Thesis

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OCULAR DRUG DELIVERY:INTRODUCTION:-
Ocular administration of the drug is primarily related with the treatment of ophthalmic diseases, not for gaining systemic action. Ophthalmic drug delivery is one of the most
interesting and challenging endeavors facing the pharmaceutical scientist. The anatomy, physiology, and biochemistry of the eye render this organ highly impervious to foreign substances. A significant challenge to the formulator is to circumvent the protective barriers of the eye without causing permanent tissue damage. Development of newer, more sensitive diagnostic techniques and novel therapeutic agents continue to provide ocular delivery systems with high therapeutic efficacy. The goal of pharmacotherapeutics is to treat a disease in a consistent and predictable fashion. An assumption is made that a correlation exists between the concentrations of a drug at its intended site of action and the resulting pharmacological effect. The specific aim of designing a therapeutic system is to achieve an optimal concentration of a drug at the active site for the appropriate duration. Ocular disposition and elimination of a therapeutic agent is dependent upon its physicochemical properties as well as the relevant ocular anatomy and physiology. A successful design of a drug delivery system, therefore, requires an integrated knowledge of the drug molecule and the constraints offered by the ocular route of administration. Major classes of the drugs that are administered through ocular route are Miotics, Mydriatics/Cycloplegics, Anti-inflammatories, Anti-infectives, Surgical adjuvants, Diagnostics etc. Historically, the bulk of the research has been aimed at delivery to the anterior segment tissues, but whenever an ophthalmic drug is applied topically to the anterior segment of the eye, only a small amount (5%) actually penetrates the cornea and
SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI
reaches the internal
anterior tissue of the eyes. Rapid and efficient drainage by the nasolacrimal apparatus, noncorneal absorption, and the relative impermeability of the cornea to both hydrophilic and hydrophobic molecules, all account for such poor ocular bioavailability. The various approaches that have been attempted to increase the bioavailability and the duration of the therapeutic action of ocular drugs can be divided into two categories. The first one is based on the use of sustained drug delivery systems, which provide the controlled and continuous delivery of ophthalmic drugs, such as implants, inserts, and colloids. The second involves maximizing corneal drug absorption and minimizing precorneal drug loss through viscosity and penetration enhancers, prodrugs, and colloids. Drug delivery to the posterior eye, where 40% of main ocular diseases are located, is another great challenge in ophthalmology. Only recently has research been directed at delivery to the tissues of the posterior globe. Development of new drug candidates and novel delivery techniques for treatment of ocular diseases has recently accelerated. Treatment of anterior-segment diseases has witnessed advances in prodrug formulations and permeability enhancers. Intravitreal, subconjunctival, and periocular routes of administration and sustained-release formulations of nanoparticles and microparticles, as well as nonbiodegradable and biodegradable implants to deliver drugs to the posterior segment of the eye, are becoming popular therapeutic approaches. Without adequate regulatory guidance for ocular drugs, such routes of administration and novel formulations can pose unique challenges to those involved in designing nonclinical programs, including considering clinical and nonclinical factors and choosing species, strains, and ocular toxicity parameters. Toxicology pathologists also contribute practical experience to evaluating morphological effects of these novel formulations. Lastly, understanding species anatomical differences is useful for interpreting toxicological and pathological responses to the eye and is important for human risk assessment of these important new therapies for ocular diseases. Certain ocular diseases are quite rare, whereas others, such as cataracts, age-related macular degeneration (AMD), and glaucoma, are very common, especially in the aging population. A rapid expansion of new technologies in ocular drug delivery and new drug candidates, including biologics, to treat these challenging diseases in the anterior and posterior segments of the eye have recently emerged. These approaches are necessary because the eye has many unique barriers to drug delivery. Current routes of administration include but are not limited to topical administration, systemic administration, intravitreal injections, and intraocular implants, each of
which has its own set of complications and disadvantages. Ocular bioavailability after topical ocular eye drop administration, the most common form of ocular medication, is less than 5% and often less than 1%, and therefore, only the diseases of the anterior segment of the eye can be treated with eye drops. Blood-ocular barriers, including tight junction complexes between ciliary and retinal pigmented epithelium, non fenestrate and iridal capillaries, and P-glycoprotein efflux pumps, are defense mechanisms to protect the eye from circulating antigens, inflammatory mediators, and pathogens. Unfortunately, they also act as a considerable barrier to systemically administered drugs. Ocular delivery from intravitreal, subconjunctival, and periocular sites to the posterior segment is becoming a popular approach to support the development of new injectable and implantable prolonged-action dosage forms. Regulatory expectations for nonclinical testing of ocular drugs are not well defined, and regional differences exist. Many toxicologists and pathologists new to this field are responsible for developing novel ocular drugs or novel delivery techniques using an existing ocular or systemic drug. The objective of this review is to briefly summarize some of the newer methods of administering ocular drugs; to provide a spectrum of toxicological and pathological viewpoints for nonclinical development, including regulatory considerations, species selection, study design, morphological evaluation, and relationship of pathology data to functional endpoints; and to ensure a comprehensive and meaningful risk assessment for humans. A major problem in ocular therapeutics is the attainment of an optimal drug concentration at the site of action. Poor bioavailability of drugs from ocular dosage forms is mainly due to the precorneal loss factors which include tear dynamics, non-productive absorption, transient residence time in the cul-de-sac, and the relative impermeability of the corneal epithelial membrane. Due to these physiological and anatomical constraints only a small fraction of the drug, effectively 1% or even less of the instilled dose is ocularly absorbed. The effective dose of medication administered ophthalmically may be altered by varying the strength, volume, or frequency of administration of the medication or the retention time of medication in contact with the surface of the eye. This review is an attempt to focus on the recent findings, development in the ocular drug delivery system. Various approaches being used to improve the corneal penetration of a drug molecule and delay its elimination from the eye are discussed in details in the present review. Eye is most interesting organ due to its drug disposition characteristics. For ailments of the eye, topical administration is usually preferred over systemic administration, before reaching the
anatomical barrier of the cornea, any drug molecule administered by the ocular route has to cross the precorneal barriers. These are the first barriers that slow the penetration of an active ingredient into the eye and consist of the tear film and the conjunctiva. The medication, upon instillation, stimulates the protective physiological mechanisms, i.e., tear production, which exert a formidable defense against ophthalmic drug delivery. Another serious concomitant of the elimination of topically applied drugs from the precorneal area is the nasal cavity, with its greater surface area and higher permeability of the nasal mucosal membrane compared to that of the cornea. Normal dropper used with conventional ophthalmic solution delivers about 50-75l per drop and portion of these drops quickly drain until the eye is back to normal resident volume of 7l. Because of this drug loss in front of the eye, very little drug is available to enter the cornea and inner tissue of the eye. Actual corneal permeability of the drug is quite low and very small corneal contact time of the about 1-2 mins in humans for instilled solution commonly lens than 10% Consequently only small amount actually penetrates the cornea and reaches intraocular tissue. Controlled drug delivery to the eye is restricted due to these limitation imposed by the efficient protective mechanism. Ideal ophthalmic drug delivery must be able to sustain the drug release and to remain in the vicinity of front of the eye for prolong period of time. Consequently it is imperative to optimize ophthalmic drug delivery, one of the way to do so is by addition of polymers of various grades, development of viscous gel, development of colloidal suspension or using erodible or non erodible insert to prolong the precorneal drug retention. Bioadhesive systems utilized can be either microparticle suspension or polymeric solution. For small and medium sized peptides major resistance is not size but charge, it is found that cornea offers more resistance to negatively charged compounds as compared to positively charged compounds. Following characteristics are required to optimize ocular drug delivery system: Good corneal penetration. Prolong contact time with corneal tissue. Simplicity of instillation for the patient. Non irritative and comfortable form (viscous solution should not provoke lachrymal secretion and reflex blinking)
Appropriate rheological properties and concentrations of the viscous system. Although lot of alternative dosage forms have been tested to avoid the drawbacks of conventional ophthalmic dosage form in last few years, each has been found to be deficient in one or more ways. The focus of this review is on the recent developments in topical ocular drug delivery systems, the characteristic advantages and limitations of each system. 1. Viscosity modifiers: Polymer forms a back bone of a dosage form developed to prolong the precorneal residence time of topically applied drugs. First attempt made to prolong the contact time of applied drug with cornea was to increase the viscosity of the preparation. The viscosity modifiers used were hydrophilic polymers such as cellulose, polyvinyl alcohol and poly acrylic acid. Polysaccharides such as xanthun gum was found to increase the viscosity and delay the clearance of the instilled solution by tear flow. Drugs of various solubility incorporated into these polymers to form gels. These polymers have high molecular weight which cannot cross the biological membrane, Patton and Robinson reported that increase in corneal penetration of ophthalmic drug would be maximum at viscosity of about 15 to 150 cp., further increase in viscosity associated with blurring of vision and resistance to eyelid movements. Formulations of polymers that display non Newtonian properties offer significantly less resistance to the eyelid movements. Viscosity of vehicles increases contact time but there is no marked sustaining effect. Next section of review will deal in detail with two main types of polymers used in ophthalmic drug delivery systems i.e. mucoadhesive and non mucoadhesive polymers. 2. Mucoadhesive polymers: Goblet cells in the cornea secrets glycoprotein which forms a thin film over cornea called as mucin. Mucin is capable of pinking about 40-80 times its weight in water as it consist of very large linear peptide chain to which large no of oligosaccharides chains are bound. Attractive drug delivery is application of natural and synthetic polymers that will attach to mucin and will remain in vicinity of mucin as long as it is present and these polymers are referred as mucoadhesive polymers. Large range of polymers is available and various researchers have given methods to characterize the bioadhesion of such polymers. Robinson reported that polyanions are better in bioadhesiveness and toxicity as compare to polycations. Ditigen found
that bioadhesion directly influence ocular elimination and corneal permeation. It is found that corneal permeation decreases as bioadhesion increases. Following mucoadhesive polymers are used most of the times in various ophthalmic drug delivery systems. 2.1 Polyacrylic Acid: a) Corbopol: Cross linked polyacrylic acid to have excellent mucoadhesive properties causing significant enhancement in ocular bioavailability. Carbopol 934 P is high cross link water swellable acrylic polymer with molecular weight approximately 3000000 Da. which is appropriate to use in pharmaceutical industry. Park Robinson and Ponchel et al. reported that poly acrylic acid interact with functional group of mucus glycol pro tien via carboxylic group. Precorneal residence of carpool solution found to be greater than that of PVA solution when devis et al. evaluated corneal clearance of pilocarpine in carpool 934P solution compare to that of end equiviscous non mucoadhesive PVA solution and buffer (PBS) in the rabbits27. Saettone et al. carried out much experiment with pilocarpine, the poly acrylic acid (5%w/v) carbopol941P form a stable precorneal film and with less solubility. Drug duration of stable film effect significantly increases as compare to pilocarpine . Weinreh et al. found that suspension beta hexabol base on the poly acrylic acid provided a more constant release of betaxol that its solution. Thermos et al. evaluated ocular bioavailibity of timolol in isoviscous solution of PVA (PAA and timolol PAA salt). The result suggested that PAA polymer produce lower ocular concentration that those after PVA and slower the release of timolol and resulting in longer retention of vehicle in cunjuctivital sac by mucoadhesion31. Use of carpool in ophthalmic drug delivery having following advantages and disadvantages: Gel prepared for ophthalmic administration using carbopol are more comfortable than solution, or soluble inserts though they are instilled like ointment less blurring of vision occurred as compare to ointment. However, disadvantages are no rate control on drug instability and it leads to matted lids.
b) Polycarbophil: It is cross linked poly acrylic acid polymer which is insoluble in water but swells and can incorporate large quantity of water. Carbophil cross linked with divinyl glycol found to give good bioadhesion as compare to conventional non bioadhesive suspention. 2.2 Carboxymethyl cellulose: Sodium CMC found to be excellent mucoadhesive polymer. Ophthalmic gel formulated using NaCMC, PVP and corbopol on the in vivo studies on the gel showed diffusion coefficient in corbopol 940 1%> NaCMC 3%> PVP 23%. Recent research suggests that adhesive strength increases as molecular weight increases up to 100000 da. 3. In situ gelling systems: In early eightys concept of in situ gelling come existence these systems will have low viscosity and will be instilled as eye drops and will change in to gel like system when in contact with corneal fluid. This sol to gel transition can be brought about by three ways. Change in temperature, change in pH and ion activation. 3.1 pH triggered system: Cellulose acetate hydrogen phthalate latex, typically shows very low viscosity up to pH 5, and forms clear gel in few seconds when in contact with tear fluid pH 7.2 to 7.4 and hence, release contents over prolong period of time. Use of such pH sensitive latex described by Gurny et al. the half-life of residence of CAP dispersion on corneal surface was approximately 400 seconds as compare to 40 second for solution. However, this system is associated to discomfort to patient due to high polymer conc. and low pH of instilled solution. 3.2 Change in temperature: Poloxamer F127 is in the form of solution in room temp and when this solution is instilled in to eye phase transition occurs from solution to gel at temp of eye thereby prolonging its contact with ocular surface. Pluronic polyol represent a class of block copolymer consisting of (polyoxyehylene and polyoxypropylene units). No of these units and their ration per mol of polymer provide wide range of polyol with different physical and chemical properties.
3.3 Ion activation: Gelrite is a polysaccharides, a low acetyl gellan gum shows phase transition in presence of mono or divalent cations. Timolol bioavailability found to be superior with gel trite over equiviscous HEC solution. 4 Colloidal systems: Main object in optimization of ocular drug delivery is to increase the contact time of drug with conjunctiva. Colloidal carriers like liposomes nanoparticles found to be useful to prolong the corneal contact time and hence more and more tested in ocular drug delivery. Liposomal suspension of idoxuridine found more efficient in the presence of herpex simplex keratitis in rabbit as compare to idoxuridine solution. Similarly significant increase of triamicinolone in aqueous humor found from the administration of encapsulated trimcinolone in liposomes. However, result after administration of pilocarpine 0.1 % in liposomes in terms of intraocular pressure found disappointing when compared with pilocarpine isotonic buffer solution. Same result obtained with dihydrosteptomycin sulphate after administration in the form of liposomes. From above result it is concluded that encapsulated drugs physicochemical properties have significant influence on the effect of liposomes. Favorable result with liposome found essentially with lipophilic drugs. Reason for this suggested being that hydrophilic drug escape rapidly out of the liposomes than lipophilic drugs. Charge on liposomes also influence drug concentration in ocular tissues. Corneal epithelium is covered by negatively charged mucin and all authors agreed that positively charged liposomes increase drug concentration in ocular tissues. Nanoparticles are polymeric colloidal particles ranging in size from 10-100nm. Various polymers like polyacrylamide, polymethyl methaacrylate, albumin gelatin, polyalkylcynoacrylate, polylactic-co-glycolic acid, -caprolactone used in the preparation of nanoparticles. First study using nanosphere done on system constituted of pilocrpine-loaded nanosphere of polymethyl methacrylate acrylic acid copolymer by Gurny et al. developed pH sensitive latex nanoparticles for pilocarpine and result found to be promising. In another study binding of pilocarpine to polybutyl cynoacrylate nanoparticles enhanced the mitotic response by about 22 to 33 %. 5 Ophthalmic insert:
Ophthalmic insert defined as sterile preparation with solid or semisolid consisting and whose size and sharp are especially designed for ophthalmic application. They offer several advantages as increase ocular residence, possibility of releasing drug at a slow constant rate, accurate dosing and increased shelf life with respect to aqueous solutions. Ocusert, pilocarpine ocular therapeutic system is the first product marketed by Alza incorporation USA from this category. Two types of Ocuserts are available in the market. Collagen shields used in animal models and in humans by Bloomfield et al. credits for first suggesting in 1977 and in 1978 use of collagen inserts as tear substitution and as delivery system for gentamicin. evaluated series of commercially available polymers as possible material for the preparation of soluble, monolithic insert. Various polymers tried in ophthalmic inserts were polyacrylic acid, polyvinyl alcohol, silicone elastomer, hydroxy propyl cellulose, ethyl cellulose acetate phthalate and polymethacrylic acid, hyluronic acid. Possibility using biopolymers such as fibrin chitosan for preparation of soluble or erodible insert has been also reported in literature. 6 Ocular Iontophorosis: Ocular iontophorosis offers drug delivery system that is fast pain less safe and result in delivery of high concentration of drug to specific site. Studies on ocular iontophorosis of 6-hydroxy dopamine and methylparatyrosine carried by number of investigators. Iontophoresis application of antibiotics may enhance bactericidal activity of the antibiotics and reduce the severity of the disease. Existing ocular drug delivery systems are fairly primitive and inefficient, but the stage is set for the rational design of newer and significantly improved systems. The focus of this review is on recent developments in topical ocular drug delivery systems relative to their success in overcoming the constraints imposed by the eye and to the improvements that have yet to be made. In addition, this review attempts to place in perspective the importance of pharmacokinetic modeling, ocular drug pharmacokinetic and bioavailability studies, and choice of animal models in the design and evaluation of these delivery systems. Five future challenges are perceived to confront the field. These are: (a) The extent to which the protective mechanisms of the eye can be safely altered to facilitate drug absorption, (b) Delivery of drugs to the posterior portion of the eye from topical dosing, (c) Topical delivery of macromolecular drugs including
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those derived from biotechnology, (d) Improved technology which will permit non-invasive monitoring of ocular drug movement, and (e) Predictive animal models in all phases of ocular drug evaluation. The main aim of pharmacotherapeutics is the attainment of an effective drug
concentration at the intended site of action for a sufficient period of time to elicit the response. A major problem being faced in ocular therapeutics is the attainment of an optimal concentration at the site of action. Poor bioavailability of drugs from ocular dosage forms is mainly due to the tear production, nonproductive absorption, transient residence time, a nd impermeability of corneal epithelium1 Binding by the lachrymal proteins. Drainage of the instilled solutions; Lachrimation and tear turnover; Limited corneal area and poor corneal Metabolism; Nonproductive absorption/adsorption; Tear evaporation and permeability; The poor bioavailability and therapeutic response exhibited by conventional ophthalmic solutions due to rapid precorneal elimination of the drug may be overcome by the use of a gel system that are instilled as drops into the eye and undergo a solgel transition in the cul-de-sac For the therapeutic treatment of most ocular problems, topical administration clearly seems the preferred route, because Various problems encountered in poor
bioavailability of the eye installed drugs are
for systemically administered drugs, only a very small fraction of their total dose will reach the eye from the general circulatory system. Even for this fraction, distribution to the inside of ey e is further hindered by the bloodretinal barrier (BRB). At first sight, the eye seems an ideal, easily accessible target organ for topical treatment. However, the eye is, in fact, well protected against absorption of foreign materials, first by the eyelids and tearflow and then by the cornea, which forms the physicalbiological barrier. When any foreign material or medication is introduced on the surface of the eye, the tearflow immediately increases andwashes it away in a relatively short time. Under normal conditions, the eye can acc
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ommodate only a very small volume without overflowing. Commercial eye drops have a volume of ~30 L, which is about the volume of the conjunctival sac in humans; however, after a single blink, only an estimated 10 L remains4 Consequently, there is a window only ~5 to 7 of
minutes for anytopically introduced drug to be absorbed and in many eye will actually
cases, no more than 2% of the medication introduced to the be absorbed. be absorbed. The nasolacrimal duct rest will the be washed mucosal
away and absorbed through the membranes of the
and
nasal, oropharyngeal, and gastrointestinal tract. For the remaining portion, the main biological barrier to penetration is represented by the cornea, which is very effective. The human cornea is composed of five tissue types with three of them, the epithelium, the endothelium, and the inner stroma, being the main barriers to absorption.
OPTHALMIC GEL :-
Ideally an in-situ gelling system should be a low viscous, free flowing liquid to allow reproducible administration to the eye as drop & the gel formed following phase transition should be strong enough to with stand the shear force in the cul-de-sac & demonstrated long residence time in the eye. In order to increase the effectiveness of the drug a dosage form should be chosen which increase the contact time of the drug in the eye. This may then prolonged residence time of the gel formed in situ along with its ability to release drug in sustained manner will assit in enhancing the bioavailability, reduce systemic absorption & reduce systemic
absorption & reduce the need for frequent administration leading to improved patient compliance.
VARIOUS APPROACHES OF IN-SITU GELATION Ideally, an in-situ gelling system should be a low viscous, free flowing liquid to allow for reprod ucible administration to the eye as drops, and the gel formed following phase transition should be strong enough long to with stand times the in shear the forces eye. in In the cul-de-sac order to the
and demonstrated
residence
increase the effectiveness of the drug a dosage form should be chosen which increases
contact time of the drug in the eye. This may then prolonged residence time of the gel
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formed insitu along with its ability to release drugs in sustained manner will assist in enhancing t he bioavailability, reduce systemic absorption and reduce the need for frequent administration leading to improved patient compliance. Depending upon the method employed to cause sol to gel phase transition on the
ocular surface, the following types of systems are recognized: pHtriggered systems: cellulose acetate phthalate(CAP) latex, carbopol, polymethacrilic acid(PMMA), polyethylene glycol (PEG), pseudolatexes. Temperature dependent systems: chitosan, pluronics, tetronics, xyloglucans, hydroxypropylmet hyl cellulose or hypromellose (HPMC). Ionactivated systems (osmotically induced gelation): gelrite, gellan, hyaluronic acid, alginates. UV induced gelation Solvent exchange induced gelation. These (liquid) vehicles undergo a viscosity increase upon instillation in the eye, thus favouring precorneal retention. Such change inviscosity can be triggered mainly by a change in temperature , pH or electrolyte composition. pH-triggered in-situ gelation: Polyacrylic acid (Carbopol 940) is used as the gelling agent in combination with hydroxypropylmethylcellulose (Methocel E50LV) which acted as a viscosity enhancing agent. The formulation with pHtriggered in-situ gel release is therapeutically of the drug efficacious, for stable, nonirritant period of and time
provided sustained
longer
than conventional eye drops. Another example cellulose acetate phthalate (CAP) is a polymer undergoing coagulation when the original pH of the solution (4.5) is raised to 7.4 by the tear flui d79.Temperaturetriggeredin-situgel: The system is designed to use Poloxamer as a vehicle for o phthalmic drug delivery using in-situ gel formation property. The gelation temperature of graft copolymers can be determined by measuring the temperature at which immobility of the meniscus in each solution was first noted. The bioadhesive and thermally gelling of these graft copolymers expected to be an excellent drug carrier for the prolonged delivery to surface of the eye. Other example Poloxamer407 (a polyoxyethylenepolyoxypropylene block copolymer, Pluronic F127) is a polymer with a solution viscosity that increases when its temperature is raised to the eye temperature1011 Ion-activated in-situ gelation: Alginate
(Kelton) is used as the gelling agent in combination with HPMC (Methocel E50Lv) which acted as a viscosityenhancing agent. Gelrite gellan gum, a novel ophthalmic
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vehicle that gels in the presence of mono or divalent cations, present in the lachrymal fluid can be used alone and in combinations with sodium alginate as the gelling agent. Worked reviewed in the field of in-situ gel: Over the last decades, an impressive number of novel temperature, pH, and ion induced in-situ fo rming solutions have been described in the literature. Each system has its own advantages and Drawbacks. The choice of aparticular hydrogel depintrinsic properties and envisaged therapeutic use. oral candidiasis using pHtriggered system containing carbopol 934P (0.21.4% w/v) and iontriggered system using gellen gum (0.10.75% w/v) along with HPMC E50 LV. Formulations were evaluated spreadability, for gelling capacity, studies viscosity, and in gel strength, release. The bioadhesive forces,
microbiological
vitro
optimized formulation was able to release the drug up to 6 h. The formulation containing gellen gum showed better sustained release compared to carbopol based gels
Formulated and evaluated in-situ gels for ciprofloxacin based on the concepts of pHtriggered insitu gelation, thermo reversible gelation and Ion activated system. Poly acrylic acid (Carbopol 940) was used as the gelling agent in combination of hydroxypropyl methylcellulose, which acted as a viscosityenhancing agent. (PHtriggered system). Pluronic F127 (14%) was used as the thermal reversible gelation in combinati on of HPMC (1.5%) incorporation of HPMC was to reduce
the concentration of pluronic required for in-situ gelling property, with 25% w/w pluronic F127 reported to form good gels. Gellan gum (Gelrite) is an anionic exocellular polysaccharide by the bacterium Pseudomonas elodea, having the characteristic property cationinduced gelation (0.6%). The developed formulation was therapeutically efficacious, stable, non irritant and provided sustained release of the drug over six hours period, but Gelrite formulation showing long duration of release followed by combination of carbopol, HPMC and pluronic F127 and HPMC. The developed system is thus a viable alternative to conventional eye drops. Prolonged the precorneal resident time and improves ocula r bioavailability of the drug; Pluronic F127gpoly (acrylic acid) copolymers were studied as in-s
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itugelling vehicle for ophthalmic drug delivery system. The rheological properties and invitro drug release of PluronicgPAA copolymer gels were investigated. The rheogram and in vitro drug release studies indicated that the drug release rates decreased as acrylic acid/Pluronic molar ratio and copolymer solution concentration increased. But the drug concentr ation had no obvious effect on drug release. The release rates of the drug from such copolymer gels were mainly dependent on the gel dissolution. In vivo resident experiments showed the drug resident time and the total resident amount in rabbits conjunctiveal sac
increased by 5.0 and 2.6 folds for in-situgel, compared with eye drops. The decreased loss angle at body temperature and prolonged precorneal resident time
also indicated that the copolymer gels had bioadhesive properties.These in results, along with the rheological properties and
vivo experimental release studies,
in vitro drug
demonstrated that in-situgels containing PluronicgPAA copolymer may significantly prolong drug resident time and thus improve bioavailability. PluronicgPAA copolymer can be a promisi ng in-situgelling vehicle for ophthalmic drug delivery system. prepared and evaluated sustained ocular drug delivery from a temperature and pH triggered novel in-situ gel system using Pluronic F127 (a thermo sensitive polymer) in combination with chitosan (pHsensitive polymer also acts as permeation enhancer) was used as gelling agent with timolol maleate investigated a novel copolymer, poly (Nisopropylacrylamide)chitosan (PNIPAAmCS), for its thermosensitive in-situ gelforming properties and potential utilization for ocular drug deli very. The thermal sensitivity and low critical solution temperature (LCST) were determined by the cloud point method. PNIPAAmCS had a LCST of 32C, which is close to the surface tempe rature of the eye. The in vivo ocular pharmacokinetics of timolol maleate in PNIPAAmCS solution were evaluated and compared to that in conventional eye drop solution by using rabbits according to the micro dialysis method. The results suggest that PNIPAAmCS is a potential thermo sensitive in-situ gelforming material for ocular drug delivery, and it may improve the bioavailability, efficacy, and compliance of some eye drugs
CONVENTIONAL DELIVERY SYSTEMS: Eye Drops: Drugs which are active at eye or eye surface are widely administered in the form of Solutions, Emulsion and Suspension. Generally eye drops are used only for anterior segment disorders as adequate drug concentrations are not reached in the posterior tissues using this drug
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delivery method. Various properties of eye drops like hydrogen ion concentration, osmolality, viscosity and instilled volume can influence retention of a solution in the eye. Less than 5 Percent of the dose is absorbed after topical administration into the eye. The dose is mostly absorbed to the systemic blood circulation via the conjunctival and nasal blood vessels. Ocular absorption is limited by the corneal epithelium, and it is only moderately increased by prolonged ocular contact. The reported maximal attainable ocular absorption is only about 10 Percent of the dose.When eye drops is administered in the inferior fornix of the conjunctiva, very small amount of the dose reaches to the intraocular tissues and major fraction of the administered drug get washed away with the lachrymal fluid or absorbed systemically in the nasolacrimal duct and pharyngeal sites.. Ointment and Gels: Prolongation of drug contact time with the external ocular surface can be achieved using ophthalmic ointment vehicle but, the major drawback of this dosage form like, blurring of vision and matting of eyelids can limits its use. Pilopine HS gel containing pilocarpine was used to provide sustain action over a period of 24 hours. A number of workers reported that ointments and gels vehicles can prolong the corneal contact time of many drugs administered by topical ocular route, thus prolonging duration of action and enhancing ocular bioavailability of drugs. Ocuserts and Lacrisert: Ocular insert (Ocusert) are sterile preparation that prolong residence time of drug with a controlled release manner and negligible or less affected by nasolacrimal damage.Inserts are available in different varieties depending upon their composition and applications. Lacrisert is a sterile rodshaped device for the treatment of dry eye syndrome and keratitis sicca and was introduced by Merck, Sharp and Dohme in 1981. They act by imbibing water from the cornea and conjunctiva and form a hydrophilic film which lubricates the cornea
Ocular disorders: According to location of diseases, ocular disorders are grouped as periocular and intraocular. Periocular disorders: Blepharitis: An infection of lid structures (usually by staphylococcus aureus) with concomitant seborrhoea, rosacea, a dry eye and abnormalities in lipid secretions
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Conjunctivitis: The condition in which redness of eye and presence of a foreign body sensation are evident. There are many causes of conjunctivitis but the great majority are the result of
acute infection or allergy. Kertitis: The condition in which patient have a decreased vision ,ocular pain, red eye, and often a cloud / opaque cornea .It is mainly caused by bacteria ,viruses, fungi etc. Trachoma: This is caused by the organism chalmydia trachoma is; it is the most common cause of blindness in North Africa and Middle East. Intraocular disorders: These conditions are difficult to manage and include intraocular infections: i.e. infections in the inner eye, including the aqueous humour, iris, vitreous humour and retina. Glaucoma: More than 2% of the population over age 40 years have this disorder in which an increased intraocular pressure greater than 22 mg Hg ultimately compromises blood flow to retina and thus causes death of peripheral optic nerves.
Routes of delivery: There are three main routes commonly used for administration of drugs to the medication to the eye .Introducing the drug directly to the conjuctival sac localizes drug effects, facilitates drug entry that is otherwise hard to achieve with systemic delivery and avoids first pass metabolism.The intraocular route is more difficult to achieve practically. Now
research is concentrating on the development of intravitreal injections and use of intraocular implants to improve delivery to eye. In systemic route, several studies have shown that some drugs can distribute into ocular tissues following systemic administration. Oral administration of carbonic anhydrase inhibitors including acetazolamide, methazolamidedemonstrates the capacity of a systemic drug to distribute into the cilliary process of eye. Pathways of drug absorption: The main route forintraocular absorption is across the cornea. Two features, which render the cornea an effective barrier to drug absorption, are its small surface area and its relative impermeability. Most effective penetration is obtained with drugs having both lipophilic and hydrophobic properties.
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Anatomical and physiological features of the eye
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The eye is a unique organ for drug delivery. Many excellent reviews can be found in the Literatures that describe the anatomical and physiological features of the eye, written from the Perspective of drug delivery4-10.Many of these anatomical and physiological features interferes with the fate of the administered drug. First and foremost are blinking, tear secretion, and nasolacrimal drainage. Lid closureupon reflex blinking protects the eye from external aggression. Tears permanently wash the surface ofthe eye and exert an anti-infectious activity by thelysozyme and immunoglobulins they contain. Eventually the lachrymal fluid is drained down the nasolacrimal pathways, then pharynx and esophagus. This means that a portion of the drug is Systematically delivered as if by the oral route. During administration, a part of an aqueous drop instilled in the patients cul-de-sac is inevitably lost by overflow/drainage, since the conjunctival pouch can accommodate only approximately 20 L of added fluid.
Drug delivery to the internal regions of the eye 1. Eye Penetration of Drugs Administered Locally to the Eye: If the drug is not intended to act on the external surface of the eye, then the active ingredient has to enter the eye. There is consensus that the most important route is transcorneal; however, a noncorneal route has been proposed and may contribute significantly to ocular bioavailability of some ingredients, e.g., timolol and insulin14. In addition, the sclera has also been shown to have a high permeability for a series of blocking drugs. Precorneal tear film produced by tear secretion keeps the cornea moist, clear, and healthy and is spread by the motion of eyelids during blinking. Drugs acting on tear secretion, physicochemical status of the tear film, and blinking can modify transcorneal drug permeation
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2. Eye penetration of systemically administered drugs: It is of interest to reflect on the eye penetration of systemically administered drugs, mostly anti infectious and anti-inflammatory drugs. There are blood-eye barriers. Aqueous humor is produced by the ciliary epithelium in the ciliary processes. It is frequently named an ultra filtrate, since the ciliary epithelium prevents the passage of large molecules, plasma proteins, and many antibiotics. Some molecules can be secreted in aqueous humor during its formation .Inflammation associated with injury, infection, or an ocular disease, e.g., uveitis, disrupts the bloodaqueous humor barrier and drugs enter the aqueous humor and reach the tissues of the anterior segment. There is a blood retina barrier and there is one between blood and vitreous humor complicated by the high viscosity of the latter, which prevents diffusion of the drug sin the posterior part of the eye. Delivery of drugs to the posterior pole and to the retina is extremely difficult.
GHEE:-
21
Ghrita is one of the Ayurvedic drugs that contain ghee as the base to dissolve or extract or hold the active therapeutic principles from the ingredients. Ghritas are medicated ghee preparations containing the fat-soluble components of the ingredients used in these preparations. The principle of preparation is the protracted boiling of ghee with prescribed kashayas (decoctions) and kalkas (a fine paste of the drug/drugs) to dehydration or near dehydration thereby effecting the transference of the fat soluble principles to the ghrita, from the drug ingredients or kashayas or swarasas as the case may be according to the formulation. In India, preservation of milk and milk products is primarily achieved by heat induced desiccation. Ghee is obtained by clarification of milk fat at high temperature. Ghee is almost anhydrous milk fat and there is no similar product in other countries. It is by far the most ubiquitous indigenous milk product and is prominent in the hierarchy of Indian dietary. Being a rich source of energy, fat soluble vitamins and essential fatty acids, and due to long shelf life at room temperature (20 to 40C), 8070 of ghee produced is used for culinary purposes. The remaining 2070 is used for confectionery, including sma/l amounts consumed on auspicious occasions like religious ceremonies (22).Since buffalo milk constitutes more than 5570 of the total milk production in India and because of its higher fat content (6-770), ghee is manufactured mostly from buffalo milk. Due to lack of carotenoids in buffalo milk, ghee prepared from milk is white unlike cow ghee which has a golden yellow color. Because of its pleasing flavor and aroma, ghee has always had a supreme status as an indigenous product in India. Physicochemical Characteristics Chemically, ghee is a complex lipid of glycerides (usually mixed), free fatty acids, phospholipids, sterols, sterol esters, fat soluble vitamins, carbonyls, hydrocarbons, carotenoids (only in ghee derived from cow milk), small amounts of charred casein and traces of calcium, phosphorus, iron, etc. It contains not more than. 370 moisture. Glycerides constitute about 9870 of the total material. Of the remaining constituents of about 270, sterols (moStly cholesterol) occur to the extent of about .5~. Ghee has a melting range of 28 to 44 C. Its butyro fractometer reading is from 40 to 45 at 40 C. The saponification number is not less than 220. Ghee is not highly unsaturated, as is evident from its iodine number of from 26 to 38. The Reichert-Meissl number (RM) of cow ghee varies from 26 to 29 whereas goat ghee is slightly less. Sheep and buffalo ghee on the other hand, have higher RM numbers of about 32. In general, ghee is
22
required to have a RM number of not less than 28. Itis, however, of interest that ghee from milk of animals fed cotton seeds has much lower RM numbers of about 20. Polenske number for cow ghee is higher (2 to 3) than buffalo ghee (1 to 1.5). No significant seasonal variations have, however, been recorded for their fat conscants. The fatty acid profile of glycerides of ghee is very complex and still not completely elucidated. Recently, Ramarnurthy and Narayanon published the fatty acid composition of buffalo and cow ghee. Layer formation is typical in ghee if stored above 20 C. The chemical properties of these layers are significantly different as shown by Singhal et al (20) (Table 1). Significant differences are evident in the RM numbers of these layers. The liquid layer always has a higher RM number than the semisolid layers. Preparation Ghee making in India is mostly a home industry. Substantial amounts come from villages where it is usually prepared by the desi method. Recently, industry has manufactured improved ghee of more uniform quality. However, it still constitutes only a small fraction (a few thousand tons only) of the total annual production (450,000 metric tons) in India. In general, ghee is prepared by four methods, namely, desi, creamery butter, direct cream and pre-stratification methods. The essential steps involved in the preparation of ghee by these methods are outlined in Figures 1 to 4 (6, 15). Basically, the high heat applied to butter or cream removes moisture. Both are usually clarified at 110 to 120 C. However, in southern India clarification is at 120 to 140 C. The desi method consists of churning curdled whole milk (dahi) with an indigenous corrugated wooden beater, separating the butter, and clarifying it into ghee by direct open pan heating. Earthenware vessels are used to boil milk and ferment it with a typical culture to convert it to dahi which in turn is churned to separate the butter. The creame~3r butter and direct cream methods are more suitable for commercial operations because less fat is lost. Direct cream method is reportedly most economical for preparing ghee and the product has better keeping quality (9). In the pre-stratification method, advantages such as economy in fuel consumption and production of ghee with low acidity and comparatively longer shelf life, have been claimed . However, this method has not been adopted by industry. Desi method accounts for more than 97% of ghee manufactured. Recently, continuous ghee making equipment has been fabricated at the National Dairy Research Institute at Karnal . The equipment is a three-stage pressurized, swept surface separator. This mechanical process is more sanitary than existing methods.
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Quality of Ghee The quality of ghee depends on milk, cream, dahi or butter, methods of preparation, temperature of clarification, storage conditions, and type of animal feed. These factors in turn will determine the physicochemical characteristics of ghee. The principal measurements of ghee quality are: peroxide value, acidity, and flavor. Peroxide value and acidity. The quality of ghee on storage has been measured by acid and peroxide values (10). However, peroxide value varies considerably at the organoleptic threshold of rancidity. More recently, that the thiobarbituric acid value (TBA value) is a more reliable index of oxidative rancidity of ghee. They found that the TBA value of buffalo ghee was always higher than that of cow ghee. Flavor. The most important factor controlling the intensity of flavor in ghee is the temperature of clarification . Ghee prepared at 120C or above has an intense flavor which is usually referred to as cooked or burnt. In contrast, ghee prepared at around 110 G has a somewhat mild flavor, often referred to as curd. The desi method generally produces ghee with the most desirable flavor. The acidity of the cream or butter affects the flavor of ghee. Sweet cream-butter yields ghee with a fiat flavor whereas cream or butter having an acidity of .15 to .25% (lactic acid) as in ripened cream-butter, produces ghee with a more acceptable flavor. However, the rate of deterioration in the market quality of ghee is least in ghee from unripened cream-butter and most in that prepared from ripened cream-butter. The flavor of stored ghee is influenced by the method of preparation and by temperature of clarification. In ghee made at 110 C, the original flavor is maintained for several months, but once deterioration begins, market quality is lost quicker than in ghee prepared at the higher temperatures of clarification. Flavor in ghee is retained longer when butter contains 1% NaCI. Elucidation of complex chemical entities responsible for ghee flavor is being pursued at this Institute (2) and sponsored by U.S. Public Law 480 funds. Some of the important findings to date are reported. There is a general similarity in the gross patterns of volatile carbonyls isolated from differently produced ghee. Of the 11 earbonyls in most of the ghee produced, six have been tentatively identified as propanone, butanone- 2, pentanone-2, heptanone-2, octanone-2 and nonanone-2. Small but significant differences in the quality and quantity of volatile earbonyls in different types of ghee have been reported. The use of ripened cream butter in the preparation of ghee improves the flavor, but the impact on the pattern of carbonylic compounds in ghee appears to be less marked. About 95% of the carbonyls in ghee
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are nonvolatile. Cow ghee contains more volatile carbonyls. The total carbonyls of buffalo ghee are higher than that of cow ghee irrespective of the method of preparation and temperature of clarification. The ketoglycerides constitute 50 to 60% of the total carbonyls in ghee, buffalo ghee (4.4 /~motes/g) having a higher proportion than cow ghee (2.4 /~moles/g). Oct-2-enal and dec-2enal are the main alk- 2-enals in the volatile as well as monocarbonyls in ghee. The patterns of alkanals frem cow and buffalo ghee are similar and consist of ethanal, pentanal, hexanal, heptanal, octanal, nonanal,decanal, undecana] and dodecanal. Changes on Storage Ghee undergoes physicochemical changes, dependent primarily on the temperature of storage. Crystallization occurs with the formation of solid, semi-solid and liquid layers. Ghee (cow and buffalo) kept either in a metal or glass container at 20 C or below, solidifies uniformly with fine crystal (3). Above 20 C and below 30 C, solidification is a loose structure. The liquid portion had a significantly higher RM number than the granular solid or hard flaky portion of the same ghee. A similar trend in the iodine number in these layers also occurs. Detailed investigation on layer formation by Singhal et al (18) suggested that it would be preferable to store ghee below 20 C to avoid layer formation. Ghee stored at high temperature is also susceptible to oxidative deterioration, rancidity, and off flavor. Due to inadequate storage facilities in India, much ghee loses its market acceptability. Shelf life of ghee is also dependent on the method of preparation. The keeping quality of desi ghee is better than that of direct cream or creamery butter ghee. Ramamurthy et al. claim that milk phospholipids in ghee improves its shelf life. Ghee having more residues, which is a source of phospholipids, has a longer storage life. Packaging and Marketing Packing of ghee is permitted ordinarily in 17, 4, 2 and i kg tinned cans . Excepting 17 kg cans, others must contain the net weight of ghee, e.g. 4, 2, or 1 kg. Permission is also given to pack ghee in 1 kg and half kg returnable glass bottles. Special permission of the Agricultural Marketing (Agmark) Adviser to the Government of India is necessary for packing in any other size package. Most ghee is marketed in 4-gallon tin containers. Cans are filled to brim with no air space to improve storage quality. Antioxidants like butyl hydroxyl anisole (BttA) are permitted to prolong shelf life. The agencies engaged in India in ghee assembling and distribution are producers, village merchants, itinerant traders, cooperative societies, state dairies, retailers, and some private and public dairy enterprises.
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Ghee Grading and Standards The grading of ghee in India is in general done by Agmark Adviser to the Government of India under provisions of Agricultural Produce (Grading and Marketing) Act of 1937. All ghee graded by Agmark has to be pure and prepared from only cow and buffalo milk. Regional specifications also exist in such grading due to variation in compositional properties of ghee influenced by the type of animal feed. The International Dairy Federation (IDF) has recently drafted a standard for ghee whereby it is defined as a product exclusively obtained from milk, cream, or butter from various animal species, by processes which result in almost the total removal of moisture and solids-not-fat. It must consist of a mixture of higher melting point fats in liquid form. It should contain not more than 3% moisture. Milk fat (mostly glycerides) constitutes 99.5% of the total solids. This IDF standard is being examined for its final acceptance. Cotton Tract Ghee During certain seasons large quantities of cotton-seeds are fed to lactating animals in cotton growing areas (Saurashtra and Madhya Pradesh). The composition of ghee prepared from the milk of such animals differs significantly from that from milks of animals fed on a concentrate mixture of oilcakes, grains, bran, etc. Dastur proposed a special standard for ghee from such
areas and it is often referred to as cotton tract ghee. The RM number requirement for cotton tract ghee is lower (e.g. 20) than that for ghee from other areas. Ghee Adulteration and its Detection It is a common practice to adulterate ghee with cheaper vegetable and animal body fats. Hydrogenated vegetable fats, popularly known as vanaspati ghee in this country, have often been used to adulterate ghee. However, the legal requirement that all vanaspati ghee marketed in this country must contain a specified amount of sesame oil which can be easily detected by Bauduin test 1. Bomer's 2 phytosterol acetate test based on the structural differences between phytosterols (e.g. sitosterol) and animal sterols (e.g. cholesterol) has also been occasionally used. More recently, Ramamurthy et al (12) reported a thin layer chromatographic method for detecting ghee adulteration with vegetable oils and fats. Detection of animal body fats in ghee is more difficult. An opacity method based on differential melting point ranges for common animal body fats (43 to 50 C) and ghee (30 to 44 C) has been developed by Singhal et al (20). It is claimed to detect 5% animal body fats in ghee. However,
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this test is useless for cotton tract ghee which has a melting point near that of animal body fats. The methylene blue reduction test developed by these authors (19), overcame this difficulty because only cotton tract ghee decolorizes methylene blue. Butteroil Versus Ghee The main differences between ghee and butteroil have been recently summarized by Ganguli (8). Butteroil has a bland flavor whereas ghee has a pleasing flavor. Ghee has less moisture, contains more protein solids and differs in fatty acid and phospholipid as compared to butteroil. Butteroil is prepared by melting butter at not exceeding 80 C, whereas ghee is manufactured at 100 to 140 C. Butteroff can be reconstituted with skimmilk powder whereas ghee cannot be.
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Drug profile: ATROPINE SULPHATE

Atropine is the best-known member of a group of drugs known as muscarinic antagonists, which are competitive antagonists of acetylcholine at muscarinic receptors. This naturally occurring tertiary amine was first isolated from the Atropa belladonna plant . Although atropine earlier enjoyed widespread use in the treatment of peptic ulcer, today it is mostly used in resuscitation, anaesthesia, and ophthalmology, usually as the more soluble sulphate salt. By competitively blocking the action of acetylcholine at muscarinic receptors, atropine may act as a specific antidote. As such, it may also be used to counteract adverse parasympathomimetic effects of pilocarpine, or neostigmine administered in myasthenia gravis. It is a specific antidote for the treatment of poisoning with organophosphorus and carbamate insecticides and
organophosphorus nerve agents. Although other anticholinergic agents (such as dexetimide) with different distribution kinetics may have advantages in rodent models, the role of atropine in the treatment of organophosphate poisoning is essentially unchallenged, though there is controversy concerning the dose of atropine necessary for optimal therapy in organophosphate poisoning. Atropine is also useful in treating muscarine poisoning following ingestion of fungi of the Clitocybe and Inocybe species. If the dose of atropine is titrated correctly, it has few serious side effects when used in organophosphate poisoning. Patients, who are hypoxic, however, are at risk of developing ventricular tachycardia or fibrillation if given atropine. It is important, therefore, to correct hypoxia by clearing airways, administering oxygen and, if necessary, mechanically ventilating the patient before giving atropine Name and chemical formula Names: Atropine and atropine sulphate Synonyms Atropine sulphate Atropina solfato (Italy); atropina sulfato (Spain, Argentina); atropine sulphate (USA); atropin siran (Czech); atropinsulfas; atropinsulfat (Germany); sulphate datropine (France); 1-alpha-H,5-
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alpha-Htropan- 3-alpha-OL-()-tropate (ester), sulfate (2:1) salt; dl-tropanyl-2-hydroxy-1phenylpropionate sulphate
IUPAC name Atropine sulphate benzeneacetic acid, alpha- (hydroxymethyl)-8-methyl-8-azabicyclo{3.2.1}oct-3-yl ester endo ()-,compounds, sulfate (2:1) (salt) CAS number: 55-48-1 (atropine sulphate anhydrous) (USP, 2002). Atropine sulphate monohydrate (C17H23NO3)2,H2SO4 .H2O (Parfitt, 1999) Physico-chemical properties Melting point. Atropine sulphate monohydrate: This salt has a melting point of 190 to 194 C Physical state Atropine sulphate: Atropine sulphate occurs as odourless, very bitter, colourless crystals or white crystalline powder Solubility Atropine sulphate monohydrate Atropine sulphate is very soluble in water. One gram dissolves in 0.4 ml water. One gram dissolves in 5 ml cold alcohol and 2.5 ml boiling alcohol, in 2.5 ml glycerol, 420 ml chloroform and 3,000 ml ether. Optical properties: Atropine sulphate atropine sulphate is almost inactive optically pH Atropine sulphate: A 2% solution in water has a pH of 4.5 to 6.2 Stability in light Atropine sulphate:
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Atropine sulphate is slowly affected by light. It should be protected from light and stored in airtight containers Reactivity. Atropine sulphate: Atropine sulphate effloresces when exposed to dry air . When heated to decomposition, toxic fumes of oxides of nitrogen and sulphide are emitted. Pharmaceutical incompatibilities Atropine sulphate Atropine sulphate is reported to be physically incompatible with noradrenaline bitartrate, metaraminol bitartrate and sodium bicarbonate injections. A haze or precipitate may form within 15 minutes when the injection is mixed with methohexital sodium solution. Immediate precipitation occurs when cimetidine and pentobarbital sodium together are mixed with atropine sulphate in solution; while aprecipitate will form within 24 hours if atropine sulphate is mixed with pentobarbital sodium alone Thiopental sodium and atropine sulphate injected together at Ysites will form white particles in the solution immediately . A haze will form in 24 hours then a precipitate at 48 hours if flucloxacillin sodium and atropine sulphate are stored together at 30 C, while no change is seen at 15C. Incompatibilities between atropine sulphate and hydroxybenzoate preservatives have occurred, with a total loss of atropine in 2-3-weeks . Atropine sulphate is incompatible with other alkalis, tannin, salts of mercury or gold, vegetable decoctions or infusions, borax, bromides and iodides. Proprietary names and manufacturers Atropine sulphate: Atropair (Pharmafair, USA); Atropine Aguettant( Aguettant, France), Atropine Meram (Cooper, France); Atropine Opthadose(Ciba-Geigy, Belgium); Atropine SDUFaure(Ciba Vision, Suisse); Atropinium sulfuricum Streuli(Streuli, Suisse); Atropinum sulfuricum AWD(ASTA Medica, Denmark); Atropisol(Ciba Vision, Canada, Iolab, USA); Atropocil(Edol, Portugal); Atropt(Sigma, Australia); Atrosol(Adilna Turkey); I-
Tropine(Americal, USA); Isopto Atropine(many countries); Liotropina(SIFI, Italy); Midrisol(Abdi Ibrahim, Turkey); Noxenur S(Galenika, Denmark);
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Sal-Tropine(Hope,
USA);Skiatropine(Cjauvin,
France,
Suisse);
Stellatropine(Stella,
Belgium, Luxembourg); Tropyn Z(Zafiro, Mexico)
Pharmaceutical formulation and synthesis Manufacturing processes Atropine is usually prepared by extraction from the plants Atropa belladonna (deadly nightshade), Datura stramonium (Jimson weed) or Duboisia myoporoides . This extracted atropine is a combination of D and L hyoscyamine. Both these isomers may bind to muscarinic receptors although the pharmacological activity is thought to be due almost entirely to L hyoscyamine . Pharmaceutical formulation Atropine sulphate Atropine sulphate is available as a sterile solution in normal saline or water for injection from several manufacturers. The preservatives parabens and sulphites, may be found in injectable products. Atropine sulphate is usually available in concentrations of 0.25-0.5 mg/ml, although some countries, such as Portugal and Germany, have a 10 mg/ml solution for use in organophosphate poisoning. Atropine sulphate injections may be adjusted to a pH of 3 to 6.5 with sulphuric acid. Oral forms (tablets) are also available . atropine sulphate Assay (USP, 2002) 1 g of atropine sulphate, accurately weighed, is dissolved in 50 ml of glacial acetic acid, then titrated with 0.1 N perchloric acid VS, determining the endpoint potentiometrically. Each ml of 0.1 N perchloric acid should be equivalent to 67.68 mg of (C17H23NO3)2 . H2SO4. Assay (BP, 2000) 0.500 g of atropine sulphate is dissolved in 30 ml of anhydrous acetic acid R, warming if necessary. The solution is cooled then titrated with 0.1M perchloric acid and the end-point determined potentiometrically (2. 2. 20). 1 ml of 0.1M perchloric acid should be equivalent to 67.68 mg of C34H48N2O10S.
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Assay (PPRC, 2000) 0.5 g of accurately weighed atropine sulfate is dissolved in a mixture of 10 ml of glacial acetic acid and 10 ml of acetic anhydride, one to two drops of crystal violet is added and the solution titrated with perchloric acid (0.1 mol/L) VS until the color is changed to pure blue. A blank determination is performed and any necessary corrections made. Each ml of perchloric acid (0.1 mol/L) VS should be equivalent to 67.68 mg of (C17H23NO3)2 .H2SO4. Limit of other alkaloids (USP, 2000) 150 mg atropine sulphate is dissolved in 10 ml water. To 5 ml of this solution is added a few drops of platinic chloride TS: no precipitate should be formed. To the remaining 5 ml of the solution, 2 ml of 6 N ammonium hydroxide is added and shaken vigorously: a slight opalescence may develop but no turbidity should be produced. Limit of foreign alkaloids and decomposition products (BP, 2000) The substance should be examined by thin-layer chromatography (2. 2. 27) using silica gel G R as the coating substance. Solutions should be made up as follows: Test solution. 0.2 g of the substance to be examined is dissolved in methanol R and diluted to 10 ml with the same solvent. Reference solution (a). 1 ml of the test solution is diluted to 100 ml with methanol R. Reference solution (b). 5 ml of reference solution (a) is diluted to 10 ml with methanol R. To the plate is applied separately 10 l of each solution. These are developed over a path of 10 cm using a mixture of 90 volumes of acetone R, 7 volumes of water R and 3 volumes of concentrated ammonia R. The plate is dried at 100 C to 105 C for 15 minutes. It is allowed to cool then sprayed with dilute potassium iodobismuthate solution R until the spots appear. Any spot in the chromatogram thus obtained with the test solution, apart from the principal spot, should not be more intense than the spot in the chromatogram obtained with reference solution (a) (1.0 per cent) and not more than one such spot should be more intense than the spot in the chromatogram obtained with reference solution (b) (0.5%). Limit of apoatropine (BP, 2000) 0.10 g atropine sulphate is dissolved in 0.01M hydrochloric acid and diluted to 100 ml with the same acid. The absorbance is determined (2. 2. 25) at 245 nm.
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Atropine sulphate injection Chromatographic methods of assay are described in USP, 2002 and BP, 2000. The pH of atropine sulphate injection USP, 2002 should be between 3.0 and 6.5. It should contain not more than 55.6 USP Endotoxin units per milligram of atropine sulfate and it should meet the standard requirements for USP, 2002 injections.
Shelf life Atropine sulphate Atropine sulphate should be stored in single or multiple-dose containers, preferably glass, at a temperature of less than 40 C (preferably between 15 to 30 C). It should be protected from light and stored in airtight containers.(USP, 2002). Freezing should be avoided .The shelf-life is 24 months from the date of manufacturing if kept under the above conditions
General properties 7.1. Mode of antidotal activity Atropine is a muscarinic cholinergic blocking agent. It competitively blocks parasympathetic, Postganglionic nerve endings from the action of acetylcholine and other muscarinic agonists. Atropinic drugs have little effect at nicotinic receptor sites. Large doses of atropine produce only partial block of autonomic ganglia and have almost no effect at the neuromuscular junction. Small doses of atropine depress sweating and salivary and bronchial secretion. Atropine is particularly useful in relieving bronco constriction and salivation induced by anticholinesterases. Doses required to inhibit gastric secretion are invariably accompanied by dry mouth and ocular disturbances. At higher doses, the heart rate increases as the effects of vagal stimulation are blocked. When given alone atropine has little effect on blood pressure, although it can block completely the hypotensive and vasodilatory effects of choline esters. Larger doses decrease the normal tone and amplitude of contractions of the bladder and ureter, thereby inhibiting micturition. Atropine inhibits both the tone and motility of the gut, reducing peristalsis. Unlike scopolamine, small doses of atropine have little depressant action on the central nervous system. However, in toxic doses, atropine initially causes central excitation (exhibited as restlessness, confusion, hallucinations, and delirium) followed by central depression with coma and death. Both atropine and scopolamine shift the EEG to slow activity, reducing the voltage and
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frequency of the alpha rhythm. Atropine normalizes increased EEG activity due to isoflurophate. For many years, the central anticholinergic effects of the belladonna alkaloids in reducing tremor were the mainstay of therapy for Parkinson's disease. Large doses of atropine impair accommodation, causing dilation of the pupil and blurred vision. The normal pupillary response to light or upon convergence may be completely abolished. These ocular effects may be seen after oral, systemic, or local administration of the drug (Weiner, 1985). The peripheral antimuscarinic effects of atropine may not be the only antidotal property of the drug in organophosphate poisoning. Atropine may also be of value in treating acute dystonic reactions occasionally observed in acute organophosphate poisoning. Patients with extrapyramidal signs have been noted to have abnormally low plasma and red blood cell cholinesterase activities, producing an excess of acetylcholine relative to dopamine. However, there is little clinical evidence available on the possible anticonvulsive effects of atropine in man. Pharmacodynamics This section will review briefly animal work relevant to the use of atropine, whether administered alone or in combination with an oxime, in the management of organophosphate poisoning. It is necessary, when reviewing animal data, to ensure that the dose of atropine given was sufficient to influence outcome. Another problem in extrapolating animal data to man is that many animal models evaluate mortality up to 24 hours, after only one injection of an antidote or antidotes given immediately following exposure to an organo phosphorus compound, a model not likely to be mimicked in clinical practice. Given the importance of adequate supportive therapy in the clinical setting, and particularly the importance of a patent airway, it is surprising that many studies do not state whether such treatment was employed, even when large animals such as buffalo calves. Mutagenicity testing Atropine caused non-specific aggregation of chromosomes, considered to be of no cytogenetic danger Atropine sulphate was assessed as negative in the Ames assay, using one or more Salmonella typhimurium standard strains (TA98, TA100, TA1535, TA1537 and TA1538). 8.3.2. Carcinogenicity testing Atropine may promote experimental carcinogenesis in rat stomach caused by N-methyl-N-nitroNnitrosoguanidine. In a long-term trial of 858 rats by Schmahl and Habs, atropine was not found to be carcinogenic.
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8.3.3. Teratogenicity testing Chick eggs were injected with 0.6 to 1.5mg atropine during the interval of 4 to 12 days incubation. No defects were produced . Atropine given to rat dams from days 7 to 19 of gestation resulted in avoidance learning deficits in their pups compared to controls. Findings suggested that prenatal exposure to sympatholytic drugs may produce adverse effects on the behavioural development of pups. 8.3.4. Behavioural toxicology In microencephalic rats, compared to normal controls the magnitude of deficits in learning the Morriswater maze increased as a function of atropine dose, suggesting that learning and memory may berelated to changes in the number and/or function of muscarinic cholinergic receptors. Behavioural alterations have been noted amongst the offspring of rats treated during pregnancy with atropine. Pharmacokinetics Absorption Oral absorption. Atropine is absorbed irregularly from the gastrointestinal tract, and more slowly than with parenteral dosing. In adults, atropine is absorbed mainly from the duodenum and jejunum rather than the stomach. Maximum radioactivity, using 3H-atropine, was found one hour after an oral dose . Absorption of orally administered atropine may be delayed if atropine has been previously administered, a 38% increase in small bowel transit time was observed following intramuscular injection of atropine. In children, who received atropine 0.03mg/kg orally, peak plasma concentrations occurred at 90 minutes with only 10-20% occupancy of muscarine-2 subtype receptors. By contrast, after 0.02mg/kg intramuscular administration, peak was at 25 minutes with 60-70% receptor occupancy. Following an oral dose of 0.03mg/kg atropine, a mean maximum serum concentration of 6.7nmol/L occurred at two hours in children, compared with 5.7 nmol/L at 30 minutes after intramuscular administration . Rectal absorption. In children, rectal absorption of atropine is slower than absorption from the Intramuscular route. Peak plasma concentrations of 0.7g/L occurred after 15 minutes, following rectal administration of atropine, compared with 2.4 g/L, five minutes after intramuscular dosing . Peak plasma concentrations after rectal dosing in children below 15kg in weight were lower than in older children (but not to a clinically significant degree) and plasma concentrations declined faster.
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Sublingual absorption. Oral sublingual atropine absorption was considered to be "of minor clinical significance" compared to absorption after intramuscular or subcutaneous administration. Absorption from the sublingual route was variable and low in pregnant women at full term given 0.02mg/kg to 0.07mg/kg compared to intramuscular or subcutaneous administration of 0.02mg/kg . A 7-month child in a systole received a sublingual injection of atropine 0.15mg (with adrenaline) with return of sinus rhythm and pulse . Inhalation. Inhalation of atropine sulphate from a pressurized metered-dose inhaler resulted in peak serum concentrations of 4.9 g/L, 6.1 g/L and 7.9 g/L from administration of 1.7mg, 3.4mg and 5.2mg respectively. By comparison, a 1.67mg intramuscular injection of atropine free base (equivalent to 2mg atropine sulphate) gave a mean peak concentration of 8.4 g/L. Ocular absorption. Some absorption of atropine can occur from the lower cul-de-sac of the eye Peak plasma concentration was reached within 8 minutes after instillation of a 1% atropine Atropine Dermal absorption. Limited absorption occurs from the intact skin. Intramuscular absorption. Intramuscular absorption of atropine and atropine sulphate depends on the method of injection, the site of injection and the pharmaceutical form. Exercise may increase the rate of absorption. Atropine and atropine sulphate reach peak plasma levels when injected intramuscularly in about 30 minutes. In pregnant women at full term, however, mean peak plasma levels were reached at 1.59 hours, following a dose of 0.01mg/kg . Absorption may be faster if atropine is injected into the deltoid muscle rather than the gluteal or vastus lateralis muscles. A study using time to peak heart rate to seek differences between routes of administration and pharmaceutical forms, found that intravenous administration was most rapid. subcutaneous absorption. There was no significant difference in the rate of absorption of doses (0.02mg/kg atropine) given intramuscularly or subcutaneously to full term pregnant women. Endotracheal absorption. Optimal drug doses and absorption parameters for administration by the endotracheal route are unknown but medications should be administered at 2 to 2.5 times the recommended intravenous dose, and diluted before use in 10ml saline or distilled water in adults . In children with normal cardiac status, Howard & Bingham (1990) found that there was no difference between effect on heart rate or speed of onset with either intravenous atropine sulphate 0.025mg/kg dilute in 2ml saline, given at the same time as 2ml saline endotracheally or twice the dose (ie 0.05mg/kg) of atropine given endotracheally at the same time as 2ml
36
intravenously. After studying 50 patients using dose titration with endotracheal atropine, it was considered that if atropine must be given by the endotracheal route in an emergency, then 0.03mg/kg or more may be comparable to the effect of 0.01mg/kg given intravenously. Any route of vascular administration was considered preferable to the endotracheal route . Intraosseous administration. Animal studies with atropine have shown similar actions and drug concentrations after intraosseous administration to those after intravenous administration. Establishment of an intraosseous route in children 6 years old or younger has been suggested, if venous access cannot be achieved. Intraosseous administration has been used in older children & adults, and has also been considered preferable to the endotracheal route. Distribution After intravenous dosing, atropine distributes rapidly with only 5% remaining in the blood compartment after five minutes . Initial distribution half-life is approximately one minute . Elimination kinetics can be fitted to a two-compartment model after therapeutic doses. The apparent volume of distribution (Vd) is 1-1.7 L/kg with a clearance of 5.9-6.8 ml/kg/minute and a half-life of 2.6-4.3 hours in the elimination phase Atropine rapidly crosses the placenta, with apparent fetal uptake. No distribution into the amniotic fluid was found in one study but significant distribution in another. In one study, concentrations in the umbilical vein were 93% of the maternal level five minutes after an intravenous injection. Small quantities of atropine are stated to appear in breast milk but there is little data to support this (atropine may also impair milk production, although this is not conclusively documented Penetration into human lumbar cerebrospinal fluid was less complete, particularly after a single Intravenous injection. It has been speculated that the cerebrospinal fluid (CSF) represents a "deep" compartment with slow drug penetration. Nonetheless, atropine penetration is assumed to be greater into the central nervous system than into lumbar cerebrospinal fluid (CSF), compatible with the well-known central anticholinergic effects of the drug. Penetration of atropine into the eye after both local and systemic administration is slow and incomplete.
Elimination After intravenous dosing, atropine elimination fits a two-compartment model with an intrinsic clearance of 5.9-6.8 ml/kg/min and a plasma half-life of 2.6-4.3 hours in the elimination phase.
37
The elimination half-life of atropine is longer in children less than two years of age, and in the elderly. In children, this is due to an increased volume of distribution (Vd), increasing the halflife up to 5-10 hours in the neonate. In the elderly (70 years and older), the half-life may be prolonged from 10 to 30 hours due to reduced clearance. These changes do not appear to be sexrelated. Not only the kinetics, but also the dynamics may change with age, making both the younger and older patient more sensitive to a given dose. Patients with Downs syndrome may exhibit abnormally greater cardioaccelerator response to intravenously administered atropine while patients with albinism may have decreased susceptibility to some of the actions of atropine. The mechanisms for these differences are unclear. Atropine is metabolized in the liver by microsomal monooxygenases. HPLC separation of urine has identified 5 compounds: atropine, noratropine, tropine, atropine-N-oxide(equatorial isomer), and tropic acid . Thus, atropine is partly metabolized and partly excreted unchanged in the urine, the unchanged portion being approximately 50% (Since biliary excretion is negligible, the hepatic plasma clearance of 519147 ml/min represents metabolism. Hepatic blood clearance and extraction ratio were 476136 ml/min and 0.32, respectively. The elimination of atropine is, therefore, partly flowdependent (Hinderling et al., 1985). Following an intravenous injection, 57% of the dose is found in the urine as unchanged atropine and 29% as tropine. Since the renal plasma clearance (656118 ml/min) was found to approach the renal plasma flow (71238 ml/min), tubular excretion may occur. Thus, both liver and renal disease can be expected to influence the kinetics of atropine. Dose and duration of atropine sulphate therapy The optimal dose of atropine sulphate required to manage moderate and severe organophosphate poisoning is controversial. Recommendations for initial intravenous dosing range from 1 mg in adults and 0.01 mg/kg in children as a "test dose" up to 5 mg in adults, and 0.05 mg/kg in children. Larger doses may, however, be necessary: in a retrospective study of 37 paediatric patients, Zweiner & Ginsburg (1988) found that one third of patients required at least 0.05 mg/kg before any decrease in cholinergic activity was observed. In one adult, up to 15 mg was given as a single bolus most cases of mild-moderate organophosphate poisoning require no more than a total of 5-50 mg atropine. A small number of patients appear to have required massive quantities of atropine, sometimes for prolonged periods, in particular those poisoned with highly lipidsoluble compounds, such as fenthion Total doses of atropine as high as 3911 mg 11 443 mg
38
and 19 590 mg have been given to patients, who recovered from their severe poisoning. 5 weeks Relapse during therapy also appears to be more common with highly lipophilic organophosphates. Because of the risk of relapse, patients should be weaned off atropine slowly. If large quantities of atropine sulphate are given, care should be taken to avoid using formulations containing preservatives such as chlorbutanol or benzyl alcohol. Route of administration In order to cater for the sometimes large doses of atropine required to treat organophosphate poisoning some manufacturers produce larger ampoules, containing 10-100 mg of atropine. It may be more practicable to administer large doses by intravenous infusion rather than by Intermittent bolus injections. Intravenous infusion may save time, produce less fluctuation in plasma atropine concentrations and make weaning much easier. On the other hand, because administration by infusionmay result in less frequent assessments, it is much easier for a patient to develop atropine toxicity while on an infusion than when receiving bolus injections. Moreover, it should be remembered that the halflife of atropine (up to 4 hours or longer in children and the elderly) necessitates using a bolus dose as well as adjusting the drip rate if a rapid increase in the degree of atropinization is required. In an emergency situation, it may be necessary to give atropine before intravenous or intraosseous access can be established. The endotracheal route has therefore been used, when vascular access was not available. Atropine was given endotracheally to a 16-month-old child with a carbamate overdose The child responded rapidly to 1.0mg, and a total of 2.5 mg atropine was given by this route. The optimal dose requirements for the endotracheal route have not yet been established, however. Oral administration of atropine has been reported as being useful for stable patients on intravenous therapy for several days or weeks, which need slow weaning. Atropine given intramuscularly in some specialized injectors may have faster onset of action than other forms of intramuscular injection. The recommended dose for nerve agent exposure in adult, otherwise healthy patients with mild to moderate symptoms is 2 to 4 mg. Initial doses of both atropine and atropine sulphate administered to adults and children by the intramuscular route appear to be similar to those given intravenously, although onset of action will be slower after intramuscular injection.
39
Adverse effects of atropine therapy Atropine toxicity was noted on at least one occasion in 16 of 61 patients (26%) in a retrospective, multicentre study noted over-atropinization in three of 232 cases. The dose of atropine should be reduced if the patient shows signs of atropine toxicity such as fever, or delirium If atropine is administered to hypoxic patients there is a risk of ventricular tachycardia or fibrillation. In this situation, atropine should be given at the same time as the patient is oxygenated. Prolonged atropinization may cause paralytic ileus. Paralytic ileus was also reported in an infant with Downs syndrome who was being treated with topical atropine. In a case reported, rigidity was observed for up to 10 days following weaning after a five-week period of therapy. Mydriasis, but no other pharmacological effects, was noted in a neonate, whose mother had been given atropine for organophosphate poisoning before the birth. Other adverse effects of atropine, not necessarily associated with treatment of organophosphorus insecticide poisoning, include precipitation of glaucoma and hypersensitivity reactions (anaphylaxis). Clinical atropine toxicity Poisoning can occur following oral, ocular, respiratory or parenteral exposure. There are numerous case reports of atropine poisoning from plants from antiquity through to the present. In a case of jimsonweed poisoning (Datura stramonium), a four-year-old boy presented with confusion, hallucinations, ataxia, and tachycardia. Symptoms developed three hours after ingestion, recovery took two days. In a 65-year-old man, 3 mg of atropine from Atropa belladonna leaves mistaken for burdock (Arctium lappa) leaves, produced not only peripheral atropinization but also a central anticholinergic syndrome with restlessness, hyperactivity, and dysphasia. Symptoms resolved within 24 hours with symptomatic therapy. Mild atropine toxicity, with a central anticholinergic syndrome, may also occur after "normal" dosing, as the prolonged half-life of atropine with increasing age puts the older patient at risk. Reported three children overdosed with atropine following a thousand-fold error in dosage. During the first 12 hours, the children were sedated and disoriented. They became increasingly restless as a central anticholinergic syndrome persisted for two days, requiring large quantities of diazepam for sedation; the pupils remained dilated for a week. In a review of nine cases of accidental poisoning with oral drops, reported toxicity with atropine dosages ranging from 0.393.55 mg/kg. One patient, a 6-week-old boy, presented with fever, irritability, warm dry skin,
40
inspiratory stridor, cyanosis of the hands and feet, and dilated and unresponsive pupils. Recovery was uneventful. Following an accidental oral overdose of 0.3 mg/kg atropine in two small children, reported maximum serum levels of 29 and 15.6 mg/L at 2 to 2.5 hours, concentrations normally found in the distribution phase following an intravenous bolus of a therapeutic dose. Symptoms of toxicity resolved uneventfully within eight hours. In three-year old children, deaths have been reported following ocular applications as low as 1.6 and 2 mg and oral doses of 100 mg, although one patient recovered following an estimated ingestion of 1 g. Drug interactions Intramuscular atropine may slow small bowel transit time by approximately 38%, which in turn determines enterohepatic cycling frequency. Gastric emptying may also be delayed by atropine. Thus, the pharmacokinetics and/or efficacy of oral drugs co administered with atropine may be changed, as may the response of drugs that undergo enterohepatic circulation. Changes in drug efficacy have occurred with levodopa (decreased effect) and (hallucinations) when anticholinergics were given concomitantly. Pre-treatment with the calcium channel blocker, verapamil has increased the tachycardia produced by atropine in healthy volunteers. Other drugs with anticholinergic effects, such as tricyclic antidepressants, some antihistamines, phenothiazines, disopyramide and quinidine, will have additive peripheral and central nervous system anticholinergic activity if given with atropine (Dollery, 1991). Tertiary amine muscarinic receptor Atropine antagonists used as antispasmodics, such as dicyclomine, oxyphencyclimine, flavoxate and oxybutynin will also act similarly, as will quaternary ammonium muscarinic receptor antagonists, for example, ipratropium, methscopolamine and homatropine. The muscarinic actions of parasympathomimetic drugs such as carbachol, bethanecol and pilocarpineare blocked by atropine. The action of anticholinesterase agents such as physostigmine, neostigmine, edrophonium, ambenonium and pyridostigmine can be antagonised at muscarinic receptor sites by atropine and vice versa, according to dose size.
41
PARACETAMOL:Paracetamol or acetaminophen is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer). It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies. In combination with opioid analgesics, paracetamol can also be used in the management of more severe pain such as post surgical pain and providing palliative care in advanced cancer patients. The onset of analgesia is approximately 11 minutes after oral administration of paracetamol, and its half-life is 14 hours. While generally safe for use at recommended doses (1,000 mg per single dose and up to 3,000 mg per day for adults), acute overdoses of paracetamol can cause potentially fatal liver damage and, in rare individuals, a normal dose can do the same; the risk is heightened byalcohol consumption. Paracetamol toxicity is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia and New Zealand. It is the active metabolite of phenacetin, once popular as an analgesic and antipyretic in its own right, but unlike phenacetin and its combinations, paracetamol is not considered carcinogenic at therapeutic doses. The words acetaminophen (used in the United States, Canada, Japan, South Korea, Hong Kong, and Iran) and paracetamol (used elsewhere) both come from a chemical name for the compound: para-acetylaminophenol and para-acetylaminophenol. In some contexts, it is simply abbreviated as APAP, foracetyl-para-aminophenol. Synonyms:4-Hydroxyanilid kyseliny octove; Abensanil; Acamol; Acetagesic; Acetalgin; Acetaminofen; Acetaminophen; Algotropyl; Alvedon; Amadil; Anaflon; Anelix; Apamid; Apamide; APAP; Ben-u-ron; Bickie-mol; Calpol; Cetadol; Clixodyne; Datril;
42
Dial-a-gesic; Dirox; Dymadon; Eneril; Excedrin; Febrilix; Febro-gesic; Febrolin; Fendon; Finimal; Hedex; Homoolan; Lestemp; Liquagesic; Lonarid; Lyteca; Lyteca syrup; Multin; NAPA; Napafen; Napap; Naprinol; NCI-C55801; Nobedon; Pacemo; Panadol; Panets; Paracetamole; Paracetamolo; Parmol; Pedric; Phendon; Pyrinazine; SK-Apap; Tabalgin; Tapar; Temlo; Tempanal; Tempra; Tralgon; Tussapap; Tylenol; Valadol; Valgesic Chemical and physical properties of the pure substance (a) Description: White crystalline powder (b) Melting-point: 170C (c) Density: 1.293 g/cm3 at 21C (d) Solubility: Insoluble in water; very soluble in ethanol (e) Octanol/water partition coefficient (P): log P, 0.31 (f) Conversion factor: mg/m3= 6.18 ppm
Production and use Paracetamol is used as an analgesic and antipyretic, in the treatment of a wide variety of arthritic and rheumatic conditions involving musculoskeletal pain and in other painful disorders such as headache, dysmenorrhoea, myalgia and neuralgia. It is also indicated as an analgesic and antipyretic in diseases accompanied by generalized discomfort or fever, such as the common
43
cold and other viral infections. Other uses include the manufacture of azo dyes and photographic chemicals, as an intermediate for pharmaceuticals and as a stabilizer for hydrogen peroxide. The conventional oral dose of paracetamol for adults is 3251000 mg (650 mg rectally); the total daily dose should not exceed 4000 mg. For children, the single dose is 40480 mg, depending on age and weight; no more than five doses should be administered within 24 h. For infants under three months of age, a dose of 10 mg/kg by is recommended.
Acetaminophen Pharmacokinetics Absorption Bioavailability Well absorbed following oral administration, with peak plasma concentration attained within 10 60 minutes (immediate-release preparations) or 60120 minutes (extended-release preparations). Poor or variable absorption following rectal administration; considerable variation in peak plasma concentrations attained; time to reach peak plasma concentration is substantially longer than after oral administration Distribution Extent Rapidly distributed to most body tissues.Crosses placenta and is distributed into breast milk. Plasma Protein Binding 25%. Metabolism Metabolized principally by sulfate and glucuronide conjugation; small amounts (510%) oxidized by CYP-dependent pathways (mainly CYP2E1 and CYP3A4) to a toxic metabolite, Nacetyl-p-benzoquinoneimine (NAPQI). NAPQI is detoxified by glutathione and eliminated; any remaining toxic metabolite may bind to hepatocytes and cause cellular necrosis. Elimination Route Mainly excreted in urine as conjugates.
44
Half-life 1.253 hours Storage Oral Tablets Room temperature. Protect orally disintegrating tablets (Tylenol Meltaways) from high humidity.Protect grape-flavored orally disintegrating tablets from light. Suspension/Solution Actions

Exhibits analgesic and antipyretic activity. Weak, reversible, isoform-nonspecific cyclooxygenase inhibitor at dosages of 1 g daily.Inhibitory effect on cyclooxygenase-1 is limited; does not inhibit platelet function
Uses for Acetaminophen Pain Symptomatic relief of mild to moderate pain. Self-medication in children 6 years of age and adults for the temporary relief of minor aches and pain associated with headache, muscular aches, backache, minor arthritis pain, common cold, toothache, and menstrual cramps. Self-medication in infants and children for the temporary relief of minor aches and pain associated with the common cold, flu, headache, sore throat, immunizations, toothache, muscle aches, sprains, and overexertion. Self-medication in fixed combination with aspirin and caffeine for the temporary relief of mild to moderate pain associated with migraine headache. This combination also can be used for the treatment of severe migraine headache if previous attacks have responded to similar nonopiate analgesics or NSAIAs.
45
Symptomatic treatment of pain associated with osteoarthritis; considered an initial drug of choice for pain management in osteoarthritis patients. Used in fixed combination with isometheptene and dichloralphenazone for symptomatic relief of tension and vascular headaches. Used in fixed combination with other agents (e.g., chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, phenylephrine, pseudoephedrine) for short-term relief of minor aches and pain, headache, fever, and/or other symptoms (e.g., rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal itching, nasal congestion, cough) associated with seasonal allergic rhinitis (e.g., hay fever), other upper respiratory allergies, or the common cold. Fever Self-medication to reduce fever in infants, children, and adults. Administration Usually administered orally; may be administered rectally as suppositories in patients who cannot tolerate oral therapy. Oral Administration Swallow extended-release tablets whole; do not crush, chew, or dissolve in liquid. Place orally disintegrating, fixed-combination acetaminophen/caffeine tablets on the tongue to dissolve; swallow with saliva. For best taste, do not chew. Because combinations and dosage strengths vary for fixed-combination preparations, consult manufacturers product labeling for appropriate dosage of the specific preparation. Pediatric Administration Acetaminophen oral drops generally used in infants 023 months of age. Use the calibrated dosing device provided by the manufacturer for measurement of the dose.
46
Oral suspension may be used in children 4 months age.Use the calibrated dosage cup provided by the manufacturer for measurement of the dose. 80-mg chewable tablets or orally disintegrating tablets may be used in children 2 years of age. 160-mg chewable tablets or orally disintegrating tablets or 325-mg conventional tablets commonly used in children 6 years of age. Orally disintegrating tablets (Tylenol Meltaways) should be allowed to dissolve in the mouth or should be chewed before swallowing. Use caution to ensure that the correct number of tablets required for the intended dose is removed from the blister package. Rectal Administration Dividing suppositories in an attempt to administer lower dosages may not provide a predictable dose. Some experts state that rectal acetaminophen preparations should not be used for selfmedication in children unless such use is specifically discussed with a clinician and parents or caregivers are instructed to adhere to dosage and administration recommendations. Pediatric Patients Dosage in children should be guided by body weight. (See Pediatric Use under Cautions.) Pain Oral Dose may be given every 46 hours as necessary (up to 5 times in 24 hours)
47
PLAN OF WORK:1. Collection of cow ghee from appropriate source. 2. Evaluation of cow ghee by some selected parameters. 3. Evaluation of cow ghee Organoleptic properties :Color Odor Taste Texture Physical parameter :Moisture: - Moisture refers to the presence of a liquid, especially water, often in trace amounts. Small amounts of water may be found, for example in foods, and in various commercial products. The moisture contained in a material comprises all those substances which vaporize on heating and lead to weight loss of the sample. The weight is determined by a balance and interpreted as the moisture content. According to this definition, moisture content includes not only water but also other mass losses such as evaporating organic solvents, alcohols, greases, oils, aromatic components, as well as d Methods of moisture content determination. The moisture content influences the physical properties of a substance such as weight, density, viscosity, refractive index, electrical conductivity and many more. Over the years, a wide range of methods has been developed to measure these physical quantities and express them in the form of the moisture content. The measurement methods can logically be divided in the following procedures: Thermo- gravimetric Chemical
48
Spectroscopic Others, decomposition and combustion products. Drying oven Principle: - A sample is dried by means of hot circulating air. To tighten up the drying conditions or to protect thermally unstable substances, drying is frequently performed under vacuum. The moisture content is determined by a differential weighing before and after drying. Importance For many substances the drying oven method is a mandatory reference method with good reproducibility. This method is frequently cited in laws governing food. Advantage the advantage of the classical drying oven method lies in the number of samples which can be investigated simultaneously. Moreover, it offers the possibility of analyzing large amounts of samples, which can be a particular advantage with in homogeneous samples. Principles These methods rely on measuring the mass of water in a known mass of sample. The moisture content is determined by measuring the mass of a food before and after the water is removed by evaporation:
Ere, MINITIAL and MDRIED are the mass of the sample before and after drying, respectively. The basic principle of this technique is that water has a lower boiling point than the other major components within foods, e.g., lipids, proteins, carbohydrates and minerals. Sometimes a related parameter, known as the total solids, is reported as a measure of the moisture content. The total solids content is a measure of the amount of material remaining after all the water has been evaporated:
49
PH :- pH is a measure of the acidity or basicity of an aqueous solution Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline. n a solution pH approximates but is not equal to p[H], the negative logarithm (base 10) of the molar concentration of dissolved hydronium ions (H3O+); a low pH indicates a high concentration of hydronium ions, while a high pH indicates a low concentration. This negative of the logarithm matches the number of places behind the decimal point, so, for example, 0.1 molar hydrochloric acid should be near pH 1 and 0.0001 molar HCl should be near pH 4 (the base 10 logarithms of 0.1 and 0.0001 being 1, and 4, respectively). The measurement of pH in an aqueous solution can be made in a variety of ways. The most common way involves the use of a pH sensitive glass electrode, a reference electrode and a pH meter. A pH meter is always recommended for precise and continuous measuring. Most laboratories use a pH meter connected to a strip chart recorder or some other data acquisition device so that the reading can be recorded or stored electronically over a user-defined time range. Mathematical definition pH is defined as a negative decimal logarithm of the hydrogen ion activity in a solution.
Where aH+ is the activity of hydrogen ions in units of mol/L (molar concentration). Activity has a sense of concentration; however activity is always less than the concentration and is defined as a concentration (mol/L) of an ion multiplied by activity coefficient. The activity coefficient for diluted solutions is a real number between 0 and 1 (for concentrated solutions may be greater than 1) and it depends on many parameters of a solution, such as nature of ion, ion force, temperature, etc. For a strong electrolyte, activity of an ion approaches its concentration in diluted solutions. Activity can be measured experimentally by means of an ion-selective electrode that responds, according to the Nernst equation, to hydrogen ion activity. pH is commonly measured by means of a glass electrode connected to a milli-voltmeter with very high input impedance, which measures the potential difference, or electromotive, E, between an electrode sensitive to the hydrogen ion activity and a reference electrode, such as a calomel electrode or a silver chloride electrode. Quite often, glass electrode is combined with the reference electrode and a temperature sensor in one body. The glass electrode can be described (to 9599.9% accuracy) by the Nernst equation:
50
Where E is a measured potential, E0 is the standard electrode potential, that is, the electrode potential for the standard state in which the activity is one. R is the gas constant, T is the temperature in Kelvins, F is the Faraday constant, and n is the number of electrons transferred (ion charge), one in this instance. The electrode potential, E, is proportional to the logarithm of the hydrogen ion activity. This definition, by itself, is wholly impractical, because the hydrogen ion activity is the product of the concentration and an activity coefficient. To get proper results, the electrode must be calibrated using standard solutions of known activity. The operational definition of pH is officially defined by International Standard ISO 31-8 as follows: For a solution X, first measures the electromotive force EX of the galvanic cell Reference electrode|concentrated solution of KCl || solution X|H2|Pt and then also measure the electromotive force ES of a galvanic cell that differs from the above one only by the replacement of the solution X of unknown pH, pH(X), by a solution S of a known standard pH, pH(S). The pH of X is then
The difference between the pH of solution X and the pH of the standard solution depends only on the difference between two measured potentials. Thus, pH is obtained from a potential measured with an electrode calibrated against one or more pH standards; a pH meter setting is adjusted such that the meter reading for a solution of a standard is equal to the value pH(S). Values pH(S) for a range of standard solutions S, along with further details, are given in the IUPAC recommendations. The standard solutions are often described as standard buffer solution. In practice, it is better to use two or more standard buffers to allow for small deviations from Nernst-law ideality in real electrodes. Note that, because the temperature occurs in the defining equations, the pH of a solution is temperature-dependent. Measurement of extremely low pH values, such as some very acidic mine waters, requires special procedures. Calibration of the electrode in such cases can be done with standard solutions
51
of concentrated sulfuric acid, whose pH values can be calculated with using Pitzer parameters to calculate activity coefficients. PH is an example of an acidity function. Hydrogen ion concentrations can be measured in nonaqueous solvents, but this leads, in effect, to a different acidity function, because the standard state for a non-aqueous solvent is different from the standard state for water. Super acids are a class of non-aqueous acids for which the Hammett acidity function, H0, has been developed. PH in its usual meaning is a measure of acidity of (dilute) aqueous solutions only. Recently the concept of "Unified pH scale" has been developed on the basis of the absolute chemical potential of the proton. This concept proposes the "Unified pH" as a measure of acidity that is applicable to any medium: liquids, gases and even solids.
Particle size:Particlesize isa notion introducedforcomparing dimensions of solid particles(flecks), liquid partic les (droplets), or gaseous particles (bubbles). Optical counting methods PSDs can be measured microscopically by sizing against a graticule and counting, but for a statistically valid analysis, millions of particles must be measured. This is impossibly arduous when done manually, but automated analysis of electron micrographs is now commercially available. The need for particle size control in the manufacture of pharmaceuticals is becoming increasingly apparent as the pharmaceutical industry attempts to capitalize on some APIs with less-than-ideal solubility profiles. Also, significant advances in drug delivery have been made in which a finely divided API, with the concomitant increase in specific surface area, has resulted in increased bioavailability. Precise particle size control technologies have also assisted in the development of drug delivery platforms for the delivery of a medicament.
Viscosity: - Viscosity is a measure of the resistance of a fluid which is being deformed by either shear or tensile stress. Viscosity is measured with various types of viscometers and rheometers. A rheometer is used for those fluids which cannot be defined by a single value of viscosity and therefore require more parameters to be set and measured than is the case for a viscometer. Close temperature control of the fluid is essential to accurate measurements, particularly in materials like lubricants, whose
52
viscosity can double with a change of only 5 C. delta p = difference in density between the sphere and the liquid
g = acceleration of gravity a = radius of sphere v = velocity = d/t = (distance sphere falls)/(time of it takes to fall) A viscometer (also called viscosimeter) is an instrument used to measure the viscosity of a fluid. For liquids with viscosities which vary with flow conditions, an instrument called a rheometer is used. Viscometers only measure less than one flow condition.
Copper content Chemical parameter Acid value acid value (or "neutralization number" or "acid number" or "acidity") is the mass of potassium hydroxide (KOH)
in milligramsthat is required to neutralize one gram of chemical substance. The acid number is a measure of the amount of carboxylic acid groups in a chemical compound, such as a fatty acid, or in a mixture of compounds. In a typical procedure, a known amount of sample dissolved in organic solvent (often isopropanol), is titrated with a solution of potassium hydroxide with known concentration and with phenolphthalein as a color indicator. The acid number is used to quantify the amount of acid present, for example in a sample of biodiesel. It is the quantity of base, expressed in milligrams of potassium hydroxide, that is required to neutralize the acidic constituents in 1 g of sample.
Veq is the amount of titrant (ml) consumed by the crude oil sample and 1ml spiking solution at the equivalent point, beq is the amount of titrant (ml) consumed by 1 ml spiking solution at the equivalent point, and 56.1 is the molecular weight of KOH. WOil is the weight of the sample in grams. The molarity concentration of titrant (N) is calculated as such:
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In which WKHP is the amount (g) of KHP in 50 ml of KHP standard solution, Veq is the amount of titrant (ml) consumed by 50 ml KHP standard solution at the equivalent point, and 204.23 is the molecular weight of KHP.
Saponification value Iodine value R M value P value Formulate the ophthalmic gel (drug) with ghee by appropriate method.

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1

OCULAR DRUG DELIVERY:INTRODUCTION:-

reaches the internal

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

bioavailability of the eye installed drugs are

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

away and absorbed through the membranes of the

vivo experimental release studies,

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

Anatomical and physiological features of the eye

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

Drug profile: ATROPINE SULPHATE

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

alpha-Htropan- 3-alpha-OL-()-tropate (ester), sulfate (2:1) salt; dl-tropanyl-2-hydroxy-1phenylpropionate sulphate

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

Belgium, Luxembourg); Tropyn Z(Zafiro, Mexico)

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

SHRI RAWATPURA INSTITUTE OF PHARMACY, KUMHARI

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