A Nanoparticle is a particle having one or more dimensions of the order of 100nm or less. Novel particles that differentiate nanoparticles form the bulk material typically develop at a critical length scale of under 100nm1.
In nanotechnology, a particle is defined as a small object that behaves as a whole unit in terms of its transport and properties.
In terms of diameter, fine particles cover a range between 100 and 2500nm, while fine particles on the other hand are sized between 1 and 1000nm. Nanoparticles may or may not exhibit size related properties that differ significantly from those observed in fine particles or bulk materials. (Wikipedia, the free Encyclopedia) Protein nanoparticles are of gelatin, albumin, gliadin and legumin3.
Nanoparticle research is currently an area of intense scientific research due to a wide variety of potential applications in biomedical, optical and electronic fields.
Nanoparticles form an effective bridge between bulk materials and atomic or molecular structures2. The properties of materials change as their size approaches the nano sale and as the percentage of atoms of the surface of a material becomes significant.
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Suspensions of nanoparticle are possible because the interaction of the particle surface with the solvent is strong enough to overcome differences in density which usually result in a material either sinking or floating in a liquid. Nanoparticles often have unexpected visible properties because they are small enough to confine their electrons and produce quantum effects4.
Nanoparticles have a very high surface area to volume ratio. This provides a tremendous driving force for diffusion especially at elevated temperatures. The large surface area to volume ratio also reduces the incipient melting temperatures of nanoparticles.
The unique size dependent properties of nanomaterials make them very attractive for pharmaceutical applications. Cytotoxic effects of certain engineered nanomaterials towards malignant cells form the basis for nanomedicine. It is inferred that size, three dimensional shape, hydrophobicity and electronic configuration make nanoparticles an appealing subject in medicinal chemistry. The unique structure of nanoparticles coupled with immense shape for derivatization forms a base for exciting developments in therapeutics. Solid Lipid Nanoparticles (SLN) forms an alternative colloidal carrier system for controlled drug delivery. Because of their versatility and wide range of properties, biodegradable polymeric nanoparticles are being used as novel drug delivery systems. Further, this class of carrier holds tremendous promise in the areas of cancer therapy and controlled delivery of vaccines
Nanoparticles are often referred to cluster, nanospheres, nano - rods, nano - fibers and nano - caps. Nanoparticles are made of semi conducting materials may also be labeled quantum dots if they are small enough (typically about 10nm) their quantization electronic energy level occurs. Such nanoparticles are used in biomedical applications as drug carriers or imaging agents.
A prototype - nanoparticle of semi - solid nature is the liposome. Various types of liposome nanoparticles are currently used clinically as delivery systems for anti - cancer drugs and vaccines.
It is done by Transmission Electron Microscopy/Scanning Electron Microscopy, (TEM/SEM), Atomic Force Microscopy (AFM), Dynamic Light Scattering (DLS), X-ray Photoelectron Spectroscopy (XPS), Powder X-ray Diffractometry (XRD), Fourier Transform Infrared spectroscopy (FTIR), Matrix Assisted Laser. Desorption Time of Flight mass spectrometry (MALD -TOF) and Ultra - Violet Visible spectroscopy
1.2 CONTROLLED DRUG DELIVERY SYSTEMS6
The controlled drug delivery systems are gaining greater attention in recent years owing to their importance and manifold advantages. These systems are designed to release one or more drugs continuously in a predetermined pattern for a fixed period of time either systematically or to a specified target organ. Drug release from these systems should be at a designed predictable reproducable rate. By employing this system, the safety, improved efficiency of drugs and patients compliance could be assumed. Through better control of plasma drug level and less frequent dosing, the objectives of controlled drug delivery system can be fully achieved. Though these systems have been designed for oral, parenteral, implantations and transdermal routes. Oral routes are considered to be the most convenient and common modes of administration Oral route includes systems in the form of coated pellets, matrix tablets, poorly soluble drug complexes and ion exchange resin complexes. Osmotic preparations which are known to release drug over an extended period of time either in a continuous manner (sustained release) or as a series of pulses (timed release).Among the various approaches, microencapsulation and microcapsules have been accepted as reliable methods to achieve controlled release
Always on Time
Marked to Standard
It is a process in which small, discrete solid particles or liquid droplets are surrounded and enclosed by an intact shell and the resulting materials are microcapsules. The capsule shells can be designed to release their contents as specific rate under specific set of conditions. Though, a variety of wall materials are used for the above, polymeric substances having film forming properties are most suited for microencapsulation.
1.3 AMOXICILLIN 7, 8
Heptane - 2 carboxylic acid. 6 [[Amino (4-hydroxyphenyl) acetyl)] Amino] - 3.3- dimethyl -7oxo-trihydrate.
D (-) - ï„ƒ Amino -p-hydroxy benzyl Penicillin C16 H19 N3 O5 S. 3H2O
Preparation: - By Acetylation of 6 - Amino penicillanic acid with D (-) - 2 - (p-hydroxylphenyl glycine)
Properties: The solubility is at 1g in 370 ml water and 2000 ml alcohol. It is a fine white to off-white crystalline powder with bitter taste; high humidity and temperatures over 37°C adversely affects stability.
By the oral route 75-90% is absorbed. An oral dose of 250mg will provide a peak plasma concentration of about 4Âµg/ml. From 50-72% is eliminated by renal tubular secretion. The half life is about 1hr when renal function is normal and 8-16hr in renal failure.
Uses: It is chemically p.hydroxyampicllin and has an antibacterial spectrum similar to that of ampicillin drug except that it is less active against Clostridium, Salmonella, Streptococcus and Shigella. Like ampicillin, it is destroyed by Î² - lactamases and hence cannot be used to treat infections caused by resistantstrain in bacteria of the Î² - lactamase producing typhi. It cannot be given parent rally. It is the drug of choice for infections by penicillinase producing Staphylococcus.
1.4 CIPROFLOXACIN HYDROCHLORIDE9, 10
3-Quinoline carboxylic acid
1-cyclopropyl - 6 fluro-1, 4 dihydro-4-oxo-7-(1 - piperazinyl) monohydro chloride, monohydrate
Preparation: It is a pale yellow amphoteric crystal prepared from 3-chloro-4-fluroamiline by condensation with ethyl ethoxy methylene malonate to form the imine which is thermocycized to ethyl 7-chloro-6-fluro-4 hydroxyguinoline-3-carboxyl-N-alkylation with cyclopropyl iodide followed by nucleophilic displacement of the 7 chlorogroup by N-methyl piperazine and hydrolysis of the ester affords the product.
Properties: It is soluble at 1g in 25ml water. The oral bioavailability is about 70-80%. A dose of 0.5g yields plasma concentration 12hrs after administration of about 0.2Î¼g.Urinary excretion accounts for the elimination of 40-50% of the dose. 20-35% is eliminated in feces. There is hepatic biotransformation of four known metabolites which accounts for 15%. The half life is about 4hrs.
Uses: It is used in the treatment of bone and joint infections caused by certain microbes. Further, it is an unlabelled but authoritatively alternate drug for the treatment of gonorrhea and salmonella infections.
The molecular weight value of ciprofloxacin-loaded PEBCA nanoparticles was shown to be reduced as compared with unloaded nanoparticles. Drug release from the colloidal carrier in medium containing esterase was found to be very slow (a maximum of 51.5% after 48hrs) suggesting that this release resulted from bioerosion of the polymer matrix. F-NMR analysis demonstrated that ciprofloxacin entrapped into nanoparticles was only in its neutral form. Ciprofloxacin HCl loaded nanoparticles of chitosan, lipid, (SLNs) albumin and gelatin showed sustained drug release avoiding burst effect of the free drugs. Further, ciprofloxacin nanoparticles and SLNs can act as promising carriers for sustained ciprofloxacin release.
C16H14N3O4S (6R)-6(alpha phenyl-D-glycyl amino) pencillanic acid
It is an antibacterial agent,effective against various types of bacterias.The daily dose is 2-6 gms in frequent intervals.It is a crystalline white substance sparingly soluable in water but insoluable in ethanol,chloroform and fixed oils,soluable in acids and alkali hydroxides.It should be stored in well closed container in a cool and dry place
Ofloxacin inhibits an enzyme called DNA gyrase that is an essential component
of the mechanism that passes genetic information onto daughter cells when a cell divides.
9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate
1.5 Sepia officinalis - ASOURCE OF NATURAL POLYMER OF DRUG DELIVERY106,107,108
Sepia melanins are negatively charged pigments that are hydrophobic, containing phenolic or indolic compounds.
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These melanins are of the following types :-
Eumelanins - black or brown in colour
Pheomelanin - yellow or reddish in colour
Pyomelanin - brownish in colour
Sepia melanins are dark in colour and they are used in the preparation of
UV-absorbing optical lenses and in cosmetic creams.
They are conductive to electricity.
Melanins are mainly used in pharmaceutical formulations and drug delivery systems in nanotechnology.
In human physiology, melanins play main role in imparting pigmentation to hair, skin and eyes, as a free radical scavenger and increases the speed of nerve and brain messages.
Melanins are synthesized by free-living microbes, even facultative microbes like "Cryptococcus neoformans"8 in soils. Melanin production in these offers an advantage of survival from environmental predators which produce hydrolytic enzymes. It is due to sequestration of enzymes on melanin or stearic hindrance.
Melanins offer protection from UV-light and prevent photoinduced damage.
1.5.1 Evidence for melanins bind to drugs In-Vitro
(i) Isotherm analysis of adsorption of drugs by melanin:
Binding of Gentamicin, Methotrexate and Chlorpromazine to melanins is explained by Isotherm binding equations to characterize the adsorption of drugs to synthetic and sepia melanins.
Best fit Freundlich equation for Gentamicin6.
[q = qo (KC) 1/n] dm3.g-1
where, q = amount absorbed (m.mol.g-1)
qo = adsorption capacity
K = energy of absorption
C = equilibrium solution concentration of solute and heterogeneity index 1/n (between 0 and 1)
(ii) Scatchard plot analysis of drug binding by melanin :
This method involves usage of radio labelled compounds to demonstrate the presence of heterologous binding sites.
Aminoglycoside antibiotics like Gentamicin and Kanamycin7 have '2' binding sites on synthetic DOPA melanin.
For Kanamycin, association constants for strong and weak binding sites were
3 X 10-5 and 4 X 10-3 m-1 respectively.
0.64Âµm Kanamycin is required to saturate binding sites in 1 mg melanin.
Scatchard plot type analysis with melanins rebealing that high and low affinity binding sites for cocaine, amphetamines and anti-arrythmics quinidine, disopyramide and metoprolol.
1.5.2 Absorption studies with anti-fungals:
Amphotecin-B and caspofungin bind to melanin which uses 2 methods.
The melanin produced by C.neoplasms and synthetic melanin to bind to these anti-fungal drugs was interfered from experiments, incubating melanins with various compounds and anti-fungal activity of solution is determined.
Testing of anti-fungal solutions in MIC and time-kill studies were performed by removing melanin particles by centrifugation and testing.
1.5.3 Binding of compounds by melanin in humans In-Vivo:-
Binding of drugs to host melanin damage certain tissues and causes pathogenecity.Eg: In Parkinson's disease, there is a loss of pigment in melanonic dopaminergic neurons in substantia nigra of the brain.
In Parkinson's disease, 1-methyl 4-phenyl 1,2,3,6 - tetrahydro pyridine (MPTP)9 caused damage of substantia nigra neurons which are concentrated with melanin.
Phenothiazines caused parkinsonian symptoms and secondary which are reversible. The specific retention of other drugs which concentrate at the pigmented tissues causes the damage of cells like skin, eye and inner eye.
The complex interactions depend on diverse factors like cysteine content, pH, Ionic Interactions7.
Chloroquine accumulates in dermal melanocytes and hair follicles where it causes irreversible hearing loss, tinnitus and dizziness.
Hearing loss is due to effect on 8th cranial nerve. Quinine accumulates in melanin in the Stria nascularis of cochlea and causes cellular degeneration.
Aminoglycosides8 become positively charged at the physiological pH. Because of high molecular weight, the penetration into tissues in impeded: Administration of which can cause permanent vestibular and auditory ototoxicity.
Aminoglycosides when administered, intravitreal injection, caused ocular pigmentation can partially protect retina turn damage.
Thioureylenes when incorporated into melanin like propylinic uracil, cause a loss or depigmentation of hair.
Ravuconazole, which is similar to voriconazole, is effective against Aspergillus fumigates and Aspergillus flavus.
1.5.4 Cuttle fish ink (Sepia)
Cuttle fishes are the ink producing marine invertebrates and they belong to the Phylum Mollusca and Class Cephalopoda which include similar ink producing animals such as octopus and squid. The cuttle fishes are soft bodied swimming animals provided with a large head ringed by tentacles and an internal cuttle bone made of chiefly calcium carbonate. These animals possess an ink pouch (sac) in which, a brownish black fluid called 'Sepia' secreted by them is stored. Cuttle fish are known to display natural camouflage. In order to escape from predators at the times of emergency, cuttle fish darkens the environment by ejecting a gelatinous and mildly narcotic dark brown ink to stun attackers and this defensive response gives them time to escape. Further, the melanin particles of sepia are easily miscible in sea water and remain dispersed in solution for more than 14 days.
Factors controlling ink production: The ink production and ejection in cuttle fish are affected and modulated by N-methyl-d-aspartate (NMDA) - nitric oxide (NO)-cyclic GMP (cGMP) signaling pathway, Glutamate NDMA receptor and NO synthase, the enzyme which is responsible for the synthesis of NO has been detected in immature ink gland cells.
1.5.5 Extraction of sepia
The crude ink obtained from the ink sac is boiled with caustic soda, filtering the extract and then adding HCl for precipitating the colouring matter. The liquid ink may also be dried by combining with lactose and then ground.
Characteristics of sepia: The liquid of cuttle fish ink has a grainy texture and is alkaloid. Hence it is not preferred by predators especially fish. The ink is not poisonous and acts solely as a decoy device. The main constituents of the ink are melanin and mucus. Melanin is a natural melanoprotein containing 10 - 15% protein. The melanin binding protein through amino acid containing sulphur which is sistein.
The ink gland contains a variety of melanogenic enzymes including tyrosinase, a peculiar dopachrome rearranging enzyme (which catalyses the rearrangement of dopachrome to 5, 6 - dihydroxyindole) and a peroxidase presumably involved in later stages of melanin biosynthesis). The ink is also believed to contain dopamine and L-DoPA and small amounts of aminoacids, including taurine, aspartic acid, glutamic acid, alamine and lysine.
Human use: While the flesh of cuttle fish is used as a food source, its ink finds applications in food colouring and in the preparation of pastries and sauces. As an important dye, cuttle fish ink has been used for centuries by humans for writing, drawing and in photographic and works.
Sepia ink is available in Italy as hard dark chips. These are smelly and hard to grind small enough to form an ink. They do not dissolve readily in water. Mixing sepia powder with gum Arabic water to make little cakes letting them dry and rubbing them up water when an ink is needed.
1.5.6 Protective and therapeutic uses:
Sepia is a long standing homeopathic remedy for females because it is effective for all menstrual and menopausal complaints. It also helps combat persistent sadness and depression. That is sepia can lift the mood of melancholy people urging them to take a more positive approach to their lives. Vaginal discharge and even severe pain from endometriosis, the growth of uterine cells in the abdominal cavity may be greatly relieved by sepia. Migraines, liver weakness constipation, hair loss, exhaustion and poor circulation with its resulting chillness can also be treated with sepia remedy.
Sepia is known to soothe disturbances of the metabolism and ANS. It also helps restore hormonal balance in women positively affecting uterus and ovaries. Further, sepia improves blood circulation in the organs especially those in abdominal cavity. 1.5.7 Bioactive properties:
The bioactive properties of ink gland of cuttle fish have been studied for antibacterial, antiviral and anticancer agents.
Purified cuttle fish ink with a mixture containing mainly of a conjugated glucide (in which agar, protein and lipid units are combined) ink may be effective in fighting cancer. It was tested on 15 mice which were implanted with tumors. The compound present in ink works by activating macrophages, a type of WBC near the site of tumour. This would increase the body's immune response to the tumour cells rather than fighting the cancer cells directly.
Cytotoxicity: An uronic acid with rich peptidolglycon isolated from the ink of cuttle fish Sepia pharaonis showed cytotoxicity against human cervical cancer.
1.5.8 Radio-protective effect:
Irradiation leads to immunosupression, haemopoiesis injury as well as subhealth of human being. The protective and therapeutic effects of cuttlefish ink on haemopoiesis in 60 Co gamma radiated model mice were investigated. The results showed that the cuttlefish ink showed significant effect on granulopoiesis. It is suggested that the increases of antioxidant level in mice, the improvement of bone marrow haematopoietic micro environment and the inducement of cellular factors promoted the proliferation and differentiation of CFU-S (colony forming unit in spleen) and CFU-GM (colony forming unit of granulocyte and monocyte) and thus enhance the defensive system of organism.
1.6 CHITOSAN11, 12, 13
It occurs naturally in fungi, yeasts, marine invertebrates and arthropods. Chitosan is the principal component of exoskeletons of marine crustaceans from which supplements are often derived.
SYNONYMS: Chitosan hydrochloride or 2-Amino-2-deoxy-(1, 4) - Î² - D- gluco pyranosoamine or Î²-1, 4 - poly-D-glucosamine or poly - (1, 4 - Î² - D - gluco pyranosoamine).
Chemical name: Poly-Î²-(1, 4) - 2 - Amino - 2 - deoxy - D - Glucose.
Partial deacetylation of chitin results in the production of chitin which is a polysaccharide comprising copolymers of glucosamine and N-acetylglucosamine. The degree of deacetylation necessary to obtain a soluble product must be greater than 80-85%. Chitosan is available with different molecular weights (10000 to 1000000).
Uses: Chitosan is widely used as an excipient in oral and other pharmaceutical formulations. It is used as a coating agent, disintegrant, film-forming agent, mucoadhesive, tablet binder and viscosity increasing agent.
1.6.1 Application in Pharmaceutical Formulations:
The suitability and performance of chitosan for drug delivery applications has been investigated. It is used in controlled drug delivery application as a component mucoadhesive dosage forms and rapid release dosage forms in improved peptide delivery and for gene delivery. Chitosan has been processed into several pharmaceutical forms including gels, films, microspheres tablets and coatings for liposome. Furthermore, chitosan may be processed into drug delivery systems using several techniques including spray drying, coacervation, direct compression and conventional granulation processes.
Although the carriers are of the same size (200nm), drug loading capacity of chitosan is 20 times higher for nanoparticle than for liposome. Polysaccharide based nanoparticles of chitosan are prepared by covalent cross linking, ionic cross linking polyelectrolyte complex and the self assembly hydrophobically modified polysaccharides. Chitosan is non-toxic, biocompatible and biodegradable and these properties make chitosan a good candidate for conventional and novel drug delivery systems. Chitosan forms colloidal particles and entraps bioactive molecules through a number of mechanisms including chemical cross linking, ionic cross linking and ionic complexation. Because of high affinity of chitosan for cell membrane, it has been used as a coating agent for liposome formulations. Chitosan is only soluble in acidic solution with <pH6 and loses its change in >pH6. Therefore, it will be insoluble in aqueous media. Synthesis of quaternary derivatives of chitosan to improve solubility in wide pH range for increasing its potential as an enhancer has been investigated. A number of factors such as degree of polymerization, level of deacetylation, types of quarternisation, installation of various hydrophobic substances, metal complexation and combination with other agents influence the structure characteristics of chitosan. Biodegradable, non-toxic and non-allergic nature of chitosan encourages its potential use as a carrier for drug delivery systems in all targets.
Chitosan occurs as odourless white or creamy powder or flakes. Fibre formation is quite common during precipitation and the chitosan may look 'cotton like'. Chitosan is a cationic polyamine with a high change density at pH <6.5. It is a linear polyelectrolyte with reactive hydroxy and aminogroups. The presence of a number of aminogroups allows chitosan to react chemically with anionic systems which results in alteration of physico - chemical characteristics of such combinations. The nitrogen in chitosan is mostly in the form of primary aliphatic aminogroups. Chitosan therefore, undergoes reactions typical of amines. All functional properties of chitosan depend on the chain length, chain density and charge distribution. Further salt form, molecular weight, degree of deacetylation and pH are known to influence chitosan in pharmaceutical applications. Particle size distribution is < 30Î¼m. Chitosan is sparingly soluble in water and is practically insoluble in ethanol (95%), other organic solvents and neutral or alkali solution at pH > 6.5. Chitosan dissolves readily in dilute and concentrated organic acids and to some extent in inorganic acids (except phosphoric and sulphuric acids). Upon dissolution, aminogroups of the polymer become protonated resulting in a positively charged polysaccharides and chitosan salts (chloride, glutamate, etc) that are soluble in water. Solubility of chitosan is affected by the degree of deacetylation. Solubility is also greatly influenced by the addition of salt to the solution.
1.6.3 Stability and storage:
Chitosan powder is a stable material at room temperature although it is hygroscopic after drying. Hence it should the stored at a temperature of 2 - 8°C.
Chitosan is prepared by chemically treating the shells of crustaceans such as shrimps and crabs. The basic preparatory process involves the removal of protein by treatment with alkali and of minerals such as calcium carbonate and calcium phosphate by treatment with acid. Before these treatments, the shells are ground to make them more accessible. The shells are initially deproteinized by treatment with an aqueous sodium hydroxide 3.5% solution. The resulting product is neutralized and calcium is removed by aqueous HCl 3.5% solution at room temperature to precipitate chitin. The chitin is dried so that it can be stored as a stable intermediate for deacetylation to chitosan at a clatter stage. N-deacetylation of chitin is achieved by treatment with an aqueous sodium hydroxide 40-45% solution at elevated temperature (110°C) and the precipitance is washed with water.
The crude sample is dissolved in 2% acetic and the insoluble material is removed. The resulting clear supernatant solution is neutralized with an aqueous sodium hydroxide solution to give a purified white precipitate of chitosan. The product can then be further purified and ground to a fine uniform powder or granules.
Chitosan, the deacetylated polymer of N-acetyl-D-glucosamine (chitin) is water soluble and chemically similar to cellulose.
1.6.5 Pharmaceutical Uses
Chitosan is believed to affect cholesterol levels and weight because it has positively charged aminogroups at the same pH as the gastrointestinal tract. These
aminogroups are believed to bind to negatively charged molecules such as lipids and bile preventing their absorption and storage by the body. The action of chitosan in cholesterol management may be explained by the theory that ingested chitosan salts react with fatty acids and binds lipids because of hydrophobic interactions; these bound lipids are extracted rather than absorbed. Animal studies in rats, mice and chickens indicate that chitosan decreases very low density lipoprotein-cholesterol levels while increasing high density-lipoprotein (HDL)-cholesterol levels. In vitro studies have also shown that O-carboxy methyl chitosan beads absorb low-density lipoprotein (LDL) cholesterol.
Chitosan acts as a 'Fat Blocker'. Chitosan is the only edible fibrin with positive charge in nature. The resulting molecule called chitosan - fat polymer is too large to be absorbed through the intestinal wall and therefore excreted via feces without digestion.
It deals with the inter-relationships of physicochemical properties of the drug in dosage form in which the drug is given and the route of administration on the rate and extent of systemic drug absorption. The factors which influence biopharmaceutics include:
protection of the activity of the drug within the drug product;
the release of the drug from a drug product;
the rate of dissolution of the drug at the absorption site and
the systemic absorption of drug.
the dynamic relationships existing in biopharmaceutics are shown hereunder.
Studies in biopharmaceutics use both In-Vitro and In-Vivo methods. In-Vitro methods are procedures employing test approaches and equipments without involving laboratory animals and humans. In-Vivo methods on the other hand involve human subjects and laboratory animals14
It involves the kinetics of drug absorption, distribution and elimination (i.e. excretion and metabolism). The drug distribution and elimination is often termed 'drug disposition'. The study of pharmacokinetics involves both experimental and theoretical approaches. The experimental aspects of pharmacokinetics involve the development of biological sampling techniques, analytical methods for the measurement of drugs and metabolites, the procedures that facilitate data collection and manipulation. The theoretical aspect of pharmacokinetics involves the development of pharmacokinetic models that predict drug disposition after drug administration.
It refers to the measurement of the rate and extent of active drug that reaches the systemic circulation and is available at the site of action.
Physico - chemical nature of the drug:
The physicochemical properties of the solid drug particles not only affect dissolution kinetics, but are important considerations in designing the dosage form.
Solubility, pH and drug absorption:
The solubility - pH profile is a plot of the solubility of drug at different pH values. While a basic drug is more soluble in acidic medium forming a soluble salt, an acid drug is more soluble in the intestine forming a soluble salt at more alkaline pH. The solubility pH profile gives a rough estimation of the completeness of dissolution for a dose of drug in the stomach or in intestine. Solubility may be improved with the addition of an acidic / basic excipient15.
Stability, pH and drug absorption:
The pH - stability profile is a plot of the reaction rate constant for drug degradation versus pH. If drug decomposition occurs by an acid or base catalysis, some precision of the degradation of the drug in the gastrointestinal tract may be made.
Particle size and drug absorption:
The effective surface area of the drug is measured enormously by a reduction in the particle size. Because dissolution takes place at the surface of solute (drug), the greater surface area the more rapid the rate of drug dissolution. The geometric shape of the particle also affects the surface area and during dissolution, the surface is constantly changing.
Particle size and particle size distribution studies are important for drugs that have low water solubility. Many hydrophilic drugs are very active intravenously but are not very effective when given orally due to poor absorption. Smaller particle size results in an increase in the total surface area of the particles enhances water penetration into the particles and increases the dissolution rates.
Polymorphic crystals, solvates and drug absorption: 16
Polymorphism refers to the arrangement of a drug in various crystal forms or polymorphs which have the same chemical structure, but different physical properties such as solubility, density, hardness, and compression characteristics. Some polymorphic crystals have much lower aqueous solubility than the amorphous forms causing a product to incompletely absorb. A drug that exists as an amorphous form generally dissolves more rapidly than the same drug in a more structurally rigid crystalline form. Some polymorphs are metastable and may get converted into more stable forms overtime.
Polymers have been used to prolong drug release in controlled release dosage forms. The basic components of site-specific polymer carriers are:
the polymeric backbone,
a site specific component for recognizing the target (horning device),
the drug covalently attached to the polymer chain and
functional chains to enhance the physical characteristics of the carrier system.
The molecular weight of the polymer carrier is an important consideration in designing the dosage forms. Generally large molecular weight polymers have longer residence time and diffuse more slowly. Insoluble polymers are used either as regular carriers or formulated into microparticles and nanoparticles.
These studies are performed for both approved active drug ingredients and therapeutic moieties not yet approved for marketing by FDA. Further, these studies are used to define the effect of changes in the physico-chemical properties of drug substance and the effect of the drug product (dosage form) on the pharmacokinetics of the drug.
Relative and Absolute availability: The area under the drug concentration-time curve (AUC) is used as a measure of the total amount of drug that reaches the systemic circulation. The AUC is dependent on the total quantity of available drug FDo divided by elimination rate constant 'K' and the apparent volume of distribution VD. F is the fraction of the dose absorbed. After IV administration, F is equal to unity because the entire dose is placed into systemic circulation. Therefore the drug is considered to be completely available after IV administration. After oral administration of the drug, F may vary from 0(no drug absorption) to 1(Complete drug absorption).
Relative Availability (Apparent availability)
It is the availability of a drug from its product as compared to a recognized standard. The availability of drug in the formulation is compared to the availability of the drug in a standard dosage formulation, usually a solution of the pure drug evaluated in a crossover study. The relative availability of two drug products gives at the same dosage level and by the same route of administration can be obtained with the following equation.
Relative availability = (AUC)A
where drug product B is the recognized reference standard. This fraction may be multiplied by 100 to give percent relative availability. When different doses are administrated, a correction for the size of dose is made as in the following equation.
Relative availability = (AUC) A/dose A
Urinary drug excretion data may also be used to measure relative availability, as long as the total amount of the intact drug, excreted in the urine is collected. The percent relative availability using urinary excretion data can be determined as follows:
Percent relative availability = (Du) (Ax) X 100
Here (Du) x is the total amount of drug excreted in the urine
The absolute availability of the drug is the systemic availability of a drug after extravascular administration (eg. oral, rectal, transdermal and subcutaneous). The absolute availability of a drug is generally measured by comparing the respective AUCs after extravascular and IV administration. This measurement may be performed as long as VD and K are independent of the route of administration. Absolute availability after oral drug administration using plasma data can be determined as follows:
Absolute availability = (AUC) po /dose po = F
(AUC) IV/ dose IV Z
Absolute availability using urinary drug excretion data can be determined by the following:
Absolute availability = (Du)x po/dosepo
1.7.4 EVALUATION OF IN-VIVO BIOAVAILABILITY DATA:
A properly designed bioavailability study is performed In-Vivo. The data are then evaluated using both pharmacokinetic and statistical analysis methods. The evaluation may include a pharmacokinetic profile, steady - state plasma drug concentrations, rate of drug absorption occupancy time and statistical evaluation of the pharmacokinetic parameters.
Pharmacokinetic Profile: Plasma drug concentrations versus time curve define the bioavailability of the drug from the dosage form. The bioavailability data should include a profile of the fraction of drug absorbed and should rule out dose dumping or lack of a significant food effect. The bioavailability data should also demonstrate the controlled -release characteristics of the dosage form compared to the reference or immediate release drug products.
Steady -state plasma drug concentration:
The fluctuation between the Câˆžmax (peak) and Câˆžmin (trough) concentration may be calculated as follows.
Fluctuation = Câˆžmax - Câˆžmin
Where Câˆžav is equals to (AUC)/T
An ideal extended release dosage form should have minimum fluctuations between Cmax and Cmin. A true zero-order release will have no fluctuations. In practice, the fluctuation in plasma drug levels after the extended release dosage form should be less than the fluctuation after the same drug given more immediate release dosage
Rate of drug absorption:
The rate of drug absorption from the conventional or immediate release dosage form is generally first order, whereas, the drug absorption after the extended release dosage form may be zero order, first order or an intermediate order. For many controlled release dosage forms, the rate of drug absorption is first order with an absorption rate constant 'ka' smaller than the elimination rate constant 'k' the pharmacokinetic models when ka<k is termed flip-flop pharmacokinetics.
Occupancy Time: For drugs for which the therapeutic window is known, the plasma drug concentrations should be maintained above the minimum effective drug concentration (MEC) and below the minimum toxic drug concentration (MTC). The time required for the maintenance of the plasma drug levels within the therapeutic window is known as occupancy time
1.7.5 Bioequivalence Studies: 18
Bioequivalent drug products that have the same systemic drug bioavailability will have the same predictable drug response. However, variable clinical responses among individuals that are unrelated to bioavailability may be due to differences in the pharmacodynamics of the drug. Differences in pharmacodynamics i.e. the relationship between drug and receptor site may be due to difference in receptor sensitivity to the drug. Bioequivalence is established if the In-Vivo bioavailability of a test drug product does not differ significantly in the product's rate and extent of drug absorption. A drug product that differs from the reference material in its rate of absorption, but not in it's extent of absorption may be considered bioavailable if the difference in the rate absorption is intentional and appropriately reflected in the labeling and the rate of absorption is not detrimental to the safety and effectiveness of the drug product.
1.7.6 Statistical Evaluation:
Variables subjected to statistical analysis generally include plasma drug concentrations at each collection time, AUC (from zero to last sampling time), AUC (from zero to infinity), Cmax, tmax and elimination half life t1/2. Statistical testing may include an analysis of variance (ANOVA) computation of 90% and 95% confidence intervals on the difference in formulation means and the power of ANOVA to detect a 20% difference from the reference mean
1.7.7 Pharmacokinetics of oral absorption: 19
The systemic absorption of a drug from the G.I. tract or any other extravascular site is dependent on the physico-chemical properties of the drug, the dosage form, and the anatomy and physiology of absorption site. Further, surface area of gut, stomach emptying rate, G.I mobility and blood flow to the absorption site may affect the rate and extent of drug absorption. The overall rate of drug absorption may be described mathematically as a first order or zero order input process. Most pharmacokinetic models assume first order absorption unless an assumption of zero order absorption improves the model significantly and it has been verified experimentally.
The rate of change in the amount of drug in the body dDB/dt is dependent on the rates of drug absorption and elimination.
The rate of drug accumulation in the body at any time is equal to the rate of drug absorption less the rate of drug elimination.
dDB = dDGI - dDe
dt dt dt
During the absorption phase of a plasma level time curve, the rate of drug absorption is greater than the rate of drug elimination.
dDGI > dDe
At the time of peak drug concentration in the plasma which corresponds to the time of peak absorption, the rate of drug absorption just equals the rate drug elimination and there is no change in the amount of drug in the body.
dDGI = dDe
1.7.8 Model of drug absorption and elimination:
Immediately after the time of peak drug absorption, some drug may still be at the absorption site (i.e., in the GI tract). However the rate of drug elimination at this time would be faster than the rate of absorption
dDaI < dDe
When the drug at the absorption site becomes depleted, the rate of drug absorption approaches zero or of DGI/dt =0. The elimination phase of the curve then represents only the elimination of drug from the body usually a first order process. Therefore, during the elimination phase, the rate of change in the amount of drug in the body is described as a first order process.
dDB = -kDB
where k is the first order elimination rate constant
Zero - order absorption Model:
In this model drug in the GI tract DGI is absorbed systemically at a constant rate ko. Drug is eliminated from the body by a first order rate process with a first order rate constant k.
The rate of elimination at any time by first order process is equal to DBk. The rate of input is ko. Therefore, the change per unit time in the body can be expressed as
dDB = ko - kDB
One compartment model for zero - order drug absorption and first order drug elimination
Integration of this equation with substitution of VD Cp for DB produces.
Cp = ko (1- e-kt)
The rate of drug absorption is constant and continues until the entire amount of drug in gut DGI is depleted. The time at which drug absorption is continuous is equal to DGI/ko. After this time, the drug is no longer available for absorption from the gut. The drug concentration in the plasma will decline in accordance with first order elimination rate process.
First order absorption model:
This model assumes a first order impact across the gut wall and first order elimination from the body. This model applies mostly to the oral absorption of drugs in solution or rapidly dissolving dosage (immediate release) forms such as tablet, capsules and suppositories. In addition, drugs given by intramuscular aqueous injections may also be described using a first order process.
After administration, the drug is absorbed from the absorption site by a first order process. In the case of a drug given orally, the drug dissolves in the fluids of GI tract and is absorbed into the body according to a first order process. The rate of disappearance of drug from the GI tract is described by the following
dDGI = ka DGI F
Where, ka is the first order absorption constant from GI tract, F is the fraction absorbed and DGI is the amount of drug in solution in GI tract at anytime.
Integration of the above differential equation gives
DGI = Doe-kat
where Do is the dose of drug. The rate of drug elimination is described by a first order rate process for most drugs and is equal to -kDB. The rate of drug change in the body dDB/dt is therefore the rate of drug in, minus the rate of drug out as given by the following differential equation.
dDB = Rate in - Rate out
where F is the fraction of drug systemically absorbed
1.7.9 One compartment model for first order absorption and first order elimination:20
F may vary from 1 for a fully absorbed drug to zero for a drug completely unabsorbed. The maximum concentration is cmax and the time needed to reach maximum concentration is tmax. The time needed to reach maximum concentration is independent of dose and is dependent on the rate constants for absorption (ka) and elimination k.
tmax = Inka - Ink = In (Ka/k)
ska - k ka - k
The time for maximum drug concentration tmax is dependent only on the rate constants ka and k. The rate of drug excretion after a single oral dose of drug is given with the following formula
dDu = Fke kaDo
where dDu/dt = rate of urinary drug excretion
K = fraction of dose absorbed
F = first order renal excretion constant and
1.8 Biopharmaceutic considerations:
The prime considerations in the design of a drug product are safety and efficiency. The drug product must effectively relieve the active drug at an appropriate rate and amount to the targeted site, so that, the intended therapeutic effect is achieved. The finished dosage form should not produce any additional side effects or discomfort due to the drug and/or the excipient. Ideally all the excipients in the drug producer should be inactive ingredients above or in combination in the final dosage form.
The finished drug product is a compromise of various factors including therapeutic objectives, pharmacokinetics, physical and chemical properties, manufacturing cost, and patient acceptance. Most importantly the drug product should meet the therapeutic objective by delivering the drug with maximum bioavailability and minimum or nil adverse effects.
Biopharmaceutical considerations in drug product design Pharmacodynamic considerations21
Physical and chemical properties of drugs.
Drug product considerations
Pharmaceutics of drug
Bioavailability of drug
Route of drug administration
Designed drug dosage form
Designed dose of drug
Compliance and acceptability of drug product cost
Availability of raw materials