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Recent Advances In Controlled Parenteral Drug Delivery System

By: Pharma Tips | Views: 76354 | Date: 02-Jul-2010

Oral drug delivery in which the systemic bioavailability of a drug is often subjected to variations in gastrointestinal transit and biotransformation in the liver by "FIRST PASS" metabolism.Parenteral drug delivery, especially intravenous injection, can gain easy access to the systemic circulation with complete drug absorption and therefore reach the site of drug action Rapidly.

Recent Advances In Controlled Parenteral Drug Delivery System

Recent Advances In Controlled Parenteral Drug Delivery System


1.
INTRODUCTION:
Oral drug delivery in which the systemic bioavailability of a drug is often subjected to variations in gastrointestinal transit and biotransformation in the liver by "FIRST PASS" metabolism.
Parenteral drug delivery, especially intravenous injection, can gain easy access to the systemic circulation with complete drug absorption and therefore reach the site of drug action Rapidly.
The intravenous, subcutaneous, intramuscular, intraperitoneal, and intrathecal routes are all examples of parenteral routes of drug administration. For a variety of reasons, the most notable being physiological and anatomical constraints, not all of these are useful as routes for controlled drug delivery. Up to the present, efforts in developing controlled release parenteral dosage fortes seem to have concentrated the subcutaneous and intramuscular routes, resulting in such products as aqueous and oil solutions, and implants.
There are currently a number of injectable depot formulation on the market.
Penicillin G procaine suspensions
Medroxy progesterone acetate suspension
Fluphenazine enanthate and decanoate in oil solution
Insulin-zinc suspensions
ACTH -Zn tannate/geletin preparation

When these formulations are injected into subcutaneous or muscular tissues, A depot is formed at the site of injection which acts as a reservoir for drug. Drug Molecules will be released continuously from the reservoir at a rate determined by the characteristics or each formulation. This continuous release of drug molecules will result in a prolonged drug blood level.

The rate of-drug absorption and hence duration of-therapeutic activities will be determined by,
The nature of the vehicle,
The physicochemical characteristics of the drug,
The interaction of drug with vehicles and tissues/fluid

The duration of action of a regular insulin injection is increased by approximately four times when it is completed with protamine to form the slowly dissolving protamine insulin. Oil solution and aqueous and oil suspension, recent efforts have been made to develop controlled and sustained release parenteral delivery systems via encapsulation, carriers, and magnetic systems. Controlled drug delivery is the phasing of drug administration to the needs of a condition at hand so that an optimal amount of drug is used to cure or control the condition in a minimum time. Research in controlled drug delivery during the past decade has led to increasingly sophisticated means to sustain drug delivery. It has also stimulated greater awareness among to pharmaceutical industry, the regulatory agencies the health care profession, and the public at large of the therapeutic advantages of controlled drug delivery systems.
The majority of these systems are based on synthetic polymers of some sort that differ in the degree in the degree of erodibility, swell ability and sensitivity to the biological environment in which they are placed. 'These polymers have been used to Fabricate sysdrogels for oral and parenteral drug delivery, the osmotic pump for oral drug delivery, and patches for transdermal drug delivery. Clearly, in order to fully utilize the potential of polymers in the broad area of drug delivery, it is necessary to understand their fundamental physical, chemical, and biological properties.
The area of controlled drug delivery is also becoming broader in scope in terms of routes of administration. Traditionally, controlled drug delivery systems were developed primarily for the oral route and, to some extent, for the parenteral route. Recently, there has been an explosion in research on drug delivery via the skin, due primarily to the success of several transdermal devices in sustaining drug delivery to the systemic circulation.

Benefits derived from the parenteral controlled release formulations are primarily the achievement of a relatively constant and substantially sustained therapeutic drug level with a reduction in the frequency of injection.
In other words, the injectable dept formulation was developed with primary of objective of stimulating the intravenous infusion an a more practical basis.

2. MAJOR ROUTES OF NARENTERAL ADMINISTRATION:
The subcutaneous and intramuscular routes are the major routes of administration for the majority of sustained/controlled parenteral delivery systems, although the intravenous and peritoneal routes have also been used.

SUBCUTANEOUS 
A dipose and connective tissues are poorly perfused with blood. This route is generally limited to non-irritating, water-soluble drugs that are well absorded, e.g., insulin. It is important that the injection site be rotated lbr chronically administered drugs to avoid local tissue damage and accumulation of unabsorbed drug. The volume of subcutaneous injection is usually restricted to 0.5-1.5 ml.

INTRAMUSCULAR
The best sites for intramuscular injection are the gluteal, deltoid and Vastus lateralis muscles it is important that the injection be deep in the muscle and away. From major nerves and arteries .To avoid tissue damage, the volume of intramuscular injection should Not exceed 2 ml .A polymeric membrane that is either impregnated with drug or Surrounds a drug reservoir can be used as the drug delivery device .a slightly Soluble from of from the drug can also serve as the drug source, there by generating desired constant rate of release. e.g. Butorphanol tartrate.

INTRAVENOUS
The intravenous rout is occasionally used as a route of administration for sustained/controlled dosage form such as liposomes, nanoparticle, erythrocytes, and polypeptides. When drug particles are injected intravenously, particle larger than about 1 micrometer are trapped in the lung, whereas particles with diameter between 0.1 and 7µm are trapped or take-up prelimary by the liver or the spleen. Only small particles with a diameter less than 0.1 µm accumulated in born marrow.

INTIRAPERITONEAL
Lymphatic channel are frequently the route by which tumor metastasize micro molecules administer intraperitoneally can gain access to the lymphatic system and return slowly to the vascular compartment. Thus, a macromolecule may be used a s a carrier to target Antineoplastic agents into the lymphatic system.
With subcutaneous and intramuscular injections, local trauma to the tissue occurs search time an injection is made. The trauma can be either chemicals due to puncture of tissue by needle and sudden distention of the tissue, or both. Thus, use of a sustained/controlled release dosage form which maintains therapeutic concentrations for a prolonged period of time is expected to produce greater tissue insult and injury. Therefore, irritating substance should be excluded form sustained/controlled-release parentral dosage forms.

ADVANTAGES OF PARENTERAL ADMINISTRATION
1.An immediate physiological response can be achieved if necessary, which can be of    prime consideration in clinical condition such as cardiac arrest, astharna and shock .
2.Parenteral therapy is required for drugs that are not effective orally or that are
destroyed by digestive secretions such as insulin other hormones and antibiotics.
3.Drug for uncooperative, nauseous or unconscious patients must he administered
by injection.
4.When desirable, parenteral therapy gives the physician control of the drug since the patient must return for continued treatment, also in some cases the patient cannot be relied upon to take oral administration.
5.Parenteral administration can results in local effect for drugs when desired., as in dentistry and  anesthesiology.
6.In case in which prolonged drug action is wanted, parenteral Forms are available, including the long intrartially and the long acting penecillins administered deep intra muscularly.
7.Parenteral therapy provides the means of correcting serious disturbances of fluid and    electronic balances.
8.When food cannot be taken by mouth, total nutritional requirement can be supplied by the parenteral route.

DISADVANTAGE OF PARENTERAL ADMINISTERED
1.The dosage form must be administered by trained personnel and require more time
than those administered by other routes.
2.Parenteral administration requires strict adherence to aseptic procedures, and some
pain on injection is inevitable.
3.It is difficult to reverse its physiological effect.
4.The manufacturing and packaging requirements, parenteral dosage forms are more
expensive than preparations of given by other routes.

3. BIOPHARMACEUTICS CHARACTERISTICS OF THE DRUG:
The performance of a drug presented as a controlled release system depends upon its;
a.Release from the formulation
b.Movement within the body during its passage to the site of action.

The former depends on fabrication of the formulation and the physicochemical properties of the drug while the latter element is dependent upon pharmacokinetics of drug. In comparison to conventional dosage form where the rate-limiting step in drug availability is usually absorption through the biomembrane, the rate-determining step in the availability of the drug from controlled delivery system is the rate of release of drug from which is much smaller than the intrinsic absorption rate for the drug.
The type of delivery system and the route of administration so the drug presented in controlled release dosage form depends upon the physicochemical properties of the drug and its biopharmaceutic characteristics. The desired biopharmaceutic properties of a drug to be used in a controlled delivery system are discussed below.

1. MOLECULAR WEIGHT OF THE DRUG:
The lower the molecular weight, the faster and more complete the absorption. For drugs absorbed by pore transport mechanism, the molecular size threshold is 150 daltons for spherical compounds and 400 daltons for linear compounds. However, more than 95% of drugs are absorbed by passive diffusion. Diffusivity, defined as the ability of a drug to diffuse through the membranes, is inversely related to molecular size. The upper limit of drug molecular size for passive diffusion is 600 daltons. Drugs with large molecular size are poor candidates for oral controlled release systems. Eg. Peptides and proteins.
2.AQUEOUS SOLUBILITY OF THE DRUG: 
A drug with good aqueous solubility, especially if pH-independent, serves as a good candidate for controlled released dosage forms e.g. Pentoxifylline. Drugs with pH-dependent aqueous solubility e.g. Phenytoin, or drugs with solubility in nonaqueous solvents e.g. Steroids are suitable for parenteral (e.g. I.m. depots) controlled released dosage forms; the drug precipitates at the injection site and thus, its release is slowed down due to change in pH or contact with aqueous body fluids. Absorption of poorly soluble drugs is dissolution rate-limited which means that the controlled release device does not control the absorption process; hence, they are poor candidates for such systems.
3.DRUG APPARENT PARTITION COEFFICIENT: 
Greater the apparent coefficient of a drug, greater is its rate and extent of absorption. Such drugs have increased tendency to cross even the more selective barriers like BBB. The apparent volumes of distribution of such drugs also increases due to increased partitioning into the fatty tissues and since the blood flow rate to such tissues is always lower than that to an aqueous tissue like liver, they may exhibit characteristics of models having two or more compartments. The parameter is also important in determining the release rate of the drug form lipophilic matrix or device.
4.DRUG pKa AND IONIZATION AT PHYSIOLOGIC pH: 
The pKa range for acidic drugs whose ionization is pH-sensitive is 3.0 to 7.5 and that for basic drugs is 7.0 to 11.0. For optimum passive absorption, the drugs should be nonionized at that site at least to an extent 0.1 to 5%. Drugs existing largely in ionized forms are poor candidates for controlled delivery e.g. Hexamethonium.
5.DRUG STABILITY:
Drugs unstable in GI environment cannot be administered as oral controlled releases formulation because of bioavailability problems. E.g. Nitroglycerine. A different route of administration should then be selected such as the transdermal route.
6. MECHANISM AND SITE OF ABSORPTION:
Drugs absorbed by carrier-mediated transport processes and those absorbed through a window are poor candidates for controlled release systems e.g. Several B vitamins.
7.BIOPHARMACEUTIC ASPECTS OF ROUTE OF DRUG ADMINISTRATION:
Oral and parenteral routes are the most popular folled by transdermal application.

INTRAMASCULAR/SUBCUTANEOUS ROUTE.
This route is suitable when the duration of action is to be prolonged from 24 hours to 12 months. Only small amount of drug, about 2ml or 2 gms, can he administrated by the route. Factor important in drug release by such as route are ;
1.Solubility of drug in the surrounding tissues,
2.Molecular weight.
3.Partition coefficient,
4.pKa of the drug and
5.Contact surface between the drug and surrounding tissues.

4. PHARMACOKINETIC CHARATERISTICS OF THE DRUG:
A detailed knowledge of the ADME characteristics of a drug is essential in the design of a controlled release product. An optimum range of a given pharmacokinetics parameter of a drug is necessary beyond which controlled delivery is difficult or impossible.
1. ABSORPTION RATE:
For a drug to be administered as controlled release formulation, its absorption must be efficient since the desired rate limiting step of drug release Kr i.e. Kr << Ka. A drug with slow absorption is a poorly candidate for such dosage forms since continuous release will result in a pool of unabsorbed drug e.g. iron. Aqueous soluble but poorly absorbed potent drug like decamethonium are also unsuitable candidates since a slight variation in the absorption may precipitate potential toxicity.
2.ELIMINATION HALF-LIFE:
Smaller the t1/2 larger the amount of drug to be incorporated in the controlled release dosage form, For drugs with t1/2 less than 2 hour, a very large dose may be required to maintain the high release rate. Drugs with half' life in the range 2 to 4 hours make good candidates for such a system e.g. amlodipine. For some drugs e.g. MAO inhibitor, the duration of action is longer than that predicted by their half-lives. A candidate drug must have t1/2 that can be correlated with its pharmacological response .In terms of MRT , a drug administered as controlled release dosage form should have MRT significantly longer than that from conventional dosage form.
3.RATE OF METABOLISM:
A drug which is extensively metabolized is suitable for controlled release system as long as the rate of metabolism is not too rapid. The extend of metabolism should be identical and predictable when the drug is administered by different routes .A drug capable of inducing or inhibiting metabolism is a poor candidate for such a product since steady state blood levels would be difficult to maintain
4.DOSAGE FORM INDEX (di):
It is defined as the ratio of Css.max to Css.min. Since the goal of controlled release formulation is to improved therapy by reducing the dosage form index while maintaining the plasma drug levels within the therapeutic window, ideally its value should as close to one as possible.

5. PHARMACODYNAMIC CHARACTERISTICS OF THE DRUG:
1. THERAPEUTIC RANGE:
A candidate drug for controlled delivery system should have a therapeutic rage wide enough such that variations in the rate do not result in a concentration beyond this level.

2. THERAPEUTIC INDEX (TL):
The release rate of a drug with narrow therapeutic index should be such that plasma concentration attained is with in the therapeutically sale and effective range. This is necessary because such drug s have toxic concentration nearer to their therapeutic range. Precise control of release rate of a potent drug with narrow margin of safety is difficult. A drug with short half-life and narrow therapeutic index should he administered more frequently than twice day .one must also consider the activity of drug metabolites since controlled delivery system controls only the release of parent drug but not its metabolism.
3. PLASMA CONCENTRATION-RESPONSE RELATIONSHIP:
Drug such as reserpine whose pharmacological activity is independent of its concentration are poor candidates poor controlled system.
6. BIOCOMPATIBILITY OF POLYMERIC MATERIALS
Sustained/controlled drug delivery systems are different from conventional drug dosage forms in that they reside at a body location for an extended period of time. With the ever-increasing, emphasis on polymers in parenteral drug delivery the issue of biocompatibility of these materials is becoming important. In general, biocompatibility of a given polymeric material with tissue is described in terms of
Acute local inflammatory responses
Chronic local inflammatory responses
TISSUE COMPATIBILITY
Tissue compatibility of five different polymeric materials in the rabbit cornea, they found that poly (hydroxyethyl methacrylat4) and alcohol-washed ethylene vinyl acetate copolymer were non-inflammatory, whereas polyacrylamide and poly (vinyl pyrrolidone) produced significant inflammation.
Polybutylcyanoacrylate, polymerized gelatin, and polylactic acid caused joint inflammation. These investigators recommended that polymerized albumin was the most acceptable polymer to use intraarticularly to sustain drug release.
Inflammatory responses, the biocompatibility of implants can be measured in terms of
ØSensitivity reaction and
ØInfections
The events occurring at the tissue/implant interface include an initial adhesion of macrophages, followed by phagocytes of wound debris and erosion, invasion, and phagocytes of the polymer by macrophages and giant cells.
Macrophages were in close contact with the implant surface within 24 hr post implantation. Thereafter, fibroblasts and connective tissue proliferated and encapsulated the implant. It is suggested that the presence of macrophages is required for activation of collagen synthesis by fibroblasts.
Macrophages b4havior affected by the shape and surface of the implant in that smooth, well-contoured implants with no acute angle have superior tissue compatibility. furthermore, the composition and degree of ionization of the polymer affect the amount of thrombus formed on the surface of implants.
In intravascular administration, thrombus formation can substantially limit the duration of therapy that can be achieved. Local Vascular constriction and thrombus formation can cause venous static and leas to drug being infused into essentially
nonperfused veins, which often results in venous phlebitis that is erroneously attributed to infusion solution components.
Should not be used as the only test to screen polymers, the mean apparent volume of fibroblast cells counted around the sub dermal implant was dependent on the initial surface energy and cleanliness of the implants. A high-energy surface has greatest cellular adhesion.
One potential method of improving the compatibility of polymers in the blood is to impregnate these polymers with heparin. The polymeric materials that are combined with heparin can be divided into two basic categories:
Those that release heparin at controlled manner at the blood/polymer interface by an ion exchange or simple diffusion mechanism and those that immobilize heparin at the surface.
The properties of surface which control its interaction with blood are complex and difficult to define. The minimum interfacial, free-energy hypothesis and the optimum polar/a polar ratio hypothesis have been postulated to explain the observed blood-materials interactions. The hydrophilic/hydrophobic ratio hypothesis says that suitable proteins will be adsorbed and remain adherent if there is a proper balance between the polar and the surface characteristics. These two hypothesis and concluded platelet adhesion is not a good indicator of "hemocompatibility".
After finding a polymer that is biocompatible, it is necessary to determine whether this biopolymer can be used as a sustained/controlled drug delivery system. Heller et al., for instance, found that water-soluble macromolecules can be entangled in a bioerodible hydrogels successfully to provide a reasonably linear macromolecule release rate from the hydrogel. This release rate is controlled by erosion and can be manipulated by simple structural variations of the hydrogel.

7. CONTROLLED RELEASE PARENTERAL DOSAGE FORMS:
A. AQUEOUS SOLUTION:
1. HIGH VISCOSITY PRODUCTS
Increasing viscosity of the vehicle, the diffusion coefficient of the drug will be reduced, thereby delayed in drug transport.
Viscosity agents:
1.Methycellulose
2.Sodium carboxymethyl cellulose and
3.PolyvinylPyrollidine.
EFFECTS OF VISCOSITY
Increase the viscosity of the medium not only decrease the molecular diffusion but also localize the injected volume thus the absorptive area is reduced and the rate drug transfer is better controlled. Incorporating gelling agents like alluminium monostearate into oil solutions.
Diffusion of low molecular weight drugs
The actual viscosity is close to that of water, thus offering little diffusion resistance.

2. COMPLEX FORMATION
The role of plasma protein and tissue binding in prolonging drug action is well known. Forming a dissociable complex of a drug with such macromolecule as methycellulose, sodium carboxyl Methycellulose and polyvinyl pyrollidone for intramuscular administration.
Constant fraction of drug is complexed and that only free drug is absorbed, the absorption rate dcldt may be expressed as
                             d [c]/dt = - k f [c]
                                        where, k = is the absorption rate constant
                                                   f = fraction of drug that is the free
                                                   [c] = Is the total concentration of drug at the absorption Site.
                              F = l/ (1+ Ka [m]) (2)
In which Ka is very much large than 1.
                                F = l /Ka [M] (3)
Various degree of control can be exercised by selecting the appropriate type and concentration of macromolecule since such each drug macromolecule pair has a characteristic association constant and since the free drug concentration is inversely proportional to macromolecule concentration.
Complex between drug molecule and macromolecules, complexes can also be formed between drug molecules and other small molecule such as caffeine. Contrast to complexes with macromolecules, complexes with small molecules can be absorbed. 
This phenomenon from the standpoint of alteration of physiochemical properties of the dug molecule upon complexation, the effect of the complexing agent on the barrier, and the stability constant of molecular complex.
ØDISADVANTAGE:
The small association constant that usually exist between small molecules. Complex formed between large drug molecules, such as peptide hormones and small complexing agent such as tannic acid fall into the same category.
1.Protamine zinc insulin
2.ACTH zinc tannate
3.Cynocobalamin zinc tannate
B. OIL SOLUTION:
It less elegent mechanism to achive parenteral controlled release is through the use of oil solutions. Drug release is controlled by partitioning of drug out of the oil into the surrounding aqueous medium. Dynamic equilibrium between drug in the oil phase and that in the aqueous phase with characteristic constant, the apparent partition co-efficient K.
             K = drug concentration in oil /drug concentration in water
             K = [Do] [Dw](I )

Where the drug concentration in water refers. To both ionized and unionized species of the drug.
The volume of the oil phase Vo and that of aqueous phase Vw that total amount of drug Dt in the system at any time can be represented by
           Dt = [Dw] [K Vo +Vw](2)
The fractional amount of the drug
           F =1 (Kα+1)
            Where, a = Vo/Vw(3)
Since absorption is driven by concentration, not amount and expression for the fractional concentration of drug that is in the aqueous phase f
             f = (1 +a)/(l + Kα)(4) 
There limiting cases,
Case- I           For α < < 1, one obtains,f  =  1 / (1 + Kα)
Case -2For α > > 1 one obtains,f  =  α / (f + Kα)
Case -3provided K is sufficient large obtains from case -2  f'=l/K

1.The fraction of drug that is available for absorption is controlled by the partition co-efficient and the ratio of the volume of two phase' a.
2.That is remain constant as long as a is constant. Vw is constant since it is
physiological parameter. So that the value of α is controlled solely by the volume of solution injected.
Drug absorption occurs via the aqueous phase an expression describing the absorption rate   {d [c] / dt} similar to that for the complex formation.
                             D [c] /dt = - Ka f' [c]
Ka f ' can be obtain from this relationship. Usually an estimate of Ka is available so, that f can be determined
Given value of α, K can be estimated from the rearranged from eq.

                            K =[(I -f')/Vo] (f'/Vw)+1/f 

LIMITATIONS:
Limitation of this method in evaluating K are immediately obvious The volume of interstitial fluid at the injection site is till defined Oil can be absorbed so, that Vo is continuosly changing with time.
IMPORTANTS OF " K "
K which is function of the drug involved and the oil selected.
APPROACHES FOR SELECTION;
The "oily solution" approach is limited to those drugs, which are appreciably oil soluble and have the optimum portion co-efficient.

C. SUSPENSION
DEFINITION
Parenteral suspension are dispersed, heterogeneous systems containing insoluble drug particle which, when resuspended in either aqueous or vegetable oil vehicles.
They should be sterile, pyrogen free, stable, resuspendable, syringable, injectable, isotonic & non-irritating.
Because of above requirements injectable suspensions are one of the most difficult dosage forms to develop in term of their stability, manufacture & usage.
The parenteral suspension may be formulated as already to use injection or require a reconstitution step prior to use.
They are usually administered by either subcutaneous (s.c.) or intramuscular
Never suspension delivery systems containing drug in microparticulate or
nanoparticfe can be injected by intravenously or intraarterially.
These suspensions usually contain between 0.5% and 5.0% solid & should have particle size less than 5 micrometer for I.M. or S.C. administration.
Certain antibiotic preparation (For example procaine Penicillin G) may contain up to 30 % solids.


Parenteral suspensions are developed due to following point.
The drugs, which are insoluble to be formulated as a solution.
For the drug which are more stable as suspended solid than in solution.
There is need to retard or control the release of drug from suspension.
The main advantages of preparation of parenteral suspension are……
It is better for the therapeutic use of drugs that are insoluble in eonventionalsolvents.
In this dosage form there is increased resistance to hydrolysis & oxidation as drug is present in the solid form.
Formulation of controlled release drug id this dosage fonn.
There is elimination of hepatic first pass effect.

DISADVANTAGES:
Difficulty in formulation:
Parenteral suspension also limit the formulator in what ingredients are parenterally acceptable as suspending agent, viscosity induce, wetting agent, stabilizers and preservative.
Difficulty in manufacturing special facilities a required to maintain aseptic condition for manufacturing processes such as Crystallization
oParticle size reduction
oWetting
oSterilization

ØThe stabilization of suspensions for the period between manufacture &use present a number of problems .e. g. solid gradually settle &may cake, causing difficulty in redisdersion prior to use. l.)ue to above reason it is discomfort to use.
ØMaintenance of physical stability is very difficult in this dosage form. 
ØThere may be chances of non-uniformity of dose at time of administration.
Example of Parenteral Suspension[15]

Table 1.Sustained Release Medroxyprogesterone Aqueous Suspension

IngredientAmount (mg.)Type
Medroxyprogesterone
acetate
100.00Active ingredient
Polyethylen glycol 335027.6Suspending vehicle
Polysorbate 801.84Surfactant
Sodium chloride888.30Tonicity agent
Methyl paraben1.75Preservative
Propyl paraben0.194Preservative
Water for injectionq.s.Vehicle

Table 2.Some marketed parenteral suspension prod ucts.I5
DrugBrand nameManufacturer
AurothioglucosesolganlSchering
I etamethasone phosphatesodiumCelesturSchering
Penicillin G procaineBicillin C-RWyeth
Methylprcdnisoine acetateDepo- MedrolUpjohn
Some of the official preparations are;
a.Sterile ampicilling suspension USN ' 95 dispense as powder which is to be
         reconstituted at time of administration.
b.Sterile Aurothioglucose suspension USP 95 -vegetable oil suspension.
c.Tetanus toxoid adsorbed USP '95 - Aq. Suspension.
d.Betan ethasone apetate suspension USP 95 -Aq. Suspension.
e.Insulin Zinc suspension USP 95 Aq. suspension.
f.Procaine penicilling suspension IP' 96.

INSULIN SUSPENSION:
Extended- acting insulin preparation are microcrystalline suspension that
provide their protracted effect by slow dissolution of the crystals and gradual release of insulin into the blood stream -There are several approaches to formulating extende acting insulin preparation.
For example;
Ultralente human insulin UHI is insulin suspension composed predominately
of small rhombohedral crystals & characterized by on intermediate to long time action profile Ultralente is one of a series of insulin zinc suspensions that where developed by halls moller colleagues who determine that the addition of zinc ions in preparations that had neutral pH & no zinc binding ions (i.e. no phosphate or citrate) lead insulin formulations with protected effects.
This series of zinc insulin suspension formulation include Ultralente (crystalline insulin particles) semilente (amorphous insulin particle & lentea mixture
of amorphous &crystalline insulin particles)
A second approach to protected insulin preparation is to be depress insulinsolubility by adding basic peptides.
This approach is exemplified by the product neutral protamine hagedron insulin (NPH). NPH is an intermediate acting formula action prepared by co - crystallization of insulin with the basic peptide protamine. Recently inventing the native sequence of the B chain Prob28 Lysb29in the C terminal of human insulin produces Lys b28 Lysb29 in the human insulin
In the presence of both zinc ions & phenolic ligands lyspro can be assembled in weakly associated hexamer without impacting its pharmacological properties. 


INSULIN MICRO SPHERE SUSPENSION:
Polyphosphazene based micro spheres for insulin delivery was prepared by following three different procedures.
1.Suspension -solvent evaporation.
2.Double emulsion solvent evaporation.
3.Suspension/ double emulsion solvent evaporation.
Method A&C allowed for higher protein loading than procedure B scanning election microscopic showed that all preparation procedures active micro particles with spherical shape porous surface and internal honeycomb structure. In all cases insulin was released in vitro by a bimodal behavior that release during the lirst 2 hours followed by show release.
However both the physical properties and the in vitro release profiles were found to depend upon the preparation condition subcutaneous administration to diabetic mice of microspheres obtained with methods A and C rapidly reduced the glucose levels of about 80 % but most of activity was lost in 100 hours. But preparations B induced remarkable decrease in glucose level and the actively was maintained through 1000 hr.
PARENTERAL SUSPENSION AS DEPOT FORINULATION:
Parenteral administration of aqueous or oleaginous suspension into suhcutanuceous or muscular tissue results in depot formulation at the site.
The depot acts as a drug reservoir which releases the drug molecules continuously at a rate determine to a large extent by the characteristics of the formulation leading to the sustained absorption of drug molecules from the
formulation.
DISSOLUTION CONTROLLED DEPOT FORMULATION:
In this type of formulation the rate of drug adsorption controlled by slow dissolution of drug particle in the formulation or in the tissue fluid.


Rate of dissolution (Q/t) under sink condition defined by,

                 (Q/t) d =Sa Ds Cs
                                     Sd
Where,
Sa = surface area of drug particles in contact
With the medium.
Ds = diffusion co- efficient it drug
Cs = saturation solubility of drug
Sd = Thickness of hydrodynamic diffusion
        layer surroundings particle.

There are two approaches that can be utilized to control the dissolution of solid drug to prolong absorption.
1.FORMATION OF SALT COMPLEX WITH LOW AQUEOUS SOLUBILITY
In this method aqueous soluble basic or acidic drug can he rendered depot effective by transformation into salts with extremely low aqueous solubility e.g. aqueous suspension of
ØPenicillin G procaine
ØPenicillin G benzathine
ØPenicillin G benzathine & penicillin procaine combination.

2.SUSPENSION OF MICRO CRYSTALS.
Large crystals are known to dissolve more slowly than small crystals. This is known as the macro crystals principle & can be applied to control the rate of drug dissolution. E.g. are aqueous suspension of testosterone isobutyrate for intramuscular administration.
The major drawback of these two types of method is that the released of drug molecules not of zero - under kinetics as expected from theoretical model. 
ØAdsorption type depot preparation:
This type of depot preparation is produced by binding of drug molecules to adsorbents in this case only unbound, free species of the drug is available for absorption.
This type of depot preparation id exemplified by vaccine preparation in which the antigens are bound to highly dispersed aluminum hydroxide (alcohols) gel.
ØEncapsulation type depot preparation:
This type of preparation is formed by encapsulating drug solids with in a diffusion barriers or dispersing drug particles in diffusion matrix.
Release of the drug molecules is controlled by diffusion barrier and the rate of biodegradation of microcapsules.
e.g. Nitroxone pamoate releasing biodegradable microcapsules.
ØEsterification type depot preparation;
This type of depot preparation is formed by synthesizing the bioerodible esters of a drug and then formulating it in an injectables formulation, which forms a drug reservoir at the site of injection.
ØTestosterone cypionate
ØFluphenazine enathate

DEPOT -PENICILLIN AQUEOUS SUSPENSION:
Penicillin in the form of aqueous soluble sodium or potassium salt rapidly absorbed from subcutaneous & intramuscular.
Due to rapid absorption high peak level of penicillin was achieved. Then its concentration is decline rapidly in mater of few hours due to the rapid urinary excretion of penicillin.
So numbers of pharmaceuticals techniques were utilize to extended the therapeutic activity of penicillin by preparing long acting formulation of penicillin.
So depo-penicillin aqueous suspensions are developed after development of depo-penicillin oleaginous suspension.
It is discovered that the therapeutic serum concentration of penicillin can also be substantially prolonged by formulating penicillin G procaine in an aqueous thixotropic suspension.
It was accomplished by maintaining a high solid /vehicle ratio (40-70% w/v of milled and microniced penicillin G procaine particles).
Its prolonged action is due to that these thixotropic suspension tend to form compact & concessive depots at the site of intramuscular injection leading to slow release of penicillin G procaine & in part to the low aqueous solubility of the procaine salt of penicillin G which renders intra muscular absorption of penicillin under the control of dissolution of penicillin G procaine in the tissue fluid.
ØFELBAMATE (FBM) INJECTION MICROSPHERE SUSPENSION[20]
Felbamate is novel ant epileptic drug and neuroprotectant. It has very low soluhility in water and most organic solvents because of strong intermolecular hydrogen bonds. FBM is encapsulated by the carrier 3,6- bis (N-fumaryl-N (n-batyl) a nino 2-5 diketopiperazine (FDKP) and parenteral solvent system.
Lyophilized FBM/FDKP microspheres were suspended in 0.9% saline containing 1% w/v methylcellulose to yield concentration of 4 mg FBM/ml. And PH adjusted 1 to 6.2. This suspension was injected in the mice in the requisite 0.01 ml/g body weight for all tests based on maximal electroshock (mes) 60 hz OF Ac current was delivered by corneal electrodes for 0.2 sec.
FBM suspension significantly protected mice from MES following its administration. It showed time & dose dependent anticonvulsant effect against MES induced seizers.

D. EMULSIONS:
Besides use in topical drug delivery, emulsions been used as drug vehicle both orally and parenterally
While not matching topical emulsions more prodrugs has been made with parenteral than with oral emulsion.
1. OIL-IN-WATER AND WATER-IN-OIL EMULSIONS:
The elevation and prolongation of antitoxin levels obtained by oily vehicles before injection using emulsified influenza.
MECHANISM OF ACTION;
One mechanism by which the adjuvant action is brought about is the slow continuous release of antigen from the emulsion.
Rate of release is treated by
                   Rate =4p(ao22 D⌂ct/d)1/2DAc 
      Where, a0 is the initial radius of the droplet 
                  D is the diffusion co-efficient 
                  d is the density of the solute
                  ⌂c is the difference in concentration between the surface ofthe droplet and bulk  phase.
The growing interest in using water-in-oil and oil-in-water emulsions as vehicles for parenteral drug delivery id the development of multiple emulsions for controlled drug release.

CONTROLLED PARAMETERS;
ØPrimary water-in-oil emulsion
Internal phase volume
Concentration of the emulsifier
Osmolarity of dispersed phase

ØMultiple emulsions
Formulation
Stability
Drug release
2. MAGNETIC EMULSIONS
The emulsion described is a magnetically responsive oil-in-water type emulsion with capacity to localize the chemotherapeutic agent.
The magnetic emulsions consist of ethyl-oleate-based magnetic fluid as dispersed phase and casein solution as continuous phase.
The magnetic emulsion had high retention by magnetic field in vitro and aver intravenous injection in the rate.
The magnetic emulsions was localized at the lungs by application of an electromagnet one the chest.
E. LIPOSOMES:[6]
LIPOSOMES IN PARENTERAL DRUG DELIVERY
ØTo avoid quick metabolism.
ØE.g. Chloroquine, superoxide, dismutase etc.
ØTo protect patient from side effect.
ØE.g. Doxorubicin on heart muscle.
ØTo reduce hemolytic effect and irritation by intradermal Subcutaneous and lM injection.
ØThe most advanced application of liposome based therapy is in the treatment of systemic fungal infections, especially with amphotericin B.
Øl,iposomes are also under investigation for treatment of neoplastic disorders.
ØE.g.: encapsulation of known antineoplastic agents such as doxorubicin and methotrexate,

ØDelivery of immune modulators such as N-acetylmuramyl-L-alanine-D-isogl utamine,
ØEncapsulation of new chemical entities that are synthesized with lipophilic segments tailored for insertion into lipid bilayers.
Modulation of Drug release rate
Boman et. Al. Showed that the therapeutic activity of vincristine encapsulated in GM 1- containing liposomes could be significantly boosted by improving the drug retention property of liposome leading to slow release GM I: Monoasioganglioside
LIPOSOME STRUCTURE
ØB layered structure of phospholipids and cholesterol
ØCapable of entrapping both water sol. And lipid soluble drugs
ØCan alter biodistribution, protect drug and body from each other
ØSpecial liposomes usable for target delivery

DEMERITS OF INJECTABLE LIPOSOME
ØRES- Mediated Clearance of liposomes
ØCritical in determining liposome half life
ØSite of liposome clearance-Liver & spleen
ØPhysiologic role of Macrophages
ØHepato-Splenic uptake of liposomes.
ØInverse correlation of blood & RES levels of Liposomcs 
Mechanism of liposome recognition by macrophages
 Phagocytosis by the Kupfercells mediated by
A.Opsonins (Promotes Phagocytosis)
1.Proteineceous components
2.Immunoglobulins & compliment systems
3.Fibrolectins, C-Reaction proteins & Tuftsin
4.Organ specific opsonins- Liver & Spleen specific


B.Dis opsonin (Supress Phagocytosis) Secretary Ig A
Strategies to impede opsonizationand pliagocytosis by niicrobes
1.By virtue of surface slime
2.Suitable orientation
3.Making bound opsonin inaccessible
4.Nature of binding (Covalent Vs Non covalent)
5.Promoting opsonin degradation
6.Mediation of factor like factor `h' to suppress opsonization
7.Capsule formation to avoid recognition
Approaches to avoid RES for long circulation
1.Physico-Chemical: Surface coation to avoid recognition; Polymer coating (PEG Coating)
2.Legend incorporation e.g.; Desialylated futuin, glycoproteins 
3.Oil based formulation (W/O) emulsion
4.Use of antibody / Antibody fragments specific to plasma membrane
5.Extra-vasation to interstitial space
Structural features of long circulating polymers
1.Structures responsible for strong in vivo interaction are Carbohydrates (galactose, mannose and fructose residues), proteins (antigens, lectins), polymers (Very high mol. Wt., hydrophobic, negatively charged)
2.Hydrophilic polymers like PEG are the suitable candidates for steric stabilization
Injectable stealth liposome
SL Doxorubicin for tumor targeting Conventional Liposomal (CL) Dox injection gets cleared up quickly by RES, while, SI Dox Inj. By virtue of reduced up take by RES and accumulated in rumor cells.
Plasma Pharrnacokinetics of S-Dox
1.Evaluation in several species and in human showed a half-life of 40-60 h following iv admn.
2.This value indicates the retention or at least 10% injected dose in plasma even after one week
3.The initial plasma levels and AUC showed linearly dose dependent kinetics
APPLICATION OF LIPOSOMES
Liposomes in the treatment of Leukemia
1.In the case of iv injected leukemia model, in which no extravasation step may be needed for liposome targeting to tumor cells
2.In the study using GM-I LS containing the drug Ara-C and the rapidly growing L1210 leukemia model, Allen et. AI reported that the faster drug leakage rate was directly correlated with efficacy
F.NIOSOMES:
1.Differs from liposomes in having surfactant in place of phospholipid 
2.Size in smaller than MLVs
3.Easy to prepare and stable. 
4.Niosomes also interact with cell surface
5.Acceptability mainly depends on the surfactant selection (For toxicity) 
Application of SLN Pareuteral
1.Ranges from intra articular to intra-venous.
2.Both stelth and non-stelth SLN are used I.V.
3.Prolonged plasma levels achieved with paclitaxal in-vivo
4.Increased uptake observed in brain, but low uptake in liver and spleen.
5.Potential application to treat arthritis- corticoid SLN injected to joints
          would phagocytosis and release drug inside reducing hyperactivity 
Applications of SLN New adjuvant for vaccine
1.To enhance the immune response and safety in
2.Comparison the traditional adjuvant like aluminum hydroxide
3.Long lasting exposure to immune system due to slow degradation (Still reducible using stealth SLN)
4.Potentiality is being worked out as effective vaccine delivery agent

G. MICRO-EMULSIONS:
1.Transparent, thermo-dynamically stable emulsion suitable as injectable even as IV. 
2.Accommodates fat soluble drugs: Cyclosporine
3.Avoids irritation and pain: E.g.: Propofol infusion
4.Reduces toxicity: Paclitaxol
Micro-emulsion of cyclosporine as IV infusion
1.Cyclosporin A is widely used as an immunosuppressant e.g., in the prevention and treatment of gram rejection following organ transplant and of graft versus host disease, e.g., following bone marrow transplant.
2. At higher dosages, however, it may affect kidney and liver function. 
3.Moreover, cyclosporin A is difficult to formulate, as it is essentially
insoluble in most pharmaceutically acceptable solvents.
4.Aqueous pharmaceutical systems, and its oral bioavailability in most formulations are variable.
Clonixic acid microemulsion injection
1.Clonixic acid is currently marketed as a salt form because of its poor water-solubility.
2.However, the commercial dosage form causes severe pain after intramuscular or intravenous injection.
3.To improve the solubility of elonixic acid and to reduce pain on injection, clonixic acid was incorporated into oil-in-water microemulsions prepared from pre-microemulsion concentrate composed of varying ratios of oil and surfactant mixture.
4.The pre-microemulsion concentrate composed of 5:12:18 weight ratio of castor oil: Tween 20: Tween 85, elonixic acid could be incorporated at 3.2 mg ml in the microemulsion with a droplet size of less than 120 nm
Diazepam microemulsion
1.An ethyl laurate- based microemulsion system with Tween 80 as surfactant, propylene glycol and ethanol as co solvents was developed for intranasal delivery of diazepam.
2.Diazepam, 3 practically water-insoluble drugs, displayed a high solubility of 41 mg/mI in a microemulsion consisting of 15% ethyl laurate, 15% H20, and 70% (W/W) surfactant/co surfactant (Tween 80: Propylene glycol: ethanol at 1:1:1 weight ratio).
3.Nasal absorption of diazepam from this microemulsion was found to be fairly rapid.
4.At 2-mg/kg doses, the maximum drug plasma concentration was arrived within 2-3 min, and the bioavailability (0-2 h) after nasal spray compared with intravenous injection was about 50.
H. M1CROSPHERES
1.Microcapsules
2.Micromatrices
1.Microcapsules
They are spherical particles containing drug concentration in the center core, which is eveloped by polymeric wall(rate controlled membrane)
2.Micromatrices
Micromatrices are solid, spherical solid particles containing dispersed drug molecules either in solution or in crystalline form.
They are part of homogenous monolithic drug release system. The monolithic microcapsules are some time called microspheres.
They are made up of polymeric, waxy or other protective materials, that is biodegradable synthetic polymer and modified natural products such as starches, gums, protein, fats and waxes. The natural polymers include Albumin and gelatin . Synthetic polymers include polylactic acid, polyglycolicacid and EC, polysteres, polycaprolactone, and polyacrylarrtide .MIS are small in size and therefore have large surface to volume ratios. At the lower and of their size range they have colloidal properties. The interfacial properties of MIS are extremely important, often dictating
their activity.
ADVANTAGES OF MICROSPHERES;
ØTaste and odor masking 
ØConversion of liquids to solids
ØProtection of drugs against environment
ØImproves the flow property of powders
ØHave controlled release
ØHave targeting property
ØAs microspheres are multiple unit product, ready distribution over a large
surface area
ØDelocalisation of the total dose in the GI tract
ØReduce side effects
ØThe drug release rate will be less dependent on gastric transit time
ØThe drug -loaded microspheres are more resistant to fracture, 
DISADVANTAGES OF MICROISPHERE:
ØBurst effect
ØInadequate shelf life of sensitive pharmaceuticals. 
ØNon reproducible
ØCostly
ØDifficult to scale up

MAGNETIC MICROSPHERES
MICROSPHERES FOR TARGETING DRUGS
It is tissue or cellular localization that increases the therapeutic index by at least half an order of magnitude_ Targeting causes drug level in liver, spleen, bone marrow, kidney and other major sites of toxicity.
Advantages:
ØCross microvascular barriers independent to Endothelial status.
ØProtect the drug, blood cells, and Endothelium during transit. 
ØDeliver up to 60% dose to target tissue.
ØDrug available in controlled fashion.
ØReduce concentration of free drug.
ØMinimize damage to normal tissue cells.
ØDecrease the dose
Disadvantages:
ØExpensive
ØIt require specialized microspheres and magnets
ØTreatment of multiple body regions require sequential targeting
ØIn long term deposition of magnetite (Fe304) 
Drug candidates:
ØDangerous drug and labile which causes toxicity when circulated in blood stream.
ØExpensive drug, and hardly 0.1% have action and 99.9% wasted in body 
ØIf drug have life threatening toxicity then MIS is alternative formulation 

PREPARATION OF MAGNETIC MICROSPHERES
It is made by preparing an aqueous mixture of water soluble drug OR
if lipophilic drug add water soluble adducting agent (γ-cyclodextrin), matrix
material (Albumin, carbohydrate and 10 nanometer Fe3O4 particle.

ØEmulsify the mixture in biodegradable oil (cotton seed oil) with surfactant
ØSonicate or shear to produce submicrons spheres (0.2-1.2µ)
ØStabilize the matrix by; heating or chemical cross linking
ØExtract the oil with volatile organic solvent (Hexane, Ether) 
ØLyophilizing the preparation to dryness.
          E.g. Albumin microspheres containing adriamycin
PULMONARY ASPERGILLOSIS is a life threatening condition
amphotericin-B is the treatment of choice, but it produces serious side effects-NEPHROTOXICITY.
Amphotericin-B in albumin-magnetite m/s prepared for targeting to Lung. Brain and R.E.organ.

INTERLEUKKIN-2 (IL-2) M/S
ØInerleukin-2 is glycoprotein. Interleukin-2 activates multiple cell types-T helper cells, Cytotoxic T - lymphocytes, Natural killer cells, Macrophases. 
ØIt is useful in Murine tumors and human melanomas and renal cell carcinomas. But IL-2 cleared from the plasma in 5 min.
ØHigh dose produce severe side effects - Anemia, Fever, Hypertension, Jaundice.
ØDue to above reason Scientist has prepared controlled release MIS form of IL-2 that is adaptable for magnetic targeting to tumor

I. IMPLANT
INTRODUCTION
Lafarge first introduced the concept of implantable therapeutic system for long term, continuous drug administration in 1861 with the development of a subcutaneous implantable drug pellet. The technique was used to administered crystalline hormone in form of solids steroids pellets. Implantable system is capable of continuous secretion ion hormones from active gland.
Implant represent novel approach in the use of solid dosage forms as parentral product. Implants are insert under the skin by cutting and stitching it alter insertion of' the sterile tablet which is cylindrical, rod and ovoid shaped and more than 8 mm in length. The sterile tablets consisting of the highly purified drug, compressed without excipients.if, intended for subcutaneous implantation in the body. Implantations tablet have been lately replaced by other dosage form such as diffusion control silicon tube, tilled with drug or biodegradable polymer.
Magnetically controlled capsules are imaginative form of' implant; such capsules are implanted in upper thigh at a depth 0.5 cm. This type of capsules is 1.2 cm long and 0.6 cm in diameter and made by moulding polycarhonatcs and also suitable for presentation of contraceptive hormone.
The subcutaneous release rate of steroid form of pellets implantation was found to be slowed down and hormonal activities was prolonged by dispersing the steroid in cholesterol matrix during pellets fabrication. The clinical use of implantable pellet for human health care has declined in recent year. The fact has triggered the research and development of novel, controllable and impalntable therapeutics system to replace pellet for long term, continous subcutaneous administration of drug.
In this case few of the traditional implant is use including desoxycorticosterone acetate,estradiol and testosterone. Some of the recently approved implantation product includes biodegradable and non-biodegradable polymer. Several impalntable forms for a prolonged drug delivery are in commercial use.

ADVANTAGES
ØImproved control of drug level at the specific site of action.
ØPreservation of the medication that are rapidly destroyed but the body.
ØImmediate removal of implants is possible in contrast to conventional drug delivery system in case of extreme allergies or side effect due to the dnig already administered.
ØLess fluctuation in plasma drug level during therapy.
ØPossible reduction in therapy costs because patient care and the potentially lower drug dose required.
ØImproved special compliance.
ØAdministration of drugs with short biological half-life may be facilitated.
ØMinimal harmful side effect of systemic administration through local therapy.
DISADVANTAGES
ØToxicity or lack of biocompatibility of the material used for the implant.
ØHarmful byproduct may be formed from the system, particularly for biodegradable types.
ØDose dumping and variable imprecise drug release may occur if not formulated properly.
ØPain and discomfort may be caused by the presence of implant.
ØThese system can be more expensive than the conventional dosage form.
ØMost impalntable controlled drug delivery system requires minor surgery to
implant and to remove from the administered site, if it is not biodegradable
type.
ØPossibility of the tissue and the body reaction to implant.
ØDanger of toxic effect in case of leakage or burst release of drug.

MECHANISM OF DRUG RELEASED FROM IMPLANTABLE THERAPEUTIC SYSTEM:
A.CONTROLLED DRUG RELEASED BY DIFFUTION;
ØMembrane permeation - controlled drug delivery.
ØMatrix diffusion -- controlled drug delivery.
ØMicro - reservoir dissolution controlled drug delivery.
B.CONTROLLED DRUG RELEASE BY ACTIVATION: 
ØOsmotic pressure activated drug delivery.
ØMagnetism - activated drug delivery.
ØUltrasound activated drug delivery.
ØVapour pressure activated drug delivery.
ØHydrolysis activated drug delivery
POLYMERDRUG
l3- l3enzyl-l,- aspartateProgesterone
Hydroxyalkyl-L-glutam ineTestosterone
NylonNorethindrone
GelatinSteroid

ØPoly (glycolic acid) was synthesis
ØPolymer used to prepare biodigrable structure
ØThe acceptance of poly (ester) as suture has made them attractive for drug delivery application.
PREPARATION OF IMPLANT
Many polymers can be used to prepare rate-limiting membrane for controlled release; few are employed for implantation purpose.
The polymer should be biocompatible and sterilizable implantable polymers can be classified into bio-degradable and non-biodegradable polymers. Non-polymeric material such as fatty substance like cholesterol and metal like titanium, stainless steel may be used in implantation device. Non-biodegradable polymers like silicon polymers, cellulose acetate, and polyethylene vinyl acetate are used.

SILICONE POLYMERS:
Silicone polymers are widely used in controlled drug delivery. They provide advantages like biocompatibility resistance to heat sterilization, high permeability for lipophilic drugs. Therapeutic products prepared with silicon elastomers includes Norplant, a subdermal implant to deliver levonorgestrel for contraception, a dual-release vaginal ring.

POLYETHYLENE VINYL ACETATE:
Ethylene vinyl acetate copolymer is used in the Alza ocular insert and in IUD reservoir type system (Progestaserb).
CELLULOSE ACETATE:
Cellulose derivatives are used in controlled drug delivery devices. Application to implants is restricted to cellulose acetate. Cellulose acetate is formed by the acetylation of hydoxyl groups in glucose.
APPLICATIONS:
1.SOLID TUMOUR CHEMOTHERAPY USING IMPLANTABLE COLLAGEN POLY HYDROGEL CONTAINING
5 -FLUOROURACIL.
Implantable collagen poly (HEMA) containing the anticancer drug 5-fluororacil has been prepared fibro sarcoma in Wister rats. The tumor was developed by inoculation of a 10 % tumor -cell suspension in the anterior control, intratumoural injection of free 5- fluorouracil subcutaneous implantation containing drug in close proximity to the tumour. The hydrogel showed an improved antitumour activity over free 5 -fluorouracil as evidenced by the gross tumor weight and this was attributed to the controlled and slow release of 5- fluorouracil. The implantation of hydrogel could be a potential alternative to free 5- fluorouracil therapy in treatment of solid tumors such as librosacroma.

2. SYNCRO-MATE -B IMPLANT
It is fabricated by dissolving norgestomet crystals in an alcoholic solution of ethylene glycomethacrylate (Hydron S) and then polymerizing the drug-polymer mixer by the addition of a cross linking agent, such as ethylene dimethacrylate and an oxidizing catalyst to from a cylinder shaped insoluble hydron implant. This tiny subdermal implant is engineered to be inserted into release norgestomet at a rate of 504 mcg/cm2 up to 16 days for estrus control and synchronization of ovulation.

3. OCULAR DISEASE
Implantable system have been evaluated to provide prolonged ocular delivery.
Ocusert is the example of membrane controlled system containing pilocarpine base and alginic acid in a drug reservoir surrounded by a release rate controlling ethylene vinyl acetate membrane. It is desined to parmit the tear fluid to penetrate the macroporous membrane to dissolve and to carry out ppilocarpine at a constant rate of 20 to 40 mcg/hr for weekly management of glaucoma
 
Implantable devices evaluated for ocular cancer treatment include silicone rubber ballons containing an Antineoplastic agent, BCNU. The devices consists of two sheets of silicone rubber glued at the edges with silicone adhesive to form a balloon like sac through which a silicone tube is inserted. BCNU solution is slowly released through the tube. Upon completion of delivery, the device is refilled.

4.CONTRACEPTION
Nor plant, a subdermal implant for long term delivery of the contraceptive agent, levonorgestrel has recently been approved dy FDA.The devices consist of six silicone membrane capsules, each containing 36 mg of levonorgestrel. The capsules are placed su bdermal ly on the inside of the upper arm or the forearm.
Other polymer based system under study for contraception include vaginal rings, composed of silicone rubber used for 3 to 6 months often with a removal period of I week monthly to allow for menstruation; the progestasert an ethylene vinyl acetate copolmer intrauterine drug releasing device which lasts for one year.

5.CANCER
Silicone rod implants used for delivery of levonorgestrone have been evaluated for delivery of testosterone propionate or cthinyl estradiol in-patient with prostate cancer. The implant consists of biodegrable microsphcres prepared from
polyactic -glycolic copoylmer containing 10 %leuprolide acetate treatment of prostate cancer. Zoladex provides release of goserelin acetate from a biodegradable implantable rod, for the treatment of prostate cancer.

J. INFUSION DEVICES:
These are also implantable devices but are versatile in the sense that they are intrinsically powered to release the medicament at a zero -order rate and the drug reservoir can be replenished from time to time. Depending upon the mechanism by which these implantable pumps are powered to release the contents, they are classified into following types;
1.Osmotic pressure activated drug delivery systems
2.Vapour pressure activated drug delivery systems
3.Battery powered drug delivery systems.

1. Osmotic pressure activated drug delivery systems
The phenomenon of osmosis is based on the fact that sub. Tend to move or diffuse from region of higher concentration to regions of lower concentration.
PROTOTYPE SYSTEM DEVELOPMENT:
The earliest application of osmotic pressure to drug delivery was by Rose and Nelson in 1955. The authors described two systems, one that delivered 0.02 ml/day for 100 days and one that delivered 0.5 ml/day for 4 days, both for use in pharmacologic research. A schematic diagram of their prototype device is shown in figure. The device consisted of a drug solution in a rigid glass ampule (D) with a delivery orifice an osmotic pressure unit made from an expandable latex bag (B) to contain an osmotic agent and a rigid circular holder (A) which houses a semi permeable membrane. The osmotic pressure unit was inserted into the glass ampule and the system was completed by addition of water sources housed in a separate rubber (I). In 1971, Stolzenberg received a U.S.patent for and osmotic system which was operationally similar to that of Rose and Nelson
 A
D B
 I
Fig:1 Schematic representation of the Rose Nelson osmotic pump.
A-membrane holder
B-Latex Bag
D-Rigid glass ampule and
I-Latex bag with water supply

Drug delivery from both the system was dependent on expansion of the osmotic pressure unit, due to the influx water, which resulted from the osmotic pressure difference between the unit and the environment. To achieve A zero order release rate, the differential osmotic and hydrostatic pressure must maintain a constant value. The internal hydrostatic pressure is a function of flexibility of osmotic pressure unit as well as the Theology of the drug solution and the dimension of the delivery orifice. We can assume that the hydrostatic pressure difference across the semipermiable membrane approaches a constant value one method for achieving a constant osmotic pressure difference is to maintain a saturated solution of the osmotically active agent in the osmotic pressure unit.
Two kinds of osmotic drug delivery system are marketed
1.Implantable osmotic pump.
2.Oral osmotic pum.
In operation, when the system is exposed to an aqueous environment as test medium, or subcutaneous space after implantation, water is drawn by the osmotically active agent through the semi permeable membrane, thereby collapsing the drug reservoir and expelling an equal volume of drug solution or suspension through the orifice in flow moderator. In this mode of operation, it is advantageous that controlled by the osmotic process regardless of its molecular weight or ionic structure.
Sodium chloride is a typical osmotic agent used in such systems. Membranes are usually constructed from cellulosic polymers. Pumps are available with a variety of delivery rates between 0.1 and 10 µl/hr for periods of 3 days to 4 weeks. Systems are marketed empty (Alzet osmotic pump), allowing formulation of choice of any concentration. The osmotic pump has been designed for oral, subcutaneous or rectal drug delivery and is especially well suited for preliminary screening of new drugs in assessing their pharmacokinetic and pharmacodynamic properties (Table I). Results from the studies are invaluable in the rational development of an optimized drug
delivery system.

ADVANTAGES:
1.Osmotic pump can be used as a useful experimental tool to determine important pharmacokinetic parameters of new drugs, which ultimately find use in the development of an optimized delivery system,
2.Osmotic systems deliver the drug at zero order release kinetic, so they are superior to older sustained release technologies in many instances because of better control over their in-vivo perfomance is possible.
3.Drug release from osmotic system is independent of variation in environment pH and hydrodynamic conditions.
4.It is possible to attain substantially higher release rates than with diffusion base drug delivery systems.
5.Osmotic systems are able to deliver very large volumes.
6.In osmotic system reformulation is not required for different drugs.
DIS ADVANTAGES:
1.Osmotic system can be much more expensive than conventional systems.
2.Quility control of osmotic systems is more complicated that most conventional tablets.
3.Implantation is required fir osmotic implants.
4.The drug which are unstable in solution, that may be inappropriate because the drug remains in solution form for extended periods before release.

MARKETED PRODUCTS:
PRODUCT NAMEACTIVE INGREDIENT
Dimetane
Brompheniramine maleate
Dimetapp
Phenylpropanolamine HCL
QuinidexQuinine sulphate
Nicobid
Nicotinic acid
Chlor trimetonChlorpheniramine maleate
TrilalonPerphenazine
Procardia XL
Nifedipine

2.Vapor pressure powered pump (infusaid)
This device on the principle that at a given temperature, a liquid in equilibrium with its vapour phase exerts a constant pressure that is independent of enclosing volume, the device is shown in figure
The disc shaped device consists of two chambers an infusate chambers containing the drug solution, which is separated by a freely movable flexible bellow from the chamber containing inexhaustible vaporizable fluid such as fluorocarbons. After implantation the volatile liquid vaporizes at the body temperature and creates a vapour pressure that compresses the bellows and expels the infusate through a series of flow regulators at a constant rate. Insulin for diabetics and morphine for terminally ill cancer patients have been successfully delivered by such a device.

3.Battery powered pumps
Two types of battery powered implantable programmable pumps used successfully to deliver insulin are peristaltic pumps and solenoid driven reciprocating pumps both with electronic controls. The system can be programmed to deliver drug at desired rate. Their design is such that the drug moves towards the exit and there is no backflow of the infusate.

8. REFERENCES
1.Josep R. Robinson and Vincent ILL-Lee, Controlled drug delivery fundamental   and application, Matcel Dekker Inc, New York, 1987; 29.
2.Remington,The science & practice of pharmacy, Lippineolt,Williams K_,Parenteral Preparation, ISE publication, Phelabelphia; 2000; 20(1): 804.
3.D.M Brahmankar & Sunil B.Jaiswal, A Textbook of Biopharmaceuitics & pharmacokinetics, Valibh Prakashan, 2002; 301: 360.
4.B.M.Mital, Textbook of Pharmaceutical Formulation, Vallabh Prakation, 1999; 276.
5.G.K. Jani, Textbook of Pharmaceutics-l, B.S. Shah Publications, 1997-1998; 2: 33.
6.N.K.Jain, Advances in controlled and Novel Drug Delivery System, C13S Publishers and Distributors, 2001; 190(1): 408-42.
7.Antal E.S., Disk C.F., WrightC.E., Welshman I.R., comparative bioavailability of two medroxy progesterone acetate suspensions, Int. .1. Pharma. Sci., 1989; 54: 33-39.
8.Alfred Martin, Physical Pharmacy, Fourth edition, BA, Waverly Pvt.Ltd. NewDelhi, 1997; 519-520.
9.Gilbert S. banker and Cristopher T. Rhodes, Morden Pharmaceutics Drug and Pharamaceutical science, Inc., New York, 1996; 72(3) : 638-596.
10.http:// www.Sciencemagg, orh/cgi/contentkill/297/5586/1538.
11.http://nanomat.Com/nanoint.htm., By Dcnna Renzo.
12.Akers, M.J., rites A.L. & Robinson, R.L. "Journal of parenteral science and technology", 1987; 41: 88.
13.Liberman. A., Martin, Rieger M. and Banker Gilbent's Pharmaceutical Dosage firms Dispersed systems vol-2 Marcel Dekker 1996; 285.
14.Avis Kenneta E, " Theory and Practice of Industrial Pharmacy", Varghese publishing Bombay, 1976; 3: 654.
15.Arky R., Physician's Desk Reference 48M ed, Medical Economics Data Production Company, Montavale N.J. 1994; 2417.
16.Nyamrk, M and frank, K.F. "Journal of Pharamceutical science" Sep. 1999; 88: 861.
17.Chien, Yiew. W., " Journal of parenteral science and technology" May/June 1981; 35: 106.
18.Harvey, se "Journal of Ph: ramceutical science" Feb. 1998; 87: 175.
19.Chien Y. W., Novel drug delivery system, 1982; 381.
20.Arky R., Physician's Desk Reference, Medical Production Company, Montavale N.J. 1994; 48: 2170.
21.James Swarbrick and James C. Boylen, Encylopedia of pharmaceutical technology, 3-5: 389.
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  • oral drug delivery systems
  • drug delivery systems
  • sustained release intravenous penicillins
  • oral administration of parenteral pharmaceutical form

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