Preparation and Evaluation of Mucoadhesive Microcapsules of Captopril for Oral Controlled Release

 

Sanjib Bahadur1*, Ranabir Chanda2, A. Roy1, A. Choudhury1, S. Das1,and S. Saha1

1GRY Institute of Pharmacy, Vidya Vihar, Borawan, Khargone, (M.P) – 451228

2Department of Pharmaceutics, Himalayan Pharmacy Institute, Majhitar, East Sikkim–737136

* Corresponding Author E-mail:  sanjib_pharmacist@yahoo.co.in

 

ABSTRACT

Captopril is an ACE inhibitor that is used for the treatment of hypertension. The purpose of this study was to encapsulate the drug in different polymer having mucoadhesive property and thus combining the advantages of microparticulates with mucoadhesive drug delivery system. The microcapsules with a coat consisting of alginate and a mucoadhesive polymer such as sodium carboxymethylcellulose (SCMC), methylcellulose, Carbopol 934P and hydroxyl propylmethylceullulose (HPMC) E15V were prepared by ionotropic gelation technique, where gelation was achieved with oppositely charged counter ions to form microparticles. The prepared microcapsules were subjected for various evaluations. The resulting microparticles were discrete, large, spherical and free–flowing. Captopril release from these microcapsules was slow and extended over longer period of time. Drug release for some formulation was diffusion controlled and others exhibited anomalous behavior. The prepared microcapsules exhibited good mucoadhesive property in the in vitro wash–off test. Among all formulations, batch containing sodium alginate and carbopol 934 showed higher encapsulation efficiencies, good flow property and maximum prolongation of drug release and good mucoadhesion properties.

 

KEY WORDS                                 Captopril , microparticulates, mucoadhesion properties.         .

 


 

INTRODUCTION:

There is always significant interest in the development of delivery systems via the oral route due to patient compliance and acceptability. These dosage forms are swallowed so that the pharmaceutically active substance can be absorbed via the Gastro-intestinal tract (GIT). The traditional oral delivery system has certain disadvantages that needed to be overcome such as the short retention time in GIT1.

 

Many concepts have been proposed in recent years to provide a dosage form with a longer transit time and therefore a more efficient absorption2–6. The concept of bioadhesion or more specifically mucoadhesion is one of them to increase gastric retention of drug. Mucoadhesion is a topic of current interest in the design of drug delivery systems to prolong the residence time of the dosage form at the site of application or absorption and to facilitate intimate contact of the dosage form with underlying absorption surface to improve and enhance the bioavailability of drugs7.

 

One of the common methods of controlling the rate of drug release is microencapsulation. Microencapsulation by various polymers and their applications are described in standard text books8. The encapsulation techniques (e.g. coacervation–phase separation, normally involve the polymers as carriers which require large quantity of organic solvents for their solubilization. As a result the doses become vulnerable to safety hazards, toxicity and increase the cost of production making the techniques non–reproducible, economically and ecologically unsuccessful at an industrial scale. These concerns demand a technique free from any organic solvent. Thus the microcapsules were prepared by using ionotropic gelation technique9. This study describes the development and evaluation of mucoadhesive microcapsules of Captopril for oral controlled release. Captopril requires controlled release owing to its short biological half life and low dose but frequent dosing interval10.

 

The objective of this study is to prepare and evaluate the controlled release mucoadhesive microcapsules of Captopril that can be tabeletted or capsulated, exhibiting same antihypertensive effect as that of conventional tablet, but reducing the frequency of dosing and thus increasing patient compliance. The novelty of this research work is in combining the advantage of particulate system (microcapsule) and mucoadhesive drug delivery system by taking sodium alginate and mucoadhesive polymers.

 

MATERIALS AND METHOD:

Materials:

Captopril was received as a gift sample from M/s Unicure (India) Pvt. Ltd. Noida (UP). Sodium carboxy- methylcellulose (Sodium CMC, with a viscosity of 1500-3000 cps of 1%w/v aqueous solution at 25°C), carbopol 934P (with viscosity of 2050–5450 cps of 0.2%w/v solution) and calcium chloride were purchased from M/s s.d fine chem. Ltd. Mumbai. Methyl cellulose (with a methoxy content of 28–32% by weight and visocity of 3000–5000 mPas in 2%w/v solution at 20°C), hydroxyl propylmethylcellulose E15V (with apparent viscosity of 15cps and methyoxy content of 23.7% by weight) and sodium alginate were procured form M/s Loba Chemie Pvt. Ltd. Mumbai. All other reagents used were of analytical grade.

 

A

B

C

Figure 1: SEM photograph of prepared microcapsules FC2 at different resolution (A – X35; B – X4000; C – X10000)

 

Preparation of microcapsules:

The ionic gelation method was used for the preparation of microcapsules. Sodium alginate and the polymers were dissolved in distilled water (40ml) to form a homogenous polymer solution. Captopril (core material) was added to the polymer solution and mixed thoroughly to form a smooth viscous dispersion. The resulting dispersion was then added dropwise to 250ml calcium chloride solution (10%w/v) through a syringe with needle of size No. 20. The added droplets were retained in the calcium chloride solution to complete the curing process and to produce spherical rigid microcapsules. The microcapsules were collected by decantation and product thus separated was washed with water and dried. The microcapsules prepared along with their coat composition are listed in table No. 1

 

Process variables:

The following process variables were investigated–needle size; concentration of calcium chloride solution; curing time; height of dropping and drying temperature and different batches then produced were analyzed for size; shape, drug content and microencapsulation efficiencies. On the basis of results obtained, all the process variables were optimized.

 

Characterization of Microcapsules:

Particle size determination 11

Particle size analysis was done by sieving method using Indian standard sieves #8, #10, #12, #20, #25. Average particle size was calculated using the formula–

d avg = Σdn / Σn  ----------------- (1)

Where, n is frequency weight and d is the mean diameter

 

Angle of repose 11               

Angle of repose was employed to assess the flowability. Angle of repose, θ, was determined by fixed funnel method and calculated as

θ = tan – 1 (h/r)   ----------------- (2)

 

Surface morphology of microcapsules

The shape and surface morphology of the microcapsules were examined by Scanning electron microscope (SEM). The samples for SEM were prepared by lightly sprinkling the microcapsules on a double adhesive tape stuck to an aluminum stub. The stubs were then coated with gold and photomicrographs were taken with a scanning electron microscope (Jeol JSM–6700F, Tokyo, Japan).

 

Drug content

Captopril content in the microcapsules was calculated by UV-spectrophotometric method based on the measurement of absorbance at 212nm in 0.1N HCl solution. 10mg of microcapsules were weighed and kept in 25ml of 0.1N HCl solution overnight so that the drug from microcapsules diffuses out. After suitable dilution the absorbance of the microcapsule were measured using a Shimadzu UV–1700 double beam spectrophotometer (SHIMADZU CORPORATION, Japan). This method was repeated 3 times

 

Microencapsulation efficiency was calculated using the formula 3,

MEE = (estimated % drug content/ Theoretical % drug content) x 100     ---------- (3)

Percentage yield of the prepared microcapsule was calculated by using the formula 4,

% Yield = (amount of microcapsules obtained / theoretical amount) x 100   ---------- (4)

 

 

Drug–polymer interaction 12

To determine any interaction between drug and polymer, Fourier Transform Infrared (FTIR) study was carried out. FTIR spectra were recorded on FTIR–8400S (SHIMADZU CORPORATION, Japan). Samples were compressed with Potassium bromide and transformed into disk. Disk was applied to the centre of the sample holding device and scanned between 4000–400cm–1 at a resolution of 4cm–1. The IR scans were processed using Shimadzu IR Solution 1.30 and represented as percentage Transmittance on a common scale.

 

Determination of Moisture content13

The prepared microcapsules were filled into empty capsule shells and the capsules were subjected to moisture content study, by placing them at 60°C for 10mins in an IR moisture balance.

 

Loose Crystal Surface Study14

10mg of microcapsules was suspended in 25ml of 0.1N hydrochloric acid. The samples were shaken vigorously for 15min in a cyclo mixer (REMI CM–101). The amount of drug leached out from the surface was analyzed spectrophotometrically at 212nm.

 

In vitro release studies

Release of Captopril form the microcapsules was studied in 0.1N hydrochloric acid (HCl) solution using an USP XXIII 8 station Dissolution Rate Test Apparatus (Model VDA–8DR USP Standard, VEEGO, Kolkata, India) with a rotating basket stirrer at 50 rpm and 37±1ºC as prescribed for Captopril tablets in Indian Pharmacopoeia 1996. Dissolution studies were carried out in triplicate for all the formulations, employing capsules filled with microcapsules equivalent to 12.5 mg of Captopril. Samples of the dissolution fluid were withdrawn at predetermined time intervals and were assayed at 212 nm for Captopril content using UV–Visible Spectrophotometer (UV–1700, SHIMADZU CORPORATION, Japan)

 

Mucoadhesion testing by in vitro wash off test15–16

The mucoadhesive property of the microcapsules was evaluated by an in vitro adhesion testing method known as the Wash–off. Freshly excised pieces of intestinal mucosa from beef were mounted onto glass slides. About 100 microcapsules were spread onto wet rinsed tissue specimen and immediately thereafter the slides were hung onto the arm of a USP tablet disintegrating test machine (EXCEL ENTERPRISE, Kolkata, India). Then, the disintegrating test machine was operated; the tissue specimen was given a slow, regular up–and–down movement in the test fluid at about 37°C contained in a 1 L vessel of the machine. At the end of 1, 2, 5, 8, 10hrs the machine was stopped and the number of microcapsules still adhering to the tissue was counted. The test was performed at both 0.1N hydrochloric acid solution and phosphate buffer pH 6.8.

 

The adhesion number was found by the following formula:

       Na = (N / N0) x 100                --------------------- (5)

Where,  

Na = adhesion Number

N0 = Initial no. of microcapsules in the intestinal mucosa

N = No. of particle attached to mucosa after washing

 

Stability of microcapsules

The formulations showing the best performance, with respect to in vitro drug release and in vitro mucoadhesion test, were stored at 4°C, room temperature and 50°C for a month. Every week samples were withdrawn and were assayed spectrophotometrically at 212nm using 0.1N hydrochloric acid solution as blank.

 

Drug release kinetics

The dissolution data obtained was fitted to zero order 17. In order to define a model, which will represent a better fit for the formulation, dissolution data was further analyzed by Peppas and Korsmeyer equation (Power law) 18

Mt/M = K . tn            ------------------------ (6)

 

Where, Mt is the amount of drug released at time t, M is the amount of drug released at time ∞.

 

Thus  is the fraction of drug released at time t, K is the kinetic constant and ‘n’ is the diffusional exponent, a measure of the primary mechanism of drug release.

 

Mean dissolution time (MDT) was considered as a basis for comparison of the dissolution rates and was estimated by the following equation

 

 

 

Mt is the fraction of dose released in time, tˆi = (ti+ ti-1)/2 where ti is the sampling time and Mcorresponds to the amount of microcapsule taken.

RESULT:

The microcapsules prepared were found to be spherical, (as revealed in SEM studies Fig 1) discrete and free flowing. However microcapsules prepared employing sodium alginate and methyl cellulose were found to be somewhat flat in nature.

 

The percent entrapment of Captopril in all formulation was found to be good. The microencapsulation efficiency of all the formulations was in the range of 72.68 to 87.96% as shown in Table 1. From the experimentally determined


Table I: Coat composition, microencapsulation efficiency, percent yield, angle of repose and particle size of the microcapsules prepared

Batch code

Coat Core ratio

Coat

composition

Microencapsulation efficiencies

± S.D (%)

Percent yield (%)

Angle of

repose±S.D

(θ)

Particle size ± S.D (µm)

FS1

1:1

Na alg : SCMC

74.79 ± 1.74

93.95

19.42 ± 0.71

475.349

FH1

1:1

Na alg : HPMC

72.68 ± 1.59

94.80

23.02 ± 2.40

683.567

FC1

1:1

Na alg : Car 934P

85.67 ± 1.50

94.90

20.25 ± 0.19

414.138

FM1

1:1

Na alg : MC

86.19 ± 1.27

84.45

24.99 ± 1.10

832.106

FS2

2:1

Na alg: SCMC

75.73 ± 2.48

91.87

24.27 ± 0.71

598.506

FH2

2:1

Na alg : HPMC

75.49 ± 1.20

92.87

24.06 ± 0.79

640.736

FC2

2:1

Na alg : Car 934P

86.76 ± 1.68

89.10

25.04 ± 2.24

568.736

FM2

2:1

Na alg : MC

87.96 ± 1.90

85.93

26.63 ± 0.29

887.192

SCMC = Sodium carboxy methyl cellulose; HPMC = Hydroxypropyl methylcellulose; Car 934P = Carbopol 934P; MC = Methylcellulose; Na alg = Sodium alginate


 

Table II: Mathematical modeling and drug release kinetics of formulated microcapsules of Captopril

 

Batch code

Zero order Release

Peppas–Korsmeryer equation

 

MDT

 

Mechanism

K

R2

n

R2

FS1

6.690

0.996

0.470

0.965

3.20

Anomalous

FH1

6.153

0.994

0.436

0.980

3.12

Fickian

FC1

5.801

0.991

0.446

0.990

3.37

Anomalous

FM1

6.718

0.992

0.549

0.989

3.58

Anomalous

FS2

7.020

0.989

0.532

0.984

3.14

Anomalous

FH2

5.760

0.991

0.410

0.976

3.14

Fickian

FC2

5.736

0.989

0.469

0.977

3.76

Anomalous

FM2

6.505

0.995

0.532

0.987

3.49

Anomalous

 

 

yields, as reported in Table 1, it was found that about all the formulations have good yield. The average particle sizes were found to be in the range of ­­­414.138 to 887.192µm. The average particle size of different formulation is reported in Table 1. The average particle size of microcapsule increases as the concentration of the polymer increases. Formulation FS1, FS2, FH1, FH2, FC1, and FM1 shows excellent flowability as expressed in terms of angle of repose (<25) and the formulation FC2, and FM2 shows good flowability.

 

Fourier Transform Infrared (FTIR) spectra for the pure drug were recorded and compared with the FTIR spectra of the formulations. Captopril gives characteristic peaks at wave numbers 1589, 1742, 1202, 1192, 1229 and 1245. The peak at 1589 and 1742 cm–1 corresponds to C=O str whereas the peaks 1202, 1245, and 1229 corresponds to peaks due to C–N vib and the peak at 1192 corresponds to C–S str. When the characteristic peaks of Captopril (Fig 2) were checked in the formulations, it was found that the peaks were also present in the formulation with little difference. Thus FTIR studies revealed that there was no shift in peaks of the formulations containing Captopril, sodium alginate and mucoadhesive polymers when compared to pure Captopril, indicating there is no interaction between Captopril and other polymers used. 

 

 

 

The in vitro release profile of the microcapsules in 0.1N HCl solution is shown in Fig 3 and 4. Captopril release from formulation FC1, FM1, FH2, FC2 and FM2 was slow and spread over extended period of time whereas the release from FS1, FH1, FS2 were comparatively faster which could be attributed to its high rate and extent of swelling.               The release rate and R2 values for different formulations when fitted into different models are presented in Table 2. Mean dissolution time (MDT) is also presented in Table 2. The R2 values show that all the formulations follow zero order release rate kinetics (R2 ≥ 0.989), Table 2. The n value for formulation with batch code FH1, FH2 is 0.436 and 0.410 respectively; this indicates that the Fickian type of transport mechanism might be operative in release of Captopril from encapsulated microcapsules. Whereas the n values for formulation FS1, FS2, FC1, FC2, FM1, FM2 ranges from 0.446 to 0.549. This indicates that the formulation follow anomalous type of mechanism for drug release from the encapsulated microcapsules. From the release profile better formulations were selected on the fact that the microcapsules were designed to control the release of the drug for 12hrs and the formulations selected were controlling and releasing almost 100 percent of drug at 12hrs. The mean dissolution time (MDT) increases with increase in the polymer concentration with exception for the formulation FM2.

 

The mucoadhesion of the selected microcapsules were studied by in-vitro wash off test. The microcapsules for this test were selected on the basis of their in-vitro drug release profile. Formulations FC2, FM1 were selected for this test. The wash off was comparatively rapid in phosphate buffer pH 6.8 than in acidic fluid 0.1N hydrochloric acid. The result of the wash off test and adhesion number is reported in Table 3 that indicates fairly good mucoadhesive property of the microcapsules prepared from sodium alginate and a mucoadhesive polymer at both acidic medium and phosphate buffer pH 6.8.

 

The % drug content of the formulation during accelerated stability studies at temperature 4°C, room temperature, and 50°C was found to in the range of 94.93–98.89 and 92.88–97.15 respectively. The % drug content of the formulation after exposure to such conditions reveals that the formulations are stable.

DISCUSSION:

The important features of good drug delivery system include versatility to carry drugs with different physicochemical properties, simplicity of method of preparation and feasibility for mass production. With the use of organic solvents for preparing particulates, there are two main problems: toxicity due to the residual organic solvents and instability of certain drugs especially those belonging to the class of peptides and proteins 19.

Thus the ionotropic gelation method was chosen to avoid the use of organic solvents. The dispersion of polymer and drug was added dropwise to the calcium chloride solution. The spherical particulates were formed spontaneously as soon as the sodium alginate drop touched the calcium chloride solution. Freshly prepared particulates were spherical. Multivalent ion such as calcium ion, exchange with sodium ion of sodium alginate solution to form calcium alginate gel. On placing the gel in a solution containing monovalent cations, the reversible process takes place, resulting in the gel to sol transform. Thus, the dried particulates swell in aqueous solution. As a result of this erosion, the encapsulated compound gets released from the particulates.

 

Table III: Adhesion number based on in vitro wash off test

 

Medium

Time (in hr)

1

2

5

8

10

Batch code

 

0.1N HCl

FC2

84

82

74

69

65

FM1

73

62

55

43

29

 

PB pH 6.8

FC2

75

68

60

52

46

FM1

68

60

51

42

30

PB = Phosphate buffer; HCl = hydrochloric acid

 

The prepared microcapsules were then subjected for various evaluations. Particle size of the microcapsule was large. Angle of repose was increased as the amount of the polymer is increased. However angle of repose indicates that the microcapsules have better flow property. The better flow property indicates that the microcapsules produced are non aggregated. Drug entrapment efficiency of microcapsules increases with increase in the concentration of sodium alginate, sodium carboxymethyl cellulose, hydroxylpropyl methyl cellulose K4M, Carbopol 934 and methyl cellulose. The extent of drug loading influenced the particle size distribution of microcapsules. When the loading is high the particles formed were of larger size. It has been reported that the drug entrapment efficiency is closely related to coat/core ratio 20. Higher cumulative amount of drug release for formulation FS1, FH1 may be due to inability of the polymer to hold the drug. In theory, the high amount of water uptake by HPMC K4M may lead to considerable swelling of the polymer matrix, allowing drug to diffuse out at a faster rate 21.

 

Figure 3: in vitro release profile of the prepared microcapsules with batch code FS1, FH1, FC1, FM1

 

The dissolution profiles were quantified by calculation of the mean dissolution time (MDT). MDT reflects the time for the drug to dissolve and is the first statistical moment for the cumulative dissolution process that provides an accurate drug release rate 22. It is a more accurate expression for drug release rate than the time of 50% dissolution (T50%). A higher MDT value indicates greater drug retarding ability 23.

 

Figure 4: in vitro release profile of the prepared microcapsules with batch code FS2, FH2, FC2, FM2

 

The release profile of each formulation was fitted into different release model and Peppas and Korsmeyer equation was used to determine the mechanism and rate of release of drug. The ‘n’ value in Peppas and Korsmeyer equation represents diffusional exponent and for spherical particles, if it is less than 0.43, diffusion is the major driving force, and is normally said to follow Fickian diffusion and when ‘n’ is between 0.43 to 0.85, the drug release is mainly controlled by both swelling and diffusion mechanism and follows anomalous release. When ‘n’ is more than 0.85, it follows perfect zero order release kinetics.

 

Drug stability is a key quality attribute to be considered during the product development process. Forced degradation studies chemical stability of the drug molecule under various stress conditions, and well designed degradation model systems can serve as a predictive tool to probe the long–term drug stability in the actual formulations. Within the pharmaceutical industry, the general practices for conducting forced degradation studies includes stressing the bulk drug under accelerated temperature/ humidity conditions alone and in the presence of excipients, as well as exposing drug solution to acid/ base, heat, light, hydrogen peroxide and radical indications to probe the intrinsic sensitivity of the drug molecule to hydrolytic, thermal, photolytic, and oxidative degradation reactions 24.

 

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Received on 27.03.2008       Modified on 22.04.2008

Accepted on 28.04.2008      © RJPT All right reserved

Research J. Pharm. and Tech. 1(2):  April-June. 2008;Page 100-105