Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
2000-08-30
2002-11-05
Pryor, Alton (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S474000, C424S475000
Reexamination Certificate
active
06475493
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a sustained release pharmaceutical composition and to a method of using and preparing same in order to control the rate of release and the site of release of the pharmaceutical composition.
BACKGROUND OF THE INVENTION
It is desirable in the treatment of a number of diseases, both therapeutically and prophylactically, to provide the active pharmaceutical ingredient in a sustained release form. Desirably, the sustained release form provides a controlled rate of release of a medicament over an extended period.
It is well known that well absorbed sustained release therapeutic drug dosage forms provide many advantages over conventional release dosage forms. The advantages include less frequent dosing of a medicament and resultant patient compliance, a more sustained drug blood level response, therapeutic action with less ingested drug and the mitigation of side effects. By providing a slow and steady release of the medicament over time, absorbed concentration spikes are mitigated or even eliminated by effecting smoother and more sustained blood level response.
Some sustained release pharmaceutical formulations are prepared such that they have a core containing the medicament or drug which is surrounded by a coating which controls the release of the drug or medicament.
A multi-particulate dosage form, especially those in which the core containing the medicament or drug is surrounded by one or more coatings, provides distinct advantages over a single component system such as a tablet since the release profile is more directly controlled by the amount of coating and the number of layers of coating. Moreover, it has the advantage of facilitating the preparation of the desired release profile from a combination of medicaments relative to the single tablet form. Although non-pH dependent polymers are often used for coatings to achieve a controlled release of active substances, they sometimes pose a problem because the release of the active substance is dependent on the solubility of the drug, and the solubility of some drugs, such as that of Verapamil hydrochloride, changes with pH. It is therefore desirable to formulate a coating which becomes more permeable as the pH is increased and the drug solubility thereof decreases.
Other coatings in pharmaceutical composition contain enteric polymers which are pH dependent. These enteric coatings are generally formulated from anionic polymers with pendent carboxyl groups which typically have a pKa of 4 to 6. Gastric fluids typically have pH values about two units below the pKa. For example, the pH value in the stomach of an ordinary person is normally between 1 and 3.5 and mostly between 1 and 2.5. Thus, in the low pH gastric fluids, only about 1% of the carboxyl groups ionize; 99% of the carboxyl groups are protonated and the carboxyl groups can form hydrogen bonds with each other and with other portions of the polymer. Thus, in these pH ranges in the stomach, enteric polymers are insoluble in the gastric fluid. The enteric polymer coating thus retains its integrity and provides a barrier to moisture. When the dosage form reaches the intestines, where the intestinal fluids have a higher pH, ionization of the carboxy group increases and the enteric material dissolves, the extent of this ionization being dependent upon the pH and the enteric coating used.
Thus, some drugs have an enteric soluble coating so as to effect release thereof in areas other than the stomach, whereby the pH values are higher. For example, the pH value in the small intestines is normally from 5 to 7; moreover, it is even higher as one goes up along the intestine and may reach 7-8 in the lower intestine. The pH value in the empty duodenum is about 6.5, although it is about 3.5 after a meal.
Some of the reasons for effecting release of the drug outside of the stomach are listed hereinbelow:
(1) prevention of decomposition of drugs that are unstable at pH values lower than a certain level;
(2) prevention of side effects brought about by the release of drugs in the stomach including irritation of the stomach wall by the drug;
(3) prevention of dilution of drug concentration in the intestines, attributable to disintegration of drugs in the stomach and their subsequent movement to the intestines; and
(4) prolonged effect.
There are, in fact, various types of enteric coated drugs, depending upon their functional requirements, as the object of using them can be different. They thus can be divided into the following types:
(a) Those that do not release drugs in the stomach, i.e., these enteric-coated drugs do not undergo dissolution, dispersion or disintegration at the pH value in the stomach of an ordinary person, and the drug is not released in the stomach through the membrane of the preparation;
(b) Those that do not need to specify the site at which disintegration takes place; these preparation will not undergo dissolution, dispersion or disintegration at pH values below a specified value, and outside liquids will not permeate into such preparations through the membrane, but they do undergo dissolution, dispersions or disintegration at pH values higher than this specified value; or
(c) Those that undergo dissolution, dispersion or disintegration at a specified site, particularly at a specified site in the intestines.
Unfortunately, the bioavailability of known enteric-coating preparations varies significantly at each administration between individuals or even in the same individual, both in terms of the quantity released and the rate of release of the active component. This inevitably gives rise to uncertainties as to the effectiveness of enteric-coating preparations. Moreover, it is a common observation that the average bioavailability of enteric coated preparations is lower than that of other preparations. This is partly because of variations in the pH in the digestive organs between individuals or in the same individual but at different times and partly because it is difficult to be certain that the enteric coat surrounding the medicament will dissolve, disperse or disintegrate sufficiently rapidly and with certainty in the digestive organs, particularly in the small intestine.
For example, if a drug is administered in a single enteric-soluble unit dosage (e.g., a tablet), which can be absorbed only in the upper small intestine, bioavailability will be 0% if, for any one of many reasons, the dose does not happen to disintegrate in the upper small intestine and, as a result, the drug may not be utilized at all. In order to avoid this risk, administration is sometimes effected by means of a large number of small unit doses (for example, a number of enteric soluble granules contained together in a conventional capsule). Administration in this way, however, means that at each administration, the bioavailability is the average of the bioavailabilities of the individual granules, which is therefore less than the theoretical maximum of 100%. Accordingly, although this expedient has the effect of ensuring that there is a reasonable likelihood that at least some of the active ingredient given with each administration is utilized, it does not improve the overall average bioavailability.
A suggestion to overcome these problems is described in U.S. Pat. No. 5,202,128 to Morella, et al., which discloses a pH-dependent sustained release pharmaceutical pellet composition for administration to a patient at a predetermined dosage and interval which comprises a core element containing a therapeutically effective amount of at least one active ingredient having an aqueous solubility of at least 1 in 30 and a coating on said core element which comprises:
(a) at least 35% by weight of a matrix polymer which is insoluble at a pH of from 1 to 7.5 and contributes to the control of the rate of release of the active ingredient in the stomach and intestines;
(b) from 1 to 30% of an enteric polymer which is substantially insoluble at a pH of from 1 to 4 sufficient to delay the release of the active ingredient in the stomach, but which is soluble a
Norstrum Pharmaceuticals, Inc.
Pryor Alton
Scully Scott Murphy & Presser
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