed on a single station tabletting machine with 8 mm round punches to prepare tablets of weight 150 mg.
Example 7: Physico-Chemical Evaluation of Tablets:
Weight, Hardness, Diameter and drug content of all the tablets prepared was estimated. Each tablet was weighed and the average weight was determined.
Strong Cobb hardness tester determined the hardness of the matrix tablet. The diameter of the both types of tablets was determined using a Screw micrometer. The drug content of the both tablets was determined by preparing the standard curve of the drug in distilled water. The tablet was placed in 50 ml of distilled water in a beaker, it was kept on a shaker at 200 rpm overnight. The temperature was maintained at 370C. At the end of 24 hours. The aliquots from the filtered solution were analyzed spectrophotometrically at 225 nm. The concentration of the drug was determined with reference to the standard curve. The drug content was represented as average drug loading.
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.
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.
Venlafaxine in solution was estimated using Ultraviolet Spectrophotometer for in vitro studies of formulations. For this purpose ,max (Absorption maxima) was determined and subsequently standard curve in 0.1 N HC1 (pFI 1.2) and USP Phosphate Buffer (pH 6.8) was prepared.
In vitro release studies:
The in-vitro dissolution studies were performed in a laboratory model by simulating conditions such as to show and predict release profiles and characteristics of the compositions of Example 1 to 5. They were performed on a Lab India dissolution apparatus (DISSO 2000) and 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 samples were analyzed using a double beam spectrometer (Shimadzu 1601). The absorption maximum in pH 1.2 and pFI 6.8 is 262.5 nm. The corresponding blank were
used as reference. The amount of drug (Nicorandil or venlafaxine HCl) was calculated using the regression line equation for the standard curves. Plots were drawn between the amount of drug released and time for all the compositions.
Table 1: Release profile of different batches of Multi-layered tablets-

(Table Removed)
As shown in the above table, the following different batches were analysed:
VXG BATCH-50J5.100 & 125 are amount of Cetyl alcohol in mg on upper and lower layer and (XG) denotes Xanthum gum (GG) denotes Guar gum batch.
VXM BATCH-Combination of Xanthum gum and MCC,where as ratio in bracket denotes XG ratio to MCC.
VXG (100) optimized for Cetyl layer then VXM-1 (14:1) is final optimized composition. A comparison of the release profiles of various compositions is shown as graphical representation in figure 1 & 2. As shown in figure 1, the profile of the composition having l00mg venlafaxine HCl is the best since it exhibits a near flat curve, which is considered advantageous because it depicts a steady release of the drug over a 24-hour period and wherein efficacy is maintained.
Table 2: Regression values of different equations (Table Removed)

Table 2 shows the regression value of compositions prepared with venlafaxine and xanthum gum.
The composition containing 100mg of venlafaxine was found to be the best as the values obtained for zero order kinetics, first order kinetics, Higuchi equation and Koser Meyer equation are nearly the same and represent a substantially straight line which is indicative of sustained release of the drug. The release kinetics of the composition containing venlafaxine, xanthum gum and micro-crystalline cellulose is shown in table 3. The regression values shown in this table also indicate that the composition containing drug:excipient in the ratio 1:2 show best results.
In table 4, the release profile of the formulation containing venlafaxine, xanthum gum and micro-crystalline cellulose is shown. It is evident from the average release profile that the drug is released at a constant rate from the composition. The results have been repeated three times which shows that they are reproducible. It also indicates that there was no initial burst of the drug and the drug has been released in a sustained manner from the composition. The release profile of this composition is captured in the graph in figure 2 wherein the cumulative percentage drug released has been plotted on the Y-axis versus the time for the release on X-axis. The curve obtained by so plotting is a substantially straight line without excessive peaks and troughs indicating that the composition releases the drug over a period of over 24 hours at a constant rate.
Table 3: (Table Removed)

Table 4: Optimised formulation VXM-1 Three Batches of VXM-1
(Table Removed)
Stability Analysis:
The tablets from the selected batch were kept at 30° C/ 65% RH sand 40° C/ 75% RH for a period of 3 months. The temperature and humidity were attained by keeping a supersaturated solution of Sodium Chloride in the well of a descicator. The formulation were packed and kept in the descicator. The desiccators were placed in an incubator. The stability samples were subjected to in vitro analysis, FTIR, DSC and SEM. The release profile is shown in figure 3.
As shown in figure 3, the cumulative percentage drug release of various compositions containing nicorandil has been plotted against the time for release of the drug. Series 1 represents the composition of the invention whereas series 2-5 represent the compositions available in the market. The composition of series 2-5 show an initial burst wherein the drug is released within first 4 hours of administration. However, in case of series 1, there is no initial burst and the drug is released at a steady rate over a period of 24 hours.
The matrix tablets were formulated using a combination of Drug, Stearyl alcohol and Xanthum gum (Al), Drug, Stearyl alcohol and Guar gum (A2), Drug, Stearyl alcohol and carbopol (A3), Drug, Stearyl alcohol and HEC (A4), Drug, Stearyl alcohol and HPMC (A5) with granulating agent. The physico chemical evaluation of the batches showed tablet to be smooth and uniform. For formulations Al, A2, A3, A4 and A5, average hardness was found to be 6.52 ± 0.16, 6.38+0.18, 6,43±0.54,6.41±0.44 and 6.35±0.35 kg/cm2 respectively. Average weight was found to be 147.9 ± 0.57, 148.4 ± 0.48, 146.8 + 1.03, 148.5 + 0.67 and 152.4+0.58 mg respectively while the average drug content was 14.81 ± 0.06, 14.98 + 0.18, 15.05 + 0.07, 15.0±0.16 & 15.04 ± 0.12 mg respectively. Tablets showed thickness of 3.74 ± 0.07, 3.68 ± 0.16, 3.84 ± 0.14,3.84+0.06 & 3.72 ± 0.11 mm respectively.
In vitro dissolution profile of matrix tablets showed that formulation Al releases 20 % of drug at 2 hours, 6mins, 50% of the drug at 7 hours, 21 mins, 80 % of the drug in 18 hours, 16 mins, 85 % of the drug in 20 hours, 12 mins and released 98.57 % of the d rug at the end of 24 hours. A2 releases 20% of the drug at 36 mins, 50 % of the drug at 2 hours, 22 mins, 80 % of the drug at 4 hours, 3 mins, 85 % of the drug in 5 hours, 1 mins and 99.57 % of drug at the end of 24 hours. A3 released 20% of the drug in 46 mins, 50 % of the
drug at 2 hours, 31 mins, 80% of the drug at 4 hours, 7 mins, 85 % of the drug at 5 hours, min and released 100.24% of the drug at the end of 24 hours. A4 releases 20 % of the drug in 37 mins, 50 % of the drug at 1 hour, 54 mins, 80 % of the drug in 4 hour, 5 mins, 85 % of the drug in 4 hour, 41 mins and released 99.74 % of the drug at the end of 24 hours. A5 releases 20 % of the drug in 49 mins, 50 % of the drug at 1 hour, 39 mins, 80 % of the drug in 3 hour, 11 mins, 85 % of the drug in 3 hour, 47 mins and released 100.23 % of the drug at the end of 24 hours.
This in vitro dissolution profile showed that stearyl alcohol sustains the release of Nicorandil when used in combination with xanthum gum.
In vitro dissolution profile of marketed formulation of Nicorandil showed that Nicorandil released 20% of the drug at 20 mins, 50 % of the drug at 51 mins, 80 % of the drug at 2 hour, 15 mins, 85 % of the drug in 2 hours, 31 mins and 104.97 % of drug at 24 hour. This is shown in figure 4.
Figure 4 is a graphical representation comparing the percentage cumulative release of a market formulation of nicorandil (nicoran) versus the composition of the invention (Al). The percentage cumulative release of the drug has been plotted against the time taken for release of the drug. It is evident from this graph that in case of the market formulation there is an initial burst and release of the drug within about 2-4 hours from the time of administration, and thereafter the desired or optimum amount of the drug in plotted area is not maintained, whereas in case of the composition of the invention, the drug is released at a constant rate for a period of beyond 24 hours, without any initial burst.
Example 8: In Vivo Evaluation:
Based on in vitro performance, the selected formulations were evaluated in Rabbits to compare the blood level profiles of the formulations with profiles obtained after oral administered of an aqueous solution of the drug in Rabbits. Rabbits of 2.0-2.5 kg of either sex were kept in normal housing conditions and were fed with commercially available diet, sprouted grams and cabbage.
Rabbits were starved for 24 hours before the administration of the sample. Two groups were formed each containing six animals. First group was given the matrix tablets;
Second group was given the aqueous drug solution. Blood samples were withdrawn from «the marginal 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. Nicorandil was analyzed by HPTLC.The pharmacokinetic profile of the formulation was compared to that of the drug solution administered orally.
The in vivo release profile of the selected formulations and aqueous drug solution were compared, Figure 5 shows comparative in vivo release profile of Al, and aqueous drug solution in rabbits. The Cmax for the drug solution (the maximum concentration of the drug achieved in the blood after administration of a dose), Al was calculated out to be 99.65 ng/µl, 100.50 respectively. The Tmax (time taken for maximum concentration of the drug to be transferred to the blood) of the drug solution as well as Al was reached in 24 hours. The AUC for the drug solution and matrix tablet was calculated to be 3132.25 and 2727.29 respectively. The formulation Al was found to sustain the drug concentration in the blood for 24 hours in rabbit. This is shown in Figure 5.
The analysis of variance calculations for comparison of in vivo drug release profile of formulation Al vs. Aqueous drug solution resulted in "F(1,15)" value of 0.494026 as compared to the corresponding tabulated "F(0.o5)" value equal to 4.54 as seen in "F table". The calculated value of "F(1,15)" is less than the tabulated value of "F(1,15)" for P = 0.05, therefore there is no statistical significance in the in vivo drug release profile of formulation Al vs. an equivalent dose of the drug given in the form of Aqueous drug solution after every eight hours interval.
ADVANTAGES:
1. The upper and lower layer of composition protects drug from direct contact with atmosphere. Composing is stabilized.
2. Stearyl alcohol in upper and lower layer also controls hydrogel formation of Xanthum gum, thereby making the composition sustained release type.
3. Multilayered tablet releases drug in a controlled manner for a prolonged period (upto 24 hours).
4. Obviates need to consume drug at frequent intervals.
5. The formulation releases 20 % of drug at 2 hours, 6mins, 50% of the drug at 7 hours, 21 mins, 80 % of the drug in 18 hours, 16 mins and 85 % of the drug in 20 hours, 12 mins.
6. The formulation also remains stable at 25°C/60% RH for six months.
7. Cmax of 90.08ng/µl can be obtained after 24 hrs of administration of formulation in rabbit.
8. AUC value in rabbit (2727.29 ng-hr /µl) shows that a single multilayered formulation can replace three doses of conventional tablet.
Aim of the present study was to formulate multi layered matrix tablet formulation of water soluble drugs like Venlafaxine HCL and Nicorandil. Venlafaxine HCL an antidepressant drug. Venlafaxine is a phenethylamine bicyclic antidepressant. The initial recommended dosage of regular-release venlafaxine is 75 milligrams (mg)/day; the dose may be titrated at 4-day intervals to a maximum dose of 375 mg/day. For depression and generalized anxiety disorder, the initial dosage of venlafaxine XR is 75 mg/day; the maximum recommended dose is 225 mg/day. Symptomatic improvement of depression occurs at about 2 weeks. The sustain effect from the tablet was desired such that only once a day dose is required thus increasing patient compliance and reducing the cost of treatment. Thus its pharmacokinetic parameters and mode of use make Venlafaxine an ideal candidate for the preparation of sustained release dosage form.




WE CLAIM:
1. A sustained release multi-layered tablet composition comprising:
a) a top layer comprising a higher alcohol selected from a stearyl alcohol, cetyl alcohol in an amount ranging from 50 mg to 125 mg by weight;
b) a middle or core layer comprising an unstable drug selected from nicorandil or venlafaxine HC1 in combination with an agent selected from xanthum gum, guar gum karaya gum, tragacanth gum, pectin gum, Carbopol, Cellulose derivative or combination thereof, optionally along with pharmaceutically acceptable excipient or carrier; wherein the drug and the total amount of agent in the middle layer are present in ratio of 1:1 to 1:10; and,
c) a bottom layer comprising a higher alcohol selected from a stearyl alcohol, cetyl alcohol in an amount ranging from 50 mg to 125 mg by weight;
2. The composition as claimed in claim 1, wherein the amount of the drug is 15 mg to
75 mg by weight.
3. The composition as claimed in claim 1, wherein the total amount of the agent in
the middle layer is in range of 50 mg to 300 mg, preferably 75 mg to 250 mg.
4. The composition as claimed in claim 1, wherein the agent in the middle layer is the
combination of Xanthum gum and Microcrystalline Cellulose in the ratio of 05:1 to
14:1.
5. The composition as claimed in claim 1, wherein the higher alcohol in upper or bottom layer is preferably cetyl alcohol.
6. The composition as claimed in claim 1, wherein the preferred agent in middle layer is xanthum gum, guar gum, Carbopol or cellulose derivative such as Hydroxy Ethyl Cellulose, Hydroxy Propyl Methyl Cellulose, Microcrystalline Cellulose or combination thereof.
7. A method for preparation of the composition as claimed in claim 1,
comprising the steps of:
a) mixing a drug selected from nicorandil or venlafaxine HC1 in ratio of 1:1 to
1:10 with a agent selected from xanthum gum, guar gum karaya gum,
tragacanth gum, pectin gum, Carbopol and cellulose derivative and preparing
granules thereof;
b) preparing a first top layer and a bottom layer comprising at least 50 mg (by weight of composition) of a saturated alcohol selected from stearyl alcohol or cetyl alcohol;
c) pouring the top layer into a die followed by the granules of step (a) and the bottom layer; and,
d) compressing the layers to obtain a three-layered tablet.
8. A composition and a method for preparing drug delivery system substantially
as herein described with reference to the accompanying examples and drawings.



Documents:

2426-DEL-2005-Abstract-(15-10-2010).pdf

2426-del-2005-abstract.pdf

2426-del-2005-claims (29-07-2011).pdf

2426-DEL-2005-Claims-(15-10-2010).pdf

2426-del-2005-claims.pdf

2426-del-2005-Correspondence (Others)- (23-05-2011).pdf

2426-del-2005-correspondence-others (29-07-2011).pdf

2426-del-2005-Correspondence-Others-(06-04-2011).pdf

2426-DEL-2005-Correspondence-Others-(15-10-2010).pdf

2426-del-2005-correspondence-others.pdf

2426-DEL-2005-Description (Complete)-(15-10-2010).pdf

2426-del-2005-description (complete).pdf

2426-DEL-2005-Drawings-(15-10-2010).pdf

2426-del-2005-drawings.pdf

2426-DEL-2005-Form-1-(15-10-2010).pdf

2426-del-2005-form-1.pdf

2426-DEL-2005-Form-2-(15-10-2010).pdf

2426-del-2005-form-2.pdf

2426-DEL-2005-Form-3-(15-10-2010).pdf

2426-del-2005-form-3.pdf

2426-del-2005-form-5.pdf

2426-del-2005-form-9.pdf

2426-DEL-2005-GPA-(15-10-2010).pdf


Patent Number 248802
Indian Patent Application Number 2426/DEL/2005
PG Journal Number 35/2011
Publication Date 02-Sep-2011
Grant Date 25-Aug-2011
Date of Filing 09-Sep-2005
Name of Patentee DELHI INSTITUTE OF PHARMACEUTICAL SCIENCES & RESEARCH
Applicant Address PUSHP VIHAR MB ROAD, NEW DELHI 110 017, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 DIPANKAR KARMAKAR PUSHP VIHAR MB ROAD, NEW DELHI 110 017, INDIA.
2 AMRISH TIWARI PUSHP VIHAR MB ROAD, NEW DELHI 110 017, INDIA.
3 MAMTA ARORA PUSHP VIHAR MB ROAD, NEW DELHI 110 017, INDIA.
4 SHAN SUNDER AGRAWAL PUSHP VIHAR MB ROAD, NEW DELHI 110 017, INDIA.
PCT International Classification Number A61K 9/30
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA