Global Sales For Drug Products

Published Date: 02 Nov 2017

Introduction

The first and foremost step in drug development is discovery of a new chemical moiety that shows pharmacological effects for curing or treating diseases or relieving symptoms. Along with the discovery of new chemical moiety, it is also essential that new chemical moiety is released in desired amount to the target at a specific time or duration. In order to ensure that optimal therapeutic outcomes are achieved, a delivery system should be designed to achieve the optimal drug concentration at a desired rate and at the desired location. 1

The global market for novel drug delivery systems in 2008 was about $134.3 billion, and was estimated to increase to $139 billion in 2009. The projection for 2014 is $196.4 billion, for a compound annual growth rate (CAGR) of 7.2% in the 5-year period. The largest portion of the market is TDDS, reached $50.9 billion in 2009 and is projected to increase to $80.2 billion in 2014, for a CAGR of 9.5%. Sustained-release products have the second-largest market portion, with estimated sales of $36.1 billion in 2009 and $45.8 billion in 2014, for a CAGR of 4.9%.5 (Refer figure 1)

Figure 1: Summary figure of global sales for drug products (2007-2014) ($ billions) 5

For many decades, conventional pharmaceutical dosage forms, such as liquids, tablets, capsules, ointments, injectables or aerosols are used as drug carriers for treatment of an acute disease or a chronic illness. A number of advances have been made during the last two decades in the development of new technologies for optimising drug delivery. These technologies are capable of regulating the rate of drug delivery, targeting the delivery of drug to a specific site, and/or sustaining the duration of therapeutic action.2

One of the approaches is ‘Time release technology’. Time release technology, also known as sustained-action (SA), sustained-release (SR), extended-release (ER, XR, or XL), modified release (MR), controlled-release (CR), or continuous-release (CR or Contin) time-release or timed-release, is a mechanism used in pill tablets or capsules to dissolve slowly and release a drug over time. The advantages of sustained-release dosage forms are that the frequency of dosing is lesser than immediate-release formulations of the same drug, and that they keep steady state concentration of the drug in the bloodstream.3

There are a number of potential limitations associated with a 'conventional' peroral oral (immediate release dosage form) dosage form. (Refer figure 2)

These limitations are:

1. The plasma concentration of drug and hence the site of action of the drug fluctuates over successive dosing intervals, even when the steady-state concentration is achieved. Hence it is impossible to maintain a constant therapeutic concentration of drug at the site of action for the duration of treatment. The average value of the maximum and minimum plasma concentrations associated with each successive dose remains constant for the period of drug treatment.

2. The fluctuations of steady-state concentrations of drug in the plasma, and hence at the site of action, can lead to a patient being over /under-medicated for periods of time if the values of Cmax and Cmin rise or fall, respectively, beyond the therapeutic range of the drug.

3. For drugs with shorter t1/2, high frequency doses are required to maintain steady state plasma concentrations within the therapeutic range. Patient non-compliance, which is more susceptible in the case of drug regimens requiring frequent administration of conventional dosage forms, is often an important reason for therapeutic inefficiency or failure.

Clearly, if the patient does not comply with peroral dosage regimen, not even one peroral dosage regimen can be designed to perfection and maintain clinically efficacious concentrations of a drug at its site of action.4

Figure 2: Plasma concentration of drug when ‘Conventional’ peroral dosage form is given in repetition to achieve steady state

Over the years there has been an enormous progress into designing drug delivery systems that can eliminate or reduce the cyclical plasma concentrations seen after conventional drug delivery systems are administered to a patient. Each novel delivery system is aimed at eliminating the cyclical changes in plasma drug concentration seen after the administration of a conventional delivery system. (Refer figure 3)

Figure 3: Cyclical changes observed during Conventional dosing system

Modified release (MR) dosage forms are defined by the USP are those whose drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional forms. It is important to note that the USP considers that the terms controlled release; prolonged release and sustained release are interchangeable with extended release. From a biopharmaceutical perspective this is not strictly a concern.4

A variety of terms are included in Modified dosage forms4:

Delayed release indicates that the drug is not being immediately released followed by administration but at a later time, e.g. enteric coated tablets, pulsatile-release capsules. (Refer figure 4; yellow curve)

Sustained release indicates that the drug is initially released to provide a therapeutic dose soon after administration, and then a gradual release over an extended period. (Refer figure 4; purple curve)

Extended release (ER) indicates that the drug is released slowly, so that plasma concentrations are maintained at a therapeutic level for a prolonged period of time (usually between 8 and 18 hours). (Refer figure 4; red curve)

Controlled release (CR) indicates that the dosage form releases the drug at a constant rate and provides plasma concentrations that remain invariant with time. (Refer figure 4; green curve)

Figure 4: Graph showing the differences between each modified dosage form

In recent years there has been an increasing effort to develop prolonged release dosage forms. The prolonged release dosage forms have many advantages in safety and efficacy over immediate release products like the frequency of dosing can be reduced and drug efficacy can be prolonged along with decreased incidence of adverse effects. Extended release drug formulations make the drug available over extended time period after oral administration and have been used since 1960’s. The extended release product optimizes therapeutic effect and safety of a drug along with improving the patient compliance by incorporating the dose for 24 hrs into one tablet from which the drug is slowly released. This formulation helps to avoid the side effects associated with low and high concentrations like the ideal drug delivery system which should show a constant zero-order release rate and maintain the constant plasma concentrations.6

Advantages: 6

Extended release products having many advantages.

The extended release formulations aims to maintain therapeutic concentrations over prolonged periods.

The use of extended release formulations avoids the high drug plasma concentration.

Extended release formulations have showed to improve the patient compliance.

Reduces the toxicity by slowing drug absorption.

Increases the stability of drug by protecting the drug from hydrolysis or other degradative changes in gastrointestinal tract.

Minimizes the local and systemic side effects.

Improves treatment efficacy.

Minimizes drug accumulation associated with chronic dosing.

Total drug utilized is less.

Improves the bioavailability of some drugs.

Improves the ability to provide special effects.

Ex: Morning relief of arthritis by bed time dosing.

Disadvantages: 6

Manufacturing cost is high.

The release rates are affected by various factors such as, food and the rate transit through the gut.

Some differences in the release rates from one dose to another dose; however these have been minimized by modern formulations.

The larger size of extended release products may cause difficulties in ingestion or transit through gut.

Drug properties which are suitable for Extended release formulation7:

Table 1: Drug properties required for formulating in Extended release dosage formulation

Types of Extended release formulation:

Many current oral extended release systems are available

1. Dissolution-controlled release system.

2. Diffusion-controlled release system.

3. Osmotic pump system.

4. Erosion controlled release systems.

A) Diffusion controlled extended release formulations8

The release of the drug is controlled mainly by its diffusion through a water insoluble polymeric layer. Drug dissolution also contributes to the release of the drug but to a lesser extent.

Reservoir system8

In these formulations, film coating constitutes the main factor in controlling drug release. The initial application involved the use of pan-coating process to apply various mixtures of fats and waxes to drug-loaded pellets. Since then, a variety of coating materials and coating machines have been developed and modified. E.g. hardened gelatin, methyl or ethyl cellulose, polyhydroxymethacrylate, methacrylate ester copolymers, various waxes.

Out of these, ethyl cellulose and methacrylate ester copolymers are the most commonly used systems in the pharmaceutical industry.

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Figure 5: Diffusion controlled Reservoir system10

Matrix system8

In these formulations, the drug is uniformly distributed through the release controlling element. Two major types of materials are used in the pharmaceutical industry to control the drug release from matrix devices; insoluble plastics and fatty compounds.

E.g.; Insoluble plastics: methylacrylatemethyl methacrylate copolymers, polyvinyl chloride, polyethylene.

Fatty compounds: carnuba wax and glyceryl tristearate.

B) Dissolution controlled extended release Formulations8

These formulations releases drug mainly by the slow dissolution or erosion of the release controlling element in the formulation. The system can be formulated into reservoir type by encapsulating the drug within slowly soluble polymeric membrane in the form of tablets or capsules. Another approach is to formulate the drug into a matrix system using hydrophilic swellable polymers. E.g. hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, sodium carboxymethyl cellulose

A major drawback in the dissolution controlled system is the difficulty to maintain a constant drug release rate since the release rate changes as the size of dosage form diminishes with time.

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Figure 6: Dissolution controlled system12

C) Osmotic controlled extended release formulations 7

They are reservoir systems into which osmotically active agents are incorporated, when the drug itself is not osmotically active, in the formulations. The dosage form is coated with a semi permeable membrane through which hole(s) are carefully drilled. Gastrointestinal fluid diffuses through the membrane and dissolves the osmotic agent(s) creating high osmotic pressure inside the reservoir. Subsequently, water pushes out of the reservoir through the hole(s) under the osmotic pressure difference carrying the drug. Drug release follows zero order kinetics independent of the pH of the gastrointestinal tract. E.g. Semi permeable membranes: Polyvinyl alcohol, Polyurethane, Cellulose acetate, Ethyl cellulose, Polyvinyl chloride

Different types of osmotic pumps have been developed and modified to provide zero-order delivery of varieties of drugs.http://www.alzet.com/downloads/Cross_section.jpg

Figure 7: Osmotic Pump9

D) Erosion controlled release systems6

In these systems, the rate of drug release is controlled by the erosion of a matrix in which the drug release is controlled by the erosion of a matrix in which the drug is dispersed. The matrix which normally is a tablet, i.e. the matrix is formed by a tabletting process, and the system can thus be described as a single unit system. The erosion in its simplest form can be described as a continuous release of matrix material (both drug and excipients) from the surface of the tablet, i.e. surface erosion. The consequence will be a continuous reduction in tablet weight during the course.

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Figure 8: Erosion controlled system11

Mechanism of drug release from an erosion based matrix tablet6

Drug release from an erosion system can thus be described in two steps.

1. Matrix material, in which the drug is dissolved or dispersed, is released from the surface of the tablet.

2. The drug is then exposed to the gastrointestinal fluids and mixed with (if the drug is dissolved in the matrix) or dissolved in (if the drug is suspended in the matrix) the fluid.

The eroding matrix can be formed from different substances like lipids or waxes, in which the drug is dispersed. Another example is polymers that gel in contact with water (Hydroxy ethyl cellulose) which will subsequently erode and release the drug dissolved or dispersed in the gel. Diffusion of the drug in the gel may occur in parallel.

Introduction to Epilepsy

Epilepsy is a major health problem both in developed and developing nations. It has been estimated that nearly 10 percent of population will have at least one seizure in their lifetime and affects approximately 3 percent of individual by the time they are 80 years old. Globally, after cardiovascular and Alzheimer’s disease, epilepsy is third most common neurological disorder.13

Although standard therapy permits control of seizures in 80 percent of these patient, millions (500,000 people in USA alone) have uncontrolled epilepsy.14

Epilepsy is defined as a condition characterized by recurrent (two or more) unprovoked seizures. Seizures are defined as episodes of abnormal electrical activity in brain that cause involuntary movements, sensation or thoughts while convulsions are involuntary contraction or series of contraction or series of contractions of voluntary muscles.

The situation, however, in India is complex due to several factors namely:

1. Dearth of epidemiological data (with respect of prevalence and incidence)

2. Large treatment gap due to ignorance and insufficiency of resources,

3. Patients' and relatives’ views regarding disease and expectations from therapy.

4. Poor compliance of therapy and

5. Patients falling for irrational modes of therapy and quacks.

The care – giver (primary care doctor, physician, paediatrician and neurologist) is often faced with the question of selecting appropriate drug for optimum control of seizures. 15

Types of epilepsy 16, 17

Gernalized seizures

Tonic – clonic seizures: tonic spasm of all body muscles clonic jerking followed by prolonged sleep and depression.

Absence seizures: momentary loss of consciousness, no muscular component or little bilateral jerking.

Atonic seizures: unconsciousness with relaxation of all muscles due to excessive inhibitory discharge.

Myoclonic seizures: shock like momentary contraction of muscles of limb or body.

Partial seizures

Simple partial seizures: convulsions are confined to group of muscle or area of cortex involved in seizures without loss of consciousness.

Complex seizures: confused behaviour and purposeless movement emotional changes for 1to 2 min with impairment of consciousness.

Simple partial or complex partial seizures secondarily gernalized:

A partial seizure occurs first and progresses into generalized tonic-clonic seizures with loss of consciousness. An epilepsy syndrome is characterized by a variety of sign and symptoms. A particular syndrom will attempt to incorporate a number of items including type seizure, etiology, anatomy, precipitation factor, age of onset, severity, chronicity, circadian cycling.

The Need of Extended Release Dosage form

Epilepsy is a chronic disorder that requires adherence to long term anticonvulsant drug therapy for successful result. 14 Most established anticonvulsant must be taken several times a day because of short half- lives and narrow therapeutic indices.

Data suggest just a small difference in compliance between once- and twice-daily administrations, with no significant difference in efficacy. Therefore, the increased compliance following once-daily administration may be counter-productive in minimising the occurrence of sub-therapeutic drug concentrations. 18

Figure 9: Graph showing plasma concentrations of drug by Conventional Immediate release formulation and Extended release formulation