DEVELOPMENT AND EVALUATION OF CONTROLLED RELEASE …

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DEVELOPMENT AND CHARACTERIZATION OF LERCANIDIPINE HYDROCHLORIDE

PULSATILE DRUG DELIVERY SYSTEM FOR CHRONOMODULATED THERAPY

M.Pharm. Dissertation Protocol

Submitted to the

Rajiv Gandhi University of Health Sciences, Karnataka.

Bangalore.

By

M. RAGHU VEERA PANI

B. Pharm.

Under the Guidance of

PRAKASH S. GOUDANAVAR

Asst. Professor

[pic]

DEPARTMENT OF PHARMACEUTICS

N.E.T. PHARMACY COLLEGE,

RAICHUR

2013

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

| | |M. RAGHU VEERA PANI |

|1 |Name of candidate and address (In Block |S/O- M. VENKATESHWARLU |

| |Letters) |BHEEMNAGAR COLONY, |

| | |GADWAL |

| | |DIST- MAHABOOBNAGAR, A.P |

| | | |

|2 |Name of the Institute |N.E.T.PHARMACY COLLEGE, RAICHUR. |

| | | |

|3 |Course of study and subject: |M.PHARM. PHARMACEUTICS. |

|4 | Date of admission of course: | 25-12-2012 |

|5 | Title of the topic: |

| |DEVELOPMENT AND CHARACTERIZATION OF LERCANIDIPINE HYDROCHLORIDE |

| |PULSATILE DRUG DELIVERY SYSTEM FOR CHRONOMODULATED THERAPY |

|6 |Brief Resume of this intended work: |

| |6.1 Need for the study Enclosure-I |

| |6.2 Review of Literature Enclosure-II |

| |6.3 Objectives of study Enclosure-III |

|7 |Materials and Methods: |

| |7.1 Source of data Enclosure-IV |

| |7.2 Method of collection of data (Including sampling procedure, if any) |

| |Enclosure-V |

| |7.3 Does the study require any investigation or interventions to be conducted on patients of humans or animals? If so, |

| |please describe briefly. |

| |Not Applicable |

| |7.4 Has ethical clearance been obtained from your institution in case of 7.3? |

| | |

| |Not Applicable |

| | |

|8 |List of References Enclosure-VI |

| | | |

|9 |Signature of the candidate | |

| | | |

|10 |Remarks of the Guide |The proposed work can be carried out in the laboratory. |

|11 | | |

| |Name and designation of (in block |PRAKASH. S. GOUDANAVAR |

| |letters) |Assistant Professor |

| |11.1 Guide |Dept. of Pharmaceutics, |

| | |N.E.T. Pharmacy college, |

| | |RAICHUR- 584103. |

| | | |

| | | |

| |11.2 Signature | |

| |11.3 Co-Guide (if any) |------------ |

| | | |

| | | |

| |11.4 Signature |------------ |

| | | |

| |11.5 Head of Department |Dr. H. DODDAYYA |

| | |Professor |

| | |Dept. of pharmaceutics, |

| | |N.E.T. Pharmacy college, |

| | |RAICHUR- 584103. |

| | | |

| |11.6 Signature | |

| | | |

| | | |

|12 | |Forwarded for scrutiny |

| |12.1 Remarks of the Chairman and Principal| |

| | |Dr. H. DODDAYYA |

| | |Principal, |

| | |N. E. T. Pharmacy College, |

| | |RAICHUR-584103. |

| | | |

| |12.2 Signature | |

| | | |

| | | |

Enclosure-I

6) Brief resume of the intended work.

6.1) Need for the study:

Traditionally, drug delivery has meant for getting a simple chemical absorbed predictably from the gut or from the site of injection. A second-generation drug delivery goal has been the perfection of continuous, constant rate delivery of bioactive agents. However, living organisms are not “zero-order” in their requirement or response to drugs. They are predictable resonating dynamic systems, which require different amounts of drug at predictably different times within the circadian cycle which will maximize desired and minimize undesired drug effects.

Nowadays, concept of chronopharmaceutics has emerged, wherein, research is devoted to the design and evaluation of drug delivery systems that release a therapeutic agent at a rhythm that ideally matches the biological requirement of a given disease therapy. Diseases where a constant drug levels are not preferred, but needs a pulse of therapeutic concentration in a periodic manner acts as a push for the development of “Pulsatile Drug Delivery Systems.” In these systems, there is rapid and transient release of a certain amount of drug molecules within a short time-period. Various techniques are available for the pulsatile delivery like pH dependent systems, time dependent systems, micro-flora activated systems, etc. which can be designed as per the physiology of disease and properties of the drug molecule.1

The pulsatile effect, 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.

Pulsatile drug delivery systems are gaining a lot of interest and attention these days. These systems have a peculiar mechanism of delivering the drug rapidly and completely after a "lag time," i.e., a period of "no drug release." Though most delivery systems are designed for constant drug release over a prolonged period of time, pulsatile delivery systems are characterized by a programmed drug release, as constant blood levels of a drug may not always be desirable2.

Lercanidipine hydrochloride (LER) is chemically 2-[(3,3-diphenylpropyl) methylamine]-1, 1-dimethylethylmethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5 pyridine carboxylic ester hydrochloride. LER is used in treatment of hypertension, because of its selectivity and specificity on the smooth vascular cells 3. The drug is administered orally in a dose of 10–20 mg daily as its hydrochloride salt, reducing significantly the diastolic blood pressure. After oral administration, LER is completely and erratically absorbed from the gastrointestinal tract. However, absolute bioavailability is reduced to approximately 10% because of extensive first pass metabolism to inactive metabolites4. Literature suggests the mean half-lives of 2.8 and 4.4 h in humans after single dose of 10 and 20 mg of LER, respectively5.

Several functions such as. Blood pressure (BP), heart rate, stroke volume, cardiac output, blood flow of the cardiovascular system are subject to circadian rhythms6, 7.

Generally in hypertension, the risk of getting heart attacks is just before the waking hours of the patient i.e. early in the morning8. Blood pressure which rises notably just before waking up is usually responsible for attacks and therefore the need of antihypertensive is typically felt during morning hours. For such cases, conventional formulations of Lercanidipine hydrochloride cannot be administered before the symptoms get worsened because at that time patients are asleep. Thus taking into consideration the pharmacokinetics as well as objective of chronotherapy, an attempt will be made to design and formulate pulsatile drug delivery of Lercanidipine hydrochloride which when administered at bed time will deliver the drug in early morning hours.

Enclosure-II

6.2) Review of literature:

1. Mastiholimath VS et al fabricated time and pH dependent colon specific, pulsatile delivery of theophylline for the treatment of nocturnal asthma. The basic design consisted of hard gelatin capsule body, filled with Eudragit microcapsules of theophylline and sealed with a hydrogel plug. The entire device was enteric coated, so that the variability in gastric emptying time can be overcome and colon-specific release can be achieved. The gamma scintigraphic studies pointed out the capability of the system to release drug in lower parts of GIT after a programmed lag time for nocturnal asthma. Programmable pulsatile, colon-specific release has been achieved from a capsule device over a 24h period, consistent with the demands of chronotherapeutic drug delivery.9

2. Shivakumar HN et al formulated, controlled onset extended release multiparticulate systems for chronotherapeutic delivery of ketoprofen. The multiparticulate system consisted of drug-loaded cellulose acetate cores which were further encapsulated using Eudragit S-100. In-vitro release studies of the Eudragit microcapsules in different pH conditions indicated that ,the microcapsules posses both pH-sensitive and controlled-release properties, showing limited drug release (6.40 to 8.94%) below pH 7.0, following which the cellulose acetate cores effectively controlled the drug release for a period of 11 h in pH 7.5. The release of ketoprofen from Eudragit microcapsules in pH 7.5 depended on the cellulose acetate levels and was characterized by Higuchi’s diffusion model.10

3. Giunchedi P et al studied the pulsatile absorption of ketoprofen from ‘multiple unit’ hydrophilic matrices. Formulation was constituted by four hydrophilic matrices of identical composition, prepared with HPMC (Methocel®) and placed in a capsule. In vivo tests carried out on 12 healthy volunteers demonstrated that pulsatile plasma levels (two peaks at second and eighth hours after dosing) correspond to an in vitro fairly constant drug release. The results confirm that by using hydrophilic matrices, which are generally believed to provide constant drug release, it is possible to achieve pulsatile plasma levels, and that this possibility is emphasized through the use of a system based on four units.11

4. Pawar A et al developed multiparticulate floating-pulsatile drug delivery system using porous calcium silicate and sodium alginate for time and site specific drug release of meloxicam in simulated intestinal fluid. Meloxicam was adsorbed on the Florite RE® (FLR) by fast evaporation of solvent from drug solution containing dispersed FLR. Drug adsorbed FLR powder was used to prepare calcium alginate beads by ionotropic gelation method. Formulations showed a lag period ranging from 1.9 to 7.8 h in acidic medium followed by rapid release of meloxicam in simulated intestinal fluid USP, without enzymes (SIF).A pulsatile release of meloxicam was demonstrated which could be useful in chronopharmacotherapy of rheumatoid arthritis.12

5. Abraham S et al developed modified Pulsincap dosage form for the colonic delivery of metronidazole. Pellets prepared by extrusion-spheronization method were incorporated into specialized capsule shells and plugged with polymers such as guar gum, HPMC 10K, carboxymethyl cellulose sodium and sodium alginate separately at concentrations 20 mg, 30 mg and 40 mg. The filled capsules were completely coated with 5% cellulose acetate phthalate to prevent variable gastric emptying. The in vitro drug release studies in buffer pH 1.2 for 2 h, pH 7.4 (simulated intestinal fluid) for 3 h and pH 6.8 (stimulated colonic fluid) for 7 h. The results indicated that significant drug release occurred only after 5 h. Thus, metronidazole could be successfully colon targeted by the use of the modified Pulsincap, thereby reducing systemic side effects.13

6. Maradny HA et al studied the modulation of a pulsatile release drug delivery system using different swellable/rupturable materials. Diclofenac sodium tablets consisting of core coated with two layers of swelling and rupturable coating on the lag time and the water uptake were investigated. Results showed the dependence of the lag time and water uptake prior to tablet rupture on the nature of the swelling layer and the coating labels. Increase in the level of the ethyl cellulose coating retarded the diffusion of the release medium to the swelling layer and the rupture of the coat, thus prolonging the lag time.14

7. Ishino R et al designed pulsatile release tablet of isoniazid using hydrogenated castor oil, PEG 6000 and microcrystalline cellulose. The system consisted of a less water permeable outer shell and swellable core tablet from which the drug was expected to be rapidly released after a certain period of time. In the in vitro dissolution test, typical pulsatile release was achieved for all the tablets prepared.15

8. Ali J et al designed chronomodulated drug delivery system of Salbutamol sulphate for the treatment of nocturnal asthma. The cores containing salbutamol sulphate were prepared by direct compression method using different ratios of MCC and effervescent agent and then coated sequentially with an inner swelling layer containing a hydrocolloid, HPMC E5 and an outer rupturable layer having Eudragit RL/RS (1:1). The lag time of the drug release decreased by increasing the inner swelling layer and increased by increasing the rupturing layer level. All the results obtained in the study suggested that osmotic pumping effect was involved which eventually lead to the drug release16.

9. Charde S et al. developed buccoadhesive controlled release tablets of Larcanidipine using polyethylene oxide and different viscosity grades of HPMC individually and in combination by direct compression technique. Results indicated acceptable physical characteristics of designed tablets with good content uniformity and minimum weight variation. Drug release and mucoadhesive strength were found to depend upon polymer type, proportion and viscosity. The formulations prepared using polyethylene oxide gave maximum mucoadhesion than those of HPMC. The release mechanism of most formulations was found to be of anomalous non-Fickian type. In vivo studies of selected formulation in rabbits demonstrated significant enhancement in bioavailability of lercanidipine hydrochloride relative to orally administered drug. It was concluded that the designed buccoadhesive controlled release tablets have the potential to overcome the disadvantage of poor and erratic oral bioavailability associated with the presently marketed formulations of lercanidipine hydrochloride.17

Enclosure-III

6.3) Objectives of the study:

The present study is planned with the following objectives:

1) To prepare lercanidipine hydrochloride loaded microspheres using cellulose acetate and coating the microspheres with enteric polymers like Eudragit S-100 and Eudragit L-100.

2) To study drug-polymer interactions by using DSC and FT-IR instruments.

3) To study the influence of formulation and process variables like concentration of coat, core, dispersion medium, stirring speed and stirring time on microsphere formation.

4) To evaluate the microspheres for size analysis, surface topography, encapsulation efficiency, in vitro release and drug release mechanism using suitable kinetic models.

5) To design pulsatile delivery device with some modifications of the original PulsincapTm technology.

6) To investigate the effect of different plugging materials like Xanthan gum, Guar gum and HPMC K100M on drug release from the developed pulsatile device.

7) To perform the stability studies for selected formulations as per ICH guidelines.

Enclosure-IV

7) Materials and Methods:

7.1) Source of data:

Primary data: This data will be collected by conducting laboratory experiment and recording the observation.

Secondary data: This data will be collected from:

← Internet.

← Review articles.

← Research publications.

← International and Indian journals.

← Textbooks and reference books

Enclosure-V

7.2) Method of collection of data:

The data for the study is planned to collect from the laboratory-based experiments:

1. Preformulation studies like solubility, melting point and characterization of the drug and polymers will be done by employing suitable methods. Compatibility of drug with polymers will be carried out by using Infra-Red Spectroscopy and Differential Scanning Calorimetry instruments adopting reported methods.

2. Preparation of Lercanidipine hydrochloride loaded cellulose acetate microspheres by emulsion solvent evaporation technique or any other suitable Methods.

3. Studying the influence of formulation and process variables like concentration of coat,core, dispersion medium, stirring speed and stirring time on microsphere formation.

4. Methods for the characterization of lercanidipine hydrochloride loaded cellulose

acetate microspheres:

A. Size analysis:

By sieve analysis technique.

B. Surface morphology:

The particle shape and surface morphology will be determined by Scanning electron

microscopy.

C. Encapsulation efficiency:

Encapsulation efficiency will be determined by estimating drug content in

Lercanidipine hydrochloride loaded cellulose acetate microspheres and by using

formula.

Encapsulation efficiency = Estimated drug content X 100

Theoretical drug content

D. In Vitro drug release study:

In vitro dissolution profile will be determined by employing USP XXIV rotating

basket type apparatus.

E. Drug release mechanism:

Lercanidipine hydrochloride loaded cellulose acetate microspheres will be evaluated

for drug release mechanism using suitable kinetic models.

5. Designing pulsatile drug delivery device with some modifications of the original

PulsincapTm technology.

6. In Vitro drug release study of pulsatile drug delivery device:

In vitro dissolution profile of pulsatile drug delivery device will be determined by

employing USP XXIV rotating basket type apparatus.

7. For selected formulations stability studies will be carried out using stability chamber

as per ICH guidelines.

Enclosure- VI

References:

1. Kumar N, Survase S. Pulsatile drug delivery: Current scenario. CRIPS 2007; 8(2):27-33.

2. Arora S, Ali J, Ahuja A, Baboota S, Qureshi J. Pulsatile drug delivery systems: An approach for controlled drug delivery, Scientific Publication of the Indian Pharmaceutical Association,2006: 68(3):295-300

3. Luscher TF, Cosentino F. The classification of calcium antagonists and their selection in the treatment of hypertension: a reappraisal. Drugs 1998; 55(4):509-17.

4. Bang LM, Chapman TM, Goa KL. Lercanidipine a review of its efficacy in the management of hypertension. Drugs 2003; 63:2449–2472.

5. Barchielli M, Dolfini E, Farina P. Clinicl pharmacokinetics of lercanidipine. J Cardiovasc Pharmacol 1997; 29:S1– S15.

6. Lemmer B. Cardiovascular chronobiology and chronopharmacology. Biological Rhythms in Clinical and Laboratory Medicine 1992; 418– 427.

7. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation. 1989; 79:733–743.

8. Zou H, Jiang X, Kong L, Gao S. J. Pharm. Sci. 2008; 97: 263-273.

9. Mastiholimath VS, Dandgi PM, Jain SS, Gadad AP, Kulkarni AR. Time and pH dependent colon specific, pulsatile delivery of theophylline for the treatment of nocturnal asthma. Int J Pharm 2007; 328: 49-56.

10. Shivakumar HN, Suresh S, Desai BG. Design and evaluation of controlled onset extended release multiparticulate systems for chronotherapeutic delivery of ketoprofen. Indian J Pharm Sci 2006; 68(1):76-82.

11. Giunchedi P, Maggi L, Conte U, Caramella C. Ketoprofen pulsatile absorption from ‘multiple unit’ hydrophilic matrices. Int J Pharm 1991; 77:177-81.

12. Pawar A, Sharma S. Low density multiparticulate systems for pulsatile release of meloxicam. Int J Pharm 2006; 313: 150-58.

13. Abraham S, Srinath MS. Development of modified pulsincap drug delivery system of metronidazole for drug targeting. Indian J Pharm Sci 2007; 69(1):24-7.

14. Maradny HA. Modulation of a pulsatile release drug delivery system using different swellable/rupturable materials. Drug Deliv 2007; 14:539-46.

15. Ishino R, Yoshino H, Hirakawa Y, Noda K. Design and preparation of pulsatile release tablet as a new oral drug delivery system. Chem Pharm Bull 1992; 40 (11): 3036-41.

16. Ali J, Qureshi J, Ahuja A, Baboota S. Chronomodulated Drug Delivery System of Salbutamol Sulphate for the Treatment of Nocturnal Asthma. Indian J Pharm Sci 2008; 70(3): 351–56.

17. Charde S et al. Development and evaluation of buccoadhesive controlled release tablets of lercanidipine. AAPS PharmSciTech. 2008; 9(1): 182–90.

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