Effect of Polysorbate 80 and Particle Size of Budesonide API on In-vitro Dissolution Profiles of Budesonide MUPS Tablets 9 mg

 

Syam Prasad Borra1, 3*, M. Chinna Eswaraiah2, G.Kamalakar Reddy3

1Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500072, Telangana, India.

2Anurag Pharmacy College, Kodad, Nalgonda (d)-508206, Telangana, India.

3Hetero Labs Ltd, Hyderabad-55, Telangana, India-500072, Telangana, India.

*Corresponding Author E-mail: syamprasadborra9@gmail.com

 

ABSTRACT:

The aim of this work was to study the effect of Polysorbate 80 concentration and particle size of Budesonide API on in-vitro dissolution profiles. Budesonide API was a BCS class-II molecule which is having low solubility and high permeability. To increase solubility particle size need to be reduced by wet milling technique using high-pressure homogenizer, Budesonide API is highly hydrophobic in nature, hence it was difficult to wet the API in purified water without wetting agent like Polysorbate-80. The optimal formulation was manufactured by using wet milling technique by using Polysorbate 80 as a wetting agent. The wet milled drug suspension was sprayed on sugar spheres, which was coated with Eudragit L100 and S100 to target the drug release in colon region, further coated with protective layer coating and compressed into MUPS tablets. Polysorbate 80 of 5 mg/unit with API particle size of 1.6 microns was found to be producing similar dissolution profile with the marketed formulation in all media from pH 4.5 to pH 7.5.

 

KEYWORDS: Budesonide, Polysorbate-80, High-pressure homogenizer, MUPS.

 

 


INTRODUCTION:

Budesonide (BUD) is an anti-inflammatory drug and its chemical name is (11beta, 16 alpha)-16, 17-(Butylidenebis (oxy))-11, 21-dihydroxypregna-1, 4-Diene-3, 20-dione1, potent corticosteroid that is used in the ulcerative colitis. The absorption variability in the Tmax is very high (30–600min.) in the patient. Budesonide, BCS Class II, with a log𝑃 of 3.2, is practically insoluble in water (28 𝜇g/mL)2. It has been well explained that solubility, dissolution and gastrointestinal permeability are fundamental parameters that control rate and extent of drug absorption and its bioavailability3. The water solubility of a drug is a fundamental property that plays an important role in the absorption of the drug after oral administration.

 

 

 

It also governs the possibility of parenteral administration of a drug and is useful in manipulating and testing of drug properties during the drug design and development process. The drug solubility is an equilibrium measure but also the dissolution rate at which the solid drug or drug from the dosage form passes into solution is critically important when the dissolution time is limited4. The bioavailability of BCS class II drugs is likely to be dissolution rate limited. But due to their high permeability, the BCS class II drugs have been on focus for solubility enhancement researches in the recent times and several formulation approaches for this class of compounds has been developed5.

 

To increase the solubility particle size need to be reduced by wet milling i.e. high-pressure homogenization in the presence of the suitable wetting agent as the drug is a hydrophobic agent. High-pressure homogenizers are widely used in the pharmaceutical, chemical, and food industries6. Homogenization involves the forcing of the suspension under pressure through a valve having a narrow aperture7. In this case, the suspension of the drug is made to pass through a small orifice that result in a reduction of the static pressure below the boiling pressure of water, which leads to boiling of water and formation of gas bubbles. When the suspension leaves the gap and normal air pressure is reached again, the bubbles implode and the surrounding part containing the drug particles rushes to the center and in the process colloids, causing a reduction in the particle size. Most of the cases require multiple passes or cycles through the homogenizer, which depends on the hardness of the drug, the desired mean particle size and the required homogeneity8. Conventional pharmaceutical dosage forms are being replaced by novel drug delivery systems which are safe, more efficacious and providing more patient compliance. Sustained release dosage forms are designed in such a way that they provide rapid onset of action and therapeutic response is maintained for a prolonged period due to the controlled release of drug from the dosage form to maintain desired drug concentration in body fluids9.

 

This type of homogenizer works by forcing cell suspensions through a very narrow channel or orifice under pressure. Subsequently, and depending on the type of high-pressure homogenizer, they may or may not impinge at high velocity on a hard-impact ring or against another high-velocity stream of cells coming from the opposite direction. Machines which include the impingement design are more effective than those which do not. Disruption of the cell wall occurs by a combination of the large pressure drop, highly focused turbulent eddies, and strong shearing forces. The rate of cell disruption is proportional to approximately the third power of the turbulent velocity of the product flowing through the homogenizer channel, which in turn is directly proportional to the applied pressure. Thus, the higher the pressure, the higher the efficiency of disruption per pass through the machine10. Oral modified drug delivery systems can be classified into two broad groups Single Unit dosage forms and  multiple unit dosage forms. Multiple unit dosage forms (MUDFs), such as granules, pellets, or mini tablets. The concept of MUDFs was initially introduced in 1950s11.

 

ER solid oral dosage forms can be classified into two broad groups:

I. Single unit dosage forms (e.g. tablets) and

II.Multiple unit dosage forms or multiparticulate pellet systems. The systems can be further subdivided into two concepts regarding the design of dosage forms:

(i) Matrix systems and

(ii) Reservoir systems.

 

Multiparticulate pellet systems:

Several advantages of multiparticulate systems over the single unit ones have been well known and documented1.

 

It includes,

1) The multiparticulates spread uniformly throughout the gastrointestinal tract. High localized drug concentrations and the risk of toxicity due to locally restricted tablets can be avoided.

2) Premature drug release from enteric coated dosage forms in the stomach, potentially resulting in the degradation of the drug or irritation of the gastric mucosa, can be reduced with coated pellets because of a more rapid transit time when compared to enteric-coated tablets.

3) The better distribution of multiparticulates along the GI-tract could improve the bioavailability, which potentially could result in a reduction in drug dose and side effects.

4) Inter and intra-individual variations in bioavailability-caused for example by food effects are reduced.

5) In the multiple-unit system, the total drug is divided into many units. Failure of few units may not be as consequential as a failure of a single-unit system. This is apparent in sustained-release single-unit dosage form, where a failure may lead to dose-dumping of the drug.

6) Various drug release profiles can be obtained by simply mixing pellets with different release characteristics; in addition, a more rapid onset of action can be achieved easier with pellets than with tablets.

7) Administration of incompatible drugs in a single dosage unit by separating them in different multiparticulates12.

 

MUPS technology has been adopted by the pharmaceutical industry as an alternative to conventional immediate or modified release tablets. Offering increased bioavailability and improved pharmacological properties, including sustained release, enteric-coated pellets containing different drugs, and subsequently tableted, can be used to protect the API from gastric media. Compressing pellets reduces the esophageal residence time, compared with capsules and improves physicochemical stability. Further, compared with other delivery systems, MUPS formulations offer a lower risk of local irritation and toxicity, reduced dose dumping, minimal plasma concentration fluctuations and the ability to administer high potency products. More reproducible pharmacokinetic behavior and lower intra/inter-subject variability compared with conventional formulations have also been reported. Other benefits include taste masking and controlled absorption13. Multiparticulate drug delivery systems like pellets, granules, microparticles, minitablets etc., prove to be promising and highly flexible systems with ease of formulating with different drug release kinetics. These Multiparticulate dosage forms are essential where drug-excipients or drug-drug physicochemical interactions are possible in a single-unit formulation14.

 

Modified release systems designed to reduce the frequency of dosing by modifying the rate of drug absorption have been available for many years. Intestinal release systems: A drug may be enteric coated for intestinal release for several known reasons such as to prevent gastric irritation, prevent destabilization in gastric pH, etc. Colonic release systems: Drugs are poorly absorbed through colon but may be delivered to such a site for two reasons- Local action in the treatment of ulcerative colitis and Systemic absorption of protein and peptide drugs15. For the past two decades, pellets5-6 made their use promising for ideal characteristics. Due to the free-flowing character of Pellets, they are packed easily without any difficulties and hence flexibility in the design and development of a uniform solid dosage form (uniform weight of capsules and tablets). The spherical shape and a low surface area-to-volume ratio of pellets made uniform film coating, two or more drugs can be formulated in a single dosage form, chemically compatible or incompatible, at the same sites or different sites in the gastrointestinal tract different release rates of the same drug can be supplied in a single dosage form. Multiple-unit dosage forms are showing a number of advantages over the single-unit dosage system16.

 

Oral sustained- and controlled-release formulations are used to modify the release rates of active substances among sustained-release dosage forms, those based on multiparticulate systems have attracted much attention due to their various benefits. Historically, the most convenient and commonly employed route of drug delivery has been by oral ingestion. The original controlled release of pharmaceuticals was through coated pills, which dates back over 1000 years. Coating technology advanced in the mid- the too late 1800s with the discovery of gelatin and sugar coatings. A major development in coating technology was the concept of coating drug-containing beads with combinations of fats and waxes. Since the mid-1900s, hundreds of publications and nearly 1000 patents have appeared on various oral-delivery approaches encompassing delayed, prolonged, sustained, and, most recently, controlled release of the active substance. Pelletization is a technique that enables the formation of spherical beads with a mean diameter usually ranging between 0.5 and 2 mm17. Oral colon-specific drug delivery system has been developing as one of the site-specific drug delivery systems This delivery system, by means of combination of one or more controlled release mechanisms, hardly releases drug in the upper part of the gastrointestinal (GI) tract, but rapidly releases drug in the colon following oral administration CDDS is convenient for treating localized colonic diseases, i.e. ulcerative colitis, Crohn's disease and constipation etc18. The adverse effects involve the gastrointestinal tract and nervous system, especially high doses. Reduction of side effect while prolonging its action by using the controlled release of oral dosages form is highly desirable19.

 

MATERIALS AND METHODS:

Materials:

UCERIS 9 mg tablets were obtained from Santarus, Inc., San Diego, CA 92130, Budesonide API was gifted by Hetero Drugs Ltd. Aqua coat ECD-30 Ad-Di-Sol gifted by FMC Biopolymer. Pharma-A-Spheres gifted by Hanns G. Werner GmbH Co. KG, Germany. TEC gifted by Vertellus Performancve. Polysorbate 80 gifted by Croda Singapore pvt ltd. Methacrylic acid copolymer types A (Eudragit L100) and Methacrylic acid copolymer type B (Eudragit S100) gifted by Evonik Industries AG Pharma polymers. Talc gifted by Luzenac Pharma. Titanium dioxide gifted by Kronos International Inc. Isopropyl alcohol gifted by Deepak Fertilizers and Petrochemicals Corporation Ltd. Acetone gifted by Klucel gifted by Aqualo Hercules. Methylene chloride gifted by Gujarat Fluro Chemicals Ltd. Silicified Microcrystalline Cellulose, NF (ProsolvHD90) gifted by JRS Pharma. Magnesium stearate gifted by Peter Greven. Polyethylene glycol 6000 gifted by Clariant Chemicals (India) Ltd

 

METHODS:

Formulation of budesonide 9 mg Delayed and Control release tablets:

Formulation includes prepared micronized suspension of Budesonide and then mixed this micronized suspension with control release polymer Aqua coat ECD-30 and loaded this suspension on sugar spheres after completion of drug and control release coating, Eudragit enteric coated solution was prepared and coated on drug-loaded pellets, finally overcoating was given on the enteric coated pellets after preparation of overcoated pellets prelubrication and lubrication was done followed by compression and film coating.

 

Preparation of Micronized suspension of Budesonide:

Polysorbate 80 was dissolved in purified water with continues stirring till a clear solution was formed and then added the budesonide slowly to this solution and continued the stirring until homogenous suspension formed. Taken this suspension and homogenized by using high-pressure homogenizer (make: Gea, panda) at the pressure of 1500 bars for 60 minutes and submitted the samples for particle size analysis.

 

 

Preparation of Drug loading-Control release polymer matrix pellets:

A bead size of 250-420 μm was selected for drug loading, as the drug is insoluble in water, hence we selected soluble core sugar spheres. The prepared budesonide dispersion was mixed with aqueous ethylcellulose dispersion aqua coat ECD-30d, Plasticizer Triethyl citrate under stirring and continues the stirring throughout the process. Selected core pellets were loaded in a Fluid bed spray processor (Glatt 1.1) and coated these core pellets with drug-Aqueous ethylcellulose dispersion by using a 1.5 mm nozzle, and parameters are compiled below table.1. After completion of coating, core pellets were cured at 60C for two hours. After increasing the Polysorbate 80 more than 5 mg/unit static charge was observed during drug loading hence batch no BD-IV was discontinued in drug loading stage.

 

Preparation of Enteric coated pellets:

Isopropyl alcohol (80% of total solvent), was taken in the container equipped with a propeller stirrer. And taken the remaining quantity of Isopropyl alcohol (20% of total solvent) in another vessel equipped with a homogenizer. Added Methacrylic acid copolymer type A (Eudragit L100), Methacrylic acid copolymer type B (Eudragit S100) slowly to the Isopropyl alcohol (80% of total solvent) while stirring. Increase the speed of stirrer if necessary. Continue stirring for 60 minutes and purified water was added under stirring then it forms the clear solution.

 

Added Talc, Titanium dioxide, and triethyl citrate slowly to the Isopropyl alcohol (20% of the total solvent) while homogenizing. Continue homogenization for 45 minutes or till smooth dispersion is obtained. Mix both solution and talc dispersion and stirred it for 15 minutes and keep the dispersion under constant agitation, at slow speed, during the entire process. Load the drug-loaded pellets in FBP (GATT) and coated these pellets with the enteric coating by using below parameter table1.

 

Preparation of Overcoating pellets:

PEG 6000 was added into IPA and methyl chloride mixture under stirring and added klucel LF slowly to the solution till to get the clear solution. And added purified water to this solution slowly under stirring. The prepared solution was coated on enteric coated pellets by using parameters compiled on the table.no.1

 

Table1: Drug loading, enteric coating, and overcoating process parameters:

S.no

Process Parameter

Drug loading

Entering coating

Overcoating

1

Coating type

Aqueous coating

Aqueous coating

Non aqueous coating

2

Product temperature

42C ±5C

42C ±5C

35C ±5C

3

Fluidization (CFM)

7-11

7-11

7-11

4

Atomization (Bar)

1-3

1-3

0.5-1.5

5

Spray rate(gm/min)

10-20 gm/min

10-20 gm/min

10-20 gm/min

6

Wurster (mm)

20

20

20

 

The overcoated pellets were mixed with extragranular and lubricants and prepared final blend, the final lubricated blend was compressed in tablets and coated final tablets film coating materials.


 

Table 2: Budesonide 9 mg controlled release MUPS Tablets Formula:

S.No

Ingredient

Function

Qty mg/unit

 

Core

 

BD-1

BD-II

BD-III

BD-IV*

BD-V

1

Suger spheres (#40/#60) Pharma-A-Spheres

Supporting Core

180

180

180

180

180

 

Drug loading

 

 

 

 

 

 

2

Budesonide

(Particle size milled suspension)

Active

9.00

(3.49 µ)

9.00

(1.69 µ)

9.00

(1.69 µ)

9.00

(1.69 µ)

9.00

(1.69 µ)

3

Aqua coat ECD30D

Control release polymer

18.00

18.00

18.00

18.00

18.00

4

Methyl cellulose

Pore former

1.80

1.80

1.80

1.80

1.80

5

Triethyl Citrate

Plasticizer

1.80

1.80

1.80

1.80

1.80

6

Polysorbate 80

Surfactant

0.00

2.50

5.00

7.50

5.00

7

Purified water

Solvent

30.00

30.00

30.00

30.00

30.00

 

The weight of control-release pellets

210.60

213.10

215.60

218.10

215.60

 

Target release Coating

 

 

 

 

 

 

8

Methacrylic acid copolymer type A

(Eudragit L100)

Enteric polymer

6.00

6.00

6.00

6.00

6.00

9

Methacrylic acid copolymer type B

(Eudragit S100)

Enteric polymer

8.00

8.00

8.00

8.00

8.00

10

Talc

Antistatic agent

2.80

2.80

2.80

2.80

2.80

11

Titanium dioxide

Pacifier

5.00

5.00

5.00

5.00

5.00

12

Triethyl citrate

Plasticizer

1.40

1.40

1.40

1.40

1.40

13

Alcohol/IPA

Solvent

110

110

110

110

110

14

Water

Solvent

10

10

10

10

10

 

The weight of control-release and targeted release pellets

233.80

236.30

238.80

241.30

238.80

 

Over coating (4%w/w solution)

 

15

Klucel

Binder

16.50

16.50

16.50

16.50

16.50

16

PEG 20000

Plasticizer

5.50

5.50

5.50

5.50

5.50

17

Alcohol/IPA

Solvent

150

150

150

150

150

18

Acetone

Solvent

75

75

75

75

75

19

Water

Solvent

20

20

20

20

20

 

Weight of Over coated pellets

255.80

258.30

260.80

263.30

263.30

20

Silicified MCC

Diluent

248.20

245.70

243.20

240.70

240.70

21

PEG 6000

Plasticizer

60.00

60.00

60.00

60.00

60.00

22

Croscarmellose

Disintegrant

30.00

30.00

30.00

30.00

30.00

23

Magnesium sterate

Lubricant

6.00

6.00

6.00

6.00

6.00

 

The weight of the MUPS Core tablet

600.00

600.00

600.00

600.00

600.00

 

Film coating

 

 

 

 

 

 

25

Opadry white

Film coating

18.000

18.000

18.000

18.000

18.00

26

Purified water

Solvent

qs

qs

qs

qs

qs

 

The weight of Final MUPS tablet

618.00

618.00

618.00

618.00

618.00

*Batch BD-IV because of more Polysorbate 80 (7.5 mg) static charge was observed during drug loading hence BD-IV was discontinued in drug loading stage.

 


Characterization:

PSD by Malvern:

 

Particle size distribution was measured by using a Malvern apparatus.

 

Differential Scanning Calorimeter (DSC):

Differential Scanning Calorimeter (DSC) studies were carried out using DSC TA Inotr, having TA Instrument. Accurately weighed samples were placed on an aluminum plate, sealed with aluminum lids and heated at a constant rate of 10 °C/min, over a temperature range of 0 °C to 350 °C.

 

Fourier Transform Infrared Spectroscopy (FTIR):

FTIR spectra of Budesonide API, Budesonide MUPS tablets, and Budesonide MUPS Tablets placebo formulations were recorded using a Fourier transform Infrared Spectrophotometer. The analysis was carried out in Shimadzu-IR affinity-1 Spectrophotometer. The IR spectrum of the samples was prepared using KBr (spectroscopic grade) disks by means of hydraulic pellet press at the pressure of 7 to 10 tons.

 

Scanningelectronmicroscopy:

The shape and surface morphology of the Budesonide over coated pellets and MUPS tablets were examined using a scanning electron microscope.

 

Weigh Variation:

To study the weight variation, twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight. The weight variation test would be a satisfactory method for determining the drug content uniformity. The percentage deviation was calculated using the following formula.

% Deviation= (Individual weight–Average weight/ Average weight)×100

 

Hardness or Crushing strength:

The hardness of the tablet is defined as the force applied across the diameter of the tablet in the order to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under the condition of storage transformation and handling before usage depends on its hardness. For each formulation, the hardness of 6 tablets was determined by using Monsanto hardness tester.

 

Friability:

It is to measure the mechanical strength of tablets. Roche friabilator (Electrolab, Mumbai, India) was used to determine the friability by the following procedure. Preweighed tablets (10 tablets) were placed in the friabilator. The tablets were rotated at 25 rpm for 4 minutes (100 rotations). At the end of a test, the tablets were re-weighed and loss in the weight of tablets is measured and is expressed in percentage as,

 

% Friability=[(W1–W2)/W1]×100

Where the W1=Initial weight of 20 tablets

W=Weight of the 20 tablets after testing

 

Disintegration Test:

Three tablets were taken and placed in USP disintegration apparatus baskets. Apparatus was run for 10 minutes and the basket was lifted from the fluid and observed whether all the tablets have disintegrated.

 

In vitro drug release profiles:

The in vitro drug release profiles for the optimized formulation of Budesonide over coated pellets, MUPS tablets and corresponding reference product (Uceris 9 mg ER tablets) was performed using below media.

Apparatus: USP Apparatus 2 (paddle)

Acid stage: 2 hours in 0.1 N HCl at 100 rpm (500 mL)

Buffer stage: Each of

1.    0.5% Macrogol Cetostearyl Ether in pH 4.5 acetate buffer at 100 rpm

2.    Without Macrogol Cetostearyl Ether in pH 4.5 acetate buffer at 100 rpm

3.    0.5% Macrogol Cetostearyl Ether in pH 6.0 phosphate buffer at 100 rpm

4.    Without Macrogol Cetostearyl Ether in pH 6.0 phosphate buffer at 100 rpm

5.    0.5% Macrogol Cetostearyl Ether in pH 6.5 phosphate buffer at 100 rpm

6.    Without Macrogol Cetostearyl Ether in pH 6.5 phosphate buffer at 100 rpm

7.    0.5% Macrogol Cetostearyl Ether in pH 6.8 phosphate buffer at 100 rpm

8.    Without Macrogol Cetostearyl Ether in pH 6.8 phosphate buffer at 100 rpm

9.    0.5% Macrogol Cetostearyl Ether in pH 7.2 phosphate buffer at 100 rpm

10. Without Macrogol Cetostearyl Ether in pH 7.2 phosphate buffer at 100 rpm

11. 0.5% Macrogol Cetostearyl Ether in pH 7.5 phosphate buffer at 100 rpm

12. Without Macrogol Cetostearyl Ether in pH 7.5 phosphate buffer at 100 rpm

 

Volume: 1000 mL

Temperature: 37şC

 

RESULTS:

PSD by Malvern

:

Particle size distribution of as such Budesonide and micronized Budesonide active presented in fig.1

 

 

Fig.1: Un-Micronized Budesonide Particle size distribution histogram

 

Fig.2: Micronized Budesonide Particle size distribution histogram

 

Un micronized Budesonide API particle size was found to be D(0.1):0.660 µ, D(0.5):1.542µ, D(0.9):3.490µ and after milling particle size was found to be D(0.1):0.241 µ, D(0.5):0.789µ, D(0.9):1.690µ

 

Differential scanning calorimetry (DSC):

The DSC measurements were performed for BudesonideAPI, Budesonide MUPS tablets and Budesonide MUPS placebo tablets tablet to study drug excipient interaction on a DSC with a thermal analyzer. The DSC thermogram is shown in fig. 3.

 

 

Fig.3: Budesonide API DSC Spectrum

 

 

Fig.4: Budesonide MUPS tablets DSC Spectrum:

 

 

Fig.5: Budesonide MUPS tablets placebo DSC Spectrum:

 

The DSC of budesonide API showed sharp endothermic peak at 258.2C which corresponding to the melting point of drug, DSC thermogram of MUPS tablets placebo showed a sharp peak at 150.5C and 217.5C,DSC thermogram of MUPS tablets which contain micronized budesonide and polysorbate 80 coated pellets showed two peaks at 62.8C and 191.8C indicates that there is some interaction between surfactant and drug during high-pressure homogenization, which is required for the improvement of solubility of budesonide in budesonide-Polysorbate 80 solid dispersion. No melting peak of the drug at 258.2C appeared in this thermogram indicating the complete dispersion of the drug in the Polysorbate 80 due to the phase transition.

 

FTIR spectral analysis:

FTIR spectral studies were performed on some selected optimized MUPS tablets of budesonide to study any drug excipients interactions. FTIR spectral studies were performed on BRUKER FTIR spectrophotometer using potassium bromide pellets. FTIR spectra of pure drugs of budesonide were taken initially to check the basic functional groups present in them. The spectra of budesonide pure drugs MUPS tablet formulations and placebo of MUPS tablet were shown below.

 

 

Fig.6: Budesonide API

 

 

Fig.7: Budesonide 9 mg MUPS Tablets

 

 

Fig.8: Budesonide 9 mg MUPS Tablets placebo

 

FT-IR spectrums are intended to determine if there is any interaction between the drug and the excipient used. The formulation BDIII showed the characteristic peaks at wave numbers close to that of Budesonide API. There was no alteration in the characteristic peaks of in the Budesonide MUPS tablets, indicates that there was no chemical interaction between the drug and polymer.


SCAN ELECTRON MICROSCOPY:

 

 

 

 

 

 

 

Fig.9: SEM analysis of Budesonide over Coated Pellets

 

 

 

 

 

 

Fig.10: SEM analysis of Budesonide MUPS Tablets

 

Budesonide MUPS Tablets Physical parameters:

Table 3: Quality control tests for MUPS tablets

Formulation

Thickness (mm)

Hardness (KP)

Friability (%)

Weight variation (mg)

Percentage drug content (%)

BD-I

6.35±0.010

12.3±0.577

0.170±0.020

603.00±2.000

100.1±0.351

BD-II

6.35±0.015

13.0±1.000

0.230±0.021

601.33±1.528

100.4±1.026

BD-III

6.34±0.016

12.5±0.650

0.147±0.015

599.67±1.528

101.3±1.058

BD-V

6.35±0.012

12.9±0.780

0.133±0.021

601.33±1.250

101.0±0.458

Values±SD, N=3

 

 

 


In vitro drug release profiles:

In vitro dissolution profile of Budesonide over coated pellets, Budesonide MUPS tablets and Innovator product are tabulated in the table-4.

 

BD-I, BD-II formulations showing slower release profiles when compared with reference tablets, BD-III dissolution profile was matching with innovator formulation. BD-IV batch was planned with 7.5 mg Polysorbate 80 but because of static charge developed during drug loading, it was not possible to coat hence that batch was discontinued.BD-V batch was planned as a reproducible batch for BD-III which is matching with innovator dissolution profile, BD-III formulation was selected for further evaluation. As the drug targeted for colon targeted drug delivery with control release, in-vitro dissolution profile have to check entire GIT pH range from pH 1.0 to 7.5.hence the selected MUPS formulation BD-V In-vitro dissolution profile was done in 0.1N followed by 4.5 acetate buffer, 6.0 phosphate buffer, 6.5 phosphate buffer, 6.8 phosphate buffer,7.2 phosphate buffer and 7.5 phosphate buffer.

 


 

Table 4: Comparative dissolution profiles of various formulations BD-I, BD-II, BD-III and BD –V in 7.2 phosphate buffer with 0.5% Macrogol Cetostearyl Ether, at 100 RPM.

Time (h)

 

Cumulative % drug release

UCERIS 9 mg Tablets

Budesonide 9 mg MUPS tablets

BD-1

BD-II

BD-III

BD-V

Acid stage: 2 h

0

0

0

0

0

Buffer stage: 1 h

4 ± 1

0± 0

2± 0

5± 1

8± 1

2 h

22 ± 3

18± 3

20± 2

32± 7

30± 1

3 h

43 ± 7

25± 6

33± 6

44± 9

50± 3

4 h

65 ± 10

48± 8

51± 8

69± 1

75± 6

6 h

94 ± 2

75± 4

80± 2

101± 1

99± 3

8 h

96 ± 2

91± 4

91± 2

101± 2

100± 3

10 h

96 ± 2

92± 2

91± 2

101± 2

103± 2

Values±SD, N=3

 


Fig.11: Comparative dissolution Profile in 0.5% Macrogol Cetostearyl Ether in pH 7.2 acetate buffer at 100 rpm of BD-I, BD-II, BD-III and BD-V

 

 

Fig.12: Comparative In-vitro dissolution profiles in Ph 4.5 Acetate buffer with surfactant

 

 

Fig.13: Comparative In-vitro dissolution profiles in Ph 4.5 Acetate buffer without surfactant

 

Fig.14: Comparative In-vitro dissolution profiles in Ph 6.0 Phosphate buffer with surfactant

 

 

Fig.15: Comparative In-vitro dissolution profiles in Ph 6.0 Phosphate buffer without surfactant

 

 

Fig.16: Comparative In-vitro dissolution profiles in Ph 6.5 Phosphate buffer with surfactant

 

Fig.17: Comparative In-vitro dissolution profiles in Ph 6.5 Phosphate buffer without surfactant

 

 

Fig.18: Comparative In-vitro dissolution profiles in Ph 6.8 Phosphate buffer with surfactant

 

 

Fig.19: Comparative In-vitro dissolution profiles in Ph 6.8 Phosphate buffer without surfactant

 

Fig.20: Comparative In-vitro dissolution profiles in Ph 7.2 Phosphate buffer with surfactant

 

 

Fig.21: Comparative In-vitro dissolution profiles in Ph 7.2 Phosphate buffer without surfactant

 

 

Fig.22: Comparative In-vitro dissolution profiles in Ph 7.5 Phosphate buffer with surfactant

 

Fig. 23: Comparative In-vitro dissolution profiles in Ph 7.5 Phosphate buffer without surfactant

 

DISCUSSION:

Budesonide is BCS class-II molecule with low solubility, to increase the solubility particle size need to be reduced. For particle size reduction we have selected wet milling with high-pressure homogenizer was selected. For wet milling, API needs to be dispersed in the purified water but budesonide is highly hydrophobic in nature, it will float in the water and suspension will not be formed. Hence wetting agent like Polysorbate 80 was used to wet the API. In this study, we have optimized the concentration of Polysorbate 80 to be used in the formulation. Different trials were planned with 0 mg, 2.5 mg, 5 mg, and 7.5 mg Polysorbate-80. Among them, the trial with 0 mg and 2.5 mg Polysorbate 80 (BD-I and BD-II) dissolution profiles were found to be on the lower side compared with and innovator, but a trial with 5 mg/ unit Polysorbate 80 (BD-III) dissolution profile was found to matching with the innovator. The trial was planned with 7.5 mg/unit Polysorbate-80, during drug loading static charge observed hence that trial (BD-IV) was discontinued. Reproducible batch for BD-III was planned and which has shown comparable results with innovator dissolution profile. BD-III batch was further studied for dissolution profile in all media from 4.5 to 7.5 with and without MCE, all the comparative dissolution profiles were matching with the innovator.

 

From FT-IR and DSC studies, it was found that there was no alteration in the characteristic peaks of budesonide in the budesonide MUPS tablets indicates that there was no interaction between the drug and excipients. On other hand based on content uniformity data, it is concluded that the tablets are having good content uniformity.

 

CONCLUSION:

In the present study, an effect of particle size and Polysorbate 80 concentration was studied budesonide targeted and controlled MUPS tablets were successfully prepared by using Eudargit polymers and insoluble polymer ethylcellulose. Based on in-vitro drug release profiles of formulation BD-III, it was clearly evident that with 5 mg/unit Polysorbate 80 and 1.6 microns API particle size showing good dissolution profile in all medias from 4.5 pH to 7.5 pH with and without MCE surfactant, drug was released in delayed and controlled manner and unit to unit variability of MUPS tablets is less compared to Reference matrix tablets (UCERIS 9 mg tablets). The results from FT-IR, DSC concluded that there was no well-defined interaction between Budesonide and excipients. Finally, it could be concluded that optimum concentration of Polysorbate 80 and lower particle size was required to achieve good dissolution profiles.

 

CONFLICT OF INTERESTS:

The authors declare no conflict of interest.

 

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Received on 11.08.2018          Modified on 10.09.2018

Accepted on 19.10.2018        © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(10): 4285-4295.

DOI: 10.5958/0974-360X.2018.00785.0