FIELD OF THE INVENTION
This invention relates to Formulation and In Vitro Evaluation of Bilayer Tablet of Olmesartan For Biphasic Drug Release.
BACKGROUND OF THE INVENTION
US 2012/0184750 A1 provides an improved process for the preparation of olmesartan medoxomil, which is free of OLM acid and has lower amount of eliminate and acetic acid impurity.
Research Gap: The process of the manufacturing of this bilayer tablet is very easy to apply as well as satisfied also. And the tabt contains the bilayer of the same drug i.e. Olmesartan which contains the immediate as well as sustained release layer of drug.
CN107998097A discloses a kind of tablet containing olmesartan medoxomil and preparation method thereof, which is made of olmesartan medoxomil, disintegrant, filler, diluent, antiplastering aid and lubricant.The present invention mixed 30 mesh sieves with antiplastering aid by handling olmesartan medoxomil air-flow crushing, then direct tablet compressing after being mixed with other pharmaceutic adjuvants.Film coating is carried out to label after tabletting, film coating pre-mix dose is made of following material:Hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol.Olmesartan medoxomil tablet provided by the invention, dissolution rate in vitro is high, bioavilability is high, stability and mechanical strength are good, peculiar smell is few, without sticking and the big production of proper scaleization.
Research Gap: The bilayer tablet contains the same drug in both layer i.e Olmesartan and Materials used in research work were procured from the various sources. Olmesartan medoxomil, HPMCK4M, Xanthan gum, MCC and Lactose Other excipients such as magnesium stearate, Talc, etc. In the current investigation, a single station compression machine was used to manually manufacture a bilayer tablet weighing 300 mg. Manually fed into the die cavity were measured quantity of the SR powder combination.
After carefully weighing the IR powder combination, it was carefully fed into the die on the SR layer and compacted using 9 mm round punches at a gentle compression force (2-3 kg/cm2). Since the sustained release layer has a white hue and the immediate release layer of the bilayer tablet has a pink colour, the layers were distinguished based on colour. Different formulations were created to achieve the required drug release from the SR layer and IR layer.
EP2883539A1 says that the present invention relates to pharmaceutical combination comprising olmesartan medoxomil, amlodipine or a pharmaceutically acceptable salt thereof and erythritol together with one or more pharmaceutically acceptable excipients. Particularly, the formulation comprises crospovidone as a disintegrant.
Research Gap: The bilayer tablet of Olmesartan for biphasic drug release were prepared by using Olmesartan medoxomil, HPMCK4M, Xanthan gum, MCC and Lactose Other excipients such as magnesium stearate, Talc, etc. all the materials are suitable for the preparation. The weight of the tablet is very low as well as handling of the procedure is very easy. In the current investigation, a single station compression machine was used to manually manufacture a bilayer tablet weighing 300 mg. Manually fed into the die cavity were measured quantity of the SR powder combination.
After carefully weighing the IR powder combination, it was carefully fed into the die on the SR layer and compacted using 9 mm round punches at a gentle compression force (2-3 kg/cm2). Since the sustained release layer has a white hue and the immediate release layer of the bilayer tablet has a pink colour, the layers were distinguished based on colour. Different formulations were created to achieve the required drug release from the SR layer and IR layer.
SUMMARY OF THE INVENTION
1) No bilayaer tablet contain the same drug i.e. Olmesartan in both layer of tablet.
2) The tablet contains both layer i.e sustained release for prolong action as well as immediate release for immediate action.
3) The drug provides immediate relief from acute heart failure and prevent the risk for prolong action also.
4) A non-peptide angiotensin II receptor antagonist called olmesartan medoxomil is used to treat mild to moderate hypertension. This medication has a very low oral bioavailability of just approximately 26%, is mildly basic, and is lipophilic. The best antihypertensive activity is produced by olmesartan medoxomil because it inhibits the type II Angiotensin receptor in the renin-angiotensin system.
5) The patient compliance when the drug has been used in a sustained release dosage form rather than conventional tablets and immediate release dosage form for the chronic patient of hypertension and angina pectoris.
6) The weight of the sustained release layer in this tablet is only 15mg which is lower than the available tablets in market.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1. Olmesartan for biphasic drug release were prepared successfully
Fig. 2. Precompression parameters of immediate release layer of the tablet
Fig. 3. Precompression parameters of sustained release layer of the bilayer tablet
Fig. 4. Copatibility study Graph I
Fig. 5. Copatibility study Graph II
DETAILED DESCRIPTION OF THE INVENTION
1. Design and characterisation of oral Olmesartan tablets for sustained and immediate release are the focus of this research, in order to offer prompt relief as well sustained relief of High Blood Pressure.
2. The preferred medicine delivery method is oral administration. It is because this method has many benefits, including easy dosing, patient compliance, and formulation versatility. Because of the brief stomach retention time, oral medication absorption is frequently restricted. Humans have a stomach retention period of 3–4 hours.
3. Retention of the drug delivery mechanism in the stomach lengthens GI transit time overall, improving the bioavailability of the medicines. The short GI transit time, uncertain gastric emptying rate, and the fact that some medications have an absorption barrier in the stomach and duodenum are some of the issues with the oral route, though.
4. Olmesartan's bilayer tablet effect was consistently stronger than its matrix tablet effect. Using instant release dose, the medication can be released from the therapeutically effective level in a short amount of time, allowing for the treatment of high blood pressure.
5. The therapeutically effective concentration can be retained for a longer period of time with sustained release dosage form than with standard dose form. The incidence of local and systemic side effects can be decreased with a sustained release dose form. When multiple medications have varied release profiles, bilayer tablets are preferred.
6. A non-peptide angiotensin II receptor antagonist called olmesartan medoxomil is used to treat mild to moderate hypertension. This medication has a very low oral bioavailability of just approximately 26%, is mildly basic, and is lipophilic. The best antihypertensive activity is produced by olmesartan medoxomil because it inhibits the type II Angiotensin receptor in the renin-angiotensin system.
7. In between 30 to 50 percent of patients, hypertension is not properly controlled by normal doses of any one antihypertensive medication. olmesartan has a 6-7 hour half-life, making it a good option for a long-term drug release system. Bilayer tablets can be used to segregate two incompatible substances, release two medications sequentially in combination, and create sustained release tablets where the first layer is an immediate release starting dose and the second layer is a maintenance dose. Rapidly delivering instant medication levels is the goal of immediate release drug delivery devices.
8. For medications with lengthy biological half-lives, high bioavailability, lesser clearance, and shorter elimination half-lives, immediate release drug delivery is preferred. However, the primary requirement for an immediate release dosage form is a drug's poor solubility and the requirement for an early response to address an undesirable defect or condition
9. . In the current instance, 5 mg of Olmesartan must be released right away, and the remaining 10 mg of Olmesartan must be released gradually in order to maintain the therapeutic concentration. In order to adjust the release pattern of the Olmesartan sustained release tablet in accordance with the needs of therapy and IP guidelines, biphasic release with varying ratios of super disintegrant in the immediate release layer and rate retarding polymer in the sustained release layer was prepared.
10. One layer of the bilayer tablet was made with super disintegrant for instant drug release, and the second layer was made with a different polymer in a different ratio for sustained release. For chronic hypertension patients, the patient compliance is higher when the medication is administered in a sustained release dosage form as opposed to traditional tablets and an instant release dosage form.
1. Materials And Methods
1.1 Material
Materials used in research work were procured from the various sources. Olmesartan medoxomil was a gift sample from Ltd, Dehradun, India. HPMCK4M, Xanthan gum, MCC and Lactose were procured from Loba Chemie Pvt.Ltd, Mumbai. Other excipients such as magnesium stearate, Talc were procured from S.D. Fine Chem. Ltd., Mumbai.
2.2 Method
2.2.1 Procedure for immediate release layer of tablet:
The formula shown in table 1 was used to create immediate release tablets. Microcrystalline cellulose was combined and the direct compression method was used. Each component was precisely weighed before being put through a sieve with a mesh size of # 80. Talc was added after the medication and polymer had been well combined for 15 minutes using a mortar and pestle. These components were properly combined before the powder mixture was run using sieve size # 44, Sifted via filter number 44 with the diluent immediately compressible lactose was microcrystalline cellulose. Disintegrants sodium starch glycolate and sifted medication were combined completely. The diluent immediately compressible lactose was microcrystalline cellulose. Disintegrants sodium starch glycolate and sifted medication were combined completely. The resulting powder mixture was assessed for a number of factors, including bulk density, true density, angle of repose, compressibility index, Hausner's ratio, and drying loss. Then, using a rotational compression machine and magnesium stearate as lubricant, this mixture was compressed.
2.2.2 Procedure for sustained release layer of tablet:
The Direct Compression process was used to create the Olmesartan Medoxomil Sustained release Tablets. Table 2 displays the chemical composition of each tablet. All ingredients needed for the formulation were gathered, precisely weighed, and put through sieve no. 40. They were thoroughly blended for 10 to 15 minutes in a plastic bag or triturate. Magnesium stearate was mixed to the powder mixture, which was then combined again for 4–5 minutes. The mixture was then compressed using a rotary tablet compressor. Both official standards and unofficial tests were used to evaluate tablets. The containers used to package the tablets were airtight and moisture proof.
2.2.3 Formation of Bilayer Tablet:
In the current investigation, a single station compression machine was used to manually manufacture a bilayer tablet weighing 300 mg. Manually fed into the die cavity were measured quantity of the SR powder combination.
After carefully weighing the IR powder combination, it was carefully fed into the die on the SR layer and compacted using 9 mm round punches at a gentle compression force (2-3 kg/cm2). Since the sustained release layer has a white hue and the immediate release layer of the bilayer tablet has a pink colour, the layers were distinguished based on colour. Different formulations were created to achieve the required drug release from the SR layer and IR layer.
3.Evaluation of Powder Blend
3.1 Partical size distribution
Vibration sieve equipment was used to measure the particle size distribution using the sieving method. The coarsest sieve of a sieve stack made up of six sieves with progressively smaller apertures was loaded with powder, and the stack as a whole was mechanically vibrated. The particles are thought to be kept on the sieve mesh after 10 minutes; the mixture retained in the sieves was then weighed, and the corresponding parameters were determined.
3.2 Active-excipient interaction study
By employing an FTIR and IR spectroscopy, the medication, polymer, and other formulation constituents were identified. The KBr discs method was used to capture the spectra.
3.3 Bulk Density
It is the proportion of powder mass to bulk volume. The particle size distribution, shape, and cohesiveness all affect the bulk density. Initial bulk volume was measured after a precisely weighed quantity of granules was carefully poured into a graduated measuring cylinder through a big funnel. It is determined by the formula and is stated in gm/ml.
Bulk density = Vo/M
Where,
M is mass of the powder
Vo is bulk volume of the powder.
3.4 Tapped Density
A 100 ml measuring cylinder that was clean and dry was filled with powder. Following that, the cylinder was struck 100 times from a fixed height, and the tapped volume was recorded. It is provided by and stated in gm/ml.
Tapped Density = M/Vt
Where,
M is the mass of powder
Vt is the final tapping volume of powder.
3.5 Angle of repose
It is described as the greatest angle that can be formed between the powder pile's surface and the horizontal. It was done with a fixed funnel. A graph paper was laid on a level horizontal plane surface to which a funnel was fixed with the tip at a specific height, h.
The conical pile's peak was slowly poured through a funnel until it touched the funnel's tip. The following equation was used to compute the angle of repose.
Angle of repose = tan Ø=1(h/r)
where,
h is the height of pile
r is the radius of the pile.
3.6 Compressibility Index (carr’s index)
Compressibility index is a crucial measure used to assess how the powder will flow. It is inextricably linked to cohesion, particle size, and relative flow property rate. It is an easy, quick, and well-liked technique for predicting flow properties. Equation can be used to represent Carr's index as follows below.
Carr’s index (%) = tapped Density- Bulk Density/Tapped Density *100
3.7 Hausner’s Ratio
In order to forecast the flowability of the powders, one uses Hausner's ratio. Comparable to the compressibility index is this approach. Equation can be used to represent Hausner's ratio as follows below.
Hausner’s ratio = Tapped density/Bulk Density
4 Evaluation Studies for Tablet
The thickness, hardness, friability, weight variation, disintegration time, medication content, and in vitro dissolution studies were all analyzed for each tablet.
Dimensional Analysis
Using a vernier calliper, the tablets' diameter and thickness were measured. Average values were computed using 20 pills from each batch.
4.1 Weight variation
Twenty randomly chosen tablets from each formulation were weighed in a single weighing balance both individually and collectively. The standard deviation was computed after noting the average weight. If no more than two tablets deviate by more than the permitted percentage and no two tablets differ by more than twice the permitted percentage, the tablets are passed.
4.2 Hardness testing
The hardness of the tablet was assessed using the Monsanto hardness tester. The tablet was kept in place by the moving jaw and fixed jaw. The load was steadily increased until the tablet shattered when the scale was set to zero. The amount of force there provides a measurement of the tablet's hardness. The measurement is in kg/cm2. Six pills from each recipe were tested for hardness, and an average value was computed.
4.3 Tablet Disintegration test
To make sure that the medication substance is completely available for dissolving and absorption from the gastrointestinal tract, disintegration is assessed. At room temperature (37°C), distilled water was used in a disintegration test utilising a tablet disintegration test instrument.
4.4 Friability test
Twenty samples of tablet were carefully weighed and put in the friabilator (Roche friabilator). Loose dust was removed from the tablets after the allotted time (4 minutes at 25 rpm). Tablets were finally weighed. The weight reduction demonstrates the tablets' resistance to this kind of wear. After then, the% friability was determined by
[(Wavg – Winitial) / (Wavg)] x 100
Result And Discussion
The bilayer tablet of Olmesartan for biphasic drug release were prepared successfully.
Formulation Code SR1

0.4
3.4
0.8
0.8
0.8
0.8
0.8
0.12
0.08 SR2

0.4
3.4
1.2
0.4
0.8
0.8
0.8
0.12
0.08 SR3

0.4
3.4
0.4
1.2
0.8
0.8
0.8
0.12
0.08
Ingredients (g)
Olmesartan
Lactose
Carbopol
HPMCK 15
Xanthan
Guar Gum
Acecia
Mg. Stearate
Talc
Combination of Sustained release layer
Formulation Code IR1

0.2
1.2
1.2
1.2
0.04
0.08
0.08 IR2

0.2
1.2
1.6
0.8
0.04
0.08
0.08 IR3

0.2
1.2
0.8
1.6
0.04
0.08
0.08
Ingredients (g)
Olmesartan
Lactose
MCC
SSG
Ferric Oxid Red
Mg
Talc
Combination of Immediate release layer

Precompression parameters of immediate release layer of the tablet:
The angle of repose, bulk density, tapped density, Hausner's ratio (HR), and compressibility index of the Olmesartan rapid release layer were all assessed. The bulk density was discovered to be between 0.571 to 0.578g/cm3, the density when tapped ranged from 0.591 to 0.595g/cm3. Angles of repose ranged between 0.536 to 0.71. The compressibility index fell between 2.94 % to 6.11%. The HR fell between the 1.02 to 1.06 range depicted in Table no.
Code

IR1
IR2
IR3 Parameter
Bulk density(g/cm3)

0.571 ± 0.02
0.578 ± 0.02
0.572 ± 0.01 Tapped density (g/cm3)

0.591 ± 0.01
0.595 ± 0.03
0.607 ± 0.01 Hausner’s ratio

1.03 ± 0.02
1.02 ± 0.02
1.06 ± 0.01 Compressibility index (%)
3.50 ± 0.05
2.94 ± 0.013
6.11 ± 0.11 Angle of repose

0.536 ± 0.19
0.613 ± 0.16
0.7 ± 0.09
Micromeritic properties of precompression immediate release layer (IR)

Precompression parameters of sustained release layer of the bilayer tablet:
Code

SR1
SR2
SR3 Parameter
Bulk density(g/cm3)

0.431 ± 0.02
0.407 ± 0.02
0.445 ± 0.01 Tapped density (g/cm3)

0.652 ± 0.01
0.593 ± 0.03
0.682 ± 0.01 Hausner’s ratio
1.51 ± 0.02
1.45 ± 0.02
1.53 ± 0.01 Compressibility index (%)
51.27 ± 0.05
45.70 ± 0.013
53.25 ± 0.11 Angle of repose

0.821 ± 0.19
0.714 ± 0.16
0.688 ± 0.09
Micromeritic properties of precompression sustained release layer (SR)

The wet granulation process was used to create the Olmesartan sustained release layer, and the powder's angle of repose, bulk density, tapped density, HR, and carr’s index were all measured. The bulk density found to be between 0.47 to 0.445 g/cm3. The density when tapped ranged from 0.593 to 0.682 g/cm3. Angles of repose ranged between 0.688 to 0.21 The compressibility index fell between 45.70 to 53.25%. The HR was within the range of 1.45 to 1.53, as shown in table no.
Compatibility study
The lack of a chemical interaction between the drug and excipients was confirmed by the FTIR spectrum analysis, which revealed that none of the distinctive peaks of active drug and excipients changed. The following figure shows the FTIR spectra of a medicine that is pure and a drug that has excipients, respectively.
Post compression parameters of the bilayer tablet:
Hardness, friability, weight, and thickness of the bilayer Olmesartan post compression parameter were all assessed. Each formulation's tablet had a hardness in the range of 6 to 10kg/cm2. Friability ranged from.0.05 % to 0.35%. The range of weights for each formulation's tablet ranged from 0.291mg to 0.295 mg, although each tablet stayed within the Indian Pharmacopoeia's weight restrictions. All of the tablets had consistent weights and a small standard variation. All of the pills were found to be 4 mm in thickness.
The range of all tablets' drug content was discovered to be between 92.34% to 97.10%. Evaluations of floating experiments and swelling indices for sustained release were made. The swelling index of each formulation's tablet was discovered to be between 123 to 155%. The floating lag time was discovered to be between. min. and. min. All tablets' floating times were discovered to be h. The yield percentage was discovered in the 82 to 86% parameter range reported in Table no.

Formulation
Code
F1
F2
F3 Hardness
(kg/cm2)

6 -9
7-10
8-10 Friability
(%w/w)

0.28 +0.06
0.05 + 0.02
035 + 0.04 Weight
Variation (mg)
0.291
0.312
0.295 Thickness
(mm)

4
4
4 Drug
Content (%)

95.20
97.10
92.34 Swelling
Index (%)
142.43
123.41
155.70 Percentage yield (%)

82
86
84
Evaluation of Olmesartan tablets

ADVANTAGES OF THE INVENTION:
1. Olmesartan medoxomil is a prodrug that is hydrolyzed during absorption and is a selective AT1 Subtype angiotensin II receptor antagonist.
2. Oral absorption of drugs is often limited due to short gastric retention time.
3. The retention of drug delivery system in the stomach prolongs overall gastrointestinal (GI) transit time, thereby resulting in improved bioavailability drugs.
4. The bilayer tablet effect of olmesartan was always greater than the matrix tablet.
5. Using immediate release dosage disintegrates rapidly and get dissolved to release the medicaments form the therapeutically effective concentration can be maintained for a shorter time and controlled the high blood pressure
6. Using sustained release dosage form the therapeutically effective concentration can be maintained for a longer time than the conventional dosage form.
7. The patient compliance when the drug has been used in a sustained release dosage form rather than conventional tablets and immediate release dosage form for the chronic patient of hypertension and angina pectoris.
8. A non-peptide angiotensin II receptor antagonist called olmesartan medoxomil is used to treat mild to moderate hypertension. This medication has a very low oral bioavailability of just approximately 26%, is mildly basic, and is lipophilic. The best antihypertensive activity is produced by olmesartan medoxomil because it inhibits the type II Angiotensin receptor in the renin-angiotensin system.
9. The drug is patients compliance.
10. This drug is cost effective.
11. This bilayer tablet of Olmesartan will be able to privent the patients from acute heart failure.
12. This drug contain olemsartan in both layer i.e immediate release for immediate or emergency conditions as well as sustsined release for the prolong action the prolong layer will show their action under 12hrs and the immediate release layer will show under only 15 min so, this tablet will be very effective for the patients suffering from hypertension.
13. The weight of the tablet is very low hence the loading as well as the maintenance of the table is very compatible.
14. the weight of the sustained release layer is only 15mg for a single tablet and 5mg for immediate release layer of the bilayer tablet.
15. There is no bilayer drug is available of Olmesartan which contains the same drug in the both layers, this drug contains Olmesartan in both layers.
16. The drug provides immediate relief from acute heart failure and prevent the risk for prolong action also.

We Claims:

1. A formulation of Bilayer Tablet of Olmesartan For Biphasic Drug Release comprises olemsartan in both layer immediate release for immediate or emergency conditions as well as sustained release for the prolong action the prolong layer shows their action under 12hrs and the immediate release layer shows under only 15 min so, this tablet is effective for the patients suffering from hypertension.
2. The formulation as claimed in claim 1, wherein weight of the sustained release layer is only 15mg for a single tablet and 5mg for immediate release layer of the bilayer tablet.
3. The formulation as claimed in claim 1, wherein Microcrystalline cellulose was combined and the direct compression method was used; and Each component was precisely weighed before being put through a sieve with a mesh size of # 80.
4. The formulation as claimed in claim 1, wherein Talc was added after the medication and polymer had been well combined for 15 minutes using a mortar and pestle; and these components were properly combined before the powder mixture was run using sieve size # 44, Sifted via filter number 44 with the diluent immediately compressible lactose was microcrystalline cellulose.
5. The formulation as claimed in claim 1, wherein Disintegrates sodium starch glycolate and sifted medication were combined completely; and the diluent immediately compressible lactose was microcrystalline cellulose; and Disintegrates sodium starch glycolate and sifted medication were combined completely.
6. The formulation as claimed in claim 1, wherein the resulting powder mixture was assessed for a number of factors, including bulk density, true density, angle of repose, compressibility index, Hausner's ratio, and drying loss; then, using a rotational compression machine and magnesium stearate as lubricant, this mixture was compressed.
7. The formulation as claimed in claim 1, wherein the steps involved in procedure for sustained release layer of tablet the Direct Compression process was used to create the Olmesartan Medoxomil Sustained release Tablets; wherein the chemical composition of each tablet; and all ingredients needed for the formulation are gathered, precisely weighed, and put through sieve no. 40; and are thoroughly blended for 10 to 15 minutes in a plastic bag or triturate; and Magnesium stearate was mixed to the powder mixture, which was then combined again for 4–5 minutes.
8. The formulation as claimed in claim 1, wherein the mixture is then compressed using a rotary tablet compressor; and Both official standards and unofficial tests were used to evaluate tablets; and the containers used to package the tablets were airtight and moisture proof.
9. The formulation as claimed in claim 1, wherein the steps involved in Formation of Bilayer Tablet: In the current investigation, a single station compression machine was used to manually manufacture a bilayer tablet weighing 300 mg; and Manually fed into the die cavity were measured quantity of the SR powder combination; and after carefully weighing the IR powder combination, it was carefully fed into the die on the SR layer and compacted using 9 mm round punches at a gentle compression force (2-3 kg/cm2); and the sustained release layer has a white hue and the immediate release layer of the bilayer tablet has a pink colour, the layers were distinguished based on colour.