Formulation design and Evaluation of Extended-Release Tablets of Oxybutynin for Effective Management of Overactive Bladder Syndrome

 

S. Nandhakumar1*, G. Sugreevudu2, N. Harikrishnan1

1Faculty of Pharmacy, Dr. M.G.R. Educational and Research Institute, Chennai-600077, Tamilnadu, India.

2Research Scientist, Alembic Pharmaceutical Ltd., Vadodara-390003, Gujarat, India.

*Corresponding Author E-mail: nandha.pharm@gmail.com

 

ABSTRACT:  

Overactive bladder syndrome (OAB) is a chronic condition with a composite of symptoms and has a significant negative impact on the physiological and psychological well-being of the patients. The present study is aimed at developing extended-release formulations of oxybutynin that is effective in reducing the side effects associated with the drug by maintaining a steady state concentration with minimal fluctuations in plasma drug concentration and thereby achieves improved patient compliance. The extended-release drug delivery of tablets can be achieved by preparing the matrix tablet of oxybutynin chloride with klucel HF in core tablet by wet granulation technique and functional coating with a combination of aquacoat ECD-30 and hypromellose E5 followed by film coating with opadry. For confirmation of compatibility, the pure drug and its physical mixtures were subjected to FTIR studies. All the formulations have shown acceptable limits in all precompression and post compression parameters. The in vitro release studies in 0.1N HCl and 6.8 phosphate buffer revealed that the optimized formulation F10 extend the release of the drug to 91% at 24 hours and the release profile was similar to the innovator’s product as revealed by the similarity factor study. The release kinetics study revealed that the release of the drug followed diffusion mechanism. Stability studies of the selected formulation tablets were carried out at 25°C ±2°C/60% RH±5% and 40°C ±2°C /75%±5% RH for different time period and all the parameter was within the limits after storage period. Thus the extended release matrix tablets of oxybutynin chloride developed in this study have immense potential to develop into a marketed product following the testing in animals and human volunteers.

 

KEYWORDS: Oxybutynin, extended release, enteric coating, film coating, in vitro release.

 

 


INTRODUCTION:

Overactive bladder syndrome (OAB) is a chronic condition with a composite of symptoms that affect the quality of life of the patients. OAB is commonly associated with heterogeneity in symptoms, underreporting of symptoms and underestimation by patients, which disguises its prevalence among millions of people all over the world. About 546 million people would have been affected by OAB by 2018, with an estimated annual cost burden of 3.9 billion upon the world economy [1,2].

 

The International Continence Society defines overactive bladder as “urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence (UI), in the absence of urinary tract infection (UTI) or other obvious pathology.” The overall prevalence of OAB increases with rising age and is more common among women, though gender is not considered a risk factor among population [3]. OAB symptoms have a significant negative impact on the physiological and psychological well-being of the patients.

 

The sensation of urgency in OAB is considered to be related with disruption of normal muscle structure, impulsive excitability of the bladder and increased smooth muscle coupling triggered by pathological partial denervation of the bladder smooth muscle [4]. Behavioural modification by educating and training to improve pelvic floor muscle strength and urge control techniques is the first line of treatment for OAB [5]. The second line of treatment for OAB is treatment with antimuscarinic medications which inhibits the parasympathetic stimulation and reduces detrusor contraction by competing with acetylcholine for the muscarinic receptors [6].

 

Oxybutynin is a commonly used and most studied antimuscarinic drug used over three decades in the treatment of urgency urinary incontinence (UI) associated with OAB [7]. Oxybutynin elicits its therapeutic effect by blocking the carbochol-induced contractions by its intrinsic binding to muscarinic receptors [8]. Yet the treatment is often discontinued by patients owing to the high incidence of side effects, including dry mouth, constipation and blurred vision [9]. The antimuscarinic side effects listed are dose limiting and can be managed by reducing initial dose and subsequent dose titration of treatment [10]. Extended-release formulations of oxybutynin are effective in reducing the side effects associated with the drug by maintaining a steady state concentration with minimal fluctuations in plasma drug concentration and thereby achieve improved patient compliance [11]. OROS® oxybutynin uses osmotic pressure to deliver the drug for 24 h in a controlled fashion with well-tolerated and effective clinical outcomes in patients with OAB, in particular elderly patients using multiple medications [12]. The usage of extended-release oxybutynin was observed to improve tolerability and treatment adherence among patients with lesser side effects [13].

 

The present investigation aims at the development of extended release matrix tablets  containing  Oxybutynin chloride  for the  effective management of  OAB and also to compare the release profile of optimized formulation with that of innovator’s product.

 

MATERIALS AND METHODS:

Materials:

Oxybutynin chloride was a gift sample from Aurabindo Pharma, Hyderabad. Hydroxy Propyl cellulose (HPC) (Klucel HF USP) was purchased from Ashland industries, Europe. Aquacoat ECD-30 USP (Ethyl Cellulose 30 % aqueous dispersion) and Hypromellose E5 (hydroxyl propyl methyl cellulose) were obtained from FMC, U.S.A and DOW Chemical company, Michign respectively. Lubritab® (Hydrogenated Cottonseed oil) was obtained from JSR Pharma Ltd. Opadry yellow, opadry pink and opadry grey were obtained from Colorcon Chemicals. All other solvents and reagents used in the work were of analytical quality.

 

Methods:

Precompression studies:

Pre-compression characterization of API and formulation blend:

The drug sample was evaluated for its colour, odour, appearance, melting pointand solubility characteristics. The API was also subjected to particle size analysis and micromeritics evaluation. The compatibility between drug and the excipients was studied using FT-IR spectroscopy [14,15]. The pre-compression characteristics such as angle of repose, bulk density, tapped density, carr’s index and Hausner’s ratio was setermined for the formulation blends. [16,17]

 

Formulation of Oxybutynin ER tablets:

Preparation of core tablets:

The extended release tablet of oxybutynin was formulated by wet granulation technique. Briefly, oxybutynin chloride, klucel HF, pharmatose 200 M, aerosol and avicel PH101 were sifted through #40 while hydrogenated vegetable oil was sifted through #60 and were collected separately. The ingredients of the core tablet were dry mixed in a rapid mixer granulator for 10 min with impeller ran at slow speed and chopper off. The granulation was done in two steps with the binder solvent added first at high impeller speed and slow chopper speed followed by the addition of binder solution. Then kneading was carried out for 120 s with slow chopper and fast impeller speed. The drying of the wet mass was done in a rapid mixer dryer at 60°C until the loss on drying was not more than 2 % w/w. Dry granules were sifted through # 60, mixed and blended together with lubritab and magnesium stearate in a double cone blender. The core tablet blend thus obtained was compressed using 7.2 mm standard concave shaped plain dies. The composition of the core tablets, enteric layer coating and film coating is shown in table 1.

 

Enteric coating:

The enteric coating solution was prepared by dissolving Hypromellose E5 in purified with continuous stirring until a clear solution was formed.  To the above solution, aquacoat ECD-30 was added with stirring to form a uniform dispersion. Triethyl cellulose and talc were then added to the above dispersion and was kept under continuous stirring, during the coating process. The coating parameters were set as shown in table 2. The coating process was continued till target weight build up was achieved. Once the desired weight was achieved, pan speed was reduced and spraying of enteric coating dispersion was stopped and the tablets were warmed at the temperature of 38°C – 40°C for one hour.

 

Film coating of Tablets:

The film coating solution was prepared by slowly dissolving opadry (aqueous moisture barrier system) in water followed by homogenization for 20 minutes. The solution was kept under continuous stirring, during the coating process. The coating was continued till target weight build up was achieved. The coating parameters were followed as shown in table 2. On completion of coating process, the tablets were warmed at 40°C for one hour and then stored in containers until further use. The specifications of various parameters used in enteric coating and film coating are shown in Table 2.


 

Table 1: Formulation of Extended Release tablets of Oxybutynine Chloride.

INGREDIENTS

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

F11

Oxybutanin chloride

15

15

15

15

15

15

15

15

10

15

5

Lactose (Pharmatose)

34.5

54.5

54.5

62.5

72.5

82.5

72.5

72.5

77.5

72.5

82.5

HPC( Klucel)

70

50

50

40

40

30

40

40

40

40

40

MCC(Avicel PH-101)

60

60

60

60

60

60

60

60

60

60

60

Purified water

-

q.s

-

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

Isopropyl Alcohol

-

-

q.s

q.s

-

-

-

-

--

-

-

Aerosil 200pharma

0.5

0.5

0.5

0.5

0.5

0.5

0.5

0.5

0.5

0.5

0.5

Hydrigenated vegetable oil (Lubritab Type1)

20

20

20

20

10

10

10

10

10

10

10

Light.Magnesium.Sterate

-

-

-

2

2

2

2

2

2

2

2

Core tablet weight

200

200

200

200

200

200

200

200

200

200

200

Extended release coating

10%

10%

5%

5%

5%

5%

5%

2.5%

5%

5%

5%

Aquacoat ECD -30

9.6

9.6

4.8

4.8

4.8

4.8

3.2

2

4

4

4

Triethylcitrate PG/NF

1.6

1.6

0.8

3.2

3.2

3.2

4.8

2

4

0.8

0.8

HPMC E5 cps

6.4

6.4

3.2

3.2

3.2

3.2

4.8

2

4

4

4

Talc

2.4

2.4

1.2

1.2

1.2

1.2

1.2

0.6

1.2

1.2

1.2

Purified water

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

ER coated Tablet weight

220

220

210

210

210

210

210

205

210

210

210

Film coating

Opadry Grey

5.5

5.5

5.25

5.25

5.25

5.25

5.25

5.125

-

5.25

 

Opadry Pink

-

-

-

-

-

-

-

-

5.25

-

-

Opadry Yellow

-

-

-

-

-

-

-

-

-

-

5.25

Purified water

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

Total tablet weight

225.5

225.5

215.25

215.25

215.25

215.25

215.25

210.125

215.25

215.25

215.25

 


Table 2: Coating Parameters

Parameter

Specifications

Enteric coating

Film Coating

Inlet Temperature

45-50°C

50-60°C

Exhaust Temperature

38-42°C

40-42°C

Atomization pressure

1.2 kg/cm2

1.2 kg/cm2

Coating pan speed

6-8 rpm

6-8 rpm

Spray rate

2-5 g/min

2-5 g/min

Needle gun diameter

0.8 mm

0.8 mm

 

Evaluation of Core, Enteric coated and Film Coated tablets: [18, 19]

The core tablets, enteric coated tablets and the filem coated tablets were tested for various post compression characteristcs such as thickness, hardness, friability, weight variation and drug content.

 

In vitro Dissolution Studies:

The in vitro drug release studies were carried out using USP type III (reciprocating cylinder) dissolution apparatus operated at 25 dpm. The dissolution was performed in 250 ml of simulated gastric fluid (0.1N HCl) for 2 h followed by testing in phosphate buffer pH 6.8 for the remaining period with the temperature maintained at 37 ± 0.5°C. An aliquot (5ml) was withdrawn at specific time intervals up to 24 h and drug content was determined by UV-visible spectrometer at 220.0 nm. Sample quantification was based on previously constructed analytical curves. The dissolution profile of each batch of tablet was then compared with the release of drug from innovator’s product (Ditropan XL®).

 

Calculation of f2 value between ER matrix tablet and innovator’s product:

There are several methods for dissolution profile comparison. f2 is the simplest among those methods. The following equation defines f2. Tt and Rt show the average dissolutions of the test and reference products at the time point (t), respectively, and n is the number of time points at which the average dissolutions are compared [20].

f2 = 50 X Log {[1 + (1/n) å t=1 n (Rt - Tt ) 2 ] –0.5  X 100}

 

Drug Release Kinetics:

The in vitro release data obtained from the dissolution studies was fitted into various kinetic models such as, zero order, first order, Higuchi and Korsemeyer-Peppas models to determine the mechanism of release of drug from the optimized ER tablets [21].

 

Stability Studies:

The stability studies were carried out for the most satisfactory formulation as per ICH guidelines Q1A (R2) to assess the drug and formulation stability. The optimized formulation was sealed in HDPC bottles and sealed with aluminium foil then capped. The samples were retained in humidity chamber maintained at 25 ºC/ 60 % RH and at 40 ºC/75% RH for two months. At the end of studies, samples were analysed for the post compression parameters and drug content for assessing the stability of the formulation [22].

 

RESULTS AND DISCUSSION:

The present study was aimed at preparation and evaluation of extended-release matrix formulations of Oxybutynin chloride by wet granulation technique for the treatment of over reactive bladder as an alternative to highly expensive and time taking process OROS technology. The formulation thus developed was compared with the dissolution profile of the innovator’s product Ditropan XL (Osmotic Bi Layered Tablet) tablets. The extended-release drug delivery of tablets can be achieved by using the matrix core tablet of Oxybutynin chloride with Klucel HF in core tablet and functional coating with Aquacoat ECD-30 and Hypromellose E5 premium LV. The film coating with given with opadry grey, opadry pink and opadry yellow. Hydroxy propyl cellulose (HPC) is non-ionic water-soluble cellulose ether with a remarkable combination of properties. HPC hydrates rapidly, leading to formation of diffusion controlling gel layer around the tablet core [18]. Aquacoat ECD 30 comprise of EC in the dispersion phase as spherical particles in the size range of 0.1 to 0.3 µm. It is used for the aqueous film coating of solid dosage forms to extend drug release, taste mask, or to protect against moisture [23]. Hypermellose is a well-established polymer for use in extended-release tablets. The combination is used in order to achieve the optimal release characteristics from the tablet. Opadry is an immediate aqueous film coating system protect drug from the effect of moisture and light for an extended period of time without interfering with the release profile of the drug and are preferred materials for producing film coating formulations in terms of performance and global acceptability [24].

 

API Characterization:

Oxybutynin chloride was subject to organoleptic characteristics such as colour, odour, taste, and appearance by visual observation. The drug was also evaluated for its melting point, loss on drying and solubility characters. The results were found satisfactory and complied with the official standards. The micrometric properties of pure drug of Oxybutynin chloride were evaluated by angle of repose (32.3°C indicated as good flow), bulk density (0.198 g/cc), tapped density (0.353g/cc), Carrs Index (43.75% indicated as very poor flow) and Hausners Ratio (1.78 indicated as very poor flow properties). The characteristics of the pure drug are tabulated in the table 3.

 

Table 3: Characterization of Oxybutynin chloride pure drug

Parameter

Characteristics

Odour

Odourless

Taste

Tasteless

Appearance

Crystalline powder

Melting point

128°C.

Loss on drying

1.5% w/w

Solubility

Freely soluble in methanol (0.8 parts per part of solute) and very freely soluble in water (3 parts per part of solute)

 

Compatibility Studies Using FTIR Spectroscopy:

The FTIR spectra of pure Oxybutynin chloride and formulation blend was performed. Similar characteristic peaks were observed for the drug-excipients mixture, indicating the absence of possible chemical interaction between the drug and excipients. From the figure 1A and1B, it can be seen that the major functional group peaks observed in spectrum of drug with all the polymers remains unchanged as compared with spectra of Oxybutynin chloride. The characteristic peaks and frequency of Oxybutynin chloride and drug-excipients is shown in table 4.

 

Table 4: Characteristic peaks of Oxybutynin chloride and drug-excipients:

Characteristic Peaks

Frequency range (cm-1)

Frequency of pure drug (cm-1)

Frequency of drug-excipients

OH stretching

3600-3500

3500.92

3530.92

OH Bending

1100-1070

1084.03

1064.03

C-H stretching

3200-3100

3095.95

3099.85

C-N stretching

1350-1100

1105.25

1208.33

C=O stretching

1750-1735

1745.61

1732.59

C=C

1600

1599.04

1578.11

 

 

Figure 1:  FTIR Spectrum; (A) Oxybutynin Chloride; (B) Formulation blend

 

Precompression characterization:

The precompression characteristics such as bulk density, tapped density, Carr’s index, Hausner’s ratio and angle of repose were studied. The granules prepared by wet granulation method were evaluated for various flow properties. The bulk densities of granules of F1 to F6 formulations ranged from 0.55 to 0.614 g/ml. The Tapped density of the powder blends of F1-F11 formulations ranged from 0.611 to 0.647 g/ml. The Carr’s index and Hausner’s ratio of F1-F11 were between 6.18 -11.29 and 1.04 to 1.12, respectively. Thus flow property of pre-compressed blends were indicated as excellent. The same composition of F7 blend used in core tablet to F8-F10. The results of the pre compression characters are shown in table 5.

 

Table 5: Physical properties of pre-compressed blend

Formulation Code

Angle of repose

(o)

Bulk density (g/mL)

Tapped density (g/mL)

Carr’s Index

(%)

Hausner’s Ratio

F1

32.5

0.607

0.647

6.18

1.066

F2

31.6

0.566

0.626

9.58

1.106

F3

28.4

0.556

0.612

9.15

1.10

F4

27.2

0.55

0.62

11.29

1.127

F5

32.96

0.611

0.639

4.38

1.046

F6

32.06

0.614

0.646

4.95

1.052

F7

31.01

0.601

0.631

10.29

1.067

F8

31.01

0.601  

0.631

10.29

1.067

F9

31.01

0.601

0.631

10.29

1.067

F10

31.01

0.601

0.631

10.29

1.067

F11

31.01

0.601

0.631

10.29

1.067

 

Post-compression Parameters for Oxybutynin Hydrochloride Extend Release tablets:

The post compression parameters of the F1-F11 tablets were evaluated for thickness, hardness, friability, weight uniformity and uniformity content. From F1-F6, the matrix polymer concentration gradually decreased from 35% to 15% in core tablet and with 60:40 ratio of 5% ethyl cellulose: hypromellose E5. From F7-F11, 20% of matrix polymer was used in all core tablets but in coating, various concentration ratios of ethylcellulose and hypromellose E5 were used. The results were tabulated in table 7. The hardness of F1-F11 formulations ranged from 13 to 14 kg/cm2 and were within the range of desired limits of hardness. Hence all the formulations passed the test for hardness. The thickness of F1-F11 formulations were found between 4.5 to 5.2 mm which was according to Pharmacopoeial specification. The weight variation test was performed and the tablets complied with the pharmacopoeial specification for weight variation limit. Friability of the tablets was determined by using Roche friabilator. The friability of all the F1-F11 formulations was determined, and the values were in the range from 0.04 to 0.17 %. Friability values below 1% were an indication of good mechanical resistance of the tablets. The percentage drug content of all the F1-F11 tablets was found to be in the range of 91.29 to 99.06 %. This was within the acceptable limits. The preparation complies with the test if the individual content of tablet is 89 to 101% of the average content.

 

In vitro Drug Release Studies:

The results of the in vitro release profile of developed formulations F1 to F11 is shown in figure 2A. The formulation F1-F8 and F10 had 15mg of label claim of Oxybutynin chloride. Here the matrix tablets were formulated using 35% HPC & Enteric coated using 10% polymer blend and film coating using Opadry grey which is very viscous in nature. The release of drug depends not only on the nature of matrix but also upon the enteric coating. As the percentage of polymer decreased, the rate of drug release increased.

 

Among all other formulations, F10 formulation prepared using 15 mg of label claim Oxybutynin chloride and 5% of 50:50 in ratio of Aquacoat ECD-30 and Hypromellose E5cps with opadry pink in 5.25 % film coating exhibited drug release very much comparable at almost all time points to innovator as shown in figure 2B. Hence formulation F10 was used for further evaluations.

 

 

Figure 2: In vitro dissolution profile of (A) Formulations F1 to  F11 in comparison with Innovator’s Product; (B) F10 in comparison with Innovator’s Product.

 

Release kinetics was showed optimized fomulation F10:

The release profile of the optimized formulation of F-10 was applied to the different kinetics equation such as zero order, first order, Higuchi, korsmeyeres peppas in order to define the most plausible mechanism of drug release from the extended release tablet [25]. As shown in figure 3 drug release data was best explained by first order equation, as the plots showed the highest linearity (r2 = 0.980) indicating that the rate of drug release is concentration dependent., followed by Higuchi’s equation (r2= 0.946). Higuchi’s kinetics explains that drug diffuses at a comparatively slower rate as the distance for diffusion increases.

 

Figure 3: Release kinetics of optimized formulation F10; (a) zero order; (b) First order; (c) Higuchi model; (d) Korsemeyer Peppas model

The corresponding plot (log cumulative % drug release vs. log time) for the Korsmeyer-Peppas equation indicated a good linearity (r2= 0.882). The diffusion exponent “n” was between 0.45-0.89, which indicates mechanism of release is non-fickian diffusion type. This indicates that the drug release was controlled by more than one process, i.e., both diffusion and dissolution[26].

 

Determination of Similarity Factor Study:

The similarity factor (f2) was defined by CDER, FDA, and EMEA as the “logarithmic reciprocal square root transformation of one plus the mean squared difference in percentage dissolved between the test and reference release profiles”. The similarity factor (f2) was calculated to optimized formulation of F-10 dissolution profile with compared to Innovator dissolution profile. The result was found to be 92.47% indicating that as Test and Reference dissolution profile were similar[27,28].

 

Stability Studies:

The stability studies of optimized formulation F-10 were evaluated after storage period by variouys physicochemical parameters. There were no changes physical appearance and thickness. While the hardness of the tablet gradually decreased, the friability of the tablet did not show any changes up to 2 month. The assay of Formulation 10 showed the drug content to be 99.30% initially, after 1 month it decreased to 98.29% and 99.05%, later it was found to be 97.30% and 98.69% after 2 months at 40°C /75%RH and 25°C /60%RH  respectively as shown in figure 4. Thus the product is considered to be stable as it did not show any significant changes in its properties under the tested conditions.

 

Figure 4: Stability Studies of Optimized Formulation of F10

 

CONCLUSION:

Extended-release Matrix tablet system is one of the approaches for controlled release systems. This approach was used for the formulation development of controlled release tablets of oxybutynin with a retarding polymer. The drug release could be achieved for 24 h with a single dose. The developed formulation reduced the frequency of dosing, with minimal side effects and were as effective as osmotic controlled release oral delivery system. It can be conclusively stated that development of extended-release formulation of hydrophilic drugs does not necessitate the inclusion of the hydrophobic polymers to hydrophilic polymers and the desired extended release of hydrophilic drugs is also viable with hydrophilic polymer alone using suitable coating materials. The optimized formulation, F10 has desirable physicochemical properties, release characteristics and stability. Thus the extended release matrix tablets of oxybutynin chloride developed in this study has immense potential to develop into a marketed product following the testing in animals and human volunteers.

 

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Received on 25.04.2020            Modified on 20.12.2020

Accepted on 08.04.2021           © RJPT All right reserved

Research J. Pharm. and Tech 2021; 14(12):6558-6564.

DOI: 10.52711/0974-360X.2021.01135