BALA GANGADHAR MANYAM, DEPT OF PHARMACEUTICAL TECHNOLOGY, SVCP, BHIMAVARAM

Pulsincap Drug Delivery Systems

Bala Gangadhar Manyam Reg No:: 610275801003 Shri Vishnu College of Pharmacy
Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

OVERVIEW
Introduction

Conditions demanding pulsatile (PULSINCAP) drug delivery

Properties Materials

Mechanism of Release
Modifications of Pulsincap Advantages and Disadvantages

Evaluation
References
3

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

INTRODUCTION
The Pulsincap system (Scherer DDS, Ltd) is made up of a Water insoluble capsule enclosing the drug reservoir with a swellable hydrogel plug that seals the drug contents into the capsule

body at the open end of the capsule. It is then closed by the water soluble cap.
Pulsincap was developed by R. P. Scherer International Corporation, Michigan, US.

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

Conditions demanding pulsatile (PULSINCAP) drug delivery :

1. Chronopharmacotherapy of diseases which shows circadian rhythms in their pathophysiology. 1. asthmatic attacks during early morning 2. heart attacks in the middle of the night 3. morning stiffness in arthritis

2. Drugs producing biological tolerance (e.g. Salbutamol sulphate)

3. For targeting specific site in intestine e.g. colon (e.g Sulfasalazine) 4. For time programmed administration of hormone and drugs, 5. For drugs having the short half life (e.g -blockers) 6. Drugs undergoing degradation in gastric acidic medium (e.g., peptide drugs). 7. Drugs undergoing extensive first-pass metabolism (-blockers).

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

PROPERTIES OF PULSINCAP
Pulsincap is an example for the pulsatile system based on capsule system. These are characterized by a programmed drug release,

The principle rationale for the use of pulsatile release is for the drugs where a constant drug release i.e., a zero order release is not desired.
This technique is suited for the preparation of better controlled release formulations . The Pulsincap drug delivery has been studied in human volunteers and was reported to be well tolerated.

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

 These systems deliver the drug at the right site of action at the right time and in the right amount, thus providing spatial and temporal delivery, thus increasing the patient compliance. The release of the drug as a pulse after a lag time has to be designed in such a way that a complete and rapid drug release follows the lag time also the Period of No Drug Release. The lag time prior to the drug release was controlled by the dimension and the position of the plug, which gets pushed away by swelling or erosion, and the drug is released as a Pulse from the insoluble capsule body.

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

 In order to assure a rapid release of the drug content, effervescent agents or disintegrants could be included in the drug formulation, in particular, with water insoluble drugs. These systems are beneficial for the drugs having chronopharmacological behavior where night time dosing is required as they are designed according to the circadian rhythm of the body. Drugs having high first-pass effect and having specific site of absorption in GIT can be formulated by this Pulsincap drug delivery system

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

MATERIALS
The Capsule body is insoluble or may be sometimes be semi permeable membrane, according to the type of release required.

Body is exposed to formaldehyde vapors to avoid the dissolution of the gelatin body in invitro. The amino groups in gelatin molecular chain react with aldehyde groups of formaldehyde by a Schiffs base condensation.

The site specific delivery of the drug to the upper intestine had been achieved by the use of the pH sensitive coatings. Enteric coated products are intended to remain intact in the stomach and release the active substance in the upper intestine.

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

BALA GANGADHAR MANYAM, DEPT OF PHARMACEUTICAL TECHNOLOGY, SVCP, BHIMAVARAM

10

The enteric coating is done over the capsule for the following reasons: To delay release of drugs inactivated by stomach To delay the release of drugs inducing nausea or bleeding or to give a repeat or pulsed action or to deliver the drug intact to its site of action.

The enteric coating is done by the weak acids, which remain undissociated at low pH. These coatings ionize at pH>5.. Example: Eudragits, Aquateric, Coateric (Cellulose vinyl acetate phthalate) .

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

11

 The drug may be packed in the insoluble capsule in the form of powder, compressed tablet, filled in the capsule either as microspheres or microcapsules etc. The drug may be added as a mixture of granules containing the drug, superdisintegrant, and osmogen filled into the capsule body. For water-insoluble drugs, a rapid release can be ensured by inclusion of effervescent agents or disintegrants. The drug may be also added with hydrophilic polymers like guar gum,carbopol940, Sodium alginate, Hydroxy Propyl Methyl Cellulose, methyl cellulose, gum karaya, poly vinyl alcohol to modify the release. Increase in the concentration of the hydrophilic polymer leads to the reduction in the release rate of the drug.
Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

12

 The drug polymer ratio can be used to alter the release rate of the drug. The order of sustaining capacity of polymers is Guar gum > HPMC > Carbopol 940 > gum karaya > Sodium alginate > MC

Guar gum has a good sustaining capacity even at a lower concentrations,

due to its rapid hydration capacity and formation of a surface barrier quickly.
The Drug- Polymer interaction or complexation can be studied by DSC

thermograms.

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

13

 The plug material consists of either insoluble but permeable and swellable polymers (eg, polymethacrylates), erodible compressed polymers (eg, various grades of hydroxypropylmethylcellulose, polyvinyl alcohol, polyethylene oxide), congealed melted polymers (eg, saturated polyglycolated glycerides, glyceryl monooleate), and enzymatically controlled erodible polymer (eg, pectin, agar). Rupturable: They are subjected to a volume increase resulting from the water uptake, causing rise in internal pressure. This alters the rate controlling membrane, expelling the plug and thus exposing the core contents to external fluids and drug is immediately available. Erodible plug: These are preparations with swellable hydrophilic polymeric materials, such as HPMC, HPC, HEC. Upon contact with aqueous media, they typically undergo combined swelling, dissolution and mechanical erosion phenomenon, which contribute to delay the onset of release.

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

14

Mechanism Of Release

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

15

First approach:

In this type of Pulsincap the capsule body is insoluble, made of gelatin treated with formaldehyde. It is covered by a soluble gelatin cap
Upon contact with the dissolution medium or gastro intestinal fluids, the cap gets dissolved in the stomach fluid. In presence of fluid the plug swelled at a controlled rate and this swelling is independent of the nature of pH of the fluid. As the plug swells it attains frustroconial shape and it gets slowly pulled out of the capsule Then the hydrogel plug swells in the upper intestine at 6.0 pH, and when swelling reaches a critical point, resulting in the popping out of the hydrogel plug after a lag time from the body of the capsule shell due to increase in the volume . Thus resulting in a rapid release of the drug content into the medium. Pulse time is controlled by:
The length of the plug and Insertion distance of plug into the capsule
Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

16

 Second approach:

Based on separation of a plug from an insoluble capsule body Consists of a water permeable body prepared from a waterswellable hydrogel i.e. crosslinked Polyethylene glycol (PEG) In cavity of capsule body, mixture of drug and a swelling agent is placed. Internal cavity is then sealed by a plug. Upon oral administration by patient, cap dissolves. Water diffuses through capsule body. Swelling causes plug to move in upward direction causing drug release. Water diffusion into the core through semi permeable membrane is controlled by:
Hydrogel composition and Wall thickness of the capsule
Water Permeable Body (Crosslinked PEG hydrogel)
Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

Plug

Drug Formulation

Swelling Agent 17

Third approach:

Steven et al. developed a Pulsincap system with erodible compressed tablet or an erodible plug instead of the hydrogel polymer plug. Upon contact with aqueous media, they typically undergo combined swelling, dissolution and mechanical erosion phenomenon, and hence the drug contents are released

The erosion or the dissolution of the erodible plug contributes to delay the onset of release. This overcomes the need for the precise dimensional tolerance between capsule and plug for sliding mechanism of the plug

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

18

 Both the composition and the weight of EP influenced the lag time of the pulsincap capsule significantly. The lag time prior to the drug release was enhanced when the content of gel forming excipient (hydroxypropylmethylcellulose, HPMC) in the EP or the weight of EP was increased. Altering the composition and weight of the erodible plug could control the release of the drug.
Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

19

Types Of Release
The release rate can be studied by the zero order, first order.

Release generally exhibits Fickian diffusion for Pulsincap models that have drug in the polymer matrix. The Fickian diffusion of the release can be explained : As a result of the rapid hydration of the polymer molecule on the opening surface of the capsule , It results in a gel or high viscous solution surrounding the opening of the capsule that restricts the water penetration into the center. Resulting in the reduction of the rate of drug release as function of time.

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

20

Modifications of Pulsincap
A hydrophilic sandwich capsule was designed by Steven et al., which is based on a system where a capsule is enclosed within a capsule and the space in between them is filled with a gel barrier layer composed of HPMC. When the outer capsule dissolves, the delay in the second pulse was provided by the barrier gel layer. The time delay was controlled by the molecular weight of the polymer and could be further manipulated by the inclusion of a soluble filler, e.g., lactose, in the hydrophilic layer.

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

21

 The empty gelatin capsule may be coated with ethyl cellulose or coated with semi permeable membrane can be used to osmotically control expulsion of the plug. keeping cap portion as such. The drug is contained in the capsule along with an osmotic agent to attract water into the formulation, increasing the pressure and expelling the water insoluble plug.

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

22

Advantages :
Well tolerated in animals and healthy volunteers, and there were no reports of gastro-intestinal irritation (Saeger et al., 2004). Bacteria exposed to antibiotics in a short repetitive bursts or pulses may be eliminated more efficiently and tend not to develop more resistant forms.

Disadvantages :

Potential problem of variable gastric residence time, which was overcome by enteric coating the system to allow its dissolution only in the higher pH region of small intestine (Binns et al., 1996)

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

23

EVALUATION OF PULSINCAP
The Physical nature of the pulsincap capsule. The change in weight of the capsule is observed by immersing the pulsincap capsule in different solutions of pH 1.2, 6.4, 6.8, 7.2. The Percentage change in the weight during 24hr is calculated. Disintegration test The polymer used in the Pulsincap dosage form should be able to swell to its maximum and eject from the capsule body in intestinal fluid. The body portion of the capsules was subjected to disintegration studies at room temperature in a buffer solution of pH 1.2, 7.4 and 6.8. Ten capsules were selected randomly from each batch and weighed individually for weight variation.

Weight Variation

Swelling and Ejection property of plug:

Swelling characteristics were determined by observing the swelling ratio in different pH solutions like 1.0, 6.0, 7.2 and in water.

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

24

Dissolution test: Dissolution studies were performed using the USP Dissolution Apparatus 2 Paddle Method (900 mL of dissolution medium, 100 rpm, 370.5 C). Capsules were tied to the paddle with a cotton thread in each dissolution vessel to prevent floating. The dissolution is carried out by Half Change Method The half of the dissolution media is replaced by the buffer at regular intervals to obtain the increase in the pH as shown in the table. Time(hr) Half of dissolution media replaced with buffer of pH pH of the dissolution media 0-2 2-3 6.0 3-4 6.0 4-5 7.4 5-6 7.6 6-7 6.0

1.2 (0.1N HCl)

3.0

5.4

6.4

7.2

6.8

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

25

Why?

How?

What

Who?

Where?
BALA GANGADHAR MANYAM, DEPT OF Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram PHARMACEUTICAL TECHNOLOGY, SVCP, BHIMAVARAM

When?
26

References
A pulsatile drug delivery system based on rupturable coated hard gelatin capsules by T. Bussemer, A. Dashevsky, R. Bodmeier in Journal of Controlled Release 93 (2003) 331 339 http://www.inventi.in/Article/ndds/151/11.aspx http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=637638 Advanced Drug Formulation Design to Optimize Therapeutic Outcomes. Robert O Williams, David R. Taft, Jason. T. McConville. Pg. 236-237

Studies on release of Rifampicin from modified PULSINCAP Pharmaceutical Sciences; July- August 2001. Pg: 337-339

Technique- Indian Journal of

Pulsatile Drug Delivery System: An approach for controlled drug delivery By J.Ali, Shweta Arora, Alka Ahuja, Sanjala Baboota, J.Qureshi. Indian Journal of Pharmaceutical Sciences Vol: May- June 2006. Pg:295-300.

Modified-Release Drug Delivery Technology ; Edited by Michael J . Rathbone , Jonathan Hadgraft , and Michael S . Roberts . Pg: 257

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

27

http://www.modernmedicine.com/modernmedicine/article/articleDetail.jsp?id=637638&sk =&date=&pageID=2

http://www.shvoong.com/medicine-and-health/1602984-preparation-vitrorelease-tetramethylpyrazine-phosphate/#ixzz1nq1T2Gvg
http://www.pharmainfo.net/pharma-student-magazine/pulsatile-drug-delivery-systemuser-friendly-dosage-form

http://www.authorstream.com/Presentation/abikesh086-235605-pulsatile-drug-deliverysystem-education-ppt-powerpoint/
Current trends in pulsatile drug delivery systems by S. R. Tajane, B. B. Kholwal, S. S.Suryawanshi and K. N. Tarkase in IJPSR (2012), Vol. 3, Issue 02 , pg: 358- 366. Design and Development of Controlled Release Diclofenac Sodium Capsules by N.L.Prasanthi1, T.E.G.K. Murthy2 in International Journal of Advances in Pharmaceutical Sciences 1 (2010) 263-266

Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram

28

Bala Gangadhar Manyam

BALA GANGADHAR MANYAM, DEPT OF Bala Gangadhar Manyam, Dept Of Pharmaceutical Technology, SVCP, Bhimavaram PHARMACEUTICAL TECHNOLOGY, SVCP, BHIMAVARAM

29