Sustained-release preparation and production thereof

The present invention concerns a sustained-release microcapsule preparation comprising an ion exchange resin with 6 to 16% crosslinking, containing a drug adsorbed in an amount not less than 80% of its theoretical ion adsorption amount and coated with a water-permeable polymer.

The present invention relates to a sustained-release preparation and the 
method of its production. 
A variety of preparations which release the base drug so that the 
pharmacological effect of the drug lasts for a sustained period have been 
produced and tested. Such preparations included sustained-release 
preparations using an ion exchange resin. It has been reported that a 
drug-ion exchange resin complex is effective in releasing the drug in the 
digestive tract for a sustained period (e.g., see the specification for 
U.S. Pat. No. 2990332). However, when prepared as fine particles suitable 
for oral administration, e.g., particles of less than 500 .mu.m diameter, 
the said drug-resin complex shows almost no sustained-release properties 
because its drug-releasing rate is too high. 
Attempts have been made to prepare sustained-release microcapsules by 
coating the drug-resin complex with various materials to overcome this 
drawback and to thereby add a sustained-release property (e.g., see 
specifications for U.S. Pat. Nos. 3,138,525, 3,499,960, and 3,594,470). 
When a sustained-release microcapsule obtained by coating a drug-resin 
complex with the material which has sustained-release properties on is 
orally administered, the drug is released by the exchange of ions in the 
digestive juice. The drug then passes through the sustained-release coat 
into the digestive juice where it is absorbed by the digestive tract. 
Then, the drug-resin complex absorbs water to swell. In the digestive 
tract, as a result, cracks are formed and rupture occurs in the 
sustained-release coat and the sustained-release property disappears. Also 
when a sustained-release microcapsule is formulated in an orally 
administered suspension, a similar problem arises in the preparation. 
These drawbacks have long been serious problems. 
In relation to these drawbacks, it has also been reported that it is 
effective to pretreat the drug-resin complex with a solvating agent, such 
as polyethylene glycol, prior to the formation of the sustained-release 
coat on the complex (See specifications for U.S. Pat. No. 4,221,778). 
Taking note of the excellent characteristic of the sustained-release 
preparation using a drug-resin complex, the present inventors worked to 
eliminate its drawbacks, and showed that the swelling of the drug-resin 
complex due to water absorption is closely related to the degree of 
crosslinking of the ion exchange resin and to the concentration of the 
drug thereby adsorbed. Thus the swelling of the drug-resin complex can be 
prevented by selecting the degree of the crosslinking of the resin and the 
drug concentration, and no rupture will occur even when the 
sustained-release coat is formed without pretreatment with a solvating 
agent. 
In consideration of the fact that drugs are normally prepared in the form 
of salts for stabilization and other purposes, the present inventors made 
further investigations in order to establish a method of producing a 
drug-resin complex which does not swell and which maintains the drug at a 
high concentration from a salt of the corresponding drug using a process 
which is favorable for drug preparation. They thereby developed the 
present invention. 
The present invention provides a sustained-release microcapsule preparation 
comprising an ion exchange resin with 6 to 16% of crosslinking, containing 
a drug adsorbed in an amount not less than 80% of its theoretical ion 
adsorption amount (the drug-resin complex), and coated with a 
water-permeable polymer coat, a method of producing the sustained-release 
microcapsule preparation comprising coating an ion exchange resin with 6 
to 16% crosslinking and containing a drug adsorbed in an amount not less 
than 80% of its theoretical ion adsorption amount with a water-permeable 
polymer. 
As for the ion exchange resin forming the abovementioned drug-resin 
complex, ordinary synthetic insoluble porous polymers, (e.g., the polymer 
which is the copolymer of styrene and divinylbenzene) may be mentioned. 
Said polymer, when it is an acidic ion exchange resin (H type), contains 
sulfonic groups, carboxylic groups, etc., and adsorbs the basic drug; when 
it is a basic ion exchange resin (OH type), it contains primary to 
quaternary amino groups, etc., and adsorbs acidic drugs. In the present 
invention, in particular, it is preferable to use a strongly acidic or 
strongly alkaline ion exchange resin. The degree of crosslinking for the 
ion exchange resin is determined depending upon the amount of crosslinking 
agent such as divinylbenzene to be used; it is preferable that 
crosslinking is from 6 to 16%, especially from 8 to 14%. 
These ion exchange resins are commercially available under the trade names 
of Diaion (Mitsubishi Chemical Industries Ltd., Japan), Dowex (Dow 
Chemical Co., USA), Amberlite (Rohm & Haas Co., USA), and others, and can 
be selected for use as appropriate. 
It is preferable that the mean particle size of the ion exchange resin is 
from 5 to 1000 .mu.m, specifically from 10 to 300 .mu.m. If desired, a 
commercially available ion exchange resin may be crushed to fine particles 
before use by means of a mill such as an atomizer. 
The theoretical ion adsorption amount (theoretical saturated adsorption 
amount, overall exchanging capacity) means the maximum amount of strongly 
basic ions (sodium ions, etc.) or strongly acidic ions (chlorine ions, 
etc.) adsorbed by a given ion exchange resin. For the present invention, 
an ion exchange resin which has adsorbed a drug in a molar ratio of more 
than 80%, specifically from 85 to 100% of this theoretical amount, is 
preferred. 
Drugs having various effects can be selected depending upon the purpose, 
but it is preferable that the basic drug is of a pKa from 6 to 10, 
specifically a pKa from 7.5 to 10, and the acidic drug is of a pKa from 2 
to 5. These drugs are normally present in the form of salts, basic drugs 
being available as salts with acids and acidic drugs being available as 
salts with bases. 
As specific examples, the following may be mentioned: 
Drugs for the respiratory tract: 
Antitussive expectorants such as dihydrocodeine phosphate, codeine 
phosphate, noscapine hydrochloride, phenylpropanolamine hydrochloride, 
potassium guaiacolsulfonate, cloperastine fendizoate, dextromethorphan 
hydrobromide and chloperastine hydrochloride; bronchodilators such as 
dl-methylephedrine hydrochloride and dl-methylephedrine saccharinate; and 
antihistamines such as dl-chlorpheniramine maleate. 
Drugs for the digestive tract: 
Digestive tract antispasmodics such as scopolamine hydrobromide, metixene 
hydrochloride and dicyclomine hydrochloride. 
Drugs for the central nervous system: 
Antipsychotic drugs such as phenothiazine derivatives (chlorpromazine 
hydrochloride, etc.) and phenothiazine-like compounds (chlorprothixene 
hydrochloride, etc.); antianxiety drugs such as benzodiazepine derivatives 
(chlordiazepoxide hydrochloride, etc.); antidepressants such as imipramine 
compounds (imipramine hydrochloride, etc.); antipyretic analgesics such as 
sodium salicylate; and hypnotics such as phenobarbital sodium. 
Drugs for the respiratory system: 
Coronary dilators such as etafenone hydrochloride; antiarrhythmics such as 
procainamide hydrochloride; Ca antagonists such as verapamil 
hydrochloride; hypotensive drugs such as hydrazine hydrochloride, 
propranolol hydrochloride and clonidine hydrochloride; and peripheral 
vasodiaators/vasoconstrictors such as tolazoline hydrochloride. 
Antibiotics: 
Macrolides such as oleandomycin phosphate; tetracyclines such as 
tetracycline hydrochloride; streptomycins such as fradiomycin sulfate; and 
penicillin drugs such as dicloxacillin sodium, pivmecillinam hydrochloride 
and carbenicillinindanyl sodium. 
Chemotherapeutic drugs: 
Sulfa drugs such as sulfisomidine sodium; antituberculosis drugs such as 
kanamycin sulfate; and antiprotozoan drugs such as amodiaquine 
hydrochloride. 
In particular, an excellent sustained releasing effect is obtained in basic 
drugs for the respiratory tract such as dihydrocodeine phosphate, 
dl-methyl-ephedrine hydrochloride and phenylpropanolamine hydrochloride. 
The water-permeable polymer coat is formed of a natural or non-natural 
biocompatible polymer. Examples of such polymers, include cellulose 
polymers such as ethylcellulose, nitrocellulose, benzylcellulose, 
acetocellulose, hydroxypropylcellulose and cellulose acetate propionate; 
and non-natural polymers such as polyacrylate, polymethacrylate, polyamide 
and acrylate-methacrylate copolymers (e.g., aminoalkyl methacrylate 
copolymer). For the present invention, in particular, aminoalkyl 
methacrylates (known as Eudragit, etc.) are favored 
The sustained-release preparation of this invention can be, for example, 
produced as follows: 
In an aqueous solvent capable of dissolving both salts and the free form of 
the drug, a drug in a salt form is reacted with an ion exchange resin to 
give an aqueous solution of the free form of the drug. 
Examples of aqueous solvents include organic solvents which are freely 
soluble in water such as primary, lower (C.sub.1-3) alcohols (e.g., 
methanol, ethanol, isopropanol) and aqueous solutions of ketones such as 
acetone and methyl ethyl ketone. 
Said aqueous solvents mentioned include aqueous solutions containing from 5 
to 95%, preferably from 10 to 90%, of the organic solvent. In particular, 
when the salt is of a basic drug, it is preferable to use an aqueous 
solution of from 40 to 85% ethanol or isopropanol, and when the salt is of 
an acidic drug, to use an aqueous solution of from 5 to 30% ethanol. 
The ion exchange resin to be used in the reaction may be those mentioned 
above, i.e. a basic ion exchange resin is used for a basic drug and an 
acidic ion exchange is used for an acidic drug to make respective free 
forms. 
The reaction with the ion exchange resin is carried out by adding an ion 
exchange resin as mentioned above to the salt of the drug in solution in 
the aqueous solvent and then stirring the mixture. In this case, it is 
preferable that the ion exchange resin is used in an amount from 1.0 to 
2.0 times the necessary amount of the drug's salt. The reaction is 
normally carried out at room temperature or ambient temperature, but the 
mixture can be warmed to about 70.degree. C. Reaction time is from 0.5 to 
6 hours. 
After the completion of reaction, the ion exchange resin is removed by 
ordinary means, then an aqueous solution of the free form of the drug is 
provided. 
The drug-resin complex can be produced by adding an ion exchange resin of a 
given particle size and degree of crosslinking to the above aqueous 
solution and causing a reaction between them. The reaction is normally 
carried out at room temperature with from 0.5 to 3 hours of stirring. 
The above reaction will give a drug-ion exchange resin complex which has 
adsorbed the drug in an amount of more than 80% of the theoretical ion 
adsorption amount, and it is preferable that the complex used contain the 
adsorbed drug in an amount of from 85 to 100% of the theoretical ion 
adsorption amount. 
Said complex is then coated with a water-permeable polymer to produce the 
microcapsule preparation of this invention. For coating with the 
water-permeable polymer, organic solvents capable of dissolving polymers 
are used, such as ethanol, toluene, chloroform, methyl ethyl ketone, 
methylene chloride, isopropanol, cyclohexane, methanol, ethylene chloride, 
dimethylformamide, or ethyl acetate 
A plasticizer or a stabilizer, such as an antioxidant, may also be added in 
any amount. Examples of plasticizers include dibasic acid esters (phthalic 
acid esters, etc.), glycol esters, and fatty acid esters. Examples of 
antioxidants for stabilization include 2(3)-t-butyl-4-hydroxyanisol(BHA), 
3,5-di-t-butyl-4-hydroxytoluene(BHT), tocopherol and tocopherol acetate. 
When the water-permeable polymer is an acrylate-methacrylate copolymer, it 
is dissolved in methylene chloride or chloroform, the drug-resin complex 
then is added to and suspended in this solution. The resulting suspension 
is treated mechanically by the spray drying method to produce 
microcapsules; this can also be done by phase separation, a 
physico-chemical method. In this procedure the polymer is dissolved in a 
good solvent, a phase separating and anti-aggregating agent (chosen from 
polybutadiene, polydimethylsiloxane, methacryl polymer, etc.) is added to 
it in any amount, and a non-solvent is added while the solution is being 
stirred. Microcapsules can also be produced by a chemical method, i.e., 
the interfacial polymerization method. No matter which method is employed, 
it is preferable that the particle size of the sustained-release 
microcapsules thus obtained be from 5 to 1000 .mu.m, or, more preferably, 
from 10 to 300 .mu.m. 
For producing an oral suspension of the sustained-release microcapsules, 
purified water (as specified by the Pharmacopoea of Japan) can be used as 
the solvent. Usually, the total amount of about 0.2 g to 10 g of the 
microcapsule is suspended in 100 ml of purified water. Antiseptics, 
correctives, dispersing agents, wetting agents, thickening agents, etc., 
may be added as required. 
As antiseptics, non-ionic methyl parahydroxybenzoate, ethyl 
parahydroxybenzoate, propyl parahydroxybenzoate, butyl 
parahydroxybenzoate, etc., may be used. As correctives, sucrose, fructose, 
lactose, sorbitol, mannitol, etc., may be used. As wetting agents, 
surfactants such as polyoxyethylene sorbitan fatty acid esters 
(Polysorbate 80, Arlacel 83, etc.), polyoxyethylene hardened castor oils 
(HCO-50, etc.) and sugar esters may be added. As dispersing agents or 
thickening agents, guaiac gum, pullulan, xanthan gum, carrageenan, 
tragacanth gum, dextrin, pectin, gelatin, locust bean gum, guar gum etc., 
may be added in any amount. In addition to these additives, non-ionic 
substances may also be added as required. 
The microcapsule preparation of this invention may be prepared as capsules 
in which the microcapsules are filled as well as a sustained-release 
suspension directly to be taken orally. The microcapsules may also be 
suspended in an oily substance such as olive oil or safflower oil to 
provide soft gelatin-like capsules. The microcapsule preparation may also 
be combined with lactose, sucrose, corn starch, hydroxypropylcellulose, 
etc., to provide granules, powders or tablets 
The sustained-release preparation of this invention is characterized as 
follows: 
(1) A drug-ion exchange resin complex is produced in a continuous process 
in which a salt of a basic drug ( or a salt of an acidic drug) is reacted 
in an aqueous solvent with a basic ion exchange resin ( or an acidic ion 
exchange resin) to give the free form of the drug, which can then be 
adsorbed by desired ion exchange resin. In this way, a complex is obtained 
which has adsorbed the drug in an amount nearer to the theoretical 
saturated adsorption amount than by the conventional production process 
based on equilibrium reaction; repetitive adsorption processes are not 
necessary, and drug loss is very small. In addition, it is possible to 
minimize the dose of the microcapsules making them economical, as well as 
easy to take; this dosage form design facilitates drug development. 
(2) In the present invention, the drug-resin complex can be produced with 
high efficiency because a higher drug adsorption rate is achieved as a 
result of the swelling of the ion exchange resin in the aqueous solvent, 
specifically a mixture of water and ethanol or methanol, to a higher 
degree than in the case in which water alone is used. 
(3) Since the drug-resin complex which has adsorbed the drug in a high 
concentration is coated with a water-permeable polymer which has a 
sustained-release property, the coats of microcapsules show neither 
cracking nor breaking (rupture) even when they are dispersed or suspended 
in a solvent. The greater the molecular weight of the drug, or the 
sterically bulkier the structure of the drug, the less likely the rupture 
is to occur. Dosage form designing can be done efficiently without using 
additives such as plasticizers in the coating materials as was previously 
done, thus ensuring the production of a preparation exhibiting an 
effective sustained-release property.

EXAMPLE 
The present invention will now be illustrated in more detail by means of 
the following working and comparative examples. 
EXAMPLE 1 
14 g of methylephedrine hydrochloride was dissolved in 50 ml of a 60% 
methanol solution. To the resulting solution, 70 g of an anion exchange 
resin [OH type; Diaion SANl (Mitsubishi Chemical Industries)] was added 
followed by 1 hour of agitation. The slurry was then separated by 
filtration, and the ion exchange resin separated by filtration was washed 
with 300 ml of a 60% methanol solution. The washings were combined with 
the former filtrate, and diluted with a 60% methanol solution to 500 ml. 
Determinations of the total content of the methylephedrine hydrochloride 
and the free base in this 500 ml solution were made by high performance 
liquid chromatography. And the content of the free base was determined by 
titration. Methylephedrine as a hydrochloride was not detected, i.e., 100% 
of the methylephedrine hydrochloride was converted to the free base. The 
content was calculated as 13.8 g methylephedrine hydrochloride, the 
recovery was 98.6%. 
Then, to a 450 ml portion of this solution was added 24.3 g (the amount in 
which the degree of methylephedrine adsorption will be 90% of the 
theoretical saturated adsorption amount for the ion exchange resin) of a 
cation exchange resin containing 8% divinylbenzene (degree of 
crosslinking: 8%) [H type; Diaion SKNUPC (Mitsubishi Chemical Industries)] 
, and the reaction was carried out for 1 hour while stirring the solution. 
After completion of the reaction, the filtrate was assayed for 
methylephedrine but no methylephedrine was detected. This meant that the 
entire amount of methylephedrine in the form of the free base in the 
solution was bound to the ion exchange resin. 
The methylephedrine resinate separated by filtration was dried, and this 
2.8 g portion was dispersed in a solution of 1 g aminoalkyl methacrylate 
copolymer RS [Eudragit RS100 (Rohm Pharma)] in 5 ml methylene chloride. 
The resulting slurry was subjected to spray drying to give microcapsules. 
The methylephedrine sustained-release property of the microcapsules thus 
obtained was evaluated by means of a dissolution test (JP XI Paddle 
Method, using 500 ml of a 0.2 M NaCl solution which contains 0.05% Tween 
80, as the eluant). The results are shown in Table 1. A good 
sustained-release property was exhibited, and no occurrence of rupture 
(such as cracking or breaking) in the microcapsule coat was noted in the 
scanning electron microscopy following the dissolution test. 
TABLE 1 
______________________________________ 
Rate (%) of 
Time (hours) elapsed 
methylephedrine 
after initiation of the 
dissolution from the 
dissolution test 
microcapsules 
______________________________________ 
0 0 
0.5 18.4 
1.0 26.1 
2.0 39.9 
3.0 48.7 
4.5 57.1 
6.0 67.5 
8.0 74.8 
______________________________________ 
EXAMPLE 2 
12 g of methylephedrine hydrochloride was dissolved in 150 ml of a 50% 
isopropyl alcohol solution. To the resulting solution, 70 g of the same 
anion exchange resin (OH type) as in Example 1 was added, and this was 
followed by 1 hour of agitation. Then, the slurry was separated by 
filtration, and the ion exchange resin separated by filtration was washed 
with 300 ml of a 50% isopropyl alcohol solution. The washings were 
combined with the former filtrate, and diluted with a 50% isopropyl 
alcohol solution to 500 ml. 
Determinations of the total content of the methylephedrine hydrochloride 
and the free base in this 500 ml solution were made by high performance 
liquid chromatography and the content of the free base was determined by 
titration method; methylephedrine as a hydrochloride was not detected, 
i.e., 100% of the methylephedrine hydrochloride was converted to the free 
base. The content was calculated as 11.2 g methylephedrine hydrochloride, 
the recovery was 93.3%. 
Then, to a 450 ml portion of this solution was added 22.1 g (the amount in 
which the degree of methylephedrine adsorption will be 85% of the 
theoretical saturated adsorption amount for the ion exchange resin) of a 
cation exchange resin containing 10% divinylbenzene (degree of 
crosslinking: 10%) [H type; Diaion SK110 (Mitsubishi Chemical Industries)] 
, and the reaction was carried out for 1 hour while stirring the solution. 
After the completion of the reaction, the filtrate was assayed for 
methylephedrine, but no methylephedrine was detected. This meant that the 
entire amount of methylephedrine in the form of the free base in the 
solution was bound to the ion exchange resin. 
The methylephedrine resinate separated by filtration was dried, and this 
3.1 g portion was dispersed in a solution of 0.7 g aminoalkyl methacrylate 
copolymer RS [Eudragit RS100 (Rohm Pharma)] and 0.3 g aminoalkyl 
methacrylate copolymer RL [Eudragit RS100L (Rohm Pharma)] in 4 ml 
chloroform. Then, 10 ml cyclohexane was slowly added to this slurry to 
induce coacervation to such a degree that no coagulation would occur. This 
slurry was then subjected to spray drying to give microcapsules. The 
methylephedrine sustained-release property of the microcapsules thus 
obtained was evaluated by means of a dissolution test (JP XI Paddle 
Method, using 500 ml of a 0.2M NaCl solution which contains 0.05% Tween 
80, as the eluant). The results are shown in Table 2. A good 
sustained-release property was exhibited, and no occurrence of rupture 
(such as cracking or breaking) in the microcapsule coat was noted in the 
scanning electron microscopy following the dissolution test. 
TABLE 2 
______________________________________ 
Time (hours) elapsed 
Rate (%) of methylephedrine 
after initiation of the 
dissolution from the 
dissolution test 
microcapsules 
______________________________________ 
0 0 
0.5 10.5 
1.0 30.8 
2.0 49.5 
3.0 64.8 
4.5 77.7 
6.0 87.4 
8.0 96.5 
______________________________________ 
EXAMPLE 3 
10 g of dihydrocodeine phosphate was dissolved in 250 ml of a 50% ethanol 
solution. To the resulting solution, 30 g of the same anion exchange resin 
(OH type) as in Example 1 was added, and this was followed by 2 hours of 
agitation. Then, the slurry was separated by filtration, and the ion 
exchange resin separated by filtration was washed with 300 ml of a 50% 
ethanol solution. The washings were combined with the former filtrate, and 
diluted with a 50% ethanol solution to 500 ml. 
Determinations of the total content of the dihydrocodeine phosphate and the 
free base in this 500 ml solution were made by high performance liquid 
chromatography and the content of the free base was determined by 
titration method; dihydrocodeine as a phosphate was not detected, i.e., 
100% of the dihydrocodeine phosphate was converted to the free base. The 
content was calculated as 9.8 g dihydrocodeine phosphate, the recovery was 
98.0%. 
Then, to a 450 ml portion of this solution was added 25.69 g (the amount in 
which the degree of dihydrocodeine adsorption will be 85% of the 
theoretical saturated adsorption amount for the ion exchange resin) of a 
cation exchange resin containing 8% divinylbenzene (degree of 
crosslinking: 8%) [H type; Diaion SKNUPC (Mitsubishi Chemical 
Industries)], and the reaction was carried out for 1 hour while stirring 
the solution. After the completion of the reaction, the filtrate was 
assayed for dihydrocodeine, but no dihydrocodeine was detected. This meant 
that the entire amount of the dihydrocodeine in the form of the free base 
in the solution was bound to the ion exchange resin. 
The dihydrocodeine resinate separated by filtration was dried, and a 3.3 g 
portion was dispersed in a solution of 0.8 g aminoalkyl methacrylate 
copolymer RS [Eudragit RS100 (Rohm Pharma)] and 0.2 g aminoalkyl 
methacrytate copolymer RL [Eudragit RS100L (Rohm Pharma)] in 8 ml acetone. 
This slurry was subjected to spray drying to give microcapsules. The 
dihydrocodeine sustained-release property of the microcapsules thus 
obtained was evaluated by means of a dissolution test (JP XI Paddle 
Method, using 500 ml of a 0.2 M NaCl solution which contains 0.05% Tween 
80, as the eluant). The results are shown in Table 3. A good 
sustained-release property was exhibited, and no occurrence of rupture 
(such as cracking or breaking) in the microcapsule coat was noted in the 
scanning electron microscopy following the dissolution test. 
TABLE 3 
______________________________________ 
Time (hours) elapsed 
Rate (%) of dihydrocodeine 
after initiation of the 
dissolution from the 
dissolution test 
microcapsules 
______________________________________ 
0 0 
0.5 10.7 
1.0 24.8 
2.0 46.8 
3.0 59.1 
4.5 74.5 
6.0 80.2 
8.0 88.3 
______________________________________ 
EXAMPLE 4 
10 g of dihydrocodeine phosphate was dissolved in 250 ml of a 50% ethanol 
solution. To the resulting solution, 30 g of the same anion exchange resin 
(OH type) as in Example 1 was added, and this was followed by 2 hours of 
agitation. Then, the slurry was separated by filtration, and the ion 
exchange resin separated by filtration was washed with 300 ml of a 50% 
ethanol solution. The washings were combined with the former filtrate, and 
diluted with a 50% ethanol solution to 500 ml. 
Determinations of the total content of the phosphate and the free base in 
this 500 ml solution were made by high performance liquid chromatography, 
and the content of the free base was determined by titration method; 
dihydrocodeine as a phosphate was not detected, i.e., 100% of the 
dihydrocodeine phosphate was converted to the free base. The content was 
calculated as 9.8 g dihydrocodeine phosphate, the recovery being 98.0%. 
Then, to a 450 ml portion of this solution was added 26.0 g (the amount in 
which the degree of dihydrocodeine adsorption will be 90% of the 
theoretical saturated adsorption amount for the ion exchange resin) of a 
cation exchange resin containing 6% divinylbenzene (degree of 
crosslinking: 6%) [H type; Diaion SK106 (Mitsubishi Chemical Industries)], 
and the reaction was carried out for 1 hour while stirring the solution. 
After the completion of the reaction, the filtrate was assayed for 
dihydrocodeine, but no dihydrocodeine was detected. This meant that the 
entire amount of dihydrocodeine in the form of the free base in the 
solution was bound to the ion exchange resin. 
The dihydrocodeine resinate separated by filtration was dried, and this 3.3 
g portion was dispersed in a solution of 1.0 g aminoalkyl methacrylate 
copolymer RS [Eudragit RS100 (Rohm Pharma)] and 0.5 g polyisobutylene (MW: 
400,000) in 5 ml chloroform. Then, to this slurry, a solution of 2.5 g 
polyisobutylene in 40 ml cyclohexane was added by drops while stirring the 
slurry. After this solution was added, microcapsules were separated by 
filtration. The polyisobutylene was washed away with cyclohexane, and the 
microcapsules were dried. The dihydrocodeine sustained-release property of 
the microcapsules was evaluated by means of a dissolution test (JP XI 
Paddle Method, using 500 ml of a 0.2M NaCl solution which contains 0.05% 
Tween 80, as the eluant). The results are shown in Table 4. A good 
sustained-release property was exhibited, and no occurrence of rupture 
(such as cracking or breaking) in the microcapsule coat was noted in the 
scanning electron microscopy following the dissolution test. 
TABLE 4 
______________________________________ 
Time (hours) elapsed 
Rate (%) of dihydrocodeine 
after initiation of the 
dissolution from the 
dissolution test 
microcapsules 
______________________________________ 
0 0 
0.5 5.3 
1.0 10.2 
2.0 16.8 
3.0 32.5 
4.5 40.1 
6.0 52.0 
8.0 65.1 
______________________________________ 
EXAMPLE 5 
31 g of dextromethorphan hydrobromide was dissolved in 600 ml of a 85% 
ethanol solution. To the resulting solution, 75 g of the same anion 
exchange resin (OH type) as in Example 1 was added, and this was followed 
by 2 hours of agitation. The slurry was then separated by filtration, and 
the ion exchange resin separated by filtration was washed with 200 ml of a 
85 % ethanol solution. The washings were combined with the former 
filtrate, and diluted with a 85% ethanol solution to 1000 ml. 
Determinations of the total content of the dextramethorphan hydrobromide 
and the free base was made by high performance liquid chromatography, and 
the content of free base was determined by titration; dextromethorphan as 
hydrobromide was not detected, i.e., 100% of the dextromethorphan 
hydrobromide was converted to the free base. The content was calculated as 
30.2 g dextromethorphan hydrobromide, the recovery was 97.4%. 
Then, to a 440 ml portion of this solution was added 16.25 g (the amount in 
which the degree of dextromethorphan adsorption will be 82% of the 
theoretical saturated adsorption amount for the ion exchange resin) of a 
cation exchange resin containing 8% divinylbenzene (degree of 
crosslinking: 8%) [H type; Diaion SKNUPC (Mitsubishi Chemical 
Industries)], and the reaction was carried out for 1 hour while stirring 
the solution. After the completion of the reaction, the filtrate was 
assayed for dextromethorphan, but no dextromethorphan was detected. This 
meant that the entire amount of dextromethorphan in the form of the free 
base in the solution was bound to the ion exchange resin. 
The dextromethorphan resinate separated by filtration was dried, and this 
3.3 g portion was dispersed in a solution of 1.0 g ethylcellulose 100 cp 
in 20 ml of methylene chloride. This slurry was then subjected to spray 
drying. The dextromethorphan sustained-release property of the 
microcapsules thus obtained was evaluated by means of a dissolution test 
(JP XI Paddle Method, using 500 ml of a 0.2M NaCl solution which contains 
0.05% Tween 80, as the eluant). The results are shown in Table 5. A good 
sustained-release property was exhibited, and no occurrence of rupture 
(such as cracking or breaking) in the microcapsule coat was noted in the 
scanning electron microscopy following the dissolution test. 
TABLE 5 
______________________________________ 
Rate (%) of 
Time (hours) elapsed 
dextromethorphan 
after initiation of the 
dissolution from the 
dissolution test 
microcapsules 
______________________________________ 
0 0 
0.5 38.3 
1.0 56.2 
2.0 79.1 
3.0 88.7 
4.5 95.0 
6.0 100.0 
______________________________________ 
EXAMPLE 6 
20 g of chlorpheniramine maleate was dissolved in 1000 ml of a 55% ethanol 
solution. To the resulting solution, 35 g of the same anion exchange resin 
(OH type) as in Example 1 was added, and this was followed by 2 hours of 
agitation. Then, the slurry was separated by filtration, and the ion 
exchange resin separated by filtration was washed with 300 ml of a 55% 
ethanol solution. The washings were combined with the former filtrate, and 
diluted with a 55% ethanol solution to 1500 ml. 
Determinations of the total content of the chlorpheniramine maleate and the 
free base in this 1500 ml solution were made by high performance liquid 
chromatography, and the content of the free base was determined by 
titration; chlorpheniramine as the maleate was not detected, i.e., 100% of 
the chlorpheniramine maleate was converted to the free base. The content 
was calculated as 19.5 g chlorpheniramine maleate, the recovery being 
97.5%. 
Then, to a 1000 ml portion of this solution was added 17.98 g (the amount 
in which the degree of chlorpheniramine adsorption will be 80% of the 
theoretical saturated adsorption amount for the ion exchange resin) of a 
cation exchange resin containing 6% divinylbenzene (degree of 
crosslinking: 6%) [H type; Diaion SK106 (Mitsubishi Chemical Industries)], 
and the reaction was carried out for 1 hour while stirring the solution. 
After the completion of the reaction, the filtrate was assayed for 
chlorpheniramine, but no chlorpheniramine was detected. This meant that 
the entire amount of chlorpheniramine in the form of free base in the 
solution was bound to the ion exchange resin. 
The chlorpheniramine resinate separated by filtration was dried, and this 
2.8 g portion was dispersed in a solution of 0.7 g aminoalkyl methacrylate 
copolymer RS [Eudragit RS100 (Rohm Pharma)], 0.2 g aminoalkyl methacrylate 
copolymer RL [Eudragit RS100L (Rohm Pharma)], and 0.05 g medium-chain 
fatty acid triglyceride in 6 ml methyl ethyl ketone. This slurry was then 
subjected to spray drying. The chlorpheniramine sustained-release property 
of the microcapsules thus obtained was evaluated by means of a dissolution 
test (JP XI Paddle Method, using 500 ml of a 0.2 M NaCl solution which 
contains 0.05% Tween 80, as the eluant). The results are shown in Table 6. 
A good sustained-release property was exhibited, and no occurrence of 
rupture (such as cracking or breaking) in the microcapsule coat was noted 
in the scanning electron microscopy following the dissolution test. 
TABLE 6 
______________________________________ 
Rate (%) of 
Time (hours) elapsed 
chlorpheniramine 
after initiation of the 
dissolution from the 
dissolution test 
microcapsules 
______________________________________ 
0 0 
0.5 19.3 
1.0 38.5 
2.0 57.9 
3.0 72.2 
4.5 84.0 
6.0 88.5 
8.0 92.4 
______________________________________ 
EXAMPLE 7 
35 g of phenylpropanolamine hydrochloride was dissolved in 400 ml of a 50% 
ethanol solution. To the resulting solution, 200 g of the same anion 
exchange resin (OH type) as in Example 1 was added, and this was followed 
by 2 hours of agitation. The slurry was then separated by filtration, and 
the ion exchange resin thus separated was washed with 100 ml of a 50% 
ethanol solution. The washings were combined with the former filtrate, and 
diluted with a 50% ethanol solution to 500 ml. 
Determinations of the total content of the phenylpropanolamine 
hydrochloride and the free base in this 500 ml solution were made by high 
performance liquid chromatography, and the content of the free base was 
determined by titration method phenylpropanolamine as a hydrochloride was 
not detected, i.e., 100% of the phenyl-propanolamine hydrochloride was 
converted to the free base. The content was calculated as 34.8 g 
phenylpropanolamine hydrochloride, the recovery was 99.5%. 
Then, to a 300 ml portion of this solution was added 38 1 g (the amount in 
which the degree of phenylpropanolamine adsorption will be 100% of the 
theoretical saturated adsorption amount for the ion exchange resin) of a 
cation exchange resin containing 8% divinylbenzene (degree of 
crosslinking: 8%) [H type; Diaion SKNUPC (Mitsubishi Chemical 
Industries)], and the reaction was carried out for 1 hour while stirring 
the solution. After completion of the reaction, the filtrate was assayed 
for phenylpropanolamine, but no phenylpropanolamine was detected. This 
meant that the entire amount of phenylpropanolamine in the form of the 
free base in the solution was bound to the ion exchange resin. 
The phenylpropanolamine resinate separated by filtration was dried, and 
this 3.0 g portion was dispersed in a solution of 0.7 g aminoalkyl 
methacrylate copolymer RS Eudragit RS100 (Rohm Pharma)] in 6 ml methylene 
chloride. This slurry was then subjected to spray drying. The 
phenylpropanolamine sustained-release property of the microcapsules thus 
obtained was evaluated by means of a dissolution test (JP XI Paddle 
Method, using 500 ml of a 0.2M NaCl solution which contains 0.05% Tween 
80, as the eluant). The results are shown in Table 7. A good 
sustained-release property was exhibited, and no occurrence of rupture 
(such as cracking or breaking) in the microcapsule coat was noted in the 
scanning electron microscopy following the dissolution test. 
TABLE 7 
______________________________________ 
Rate (%) of 
Time (hours) elapsed 
phenylpropanolamine 
after initiation of the 
dissolution from the 
dissolution test 
microcapsules 
______________________________________ 
0 0 
0.5 33.7 
1.0 45.6 
2.0 61.5 
3.0 71.0 
4.5 76.5 
6.0 80.6 
8.0 84.2 
______________________________________ 
EXAMPLE 8 
3.3 g the dihydrocodeine resinate prepared in Example 3 (the degree of 
dihydrocodeine adsorption onto the cation exchanger resin containing 8% 
divinylbenzene (degree of crosslinking: 8%) [H type; Diaion SKNUPC 
Mitsubishi Chem. Ind.)] was 85% of the theoretical saturated adsorption 
amount for the ion exchange resin) was dispersed into a solution of 0.8 g 
aminoalkyl methacrylate copolymer RS [Eudragit RS100 (Rohm Pharma)] and 
0.2 g aminoalkyl methacrylate copolymer RL [Eudragit RS100L (Rohm Pharma)] 
in 5 ml of methylene chloride. To this resulting slurry, 2 ml of 50% 
ethanol solution was added, and this slurry was well-agitated. This final 
slurry was subjected to spray drying to produce microcapsules. 
On the other hand, the methylephedrine resinate was prepared from the 
methylephedrine free base solution as in Example 1 and the cation 
exchanger resin containing 12% divinylbenzene (degree of crosslinking: 
12%) [H type: Diaion SK-112 (Mitsubishi chemical Industries)]. This 
resinate was 82% of the theoretical saturated adsorption amount for the 
ion exchanger resin. 3 g of this methylephedtine resinate was dispersed 
into a solution of 10 g aminoalkyl methacrylate copolymet RS [Eudragit 
RS100 (Rohm Pharma)] in 5 ml of methylene chloride. To this resulting 
slurry, 2 ml of 50% ethanol solution was added, and this slurry was 
well-agitated. This final slurry was subjected to spray drying to produce 
microcapsules. 
EXAMPLE 9 
Two above sustained-release microcapsules in Example 8, the 
dihydrocodeine-microcapsule and the methylephedrine microcapsule, and 
clorpheniramine microcapsule in Example 6 were used to produce the syrup 
of a sustained-release suspension to be taken orally as an antitussive 
expectorant preparation, the formula I of which was the following. 
______________________________________ 
formula I 
______________________________________ 
dihydrocodeine SR- 12.5 g 
microcapsule 
methylephedrine SR- 45.0 g 
microcapsule 
chlorphenyramine SR- 4.9 g 
microcapsule 
guaiacol glyceryl ether 8.0 g 
caffein anhydrate 10.0 g 
D-sonbitol 1.0 kg 
sucrose 1.0 kg 
locust bean gum 10.0 g 
benzoic acid 3.0 g 
butyl p-hydroxybenzoate 0.25 g 
Tween 80 0.5 g 
Total (added purified water) 
5.0 l 
______________________________________ 
The procedure for making above syrup is detailed below. 
2.0l of purified water was heated to about 85.degree. C. and 3 g of 
benzoic acid and 0.25 g butyl p-hydroxybenzoate were dissolved therein. 
Then after cooling, 0.5 g Tween 80 was added following addition of 10 g 
locust bean gum. Then, 10 g of caffeins anhydrate and 8 g of guaiacol 
glycerylether were dissolved, and 1 kg of D-sorbitol and 1 kg of sucrose 
were added and dissolved. Three kinds of SR-microcapsule were wetted and 
suspended into 1 l purified water containing 0.5 g Tween 80. Above syrup 
and suspension containing these three kinds of SR-microcapsule were mixed, 
then the total volume became 5 l by addition of purified water. 
The obtained suspension is administered to an adult in an amount of 10 ml 
each per day. 
COMATIVE EXAMPLE 1 
5 g of potassium guaiacolsulfonate was dissolved in 500 ml of distilled 
water. To the resulting solution, 6.08 g of an anion exchange resin 
containing 8% divinylbenzene (degree of crosslinking: 8%) [OH type; Diaion 
SAN1 (Mitsubishi Chemical Industries)] was added, and this was followed by 
3 hours of agitation (the mixing ratio was such that the amount of 
potassium guaiacolsulfonate was 200% of the equivalent of the ion exchange 
resin). The resulting slurry was then filtrated, and the filtrate was 
assayed for potassium guaiacolsulfonate; it was found that 36.3% of the 
initial amount was bound to the resin and 63.7% of the initial amount 
remained in the filtrate. 
In the produced guaiacolsulfonic acid resinate, 71.3% of the ion exchange 
resin's exchange groups had guaiacolsulfonic acid bound thereto. 
The produced resinate was then separated by filtration and dried. This 2.5 
g portion was dispersed in a solution of 1.0 g aminoalkyl methacrylate RS 
[Eudragit RS100 (Rohm Pharma)] in 5.0 ml methylene chloride. The slurry 
thus obtained was sprayed for coating; the resulting microcapsules were 
dried. Guaiacolsulfonic acid dissolution from the microcapsules was tested 
at 37.degree. C. using the dissolution test apparatus of the JP XI. As the 
eluant, 500 ml of a 0.2M NaCl solution which contains 0.05% Tween 80 was 
used. The results are shown in Table 8. Bursting due to rupture was noted 
immediately after initiation of the test, and also the sustained-release 
property was not good. In scanning electron microscopy following the test, 
the occurrence of ruptures such as cracking and breaking was noted in the 
microcapsule coat due to the swelling of the resinate. 
TABLE 8 
______________________________________ 
Rate (%) of 
Time (hours) elapsed 
guaiacolsulfonic acid 
after initiation of the 
dissolution from the 
dissolution test 
microcapsules 
______________________________________ 
0 0 
0.25 60.5 
0.5 82.5 
1.0 92.2 
2.0 95.3 
3.0 97.0 
5.0 98.0 
______________________________________ 
COMATIVE EXAMPLE 2 
5 g of potassium guaiacolsulfonate was dissolved in 500 ml of distilled 
water. To the resulting solution was added 23.9 g of an anion exchange 
resin containing 8% divinylbenzene (degree of crosslinking: 8%) [OH type; 
Diaion SAN1 (Mitsubishi Chemical Industries)], and this was followed by 3 
hours of agitation (the mixing ratio was such that the amount of potassium 
guaiacolsulfonate was 50.8% of the equivalent of the ion exchange resin). 
The resulting slurry was then filtered, and the filtrate was assayed for 
potassium guaiacolsulfonate; it was found that 92.1% of the initial amount 
was bound to the resin, 7.9% of the initial amount remained in the 
filtrate. 
In the produced guaiacolsulfonic acid resinate, 46.8% of the ion exchange 
resin's exchange groups had guaiacolsulfonic acid bound thereto. 
The produced resinate was then separated by filtration and dried. This 2.0 
g portion was dispersed in a solution of 1.0 g of aminoalkyl methacrylate 
RS [Eudragit RS100 (Rohm Pharma)] in 5.0 ml methylene chloride. The 
slurry thus obtained was sprayed for coating; the resulting microcapsules 
were dried. Guaiacolsulfonic acid dissolution from the microcapsules was 
tested at 37.degree. C. using the dissolution test apparatus of the JP XI. 
As the eluant, 500 ml of a 0.2M NaCl solution which contains 0.05% Tween 
80 was used. The results are shown in Table 9. Bursting due to rupture 
was noted immediately after initiation of the test, and also the 
sustained-release property was not good. In scanning electron microscopy 
following the test, the occurrence of ruptures such as cracking and 
breaking was noted in the microcapsule coat due to the swelling of the 
resinate. 
TABLE 9 
______________________________________ 
Rate (%) of 
Time (hours) elapsed 
guaiacolsulfonic acid 
after initiation of the 
dissolution from the 
dissolution test 
microcapsules 
______________________________________ 
0 0 
0.25 92.5 
0.5 95.5 
1.0 96.0 
2.0 97.3 
3.0 98.0 
5.0 99.3 
______________________________________ 
COMATIVE EXAMPLE 3 
10 g of phenylpropanolamine hydrochloride was dissolved in 500 ml of 
distilled water. To the resulting solution was added 25.81 g of a cation 
exchange resin containing 8% divinylbenzene (degree of crosslinking: 8%) 
[H type; Diaion SKNUPC (Mitsubishi Chemical Industries)], and this was 
followed by 3 hours of agitation (the mixing ration was such that the 
amount of phenylpropanolamine hydrochloride was 74.2% of the equivalent of 
the ion exchange resin). The resulting slurry was filtered, and the 
filtrate was assayed for phenylpropanolamine hydrochloride; it was found 
that 84.0% of the initial amount was bound to the resin, 16.0% of the 
initial amount remained in the filtrate. 
In the produced phenylpropanolamine resinate, 62.3% of the ion exchange 
resin's exchange groups had phenylpropanolamine bound thereto. 
The produced resinate was then separated by filtration and dried. This 2.8 
g portion was dispersed in a solution of 1.0 g aminoalkyl methacrylate RS 
[Eudragit RS100 (Rohm Pharma)] in 5.0 ml of methylene chloride. The slurry 
thus obtained was sprayed for coating; the resulting microcapsules were 
dried. Phenylpropanolamine dissolution from the microcapsules was tested 
at 37.degree. C. using the dissolution test apparatus of the JP XI. As the 
eluant, 500 ml of a 0.2 M NaCl solution which contains 0.05% Tween 80 was 
used. The results are shown in Table 10. Bursting due to rupture was noted 
immediately after initiation of the test, and also the sustained-release 
property was not good. In scanning electron microscopy following the test, 
the occurrence of ruptures such as cracking and breaking 0 was noted in 
the microcapsule coat due to the swelling of the resinate. 
TABLE 10 
______________________________________ 
Rate (%) of 
Time (hours) elapsed 
phenylpropanolamine 
after initiation of the 
dissolution from the 
dissolution test 
microcapsules 
______________________________________ 
0 0 
0.25 46.8 
0.5 61.2 
1.0 79.5 
2.0 90.1 
3.0 95.0 
5.0 98.3 
______________________________________ 
COMATIVE EXAMPLE 4 
10 g of methylephedrine hydrochloride was dissolved in 500 ml of distilled 
water. To the resulting solution was added 34.6 g of a cation exchange 
resin containing 8% divinylbenzene (degree of crosslinking: 8%) [H type; 
Diaion SKNUPC (Mitsubishi Chemical Industries)], and this was followed by 
3 hours of agitation (the mixing ratio was such that the amount of 
methylephedrine hydrochloride was 48.4% of the equivalent of the ion 
exchange resin); it was found that 93.0% of the initial amount was bound 
to the resin, 7.0% of the initial amount remaining in the filtrate. 
In the produced methylephedrine resinate, 45.0% of the ion exchange resin's 
exchange groups had methylephedrine bound thereto. 
The produced resinate was then separated by filtration and dried. This 2.2 
g portion was dispersed in a solution of 1.0 g aminoalkylmethacrylate RS 
[Eudragit RS100 (Rohm Pharma)] in 5.0 ml of methylene chloride. The slurry 
thus obtained was sprayed for coating; the resulting microcapsules were 
dried. Methylephedrine dissolution from the microcapsules was tested at 
37.degree. C. using the dissolution test apparatus of the JP XI. As the 
eluant, 500 ml of a 0.2 M NaCl solution which contains 0.05% Tween 80 was 
used. The results are shown in Table 11. Bursting due to rupture was noted 
immediately after initiation of the test, and also the sustained-release 
property was not good. In scanning electron microscopy following the test, 
the occurrence of ruptures such as cracking and breaking was noted in the 
microcapsule coat due to the swelling of the resinate. 
TABLE 11 
______________________________________ 
Time (hours) elapsed 
Rate (%) of methylephedrine 
after initiation of the 
dissolution from the 
dissolution test 
microcapsules 
______________________________________ 
0 0 
0.25 72.1 
0.5 87.3 
1.0 92.1 
2.0 97.0 
3.5 98.3 
5.0 99.1 
______________________________________