I first and foremost express my revered regard and obeisance to the ALMIGHTY GOD with whose blessings I was able to complete my project.

DESIGN, DEVELOPMENT AND EVALUATION OF PULSATILE DRUG

DELIVERY SYSTEM OF PERINDOPRIL ERBUMINE USING MODIFIED PULSINCAP TECHNOLOGY

A Dissertation submitted to

THE TAMIL NADU Dr. M.G.R. MEDICAL UNIVERSITY CHENNAI - 600 032

In partial fulfillment of the requirements for the award of the Degree of MASTER OF PHARMACY

IN

BRANCH - I PHARMACEUTICS

Submitted by C.SUGANYA (Reg. No. 261711308)

Under the guidance of

Prof. Dr. A.ABDUL HASAN SATHALI, M.Pharm., Ph.D.

Department of Pharmaceutics

COLLEGE OF PHARMACY MADURAI MEDICAL COLLEGE

MADURAI – 625 020 MAY - 2019

ACKNOWLEDGEMENT

I first and foremost express my revered regard and obeisance to the ALMIGHTY GOD with whose blessings I was able to complete my project.

It is pleasure to express my respectful regards and thanks to

all kinds of supportive facilities required to carry out my project work.

I am thankful to

(Physiology) Vice Principal, Madurai Medical College, Madurai for her support and encouragement to carry out on my project work.

It is immense pleasure and honour to express my deep sense of gratitude and heartfelt thanks to Prof. Dr.A.ABDUL HASAN SATHALI, M.Pharm., Ph.D., College of Pharmacy, Madurai Medical College, Madurai for his excellence in guidance, contribution and encouragement which helped me in the successful completion of each and every stage of my project work.

I would like to thank assistant professors of our college Prof.

and encouragement throughout the work.

I also express my thanks to my senior

Erbumin drug sample to carry out my project work

I also thank Sastra University, Thanjavur, for their help in carrying out the evaluation of SEM studies.

I also thank PSG college of pharmacy, Coimbatore, for their help in carrying out

the evaluation of FTIR studies.

I also extent my thanks to

chemistry MMC, Madurai for permitting me to carry out the UV spectrometric studies in connection to my dissertation work

I would like to give my sincere thanks to my classmates

I express my special thanks to my juniors

I also extent my thanks to our department staff

for their contribution throughout my project work.

I am extremely thankful to the Library Madurai Medical college and staff of Chennai Xerox, laser point, for their kind co-operation regarding printing and binding of this dissertation work.

I Sincerely thank my juniors, all the staff members and P.G. Students of Department of Pharmaceutical Chemistry and Pharmacognosy for their Co-operation.

I specially thank my friends

Ponnudurai, M.pharm., Ms.M.Muthumari, M.pahram., Mrs.S.Swathi,M.pharm., P.Mohanasudha, K.Devaki, M.Geetha, P.Jothimani for their timely help in carrying

out my project work.

Finally, my eternal thanks to my exalted Parents Father

Mother (Mrs.C.Sampooranam) and my brother

endeavor of education successfully.

Place:

Date: (C.SUGANYA)

LIST OF ABBREVIATIONS

ºC Degree Centigrade

Abs Absorbance

μg/ml micro gram per millilitre

λmax Lambda maximum

mg Milligrams

g Grams

ml Milli litre

nm Nanometre

RPM Rotation per minute

Hr Hour

Sec Second

Vd Volume of distribution

cm Centimetre

nm Nanometre

Q.S Quantity Sufficient

FTIR Fourier Transfer Infrared Spectroscopy

UV Ultra Violet spectroscopy

SEM Scanning Electron Microscopy

API Active Pharmaceutical ingredient

CCS Cross Carmellose Sodium

SSG Sodium Starch Glycollate

IP Indian Pharmacopoeia

USP United States Pharmacopoea

HPMC Hydroxy Propyl Methyl Cellulose

FROF Flash Release Oral Film

CONTENT

CHAPTER

NO TITLE PAGE NO

I INTRODUCTION - PULSATILE DRUG

DELIVERY SYSTEM-A REVIEW 1

II LITERATURE REVIEW 34

III AIM AND PLAN OF THE WORK 44

IV DISEASE PROFILE 46

V DRUG PROFILE 51

VI EXCIPIENTS PROFILE 56

VII MATERIALS AND EQUIPMENTS 76

VIII EXPERIMENTAL PROTOCOL 78

IX RESULTS AND DISCUSSION 92

X SUMMARY AND CONCLUSION 123

XI REFERENCE 126

CHAPTER-1

INTRODUCTION

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 1

INTRODUCTION

Oral drug delivery is the most preferred route for drug administration. The oral controlled-release system show a typical pattern of drug release in which the drug concentration is maintained in the therapeutic window for a prolonged period of time, thereby ensuring sustained therapeutic action [1]. But there are certain conditions which demand release of drug after a lag time. i.e., Chronopharmacotherapy of disease which shows Circadian rhythms in their pathophysiology. Recent studies have revealed that diseases have predictable cyclic rhythms and that the timing of medication regimens can improve outcome is selected chronic conditions. Many body functions that follow circadian rhythm. e.g: Secretion of hormones , acid secretion in stomach, gastric emptying, and gastrointestinal blood transfusion.

Chronopharmacotherapy of diseases which shows circadian rhythms in their pathophysiology like bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease, ulcer and hypertension. Drugs that produce biological tolerance demand for a system that will prevent their continuous presence at the biophase as this tends to reduce their therapeutic effect. The lag time is essential for the drugs that undergo degradation in gastric acidic medium (e.g: peptide drugs) and irritate the gastric mucosa or induce nausea and vomiting. Targeting a drug to distal organs of gastro-intestinal tract (GIT) like the colon requires that the drug release is prevented in the upper two-third portion of the GIT. The drugs that undergo first-pass metabolism resulting in reduced bioavailability, altered steady state levels of drug and metabolite and potential food-drug interactions require delayed release of the drug to the extent possible. All of these conditions demand for a time-controlled therapeutic scheme releasing the right amount of drug at the right time. This requirement is fulfilled by Pulsatile Drug Delivery Systems [2].

Pulsatile drug delivery system (PDDS) are gaining lots of importance because it provides the delivery of drug at specific site, at specific amount and at specific site.

Patient compliance and therapeutic efficacy are better improved by such type of drug delivery systems. Many diseases like hypertension, asthma, peptic ulcer, arthritis and hypercholesterolemia and attention deficit syndrome in children may be better controlled and treated by pulsatile drug delivery system, because in such type of system

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 2 drug is released in a programmed manner. Pulsatile drug delivery system offers maximum benefits with fewer side effects. Pulsatile drug delivery system shows maximum benefits over conventional dosage form. In this system, drug is releases rapidly after predetermined lag time, which is very useful for disease treatment.

Pulsatile drug delivery system low the risk of dose dumping, provide flexibility in design and desirable release patterns with less inter and intra subject variability. [3]

CHRONOBIOLOGY:

Chronobiology is the study of concerned with the biological mechanism of the disease according to a time structure. “Chrono” pertains to time and “biology” pertains to the study, or science, or life[4]. Time is a component of a measuring system used to sequence events, to compare the duration of events and the interval between them, and to quantify the motion of objects. Every event in life depends on time. It is not possible to imagine the life we are leading without the invention of the concept of time. Time brings regulation in our life unless we regulate ourselves we are not able to do anything.[5]

BIOLOGICAL RHYTHMS:

The study of biological rhythms and mechansisms is known as chronobiology. They are regulated by sunlight. There are three types of mechanical rhythms in our body.

• Ultradian

• Infradian

• Circadian

ULTRADIAN RHYTHMS:

They are the rhythms that have a period of shorter than 24 hours.

Ex: 90-120 minute sleep cycling of the sleep stages during human sleep.

INFRADIAN RHYTHMS:

They are the rhythms which have a frequency ranging from 28 hours to 6 days.

Ex: Menstrual cycle.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 3 CIRCADIAN RHYTHMS:

The term “circadian”, coined by Franz Halberg, comes from the Latin circa,

“around” and diem of dies, “day”, meaning literally “approximately one day”. Our body appears to be genetically programmed to function on roughly a 24-hour cycle.

These rhythms allow organisation to anticipate and prepare for precise and regular environment all changes. They are important in determining the sleeping and feeding patterns of animals, including human beings. There are clear patterns of core body temperature, brain wave activity, hormone production, and others have their peak in the noon or evening. If our normal rhythm is disrupted we tend to become anxious.

E.g. many people have difficulty in adjusting to swing-shift work schedules. E.g. in sleep wake cycle an animal will settle into a 24 hour cycle activity and sleep even if deprived of light. Diurnal blood pressure fluctuations are super imposed by a 24-hour rhythm with lower levels during the night and higher in the day.[5]

FIGURE:1 CYCLE OF CIRCADIAN RHYTHMS

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 4 CHRONOPHARMACOLOGY:

Chronopharmacology is the science concerned with the variations in the pharmacological actions of various drugs over a period of time of the study.

CHRONOPHARMACOKINETICS:

Chronopharmacokinetics involves study of temporal changes in drug absorption, distribution, metabolism and excretion. Pharmacokinetic parameters, which are conventionally considered to be constant in time, are influenced by different physiological functions displaying circadian rhythm. Circadian changes in gastric acid secretion, gastrointestinal motility, gastrointestinal blood flow, drug protein binding, liver enzyme activity, renal blood flow and urinary pH can play role in time dependent variation of drug plasma concentrations.

CHRONOTHERAPY:

Co-ordination of biological rhythms and medical treatment is called chronotherapy.

CHRONOTHERAPEUTICS:

Chronotherapeutics is the discipline concerned with the delivery of drugs according to inherent activities of a disease over a certain period of time. It is becoming highly more evident that the specific time that patients take their medication may be even more significant than was recognized in the past.[4]

ADVANTAGES OF PULSATILE DRUG DELIVERY SYSTEM: [4,6]

• Extended day time or night time activity.

• Reduced dosage frequency.

• Reduction in dose size.

• Reduced side effects.

• Improved patient compliance.

• Lower daily cost of drug therapy.

• Drug targeting to specific site like colon.

• Protection of mucosa from irritating drugs.

• No risk of dose dumping.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 5

• Improved bioavilability, tolerability and reduces side effects.

• Avoidance of undesirable side effects.

• Flexibility in design.

• Improved stability.

• Drug loss is prevented by extensive first pass metabolism.

• Metabolism e.g. proteins and peptide.

DISADVANTAGES: [7]

• Lack of formulation reproducibility and efficacy.

• Large number of process variables

• Multiple manufacturing steps.

• Production of high cost.

• Need of advanced technology.

• Trained/skilled person needed for production.

NEED OF PULSATILE DRUG DELIVERY:[6]

• Bronchial disease like bronchial asthma, myocardial infraction, angina pectoris, rheumatic disease, ulcer and hypertension need the drug after a suitable lag time.

• Lag time essential for the drugs that undergo degradation in gastric acidic medium.

• It is possible to targeted deliver the drugs to specific sites of GIT like colon targeting with pulsatile drug delivery.

• PDDS needs when rhythmic variation seen in acid secrection in stomach, gastric emptying, and gastrointestinal blood transfusion.

• This dosages form is suitable for drug undergo extensive first-pass metabolism are administered successfully as pulsatile drug delivery systems.

• To prolong therapeutic effect by continuously releasing the medication over as extended period of time after administration of single dose.

• To delay the release of drug hence control the onset of drug action.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 6 DISEASES REQUIRING PULSATILE DRUG DELIVERY:[1,8,13]

The disease currently targeted for chronopharmaceutical formulations are those for which there are enough scientific backgrounds to justify pulsatile drug delivery system compared to the conventional drug administration approach. These include:

CARDIOVASCULAR DISEASES:

In cardiovascular disease capillary residence and vascular reactivity are higher in the morning and decreases latter in the day. Platelet agreeability is increased and fibrinolytic activity is decreases in the morning, leading to a state of relative hypercoagulability of the blood. Because of this reason the frequencies of myocardial infarction and of sudden cardiac death are more during a period from morning to noon.

Ambulatory blood pressure measurements show a significant circadian variation to characterize blood pressure. This variation is affected by a variety of external factors such as ethnicity, gender, autonomic nervous system tone, circulating level of catecholamine controlling the cardiac arrhythmias. Atrial arrhythmias appear to exhibit circadian pattern usually with a higher frequency in the daytime and lower frequency in the night time with the abnormal foci under the same long-term autonomic regulation as normal pacemaker tissue. According to study ventricular tachyarrhythmias shows late morning peak in the patients with myocardial infarction sometime in the distant past morning peak and afternoon peak in patients with recent myocardial infarction.[1,8]

ARTHRITIS:

The chronobiologies of pain have been extensively reviewed. For instance, there is a circadian rhythm in the plasma concentration of C – reactive protein and interleukin- 6 in patients with rheumatoid arthritis. Increasingly, the arthritis have shown statistically quantifiable rhythmic parameters. Included in the latter group are joint pain and joint size. In addition, a number of drugs used to treat rheumatic diseases have varying therapeutic and toxic effects based on the time of day of administration patients with osteoarthritis tend to have less pain in the morning and more at night; while those with rheumatoid arthritis using NSAIDs such as ibuprofen should be timed to ensure that the highest blood levels of the drug coincide with peak pain. For osteoarthritis sufferers, the optimal time for a non steroidal anti-inflammatory drug such as ibuprofen would be around noon or mid-afternoon. The same drug would be more effective for people with

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 7 rheumatoid arthritis when taken after the evening meal. The exact dose would depend on the severity of the patient’s pain and his or her individual physiology.[1]

ASTHMA:

The chronotherapy of asthma has been extensively studied. The role of circadian rhythms in the pathogenesis and treatment of asthma indicates that airway resistance increases progressively at night in asthmatic patients. Circadian changes are seen in normal lung function, the later reaches a low point in the early morning hours. This dip is particularly pronounced in people with asthma. Because bronchoconstriction and exacerbation of symptoms vary in a circadian fashion, asthma is well suited for chronotherapy. Chronotherapies have been studied for asthma with oral corticosteroids, theophylline, and B2-agonists.[8]

DUODENAL ULCER:

Many of the function of the gastrointestinal tract are subject to circadian rhythms:

gastric acid secretion is highest at night, while gastric and small bowel motility and gastric emptying are all slower at night. These biorhythms have important implications in the pharmacokinetics of orally administered drugs. At night time, when gastric motility and emptying are slower, drug disintegration, dissolution, and absorption may be slower.

In peptic ulcer patients, gastric acid secretion is highest during the night. Suppression of nocturnal acid is an important factor in duodenal ulcer healing. Therefore, for active duodenal ulcer, once daily at bedtime is the recommended dosage regimen for H2 antogonists. Theoretical problems associated with a sustained or profound decrease of 24- h intra gastric acidity include the threat of enteric infection and infestation, potential bacterial overgrowth with possible N-nitrosamine formation, drug-induced hyper gastrinaemia and disturbed protein digestion. In light of these potential problems, for the management of simple peptic ulceration, it appears sensible to use the minimum intervention required. Bedtime H2-receptor blockade is one such regimen.[8]

HYPERCHOLESTEROLEMIA:

Diverse directions of circadian changes in lipid fractions in patients and normal subjects may contribute to alteration in the rhythm city of other metabolisms and in the blood coagulation system, thus leading to various complications. A circadian rhythm occurs during hepatic cholesterol synthesis. However, this rhythm varies according to

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 8 individuals. Indeed, there is a large variation in plasma mevalonate concentrations between individuals. Therefore cholesterol synthesis is generally higher during the night than during daylight, and diurnal synthesis may represent up to 30-40% of daily cholesterol synthesis. Many individuals display a paradoxical synthesis, with an inverted diurnal cholesterol synthesis. It seems therefore that cholesterol is synthesized during the night as well as during daylight; however the maximal production occurs early in the morning, i.e. 12 h after the last meal. Studies with HMG COA reductase inhibitors have suggested that evening dosing was more effective than morning dosing.[1]

NEUROLOGICAL DISORDERS:

As an integrative discipline in physiology and medical research, chronobiology renders possible the discovery of new regulation processes regarding the central mechanisms of epilepsy. Chronophysiology investigations considered at a rhythmometric level of resolution suggest several heuristic perspectives regarding (i) the central pathophysiology of epilepsy and (ii) the behavioural classification of convulsive events.

Such circadian studies also show that chronobiology raises some working concepts in the field of neurological science. It is also well known that the brain area with the highest concentration in noradrenergic nerve terminals and noradrenaline (NA) have a circadian rhythm in their content of NA. Moreover, it has been shown that the human sleep, its duration and organization depend on its circadian phase. A breakthrough chronopharmaceutical formulation against insomnia that plagues many people would be one that addresses the entire oscillatory cycle of human sleeping process.[8]

DIABETES:

There circadian variations of glucose and insulin in diabetes have been extensively studied and their clinical importance in case of insulin substitution in type 1 diabetes has been well established. The goal of insulin therapy is to mimic the normal physiologic pattern of endogenous insulin secretion in healthy individuals, with continuous basal secretion as well as meal-stimulated secretion. Providing basal insulin exogenously to patients with diabetes inhibits hepatic glucose production. Exogenous administration of mealtime doses promotes peripheral glucose uptake (i.e. it prevents postprandial increases in blood glucose concentration) as well as reducing hepatic glucose release.[8]

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 9 CANCER:

Human and animal studies suggest that chemotherapy may be more effective and less toxic if cancer drugs are administered at carefully selected times that take advantage of tumor cell cycles while less toxic to normal tissue. The rhythmic circadian changes in tumor blood flow and cancer growth are relevant both when tumors are small and growing most rapidly and when they are larger and growing more slowly. The blood flow to tumors and tumor growth rate are each up to threefold greater during each daily activity phase of the circadian cycle than during the daily rest phase. Clinical studies testing whether circadian chemotherapy timing meaningfully affects drug toxicity patterns and severity, maximum tolerated dose, average dose intensity, tumor response quality and frequency and the survival of patients with cancer, have been indicated since the pioneer work of Haus et al. on leukemic mice. The chronotherapy concept offers further promise for improving current cancer-treatment options, as well as for optimizing the development of new anticancer or supportive agents.

TABLE:1 Drugs used in the pulsatile drug delivery system:[13]

Asthma Precipitation of attacks during night

or at early morning hour B2 agoinst, Antihistaminics Peptic ulcer Acid secretion is high in the

afternoon and at night H2 blockers Arthritis Pain in the morning and more pain at

night NSAIDs, Glucocorticoids.

Diabetes mellitus Increased blood sugar level after meal

Sulfonylurea, Insulin, Biguanide

Angina pectoris Chest pain and ECG changes more common in early morning

Anti anginal drugs Hypercholesterolemia Cholesterol synthesis is generally

higher during night than day time HMG CoA reductase inhibitors

Myocardial infraction Incidences higher in the early

morning Cardiovascular agent

Attentiondeficit

syndrome Increase in DOPA level in afternoon Methylphenidate Allergic rhinitis Worse in the morning/upon rising Antihistamines

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 10 MECHANISM OF DRUG RELEASE FROM PULSATILE DRUG DELIVERY SYSTEM:

The mechanism of drug release from Pulsatile Drug Delivery System can be occurring in the following ways.[9]

Diffusion: Water diffuses into the interior of the particle when particle come in contact with aqueous fluids in gastrointestinal tract and resultant drug solutions diffuse across the release coat to the exterior.

Erosion: Some coatings designed to erode gradually with time, result in the release of drug contained within the particle.

Osmosis: An osmotic pressure can be built up within the interior of the particle when water allows entering under the right circumstances. The drug is forced out of the particle into the exterior through the coating.

METHODS OF DEVELOPMENT OF PULSATILE DRUG DELIVERY SYSTEM:

Methodologies for the PDDS can be broadly classified into four classes [9,10,11,12,13,14,15]

1. Time controlled Pulsatile release A. Single unit system

i. Capsular system ii. Port system

iii. Delivery by solubility modulation iv. Delivery by reservoir systems.

B. Multi-particulate system

i. Pulsatile system based on rupturable coating ii. Time controlled expulsion system

iii. Pulsatile delivery by change in membrane permeability iv. Sigmoidal release system

v. Low density floating multiparticulate pulsatile systems.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 11 2. Internal stimuli induced pulsatile system

i. Temperature induced system ii. Chemical stimuli induced system iii. pH sensitive drug delivery system 3. External stimuli induced system

i. Electrically stimulates Pulsatile system ii. Magnetically stimulated Pulsatile system iii. Ultrasonically stimulated Pulsatile system iv. Photo chemically stimulated Pulsatile system

4.Pulsatile release system for vaccine and hormone products

1. Time controlled pulsatile release A. Single unit system

i. Capsular system

A capsular system consists of an insoluble capsule body housing a drug and a plug. The plug is removed after a predetermined lag time owing to swelling, erosion, or dissolution. The lag time is continued by a plug that gets pushed away by swelling or erosion, releasing the drug as a pulse from the insoluble capsule body. The system is comprised of a water insoluble capsule enclosing the drug reservoir. A swellable hydrogel plug was used to seal the drug contents into the capsule body. When the capsule comes in contact with dissolution fluid, the plug gets swells, and after a lag time, the plug pushes itself outside the capsule and rapidly releases the drug. The length of the plug and its point of insertion into the capsule controlled the lag time. The pulsincap system developed by R.P. Scherer International Corporation, Michigan. It is made up of a water insoluble capsule body filled with drug formulation. The body is closed at the open end with a swellable hydrogel plug. Upon contact with dissolution medium or Gastro-intestinal fluids, the plug swells, pushing itself out of the capsule after a lag time. This is followed by a rapid drug release. Manipulating the dimension and the position of the plug can control the lag time. For water-insoluble drugs, a rapid release can be ensured by inclusion of effervescent agents or disintegrants. The plug material consists of insoluble but permeable and swellable polymers (e.g., polymethacrylates), erodible compressed polymers (e.g., hydroxypropylmethyl cellulose, polyvinyl alcohol, polyethylene oxide), and congealed melted polymers (e.g., saturated polyglycolated glycerides, glyceryl monooleate), and enzymatically controlled

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 12 erodible polymer (e.g. pectin). This formulation does not cause GI irritation and some time it is overcome but enteric coating.[13]

FIGURE:2 PULSINCAP SYSTEM

ii. Port system (Programmable oral release technology)

Port system consist of a gelatin capsule coated with a semi permeable membrane (e.g., cellulose acetate) housing an insoluble plug (e.g. lipidic) and an osmotically active agent along with the drug formulation. When in contact with the aqueous medium, water diffuses across the semi permeable membrane, resulting in increased inner pressure that ejects the plug after a lag time. Coating thickness controls the lag time. The system was proposed to deliver methylphenidate for the treatment of attention deficit hyperactivity disorder (ADHD) in school-age children. Such a system avoids a second daily dose that otherwise would have been administered by a nurse during school hours.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 13 It is further classified as –

Based on expandable delivery orifices

It is used to delivers the drug in liquid dosage form. Osmotic pressure develops on the drug reservoir and drug release occurs through delivery orifices. The lag time is modified by changing the Thickness of barrier membrane.

Delivery by series of stops

It is for implantable capsule. It contains a drug and water absorptive osmotic engine placed in compartments separated by movable partition. Pulsatile drug delivery is achieved by series of stops. The number and frequency of stops and longitudinal placements of stop along with length of movable partition. Pulsatile drug delivery is achieved by series of stop.

iii. Pulsatile drug delivery by modulating solubility

These system contain a solubility modulator for pulsed delivery of variety of drugs. The system was especially developed for delivery of antiasthmatic drugs like salbutamol sulphate. The compositions contain the drug and a modulating agent, sodium chloride (Nacl). The amount of Nacl was such that it was less than the amount needed to maintain saturation in a fluid that enters the osmotic device. The pulsed delivery is based on drug solubility.

iv. Delivery by reservoir systems with erodible or soluble barrier coatings

The drug reservoir is coated with soluble erodible barrier. After its dissolution or erosion of that barrier drug is released from the reservoir.

Delivery systems with rupturable coating layer :

These systems consist of an outer release controlling water insoluble but permeable coating layer which produces mechanically induced rupturing. The film rupture may be attained by including swelling, osmotic or effervescent additives in the reservoir. By optimizing the system, drug release can be obtained at specific time interval.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 14 Delivery system with erodible coating layer :

In these systems the drug release is controlled by the dissolution or erosion of the outer coat which is applied on the core containing drug. Time dependent release of the active ingredient can be obtained by optimizing the thickness of the outer coat .

EXAMPLE:

i) Time clock system: (West Pharmaceutical Services Drug Delivery and Clinical Research Centre) consist of solid dosage form coated with lipidic barrier containing carnauba wax and bees wax, along with surfactant like polyethylene sorbitan monooleate. The coat erodes or emulsifies in the aqueous environment. The thickness of coat is directly proportional to the time required to release the drug. The lag time is increase with increase in thickness of the coating. This type of system is suitable for water soluble drugs. The main advantage of this system is to formulate without any special equipment. The premature drug release occurs and it will dissolve with dissolution medium and release with sustained manner without complete erosion their by it retard the release in pulsatile manner.

ii) Chronotropic system: It is based on a drug reservoir coated with soluble barrier coating of hydroxy propyl methyl cellulose (HPMC). This barrier layer erodes or dissolved after predetermined lag time. The lag time is depending upon the thickness of coating and use of viscosity grade HPMC. The coating helps to overcome variability in gastric emptying and colon specific release can be obtained. This system is suitable for both tablet and capsules. Multiparticulate formulations are beneficial for oral bioavailability of peptides and proteins.

B.Multi-particulate system[14]

The designing multiparticulate dosage form has more advantageous than single unit dosage form. The mechanism by which the drug is released from pellets depends on the type of coating, insoluble coating under all physiological conditions, pH- dependent coating whose solubility changes dramatically at some point in GI tract and slowly erodes coating. The method of preparation and processing parameters are affected on pellets preparation.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 15 i. Reservoir systems with rupturable polymeric coating

Most multiparticulate pulsatile delivery systems are reservoir devices coated with a rupturable polymeric layer. Upon water ingress, drug is released from the core after rupturing of the surrounding polymer layer, due to pressure build-up within the system. The pressure necessary to rupture the coating can be achieved with swelling agents, gas producing effervescent excipients or increased osmotic pressure. Water permeation and mechanical resistance of the outer membrane are major factors affecting the lag time. Water soluble drugs are mainly released by diffusion; and water insoluble drug, the release is dependent on dissolution of drug. In time-controlled explosion systems (TES), where drug is released by a quite novel mechanism which is neither diffusion control nor dissolution control, but by explosion of the outer membrane. TES were developed for both single and multiple unit dosage forms. In both cases, a core contains drug plus an inert osmotic agent and suitable disintegrants.

Individual units can be coated by protective layer and then by a semi permeable layer, which is the rate controlling membrane for the influx of water into the osmotic core.

Osmotic pressure is exerted and delivery of drug occurs. A four layered time-controlled explosion system was developed where, drug was layered on an inner core (polystyrene balls or non-pareil sucrose beads), followed by a swellable layer (e.g., hydroxypropyl cellulose) and an insoluble polymeric top layer (e.g., ethylcellulose). Advantage of this system is to release the drug completely, independent of the environmental pH and drug solubility.

ii. Time controlled expulsion system

This system is based on a combination of osmotic and swelling effects. The core contains the drug, a low bulk density solid and/or liquid lipid material (e.g. mineral oil) and a disintegrants. The core is further coated with cellulose acetate. After immersion in aqueous medium, water penetrates the core displacing the lipid material. After the depletion of lipid material, internal pressure increases until a critical stress is reached, which results in rupture of the coating material. Another system is based on a capsule or tablet composed of a large number of pellets consisting of two or more pellets or part.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 16 iii. Pulsatile delivery by change in membrane permeability

The permeability and water uptake of acrylic polymers with quaternary ammonium groups can be influenced by the presence of different counter-ions in the medium. Several delivery systems based on this ion exchange have been developed.

Eudragit RS 30D is reported to be a polymer of choice for this purpose. Typically contains positively polarized quaternary ammonium group in the polymer side chain, which is always accompanied by negative hydrochloride counter-ions. The ammonium group being hydrophilic it facilitates the interaction of polymer with water, thereby changing its permeability and allowing water to permeate the active core in a controlled manner.

iv. Sigmoidal release system

Sigmoidal release pattern is therapeutically beneficial for timed release and colonic drug delivery, and observed in coated systems. A sigmoidal release pattern is reported based on the permeability and water uptake of Eudragit RS or RL, influenced by the presence of different counterions in the release medium. Pulse release depending on the change in diffusion properties of Eudragit RS. A core of theophylline coated with Eudragit RS showed very slow

release rates in pure water but significant increase in the release rate was found when the microcapsules were immersed in an organic acid solution containing succinic, acetic ,glutaric, tartaric, malic, or citric acid. Because the higher hydration of the film containing quaternary ammonium groups on interaction with the acids.

v. Low density floating multiparticulate pulsatile systems

Low density floating multiparticulate pulsatile dosage forms reside in stomach only and not affect by variability of pH, local environment or gastric emptying rate.

These dosage forms are also specifically advantageous for drugs either absorbed from the stomach or requiring local delivery in stomach. In short multiparticulate pulsatile release dosage forms possessing gastric retention capabilities. Multiparticulate floating pulsatile drug delivery system was developed using porous calcium silicate (Florite RE) and sodium alginate, for time and site specific drug release of meloxicam for chronopharmacotherapy of rheumatoid arthritis.[14]

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 17 Stimuli – induced pulsatile systems

In these systems, stimulation by any biological factor like temperature or any other chemical stimuli leads to release of the drug. Further classification is as follows

2.Internal Stimuli Induced Pulsatile System i.Thermo – responsive Pulsatile Release

Thermo – responsive hydrogel systems have been developed for pulsatile release. In these systems, the polymer swells or deswells in response to temperature which modulate drug release in swollen state.

ii. Chemical stimuli induced Pulsatile system a). Glucose – responsive Insulin release devices

In the case of Diabetes mellitus, a rhythmic increase in the levels of glucose is noticed in the body, requiring an injection of insulin at proper time. Several systems which are able to respond to changes in glucose concentration have been developed.

One such system includes pH sensitive Hydrogel containing glucose oxidase immobilized in the hydrogel. Upon the increment of glucose concentration in the blood, Glucose is converted into Gluconic Acid by Glucose oxidase which changes the pH of the system. This change in the pH induces swelling of polymer which results in insulin release. Insulin by its action, reduces blood glucose level and consequently gluconic acid level is also decreased and the system turns to deswelling mode thereby decreasing the insulin release. Examples of pH sensitive polymers include N, N – dimethyl aminoethyl methacrylate, chitosan, polyol etc.

b). Inflammation induced pulsatile release

Inflammation is a natural phenomenon that occurs on receiving any physical or chemical stress such as injury, fracture etc. at the injured site. These inflammation responsive cells produce hydroxyl radicals. It is possible to treat patients with inflammatory diseases like rheumatoid arthritis, using anti – inflammatory drug incorporated HA gels or Hyaluronic Acid gels as new implantable drug delivery system.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 18 c). Drug release form intelligent gels responding to antibody concentration

Numerous kinds of bioactive compounds exist in the body. Recently, novel gels were developed which responded to the change in concentration of bioactive compounds to alter their swelling/ deswelling characteristics. The antigen – antibody complex formation was given special attention as cross – linking units in the gel, since such interaction is very specific. Utilizing the difference between polymerized antibodies and naturally derived antibodies‘ association constants towards specific antigens, reversible gel swelling/ deswelling and drug permeation changes occurs.

d). pH sensitive Drug Delivery System

This system comprises of 2 components – fast release type and pulsed release type. The pulsed release type releases drug in response to change in pH. Its main advantage is the fact that there exists different pH environment at different parts of the GIT. Drug release at specific location can be obtained by selecting pH dependent polymers like acetate phthalate, poly acrylates and sodium carboxy methyl cellulose.

The polymers are used as enteric coating materials so as to provide release of drug in the small intestine.[15,16]

II. External stimuli induced system

These types of open-loop systems are not self-regulated. But for delivery of the drug in pulse manner another way in which drug release in programmed pattern can be the external regulated system. These systems are magnetically stimulated, ultrasonically modulated and photo stimulated.

1. Electro responsive pulsatile release

This system provides the drug release by action of applied electric field on rate limiting membrane and/ or directly on solute, thus controls it transport across the membrane. The polymer has two redox states, only one of which is suitable for ion binding. Drug ions are bound in redox state and release. The mechanism of drug transport of proteins and natural solutes across hydrogel membranes. electrically induced swelling of membrane to alter effective pore size and permeability.

Electrophoretic and electroosmotic agumentation of solute flux within a membrane.

Electrostatics partitioning of charged solutes in charged membrane.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 19 2. Magnetically stimulated pulsatile system

In this system magnetic steel beads can be embedded in a polymer matrix with model drug. During exposure to the magnetic field, the beads oscillate within the matrix, alternatively creating compressive and tensile forces. This in turn acts as a pump to push an increased amount of the drug molecule out the matrix. Magnetic response comes from incorporated magnetic particle like magnetite, iron, nickel, cobalt and steel. Langer developed one system of polymeric matrix containing dispersed drug along with magnetic beads. Generally ethylene-vinyl acetate copolymer is used for this purpose. An oscillating magnetic field is generated to trigger the release of drug.

Saslawski applied an oscillating magnetic field to trigger the release of insulin in pulsatile manner from alginated microspheres. Here ferrite micro particles and insulin were dispersed in sodium alginate aqueous solution. This suspension was added to calcium chloride solution which causing formation of cross-linked alginate spheres.

These spheres were again cross-linked with aqueous solution of poly (Llysine) or poly (ethylene imine). The release rate was improved in absence of a magnetic field.

3. Ultrasonically stimulated pulsatile system

Pulsed drug delivery can be achieved by the on–off application of ultrasound.

During polymer degradation incorporated drug molecules are released by repeated ultrasonic exposure. It can be used for the augmentation of drug permeation through biological barriers such as skin, lungs, intestinal wall and blood vessels. Ultrasonic waves cause the erosion of the polymeric matrix thereby modulating drug release.

Miyazaki and co-worker, (1998), evaluated the effect of ultrasound (1 MHz) on the release rates of bovine insulin from ethylenevinyl alcohol copolymer matrices and reservoir-type drug delivery systems in which they found sharp drop in blood glucose levels after application of ultrasonic waves.The cavitations is responsible for degradation and release from bioerrodible polymers.

4. Photo chemically stimulated pulsatile system

In this system the interaction between light and the material can be used for modulating the drug delivery system. The study material should absorbs the light at desired wavelength and material uses energy from the absorb light. e.g Gold nanoshell (a thin layer of gold surrounding a core of active nano particle). Embedding the nanoshells in a NIPAAm-co-AAM hydrogel formed the required composite material.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 20 When exposed to near infrared light, nanoshells absorb the light and convert it to heat, raising the temperature of composite hydrogel above its LCST. That’s result in the increase of release rate of the drug from the matrix system. Photo responsive gels reversibly change their physical or chemical properties upon photo radiation[13,14]

4.PULSATILE RELEASE SYSTEMS FOR VACCINE AND HORMONE PRODUCTS:

Vaccines are traditionally administered as an initial shot of an antigen followed by repeated booster shots to produce protective immunity. The frequency of the booster shots, and hence the exact immunization- schedule is antigen dependent. Also, co- administration of vaccine adjuvant is often required to enhance the immune response to achieve protective immunity. PDDS offer the possibility of single-shot vaccines if initial booster release of the antigen can be achieved from one system in which timing of booster release is controlled. Vizcarra et al found in nutritionally anoestrous cows, GnRH administered in pulses of 2 mg over 5 min every hour for 13 days produced a higher frequency of luteal activity by 13th day than cows given continuous infusions or pulses every 4 H[9]

TABLE:2 POLYMERS EMPLOYED IN PDDS:[13]

Synthetic Natural

HPMC K4M Sodium alginate

HPMC K15M Pectin

HPMC K100 Karaya gum

Eudragit Gelatin

Ethyl cellulose Xanthan gum

Cellulose acetate phthalate Chitosan

Polymethacylic acid Guar gum

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 21 TYPES OF DOSAGE FORMS THAT CAN BE DESIGNED [17]

Compression coated/press coated tablets

These are timed release formulations, simple to manufacture, comprised of an inner core that contains an active pharmaceutical ingredient and excipients surrounded by an outer layer that dissolves or disintegrates slowly to produce the lag time. The core is placed between two layers of polymer and directly compressed by flat punches of tablet machine. Surrounding polymeric layers protect the drug from release before the desired lag time, hence effective delivery in chronotherapy as it allows the drug release at the point in circadian cycle when clinical signs develop and increase.

FIGURE:3 Design of the press coated tablet composed of an active FELODIPINE/PVP core and an inactive PVP/HPMC coating layer.

Core in cup tablets

It is a novel oral pulsatile release drug delivery system based on a core-in-cup dry coated tablet, where the core tablet surrounded on the bottom and circumference wall with inactive material. The system consists of three different parts, a core tablet, containing active ingredient, an impermeable outer shell and a top cover layer-barrier of a soluble polymer. The impermeable coating cup consisted of cellulose acetate propionate and the top cover layer of hydrophilic swellable materials such as polyethylene oxide, sodium alginate or sodium carboxy methyl cellulose. The system releases the drug after a certain lag time generally due to the erosion of top cover layer.

The quantity of material, its characteristics (viscosity, swelling, gel layer thickness) and the drug solubility was found to modify lag time and drug release. The lag time increases when quantity of top layer increases, whereas drug release decreases.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 22

FIGURE:4 CORE IN CUP TABLET

Pulsincap systems

As discussed previously that these are the well designed pulsatile release drug delivery systems capable of releasing drug at pre determined time. Drug formulation is contained within the insoluble capsule body which is sealed by means of a hydrogel plug. On oral administration the water soluble capsule cap dissolves in the gastric juices and hydrogel plug swells. At a controlled and predetermined time point after the ingestion, the swollen plug is ejected from the pulsincap dosage form after which the encapsulated dosage formulation is then released. To simplify this technology, the hydrogel plug has been replaced by an erodible tablet, which has a tight fit in capsule to prevent the entry of fluid. During the release process it erodes away from the mouth of capsule. The effect of various parameters such as type and weight of swellable polymer, type of hydrophilic polymers used in erodible tablet formulation and erodible tablet weight was investigated in order to characterize the lag time and drug release profiles.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 23 FIGURE:5 The pulsatile capsule is designes for two drug doses. First is placed into the capsule cap while the second dose is released from an insoluble capsule body. Lag time is determined by an osmotic system which presses an insoluble plug out of the capsule body.

Double coated hard gelatin capsules and double coated tablets

These are time controlled rupturable pulsatile drug delivery systems either in form of hard gelatin capsules tablets. The capsules are filled with active pharmaceutical ingredient either for single pulse or multi-pulse release (in form of multiparticulates) and coated with a swelling layer followed by an external water insoluble semipermeable polymeric coating. Upon water ingress the swelling layer swells to attain a threshold hydrodynamic pressure required to rupture the outer coating and allowing the release of contents in surrounding medium. The time required by swelling layer to rupture outer coating surves the purpose of desired lag time required in chrono therapy of disease.

The tablets are manufactured and coated on the same principle as that of double coated gelatin capsules.

Pulsatile release muliparticulate systems

These systems have been developed on the basis of various approaches of designing pulsatile drug delivery system discussed earlier( like time controlled, stimuli induced or externally regulated pulsatile drug delivery systems).these can be developed in various types of dosage forms like:

1. Pellets 2.Granules 3.Microspheres

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 24 4.Beads

5.Nanoparticles 6.Microsponges

In recent pharmaceutical applications involving pulsatile drug delivery, multiparticulate dosage forms are gaining much favour over single unit dosage forms.

The potential benefits include increased bioavailability, predictable, reproducible, and generally short gastric residence time; no risk of dose dumping; reduced risk of local irritation; and flexibility to blend pellets with different compositions or release patterns.

Because of their smaller particle size, these systems are capable of passing through gastrointestinal tract easily, leading to less inter- and intra-subject variability. A no. of multiparticulate pulsatile drug delivery systems have been developed for chronotherapy.

For instance, colonic delivery of theophylline in form of microspheres and coated pellets for nocturnal asthma , formulation of indomethacin, ibuprofen, flurbiprofen, meloxicam, aceclofenac, diclophenac pellets and microspheres for chronotherapy of rheumatoid arthritis and floating beads of alginates encapsulating the active drug component in core, have been attempted to deliver many of the drugs which are absorbed in upper gastrointestinal tract. Numerous advanced technologies have been developed in designing of pulsatile release multiparticulate dosage forms and many of them are FDA approved and being marketed.

FIGURE:6 A) Design of a pellet with multiple coating B) Predicted bio-model plasma concentration profile.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 25 Chronomodulating infusion pumps

Externally and internally controlled systems across a range of technologies including pre-programmed systems, as well as systems that are sensitive to modulated enzymatic or hydrolytic degradation, pH, magnetic fields, ultrasound, electric fields, temperature, light and mechanical stimulation have been reviewed in detail elsewhere.

To our knowledge infusion pumps on the market that have been referred to as chronomodulating for drug delivery application include the Melodie, programmable Synchromed, Panomat V5 infusion, and the Rhythmic pumps. The portable pumps are usually characterized by a light weight (300-500 g) for easy portability and precision in drug delivery. For example portable programmable multi-channel pumps allowed demonstration of the clinical relevance of the chronotherapy principle in a sufficiently large patient population. Specifically, a clinical phase III trial involving several patients with metastatic gastrointestinal malignancies compared a flat versus the chronomodulated three-drug regimen, and demonstrated large, simultaneous improvements in both tolerability and response rates in patients with metastatic colorectal cancer receiving chronotherapy. In case of insulin therapy, implantable infusion pumps containing a reservoir of insulin may be surgically placed within the subcutaneous tissue of the abdomen in the left upper or lower quadrant (above or below the belt). A catheter leads from the pump through the muscle layers into the peritoneal cavity, where it floats freely, and insulin delivery is by the intraperitoneal route. The insulin reservoir is refilled once a month or every 3 months at a physician’s office by inserting a needle through the skin into the pump (a local anaesthetic is first used).

Doses adjustments are made by the patient (within ranges established by the physician) using radiotelemetry and an electronic device that is held over the pump. Their advantages include the fact that the peritoneum provides a large, well-vascularized surface area, and absorption is faster by this route than after subcutaneous injection (better insulin gradient), improved glycemic control and a reduction in the frequency of hypoglycemic episodes. Possible drawbacks of this approach include eventual formation of fibrous tissue pocket and local skin erosion. Catheter blockade which can reduce insulin delivery, are the most common problems with implantable pumps.

However, these pumps have been effectively used in the chronotherapy of several diseases such as cancer and diabetes.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 26 Controlled-release microchip

An alternative method to achieve pulsatile or chronopharmaceutical drug release involves using microfabrication technology. The release mechanism was based on the electrochemical dissolution of thin anode membranes covering microreservoirs filled with chemicals in solid, liquid or gel form. Initially the authors conducted proof-of- principle release studies with a prototype microchip using gold and saline solution as a model electrode material and release medium, and demonstrated controlled, pulsatile release of poly (L-lactic acid) and had poly (D, L-lacticco- glycolic acid) membranes were fabricated that released four pulses of radio-labelled dextran, human growth hormone or heparin in vitro. This technology has the potential to be used in the design of chronotropic drug delivery systems with a better control over drug release kinetic in order to match biological requirement over a versatile period of time.

MICROSPHERES:[18,19,20,21,22,23]

Drug delivery systems (DDS) that can precisely control the release rates or target drugs to a specific body site have had an enormous impact on the health care system. The ideal drug delivery system delivers drug at rate decided by the need of the body throughout the period of treatment and it provides the active entity solely to the site of action. So, carrier technology offers an intelligent approach for drug delivery by coupling the drug to a carrier particle such as microspheres, nanoparticles, liposomes, etc which modulates the release and absorption characteristics of the drug. Types of drug delivery system are

i. LIPOSOME ii. NIOSOME

iii. NANOPARTICAL iv MICROSPHERE .

Microspheres are solid spherical particles ranging in size from 1-1000μm. They are spherical free flowing particles consisting of proteins or synthetic polymers. The microspheres are free flowing powders consisting of proteins or synthetic polymers, which are biodegradable in nature. There are two types of microspheres;

i.Microcapsules.

ii.Micromatrices.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 27 Microcapsules are those in which entrapped substance is distinctly surrounded by distinct capsule wall and micromatrices in which entrapped substance is dispersing throughout the microspheres matrix. Solid biodegradable microspheres incorporating a drug dispersed or dissolved through particle matrix have the potential for the controlled release of drug. They are made up of polymeric, waxy, or other protective materials, that is, biodegradable synthetic polymers and modified natural products.[18]

ADVANTAGES [19,21]

• Microspheres provide constant and prolonged therapeutic effect.

• To reduce dosing frequency and thereby improve the patient compliance.

• They could be easily injected into the body due to the spherical shape and smaller size.

• Duration for short half life drug may be increased.

• Better drug utilization will improve the bioavailability and reduce the incidence or intensity of adverse effects.

• Microsphere morphology allows a controllable variability in degradation and drug release.

• Taste and odour masking.

• Protection of drugs against the environmental factors (moisture, light, heat and /or oxidation) and protection of body from adverse effects of drugs (prevention of pain on injection).

• For ease of handling (e.g. conversion of oils and other liquids to solids).

• Improvement of flow properties of powders.

• Safe handling of toxic substances.

• Prevention or delay of volatilization.

• Separation of incompatible materials (other drugs or excipients

• For dispersing water-insoluble substances in aqueous media.

DISADVANTAGES:[19,21]

• Poor in vitro-in vivo correlation.

• Higher cost of formulation.

• Retrieval of drug is difficult in case of toxicity, poisoning.

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 28 Polymers used in microspheres:[18,19,23]

1.Synthetic Polymers.

2.Natural polymers.

1.Synthetic polymers

a. Non-biodegradable polymers

example: Polymethyl methacrylate (PMMA), Acrolein, Glycidyl methacrylate, Epoxy polymers.

b. Biodegradable polymers

example: Lactides, Glycolides & their co polymers, Poly alkyl cyano acrylates Poly anhydrides.

2.Natural Polymers

These are obtained from different sources:

Proteins: Albumin, Gelatin, and Collagen.

Carbohydrates: Agarose, Carrageenan, Chitosan, Starch.

Chemically modified carbohydrates: Polydextran, polystarch.

In case of non-biodegradable drug carriers, when administered parentally the carrier remaining in the body after the drug is completely released poses possibility of carrier toxicity over a long period of time. Bio degradable carriers which degrade in the body to non-toxic degradation products do not pose the problem of carrier toxicity and are more suited for parenteral applications.

TYPES OF MICROSPHERES[19,22]

Bioadhesive microspheres

Adhesion can be defined as sticking of drug to the membrane by using the sticking property of the water soluble polymers. Adhesion of drug delivery device to the mucosal membrane such as buccal, ocular, rectal, nasal etc can be termed as bioadhesion. The term “bioadhesion” describes materials that bind to biological substrates’, such as mucosal members. Adhesion of Bioadhesive drug delivery devices to the mucosal tissue offers the possibility of creating an intimate and prolonged contact at the site of administration. This prolonged residence time can result in enhanced absorption and in combination with a controlled release of drug also improved patient

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 29 compliance by reducing the frequency of administration. Carrier technology offers an intelligent approach for drug delivery by coupling the drug to a carrier particle such as microspheres, nanospheres, liposomes, nanoparticles, etc., which modulates the release and absorption of the drug. Microspheres constitute an important part of these particulate drug delivery systems by virtue of their small size and efficient carrier capacity.

Magnetic microspheres

This kind of delivery system is very much important which localises the drug to the disease site. In this larger amount of freely circulating drug can be replaced by smaller amount of magnetically targeted drug. Magnetic carriers receive magnetic responses to a magnetic field from incorporated materials that are used for magnetic microspheres are chitosan, dextran etc. The different type are therapeutic magnetic microspheres are used to deliver chemotherapeutic agent to liver tumour. Drugs like proteins and peptides can also be targeted through this system.

Diagnostic microspheres.

Magnetic drug transport technique is based on the fact that the drug can be either encapsulated into a magnetic microsphere or conjugated on the surface of the microsphere. The accumulation of the carrier at the target site allow them to deliver the drug locally.

Floating microspheres

In floating types the bulk density is less than the gastric fluid and so remains buoyant in stomach without affecting gastric emptying rate. The drug is released slowly at the desired rate, if the system is floating on gastric content, increases gastric residence and fluctuation in plasma concentration. It also reduces chances of striking and dose dumping and produces prolonged therapeutic effect. Drug (ketoprofen) given through this form.

Radioactive microspheres

Radio immobilization therapy microspheres sized 10-30 nm are of larger than capillaries and gets tapped in first capillary bed when they come across. They are injected to the arteries that lead to tumour of interest. So these radioactive microspheres

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 30 deliver high radiation dose to the targeted areas without damaging the normal surrounding tissues. It differs from drug delivery system, as radio activity is not released from microspheres but acts from within a radioisotope typical distance and the different kinds of radioactive microspheres are α emitters, β emitters, γ emitters.

Mucoadhesive microspheres

Mucoadhesive microspheres which are of 1-1000mm in diameter and consisting either entirely of a mucoadhesive polymer or having an outer coating of it and coupling of mucoadhesive properties to microspheres has additional advantages, e.g. efficient absorption and enhanced bioavailability of the drugs due to a high surface to volume ratio, a much more intimate contact with the mucus layer, specific targeting of drug to the absorption site achieved by anchoring plant lectins, bacterial adhesions and antibodies, etc. on the surface of the microspheres. Mucoadhesive microspheres can be tailored to adhere to any mucosal tissue including those found in eye, nasal cavity, urinary and gastrointestinal tract, thus offering the possibilities of localized as well as systemic controlled release of drugs.

Polymeric microspheres

The different types of polymeric microspheres can be classified as:

Biodegradable polymeric microspheres

Natural polymers such as starch are used with the concept that they are biodegradable, biocompatible, and also Bioadhesive in nature. Biodegradable polymers prolongs the residence time when contact with mucous membrane due to its high degree of swelling property with aqueous medium , results gel formation. The rate and extent of drug release is controlled by concentration of polymer and the release pattern in a sustained manner. The main drawback is, in clinical use drug loading efficiency of biodegradable microspheres is complex and is difficult to control the drug release.

Synthetic polymeric microspheres

The interest of synthetic polymeric microspheres are widely used in clinical application, moreover that also used as bulking agent, fillers, embolic particles, drug delivery vehicles etc and proved to be safe and biocompatible. But the main

INTRODUCTION

DEPARTMENT OF PHARMACEUTICS, COP, MMC, MADURAI-20 31 disadvantage of these kind of microspheres, are tend to migrate away from injection site and lead to potential risk, embolism and further organ damage.

METHODS OF PREPARATION:[20]

Single Emulsion Technique:

The micro-particulate carriers of natural polymers i.e. those of proteins and carbohydrates are prepared by single emulsion technique. The natural polymers are dissolved/dispersed in aqueous medium followed by dispersion in the non-aqueous medium e.g. oil. In the second step of preparation, crosslinking of dispersed globule is carried out. The cross linking is achieved by two methods i.e. either by heat or by means of chemical cross linking agents including glutaraldehyde,formaldehyde, di acid chloride etc.

Double Emulsion Technique:

This method involves the formation of the multiple emulsion or double emulsion of type w/o/w. It is best suited to water soluble drugs, peptides, proteins and vaccines. This method can be used with both the natural as well as the synthetic polymers. The aqueous protein solution is dispersed in a lipophilic organic continuous phase .This protein solution may contain the active constituents. The continuous phase is generally consisted of the polymer solution that eventually encapsulates of the protein contained in dispersed aqueous phase. The primary emulsion is then subjected to the homogenization or the sonication before addition to the aqueous solution of the poly vinyl alcohol (PVA).This results in formation of a double emulsion. Emulsion is then subjected to solvent removal either by solvent evaporation or by solvent extraction process. The solvent evaporation is carried out by maintaining emulsion at reduced pressure or by stirring the emulsion so that the organic phase evaporates out. The emulsion is then added to large quantity of water into which organic phase diffuses out.

The solid microspheres are subsequently obtained by filtration and washing with n- hexane, acetone or any organic solvent to remove traces of oil from the surface.

Polymerization:

The polymerization techniques conventionally used for the preparation of the microspheres are mainly classified as:

Normal polymerization and Interfacial polymerization