Effervescent composition and its production

An effervescent composition comprising a core-shell powder consisting of a fine granular core spray-coated with a liquid mixture containing a water-soluble polymer such as hydroxypropylcellulose or hydroxypropylmethylcellulose, and at least one physiologically active substance, especially an acid-sensitive drugs, and enteric coating film, an effervescing component and an auxiliary effervescing agent which provides for controlled release of the physiologically active substance and in useful for preparing uniform solution or suspension having a refreshing sensation on ingestion.

FIELD OF THE INVENTION 
The present invention relates to an effervescent composition providing for 
the optimal control of the rate of release of physiologically active 
substances, which finds application in the food, pharmaceutical, and 
agrochemical fields and to a method of producing said composition. 
BACKGROUND OF THE INVENTION 
In general, much research is being done in the field of drug delivery 
systems (DDS) for foods, medicines, farm chemicals, etc. Particularly 
among oral dosage forms, granules show no remarkable 
individual-to-individual variation in gastric emptying rate and absorption 
rate and are less susceptible to the influence of diets as compared with 
tablets. Therefore, oral compositions are sometimes provided in the form 
of granules, in the form of tablets containing granules Drug Development 
and Industrial Pharmacy, 9 (7), 1379-1396 (1983)!, or in the form of 
capsules filled with granules. 
Referring to granules, JP-A-S63(1988)-222121 discloses a production method 
which comprises extrusion-molding a drug, hydroxypropylcellulose, and an 
ethanol-soluble plasticizer to provide granules. In this process, the 
plasticizer is used in a large amount to provide sufficient plasticity. 
JP-A-S63(1988)-99009, which corresponds to EPO 248211, discloses a 
production method such that while drug-containing solid particles are 
agitated or tumbled, an aqueous or alcohol solution of a binder is sprayed 
against the particles and, in addition, a hydrophobic solid powder hardly 
soluble in the gastric and intestinal fluids is dusted on the particles. 
By this process, long-acting granules can be obtained. 
JP-A-S63(1988)-222112 discloses a preparation of a long-acting granular 
preparation comprising a drug, an ethanol-insoluble, water-soluble 
polymer, and an ethanol-soluble, water-soluble polymer. To manufacture 
this preparation, the ethanol-insoluble, water-soluble polymer must be 
used in a large amount such that the ethanol-insoluble, water-soluble 
substance is used in a proportion of at least 55% in working examples. 
JP-A-S-63(1988)-243036 discloses an intragastric resident long-acting 
granular preparation containing calcium silicate and 
hydroxypropylmethylcellulose. In this technology, dry calcium silicate 
powder is formulated to give an apparent specific gravity of not greater 
than 1.0. 
JP-A-H2(1990)-1749431, which corresponds to EPO 361874, proposes a 
production which comprises spray-coating core-granules with a dispersion 
of low-substituted hydroxypropylcellulose to provide core-shell granules. 
The granules obtained by this process are high in mechanical strength and 
yet high in disintegratability. 
EP 0452862A2 discloses spherical granules comprising inactive spherical 
cores containing at least 50 weight % of microcrystalline cellulose and 
having a average particle diameter of 100-1000 .mu.m coated with an active 
ingredient-containing powder with the aid of an aqueous binder solution 
and further spray-coated with an aqueous solution or dispersion of a 
coating agent. 
The granules prepared by those production technologies are invariably 
characterized in that a large majority of particles have diameters over 
500 .mu.m. The particle diameters of these granules are not only large but 
are substantially uniform. Therefore, when coated with a 
release-controlling vehicle for optimizing the release of the active 
substance, these granules offer the advantage of small variations in 
coating amount. However, because of their large particle size, these 
granules are not only poor in prescription characteristics but, when used 
for tablets or capsules, cause large variations in content. Furthermore, 
when provided in granular form, the particle size test and disintegration 
test are essential under the Pharmacopoeia of Japan XI (hereinafter 
sometimes referred as JP), General Rules, 5. Granules, and it is difficult 
to design a controlled release formulations satisfying the test 
requirements. 
On the other hand, JP does not specify for a disintegration test for 
powders. Moreover, because their particle size is not greater than 500 
.mu.m, powders are better compoundable than granules and, when processed 
into tablets and capsules, cause a smaller variation in content. 
Furthermore, powders are generally higher than granules in gastric 
emptying rate and absorption rate. However, because of this high gastric 
emptying rate, powders may cause an early rise in blood concentration 
depending on drugs, thus leading to development of side effects. 
Furthermore, when the method, among the above-mentioned prior art 
technologies relating to granules, which comprises incorporating a drug in 
the core phase and controlling the release of the substance by means of a 
polymeric carrier coating is applied as it is to powders, a large 
variation in content, poor coating accuracy, and an increased coating 
amount are inevitable. Thus, as far as powders are concerned, the release 
of drug can hardly be controlled with precision because of their 
relatively small particle size compared with granules. 
JP-A-H5(1933)-92918 proposes a technology for producing core-shell powders 
having particle diameters substantially not larger than 500 .mu.m which 
comprises coating fine granular cores with at least one kind of 
physiologically active substance and a water-soluble polymer. The 
core-shell powders thus obtained have the advantage that even through they 
are of small particle size, the release of the bioactive substance can be 
controlled with comparatively high precision. 
Referring to the effervescent pharmaceutical preparations, it has been 
possible only with difficulty to incorporate acid-sensitive drugs in 
stable form into effervescent tablets of effervescent instant granular 
products, since in contact with the acid of the effervescent system such 
compositions hydrolyze or decompose, i.e. they are not shelf-stable. 
Furthermore, whenever such a substance also affects the surface tension of 
water, hydrophobic particles of the drug tend to creep upward on the glass 
or deposit at the bottom of the glass. On the other hand, in certain 
cases, the antacid side-effect of an effervescent tablet is undesirable 
for many drugs. To provide an effervescent system which will avoid the 
aforesaid disadvantages and offer the possibility of administering to a 
patient pharmaceutical substances in pleasant-to-drink effervescent 
solutions, EP067016OA1 proposes a granular effervescent product suitable 
for preparing an aqueous solution or suspension of one or more 
pharmaceutically active substances, especially acid-sensitive drugs such 
as for example, beta carotene, cimetidine, ranitidin or cisapride, for 
oral administration. This product comprises effervescent grains obtained 
from carrier crystals of at least one solid, edible organic acid which are 
substantially covered by at least one coating containing at least one 
water-soluble neutral substance, wherein said neutral substance is 
effective for depressing the melting point of the acid crystals on their 
surface, and at least one substance selected from the group consisting of 
alkali carbonate, alkali bicarbonate, alkaline earth carbonate, alkaline 
earth bicarbonate, alkali salt of at least one solid edible organic acid, 
and alkaline earth salt of at least one solid edible organic acid is 
applied onto said coating. 
SUMMARY OF THE INVENTION 
The object of the present invention is to provide a powder composition 
capable of physiologically active for accurate control of the rate of 
release of a bioactive substance despite its small particle size and a 
method for its production, as well as a pharmaceutical preparation 
containing said powder composition such as a granule, tablet, or capsule. 
Another object of the present invention is to provide an effervescent 
composition which, when dispersed in water, provides for substantially the 
same rate of release of a physiologically active substance, especially an 
acid-sensitive pharmaceuticals as that after administration of the same 
substance alone. The preferable embodiment of the effervescent composition 
is one which is suitable for preparing an uniform suspension of an 
acid-sensitive active substance for oral administration. 
To solve the aforesaid problems, the inventors of the present invention did 
much research and found core-shell powders with a minimum of variation in 
coating amount and an increased content of an active substance, which are 
obtained by spraying small-diameter cores with a liquid mixture of a 
water-soluble polymer and the active substance to provide an 
drug-containing shell layer, whereby there can be properly controlled the 
release of the active substance in combination with an effervescing 
component. Further, a refreshing sensation on ingestion can be imparted by 
using the core-shell powders and the effervescent component in 
combination. The present invention has been developed on the basis of the 
above findings. 
That is, the present invention relates to an effervescent composition which 
comprises 
(a) a core-shell powder which essentially consists of fine granular core 
having a specific volume not exceeding 5 ml/g coated with a layer 
comprising a water-soluble polymer and an effective amount of an 
acid-sensitive physiologically active substance and an enteric coating 
layer, wherein the average particle diameters of the core-shell powder is 
not exceeding about 300 .mu.m; 
(b) an effervescing component; and 
(c) an auxiliary effervescing agent; wherein the proportion of (c) is from 
about 1.0 to about 2.0 equivalents relative to (b). 
According to the production method of the present invention, an 
effervescent core-shell powder composition is produced by admixing said 
core-shell powders with said effervescing component and effervescing agent 
of separate particles. 
DETAILED DESCRIPTION OF THE INVENTION 
Throughout this specification, the term "coating" or "coated" means not 
only a complete coverage of the core but also a partial coverage of the 
core as well as adsorption on the surface of the core or adsorption into 
the core. 
The term "spherical" as used herein is not only synonymous with globose but 
broadly synonymous with ellipsoidal, pyriform, tear drop-shaped, etc., 
which can be defined by curved planes. 
The average diameter of the fine granular cores is not exceeding about 250 
.mu.m and may be about 50-250 .mu.m, preferably about 100-250 .mu.m. As 
cores having diameters within the above range, the particle should pass 
through #50 (300 .mu.m) sieve, and not more than about 5 w/w % of them may 
remain on #60 (250 .mu.m) sieve and not more than about 10 w/w % of them 
may pass through #282 (53 .mu.m) sieve. 
The specific volume of the fine granular cores is not more than about 5 
ml/g, preferably not more than 3 ml/g. Examples of the fine granular cores 
includes crystalline cellulose beads of the size range about 150-250 .mu.m 
(Avicel SP, Asahi Chemical Industry Co., Ltd.; hereinafter referred to as 
Avicel SP), crystalline cellulose-lactose beads about 150-250 .mu.m beads 
composed of crystalline cellulose (3 parts) and lactose (7 parts) 
(Nonpareil, Freund Industries; hereinafter referred to as NP-7:3), about 
150-250 .mu.m beads composed of crystalline cellulose (5 parts) and 
lactose (5 parts) (Nonpareill, Freund Industries; hereinafter referred to 
as NP-5:5 etc.), about 50-250 .mu.m beads composed of lactose (9 parts) 
and Pregelatinized starch (1 part) as manufactured by 
agitation-granulation, a fraction of granules up to 250 .mu.m in diameter 
among microcrystalline cellulose beads as described in 
JP-A-S61(1987)-213201, wax or other beads obtainable by spray-chilling or 
melt-granulation, oil fraction-gelatin or other beads, porous granules 
made of calcium silicate, starch, chitin, cellulose, chitosan, etc., 
sucrose, crystalline lactose, crystalline cellulose, sodium chloride, 
etc., either in bulk form or in processed form. Further, the core may be 
prepared in a desired particle size by known pulverization or granulation 
using the foregoing substance and sieving the resulting granules. 
The above-mentioned core may contain any of the drugs to be mentioned 
hereinafter but since the release of the drug is controlled by the 
drug-containing coating-layer, the core need not contain the drug. 
There is no particular limitation on core morphology. It may for example be 
a fine granule or, in order to reduce the variation in coating amount and 
increase the coating amount, it is preferably spherical. 
The water-soluble polymer that can be used includes ethanol-soluble, 
water-soluble polymers e.g. cellulose derivatives such as 
hydroxypropylcellulose (hereinafter referred to as HPC), 
polyvinylpyrrolidone, etc.! and ethanol-insoluble, water-soluble polymers 
e.g. cellulose derivatives such as hydroxypropylmethylcellulose 
(hereinafter referred to as HPMC), methylcellulose, carboxymethylcellulose 
sodium, etc., sodium polyacrylate, polyvinyl alcohol, sodium alginate, 
guar gum, etc.!. The release rate of the physiologically active substance 
can be controlled by using an ethanol-soluble, water-soluble polymer in 
combination with an ethanol-insoluble, water-soluble polymer or using a 
plurality of water-soluble polymers differing in viscosity. 
The preferred water-soluble polymer includes cellulose derivatives such as 
HPC, HPMC, methyl-cellulose, etc., and polyvinyl alcohol. Particularly 
preferred are cellulose derivatives such as HPC and HPMC. 
HPC contains 53.4-77.5 weight % of hydroxypropoxy groups. The preferred 
content is 60-70 weight %. A 2 weight % aqueous solution of HPC at 
20.degree. C. is generally about 1-150000 cps (centipoise). As a typical 
grade of HPC, JP (Japanese Pharmacopoeia) hydroxypropylcellulose can be 
mentioned. The viscosity values of HPC mentioned below are the values 
determined using 2 weight % aqueous solutions at 20.degree. C. The HPC for 
use in the present invention is different from the low-substituted 
hydroxypropylcellulose mentioned in said JP-A-H2(1990)-174931 in the 
degree of hydroxypropoxy group. 
HPMC is a mixed ether containing both methoxy and hydroxypropoxy groups. 
The methoxy content of HPMC may be about 19-30 weight % and the 
hydroxypropoxy content thereof may be about 4-12 weight %. The viscosity 
of a 2 weight % aqueous solution of HPMC at 20.degree. C. is generally 
about 1-40000 centistokes. As HPMC of this grade, JP 
hydroxypropylmethylcellulose 2208, JP hydroxypropylmethylcellulose 2906, 
and JP hydroxypropylmethylcellulose 2910, among others, can be used. These 
hydroxypropylmethylcellulose can be used independently or as a mixture. 
The physiologically active substances that can be used in the invention 
includes a variety of drugs which are employed in the fields of food, 
medicine, agriculture, etc., only provided it can be administered orally. 
The preferred physiologically active substance includes but is not limited 
to the following medicinally active substances: central nervous system 
drugs (diazepam, idebenone, aspirin, ibuprofen, paracetamol, naproxen, 
piroxicam, diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, 
phenytoin, acetaminophan, ethenzamide, ketoprofen, etc.), cardiovascular 
system drugs (molsidomine, vinpocetine, delapril hydrochloride, 
propranolol, methyldopa, dipyridamole, furosemide, triamterene, 
nifedipine, atenolol, spironolactone, metoprolol, pindolol, captopril, 
isosorbide dinitrate, etc.), respiratory system drugs (amlexanox, 
dextromethorphan, theophylline, pseudoephedrine, salbutamol, guaifenesin, 
etc.), gastrointestinal system drugs (benzimidazole drugs such as 
lansoprazole, omeprazole, etc., cimetidine, ranitidine, panoreatin, 
bisacodyl, 5-aminosalicylic acid, etc.), antibiotics and chemotherapeutic 
agents (cefalexin, cefaclor, cefradine, amoxicillin, pivampicillin, 
bacampicillin, dicloxacillin, erythromycin, erythromycin stearate, 
lincomycin, doxycycline, sulfamethoxazole-trimethoprim, etc.), metabolic 
system drugs (serrapeptase, lysozyme chloride, adenosine triphosphate, 
glibenclamide, potassium chloride, etc.), vitamins (vitamin B.sub.1, 
vitamin B.sub.2, vitamin B.sub.6, vitamin C, fursultiamine, vitamin A, 
vitamin E, vitamin D, vitamin K, etc.), and antacids. These drugs can be 
used independently or in combination. Among the others, an acid-sensitive 
medicament which may unstable and/or inactivated with acid, such as 
vitamins (vitamin B.sub.12, Vitamin C, fursultiamine, folic acid, vitamin 
B.sub.12, Vitamin A, vitamin D or like), peptide drugs such as, enzymes 
(serrapeptase etc), antibiotics, cimetidine, ranitidine, known 
benzimidazole drugs having antiulcer activity, represented by the formula: 
##STR1## 
wherein ring A may optionally be substituted, R.sup.1, R.sup.3, and 
R.sup.4, which are the same or different, are hydrogen, an alkyl group or 
an alkoxy group; R.sup.2 is a C.sub.1-4 alkyl group which may optionally 
substituted with halogen, hydroxy or C.sub.1-4 alkoxy groups; and n is 0 
or 1; or a salt thereof, such as lansoprazole or omeprazole are preferably 
used. 
Referring to the above formula, the substituent on ring A includes halogen, 
C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, C.sub.2-16 alkenyl or C.sub.1-10 
alkoxy group which may be substituted, cyano, carboxy, carbalkoxy, 
carbalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, hydroxyalkyl, acyl, 
carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio and alkylsulfinyl, 
among others. 
The alkyl group represented by R.sup.1, R.sup.3 or R.sup.4 includes 
C.sub.1-10 straight-chain or branched alkyl groups. Among such alkyl 
groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 
sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, 
octyl, nonyl, decyl and so on. Among others, C.sub.1-5 straight-chain or 
branched alkyl groups are particularly desirable. 
The alkoxy group represented by R.sup.1, R.sup.3 or R.sup.4 includes 
C.sub.1-10 alkoxy groups. Among such alkoxy groups are methoxy, ethoxy, 
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 
n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, 
nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy and so on. The 
preferred groups are C.sub.1-6 alkoxy groups. The more desirable are 
C.sub.1-3 alkoxy groups. 
The alkyl group represented by R.sup.2 and the alkoxy group used as 
substituent thereof may includes the above exemplified C.sub.1-4 alkyl and 
C.sub.1-4 alkoxy groups. The number of substituents is preferably 1 to 3. 
These compounds are described in, for example. U.S. Pat. Nos. 4,045,563, 
4,255,431, 4,359,465, 4,472,409, 4,508,905, JP-A-59 181277, U.S. Pat. Nos. 
4,628,098, 4,378,975, 5,045,321, 4,786,505, 4,853,230, 4,769,456, 
5,045,552, 5,536,735, EP-A-295603, U.S. Pat. Nos. 5,312,824, EP-A-166287 
and EP-A-519365, etc. 
The benzimidazole drugs are the most preferable physiologically active 
substance. 
Thus, the preferable embodiment of the core-shell powder of the invention 
is a powder consisting of a fine granular core coated with a layer 
(shell-layer) comprising a water-soluble polymer and an effective amount 
of an acid-sensitive pharmaceutically active drug and an enteric-coating 
layer (shell-layer). 
For increased strength of the core-shell powders, the drug-containing layer 
may contain various additives inclusive of the low-substituted 
hydroxypropylcellulose (hereinafter referred to as L-HPC) described in 
JP-A-H2(1990)-174931. 
The additives mentioned above may be the substances usually added in the 
production of powders. Thus, various excipients such as lactose, corn 
starch, sucrose, talc, crystalline cellulose, mannitol, light silicic 
anhydride, magnesium carbonate, calcium carbonate, L-cysteine, etc.; 
binders such as pregelatinized starch, partially pregelatinized starch, 
methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullulan, 
dextrin, gum arabic, etc.; disintegrators such as carboxymethylcellulose 
calcium, starches, crosslinked carboxymethylcellulose sodium, crosslinked 
insoluble polyvinylpyrrolidone, etc.; and coloring agents such as titanium 
dioxide, red iron oxide, tar pigment, etc. can be mentioned. Stabilizer 
may preferably added for stabilizing the shell-unstable drugs as the 
additives. More than one species each of such additives can be employed. 
The proportion of the water-soluble polymer such as HPC and/or HPMC may 
only be within the range capable of controlling the release of a drug 
contained in the core-shell powders. Based on the total weight of the 
whole core-shell powders, the proportion may for example be from or about 
0.1 to or about 50 weight % and preferably from or about 1 to or about 30 
weight %. If the proportion of the water-soluble polymer is smaller than 
about 0.1 weight %, it will be difficult to control the release of the 
drug, while the use of said polymer in excess of about 50 weight % results 
in a reduced drug content. 
The proportion of the coating-layer with respect to the core can be 
liberally selected within the range permitting control of the release of 
the drug and may for example be from or about 50 to or about 400 parts by 
weight based on 100 parts by weight of the core. If the proportion of the 
coating-layer is smaller than about 50 parts by weight, the release of the 
active substance can hardly be controlled. On the other hand, if the limit 
of about 400 parts by weight is exceeded, there will occur a marked growth 
of particles to cause more deviations from the particle size specification 
of the powders. 
The coating may be comprised of a single layer or consist of a plurality of 
layers and it is sufficient that the bioactive substance be contained in 
at least one coating-layer. The plurality of coating-layers may consist of 
the layers such as an undercoat layer, an inactive layer and an enteric 
layer in any combination. 
For the purpose of protecting an acid-sensitive drug or insuring 
dissolution in the intestinal fluid, the core-shell powders should be 
coated with an enteric coating. The enteric-coating agent that can be used 
for such purposes includes but is not limited to cellulose acetate 
phthalate(CAP), hydroxypropylmethylcellulose phthalate (hereinafter 
referred to as HP-55), hydroxymethylcellulose acetate succinate, acrylic 
copolymers (e.g. Eudragit L30D-55), carboxymethylethylcellulose and 
shellac. 
The proportion of the enteric-coating layer may be selected within the 
range of from or about 35 weight % to or about 50 weight % based on the 
total amount of the enteric core-shell powder. If the portion of the 
enteric coating layer is smaller than about 35%, the acid sensitive drug 
can be unstable is a gastric fluid. On the other hand if the portion of 
enteric coating layer exceeds about 50%, the release of the active 
substance would be decreased. 
The average particle diameter of the core-shell powder is not larger than 
about 300 .mu.m, preferably in the range of from or about 100 to or about 
300 .mu.m, and for still better results, in the range of about 150-300 
.mu.m. As the core-shell powder having a diameter within the range, the 
granule of the powder should pass through a sieve of 400 .mu.m screen, and 
not more than about 5 w/w % of the total amount of the powder may remain 
in a #42 (355 .mu.m) sieve and not more than about 5 w/w % thereof may 
pass through #100 (150 .mu.m) sieve. For effervescent use, smaller size of 
particles is advantageous for rapidly preparing a uniform solution or 
suspension and keeping there uniformity. However, if the particle size is 
too small, there tends to occur the trouble that in the course of 
production the powders are attracted to the equipment walls by static 
electricity. 
The specific volume of the core-shell powder is not exceeding about 3 ml/g, 
preferably not exceeding 2 ml/g. For insuring a stable uniformity in the 
effervescent solution, the specific volume of the core-shell powder is 
preferably selected in accordance with that of the solution. 
The release rate of the drug in the core-shell powders can be controlled by 
using a plurality of the water-soluble polymer (e.g. HPC, HPMC, etc.) 
solutions varying in viscosity or content or modifying the ratio of an 
ethanol-soluble, water-soluble polymer (e.g. HPC) to an ethanol-insoluble, 
water-soluble polymer (e.g. HPMC). Further, the release of drug can also 
be controlled without being much influenced by the pH of the environment 
in which they are released. 
The effervescent composition of the present invention contains an 
effervescing component for providing a refreshing sensation or ingestion. 
With this effervescent dosage form, the release of a physiologically 
active ingredient can be accurately controlled as it is the case with the 
core-shell powders as such. As the effervescing component, a variety of 
substances can be utilized unless the safety of the composition is 
compromised. To mention a few examples, alkali metal carbonates (e.g. 
sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen 
carbonates (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, 
etc.), and ammonium carbonate can be employed. These effervescing agents 
can be used singly or in combination. Among preferred effervescing agents 
are sodium carbonate, sodium hydrogen carbonate, and ammonium carbonate. 
The proportion of the effervescing component can be selected from the 
range providing the required effervescence and, based on 100 parts by 
weight of the core-shell powders, may for example be from about 10 to 
about 2500 parts by weight, preferably about 50-2000 parts by weight (e.g. 
75-1500 parts by weight), or for still better results, about 100-1000 
parts by weight. 
The effervescing component mentioned above can be used either independently 
or in combination with an auxiliary effervescing agent. The auxiliary 
effervescing agent includes a variety of edible organic acids, typically 
hydroxycarboxylic acids such as citric acid, tartaric acid, malic acid, 
lactic acid, gluconic acid, etc., saturated aliphatic carboxylic acids 
such as acetic acid, succinic acid, etc., and unsaturated aliphatic 
carboxylic acids such as fumaric acid. These auxiliary effervescing agents 
can also be used singly or in combination. Among preferred edible 
auxiliary effervescing agents are hydroxy-carboxylic acids such as citric 
acid and tartaric acid. The proportion of the auxiliary effervescing agent 
is generally about 0.1-2.0 equivalents and preferably about 0.3-1.7 
equivalents based on said effervescing component. The proportion of the 
auxiliary effervescing agent for enteric-coated core-shell powders should 
be about 1.0-2.0 equivalents and preferably about 1.3-1.7 equivalents 
relative to the effervescing component in order that the pH of the system 
may be maintained on the acidic side, while the proportion for gastric 
fluid soluble core-shell powders should be about 0.1-1.0 equivalent and 
preferably about 0.3-0.7 equivalents, in order that the system pH of the 
composition may be maintained on the alkaline side. 
The effervescent composition of the present invention need only contain 
said core-shell powders and said effervescing component but may further 
contain said additives (e.g. excipients, binders, disintegrants, etc.) 
where necessary. 
The effervescent composition of the present invention can be manufactured 
by coating said fine granular cores with a liquid mixture containing a 
water-soluble polymer and at least one physiologically active substance to 
give core-shell powders and mixing the core-shell powders with said 
effervescing component. The auxiliary effervescing agent may preferably 
contained in said mixture. 
The liquid mixture mentioned above may be a solution or a dispersion. The 
liquid mixture can be prepared by using water, an organic solvent such as 
ethanol, or a mixture thereof. 
The concentration of said water-soluble polymer in the liquid mixture 
should vary with the formulating amounts of the drug and additives but is 
generally from or about 0.1 to or about 50 weight % and preferably about 
0.5-10 weight %. If the concentration is less than about 0.1 weight %, the 
drug will not be well immobilized on the core granules. If the limit of 
about 50 weight % is exceeded, the viscosity of the liquid mixture will be 
too high to provide practically acceptable workability. 
The coating-layer is not limited to a single layer but may be made up of a 
plurality of layers. Thus, one may select the optimum formulating amount 
and viscosity grade for the water-soluble polymer and/or apply successive 
coats using liquid mixtures varying in the concentrations of the drug and 
additives to thereby create a continual or stepwise gradation in the 
distribution of the drug in the shell. In this connection, insofar as the 
whole coating-layer contains from about 0.1 to or about 50 weight % of the 
water-soluble polymer, liquid mixtures deviating from the above 
concentration range of from or about 0.1 to or about 50 weight % may be 
employed. Furthermore, an inert film may be interposed between layers by 
known technology to isolate the drug containing layers from each other. 
In the event two or more physiologically active substances which are hardly 
compoundable are employed, the fine granular core may be coated with 
liquid mixtures containing such drug respectively either concurrently or 
in a sequence. 
As an alternative production process according to the present invention, 
core-shell powders can be manufactured by spraying a fine granular core 
with said liquid mixture and simultaneously dusting a dusting powder 
containing the drug and/or additives over the cores. In this process, the 
required shell can be provided by the simple procedure of dusting a 
dusting powder. The particle size of such a dusting powder is preferably 
not greater than about 50 .mu.m. 
The granulation process comprising coating the fine granular core with said 
liquid mixture in the above manner. The granulation temperature should be 
within the range not adversely affecting the stability of the drug. Where 
the stability of the drug is good, the temperature of the liquid mixture 
need not be carefully controlled. Generally, the temperature of the liquid 
mixture may be equal to the room temperature (e.g. about 
1.degree.-30.degree. C.). There is no particular limitation on the method 
of covering the core. For example, the centrifugal fluidized coating 
granulator, fluidized coating granulator, agitation-granulator, or any 
other routine granulation equipment can be employed. As specific models of 
centrifugal fluidized coating granulator, there can be mentioned "CF 
apparatus" and "Spira-flow" available from Freund Industries, "Multiplex" 
from Powrex, and "New-Marume" from Fuji Paudal can be mentioned. The 
method of spray coating with said liquid mixture can be selected according 
to the type of available granulation equipment. Thus, for example, any of 
bottom spray, tangential spray and other coating modes can be selectively 
employed. 
The granulation thus obtained is dried and sieved to provide core-shell 
powders uniform in particle size. Since the shape of powders generally 
corresponds to the shape of the fine granular cores used, even truly 
spherical core-shell powders can be successfully obtained. As the sieve, a 
50-mask (300 .mu.m) circular sieve, for instance, can be used and by 
collecting particles passing through such a sieve, the desired core-shell 
powders can be obtained. 
For the purpose of masking the taste or insuring dissolution in the 
intestinal fluid or in the gastric fluid, the core-shell powders obtained 
as above may be further coated in the routine manner. 
The coating agent that can be used for such purposes includes but is not 
limited to HPMC, ethylcellulose, hydroxymethylcellulose, 
hydroxypropylcellulose, polyoxyethylene glycol (e.g. Macrogel 6000), Tween 
80, Pluronic F68, castor oil, cellulose acetate phthalate, 
hydroxypropylmethylcellulose phthalate (hereinafter referred to as HP-55), 
hydroxymethylcellulose acetate succinate, acrylic copolymers (e.g. 
Eudragit L30D-55), carboxymethylethylcellulose, poly vinyl acetal 
diethylaminoacetate, shellac, wax, talc, titanium dioxide, and red iron 
oxide. 
If desired, a plurality of coating-layers (e.g. an HPMC undercoat layer, an 
acrylic copolymer or other enteric or gastric fluid soluble layer) may be 
formed on the core-shell powders using a plurality of coating 
compositions. 
The effervescent composition obtained by mixing said core-shell powders 
with said effervescing agent can be used directly as an effervescent 
dosage form. The composition can be further formulated with said additives 
such as an excipient, binder, disintegratant, etc. and granulated or 
compressed to provide granules or tablets. The core-shell powder of the 
invention may be filled into capsule shells to provide capsules in 
addition to these dosage forms. 
Since the effervescent composition of the present invention contains the 
core-shell powders described above, it lends itself well to compounding 
with a minimum of variation in content. Moreover, since it contains an 
effervescing component in addition to core-shell powders, the release rate 
of the drug can be accurately controlled despite the small particle 
diameter. In addition, the composition provides an uniform effervescent 
solution of acid-sensitive drugs with a refreshing sensation on ingestion. 
Thus, in accordance with the present invention, compositions having the 
above useful characteristics can be easily obtained by the expedient 
procedure of mixing core-shell powders with an effervescing agent.

EXAMPLES 
The following examples are merely intended to illustrate the present 
invention in further detail and should by no means be construed as 
defining the scope of the invention. 
Example 1 
Production of Core-Shell Powders 
A centrifugal fluidized coating granulator (Powrex, MP=10) was charged with 
800 g of Avicel SP (particle diameter=100-200 .mu.m) and with the inlet 
air temperature and the temperature of the load being controlled at 
80.degree. C. and about 38.degree. C., respectively, a bulk liquid of the 
following composition was coated on the Avicel by the tangential spray 
method. The spraying operation was stopped when the specified amount of 
the bulk liquid had been delivered and the load was dried in the 
granulator for 5 minutes. The resulting granules were sieved through a #60 
circular sieve (250 .mu.m) and a #100 circular sieve (150 .mu.m) to 
provide 1450 g of core-shell powders. 
Bulk Liquid Composition! 
Lansoprazole 300 g 
Magnesium carbonate 200 g 
L-HPC 50 g 
Talc 50 g 
HPC (Type SSL) 100 g 
Water 3200 g 
Production of an Undercoated Core-Shell Powder 
The same fluidized coating granulator as above (MP-10) was charged with 
1200 g of the above core-shell powders and with the inlet air temperature 
and the load temperature being controlled at 85.degree. C. and about 
40.degree. C., respectively, a undercoating liquid of the following 
composition was applied by the tangential spray method at a spray rate of 
12 g/min, to provide film-undercoated core-shell powders. 
Undercoating Liquid! 
HPMC (Type 2910, viscosity=3 centistokes) 80 g 
Water 1520 g 
Production of Enteric-Coated Core-Shell Powder 
The same fluidized coating granulator as above (MP-10) was charged with 960 
g of the above undercoated core-shell powders and with the inlet air 
temperature and the load temperature being controlled at 65.degree. C. and 
about 38.degree. C., respectively, an enteric film-coating liquid of the 
following composition was applied by the tangential spray method at a 
spray rate of 15 g/min. The coated powders were dried in vacuum oven at 
40.degree. C. for 16 hours and sieved through a #42 circular sieve (355 
.mu.m) and a #80 circular sieve (177 .mu.m) to provide 1500 g of 
enteric-coated core-shell powders. 
Enteric Film Coating Composition! 
Eudragit L30D-55 1783.8 g 
Talc 160.8 g 
Macrogol 6000 52.8 g 
Titanium dioxide 52.8 g 
Polysorbate 80 24.0 g 
Water 3744.0 g 
To eliminate static charge, a tumbling-mixer (TM-15, Showa Chemical) was 
charged with 1500 g of the above enteric-coated core-shell powders, 6 g of 
talc, and 6 g of light silicic anhydride and the load was mixed at 30 rpm 
for 3 minutes. The resulting enteric-coated core-shell powders showed a 
sharp particle size distribution meeting the requirements of the JP 
particle size test. 
______________________________________ 
Sieve Weight ratio 
______________________________________ 
residued on #18 (850 .mu.m) sieve 
0% 
residued on #30 (500 .mu.m) sieve 
0% 
residued on #200 (75 .mu.m) sieve 
100% 
passed through #200 (75 .mu.m) sieve 
0% 
______________________________________ 
Example 2 
Production of an Effervescent Composition 
An effervescent composition was produced by mixing 300 mg of the 
enteric-coated core-shell powders obtained in Example 1, 1800 mg of citric 
acid powder, and 900 mg of sodium hydrogen carbonate powder. 
Example 3 
Production of Core-Shell Powders 
A centrifugal fluidized coating granulator (Powrex, MP-10) was charged with 
800 g of Avicel SP (particle diameter=100-200 .mu.m) and with the inlet 
air temperature and the load temperature being controlled at 80.degree. C. 
and about 38.degree. C., respectively, a bulk liquid composition prepared 
according to the following recipe was applied by the tangential spray 
method. The spraying operation was stopped when the specified amount of 
the bulk liquid composition had been sprayed and the load was dried in the 
granulator for 5 minutes. The resulting granules were sieved through a #60 
circular sieve (250 .mu.m) and a #100 circular sieve (150 .mu.m) to 
provide 1450 g of core-shell powders. 
Bulk Liquid Composition! 
Lansoprazole 300 g 
Magnesium carbonate 300 g 
L-HPC 50 g 
Talc 50 g 
HPC (Type SSL) 100 g 
Water 3200 g 
Production of Enteric-Coated Core-Shell Powders 
The same fluidized coating granulator as above (MP-10) was charged with 960 
g of the above core-shell powders and with the inlet air temperature and 
the load temperature being controlled at 65.degree. C. and about 
38.degree. C., respectively, an enteric film coating composition prepared 
according to the following recipe was applied by the tangential spray 
method at a spray rate of 15 g/min. The coated powders were dried in 
vacuum oven at 40.degree. C. for 16 hours and sieved through a #42 (355 
.mu.m) circular sieve and a #80 (177 .mu.m) circular sieve to provide 1500 
g of an enteric film-coated core-shell powders. 
Enteric Film Coating Composition! 
Eudragit L30D-55 1783.8 g 
Talc 160.8 g 
Macrogol 6000 52.8 g 
Titanium dioxide 52.8 g 
Polysorbate 80 24.0 g 
Water 3744.0 g 
To eliminate static charge, a tumbling-mixer (TM-15, Showa Chemical) was 
charged with 1500 g of the above enteric-coated core-shell powders, 6 g of 
talc, and 6 g of light silicic anhydride and the load was agitated at 30 
rpm for 3 minutes. The resulting enteric-coated core-shell powders 
satisfied the requirements of the JP particle size test. 
______________________________________ 
Sieve Weight ratio 
______________________________________ 
residued on #18 (850 .mu.m) sieve 
0% 
residued on #30 (500 .mu.m) sieve 
0% 
residued on #200 (75 .mu.m) sieve 
100% 
passed through #200 (75 .mu.m) sieve 
0% 
______________________________________ 
Example 4 
Production of a Effervescent Composition 
An effervescent composition was produced by mixing 300 mg of the 
enteric-coated core-shell powders obtained in Example 3, 1800 mg of citric 
acid powder, and 900 mg of sodium hydrogen carbonate powder. 
Test Example 1 
The release characteristics of the enteric-coated core-shell powders 
obtained in Examples 1 and 3 and the effervescent compositions obtained in 
Examples 2 and 4 were evaluated by JP Dissolution Test, No. 2 Method (150 
rpm). Since the test materials were enteric powders, the test was 
performed by using JP with the 1st fluid and then using the 2nd fluid. The 
effervescent compositions were respectively dispersed in 100 ml of 
purified water for the development of effervescence and allowed to stand 
for 5 minutes prior to testing. The test results are shown in Table 1. 
TABLE 1 
______________________________________ 
Test fluid the 1st fluid 
the 2nd fluid 
Release time 
60 min. 20 min. 40 min. 
60 min. 
______________________________________ 
Example 1 0% 90% 95% 95% 
Enteric-coated 
core-shell powders 
Example 2 0% 90% 95% 95% 
Effervescent 
composition 
Example 3 0% 90% 95% 95% 
Enteric-coated 
core-shell powders 
Example 4 0% 90% 95% 95% 
Effervescent 
composition 
______________________________________ 
It will be apparent from Table 1 that the two enteric-coated core-shell 
powders are equivalent in acid resistance and drug release rate and that 
even when an effervescing component is formulated for effervescence and 
the formulation administered, the powders still show virtually the same 
acid resistance and drug release rate, thus providing the efficacy 
equivalent to that of fine granules. 
Test Example 2 
The specific volume of Avicel SP, the core substance, the core-shell 
powder, undercoated core-shell powder, and the enteric-coated core-shell 
powder prepared in Example 1 were determined as in the following volume 
test. 
50 g each of the powders were weighed and transferred gradually to a 200-ml 
measuring cylinder respectively, and allowed to stand. The specific volume 
was calculated by dividing the thus measured volume by weight. 
The results are shown in Table 2. 
TABLE 2 
______________________________________ 
undercoated 
enteric film 
core-shell core-shell 
coated core- 
Avicel SP 
powder powder powder 
______________________________________ 
Specific 
1.22 1.24 1.20 1.16 
volume 
(ml/g) 
______________________________________