Introduction

Famotidine is a H2 receptor antagonist1. A thiazole ring containing H2 blocker which binds tightly to H2 receptor and exhibit longer duration of action despite elimination2. Famotidine after oral administration has anonset of effect within 1 hr and inhibition of gastric secretion is present for the next 10-12 hrs3. Elimination is by renal and metabolic route. It is therefore important to decrease the dose of the drug for patient with kidney or renal failure^2,3. Famotidine not only decrease both basal, food-stimulated acid secretion by 90% or more but also promote healing of duodenal ulcer^4,5.Many patients find it difficult to swallow tablets and hard gelatin capsules and do not take their medicines as prescribed. The concept of mouth dissolving drug delivery system emerged from the desire to provide patient with more conventional means of taking their medications. Mouth dissolving tablets (MDT)disintegrate and are dissolving rapidly in the saliva without the need of water. Disintegrant play a major role in the disintegration and dissolution of MDT. Super disintegrants provide quick disintegration due to combined effect of swelling and water absorption. Due to swelling of superdisintegrants, the wetted surface of the carrier increases, this promotes the wettability and dispersibility of the system thus enhancing the disintegration and dissolution^6,7.

Materials and methods

Famotidine was obtained from Geltec Labs Ltd., Bangalore, India. Crospovidone and mannitol were procured from Colorcon Pvt. Ltd, Goa, India. SSG were received as gift samples from S.D. Fine-Chem Ltd., Mumbai, India. Magnesium stearate and Talc were obtained from HiMedia Laboratories Pvt. Ltd., Mumbai, India. Isopropyl alcohol was kindly provided by Qualigens Fine Chemicals, Mumbai, India.

Preparation of Famotidine Orodispersible Tablets:

The drug and the excipients were passed through #22-sieve. Weighed amount of drug and excipients except magnesium stearate and talc were mixed in a poly bag by geometric addition method for 20 minutes manually. The blend was then lubricated by further mixing with magnesium stearate and talc (#22-sieve). The mixture blend was subjected for drying to remove the moisture content at 40 to 45ºC, the mixture was blended with sweetener and the powder blend was then compressed on ten-station rotary punching machine using concave faced punches. Concave faced punches measuring 8 mm diameter were used.

 

Table No: 1. Formulation of FamotidineOrodispersible tablets.

INGREDIENTS(mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9
Famotidine	40	40	40	40	40	40	40	40	40
Sodium Starch Glycolate	6	12	18	-	-	-	2.5	5	7.5
Crospovidone	-	-	-	6	12	18	2.5	5	7.5
Microcrystalline Cellulose	35	35	35	35	35	35	35	35	35
Saccharin Sodium	8	8	8	8	8	8	8	8	8
Mannitol	105	99	93	105	99	93	106	101	96
Talc	2	2	2	2	2	2	2	2	2
Magnesium Stearate	4	4	4	4	4	4	4	4	4
IPA	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s
Menthol	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s
Total	200	200	200	200	200	200	200	200	200

Compatibility Studies by FT-IR Studies:

It is one of the most powerful analytical technique for chemical identification of drug^8,9. The pure drug and its formulation were subjected to IR studies. In the present study, the potassium bromide disc (pellet) method was employed.

Evaluation of Granules;

Prior to compression, granules were evaluated for their characteristic parameters, such as Bulk density, tapped density, Carr’s index, Hausner’s ratio and angle of repose¹⁰. The angle of repose was determined by the fixed funnel method. Bulk density, tapped density, Carr’s index and Hausner’s ratio were calculated using tap density apparatus (Electrolab, USP)¹¹.

Evaluation of Tablets:

The prepared tablets were evaluated for uniformity of weight using 20 tablets. Hardness, thickness and friability were measured with Pfizer hardness tester, verniercalliper and Roche friabilator respectively. The results were expressed as mean ± Standard deviation^12-14.

In-vitro Dissolution Study:^15,16

In vitro dissolution studies were carried out using USP dissolution apparatus type II at 50 rpm. The dissolution medium consisted of 900 ml of pH 6.8 phosphate buffer, maintained at 37 ± 0.5°C. 10 ml of the sample was withdrawn at suitable time intervals and immediately replaced with an equal volume of 6.8 pH buffer to maintain the volume constant. The samples were filtered through a 0.45 μm membrane filter, diluted sufficiently and analysed at 265 nm using UV/Visible double-beam spectrophotometer .

Disintegration Time:^17,18

Wetting Time:

            Five circular tissue paper of 10cm diameter were placed in a petridish with a 10cm diameter. 10 ml of simulated saliva pH (phosphate buffer pH 6.8) was poured into the tissue paper placed in the petridish. Few drops of eosin solution were added to the petridish. A tablet was placed carefully on the surface of the tissue paper. The time required for the solution to reach upper surface of the tablet was noted as the wetting time.¹⁹

Water Absorption Ratio:

The weight of the tablet before keeping in the petridish was noted (Wb). Fully wetted tablet from the petridish was taken and reweighed (Wa)²⁰. The water absorption ratio R can be determined according to the followingformula.

R= (Wa – Wb)/Wa x 100

Estimation of Drug Content:

Ten tablets from each formulation were powdered. Thepowder equivalent to 100mg of famotidine was weighedand dissolved in phosphate buffer pH 6.8 in 100mlstandard flasks. From this suitable dilution was preparedand the solution was analyzed at 265nm using UV doublebeam spectrophotometer (Elico SL164) using pH 6.8 as blank²⁰.

Stability Studies:

Stability studies were carried out at 25⁰ C and 40⁰ C for the selected formulation for three months.The selected formulations were packed in amber-colored bottles, which were tightly plugged with cotton and capped. They were then stored at 25⁰ C and 40⁰ C for three months and evaluated for their physical appearance, hardness and in vitro drug release at specified intervals of time²⁰.

RESULTS AND DISCUSSION

      The data obtained from angle of repose for all the formulations were found to be in the range of22.52°and29.32°.  All the formulations shows the angle of repose less than 30°, which reveals good flow property for compression into tablets. Loose bulk density (LBD) and tapped bulk density (TBD) forth blend was performed. The loose bulk density variedfrom0.3738 ± 0.019g/cm3 to0.4276 ± 0.089 g/cm3. The tapped density for the entire formulation blend varied from 0.4837 ± 0.032g/cm3 to 0.4531 ± 0.042 g/cm3.   Hausner’s ratio of entire formulation showed between 1.0907 ± 0.045to 1.2121± 0.082 indicates better flow properties. The results of Carr’s consolidation index or compressibility index(%) for the entire formulation blend drangedfrom12.83 ± 1.83 %to15.54 ± 1.72%. All the formulations show good results which indicate good flow properties. The peaks obtained in the spectra of each sample of drug and excipient correlates with the peaks of drug spectrum.  This indicates that the drug is compatible with the formulation components.  Tablets are in circular, flat shape and white in color.  The directly compressed tablets showed hardness of 2.7 kg/cm² to 3.5 kg/cm². The friability values ranges from 0.42to0.60% .The friability study results were tabulated.

The weight variation for all the formulations was found to be in the range 198.30±1.11 to 200.50 ± 1.71 mg. Allthetabletspassedweightvariationtestastheaveragepercentageweight variation was within 7.5%i.e. in thepharmacopoeiallimits.Themeanthicknesswasalmostuniforminalltheformulationsand values ranged from3.95±0.10mmto4.10±0.12mm.The standard deviation values indicated that all the formulations were within the range. The percentage drug content of the tablets was found to be between 96.92 ± 0.65 to 99.26 ± 0.79 % of Famotidine.  The results were within the range and that indicated content uniformity of drug in all formulations.  The wetting time of formulations were found to be in the range of 40 to79sec. Wetting time was closely related to time of in vitro disintegration. As the concentration of the superdisintegrants increased, wetting time decreased up to optimum concentration of superdisintegrants.  FormulationsF9with super disintegrant Crospovidone and SSG showed least wetting time of 40secs.  Formulations with Crospovidone and SSG have shown least wetting times of all, attributing to the high wicking, swelling and rapid dispersing property.  The formulations shows water absorption ratio in the range 60 ±1.18 to 85 ±1.13. The values of in vitro dispersion time for the formulations prepared were tabulated in table. As the concentration of super disintegrants increased, the in vitro time for dispersion decreased up to optimum concentration. The in vitro dispersion times for the formulations were 25 to 41 sec respectively. The formulation F9has shown the least time for in vitro dispersion i.e. 25 seconds. The in vitro disintegration time of formulations were found to be in the range of 23 ±1.36 to 49 ±2.01 fulfilling the official requirements. Disintegrating study showed that the disintegrating times of the tablets decreased with increase in the concentration of the superdisintegrants SSG and Crospovidone up to optimum concentration.

 DissolutionStudy:

                    From the in vitro dissolution study data, it was found that the drug release increased as the concentration ofsuperdisintegrants increased irrespective of the superdisintegrant employed. The maximum drug release for the directly compressed tablets with superdisintegrants 9% SSG shows 87.16% drug release, 9% CP shows 90.02%, 4.5% of SSG and 4.5% of CP shows maximum drug release of 97.18%.   Stability Studies:

The slight increase in the disintegration time was observed, this may be due to increase in hardness of the tablets during storage. No significant changes in other parameters were observed in the tablets, the formulation was within the acceptable limits.

 

Table No:2 Standard Calibration Curve of Famotidine at 265 nm in pH 6.8 phosphate Buffer

S. No.	Concentration (µg/ml)	Absorbance
1	0	0
2	5	0.1981
3	10	0.3522
4	15	0.5682
5	20	0.7468
6	25	0.9370
7	30	1.1162

 

 

            Figure 1: Standard Calibration  curve of Famotidine in pH 6.8Phosphate Buffer

 

 

Results for pre-compression parameters

 

Table-3 Pre compression parameters of powder blend

 

 

 

 

 

Results for drug polymer interaction studies- FTIR studies:

The peaks obtained in the spectra of each formulation correlates with the peaks of drug spectrum.  This indicates that the drug is compatible with the formulation components. The spectra for all formulations are shown below.

 

Drug-Excipient Interactions Studies by FT-IR:

 

Figure No. 2: IR spectrum of Famotidine

 

Figure No. 3: IR spectrum of Famotidine+ SSG

 Figure No. 4: IR Spectrum of Famotidine+ Crospovidone

 

 

Figure No. 5: IR spectrum of Famotidine + Mannitol

 

 

 

 

 

 

 

 

 

 

 

 

 

           

 

 

 

 

 

 

Batch Code	Hardness* (Kg/cm²)	Friability* (%)	Thickness* (mm)	Weight variation* (mg)
F1	2.8+ 0.18	0.52±0.013	3.97+ 0.14	200.1±0.31
F2	2.9+ 0.17	0.49±0.021	3.89+ 0.08	200.30+ 1.7
F3	3.0+ 0.15	0.60±0.030	3.95+ 0.18	199.5±1.40
F4	2.8+ 0.16	0.57±0.014	3.82+ 0.17	199.7+ 1.5
F5	3.2+ 0.17	0.54±0.027	3.97+ 0.22	199.4±0.28
F6	3.1+ 0.18	0.47±0.052	4.07+ 0.23	198.3+1.11
F7	2.7+ 0.19	0.45±0.011	4.10+ 0.12	199.3±0.45
F8	2.8+ 0.15	0.43±0.013	3.96+ 0.14	200.4+ 0.52
F9	3.5+ 0.14	0.42±0.021	3.95+ 0.10	200.5+ 1.71

 

 

Table No. 4: Interpretation of IR spectrum of pure Famotidine and combination with Polymers

Compound Frequency (cm-1)	ABSORPTION PEAKS (cm-1)
	Actual Frequency	PureDrug	Drug + SSG	Drug + CCS
N-H str	3420-3620	3440.93	3575.16	3596.18
O-H str	3260-3400	3336.66	3300.29	3264.92
C-Hstr	2900-3300	2932.66	2929.40	2917.12
N-H1	2645	-	2152.79	2164.79

 

Table No.6:Post-Compression Parameters of formulations by Direct Compression

INTRODUCTION

Pellets¹: Pellets can be defined as small, free flowing,spherical or semi-spherical solid units, typically from about 0.5 mm to 1.5 mm, and intended usually for oral Administration, manufactured by the agglomerates of fine powders or granules of bulk drugs and Excipients using appropriate processing equipment. Pellets can be prepared by many methods, the compaction and drug-layering being the most widely used to day.glimepride is an antidiabetic drug used in treatment of diabetes mellitus type 1&2.the biological halflife of Glimepride is 5hours. It requires multiple dosing to maintain therapeutic drug sugar blood level so it is best candidate to formulate as modified release dosage form. The present study was to develop a pharmaceutically equivalent stable and quality improved formulation. The active pharmaceutical active  Glimepride was subjected to pre formulation study.which encompasses the “Accelerated drug excipients compatability study” and the results obtained with selected excipients showed good compatability with Glimepride. The manufacturing procedure was standardized and found to be reproducible.

 

 

MATERIALS AND METHODS

Glimepride,Ethylcellulose,Isopropylalcohol,Starch,MicrocrystallineCellulose,Copovidone,HydroxyPropyl Methyl Cellulose.

 

Melting Point

Melting point of the sample was determined by capillary method.Solubility data of Glimepridewas determined by saturated solubility method.Different solvents were prepared according to the procedure given in I.P.drug was added in excess to 3ml of each solvent in separate test tubes.The test tubes were kept in an ultrasonicator for 15min and on mechanical shaker for 6 hours for equilibration.After, 6hours contents of each test tube were filtered,suitable diluted and analyzed for the drug content using UV spectroscopy.

 

Calibration curve of Glimepride in pH 7.8 phosphate buffer

The standard solutions of Glimepride was subsequentiy diluted withpH7.8 phosphate buffer containing 1% methanol to obtain series of dilutions containing 2,4,6,8,10 and 12µg/ml of Glimepride in solution.The absorbance of the above solutions was measured in UV spectrophotometer andabsorbance values were plotted against concentration of drug.

 

PreformulationStudy²

 

Physical Characteristics:

 

Determination of Bulk Density and Tap Density:

An accurately weighted quantity of the powder (W) was carefully poured into the granulated cylinder and volume (V_o) was measured. Then the graduated cylinder was closed with lid and set into the density determination apparatus (bulk density apparatus)the density apparatus was set for 500 taps,750 taps , and 1250 taps.

 

                 After that the volume(V_f) was measured and continued the operation till the two consecutive reading were equal. The bulk density and the tapped density were calculated using the formulas.

Bulk Density – W/V_o

Tapped Density- W/V_f

Where W- Weight of the powder.

V_o- Initial volume.

V_f- Final volume.

Bulk density of Glimepride was found to be 0.41g/ml.

Tap density of Glimepride powder was found to be 0.65g/ml.

 

Hausner ratio:–

It indicates the flow properties of the powder and measured by the ratio ofTapped density to bulk density.

Hauser ratio- Tapped density /Bulk density

Table No.1: Range of Hausner Ratio and Its Properties

No.	Hausner ratio	Properties
1	0-1.2	Free flowing
2	1.2-1.6	Cohesive powder

 

 

GlimeprideHausner Ratio was found to be 0.63g/ml.

 

Sieve Analysis:

The main aim of sieve analysis was to determine the different size of drugParticles present. series of standard sieve were stacked one above the other so that sieves with larger pore size (less sieve number)occupy top position followed by sieve of decreasing pore size (large sieve number) towards the bottom.

 

 

Procedure:

A series of sieves were arranged in the order of their decreasing pore diameter(increasing sieve number) i.e. sieve no. ASTM 40, 60, 80, 100 with 40grams of drug were weighed accurately and transferred to sieve 40 which were kept on top. The sieves were shaken for about 5-10 minutes .Then the drug retained on each sieves were taken, Weighted separately and expressed in terms of percentage.69.4% Glimepride powder pass through sieve 100 (NLT 65% should pass through 100 mesh).

 

Solubility- Slightly soluble in methanol, freely soluble in acetonitrile.

 

Melting Point-205^oC

 

Description- White Crystalline Form

Preparation of Drug Pellets:

 

            Inert pellets (1.0-18 mm) were first prepared by extrusion – spheronizationmethod using Standard formula; lactose: Avicel: water (1:1:0:9) and were used for drug pellets.

 

Formulation Development^3,4

 

 

Drug Loading(stage-1):

The raw materials were collected. Suffiecient quantity of isopropyl alcohol was weighed and to this 5gm of glimepride ,pvp-k-305gms  and non pariel seeds 90gms was  and pass all owderded material through 100mesh size sieve before adding to get uniform particle size.

 

Drying(Stage - 2):

Dry the Stage I pellets in SS Tray Drier at 45⁰C for 8 hours.Check moisture content. It should be below 1%. Pass the dried Pellets through sifter to remove fines.

 

Sub Coating(Stage-3):

 

              In clean and dry SS vessel, Charge Purified Water and Hydroxy Propyl Methyl Cellulose 5 cps and stir till dissolution to form clear colloidal subcoating solution. In clean, dry Fluid Bed Coater, charge dried Pellets. Spray above coating solution through Nozzle on Pellets along with continuous flow of warm air in to dry the coat as soon as it forms for uniform coating. Continue coating till minimum weight gain of coated Pellets is achieved.

 

Sustain release Coating( stage-4):preparation of coating solution

             

              HPMC E15-  4%,8%

              ECN-14     - 4%,8%

              ECN-50     -4%,8%

              IPA+MDC-Q.S

 

The above solutions are mixed together and stirred for 15 min.

              The Stage-3 pellets were loaded into fluidized bed coater and the sustain release coating solution was sprayed.Drying and sifting for sustain release coated pellets. The pellets were dried under maintained temperature of 48^oc-50^oc for 30min and sifted using 18-20# mesh.The pellets retained on #20 mesh were collected. 30 mg equivalent of glimepride pellets were filled in capsules according to the bulk density data obtained.These capsules were used for drug content analysis and the invitro dissolution studies. The whole process preparation of solution,Coating and capsule filling performed under mercury lamp to avoid photo degradation of the drug.

 

Evaluation of pellets⁵

 

Bulk density:

Apparent bulk density was determined by pouring the blendinto graduated cylinder and calculated bulk density of the pellets.

 

Friability test:-

The essential requirement of pellets is to have an acceptable friability to with stand further processing.Friability less than 0.08% is generally accepted for tablets,but for pellets this value could be higher due to the higher surface /unit and subsequent involvement of frictional force.45g of pellets were placed in friabilator which was then operated for 100 revolutions at 25rpm.

Angle of repose:-

The angle of repose of glimepride pellets was determined by the funnel method.

 

Hard ness:

Hardness of pellets in the range of 9 -17 N determined by Dr.Schieunigerhardness tester.

          Hardness of pellets of different formulation:

Formulation	F1	F2	F3	F4	F5
Hardness (N)	9 N	10 N	14 N	17 N	17 N

 

Evaluation of sustain release capsules

Drug content analysis:-

 

Standard preparation:-

Accurately 100mg of glimepride was weighed and transferred into 100ml volumetric flask.50 ml of methanol was added to dissolve and made up to volume with water. From the above solution 2ml was transferred into another 100ml volumetric flask and made up to volume with methanol.

 

Sample preparation:-

Accurately weighed pellets equivalent to 100mg of glimepride was transferred into 100ml volumetric flask and 50 ml of methanol was added to dissolve and made up to volume with water. From the above solution 2ml was transferred into another 100ml volumetric flask and made up to volume with methanol.

 

DissolutionProcedure^6,7,8

In vitro release studies were carried out in the dissolution test apparatus (USP Type II). The tests were carried out in 900 ml of Phosphate buffer P^H-7.8 for 6hrs at 75 rpm at 37±0.5^oC. 10 ml of the aliquot were withdrawn at different predetermined time intervals (1, 2, 3, 4, 5, 6hr) and filtered. The required dilutions were made with 0.1N HCl and the solution was analyzed for the drug content by UV spectrophotometer detecting at λ max 228 nm, Phosphate buffer 7.8pH was replaced in the vessel after each withdrawal to maintain sink condition. From this percentage drug release was calculated and this was plotted against function of time to study the pattern of drug release.The apparatus was allowed to run for 6 hours during the release studiesa 5ml of medium was taken out in amber colored glass vials and filtered and drug analysis by UV Spectrophotometer.

 

Dissolution Parameters:

 

Apparatus: Dissolution apparatus Type I of USP (basket)

 

Medium:900ml,7.8 pH phosphate buffer

 

Speed:75rpm

 

Time: 6hrs.

 

RESULTS AND DISCUSSION

Compatibility study data at 25ºC/60%RH and 40ºC/75%RH for one month revealed that there were no physical and chemical change and discoloration observed between drug and different excipients.All formulation trials were met their specifications like bulk density,friability,and angle of repose test.The hardness of the pellet was found to be in the range of 9N to 17N.

All parameters were found within the limit. In the present study, an attempt has been made to formulate and evaluate sustained release pellets of Glimepride by solution spray technique method; employing release retard polymers like ethyl cellulose with 8%.

In vitro dissolution study:

In vitrodissolution studies were performed in pH 7.8 phosphatebuffers on the above promising formulation, namely, formulation 8 .From the above data it is evident that the promising formulation 8 released 94 drug in 6hours (pH 7.8 phosphate buffer).

 

FT-IR STUDIES: The above IR graphs the Drug Functional groups are identified

withpolymers and there is no interaction observed in formulation.

 

 

Time (hrs)	FG1	FG2	FG3	FG4	FG5	FG6	FG7	FG8
1	94.3	87.74	20.95	18.33	22.26	18.99	18.33	15.6
2	98.23	94.3	35.36	28.16	38.63	30.77	36.42	31.86
3			53.04	47.8	60.24	45.18	57.23	50.72
4			73.34	68.1	75.96	62.86	66.98	68.28
5			88.4	74.65	85.78	75.3	81.3	84.54
6			89.71	91.02	88.4	90.36	88.44	94.3[i]

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

REFERENCES

1. Ghebresellaise, A General overview- pharmaceutical pellatization technology,1^st edition, marcel dekker Inc;1989;45-56.
2. Gibson, pharmaceutical preformulation and formulation,p.450,429-431.
3. D.Wurster method for Applying coating to tablets,us patent 2,648,609,(1953).
4. Claudio N,’Influence of  formulation and process parameter on pellets production by powder layering technique using aqueous solution;AAPS pharm scitech L(2)Article1,(January2000).
5. Heinamalk J, ‘Diffusion of  freely water soluble drug in aqueous enteric coated pellets’,AAPS pharm scitech 3(2) Article 16,(may2002).
6. Bramankar DM andJaiswal SB,’Biopharmaceutics and pharmacokinetics A Treaties’,led,vallabh prakashan,Delhi,p-335,337(1995).
7. Lachman L and Leiberman HA, KaingJL,’The theory and practice of industrial pharmacy’,3rded,Bombay,Varghese publishing house p.(1987).
8. Vyas SP and kharRK,’controlled drug delivery system.,conceptsadvances,’led, vallabhprakashan, NewDelhi,p.167(2002).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table1. Dissolution of Glimepride

Time (hrs)	FG1	FG2	FG3	FG4	FG5	FG6	FG7	FG8
1	94.3	87.74	20.95	18.33	22.26	18.99	18.33	15.6
2	98.23	94.3	35.36	28.16	38.63	30.77	36.42	31.86
3			53.04	47.8	60.24	45.18	57.23	50.72
4			73.34	68.1	75.96	62.86	66.98	68.28
5			88.4	74.65	85.78	75.3	81.3	84.54
6			89.71	91.02	88.4	90.36	88.44	94.3

 

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INTRODUCTION

Dual release is a unit compressed tablet dosage form intended for oral application. It contains two parts, in which one part is having conventional or immediate release part while the other is sustained or controlled released part. In this chemically incompatible materials or those which separate in a mixed granulation present in the same tablet. For sustained action of products each layer may be formulated for different release characteristics. Sometimes different drug formulated in a same tablet to achieve different pharmacological action from a single tablet.

 

ADVANTAGES OF BILAYER TABLETS:

• Bilayer tablet is suitable for preventing direct contact of two drugs and thus to maximize the efficacy of combination of two drugs.
• Extension of a conventional technology. Potential use of single entity feed granules.
• Separation of incompatible components.
• Patient compliance is enhanced leading to improve drug regimen efficiency.
• Maintain physical and chemical stability.
• Retain potency and ensure dose accuracy.

 

DISADVANTAGES OF BILAYER TABLETS:

• Insufficient hardness, Layer separation, reduced yield.
• Inaccurate individual layer weight control.
• Cross contamination between the layers.

 

APPLICATIONS:

a) Used in the combination therapy and to deliver the  loading dose a sustained dose of the same or different drugs.

b) Used for bilayer floating tablet in which one layer is floating layer and another one is releases layer of the drug and to deliver two different drugs having different releases profiles.

 

OlmesartanMedoxomil and Hydrochlorothiazide:²³

OlmesartanMedoxomil and hydrochlorothiazide are used in combination to treat high blood pressure. The OlmesartanMedoxomil acts as a Angiotensin II receptor antagonists, while hydrochlorothiazide component acts as a diuretic.

Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT₁ receptor in vascular smooth muscle.

Hydrochlorothiazide helps remove salt and water from the body, providing further action to decrease  high blood pressure.

OlmesartanMedoxomil belongs to the class of medicines called angiotensin II receptor antagonist to treat high blood pressure.

 

FigureNo:1OlmesartanMedoxomilStructural Formula

 

 

 

 

 

 

 

 

Figure No:2Structural Formula of Hydrochlorothiazide

 

MATERIALS AND METHODS

Olmesartanmedoxomil and Hydrochlorothiazide was received as gift sample from BafnaPharmaceuticalsLtd. Chennai. Lactose Monohydrate, Low – Substituted Hydroxy Propyl Cellulose (LHPC -11), Hydroxypropyl Cellulose (Klucel LF), Brilliant Blue(ColouringAgent), Magnesium Stearate, Lactose 30 GR, Hypromellose E-15, Hypromellose E-5, Macrogol 6000 was received as gift sample from  Bafna pharmaceuticals  Ltd. Chennai.

 All other chemical and reagent used in this study were of analytical grade.

 

Method of preparation⁴

Steps involved in formulation of Olmesartanmedoxomil granules

Binder solution:

            Take 12.5g of Purified  water (temp 65ºC) in 100L stainless steel vessel. Then dissolve 0.80g of HPC (Klucel LF) by stirring with stainless steel paddle. Then take 0.050g of  Brilliant blue and dissolved in water separately in small vessel and add to above binder solution slowly.

 

Dry mixing:

Check weight of OlmesartamMedoxomil  and sift through 30# mesh and sift Lactose monohydrate and Low – substituted hydroxy propyl cellulose (LHPC -11) through 40# mesh load in to rapid mixer granulation. Dry mix for 10min at low speed.

Granulation:

Add 70 % of binder to dry mix present in RMG under slow speed for 2 minutes. Rake the mass in RMG, if necessary. Add remaining quantity of binder, continue mixing for 4 - 5 minutes with impeller at SLOW speed and chopper (if required) until desired wet mass obtained. If required add additional quantity of purified water and mix for two more minutes. Discharge the wet mass into Fluid Bed Drier Bowl by opening the discharge port and Operating the impeller and chopper at SLOW speed.

 

Drying :

Dry the wet milled granules in Fluidized bed dryer for 10min.Rake and check for loss on drying carry on drying for 10min and rake again. Limit: Between 1.0 - 2.0 % W/W ( Target 1.5 % w/w) LOD parameter :(105 º C)Dry till loss on drying at 0.6 - 1.2% achieved. Check loss on drying at 105ºC in halogen moisture balance.

 

Sifting and Dry mixing:

Sift the dried granules through 20 # SS sieve using vibratory sifter. Collect the retention in a poly bag. Pass the retention granules through multimill fitted with 1.5 mm screen Knives forward at slow speed. Collect the milled granules in the IPC bin and transfer to Blender. Pass the milled granules through 20 # SS sieve using vibratory sifter. Collect all the granules passing through 20 # SS sieve and load the granules into the octagonal blender.

 

Blending and Lubrication:

Load the granules in octagonal blender and blend for 5min at 6rpm. And Prelubrication was done with  sifted Low substituted Hydroxy propyl cellulose(L-HPC 11) through #40 mesh to octagonal blender. Add sifted magnesium stearate through #60 mesh to octagonal blender and blend for 5min at 6rpm.

 

Steps involved in formulation of Hydrochlorothiazide granules

D

ry mixing:

Check weight of Hydrochlorothiazide and sift through 30# mesh and sift Lactose 30GR and Low – substituted hydroxy propyl cellulose (LHPC -11) through 40# mesh load in to rapid mixer granulation. Dry mix for 10min at low speed.

 

Lubrication:

After dry mixing , Add sifted magnesium stearate through #60 mesh to octagonal blender and blend for 5min at 6rpm.

 

Formulation Development of OlmesartanMedoxomil& Hydrochlorothiazide Bilayer Tablets.(Table-1)

S. No	Ingredients (mg Per Tablet)	F1	F2	F3	F4	F5
1	OlmesartanMedoxomil	20	20	20	20	20
2	Lactose Monohydrate	61.9	68.2	65.9	65.5	66.3
3	Low Substituted Hydroxy Propyl Cellulose(L-HPC 11)	6	-	2.5	3	3
4	HydroxyPropyl Cellulose (KLUCEL LF)	2.6	1.6	3.1	1.7	2.5
5	Brilliant Blue	0.5	0.8	0.4	0.1	0.4
6	Purified Water USP #	30	28	27	25	27
7	Low substituted hydroxy propyl cellulose(L-HPC 11)	4.5	5.3	3.8	5.5	3.5
8	Magnesium stearate	1	0.6	0.8	0.7	0.8
	Total Weight	96.5	96.5	96.5	96.5	96.5
9	Hydrochlorothiazide	12.5	12.5	12.5	12.5	12.5
10	Lactose 30 GR	74.3	72.9	75.3	72	75
11	Low substituted hydroxy propyl cellulose(L-HPC 11)	8.5	9.6	7.5	11	7.6
12	Magnesium stearate	0.7	1	0.7	0.5	0.9
	Total Weight	96	96	96	96	96
	Core Tablet Weight	192.5	192.5	192.5	192.5	192.5
COATING
13	Hypromellose E-15	1.95	1.95	2.2	2.2	2.850
14	Hypromellose E-5	2.9	2.9	2.3	2.3	1.900
15	Macrogol 6000	0.65	0.65	1	1	0.750
16	Purified water #	89	89	89	89	89
17	Isopropyl alcohol BP #	1	1	1	1	1
	Coated Tablet weight	198	198	198	198	198

 

 

 

 

(Table No: 2)

S.No	Ingredients( mg per tablet)	F6	F7	F8	F9
1	Olmesartanmedoxomil	20	20	20	20
2	Lactose Monohydrate	67.9	69.3	66.7	70.4
3	Low substituted hydroxyl propyl cellulose(L-HPC 11)	3	4.8	4	-
4	Hydroxyl propyl cellulose  (KLUCEL LF)	1.6	1.5	1.6	1
5	Brilliant blue	0.2	0.1	0.1	0.1
6	Purified Water USP #	27	23	25	22
7	Low Substituted Hydroxyl Propyl Cellulose(L-HPC 11)	3.2		3.5	4.1
8	Magnesium Stearate	0.6	0.8	0.6	0.9
	Total Weight	96.5	96.5	96.5	96.5
9	Hydrochlorothiazide	12.5	12.5	12.5	12.5
10	Lactose 30 GR	80	79.2	80.5	78.6
11	Low Substituted Hydroxyl Propyl Cellulose(L-HPC 11)	3	3.5	2.6	4.6
12	Magnesium Stearate	0.5	0.8	0.4	0.3
	Total Weight	96	96	96	96
	Core Tablet Weight	192.5	192.5	192.5	192.5
COATING
13	Hypromellose E-15	2.850	2.850	2.850	2.850
14	Hypromellose E-5	1.900	1.900	1.900	1.900
15	Macrogol 6000	0.750	0.750	0.750	0.750
16	Purified Water #	89	89	89	89
17	Isopropyl Alcohol BP #	1	1	1	1
	Coated Tablet Weight	198	198	198	198

 

Evaluation of Bilayer tablets

1. General Appearance:

The control of general appearance involves measurement of attributes such as a tablet’s size, shape, color, presence or absence of odor, taste, surface textures, physical flaws and consistency.

 

 

2. Size and shape:

The type of tooling determines the shape and dimensions of compressed tablets during the compression process.

 

3. Thickness:

The thickness of individual tablets may be measured with a micrometer, which permits accurate measurements and provides information of the variation between tablets. Tablet thickness should be controlled within a ± 5% variation of a standard value. Any variation in thickness within a particular lot of tablets or between manufacturer’s lots should not be apparent to the unaided eye for consumer acceptance of the product

 

4. Weight variation:

This test is also known as uniformity of weight. This does not apply to layer or enteric coated tablets. Weights of individual 20 tablets was noted and their mean weight was calculated, and the percentage deviation was calculated by using the formula

Percentagedeviation

Where,

            X = actual weight of the tablet

           X¹ = average weight of the tablet

 

5. Content uniformity:

The content uniformity test is used to ensure that every tablet contains the amount of drug substance intended with little variation among tablets within a batch.. For content uniformity test, representative samples of 30tablets are selected and 10 are assayed individually. At least 9 must assay within ±15% of the declared potency and none may exceed ± 25%.

 

6. Friability:

Friction and shock are the forces that most often cause tablets to chip, cap or break. It is usually measured by the use of the Roche friabilator. A number of tablets are weighed and placed in the apparatus where they are exposed to rolling and repeated shocks as they fall 6 inches in each turn within the apparatus. After four minutes of this treatment or 100 revolutions, the tablets are weighed and the weight compared with the initial weight. The loss due to abrasion is a measure of the tablet friability. The value is expressed as a percentage. A maximum weight loss of not more than 1% of the weight of the tablets being tested during the friability test is considered generally acceptable and any broken or smashed tablets are not picked up.

                                Friability index 

7. Hardness:

The resistance of tablets to capping, abrasion or breakage under conditions of storage, transportation and handling before usage depends on its hardness. It is now designated as either the Monsanto or Stokes hardness tester. The instrument measures the force required to break the tablet when the force generated by a coil spring is applied diametrally to the tablet.

 

8. Dissolution:

Dissolution is the process by which a solid solute enters a solution. In the pharmaceutical industry, it may be defined as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition.

IR studies:

The IR spectra of pure drug OlmesartanMedoxomil& Hydrochlorothiazide and physical mixture with other  excipients  were compared  and  are found   to be compatable  with each other as indicated  by no significant change in the drug peaks.

 

 

 

 

 

 

 

 

 

 

RESULTS AND DISCUSSION

Figure No: 3 IR Spectra of Olmesartanmedoxomil +  Excipients.

Inference: The IR spectra of pure drug  Olmesartanmedoxomil and physical mixture with other  excipients  were compared  and  are found   to be compatable  with each other as indicated  by no significant change in the drug peaks.

 

Figure No: 4  IR Spectra of Hydrochlorothiazide + Excipients.

Inference: The IR spectra of pure drug Hydrochlorothiazide and physical mixture with other excipients were compared and are found to be compatable with each other as indicated by no significant change in the drug peaks between pure drug sample and drug excipient physical mixture.

PRE COMPRESSION PARAMETER:

Table No: 3Precompression Parameter of OlmesartanMedoxomilGranules Trials:

Formulations

Bulk density (gm/cm2)

Tapped density (gm/cm2)

C.I (%)

Angle of repose (0)

H.R

Moisture Content

F1	0.44	0.55	27.0	50⁰.12’	1.44	0.681
F2	0.41	0.51	28.33	47⁰.32’	1.42	0.630
F3	0.43	0.52	27.3	48⁰.26’	1.382	0.612
F4	0.41	0.51	29.61	46⁰.56’	1.255	0.586
F5	0.42	0.54	32.22	42⁰.21’	1.383	0.323
F6	0.49	0.50	20.0	38⁰.65’	1.222	0.311
F7	0.48	0.55	18.15	36⁰.23’	1.25	0.262
F8	0.48	0.51	15.69	28⁰.13’	1.146	0.216
F9	0.47	0.55	20.0	30⁰.23’	1.25	0.218

 

Inference: Formulations F1 to F5 has high angle of repose and Hausners ratio indicating poor flow of granules and the flow property increased in case of F6 and F7 because of inclusion of a dry binder and F8 and F9 has shown good flow as indicated by angle of repose and Hausners ratio because of increase in concentration of lubricant.

 

 

Table No: 4Precompression Parameter of Hydrochlorothiazide Granules Trials:

Formulations

Bulk Density (gm/cm2)

Tapped Density (gm/cm2)

C.I (%)

Angle of Repose (0)

H.R

Moisture Content

F1	0.45	0.56	28.64	46⁰.66’	1.39	0.621
F2	0.44	0.57	31.8	48⁰.2’	1.38	0.627
F3	0.41	0.59	30.5	50⁰.56’	1.40	0.612
F4	0.44	0.57	32.8	46⁰.99’	1.383	0.531
F5	0.44	0.56	24.42	47⁰.3’	1.382	0.523
F6	0.43	0.54	20.37	42⁰.21’	1.255	0.322
F7	0.47	0.59	18.64	34⁰.56’	1.208	0.292
F8	0.48	0.58	17.24	30⁰.12’	1.124	0.242
F9	0.45	0.55	18.18	31⁰.63’	1.125	0.245

 

Inference: Formulation F1 to F7 has high angle of repose and Hausners ratio and the values reduced by addition of increasing concentration of lubricant that enhanced flow property.

 

 

 

 

 

 

 

POST COMPRESSION PARAMETER OF OLMESARTAN MEDOXOMIL AND HYDROCHLOROTHIAZIDE TABLETS:

Table No: 5 Post Compression Parameter of Olme

sartanmedoxomil and Hydrochlorothiazide Tablets.

Formulations	Weight Variation (mg)	Hardness (kg/cm2)	Thickness (mm)	Disintegration time (min)	Friability (%)
F1	195-200	7.1	3.60	4	0.008
F2	197-202	7.8	3.59	5	0.068
F3	194-199	6.8	3.61	6	1.062
F4	196-200	7.0	3.70	6	1.076
F5	193-196	7.5	3.69	5	0.089
F6	198-201	7.8	3.60	4	1.174
F7	197-202	8.0	3.62	5	0.041
F8	195-199	8.3	3.60	6	0.055
F9	198-202	8.5	3.70	5	0.050

 

DRUG RELEASE:

 INNOVATOR DRUG RELEASE PROFILE:

Table No: 6. Innovator Drug Release Profile:

TIME (MIN)	INNOVATOR (OLMESARTAN MEDOXOMIL)	INNOVATOR (HYDROCHLOROTHIAZIDE)
10	72.4%	70.7%
15	84.2%	82.6%
30	93.2%	91.3%
45	96.8%	94.9%
60	98.2%	96.4%

 

Comparison of Dissolution Profile of Formulations With Innovator

Table No: 7. Comparison of dissolution profile of formulations with innovator

Time (min)	Innovator (O)	Innovator (H)	% Drug Release
			O	H	O	H	O	H	O	H
			F6	F6	F7	F7	F8	F8	F9	F9
10	72.4	70.7	85.8	59.3	90.2	60.5	70.4	68.7	70.1	68.2
15	84.2	82.6	90.1	70.6	93.4	73.6	83.1	80.5	81.9	80.1
30	93.2	91.3	92.5	83.2	95.5	85.6	91.7	89.4	91.2	89.1
45	96.8	94.9	95.2	86.4	97.3	89.7	95.2	93.2	94.8	93.0
60	98.2	96.4	96.7	90.2	96.6	91.5	97.2	95.8	97.0	95.4

Where,O = Olmesartanmedoxomil,H = Hydrochlorothiazide

Comparative Release Profile of OlmesartanMedoxomil in Various Formulations with Innovator

 

Figure No: 5 Comparative release profile of Olmesartanmedoxomil  in various formulation with innovator

 

 

Inference: Comparative Release profile of OlmesartanMedoxomilfrom various formulations showing that the release from formulation F8 matching with that of innovator

 

Figure No: 6 Hydrochlorothiazide release from various formulations compared to innovator

 

 

 

Inference: Comparative release profile of Hydrochlorothiazide from various formulations showing that the release from formulation F8 matching with that of innovator.

 

Comparative Release of  OlmesartanMedoxomil From Innovator and  F8

Table No: 8. Comparative Release of Olmesartanmedoxomil from innovator and F8

Time(min)	% Release of innovator	% Release from F8
10	72.4	70.4
15	84.2	83.1
30	93.2	91.7
45	96.8	95.2
60	98.2	97.8

 

 

 

 

 

 

 

 

 

 

Figure No: 7 Comparative release of Olmesartanmedoxomil from innovator and F8

 

 

Inference: The Release profile of Olmesartanmedoxomilfrom F8 was compared to innovator and  the release was almost equal and comparable to that of inovator at the end of 45 and 60min.

 

 

 

Comparative Release of Hydrochlorothiazide From Innovator and  F8

 

 

 

Table No: 9. Comparative release of Hydrochlorothiazide from innovator and F8

Time(min)	% Release of Innovator	% Release from F8
10	70.7	68.7
15	82.6	80.5
30	91.3	89.4
45	94.9	93.2
60	96.4	95.1

 

 

 

 

 

Figure No: 8 Comparative release of Hydrochlorothiazide from innovator and F8

 

Inference: The Release profile of Hydrochlorothiazide from F8 was compared to innovator and  the  release was almost equal and comparable to that of inovator at the end of 45 and 60min.

 

 

                                                                     

Table No: 10. Drug release of OlmesartanMedoxomiland Hydrochlorothiazide at 25^oC & 60%RH

 

 

 

 

Figure No: 9 Drug Releaseof OlmesartanMedoxomiland Hydrochlorothiazide at 25^oC & 60%RH

Inference: The drug release was not significantly reduced at the end of 30days and 45days storage at 25^oC & 60%RH indicating stability of the formulation. All the parameters are with in the limits specified at the end of storage period.

Table No: 11.  Drug release of Olmesartanmedoxomil and Hydrochlorothiazide at 40^oC & 75%RH

 

 

OlmesartanMedoxomil	97.2	97.0	97.0
Hydrochlorothiazide	97.2	96.6	96.6

 

 

 

Figure No: 10  Drug release of OlmesartanMedoxomiland Hydrochlorothiazide at 40^oC & 75%RH

Inference: The Drug Release was not significantly reduced at the end of 30days and 45days storage at 40^oC & 75%RH indicating stability of the formulation. All the parameters are with in the limits specified at the end of storage period.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

SUMMARY AND CONCLUSION

The present study was aimed for developing a bilayer tablet of Olmesartanmedoxomil and Hydrochlorothiazide. Nine formulations are prepared with of Olmesartanmedoxomil and Hydrochlorothiazide granules prepared separately in a rapid mixergranules. Pre compression parameters like Bulk density, True density, Angle of repose indicate all the formulations are showing good flow properties.

Tablets are compressed using SEJONG bilayer compression machine and tablets are evaluated for post compression parameters Weight variation, Hardness, Friability, Disintegration and Dissolution parameters.

Formulations F1-F4 does not meet the direct criteria for Hardness and Disintegration time due to improper mixing of binder with the dry mixture.

Formulations F5-F9 has shown post compression parameters within the specified limits of the innovator. The release profile of formulations F5-F9 was compared with innovator and all the formulations has shown a release of 70-95% and formulation F8 has matched the innovator release profile.

The compressed bilayer tablets was packed in blisters and subjected to stability studies at 40^oC & 75%RH  , 25^oCand 60% RH. Samples were analyzed at  regular  intervals as mentioned  in stability protocol.

From the study, it may be concluded that bilayer tablet of  Olmesartanmedoxomil and Hydrochlorothiazide can be prepared as  immediate release formulation compared to conventional formulations.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ACKNOWLEDGEMENTS

 

Olmesartanmedoxomil and Hydrochlorothiazide was received as gift sample from BafnaPharmaceuticals Ltd. Chennai, India, We also thank Chairman and Principal, Krishna Teja Pharmacy College for providing infrastructure facilities for the work.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

REFERENCES

1. Alalfonsa-R.Gennare, 1990, “Remington’s pharamaceutical sciences”, 18^th edition, pp.1677-78.
2. Cooper.J, Gunn, 1986, “Tutorial pharmacy” , New Delhi, CBS publishers and distributors; New Delhi; pp:211-233.
3. Gilbert S.banker, Christopher T.rhodes, “Modern pharmaceutics”, fourth edition,MarcelDecker,New York, pp.501
4. Gibaldi M.,parrierD,Pharmacokinetics, Decker 1982 ,2^nd edition ,pp 189.
5. The Merck Index, 13^th edition, pp 5966.
6. Remington: the science and practice of pharmacy,20^th edition,p.no.898-903.
7. J.C.Johnson, ―Tablet Manufacture‖, 1974, 1st edition, Page 144-155.
8. B.M.Mithal, ―A Text Book of Pharmaceutical Formulations‖, 2003, 12th edition, Page 101.
9. Rowe, Raymond.C, Sheskey, Paul.J.Owen, Sian.C ―Hand Book of Pharmaceutical Excipients‖ 2006, 5th Edition, Pages 124 to 2150.
10. H.A.Liberman, Lachman and J.B.Kannig, ―Theory and Practice of Industrial Pharmacy, 1990, 3rd edition, Page 293-345.
11. http://www.gea-ps.com/npsportal/cmsresources.nsf/filenames/Bi layer_Tabletting_Technology.pdf/$file/Bi-layer_Tabletting_Technology.pdf
12. Bilayer tablets-Why special technology is required, Pharmaceutical online, GEA process engineering. Inc www.pharmaceuticalonline.com

Introduction:

Generic pharmaceuticals and encourage competition through the Drug Price Competition and Patent Term Restoration Act of 1984 (the “Hatch- Waxman Act”). The Act established a new process for generic drugs to enter the market, the Abbreviated New Drug Application (“ANDA”). Congress intended the Act to “make available more low-cost generic drugs by establishing a generic drug approval procedure for pioneer drugs first approved after 1962.” However, with the Hatch-Waxman Act, Congress also sought to balance the ability of competitors to bring cheap generics to the marketplace with the need for companies producing brand-name drugs to research and develop new pharmaceuticals. To accomplish the first objective, the Hatch-Waxman Act’s ANDA provided generics with a new approval process, during which generic producers need only prove the equivalency of their generic product to the pioneer drug on which FDA testing and approval had already taken place. This was intended to allow generic manufacturers to avoid the enormous costs inherent in duplicating the NDA process, particularly the expensive data on human subjects.The Act also gave generic manufacturers the opportunity to petition for generic drugs that list different drugs as the active ingredient or have a different dosage or strength, provided that the change does not require a separate review of clinical data. Additionally, Hatch-Waxman aimed to maintain investment in research and development of new innovator pharmaceuticals. To this end, the Act established two new FDA pharmaceutical approval processes: the ANDA and the Section 505(b)(2) application. These approval processes allow manufacturers of equivalent pharmaceuticals, similar but non-equivalent pharmaceuticals, and pharmaceuticals for which significant safety and efficacy testing have been heretofore conducted by third parties to avoid duplicative innovator research and to develop products during innovator exclusivity periods. To aid concurrent development of generics, the Hatch-Waxman Amendments also allowed generic manufacturers to use the patented pioneer drug during the patent life to test and develop generics, which might otherwise be patent infringement. Thus, proprietary pioneer drugs and their testing data were made available to generic manufacturers, allowing the manufacturers to put a competitor pharmaceutical on the market sooner. However, in accordance with the first goal of maintaining the incentives for research and development, several restrictions on competition were included in the Hatch-Waxman Act. First, pioneer drugs, those with NCEs new to the market, receive a five-year exclusivity period, during which time no ANDA may be submitted. When generic manufacturers wish to market a bioequivalent, the Act requires that producers notify the corresponding pioneer pharmaceutical’s patent owners of a possible exclusivity infringement so that the issue may be litigated promptly. Once a generic manufacturer files an ANDA, if a patent infringement action is brought within forty-five days after notice of final certification, approval is stayed for thirty months, or until a court decides that the patent is not infringed.If after thirty months no federal court has ruled on the validity of the patent infringement, the generic manufacturer who filed the ANDA may distribute and market the drug; however, the ANDA filer that chooses to follow this course may thereafter become liable for infringement damages if infringement is found later by a court. Once a generic pharmaceutical has filed for final ANDA certification, the Hatch-Waxman Act gives the marketer of the generic drug 180 days of market exclusivity for that generic.In implementing this provision of the Hatch-Waxman Act, however, the FDA determined that the provision could not be read literally; it then added the requirement that the first applicant must have “successfully defended against a suit for patent infringement” before the exclusivity period can begin to run. Thus the FDA inserted an additional hurdle of litigation before the generic manufacturer can enjoy the 180-day exclusivity period.Furthermore, federal courts have limited the 180-day generic exclusivity period, allowing the producer of the innovator drug (the NDA holder) to market its own generic version of the drug during the ANDA holder’s 180-day exclusivity period. Thus, during their period of supposed exclusivity, generic manufacturers may have to defend patent infringement suits and face generic competition from the innovator drug producer, a company already equipped and engaged in the manufacture of the same pharmaceutical.

The Hatch-Waxman Act also provides the section 505(b)(2) application for innovative pharmaceuticals that offer a new therapeutic benefit or alternative for consumers. In essence, section 505(b)(2) constitutes a hybrid between the NDA and ANDA processes, allowing applicants to avoid duplicative research for drugs that would not qualify as bioequivalent for the ANDA process. Section 505(b)(2) provides this alternative for two types of drugs: drugs that cannot be approved solely on the basis of studies conducted or compensated by the applicant and drugs that are similar to innovators but not sufficiently similar to constitute therapeutic equivalents. In practice, section 505(b)(2) applications are used by producers of NCEs and new molecular entities (“NMEs”) that rely on FDA findings or studies to which the applicant has not been afforded a right of reference. Also, section 505(b)(2) applications are used by producers of pharmaceuticals that modify previously approved drugs, creating equivalents not similar enough to warrant the approval of an ANDA. A section 505(b)(2) applicant pharmaceutical may receive a five-year exclusivity period for an NCE or NME; if the drug is not an NCE, and one or more of the clinical studies was conducted or sponsored by the applicant, the section 505(b)(2) applicant can receive a three-year exclusivity period. The section 505(b)(2) applicant may also be eligible for orphan drug or pediatric exclusivity. Furthermore, a brand-name drug manufacturer that takes anticompetitive measures beyond the FDA-prescribed windows of market exclusivity can face antitrust liability in the American system. The Sherman Act punishes all behavior that “attempt[s] to monopolize” in restraint of trade, aiming to protect competition in a market, and thus the consumer, rather than merely the rights of the competitor. In this regard, federal courts have found that brand-name drug manufacturers attempting to block generic entry through unfounded lawsuits would be guilty of antitrust violations. Holding that filing frivolous lawsuits constitutes an antitrust violation rather than a minor violation of the Federal Rules of Civil Procedure perhaps demonstrates the federal judiciary’s acknowledgement of the time required for effective marketing and for a consumer to switch to generics.

OBJECTIVES:

            The present work aims to develop a robust core dossier for regulatory filing so as to reduce the risk of regulatory delays by anticipating the questions raised by the individual regulatory authorities.

The objectives of the proposed work includes

• To review the regulatory framework in ICH region.

• To review the drug registration and approval procedures in  US
• To review the regulatory requirements for the preparation of CTD

• To compare the regional and technical requirements between  US

• To review the BA/BE concepts, approaches, design and various basic regulatory considerations for conducting BA/BE studies.

 

RESEARCH METHODOLOGY:

Literature review was done mainly on collection of the legislations, concentrating on their generic drug registration procedures in EU and US. The research carried out with the collected data by analyzing the terms of the below parameters:

 

 

Methodology:

Each and every study has some patterns and follows certain pathways in order to reach the objective. Thus, the method to be followed plays an important role in determining the outputs as well as the consequences of study.

Types of study:

The study was conducted with an objective to chalk out the regulatory framework for generic drug registration, legislations and guidelines. The major emphasis has been provided to regulatory requirements of EU and US. In addition emphasis is made on the administrative documents in the emerging nations.

Source of data:

Major part of the proposed data was collected by means of following sources:

Literature Review:

Typically reviewed the dossiers, covered the books and regulatory guidelines published officially by government authorities, including the academic journals, online journals, market research reports, news paper articles and world fact and other resources.

Internet using the Web Page Content:

The literature was collected using numerous search engines.E.g. Pharmabiz, RAPS, Pub med, online journals, Google Scholar and many more. Online books also served as a good source of information. Key words in the search involved generic drug registration requirements, administrative documents along with the name of various parameters associated to pharmaceutical field, name of regulatory bodies and other variations were used.

 

 

DRUG (ANDA) APPROVAL PROCEDURE IN US:

Hatch­-- Waxman Act

 

In 1984 Hatch- Waxman Amendments to Federal Food, Drug and Cosmetic Act (FD&C Act) came and it was considered one of the most successful pieces of legislation ever passed and created the generic drug industry (Drug Price Competition and Patent Term Restoration Act of 1984). The act required FDA to publish received patent information and began printing the patent listings in a volume entitled “Approved Drug Products with Therapeutic Equivalence” – Orange Book.  Under this act four type of certification are possible. They are

 

 

• “Paragraph I” certification states that the application does not cite patented information previously listed in the Orange Book
• “Paragraph II” certification states that the patented information cited in the application, and listed in the Orange Book, has expired
• “Paragraph III” certification states the date on which the listed Orange Book patents for the information cited in the ANDA application will expire
• “Paragraph IV” certification attests to the manufacturer’s opinion that the listed Orange Book patent is invalid, or will not be infringed by the use, manufacture, or sale of the new drug for which the ANDA is submitted

Generic manufacturers filing Paragraph IV certifications were required to provide notice to the relevant pioneer drug companies and patent holders explaining why the listed patents cited in the ANDA were either invalid or not infringed by the ANDA submission. At the same time a NDA or patent holder could file a valid infringement suit within 45 days of receipt of a Paragraph IV notice. In addition the Act created an automatic thirty-month window in which the patent infringement dispute could be litigated without risk of generic entry into the market. The effective date of FDA approval was delayed until a judicial ruling on the infringement of validity of the patent, or until thirty months have elapsed, whichever occurred sooner. The Act provided additional incentives to the generic companies in the form of a marketing exclusivity provision. The first company that filed an ANDA with a Paragraph IV certification as to a particular patent or patents was granted a 180-day monopoly by the FDA. During this time, the FDA would not give any other ANDA approval for subsequent generics for 180 days.  Thus this act made following three important provisions: I) it provided for the extension of the term of one existing patent for innovator drugs; II) it made provisions for the marketing of generics of patented drugs on the day after patent expiry; and III) it provided opportunities to challenge the validity of patents issued to innovator drug companies.

A generic drug product is one that is comparable to an innovator drug product (also known as the reference listed drug (RLD) product as identified in the FDA's list of Approved Drug Products with Therapeutic Equivalence Evaluations) in dosage form, strength, route of administration, quality, performance characteristics and intended use. "ANDA" contains data which when submitted to FDA's Center for Drug Evaluation and Research, Office of Generic Drugs (OGD), provides for the review and ultimate approval of a generic drug product. Once approved an applicant may manufacture and market the generic drug product provided all issues related to patent protection and exclusivity associated with the RLD have been resolved.

The OGD ensures the safety and efficacy of generic drugs by employing a review process that is similar to the NDA process. The primary difference between the Generic Drug Review process and the NDA review process is the study requirements. For example, an ANDA generally requires a bioequivalence study between the generic products and the reference listed drug (RLD) product. The safety and efficacy of the RLD product were established previously through animal studies, clinical studies and bioavailability studies. Thus, these studies need not be repeated for the ANDA.