Bio-degradable Parenteral Depot System: A Best Approach Of Controlled Release

Bharadwaj Sudhir

In recent years, considerable attention has been focused on the development of drug delivery system. There are number of reasons for the intense interest in new system.

·Recognition of the possibility of repatenting successful drugs by applying the concepts and techniques of controlled release drug delivery systems coupled with the increasing expense bringing new drug entities to market, has encouraged the development of new drug delivery system.

·New systems are needed to deliver the novel, genetically engineered pharmaceuticals, i.e. peptides and proteins to their site of action without incurring significant immunogenicity or biological inactivation.

·Treating enzyme deficient disease and cancer therapies can be improved by better targeting.

·Therapeutics efficacy and safety of drugs, administered by conventional methods, can be improved by more precise spatial and temporal placement within the body. Thereby reducing both size and number of doses.

Rationale of Controlled Drug Delivery:

The basic rationale for controlled drug delivery is to alter the pharmacokinetics and pharmacodynamics of pharmacologically active moieties by using novel drug delivery systems or by modifying the molecular structure and physiological parameter inherent in selected route of administration. It is desirable that the duration of drug action become more a designed property of a rate controlled dosage form and less or not at all, a property of the drug molecules inherent kinetic properties. Thus optimal design of controlled release systems requires a through understanding of pharmacokinetics and pharmacodynamics of drug.

As mentioned earlier, the primary objectives of controlled drug delivery are to ensure safety and to improve efficacy of drugs as well as patients compliance. This is achieved by better control of plasma drug levels and less frequent dosing. For conventional dosage forms, only the dose (D) and dosing interval (C) can vary and for each drug, there exists a therapeutic window of plasma concentration, below which, therapeutic effect is insufficient and above which undesirable or toxic side effects, are elicited.

In general, the dosing interval may be increased either by modifying the drug molecule to decrease the rate of elimination (Kcl) or by modifying the release rate of a dosage form to decrease the rate of absorption (Ka)

Both the approaches seek to decrease fluctuations in plasma level during multiple dosing, allowing the dosing interval to increase without either over dosing or under dosing. When attempts are made to extend the dosing interval by decreasing the rate of absorption, the formulator will be controlled with the physiological constraint of a finite residence time at the absorption site. For example an effective absorption time for orally administered drugs in about 9-12  hrs. If the rate of absorption decreases too much, some of the unabsorbed drug will pass in to the large intestine, where absorption, is slower and more variable and where bacterial degradation of the drug may occur. Thus drugs with half lives of 6 hrs or less and possessing therapeutic indices less than 3 must be given no less frequently than every 12 hrs (2) unless gastrointestinal transit time can be lengthened, once daily oral dosing may prove to be difficult to achieve for drugs with such extremely short half lives. For other routes of administration where residence time is less is a problem, dosing intervals can be lengthened to months or even years for example; implants containing contraceptives may be effective for a year or two. In summary only when the rate limiting step resides in the drug delivery system and not in physiological constraints, control over drug administration can be achieved.

Factors Influencing the Design and Performance of Controlled Release Product:

To, establish criteria for the design of controlled release products, a number of variables must be considered.

1.Drug properties

2.Routes and drug delivery

3.Target sites

4.Acute or chronic therapy

5.The disease

6.The patient

Parenteral Controlled Drug Delivery System:

The Parenteral administration route is the most effective and common form of delivery for active drug substances with metabolic bio-availabilities drug for which the bio-availability in limited by high first pass metabolism effect of other physicochemical limitation and for drugs with a narrow therapeutic index.

For this reason, whatever drug delivery technology that can reduce the total number of injection throughout the drug therapy period will be truly advantageous not only in terms of compliance, but also for potential to improve the quality of the therapy. Such reduction in frequency of drug dosing is achieved, in practice, by the use of specific formulation technologies that guarantee that the release of the active drug substance happens in a slow and predictable manner.

For several drugs, depending on the dose, it may be possible to reduce the injection frequency from daily to once or twice monthly or even less frequently. In addition to improving patient comfort, less frequent injection of drugs in the form of depot formulation smoothes out the plasma concentration time profiles by eliminating the peaks and valleys. Such smoothing out of the plasma profiles has the potential to not only boost the therapeutic benefit but also to reduce unwanted events and side effects.³

The development of new injectable drug delivery system has received considerable attention over the past few years^4-6. This interest has been sparked by the advantages this delivery system possess, which include ease of application, localized delivery for a site specific action.^7-8 prolonged delivery periods, decreased body drug dosage with concurrent reduction in possible undesirable side effect common to most forms of systemic delivery and improved patient compliance and comfort.

The release can either be continuous or pulsatile depending on the structure of the device and the polymer characteristics, continuous release profiles are suitable to generate on ‘infusion like’ plasma level time profile in the systemic circulation without the necessity of hospitalization.^9-10

Reason for development of PDS (Parenteral Depot System)

1. No surgical removal of depleted system is required as it is metabolized in non toxicological by product.

2. The drug release from this system can be controlled by following

·Diffusion of drug through the polymer

·Erosion of the polymer surface with concomitant release of physically entrapped drug.

·Cleavage of covalent bond between the polymer bulks or at the surface followed by diffusional drug loss.

·Diffusion controlled release at the physically entrapped drug with bio adsorption of the polymer until drug depletion.

Advantage and Disadvantage:¹¹

1.Advantage:

(a)Convenience

(b)Compliance Potential for controlled release

(c)Avoiding the peak (risk of toxicity) at troughs (risk of ineffectiveness of  conventional therapy)

(i)Reducing the dosing frequency.

(ii)Increasing patient compliance.

(d)Improved drug delivery

(e)Flexibility

2. Disadvantage:

(a)Invasive

(b)Danger of device failure

(c)Limited to potent drug

(d)Commercial disadvantage

Parenteral Depot System: ¹²

Depot: Long acting parenteral drug formulation are designed, ideally to provide slow constant, sustained, prolonged action.

Approaches used in Depot formulation:

1.Use of low aqueous solubility salt

2.Use of larges partical with crystalinity.

3.The suspension of the drug particle in vegetable oil and especially of gels with substances such as aluminum monasteries produces prolonged absorption rates.

Type of Depot:

1.In one type of depot formulation which is referred to as dissolution controlled’ the rate of drug absorption controlled by the slow dissolution of drug particles, with subsequent release to tissue fluid surrounding the bolus of product in tissue.

2.Many type of depot formulation are prepared in which one of the formulation prepared by binding of drug molecule to absorbents. Only the free portions in equilibrium with that which is bound, can be adsorbed. As drug is absorbed, a shift in equilibrium is established, and the drug is slowly released from the bound state to free state. e.g. binding of vaccines to aluminum hydroxide gel to provide a sustained release.

3.Encapsulation type: In this bio-absorbable or biodegradable macro-molecules such as gelatin, phospholipids and long chain fatty acids become a diffusion barrier and by the rate of biodegradation of the barrier macromolecules.

4.Esterification Type Depot Preparation: Esters of drug that are biodegradable are synthesized the esterifies drug is deposited in tissue at the site of injection to form a reservoir of drug. The rate of drug absorption is controlled by the partitioning of the drug ester from the reservoir to tissue which fluid and by the rats at which the drug ester regenerates the active drug molecule. Often these esters are dissolved or suspended in a vehicle, which further slow the release.

Polymeric Drug Delivery Systems  

Many classes of cross-linked polymer gels display phase transition characteristics i.e. abrupt change in swollen volume in response to small environmental changes like pH, light, temperature, intensity, electric field, ionic strength, and even specific stimuli like glucose concentration.  Drugs containing charged hydrogel networks have been recognized as useful matrices for delivering drugs because their volume, consequently, deliver drug solution in response to external pH variation.  Such hydrogels have been applied in glucose sensitive insulin releasing devices (Kost et al., 1985), an osmotic insulin pump (Siegel et al., 1992) and site specific delivery in the gastrointestinal tract (Dong et al., 1989).  Dong et al., (1990) studied the rheological behaviour of a poloxamer 20% thermoreversible get and showed that its behaviour was Newtonian below the transition temperature and became non-Newtonian above this temperature.¹³

The polymeric devices are generally classified into the following categories:

1. Diffusion controlled devices

·Monolithic devices

·Reservoir devices

2.Solvent controlled devices

·Osmotically controled devices

·Swelling controlled devices

3.Chemically controlled devices

·Bioerodible system

·Drug polymer conjugates

Monolithic Devices

It is necessary to consider two types of devices

1.The active agent is dissolved in the polymer.

2.The active agent is dispersed in the polymer.(Wu. Xs et al.,1995)

For an active agent dissolved in the matrix, the release kinetics can be calculated by two equations.¹⁴ Eq.(1) is known as the early time approximation eq (2) is known as late time approximation

dM_t/dt = 2M_x (D/I²t)^1/2 ----------------------------(1).

dM_t/dt = 8D M_x/I² exp Dt/I² ----------------------(2).

Where,

I = Thicknes of the slab from which the active agent releases

D = Diffusion coefficient.

M_x = The total amount of the active agent dissolved in the polymer.

M_t = The amount of active agent released at time t.

eq (1) shows that the first 60% of drug follows square root of time diffusion while remaining releases exponentially according to eq (2)

When the active agent is dispersed in the polymer, drug release kinetics have been derived by Higuchi.

dM_t / dt = A/2 (2DC_sC/t)^1/2 --------------------(3).

where

A = Area                 Cs = Solubility of active agent in the matrix

Co = Total concentration in the matrix (dissolved plus dispersed)¹⁵

Unlike the slab with dissolved active agent where the rate is proportional to t^1/2 only during the early portion of the release curve, slab with the dispersed active agent maintain a t^1/2 dependence over the major portion of the release curve and deviate from this dependence only when the concentration of the active agent remaining in the matrix falls below the saturation value.

Reservoir Devices:

In the reservoir devices the active agent is contained in a core that is surrounded by the rate controlling membrane. Transport of the material from the core through the surrounding non-porous, homogeneous polymer film occurs by dissolution at one interfaces of the membrane and then diffuses down a gradient in thermodynamic activity, which is described by Ficks first law:

J = -D dC_m / dx-------------------------------------------(4)

Where,

J = Flux in gm/cm² sec.

Cm =Concentration of the permeant in the membrane in gm/cm³

D = Diffusion coefficient of the permeant in the membrane in cm²/sec

Because the concentration of the permeant just inside the membrane is not known, it is related to the concentration in the medium surrounding the membrane by

Cm (O) = KCo at the upstream (X = 0)

Cm (I) = KC at the downstream (X =I)----------------------(5)

where

k = distribution coefficient analogous to liquid-liquid partition coefficient

Figure 1 Schematic representation of the conc. gradient across the membrane

At steady state, eq (4) can be integrated to give

J = D Cm (0) .Cm (I) / I = DCm / I-------------------(6)

using eq. (5), eq. (6) can be rewritten as

J = DKC/1------------------------------------------------(7)

where

C =difference is concentration between the solutions on either side of the membrane

Rate of the active agent will be constant and can be predicted from permeability and device configuration. If the thermodynamic activity of the active agent in the reservoir remains constant. No change in the rate limiting characterstics and the infinite sink conditions are maintained at down stream side of the membrane.

Thus for a slab having the total surface area A, Ficks law can be related as follows.    dM_t/dt = ADKC / I ----------------8

Where,

dM_t / dt = Release rate at time t.

Burst effect is always seen in these type of devices. Although, reservoir devices may require more complex fabrication procedures than monolithic devices, they are capable of very long term, nearly zero order kinetics and for this reason are of considerable commercial importance.

Uses of biodegradable polymers in Parenteral Depot System

Bio-degradable polymer may be defined as synthetic or natural polymer which is degradable in vivo either enzymatically or non enzymatically to produce bio-compatible or non-toxic by products. These can be further metabolized or excreted via normal physiological pathway. In another word, biodegradable polymers are those polymers that degrade in biological fluid with progressive release of dissolved or dispersed materials. The most promising area of application on biodegradable polymers are implants, which are either injected or inserted for prolonged release of medicaments. (Lenzer et al.,1981)

The major advantage of the use of biodegradable polymers is that, it does not  required surgical removal even after complete drug exhaution. In addition the breakdown products are natural biocompatible which overcome the problem of toxicity associated with non-biodegradable implants (Boxambom et al.,1989)

Another advantage of the biodegradable polymers in implants or drug delivery devices is that it releases drug by diffusion controlled mechanism hence predetermined drug delivery rate can be achieved easily. (Wise et al., 1987)

Classification of Biodegradable Polymer¹⁶

Biodegradable polymer may be classified based on the mechanism of release of the drug entrapped in it:

 Natural - albumin starch, dextran, gelatin, fibrinogen, hemoglobin.

 Synthetic - poly (alkyl -cynoacrylates), poly ethyl --cynoacrylates, poly butyl cynoacrylates, poly amides. Nylon 6-10 nylon 6-6, poly acryl amides, poly amino acid, poly urethane.

Aliphatic poly esters are poly (lactic acid) poly lactide - co glycolide) poly glycolic acid, poly caprolactone, polydihydroxy butyrate, poly hydroxy butyrate co-valently cross linked protein, hydrogel, cross linked ampipathic block co-polymer.

Biodegradable polymers investigated for controlled drug delivery are

1.Poly lactide / poly glycolide polymers.

2.Poly anhydrides.

3.Poly caprolactone

4.Poly orthoesters

5.Psuedo polyamino acid

6.Poly phosphazenes

7.Natural polymers

Interest in poly lactide material has been generated due to its considerable chemical, biological and mechanical characteristic¹⁷       

Most of PDS developed so far are designed to deliver drugs to the systemic compartment. Also local drug delivery is a possibility in this case one attempts to achieve high drug concentration at the site of implantation without exposing non affected tissue to the drug¹⁸.

Implants are used as depot formulations either to limit high drug concentrations to the immediate area surrounding the pathology or to provide sustained drug release for systemic therapy. Clinically, implant systems have been used in situations where chronic therapy is indicated, such as hormone replacement therapy and chemical castration in the treatment of prostate cancer^19-23.

Parenteral implants may take the form of highly viscous liquids or semi-solid formulations, both of which may be injected with a needle. Alternatively, implants may be in the form of tiny rods impregnated with drug substances or a liquid, which gels in situ. In situ forming gels either gel when the polymer solubilising solvent diffuses away from the injection site, leaving the polymer in contact with an aqueous environment in vivo, or gel on cooling after being injected at an elevated temperature. In situ forming gels may be used to prepare sustained release formulations of oligonucleotides and non-steroidal anti-inflammatory agents. Implants are prepared from a variety of polymeric materials, such as polysaccharides, polylactic acid co-glycolic acid, and the non-biodegradable methacrylates. Biodegradable materials, such as polylactic acid co-glycolic acid, are of course preferred as this removes the need for surgical removal of the implant after treatment has ended. However, non-biodegradable materials do provide therapeutic levels of drug for up to one year in vivo^24-27.

Drug release may also be controlled by various stimuli, such as electrical stimuli in polyelectrolyte system. This allows the fabrication of pulsatile delivery systems such as the electrically triggered release of insulin from poly-di-methylaminopropyl acryl amide gels^28-29

Implants may also be used to achieve high drug doses in traditionally inaccessible such as the central nervous system, bone tissue and beyond the blood-retinal barrier. Ethylene vinyl acetate copolymer dexamethasone intracranial implants achieve high drug levels in the brain without correspondingly increased plasma levels and a polylactic acid co-glycolic acid gentamicin bone implant is superior to an intramuscular injection of the drug at eradicating bone infections in a canine model. Additionally, polylactic acid co-glycolic acid scleral implants of gancyclovir for the treatment of cytomegalo virus infection maintained sufficient therapeutic levels of the drug in the vitreous humor and retina/choroids for three to five months. The use of implant systems is often associated with inflammation at the site of implantation. The development of this inflammation is thought to be necessary for the processing of the delivery system^30-34.

Lactide /Glycolide Based Drug Delivery Systems

One of the reasons for the popularity of the lactide/ glycolide material in drug delivery system is their relative ease of fabrication into various types of delivery systems:

· Micro particulars (Microspheres and microcapsules)

·Implants

·Fibers

Microsphere and microcapsules of these polymers are generally  prepared by three methods.                                         

· Solvent evaporation

·Phase separation

·Fludized bed coating

The solvent evaporation method particularly developed for biodegradable polymers involves, dissolving the polymer in a volatile organic solvent, containing drug, emulsified and finally removing the solvent under vacuum to form discrete monolithic microspheres.

Phase separation microencapsulation procedures are suitable for entraping water soluble agents in lactide/ glycolide excipients. These processes involve coacervation of polymers from an organic solvent by addition of a non-solvent such as silicone oil.

In the fludized bed coating technique the bioactive agent is dissolved in the organic solvent along with the polymer. The solution is then processed in Wurster air suspension coating apparatus to form microcapsules.

Implants of PLGA/PLA matrix are prepared using following method.

·Compression molding.

·Injection molding

·Screw extrusion

·Thixotropically based

Implants of few millimeters to several centimeters in size have been tested for drug delivery environment. It is extremely important to dry the bulk polymer and the bioactive agent, usually at ambient temperature under vaccum prior to processing Dry nitrogen blankets over critical process equipment such as extrusion feed hoppers are essential. The limiting factor with regard to melt process of implant for drug delivery is of course the heat stability of the active agent.

Most of the lactide/ glycolide are injection molded at temperatures between 140^oC and 175^o C, hence they are not suitable for thermo labile drugs. Monomers levels greater than 2-3% by weight often cause substantial degradation of lactide/ glycolide copolymer in injection molding operation.

Drug loaded fibers of both monolithic and reservoir types using lactide/ glycolide polymers have been reported. Monolithic formulation can readily be produced with melt extrusion using the blend of the active agent and polymer extruded under pressure at the lowest possible temperature. Reservoir or coaxial fiber can be produced from the glycolide/ lactide polymers by two important methods.

·Melt spinning technique in which the drug was introduced during the spinning process as a suspension or solution in a suitable lumen fluid.

·Dry wet phase process for poly lactide fibers, in which the drug must be added to the hollow fiber after the fibers are produced. The method was developed by Eenink  et al., in 1987.³⁵

Biodegradation of Poly-lactide-Co-glycolide^36-39

Aliphatic poly esters undergo biodegradation by bulk erosion the lactide/glycolide polymer chains are cleaved by hydrolysis to the monomeric acids and are eliminated from body through Krebs cycle, Primarily as carbon dioxide and in urine. Very little difference in observed in the rate of degradation at different body sites as the hydrolysis rate is dependent only on significant changes in temperature and pH or presence of catalysts.

The role of enzyme in the biodegradation of the polymers has been still unclear. Though earlier reports concluded that bioerosion of lactide/ glycolide polymers occurred strictly through hydrolysis with no enzymatic involvement, recent investigation by Willam, Herrman and Reed suggested that the enzymes do play a significant role in the breakdown of these polymer in body. However much of these speculation are based on the difference observed between in vitro and in vivo disintegration rates rather than direct study. Maulding et al (1986) observed on unusual accelaration in biodegrdation rate of polylactide/ glycolide in presence of tertiary amino compound, thioridazine. ⁴⁰

Ethoxylation of the carboxylic acid and groups of aliphatic polyester significantly changes the biodegradation rates as well as the crystallinity of these polymer.

Biodegradation of lactide/glycolide polymers are summarized in table.

Polymer	Months
Polylactide	18-24 months
Poly dl-lactide	12-16 months
Poly glycolide	2-4 months
PLGA 50:50	2 months
PLGA 85:15	5 months
PLGA 90:10	2 months

Lactide glycolide polymers show wide range of hydrophilicity which makes them versatile in designing controlled release system. It has been demonstrated by Gilding 8 Reed (1979) that the water up take increase as the glycolide ratio in the co-polymer increases.⁴¹

Synthesis of lactide/glycolide polymers branched with different poly ols polyvinyl alcohol and dextran acetate was reported (Birch et al 1988) whereas significant change in the degradation profile of these polymers from that of linear polylactides was reported.⁴²

Evaluation of Parenteral Depot System:

Viscosity⁴³:

The viscosity of intradermal liquid depots were determined by measuring the time required for liquid to pass between two marks as it flows by gravity through a vertical capillary tube, known as Ostwald Viscometer.

The time of flow of the liquid under test is compared with the time required for liquid known viscosity (distilled water) to pass between the two marks.

If h₁ and h₂ are the viscosities of the unknown and the standard liquids, d₁ and d₂ are densities of the liquids and t₁ and t₂ are the respective flow times in seconds, The absolute viscosity intradermal liquid depots h₁ were determined by substituting the experimental values in the equation –

Drug Content:

A known amount of formulation of given sample is suitably diluted with  solvent like N-methyl-2-pyrilidone and stirred for 12 hours at 37+1^oC. The drug content of formulations is determined by measuring the absorbance of the solution against solvent like N-methyl-2-pyrilidone as a blank using spectrophotometer at particular wavelength. This procedure is followed for determining drug content of all prepared formulations.

In vitro release study⁴⁴:

Commercial dialysis membrane is employed for the in vitro release study. The membrane, which is, used transparent and regenerated cellulose type, which is permeable to perticular molecular weight substances. The semipermeable membrane is tied to one end of open ended cylinder made up of glass (15 mm x 75 mm) which act as a donor compartment. Intradermal liquid depot system containing drug placed inside the compartment. This set up is placed over a beaker containing 100 ml phosphate buffer saline pH 7.4 and its content were continuously stirred using a magnetic stirrer at 37+1^oC. 5 ml sample is withdrawn from the receptor compartment at the end of 24 hours interval up to a period of 7 days.  After each withdrawal an equal volume of phosphate buffer saline pH 7.4 was replaced in the receptor compartment. The collected sample is analyzed spectrophotometrically at given wavelength nm against blank.

Current investigation on Parenteral Depot System

Packhaeuser C. B. et al., (2007), were investigated the feasibility to generate in situ forming parenteral depot systems from insulin loaded dialkylaminoalkyl-amine-poly(vinyl alcohol)-g-poly(lactide-co-glycolide) nanoparticles,. Biodegradable nanoparticles formed polymeric semi-solid depots upon injection into isotonic phosphate buffered saline (PBS) with no additional initiators. Nanoparticles (NP) prepared from the different amine-modified polyesters displayed a pronounced positive zeta-potential of >25 mV. Diethylaminopropyl-amine-poly(vinyl alcohol)-g-poly(lactide-co-glycolide) (DEAPA(68)-PVAL-g-PLGA(1:20)), diethylaminoethyl-amine-poly (vinyl alcohol)-g-poly(lactide-co-glycolide) (DEAEA (33) - PVAL- g – PLGA (1:20)), and dimethylaminopropyl-amine-poly(vinyl alcohol)-g-poly(lactide-co-glycolide) (DMAPA(33)-PVAL-g-PLGA(1:20)), formed in situ depots by an ion-mediated aggregation with subsequent fusion of nanoparticles, related to a decreased glass transition temperature in the presence of PBS. Moreover, two factors, namely, polymer and insulin-nanocomplex concentration, were evaluated using a response surface design with respect to nanoparticles formation and insulin loading. Nanoparticles and implants were investigated by atomic force microscopy (AFM). The in vitro release from implants loaded with 2% insulin was carried out in a flow trough cell and quantified by high performance liquid chromatography (HPLC). The release showed a triphasic profile with an initial burst, pore diffusion and diffusion from the swollen matrix over more than two weeks. Insulin distribution in the implants during the release was followed by confocal laser scanning microscopy (CLSM). These findings combined with the protection of the model peptide against competitive macromolecules and the possibility to get dry powders by lyophilization make these nanoparticles-based depots suitable candidates for the design of controlled release devices for bioactive macromolecules⁴⁵.

Deepak Chitkara et. Al., (2006), The scope of drug-delivery systems has expanded significantly in recent years providing new ways to deliver life saving therapeutics to patients. The development of new injectable drug-delivery systems has provided new vistas and opened up unexplored horizons in the field of science, particularly in controlled drug delivery since these systems possess unique advantages over traditional ones, which include ease of application, and localized and prolonged drug delivery. In the past few years, an increasing number of such systems has been reported in the literature for various biomedical applications, including drug delivery, cell encapsulation, and tissue repair. These are injectable fluids that can be introduced into the body in a minimally invasive manner prior to solidifying or gelling within the desired site. For this purpose both natural (chitosan, alginates) as well as synthetic polymers (PEGylated polyesters, ricinoleic acid-based polymers) have been utilized. These systems have been explored widely for the delivery of various therapeutic agents ranging for anti-neoplastic agents like paclitaxel to proteins and peptides such as insulin, almost covering every segment of the pharmaceutical field. This manuscript focuses on the recent advancements in the area of in situ forming biodegradable polymeric drug-delivery systems Biodegradable⁴⁶

A.J. McHugh,(2005), has presented the role of polymer membrane-based drug delivery systems. .This is followed with a review of recent studies in there laboratories of the membrane formation and drug delivery characteristics of injectable polymer solution platforms. Attention is focused on the role of depot formulation in terms of solvent quality and water miscibility and polymer type (amorphous versus crystallizable), as well as the effects of bath-side additives on the in vitro release behavior. A quantitative model describing the protein release dynamics in fast phase inverting systems (FPI) is also discussed⁴⁷

Chourasia M. K., et .al.,(2004),  In the present work an implantable delivery system have been developed which when comes in contact with biological fluid, solidifies immediately and release the drug in a controlled manner for prolonged period of time. Polylactic acid, polyglycolic acid and copolymers of polylactic acid and polyglycolic acid were synthesized and characterized for various physicochemical attributes. IR spectra of the synthesized polymers was determined and it was found to be identical to that reported in the literature. Molecular weight of the polymers was determined with the help of viscosity measurement. Solubility and hydrolysis of the polymers was determined. Drug delivery systems were fabricated using synthesized polymers and characterized in vitro for various parameters. Drug content was estimated by direct measurement of absorbance whilst viscosity was determined using Ostwald viscometer. In Vitro release for the formulations was determined for 10 d using dialysis tube diffusion technique, which revealed slow release of drug from formulation. On the basis of In Vitro characterization studies, selected formulations were subjected to invivo performance where drug plasma level was monitored after intradermal administration. In vivo studies revealed sustained release of the entrapped drug from formulations, which is reflected from the persistence of drug in blood for longer period of time.⁴⁸

Pechenov S. et al., (2004), have been worked for development of ready-to-inject in situ formable controlled release gel systems for proteins is extremely challenging due to poor stability of proteins in the organic solvents typically used to fabricate these systems and because of the need of initial drying of proteins. The focus of the present study was to develop and characterize injectable controlled release systems composed of crystals of amylase, a model protein, suspended in solutions of polymeric and non-polymeric matrix materials in organic solvents. In this study, alpha-amylase derived from Aspergillus oryzae was crystallized and crystals were suspended in a poly(DL-lactide-co-glycolide) (PLGA) solution in acetonitrile (PLGA/acetonitrile), or in sucrose acetate isobutyrate (SAIB) plasticized with ethanol (SAIB/ethanol) systems. The results indicate that the protein crystals could be incorporated in these in situ formable gels without the need for initial drying. The crystals withstand organic solvents and water/organic solvent interfaces, and provide high protein loading (>30%) in these systems. Moreover, changing the morphology of the amylase crystals successfully modulated amylase release profiles. Study of long-term stability at 4 degrees C revealed a greater stability of crystalline protein compared to amorphous amylase. The above-mentioned data suggest that protein crystals might offer greater feasibility in developing sustained release injectable in situ formable protein depot systems⁴⁹

Shenoy D.B. et al., (2003), developed an injectable, depot-forming drug delivery system for insulin based on micro particle technology to maintain constant plasma drug concentrations over prolonged period of time for the effective controlled blood sugar levels. Formulations were optimized with two well-characterized biodegradable polymers namely, Poly (DL-Lactide-co-glycolide) and poly-epsilon-caprolactone and evaluated in vitro for physicochemical characteristics, drug release in phosphate buffered saline (pH 7.4), and evaluated in vivo in sterptozotocin- induced hypoglycemic rats⁵⁰.

Sinha, V.R. et al., (2003), prepared biodegradable microspheres as parenteral depot formulation occupy an important place because of several aspects like protection of sensitive proteins from degradation, prolonged or modified release, pulsatile release patterns. The main objective in developing controlled release protein injectable is avoidance of regular invasive doses which in turn provide patient compliance, comfort as well as control over blood levels⁵¹.

Shenoy, D.B. et al., (2002), studied a Poly (DL-co-glycolide) (PLG) – based, microspheric depot system for Bleomycin (BLM) has been formulated, and the same has been evaluated in-vivo in mice bearing transplantable melanoma murine solid tumor. The micro particulate delivery systems were formulated employing water in oil in water emulsion solvent evaporation technique and characterized in vitro⁵².

Periti , P. et al., (2002), leuprorelin acetate is a synthetic agonist analogue of gonadotropin-releasing hormone. Continued leuprorelin administration results in suppression of gonadal steroid synthesis, resulting in pharmacological castration. Since leuprorelin is a peptide, it is orally inactive and generally given subcutaneously or intramuscularly. Sustained release parentreral depot formulations, in which the hydrophilic leuprorelin is entrapped in biodegradable highly lipophillic synthetic polymer microspheres, have been developed to avoid daily injections⁵³.

Kumar, V. et al.,(2002), formulated prolonged release biodegradable microspheres for treatment of inflammation. Natural biodegradable polymers, namely, bovine serum albumin and chitosan were used to encapsulate curcumin to form a depot forming drug delivery system. Microspheres were prepared by emulsion-solvent evaporation method coupled with chemical cross-linking of the natural polymers⁵⁴.

Ravivarapu , H.B., (2000), studied about sustained suppression of pituitary gonadal axis with an injectable, in situ forming implant of leuprolide acetate⁵⁵.

Jain, R.A. et al., (2000), compared various injectable protein loaded biodegradable poly (lactide co-glycolide) (PLGA) devices: In-situ-formed implant versus in-situ formed micro spheres versus isolated microspheres⁵⁶.

Jain, R.A. (2000), formed a stable dispersion of PLGA microglobules (‘Premicrospheres’ or ‘Embryonic microspheres’) in a vehicle mixture on injection, comes in contact with water from aqueous buffer or physiological fluid, thereby hardening the microglobules into solid matrix type microparticles entrapping the drug (in situ formed microspheres). The drug is then released from these microspheres in a controlled fashion⁵⁷.

Ravivarapu, H.B. et al., (2000) studied the effect of drug loading on the release of leuprolide acetate from an injectable polymeric implant, formed in situ, and efficacy of the released drug in suppressing serum testosterone levels in dogs for at least 90 days⁵⁸.

Jain, R.A. et al.,(2000), studied a novel method for in situ preparation of injectable biodegradable micro spheres from the copolymer, poly (Lactide-co-glycolide) (PLGA), without incorporating unacceptable organic solvents is described⁵⁹.

Chenite, A. et al., (2000), gives a novel approach to provide, thermally sensitive neutral solutions based on chitosan/ polyol salt combinations is described. These formulations possess a physiological pH and can be held liquid below room temperature for encapsulating living cells and therapeutic proteins; they form monolithic gels at body temperature. When injected in vivo the liquid formulations turn into gel implants in situ⁶⁰.

He, S. et al., (2000), formed injectable biodegradable polymer composites based on poly (propylene fumarate) cross linked with poly (ethylene glycol) – dimethacrylate) ⁶¹.

Sidman,K.R. et al., (1980),studied the sustained action and inhibition of growth of ah-130 ascites hepatoma implemented intradermal in ratio using 5-flurouracil in polylactide-co-glycolide based delivery⁶².

Vert , M et al., (1981), reported the bioresorbable characteristic of some implantable controlled release formulation of polylactide and glycolic acid pellets, microsphere, and microcapsules⁶³.

Royals, M.A. et al.,(1999), formulated a polymeric delivery system containing a 75/25 poly (DL-Lactide-Co-caprolactone dissolved in either N-methyl-2-pyrrolidone or dimethyl sulfoxide were injected both subcutaneously (SC) and intramuscularly (IM) into rhesus monkeys⁶⁴.

References

1. Vinceut, H.K.L.; In; Robinson R.J. eds – Controlled drug delivery fundamentals and applications II^nd Edn., Marcel dekker, INC. Network. 1978 (4-34).
2. Gibaldi, M. and M.C. Nanara P.J., Int. J. Pharm., 1979 : 2-167.
3. Alessandro, M. and Sara Lawria, American Pharmaceutical Review. A:, SMER, CNJ. HTM 2004. 3.
4. Heller, R. et al., New methods of drug delivery science 1990 (249) 1527-1533.
5. Reddy, K.R. et al. Controlled Release, Ann. Pharmacother (2000). 915-922.
6. Tipton, A.J., Dunn, R.L. In ; Senior J.H., Radnsky M Eds. Sustained release injectable products Literpharm Press, Denver, 2000. 71-102.
7. Hollister, L.E. et al., Newrobiol; Ageing 10 (1989) 628-631.
8. Cleary, G.W. In : Shah V.P eds. Topical drug bioavailability bioequivalence and Penetration, H.I. Plenus Press New york 1993, 70.
9. Dzuik, P.J. and Cook Endocrinology, 1996, 78, 208, 211.
10. Sah, H. and Chien, Y.W. In: Hel;leery A.M. et al Eds. Drug delivery and Targeting, Taylor and Francis Inc. New York, 2001, 85-87.
11. Kenneth, E.A. In Lachmanleon, Liberman A.H., Eds. The Thory and practice of industrial pharmacy Varghese Publishing House, Bombay , 1991, 634.
12. Muysthy, R.S.R. In: Jain N.K. Eds. Controlled and Novel drug delivery Ist Edition, CBS Publishers and distributors. New Delhi , 2004. 29-30.
13. Heller, J. In Robinson, R.J. Eds. Controlled drug delivery. Fundamental and application IInd Edition, Marcel Dekker INC. New York 1987. 179-183.
14. Baker, R.W. Eds. Controlled release of biologically active agents, Plenum Press New York 1974, 1571.
15. Higuchi, T. et al. J. Pharm. Sci. 1961; 50, 874-75.
16. Murthy R.S.R.
17. Conway, B.R. and Alpan H.O., Euro, J. Biopham. 1996, 45, 5-48.
18. Harrish, F.W., Medical Application of controlled release. Controlled release from polymer containing pendent bioactive substituent, 1984 CRC Press Bocaroton, 289.
19. Garvin, K.L., Miyano J.A., Robinson D., J. Bone. Join Surg. Am. Vol. 1994; 76:1500-6.
20. Fujita T., Tamura, T. et al. J. Dlrug Target, 1997 4:289-96.
21. Labhasetwar V., Underood T., et al. J. Pharm Sci. 1994; 83 : 156-64.
22. Reinhard, C.S. et al. J. Control Rel. 1991; 16:331-40.
23. Moo-Young A.J., et al Int. Synp. Control Rel. Bioact Mater 1998; 25 : 64-5.
24. Lesser G.J., et al. Pain, 1996 ; 65:265-72.
25. Suhonen S.P. allonen H.O. et al. Am. J. Obstet Gynecol 1995; 172:562-7.
26. Bernatchez S.F. et al. J. Biomed Mater Res. 1993; 27: 677-81.
27. Chandrashekar G., Udupa N. J. Pharm Pharmacol 1996; 48: 669-74.
28. Chen J. Jo S., Carbohydrate Polyn. 1995; 28: 69-76.
29. Konou, N., Ogura, Y. et al. J. Control Rel 1995;37:143-50.
30. Kagatani S. Shinoda T., et al J. Pharm sci., 1997;86:1273-7.
31. Meshri M., Benoit J.P. et al. Int. J. Pharm 1998; 172:27-32.
32. Suisha, F., et al Int J. Pharm 1998; 172: 27-32.
33. Seymour L.W., et al J. Control Rel. 1994; 31: 201-6.
34. Imasaka K. Yoshida M., Fukozaki H., Int. J. Pharm 1992; 81: 31-8.
35. Enink M.J.D., Feijen J., Oligslonger J., Albersthm, et al J. Controlled release 1987, 6: 225.
36. Williams, D.F., Most E., J. Bio Eng 1977, 1 : 231.
37. Williams, D.F., Eng Med. 1981, 10 : 5.
38. Herrmava J. B. et al. Arch Surg 1970, 100 Kelly, R.j., Higgins, G.A.
39. Reed, A.N. In vitro invivo studies of biodegradable polymer for use in medicine and surgery. Ph.D. Thesis, University of Liverpool – 1988.
40. Moulding H.V. et al J. control release 1986 3 : 103. Tice, T.R., Cowsar, D.R., Fong, J.W.
41. Gilding D.K., Reed A.M. (1979). Polymer 20:1459.
42. Petri, A.W. In Hardman G.J. and Linbard L.E. Eds. Goodman gillman the pharmacological basis of therapeutics, 10^th edition (INT eds) Mc Graw hill Medical Publicing Div. New York 2001, 1275, 1760
43. Martin A. Eds. Physical, Pharmacy 4^th Edi Lippincott Willams and Wilkins 2003 – 212.
44. Raghvraman S., Velrajan G., Ravi R. Ind. Jour. of Pharm. Sci. 2002, 64 (1) 32-36.
45. Packhaeuser CB, Kissel T. J Control Release. 2007 Nov 6; 123(2): 131-40. Epub 2007 Aug 16 46.
46. Deepak Chitkara et al, Macromolecular Bioscience Volume 6, Issue 12 Pages 977 – 990, 24 Nov 2006
47. A.J. McHugh Journal of Controlled Release,Volume 109, Issues 1-3, 5 December 2005, Pages 211-22148 
48. Chourasia MK, Ashawat M S, et. al., Ind.jour.pharm.scienceYear : 2004  Volume : 66  Issue : 3    Page : 322-328
49. Pechenov S et al J Control Release. 2004 Apr 16;96(1):149-58.
50. Shenoy, D.B., D’souza R.J., Udupa, Drug Delivery Ind. Pharm., (2003) 29 (5) :555-563
51. Sinha V.R., Trehan A., Controlled Release, 2003, 61 90 (3), 261-80.
52. Shenoy, D.B., D’souza, R.J. Udupa N.,J. Microencapsulated, (2002), 19 (4) 525-535.
53. Periti, P., Mazzei,T., Mini E., Clin. Pharmaceokinet., (2002), 41 (7) 485-504.
54. Kumar, V. Eld Indian,J. Physiol. Pharmacol. (2002) 46 (2), 209-217.
55. Ravivarapa,H.B. Moyer, K.L., Dunn R.L., Jour. Pharm. Sci. 2000 89 (6) : 732-741.
56. Jain R.A., et al. Pharm. Dev. Technol.,2000, 5 (2) : 201-207.
57. Jain R.A. et al., Eur. J.Pharm. Biopharm., 2000, 50 (2) 257-263.
58. Ravivarapu, H.B., Moyer,K.L. Dunn, R.L., AAPS Pharm Sci. Tech., 2000 1 (1) E1.
59. Jain R.A., Rhodes, C.T.,Raikar, A.M. J. Microencapsul. (2000) 17 (3) 343-362.
60. Chenite, A., et al Biomaterials (2000) 21 (21) 2155-2161.
61. He S., et al., (200) Biomaterials 21 (23) : 2389-94.
62. Sidman, K.R. et al., J. Member Sci.,7, 277.
63. Vert, M.and Chabot, F., Makronnol. Chem. Suppl. (1984),530-41
64. Royals, M.A. et al., J. Biomed Mater. Res. 1999, 5, 45 (3) 231-237

About Authors

Sudhir Bhardwaj is working a lecturer cum research scholar in department of pharmaceutics in ASBASJSM College of Pharmacy, Bela, Ropar, India. Mr. Bhardwaj  has author of number of books and published several Research Paper / Abstract in National and International conferences. He is a Memership Coordinator for INPHARM Association,  active member of FIP, International Society of Agriculture and Applied Science, and APTI

Shailesh Sharma is working a lecturer cum research scholar in department of pharmaceutics in ASBASJSM College of Pharmacy, Bela, Ropar, India.He had completed his graduation from B . R. Nahata College of pharmacy, Mandsaur, (MP) and  post graduation from B.N.College of pharmacy, Udaipur, Raj. He has very good academic and extra circular record.

Dr.G.D.Gupta is working as a professor and principal in ASBASJSM College of Pharmacy, Bela, Ropar, India. Dr. Gupta has author of number of books and published more than 100 Research Paper / Abstract in National and International conferences.

Dr.Y.S.Tanwar is working as a Professor in BN College of Pharmacy, Udaipur, India. Dr. Tanwar is having more than 9 years of teaching and research experience. He has supervised 15 M. Pharm.(Pharmaceutics) thesis and has publications in international and national journals of repute. He is executive member of APTI (Rajasthan State Branch) and also been appointed as an expert by various departments, institutions and universities throughout India.

Mr.P.S.Naruka, is working as a Reader in BN College of Pharmacy, Udaipur, India. Mr. Naruka is having more than 7 years of teaching and research experience. He has supervised 05 M. Pharm.(Pharmaceutics) thesis.

Mr. K. Gaurave, is working as a Reader in Khalsa College of Pharmacy, Yamunanagar,Haryana, India.

Mr. A. Sharma, is working as a Lecturer in Bharti Vidhyapeeth, Pune, Maharashtra, India.