Regulatory Consideration In Control Release Drug : Regulatory Consideration In Control Release Drug Guided By:
Pawan Chowdhary 1. INTRODUCTION : 1. INTRODUCTION Keep steadier level of the drug in the bloodstream.
First control release drug made by Howard Press.
Active ingredient is embedded in a matrix of insoluble substances like acrylics, chitin,etc.
Control release is a perfectly zero order release.
Release of the active agent may be constant over a long period.
Maintain of drug level within a desired range.
Increased patient compliance.
Deliver an adequate amount of drug. Slide 3: Main principle of control drug delivery is solid dispersion.
Improve the drug release.
Improve the drug solubility.
Improve the drug absorption.
Achieve a super saturation of drug.
Improvement of bioavailability of drug. Control drug delivery : Control drug delivery Goal of drug delivery techniques;
Deploy to a target site to limit side effects.
Shepard drugs through specific areas of the body without degradation.
Predictable controllable release rates.
Maintain a therapeutic drug level for prolonged periods of time.
Reduce dosing frequent and increase patient compliance.
Greater selectivity of pharmacological activity.
More constant and therapeutic effect.
A decreased incidence or intensity of the side effects. Drug Properties : Drug Properties Aqueous solubility first be considered in the selection of appropriate delivery mechanism.
Site of absorption.
pH dependency of the solubility.
Specific surface area. Biomaterials for delivery system : Biomaterials for delivery system Range of materials (polymers) have been employed to control the release of drugs and other active agents.
Chemically inert and free of leachable impurities.
Polyglycolides (PGA). Drug release mechanisms : Drug release mechanisms Dissolution of the active component and the diffusion of dissolved or solubilized species.
Four processes operating;
Hydrating of the device.
Diffusion of water into the device.
Dissolution of the drug.
Diffusion.of.the.dissolved.(or.solubilized).drug.out.of.the.device. Rationale of Controlled –Drug Delivery: : Rationale of Controlled –Drug Delivery: Basic rationale for controlled drug delivery is to alter the pharmacokinetic and pharmacodynamics of pharmacologically active moieties
Primary objectives of controlled drug delivery are to ensure safety and to improve efficiency of drugs as well as patient compliance.
This achieved by better control of plasma drug levels and frequent dosing. Controlled Release Systems: : Controlled Release Systems: Diffusion controlled systems:-
Characterized by release rate of drug is dependent on its diffusion through inert water insoluble membrane barrier.
Water Penetration Controlled Systems:-
Rate control is obtained by the penetration of water into the system.
Swelling Controlled Systems:-
Initially dry and when placed in the body absorb water or other body fluids and swell.
Swelling increases the aqueous solvent content within the formulation as well as the polymer mesh size, enabling the drug to diffuse through the swollen network into the external environment. Characteristic and Factors Affecting controlled release system:- : Characteristic and Factors Affecting controlled release system:- Physicochemical properties of drug:
Aqueous Solubility :
Drug Stability :
Molecular size and diffusivity:
Protein binding: Slide 11: Biological factors:
Biological Half Life:
d) Metabolism: 2. LAW-REGULATION AND GUIDENCE FOR CONTROL RELEASE PRODUCT : 2. LAW-REGULATION AND GUIDENCE FOR CONTROL RELEASE PRODUCT Controlled Substances Act:-
Enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970.
The CSA is the federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain substances is regulated.
Legislation created five Schedules.
Proceedings to add, delete, or change the schedule of a drug or other substance may be initiated by the Drug Enforcement Administration (DEA), the Department of Health and Human Services (HHS). Slide 13: Schedules of controlled substances:-
Divided in five categories.
Schedule I controlled substances :
The drug or other substance has a high potential for abuse.
There is a lack of accepted safety for use of the drug or other substance under medical supervision.
Gamma-Hydroxybutyric acid (GHB)
12-Methoxyibogamine (Ibogaine) Slide 14: Schedule II controlled substances:-
Abuse of the drug or other substances may lead to severe psychological or physical dependence.
Opium and opium tincture
Short-acting barbiturates, such as pentobarbital Slide 15: Schedule III controlled substances :-
The drug or other substance has a potential for abuse less than the drugs or other substances in schedules I and II.
Abuse of the drug or other substance may lead to moderate or low physical dependence or high psychological dependence.
Ex. Anabolic steroids (including prohormones such as androstenedione);
Intermediate-acting barbiturates, such as talbutal or butalbital
Marinol. Slide 16: Schedule IV controlled substances :-
The drug or other substance has a low potential for abuse relative to the drugs or other substances in schedule III.
Ex. Long-acting barbiturates such as phenobarbital.
Benzodiazepines, such as alprazolam
Some partial agonist opioid analgesics, such as pentazocine. Slide 17: Schedule V controlled substances:-
The drug or other substance has a low potential for abuse relative to the drugs or other substances in schedule IV.
Ex. Cough suppressants containing small amounts of codeine (e.g., promethazine+codeine);
Preparations containing small amounts of opium or diphenoxylate (used to treat diarrhea);
Pregabalin (Lyrica), an anticonvulsant and pain modulator. 3. CONTROL RELEASE NEW DRUG APPLICATIOIN : 3. CONTROL RELEASE NEW DRUG APPLICATIOIN FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or potential marketer) having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans.
At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system. Slide 19: Investigation New Drug application must contain information in three broad areas:
Animal Pharmacology and Toxicology Studies.
Manufacturing Information .
Clinical Protocols and Investigator Information .
Laws, Regulations, Policies and Procedures
The mission of FDA is to enforce laws enacted by the U.S. Congress and regulations established by the Agency to protect the consumer's health, safety, and pocketbook.
The law is intended to assure consumers that drugs and devices are safe and effective for their intended uses. 4. NEW DRUG APPLICATION AND ABBREVIATED NEW DRUG APPLICATION : 4. NEW DRUG APPLICATION AND ABBREVIATED NEW DRUG APPLICATION New Drug Application:-
The New Drug Application (NDA) is the vehicle in which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing.
Goals of the NDA ;
Drug safe and effective in its proposed use.
Methods used in manufacturing.
Maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality, and purity. Slide 21: Before trials:-
This application is based on pre-clinical data, typically from animal studies, that shows the drug is safe enough to be tested in humans.
The legal requirement for approval is "substantial" evidence of efficacy demonstrated through controlled clinical trials.
This standard lies at the heart of the regulatory program for drugs.
Data for the submission must come from rigorous clinical trials.
The trials are typically conducted in three phases: Slide 22: Phase 1: The drug is tested in a few healthy volunteers to determine if it is acutely toxic.
Phase 2: Various doses of the drug are tried to determine how much to give to patients.
Phase 3: The drug is typically tested in double-blind, placebo controlled trials to demonstrate that it works.
Phase 4: These are post-approval trials that are sometimes a condition attached by the FDA to the approval.
The legal requirements for safety and efficacy have been interpreted as requiring scientific evidence that the benefits of a drug outweigh the risks and that adequate instructions exist for use, since many drugs are toxic and technically not "safe" in the usual sense. Slide 23: The actual application:-
The results of the testing program are codified in an FDA-approved public document that is called the product label, package insert or Full Prescribing Information.
The documentation required in an NDA is supposed to tell the drug’s whole story, including what happened during the clinical tests, what the ingredients of the drug formulation are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged.
Once the application is submitted the FDA will decide if it will get a standard or accelerated review.
A standard review implies an FDA decision within about 9 months. Slide 24: Abbreviated New Drug Application:-
An Abbreviated New Drug Application (ANDA) is an application for generic drug approval for an existing licensed medication or approved drug.
The ANDA contains data which when submitted to FDA's Center for Drug Evaluation and Research, provides for the review and ultimate approval of a drug product
A drug product is one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use.
All approved products, listed in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations 5. BIOAVAILABILITY : 5. BIOAVAILABILITY In pharmacology, bioavailability is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs.
Bioavailability is a measurement of the rate and extent of a therapeutically active drug that reaches the systemic circulation and is available at the site of action. Slide 26: Types:-
Absolute bioavailability compares the bioavailability of the active drug in systemic circulation following non-intravenous administration (i.e., after oral, rectal, transdermal, subcutaneous, or sublingual administration), with the bioavailability of the same drug following intravenous administration.
It is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug. Slide 27: The reason for this is that its assessment requires an intravenous reference, that is, a route of administration that guarantees that all of the administered drug reaches the systemic circulation.
Intravenous administration of a developmental drug can provide valuable information on the fundamental pharmacokinetic parameters of volume of distribution (V) and clearance (CL).
This measures the bioavailability of a certain drug when compared with another formulation of the same drug, usually an established standard, or through administration via a different route.
When the standard consists of intravenously administered drug, this is known as relative bioavailability. Slide 28: FACTORS INFLUENCING BIOAVAILABILITY:
Physical properties of the drug (hydrophobicity, pKa, solubility)
The drug formulation.
Gastric emptying rate.
Enzyme induction/inhibition by other drugs/foods.
Individual Variation in Metabolic Differences.
Disease state. 6. BIOEQUIVALENCE : 6. BIOEQUIVALENCE The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.
Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two drug. Slide 30: Birkett (2003) defined bioequivalence by stating that, "two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their bioavailabilities (rate and extent of availability) after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, can be expected to be essentially the same. Pharmaceutical equivalence implies the same amount of the same active substance(s), in the same dosage form, for the same route of administration and meeting the same or comparable standards."
Approaches to Determining BE
In vivo measurement of active moiety in biologic fluid.
In vivo pharmacodynamic comparison.
In vivo clinical comparison.
In vitro comparison . Slide 31: Bioequivalence testing
In determining bioequivalence, for example, between two products such as a commercially-available Brand product and a potential to-be-marketed Generic product, pharmacokinetic studies are conducted whereby each of the preparations are administered in a cross-over study to volunteer subjects, generally healthy individuals but occasionally in patients.
Serum/ plasma samples are obtained at regular intervals and assayed for parent drug (or occasionally metabolite) concentration.
Testing should be conducted at several different doses, especially when the drug displays non-linear pharmacokinetics. 7. CONCLUSION : 7. CONCLUSION Control over the drug delivery can be the most important factor at times when traditional oral or injectable drug formulations cannot be used.
Controlled-release products are formulated to release the drug's active ingredient gradually and predictably over a 12-hour to 24-hour period.
These formulations potentially provide for greater effectiveness in the treatment of chronic conditions through more consistent delivery of the medication; reduced side effects; greater convenience; and higher levels of patient compliance due to a simplified dosage schedule, compared with those of immediate-release drugs.
Duration of release of the drug is a further factor that must be considered (including the transit time of the dosage form through the body, or to the required site of release) as must the means of administration (eg. oral or other means, ie, parenteral). Slide 33: Thanking You