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Depot Preparations

Presented by-Miss Shraddha M. KumbharM. Pharm (Pharmaceutics)Satara college of Pharmacy,Satara

Under the guidance of -Dr. Ajit S. KulkarniVice-PrincipalSatara college of Pharmacy,Satara

AColloquium

on

Introduction•Parenteral route: most effective •To achieve constant drug level in the systemic circulation, two strategies can be employed: 1)To control the rate of absorption of a drug. 2)To control the rate of excretion i. e. by modifying physiology of body.Depot: Long acting parenteral drug formulation is designed, ideally to provide slow, constant, sustained, prolonged action.The release can either be continuous or pulsatile depending on the structure of the device and the polymer characteristics.

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Parenteral depot system:

Properties:• Safe from accidental release• Simple to administer and remove• Inert and Biocompatible• Comfortable for the patient• Capable of achieving high drug loading• Easy to fabricate and sterilize• Free of leachable impurities

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Approaches used… • Use of viscous, water miscible vehicles – aq.

Solution of gelatin• Use of water immiscible vehicles –

vegetable oils + aluminium monosterate• Formation of thixotropic suspension• Preparation of water insoluble drug

derivatives – salts, complexes and esters•Dispersion in polymeric microspheres and

microcapsules like- lactide-glycolide homopolymers/ co-polymers.

• Co-administration of vasoconstrictors4

Polymers used……

Generally, Biodegradable polymers are used as it get degraded in the body.

•Natural- albumin, starch, dextran, gelatin, fibrinogen, hemoglobin.  •Synthetic- poly ethyl-polyalkyl  cynoacrylates, poly amides, poly acryl amides, poly amino acid, poly urethane. 

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Desirable characteristics of an ideal Parenteral drug carrier

• Versatile• High capacity to carry a sufficient quantity

of drug• Uniform distribution• Restricting drug activity at the target site

over a prolonged period.• Protecting drug from inactivation by

plasma enzymes.• Biocompatible and minimally antigenic.• Undergoing biologic degradation with

minimal toxicity . 6

TYPES OF DEPOT FORMULATION

1. Dissolution controlled depot formulation2. Adsorption type depot formulation 3. Encapsulation type depot formulation 4. Esterification type depot formulation

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Dissolution controlled depots

RDS of drug absorption is dissolution of drug.

• Approaches : Formation of salt or complexes with low

aqueous solubility. Example: penicillin G procaine (Cs = 4 mg/ml) and

penicillin G benzathine (Cs = 0.2 mg/ml).Suspension of Macrocrystals: to control the rate of drug dissolution. Example: aqueous suspension of

testosterone isobutyrate for intramuscular administration.

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Adsorption type depots

This depot preparation is formed by the binding of drug molecules to adsorbents.

Example: vaccine preparations in which the antigens are bound to highly dispersed aluminum hydroxide gel to sustain their release and hence prolong the duration of stimulation of antibody formation.

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Encapsulation-type depots -prepared by encapsulating drug solids .-The release is controlled by the rate of permeation across the permeation barrier and the rate of biodegradation.Biodegradable or bio absorbable macromolecules are used, e. g. gelatin, dextran, poly lactic acid, lactide-glycolide copolymers, phospholipids, and long-chain fatty acids and glycerides.Example: naltrexone pamoate –releasing biodegradable microcapsule,

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Esterification-type depots -produced by esterifying a drug to form a bioconvertible prodrug-type ester.The rate of drug absorption is controlled by the interfacial partitioning of drug esters from the reservoir to the tissue fluid and the rate of bioconversion.Example: fluphenazine enanthate,nandrolone decanoate in oleaginous solution.

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Parenteral Controlled Drug Delivery System

A. Inject able drug deliveryB. Implantable drug delivery

systemC. Infusion devicesD. Recent advances

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Injectable Drug Delivery

1. Thermoplastic pastes 2. In situ cross linked systems 3. In situ polymer

precipitation 4. Thermally induced gelling

system 5. In situ solidifying

organogels.13

Thermoplastic pastes •In this semisolid polymers are injected as a melt and form a depot upon cooling to body temperature.•having a low melting point (25-65˚C) intrinsic viscosity (0.05-0.8 dl/g). •Drugs are incorporated into the molten polymer by mixing without the application of solvents.•Polymers: D, L-lactide, glycolide, E-caprolactone, dioxanone orthoesters etc.•polycaprolactone (PCL) requires injection temperature at least 60˚C i.e. painful injections and necrosis at the injection site,POE have good biocompatibility, relatively low softening temperatures in the range of 35-45˚C

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In situ polymer precipitation

water-insoluble, biodegradable polymer+ biocompatible organic solvent + drug

solution or suspension after mixing.

When this formulation is injected into the body, the water miscible organic solvent dissipates and water penetrates into the organic phase.

This leads to phase separation and precipitation of the polymer forming the depot at the site of injection

The concept was first

developed by Dunn and

coworkers in 1990

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Thermally induced gelling system

•Environmental temperature causes change in solubility of thermo sensitive polymers.

•Example: Poly (NIPAAM) exhibit sharp lower critical solution temperature, LCST at about 32˚C, poly NIPAAM based gels with salt and surfactant shows release over 10-20d.

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Injectables

• Solid Lipid Nanoparticle (SLN)• Nanodispersions• Suspensions• Niosomes• Liposomes• Microspheres• Emulsomes• Resealed Erythrocytes• Cyclodextrins • Aquasomes• Dendrimers

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SLN•SLN are submicron colloidal particles composed of a biocompatible/biodegradable lipid matrix that is solid at body temperature.•size range : 100-400 nm. •Generally physiological lipid dispersed in water or in aqueous surfactant solution. SLNs combine advantages of polymeric nanoparticles, fat emulsions and liposomes.Advantages:•Particulate nature•encapsulate hydrophilic and hydrophobic drugs•Ability to sustain the release, to prevent chemical, photochemical, or oxidative degradation of drug•Low cost

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Nanodispersions

Nanoemulsions / miniemulsions / submicron emulsions:These are transparent or translucent oil-in-water (o/w) or water-in-oil droplets with a mean droplet diameter in the range between 100 and 500 nm. great stability due to their small droplet size.

Nanosuspensions:Nanosuspensions of drugs are submicron colloidal dispersions of drug particles which are stabilized by surfactants. Nanocrystals are crystals of poorly water soluble drug in nanosize.

Advantages: Used to formulate drugs that are insoluble in both water and oil, have higher loading (upto 90% of crystalline particle is drug).Used when drug have high melting point.

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Suspensions•Drug release dependent upon both the intrinsic aqueous solubility of the drug and the dissolution of the drug particles.•Example: Abbott laboratories developed aqueous thixotropic suspension of penicillin procaine (40-70%w/w), such as Duracillin (Lilly), Crystacillin (Squibb) which on intramuscular injection produces therapeutic blood level of penicillin in both animal and human for 162hr

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NiosomesThese are nonionic surfactant vesicles obtained on hydration, with or without incorporation of cholesterol or other lipids.•These are bilayered structure which can entrap both hydrophilic and lipophilic drugs. •Drug is incorporated into by….Ether injection-Doxorubicin,Hand shaking- Methotrexate, Sonication- Vasopressin

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Liposomes•Liposomes are formed by the self-assembly of phospholipids molecules in an aqueous environment.

•Drug incorporated in alternating aqueous and lipid compartments , •Sustained release•lasting over several days to weeks.

•Example: myelopoietin (Leridistim)

Microspheres

•Contains dispersed molecules either in solution or in crystalline form, biodegradable polymers are used.Magnetic microspheres increases target site specificity & non-toxic and non-reactive with blood components.Examples:Minocycline Arestin® Orapharma,Bromocriptine Parlodel LAR ™ Novartis

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EMULSOMES

•Emulosomes are lipid based drug delivery systems, which are poorly water soluble.• Emulosome particles are basically consisting of microscopic lipid assembly with a polar core. •Prepared by- melt expression/ emulsion solvent diffusive extraction. •Used as adjuvants for vaccines, as carrier container for targeted drug delivery to liver, brain and RES rich organs

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Resealed Erythrocytes

•Here erythrocytes lose their haemoglobin content when they are processed by various methods i.e. osmolysis, electrical breakdown/electro-encapsulation, endocytosis etc. •Hb loss provides intracellular space for drug incorporation. Erythrocytes membrane can be resealed by restoring tonicity of the media and incubating them at 37°C.•t1/2= 60-120 days.•biodegradable, biocompatible, and non-immunogenic.

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Cyclodextrins• Cyclodextrins are water soluble

cyclic carbohydrate compounds with hydrophobic cavity.

• forms inclusion complexes with hydrophobic molecules

• Example: • Sulphobutyl β- cyclodextrin

Nimodipine aq. suspension –the relative solubility of the drug is increased with no change in drug AUC.

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AQUASOMES• Aquasomes are 3-layered self assembling

composition.• solid or glassy particles dispersed in an aq.

Environment & MOA is controlled by their surface chemistry.

• For gene therapy, a 5- layered composition of Aquasome comprised of the ceramic mono crystalline core, the polyhydroxyl oligomeric film coating, the noncovalently bound layer of therapeutic gene segment, an additional conserve viral membrane proteins have been proposed for gene therapy 27

Dendrimers• Dendrimers are highly branched 3-D-

macromolecules with highly controlled structures with all bounds emanating from a central core.

• Methods- Divergent method- one branching unit after another is successfully attached to the core molecule.Convergent method- where the skeleton in built stepwise starting from the end group towards the inside and finally treated with a core molecule to produce the Dendrimer.

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Implantable drug delivery system• Implant systems are indicated in case of

chronic therapy, such as hormone replacement therapy. Parenteral implants can be highly viscous liquids or semisolid formulations.

• Polymers used – polysaccharides, polylactic acid coglycolic acid (no need for surgical removal of the implant after treatment) and non degradable methacrylates.

• Types:1. Solid implants2. In situ forming implants

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Infusion devices• Osmotic pumps(alzet):

After implantation, water from the surrounding tissue fluids is imbibed through the semi permeable membrane.Drug release osmotic pressure difference.Ionized drugs macromolecules, steroids, and peptides (insulin) can be delivered by such a device.

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• Vapour pressure powered pumps (Infusaid):

After implantation, the volatile liquid vaporizes at the body temperature and creates a vapor pressure.Example:Insulin for diabetics and morphine for terminally ill cancer.shows back flow of infusate.• Battery powered pumps:Types:1. Peristaltic pump 2. Reciprocating pump, both with electronic controls.Do not show back flow of the infusate. 31

Evaluation of depots

Viscosity

Drug Content

In vitro release study

Sterility testing

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Development of depots:• Long acting antibiotic preparations:aqueous solubility of penicillin is reduced by converting to penicillin G procaine (aq. Solubility 4mg/ml) e.g. Duracillin (Lilly)• Long acting insulin preparations: Plasma t1/2 of insulin = 40 mininsulin-protamine complex has isoelectric point at pH 7.3 and therefore it is insoluble in body fluid which shows sustained release upto 24 hrs, stability issues arises but solved by adding zinc chloride.

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Development of depots:

• Long acting vit.B12 preparations:Vit.B12–zinc-tannate complex is suspended in sesame oil gelled with aluminium-monostearate having significant prolonged effect. • Long acting adrenocorticotropic hormone

preparations:

when given parenterally ACTH gets disappeared cause of plasma t1/2 15 min. addition of partially hydrolyzed gelatin solution into injectable ACTH solution shows prolonged release. Gelatin inhibits protein binding of ACTH and enhances response.

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Development of depots:

• Antipsychotic depots:

Example:Piportil-Pipothiazinepalmitate up to 200 milligrams 1 injection every 4 weeks• Long acting anti-narcotic preparations:Gelled oleaginous suspension of narcotic antagonist –salt complex shows sustained release for 72 hrs• Long acting contraceptive preparations:Norethindrone in a biodegradable polymer beads.Norgestrel 17β-fatty acid esters in oleaginous solution.

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ConclusionParenteral controlled drug delivery system is designed to achieve a desired pharmacological response in a sustained manner at a selected site without undesirable interactions at the other sites. Extended release parenteral products are complex dosage forms, requiring careful development of test methods and acceptance criteria for the specifications

References• Bari H.(July-Aug2010)A Prolonged Release

Parenteral Drug Delivery System- An Overview, ISSN(vol 3,p.1-11)

• Chien Y. W., Novel Drug Delivery Systems; Drugs and Pharmaceutical Sciences(2nded, vol-50) Parenteral Drug Delivery (pp-381-528),New York: Marcel Dekker.

• David A. S. & Adams C.(2001) Depot antipsychotic medication in treatment of patients with schizophrenia, Health Technology Assessment (vol 5, 34), Basingstoke: Queen’s printer and controller of HMSO

• Gothoskar A. V. (March 2004),Resealed erythrocytes: A review, Pharmaceutical technology (pp.140-158)

• Kempe S. & Mader K.(July 2012),In-situ forming implants-an attractive formulation principle for parenteral depot formulation, Journal of Controlled Release (pp.668-679)

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References• Lachman L. & Libberman H. & Kanig J.(2007)

Sterile products(pp.653-654),Bombay: Varghese Publishing House.

• M. Kalyani & P.Surendra & V. Sirisha(2013).Parenteral Controlled Drug Delivery System, International Journal Of Research In Pharmaceutics & Nanosciences (pp.572-580)

• Malik K. & Sigh I. & Nagpal M. & Arrora S.(2010), Atrigel: A potential Parenteral control Drug delivery system, pelagia research lab der pharmacia sinica (pp.74-81)

• Mischel N. & Cox L.(2012),Allergen Immunotherapy Extract Preparation Manual, AAAAI Practice Management Resource Guide(pp.1-39)

• Tarmarakar S. M. & Koirala N. R.(2007), Latest Advances in De-Addiction Strategies, Kathmandu University Medical Journal (pp.124-128)

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References• Vyas S. P. & Khar R. K.(2006), Targeted and Controlled

Drug Delivery Novel Carrier Systems(pp.3-38;173-279; 387-457) New Delhi: CBS Publishers and Distributors.

• Wheeler A. M. & Newland B. Advantages of L-tyrosine as a depot adjuvant for formulation of therapeutic allergy vaccines; Allergy therapeutics: transforming allergy treatment

• www.pharmatutor.org/articles/aquasomes-potential-approach-novel -drug-delivery

• www.pharmatutor.org/articles/information-and-article-on-erythrocytes-as-a-drug carrier.

• www.pharmatutor.org/articles/review-parenteral-controlled-drug -delivery-system

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