Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-09-24
2001-07-10
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S056000, C536S058000, C536S063000, C536S115000, C536S119000, C536S124000
Reexamination Certificate
active
06258799
ABSTRACT:
This invention relates to an aqueous coating composition suitable for use in forming an acid-resistant protective coating on a solid pharmaceutical preparation and a process for preparing a coated solid pharmaceutical preparation using the same.
BACKGROUND OF THE INVENTION
Enteric coatings are widely used for various purposes including the protection of acid-labile medicaments from gastric acid and the protection of gastric mucosa from irritative or attacking medicaments. Known enteric coating compositions include cellulose compounds such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, and carboxymethyl ethyl cellulose; vinyl compounds such as polyvinyl alcohol acetate phthalate; and acrylic compounds such as methacrylic acid-ethyl acrylate copolymers. These bases are used in coating after the polymers are dissolved in organic solvents or aqueous latexes or water dispersions of the polymers are formed.
However, since these commercially available enteric polymers have a dissolution pH in the range of 5 to 7, they suffer from a decline of bioavailability. More particularly, when the polymer is applied to a medicament whose absorption site is limited to the upper portion of the small intestine, the enteric preparation (in the form of polymer-coated tablets or granules) will travel past the absorption site before it is sufficiently dissolved to release the medicament.
As a solution to this problem, JP-A 8-133989 and 8-301790 propose hydroxypropyl methyl cellulose acetate maleate and hydroxypropyl methyl cellulose trimellitate having a dissolution pH reduced to about 4, respectively. Because of the low dissolution pH, these polymers, apart from the concept of prior art enteric coating, are expected to find an application as an acid-resistant protective coating composition specialized for protecting medicaments from strong acidity. These polymers, however, are used as solutions in organic solvents which have the danger of explosion and fire, are hazardous to the safety and hygiene of workers, and cause environmental pollution as a result of release to the atmosphere. There is also a possibility that a minor amount of solvent be left in the coated solid preparation.
SUMMARY OF THE INVENTION
An object of the invention is to provide an aqueous coating composition which enables the use in an aqueous form of hydroxypropyl methyl cellulose trimellitate which is a low pH dissolution type base. Another object of the invention is to provide a process for preparing a coated solid pharmaceutical preparation using the same.
The inventors have found that an aqueous coating composition obtained by dispersing powder particulate hydroxypropyl methyl cellulose trimellitate (sometimes referred to as HPMCT), especially having a mean particle size of up to 10 &mgr;m, in water in the presence of a plasticizer is effective in forming an acid resistant protective coating on a solid pharmaceutical preparation by spraying and drying the composition thereon. The thus coated solid preparation has an increased bioavailability.
With respect to aqueous enteric coating compositions, JP-B 56-12614 discloses a method of forming a coating composition by dispersing enteric cellulose derivative powder having a mean particle size of up to 100 &mgr;m in water containing a compatible gelling agent having a boiling point of at least 100° C.; and JP-B 58-55125 discloses the use of triethyl citrate as the gelling agent in this method. Additionally, JP-A 59-167521 and 59-190925 disclose a method of forming a coating composition by dispersing enteric cellulose derivative powder having a mean particle size of up to 10 &mgr;m in triethyl citrate-containing water.
However, the cellulose derivatives used in the prior art enteric coating compositions have a monobasic carboxylic acid introduced into a cellulose skeleton by way of ester or ether bonds, whereas HPMCT has a dibasic carboxylic acid introduced into a cellulose skeleton. Thus the prior art cellulose derivatives and the HPMCT differ in affinity to plasticizers, etc. It is the inventors' discovery that an aqueous coating composition obtained by blending the HPMCT (different from the cellulose derivatives used in the prior art enteric coating compositions) with a plasticizer exhibits good disintegration at pH 4.0 to 4.5 as demonstrated later in Examples and allows the HPMCT to exert its effect to a full extent.
In a first aspect, the invention provides an aqueous coating composition comprising hydroxypropyl methyl cellulose trimellitate and a plasticizer. Preferably the HPMCT has a mean particle size of up to 10 &mgr;m. The aqueous coating composition is suitable for use in coating on a solid pharmaceutical preparation.
In a second aspect, the invention provides a process for preparing a coated solid pharmaceutical preparation comprising the steps of spraying the aqueous coating composition to a solid pharmaceutical preparation and drying the composition to form a coating of HPMCT on the surface of the solid pharmaceutical preparation.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The hydroxypropyl methyl cellulose trimellitate (HPMCT) used herein can be synthesized by any well-known process as disclosed in JP-A 8-301790. After synthesis, the HPMCT may be ground by any well-known method, for example, in an air blast pulverizer, ball mill or vibrating mill. The HPMCT should preferably have a mean particle size of up to 10 &mgr;m, and more preferably up to 7 &mgr;m. If the mean particle size exceeds 10 &mgr;m, sometimes a large amount of the coating solution must be applied in order to form an acid resistant coating. The lower limit of the mean particle size is not critical although a particle size of 2 &mgr;m or more is recommended for practical use. With a particle size of less than 2 &mgr;m, it sometimes becomes difficult to disperse the HPMCT to primary particles by ordinary agitation, failing to achieve the desired effect.
The aqueous coating composition of the invention has the HPMCT dispersed in water in the presence of a plasticizer. The aqueous coating composition or dispersion preferably contains about 3 to 15%, more preferably about 5 to 10% by weight of the HPMCT. A low HPMCT concentration of less than 3% by weight would take a long time in coating. A high HPMCT concentration in excess of 15% by weight would be inconvenient to apply because, for example, clogging of a spray gun can occur due to the agglomeration of HPMCT particles in the dispersion.
Examples of the plasticizer used herein include triethyl citrate, glycerol triacetate (or triacetin), acetylated monoglyceride, and phthalic esters such as dimethyl phthalate, diethyl phthalate, and dibutyl phthalate.
An appropriate amount of the plasticizer added is about 20 to 60%, more preferably about 25 to 50% by weight based on the HPMCT. Amounts of less than 20% by weight correspond to the shortage of the plasticizer so that film formation might not fully take place, failing to produce a fully acid resistant coated preparation. Amounts of more than 60% by weight correspond to the excess of the plasticizer, sometimes giving rise to the problem that granules or tablets stick together during coating or storage.
The aqueous coating composition may be obtained by dispersing finely divided HPMCT in an aqueous solution containing a plasticizer such as triethyl citrate under ordinary agitation. The solution should preferably be at a temperature of 40° C. or lower in order to prevent the HPMCT from agglomerating. Most often, dispersion is carried out at room temperature.
If desired, the plasticizer may be added after the HPMCT has been dispersed.
When the coating composition is prepared, additives that can be used in drugs, for example, surfactants and protective colloids may be added in order to improve the stability of the coating composition or water dispersion. Similarly, talc, titanium oxide and silicon dioxide may be added for the purpose of preventing the pharmaceutical preparation (in the form of granules
Kokubo Hiroyasu
Nishiyama Yuichi
Millen White Zelano & Branigan
Peselev Elli
Shin-Etsu Chemical Co. , Ltd.
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