Formulation Development and Evaluation of Sumatryptan Pulsatile Drug Delivery using Pulsincap Technology

 

Archana A.*, Manikanta Kumar A., K.S. Manjunath Shetty

Srinivasa Pharmaceutical Institute and Centre for Research, Burugupally (V),

Vikarabad (M), R.R. District. A.P, India.

*Corresponding Author E-mail: anju.anpur@gmail.com

 

 

ABSTRACT:

In the present study we report, the various processing parameters and formulations aspects for developing a pharmaceutical equivalent, stable, cost improved and quality improved formulation of pulsatile drug delivery using pulsing cap technology of sumatryptan comparable with innovator and optimize certain process parameters to get burst release of the product by maintaining the lag time. Present study has been done for burst release of the drug  by maintaining the lag time in order to establish pulsin cap technology of sumatyrptan by pulsatile drug delivery. Three formulations were prepared by using of hpmc k4 m, ethylcellulose, hpmc k 15 m, with combination of carbapol, as swellable polymers. The length of the polymer tablet plug decides the lag time and after the lag time burst release of the drug occurs. In vitro drug release, kinetic data and stability studies after optimization of promising formulation of selected drug are being done to exhibit diffusion dominant drug release and its stability may be attributed to that the present problem certainly will be helpful and surely will open an avenue for new trend of pulsatile drug delivery using pulsincap technology.The results of dissolution studies indicated that the formulation F11 (HPMC K 15 M-CARBOPOL 1:3 ratio) is the most successful of the study. On increasing polymer ratio a decrease in release rate of the drug was observed after lag time. The optimized formula F11 was best fitted formulation.

     

KEYWORDS: pulsatile drug delivery, pulsing cap technology, lag time, burst release.

 


 

INTRODUCTION:

In recent years considerable attention has been focused on the development of pulsatile drug delivery system. Delivery system with pulsatile release pattern has gained most popular form of controlled drug delivery system because conventional systems with a continuous release are not ideal. Oral controlled drug delivery systems are generally used due to convenient dosage form, and it also releases drug in constant or variable rates1-3. In these systems drug release generally occurs within therapeutic window for prolong period of time. Hence these systems show sustained release of drug from dosage form. Among modified release oral dosage forms, increasing interest has currently turned to systems designed to achieve time specific (delayed, pulsatile) and site specific delivery of drugs. These systems constitute a relatively new class of devices the impotence of which is especially connected with the recent advances in chronopharmacology.

 

Pulsatile systems are gaining a lot of interest as they deliver the drug at right site of action at the right time thus providing spatial and temporal delivery and increasing patient compliance.

 

These systems are designed according to the circadian rhythm of the body4. Circadian rhythm regulates many body functions in humans, viz., metabolism, physiology, behaviour, sleep patterns, hormone production. The pulsatile effect4,5, i.e., the release of drug as a “pulse” after a lag time has to be designed in such a way that a complete and rapid drug release should follow the lag time. Such systems are also called time controlled as the drug released is independent of the environment. A pulsatile drug delivery system that can be administered at night (before sleep) but that release drug in early morning would be a promising chronotherapeutic system6. So by developing the pulsatile device for specific colonic delivery, plasma peak is obtained at an optimal time, number of doses per day can be reduced: saturable first pass metabolism and tolerance development can also be avoided.

 

Sumatriptan is structurally similar to serotonin (5HT), and is a 5-HT (types 5-HT1D and 5-HT1B7) agonist. The specific receptor subtypes it activates are present on the cranial arteries and veins. Acting as an agonist at these receptors, sumatriptan reduces the vascular inflammation associated with migraines. The specific receptor subtype it activates is present in the cranial and basilar arteries. Activation of these receptors causes vasoconstriction of those dilated arteries. Sumatriptan is also shown to decrease the activity of the trigeminal nerve, which, it is presumed, accounts for sumatriptan's efficacy in treating cluster headaches8.Hence sumtryptan is the drug of choice for the treatment of migraine. The sumatryptan capsules are not in the market. In the present investigation sumatryptan capsules are prepared by using excipients cross povidone, aerosil, magnesium sterate, maniitol and excipients HPMC K 4 M, ethyl cellulose, HPMC K 15 M, and carbopol in different ratios by using pulsincap technology.

 

MATERIALS AND METHODS:

Sumatriptan was received as a gift sample from spectrum pharma research solutions, Hyderabad. Crosspovidone, aerosil, mannitol, magnesium sterate are obtained from spectrum pharma research solutions, Hyderabad. polymers hpmc k4 m, ec, hpmc k 15 m are obtained from SD fine chemicals, Mumbai and Narmada chemicals-Hyderabad. All the chemicals were of laboratory grade and used as such without any further purification.

 

Pre formulation characterization of the pure drug was performed for comparing the data with different developed formulations (F1 to F11), obtained from the analysis of formulation of sumatryptan. Physical Description done as general appearance of the drug its visual identity and overall ‘elegance’ is essential, this parameter was done and it was noticed by observing the colour of the drug simply, the solubility of the drug with the standard descriptive term with solvent series was checked. Similarly melting point of the pure drug was considered for the temperature at which the vapour pressure of the drug and the liquid were found equal and exists in equilibrium.

 

Preparation of Sumatryptan Capsules by Pulsincap Technology:

 The body and the cap of the hard gelatin capsules were separated. The body portion of the capsules was placed on a wire mesh into a dessicator, which was then exposed to formaldehyde vapours for3, 6, 9,12, 24 h at room temperature and dried at 50 °C for 48 h in a hot air oven. The treated capsule bodies were capped with untreated caps and stored at ambient conditions in a sealed glass container. Formaldehyde treatment was used to modify the solubility of the hard gelatin capsules. The solubility test was conducted for normal capsules and formaldehyde treated capsules for 24 h. For the normal capsules, both cap and body dissolved within 15 min whereas, with the formaldehyde treated capsules, only the cap dissolved within 15 min, while the capsule body remained intact for about 24 h. This insolubility indicates suitability.

 

Formulation Development Strategy:

Following ingredients are selected for formulation development of  pulsincap pulsatile drug delivery based on literature search.

 

Manufacturing Process:

The model drug sumatryptan, and the excipients crosspovidone, mannitol, aerosol, magnesium sterate are taken. The excipients are mixed with the drug properly. The swellable hydrogel plugs are prepared by using the  polymers HPMC K4 M,EC, HPMC K 15 M in combination with carbopol in different ratios OF 1:1,1:2,1:3..The drug formulation was filled into the treated capsule body. The swellable hydrogel plug of different polymers with combination of carbopol are placed above the formulation and the untreated cap is fitted on to the body. The weight of the drug along with the excipient was 200mg, and the polymer weight was 100 mg. so the total weight is 300 mg.

 

Evaluation parameters:

1. Bulk density (DB):

The bulk density depends on particle size distribution, shape and cohesiveness of particles. Accurately weighed quantity of powder was carefully poured into graduated measuring cylinder through large funnel and volume was measured which is called initial bulk volume. Bulk density is expressed in gm/cc and is given by,           

 

Db = M / VO

Where, Db = Bulk density (gm/cc)

M =Mass of powder (g)

VO=Bulk volume of powder (cc)

 

2. Tapped density (DT):

Ten grams of powder was introduced into a clean, dry 100ml measuring cylinder. The cylinder was then tapped 100 times from a constant height and tapped volume was read. It is expressed in gm/cc and is given by,

 

Dt = M / Vt

Where, Dt = Tapped density (gm/cc)

M = Mass of powder (g)

Vt= Tapped volume of powder (cc)

 

3. Angle of repose(θ):

It is defined as the maximum angle possible between the surface of pile of the powder and the horizontal plane. Fixed funnel method was used. A funnel was fixed with its tip at a given height (h), above a flat horizontal surface on which a graph paper was placed. Powder was carefully poured through a funnel till the apex of the conical pile just touches the tip of funnel. The angle of repose was then calculated using the formula,

θ = tan-1(h/r)

Where, θ = angle of repose

h = height of pile,

r = radius of the base of the pile.

 

4. Compressibility index:

The compressibility index is indirectly related to relative flow rate, cohesiveness and particle size of the powder.  The compressibility index of material can be estimated from the tapped and bulk density of power.

 

% Compressibility Index = Tapped density- bulk density/ tapped density×100

 

5. In-vitro dissolution studies:

The drug release rate was determined using USP dissolution apparatus I. Dissolution media was 900ml of 7.4 phosphate buffer maintained at 37± 0.10C and stirred at 75 rpm. Samples were withdrawn at suitable time intervals and compensated with fresh dissolution medium and assayed spectrophotometrically at 227nm in Shimadzu U.V. spectrophotometer. Samples were assayed in triplicate.

 

RESULTS AND DISCUSSION:

During the study period, pre formulation study of selected drug Sumatryptan was done first for physical observation, as the general appearance of the drug, its visual identity and overall ‘elegance’ is essential and it was found a white or almost white powder having slight drug smell and also found there is no leakage and crushing of the packet. The solubility of the pure drug was found maximum in 7.4 buffer. Melting point of the pure drug was found with a range between 1690c - 1710c and this range complies the USP which shows the drugs purity specification. To obtain obsorbance maxima maxima which were found at 227nm, solution was prepared as 10mg/ml using medium 7.4 buffer. To identify the active site of the selected drug sumatryptan FTIR scanning was done with full range, and the possible Structure Units (PSU) was found as Alkyl group, indole group, sulphonamide groups of the drug as expressed in the molecule formula of the standard drug sumatryptan. The stability testing of the selected formulation F11 was carried out as per the ICH guidelines.  The optimized formulation was subjected to stability studies at 400C and 75%RH for a period of one month.

 

The physical stability was assessed by the appearance and there was no change in colour or shape of the tablet and the chemical stability by change in the drug content as mentioned in the table. which  concludes  that  there  was  no  change  in  the  physical  and chemical properties of formulation. So the F11 formulation was stable at the end of one month.

 

 In-vitro Dissolution studies:

The  drug-polymer  ratio  was  found  to  influence  the  release  of  drug  from  the formulation. The drug release was influenced by the ratio of the polymers. F1, F2, F3, andF4 failed. Because the drug is sustainely released. In F5, F6, F7, F8 lag time is not maintained and also total amount of the drug is not maintained after 8 hours. Hence F4- F8 formulations are also failed. In F9 and F10  maximum amount of drug is released in 8th hour but the lag time is not maintained properly. By increasing the ratio of polymer in F11 lag time is maintained and the burst release of the drug occurs after the lag time which indicates that F11 is the optimised formulation. Short term stability studies indicated no appreciable changes in the drug content and in vitro drug release rates of optimized formulation.

 


 

 

Table no:1  Polymer Concentrations F1-F5

Compositions of Various Formulations

 

F1(1:1)

F2(1:2)

F3(1:3)

F4(1:4)

F5(1:1)

DRUG

25mg

25mg

25

25mg

25mg

CROSS-POVIDONE

10mg

10mg

10mg

10mg

10mg

MANNITOL

160mg

160mg

160mg

160mg

160mg

AEROSIL

15mg

15mg

15mg

15mg

15mg

Mg.STERATE

4mg

4mg

4mg

4mg

4mg

HPMCK4M

50mg

33.3mg

25mg

20mg

 

EC

 

 

 

 

50mg

HPMCK15 M

 

 

 

 

 

CARBOPOL

50mg

66.6mg

75mg

80mg

50mg

 

Table no: 2 POLYMER CONCENTRATIONS F6-F11

Compositions of Various Formulations

 

F6(1:2)

F7(1:3)

F8(1:4)

F9(1:1)

F10(1:2)

F11(1:3)

DRUG

25mg

25mg

25mg

25mg

25mg

25mg

CROSSPOVIDONE

10mg

10mg

10mg

10mg

10mg

10mg

MANNITOL

160mg

160mg

160mg

160mg

160mg

160mg

AEROSIL

15mg

15mg

15mg

15mg

15mg

15mg

Mg.STERATE

4mg

4mg

4mg

4mg

4mg

4mg

HPMCK4M

 

 

 

 

 

 

EC

33.3mg

25mg

20mg

 

 

 

HPMCK15M

 

 

 

50mg

33.3mg

25mg

CARBOPOL

66.6mg

75mg

80mg

50mg

66.6mg

75mg

                                                                                                 

Table no:3 F1-F5% cdr

 

 

Time

F 1%cdr

F2%cdr

F3%cdr

F4%cdr

F5%cdr

0

0

0

0

0

0

1

12.1889

9.3711

5.5702

1.2451

5.111513

2

16.907

13.630

8.388

2.0970

9.698769

3

41.154

19.8562

10.223

4.456

14.08943

4

71.954

30.472

15.400

6.8808

23.32947

5

98.822

62.648

18.6111

12.385

32.50398

6

 

98.101

46.527

24.3124

41.21977

7

 

 

65.0079

50.721

49.54236

8

 

 

81.456

97.774

55.44026

 

Table no:4 F6-F10%cdr

Time

F6%cdr

F7%cdr

F8%cdr

f9%cdr

F10%cdr

0

0

0

0

0

0

1

4.390

2.293

1.900

10.0264

6.684

2

7.536

3.538

2.883

14.220

10.812

3

11.468

4.325

3.800

18.938

13.827

4

19.463

7.143

6.749

27.523

19.921

5

25.033

8.257

8.060

32.372

24.967

6

36.173

10.878

11.402

56.095

50.525

7

40.105

20.118

21.297

75.034

78.502

8

48.821

35.846

29.882

93.121

94.628

 

 


Table no:5. Best formulation f11(1:3)  (HPMC K 15 M+carbopol)

 Time

F1 1%cdr

0

3.121

1

5.3081

2

6.815

3

7.929

4

9.240

5

10.157

6

88.743

7

99.346

 

 

Graph 1: graph of f1-f5 (%cdr vs time)

 

 

 

 

 

Graph 2: graph of f6-f10 (%cdr vs time)

 

Graph 3: Best formulation graph

 

CONCLUSION:

Capsules were formulated and evaluated using sumatryptan as drug, crosspovidone, aerosil, mannitol, magnesium state as excipients. HPMC K 4 M, EC, HPMC K 15 M and carbopol used as polymers, by varying concentrations. All the formulations were prepared by using pulsincap technology, where the concentration of the drug kept constant and concentration of polymers varied. Of  all  the  batches  formulated  from  F1 – F11 using  fixed   amount  of  drug  and  different  quantities  of   polymers the  observations  are:

ü  F11 maintains the lag time compared to all other batches.

ü  It complies with all the physicochemical parameters

ü  It shows burst release of the drug.

 

ACKNOWLEDGMENT:

One of author gives thanks to Dr A. Manikanta Kumar, Associate Professor, Department of Pharmaceutical analysis and Dr. K.S. Manjunatha Shetty, Professor and Principal, also to Mr. Srinivas, Chairman, Srinivasa Pharmaceutical Institute and Center for Research, Burugupally for their enduring support and providing facilities to carry out the work.

 

REFRENCES:

1.       Shweta Arora, Ali. J, Alaka ahuja, Sanjula Baboota, and Qureshi. J, “Pulsatile drug delivery systems: An approach for controlled drug delivery”, Indian. Pharm. Sci., 2006, 68(3):295-300.

2.       Sachin Sutvase, Neeraj Kumar. “Review of pulsatile drug delivery: Current Scenarioa’, CRIPS2007:8(2):27-33.

3.       Gayatri. C. Patel, Madhabhai M. Patel. “Modified pulsincap system”. Pharmaceutical Technology Europe 2009:21(11):89-97.

4.       Sameer Sharma, Atmaram Pawar, “Low density multiparticulate system for pulsatile release of meloxicam”, Int. J. Pharm 2006: 313(1-2):150-158.

5.       Rathod Shruti. “Colon targeted pulsatile drug delivery: A Reviea”, Pharmainfo.net 2007:5(2):33-66.

6.       Pawar A, Ssharmaa S. Low density multiparticulte system for pulsatile release of meloxicam. Int J Pharm 2006:313:150-58.

7.       Razzaque Z, Heald MA, Pickard JD, et al. (1999). "Vasoconstriction in human isolated middle meningeal arteries:  determining the contribution of 5-HT1B- and 5-HT1F-receptor activation". Br J Clin Pharmacol 47 (1): 75–82. doi:10.1046/ j.1365-2125.1999.00851.x.PMC 2014192.

8.       PMID 10073743.Treatment of acute cluster headache with sumatriptan. The Sumatriptan Cluster Headache Study Group. N Engl J Med 1991; 325:322-6..

 

 

 

Received on 14.09.2013       Modified on 10.10.2013

Accepted on 15.10.2013      © RJPT All right reserved

Research J. Pharm. and Tech. 6(12): Dec. 2013; Page 1375-1379