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PRESENTATION ON CYCL DEXTRINS AS EXCIPIENTS

PRESENTED BY: ASHWANI GOYAL M.PHARMACY 1ST SEMESTER DEPARTMENT OF PHARMACEUTICS CHITKARA SCHOOL PHARMACY

INTRODUCTION
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EXCIPIENTS 1.WHAT ARE EXCIPIENTS? 2.WHY WE USE EXCIPIENTS? 3.WHAT TYPE OF EXCIPIENTS ARE USED IN PHARMACEUTICALS?

EXCIPIENTS
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EXCIPIENTS
An excipient is an inactive substance used as a carrier for the active ingredients of a medication.

BINDE R
DISINTEGR ANT

In many cases, an "active" substance (such as aspirin) may not be easily administered and absorbed by the human body

LUBRICAN T

DILUENT

Example: Binders, Disintegrants, Diluents, Flavours,Cyclodextrins.

TYPES OF EXCIPIENTS
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Antiadherents USED to reduce the adhesion between the powder (granules)

Binders Binders hold the ingredients in a tablet together

Coatings tablet ingredients from deterioration by moisture

Disintegrants dissolve when wet causing the tablet to break apart

Fillers and diluents fill out the size of a tablet

Flavours used to mask unpleasant tasting active ingredients

Colours improve the appearance of a formulation

Glidants promote powder flow by reducing interparticle friction

Lubricants Prevent ingredients from clumping together and from sticking to the tablet punches

Preservatives PRESERVE THE FORMULATION

CYCL
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DEXTRINS

1.WHAT ARE CYCLODEXTRINS? 2.HOW THEY ARE DISCOVERED? 3.WHAT IS THE PRESENT STATUS OF CDs? 4.HOW THEY ARE PRODUCED? 5.WHAT IS THE USE OF CDs IN PHARMACEUTICALS?

CYCL
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DEXTRINS

DEFINATION: CDs are cyclic oligosaccharides derived from starch containing six (CD), seven (CD), eight (CD), nine (CD), ten (CD) or more (-1,4)-linked -Dglucopyranose units.

HISTORY
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In 1891 a French scientist, A. Villiers, described a bacterial digest that he had isolated from starch. results indicated that the substance was a dextrin Later Franz Schardinger, described two crystalline compounds -dextrin and -dextrin Schardinger identified -dextrin as Villiers' cellulosine

Now these compounds are commonly called cyclodextrins

TYPES OF CDs
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CDs

NATURAL -, -, and -CDs

SYNTHETIC Sulfobutylether--CD Methyl--CD

COMMERCIAL AVAILABILITY
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The world's first CD-containing pharmaceutical product, prostaglandin E2/CD (Prostarmon Esublingual tablets), was marketed in Japan in 1976. Twelve years later, the first European CD-based pharmaceutical product, piroxicam/CD (Brexin tablets), was marketed and in 1997, the first US-approved product Worldwide, 35 different drugs are currently marketed as solid or solution-based CD complex formulations In these pharmaceutical products, CDs are mainly used as complexing agents to increase the aqueous solubility of poorly water-soluble drugs, to increase their bioavailability and stability

SOME MARKETED CDs BASED PCEUTICALS.

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Drug/cyclodextrin

Trade name

Formulation

Company (Country)

Alpha Cyclodextrin
Alprostadil Cefotiam-hexetil HCl Caverject Dual Pansporin T i.v. solution Tablet Pfizer (Europe) Takeda (Japan)

-Cyclodextrin (CD)
Nimesulide Nimedex Tablets Novartis (Europe)

STRUCTURE AND PRODUCTION OF CDs.

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Due to the chair conformation of the glucopyranose units, the CDs take the shape of a truncated cone or torus rather than a perfect cylinder.

STRUCTURE
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-cyclodextrin- 7 sugar molecules

-cyclo-dextrin- 6 sugar molecules

-cyclodextrin- 5 sugar molecules

Secondary Hydroxyl rim

PRODUCTION
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Bacillus Circulans
The source of cyclodextrins

Treatment of starches with amylase from B. macerans gives a crude mixture of CD (60%), CD (20%) and CD (20%) together with small amounts of CDs with more that 8 glucopyranose units. In reaction vats at pH 6.0-7.0 at 35-40 C.

TOXOLOGICAL CONSIDERATIONS
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CONSIDERED SAFE

REGULATORY STATUS
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CD is listed in a number of pharmacopoeia sources including the US Pharmacopoeia/National Formulary (USP/NF), European Pharmacopoeia (Ph.Eur.) and Japanese Pharmaceutical Codex (JPC). CD is similarly listed in the Ph.Eur., USP/NF and JPC and CD is referenced in the JPC and will soon be included in the Ph.Eur

ROLE OF CDs IN PCEUTICALS

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CYCLODEXTRINS EFFECT THE FOLLOWING PROPERTIES 1.Effect on Drug Solubility and Dissolution Playing a very important role in formulation of poorly water-soluble drugs by improving apparent drug solubility and/or
dissolution through inclusion complexation or solid dispersion, by acting as hydrophilic carriers .

Examples of CD-enhanced Solubility and Dissolution

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CYCLODEXTRIN -CD

DRUGS Nimesulide, Sulfomethiazole, Lorazepam, Ketoprofen, Griseofulvin, Praziquantel, Chlorthalidone, Etodolac, Piroxicam,, Itraconazole, Ibuprofen Praziquantel Praziquantel, Omeprazole, Digoxin Albendazole, DY9760e, ETH615, Levemopamil HCl, Sulfomethiazole, Ketoprofen,, Griseofulvin, Itraconazole, Carbamazepine Zolpidem, Phenytoin, Rutin Spiranolactone

-CD -CD HP--CD

SBE--CD

EFFECT ON DRUG BIOAVAILABILITY

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CDs enhance the bioavailability of insoluble drugs by increasing the drug solubility, dissolution, and/or drug permeability. CDs increase the permeability of insoluble, hydrophobic drugs by making the drug available at the surface of the biological barrier, e.g, skin, mucosa, or the eye cornea, from where it partitions into the membrane without disrupting the lipid layers of the barrier.

EFFECT ON DRUG SAFETY

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CDs have been used to ameliorate the irritation caused by drugs. The increased drug efficacy and potency (i.e, reduction of the dose required for optimum therapeutic activity), caused by CD-increased drug solubility, may reduce drug toxicity by making the drug effective at lower doses.

The toxicities associated with crystallization of poorly water-soluble drugs in parenteral formulations can often be reduced by formation of soluble drug:CD complexes.

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EFFECT ON DRUG STABILITY

CDs can improve the stability of several labile drugs against dehydration, hydrolysis, oxidation, and photodecomposition and thus increase the shelf life of drugs. It was reported that CD-induced enhancement of drug stability may be a result of inhibition of drug interaction with vehicles and/or inhibition of drug bioconversion at the absorption site. By providing a molecular shield, CD complexation encapsulates labile drug molecules at the molecular level and thus insulates them against various degradation processes. PROPERTY Photostability Thermal stability in solid state Stability against hydrolysis Photoreactivity DRUG Promethazine Diclofenac sodium Digoxin Flutamide

CYCLODEXTRIN HP--CD, DM--CD -CD HP--CD -CD

APPLICATIONS OF CDs
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Oral Drug Delivery

include improvement of drug bioavailability due to increased drug solubility, improvement of rate and extent of dissolution, and/ or stability of the drug at the absorption site, e.g. the gastrointestinal tract (GIT) or in formulation, reduction of druginduced irritation, and taste masking .

APPLICATIONS
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Parenteral Drug Delivery

CD derivatives such as amorphous HP-- and SBE--CDs have been widely investigated for parenteral use on account of their high aqueous solubility and minimal toxicity. Applications of CDs in parenteral delivery are solubilization of drugs, reduction of drug irritation at the site of administration, and stabilization of drugs unstable in the aqueous environment.

APPLICATION
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Ocular Delivery

Applications of CDs in aqueous eye drop preparations include solubilization and chemical stabilization of drugs, reduction of ocular drug irritation, and enhancement of ocular drug permeability.
DRUG CYCLODEXTRIN

Acetazolamide
Diclofenac Pilocarpine Dexamethasone

HP--CD, -CD, HP--CD

HP--CD, M--CD HP--CD, -CD, -CD, HP--CD

APPLICATIONS
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Nasal Drug Delivery

CDs are effective excipients in nasal drug delivery. CDs improve nasal drug absorption either by increasing aqueous drug solubility and/or by enhancing nasal drug permeability. CDs can also be used to reduce the nasal toxicity of other enhancers

APPLICATIONS
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Rectal Drug Delivery

Applications of CDs in rectal delivery include enhancing drug absorption from a suppository base either by enhancing drug release from the base or by increasing drug mucosal permeability, increasing drug stability in the base or at the absorption site, providing sustained drug release, and alleviating drug-induced irritation. CDs enhance rectal drug stability either by inhibiting the drug/vehicle interaction (by making the drug insoluble in oleaginous base) or by inhibiting the drug bioconversion in the rectum. -CD improved the rectal bioavailability of morphine by inhibiting the upward movement of the drug from areas impacted by first pass metabolism.

RECTUM

APPLICATIONS
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Controlled Drug Delivery

CDs, due to their ability either to complex drugs or to act as functional carrier materials in pharmaceutical formulations, can serve as potential candidates for efficient and precise delivery of required amounts of drugs to targeted site for a necessary period of time. -CD derivatives are classified as hydrophilic, hydrophobic, and ionizable derivatives. The hydrophilic derivatives improve the aqueous solubility and dissolution rate of poorly soluble drugs, while the hydrophobic derivatives retard the dissolution rate of water-soluble drugs from vehicles.
RELEASE PATTERN AIM USE OF CD

Delayed, pH-dependent

(Enteric) Acid protection

CME--CD

release

of drugs

Site-specific release

Colon-targeting

Drug/CD conjugate

APPLICATION
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Colon-Specific Drug Delivery

CDs are barely hydrolyzed and only slightly absorbed in the stomach and small intestine but are absorbed in the large intestine after fermentation into small saccharides by colonic microbial flora. The peculiar hydrolyzing property of CDs makes them useful for colon drug targeting. Biphenyl acetic acid (BPAA) prodrugs for colon-specific delivery were developed by conjugation of the drug onto one of the primary hydroxyl groups of -, -, and -CDs through an ester or amide linkage.

APPLICATION
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Peptide and Protein Delivery

Various problems associated in practical use of therapeutic peptides and proteins are their chemical and enzymatic instability, poor absorption through biological membranes, rapid plasma clearance, peculiar dose response curves, and immunogenicity. CDs, because of their bioadaptability in pharmaceutical use and ability to interact with cellular membranes, can act as potential carriers for the delivery of proteins, peptides, and oligonucleotide drugs

APPLICATION
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Dermal and Transdermal Delivery

CDs have been used to optimize local and systemic dermal drug delivery. Applications of CDs in transdermal drug delivery include enhancement of drug release and/or permeation, drug stabilization in formulation or at absorptive site, alleviation of drug-induced local irritation, sustaining of drug release from vehicle, and alteration of drug bioconversion in the viable skin. CDs, by enhancing apparent drug solubility, enhance the drug thermodynamic activity in vehicles and thus cause enhancement of drug release from vehicles. The enhancement of drug release from vehicles by CDs in turn enhances the dermal drug absorption by improving the drug availability at the lipophilic absorptive barrier surface

APPLICATION
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Brain Drug Delivery or Brain Targetting:

The very low penetration across the BBB greatly hinders the therapeutic use of peptides, and whenever unexplainable poor peptide absorption is seen the role of the efflux pumps should be examined. It was reported that P-gpmediated peptide transport may play an important role in greatly reducing the peptide delivery to the central nervous system in vivo. It was also indicated that CDs such as DM--CD, due to their inhibitory effect on P-gp efflux function, may enhance drug delivery to brain.

APPLICATIONS
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CD Applications in the Design of Some Novel Delivery Systems Liposomes,Microspheres,Microcapsules,Nanopa rticles

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