USP Requirements and FDA Guidance for Modified Release Dosage Forms

Drug ReleaseTest for drug release for ER and delayed-release articles:

Based on drug dissolution from dosage unit against elapse time.

Varian Biodis Dissolution Apparatus• Determines dissolution characteristics of

modified-release products.

Uniformity of Dosage Units

Demonstrated by either of the 2 methods:

Weight variation

Content uniformity

In Vitro-In Vivo correlations (IVIVCs)Critical to development of oral extended-release

products.

Assessing IVICRs is important throughout: A. product development B. clinical evaluation C. submission of an application for FDA approval for marketing D. Post approval for any proposed formulation or manufacturing changes.

Extended Release Oral Dosage Forms: Development, Evaluation and

Application of IVIVCsPublished by FDA in 1997

Provides guidance to sponsors of NDAs for extended-release oral products.

Developing IVIVC and

evaluating its predictability

Using an IVIVC to establish dissolution

specifications

Applying an IVIVC as a surrogate for in

vivo bioequivalence during approval/post approval for certain

formulation or manufacturing

changes.

3 categories of IVIVCs Level A

Predictive mathematical model for the relationship between the entire in vitro in vivo dissolution and release time course and the entire in vivo response time course

• Example: time course of plasma drug concentration of amount of drug absorbed

Level BPredictive mathematical model of the relationship between summary parameters that characterize the in vitro and in vivo time courses.

• Example: models that relate the mean in vitro dissolution time to the mean in in vivo dissolution time.

• Mean in in vitro dissolution time to the mean residence time in vivo, or the vitro dissolution rate constant.

Level CPredictive mathematical model between the amount dissolved in vitro at a particular time and a summary parameter that characterizes the in vivo time course.

Most common process for developing an IVIVC modelDevelop formulations with different release rates

or a single release rate if dissolution is independent of condition

Obtain in vitro dissolution profiles and in vivo plasma concentration profiles for these formulations

Estimate the in vivo absorption or dissolution time course for each formulation and subject using appropriate mathematical approaches.

Criteria to the Development of IVIVCsIn determining in vitro dissolution, USP dissolution apparatus, type I (basket)Type II (paddle) are preferred.

Preferred medium for dissolution is aqueous medium with pH not exceeding 6.8. If poorly soluble, surfactant may be added.

Dissolution profiles of at least 12 individual dosage units from each lot should be determined.

In in vivo studies, human subjects should be in the fasted state. Accepted data sets have been shown to be generated with use of 6-36 human subjects.

Crossover studies are preferred, but parallel studies/cross-study analysis may be acceptable using common reference treatment product.

LabelingMust be specific to the monograph article

Example:Aspirin delayed-release tablets must state that

the tablets are enteric coated.

Theophylline extended-release capsules must indicate whether drug dosing is every 12 or 24 hours and state with which in vivo drug release test the product complies.

Clinical Considerations in the Use of Oral Modified Release Dosage FormsPatients should be advised of:Dose

Dosing frequency

Not to use interchangeably with immediate-release forms of same drug.

Modified release tablets and capsules should not be crushed or chewed.

Patients fed by parenteral nutrition may through nasogastric tube may receive modified-release medication.

Patients and caregivers should be advised that nonerodible plastic matrix shells and osmotic tablets:

Remain intact throughout gastrointestinal transit

Empty shells/ghosts from osmotic tablets may be seen in the stool.

Vaginal Insert• Cervidil vaginal insert (Forest Pharmaceutical)• - rectangular polymeric pouch containing

dinoprostone ( Prostaglandin E2) in a cross-linked polyethylene oxide or urethane polymer releasing the drug at a predetermined controlled release rate for induction of labor.

• Crinone gel (Wyeth-Ayerst) • - contains micronized progesterone and the

polymer polycarbophil in an oil in water emulsion system

• -assist in reproduction

• Estradiol vaginal ring (Estring pharmacia and Upjohn)

• - unique method of administering estradiol• - core of ring contains a reservoir of estradiol

which releases immediately and at a continuous rate of 75ug per 24 hrs over 90 days

• -treatment of urogenital symptoms associated with postmenopausal atrophy of vagina, inserted into the upper 1/3 of the vaginal vault and worn continuously

Subdermal Implant• -inserted under the skin by special injectors or by

surgical incision termed implants• -Provides continuous long term through the slow

release medication• EXAMPLES:• Goserelin acetate (zoladex implant, zeneca)• Treatment of advanced prostatic cancer• Biodegradable product for subcutaneous injection

with continuous medication release over a 4-12 week period

• Levonorgestrel (Norplant System)• -provides 5 year protection from pregnancy after

subcutaneous insertion

Parenteral System• Extended rate of drug action following injection

may be achieved in a number of ways• - use of crystal/amorphous drug forms having

prolonged dissolution characteristics• * slowly dissolving chemical complexes of the

drug entity: solutions or suspensions of drug in slowly absorbed carriers or vehicles

• * increased particle size of drug in suspension• * injection of slowly eroding microspheres of the

drug• * slow IV infusion using controlled drug infusion

pumps

Ocular Drug Product• Problems associated with ophthalmic solutions

• *rapid loss of administered drug

• * extended products of therapy achieved by:

• - formulations increase in contact time between the medication and the corneal surface by use of agents that increase viscosity of solutions by ophthalmic suspensions where drug particles slowly dissolve by slowly dissipating ophthalmic ointments

Preparations that increase corneal contact time: Pilocarpine HS GelTimoptic XF

Ophthalmic Inserts:Occusert system :- Elliptical- Flexible- Drug containing core surrounded on each side by a

layer of hydrophobic ethylene or vinyl acetate through which drug diffuses at a constant rate

Lacrisert- Rod shaped- Water soluble - Soften and slowly dissolve- Thickens precorneal tear film- Prolonging the tear film breakup