Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-08-30
2002-08-20
Pryor, Alton (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S646000, C514S964000, C514S970000
Reexamination Certificate
active
06437000
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a formulation of a water insoluble controlled release carrier to provide controlled release of medicaments.
BACKGROUND OF THE INVENTION
Sustained or slow release compositions containing pharmaceutical medicaments or other active ingredients are designed to contain higher concentrations of the medicament and are prepared in such a manner as to effect sustained or slow release into the gastro-intestinal digestive tract of humans or animals over an extended period of time. Well absorbed oral sustained or slow release therapeutic drug dosage forms have inherent advantages over conventional, immediate release dosage forms. The advantages include less frequent dosing of a medicament and resultant patient regime 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 drug concentration spikes are mitigated or eliminated by effecting a smoother and more sustained blood level response.
For this purpose, a controlled release formulation has to meet some criteria; namely it must effect an uniform and constant dissolution of the drugs and it must be effective for an extended period of time. It is also important that such a formulation be simple to make, that the manufacturing process be reproducible and that the product produced by the manufacturing process be uniform. Moreover, if different drugs are used as the active component in the sustained released formulation, it is important that the manufacturing process be easily adaptable to accommodate these various drugs.
To prepare sustained release formulations in the form of a solid oral dosage, such as tablets, various hydrophilic as well as hydrophobic polymers have been utilized. Materials such as waxes have also been used. Formulations made using many of these materials not only offer different release characteristics, but also have several disadvantages associated therewith. For example, the wax matrices are unstable towards heat which can cause sudden release of the drug from the dosage form. On the other hand, the hydrophilic matrices provide sustained release by forming a gel as a protective barrier, which has proven to be an effective method for controlling drug release. However, the swelling of hydrophilic polymers is often affected by the ionic environment of the gastrointestinal tract, which may affect the release rate. Sometimes failure of the matrix has also been observed. Because the hydrophilic matrices swell and erode over a period of time, they can not provide a constant surface area for the release of the drug and in some cases, where the solubility thereof in water is high and the concentration of the drug in the dosage form is very high, they fail to offer controlled release over a long period of time. Thus, there is a need to find a system which does not suffer from these disadvantages.
Various methods such as solvent evaporation, heat melting, direct compression as well as wet granulation have been used to prepare sustained release pharmaceuticals. The only methods which are practical for industrial manufacture of such matrices are direct compression and wet granulation.
Various hydrophobic polymers have been used for fabrication of controlled release matrices. These polymers are elastic and often have poor flow characteristics, thus making them quite unsuitable for commercial manufacture. It is also necessary that the polymer particles coalesce to form an insoluble matrix in order to control the release of the active agent; very high concentrations are often needed. Wet granulation using solutions of such polymers in organic solvents tends to be difficult because solutions containing high polymer content tend to be viscous; therefore to achieve an effective amount of polymer concentration, large amounts of organic solvent are needed. However, many organic solvents are toxic and are quite volatile and flammable, thereby exposing the chemist or other persons directly involved in the manufacture thereof to health and safety hazards. Moreover, multiple granulation procedures are often required.
Aqueous dispersions of such polymers have also been used for wet granulation. Once again multiple granulations are needed to obtain effective amounts of the polymer in the tablet. Unfortunately, high polymer concentration also creates difficulties in granulation by forming rubbery masses.
Mulye, et al. in
Drug Development and Industrial Pharmacy
, 20(17), 2621-2632 (1994) disclose a matrix formulation in the form of a tablet comprising a highly water soluble drug, i.e., chlorpheniramine maleate (“CPM”), bromopheniramine maleate, dextromethorphan•HBr, procaine•HCl, diphenhydramine•HCl, theophylline and niacinamide. These tablets contained, in addition, dicalcium phosphate dihydrate (DCPD) or Eudragit and optionally magnesium stearate. This publication discloses that Eudragit is virtually ineffective in controlling the release profile. It also showed that DCPD was more effective than the Eudragit in controlling the release of the water soluble drug, such as CPM, but that the DCPD containing matrix had a major limitation; when the drug concentration was greater than 5% by weight, the tablet disintegrated.
Mulye, et al., in
Drug Development and Industrial Pharmacy
, 20(17), 2633-2643 (1994) continued the study described hereinabove. In this paper, Mulye, et al. prepared a tablet containing CPM, DCPD and Eudragit. Their study showed that the addition of Eudragit did not affect the drug release profile relative to that obtained with CPM and DCPD in the absence of Eudragit. It was postulated that the hydrophobic polymer had difficulty binding with the hydrophilic surface of the drug, and it was thus ineffective in reducing the release rate. However, when a plasticizer, such as diethylphthalate was added, there was a significant decrease in release rate. These study showed that a plasticizer was required to be present with the DCPD to release the drug in a controlled manner.
However, the present inventor searched for a system wherein a plasticizer was not a necessary component. The present inventor has found such a system.
The present inventor has also overcome the inadequacies of the prior art and is able to prepare a tablet containing the drug and DCPD wherein the drug is present in a concentration greater than 5% by weight. More specifically, he has found a means of preparing a formulation matrix comprising the drug, the hydrophobic salt and a hydrophobic polymer in which the drug is present in greater than 5% by weight.
The present inventor has found that by utilizing a water insoluble inorganic salt in combination with a water insoluble polymer in a ratio within a certain range in the carrier system of the sustained release formulation, the formulation does not suffer from the disadvantages described hereinabove.
SUMMARY OF THE INVENTION
The present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a medicament and a controlled release carrier, such carrier comprising a water insoluble polymer and a water insoluble inorganic salt, both being present in a sufficient amount to interact with the drug and form a water insoluble barrier thereover sufficient to retard the release of the medicament in aqueous medium, e.g., the gut, said polymer being present from about 1% up to about 50% by weight of the carrier and said inorganic salt being present from about 1% up to about 95% by weight of the carrier, wherein said carrier is present in an amount ranging from about 1% to about 95% by weight of the composition, and said medicament is present in greater than 5% by weight of the composition.
DETAILED DESCRIPTION OF THE INVENTION
The present invention utilizes a combination of a water insoluble inorganic salt and a hydrophobic polymer to provide a controlled release pharmaceutical composition whereby the active ingredient or medicament is present in amounts great
Norstrum Pharmaceuticals, Inc.
Pryor Alton
Scully Scott Murphy & Presser
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