AU2021105584A4

AU2021105584A4 - Fabrication and Evaluation of Gastro Retentive Tablet of Trandolapril in Treatment of Essential Hypertension

Info

Publication number: AU2021105584A4
Application number: AU2021105584A
Authority: AU
Inventors: Prakash Chandra Gupta; Anupriya Kapoor; Shashi Kiran Misra; Nisha Sharma; Anjali Sudha; Mamta Tiwari
Original assignee: Individual
Current assignee: Individual
Priority date: 2021-08-16
Filing date: 2021-08-16
Publication date: 2021-12-02
Anticipated expiration: 2029-08-16

Abstract

: In the present invention we have formulated and evaluated the floating drug delivery system containing Trandolapril, an antihypertensive drug, using different polymers and also optimized the best formulation. Different excipients were tested for the IR compatibility with Trandolapril by the FTIR studies. Present Invention has also demonstrated the successful utilization of technique for FTIR to assess the compatibility of Trandolapril with the excipients used in the development of floating drug delivery system of Trandolapril. Based on the results of FT-IR studies, majority of the excipients were found to be compatible with Trandolapril which were then used in the preparation of Trandolapril floating tablets. Trandolapril tablets were prepared by wet granulation technique using HPMC, HPMC K4M and chitosan as polymers, stearic acid, citric acid, lactose and gas generating agent such as sodium bicarbonate were taken as independent variables. It was then evaluated by using USP II (Paddle) apparatus containing 0.1 N HCl as a dissolution media. The release mechanisms of Trandolapril from floating tablet were evaluated by the n value of KrosmeyerPeppas model. The n value of all formulations except "F4, F5 and F9" ranges from lowest 0.147 to highest 0.496 which is in the range of n = 0.5 which indicate the mechanism of release of Trandolapril is by Fickian diffusion. However, the n value of the F2 and F8 was 0 .6 0 3 and 0. 6 7 2 which is in the range of 0.5 < n< 1 .0 which indicate the mechanism of release of Trandolapril in by non Fickian transport. Then value of the best formulation is above 1.0, which indicated that, the mechanism of release of Trandolapril from the dosage form is followed the zero-order release kinetics. The optimized formula was following the zero-order release kinetics, which meet the condition of controlled drug delivery system. HPMC retarded the drug release as a function of polymer concentration. A combination of sodium bicarbonate and citric acid was found to achieve in vitro buoyancy.

Description

Title of Invention Fabrication and Evaluation of Gastro Retentive tablet of trandolapril in Treatment of Essential Hypertension

Background: Oral route is the most convenient and extensively used route for drug administration. This route has high patient acceptability, primarily due to ease of administration. Oral route of administration has been received more attention in the pharmaceutical field because of more flexibility in the designing of dosage form than drug deliver y design for other routes. Most of the oral controlled drug delivery systems are based on diffusion, dissolution or combination of both mechanisms to release the drug in a controlled manner to the gastrointestinal tract (GIT) and o n t h e drug profile data, such as dose, absorption properties and the quantity of drug needed, to determine the desired release rate of the drug from controlled release dosage form. Drugs that are easily absorbed from the GIT and have short half-lives is eliminated quickly from the blood circulation. To avoid this problem the oral controlled release formulation has been developed, as these will release the drug slowly into the GIT and maintain a constant drug concentration in the serum for a longer period of time. More than % of drug delivery systems available in the market are oral drug delivery systems. These systems have the obvious advantages of ease of administration and patient acceptance. One would always like to have an ideal drug delivery system that possesses two main properties: 1. It will be a single dose for the whole duration of treatment and 2. It will deliver the active drug directly at the site of action. Unfortunately, such ideal systems are not available. Thus, scientists try to develop systems that can be as close to an ideal system as possible. There are certain situations in which gastric retention is not desirable. Aspirin and non-steroidal anti-inflammatory drugs are known to cause gastric lesions and slow release of such drugs in the stomach is unwanted. Thus, drugs that may irritate the stomach lining or are unstable in its acidic environment, should not be formulated in gastro retentive systems. Furthermore, other drugs, such as Isosorbide dinitrate, that are absorbed equally well throughout the GI tract will not benefit from incorporation into a gastric- retention system. Certain types of drugs can benefit from using gastro retentive devices. These include drugs that act locally in the stomach, are primarily absorbed in the stomach, are poorly soluble at an alkaline pH, have a narrow window of absorption and degrade in the colon. The goal of an y drug delivery system is to provide a therapeutic amount of drug to the proper site of the body, to achieve promptly and then maintain the desired therapeutic drug concentration that elicits the pharmacological action and to minimize the incidence and severity of unwanted adverse effects. To achieve this goal, it would be advantageous and more convenient to maintain a dosing frequency to once, or at most, a twice-daily regimen. An appropriately designed extended-release dosage form can be a major advance in this direction. Many attempts have been made to develop sustained -release preparations with extended clinical effects and reduced dosing frequency. In order to develop oral drug deliver y systems, it is necessary to optimize both the release rate of the drug from the system and the residence time of the system within the gastrointestinal tract. The present investigation concerns the development of the floating tablets, which after oral administration are designed to prolong the gastric residence time, increase bioavailability of the drug and diminish the side effects of irritating drugs. To provide good floating behavior in the stomach, the density of the device should be less than that of the gastric contents (1.004 g/cm3).

Summary: In the present invention an attempt has been made to formulate and evaluate a floating drug

delivery system of Trandolapril using different polymers. The basic aim of developing any controlled release formulation is to allow a reduction in dosing frequency as compared to when the drug is present in an immediate release dosage form. These drug products can also be developed to reduce fluctuations in plasma concentrations. The basic goal of the therapy is to achieve a stead y state blood and tissue level that is therapeutically effective and non- toxic for an extended period of time. The main aim of the project was to develop uniform absorption of the drug throughout the GIT for extended period of time. Prior to the experimental work, a detailed literature review was carried on the drug profile, excipients 'literature and previous similar or related work done. At first, Preformulation studies were undertaken and results so obtained directed the further course of the formulation part. In the Preformulation studies standard calibration curve Trandolapril was plotted using Shimadzu-1601 UV-Spectrophotometer at lambda max 222 nm in 0.1 N HCl. The method had a good reproducibility and hence was used in the study. The results of the drug-excipients compatibility studies revealed that there was no chemical interaction between the pure drug and the excipients used. The results of the FTIR Spectrophotometric study showed that IR spectrum of pure Trandolapril matched with each other. Hence there was no chemical interaction between the drug and the excipients used in the optimized formula. Lactose was added to the formulation in dried powder as a diluent to give good flow property to the formulation. During formulation of Trandolapril floating tablets most challenging parameters were adequate hardness, floating properties and controlled drug release. The wet granulation method gives good flow property to granules which is essential in the compression of tablets for their proper hardness and friability. The compressibility index (%) and Hausner ratio of the final granules were found to be 14.30 and 1.167, respectively. The observed values revealed that the granules showed good flow properties which were important for the compression of tablets. Wet granulation method was used for the preparation of Trandolapril floating tablets containing HPMC, HPMC K4M, chitosan, stearic acid, citric acid, lactose and sodium bicarbonate (gas generating agent) alone or in combination. As post compression parameter, the hardness of the optimized formulation was found to be 4.7 kg/cm2. It had good mechanical strength. The friability of the optimized formulation was found to be 0.18% which was acceptable as per USP limit. In all the trial batches sodium bicarbonate was incorporated as a gas generating agent. However, in the optimized formula, 100 mg of sodium bicarbonate and 30 mg citric acid were added in the formulation leading to the floating lag time of 8 min 20 see and the total floating time was found to be more than 22 hr. Citric acid has effect on the total floating time. The addition of gel forming polymer HPMC, HPMC K4M and chitosan and gas generating agent sodium bicarbonate along with citric acid were essential to achieve in vitro buoyancy. The effect of citric acid on drug release profile and floating properties was investigated. All the prepared trial batches showed good in vitro buoyancy. The use of different concentrations of HPMC, HPMC K4M and chitosan retarded the % drug release as a function of polymer concentration. The % drug content of all trial batches were within limit as per IP. The % drug content of the optimized batch was found to be 97.15 0.14. The kinetics of Trandolapril was determined by finding the best fit plot of the dissolution data following distinct models Zero order, first Order, Krosmeyer peppas model, Higuchi model Hixson-Crowell model. The n value of all the formulations except F4, F5 and F9 ranged 0.147 to 0.496 which was in the range of n=0.5 indicating that the mechanism of release of Trandolapril followed Fickian diffusion. However, the n value for the F4 and F5 was 0.603 and 0.672 respectively, which was in the range of n 0.5<n<1.0 indicating the mechanism of release of Trandolapril by non

Fickian transport. The n value of the best formulation was above 1.0, which indicated that the mechanism of release of Trandolapril from the dosage form was following zero order kinetics. The optimized formula followed zero order release kinetics, which met the rule of controlled drug delivery system. Thus, the optimized formula was found to be F4 which gave favorable results. This optimized formulation was evaluated for any drug excipient compatibility study by FTIR spectroscopy. By this study we found that there was no interaction between the drug and the excipients and they were compatible with each other. Stability and in vivo studies can be performed in future for large scale production and commercialization of the Trandolapril floating tablet.

MODES FOR CARRYING OUT THE PREFERRED EMBODIMENTS

The embodiments herein and the various features and advantageous details thereof are

explained more fully with reference to the non-limiting embodiments that are illustrated in

the accompanying drawings and detailed in the following description. Descriptions of well

known components and processing techniques are omitted so as to not unnecessarily obscure

the embodiments herein. The examples used herein are intended merely to facilitate an

understanding of ways in which the embodiments herein may be practiced and to further

enable those of skill in the art to practice the embodiments herein. Accordingly, the examples

should not be construed as limiting the scope of the embodiments herein.

Throughout this specification and the claims which follow, unless the context requires

otherwise, the word "comprise", and variations such as "comprises" and "comprising", will

be understood to imply the inclusion of a stated integer or step or group of integers or steps

but not the exclusion of any other integer or step or group of integers or steps.

As used herein, the singular forms "a", "an", "the" include plural referents unless the context

clearly dictates otherwise. Further, the terms "like", "as such", "for example", "including" are

meant to introduce examples which further clarify more general subject matter, and should be contemplated for the persons skilled in the art to understand the subject matter. Although this invention has been described in conjunction with the exemplary embodiments' below, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, the exemplary embodiments of the invention as set forth above are intended to be illustrative and not limiting. Various changes may be made without departing from the spirit and scope of the invention.

Working (Method of preparation): The formulations were prepared using various steps. The different formulation of Trandolapril floating tablets is given in tablet are given in tablets are given in table 1. In the first 5 formulations all ingredients were mixed together in appropriate proportion and made a dough like mass prepared using water as a granulating media. Granules were prepared by passing the mass through 20# mesh sieve. After that granule were dried in hot air oven at 0C for 2 hr. In the last 3 formulations all the ingredients were mixed, except HPMC. HPMC K4M was added to ethanol and the ethanolic solution was used as a granulating media to prepare the granules. The granules were evaluated for pre-compression parameters. The granules were compressed by tablet punching machine. Finally, the prepared tablets were evaluated according to the official parameters.

Evaluation:

Pre-Compression Parameters Compressibility index: This parameter gives an idea regarding the flow characteristics of powder and granules. It can be determined by the following formula Compressibility index (%)= [Tapped density - Bulk density/ Tapped density] x 100 A value 5-20 shows good / acceptable flow while values above this range indicate poor flow and can be improved by addition of glidant. Hausner ratio: Hausner has defined a similar index and it is calculated by following formula Hausner ratio = Tapped density / Bulk density

Values less than 1.25 indicate good flow, while greater than 1.25 indicates poor flow. For values between 1.25 to 1.5, addition of glidant normally improves the flow. Angle of repose: Angle of repose was calculated by passing granules through a cut funnel. It was determined by the following formula: Tan 0 = 2h/r, where h = height of the granules heap, r = radius of the granules heap made at horizontal plane (average of three readings). It is the maximum angle that can be obtained between the free-standing surface of a powder heap and the horizontal plane. Significance of 0 as an indication of flow properties: When 0 < 20, flow is excellent, o is between 20-30, flow is good, o is between 30-34, powder is passable and o >40, flow is very poor. Loss on drying (LOD) The moisture content of the lubricated granules was analyzed by using Halogen Moisture Analyzer. Approximately one g quantity of blend was heated at 105 0 C until the change in the weight was no more observed by the instrument. The % loss in weight was recorded. % LOD = 100 (Initial Weight - Final Weight) / Initial Weight

Post Compression Parameters After compression the different batches of tablets were evaluated for the following parameters: Hardness: The hardness (expressed in kg / cm) of the tablet was determined using Monsanto hardness tester. Weight variation: Twenty tablets were selected randomly from the lot and weighed individually to check for weight variation. IP limit for weight variation in case of tablets weighing 130 - 324 mg was 7.5 % and for more than 324 mg was± 5%. Friability: Friability was evaluated from the percentage weight loss of 20 tablets tumbled in a friabilator (USP XXIII, Electrolab, model EF2, Mumbai) at 25 rpm for 4 min. The tablets were dedusted and the loss in weight caused by fracture or abrasion was recorded as the percentage weight loss. Friability below 1% wasconsidered acceptable. In vitro floating study: The in vitro floating behavior of the tablets was studied by placing them in 900 ml of plastic containers filled with 500 ml of 0.1 N HCl. (pH 1.237 0.5oC). The floating lag times (time period between placing the tablet in the medium and the floating of the tablet) and floating durations of the tablets were determined by visual observation. In vitro dissolution study: In vitro dissolution of Trandolapril tablets was performed in 0.IN HCl as media under the official condition. The percentage of drug released was determined at an interval of 1 hr. up to 12 hr. Drug Release Kinetics The drug release data obtained for each formulation were fitted into the mathematical model given below in order to determine the drug release kinetics of the prepared formulation: • Cumulative drug release v/s Time (Zero Order kinetics) • Log percent drug remaining to be released v/s Time (First order rate kinetics) • Cumulative percent drug released v/s Root time (Higuchi matrix) • (Cube root of % drug remaining to be released)1/3 v/s Time (Hixson-Crowell erosion equation)

Stability Testing Stability of the formulation may be defined as its ability to retain, within specific limits and throughout its period of storage and use (i.e., the shelf life), the same properties and characteristics that it possessed at the time of its formulation. Stability of the formulation is necessary to determine its fitness for consumption until the end of the shelf life. Two formulations were subjected to stability testing (at ambient humidity conditions (605%) at 4+2 °C and room temperature (252 °C) with (75+5%) relative humidity and at 60+5 °C with ambient humidity 605%) for a period of 1 month. The samples were withdrawn at the interval of 7, 14 and 28 days and were tested for drug content.

Many modifications will be apparent to those skilled in the art without departing from the scope of the present invention as herein before described with reference to the accompanying drawings. The reference in this specification to any prior art publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgement or admission or any form of suggestion that the prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of Endeavour to which this specification relates. The foregoing descriptions of exemplary embodiments of the present disclosure have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the disclosure to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to best explain the principles of the disclosure and its practical application, to thereby enable others skilled in the art to best utilize the disclosure and various embodiments with various modifications as are suited to the particular use contemplated. It is understood that various omissions, substitutions of equivalents are contemplated as circumstance may suggest or render expedient but is intended to cover the application or implementation without departing from the spirit or scope of the claims of the present disclosure.

Claims

Claims: 1. Herein we claim a gastro retentive tablet of Trandolapril in treatment of essential hypertensionhaving better therapeutic success when compared to conventional dosage form of the same drug.
2. The formulation claimed in 1 has decreased cost of therapy as no frequent administration of drug is required.
3. The formulation claimed in 1 has sustained release effect, and has very less fluctuating plasma drug level.
4. The formulation claimed in 1 exhibits better patient compliance and convenience.
5. We also claim the method of preparation through wet granulation method of Trandolapril floating tablets containing HPMC, HPMC K4M, chitosan, stearic acid, citric acid, lactose and sodium bicarbonate (gas generating agent) alone or in combination.