Controlled Release Parenteral Dosage Forms

By: Pharma Tips | Views: 14380 | Date: 24-Apr-2011

A. AQUEOUS SOLUTION:B. OIL SOLUTIONC. SUSPENSIOND. EMULSIONS:E. LIPOSOMES:F. NIOSOMES:G. MICRO-EMULSIONS:H. MICROSPHERESI. IMPLANT

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.
Ø    DISADVANTAGE:
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 -2        For α > > 1 one obtains,    f  =  α / (f + Kα)
Case -3        provided 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:[12,13]
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
o    Particle size reduction
o    Wetting
o    Sterilization

Ø    The 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.
Ø    Maintenance of physical stability is very difficult in this dosage form.
Ø    There may be chances of non-uniformity of dose at time of administration.

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
Ø    Penicillin G procaine
Ø    Penicillin G benzathine
Ø    Penicillin 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.
Ø    Adsorption 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.
Ø    Encapsulation 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.
Ø    Esterification 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.
Ø    Testosterone cypionate
Ø    Fluphenazine 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.
Ø    FELBAMATE (FBM) INJECTION MICROSPHERE SUSPENSION
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)1/2    DAc
      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 of    the 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;
Ø    Primary water-in-oil emulsion
•    Internal phase volume
•    Concentration of the emulsifier
•    Osmolarity of dispersed phase

Ø    Multiple 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:
LIPOSOMES IN PARENTERAL DRUG DELIVERY
Ø    To avoid quick metabolism.
Ø    E.g. Chloroquine, superoxide, dismutase etc.
Ø    To protect patient from side effect.
Ø    E.g. Doxorubicin on heart muscle.
Ø    To reduce hemolytic effect and irritation by intradermal Subcutaneous and lM injection.
Ø    The most advanced application of liposome based therapy is in the treatment of systemic fungal infections, especially with amphotericin B.
Ø    l,iposomes are also under investigation for treatment of neoplastic disorders.
Ø    E.g.: encapsulation of known antineoplastic agents such as doxorubicin and methotrexate,

Ø    Delivery of immune modulators such as N-acetylmuramyl-L-alanine-D-isogl utamine,
Ø    Encapsulation 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

Ø    B layered structure of phospholipids and cholesterol
Ø    Capable of entrapping both water sol. And lipid soluble drugs
Ø    Can alter biodistribution, protect drug and body from each other
Ø    Special liposomes usable for target delivery

DEMERITS OF INJECTABLE LIPOSOME
Ø    RES- Mediated Clearance of liposomes
Ø    Critical in determining liposome half life
Ø    Site of liposome clearance-Liver & spleen
Ø    Physiologic role of Macrophages
Ø    Hepato-Splenic uptake of liposomes.
Ø    Inverse 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. MICROSPHERES

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;
Ø    Taste and odor masking
Ø    Conversion of liquids to solids
Ø    Protection of drugs against environment
Ø    Improves the flow property of powders
Ø    Have controlled release
Ø    Have targeting property
Ø    As microspheres are multiple unit product, ready distribution over a large surface area
Ø    Delocalisation of the total dose in the GI tract
Ø    Reduce side effects
Ø    The drug release rate will be less dependent on gastric transit time
Ø    The drug -loaded microspheres are more resistant to fracture,

DISADVANTAGES OF MICROISPHERE:
Ø    Burst effect
Ø    Inadequate shelf life of sensitive pharmaceuticals.
Ø    Non reproducible
Ø    Costly
Ø    Difficult 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:
Ø    Cross microvascular barriers independent to Endothelial status.
Ø    Protect the drug, blood cells, and Endothelium during transit.
Ø    Deliver up to 60% dose to target tissue.
Ø    Drug available in controlled fashion.
Ø    Reduce concentration of free drug.
Ø    Minimize damage to normal tissue cells.
Ø    Decrease the dose
Disadvantages:
Ø    Expensive
Ø    It require specialized microspheres and magnets
Ø    Treatment of multiple body regions require sequential targeting
Ø    In long term deposition of magnetite (Fe304)
Drug candidates:
Ø    Dangerous drug and labile which causes toxicity when circulated in blood stream.
Ø    Expensive drug, and hardly 0.1% have action and 99.9% wasted in body
Ø    If 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.

Ø    Emulsify the mixture in biodegradable oil (cotton seed oil) with surfactant
Ø    Sonicate or shear to produce submicrons spheres (0.2-1.2µ)
Ø    Stabilize the matrix by; heating or chemical cross linking
Ø    Extract the oil with volatile organic solvent (Hexane, Ether)
Ø    Lyophilizing 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
Ø    Inerleukin-2 is glycoprotein. Interleukin-2 activates multiple cell types-T helper cells, Cytotoxic T - lymphocytes, Natural killer cells, Macrophases.
Ø    It is useful in Murine tumors and human melanomas and renal cell carcinomas. But IL-2 cleared from the plasma in 5 min.
Ø    High dose produce severe side effects - Anemia, Fever, Hypertension, Jaundice.
Ø    Due 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
Ø    Improved control of drug level at the specific site of action.
Ø    Preservation of the medication that are rapidly destroyed but the body.
Ø    Immediate 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.
Ø    Less fluctuation in plasma drug level during therapy.
Ø    Possible reduction in therapy costs because patient care and the potentially lower drug dose required.
Ø    Improved special compliance.
Ø    Administration of drugs with short biological half-life may be facilitated.
Ø    Minimal harmful side effect of systemic administration through local therapy.
DISADVANTAGES
Ø    Toxicity or lack of biocompatibility of the material used for the implant.
Ø    Harmful byproduct may be formed from the system, particularly for biodegradable types.
Ø    Dose dumping and variable imprecise drug release may occur if not formulated properly.
Ø    Pain and discomfort may be caused by the presence of implant.
Ø    These system can be more expensive than the conventional dosage form.
Ø    Most impalntable controlled drug delivery system requires minor surgery to implant and to remove from the administered site, if it is not 
      biodegradable
type.
Ø    Possibility of the tissue and the body reaction to implant.
Ø    Danger 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;
Ø    Membrane permeation - controlled drug delivery.
Ø    Matrix diffusion -- controlled drug delivery.
Ø    Micro - reservoir dissolution controlled drug delivery.
B.    CONTROLLED DRUG RELEASE BY ACTIVATION:
Ø    Osmotic pressure activated drug delivery.
Ø    Magnetism - activated drug delivery.
Ø    Ultrasound activated drug delivery.
Ø    Vapour pressure activated drug delivery.
Ø    Hydrolysis activated drug delivery

POLYMER    DRUG

l3- l3enzyl-l,- aspartate    Progesterone
Hydroxyalkyl-L-glutam ine    Testosterone
Nylon    Norethindrone
Gelatin    Steroid

Ø    Poly (glycolic acid) was synthesis
Ø    Polymer used to prepare biodigrable structure
Ø    The 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-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.

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DRx Asim Pasha  |  20-May-2017 11:35:15 IST
Goof
Raman  |  16-May-2018 14:06:27 IST
Thanx....Nice collection of information
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