CA2127111C - A method for preparing enteric-coated oral drugs containing acid-unstable compounds - Google Patents
A method for preparing enteric-coated oral drugs containing acid-unstable compoundsInfo
- Publication number
- CA2127111C CA2127111C CA002127111A CA2127111A CA2127111C CA 2127111 C CA2127111 C CA 2127111C CA 002127111 A CA002127111 A CA 002127111A CA 2127111 A CA2127111 A CA 2127111A CA 2127111 C CA2127111 C CA 2127111C
- Authority
- CA
- Canada
- Prior art keywords
- group
- cyclodextrin
- buffer
- alkaline
- combinations
- 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 - Lifetime
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
Abstract
The present invention relates to a method for preparing enteric-coated oral drugs containing acid-unstable compound, in particular an enteric-coated oral drug prepared in the form of acid-stable dosage units as inclusion complex formed by reacting benzimidazole derivative, acid-unstable compound, with cyclodextrin in alkaline solution.
Description
212~111 .
A METHOD FOR PREPARING ENTERIC-COATED ORAL DRUGS
CONTAINING ACID-UNSTABLE COMPOUNDS
BACKGROUND OF THE INVENTION
The present invention relates to a method for preparing enteric-coated oral drugs containing acid-unstable compounds, in particular an enteric-coated oral drug prepared in the form of acid-stable dosage units as inclusion complex formed by reacting benzimidazole derivative, acid-unstable compound, with cyclodextrin in alk~line solution.
o Acid-unstable compounds, especially the benzimidazole compounds, are easily discolored and degraded under acidic and neutral conditions. For example, omeprazole, a ben7.imifl~7ole derivative, has half-life of 10 minutes in medium of below pH 4, but 18 hours at pH 6.8 and about 300 days at pH 11. Omeprazole has been reported to be stable in alkaline condition [Pilbrant A and Cederberg C. Scand. J.
s Gastroenterology, S uppl. 108, 113- 120(1985)] . The acid-unstable compounds when exposed to the environment also get discolored and degraded by getting in contact with moisture and organic solvents. In therapeutically using the acid-unstable compounds, omeprazole and ben7imitl~7Ole derivatives, which show a powerful inhibitory actions against secretion of gastricjuice and can be used for the treatment of gastric and duodenal ulcers, it is very important that an oral dosage form of them must be protected from the acidic gastricjuice in order to be absorbed in small intestinal withoutdegradation. Methods for stabilizing the acid-unstable compound, in particular omeprazole has been known to be as follows; Omeprazole is combined with alkalinesalt such as Na+, K+, Mg~2, Ca~2 and so on to maintain the stability for compound itself. PCT Publication No. 86-00913(PCT/EP 85/00371) discloses to form a stablecomplex by mixing and reacting omeprazole with ~ -cyclodextrin in 96% ethanol and cooling the reactant.
The latter process seems to have the problem as the reaction is conducted at a temperature 25 ~ 38C for 15 hours in ethanol, during the reaction itself omeprazole ~o can get discolored and degraded. Furthermore, it is difficult to e~cpect the formation 2 1 2 7 1 1 1 Pcr/KRg2/00083 2 ~
of inclusion compound because both omeprazole and cyclodextIin are dispersed in the reaction as solid particles, not dissolved. For forming an inclusion compound ofcyclodextIin, the reaction must be carried out in presence of water molecules [K. Hara, H. Hashimoto, J. Jpn. Soc. Starch. Sci., 32(2) 152-161(1986)]. Therefore, the latter 5 method not expected to give inclusion compound since the above reacting condition has not been considered.
On the other hand, Une~c,.mined Korean Patent No. 87-9718 and Korean Patent Publication No. 91-4579 disclose processes for preparing omeprazole preparation consisting of mixing omeprazole with ~lk~lin~ substance to form core material, forming o a watersoluble internal layer on the core and forming an enteric coating to stabilize omeprazole.
It has, however, been found that the stabilizing methods known in the Korean Patents have several problems as followings; The process for prepaIing core material and forming enteric-coating is very complicated. The stabilized omeprazole is 5 discolored and degraded during stay in stomach after oral aflmini~tration, because gastIic juice passes through the enteric-coating to partially dissolve the watersoluble internal layer and then infiltrated into the core to dissolve the alkaline substance partially destroying the enteric-coating. The stability of omeprazole by this process is not secured concretely. For formulating omeprazole, it is necessary to give good20 attention to omeprazole itself. For example, it must be kept at below -20C of low temperature and immediately used for formulating after removing moisture, or immediately after synthesis, to maintain the starting stability.
After all, for stabilizing the acid-unstable compound a primary factor is not only to secure the stability of preperation but also to stabilize the compound itself. Thus 25 the attempt to stabilize acid-unstable compound must take into account the stability of the compound during the stablization process, its stability against gastric juice and the need to quickly and completely dissolve are made the available main drug for absorption in the intestine.
As discussed above most of the previously described methods are either very 3û partialy successful in stabilization or the stable inclusion compound is not produced at WO 93/13138 PCl/KR92/00083 ~ 2127111 all conjugation attempt to add ~lk~line salt to omeprazole have also been unsatisfactory.
SU~IMARY OF THE INVENTION
The object of the present invention is to obtain oral drugs of acid-unstable 5 compound, having excellent storage stability, dissolution and absorption properties after oral ~clmini~tration and a simplified manufacturing process principally involving formation of inclusion complex by reacting the acid-unstable compound with cyclodextrin to give stabilized compound.
The present invention is a method for preparing enteric-coated oral drugs by o using cyclodextrin to stabilize acid-unstable compound, characterized in which acid-unstable compound is reacted with cyclodextrin of 1 ~ 10 mole based on lmole of acid-unstable compound in an alkaline solution to obtain inclusion complex without existance of alk~line substance.
i 5 DETAILED DESCRIPTION OF THE INVENTION
The present invention is accomplished by using a new solution system, instead of organic solvent such as ethanol used in prior art, in which acid-unstable compound is reacted with cyclodextrin for stabilizing. The ~lk?line solution used in the present invention performs a dirrGlGnt function from ~lk~linc solvent in prior art. As a result 20 the inclusion complex obtained by the present invention dose not include the aLkaline components.
According to the present invention when acid-unstable compound is reacted with cyclodextrin in ~lk~line solution, the reaction is carried out under homogeneous solution system for 1 ~ 30 mins at 40 ~ 70C, and after cooling to room temperature the 25 reacted solution is allowed to stand at 4C to deposit inclusion complex. The reactant is filtered to remove residual alkaline component and to obtain pured stable inclusion complex as the desired product.
In the above reaction, if the temperature is below 40C, since the solubility ofcyclodextrin is decreased and an excessive of alkaline solution is ntoe~ the reation ~o scale becomes unnecessarily large and the yield is decreased, and if the reaction temperature is more than 70C, acid-unstable compound may be discolored or degraded.
Furthermore, under the condition if the reaction time is below 1 min, acid-unstable compound and cyclodextrin not are entirely dissolved in the ~lk~line solution,5 and if the reaction time over 30 mins, acid-unstable compound is also discolored and degraded.
In the present invention, ben7imid~7ole derivative having the following structural formula(I) and pharmaceutically acceptable salt thereof, especially omeprazole and its sodium salt, is preferably used as acid-unstable compound.
o R3 R~ ~N~ S -- CH, $~
H
Wherein, R~ is selected from the group consisting of hydrogen atom, methoxy, trifluoromethyl and tetrafluoroethoxy group;
R2 is selected from the group consisting of hydrogen atom, methylamine and dimethylamine group;
R3 is selected from the group consisting of hydrogen atom, methoxy, aryloxy and propagyloxy group; and R4 is hydrogen atom or methyl group.
A pharmaceutical preparation containing said acid-unstable compounds in pharmaceutically effective amount may be prepared by the present invention in form of dosage units for oral administration such as tablets, granules, capsules, spherical pellets, - microgranules, or microcapsules.
According to the present invention, acid-unstable compound is reacted with cyclodextrin structurally having hydrophobic cavity of a defined size, and at this time an inclusion complex is obtained because of the property of cyclodextrin to protect hydrophobic compounds from outside by entrapping them into the cavity.
,WO 93/13138 21% 7 111 PCI/KR92/00083 Cyclodextrin may be prepared by resolving starch with cyclodextrin glycosyltransferase and are classified according to the properties and size shown as following Table A.
In accordance with the present invention, a cyclodextrin(CD) selected from the group consisting of ~ - and y -cyclodextrin, and cyclodextrin derivatives such as methyl-5 ,~ -cyclodextrin, hydroxyethyl ~ -cyclodextrin, hydroxypropyl a-cyclodextrin, hydroxypropyl ~ -cyclodextrin, hydroxypropyl y -cyclodextrin, etc. may be used.
Table A. Comparison of Properties for Natural Cyclodextrins o Properties a -CD ~ -CD y -CD
A Number of Glucose Units 6 7 8 ~[olecular Weight 973 1135 1297 Solubility in 25C Water (g/lOOml) 14.5 1.85 23.2 CavityDiameter(A ) 4.7-5.3 6.0-6.5 7.5-8.3 Ring-opening Half-life (h) * 6.2 5.4 3.0 * (Note) Ring-opening half-life was measured under the condition of 60C ,lN HCl.
In the present invention, to obtain stable inclusion complex powder, the used alkaline solution is a aqueous solution of one selected from the group consisting of hydroxides of ~lk~line metal, ~lk~line salts of organic or inorganic acid, amines, buffers and combinations thereof.
The alkaline compounds in the present invention as alkaline aqueous solution 25 may be typically illustrated as followings: Hydroxide of :~lk~line metal may be selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide and combinations thereof. Alkaline salt may be selected from the group consisting of sodium borate, sodium carbonate, sodium phosphate, potassium borate, potassium carbonate, potassium phosphate, sodium ~o acetate, sodium citrate and combinations thereof. Amines may be selected from the WO 93/13138 212 7111 PCr/KR92/00083 group consisting of diethylamine, triethylamine, butylamine, ethylene~ mine, triethanolamine, propylamine, dipropylamine, diethanolamine, monoethanolamine, isobutylamine, diisopropylamine, tert-butylamine, dibutylamine, diisobutylamine,tributylamine, pentylamine, dipentylamine and combinations thereof. Buffer 5 solution may be selected from the group consisting of carbonate buffer, phosphate buffer, borate buffer, amine salt buffer and combinations thereof.
When the aqueous solution of hydroxide of alkaline metal, alkaline salt of organic or inorganic acid, or buffer solution are used as alkaline solution, the lower pH
of alkaline solution affects the acid-unstable compound which may be discolored or 0 degraded during stabilizing reaction. Also, the higher pH of the reaction solution requires longer water-washing time to obtain neutral inclusion complex of acid-unstable compound included in cyclodextrin and the yield is decreased due to partialy washing out the inclusion complex during the water-washing. Therefore, ~lk~line solution may be preferably used between pH 8.0 and 12Ø
In the case of independently using amine in alkaline solution, an amine water solution of 0.01 ~ 0.5M may be preferably used to form inclusion complex under stable condition and to reduce after-treatment time.
On the other hand, the above cyclodextrin in the present invention is preferably used in a ratio of 1 ~ 10 mole based on 1 mole of acid-unstable compound. If the 20 used amount of cyclodextrin is below 1.0 mole, unincluded acid-unstable compound is remain in excess of quantity, and if over 10 mole, the amount of acid-unstable compound in the obtained inclusion complex is decreased by existance of unreacted cyclodextrins.
In accordance with the present invention the clear solution obtained by the 25 above reaction is cooled to low temperature(4C ) and maintained for 3 ~ 15 hours at that temperature to afford the desired inclusion complex formation as microcrystalline powder. The cooling of reaction mixture to give inclusion complex must be very carefully observed to see how the crystalline deposit is forrned. If the treating time is below 3hours, inclusion complex is not sufficiently deposited, and if over 15 hours, 30 the productivity of desired product is decreased and the inclusion complex may be WO 93/13138 ~127 1 11 PCI/KR92/00083 discolored in the reacted solution.
The obtained inclusion complex is washed with some cooled-water several times to completely remove the remaining alkaline component on the inclusion complex, and then the refined complex of nutrality is obtained. Otherwise, the 5 reacted solution may be purified by spray drying, freeze drying, vacuum evaporating or recrystalline method to obtain a refined inclusion complex power as stable compound, and at this time the refining procss may be carried out as per prior art according to ~lupGl~ies of solusion system, namely kind of solution.
The above inclusion complex obtained by the present invention is to obviously o improve storage stability of compound itself, and simultaneously to entirely m~int~in the stability during formulating process and in gastric juice with excellent dissolution and absorption properties. In the stabilized inclusion complex, there is no alk~line component, because the alkaline solution according to the present invention was only used as reacting solution in the stabilizing process. This process is different in the 5 used art and objective because the core material obtained is free from alkali component common with prior art.
In the formulation of pharmaceutical preparation containing the inclusion complex of the present invention in the form of dosage units for oral a-lmini~tration, the above inclusion complex may be mixed with excipients such as microcrystalline 20 cellulose, starch, m~nitol, etc., disintegrants such as sodium starch glycolate, etc. and lubricants such as magnesium stearate. The mixture is then pressed into tablets including active component, for example omeprazole of 20mg per tablet. The prepared tablets may be coated with a watersoluble substance selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylidone 25 and polyvinylalcohol, and thereafter coated with an enteric-coating agent selected from the group consisting of hydroxypropylmethyl cellulose phth~l~te., celluloseacetate phth~l~te and metacrylic acid-methyl metacrylate copolymer, which is mixed with plasticizer in organic solvent.
The enteric-coated oral drugs formulated according to the present invention may ~0 be, as stabilized preparation including acid-unstable compound as active component, WO 93/13138 PCI~/KR92/00083 21~7 lll : 8 ~
therapeutically ~lmini~trated for the treatment of gastrointestinal disorders. The process described herein is successful in improving stability of acid-unstable compounds against acid, improves dissolution properties and improve preservability.
Especially in case of omeprazole, this process entirely resolves the problems related to 5 stability.
The followings illustrate a preferred embodiment of the present invention without being limited thereto.
Preparing Example 1 : Buffer Solution(Phosphate) To prepare an alkaline solution for stabilizing acid-unstable compound, 0.1M
NaOH was added in 500ml of 0.1M KH2PO4 as following Table 1.
Those solutions were diluted with water to obtain phosphate buffer solutions of each 1000ml. Each pH of the resulted buffer solutions was measured to be selectively 5 used for an alkaline solution.
Table 1.
PreparingEx. 1 0.1M NaOH (ml ) pH
1 - 1 224 6.8 1 - 2 291 7.0 1 - 3 347 7.2 1 - 4 391 7.4 1 - 5 428 7.6 1 - 6 453 7.8 1 - 7 467 8.0 WO 93/13138 PCr/KR92/00083 29127111`,~t Preparin~Example 2: Buffer Solution(Borate) 0.1M NaOH was added in 500ml of 0.1M H3BO3-KCl to obtain borate buffer 5 solutions according to the above Preparing Example 1 as following Table 2. Each pH
of the resulted buffer solutions was measured to be selectivly used for an alkaline solution.
0 Table 2.
Preparing Ex. 2 0.1M NaOH (mt ) pH
2- 1 39 8.0 2 - 2 60 8.2 2 - 3 86 8.4 2 - 4 118 8.6 2 - 5 158 8.8 2 - 6 208 9.0 2 - 7 264 9.2 2- 8 321 9.4 2 - 9 369 9.6 2- 10 406 9.8 2 - 11 437 10.0 2- 12 462 10.2 ~0 W O 93/13138 PC~r/KR92/00083 21271~ lo Preparin~Example 3: Tris Buffer Solution O.lM HCl was added in 500ml of O.lM tris(hydroxymethyl) amino methane to 5 obtain amine salt buffer solutions according to the above Preparing Example 1 as following Table 3. Each pH of the resulted buffer solutions was measured to be selectivly used for an aLkaline solution.
o Table 3.
Preparing Ex. 3 O.lM HCl (ml ) pH
A METHOD FOR PREPARING ENTERIC-COATED ORAL DRUGS
CONTAINING ACID-UNSTABLE COMPOUNDS
BACKGROUND OF THE INVENTION
The present invention relates to a method for preparing enteric-coated oral drugs containing acid-unstable compounds, in particular an enteric-coated oral drug prepared in the form of acid-stable dosage units as inclusion complex formed by reacting benzimidazole derivative, acid-unstable compound, with cyclodextrin in alk~line solution.
o Acid-unstable compounds, especially the benzimidazole compounds, are easily discolored and degraded under acidic and neutral conditions. For example, omeprazole, a ben7.imifl~7ole derivative, has half-life of 10 minutes in medium of below pH 4, but 18 hours at pH 6.8 and about 300 days at pH 11. Omeprazole has been reported to be stable in alkaline condition [Pilbrant A and Cederberg C. Scand. J.
s Gastroenterology, S uppl. 108, 113- 120(1985)] . The acid-unstable compounds when exposed to the environment also get discolored and degraded by getting in contact with moisture and organic solvents. In therapeutically using the acid-unstable compounds, omeprazole and ben7imitl~7Ole derivatives, which show a powerful inhibitory actions against secretion of gastricjuice and can be used for the treatment of gastric and duodenal ulcers, it is very important that an oral dosage form of them must be protected from the acidic gastricjuice in order to be absorbed in small intestinal withoutdegradation. Methods for stabilizing the acid-unstable compound, in particular omeprazole has been known to be as follows; Omeprazole is combined with alkalinesalt such as Na+, K+, Mg~2, Ca~2 and so on to maintain the stability for compound itself. PCT Publication No. 86-00913(PCT/EP 85/00371) discloses to form a stablecomplex by mixing and reacting omeprazole with ~ -cyclodextrin in 96% ethanol and cooling the reactant.
The latter process seems to have the problem as the reaction is conducted at a temperature 25 ~ 38C for 15 hours in ethanol, during the reaction itself omeprazole ~o can get discolored and degraded. Furthermore, it is difficult to e~cpect the formation 2 1 2 7 1 1 1 Pcr/KRg2/00083 2 ~
of inclusion compound because both omeprazole and cyclodextIin are dispersed in the reaction as solid particles, not dissolved. For forming an inclusion compound ofcyclodextIin, the reaction must be carried out in presence of water molecules [K. Hara, H. Hashimoto, J. Jpn. Soc. Starch. Sci., 32(2) 152-161(1986)]. Therefore, the latter 5 method not expected to give inclusion compound since the above reacting condition has not been considered.
On the other hand, Une~c,.mined Korean Patent No. 87-9718 and Korean Patent Publication No. 91-4579 disclose processes for preparing omeprazole preparation consisting of mixing omeprazole with ~lk~lin~ substance to form core material, forming o a watersoluble internal layer on the core and forming an enteric coating to stabilize omeprazole.
It has, however, been found that the stabilizing methods known in the Korean Patents have several problems as followings; The process for prepaIing core material and forming enteric-coating is very complicated. The stabilized omeprazole is 5 discolored and degraded during stay in stomach after oral aflmini~tration, because gastIic juice passes through the enteric-coating to partially dissolve the watersoluble internal layer and then infiltrated into the core to dissolve the alkaline substance partially destroying the enteric-coating. The stability of omeprazole by this process is not secured concretely. For formulating omeprazole, it is necessary to give good20 attention to omeprazole itself. For example, it must be kept at below -20C of low temperature and immediately used for formulating after removing moisture, or immediately after synthesis, to maintain the starting stability.
After all, for stabilizing the acid-unstable compound a primary factor is not only to secure the stability of preperation but also to stabilize the compound itself. Thus 25 the attempt to stabilize acid-unstable compound must take into account the stability of the compound during the stablization process, its stability against gastric juice and the need to quickly and completely dissolve are made the available main drug for absorption in the intestine.
As discussed above most of the previously described methods are either very 3û partialy successful in stabilization or the stable inclusion compound is not produced at WO 93/13138 PCl/KR92/00083 ~ 2127111 all conjugation attempt to add ~lk~line salt to omeprazole have also been unsatisfactory.
SU~IMARY OF THE INVENTION
The object of the present invention is to obtain oral drugs of acid-unstable 5 compound, having excellent storage stability, dissolution and absorption properties after oral ~clmini~tration and a simplified manufacturing process principally involving formation of inclusion complex by reacting the acid-unstable compound with cyclodextrin to give stabilized compound.
The present invention is a method for preparing enteric-coated oral drugs by o using cyclodextrin to stabilize acid-unstable compound, characterized in which acid-unstable compound is reacted with cyclodextrin of 1 ~ 10 mole based on lmole of acid-unstable compound in an alkaline solution to obtain inclusion complex without existance of alk~line substance.
i 5 DETAILED DESCRIPTION OF THE INVENTION
The present invention is accomplished by using a new solution system, instead of organic solvent such as ethanol used in prior art, in which acid-unstable compound is reacted with cyclodextrin for stabilizing. The ~lk?line solution used in the present invention performs a dirrGlGnt function from ~lk~linc solvent in prior art. As a result 20 the inclusion complex obtained by the present invention dose not include the aLkaline components.
According to the present invention when acid-unstable compound is reacted with cyclodextrin in ~lk~line solution, the reaction is carried out under homogeneous solution system for 1 ~ 30 mins at 40 ~ 70C, and after cooling to room temperature the 25 reacted solution is allowed to stand at 4C to deposit inclusion complex. The reactant is filtered to remove residual alkaline component and to obtain pured stable inclusion complex as the desired product.
In the above reaction, if the temperature is below 40C, since the solubility ofcyclodextrin is decreased and an excessive of alkaline solution is ntoe~ the reation ~o scale becomes unnecessarily large and the yield is decreased, and if the reaction temperature is more than 70C, acid-unstable compound may be discolored or degraded.
Furthermore, under the condition if the reaction time is below 1 min, acid-unstable compound and cyclodextrin not are entirely dissolved in the ~lk~line solution,5 and if the reaction time over 30 mins, acid-unstable compound is also discolored and degraded.
In the present invention, ben7imid~7ole derivative having the following structural formula(I) and pharmaceutically acceptable salt thereof, especially omeprazole and its sodium salt, is preferably used as acid-unstable compound.
o R3 R~ ~N~ S -- CH, $~
H
Wherein, R~ is selected from the group consisting of hydrogen atom, methoxy, trifluoromethyl and tetrafluoroethoxy group;
R2 is selected from the group consisting of hydrogen atom, methylamine and dimethylamine group;
R3 is selected from the group consisting of hydrogen atom, methoxy, aryloxy and propagyloxy group; and R4 is hydrogen atom or methyl group.
A pharmaceutical preparation containing said acid-unstable compounds in pharmaceutically effective amount may be prepared by the present invention in form of dosage units for oral administration such as tablets, granules, capsules, spherical pellets, - microgranules, or microcapsules.
According to the present invention, acid-unstable compound is reacted with cyclodextrin structurally having hydrophobic cavity of a defined size, and at this time an inclusion complex is obtained because of the property of cyclodextrin to protect hydrophobic compounds from outside by entrapping them into the cavity.
,WO 93/13138 21% 7 111 PCI/KR92/00083 Cyclodextrin may be prepared by resolving starch with cyclodextrin glycosyltransferase and are classified according to the properties and size shown as following Table A.
In accordance with the present invention, a cyclodextrin(CD) selected from the group consisting of ~ - and y -cyclodextrin, and cyclodextrin derivatives such as methyl-5 ,~ -cyclodextrin, hydroxyethyl ~ -cyclodextrin, hydroxypropyl a-cyclodextrin, hydroxypropyl ~ -cyclodextrin, hydroxypropyl y -cyclodextrin, etc. may be used.
Table A. Comparison of Properties for Natural Cyclodextrins o Properties a -CD ~ -CD y -CD
A Number of Glucose Units 6 7 8 ~[olecular Weight 973 1135 1297 Solubility in 25C Water (g/lOOml) 14.5 1.85 23.2 CavityDiameter(A ) 4.7-5.3 6.0-6.5 7.5-8.3 Ring-opening Half-life (h) * 6.2 5.4 3.0 * (Note) Ring-opening half-life was measured under the condition of 60C ,lN HCl.
In the present invention, to obtain stable inclusion complex powder, the used alkaline solution is a aqueous solution of one selected from the group consisting of hydroxides of ~lk~line metal, ~lk~line salts of organic or inorganic acid, amines, buffers and combinations thereof.
The alkaline compounds in the present invention as alkaline aqueous solution 25 may be typically illustrated as followings: Hydroxide of :~lk~line metal may be selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide and combinations thereof. Alkaline salt may be selected from the group consisting of sodium borate, sodium carbonate, sodium phosphate, potassium borate, potassium carbonate, potassium phosphate, sodium ~o acetate, sodium citrate and combinations thereof. Amines may be selected from the WO 93/13138 212 7111 PCr/KR92/00083 group consisting of diethylamine, triethylamine, butylamine, ethylene~ mine, triethanolamine, propylamine, dipropylamine, diethanolamine, monoethanolamine, isobutylamine, diisopropylamine, tert-butylamine, dibutylamine, diisobutylamine,tributylamine, pentylamine, dipentylamine and combinations thereof. Buffer 5 solution may be selected from the group consisting of carbonate buffer, phosphate buffer, borate buffer, amine salt buffer and combinations thereof.
When the aqueous solution of hydroxide of alkaline metal, alkaline salt of organic or inorganic acid, or buffer solution are used as alkaline solution, the lower pH
of alkaline solution affects the acid-unstable compound which may be discolored or 0 degraded during stabilizing reaction. Also, the higher pH of the reaction solution requires longer water-washing time to obtain neutral inclusion complex of acid-unstable compound included in cyclodextrin and the yield is decreased due to partialy washing out the inclusion complex during the water-washing. Therefore, ~lk~line solution may be preferably used between pH 8.0 and 12Ø
In the case of independently using amine in alkaline solution, an amine water solution of 0.01 ~ 0.5M may be preferably used to form inclusion complex under stable condition and to reduce after-treatment time.
On the other hand, the above cyclodextrin in the present invention is preferably used in a ratio of 1 ~ 10 mole based on 1 mole of acid-unstable compound. If the 20 used amount of cyclodextrin is below 1.0 mole, unincluded acid-unstable compound is remain in excess of quantity, and if over 10 mole, the amount of acid-unstable compound in the obtained inclusion complex is decreased by existance of unreacted cyclodextrins.
In accordance with the present invention the clear solution obtained by the 25 above reaction is cooled to low temperature(4C ) and maintained for 3 ~ 15 hours at that temperature to afford the desired inclusion complex formation as microcrystalline powder. The cooling of reaction mixture to give inclusion complex must be very carefully observed to see how the crystalline deposit is forrned. If the treating time is below 3hours, inclusion complex is not sufficiently deposited, and if over 15 hours, 30 the productivity of desired product is decreased and the inclusion complex may be WO 93/13138 ~127 1 11 PCI/KR92/00083 discolored in the reacted solution.
The obtained inclusion complex is washed with some cooled-water several times to completely remove the remaining alkaline component on the inclusion complex, and then the refined complex of nutrality is obtained. Otherwise, the 5 reacted solution may be purified by spray drying, freeze drying, vacuum evaporating or recrystalline method to obtain a refined inclusion complex power as stable compound, and at this time the refining procss may be carried out as per prior art according to ~lupGl~ies of solusion system, namely kind of solution.
The above inclusion complex obtained by the present invention is to obviously o improve storage stability of compound itself, and simultaneously to entirely m~int~in the stability during formulating process and in gastric juice with excellent dissolution and absorption properties. In the stabilized inclusion complex, there is no alk~line component, because the alkaline solution according to the present invention was only used as reacting solution in the stabilizing process. This process is different in the 5 used art and objective because the core material obtained is free from alkali component common with prior art.
In the formulation of pharmaceutical preparation containing the inclusion complex of the present invention in the form of dosage units for oral a-lmini~tration, the above inclusion complex may be mixed with excipients such as microcrystalline 20 cellulose, starch, m~nitol, etc., disintegrants such as sodium starch glycolate, etc. and lubricants such as magnesium stearate. The mixture is then pressed into tablets including active component, for example omeprazole of 20mg per tablet. The prepared tablets may be coated with a watersoluble substance selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylidone 25 and polyvinylalcohol, and thereafter coated with an enteric-coating agent selected from the group consisting of hydroxypropylmethyl cellulose phth~l~te., celluloseacetate phth~l~te and metacrylic acid-methyl metacrylate copolymer, which is mixed with plasticizer in organic solvent.
The enteric-coated oral drugs formulated according to the present invention may ~0 be, as stabilized preparation including acid-unstable compound as active component, WO 93/13138 PCI~/KR92/00083 21~7 lll : 8 ~
therapeutically ~lmini~trated for the treatment of gastrointestinal disorders. The process described herein is successful in improving stability of acid-unstable compounds against acid, improves dissolution properties and improve preservability.
Especially in case of omeprazole, this process entirely resolves the problems related to 5 stability.
The followings illustrate a preferred embodiment of the present invention without being limited thereto.
Preparing Example 1 : Buffer Solution(Phosphate) To prepare an alkaline solution for stabilizing acid-unstable compound, 0.1M
NaOH was added in 500ml of 0.1M KH2PO4 as following Table 1.
Those solutions were diluted with water to obtain phosphate buffer solutions of each 1000ml. Each pH of the resulted buffer solutions was measured to be selectively 5 used for an alkaline solution.
Table 1.
PreparingEx. 1 0.1M NaOH (ml ) pH
1 - 1 224 6.8 1 - 2 291 7.0 1 - 3 347 7.2 1 - 4 391 7.4 1 - 5 428 7.6 1 - 6 453 7.8 1 - 7 467 8.0 WO 93/13138 PCr/KR92/00083 29127111`,~t Preparin~Example 2: Buffer Solution(Borate) 0.1M NaOH was added in 500ml of 0.1M H3BO3-KCl to obtain borate buffer 5 solutions according to the above Preparing Example 1 as following Table 2. Each pH
of the resulted buffer solutions was measured to be selectivly used for an alkaline solution.
0 Table 2.
Preparing Ex. 2 0.1M NaOH (mt ) pH
2- 1 39 8.0 2 - 2 60 8.2 2 - 3 86 8.4 2 - 4 118 8.6 2 - 5 158 8.8 2 - 6 208 9.0 2 - 7 264 9.2 2- 8 321 9.4 2 - 9 369 9.6 2- 10 406 9.8 2 - 11 437 10.0 2- 12 462 10.2 ~0 W O 93/13138 PC~r/KR92/00083 21271~ lo Preparin~Example 3: Tris Buffer Solution O.lM HCl was added in 500ml of O.lM tris(hydroxymethyl) amino methane to 5 obtain amine salt buffer solutions according to the above Preparing Example 1 as following Table 3. Each pH of the resulted buffer solutions was measured to be selectivly used for an aLkaline solution.
o Table 3.
Preparing Ex. 3 O.lM HCl (ml ) pH
3 - 1 466 7.0 3 - 2 447 7.2 3 - 3 420 7.4 3 - 4 385 7.6 3 - 5 345 7.8 3 - 6 292 8.0 3 - 7 229 8.2 3 - 8 172 8.4 3 - 9 124 8.6 3- 10 85 8.8 3 - 11 57 9.0 WO 93/13138 212 71~ ~ PCI/KR92/00083 Preparing Example 4: Buffer Solution (Borate) O.lM HCl was added in 500ml of 0.025M Na2B4O7 to obtain borate buffer 5 solutions according to the above Preparing Example 1 as following Table 4. Each pH
of the resulted buffer solutions was measured to be selectivly used for an alkaline solution.
Table 4.
Preparing Ex. 4 O.lM HCl (ml ) pH
of the resulted buffer solutions was measured to be selectivly used for an alkaline solution.
Table 4.
Preparing Ex. 4 O.lM HCl (ml ) pH
4 - 1 205 8.0 4 - 2 188 8.2 4 - 3 166 8.4 4 - 4 135 8.6 4 - 5 94 8.8 4 - 6 46 9.0 Preparing Example 5: Buffer Solution (Borate) 0.1M NaOH was added in 500ml of 0.025M Na2B4O7 to obtain borate buffer 5 solutions according to the above Preparing Example 1 as following Table 5. Each pH
of the resulted buffer solutions was measured to be selectivly used for an alkaline solution.
o Table 5.
PreparingEx.5 0.1MNaOH (ml) pH
5 - 1 9 9.2 5 - 2 62 9.4 5 - 3 111 9.6 5 - 4 150 9.8 5 - 5 183 10.0 5 - 6 205 10.2 5 - 7 221 10.4 5 - 8 233 10.6 5 - 9 242.5 10.8 13 ~ - -PreparingExample 6: Buffer Solution (Carbonate) 0. lM NaOH was added in 500ml of 0.05M NaHCO3 to obtain carbonate buffer 5 solutions according to the above Preparing Example 1 as following Table 6. Each pH
of the resulted buffer solutions was measured to be selectivly used for an alkaline solution.
Table 6.
PreparingEx. 6 0.1M NaOH (ml ) pH
of the resulted buffer solutions was measured to be selectivly used for an alkaline solution.
o Table 5.
PreparingEx.5 0.1MNaOH (ml) pH
5 - 1 9 9.2 5 - 2 62 9.4 5 - 3 111 9.6 5 - 4 150 9.8 5 - 5 183 10.0 5 - 6 205 10.2 5 - 7 221 10.4 5 - 8 233 10.6 5 - 9 242.5 10.8 13 ~ - -PreparingExample 6: Buffer Solution (Carbonate) 0. lM NaOH was added in 500ml of 0.05M NaHCO3 to obtain carbonate buffer 5 solutions according to the above Preparing Example 1 as following Table 6. Each pH
of the resulted buffer solutions was measured to be selectivly used for an alkaline solution.
Table 6.
PreparingEx. 6 0.1M NaOH (ml ) pH
6 - 1 50 9.6 6 - 2 76 9.8 6 - 3 107 10.0 6 - 4 138 10.2 6 - 5 16~ 10.4 6 - 6 191 10.6 6 - 7 212 10.8 6 - 8 227 11.0 212711~` .l 14 ~
PreparingExample 7: Buffer Solution(Phosphate) 0.1M NaOH was added in 500ml of 0.05M Na2HPO4 to obtain phosphate buffer 5 solutions according to the above Preparing Example 1 as following Table 7. Each pH
of the resulted buffer solutions was measured to be selectivly used for an alkaline solution.
o Table 7.
PreparingEx.7 0.1MNaOH (ml) pH
PreparingExample 7: Buffer Solution(Phosphate) 0.1M NaOH was added in 500ml of 0.05M Na2HPO4 to obtain phosphate buffer 5 solutions according to the above Preparing Example 1 as following Table 7. Each pH
of the resulted buffer solutions was measured to be selectivly used for an alkaline solution.
o Table 7.
PreparingEx.7 0.1MNaOH (ml) pH
7 - 1 41 1 1.0 7 - 2 63 11.2 7 - 3 91 11.4 7 - 4 13~ 11.6 7 - 5 194 11.8 7 - 6 269 12.0 ~212~11.~
PreparingExample 8: Buffer Solution(Chlorate) 0.2M NaOH was added in 250ml of 0.2M KCl to obtain chlorate buffer 5 solutions according to the above Preparing Example 1 as following Table 8. Each pH
of the resulted buffer solutions was measured to be selectivly used for an alkaline solution.
Table 8.
1 o PreparingEx. 80.2M NaOH (ml ) pH
8 - 1 60 12.0 8 - 2 102 12.2 8 - 3 162 12.4 8 - 4 256 12.6 8 - 5 412 12.8 8 - 6 660 13.0 The obtained buffer solutions may be preferably used in range of pH 8.0 ~ 12.0 for aLkaline solution, and hydroxides of ~lk~line metal or aLkaline salt of organic or inorganic salt may be also used by adjusting to range of pH 8.0 ~ 12Ø
But, it is necessary for amines to define the preferable range of ~lk~line solution - 25 by molarity. According to the present invention, water-soluble or water-miscible amines shown on following Table 9, preferably 0.01 ~ 0.5M amines, may be preferably used, but methylamine, dimethyl amine, trimethylamine, ethylamine, isopropylamine, etc. were excluded from studies because of having low boiling point.
~0 212711i 16 Table 9.
Amines b.p. (C ) pKa Diethylamine 55.5 10.98 Triethylamine 89 - 90 11.01 Butylamine 77 10.77 Ethylçnçfli~minç 116 - 117 10.71 o Triethanolamine 335.4 9 50 Propylamine 48 - 49 10.57 Dipropylamine 110 11.0 Diethanolamine 268.8 8.88 Monoethanolamine 170.8 9.50 Isobutylarnine 68 - 69 10.42 Diisopropylamine 83.5 11.05 Tert-butylamine 43.6 10.87 Dibutylamine 159.6 11.31 Diisobutylamine 136- 140 10.5 Tributylamine 91 - 92 (9mmHg) 10.87 Pentylamine 104 10.63 Dipentylamine 91 - 93(14mmHg) 11.18 ~ 2712711l Example 1 ,~ -Cyclodextrin of 24g was dissolved in each 900ml of buffer solutions according to following Table 10 at 40~, and 3.4g omeprazole was added in the solution under stirring to react for lS mins.
The reactant was concentrated to lOOml in vacuum evaporator, and after cooling to room temperature, it was left for 6 hrs in a refrigerator to deposit inclusion complex.
The filtered inclusion complex was washed with water several times and dried under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex.
o The result of reaction and an amount of the obtained inclusion complex were shown as following Table 10.
Table 10.
Inclusion Complex Example 1 BuffersolutionpH
Color Amount 1 - A PreparingEx. 1-27.0 + 24.2 1 - B PreparingEx. 2-18.0 + 24.9 1 - C PreparingEx. 2-69.0 - 25.9 1 - D PreparingEx.2-1110.0 - 26.2 1 - E PreparingEx. 6-811.0 - 26.0 1 - F PreparingEx. 7-612.0 - 25.3 1 - G PreparingEx. 8-613.0 - 24.5 (Note) - : Non discoloration + : Light-violet color As the result shown in Table 10, it was found that when pH is low the inclusion complex is discolored to light-violet color, and when pH is high the obtained amount of inclusion complex is decreased due to washing with excess water. Therefore a buffer solution was preferably selected between pH 8.0 and pH 12.0 for an ~lk~line solution.
Example 2 ~ -Cyclodextrin of 24g was dissolved in each 900ml of buffer solutions(pH
PreparingExample 8: Buffer Solution(Chlorate) 0.2M NaOH was added in 250ml of 0.2M KCl to obtain chlorate buffer 5 solutions according to the above Preparing Example 1 as following Table 8. Each pH
of the resulted buffer solutions was measured to be selectivly used for an alkaline solution.
Table 8.
1 o PreparingEx. 80.2M NaOH (ml ) pH
8 - 1 60 12.0 8 - 2 102 12.2 8 - 3 162 12.4 8 - 4 256 12.6 8 - 5 412 12.8 8 - 6 660 13.0 The obtained buffer solutions may be preferably used in range of pH 8.0 ~ 12.0 for aLkaline solution, and hydroxides of ~lk~line metal or aLkaline salt of organic or inorganic salt may be also used by adjusting to range of pH 8.0 ~ 12Ø
But, it is necessary for amines to define the preferable range of ~lk~line solution - 25 by molarity. According to the present invention, water-soluble or water-miscible amines shown on following Table 9, preferably 0.01 ~ 0.5M amines, may be preferably used, but methylamine, dimethyl amine, trimethylamine, ethylamine, isopropylamine, etc. were excluded from studies because of having low boiling point.
~0 212711i 16 Table 9.
Amines b.p. (C ) pKa Diethylamine 55.5 10.98 Triethylamine 89 - 90 11.01 Butylamine 77 10.77 Ethylçnçfli~minç 116 - 117 10.71 o Triethanolamine 335.4 9 50 Propylamine 48 - 49 10.57 Dipropylamine 110 11.0 Diethanolamine 268.8 8.88 Monoethanolamine 170.8 9.50 Isobutylarnine 68 - 69 10.42 Diisopropylamine 83.5 11.05 Tert-butylamine 43.6 10.87 Dibutylamine 159.6 11.31 Diisobutylamine 136- 140 10.5 Tributylamine 91 - 92 (9mmHg) 10.87 Pentylamine 104 10.63 Dipentylamine 91 - 93(14mmHg) 11.18 ~ 2712711l Example 1 ,~ -Cyclodextrin of 24g was dissolved in each 900ml of buffer solutions according to following Table 10 at 40~, and 3.4g omeprazole was added in the solution under stirring to react for lS mins.
The reactant was concentrated to lOOml in vacuum evaporator, and after cooling to room temperature, it was left for 6 hrs in a refrigerator to deposit inclusion complex.
The filtered inclusion complex was washed with water several times and dried under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex.
o The result of reaction and an amount of the obtained inclusion complex were shown as following Table 10.
Table 10.
Inclusion Complex Example 1 BuffersolutionpH
Color Amount 1 - A PreparingEx. 1-27.0 + 24.2 1 - B PreparingEx. 2-18.0 + 24.9 1 - C PreparingEx. 2-69.0 - 25.9 1 - D PreparingEx.2-1110.0 - 26.2 1 - E PreparingEx. 6-811.0 - 26.0 1 - F PreparingEx. 7-612.0 - 25.3 1 - G PreparingEx. 8-613.0 - 24.5 (Note) - : Non discoloration + : Light-violet color As the result shown in Table 10, it was found that when pH is low the inclusion complex is discolored to light-violet color, and when pH is high the obtained amount of inclusion complex is decreased due to washing with excess water. Therefore a buffer solution was preferably selected between pH 8.0 and pH 12.0 for an ~lk~line solution.
Example 2 ~ -Cyclodextrin of 24g was dissolved in each 900ml of buffer solutions(pH
9.0, pH 10.0, pH 11.0) according to following Table 11 at 40C, and 3.4g omeprazole was added in the solution under stirring to react for 15 mins.
o The reactant was concentrated to lOOm~ in vacuum evaporator, and after cooling to room ~ e-~ture, it was left for 6 hrs in a refrigerator to deposit inclusion complex. The filtered inclusion complex was washed with water several times and dried under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex.
The results of reaction were shown as following Table 11.
Table 11.
Example 1Buffersolution pH Colorof Rateof Inclusion Complex Inclusion(%) 2 - A PreparingEx. 2-6 9.0 - 89.0 2 - B PreparingEx.3-11 9.0 - 91.2 2 - CP~c;~ua ing Ex. 4-6 9.0 - 90.1 252 - D PreparingEx.2-11 10.0 - 98.6 2 - E PreparingEx.5-5 10.0 - 99.1 2 - F PreparingEx. 6-3 10.0 - 98.9 2 - G PreparingEx.6-8 11.0 - 99.2 2 - H ~ingEx. 7-1 11.0 - 98.8 (Note) - : Nondiscoloration As the result shown in Table 11, it is was found that when pH of buffer solutionis the same the effectiveness of inclusion is not influenced by kind of buffer solution, and when it is more than pH 10 the rate of inclusion was higher than 98.6%.
Example 3 ~ -Cyclodextrins according to following Table 12 were respectively dissolved in 900ml of buffer solutions(pH 10.0) prepared by the above Preparing Example 2-11 to add omeprazole, and then the reaction temperature was changed to 40C, 50C ,60C
o ,and 70C as the reaction being carried out for 15 mins.
The reactant was concentrated to 100ml in vacuum evaporator, and after cooling to room temperature, it was left for 6 hrs in a refrigerator to deposit inclusion complex. The filtered inclusion complex was washed with water on several times and dried under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex.
5 The results of reaction were shown as following Table 12.
Table 12.
Example 3 Reaction Amount of Amount of Color of Rate of Temp.(C ) ~ -CD (g) Omeprazole(g) Inclusion complex Inclusion(%) 3 - A 40 24.0 3.4 - 98.6 3 - B 50 54.0 8.2 - 98.8 3 - C 60 85.0 12.9 - 99.0 3 - D 70 135.0 20.5 - 98.0 30 (Note) - : Non discoloration -CD: ,~ -cyclodextrin WO 93/13138 PCr/KR92/00083 21~7111- 20 Example 4 ~ -Cyclodextrines according to following Table 13 were respectively dissolved in 900mZ of buffer solution(pH 10.0) prepared by the above Preparing Example 2-11 at 5 50DC, and omeprazole was added in the solution under stirring to react for 15 mins.
The reactant was concentrated to 100ml in vacuum evaporator, and after cooling to room lel,lyeldture, it was left for 6 hrs in a refrigerator to deposit inclusion complex. The filtered inclusion complex was washed with water on several times and dried under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex.
o The results of reaction were shown as following Table 13.
Table 13.
Example 4 Kind of CDAmount of Amount of Rate of CD(g) Omeprazole(g) Inclusion(%) 4 - A ~-CD 4.2 5.9 97.2 4 - B HP-~-CD 1.8 0.25 9g.0 4- C ~ -CD 54.0 8.2 98.8 4 - D Hp-~B -CD 1.5 0.17 99.2 4 - E HE~ -CD 1.95 0.23 99.0 4 - F M-~ -CD 2.4 0.3 98.5 4 - G y -CD 7.0 0.74 99.1 4 - H HP-y-CD 2.4 0.25 99.0 (Note) CD : Cycloc~exh in HP: Hydroxypropyl HE: Hydroxyethyl M: Methyl ~o ,WO 93/13138 PCI/KR92/00083 21~ 2127 Example 5 ~ -cyclodextrin of 54g was dissolved in each 900ml of O.lM amine aqueous sollltion~ according to following Table 9 at 50C, and 8.2g omeprazole was added in 5 the solution under stirring to react for 15 mins.
The reactant was cooled to room temperature and/or concentrated to lOOml in vacuum evaporator, and it was left for 6 hrs in a refrigerator to deposit inclusion complex.
The filtered inclusion complex was washed with water several times and dried o under reduced pressure to obtain omepr~. ~)le-cyclodextrin inclusion complex. The results of reaction were shown as following Table 14.
~1~7~ 22 Table 14.
Example 5Kind of Amine Deposition Method Rate of Inclusion(%) 5 - ADiethylamine Cool 89.2 5 - BTriethylamine Cool/Conc. 95.7 5 - C Propylamine Cool 90.3 5 - DDipropylamine Conc. 98.0 5 - EIsobutylamine Cool 89.7 o 5 - FDiisopropylamine CooVConc. 92.3 5 - G Butylamine Cool 96.7 S - HEthylenç~ mine Conc. 97.1 5 - IMonoethanolamine Conc. 98.9 5 - JDiethanolamine Conc. 99.1 5 - KTriethanolamine Conc. 99.1 5 - LTert-butylamine Cool 89.0 5 - MDibutylamine Conc. 97.3 S - NDiisobutylamine Conc. 96.8 5 - OTributylamine Conc. 98.3 5 - P Pentylamine Conc. 98.7 S - QDipentylamine Conc. 99.3 (Note) Cool: Cooling to room temperature Conc.: Concentrating in vacuum evaporator ~o Example 6 According to following Table 15, ~ -cyclodextrin was dissolved in 900ml water, and on the other hand omeprazole was dissolved in 40% (v/v) triethylamine5 aqueous solution to obtain 27% solution. The resulted omeprazole solution was dropwise added in cyclodextrin aqueous solution.
The reactant was cooled to room temperature, and left for 6 hrs in a refrigerator to deposit inclusion complex.
The filtered inclusion complex was washed with water several times and dried 0 under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex. The resul~s of reaction were shown as following Table 15.
Table 15.
Example 6 ReactionAmount of Amount of Rate of Temp. (C )~ -CD(g) Omeprazole (g) Inclusion (%) 6 - A 40 24.0 3.4 99.5 6 - B 50 54.0 8.2 99.1 6- C 60 85.0 12.9 98.1 6 - D 70 135.0 20.5 98.5 WO 93/13138 PCl/KR92/00083 212~1ii 24 ~
Example 7 24g ~ -cyclodextrin was dissolved in 900ml of pH 12 aqueous solutions of hydroxide of ~lk~line metals according to following Table 16, and 3.4g omeprazole was 5 added in this solution under stirring to react for 15 mins.
The reactant was concentrated to 100ml in vacuum evaporator, and after cooling to room tempelalu,~, it was left for 6 hrs in a refrigerator to deposit inclusion complex.
The filtered inclusion complex was washed with water several times and dried 0 under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex. The results of reaction were shown as following Table 16.
Table 16.
Example 7 Kind of Reaction Amount of Amount of Rate of Hydroxide Temp.(~C ) ,B -CD (g) Omeprazole(g) Inclll~ion(%) 7 - A NaOH 40 24.0 3.4 99.3 7 - B KOH 40 24.0 3.4 99.1 7- C Ca(OH)2 40 24.0 3.4 98.8 7 - D Ba(OH)2 40 24.0 3.4 98.7 ~o Example 8 This experiment was conducted in same manner as previous Example 7 except that the other alk~line salt solutions according to following Table 17 were used to 5 obtain omeprazole-dextrin inclusion complex.
The filtered inclusion complex was washed with water several times and dried under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex. The results of reaction were shown as following Table 17.
Table 17.
Example 8 Kind of pH Reaction Amount of Amount of Rate of ~lk~line salts Temp.(C) ~ -CD (g) Omeprazole(g) Inclusion(%) 8 - ANa2B407 10.0 40 24.0 3.4 99.2 8 - BK2B4O7 10.0 40 24.0 3.4 99.3 8 - CNa2CO3 10.0 40 24.0 3-4 99.8 8 - DK~CO3 10.0 40 24.0 3.4 99.5 8 - ENa2HPO4 10.0 40 24.0 3-4 99.1 8 - FK~HPO4 10.0 40 24.0 3.4 99.3 8 - GCH3COONa 8.5 40 24.0 3.4 98.7 8 - HSodium citrate 9.0 40 24.0 3.4 98.5 W O 93/13138 212 7 ~ ~ ~ i PC~r/KR92/00083 [ Methods for measuring rate of inclusion ]
Amount of omeprazole in the obtained inclusion complex (g) X 100 = Rate of inclusion(%) Amount of used omeprazole (g) The amount of omeprazole in the obtained inclusion complex was measured by o HPLC under following conditions.
Solvent: pH 9.8 Carbonate buffer solution: ethanol = 80: 20 Colllmn: ~ Bondapak C~8 3.9mm (the inside diameter) X 300mm (length) Mobile Phase: pH 7.6 Phosphate buffer solution: Aceto~ ile = 66: 34 Detection Wave-length: 302 nm 15 Injection Volum: 20f~1 nOw Rate: 1.0 ml/min Comparative Example 1 5.67g ~ -cyclodextrin and 1.73g omeprazole were added in 96% ethanol of 20 20 ml and stirred at 30 ~ 32C for 15 hrs.
After leaving at 10~C for 3hrs, the reacted solution was filtered, and washed with ethanol of l0C, dried under reduced pressure to obtain the desired product of reddish brown color. At this time the reactant solution was of purple color.
25 Comparative Example 2 2.0g Omeprazole was well mixed with 2.0g Na2HPO4, and the mixed compound was dried under reduced pressure to obtain the stabilized core of omeprazole preparation as a co,l".~ative sample.
~093/13138 2127111 PCI/KR92/00083 Comparative Example 3 This test was conducted in process of the above Comparative Example 2 except to use 2.0g omeprazole and 2.0g Mg(OH)2. The obtained core was used as a 5 co~ ~dtive sample.
Experimental Example 1 (Storage Stability of Inclusion Complex) To verify stabilized result for the above Example 1 to 8 and Comparative o Example 1 to 3, the change of appearance was surveyed with the passing of time under 4(~ 75% RH of accelarated condition. The results were shown on following Table 18.
Under the above condition, storage stability during 6 months means to secure stability for 3 years at normal condition. As the result of Table 18, it was confirmed 5 that the cases of Example 1 ~ 8 according to the present invention is obviously showing higher stability than the cases of Comparative Example 1 ~ 3.
~0 W O 93/13138 P~r/K W 2/00083 212711~ 28 Table 1 8.
The Change of Appearance Sample Start After lmonth After2months After4months After6months s Example 1-D
Example 2-B
Example 2-E - - - - -Example 2-G
Example 3-A - - - - -o Example 3-D
Example 4-A
Example 4-B
Example 4-D
Example 4-E
5 Example 4-F
Example 4-G
Example 4-H
Example 5-B - - - - -Example 5-I
20 Example 6-A
Example 6-D
Example 7-A
Example 8-C
Comp. Ex. 1 +++ ++ ++ ++
Comp. Ex. 2 - + + ++ ++
Comp. Ex. 3 - - + + +
(Note) - : Non discoloration + : Some discoloration + : Discoloration ++ : Deepdiscoloration ,WO 93/13138 ~12 7~1 PCr/KR92/00083 Formulation of Inçlusion Complex To forrnulate enteric-coated oral drugs, the omeprazole-cyclodextrin inclusion complexs obtained by Example 1 ~ 8 were used as followings.
5 [ Preparing of Uncoated Tablets ]
According to following Table 19, omeprazole of 20mg was homogeneousely mixed with excipients, disintegrants and lubricants, and the mixture was tableted to 230mg per unit by Rotary Tableting Machine.
Table 19.
(Unit: mg~
Mixed Example No.
Components Inclusion complex 165 165 165 165 165 165 165 165 Microcrystalline 42 40 30 30 23 20 20 20 cellulose Dibasic calcium 20 lS 10 S - S
phosphate Anhydrous Com starch - 7 22 27 24.7 20 12.7 Mannitol - - - - - 7.7 lS 27.7 So~ium starch - - - - lS 10 lS lS
glycolate Ma~nesium 3.0 3.0 3.0 3.0 2.3 2.3 2.3 2.3 stearate 2127~11 30 In the above, when microcrystalline cellulose and dibasic calcium phosphate anhydrous of an excess of quantity were used, hardness of tablets is excellent but disintegration rate was decreased. Therefore, microcrystalline cellulose of small s amount was preferably used, and at that time the used amount of corn starch and/or Mannitol were increased and minimum amount of dibasic calcium phosphate anhydrous was used.
[ Coating of Watersoluble Substance ]
According to following Table 20, a watersoluble substance was coated on o uncoated tablets.
Table 20.
(Unit : mg ) Components (Tl) (T2) (T3) (T4) (Ts) (T6) (T7) (T8) (T9) of Watersoluble Substance Hydroxy propylmethyl cellulose 10 9 9 9 9 9 - - -Hydroxypropyl cellulose - - - - - ~ 9 Polyvinylpynolidone - - - - - - - 9 Polyvinylalcohol - - - - - - - - 9 Propyleneglycol Polyethyleneglycol 600 Water 190 190 190 38 38 38 38 38 38 Ethanol - - - 152 152 152 152 152 152 -In the above tes~, when water was only used as solvent or excessive water was used, dry time in coating pan was pr~longed.
Since tablets were observed to stick with each other and rendering the coating 5 surface ununiform, ethanol, preferably 80% ethanol water solution, was used in this process as main solvent.
[ Coating of Enteric Substance 3 According to following Table 21, an enteric substance was coated on tablets o coated with watersoluble substance to obtain the desired enteric-coated oral drug.
Table 21.
Components of Enteric Substance a b c d e s Hydroxypropyl,-icll-yl ~elllllnse18.6 - - 18.6 phth,.l~te Cellulose acetate phsh~ t~ 18.6 - - 18.6 Eudragit L100 - - 18.0 Cetylalcohol 1.4 1.4 Myvacet 9-40T - - - 1.4 1.4 Dibutylph~h~l~te - - 2.0 Ace~one 152 190 152 152 190 Ethyl,.lcohol 228 190 - 228 190 Isopropy~ ohQl - - 228 WO93/13138 12 11 1 32 PCI~/KR92/00083 Experimental Example 2: Property Test for Oral Drugs The obtained inclusion complexs of Examples were used to formulate enteric-coated oral drugs. To survey the properties for the oral drugs, the watersoluble 5 substance according to the method of Table 20(Ts) was respectively coated on tablets prepared from Example 4-A, 5-I, 6-B, 7-A and 8-C, and there after the enteric substance according to the method of Table 21 "d" was coated on the above tablets.
The formulated oral drugs were compared with control product, Astra's LOSEC, to survey acid-resistance property, dissolution property, and storage stability 0 as followings.
[ Test for Acid-resi~t~nce Property ]
The formulated oral drugs were put into artificial gastric fluid [USP, 1st solution] without enzyme and stirred at 37~C by paddle at 100 rpm.
The test solution was left for 2hrs to survey the change of appearance, and the 5 omeprazole existing in preparation was measured by HPLC. The results were shown on following Table 22.
Table 22.
Testing SampleAmount of the The Change of Existing Omeprazole(%) Appearance Example 4-A 99.0 Non discoloration Example 5-I 99.1 "
Example 6-B 99.5 "
Exarnple 7-A 100.0 "
Example 8-C 99.2 "
Control (Losec) 96.7 Brown spots in pellets ~o 2127 11~ ~
The above test showed brown spots on 40 ~ 75% of pellets for the control(LOSEC), and it was also found that omeprazole content was decreased.
But, the oral drugs prepared according to examples were not affected in the 5 appearance and omeprazole content was scarcely decreased, thus giving superior characteristies .
[ Test for Dissolution Property ]
To survey the rate of dissolution in the small intestines, the formulated oral 0 drugs were added to simulated gastric fluid [USP, 37~C, 100 rpml.
After 2hrs, the above drugs were moved to simulate intestinal fluid [USP, dissolution apparatus No. 2, Paddle Method], and then the amount of dissolved omeprazole was determined by the method of HPLC. The results were shown on Table 23.
Table 23.
(Unit: %) Rate of Dissolution for Passing Time Testing Sample 10 min 20 min 30 min Example 4- A 85.9 97.6 99.2 Exarnple 5 - I 98.2 100.0 100.0 Example 6-B 90.3 98.0 99.5 Example 7 - A 98.5 99.7 100.0 Example 8 - C 98.0 99.2 99.8 Control (Losec) 91.5 92.0 93.5 ~o WO 93/13138 PCI/KR92/0~083 2 ~ 34 As the result from the above experiment show, the dissolution rate for all samples was good only Example 4-A and 5-I produced using dibasic calcium phosphate anhydrous as excipient showed Somewhat slow dissolution rate in first 10 mimltes.
The rate of dissolution after 20mins and 30mins, testing samples of Examples were obviously higher than the control.
[ Test for Storage Stability ]
According to the process of Experiment Example 1, the drugs were kept in glass o bottle for 6 months under 40C, 75% RH of accelerated condition and 50C, 75% RH
of harsh concliti-~n.
The changes of appearance for the resulted samples were surveyed. The results were shown on Table 24.
Table 24.
Test condition Testing Sample 40C, 75% RH 50C, 75% RH
Example 4 - A
Example 5 - I
Example 6 - B
Example 7 - A
Example 8 - C
Control (Losec) + ++
(Note) - : Nondiscoloration + : Somediscoloration + : Discoloration ++ : Deepdiscoloration ~0 93/13138 PCI/KR92/00083 ~ 2127111 3~
As the result of above, it was confirmed that the storage stabilities of Examples were obviously higher than the control.
As the result of Experimental Example 2, it was found that the enteric-coated oral drugs of the present invention formulated with omeprazol-cyclodextrin inclusion 5 complex have excellent stability and dissolution ~urc~elLy as compared with known preparations.
o The reactant was concentrated to lOOm~ in vacuum evaporator, and after cooling to room ~ e-~ture, it was left for 6 hrs in a refrigerator to deposit inclusion complex. The filtered inclusion complex was washed with water several times and dried under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex.
The results of reaction were shown as following Table 11.
Table 11.
Example 1Buffersolution pH Colorof Rateof Inclusion Complex Inclusion(%) 2 - A PreparingEx. 2-6 9.0 - 89.0 2 - B PreparingEx.3-11 9.0 - 91.2 2 - CP~c;~ua ing Ex. 4-6 9.0 - 90.1 252 - D PreparingEx.2-11 10.0 - 98.6 2 - E PreparingEx.5-5 10.0 - 99.1 2 - F PreparingEx. 6-3 10.0 - 98.9 2 - G PreparingEx.6-8 11.0 - 99.2 2 - H ~ingEx. 7-1 11.0 - 98.8 (Note) - : Nondiscoloration As the result shown in Table 11, it is was found that when pH of buffer solutionis the same the effectiveness of inclusion is not influenced by kind of buffer solution, and when it is more than pH 10 the rate of inclusion was higher than 98.6%.
Example 3 ~ -Cyclodextrins according to following Table 12 were respectively dissolved in 900ml of buffer solutions(pH 10.0) prepared by the above Preparing Example 2-11 to add omeprazole, and then the reaction temperature was changed to 40C, 50C ,60C
o ,and 70C as the reaction being carried out for 15 mins.
The reactant was concentrated to 100ml in vacuum evaporator, and after cooling to room temperature, it was left for 6 hrs in a refrigerator to deposit inclusion complex. The filtered inclusion complex was washed with water on several times and dried under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex.
5 The results of reaction were shown as following Table 12.
Table 12.
Example 3 Reaction Amount of Amount of Color of Rate of Temp.(C ) ~ -CD (g) Omeprazole(g) Inclusion complex Inclusion(%) 3 - A 40 24.0 3.4 - 98.6 3 - B 50 54.0 8.2 - 98.8 3 - C 60 85.0 12.9 - 99.0 3 - D 70 135.0 20.5 - 98.0 30 (Note) - : Non discoloration -CD: ,~ -cyclodextrin WO 93/13138 PCr/KR92/00083 21~7111- 20 Example 4 ~ -Cyclodextrines according to following Table 13 were respectively dissolved in 900mZ of buffer solution(pH 10.0) prepared by the above Preparing Example 2-11 at 5 50DC, and omeprazole was added in the solution under stirring to react for 15 mins.
The reactant was concentrated to 100ml in vacuum evaporator, and after cooling to room lel,lyeldture, it was left for 6 hrs in a refrigerator to deposit inclusion complex. The filtered inclusion complex was washed with water on several times and dried under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex.
o The results of reaction were shown as following Table 13.
Table 13.
Example 4 Kind of CDAmount of Amount of Rate of CD(g) Omeprazole(g) Inclusion(%) 4 - A ~-CD 4.2 5.9 97.2 4 - B HP-~-CD 1.8 0.25 9g.0 4- C ~ -CD 54.0 8.2 98.8 4 - D Hp-~B -CD 1.5 0.17 99.2 4 - E HE~ -CD 1.95 0.23 99.0 4 - F M-~ -CD 2.4 0.3 98.5 4 - G y -CD 7.0 0.74 99.1 4 - H HP-y-CD 2.4 0.25 99.0 (Note) CD : Cycloc~exh in HP: Hydroxypropyl HE: Hydroxyethyl M: Methyl ~o ,WO 93/13138 PCI/KR92/00083 21~ 2127 Example 5 ~ -cyclodextrin of 54g was dissolved in each 900ml of O.lM amine aqueous sollltion~ according to following Table 9 at 50C, and 8.2g omeprazole was added in 5 the solution under stirring to react for 15 mins.
The reactant was cooled to room temperature and/or concentrated to lOOml in vacuum evaporator, and it was left for 6 hrs in a refrigerator to deposit inclusion complex.
The filtered inclusion complex was washed with water several times and dried o under reduced pressure to obtain omepr~. ~)le-cyclodextrin inclusion complex. The results of reaction were shown as following Table 14.
~1~7~ 22 Table 14.
Example 5Kind of Amine Deposition Method Rate of Inclusion(%) 5 - ADiethylamine Cool 89.2 5 - BTriethylamine Cool/Conc. 95.7 5 - C Propylamine Cool 90.3 5 - DDipropylamine Conc. 98.0 5 - EIsobutylamine Cool 89.7 o 5 - FDiisopropylamine CooVConc. 92.3 5 - G Butylamine Cool 96.7 S - HEthylenç~ mine Conc. 97.1 5 - IMonoethanolamine Conc. 98.9 5 - JDiethanolamine Conc. 99.1 5 - KTriethanolamine Conc. 99.1 5 - LTert-butylamine Cool 89.0 5 - MDibutylamine Conc. 97.3 S - NDiisobutylamine Conc. 96.8 5 - OTributylamine Conc. 98.3 5 - P Pentylamine Conc. 98.7 S - QDipentylamine Conc. 99.3 (Note) Cool: Cooling to room temperature Conc.: Concentrating in vacuum evaporator ~o Example 6 According to following Table 15, ~ -cyclodextrin was dissolved in 900ml water, and on the other hand omeprazole was dissolved in 40% (v/v) triethylamine5 aqueous solution to obtain 27% solution. The resulted omeprazole solution was dropwise added in cyclodextrin aqueous solution.
The reactant was cooled to room temperature, and left for 6 hrs in a refrigerator to deposit inclusion complex.
The filtered inclusion complex was washed with water several times and dried 0 under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex. The resul~s of reaction were shown as following Table 15.
Table 15.
Example 6 ReactionAmount of Amount of Rate of Temp. (C )~ -CD(g) Omeprazole (g) Inclusion (%) 6 - A 40 24.0 3.4 99.5 6 - B 50 54.0 8.2 99.1 6- C 60 85.0 12.9 98.1 6 - D 70 135.0 20.5 98.5 WO 93/13138 PCl/KR92/00083 212~1ii 24 ~
Example 7 24g ~ -cyclodextrin was dissolved in 900ml of pH 12 aqueous solutions of hydroxide of ~lk~line metals according to following Table 16, and 3.4g omeprazole was 5 added in this solution under stirring to react for 15 mins.
The reactant was concentrated to 100ml in vacuum evaporator, and after cooling to room tempelalu,~, it was left for 6 hrs in a refrigerator to deposit inclusion complex.
The filtered inclusion complex was washed with water several times and dried 0 under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex. The results of reaction were shown as following Table 16.
Table 16.
Example 7 Kind of Reaction Amount of Amount of Rate of Hydroxide Temp.(~C ) ,B -CD (g) Omeprazole(g) Inclll~ion(%) 7 - A NaOH 40 24.0 3.4 99.3 7 - B KOH 40 24.0 3.4 99.1 7- C Ca(OH)2 40 24.0 3.4 98.8 7 - D Ba(OH)2 40 24.0 3.4 98.7 ~o Example 8 This experiment was conducted in same manner as previous Example 7 except that the other alk~line salt solutions according to following Table 17 were used to 5 obtain omeprazole-dextrin inclusion complex.
The filtered inclusion complex was washed with water several times and dried under reduced pressure to obtain omeprazole-cyclodextrin inclusion complex. The results of reaction were shown as following Table 17.
Table 17.
Example 8 Kind of pH Reaction Amount of Amount of Rate of ~lk~line salts Temp.(C) ~ -CD (g) Omeprazole(g) Inclusion(%) 8 - ANa2B407 10.0 40 24.0 3.4 99.2 8 - BK2B4O7 10.0 40 24.0 3.4 99.3 8 - CNa2CO3 10.0 40 24.0 3-4 99.8 8 - DK~CO3 10.0 40 24.0 3.4 99.5 8 - ENa2HPO4 10.0 40 24.0 3-4 99.1 8 - FK~HPO4 10.0 40 24.0 3.4 99.3 8 - GCH3COONa 8.5 40 24.0 3.4 98.7 8 - HSodium citrate 9.0 40 24.0 3.4 98.5 W O 93/13138 212 7 ~ ~ ~ i PC~r/KR92/00083 [ Methods for measuring rate of inclusion ]
Amount of omeprazole in the obtained inclusion complex (g) X 100 = Rate of inclusion(%) Amount of used omeprazole (g) The amount of omeprazole in the obtained inclusion complex was measured by o HPLC under following conditions.
Solvent: pH 9.8 Carbonate buffer solution: ethanol = 80: 20 Colllmn: ~ Bondapak C~8 3.9mm (the inside diameter) X 300mm (length) Mobile Phase: pH 7.6 Phosphate buffer solution: Aceto~ ile = 66: 34 Detection Wave-length: 302 nm 15 Injection Volum: 20f~1 nOw Rate: 1.0 ml/min Comparative Example 1 5.67g ~ -cyclodextrin and 1.73g omeprazole were added in 96% ethanol of 20 20 ml and stirred at 30 ~ 32C for 15 hrs.
After leaving at 10~C for 3hrs, the reacted solution was filtered, and washed with ethanol of l0C, dried under reduced pressure to obtain the desired product of reddish brown color. At this time the reactant solution was of purple color.
25 Comparative Example 2 2.0g Omeprazole was well mixed with 2.0g Na2HPO4, and the mixed compound was dried under reduced pressure to obtain the stabilized core of omeprazole preparation as a co,l".~ative sample.
~093/13138 2127111 PCI/KR92/00083 Comparative Example 3 This test was conducted in process of the above Comparative Example 2 except to use 2.0g omeprazole and 2.0g Mg(OH)2. The obtained core was used as a 5 co~ ~dtive sample.
Experimental Example 1 (Storage Stability of Inclusion Complex) To verify stabilized result for the above Example 1 to 8 and Comparative o Example 1 to 3, the change of appearance was surveyed with the passing of time under 4(~ 75% RH of accelarated condition. The results were shown on following Table 18.
Under the above condition, storage stability during 6 months means to secure stability for 3 years at normal condition. As the result of Table 18, it was confirmed 5 that the cases of Example 1 ~ 8 according to the present invention is obviously showing higher stability than the cases of Comparative Example 1 ~ 3.
~0 W O 93/13138 P~r/K W 2/00083 212711~ 28 Table 1 8.
The Change of Appearance Sample Start After lmonth After2months After4months After6months s Example 1-D
Example 2-B
Example 2-E - - - - -Example 2-G
Example 3-A - - - - -o Example 3-D
Example 4-A
Example 4-B
Example 4-D
Example 4-E
5 Example 4-F
Example 4-G
Example 4-H
Example 5-B - - - - -Example 5-I
20 Example 6-A
Example 6-D
Example 7-A
Example 8-C
Comp. Ex. 1 +++ ++ ++ ++
Comp. Ex. 2 - + + ++ ++
Comp. Ex. 3 - - + + +
(Note) - : Non discoloration + : Some discoloration + : Discoloration ++ : Deepdiscoloration ,WO 93/13138 ~12 7~1 PCr/KR92/00083 Formulation of Inçlusion Complex To forrnulate enteric-coated oral drugs, the omeprazole-cyclodextrin inclusion complexs obtained by Example 1 ~ 8 were used as followings.
5 [ Preparing of Uncoated Tablets ]
According to following Table 19, omeprazole of 20mg was homogeneousely mixed with excipients, disintegrants and lubricants, and the mixture was tableted to 230mg per unit by Rotary Tableting Machine.
Table 19.
(Unit: mg~
Mixed Example No.
Components Inclusion complex 165 165 165 165 165 165 165 165 Microcrystalline 42 40 30 30 23 20 20 20 cellulose Dibasic calcium 20 lS 10 S - S
phosphate Anhydrous Com starch - 7 22 27 24.7 20 12.7 Mannitol - - - - - 7.7 lS 27.7 So~ium starch - - - - lS 10 lS lS
glycolate Ma~nesium 3.0 3.0 3.0 3.0 2.3 2.3 2.3 2.3 stearate 2127~11 30 In the above, when microcrystalline cellulose and dibasic calcium phosphate anhydrous of an excess of quantity were used, hardness of tablets is excellent but disintegration rate was decreased. Therefore, microcrystalline cellulose of small s amount was preferably used, and at that time the used amount of corn starch and/or Mannitol were increased and minimum amount of dibasic calcium phosphate anhydrous was used.
[ Coating of Watersoluble Substance ]
According to following Table 20, a watersoluble substance was coated on o uncoated tablets.
Table 20.
(Unit : mg ) Components (Tl) (T2) (T3) (T4) (Ts) (T6) (T7) (T8) (T9) of Watersoluble Substance Hydroxy propylmethyl cellulose 10 9 9 9 9 9 - - -Hydroxypropyl cellulose - - - - - ~ 9 Polyvinylpynolidone - - - - - - - 9 Polyvinylalcohol - - - - - - - - 9 Propyleneglycol Polyethyleneglycol 600 Water 190 190 190 38 38 38 38 38 38 Ethanol - - - 152 152 152 152 152 152 -In the above tes~, when water was only used as solvent or excessive water was used, dry time in coating pan was pr~longed.
Since tablets were observed to stick with each other and rendering the coating 5 surface ununiform, ethanol, preferably 80% ethanol water solution, was used in this process as main solvent.
[ Coating of Enteric Substance 3 According to following Table 21, an enteric substance was coated on tablets o coated with watersoluble substance to obtain the desired enteric-coated oral drug.
Table 21.
Components of Enteric Substance a b c d e s Hydroxypropyl,-icll-yl ~elllllnse18.6 - - 18.6 phth,.l~te Cellulose acetate phsh~ t~ 18.6 - - 18.6 Eudragit L100 - - 18.0 Cetylalcohol 1.4 1.4 Myvacet 9-40T - - - 1.4 1.4 Dibutylph~h~l~te - - 2.0 Ace~one 152 190 152 152 190 Ethyl,.lcohol 228 190 - 228 190 Isopropy~ ohQl - - 228 WO93/13138 12 11 1 32 PCI~/KR92/00083 Experimental Example 2: Property Test for Oral Drugs The obtained inclusion complexs of Examples were used to formulate enteric-coated oral drugs. To survey the properties for the oral drugs, the watersoluble 5 substance according to the method of Table 20(Ts) was respectively coated on tablets prepared from Example 4-A, 5-I, 6-B, 7-A and 8-C, and there after the enteric substance according to the method of Table 21 "d" was coated on the above tablets.
The formulated oral drugs were compared with control product, Astra's LOSEC, to survey acid-resistance property, dissolution property, and storage stability 0 as followings.
[ Test for Acid-resi~t~nce Property ]
The formulated oral drugs were put into artificial gastric fluid [USP, 1st solution] without enzyme and stirred at 37~C by paddle at 100 rpm.
The test solution was left for 2hrs to survey the change of appearance, and the 5 omeprazole existing in preparation was measured by HPLC. The results were shown on following Table 22.
Table 22.
Testing SampleAmount of the The Change of Existing Omeprazole(%) Appearance Example 4-A 99.0 Non discoloration Example 5-I 99.1 "
Example 6-B 99.5 "
Exarnple 7-A 100.0 "
Example 8-C 99.2 "
Control (Losec) 96.7 Brown spots in pellets ~o 2127 11~ ~
The above test showed brown spots on 40 ~ 75% of pellets for the control(LOSEC), and it was also found that omeprazole content was decreased.
But, the oral drugs prepared according to examples were not affected in the 5 appearance and omeprazole content was scarcely decreased, thus giving superior characteristies .
[ Test for Dissolution Property ]
To survey the rate of dissolution in the small intestines, the formulated oral 0 drugs were added to simulated gastric fluid [USP, 37~C, 100 rpml.
After 2hrs, the above drugs were moved to simulate intestinal fluid [USP, dissolution apparatus No. 2, Paddle Method], and then the amount of dissolved omeprazole was determined by the method of HPLC. The results were shown on Table 23.
Table 23.
(Unit: %) Rate of Dissolution for Passing Time Testing Sample 10 min 20 min 30 min Example 4- A 85.9 97.6 99.2 Exarnple 5 - I 98.2 100.0 100.0 Example 6-B 90.3 98.0 99.5 Example 7 - A 98.5 99.7 100.0 Example 8 - C 98.0 99.2 99.8 Control (Losec) 91.5 92.0 93.5 ~o WO 93/13138 PCI/KR92/0~083 2 ~ 34 As the result from the above experiment show, the dissolution rate for all samples was good only Example 4-A and 5-I produced using dibasic calcium phosphate anhydrous as excipient showed Somewhat slow dissolution rate in first 10 mimltes.
The rate of dissolution after 20mins and 30mins, testing samples of Examples were obviously higher than the control.
[ Test for Storage Stability ]
According to the process of Experiment Example 1, the drugs were kept in glass o bottle for 6 months under 40C, 75% RH of accelerated condition and 50C, 75% RH
of harsh concliti-~n.
The changes of appearance for the resulted samples were surveyed. The results were shown on Table 24.
Table 24.
Test condition Testing Sample 40C, 75% RH 50C, 75% RH
Example 4 - A
Example 5 - I
Example 6 - B
Example 7 - A
Example 8 - C
Control (Losec) + ++
(Note) - : Nondiscoloration + : Somediscoloration + : Discoloration ++ : Deepdiscoloration ~0 93/13138 PCI/KR92/00083 ~ 2127111 3~
As the result of above, it was confirmed that the storage stabilities of Examples were obviously higher than the control.
As the result of Experimental Example 2, it was found that the enteric-coated oral drugs of the present invention formulated with omeprazol-cyclodextrin inclusion 5 complex have excellent stability and dissolution ~urc~elLy as compared with known preparations.
Claims
The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A method for stabilizing an acid-unstable compound by forming an inclusion complex of omeprazole with cyclodextrin comprising:
dissolving cyclodextrin in an aqueous alkaline solution at 40°-70°C., and reacting said omeprazole with a cyclodextrin for 1 to 30 minutes in said alkaline solution, the ratio of said acid-unstable compound to said cyclodextrin in said reaction being from about 1:1 to about 1:10, on a number of moles basis.
2. In the method of claim 1, said alkaline solution consists essentially of an aqueous solution of an alkali selected from the group consisting of alkaline hydroxides, alkaline salts, amines, buffers, and combinations thereof.
3. In the method of claim 2, said alkaline hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide and combinations thereof.
4. In the method of claim 2, said alkaline salt is selected from the group consisting of sodium borate, sodium carbonate, sodium phosphate, potassium borate, potassium carbonate, potassium phosphate, sodium acetate, sodium citrate and combinations thereof.
5. In the method of claim 2, said amine is se-lected from the group consisting of diethylamine, triethylamine, butylamine, ethylenediamine, trietha-anolamine, propylamine, dipropylamine, diethanol-amine, monoethanolamine, isobutylamine, diiso-propylamine, tert-butylamine, dibutylamine, diiso-butylamine, tributylamine, pentylamine, dipentyl-amine and combinations thereof.
6 In the method of claim 2, said buffer is selected from the group consisting of carbonate buffer, phosphate buffer, borate buffer, amine salt buffer, and combinations thereof.
7. A method for stabilizing a benzimidazole derivative having the following structural formula:
wherein:
R1 is selected from the group consisting of hydrogen, methoxy, trifluoromethyl and tetra-fluoroethoxy radicals;
R2 is selected from the group consisting of hydrogen, methylamine and dimethylamine radicals;
R3 is selected from the group consisting of hydrogen, methoxy, aryloxy and propaziloxy radicals; and R4 is selected from the group consisting of hydrogen and methyl radicals;
by forming an inclusion complex of said benzimidazole derivative with cyclodextrin comprising:
A. Dissolving said cyclodextrin in an aqueous alkaline solution at a temperature between about 40° and 70° C.; and B. Reacting said cyclodextrin with said benzimidazole derivative for 1 to 30 minutes in said aqueous alkaline solution, the ratio of said benzimidazole derivative to said cyclodextrin being from about 1 to 10 moles of said cyclodextrin for each mole of said benzimidazole derivative.
8. In the method of claim 7, said alkaline solution consists essentially of an aqueous solution of an alkali selected from the group consisting of alkaline hydroxides, alkaline salts, amines, buffers and combinations thereof.
9. In the method of claim 8, said alkaline hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide and combinations thereof.
In the method of claim 8, said alkaline salt is selected from the group consisting of sodium borate, sodium carbonate, sodium phosphate, potassium borate, potassium carbonate, potassium phosphate, sodium acetate, sodium citrate and combinations thereof.
11. In the method of claim 8, said amine is selected from the group consisting of diethylamine, triethylamine, butylamine, ethylenediamine, trieth-anolamine, propylamine, dipropylamine, diethanol-amine, monoethanolamine, isobutylamine, diisopropyl-amine, tert-butylamine, dibutylamine, diisobutyl-amine, tributylamine, pentylamine, dipentylamine and combinations thereof.
12. In the method of claim 8, said buffer is selected from the group consisting of carbonate buffer, phosphate buffer, borate buffer, amine salt buffer, and combinations thereof.
1. A method for stabilizing an acid-unstable compound by forming an inclusion complex of omeprazole with cyclodextrin comprising:
dissolving cyclodextrin in an aqueous alkaline solution at 40°-70°C., and reacting said omeprazole with a cyclodextrin for 1 to 30 minutes in said alkaline solution, the ratio of said acid-unstable compound to said cyclodextrin in said reaction being from about 1:1 to about 1:10, on a number of moles basis.
2. In the method of claim 1, said alkaline solution consists essentially of an aqueous solution of an alkali selected from the group consisting of alkaline hydroxides, alkaline salts, amines, buffers, and combinations thereof.
3. In the method of claim 2, said alkaline hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide and combinations thereof.
4. In the method of claim 2, said alkaline salt is selected from the group consisting of sodium borate, sodium carbonate, sodium phosphate, potassium borate, potassium carbonate, potassium phosphate, sodium acetate, sodium citrate and combinations thereof.
5. In the method of claim 2, said amine is se-lected from the group consisting of diethylamine, triethylamine, butylamine, ethylenediamine, trietha-anolamine, propylamine, dipropylamine, diethanol-amine, monoethanolamine, isobutylamine, diiso-propylamine, tert-butylamine, dibutylamine, diiso-butylamine, tributylamine, pentylamine, dipentyl-amine and combinations thereof.
6 In the method of claim 2, said buffer is selected from the group consisting of carbonate buffer, phosphate buffer, borate buffer, amine salt buffer, and combinations thereof.
7. A method for stabilizing a benzimidazole derivative having the following structural formula:
wherein:
R1 is selected from the group consisting of hydrogen, methoxy, trifluoromethyl and tetra-fluoroethoxy radicals;
R2 is selected from the group consisting of hydrogen, methylamine and dimethylamine radicals;
R3 is selected from the group consisting of hydrogen, methoxy, aryloxy and propaziloxy radicals; and R4 is selected from the group consisting of hydrogen and methyl radicals;
by forming an inclusion complex of said benzimidazole derivative with cyclodextrin comprising:
A. Dissolving said cyclodextrin in an aqueous alkaline solution at a temperature between about 40° and 70° C.; and B. Reacting said cyclodextrin with said benzimidazole derivative for 1 to 30 minutes in said aqueous alkaline solution, the ratio of said benzimidazole derivative to said cyclodextrin being from about 1 to 10 moles of said cyclodextrin for each mole of said benzimidazole derivative.
8. In the method of claim 7, said alkaline solution consists essentially of an aqueous solution of an alkali selected from the group consisting of alkaline hydroxides, alkaline salts, amines, buffers and combinations thereof.
9. In the method of claim 8, said alkaline hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide and combinations thereof.
In the method of claim 8, said alkaline salt is selected from the group consisting of sodium borate, sodium carbonate, sodium phosphate, potassium borate, potassium carbonate, potassium phosphate, sodium acetate, sodium citrate and combinations thereof.
11. In the method of claim 8, said amine is selected from the group consisting of diethylamine, triethylamine, butylamine, ethylenediamine, trieth-anolamine, propylamine, dipropylamine, diethanol-amine, monoethanolamine, isobutylamine, diisopropyl-amine, tert-butylamine, dibutylamine, diisobutyl-amine, tributylamine, pentylamine, dipentylamine and combinations thereof.
12. In the method of claim 8, said buffer is selected from the group consisting of carbonate buffer, phosphate buffer, borate buffer, amine salt buffer, and combinations thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1991/25847 | 1991-12-31 | ||
| KR910025847 | 1991-12-31 |
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| US (1) | US5399700A (en) |
| EP (1) | EP0619825B1 (en) |
| JP (1) | JP2662518B2 (en) |
| KR (1) | KR960008231B1 (en) |
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| WO (1) | WO1993013138A1 (en) |
Families Citing this family (46)
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| AU5780696A (en) * | 1995-06-02 | 1996-12-18 | Takeda Chemical Industries Ltd. | Stabilized composition comprising an antiulcerative benzimid azole |
| AU745707B2 (en) * | 1995-09-21 | 2002-03-28 | Pharma Pass Llc | novel composition containing an acid-labile omeprazole and process for its preparation |
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| US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| US6645988B2 (en) | 1996-01-04 | 2003-11-11 | Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
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| US6174548B1 (en) | 1998-08-28 | 2001-01-16 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| KR100281521B1 (en) * | 1998-03-31 | 2001-02-15 | 김종인 | Pharmaceutical Compositions Containing Sodium Pravastatin |
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| IL143407A0 (en) * | 1998-12-18 | 2002-04-21 | Abbott Lab | Controlled release formulation of divalproex sodium |
| US6245913B1 (en) | 1999-06-30 | 2001-06-12 | Wockhardt Europe Limited | Synthetic procedure for 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-IH-benzimidazole hydrochloride and its conversion to omeprazole |
| US6326384B1 (en) | 1999-08-26 | 2001-12-04 | Robert R. Whittle | Dry blend pharmaceutical unit dosage form |
| US6316020B1 (en) | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
| US6268385B1 (en) | 1999-08-26 | 2001-07-31 | Robert R. Whittle | Dry blend pharmaceutical formulations |
| US6312712B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Method of improving bioavailability |
| US6262085B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6312723B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US6262086B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US6369087B1 (en) | 1999-08-26 | 2002-04-09 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6780880B1 (en) | 1999-08-26 | 2004-08-24 | Robert R. Whittle | FT-Raman spectroscopic measurement |
| GB2376231A (en) * | 2001-06-06 | 2002-12-11 | Cipla Ltd | Benzimidazole-cyclodextrin inclusion complex |
| US6462237B1 (en) * | 2001-06-14 | 2002-10-08 | Usv Limited | Cyclodextrin stabilized pharmaceutical compositions of bupropion hydrochloride |
| PL369966A1 (en) * | 2002-01-15 | 2005-05-02 | Altana Pharma Ag | Pantoprazole cyclodextrin inclusion complexes |
| MXPA04007169A (en) * | 2002-01-25 | 2004-10-29 | Santarus Inc | Transmucosal delivery of proton pump inhibitors. |
| WO2004066924A2 (en) * | 2003-01-24 | 2004-08-12 | Andrx Labs Llc | Novel pharmaceutical formulation containing a proton pump inhibitor and an antacid |
| CA2517005A1 (en) * | 2003-02-20 | 2004-09-02 | Santarus, Inc. | A novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid |
| EP1633736A1 (en) * | 2003-05-05 | 2006-03-15 | Ranbaxy Laboratories Limited | Barium salt of benzimidazole derivative |
| KR100473422B1 (en) * | 2003-06-12 | 2005-03-14 | 박원봉 | A composition for an enteric coating of natural product containing lectin |
| MXPA06000524A (en) * | 2003-07-18 | 2006-08-11 | Santarus Inc | Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders. |
| AR045062A1 (en) * | 2003-07-18 | 2005-10-12 | Santarus Inc | PHARMACEUTICAL FORMULATIONS TO INHIBIT THE SECRETION OF ACID AND METHODS TO PREPARE AND USE THEM |
| US8993599B2 (en) * | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US20070292498A1 (en) * | 2003-11-05 | 2007-12-20 | Warren Hall | Combinations of proton pump inhibitors, sleep aids, buffers and pain relievers |
| KR20050105565A (en) * | 2004-04-30 | 2005-11-04 | 에스케이케미칼주식회사 | Stable pharmaceutical composition containing benzimidazole compounds and method of manufacturing the same |
| US8906940B2 (en) * | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US8815916B2 (en) * | 2004-05-25 | 2014-08-26 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| WO2006085335A2 (en) * | 2005-01-03 | 2006-08-17 | Lupin Limited | Pharmaceutical composition of acid labile substances |
| US20100297226A1 (en) * | 2006-06-01 | 2010-11-25 | Dexcel Pharma Technologies Ltd. | Multiple unit pharmaceutical formulation |
| US20090092658A1 (en) * | 2007-10-05 | 2009-04-09 | Santarus, Inc. | Novel formulations of proton pump inhibitors and methods of using these formulations |
| US20100233259A1 (en) * | 2008-12-12 | 2010-09-16 | Pascal Grenier | Dosage form of ropinirole |
| ITMI20121264A1 (en) * | 2012-07-19 | 2014-01-20 | Recordati Ind Chimica E Farma Ceutica S P A | PHARMACEUTICAL FORM GASTRO-RESISTANT WITH DELAYED RELEASE |
| US20170042806A1 (en) | 2015-04-29 | 2017-02-16 | Dexcel Pharma Technologies Ltd. | Orally disintegrating compositions |
| US10076494B2 (en) | 2016-06-16 | 2018-09-18 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2260536C3 (en) * | 1972-12-11 | 1975-07-10 | Fa. H. Trommsdorff, 5100 Aachen | Molecular inclusion compounds of a silver alkanolamine complex and beta-cycloheptaamylose, processes for their preparation and pharmaceuticals containing these compounds |
| DE3427787A1 (en) * | 1984-07-27 | 1986-01-30 | Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz | ACTIVE SUBSTANCE COMPLEXES OF 5-METHOXY-2 ((4-METHOXY-3,5-DIMETHYL-2-PYRIDYL) METHYLSULFINYL) -1H-BENZIMIDAZOLE WITH CYCLODEXTRINES, THEIR PRODUCTION AND MEDICINAL PRODUCTS |
| US5053240A (en) * | 1989-10-24 | 1991-10-01 | Kalamazoo Holdings, Inc. | Norbixin adducts with water-soluble or water-dispersible proteins or branched-chain or cyclic polysaccharides |
-
1992
- 1992-12-22 TW TW081110281A patent/TW224049B/zh not_active IP Right Cessation
- 1992-12-29 US US07/997,791 patent/US5399700A/en not_active Expired - Lifetime
- 1992-12-30 DE DE69222950T patent/DE69222950T2/en not_active Expired - Lifetime
- 1992-12-30 EG EG81292A patent/EG20115A/en active
- 1992-12-30 HU HU9401666A patent/HU217135B/en unknown
- 1992-12-30 ES ES93901497T patent/ES2111148T3/en not_active Expired - Lifetime
- 1992-12-30 CN CN92115345A patent/CN1033790C/en not_active Expired - Fee Related
- 1992-12-30 WO PCT/KR1992/000083 patent/WO1993013138A1/en active IP Right Grant
- 1992-12-30 BR BR9207000A patent/BR9207000A/en not_active Application Discontinuation
- 1992-12-30 JP JP5511564A patent/JP2662518B2/en not_active Expired - Fee Related
- 1992-12-30 EP EP93901497A patent/EP0619825B1/en not_active Expired - Lifetime
- 1992-12-30 CA CA002127111A patent/CA2127111C/en not_active Expired - Lifetime
- 1992-12-30 RU RU94031478A patent/RU2105773C1/en active
- 1992-12-31 MX MX9207676A patent/MX9207676A/en not_active IP Right Cessation
- 1992-12-31 KR KR1019920027146A patent/KR960008231B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CN1076124A (en) | 1993-09-15 |
| CA2127111A1 (en) | 1993-07-08 |
| BR9207000A (en) | 1995-11-28 |
| KR960008231B1 (en) | 1996-06-21 |
| HU9401666D0 (en) | 1994-09-28 |
| ES2111148T3 (en) | 1998-03-01 |
| US5399700A (en) | 1995-03-21 |
| JPH07506088A (en) | 1995-07-06 |
| HUT70494A (en) | 1995-10-30 |
| DE69222950T2 (en) | 1998-05-28 |
| RU2105773C1 (en) | 1998-02-27 |
| CN1033790C (en) | 1997-01-15 |
| DE69222950D1 (en) | 1997-12-04 |
| EP0619825A1 (en) | 1994-10-19 |
| EG20115A (en) | 1997-07-31 |
| JP2662518B2 (en) | 1997-10-15 |
| EP0619825B1 (en) | 1997-10-29 |
| KR930012016A (en) | 1993-07-20 |
| MX9207676A (en) | 1993-06-01 |
| TW224049B (en) | 1994-05-21 |
| WO1993013138A1 (en) | 1993-07-08 |
| HU217135B (en) | 1999-11-29 |
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