CA2148465C - Oral pharmaceutical preparation releasable in the lower digestive tract - Google Patents
Oral pharmaceutical preparation releasable in the lower digestive tractInfo
- Publication number
- CA2148465C CA2148465C CA002148465A CA2148465A CA2148465C CA 2148465 C CA2148465 C CA 2148465C CA 002148465 A CA002148465 A CA 002148465A CA 2148465 A CA2148465 A CA 2148465A CA 2148465 C CA2148465 C CA 2148465C
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical preparation
- oral pharmaceutical
- release
- acid
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
Abstract
An oral pharmaceutical preparation releasable in the lower digestive tract, characterized by having a double-coated structure wherein a solid drug having a core containing an active ingredient is covered with both an inner coat made of a cationic polymer and an outer coat made of an anionic polymer.
Description
2~4846~
SPECIFICATION
ORAL PHARMACEUTICAL PREPARATION RELEASABLE
IN THE LOWER DIGESTIVE TRACT
Technical Field The present invention relates to an oral pharmaceutical preparation which is releasable in the lower digestive tract. In particular, the present invention relates to a pharmaceutical preparation for oral administration which passes through the stomach without being affected by gastric juice, does not undergo any change in the small intestine, and begins to disintegrate for the first time when it arrives at the large intestine to release the active ingredient, which is absorbed therein.
Background Art The pharmaceutical preparations for oral administration according to the prior art begin to disintegrate or dissolve before the arrival at the large intestine. Therefore, it has been a practice in the prior art to employ an intravenous, intranasal or rectal administration method in the administration of an active substance which is expected to exhibit a local action on the large intestine or is decomposed by the lyase present in the small intestine.
However, an oral pharmaceutical preparation has the following advantages. Namely, if an oral ~°~4~~~~
pharmaceutical preparation releases a pharmacologi-tally active substance selectively in the large intestine, the concentration of the active substance at the release site can be increased to give a more effective local action than that of the preparation according to the prior art. Further, if a pharmacologically active protein or peptide which is . decomposed in the small intestine to lose its activity is released selectively in the large intestine, the Protein or peptide will be able to be absorbed in the large intestine wherein the protease activity is poor.
Owing to the above advantages, it is apparent that an oral pharmaceutical preparation is a dosage form far more useful than injection or suppository.
For the reason described above) many attempts have recently been made to develop oral pharmaceutical preparations targeting the large intestine.
For example, there have been reported an oral preparation targeting the large intestine) which is Prepared by combining a polymer soluble only at a pH
of 5.5 or above with an insoluble polymer (EP40590); a solid oral preparation coated with a suitable amount of an anionic polymer soluble at a pH of 7.0 or above (trade-mark: Eudragit S, a product of RdHM) (W083/00435); an oral preparation coated with a mixture comprising an anionic polymer soluble at a pH
of 7.0 or above (trade-mark: Eudragit S or L, a ~:i . r~ :;.'s product of RdHM) and a methacrylate copolymer difficultly soluble in water (trade-mark: Eudragit RS) a product of ROHM) at a suitable ratio (EP225189); an osmotic-pump preparation coated with an enteric polymer (BE903502); a colon-reaching oral preparation covered with an inner coat soluble at a pII of 7.0 or above, an intermediate coat made of a gelatinized polymer, and a acid-resistant outer coat soluble at a pH of 5.5 or above (Japanese Patent Publication No.
501411/1992); and so forth.
All of these preparations are characterized in that a drug is released by a pH increase in the intestinal tract, and they are each prepared by applying a proper amount of an anionic polymer or by adding or applying an insoluble polymer to prevent the drug from being released during its residence in the small intestine.
Meanwhile) a recent study on humans (D. F.
Evans, Gut) 1988, vo1.29) p.1035) reported that the pH
of the intermediate and lower parts of the small intestine ranges from 7.4 to 7.5 (standard deviation:
0.4 to 0.5), while the average pH rapidly drops to 6.4 (standard deviation: 0.4) in the upper part of the large intestine and gradually increases to reach 7.0 (standard deviation: 0.7) in the lower part of the large intestine.
SPECIFICATION
ORAL PHARMACEUTICAL PREPARATION RELEASABLE
IN THE LOWER DIGESTIVE TRACT
Technical Field The present invention relates to an oral pharmaceutical preparation which is releasable in the lower digestive tract. In particular, the present invention relates to a pharmaceutical preparation for oral administration which passes through the stomach without being affected by gastric juice, does not undergo any change in the small intestine, and begins to disintegrate for the first time when it arrives at the large intestine to release the active ingredient, which is absorbed therein.
Background Art The pharmaceutical preparations for oral administration according to the prior art begin to disintegrate or dissolve before the arrival at the large intestine. Therefore, it has been a practice in the prior art to employ an intravenous, intranasal or rectal administration method in the administration of an active substance which is expected to exhibit a local action on the large intestine or is decomposed by the lyase present in the small intestine.
However, an oral pharmaceutical preparation has the following advantages. Namely, if an oral ~°~4~~~~
pharmaceutical preparation releases a pharmacologi-tally active substance selectively in the large intestine, the concentration of the active substance at the release site can be increased to give a more effective local action than that of the preparation according to the prior art. Further, if a pharmacologically active protein or peptide which is . decomposed in the small intestine to lose its activity is released selectively in the large intestine, the Protein or peptide will be able to be absorbed in the large intestine wherein the protease activity is poor.
Owing to the above advantages, it is apparent that an oral pharmaceutical preparation is a dosage form far more useful than injection or suppository.
For the reason described above) many attempts have recently been made to develop oral pharmaceutical preparations targeting the large intestine.
For example, there have been reported an oral preparation targeting the large intestine) which is Prepared by combining a polymer soluble only at a pH
of 5.5 or above with an insoluble polymer (EP40590); a solid oral preparation coated with a suitable amount of an anionic polymer soluble at a pH of 7.0 or above (trade-mark: Eudragit S, a product of RdHM) (W083/00435); an oral preparation coated with a mixture comprising an anionic polymer soluble at a pH
of 7.0 or above (trade-mark: Eudragit S or L, a ~:i . r~ :;.'s product of RdHM) and a methacrylate copolymer difficultly soluble in water (trade-mark: Eudragit RS) a product of ROHM) at a suitable ratio (EP225189); an osmotic-pump preparation coated with an enteric polymer (BE903502); a colon-reaching oral preparation covered with an inner coat soluble at a pII of 7.0 or above, an intermediate coat made of a gelatinized polymer, and a acid-resistant outer coat soluble at a pH of 5.5 or above (Japanese Patent Publication No.
501411/1992); and so forth.
All of these preparations are characterized in that a drug is released by a pH increase in the intestinal tract, and they are each prepared by applying a proper amount of an anionic polymer or by adding or applying an insoluble polymer to prevent the drug from being released during its residence in the small intestine.
Meanwhile) a recent study on humans (D. F.
Evans, Gut) 1988, vo1.29) p.1035) reported that the pH
of the intermediate and lower parts of the small intestine ranges from 7.4 to 7.5 (standard deviation:
0.4 to 0.5), while the average pH rapidly drops to 6.4 (standard deviation: 0.4) in the upper part of the large intestine and gradually increases to reach 7.0 (standard deviation: 0.7) in the lower part of the large intestine.
However, all of the above oral preparations releasable in the large intestine according to the prior art are coated with a polymer soluble or swelling at a pH of 7.0 or above) on the assumption that the phi in the colon or large intestine is 7.0 or above. The inventors of the present invention have also made intensive studies on this respect and have found that the pH of cecal contents of a rat or rabbit is below the range of 6.4 to 5.5 owing to the organic acids generated by enteric bacteria. This result agrees with that disclosed in the above literature on humans. Accordingly, the inventors of the present invention have started studies to develop an oral pharmaceutical preparation from which a drug is released in the lower digestive tract (large intestine) by a pH change to below the range of 7.0 to 5.5.
Further, W090/13286 discloses an oral preparation comprising a core containing a basis and a filler, a first layer which covers the core and is composed of an enteric component, a second layer which covers the first layer and is composed of a nonenteric component, and a third layer which covers the second layer and is composed of an enteric component. In this oral preparation, the second layer) which is composed of a cationic polymer) is covered with the third layer to regulate the release of a drug, so that ,..Y 2I48465 it is very difficult to regulate the preparation so as to release a drug specifically in the large intestine.
Further, since the core always contains an acidic substance, the second layer is liable to be dissolved in the small intestine to release a drug prior to the arrival at the large intestine.
The coat according to the prior art has such a property that the dissolution or swelling thereof proceeds before the arrival of the preparation at the large intestine. Therefore, the preparation of the prior art has a disadvantage that when the actual residence time in the small intestine, which has a great physiological influence, is shorter than the one assumed in the dosage form design, the preparation is discharged as such, while when the actual residence time is longer than the assumed one, the release of a drug has been completed before the arrival at the target site.
Disclosure of the Invention The present invention aims at solving the above problem of the prior art to develop an oral pharmaceutical preparation which passes through the stomach without being affected by gastric juice, does not undergo any change in the small intestine, and begins to disintegrated for the first time when it arrives at the large intestine to release the active ingredient, which is absorbed therein.
Further, W090/13286 discloses an oral preparation comprising a core containing a basis and a filler, a first layer which covers the core and is composed of an enteric component, a second layer which covers the first layer and is composed of a nonenteric component, and a third layer which covers the second layer and is composed of an enteric component. In this oral preparation, the second layer) which is composed of a cationic polymer) is covered with the third layer to regulate the release of a drug, so that ,..Y 2I48465 it is very difficult to regulate the preparation so as to release a drug specifically in the large intestine.
Further, since the core always contains an acidic substance, the second layer is liable to be dissolved in the small intestine to release a drug prior to the arrival at the large intestine.
The coat according to the prior art has such a property that the dissolution or swelling thereof proceeds before the arrival of the preparation at the large intestine. Therefore, the preparation of the prior art has a disadvantage that when the actual residence time in the small intestine, which has a great physiological influence, is shorter than the one assumed in the dosage form design, the preparation is discharged as such, while when the actual residence time is longer than the assumed one, the release of a drug has been completed before the arrival at the target site.
Disclosure of the Invention The present invention aims at solving the above problem of the prior art to develop an oral pharmaceutical preparation which passes through the stomach without being affected by gastric juice, does not undergo any change in the small intestine, and begins to disintegrated for the first time when it arrives at the large intestine to release the active ingredient, which is absorbed therein.
The oral pharmaceutical preparation releasable in the lower digestive tract according to the present invention is characterized by having a double-coated structure wherein a solid drug having a core containing an active ingredient is covered with both an inner coat made of a cationic polymer and an outer coat made of an anionic polymer.
Namely, the present invention relates to a novel oral pharmaceutical preparation which comprises l0 a solid drug having a core containing a therapeutically active ingredient which is releasable in the lower digestive tract, and the following coats ( 0 ) and ( 2(, ) coat ( O1 ) . inner coat which contains a suitable plasticizer or binding inhibitor and is made of a cationic polymer soluble or swelling at a pH of 6.0 or below, and coat ( 02 ): outer coat made of an anionic polymer soluble at a pH of 5.5 or above.
The solid drug having the core is made-of a therapeutically active ingredient alone or a mixture thereof with a filler, binder, disintegrator and/or sorbefacient.
Examples of the filler include lactose) 2, crystalline cellulose, crystalline cellulose sodium carboxymethylcellulose, wheat starch, and magnesium stearate.
Examples of the binder include crystalline cellulose, pullulan, acacia, sodium alginate, polyvinyl pyrrolidone and macrogol.
Examples of the disintegrator include ordinary inert substances for pharmaceutical preparations, such as carboxymethylcellulose, calcium carboxylmethylcellulose) hydroxypropylcellulose) hydroxypropylstarch, starch and sodium alginate.
Further, a sorbefacient may be used in the Preparation of the solid drug to accelerate the absorption of the active ingredient, and examples of such a sorbefacient include sugar ester, sucrose esters of fatty acid, glycyllysinate salts, glycyrrhetinic acid, dipotassium glycyrrhizinate) bile acid, glycerol esters of fatty acid, 1-[(2-(decyl-thio)ethyl]azacyclopentan-2-one) adipic acid) basic amino acids, po~_yethylene glycol and sodium caprate.
The solid drug may be encapsulated with gelatin or may be granulated or tabletted.
The therapeutically active ingredient to be contained in the solid drug is not particularly limited but may be any substance which exhibits its effect when released in the lower digestive tract.
Examples of the therapeutically active ingredient include peptides, proteins, anti-inflammatory agents, antineoplastic agents, antibiotics, chemotherapeutics) ulcerative colitis remedy, irritable colitis remedy (choline blocker), and constipation remedy. Specific examples of the therapeutically active ingredient include somatostatin, insulin, calcitonin, vasopressin) gastrin, EGF (epidermal growth factor)) a-hANP (a-human atri_al natri.uretic peptide), enkephalin, endorphin, GM-CSF (granulocyte macrophage colony-stimulating factor), G-CSF (granulocyte colony-stimulating factor), human growth hormone, glucagon, t-PA (tissue plasminogen activator), TNF
(tumor necrosis factor), TCGF (T cell growth factor), ACTH (adrenocorticotrophic hormone), interleukins, interferon, EPO (erythropoietin), urokinase, neocarcinostatin) bradykinin, immunoglobulin and its digestion product, various allergens and their digestion products, ketoprofen) ibuprofen, dicl_ofenac, indometacin, ketrolac, fenbufen, loxoprofen, tenidap) piroxicam, tenoxicam) salazosulfapyridine, pipethanate hydrochloride, mepenzolate bromide, and sennosides A
and B.
The cationic polymer which is soluble or swe7_ling at a pH of 6.0 or below and is used in the formation of the inner coat is an aminoalkyl methacrylate copolymer (a copolymer cornpri.sing methyl_ methac:rylate, butyl methacrylate and dimethylaminoethyl methacrylate, trade-mark: Eudragit E) a product of R(~HM) or a polyvinyl acetal diethyl_aminoacetate (trade-mark: AEA, a product of - 9 - ~ ~ ~'.9 Sankyo). The inner coat is formed by applying 1 to 40% by weight (based on the solid drug) of the above polymer to the solid drug in a film thickness of 10 to 300 11m, by which the resulting preparation is regulated so as to release the active ingredient therefrom speedily when the pH condition of 6.0 or below continues.
It is preferable that a suitable plasticizes be used in the formation of the inner coat to make the coat smooth. The plasticizes includes triacetin, citrate ester and polyethylene glycol. The binding inhibitor includes talc, titanium oxide, calcium phosphate) hydrophobic light anhydrous silicic acid, and so forth.
The outer coat is made of an anionic polymer which is easily soluble at a pH of 5.5 or above.
Examples of the anionic polymer usable in the present invention include methacrylic acid copolymer L (a copolymer comprising methacrylic acid and methyl methacrylate, trade-mark: Eudragit L100, a product of ROHM), methacrylic acid copolymer S (a copolymer comprising methacrylic acid and methyl methacrylate, trade-mark: I?udragit S, a hroduc:t of LWIIM) , hydroxy-propylcellulose, hydroxyethylcellulose phthalate, Polyvinyl acetate phthalate, cellulose acetate phthalate, and cellulose acetate tetrahydrophthalate.
214~4fi.3 The anionic polymer is applied in an amount of 1 to 40% by weight based on the solid drug.
Brief Description of Drawings Fig. 1 is a graph showing the results of in vitro test on the release of drug.
Fig. 2 is a graph showing the results of in vivo test on blood drug concentration.
Fig. 3 is a graph showing the influence of coating weight on the release of drug in vitro.
Fig. 4 is a graph showing the influence of pH
on the release of ketoprofen.
Fig. 5 is a graph showing the influence of pH
on the release of FITC dextran.
Fig. 6 is a graph showing the influence of pH
on the release of calcitonin.
Fig. 7 is a graph showing the results of the blood calcium concentration test using dog.
Fig. 8 is a graph showing the influence of coating weight on the release of drug in vitro.
Fig. 9 is a graph showing the effect of sorbefacient in vivo.
Best Mode for Carrying Out the Invention The present invention will now be specifically described by referring to the following Examples.
Example 1 A ketoprofen-containing solid drug was prepared according to the following formula:
ketoprofen 24.0 pt. by wt.
magnesium stearate 1.0 pt. by wt.
lactose 75.0 pt. by wt.
Ketoprofen, lactose and magnesium stearate were mixed together to form a homogeneous mixture.
This mixture was compressed with a tablet machine into tablets having a diameter of 7 mm and a weight of 210 mg- The obtained solid drug was coated as follows.
Eudragit E (trade-mark) 7.0 pt. by wt.
. ethanol 70.0 pt. by wt.
water 19.5 pt. by wt.
talc 3.5 pt. by wt.
~-5 A solution comprising the above components was continuously sprayed at 50 °C on the solid drug preheated to 50 °C to form an inner coat. The weight increase of the solid drug was 30 mg.
After the completion of the spraying, the ~ resulting drug was dried and further coated as follows.
Eudragit S (trade-mark) 7.0 pt. by wt.
ethanol 70.0 pt. by wt.
water 18.8 pt. by wt.
talc 3. 5 pt. by wt.
polyethylene glycol 6000 0.7 pt. by wt.
.~..::
lZ
A solution comprising the above components was continuously sprayed at 50 °C on the resulting drug preheated to 50 °C to form an outer coat. The weight increase of the solid drug was 20 mg.
Comparative Example 1 A ketoprofen-containing solid drug was prepared according to the following formula:
ketoprofen 24.0 pt. by wt.
magnesium stearate 1.0 pt. by wt.
lactose 75.0 pt. by wt.
Ketoprofen, lactose and magnesium stearate were mixed together to form a homogeneous mixture.
This mixture was compressed with a tablet machine into tablets having a diameter of 7 mm and a weight of 210 mg. The obtained solid drug was coated as follows.
Eudragit S (trade-mark) X7.0 pt. by wt.
ethanol 70.0 pt. by wt.
water lg,g pt. by wt.
talc 3.5 pt. by wt.
polyethylene glycol 6000 0.7 pt. by wt.
A solution comprising the above components was continuously sprayed at room temperature on the solid drug preheated to 50 °C i=o form an inner coat.
The weight increase of the solid drug was 30 mg. The resulting drug was dried and further coated as follows.
hydroxypropyl.methylcellulose 4.0 pt. by wt.
- 13 - ,~~y 3zi polyethylene glycol 400 0.5 pt. by wt.
95~ ethanol 85.5 pt. by wt.
water 10.0 pt. by wt.
Hydroxypropylcellulose was suspended in 95~
ethanol, followed by the addition of a solution of polyethylene glycol 400. The obtained solution was sprayed on the above solid drug preheated to 50 °C to form an intermediate coat. The weight increase of the solid drug was 10 mg.
The resulting solid drug was furthermore coated by spraying a solution comprising the following components like in the formation of the above coat.
The weight increase of the solid drug was 10 mg.
Eudragit L100 (trade-mark) 7.0 pt. by wt.
~_5 ethanol 70.0 pt. by wt.
water 18.8 pt. by wt.
talc 3.5 pt. by wt.
polyethylene glycol 6000 0.7 pt. by wt.
(A) In vitro test on the release of drug The tablets prepared in Example 1. and Comparative Example 1 were examined for the release of ketoprofen. Each tablet was incubated in a buffer of pH2.0 for 2 hours, in a buffer of ptI7.4 for 6 hours) and then in a cecal solution prepared by suspending the cecal contents in a phosphate buffer of pH7.4 containing 125 mg of glucose and 4.1 mg of benzyl viologen. The amount of the released ketoprofen was 2148~~
determined by liquid chromatography. The results are given in Fig. 1) wherein ~ represents the release pattern of the tablet prepared in Example 1 and, represents that of the tablet prepared in Comparative Example 1.
As apparent from the results of Fig. 1, the release of ketoprofen from the tablet prepared in Example 1 was observed specifically in a cecal solution, though it was not observed in a buffer of PH2.0 or 7.4 at all. On the other hand, most of the ketoprofen contained in the tablet prepared in Comparative Example 1 was released in a buffer of pH7.4.
(B) In vivo test on blood drug concentration The tablet prepared in Example 1 was administered to a laboratory animal (beagle dog, male, weight: 10 kg) without anesthesia. The result is given in Fig. 2, wherein ~ represents the result of the tablet of Example 1.
As apparent from the result of Fig. 2, no ketoprofen was observed in the plasma in the early stages, though ketoprofen is very readily absorbable.
After 14 hours and later, however, ketoprofen was observed in the plasma at extremely high concentrations.
Example 2 Five kinds of tablets were prepared by repeating the same procedure as that of Example 1 except that the coating weights of the inner and outer coats were varied as specified in Table 1.
Table 1 Coating wt. of Coating wt. of Sample No. Eudragit E Eudragit S
(inner coat) (outer coat) to 5 0 20i 02 20~ 20%
~3 40~ 20 a I_5 ~ 20i 5i 20 a 40 0 each percentage is given by weight and based on the solid drug (c) In-vitro test on the influence of coating weight on the release of drug The tablets (Sample Nos. ~ to ~5) were tested for the release of ketoprofen. Each tablet was incubated in a buffer of pH7.4 for 4 hours and put in a cecal. solution. The results of the test were given in Fig. 3, wherein ~ represents the result of Sample No. 0 , ~ represents the result of Sample No. 02, Q
_ 16 _ that of Sample No. 03 ~ ~ that of Sample No. ~ and that of Sample No. ~5.
As apparent from the results of Fig. 3, equivalent release patterns were exhibited even when the coating weight of EUDRAGIT S (outer coat) was varied. On the other hand, when the coating weight of EUDRAGIT E (inner coat) was varied) however, somewhat different release patterns were exhibited.
Example 3 l0 Ketoprofen-containing granules were prepared according i=o i=he following formula:
ketoprofen 20.0 pt. by wt.
lactose 25.0 pt. by wt.
corn starch 30.0 pt. by wt.
15 crystalline cellulose 20.0 pt. by wt.
hydroxypropylcellulose 5.0 pt. by wt.
Ketoprofen, Lactose, corn starch and crystalline cellulose were together mixed homogeneously, followed by the addition of a solution 20 or hydroxypropylcellulose i.n purified water. The obtained mixture was kneaded and granulated with an extrusion granulator having a cylinder bore of 1 mm.
The obtained granu7.es were dried and subjected to size classification. The resulting granules were coated as 25 follows to form an inner coat. The weight increase was 5 mg per 100 mg of the granules.
Eudragit E (trade-mark)' 7.0 pt. by wt.
ethanol 70.0 pt. by wt.
water 19.5 pt. by wt.
talc 3.5 pt. by wt.
A solution comprising the above components was continuously sprayed on the granules preheated to 50 °C by the use of a flow coater at room temperature.
After the completion of the spraying, the resulting granules were dried and further coated with a solution comprising the following components to form an outer coat. The weight increase was 10 mg per 100 mg of the granules.
Eudragit L (trade-mark) 7.0 pt. by wt.
ethanol 70.0 pt. by wt.
water 18.8 pt. by wt.
talc 3.5 pt. by wt.
polyethylene glycol 6000 0.7 pt. by wt.
(D) Test on the influence of pH on the release of ketoprofen This test was conducted in the same manner as that of Example 7_. The results are given in Fig. 4, wherein ~ represents the release pattern at pH2.0) represents that at pH7.4, and 0 represents that exhibited when Lhe granu:l.es were ullowecl to stand io a buffer of pH7.4 for 4 hours and put in a cecal solution.
As apparent from the results of Fig. 4, no ketoprofen was released at pI-I2.0 or pI-I7.4, while ~14~46 specific release of ketoprofen was observed only in a cecal solution.
Example 4 A solid drug was prepared according to the following formula wherein fluorescein isothiocyanate dextran (hereinafter abbreviated to "FITC dextran") was used as a model compound having dissolution characteristics different from those of ketoprofen.
FITC dextran 2.5 pt. by wt.
magnesium stearate 1.0 pt. by wt.
lactose 96.4 pt. by wt.
carboxynethylcellulose 0.1 pt. by wt.
Both inner and outer coats were formed on the solid drug in the same manner as that of Example 1.
(E) Test on the influence of pH on the release of FITC dextran This test was conducted in the same manner as that of Example 1. The results are given in Fig. 5, wherein ~ represents the release pattern at pH2.0, that at pI-I7.4, and ~ represents that exhibited when the preparation was allowed to stand in a buffer of pH7.4 for 4 hours and put in a cecal solution.
As apparent from the resu7_ts of Fig. 5) little FITC dextran was released in a buffer of pH2.0 or pH7.4) while rapid release of FITC dextran was observed in a cecal solution.
Example 5 214~46~
A solid drug having a ca7_citonin-containing core was prepared according to the following formula:
calcitonin 4.0 pt. by wt.
sucrose ester of fatty acid 5.0 pt. by wt.
(F-160) magnesium stearate 1.0 pt. by wt.
lactose 90.0 pt. by wt.
Calcitonin) lactose, magnesium stearate and sucrose ester of fatty acid were mixed together to form a homogeneous mixture. This mixture was compressed with a tablet machine into tablets having a diameter of 2 mm and a weight of 7 mg. The tablets were coated with a mixture comprising magnesium stearate (1 part by weight) and lactose (99 parts by weight). Both inner and outer coats were formed on the resulting tablets in the same manner as that of Example 1.
(F) Test on the influence of pH on the release of calcitonin This test was conducted in the same manner as that of Example 1. The results are given in Fig. 6, wherein ~ represents the release pattern at pH2.0, represents that at pH7.4, and ~ represents that exhi_bi.ted when the tablet was allowed to stand in a buffer of pH7.4 for 4 hours and put in a cecal so7_ution .
As apparent from the results of Fig. 6, little calcitonin was released in a buffer of pH2.0 or pH7.4, while rapid release of calcitonin was observed in a cecal solution.
(G) Blood calcium concentration test using dog In a similar manner to that of Example 1, the tablet prepared in Example 5 was administered to dogs to determine the blood calcium concentration. The results are given in Fig. 7, wherein ~ represents the result exhibited when the tablet of Example 5 was administered) and ~ represents the result exhibited when the tablet of Example 5 was not coated at all.
As apparent from the results of Fig. 7, little lowering was observed in the blood calcium concentration, when the uncoated tablet was administered. On the other hand, lowering was observed in the blood calcium concentration 10 hours after the administration and later, when the double-coated tablet was administered.
Example 6 Five kinds of tablets were prepared in a similar manner to that of Example 1 except that the coating weights of the inner and outer coats were varied as specified in Table 2.
_ 21 _ Table 2 Coating wt. of Coating wt. of Sample No. EUDRAGIT E EUDRAGIT S
(inner coat) (outer coat) 3i 20i 5i 20i 7i 20~
~ 5~ 5~
5~ 3i ~: each percentage is given by weight and based on the solid drug (H) In vitro test on the influence of coating weight on the release of drug These tablets were tested for the release of ketoprofen. Each tablet was incubated in a buffer of pH7.4 for 4 hours and put in a cecal solution. The results are given in Fig. 8, wherein ~ represents the result of Sample No. ~1 , ~ represents that of Sample No. 20 , 0 represents that of Sample No. ~3 , represents that of Sample No. ~ , and ~ represents that of Sample No. ~5 .
As apparent from the results of Fig. 8, equivalent release patterns were exhibited, even when the coating weight of EUDRAGIT S (outer coat) was varied. On the other hand) when the coating weight of ~.,, EUDRAGIT C (inner coat) was 5~ by weight or below, excellent release patterns were exhibited.
Example 7 Calcitonin-containing solid drugs were prepared according to the following formulae:
21454~~
~_ Tab7_e 3 Sample No. (~1 ~ O
calcitonin 0.28 mg 0.28 mg 0.28 mg 0.28 mg 0.28 mg sucrose ester of fatty acid (F-160) 25%
sodium caprate 25~ 25%
dipotassium glycyrrhizinate 250 25~
magnesium stearate 1~ 1% 1~ 1~ l~
lactose 74.0% 74.0 74.Oo 49.0% 99.0 each percentage is given by weight The components of each formula were mixed together to form a homogeneous mixture. This mixture was compressed into tablets having a diameter of 7 mm and a weight of 200 mg with a tablet machine. These tablets were each coated as follows.
Eudragit E (trade-mark) 7.0 pt. by wt.
ethanol 70.0 pt. by wt.
water 19.5 pt. by wt.
talc 3.5 pt. by wt.
A solution comprising the above components was continuously sprayed at 50 °C on the tablet preheated to 50 °C. The weight increase of the solid drug was 14 mg. The resulting tablets were dried and further coated as follows.
Eudragit S 7.0 pt. by wt.
ethanol 70.0 pt. by wt.
water 1.8.8 pt. by wt.
talc 3.5 pt. by wt.
polyethylene glycol 6000 0.7 pt. by wt.
A solution comprising the above components was continuously sprayed at 50 °C on the tablets preheated to 50 °C. The weight increase of the solid drug was 14 mg.
(I) In vivo test on the effect of sorbefacient In a similar manner to that of Example 5, the tablets prepared in Example 7 were each administered .., ~:, :., n..
~14846~
to dogs to determine the blood calcium concentrations.
The results are given in Fig. 9, wherein ~ represents the result of Sample No. 1~, ~J,represents that of Sample No. ~ , 0 represents that of Sample No. ~3 , (.
represents that of Sample No. ~ , and (~ represents that of Sample No. 0 .
As apparent from the results of Fig. 9, lowering in the blood calcium concentration was observed 10 hours after the administration and later when Sample No. O1) ~2 ) ~3 or ~ was administered, while no lowering was observed when Sample No. ~5 not containing any sorbefacient was administered.
Particularly excellent lowering in the blood calcium concentration was observed when sodium caprate or dipotassium glycyrrhizinate was used as the sorbefacient.
Industrial Applicability The oral pharmaceutical preparation releasable in the lower digestive tract according to the present invention is characterized by the specific release of the active ingredient therefrom caused by the unique pH change in the digestive tract, so that the preparation little causes lowering or loss in the avai_labi.l_ity and scattering among i.ndividual_s, though the preparation targetting the lower digestive tract (such as the large intestine) according to the prior art suffered from these disadvantageous phenomena.
_..
In particular, the oral preparation of the present invention passes through the stomach and small intestine without being affected, and is disintegrated for the first time on arrival at the large intestine (i.e., the lower digestive tract) to release the active ingredient which is then effectively absorbed in the large intestine to give a remarkably enhanced thera-peutic effect and other excellent effects. Accordingly, the preparation of the present invention is useful as a pharmaceutical preparation for oral administration for treating a patient with a colonic or large intestine disease.
Namely, the present invention relates to a novel oral pharmaceutical preparation which comprises l0 a solid drug having a core containing a therapeutically active ingredient which is releasable in the lower digestive tract, and the following coats ( 0 ) and ( 2(, ) coat ( O1 ) . inner coat which contains a suitable plasticizer or binding inhibitor and is made of a cationic polymer soluble or swelling at a pH of 6.0 or below, and coat ( 02 ): outer coat made of an anionic polymer soluble at a pH of 5.5 or above.
The solid drug having the core is made-of a therapeutically active ingredient alone or a mixture thereof with a filler, binder, disintegrator and/or sorbefacient.
Examples of the filler include lactose) 2, crystalline cellulose, crystalline cellulose sodium carboxymethylcellulose, wheat starch, and magnesium stearate.
Examples of the binder include crystalline cellulose, pullulan, acacia, sodium alginate, polyvinyl pyrrolidone and macrogol.
Examples of the disintegrator include ordinary inert substances for pharmaceutical preparations, such as carboxymethylcellulose, calcium carboxylmethylcellulose) hydroxypropylcellulose) hydroxypropylstarch, starch and sodium alginate.
Further, a sorbefacient may be used in the Preparation of the solid drug to accelerate the absorption of the active ingredient, and examples of such a sorbefacient include sugar ester, sucrose esters of fatty acid, glycyllysinate salts, glycyrrhetinic acid, dipotassium glycyrrhizinate) bile acid, glycerol esters of fatty acid, 1-[(2-(decyl-thio)ethyl]azacyclopentan-2-one) adipic acid) basic amino acids, po~_yethylene glycol and sodium caprate.
The solid drug may be encapsulated with gelatin or may be granulated or tabletted.
The therapeutically active ingredient to be contained in the solid drug is not particularly limited but may be any substance which exhibits its effect when released in the lower digestive tract.
Examples of the therapeutically active ingredient include peptides, proteins, anti-inflammatory agents, antineoplastic agents, antibiotics, chemotherapeutics) ulcerative colitis remedy, irritable colitis remedy (choline blocker), and constipation remedy. Specific examples of the therapeutically active ingredient include somatostatin, insulin, calcitonin, vasopressin) gastrin, EGF (epidermal growth factor)) a-hANP (a-human atri_al natri.uretic peptide), enkephalin, endorphin, GM-CSF (granulocyte macrophage colony-stimulating factor), G-CSF (granulocyte colony-stimulating factor), human growth hormone, glucagon, t-PA (tissue plasminogen activator), TNF
(tumor necrosis factor), TCGF (T cell growth factor), ACTH (adrenocorticotrophic hormone), interleukins, interferon, EPO (erythropoietin), urokinase, neocarcinostatin) bradykinin, immunoglobulin and its digestion product, various allergens and their digestion products, ketoprofen) ibuprofen, dicl_ofenac, indometacin, ketrolac, fenbufen, loxoprofen, tenidap) piroxicam, tenoxicam) salazosulfapyridine, pipethanate hydrochloride, mepenzolate bromide, and sennosides A
and B.
The cationic polymer which is soluble or swe7_ling at a pH of 6.0 or below and is used in the formation of the inner coat is an aminoalkyl methacrylate copolymer (a copolymer cornpri.sing methyl_ methac:rylate, butyl methacrylate and dimethylaminoethyl methacrylate, trade-mark: Eudragit E) a product of R(~HM) or a polyvinyl acetal diethyl_aminoacetate (trade-mark: AEA, a product of - 9 - ~ ~ ~'.9 Sankyo). The inner coat is formed by applying 1 to 40% by weight (based on the solid drug) of the above polymer to the solid drug in a film thickness of 10 to 300 11m, by which the resulting preparation is regulated so as to release the active ingredient therefrom speedily when the pH condition of 6.0 or below continues.
It is preferable that a suitable plasticizes be used in the formation of the inner coat to make the coat smooth. The plasticizes includes triacetin, citrate ester and polyethylene glycol. The binding inhibitor includes talc, titanium oxide, calcium phosphate) hydrophobic light anhydrous silicic acid, and so forth.
The outer coat is made of an anionic polymer which is easily soluble at a pH of 5.5 or above.
Examples of the anionic polymer usable in the present invention include methacrylic acid copolymer L (a copolymer comprising methacrylic acid and methyl methacrylate, trade-mark: Eudragit L100, a product of ROHM), methacrylic acid copolymer S (a copolymer comprising methacrylic acid and methyl methacrylate, trade-mark: I?udragit S, a hroduc:t of LWIIM) , hydroxy-propylcellulose, hydroxyethylcellulose phthalate, Polyvinyl acetate phthalate, cellulose acetate phthalate, and cellulose acetate tetrahydrophthalate.
214~4fi.3 The anionic polymer is applied in an amount of 1 to 40% by weight based on the solid drug.
Brief Description of Drawings Fig. 1 is a graph showing the results of in vitro test on the release of drug.
Fig. 2 is a graph showing the results of in vivo test on blood drug concentration.
Fig. 3 is a graph showing the influence of coating weight on the release of drug in vitro.
Fig. 4 is a graph showing the influence of pH
on the release of ketoprofen.
Fig. 5 is a graph showing the influence of pH
on the release of FITC dextran.
Fig. 6 is a graph showing the influence of pH
on the release of calcitonin.
Fig. 7 is a graph showing the results of the blood calcium concentration test using dog.
Fig. 8 is a graph showing the influence of coating weight on the release of drug in vitro.
Fig. 9 is a graph showing the effect of sorbefacient in vivo.
Best Mode for Carrying Out the Invention The present invention will now be specifically described by referring to the following Examples.
Example 1 A ketoprofen-containing solid drug was prepared according to the following formula:
ketoprofen 24.0 pt. by wt.
magnesium stearate 1.0 pt. by wt.
lactose 75.0 pt. by wt.
Ketoprofen, lactose and magnesium stearate were mixed together to form a homogeneous mixture.
This mixture was compressed with a tablet machine into tablets having a diameter of 7 mm and a weight of 210 mg- The obtained solid drug was coated as follows.
Eudragit E (trade-mark) 7.0 pt. by wt.
. ethanol 70.0 pt. by wt.
water 19.5 pt. by wt.
talc 3.5 pt. by wt.
~-5 A solution comprising the above components was continuously sprayed at 50 °C on the solid drug preheated to 50 °C to form an inner coat. The weight increase of the solid drug was 30 mg.
After the completion of the spraying, the ~ resulting drug was dried and further coated as follows.
Eudragit S (trade-mark) 7.0 pt. by wt.
ethanol 70.0 pt. by wt.
water 18.8 pt. by wt.
talc 3. 5 pt. by wt.
polyethylene glycol 6000 0.7 pt. by wt.
.~..::
lZ
A solution comprising the above components was continuously sprayed at 50 °C on the resulting drug preheated to 50 °C to form an outer coat. The weight increase of the solid drug was 20 mg.
Comparative Example 1 A ketoprofen-containing solid drug was prepared according to the following formula:
ketoprofen 24.0 pt. by wt.
magnesium stearate 1.0 pt. by wt.
lactose 75.0 pt. by wt.
Ketoprofen, lactose and magnesium stearate were mixed together to form a homogeneous mixture.
This mixture was compressed with a tablet machine into tablets having a diameter of 7 mm and a weight of 210 mg. The obtained solid drug was coated as follows.
Eudragit S (trade-mark) X7.0 pt. by wt.
ethanol 70.0 pt. by wt.
water lg,g pt. by wt.
talc 3.5 pt. by wt.
polyethylene glycol 6000 0.7 pt. by wt.
A solution comprising the above components was continuously sprayed at room temperature on the solid drug preheated to 50 °C i=o form an inner coat.
The weight increase of the solid drug was 30 mg. The resulting drug was dried and further coated as follows.
hydroxypropyl.methylcellulose 4.0 pt. by wt.
- 13 - ,~~y 3zi polyethylene glycol 400 0.5 pt. by wt.
95~ ethanol 85.5 pt. by wt.
water 10.0 pt. by wt.
Hydroxypropylcellulose was suspended in 95~
ethanol, followed by the addition of a solution of polyethylene glycol 400. The obtained solution was sprayed on the above solid drug preheated to 50 °C to form an intermediate coat. The weight increase of the solid drug was 10 mg.
The resulting solid drug was furthermore coated by spraying a solution comprising the following components like in the formation of the above coat.
The weight increase of the solid drug was 10 mg.
Eudragit L100 (trade-mark) 7.0 pt. by wt.
~_5 ethanol 70.0 pt. by wt.
water 18.8 pt. by wt.
talc 3.5 pt. by wt.
polyethylene glycol 6000 0.7 pt. by wt.
(A) In vitro test on the release of drug The tablets prepared in Example 1. and Comparative Example 1 were examined for the release of ketoprofen. Each tablet was incubated in a buffer of pH2.0 for 2 hours, in a buffer of ptI7.4 for 6 hours) and then in a cecal solution prepared by suspending the cecal contents in a phosphate buffer of pH7.4 containing 125 mg of glucose and 4.1 mg of benzyl viologen. The amount of the released ketoprofen was 2148~~
determined by liquid chromatography. The results are given in Fig. 1) wherein ~ represents the release pattern of the tablet prepared in Example 1 and, represents that of the tablet prepared in Comparative Example 1.
As apparent from the results of Fig. 1, the release of ketoprofen from the tablet prepared in Example 1 was observed specifically in a cecal solution, though it was not observed in a buffer of PH2.0 or 7.4 at all. On the other hand, most of the ketoprofen contained in the tablet prepared in Comparative Example 1 was released in a buffer of pH7.4.
(B) In vivo test on blood drug concentration The tablet prepared in Example 1 was administered to a laboratory animal (beagle dog, male, weight: 10 kg) without anesthesia. The result is given in Fig. 2, wherein ~ represents the result of the tablet of Example 1.
As apparent from the result of Fig. 2, no ketoprofen was observed in the plasma in the early stages, though ketoprofen is very readily absorbable.
After 14 hours and later, however, ketoprofen was observed in the plasma at extremely high concentrations.
Example 2 Five kinds of tablets were prepared by repeating the same procedure as that of Example 1 except that the coating weights of the inner and outer coats were varied as specified in Table 1.
Table 1 Coating wt. of Coating wt. of Sample No. Eudragit E Eudragit S
(inner coat) (outer coat) to 5 0 20i 02 20~ 20%
~3 40~ 20 a I_5 ~ 20i 5i 20 a 40 0 each percentage is given by weight and based on the solid drug (c) In-vitro test on the influence of coating weight on the release of drug The tablets (Sample Nos. ~ to ~5) were tested for the release of ketoprofen. Each tablet was incubated in a buffer of pH7.4 for 4 hours and put in a cecal. solution. The results of the test were given in Fig. 3, wherein ~ represents the result of Sample No. 0 , ~ represents the result of Sample No. 02, Q
_ 16 _ that of Sample No. 03 ~ ~ that of Sample No. ~ and that of Sample No. ~5.
As apparent from the results of Fig. 3, equivalent release patterns were exhibited even when the coating weight of EUDRAGIT S (outer coat) was varied. On the other hand, when the coating weight of EUDRAGIT E (inner coat) was varied) however, somewhat different release patterns were exhibited.
Example 3 l0 Ketoprofen-containing granules were prepared according i=o i=he following formula:
ketoprofen 20.0 pt. by wt.
lactose 25.0 pt. by wt.
corn starch 30.0 pt. by wt.
15 crystalline cellulose 20.0 pt. by wt.
hydroxypropylcellulose 5.0 pt. by wt.
Ketoprofen, Lactose, corn starch and crystalline cellulose were together mixed homogeneously, followed by the addition of a solution 20 or hydroxypropylcellulose i.n purified water. The obtained mixture was kneaded and granulated with an extrusion granulator having a cylinder bore of 1 mm.
The obtained granu7.es were dried and subjected to size classification. The resulting granules were coated as 25 follows to form an inner coat. The weight increase was 5 mg per 100 mg of the granules.
Eudragit E (trade-mark)' 7.0 pt. by wt.
ethanol 70.0 pt. by wt.
water 19.5 pt. by wt.
talc 3.5 pt. by wt.
A solution comprising the above components was continuously sprayed on the granules preheated to 50 °C by the use of a flow coater at room temperature.
After the completion of the spraying, the resulting granules were dried and further coated with a solution comprising the following components to form an outer coat. The weight increase was 10 mg per 100 mg of the granules.
Eudragit L (trade-mark) 7.0 pt. by wt.
ethanol 70.0 pt. by wt.
water 18.8 pt. by wt.
talc 3.5 pt. by wt.
polyethylene glycol 6000 0.7 pt. by wt.
(D) Test on the influence of pH on the release of ketoprofen This test was conducted in the same manner as that of Example 7_. The results are given in Fig. 4, wherein ~ represents the release pattern at pH2.0) represents that at pH7.4, and 0 represents that exhibited when Lhe granu:l.es were ullowecl to stand io a buffer of pH7.4 for 4 hours and put in a cecal solution.
As apparent from the results of Fig. 4, no ketoprofen was released at pI-I2.0 or pI-I7.4, while ~14~46 specific release of ketoprofen was observed only in a cecal solution.
Example 4 A solid drug was prepared according to the following formula wherein fluorescein isothiocyanate dextran (hereinafter abbreviated to "FITC dextran") was used as a model compound having dissolution characteristics different from those of ketoprofen.
FITC dextran 2.5 pt. by wt.
magnesium stearate 1.0 pt. by wt.
lactose 96.4 pt. by wt.
carboxynethylcellulose 0.1 pt. by wt.
Both inner and outer coats were formed on the solid drug in the same manner as that of Example 1.
(E) Test on the influence of pH on the release of FITC dextran This test was conducted in the same manner as that of Example 1. The results are given in Fig. 5, wherein ~ represents the release pattern at pH2.0, that at pI-I7.4, and ~ represents that exhibited when the preparation was allowed to stand in a buffer of pH7.4 for 4 hours and put in a cecal solution.
As apparent from the resu7_ts of Fig. 5) little FITC dextran was released in a buffer of pH2.0 or pH7.4) while rapid release of FITC dextran was observed in a cecal solution.
Example 5 214~46~
A solid drug having a ca7_citonin-containing core was prepared according to the following formula:
calcitonin 4.0 pt. by wt.
sucrose ester of fatty acid 5.0 pt. by wt.
(F-160) magnesium stearate 1.0 pt. by wt.
lactose 90.0 pt. by wt.
Calcitonin) lactose, magnesium stearate and sucrose ester of fatty acid were mixed together to form a homogeneous mixture. This mixture was compressed with a tablet machine into tablets having a diameter of 2 mm and a weight of 7 mg. The tablets were coated with a mixture comprising magnesium stearate (1 part by weight) and lactose (99 parts by weight). Both inner and outer coats were formed on the resulting tablets in the same manner as that of Example 1.
(F) Test on the influence of pH on the release of calcitonin This test was conducted in the same manner as that of Example 1. The results are given in Fig. 6, wherein ~ represents the release pattern at pH2.0, represents that at pH7.4, and ~ represents that exhi_bi.ted when the tablet was allowed to stand in a buffer of pH7.4 for 4 hours and put in a cecal so7_ution .
As apparent from the results of Fig. 6, little calcitonin was released in a buffer of pH2.0 or pH7.4, while rapid release of calcitonin was observed in a cecal solution.
(G) Blood calcium concentration test using dog In a similar manner to that of Example 1, the tablet prepared in Example 5 was administered to dogs to determine the blood calcium concentration. The results are given in Fig. 7, wherein ~ represents the result exhibited when the tablet of Example 5 was administered) and ~ represents the result exhibited when the tablet of Example 5 was not coated at all.
As apparent from the results of Fig. 7, little lowering was observed in the blood calcium concentration, when the uncoated tablet was administered. On the other hand, lowering was observed in the blood calcium concentration 10 hours after the administration and later, when the double-coated tablet was administered.
Example 6 Five kinds of tablets were prepared in a similar manner to that of Example 1 except that the coating weights of the inner and outer coats were varied as specified in Table 2.
_ 21 _ Table 2 Coating wt. of Coating wt. of Sample No. EUDRAGIT E EUDRAGIT S
(inner coat) (outer coat) 3i 20i 5i 20i 7i 20~
~ 5~ 5~
5~ 3i ~: each percentage is given by weight and based on the solid drug (H) In vitro test on the influence of coating weight on the release of drug These tablets were tested for the release of ketoprofen. Each tablet was incubated in a buffer of pH7.4 for 4 hours and put in a cecal solution. The results are given in Fig. 8, wherein ~ represents the result of Sample No. ~1 , ~ represents that of Sample No. 20 , 0 represents that of Sample No. ~3 , represents that of Sample No. ~ , and ~ represents that of Sample No. ~5 .
As apparent from the results of Fig. 8, equivalent release patterns were exhibited, even when the coating weight of EUDRAGIT S (outer coat) was varied. On the other hand) when the coating weight of ~.,, EUDRAGIT C (inner coat) was 5~ by weight or below, excellent release patterns were exhibited.
Example 7 Calcitonin-containing solid drugs were prepared according to the following formulae:
21454~~
~_ Tab7_e 3 Sample No. (~1 ~ O
calcitonin 0.28 mg 0.28 mg 0.28 mg 0.28 mg 0.28 mg sucrose ester of fatty acid (F-160) 25%
sodium caprate 25~ 25%
dipotassium glycyrrhizinate 250 25~
magnesium stearate 1~ 1% 1~ 1~ l~
lactose 74.0% 74.0 74.Oo 49.0% 99.0 each percentage is given by weight The components of each formula were mixed together to form a homogeneous mixture. This mixture was compressed into tablets having a diameter of 7 mm and a weight of 200 mg with a tablet machine. These tablets were each coated as follows.
Eudragit E (trade-mark) 7.0 pt. by wt.
ethanol 70.0 pt. by wt.
water 19.5 pt. by wt.
talc 3.5 pt. by wt.
A solution comprising the above components was continuously sprayed at 50 °C on the tablet preheated to 50 °C. The weight increase of the solid drug was 14 mg. The resulting tablets were dried and further coated as follows.
Eudragit S 7.0 pt. by wt.
ethanol 70.0 pt. by wt.
water 1.8.8 pt. by wt.
talc 3.5 pt. by wt.
polyethylene glycol 6000 0.7 pt. by wt.
A solution comprising the above components was continuously sprayed at 50 °C on the tablets preheated to 50 °C. The weight increase of the solid drug was 14 mg.
(I) In vivo test on the effect of sorbefacient In a similar manner to that of Example 5, the tablets prepared in Example 7 were each administered .., ~:, :., n..
~14846~
to dogs to determine the blood calcium concentrations.
The results are given in Fig. 9, wherein ~ represents the result of Sample No. 1~, ~J,represents that of Sample No. ~ , 0 represents that of Sample No. ~3 , (.
represents that of Sample No. ~ , and (~ represents that of Sample No. 0 .
As apparent from the results of Fig. 9, lowering in the blood calcium concentration was observed 10 hours after the administration and later when Sample No. O1) ~2 ) ~3 or ~ was administered, while no lowering was observed when Sample No. ~5 not containing any sorbefacient was administered.
Particularly excellent lowering in the blood calcium concentration was observed when sodium caprate or dipotassium glycyrrhizinate was used as the sorbefacient.
Industrial Applicability The oral pharmaceutical preparation releasable in the lower digestive tract according to the present invention is characterized by the specific release of the active ingredient therefrom caused by the unique pH change in the digestive tract, so that the preparation little causes lowering or loss in the avai_labi.l_ity and scattering among i.ndividual_s, though the preparation targetting the lower digestive tract (such as the large intestine) according to the prior art suffered from these disadvantageous phenomena.
_..
In particular, the oral preparation of the present invention passes through the stomach and small intestine without being affected, and is disintegrated for the first time on arrival at the large intestine (i.e., the lower digestive tract) to release the active ingredient which is then effectively absorbed in the large intestine to give a remarkably enhanced thera-peutic effect and other excellent effects. Accordingly, the preparation of the present invention is useful as a pharmaceutical preparation for oral administration for treating a patient with a colonic or large intestine disease.
Claims (4)
1. An oral pharmaceutical preparation releasable in the lower digestive tract, characterized by having a double-coated structure wherein a solid drug having a core containing an active ingredient is covered with both 1) an inner coat made of an aminoalkyl methacrylate copolymer which is soluble or swelling at a pH of 6.0 or below, and 2) an outer coat made of a methacrylic acid copolymer comprising methacrylic acid and methyl methacrylate, said methacrylic acid copolymer being soluble at a pH of 5.5 or above.
2. An oral pharmaceutical preparation according to claim 1, wherein the core contains a sorbefacient.
3. An oral pharmaceutical preparation according to claim 2, wherein the sorbefacient is selected from the group consisting of sugar ester, sucrose esters of fatty acid, glycyllysinate salts, glycyrrhetic acid, dipotassium glycyrrhizinate, bile acid, glycerol esters of fatty acid, 1-[(2-(decylthio)ethyl]azacyclopentan-2-one, adip-ic acid, basic amino acids, polyethylene glycol and sodium caprate.
4. An oral pharmaceutical preparation according to claim 1, 2 or 3, wherein the active ingredient is selected from the group consisting of peptides, proteins, anti-inflammatory agents, antineoplastic agents, antibiotics and chemotherapeutic agents.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JPHEI4-322478 | 1992-11-06 | ||
JP32247892 | 1992-11-06 | ||
PCT/JP1993/001608 WO1994010983A1 (en) | 1992-11-06 | 1993-11-05 | Peroral pharmaceutical preparation releasable in lower digestive tract |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2148465A1 CA2148465A1 (en) | 1994-05-26 |
CA2148465C true CA2148465C (en) | 1999-11-02 |
Family
ID=18144084
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002148465A Expired - Fee Related CA2148465C (en) | 1992-11-06 | 1993-11-05 | Oral pharmaceutical preparation releasable in the lower digestive tract |
Country Status (9)
Country | Link |
---|---|
US (1) | US5654004A (en) |
EP (1) | EP0667148B1 (en) |
KR (1) | KR0157280B1 (en) |
AU (1) | AU5376894A (en) |
CA (1) | CA2148465C (en) |
DE (1) | DE69332082T2 (en) |
DK (1) | DK0667148T3 (en) |
ES (1) | ES2176209T3 (en) |
WO (1) | WO1994010983A1 (en) |
Families Citing this family (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5514663A (en) * | 1993-10-19 | 1996-05-07 | The Procter & Gamble Company | Senna dosage form |
US6117453A (en) * | 1995-04-14 | 2000-09-12 | Pharma Pass | Solid compositions containing polyethylene oxide and an active ingredient |
SG80553A1 (en) | 1995-07-20 | 2001-05-22 | Tanabe Seiyaku Co | Pharmaceutical preparation in form of coated capsule releasable at lower part of digestive tract |
JPH10152431A (en) * | 1996-08-02 | 1998-06-09 | Hisamitsu Pharmaceut Co Inc | Capsule for oral pharmaceutical preparation and oral capsule pharmaceutical preparation |
EP0919228A4 (en) * | 1996-08-02 | 2001-12-12 | Hisamitsu Pharmaceutical Co | Capsules for oral preparations and capsule preparations for oral administration |
US5891474A (en) | 1997-01-29 | 1999-04-06 | Poli Industria Chimica, S.P.A. | Time-specific controlled release dosage formulations and method of preparing same |
KR100522248B1 (en) * | 1997-05-29 | 2006-02-01 | 동아제약주식회사 | Oral sustained release preparation of double controlled release membrane structure and its manufacturing method |
DE19726282A1 (en) | 1997-06-20 | 1998-12-24 | Inst Neue Mat Gemein Gmbh | Nanoscale particles with an iron oxide-containing core surrounded by at least two shells |
JPH11246439A (en) * | 1998-03-02 | 1999-09-14 | Hisamitsu Pharmaceut Co Inc | Transmucosal absorption accelerator |
EP0972563A1 (en) * | 1998-07-15 | 2000-01-19 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Fabrication of multilayer-coated particles and hollow shells via electrostatic self-assembly of nanocomposite multilayers on decomposable colloidal templates |
ATE524165T1 (en) * | 1998-03-19 | 2011-09-15 | Max Planck Gesellschaft | METHOD FOR PRODUCING CAPSULES WITH A POLYELECTROLYTE SHEATH |
US7101575B2 (en) | 1998-03-19 | 2006-09-05 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. | Production of nanocapsules and microcapsules by layer-wise polyelectrolyte self-assembly |
EP1064088B1 (en) * | 1998-03-19 | 2002-12-04 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Fabrication of multilayer-coated particles and hollow shells via electrostatic self-assembly of nanocomposite multilayers on decomposable colloidal templates |
JPH11335269A (en) * | 1998-05-19 | 1999-12-07 | Hisamitsu Pharmaceut Co Inc | Solid pharmaceutical preparation for oral administration of gene-related medicine |
US6197347B1 (en) | 1998-06-29 | 2001-03-06 | Andrx Pharmaceuticals, Inc. | Oral dosage for the controlled release of analgesic |
FR2781666B1 (en) * | 1998-07-30 | 2000-09-08 | Oreal | SOLID COSMETIC COMPOSITION AND USES THEREOF |
KR100336975B1 (en) * | 1998-08-11 | 2002-08-22 | 한국화학연구원 | A Pharmaceutical Patch for Controlling the Release of Drug |
CN1181827C (en) * | 1998-09-21 | 2004-12-29 | 天藤制药株式会社 | Oral drug delivery system for enhancing the bioavailability of activated glycyrrhetin |
JP4599714B2 (en) * | 1999-01-22 | 2010-12-15 | アステラス製薬株式会社 | Oral absorption improving pharmaceutical composition |
JP2002537321A (en) * | 1999-02-22 | 2002-11-05 | エラン コーポレイション ピーエルスィー | Solid oral dosage form containing enhancer |
US7658938B2 (en) | 1999-02-22 | 2010-02-09 | Merrion Reasearch III Limited | Solid oral dosage form containing an enhancer |
US8119159B2 (en) | 1999-02-22 | 2012-02-21 | Merrion Research Iii Limited | Solid oral dosage form containing an enhancer |
JP2000247911A (en) * | 1999-02-26 | 2000-09-12 | Hisamitsu Pharmaceut Co Inc | Absorption promoter for large intestine |
EP1194128A2 (en) | 1999-06-23 | 2002-04-10 | Sedum Laboratories | Ionically formulated biomolecule microcarriers |
WO2001002014A1 (en) | 1999-07-02 | 2001-01-11 | Hisamitsu Pharmaceutical Co., Inc. | Medicinal compositions for treating colorectal cancer |
DE19943420A1 (en) * | 1999-09-08 | 2001-03-15 | Beiersdorf Ag | Mascara or eyebrow pencil preparations containing water-soluble or -dispersible comb polymers with sulfonated, fluorine-containing polyester side chains |
US20020015730A1 (en) * | 2000-03-09 | 2002-02-07 | Torsten Hoffmann | Pharmaceutical formulations and method for making |
ES2284643T3 (en) | 2000-04-20 | 2007-11-16 | Novartis Ag | COMPOSITION OF MASK COVERING OF FLAVOR. |
US6551617B1 (en) | 2000-04-20 | 2003-04-22 | Bristol-Myers Squibb Company | Taste masking coating composition |
KR100411195B1 (en) * | 2000-09-26 | 2003-12-18 | 한국화학연구원 | Controlled release of ketorolac tromethamine using pellet-tape dosage form |
CA2359812C (en) | 2000-11-20 | 2004-02-10 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures |
AU2002363182A1 (en) * | 2001-11-02 | 2003-05-12 | Ribopharma Ag | Smad7 inhibitors for the treatment of cns diseases |
JP2003201256A (en) * | 2001-12-28 | 2003-07-18 | Hisamitsu Pharmaceut Co Inc | Colic delivery oral pharmaceutical preparation, oral pharmaceutical preparation for treatment of colon cancer and oral pharmaceutical preparation for treating colitis |
US7007417B2 (en) * | 2002-01-18 | 2006-03-07 | M.H. Segan Limited Partnership | Audio-visual display device for pictorial artwork |
TWI355276B (en) * | 2003-01-14 | 2012-01-01 | Akira Tsuji | Gastrointestinal absorption enhancer mediated by p |
FR2850577B1 (en) * | 2003-02-03 | 2005-04-15 | Ethypharm Sa | MASK TASTE ENRICHED PARTICLES, PROCESS FOR THEIR PREPARATION AND ORODISPERSIBLE COMPRESSES CONTAINING SAID PARTICLES |
WO2004087109A1 (en) * | 2003-03-27 | 2004-10-14 | Hisamitsu Pharmaceutical Co., Inc. | Medicinal oral preparations for colon delivery, medicinal oral preparations for treating colon cancer and medicinal oral preparations for treating colitis |
ITRM20030149A1 (en) | 2003-04-02 | 2004-10-03 | Giuliani Spa | ANTISENSE OLIGONUCLEOTIDES (ODN) FOR SMAD7 AND THEIR USE IN THE MEDICAL FIELD |
US7348399B2 (en) | 2003-08-29 | 2008-03-25 | Louisiana Tech University Foundation, Inc. | Nanofabricated polypeptide multilayer films, coatings, and microcapsules |
US7550557B2 (en) | 2003-08-29 | 2009-06-23 | Louisiana Tech University Foundation, Inc. | Multilayer films, coatings, and microcapsules comprising polypeptides |
US7544770B2 (en) | 2003-08-29 | 2009-06-09 | Louisiana Tech Foundation, Inc. | Multilayer films, coatings, and microcapsules comprising polypeptides |
US7670624B2 (en) * | 2004-01-29 | 2010-03-02 | Astella Pharma Inc. | Gastrointestinal-specific multiple drug release system |
DE102004013637A1 (en) | 2004-03-19 | 2005-10-13 | Capsulution Nanoscience Ag | Process for the preparation of CS particles and microcapsules using porous templates as well as CS particles and microcapsules |
JP4521554B2 (en) * | 2004-03-31 | 2010-08-11 | マイラン製薬株式会社 | Cyclosporine preparation |
DE102004035936A1 (en) * | 2004-07-23 | 2006-03-16 | Röhm GmbH & Co. KG | Multilayer dosage form |
CN100486568C (en) * | 2004-08-26 | 2009-05-13 | 复旦大学 | Loxoprofen sodium sustained release preparation |
CN101437522A (en) | 2006-04-07 | 2009-05-20 | 默里昂研究Ⅲ有限公司 | Solid oral dosage form containing an enhancer |
CN101259140B (en) * | 2007-03-08 | 2012-08-22 | 重庆北碚现代应用药物研究所 | Compound medicaments treating gastritis, gastric ulcer, and duodenal ulcer and preparation thereof |
US20100209520A1 (en) * | 2007-03-26 | 2010-08-19 | Hiroyuki Kubo | Oral pharmaceutical preparation for colon-specific delivery |
WO2009048073A1 (en) * | 2007-10-09 | 2009-04-16 | Takeda Pharmaceutical Company Limited | Method of coating granules |
DE102008003615A1 (en) | 2008-01-09 | 2009-07-16 | Magforce Nanotechnologies Ag | Magnetic transducers |
BRPI0912384A2 (en) | 2008-05-07 | 2015-10-13 | Merrion Res Iii Ltd | composition and method for preparing a composition |
EP2172193A1 (en) * | 2008-10-02 | 2010-04-07 | Capsulution Nanoscience AG | Improved nanoparticulate compositions of poorly soluble compounds |
WO2011120033A1 (en) | 2010-03-26 | 2011-09-29 | Merrion Research Iii Limited | Pharmaceutical compositions of selective factor xa inhibitors for oral administration |
KR20140026354A (en) | 2011-01-07 | 2014-03-05 | 메리온 리서치 Ⅲ 리미티드 | Pharmaceutical compositions of iron for oral administration |
WO2013020701A2 (en) | 2011-08-10 | 2013-02-14 | Magforce Ag | Agglomerating magnetic alkoxysilane-coated nanoparticles |
EP2659881B1 (en) * | 2012-04-30 | 2017-11-29 | Tillotts Pharma Ag | A delayed release drug formulation |
EP2953619A1 (en) | 2013-03-15 | 2015-12-16 | Warner Chilcott Company, LLC | Mesalamine pharmaceutical composition with multiple dosage elements for reduced delivery variability |
WO2016120378A1 (en) | 2015-01-29 | 2016-08-04 | Novo Nordisk A/S | Tablets comprising glp-1 agonist and enteric coating |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2246037B2 (en) * | 1972-09-20 | 1975-02-27 | Taeschner & Co, 8831 Kipfenberg | Orally applicable drug with delayed absorption in suspension form |
FR2471186A1 (en) * | 1979-12-10 | 1981-06-19 | Roussel Uclaf | NEW COLIC DELITESCENCE TABLETS AND THEIR PREPARATION PROCESS |
ZA825384B (en) * | 1981-07-31 | 1983-05-25 | Tillott J B Ltd | Orally administrable pharmaceutical compositions |
SE457505B (en) * | 1984-01-10 | 1989-01-09 | Lejus Medical Ab | LAMINATED ORAL PHARMACEUTICAL COMPOSITION AND PROCEDURES FOR ITS PREPARATION |
US4627851A (en) * | 1984-10-26 | 1986-12-09 | Alza Corporation | Colonic-therapeutic delivery system |
FR2576213B1 (en) * | 1985-01-21 | 1989-02-24 | Cortial | NEW PROCESS FOR OBTAINING EXTENDED RELEASE PHARMACEUTICAL FORMS |
US4775536A (en) * | 1986-02-24 | 1988-10-04 | Bristol-Myers Company | Enteric coated tablet and process for making |
US5296236A (en) * | 1988-09-16 | 1994-03-22 | Recordati S.A., Chemical And Pharmaceutical Company | Controlled release therapeutic system for a liquid pharmaceutical formulations |
US4996047A (en) * | 1988-11-02 | 1991-02-26 | Richardson-Vicks, Inc. | Sustained release drug-resin complexes |
JPH0813748B2 (en) * | 1990-04-23 | 1996-02-14 | 帝國製薬株式会社 | Colon disintegrating polypeptide oral preparation |
-
1993
- 1993-11-05 EP EP93924185A patent/EP0667148B1/en not_active Expired - Lifetime
- 1993-11-05 DK DK93924185T patent/DK0667148T3/en active
- 1993-11-05 US US08/432,202 patent/US5654004A/en not_active Expired - Fee Related
- 1993-11-05 ES ES93924185T patent/ES2176209T3/en not_active Expired - Lifetime
- 1993-11-05 CA CA002148465A patent/CA2148465C/en not_active Expired - Fee Related
- 1993-11-05 AU AU53768/94A patent/AU5376894A/en not_active Abandoned
- 1993-11-05 DE DE69332082T patent/DE69332082T2/en not_active Expired - Fee Related
- 1993-11-05 WO PCT/JP1993/001608 patent/WO1994010983A1/en active IP Right Grant
- 1993-11-05 KR KR1019950701773A patent/KR0157280B1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
ES2176209T3 (en) | 2002-12-01 |
EP0667148A4 (en) | 1997-02-26 |
AU5376894A (en) | 1994-06-08 |
EP0667148A1 (en) | 1995-08-16 |
US5654004A (en) | 1997-08-05 |
WO1994010983A1 (en) | 1994-05-26 |
DE69332082T2 (en) | 2003-02-06 |
DK0667148T3 (en) | 2002-07-22 |
CA2148465A1 (en) | 1994-05-26 |
EP0667148B1 (en) | 2002-07-03 |
KR0157280B1 (en) | 1998-11-16 |
DE69332082D1 (en) | 2002-08-08 |
KR950703938A (en) | 1995-11-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2148465C (en) | Oral pharmaceutical preparation releasable in the lower digestive tract | |
US7018658B2 (en) | Pharmaceutical pellets comprising tamsulosin | |
US8709996B2 (en) | Pharmaceutical treatment process using chitosan or derivative thereof | |
US6296876B1 (en) | Pharmaceutical formulations for acid labile substances | |
CA1248023A (en) | Diffusion coated multiple-units dosage form | |
US20070148228A1 (en) | Solid oral dosage form containing an enhancer | |
US20070059368A1 (en) | Modified release formulations of anti-irritability drugs | |
EA003101B1 (en) | Biphasic controlled release delivery system for high solubility pharmaceuticals and method | |
JPH11510506A (en) | Composition for enhancing the uptake of polar drugs from the colon | |
SK285152B6 (en) | Enteric coated pharmaceutical composition a method for its preparation | |
JPS601128A (en) | Long-acting cefaclor preparation | |
EP0136103B1 (en) | Amosulalol hydrochloride long acting formulations | |
JP3134187B2 (en) | Controlled release composition | |
US20020106408A1 (en) | Prolamin-based sustained-release compositions and delayed-onset compositions | |
JP2821952B2 (en) | Oral pharmaceutical preparation with lower gastrointestinal release | |
JPH0624962A (en) | Enteric sustained release solid pharmaceutical preparation | |
US20050106253A1 (en) | Pharmaceutical pellets comprising tamsulosin | |
JP3282832B2 (en) | Sustained tablets | |
JP3122478B2 (en) | Lower gastrointestinal release oral formulation | |
SK1795A3 (en) | Drug delivery device and method of this production | |
US20230263901A1 (en) | Mucus adhesion drug delivery | |
CA2251022A1 (en) | Oral coated active drugs |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
MKLA | Lapsed |