A coating dispersion soluble in the lower digestive tract which is prepared by blending a hydroxypropyl methylcellulose acetate succinate (HPMCAS) soluble at around pH 7 with a conventional plasticizer and an anion surfactant and further adding an acid, wherein the HPMCAS has an average particle size of 10 .mu.m or less and is dispersed at a concentration of 2 to 20% by weight, and the acid is used in an amount of 1 to 10 parts by weight per 100 parts by weight of HPMCAS, and a sustained release coated preparation capable of releasing a medicament in the large intestine at the lower digestive tract, which is prepared by coating a medicament-containing solid preparation such as a granular core with the coating dispersion.

TECHNICAL FIELD

The present invention relates to a coated preparation soluble in the lower digestive tract which can promote release of a medicament at the lower digestive tract, more particularly to a coating base dispersion suitable for preparing a coated preparation soluble in the lower digestive tract by coating the surface of a medicament-containing core granule, etc., and further to a coated granule for delivery to the large intestine which is prepared by coating a medicament-containing core granule with the coating dispersion soluble in the lower digestive tract.

BACKGROUND ART

Recently, many studies have been done for the development of sustained release preparations with enteric coating base materials. However, when these known preparations are administered, the medicament contained therein is mostly released during passing the small intestine. In some kinds of medicaments, it is desired to be prepared in a sustained release preparation which can also release the medicament in the large intestine as well as in the small intestine and thereby can exhibit the medical activity for a long period. However, when a pharmaceutical preparation is orally administered, it passes through various pH range regions until reaching to the large intestine, that is, from the stomach which is a strong acidic region to the small intestine which is a neutral or alkaline region. Accordingly, it is a great task to find a pharmaceutical preparation which can reach to the large intestine of the lower digestive tract after passing through the digestive tract having variable pH ranges. Particularly, in order to prepare a pharmaceutical preparation which can release the active ingredient in the large intestine by administration once a day or to prepare a large intestine delivery preparation, it is required to keep the medicament without dissolution of the coating base material during passing through the ileum where the pH value raises to about 7.

Besides, when a pharmaceutical preparation is administered orally, it will usually take about 4 to 6 hours until reaching to the large intestine, and in case of a sustained release preparation which is formulated so as to administer once a day, it shall gradually release the medicament even after reached to the large intestine. Otherwise, a sufficiently high blood concentration of the medicament can not be maintained for 24 hours and hence the desired therapeutic effects can not be obtained. In other words, such a pharmaceutical preparation shall satisfy the requirements that it surely reaches to the large intestine and releases a sufficient amount of the medicament in the large intestine.

The conventional enteric coating base materials are mostly dissolve at a pH range lower than 7, and the enteric coating base materials soluble at around pH 7 are an acrylic coating material such as methacrylic acid-methyl methacrylate copolymer (Eudragit S, manufactured by Roehm) and a cellulosic coating material (e.g. hydroxypropyl methylcellulose acetate succinate (AQOAT AS-HF, manufactured by Shin-Etsu Chemical Co., Ltd.). These enteric coating materials are used for the coating in the form of a solution in an organic solvent or in the form of an aqueous dispersion. In view of the recent environmental restriction, an organic solvent is limited to use and hence it tends to use an aqueous coating material (e.g. an aqueous dispersion).

JP-60-43334 discloses an acrylic coating emulsion as a coating material, but when such an acrylic coating emulsion is used, the enteric coating film is contaminated with a polymerization initiator, a chain transfer agent, unreacted monomers, etc., which are not suitable for medication in view of safety.

JP-56-12614 discloses an aqueous dispersion comprising a cellulosic coating material having an average particle size of 100 .mu.m or less and a plasticizer. Such an aqueous dispersion has less stability to heat and has defects that the coating base material aggregates and then precipitates.

JP-7-109219 discloses an enteric coating dispersion comprising an enteric coating material having an average particle size of 10 .mu.m or less, a plasticizer and an anionic surfactant, which is stably dispersed for a long period without aggregation even by change of temperature. However, the hydroxypropyl methylcellulose acetate succinate (HPMCAS) used therein has a dissolving pH value of about 7 even at a grade of the highest dissolving pH value and it dissolves in a wide range of pH values. Accordingly, when a pharmaceutical preparation coated with such a coating material is administered orally, it dissolves in a small intestine and releases the medicament mostly in the small intestine.

JP-2-289512 discloses a pharmaceutical preparation comprising an enteric coated core granule and a large amount of an organic acid (30 to 50% by weight based on the weight of the core granules) so as to give an alkaline resistance even at a raised pH value. However, it is reported by Nykanen et al. (International Journal of Pharmaceutics, vol. 184, pp. 251 261, 1999) that even when a large amount of an acid is added to the core granule in an enteric coated granule preparation coated with HPMCAS, said preparation could not show the desired sustained release of the medicament (ibuprofen) in vivo test, and the blood level profile of the ibuprofen was similar to that in a granule to which no acid was added.

DISCLOSURE OF INVENTION

An object of the present invention is to provide a coated preparation for oral administration which can release the medicament even in the lower digestive tract, i.e. in the large intestine when administered orally, and to provide a coating dispersion soluble in the lower digestive tract suitable for achieving such a purpose, said coating base material used therein being not immediately dissolved during passing the ileum where the pH value raises to about 7.

The present invention provides also a large intestine delivery coated granule preparation which can sufficiently release the medicament in the large intestine and even after reached thereto, said preparation being prepared by coating a medicament-containing core granule with said coating dispersion soluble in the lower digestive tract. That is, the present invention provides a coating dispersion soluble in the lower digestive tract which is prepared by blending a hydroxypropyl methyl-cellulose acetate succinate (HPMCAS) soluble at around pH 7 with a conventional plasticizer and an anion surfactant and further adding an acid, wherein HPMCAS has an average particle size of 10 .mu.m or less and is dispersed in a concentration of 2 to 20% by weight, and the acid is incorporated in an amount of 1 to 10 parts by weight per 100 parts by weight of HPMCAS. The present invention provides also a large intestine delivery coated granule preparation being able to release a medicament even in the large intestine region which is prepared by coating a medicament-containing core granule with said coating dispersion soluble in the lower digestive tract.

BEST MODE FOR CARRYING OUT THE INVENTION

The HPMCAS soluble at around pH 7 includes, for example, a commercially available AQOAT AS-HF (manufactured by Shin-Etsu Chemical Co., Ltd.) but should not be limited thereto.

The acid includes, for example, organic acids, such as citric acid, ascorbic acid, adipic acid, ethylenediaminetetraacetic acid, lactic acid, succinic acid, etc., phosphoric acid, a high molecular acid, and an acidic iron exchange resin. These may be used alone or in a combination of two or more thereof. Preferred acid is an organic acid, particularly citric acid.

The plasticizer includes, for example, triethyl citrate or triacetyl. These may be used alone or in a combination of two or more. Preferred one is triethyl citrate.

The anion surfactant includes, for example, sodium alkylsulfate (e.g. sodium laurylsulfate, dioctyl sodium sulfosuccinate, etc.), fatty acid sodium salt (e.g. sodium oleate, etc.), and fatty acid potassium salt (e.g. potassium sorbate, etc.). These may be used alone or in a combination of two or more thereof. Preferred one is sodium alkylsulfates, particularly sodium laurylsulfate.

For coating of granules, it is effective to add talc and the like in order to prevent aggregation of the granules during coating procedure.

The coating dispersion soluble in the lower digestive tract of the present invention is easily prepared by adding an acid to the coating dispersion prepared by a conventional method.

HPMCAS soluble at around pH 7 is used in an amount of 2 to 20% by weight, preferably 5 to 15% by weight, based on the whole weight of the coating dispersion soluble in the lower digestive tract. When HPMCAS is used in a concentration lower than the above range, the coating procedure takes undesirably a longer time, and on the other hand, when its concentration is higher than the above range, the coating base material undesirably aggregates with raising of temperature during storage of the coating preparation or during coating procedure.

The acid is added in an amount of 1 to 10 parts by weight, preferably 2 to 5 parts by weight, per 100 parts by weight of HPMCAS. When the acid is used in an amount less than the above, the coating layer of the preparation will dissolve before reaching to the lower digestive tract when administered, which results in insufficient release of the medicament in the large intestine, that is, it results in less extension of lag time. On the other hand, when the acid is added in too much amount, the coating base material easily aggregates, which undesirably causes unstable coating film.

The plasticizer is incorporated in an amount of 10 to 50 parts by weight, preferably 30 to 50 parts by weight, per 100 parts by weight of HPMCAS.

The anion surfactant is incorporated in an amount of 0.5 to 10 parts by weight, preferably 1 to 5 parts by weight, per 100 parts by weight of HPMCAS.

The coating dispersion soluble in the lower digestive tract of the present invention may optionally be incorporated by an aggregation inhibitor (e.g. talc), a colorant (e.g. pigment), a flavoring substance (e.g. thaumatin), and the like.

The large intestine delivery coated granule preparation of the present invention may be prepared by coating a medicament-containing core granule with the coating dispersion soluble in the lower digestive tract according to a conventional coating method.

The coating is usually carried out by spraying the above coating dispersion soluble in the lower digestive tract onto medicament-containing core granules and treating the sprayed granules with a coating apparatus in a usual manner. The spray of the dispersion onto the medicament-containing core granules is carried out by any spray apparatus such as an air spray apparatus or an airless spray apparatus. When there is a possibility that a solid material (i.e. pigment) deposits, the spraying may preferably be done with stirring the dispersion. The coating machine may be, for example, a pan coating machine, a drum type coating machine, a fluidized bed coating machine, or a fluid agitating coating machine.

The coating dispersion soluble in the lower digestive tract may be used in such an amount that the coating thickness is in the range of 30 to 150 .mu.m, preferably 50 to 150 .mu.m. When the coating amount is converted to the amount of HPMCAS soluble at around pH 7, it is in the range of 20 to 200 parts by weight, preferably 30 to 100 parts by weight, per 100 parts by weight of the medicament-containing granule.

The medicament-containing core granule is not limited with respect to the medicament and the pharmaceutically acceptable carrier. It may be a medicament alone, or it may contain an acid within the core granule.

The large intestine delivery coated granule preparation of the present invention is usually used as a pharmaceutical preparation in the form of granules, capsules, or tablets, and optionally it may be combined with granules or tablets having different dissolution rate of a medicament.

These pharmaceutical preparations may be prepared by a conventional method.

The coating dispersion soluble in the lower digestive tract of the present invention may also be used for forming a coating film soluble in the lower digestive tract onto other medicament-containing solid pharmaceutical preparation such as pills, tablets or capsules in addition to the above-mentioned medicament-containing core granule.
 

Claim 1 of 8 Claims

1. A coating dispersion soluble in the lower digestive tract comprising a hydroxypropyl methylcellulose acetate succinate soluble at around pH 7, an acid, a plasticizer and an anion surfactant, wherein the hydroxypropyl methylcellulose acetate succinate has an average particle size of 10 .mu.m or less which is dispersed at a concentration of from 2 to 20% by weight in water, and the acid is present in an amount of from 1 to 10 parts by weight per 100 parts by weight of the hydroxypropyl methylcellulose acetate succinate.

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