1
DESIGN AND CHARACTERISATION OF ROSUVASTATIN CALCIUM NANOSPONGE USING A NATURAL POLYMER AT DIFFERENT
CONCENTRATION
DISSERTATION Submitted to
THE TAMILNADU Dr. MGR. MEDICAL UNIVERSITY CHENNAI-600 032
In partial fulfillment of the requirements for the award of the degree of MASTER OF PHARMACY
IN
PHARMACEUTICS Submitted by A.J.MARIYAM BEE
(261710955) Under the guidance of
Mrs. M.BHARATHI M.Pharm.,
Assistant Professor, Department of Pharmaceutics.
KAMALAKSHI PANDURANGAN COLLEGE OF PHARMACY,
AYYAMPALAYAM, TIRUVANNAMALAI -606603.
NOVEMBER 2019.
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KAMALAKSHI PANDURANGAN COLLEGE OF PHARMACY AYYAMPALAYAM, TIRUVANNAMALAI.
CERTIFICATE
This is to certify that dissertation work entitled “DESIGN AND CHARACTERISATION OF ROSUVASTATIN CALCIUM NANOSPONGE USING NATURAL POLYMER AT DIFFERENT
CONCENTRATION” submitted work done by A.J.MARIYAM BEE (261710955) in partial fulfillment of the requirements for the award of the
degree MASTER OF PHARMACY, by the Tamilnadu Dr. M.G.R Medical University, Chennai. The work performed under the guidance and supervision of Mrs.M.Bharathi, M.Pharm., Assistant professor, Department of Pharmaceutics, Kamalakshi Pandurangan College of Pharmacy, during the academic year 2018-2019.
Date: Dr.R.P.Ezhil muthu, M.pharm, Ph.D., Place: Tiruvannamalai Principal,
Kamalakshi Pandurangan College of Pharmacy, Ayyampalayam, Tiruvannamalai-606603
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KAMALAKSHI PANDURANGAN COLLEGE OF PHARMACY AYYAMPALAYAM, TIRUVANNAMALAI.
CERTIFICATE
This is to certify that dissertation work entitled “DESIGN AND CHARACTERISATION OF ROSUVASTATIN CALCIUM NANOSPONGE USING NATURAL POLYMER AT DIFFERENT
CONCENTRATION” submitted work done by A.J.MARIYAM BEE ( 261710955), in partial fulfillment of the requirements for the award of the
degree MASTER OF PHARMACY, (Pharmaceutics) by the Tamilnadu Dr.M.G.R Medical University, Chennai, is a bonafide record work done by her under my guidance in the Department of Pharmaceutics, Kamalakshi Pandurangan College of Pharmacy, Ayyampalayam, Tiruvannamai during the academic year 2018-2019.
Date: Mrs.M.Bharathi M.pharm., Place:Tiruvannamalai Assistant professor,
Kamalakshi pandurangan college of Pharmacy,
Ayyampalayam,Tiruvannamalai-606603
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DECLARATION
I hereby declare that this dissertation entitled “DESIGN AND CHARACTERIZATION OF ROSUVASTATIN CALCIUM NANOSPONGE USING NATURAL POLYMER AT DIFFERENT CONCENTRATION” submitted by A.J. MARIYAM BEE( 261710955), in the partial fulfilment for the degree MASTER OF PHARMACY (Pharmaceutics) by the Tamilnadu Dr.M.G.R Medical University, Chennai, is the result of my original and independent research work carried out under guidance of Mrs.M.Bharathi, M.pharm., Asst professor Department of pharmaceutics, Kamalakshi Pandurangan College of pharmacy, Ayyampalayam, Tiruvannamalai-606603, during the academic year 2018- 2019.
Date:
Place:Tiruvannamalai
Signature of the candidate A.J.MARIYAMBEE
(261710955)
Evaluated by :
Date of Examination :
Signature of the Internal examiner :
Signature of the External examiner :
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ACKNOWLEDGEMENT
We wish to acknowledge my sincere thanks and express my heartfelt gratitude to following persons with whose help and encouragement,I have completed this project work successfully. Foremost,I thank ALMIGHTY GOD for blessing me to bring out the work successfully.
I would like to bring to light those who have helped us in the completion of our research work without which this work would not have reached its destination.
I extent my grateful thanks to Dr.R.P.Ezhil Muthu, M.pharm., Ph.D., Prinicipal, Department of Pharmaceutics Kamalakshi Pandurangan College of Pharmacy, Ayyampalayam, Tiruvnnamalai-606603, for providing encouragement and support throughout my project.
My sincere thanks to Dr.N.Gnanasekar M.Pharm.,Ph.D., Vice Principal, Deparment of Pharmacology, Kamalakshi Pandurangan College of Pharmacy, Ayyampalayam, Tiruvannamalai-606603, for providing encouragement and support throughout my project.
I am very much privileged to take this opportunity with pride and immense thanks expressing my deep sense of gratitude to my guide Mrs.M.Bharathi, M.pharm., Assistant Professor, Department of Pharmaceutics, for here constant inspiration, endless consideration and memorable guidance for the successful completion of my work.
I would like to thanks Dr.D.Ragalingam, M.Pharm., Ph.D., Professor, Dr.
A.Elayaraja, M.pharm., Ph.D., Department of Pharmaceutical chemistry Kamalakshi Pandurangan College of Pharmacy, Ayyampalayam, Tiruvannamalai-606603, for their powerful support to my project.
It’s a great pleasure for me to acknowledge our sincere thanks to all the teaching staff members Mr.V.Senthilkumar M.Pharm., Mr.R.Manikandan M.Pharm., Mr.N.Sridhar M.Pharm., Mr.V Sakthivel M.Pharm., Mrs.G.Ragunath M.pharm., Mrs.O.Mullaikodi M.pharm., Miss. Preethi B.Pharm., Mrs.Deepa B.pharm., Kamalakshi Pandurangan College of Pharmacy, Ayyampalayam, Tiruvannamalai-606603 for their valuable guidance encouragement throughout the project work.
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I extent my thanks to Mr.S.Selvaraj (Librarian) for helping my project in all steps.
I express our special thanks to non teaching staffs of Kamalakshi Pandurangan College of Pharmacy, Ayyampalayam, Tiruvannamalai-606603, for their support and timely help.
I also extent my sincere thank to my friends Mr.S.Brito raj M.Pharm., for their help during the research work.
We are blessed to have such caring and loving parents and all my family members without their support,engragement and blessing my work wouldnot have come to an end.
I also my extent my sincere thanks to all those who have directly or indirectly helped me during this tenure.
A.J. MARIYAM BEE ( 261710955 )
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DEDICATED TO MY BELOVED
PARENTS
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CONTENT
CHAPTER
TITLE
PAGE NO.
1
INTRODUCTION 1
2
AIM AND OBJECTIVE 47
3
PLAN OF WORK 48
4
LITERATURE REVIEW 49
5
DRUG AND EXCIPIENTS PROFILE 61
6
MATERIALS AND METHODS 77
7
PREFORMULATION STUDIES 78
8
FORMULATION AND
CHARACTERISATION OF NANOSPONGE
81
9
RESULTS AND DISCUSSION 86
10
SUMMARY AND CONCLUSION 105
11
BIBLIOGRAPHY 107
9
LIST OF TABLES
Tables
CONTENT
PAGE NO
1
Important properties influencing drug targeting 6
2
Development technique of TDDS 7
3
Polymers and Crosslinkers 18
4
Biopharmaceutical classification system class II drugs 19
5
Application of Nanosponge 28
6 Classification of hyperlipidemic drugs 42
7
List of material used 77
8
List of Apparatus used 77
9
Standard graph for Rosuvastatin 79
10 Formulation of Nanosponge 81
11
Solute diffusion mechanism 85
12
Drug content, %EE, PI, Zeta Potential of Rosuvastatin Nanosponge
88
13
Cumulative % amount of drug release of Rosuvastatin Nanosponge
99
14 Release kinetics studies of Rosuvastatin Nanosponge formulation 100
15 Stability Studies data 104
10
LIST OF FIGURES
FIGURES
CONTENT
PAGE NO
1 Generation of dosage forms 4
2 Need of targeted drug delivery 5
3 Structure of Nanosponge showing a cavity of drug loading 16
4 Representation of Emulsion solvent diffusion method 21
5 Representation of Ultra sound assisted synthesis 22
6 Types of Nanosponge 23
7 Hyperlipidemia 39
8 Classification of Hyperlipidemic drugs 43
9 Rosuvastatin pathway 63
10 Tamarind seed powder 65
11 Hibiscus Rosa Sinensis 67
12 Urad dhal powder 69
13 Fenugreek seed powder 71
14 Agar powder 74
15 Absorption maxima for Rosuvastatin 78
16 Rosuvastatin standard graph in 6.8 pH at 254nm 80
17 FTIR Graph of Rosuvastatin (pure drug) 86
18 FTIR spectra of Rosuvastatin formulation 86
19 % EE & %DC of Rosuvastatin Nanosponge 89
20 Particle size and surface charge potential for formulation F1 90 21 Particle size and surface charge potential for formulation F2 90 22 Particle size and surface charge potential for formulation F3 91 23 Particle size and surface charge potential for formulation F4 91 24 Particle size and surface charge potential for formulation F5 92 25 Particle size and surface charge potential for formulation F6 92 26 Particle size and surface charge potential for formulation F7 93 27 Particle size and surface charge potential for formulation F8 93 28 Particle size and surface charge potential for formulation F9 94
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29 Particle size and surface charge potential for formulation F10 94 30 Particle size and surface charge potential for formulation F11 95 31 Particle size and surface charge potential for formulation F12 95
32 Particle size analysis 95
33 Scanning electron microscopy of F6 96
34 Scanning electron microscopy of F7 97
35 Scanning electron microscopy of F10 97
36 Cumulative % amount of drug release of Rosuvastatin Nanosponge 99
37 Zero order kinetics model for F6 101
38 Korsmeyer Peppas model for F6 101
39 Zero order kinetics model for F7 102
40 Korsmeyer peppas model for F7 102
41 Zero order kinetics model for F10 103
42 Korsmeyer Peppas model for F10 103
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1. INTRODUCTION
1.1 NOVEL DRUG DELIVERY SYSTEM
Recent advances in the understanding of pharmacokinetics and pharmacodynamic behaviours of drugs have offered a more rational approach to the development of optimal drug delivery systems. In addition, it has now become apparently appreciable that future successes in drug delivery research will largely be the result of multidisciplinary efforts.
Any therapeutic agents that can be more efficacious and safe using an improved drug delivery system represents both lucrative marketing opportunities for pharmaceutical companies and advances in the treatment of diseases of mankind.
An ideally designed drug delivery system delivers a specified amount of drug to the target site at an appropriate time and rate as dictated or desired by the etiological and physiological needs of the body. Conventional pharmaceutical dosage forms are incapable of controlling the rate of drug delivery to the target site. As a result, the massive distribution of drug in non-target tissues and body fluids necessitate therapeutic doses often lead to serious adverse effects during treatment. Thus, novel drug delivery system (NDDS) are the carriers which maintain the drug concentration in therapeutic range for longer period of time and also, in addition, may deliver the content to the site of action if so desired as per requirements1. And they have revolutionized the method of medication, provides a number of therapeutic benefits. The method by which a drug is delivered can have a significant effect on its efficacy.
Some drugs have an optimum concentration range within which maximum benefit is derived, and concentrations above or below this range can be toxic or produce no therapeutic benefit at all. From this, new ideas on controlling the pharmacokinetics, pharmacodynamics, non-specific toxicity, immunogenicity, bio recognition, and efficacy of drugs were generated. These new strategies, often called drug delivery systems (DDS), are based on interdisciplinary approaches that combine polymer science, pharmaceutics, bioconjugate chemistry, and molecular biology.
Controlled drug release and subsequent biodegradation are important for developing successful formulations. Potential release mechanisms involve.
Desorption of surface-bound /adsorbed drugs;
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Diffusion through the carrier matrix;
Diffusion (in the case of nanocapsules) through the carrier wall;
Carrier matrix erosion.
A combined erosion /diffusion process2.
There are several advantages of novel drug delivery systems conventional drug delivery.
Optimum therapeutic-drug concentration in the blood or in a tissue may be maintained over a prolonged period of time.
Pre-determined release rates for an extended period of time may be achieved.
Duration for short half-life drugs may be increased.
By targeting the site of action, side effects may be eliminated.
Frequent dosing and wastage of the drug may be reduced and excluded.
Better patient compliance may be ensured.
Various drug delivery systems been developed and some of them are under development with an aim to minimize drug degradation or loss, to prevent harmful side effects, and to improve drug bioavailability and also to favour and facilitate the accumulation of the drug in the required bio-zone (site). There are number of novel carriers which have been established and documented to be useful for controlled and targeted drug delivery. It is important to critically evaluate different terms used under different broad categories of novel drug delivery system:
Sustained-or controlled-drug delivery systems provide drug action at a per-determined rate by providing a prolonged or constant (zero-order) release, respectively at therapeutically effective levels in the circulation.
Localized drug delivery devices provide drug through spatial or temporal control of drug release (usually rate-limiting) in the vicinity of the target.
Rate-preprogrammed drug delivery systems provide drug action by manipulating the release of drug molecules by system design, which controls the molecular diffusion of drug molecules.
Targeted drug delivery provides drug action by using targeting or one based on self- programmed approach, usually anchored with suitable sensory devices, which recognize their receptor at the target.
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Carrier systems for the targeted and controlled drug delivery purpose may be classified on the basis of their nature, mechanism of drug release and the nature of drug incorporation. Diffusion occurs when bioactive agent is hydrophilic and passes through the polymers, the latter constitutes the key buildings block of controlled-release concept. Many environmentally- responsive systems are also designed that retain their content until appropriately placed in biological by an external or internal stimulus for the release of drug1. 1.1.1 TYPES:
Novel drug delivery system is a system that offers multiple drug delivery solutions such as.
Oral Drug Delivery Systems and Materials
Parenteral and Implant Drug Delivery Systems
Pulmonary and Nasal Drug Delivery
Transmucosal Drug Delivery
Transdermal and Topical Drug Delivery
Delivery of Proteins and Peptides
Drug Delivery Pipelines3.
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1.2 TARGETED DRUG DELIVERY
For many decades, medication of an acute disease or chronic illness has been accomplished by delivering drugs to patients via various dosage forms like tablets, capsules, pills, creams, ointments, liquids, aerosols, injectables and suppositories etc. Even today these drug delivery systems are still the primary pharmaceutical products. But these conventional drug delivery systems do not ensure maximum therapeutic responses. To achieve and then to maintain the concentration of drug at the site of action, it is of necessary to take conventional type of delivery system several times a day. This results in a fluctuating drug level, premature biodegradation of the drug, drug toxicity, inability to attain effective drug concentration and patient compliance.
In the year of 1981, Gregoriadis described drug targeting using novel drug delivery system as ´old drug in new clothes4 The concept of designing targeted delivery system has been originated from the Paul Ehrlich, who was a microbiologist, proposed the idea of drug delivery in the form of magic bullet. Selective drug targeting yet remains unachieved.
Targeted drug delivery means accumulation of pharmacologically active moiety at desired target in therapeutic concentration at the same restricting its access to normal cellular lining, thus minimizing therapeutic index. In site specific targeted drug delivery, active drug is delivered to very specific preselected compartments with maximum activity while reducing the concentration of drug to normal cells.
Figure 1: Generations of dosage forms
16
A Targeted drug delivery system is preferred in the following situations:
Figure 2: Need of Targeted drug delivery6
1.2.1 Properties of ideal Targeted drug delivery
It should be nontoxic, biocompatible, biodegradable, and physicochemical stable in vivo and in-vitro.
Restrict drug distribution to target cells or tissue or organ or should have uniform capillary distribution.
Controllable and predictable rate of drug release.
Drug release should not affect the drug distribution.
Therapeutic amount of drug release.
Minimal drug leakage during transit
Carrier used must be biodegradable or readily eliminated from the body without any problem and no carrier should induce modulation of diseased state.
The preparation of drug delivery system should be easy or reasonably simple, reproductive and cost effective.
1.2.2 Component of targeted drug delivery7:
1.2.2.1 Targets
Target means specific organ or a cell or group of cells, which in chronic or acute condition need treatment.
17 1.2.2.2 Carrier or markers
Targeted drug delivery can be achieved by using carrier system. Carrier is one of the special molecule or system essentially required for effective transportation of loaded drug up to the pre selected sites. They are engineered vectors, which retain drug inside or onto them either via encapsulation and/ or via spacer moiety and transport or deliver it into vicinity of target cell.
Drug -Concentration, Particulate location and Distribution -Molecular Weight, Physiochemical properties -Drug Carrier Interaction
Carrier -Type, Amount of Excipients-Surface, Surface Characteristics, size, Density
In Vivo Environment -PH, Polarity, Ionic Strength -Surface Tension, Viscosity -Temperature
-Enzyme -Electric Field
Table 1: Important Properties Influencing Drug Targeting
1.2.3 Development Technique of Formulation System and targeting Strategies
There is a growing need for multidisciplinary approach to the delivery of therapeutics to targets in tissues. From this, new ideas to control the pharmacokinetics, pharmacodynamics, non-specific toxicity, immunogenicity, biorecognition, and efficacy of drugs must be taken into consideration. To develop a dosage forms formulation scientist apply knowledge of polymer science, pharmaceutics biopharmaceutics bio-conjugate chemistry, and molecular biology, microbiology.
18
Development Technique of TDDS
Consideration of specific property of target cell
Consideration of nature of marker or transport carrier or vehicle, which convey drug to specific receptor.
Ligand or physically modulated components.
Table 2: Development Technique of TDDS 1.2.3 Strategies of drug targeting8:
1.2.3.1 Passive Targeting:
Drug delivery systems which are targeted to systemic circulation are characterized as Passive delivery systems. In this technique drug targeting occurs because of the body’s natural response to physicochemical characteristics of the drug or drug carrier system. The ability of some colloid to be taken up by the Reticulo Endothelial Systems (RES) especially in liver and spleen made them ideal substrate for passive hepatic targeting of drugs.
1.2.3.2 Inverse Targeting:
In this type of targeting attempts are made to avoid passive uptake of colloidal carrier by RES and hence the process is referred to as inverse targeting. To achieve inverse targeting, RES normal function is suppressed by preinjecting large amount of blank colloidal carriers or macromolecules like dextran sulphate9. This approach leads to saturation of RES and suppression of defense mechanism. This type of targeting is a effective approach to target drug(s) to non-RES organs.
1.2.3.3 Active targeting:
In this approach carrier system bearing drug reaches to specific site on the basis of modification made on its surface rather than natural uptake by RES. Surface modification technique include coating of surface with either a bioadhesive, nonionic surfactant or specific cell or tissue antibodies (i.e. monoclonal antibodies) or by albumin protein.
19 1.2.3.3.1 First order targeting:
It involves distribution of drug carrier system to capillary bed of target site or organ.
For example lymphatic’s, peritoneal cavity, plural cavity, cerebral ventricles, etc.
1.2.3.3.2 Second order targeting:
It involves delivery of drug to special cells such as tumor cells or kupffer cells in lives.
1.2.3.3.3 Third order targeting:
Third order targeting means intracellular localization of carrier bearing drug by the process of endocytosis or via receptor based ligand mediated entry of drug carrier system, where lysosomal degradation of drug complex causes release of drug or gene delivery to nucleolus.Active Targeting can be further classified into ligand mediated & physical targeting.
1.2.3.3.4 Ligand mediated targeting:-
All the drug carrier system can become functional when they are attached with biologically relevant molecular ligand including antibodies polypeptides oligosaccharides viral proteins and fusogenic residues.10 These types of engineered carrier selectively make the drug available to the cell or group of cells generally referred as target. In ligand mediated active targeting reaction of a ligand to corresponding receptor enhances the uptake of the entire drug delivery system into the cell. An example of this approach is folate receptor targeting.
The folate receptor is 38-KD glycosyl phosphatidylinositol-anchored protein that binds the vitamin folic acid with high affinity (<1nm). Following receptor binding, folate is rapidly internalized by endocytosis, endosomes. It was found that conjugation of folate with radioactive material, small molecule, macromolecule, protein, liposomes does not alter the ability of vitamin to bind the receptor and therefore uptake of such conjugates through receptor mediated endocytosis is enhanced11.With exception of kidney and placenta, normal tissue expresses low level of folate receptor. In contrast, this receptor is over expressed in many malignant tissues including tumor of ovary, brain kidney, breast, myeloid cells and lung. Moreover, the density of folate receptor on cellular membrane appears to increase as the stage/severity of the cancer worsens.
20 1.2.3.3.5 Physical Targeting:-
In this type of targeting some characteristics of environment changes like pH, temperature, light intensity, electric field, ionic strength small and even specific stimuli like glucose concentration are used to localize the drug carrier to predetermined site. This approach was found exceptional for tumor targeting as well as cytosolic delivery of entrapped drug or genetic material.
1.2.3.4 Dual Targeting:
In this targeting approach carrier molecule itself have their own therapeutic activity and thus increase the therapeutic effect of drug. For example, a carrier molecule having its own antiviral activity can be loaded with antiviral drug and the net synergistic effect of drug conjugate was observed12.
1.2.3.5 Double Targeting
When temporal and spatial methodologies are combined to target a carrier system, then targeting may be called double targeting. Spatial placement relates to targeting drugs to specific organs, tissues, cells or even subcellular compartment .whereas temporal delivery refers to controlling the rate of drug delivery to target site.
1.2.2.4 Advanced carrier for targeted drugs:
1.2.14.1 Microspheres and Microcapsules:
Lim and Moss (1981)13 defined microcapsulation as a process in which solids, liquids or gases are enveloped in a membrane that may be impermeable or semiperrneable.
Microsphere or Microparticle differs from the reservoir system known as microcapsules in that they consist of a solid matrix throughout which the drug is distributed.
Spenlhaues et.al., (1986)14 reported on the incorporation of cisplatin. a potent anticancer agent into poly (d.l Iactide) microsphere by a process known as solvent evaporation.
Targeting of microspheres is based on the fact the capillary of human body are in microns, so one can easily target the capillary of lungs blood liver etc. by use of microspheres.
21 1.2.4.2 Nanoparticles:
Rolland et. al., (1989)15 designed a site specific drug delivery system consisting of polymethacrylic nanoparticles. Gipps et. al., (1986)16 labeled polyhexylcyanoacrylate nanoparticles with carbon-14 and injected them into mice to ascertain the distribution of particle in the body using liquid scintillation counting.
1.2.4.2 Liposomes:
Liposomes are simple microscopic vesicles in which an aqueous volume is entirely composed by membrane of lipid molecule various amphiphilic molecules have been used to form liposomes. The drug molecules can either be encapsulated in aqueous space or intercalated into the lipid bilayers. The extent of location of drug will depend upon its physico-chemical characteristics and composition of lipids (Gregoriadis, 1976)17.
1.2.4.4 Niosomes:
Niosomes are nonionic surfactant vesicles which can entrap both hydrophilic and lipophilic drugs either in aqueous phase or in vesicular membrane made up of lipid materials It is reported to attain better stability than liposome’s. It may prove very useful for targeting the drugs for treating cancer, parasitic, viral and other microbial disease more effect ively (Udupa and Pillai, 1992)18.
1.2.14.5 Ufasomes:
These are bilayer structures formed by using single chain unsaturated fatty acids.
1.2.4.6 Pharmacosomes:
The term pharmacosome comprises of two main parts - Pharmacon (active principle) and some carriers (Goymann and Hamann, 1991)19 Vaizogle and Speiser (1986)20 postulated that amphipathic drug can self assemble to form vesicle and these vesicles are termed as pharmacosomes. Drug covalently bound to lipid may exist in a colloidal dispersion as ultrafine, micelles or hexagonal aggregates which are known as pharmacosomes.
1.2.4.7 Virosomes:
Virosomes are immuno modulating liposomes consisting of surface glycoprotein of influenza virus (immune stimulating reconstituted influenza virosome) muramyl dipeptide
22
etc. Virosomes must be target oriented and their fusogenic characteristics could be exploited in genome grafting and cellular micro injection21.
1.2.4.8 Proteosomes:
It is the term that has been used to describe certain preparation of other membrane protein of meningococci. Proteosome proteins are highly hydrophobic & their hydrophobic protein-protein interaction causes them to form multimolecular membrane vesicles.
1.2.4.8 Cubosomes:
Cubosomes are liquid crystalline phase forming small cubic particles suitable for injection.
1.2.4.10 Neutrophils:
Neutrophils are an attractive carrier system for the transport of diagnostic or therapeutic agents to areas of acute inflammation. They are present in large numbers, can be highly purified to contain carrier proteins within their granules and are designed to accumulate in large number at area of pathology.
1.2.4.11 Lymphocytes:
The concept of lymphocytes as a source of transferring of macromolecules particularly DNA is more defined function of these cells in immune process. Hence it is accepted that lymphocytes acts as a source of macromolecule particularly DNA for other cells.
1.2.4.12 Fibroblasts:
Fibroblasts are used as a source of lysosomal enzymes. The ability of skin fibroblasts to provide continuous source of lysosomal enzymes in-vitro was established by Dean et al (1975)22. Fibroblasts are advantageous in replacement therapy because no surgery is needed for the recipient. Normal fibroblasts in-vitro produce all the enzymes necessary to correct each type of mucopolysaccharides and this obviates the need to isolate and purify or to encapsulate each enzyme.
23 1.2.4.13 Artificial cells:
Artificial cells envelopes smaller spherical ultrathin membrane systems which contain different enzyme systems. This is useful for sequential type of action in multi enzyme systems and intracellular compartmentalization. Cross-linked protein artificial cells are prepared by using interfacial polymerization of protein. Artificial cells can be used for any type of material which need be microencapsulated by interfacial polymerization technique.
For example, microencapsulation of insulin into polylactic acid membrane artificial cells.
This is also proved to have great potential as a carrier for vaccines, antibodies, hormones, drugs and biologically active materials.
1.2.4.14 Resealed erythrocytes:
Carrier erythrocytes have many attributes of ideal carrier. Since the patients own erythrocytes may be used, these are no danger of adverse effects from foreign net negative charge due largely to hydroxyl group of sialic acid. The phospholipid content of the membrane is about 50% of the total lipid content. The RBCs membrane mainly encloses cytoplasm and haemoglobin. Some of the haemoglobin is lost and other cellular constituents are retained, the cells on resealing lose some of the properties of normal erythrocyte and termed as resealed erythrocytes. A wide variety of biologically active substances (500- 600,000 daltons in size) can be entrapped in erythrocytes.
Generally the molecule should be polar or hydrophilic. The term "ghost" refers to almost any preparation of erythrocytes that have been haemolyzed. This haemolysis can be produced by exposure to a hypotonic medium, ultrasounds, heat on low temperature. Ghost preparations are referred to as either resealed (pink) or white ghosts. Conventionally haemoglobin containing preparations are referred to as resealed or pink ghosts while haemoglobin free preparations are referred to as white ghosts. Ideally, white ghost technique should completely remove all intracellular material but no membrane material.
1.2.4.15 Nanoerythrosomes:
Nanoerythrosomes are derivative of erythrocyte ghosts regarded as a new model of drug carrier23. Nanoerythrosomes are vesicles prepared by extrusion, sonication or electric breakdown of red blood cell ghosts, the average diameter of these vesicles are 0.1 to 0.2 nm.
These spheroid vesicles are known as nanoerythosomes and appear to be stable and to keep
24
both the cytotoxic and antineoplastic activity of daunorubicin against mice leukemia P338D4 cells24.
1.2.4.16 Prodrug (s):
Prodrugs have also been called latentiated drugs, bioreversible derivatives and congeners. Usually prodrug implies a covalent link between a drug and chemical moiety, although some times this term is used to characterize some salt of active drug. These approaches are not only very useful in decreasing side effects but also increase/decrease solubility as required, lipophilicity, mask taste and enhance bioavailability. Prodrug technology is generally considered as a useful technique in improving corneal permeability of ophthalmic drug. A more advanced version of prodrug is chemical delivery system (CDS) in which drug is transformed into an inactive derivative which involve a cascade of enzymatic reaction for activation. Chemical drug delivery systems are utilized for sustained drug delivery systems well as site specific targeted drug delivery system .These chemically modulated system can be designed to target specific enzyme or carrier by considering enzyme substrate specificity or carrier substrate specificity in order to overcome various undesirable drug property.
In chemical delivery system for eye. Currently the drugs used for ophthalmologic therapy have not been optimized for eye but are basically systemic drugs as β adrenergic agonists or antagonists which are having profound effect when enters into systemic circulation thereby many systemic side effect can be precipitated after topical dosing of drugs in the eye when β blocker such as betaxolol or timolol are used for glaucoma treatment, peripheral bronchial β adrenoreceptor blockade can be precipitated ,which may cause respiratory distress and even death therefore selective drug delivery to eye can conceal many of these unwanted effect.
1.2.4.17 Monoclonal antibodies (MABs):
Research in immunology and cell biology has resulted in the commercialization of naturally produced active drug substances for therapy. Until recently many of these active drug substances were only produced in-vivo in the body. Many naturally produced substances are complex molecules and have potential to form drug conjugates which can be selectively taken up by target cells and digested by lysosomal enzymes. MABs are highly specific and recognize only are antigenic determinant or receptor site. MABs coupled with an active drug
25
hold great promises for site specific delivery of biological substances, particularly in cancer chemotherapy. MABs are used together with radioactive markers to locate and visualize the extent of tumors. In kidney transplant, a T -cells MAB against CD" a protein of cytotoxic that causes rejection reaction is very useful in suppressing rejection and allowing the transplant to function. This conjugate is reported as OKT3.25
1.2.5 Advantages:
Drug administration protocols may be simplified.
Toxicity is reduced by delivering a drug to its target site, thereby reducing harmful systemic effects.
Drug can be administrated in a smaller dose to produce the desire effects.
Avoidance of hepatic first pass metabolism.
Enhancement of the absorption of target molecules such as peptides and particulates.
Dose is less compared to conventional drug delivery system.
No peak and valley plasma concentration
Selective targeting to infections cells that compare to normal cells.
1.2.6 Disadvantages:
Rapid clearance of targeted systems.
Immune reactions against intravenous administered carrier systems.
Insufficient localizations of targeted systems into tumour cells.
Diffusion and redistribution of released drugs.
Requires skill for manufacturing storage, administration.
Drug deposition at the target site may produce toxicity symptoms.
Difficult to maintain stability of dosage form. E.g. Resealed erythrocytes have to be stored at 4oC.26
26
1.3 NANOTECHNOLOGY
Nanosponges are porous polymeric delivery systems that are small spherical particles
with large porous surface. These are used for the passive targeting of cosmetic agents to skin, there by achieving major benefits such as reduction of total dose, retention of dosage form on the skin and avoidance of systemic absorption.1 These nanosponges can be effectively incorporated onto topical systems for prolonged release and skin retention thus reducing the variability in drug absorption, toxicity and improving patient compliance by prolonging dosing intervals. Nanosponges can significantly reduce the irritation of drugs without reducing their efficacy.
.
Nanosponges were originally developed for topical delivery of drugs. Nanosponges are tiny sponges with a size of about a virus with an average diameter below 1μm. These tiny sponges can circulate around the body until they encounter the specific target site and stick on the surface and began to release the drug in a controlled and predictable manner.Because the drug can be released at the specific target site instead of circulating throughout the body it will be more effective for a particular given dosage27-28
Nanosponge is a novel approach which offers controlled drug delivery for topical use.
Nanosponge is an emerging technology for topical drug delivery. Nanosponge drug delivery system is employed for the improvement of performance of topically applied drugs. Nanosponges are tiny sponges with a size of about a virus, which can be filled with a wide variety of drugs.29
Nanosponges have emerged as one of the most promising fields of life science because of their application in controlled drug delivery. Nanosponge technology offers entrapment of ingredients and is believed to contribute towards reduced side effects, improved stability, increased elegance and enhanced formulation flexibility.30 Nanosponges are non- irritating, non-mutagenic, non-allergenic and non-toxic.31
27
Nanosponges are tiny mesh-like structures that may revolutionize the treatment of many diseases and this technology is five times more effective at delivering drugs for breast cancer than conventional methods.32
Figure 3: Structure of Nanosponge showing a cavity for drug loading
Nanosponges are made up of microscopic particles with few nanometers wide cavities, in which a large variety of substances can be encapsulated. These particles are capable of carryinssg both lipophilic and hydrophilic substances and of improving the solubility of poorly water soluble molecules.33
Nanosponges are encapsulating type of nanoparticles which encapsulates the drug molecules within its core. As compared to other nanoparticles, nanosponges are insoluble in water and organic solvents, porous, non-toxic and stable at high temperatures up to 3000C.
The Nanosponges are solid in nature and can be formulated as oral, parenteral, topical or inhalational dosage forms. For oral administration, these may be dispersed in a matrix of excipients, diluents, lubricants and anticaking agents which is suitable for the preparation of tablets or capsules.
28
For parenteral administration, these can be simply mixed with sterile water, saline or other aqueous solutions.34 For topical administration, they can be effectively incorporated into topical hydrogel.35
1.3.1 ADVANTAGES OF NANOSPONGES36, 37
This technology offers entrapment of ingredients and reduces side effects.
Improved stability, increased elegance and enhanced formulation flexibility.
These formulations are stable over range of pH 1 to 11.
These formulations are stable at the temperature up to 1300C.
These formulations are compatible with most vehicles and ingredients.
These are self-sterilizing as their average pore size is 0.25μm where bacteria cannot penetrate.
These formulations are free flowing and can be cost effective.
These modify the release of drug.
They increase the solubility of poorly soluble drug.
They increase the bioavailability of drug.
1.3.1.1 DISADVANTAGES
Nanosponges include only small molecules.
Depend only upon loading capacities of drug molecules.
1.3.1.2 COMPOSITION AND STRUCTURE OF NANOSPONGES 38
Nanosponges are complex structures, normally built up from long linear molecules that are folded by cross linking into a more or less spherical structure, about the size of a protein. Typical nanosponges have been constructed from cyclodextrin cross linked with organic carbonates. Nanosponges mainly consists three components. They are A. Polymer B.
Cross linking agent C. Drug substance.
1.3.1.2.1 Polymer
Type of polymer used can influence the formation as well as the performance of Nanosponges. For complexation, the cavity size of nanosponge should be suitable to accommodate a drug molecule of particular size. The ability of the polymer to be cross-linked depends on the functional groups and active groups to be substituted.
29
The selection of polymer depends on the required release and the drug to be enclosed.
The polymers can be used to enclose the drug or to interact with the drug substance. For the targeted drug release the polymer should have the property to attach with the specific ligands.
1.3.1.2.2 Cross linking agent
Selection of cross linking agent depends on the structure of polymer and the drug to be formulated. The list of polymers and cross linking agents used for the synthesis of nanosponges are presented in Table-3.38
POLYMERS CROSSLINKERS
Hyper cross linked Polystyrenes Carbonyldiimidazoles
Cyclodextrins and its derivatives like Methyl β-Cyclodextrin
Diphenyl Carbonate
Alkyloxycarbonyl Cyclodextrins Diarylcarbonates
2-Hydroxy Propyl β-Cyclodextrins Di isocyanates
Copolymers like Poly(valerolactone- allylvalerolactone)
Pyromellitic anhydride, Epichloridrine, Glutarldehyde
Poly(valerolactone allylvalerolactone oxepanedione)
Carboxylic acid di anhydrides
Ethyl Cellulose 2,2-bis(acrylamido) Acetic acid
PVA Dichloromethane
Table 3: Polymers and Crosslinkers
30 1.3.1.2.3 Drug substance
Drug molecules to be formulated as nanosponges should have certain characteristics mentioned below.
Molecular weight between 100 and 400 Daltons.
Drug molecule consists of less than five condensed rings.
Solubility in water is less than 10 mg/ml.
Melting point of the substance is below 2500C.
Some BCS Class II dugs which can be developed as Nanosponges are given in Table 4 39.
CATEGORY OF DRUG
LIST OF DRUG
Antianxiety drugs Lorazepam
Antiarrhythmic agents Amiodarone hydrochloride
Antibiotics Azithromycin, Ciprofloxacin, Erythromycin, Ofloxacin, Sulfamethoxazole
Anticoagulant Warfarin
Anticonvulsants Carbamazepine, Clonazepam, Felbamate, Oxycarbazepine, Primidone
Antidiabetic and antihyperlipedimic drugs Atorvastatin, Fenofibrate, Glibenclamide, Glipizide, Lovastatin, Troglitazone
Antiepileptic drugs Phenytoin
Antifungal agents Econazole nitrate, Griseofulvin, Itraconazole, Ketoconazole, Lansoprazole,Vericonazole
Antihistamines Terfenadine
31
Antihypertensive drugs Felodipine, Nicardipine, Nifedipine, Nisoldipine
Antineoplastic agents Camptothecin, Docetaxel, Etoposide, Exemestane, Flutamide, Irinotecan,Paclitaxel,
Raloxifene, Tamoxifen, Temozolamide, Topotecan
Antipsychotic agents Chlorpromazine Hydrochloride
Antiretrovirals Indinavir, Nelfinavir, Ritonavir, Saquinavir
Antiulcer drugs Lansoprazole, Omeprazole
Antioxidants Resveratrol
Anthelmintics Albendazole, Mebendazole, Praziquantel
Cardiac drugs Carvedilol, Digoxin, Talinolol
Diuretics Chlorthalidone, Spironolactone
Gastroprokinetic agent Cisapride
Immunosupressants Cyclosporine, Sirolimus, Tacrolimus
NSAIDs Dapsone, Diclofenac, Diflunisal, Etodolac,
Etoricoxib, Flurbiprofen, Ibuprofen,Indomethacin, Ketoprofen, Mefenamic acid, Naproxen, Nimesulide,
Oxaprozin,Piroxicam
Steroids Danazol, Dexamethazone
Table 4: Biopharmaceutical classification system class II drugs.
32
1.3.1.3 METHODS OF PREPARATION OF NANOSPONGES
Nanosponges are prepared depending on type of delivery system. Nanosponges can be prepared by optimizing formulation parameters such as drug: polymer ratio, polymer, crosslinking agent ratio and agitation or stirring speed.
1.3.1.3.1 Emulsion solvent diffusion method40
In this method the two phases used are organic and aqueous. Aqueous phase consists of polyvinyl alcohol and organic phase include drug and polymer. After dissolving drug and polymer to suitable organic solvent, this phase is added slowly to the aqueous phase and stirred for two or more hours and then nanosponges are collected by filtration, washed and then dried in air at room temperature or in vacuum oven 400 0 C for 24 hrs. See Fig.
Figure 4: Emulsion sovent diffusion method 1.3.1.3.2 Quasi-emulsion solvent diffusion 41,42
The nanosponges can also be prepared by quasi-emulsion solvent diffusion method using the different polymer amounts. To prepare the inner phase, Eudragit RS100 was dissolved in suitable solvent. Then, drug can be added to solution and dissolved under ultrasonication at 350 0C. The inner phase was poured into the poly vinyl alcohol solution in water (outer phase). Following 60minutes of stirring, the mixture is filtered to separate the nanospnges. The naosponges are dried in an air-heated oven at 400 0C for 12 hrs.
1.3.1.3.3 Solvent method
Mix the polymer with a suitable solvent, in particular polar aprotic solvent such as di methyl formamide, di methyl sulfoxide. Then add this mixture to excess quantity of the cross-linker, preferably in crosslinker/polymer molar ratio of 4 to 16. Carry out the reaction at
33
temperature ranging from 10°C to the reflux temperature of the solvent, for time ranging from 1 to 48hrs. Preferred crosslinkers are carbonyl compounds (Di methyl carbonate and Carbonyl di imidazole).43
After completion of the reaction, allow the solution to cool at room temperature, then add the product to large excess of bi distilled water and recover the product by filtration under vacuum and subsequently purify by prolonged soxhlet extraction with ethanol. Dry the product under vacuum and grind in a mechanical mill to obtain homogeneous powder.44
1.3.1.3.4 Ultra sound-Assisted synthesis
Nanosponges can be obtained by reacting polymers with cross-linkers in the absence of solvent and under sonication. The obtained nanosponges will be spherical, uniform in size and smaller than 5 microns. In this method di-phenyl carbonate or pyromellitic anhydride is used as cross-linker.
An amount of anhydrous cyclodextrin (CD) was put to react in melted di-phenyl carbonate at 900 0C for at least 5 hrs. Then, the solid was ground in a mortar and Soxhlet extracted with ethanol to remove either impurities or unreacted diphenyl carbonate. After purification nanosponges were stored at 250 0C until further use.44,45
Figure 5: Ultra sound-assited synthesis
34
1.3.1.4 LOADING OF DRUG INTO NANOSPONGES:
Nanosponges for drug delivery should be pretreated to obtain a mean particle size below 500nm. Suspend the nanosponges in water and sonicate to avoid the presence of aggregates and then centrifuge the suspension to obtain the colloidal fraction. Separate the supernatant and dry the sample by freeze drying.44
Prepare the aqueous suspension of nanosponge and disperse the excess amount of the drug and maintain the suspension under constant stirring for specific time required for complexation. After complexation, separate the uncomplexed (undissolved) drug from complexed drug by centrifugation. Then obtain the solid crystals of nanosponges by solvent evaporation or by freeze drying.43,44
Crystal structure of nanosponge plays a very important role in complexation with drug. A study revealed that paracrystalline nanosponges showed different loading capacities when compared to crystalline nanosponges. The drug loading is greater in crystalline nanosponges than paracrystalline one. In poorly crystalline nanosponges, the drug loading occurs as a mechanical mixture rather than inclusion complex.46
1.3.1.4 TYPES OF NANOSPONGE47-55
Figure 6: Types of Nanosponge Nanosponge
Titanium based Nanosponge
Sliconnanosp onge
Cyclodextrin based nanosponge Cyclodextrin
based carbamate Nanosponge
Cyclodextrin based carbonate
Cyclodextrin based ester
Poly amidoamine Nanosponge
Modified Nanosponge hypercrosslin
ked polystrene
35
1.3.1.5 FACTORS INFLUENCING NANOSPONGES FORMATION 1.3.1.5.1 Type of polymer
Type of polymer used can influence the formation as well as the performance of nanosponges. For complexation, the cavity size of nanosponges should be suitable to accommodate a drug molecule of particular size.56
1.3.1.5.2 Type of drug
Drug molecules to be complexed with nanosponges should have certain characteristics as mentioned below.56
Molecular weight of drug should be in between 100 to 400 Daltons.
The structure of the drug molecule should contain not more than five condensed rings.
Solubility in water should be less than 10 mg/ml.
Melting point of the substance should be less than 2500 0C.
1.3.1.5.3 Temperature
Temperature changes can affect drug/nanosponges complexation. In general, increase in the temperature decrease the magnitude of the apparent stability constant of the drug/nanosponges complex which may be due to a result of possible reduction of drug/nanosponges interaction forces, such as van-der Waal forces and hydrophobic forces with rise of temperature.57
1.3.1.5.4 Method of Preparation
The method of loading drug into the nanosponges can affect drug/nanosponge complexation. However, the effectiveness of a method depends on the nature of the drug and polymer, in many cases freeze drying was found to be most effective method for drug complexation.57
1.3.1.5.5 Degree of Substitution
The complexation ability of the nanosponges may be greatly affected by type, number and position of the substituent on the parent molecule.57
36 1.3.1.6 EVALUATION OF NANOSPONGES
Inclusion complexes formed between the drug and nanosponges can be characterized by following methods.
1.3.1.6.1 Thermo-analytical methods
Thermo-analytical methods determine whether the drug substance undergoes some change before the thermal degradation of the nanosponge. The change of the drug substance may be melting, evaporation, decomposition, oxidation or polymorphic transition. The change of the drug substance indicates the complex formation.
The thermogram obtained by DTA and DSC can be observed for broadening, shifting and appearance of new peaks or disappearance of certain peaks. Changes in the weight loss also can provide supporting evidence for the formation of inclusion complexes.58 1.3.1.6.2 Microscopy studies
Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) can be used to study the microscopic aspects of the drug, nanosponges and the product (drug/nanosponge complex). The difference in crystallization state of the raw materials and the product seen under electron microscope indicates the formation of the inclusion complexes.46,58
1.3.1.6.3 X-ray diffraction studies
Powder X-ray diffractiometry can be used to detect inclusion complexation in the solid state. When the drug molecule is liquid since liquid have no diffraction pattern of their own, then the diffraction pattern of a newly formed substance clearly differs from that of uncomplexed nanosponge.
This difference of diffraction pattern indicates the complex formation. When the drug compound is a solid substance, a comparison has to be made between the diffractogram of the assumed complex and that of the mechanical mixture of the drug and polymer molecules.
A diffraction pattern of a physical mixture is often the sum of those of each component, while the diffraction pattern of complexes are apparently different from each constituent and lead to a new solid phase with different diffractograms.
37
Diffraction peaks for a mixture of compounds are useful in determining the chemical decomposition and complex formation. The complex formation of drug with nanosponges alters the diffraction patterns and also changes the crystalline nature of the drug.
The complex formation leads to the sharpening of the existing peaks, appearance of a few new peaks and shifting of certain peaks.58
1.3.1.6.4 Single crystal X-ray structure analysis
Single crystal X- ray structure analysis is used to determine the detailed inclusion structure and mode of interaction. The interaction between the host and guest molecules can be identified and the precise geometrical relationship can be established.58
1.3.1.6.5 Solubility studies
The most widely used approach to study inclusion complexation is the phase solubility method described by Higuchi and Connors, which examines the effect of a nanosponge, on the solubility of drug. Phase solubility diagrams indicate the degree of complexation.43,59
1.3.1.6.6 Infra-Red spectroscopy
Infra-Red spectroscopy is used to estimate the interaction between nanosponges and the drug molecules in the solid state. Nanosponge bands often change only slightly upon complex formation and if the fraction of the guest molecules encapsulated in the complex is less than 25%, bands which could be assigned to the included part of the guest molecules are easily masked by the bands of the spectrum of nanosponges.
The technique is not generally suitable to detect the inclusion complexes and is less clarifying than other methods. The application of the Infra-red spectroscopy is limited to the drugs having some characteristic bands, such as carbonyl or sulfonyl groups. Infrared spectral studies give information regarding the involvement of hydrogen in various functional groups.
This generally shifts the absorbance bands to the lower frequency, increases the intensity and widens the band caused by stretching vibration of the group involved in the formation of the hydrogen bonds. Hydrogen bond at the hydroxyl group causes the largest shift of the stretching vibration band.58
38 1.3.1.6.7 Thin Layer Chromatography
In Thin Layer Chromatography, the Rf values of a drug molecule diminish to considerable extent and this helps in identifying the complex formation between the drug and nanosponge.58
1.3.1.6.7 Loading efficiency
The loading efficiency (%) of Nanosponge can be determined by.59
Loading Efficiency = Actual drug content / Theoretical drug content × 100.
1.3.1.6.7 Particle size and polydispersity
The particle size can be determined by dynamic light scattering using 90 Plus particle sizer equipped with MAS OPTION particle sizing software. From this the mean diameter and polydispersity index can be determined.55
1.3.1.6.8 Zeta potential
Zeta potential is a measure of surface charge. It can be measured by using additional electrode in the particle size equipment.55
1.3.1.6.9 Production yield
The production yield (PY) can be determined by calculating initial weight of raw materials and final weight of nanosponges.59
Production Yield = Practical mass of nanosponges / Theoretical mass × 100.
1.3.1.7 APPLICATIONS OF NANOSPONGES
Due to their biocompatibility and versatility, nanosponges have many applications in the pharmaceutical field. They can be used as excipients in preparing tablets, capsules, pellets, granules, suspensions, solid dispersions or topical dosage forms.60
They can encapsulate variety of drugs as shown in Table 5.
39 Drug
Nanosponges vehicle
Therapeuti
c activity
Attributes Adminis tration route
Refer ence
Dexamethasone β-CD, diphenyl carbonate
Anti- inflammatory
Enhanced drug solubility
Oral, parenteral
Flurbiprofen β-CD, di phenyl carbonate
Anti- inflammatory
Sustained drug release
Oral
Doxorubicin β-CD, di phenyl carbonate
Antineoplastic Sustained drug release
Parenteral
Itraconazole β-CD,
copolyvidonum
Antifungal Enhanced drug solubility
Oral, topical
61
Nelfinavirmesyl- ate
β-CD, di methyl carbonate
Antiviral Enhanced drug solubilization
Oral 62
5-Fluorouracile β-CD Antineoplastic Enhanced drug stability
Parenteral, topical
62
Gammaoryizanol β-CD, di phenyl carbonate
Antioxidant Enhanced stability, solubility, permeation
Topical 63
Tamoxifen β-CD,
carbonyldiimidazol e
Antiestrogen Enhanced bioavailability,
solubility
Oral 64
Resveratrol β-CD,
carbonyldiimidazol e
Antioxidant Enhanced stability, permeation, cytotoxicity, controlled drug release
Oral, topical
65
Acetylsalicylic β-CD, pyromellitic Anti- Prolonged Oral 66
40
acid di anhydride inflammatory drug release
Curcumin β-CD, di methyl carbonate
Antineoplastic Enhanced activity, solubilization
Parenteral 67
Paclitaxel β-cyclodextrin Antineoplastic Enhanced bioavailability,
Cytotoxicty
Parenteral 68 69
Camptothecin β-cyclodextrin Antineoplastic Haemolytic activity, Cytotoxicty
Parenteral 70
Atorvastatin β-Cyclodextrin Anti hyperlipidemic
Enhanced bioavailability
Oral 71
Voriconazole Ethyl cellulose, Poly (methyl methacrylate),
Pluronic F-68
Antifungal Controlled release
Oral, topical
72
Table 5: Application of Nanosponge
Nanosponges can act as multifunctional carriers for enhanced product performance and elegancy, extended release, reduced irritation, improved thermal, physical and chemical stability of product. Following are the application of nanosponges which shows versatility of nanosponges.
1.3.1.7.1 Nanosponges as a sustained delivery system
Acyclovir is a widely used antiviral agent due to of its efficacy in the treatment of herpes simplex virus infections.73 However, neither the parenteral nor the oral administration of the currently available formulations of acyclovir is able to result in suitable concentrations of the agent reaching at target sites.
Acyclovir’s absorption in the gastrointestinal tract is slow and incomplete; what’s more, its pharmacokinetics following oral medication is highly variable. The in vitro release profiles of acyclovir from the two types of nanosponges showed a sustained release of the
41
drug from the two types of nanosponges indicating the encapsulation of acyclovir within the nanostructures. The percentages of acyclovir released from Carb-nanosponges and nanosponges after 3 h in vitro were approximately 22% and 70%, respectively. No initial burst effect was observed for either formulation, proved that the drug was not weakly adsorbed on to the nanosponge surfaces.74
1.3.1.7.2 Nanosponges in solubility enhancement
Swaminathan et al. (2007) studied a formulation of itraconazole in Nanosponges.61Itraconazole is a BCS Class II drug that has a dissolution rate limited poor bioavailability. Nanosponges improved the solubility of the drug more than 27-fold. When copolyvidonum was added as a supporting component of the nanosponge formulation, this exceeded to 55-fold. Nanosponges solubilize drug by possibly masking the hydrophobic groups of itraconazole, by increasing the wetting of the drug, and/or by decreasing the crystallinity of the drug.61
1.3.1.7.3 Nanosponges in drug delivery
Nanosponges are nanomeric in size and have spherical shape; therefore, nanosponges can be prepared in different dosage forms like topical, parenteral, aerosol, tablets and capsules.38 Telmisartan (TEL) is a BCS Class II drug having dissolution rate limited bioavailability. Beta- cyclodextrin (β-CD) based nanosponges were formed by cross- linking β-CD with carbonate bonds.
TEL was incorporated into the nanosponges. Saturation solubility and In vitro dissolution study of β-CD complex of TEL was compared with plain TEL and nanosponge complexes of TEL. It was found that solubility of TEL was increased by 8.53- fold in distilled water, 3.35-fold in 1 mol HCl and 4.66- fold in phosphate buffer pH 6.8 by incorporating NaHCO3 in drug-nanosponges complex than TEL.
The highest solubility and in vitro drug release was observed in inclusion complex prepared from nanosponges and NaHCO3.75Paclitaxel is used for cancer chemotherapy having poor water solubility.
β-CD based nanosponges to deliver paclitaxel are an alternative to classical formulation in cremophor EL because cremophor reduces the paclitaxel tissue penetration.
