Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-06-23
2001-11-06
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S472000, C424S489000, C424S480000, C424S482000, C424S494000, C424S468000, C424S458000, C424S496000, C424S497000, C424S498000, C424S481000, C424S476000, C424S495000
Reexamination Certificate
active
06312728
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to sustained release pharmaceutical preparations and to a method for making them. The novel drug delivery system contains a core comprising the active pharmaceutical, an enteral coating over the core comprising a pH dependent water soluble polymer, a second coating of the active pharmaceutical, and thereafter a coating which is soluble in gastric juices. The invention, in another embodiment, comprises a core of active, an enteral coating over the core comprising a pH dependent soluble polymer that breaks down in the colon and/or large intestine, a second coating of active, a second enteral coating that dissolves primarily in the small intestine, a third layer of active and, a protective coating that is soluble in gastric juices. The drug delivery system of the invention may be utilized with a wide variety of pharmaceutically active agents which have pH dependent solubilities to prepare sustained release compositions. This invention also relates to a novel method for preparing these drug delivery systems and to sustained release compositions made thereby.
BACKGROUND OF THE INVENTION
A sustained release dosage form may be defined as a preparation which releases a drug, in vivo, at a considerably slower rate than is the case from an equivalent dose of a conventional (non-sustained release) dosage form. The objective of employing a sustained release product is to obtain a satisfactory drug response while at the same time, reducing the frequency of administration. An example of a drug which is popularly used in a sustained release form is chlorpheniramine maleate. In conventional form, the drug may be given as 4 mg doses every four (4) hours or in sustained release form as 12 mg every twelve (12) hours.
Sustained release compositions for the sequential or timed release of medicaments are well known in the art. Generally, such compositions contain medicament particles, normally administered in divided doses two (2) or three (3) times daily, mixed with or covered by a coating material which is resistant to degradation or disintegration in the stomach and/or in the intestine for a selected period of time. Release of the medicament may occur by leeching, erosion, rupture, diffusion or similar actions depending upon the nature and thickness of the coating material.
It is known that different pharmaceutical preparations of the same active ingredient will result in different bioavailabilities of the active ingredient to the mammal. Bioavailability or biological availability may be defined as the percentage of the drug liberated from the dosage form administered that becomes available in the body for biological effect. Different formulations of the same drug can vary in bioavailability to a clinically relevant extent and variation may even occur between batches of the same product due to subtle variations in manufacturing procedures.
Many drugs that are usually administered in tablet or capsule form have a low solubility in biological fluids. For many drugs of low solubility, there is considerable evidence that the dissolution rate, partially or completely controls the rate of absorption. Bioavailability can also be affected by a number of factors such as the amounts and types of adjuvants used, the granulation process, compression forces (in tablet manufacturing), surface area available for dissolution and environmental factors such as agitation in the stomach and the presence of food. Due to these numerous factors, specific formulations play an important role in the preparation of prolonged action solid dosage forms.
Epilepsy is an ancient disease which affects about 1% of the global population. Despite the progress made in antiepileptic drug therapy, there are still many patients who continue to suffer from uncontrolled seizures and medication toxicity. At present, only four (4) major antiepileptic drugs are in use: phenobarbital, phenytoin sodium, carbamazepine and valporic acid.
Pharmacological activity, in general, and antiepileptic activity in particular, correlate better with a concentration of the drug in the blood (or in some other biophase) than with the administered dose. This phenomenon is due, in part, to variability in drug absorption and disposition between and within individuals, particularly when the drug is given orally. Optimizing drug therapy aims at achieving and maintaining therapeutic and safe drug concentrations in the patient's plasma. It would thus be advantageous that the patient receive a once- or twice-daily dosage regimen.
Phenytoin is 5,5-diphenyl-2,4-imidazolidinedione. It is a well-known pharmaceutical agent having anti-convulsant and antiepileptic activity. Due to phenytoin's poor solubility in water, phenytoin sodium, of empirical formula C
15
H
11
N
2
NaO
2
,which is much more soluble, is employed in the preparation of injectable solutions of the drug and in solid enteral dosage forms.
While phenytoin is the antiepileptic drug of choice for most types of epileptic seizures, except for petit mal, therapeutic drug monitoring is required because of the difficulty in maintaining an effective therapeutic plasma level of between 10 and 20 &mgr;g/ml. In addition to the problems of narrow therapeutic plasma levels, phenytoin has exhibited great variations in bioavailability following its oral administration to patients because of its poor water solubility.
With even the new approaches to phenytoin delivery (i.e., Parke-Davis' Dilantin® Kapseals®, which are 100 mg extended phenytoin sodium capsules), it is still necessary for patients to take the drug several times a day to maintain an effective therapeutic plasma level without side effects. While many encapsulation techniques have been attempted, none have been found to be satisfactory. Karakasa et al.,
Biol. Pharm. Bull
., 17(3) 432-436 (1994) in an article entitled “Sustained Release of Phenytoin Following) the Oral Administration of Phenytoin Sodium/Ethylcellulose Microcapsules in Human Subjects and Rabbits”, studied the release patterns of phenytoin as the sodium salt in combination with ethylcellulose. The phenytoin sodium microcapsules were prepared by mixing 80 weight % of the phenytoin sodium in a 10% (w/v) ethylcellulose solution in ethylacetate. The suspension was stirred and n-pentane was added dropwise until a phase separation occurred and the microcapsules were obtained. The microcapsules were collected on filter paper, dried and stored. Karakasa et al. point out that following the oral administration of phenytoin sodium, the salt might be easily transferred into free-phenytoin in the acidic fluids of the stomach. As free-phenytoin is practically insoluble in water, its absorption might be incomplete in the gastrointestinal tract. On the other hand, while passing through the stomach, the volume of water penetrating into the ethylcellulose microcapsules might be minimal. Thus, most of the phenytoin sodium in the microcapsules might not be converted into free-phenytoin. This reference fails to suggest a dosage form wherein a portion of the active ingredient is released in the stomach and the remaining portion is released in the intestines.
A review article by Boxenbaum in
Drug Development & Industrial Pharmacy
, 1982, 8(v), 1-25, entitled “Physiological and Pharmacokinetic Factors Affecting Performance of Sustained Release Dosage Forms” actually suggests that sustained release formulations for drugs such as phenytoin are unnecessary. Boxenbaum points out that dosing schedules of once a day versus three times daily produce similar plasma curves. This results from both the slow absorption, disposition of the drug and the low solubility.
It is the inventor's position that slow release, delayed release, prolonged release or sustained release phenytoin is a desirable objective. Controlled release oral dosage forms of drugs with long half lives, such as phenytoin, have been previously disregarded for sustained release formulation since they produce little chance in the blood concentration after multiple doses have been administered. The
Beiman Elliott
Landsman Fred
Cascade Development, Inc.
Fubara Blessing
Nickey Donald O.
Spear James M.
Steffensmeier Michael D.
LandOfFree
Sustained release pharmaceutical preparation does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Sustained release pharmaceutical preparation, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Sustained release pharmaceutical preparation will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2606118