Parenteral Controlled Drug Delivery System

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Parenteral Controlled Drug Delivery System

The Parenteral administration route is the most effective and common form of delivery for active drug substances with poor bio-availability and the 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 years4. This interest has been sparked by the advantages this delivery system possess, which include ease of application, localized delivery for a site specific action,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.

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.  

Parenteral Depot System:

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 soluble salt 2.Use of largest particle 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 adsorbents. Only the free portions in equilibrium with that, which is bound, can be adsorbed. As drug is adsorbed, 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, an osmotic insulin pump and site specific delivery in the gastrointestinal tract .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  

Classification of Biodegradable Polymers 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 - -cynoacrylates), poly ethyl-a-poly (alkyl  cynoacrylates, poly amides. Nylon 6-10 nylon - a-cynoacrylates, poly butyl a- 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.

            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 characteristic.    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 drug. 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. 

 

Figure 1. Characteristics of PLGA microspheresA: Picture of rhGDNF-loaded microspheres analyzed by scanning electron microscopy. Scale bar in A represents 10 µm.

B: Scanning electronic photomicrograph of PLGA microspheres obtained by the multiple emulsion W/O/W method. Bar = 5 µm 

          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.

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 particles (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 140oC and 175o 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.  

Biodegradation of Poly-lactide-Co-glycolide

        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.

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.

 References

 

  1. Vinceut, H.K.L.; In; Robinson R.J. eds – Controlled drug delivery fundamentals and applications IInd 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.

 

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Comments

kranthi kumar's picture

Dear naveen,
Good stuff, very interesting. The Biodegradable Polymers, classification, referances, Approaches used in Depot formulation, you have mentioned are very good.
My doubt is you have mentioned "Use of largest particle with crystalinity." will not this size becomes an obstracle for the parentral administration like needle size has to be increased there by causing discomfort to patient.
Can you mention some companys who worked on this and is the products released into the market ?
Does not it carry any disadvantages or side effects ?

Regards
Kranthi  
" "

 http://www.pharmainfo.net/kranthikumar

Raghavendhra naveen Chennoju's picture

As you asked size becomes an obstracle for the parentral administration like needle size has to be increased there by causing discomfort to patient.But this is not the caes Kranthi ,parentral depot systems have particles like droplets and microspheres which have size range from 2-100 &1-50 micron respectively .So we can assume that these particles will not require further more increase in the inner diameter of needle and needle length.

Many companies are manufacturing these parentral biodegradable polymers.
Ex: SUNPHARMA is manufacturing these under trade name SUNPOLYMER.

As you asked disadvantage which i have mentioned below:
(a)Invasive
(b)Danger of device failure
(c)Limited to potent drug
(d)Commercial disadvantage

Ragha Naveen
http://www.pharmainfo.net/raghanaveen

My Team
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kranthi kumar's picture

Eswar GsnkRao's picture

Dear Naveen,
Your blog is very useful to todays control drug delivery scenario. Keep rocking!
A small suggestion is while posting a blog be patient and edit properl such that it will add cosmetic look to the original stuff and give final essence till attracting ther eaders. What do U say?
And I have a small doubt, since there is a good control over the particle or globule size based on the production parameters, what is the maximum size limit ingeneral that can be opted in these systems.
Regards
eswar :-)

Regards

ESWAR :-) 

Raghavendhra naveen Chennoju's picture

Thanks for your valuble suggestion sir and I definitely work on it and I will rectify my mistake in up coming blogs.
As you asked about maximum size limit , Currently droplets in the range of 2 to 100 microns and microspheres in the range 1 to 50 microns are routinely manufactured ,but an
average microsphere diameter of about 30 microns seems ideal for depot applications.
Ragha Naveen
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Bobby's picture

Dear Navin,
ur blog is very useful for me.......it will b better to place some more photos in ur blog...

\-gopidalai
http://www.pharmainfo.net/bobby3nad

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Raghavendhra naveen Chennoju's picture

Thanks for your suggestion Trinadh .I will try to rectify my mistake in my up coming blogs
Ragha Naveen
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My Team
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Akhil's picture

hai Mr naveen.good work man.but 4 a person 2 have a glance at ur presentation,it should b attractive.so try 2 hve some colorful pic.not jst like notes.

Raghavendhra naveen Chennoju's picture

Thanks for your suggestion sir .I will try to rectify my mistake in my up coming blogs
Ragha Naveen
http://www.pharmainfo.net/raghanaveen

My Team
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