PHARMACEUTICAL FORMS & DRUG

DELIVERY METHODS

SystemicAdministration Pharmaceutical Forms

Oral Solid, Liquid

Paranteral Solution, suspension, emulsion

Inhalational Gas, aerosol, vapor, inhalator, nebulizer

Transdermal Plaster, pommade

Others Nasal spray, intratecal

• The enteral route is very convenient• Numerous factors influence absorption→ make it

quite unpredictable• It is subject to variability from patient to patient

and even in the same patient at different timesPharmaceutical firms try to develop drug

formulations with better absorption characteristics.

Enteric coating was introduced long ago to resist the action of gastric fluids and to disintegrate and dissolve after passage into the intestine.

The purpose was • to protect a drug that would be degraded in the

stomach, • to prevent nausea and vomiting caused by local

gastric irritation, • to achieve a high local concentration of a drug

intended to act locally in the intestine,• to produce a delayed drug effect, or to deliver a

drug to the intestine for optimal absorption there.

CONTROLLED-RELEASE FORMULATIONS

• The rate of absorption of a drug adm as tablet or other solid form is dependent on its rate of dissolution in GI fluids → controlled-release, sustained-release, extended-release, prolonged action → slow uniform abs of drugs for 8 h or longer

• Reduction of the frequency of adm (improved compliance by the patient)

• Maintenance of therapeutic effect overnight drawbacks: the dosage form may fail “dose dumping”

most appropriate for drugs with short half lives

If two formulations of a drug contains the same amount of the active ingredient, will both actually

yield the same amount at the same rate of absorption into the circulation?

• Considerable variability has been found, attributable to differences in particle size, binders, compression of the tablet, or thickness of the capsul wall.

• Dissolution, disintegration• The most satisfactory test is to measure blood or

plasma concentration.

DIFFERENCES IN ABSORPTION OF 4 DIGOXIN PRODUCTS IN 4

SUBJECTS

• Preparations B2 and C were distinctly inferior to A and B1.

• An important lesson is the potential danger of switching preparations after a patient has been stabilized on any one preparation (narrow therapeutic margin)

SPECIAL DRUG DELIVERY SYSTEMS

• biologically erodable microspheres

• prodrugs

• antibody-drug conjugates

• packaging in liposomes

• coating implantable devices.

• Microspheres of biologically erodable polymers can be engineered to adhere to mucosal epithelium in the gut.

• Such microspheres can be loaded with drugs, including high-molecular-weight substances, as a means of improving absorption

• This approach has yet to be used clinically, but microspheres made from polyanhydride copolymers of fumaric and sebacic acids by a technique known as phase inversion nanoencapsulation have been used to produce systemic absorption of insulin and of plasmid DNA following oral administration in rats potentially enabling gene therapy.

Prodrugs

• the cytotoxic drug cyclophosphamide becomes active only after it has been metabolized in the liver; it can therefore be taken orally without causing serious damage to the gastrointestinal epithelium.

• Levodopa is absorbed from the gastrointestinal tract and crosses the blood-brain barrier via an amino acid transport mechanism before conversion to active dopamine in nerve terminals in the basal ganglia

• Zidovudine is phosphorylated to its active trisphosphate metabolite only in cells containing appropriate reverse transcriptase, hence conferring selective toxicity towards cells infected with HIV

Antibody-drug conjugates

• One of the aims of cancer chemotherapy is to improve the selectivity of cytotoxic drugs

• One possibility is to attach the drug to an antibody directed against a tumor-specific antigen, which will bind selectively to tumor cells. Such approaches look promising in experimental animals, but it is still too early to say whether they will succeed in humans.

•

Packaging in liposomes

• Liposomes are minute vesicles produced by sonication of an aqueous suspension of phospholipids. They can be filled with non-lipid-soluble drugs or nucleic acids , which are retained until the liposome is disrupted. Liposomes are taken up by reticuloendothelial cells, especially in the liver. They are also concentrated in malignant tumors, and there is a possibility of achieving selective delivery of drugs in this way.

• Amphotericin, an antifungal drug used to treat systemic mycoses , is available in a liposomal formulation that is less nephrotoxic and better tolerated than the conventional form, but considerably more expensive.

Coated implantable devices

• coatings have been developed that permit localised drug delivery from implants. Examples include hormonal delivery to the endometrium from intrauterine devices, and delivery of antithrombotic and antiproliferative agents (drugs or radiopharmaceuticals) to the coronary arteries from stents (devices inserted via a catheter after a diseased coronary artery has been dilated with a balloon). Stents reduce the occurrence of restenosis, but this can still occur at the margin of the device. Coating stents with drugs such as sirolimus (a potent immunosuppressant) embedded in a surface polymer prevents this important clinical problem.

• Approved in USA & CE marked in Europe• Commercial status

– Currently marketed for insulin – Licensed for growth hormone

• Two configurations developed– Intra-muscular – Subcutaneous

• Variable dose up to 0.5 ml• Disposable needle-free syringe

Current “state of the art” in needle-free injection

Needle-Free Injection DevicesAntares MJ 7 - Vision™

• Mini-needle combined with low pressure “jet injection”– Virtually no incomplete injections

– Safe in glass cartridge

– Faster injection of larger volumes than conventional needles• Retracting / locking collar

– Patient never sees the needle

– Eliminates sharps hazards• Pre-filled and assembled

– Ultimate convenience for patients• Conventional glass cartridge & stopper materials

– Improves compatibility with existing filling methods

– Minimizes stability and compatibility issues• Capable of delivering up to 1.0 ml• Proprietary technology

AJ1 Mini-Needle AJ1 Mini-Needle DeviceDevice

OSMOTIC TABLET FOR CONTROLLED DRUG DELIVERY

NEW TECHNIQUES FOR CONTROLLED DRUG

ADMINISTRATIONOsmotic and mechanical pumps have been

designed for drug infusion.

Osmotic pumps have been developed for both oral administration and sc implantation. They can be either in the shape of tablets or capsuls. They employ the force generated by an osmotic gradient to push the drug-containing infusion fluid out through a small hole ar a controlled rate

Benzathine penicillin can be administered once monthly to achieve prophylaxis against beta-hemolytic streptococcal infection. Daily self administration of penicillin is harder to comply.

Only 0.02% soluble in water. Absorbed very slowly from im depots

1.2 million units im produces a conc of 0.09 μg/mL on day1

0.02 μg/mL on day14

0.002 μg/mL on day32

• The discovery of the structure of DNA in thew 50s→manipulate the genetic material from cells useful in practical therapeutics

• Gene of interest can be expressed in vitro to generate useful proteins that could not be prepared synthetically

• Gene could be directly introduced in vivo and persuaded to synthesize some crucial cellular component

• Use of proteins as therapeutic agents

• Insulin extracted from animal pancreas, GH extracted from human cadaver pituitary glands

• Danger of transmission of infectious agents across species

• Therapeutic monoclonal antibodies

• First generation and second generation biopharmaceuticals

• First generation ?

• Second generation ?

Engineered proteins

• Modification of PK properties

• Generation of novel fusion proteins

• Reducing immugenicity, humanizing

GENE THERAPY

• Recombinant genes are transferred using a vector often a suitably modified virus

• İn vivo injection of the vector directly into the patient (malignant tumor)

• Ex vivo treatment of cells from the patient (stem cells from marrow or circulating blood) then returned to the patient

• Safety concerns (polycythemia from overexpression of erythropoietin)

• Viral vectors

might acquire virulence during use

contain viral proteins that can be immunogenic

can elicit inflammatory response

could damage the host genome, interfere with the cell cycle provoke malignancy

• Gene therapy for cancer• Restoring protective proteins p53• İnactivating oncogenes• Delivering a gene to malignant cells that

renders them sensitive to drugs• Delivering a gene to healthy host cells to

protect them from chemotherapy• Tagging cancer cells with genes that make

them immunogenic