Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-02-25
2001-03-06
Kulkosky, Peter F. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C514S974000
Reexamination Certificate
active
06197348
ABSTRACT:
The present invention relates to a taste-masked pharmaceutical composition. In particular the invention relates to suspensions of microcapsules taste-masked as a function of a polymer coating and the pH of a suspending medium. Surprisingly, a polymer considered permeable maintains tastemasking in this media whereas a polymer considered impervious by the industry does not.
Many drugs are less soluble at higher or lower pH than at the pH value of the mouth, which is around 5.9. Some pharmaceutical compositions have utilised this concept and suspended the drug at a pH in which it remains insoluble. In this condition, the drug can be insufficiently solubilised to be available to taste if the equilibrium concentration is below the taste threshold.
However, problems can arise if all of the suspended particles are not swallowed. If all of the drug particles are not swallowed, the drug which remains in the mouth is able to dissolve at the pH of the mouth which is approximately 5.9. In cases where insolubility is at either end of the pH range, dissolution at a pH of 5.9 could result in a concentration above taste threshold and that the drug becomes available to be tasted.
One means of overcoming the taste problems with delivery of drugs in suspension is the use of polymeric coatings on the drug particles which inhibit or retard the rate of dissolution and solubilisation of the drug. This allows time for all of the particles to be swallowed before the threshold concentration is reached in the mouth and the taste is perceived.
Whilst the use of polymer coats may be effective for retarding dissolution during the time in contact with saliva during the process of swallowing, they have disadvantages in preparing taste-masked liquid formulations intended for long term storage in contact with a liquid medium.
The principal disadvantages are that the drug will equilibrate with the suspension media, and that the coat may weaken, soften, or rupture on prolonged storage.
Japanese Patent No. 80,129,224 provides a method for coating a bitter drug substance with a coating agent containing ethyl cellulose and an antacid. Incorporation of an antacid in the polymer coat on the drug may be unsuitable for maintaining a drug at a predetermined pH (to maintain insolubility) for the reason that when water soluble antacids are used in the coat in a water-based suspension, the antacid would tend to dissolve and leach out, thereby drawing away any means of maintaining a predetermined pH environment and causing instability on the polymer coat. The processes for making such coated drug particles is also difficult since the antacid and polymer have opposite solubilities in the usual coating solvents.
In U.S. Pat. No. 4,656,027 there is provided a method and product wherein a basic substance is mixed with a bitter tasting drug which is insoluble at high pH. The mixture is encapsulated with a polymer which is a cellulose derivative, vinyl derivative or an acid soluble polymer such as a copolymer of dimethylaminomethyl methacrylate. In addition, a method for a mixture of polymer-coated drug with a basic substance is also claimed to give suspensions on reconstitution that give stable taste-masked products.
A major drawback in incorporating the basic substance within the coated drug particle emerges on suspending the particles in aqueous solutions. When suspended in water, the microcapsules absorb water through the pores on the polymer coat, the basic substance dissolves in the absorbed water and exerts a large osmotic pressure that results in either the rupture of the coat or diffusion of the basic substance into the medium. The mixture of basic substance with coated drug particles described in U.S. Pat. No. 4,656,027 is intended as a mixture for reconstitution ie; to be added to water just before use. While this may well serve the purpose, it has been found that the product may not taste-mask as a suspension for a prolonged period.
Australian Patent AU-B-52269/90 describes a method of providing a taste-masked suspension of ibuprofen by maintaining a pH of 1.5-3.5 in a suspension of the drug and providing a buffering capacity within the range of 0.03-0.05 between the initial pH of the formulation and 1.0 pH unit higher.
U.S. Pat. No. 4,788,220 describes a composition for ibuprofen wherein the drug is maintained in suspension with suspending agents and the pH is maintained between 3.5 to 5.
In U.S. Pat. No. 4,788,220 and Australian patent 52269/90 simple suspensions of drug are provided at defined pH ranges. It is now recognised that even if the drug is insolubilised in the formulation by adjustment of the pH, on swallowing a dose, sufficient residue of the drug remains in the oral cavity that after some time when the pH of the mouth equilibrates back to the normal pH of the mouth (average 5.9), the residual drug dissolves rapidly in the mouth leading to a bad taste.
Nowhere in the prior art is it found that a permeable polymer can be applied to drug particles, the polymer coated particles formulated into a suspension, and the resulting suspension remain taste masked for a commercially viable shelf life.
Regarding the pH of the suspension medium the prior art fails to consider several factors that would impact on the long-term physical, chemical and taste stability of the formulation. Whilst the use of an acid or base substance to insolubilise the drug and hence render it unavailable for the taste receptors is a reasonable strategy, an optimum formulation is obtained only when consideration is given to:
(i) the pH of maximum insolubility of the drug;
(ii) the threshold concentration for bitter taste of the drug;
(iii) the minimum buffer strength required in the medium to avoid delayed or after taste;
(iv) the pH limit beyond which further increase or decrease of pH leads to unacceptable instability of the drug; and
(v) the compatibility and chemical, physical and microbial stability of the other ingredients to the pH values of the medium.
Therefore there is a need for a stable taste-masked formulation capable of being maintained in a liquid suspension for a long period of time.
Accordingly, it is an object of the present invention to overcome or at least alleviate one or more of the difficulties related to the prior art.
In a first aspect of the present invention there is provided a taste masked oral pharmaceutical composition including:
a pharmaceutically active ingredient having a pH-dependent solubility;
a polymer encapsulating said pharmaceutically active ingredient, said polymer having a quaternary ammonium functionality;
a suspending medium for suspending the encapsulated pharmaceutically active ingredient, said medium adjusted to a predetermined pH at which the pharmaceutically active ingredient remains substantially insoluble; and
wherein the pharmaceutically active ingredient is taste masked by the combination of the polymer and suspending medium.
The applicants have found that when microcapsules of a bitter-tasting drug using ethyl cellulose as the polymer coat are formulated in water-based suspensions at a suitable pH, the suspension obtained may be taste-masked for short periods of time but not for longer periods of time, since after a few days the suspension tasted bitter. However, when water permeable cationic methacrylate polymers having a quarternary ammonium functionality such as Eudragit RS100 and Eudragit RL100, were substituted for ethylcellulose as the polymer membrane used in the microencapsulation and formulation of the suspension at the same pH, the resulting suspension remained taste masked for longer.
The pharmaceutically active ingredient may be any one of the class of basic or acidic drugs that dissolve in aqueous systems. As the pH and ionic strength of the medium is selected on the basis of drug stability, solubility and taste threshold, an optimum taste-masking effect that is compatible with the stability of the drug is obtained. The optimum pH is also beneficial in maintaining the stability of the drug, the coating polymer and the coating excipients.
The pharmaceutically active ingredie
Heinicke Grant Wayne
Morella Angelo Mario
Pitman Ian Hamilton
Birch & Stewart Kolasch & Birch, LLP
F H Faulding & Co., Limited
Kulkosky Peter F.
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