Modified release drug delivery system for antiepileptic drug (Formulation development and evaluation).

Transcription

1 TITLE OF THE THESIS / RESEARCH: Modified release drug delivery system for antiepileptic drug (Formulation development and evaluation). INTRODUCTION: Epilepsy is a common chronic neurological disorder characterized by pattern of repeated seizure. The term Epilepsy originated from the Ancient Greek word epilepsia, means "seizure". These seizures are electrical impulses fired by nerve cells in the brain at a rate of up to four times higher than normal rate which causes a sort of electrical storm in the brain. Probable causes of seizures include head injuries, brain tumors, and maldevelopment of the brain, genetic and infectious illness but in half of the cases, no causes are identified. Proper medication controls seizures for majority of patients. [1] About 50 million people worldwide have epilepsy and nearly 90% of the people suffering from epilepsy are discovered in developing countries. 70% of the time, Epilepsy responds to its treatment and about three fourths of the affected people in developing countries do not get the proper treatment. Onset of new cases occurs most frequently in infants and the elderly. Another cause is a consequence of brain surgery, epileptic seizures may occur in recovering patients. Epilepsy is usually controlled with medication but it cannot be cured. However, more than 30% of people with epilepsy do not have seizure control even with the best available medications. Surgery may be adopted in difficult cases. Epilepsy is not a single disorder but rather it is syndromic with various divergent symptoms involving episodic abnormal electrical activity in the brain. Antiepileptic drugs are different group of pharmaceuticals used in the treatment of epileptic seizures. Main role of anti-epileptic is to reduce the successive firing of the neuron that starts seizures. Anti-epileptic drugs are also known as anticonvulsant or anti-seizure drugs. [1,2] The major targets for the marketed anti-epileptic drugs are voltage gated sodium channel and components of GABA system (GABA A receptor, GAT-1 GABA transporter). Other considerable targets are voltage gated calcium channels, SV2A & α2δ. [3]

2 For a long time it was tried to develop a single drug for the treatment of all type of epilepsies but the causes of epilepsy are extremely diverse and for the treatment of Epilepsy, it should be according to the type of epilepsy. [4] Advanced drug delivery technologies can potentiate a product's clinical and commercial value, it differentiates the product from its competitors. route of drug administration is the most preferred mode of administering drugs for systemic effects for solid oral dosage forms. Pharmacologically, they improve the pharmaco-economics of drugs by reducing adverse effects, improving therapy, safety, efficacy, convenience and compliance. New drug delivery technologies make medicines more convenient to patients by simplifying the dosing regimen and improving oral administration with reducing dosing frequency. These improvements booster patient compliance and quality of life with reduce costs. Commercially, drug delivery technologies give new life to drugs with a new or improved therapeutic benefit and a competitive edge. The drug's market value can be sustained by extending the product's life cycle with a line extension by making new and effective drug delivery systems as: a) To give a product a competitive edge. b) To enable or accelerate market entry. c) Novel drug delivery systems can protect or prolong a product's patent exclusivity. d) Develop an improved product. [5] Anti-epileptic Modified Drug Delivery System (MDDS ) Technology rational: Modified Release Technology also known as Sustained-release (SR), extended-release (ER, XR, or XL) or controlled-release (CR) technology formulated to control the drug release over a period of time. Modified release (MR) dosage form is defined by USP as The one for which the drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms, whereas one class of MR dosage form is an extended-release (ER) dosage form defined as the one which allows a twofold reduction in dosing frequency or increase in patient compliance or therapeutic performance. The USP considers that the terms controlled release; prolonged release and sustained release are interchangeable with extended release. The rational for the MDDS technology is as follows; 1) The basic goal of this technology is to achieve a steady state blood or tissue level that is therapeutically effective & non toxic for an extended period of time.

3 2) This objective can be accomplished by maximizing drug availability. 3) This can be done by increasing the drug absorption. 4) Patient compliance for ease to administer as once a day dosage frequency. 5) Protecting the stomach from the exposure of the active compound. Problems with conventional drug therapy: If the dosing interval is not appropriate for the biological half life of the drug, large peaks and troughs in drug blood level may results. The drug blood level may not be within therapeutic range at sufficiently early time. Patient non compliance with multiple dosing regimens. Potential advantages of controlled drug delivery: Avoid patient compliance problem Employ less total drug a) Minimizing or eliminating local side effects b) Minimizing or eliminating systemic side effects Improve the efficiency of the treatment a) Reduce the fluctuation in drug level b) Improve bioavailability Immediate Release versus Controlled release formulations: Compared with immediate release formulations, controlled release formulations can decrease the frequency of administration required to maintain therapeutically effective plasma drug levels. In addition by producing more constant blood levels, such formulations can reduce the large changes in plasma levels observed between doses. With controlled release formulations, the time to peak plasma concentration is extended because the amount of drug released at once is not as high as it with immediate release formulation. Limitations of CRDDS On the other hand oral MDDS suffer from a number of potential disadvantages as follows; Dose dumping

4 Reduced potential for dose change or withdrawal in the event of toxicity Loss of effect due to diarrhea (too fast transit time) Not suitable for drugs having instability in the GI environment Regulation for MDDS FDA of USA introduced regulations governing bioequivalence and in vitro in vivo correlations for controlled-release products. Required Pharmacokinetic evaluations involve: relative bioavailability following single dose; relative bioavailability following multiple doses; effect of food; dose proportionality unit dosage strength proportionality; single-dose bioequivalence study (at various strengths); in vivo in vitro correlation; pharmacokinetic/pharmacodynamic (PK/PD) relationship. Against this background, pharmaceutical companies are recognizing that drug delivery technologies are a powerful strategic marketing tool to differentiate products and extend product life cycles, thereby overcoming many marketplace challenges. Delivery of a drug with new and innovative therapeutic benefits, drug delivery systems extend products' profitable life cycle, giving pharmaceutical companies competitive and financial advantages and providing patients with improved medications. [5,6] Following list of drugs were converted from IR formulation to Extended Release formulation as a part of product life cycle management. This in turn extends the life of the product. Hence with this background it is hypothesized to develop controlled drug delivery of some anti-epileptic drugs. Following list of drug provides an overview on life cycle management of some of the existing drugs. It can be inferred that most of the drugs are being converted from multiple dosing to single CR dosing. Drugs used in Partial Seizures and Generalized Seizures: Drug Dosage form Route Acetazolamide (ER) Injectable Parenteral

5 /Chewable Carbamazepine Suspension (ER) Clonazepam ly disintegrating Clorazepate dipotassium Diazepam Injectable Parenteral Concentrate (DR) Divalproex sodium (ER) (DR pellets) Ethosuximide Syrup Felbamate Suspension Gabapentin Solution Oxcarbazepine Solution Lamotrigine Lorazepam Injectable Parenteral Phenytoin Chewable Suspension Phenytoin sodium Pregabalin Primidone

6 Tiagabine HCL Topiramate Trimethadione Valproic acid Syrup Zonisamide The major companies in the antiepileptic market include Abbott Laboratories, GlaxoSmithKline, Cephalon, Johnson & Johnson, Novartis AG, Pfizer, Sanofi-Aventis SA, Shire, and UCB Pharma. Pfizer maintains the largest market share in the antiepileptic market with 26% for its two products, Lyrica and Neurontin ($2.96 billion combined sales in 2008). The antiepileptic drug market of Innovators is threatened by generic competition which has risen dramatically after patent expirations among several of the major branded antiepileptics. Generic drugs are usually 40-60% cheaper than branded drugs, can drive down prices and decrease sales achievable by branded antiepileptics. [7] Many newer anti-epilepsy drugs (AEDs) are better tolerated than the older AEDs. They often cause less sedation and require less monitoring. Specific choices of AED depend on the individual patient s condition and the particular side effects of the AED. None has emerged as being superior to either old standard or newer AED drugs. [8] All antiepileptic drugs can increase the risks of suicidal thoughts and behaviour. Some of the newer AEDs are as follows; [8] Valproate and Divalproex Sodium Gabapentin Carbamazepine Pregabalin Phenytoin Topiramate Barbiturates (Phenobarbital and Primidone) Oxcarbazepine

7 Ethosuximide and Similar Drugs Clonazepam and Similar Drugs Lamotrigine Zonisamide Levetiracetam Tiagabine Topiramate is a sulfamate substituted monosaccharide which is available under the trade name TOPAMAX (Ortho-McNeil Pharmaceutical, Inc., Raritan, N.J., U.S.A.) as immediate release tablet and sprinkle capsules, have been approved for use as an antiepileptic agent, as an adjuvant therapy for patients with partial onset seizures or primary generalized tonic-clonic seizures, and for the prevention of migraine. [1,9] For the treatment of epilepsy, the recommended dose of Topamax is 400 mg/day in one or multiple doses. For adults with epilepsy, treatment is initiated with a dose of mg/day, with the dose being titrated in increments of mg at weekly intervals to the recommended or effective dose. Adverse effects associated with the administration of immediate release Topamax include dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia, diplopia, renal calculi (kidney stones), hepatic failure, pancreatitis, renal tubular acidosis, acute myopia and secondary angle closure glaucoma. [1,9] Even though, topiramate has a relatively long half-life of 21 hours in vivo, it has not been prescribed as a single daily-dose due to severe side-effects due to peak plasma levels of the drug when taken in high doses. Instead, Topamax is prescribed in multiple, divided doses, usually twice-a-day. Administration of the medicament in this manner is cumbersome and patients may forget to take their medication in a timely manner and each administration of a dose is associated with a peak and valley in plasma concentrations of the drug. The fluctuations associated with the peaks and valleys of blood plasma levels of the drug are undesirable. Hence, there is a need for a formulation of topiramate, which reduces or eliminates the side effects, associated with peak fluctuation in plasma levels of the drug and preferably may be administered in a once-daily regimen to improve patient compliance. [1,9]

8 It is an intention of this research proposal to satisfy the unmet need of the anti-epileptic disease area to provide better patient compliance by selecting molecules which has significant effect. Topiramate is selected here as one of the Anti-epileptic drug (AED) to focus of this research proposal. It is similar to phenytoin and carbamazepine and is effective and safe for a wide variety of seizures in adults and children. [1,8] Topiramate is one of the drugs belonging to the class of antiepileptic drugs used in treatment of epilepsy and migraine. For an effective therapy for these chronic indications, drugs have to be delivered at a controlled or modified rate with minimal fluctuations in the plasma concentration for longer duration. Various technologies can be developed to achieve this; the aim of this research work is to develop a generic formulation of single unit oral modified release drug delivery technology comprising of loading and maintenance dose for delivery of drugs throughout the GI track. A NDA application for formulation of topiramate extended release oral capsule is under review by USFDA and the probable innovator is Supernus Pharmaceuticals Inc. Innovator uses multiple bead technology such as immediate release bead population, first extended release bead population and second extended release bead population in their extended release dosage form which offers sustained and continuous delivery of drug for 24 hrs. In order to decrease the cost of the product and to provide a cost effective alternative medicine, a generic product is highly desirable and since the technology is patented, there is a need to develop for a different technology which behaves similarly as that of the innovator in-vitro and in-vivo. Strategies were chosen as the innovator profile had an initial slow release followed by a faster profile maintained over 24 hours.