logo

International Journal
of Pharmaceutical Sciences and Drug Research

ISSN 0975-248X
CODEN (USA): IJPSPP
DOI PreFix: 10.25004

Volume No.: 1 (2009) Issue No: 2

International Journal of Pharmaceutical Sciences and Drug Research
12009 (2009) ,102Pages

ResearchArticle

Design, Development and Characterization of Extended Release Multiunit Particulate System of Anti-Inflammatory Drug


Dhiren Daslaniya*, Manish Patel, Amarish Shah

UGC Approved Journal

  • Views 3
  • Citations 46
  • ePub 5
  • PDF 1

1. Abstract


Multi unit particulate system has long been employed to improve the bioavailability of drugs. Mesalamine pellets were prepared by Coating drug solution on sugar sphere followed by various functional coating. The influence of rate controlling membrane made up of Eudragit RSPO and Eudragit RLPO in combination with delay release polymer coating with Eudragit L100 in different proportions on drug release kinetics was studied. Pellets were for the various parameter like Physical characteristics, assay and in-vitro dissolution profile. The study confirmed that mesalamine can be delivered by multi unit particulate system into lower part of intestine. Optimized formulations were evaluated for In-vitro release profile. The optimized formula was stable at accelerated storage condition 40°C / 75 % RH. Prepared Pellets can be used in the treatment of the ulcerative colitis.


Introduction


Pelletization is an agglomeration process that converts fine powders or granules of bulk drugs and excipients into small, free flowing, spherical or semi spherical units, referred to as pellets [1]. Pellets range in size, typically, between 0.5 – 1.5 mm, though other sizes could be prepared. Pellets are for pharmaceutical purposes and produced primarily for the purpose of oral controlled-release dosage forms having gastro resistant or sustained-release properties or the capability of site-specific drug delivery. For such purposes, coated pellets are administered in the form of hard gelatin capsules or disintegrating tablets that quickly liberate their contents of pellets in the stomach. Controlled-release oral solid dosage forms are usually intended either for delivery of the drug at a specific site within the gastrointestinal tract or to sustain the action of drugs over an extended period of time. With pellets, the above mentioned goals can be obtained through the application of coating materials (mainly different polymers), providing the desired function. Pellets may be manufactured by using different methods according to the application and the choice of producer. The most widely used processes are extrusion and Spheronization and solution or suspension layering, and powder layering. One of

*Corresponding author: Mr. Dhiren Daslaniya

Arihant School of Pharmacy and BRI, Gandhinagar, Gujarat, India. Phone No.: +919428605283

Email: dhirendaslaniya@yahoo.co.in

the new classes of drug delivery systems, multi unit particulate system, which offer many advantages over conventional dosage forms, like increased GI residence, possibility of releasing drug at a slow and constant rate, accurate dosing and increased shelf life. [2- 3]

Mesalamine (5-aminosalicylic acid) is the active component of sulfasalazine; the specific mechanism of action of mesalamine is unknown; however, it is thought that it modulates local chemical mediators of the inflammatory response, especially leukotrienes; action appears topical rather than systemic. [4]

The aim of the present investigation is to study the drug release kinetics of mesalamine from pellets with rate controlling membrane made up of Eudragit RSPO and Eudragit RLPO.

MATERIALS AND METHODS

Mesalamine was obtained as gift sample from Cadila health care Ltd. Moraiya, Gujarat. Eudragit RSPO, Eudragit RLPO and Eudragit L100 were obtained as a gift sample from Relax Pharmaceuticals, Baroda, Gujarat.

Preparation of drug layered Pellets

Drug layered pellets were prepared by aqueous drug layering coating method. In the present study two different type of drug layered pellets. F1 and F2, were prepared. The detail compositions are given in Table 1.

Preparation of delay release coating on ER polymer coating

Table 1: Formulation of Aqueous drug layering on Sugar sphere.

Ingredients

F01 (530%)

F02 (796%)

Sugar sphere

600

400

Mesalamine

3000

3000

HPMC 50 cps

144(4% w/w)

144(4% w/w)

Talc

24

24

PEG - 400

16

16

Purified water

9552

9552

Total

3784

3584

All quantity in gm

Table 2: Formulation of extended release polymer coating on drug loaded pellets.

Ingredients

F02A (10% )

(7:3)

F02B (12%)

(6:4)

F02C

(10%)

F02D

(14%)

F02E (7%) (7:3)

F02F (10%) (7:3)

F02G

(15%)

Drug loaded pellets (F01 & 02)

250

250

250

250

250

250

275

Ethyl Cellulose 7 cps

17.5

18.0

--

--

--

--

--

Hypromellose 3 cps

7.5

12.0

--

--

--

--

--

Eudragit NE 30 D*

--

--

83.30

--

--

--

--

Eudragit RLPO

--

--

--

35.0

5.25

7.5

--

Eudragit RSPO

--

--

--

--

12.25

17.5

--

Eudragit L 100

--

--

--

--

--

--

41.25

Acetyl mono Glycerate

1.0

1.2

--

--

--

--

--

Tri ethyl Citrate (20%)

--

--

--

7.0

3.50

5.0

8.25

Talc (30%)

--

--

7.50

10.5

5.25

7.5

12.38

Isopropyl Alcohol

222.3

266.76

--

301.87

151.0

215.6

569.2

Acetone

--

--

--

301.87

150.0

215.6

--

Methylene Chloride

222.3

266.76

--

--

--

--

--

Purified water

49.4

59.28

83.4

--

--

--

142.30

Total

All quantity in gm

  • Solid of 25 g of Eudragit NE 30 D ≈ 83.30 g of Eudragit NE 30 D Solution

Preparation of extended release polymer coating

The pellets were taken from the optimized drug loaded pellets. Here formulation for polymer coating on drug loaded pellets was carried out by taking different coating levels. Different concentration of different polymers used for controlling the release of drug from the drug loaded pellets. The composition of formulation of trial series for obtaining extended drug release from pellets was shown in the Table 2.

This delay release coating was applied on the extended release polymer coated pellets because formulation have target to release the drug in colon for local effect. The delay release coating will be done with Eudragit L100. The film of Eudragit L100 is not degrade in stomach and protect the formulation from the acidic environment and also soluble in basic pH. So, different coating was done with the Eudragit L100 polymer to get the desired release profile. The most recommended plasticizer is Triethyl citrate in the concentration of 20%. The detail compositions are given in Table 3.

Evaluation of pellets [5, 6, 7]

The above pellets were evaluated for various parameters like, Physical Description, Density, Particle size Analysis, Aspect ratio, Assay, Related Substances and In-vitro dissolution profile. The pellets were free flowing; light pink in color with rough surface. Particle size analysis was done by the Sieve analysis by USP sieve shaker. Pellets were passed from the #16 and retained from the #30 sieve. Assay of mesalamine was carried out by the HPLC method by dissolving the drug to 150 ml of water and sonicate with occasional shaking for about 45 minutes. . Make volume up to the mark with water. Dilute 5.0 ml 0f this solution to 25 ml with water and mix. Filter the solution through 0.45 µm Millipore PVDF filter; collect the filtrate and analyzed for mesalamine content at 220 nm in HPLC.

In-vitro Release studies

In-vitro drug dissolution study was performed for the % drug release of the mesalamine from the formulation at the regular time interval. The detail of % drug release from various formulations is given in Table 4.

Capsule filling of pellets

Capsules were filled with two different kinds of pellets in different percentages. The detail of capsule filling was given in Table 5.

Stability study

The optimized formulation was packed in aluminum foil. It was than stored at 40°C / 75 % RH and 60°C / 85 % RH according to ICH. Samples were withdrawn after three month and evaluated for change in drug release pattern. The detail of stability study was given in Table 6.

Table 3: Formulations for Delay release Pellets

Ingredients

F02Fa

(5% w/w)

F02Fb

(10% w/w)

F02Fc

(15% w/w)

SR coated pellets (F08)

300

300

300

Eudragit L100

15

30

45.0

Talc (30%)

4.5

9.0

13.5

Tri ethyl citrate (20%)

3.0

6.0

9.00

Isopropyl Alcohol

207.0

414.0

621.0

Water

51.5

103.0

155.0

Total

322.5

345.0

367.5

All quantities are in gm

Table 4: Result of in vitro drug release from pellets

Medium

TIME

(Hrs.)

% DRUG RELEASE

F02G

F02Fc

F02G (20%) and

F02Fc (80%)

0.1 N

HCl

0

0

0

0

2

0

0

0

pH 6.8 Phosphate Buffer

3

17.3

36.1

36.2

4

31.8

46.9

50.7

5

45.7

57.7

63.5

6

58.8

67.3

71.2

7

70.7

77.6

79.9

8

78

80.1

84.7

Above results are averages of the 6 samples.

Table 5: Filled composition in Capsule

Ingredients

Quantity

Quantity per capsule

Pellets of F02Fc

80%

485.2 mg

Pellets of F02G

20%

110.0 mg

Total

100%

595.2

Table 6: Dissolution profile of stability batch

Medium

TIME

(Hrs.)

% DRUG RELEASE

Controlled

40° C / 75% RH

60° C / 85%

RH

0.1 N

HCl

0

0.0

0.0

0.0

2

0.0

0.0

0.0

pH 6.8 Phospahte Buffer

3

36.2

36.1

35.9

4

50.7

50.5

50.3

5

63.5

63.6

63.4

6

71.2

71.0

70.9

7

79.9

79.7

79.5

8

84.7

84.5

84.3

Fig. 1: Graphical presentation of %Drug dissolution versus Time (h)

Fig. 2: Graphical presentation of %Drug dissolution versus Time (h)

Fig. 3: Graphical presentation of %Drug dissolution versus Time (h)

Fig. 4: Graphical presentation of % Drug dissolution of stability batch

RESULT AND DISSCUSSION

The prepared pellets were free flowing, light pink in color, uniform in appearance and with slightly rough surface. The drug content was consistent in all batches. The formulation containing 796% drug loading on sugar sphere followed by coated with Eudragit L100 (15%) and Eudragit RSPO & RLPO (10% in ratio of 7:3) separately. Eudragit RSPO & RLPO polymer Coated pellets were coated with delay release polymer Eudragit L100 (15%). The pellets were filled in hard gelatin capsule and evaluated for In-vitro drug release study. Multiunit particulate drug delivery system gives unique release pattern. This product was further subjected to stability study, the results of which indicated no significant change with respect to Shape, color, surface and in vitro drug release.

Developed pellets achieved the targets of present study, such as increased residence time, prolonged release profile, reduction in frequency of administration, an thus improve patient compliance.

ACKNOWLEDGMENTS

Authors are thankful to Cadila health care Ltd. Moraiya, Gujarat, for providing gift sample of Mesalamine, to Relax Pharmaceuticals, Baroda, Gujarat for providing Eudragit RSPO, Eudragit RLPO and Eudragit L100.








2. Refrence


  1. Ghebre-Sellassie, Marcel Dekker, Pharmaceutical Pelletization Technology, New York, 1989.

  2. Jalal IM, Malinowski HJ, Smith WE. Tablet granulations composed of spherical-shaped particles. J Pharm Sci 1972; 61:1466-790.

  3. Malinowski HJ, Smith WE. Effect of spheronization process variables on selected tablet properties. J Pharm Sci 1974; 63: 285-288.

  4. Nakahara, US Patent 3, 277, 520. October 1966.

  5. Herbert A. Liberman and Leon Lachman: The Theory and Practice of Industrial Pharmacy”, IIIrd Edition. Verghese Publication House, 171, 293.

  6. ICH topic 8 Pharmaceutical guidelines: Note for Guidance on Pharmaceutical Developments, (EMEA/CHMP167068/2004)

  7. ICH Q1A (R2), Stability Testing Guidelines: Stability testing of a new drug product and new drug substance.