CN101014333A - Loxoprofen-containing composition for oral administration - Google Patents
Loxoprofen-containing composition for oral administration Download PDFInfo
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- CN101014333A CN101014333A CNA2005800303268A CN200580030326A CN101014333A CN 101014333 A CN101014333 A CN 101014333A CN A2005800303268 A CNA2005800303268 A CN A2005800303268A CN 200580030326 A CN200580030326 A CN 200580030326A CN 101014333 A CN101014333 A CN 101014333A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
A loxoprofen-containing composition for oral administration which is reduced in the fear of arousing gastric mucosal disorders. The composition for oral administration comprises loxoprofen and an antacid agent.
Description
Invention field
The present invention relates to a kind of combination of oral medication that comprises loxoprofen and antacid, or a kind of combination of oral medication that except loxoprofen and antacid, also comprises lactose or xanthine derivative.
Background of invention
NSAID (non-steroidal anti-inflammatory drug) (NSAIDS) for example loxoprofen, ibuprofen, aspirin etc. often is used for the treatment of cold symptoms etc.Yet NSAID (non-steroidal anti-inflammatory drug) is to bring into play pharmacologically active by suppressing the prostaglandin biosynthesis, and their side effect such as gastric mucosa injury etc. extensively are familiar with.In order to alleviate the gastric mucosa injury side effect that NSAIDS causes, these medicines often and antacid, gastric mucosa protectant, proton pump inhibitor and H2 acceptor inhibitor etc. unite use.
In addition, because loxoprofen is prodrug, to compare gastric mucosa injury lighter with other NSAIDS for it.Even so, in the clinical practice, when loxoprofen is used as antiinflammatory, still to use above-mentioned therapeutic alliance to prevent gastric mucosa injury.Yet, also do not contain the disclosing of Pharmaceutical composition of loxoprofen and antacid so far.In addition, the disclosing of Pharmaceutical composition that does not also contain loxoprofen, antacid and lactose or xanthine derivative.
In addition, compositions related to the present invention also comprises:
Existing report use lactose and/or corn starch are as the pharmaceutical composition that contains loxoprofen (seeing patent documentation 1) of filler.
Existing report is united the use caffeine can work in coordination with increase loxoprofen analgesic activities (seeing patent documentation 2).
Existing being reported under the situation about needing adopts conducts such as surfactant, viscosifier, pH regulator agent, solubilizing agent, buffer agent, antiseptic, spice, pigment, sweeting agent to contain the additive of the oral liquid of loxoprofen and expectorant.According to open source literature, the object lesson of viscosifier comprises synthetic aluminium silicate, magnesium silicate, magnesium carbonate, magnesium oxide, Magnesiumaluminumsilicate etc.(seeing patent documentation 3).
But, concrete example of formulations is not done open.
Because previous example is different with the present invention in itself, so content of the present invention is also never related to and hinted.
[patent documentation 1] spy opens flat 9-255569 communique (Japanese Patent Publication (Kokai) Number Hei9-255569 pamphlet)
[patent documentation 2] spy opens flat 11-139971 communique (Japanese Patent Publication (Kokai) Number Hei 11-139971 pamphlet)
[patent documentation 3] spy opens flat 2001-172175 communique (Japanese PatentPublication (Kokai) Number 2001-172175 pamphlet)
Disclosure of the Invention
If the gastric mucosa injury that loxoprofen causes can alleviate, the method that alleviates so also can be thought useful.In addition, if these methods that alleviate are simple, low price, this method will be more useful.
Under this background, the inventor does a lot of work to realize this target.Finally, the inventor finds that first gastric mucosa injury that NSAIDs that traditional view is thought causes can to obtain alleviating this viewpoint not necessarily correct by taking antacid simultaneously, finds that simultaneously effect that antacid alleviates the gastric mucosa injury that NSAIDs causes depends on the consumption of antacid.
In the pharmaceutical composition that comprises loxoprofen and antacid, gastric mucosa injury and ibuprofen that antacid prevention loxoprofen causes are made a world of difference, although loxoprofen and ibuprofen belong to benzenpropanoic acid esters NSAIDs derivant.Therefore, even if the relation between the gastric mucosa injury degree that the optimal dose of ibuprofen and antacid and ibuprofen cause is clear and definite, the gastric injury effect that antacid protection loxoprofen causes also is difficult to prediction.In addition, the inventor find gastric mucosa injury that antacid causes loxoprofen alleviate damage that effect comparison ibuprofen causes alleviate effect more obviously (see below and state table 5).
In addition, the inventor also find lactose join can significantly increase gastric mucosa injury that antacid causes loxoprofen in antacid and the loxoprofen compositions alleviate effect (see below and state table 6).Therefore, the inventor finishes the present invention based on above-mentioned discovering.
On the other hand, some nonprescription drugss (OTC) (particularly coldrex), the medicine that contains NSAID (as ibuprofen) that promptly is added with caffeine (xanthine derivative) has commercially available.The inventor studies loxoprofen and xanthine derivative is united the effect of use in the OTC medicine, and confirms this risk that use might increase gastric mucosa injury of uniting first.Therefore, the inventor studies how to solve the side reaction that this drug combination produces simultaneously, research obtains surprising discovery, in loxoprofen and xanthine derivative compositions, add antacid, the deterioration of its gastric mucosa injury significantly improves, even than the loxoprofen and the Actacid composition also low (see below and state table 7) of expecting.Therefore, the inventor finishes the present invention based on above-mentioned discovering.
As everyone knows, take NSAID after the meal and can alleviate the gastric mucosa injury that it causes to a certain extent.Yet, in the time must taking analgesia antipyretic and anti-inflammatory agent, be difficult to the restriction patient and take said medicine after the meal.Therefore, the loxoprofen preparation is owing to can obviously lower gastric mucosa injury very needs that become, particularly to taking NSAID patient for a long time and limitting eclipse limit water patient particularly useful.
The invention provides:
(1) contain the pharmaceutical composition of oral loxoprofen and antacid,
(2) as (1) described pharmaceutical composition, wherein also be added with lactose,
(3) as (1) or (2) described pharmaceutical composition, wherein also be added with xanthine derivative,
(4) as each described pharmaceutical composition in (1)-(3), wherein loxoprofen is the loxoprofen sodium salt,
(5) as each described pharmaceutical composition in (1)-(3), wherein loxoprofen is a loxoprofen sodium monocalcium salt compound,
(6) as each described pharmaceutical composition in (1)-(5), wherein antacid is to be selected from the following antacid one or more: anhydrous gel aluminum hydroxide, Magnesiumaluminumsilicate, magnesium silicate, synthetic aluminium silicate, natural aluminium silicate, synthetic hydrotalcite, magnesium oxide, magnesium hydroxide-aluminium hydroxide coprecipitate, gel aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, magnesium carbonate, winnofil, positive Magnesiumaluminumsilicate, calcium phosphate dibasic anhydrous, calcium hydrogen phosphate, conch meal and glycine
(7) as each described pharmaceutical composition in (1)-(5), wherein antacid is to be selected from the following antacid one or more: magnesium oxide, winnofil, sodium bicarbonate and glycine,
(8) as each described pharmaceutical composition in (1)-(5), wherein antacid is a magnesium oxide,
(9) as each described pharmaceutical composition in (3)-(8), wherein xanthine derivative is to be selected from the following xanthine derivative one or more: caffeine derivant, theophylline, aminophylline, theobromine, diprophylline, brontyl, pentoxifylline
(10) as each described pharmaceutical composition in (3)-(8), wherein xanthine derivative is to be selected from the following xanthine derivative one or more: caffeine derivant, theophylline, aminophylline,
(11) as each described pharmaceutical composition in (3)-(8), wherein xanthine derivative is selected from caffeine, Caffeine Anhydrous, caffeine sodium benzoate, caffeine hydrochloride and caffeine citrate,
(12) as each described pharmaceutical composition in (11), wherein xanthine derivative and caffeine derivant are to be selected from following one or more: caffeine and Caffeine Anhydrous,
(13) as each described pharmaceutical composition in (1)-(12), as antipyretic,
(14) as each described pharmaceutical composition in (1)-(12), as analgesic,
(15) as each described pharmaceutical composition in (1)-(12), as anti-inflammatory agent,
(16) as each described pharmaceutical composition in (1)-(12), as coldrex,
(17) as each described pharmaceutical composition in (1)-(16), (inter cibos) takes between serving the meals,
(18) as each described pharmaceutical composition in (1)-(7), it is long-term that supply and demand is wanted
The patient who takes medicine takes, and
(19), take for the patient who limits eclipse limit water as each described pharmaceutical composition in (1)-(18).
In addition, the present invention also provide compositions that a kind of above-mentioned by giving (1) take during any feed in (12) with bring down a fever, the method for analgesia, antiinflammatory and treatment flu,
A kind of by any compositions among the patient who gives to take medicine for a long time above-mentioned (1) to (12) with bring down a fever, the method for analgesia, antiinflammatory and treatment flu,
Any compositions makes the limit food in a kind of employing above-mentioned (1) to (12), the patient that restricts water supply brings down a fever, the method for analgesia, antiinflammatory and treatment flu,
The Pharmaceutical composition that a kind of employing contains loxoprofen and antacid or also contain lactose and xanthine derivative except that loxoprofen and antacid with bring down a fever, the method for analgesia, antiinflammatory and treatment flu,
In the present invention, " loxoprofen " refers to loxoprofen or its salt (hydrate is also included within the Pharmaceutical composition of the present invention), and wherein the loxoprofen sodium salt is preferred, more preferably loxoprofen sodium monocalcium salt compound.
In the present invention, " antacid " refers to the medicine with neutralizing acid ability, preferred anhydrous gel aluminum hydroxide, Magnesiumaluminumsilicate, magnesium silicate, synthetic aluminium silicate, natural aluminium silicate, synthetic hydrotalcite, magnesium oxide, magnesium hydroxide-aluminium hydroxide coprecipitate, gel aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, magnesium carbonate, winnofil, positive Magnesiumaluminumsilicate, calcium phosphate dibasic anhydrous, calcium hydrogen phosphate, conch meal and glycine
Wherein, more preferably magnesium oxide, winnofil, sodium bicarbonate or glycine reach
Magnesium oxide most preferably.
In the present invention, " lactose " refers to the sugar in the milk, is oligosaccharide.
In the present invention, " xanthine derivative " refers to the purine base in coffee, tea and the cocoa, is caffeine derivant, theophylline, aminophylline, theobromine, diprophylline, brontyl, pentoxifylline etc.In addition, " caffeine derivant " comprises caffeine, Caffeine Anhydrous, caffeine sodium benzoate, caffeine hydrochloride and caffeine citrate etc.Serves as preferred as " xanthine derivative " with caffeine derivant, theophylline and aminophylline, and wherein the coffee derivant is for more preferably, and caffeine and Caffeine Anhydrous are for wherein preferred.
In the present invention, " gastric mucosa injury " refers to gastric mucosa injury (corrode, hemorrhage and edema), and the upper gastrointestinal that causes of acute and chronic gastritis comprises the ulcer and the damage of duodenum stomach function regulating joint portion.
In the present invention, " between meal (inter cibos) " refers to int cib crack or empty time of stomach.
In the present invention, " patient who takes medicine for a long time " there is no particular limitation, referring generally to prevention or treatment chronic disease is the patient that purpose is taken medicine, as chronic rheumatoid arthritis patient, osteoarthritis patient, chronic cervical region and the stiff patient of shoulder, and back dull pain patient etc.
In the present invention, " limitting eclipse limit water patient " there is no particular limitation, and referring generally to prevent or to treat is that purpose needs to limit the patient who eats or restrict water supply with healthy people's ratio.As acute and chronic kidney disorder patient, kidney dialysis patient, dialysis treatment such as patients undergoing peritoneal dialysis, diabetic nephropathy patient etc.
Antipyretic described in the present invention, analgesics, antiinflammatory or common cold treatment medicine be specific finger with " use in conjunction of loxoprofen and antacid " or except that loxoprofen and antacid and the medicine of " further use in conjunction lactose or xanthine derivative ", these medicines can the while or the similar same time with loxoprofen with Actacid composition or comprise that loxoprofen and antacid lactose or xanthic pharmaceutical composition use.
Among the present invention, the pharmaceutical composition that contains the compositions of loxoprofen and antacid or also contain lactose or xanthine derivative except that loxoprofen and antacid can well alleviate the gastric mucosa injury that loxoprofen causes.Therefore, as an advantage of the present invention, the antipyretic among the present invention, analgesics, antiinflammatory or common cold treatment medicine are for taking these medicines between requiring to eat or taking these medicines for a long time or because the patient that the medical reasons limit is eaten/restricted water supply is safe.
Loxoprofen, anhydrous gel aluminum hydroxide, Magnesiumaluminumsilicate, magnesium silicate, synthetic aluminium silicate, natural aluminium silicate, synthetic hydrotalcite, magnesium oxide, magnesium hydroxide-aluminium hydroxide coprecipitate, gel aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, magnesium carbonate, winnofil, positive Magnesiumaluminumsilicate, calcium phosphate dibasic anhydrous, calcium hydrogen phosphate, conch meal and glycine, caffeine, Caffeine Anhydrous, caffeine sodium benzoate, theophylline and aminophylline are all included at Pharmacopeia of Japan (14 editions).
In addition, loxoprofen salt or hydrate can prepare according to known method.
Magnesiumaluminumsilicate, synthetic hydrotalcite, magnesium hydroxide, positive Magnesiumaluminumsilicate, diprophylline, brontyl all outside Pharmacopeia of Japan pharmaceuticals specification version in 2002 include.
Gel aluminum hydroxide is included pharmaceuticals additive specification 2003 editions, and theobromine can be used as drug abuse test standard substance form and obtains, and other can prepare by known method.
Described in the present invention antipyretic, analgesics, antiinflammatory or common cold treatment medicine are specific fingers with " use in conjunction of loxoprofen and antacid " or except that loxoprofen and antacid in the medicines such as " also further use in conjunction lactose or xanthine derivatives ", antacid, lactose, xanthine derivative and loxoprofen can be made compound medicines, or under certain conditions, these medicines can be simultaneously or the almost same time use separately with the appropriate formulations form.
Loxoprofen single dose scope depends on indication and person's age etc., and generally in 20mg to 180mg, this dosage can be taken 1-3 time to the adult according to the order of severity of patient's symptom every day.
In the present invention, if drug compound preparation is a solid dosage forms, the content range of loxoprofen in compound recipe is at 10-400mg, and the preferred dose scope is at 20-180mg.
In the present invention, if drug compound preparation is liquid or solution dosage, the content range of loxoprofen in compound recipe is at 0.1-200mg/mL, and the preferred dose scope is at 1-100mg/mL.
The suitable weight ratio of antacid in the pharmaceutical composition and loxoprofen is 1 to calculate and be preferably 0.01 or be higher than 0.01 with loxoprofen, more preferably 0.02 or be higher than 0.02.Although this ratio does not have the upper limit, this content ratio is preferably 100 or be lower than 100, more preferably 30 or be lower than 30.
If also contain lactose in the pharmaceutical composition except loxoprofen and antacid, then the weight ratio that lactose content is suitable is that 1 calculating is preferably 0.01-1, more preferably 0.05-0.9 with loxoprofen.
In addition, as described herein, if also contain xanthine derivative in the pharmaceutical composition except loxoprofen and antacid, its suitable weight ratio is that 1 calculating is preferably 0.01-10, more preferably 0.1-2 with loxoprofen.
Under the situation of needs, except above-mentioned active component, can in the compound preparation of combination medicine of the present invention, add following medicine under the situation of not damaging advantage of the present invention: sedative hypnotic, cough medicine, apophlegmatisant, antihistaminic, antiallergic agent, sympathomimetic, parasympatholytic, anti-inflammatory enzyme preparation, vitamin, crude drug etc.
The concrete dosage form of these pharmaceutical compositions can be tablet, granule (comprising powder), capsule, solution (comprising syrup) etc.These dosage forms can adopt suitable additive or preparation raw material, according to the classical way preparation of Pharmacopeia of Japan record.
In above-mentioned each dosage form, each dosage form all has a lot of adjuvants commonly used to use, as excipient, stabilizing agent, coating materials, lubricant, adsorbent, binding agent, disintegrating agent, surfactant, coloring agent, pH regulator agent, spice etc.
[embodiment]
The present invention will be hereinafter be described in detail with the mode of embodiment and experimental example, but scope of the present invention is not limited only to these embodiment.
(embodiment 1) tablet
Form:
| Composition in the 1-2 sheet (mg) | ?(1a) | ?(1b) | ?(1c) | ?(1d) | ?(1e) |
| Loxoprofen sodium 2 hydrates | ?60 | ?60 | ?60 | ?60 | ?60 |
| Magnesium oxide | ?60 | ?240 | ?- | ?- | ?- |
| Winnofil | ?- | ?- | ?60 | ?- | ?- |
| Glycine | ?- | ?- | ?- | ?480 | ?- |
| Sodium bicarbonate | ?- | ?- | ?- | ?- | ?240 |
| Lactose | ?15 | ?- | ?- | ?- | ?- |
| Caffeine or theophylline | ?- | ?30 | ?- | ?- | ?- |
| Hyprolose | ?40 | ?50 | ?30 | ?80 | ?70 |
| Magnesium stearate | In right amount | In right amount | In right amount | In right amount | In right amount |
(2) method for making:
Make tablet by separately amount weighing mentioned component and according to the method for Pharmacopeia of Japan rules of preparations (tablet) preparation.
(embodiment 2) granule
Form:
| Composition (mg) in 1 packing | ?(2a) | ?(2b) | ?(2c) | ?(2d) | ?(2e) |
| Loxoprofen sodium 2 hydrates | ?60 | ?60 | ?60 | ?60 | ?60 |
| Magnesium oxide | ?60 | ?240 | ?- | ?- | ?- |
| Winnofil | ?- | ?- | ?60 | ?- | ?- |
| Glycine | ?- | ?- | ?- | ?480 | ?- |
| Sodium bicarbonate | ?- | ?- | ?- | ?- | ?240 |
| Lactose | ?15 | ?- | ?- | ?- | ?- |
| Caffeine or theophylline | ?- | ?30 | ?- | ?- | ?- |
| Hyprolose | ?200 | ?100 | ?200 | ?150 | ?100 |
| Magnesium stearate | ?5 | ?10 | ?7 | ?9 | ?10 |
| Low-substituted hydroxypropyl cellulose | In right amount | In right amount | In right amount | In right amount | In right amount |
Method for making:
Make granule by separately amount weighing mentioned component and according to the method for Pharmacopeia of Japan rules of preparations (granule) preparation.
(embodiment 3) capsule
Form:
| Composition in the 1-2 capsules (mg) | (3a) | (3b) | (3c) | (3d) | (3e) |
| Loxoprofen sodium 2 hydrates | 60 | 60 | 60 | 60 | 60 |
| Magnesium oxide | 60 | 240 | - | - | - |
| Winnofil | - | - | 60 | - | - |
| Glycine | - | - | - | 480 | - |
| Sodium bicarbonate | - | - | - | - | 240 |
| Lactose | 15 | - | - | - | - |
| Caffeine or theophylline | - | 30 | - | - | - |
| Hyprolose | 40 | 50 | 30 | 80 | 70 |
| Magnesium stearate | 5 | 10 | 7 | 9 | 10 |
| Polysorbate80 | 10 | 15 | 10 | 10 | 20 |
| Corn starch | In right amount | In right amount | In right amount | In right amount | In right amount |
Method for making:
Make tablet by separately amount weighing mentioned component and according to the method for Pharmacopeia of Japan rules of preparations (granule) preparation.The present embodiment capsule is to be formed by the above-mentioned granule of filling in the hard capsule.
(embodiment 4) syrup
Form:
| Composition among the 60mL (mg) | ?(4a) | ?(4b) | ?(4c) | ?(4d) | ?(4e) |
| Loxoprofen sodium 2 hydrates | ?60 | ?60 | ?60 | ?60 | ?60 |
| Magnesium oxide | ?60 | ?240 | ?- | ?- | ?- |
| Winnofil | ?- | ?- | ?60 | ?- | ?- |
| Glycine | ?- | ?- | ?- | ?480 | ?- |
| Sodium bicarbonate | ?- | ?- | ?- | ?- | ?240 |
| Lactose | ?15 | ?- | ?- | ?- | ?- |
| Caffeine or theophylline | ?- | ?30 | ?- | ?- | ?- |
| Hyprolose | ?40 | ?50 | ?30 | ?80 | ?70 |
| Sodium benzoate | ?130 | ?140 | ?130 | ?110 | ?140 |
| Citrate | ?50 | ?80 | ?60 | ?70 | ?80 |
| Concentrated glycerin | ?460 | ?530 | ?510 | ?490 | ?540 |
| Polyvinyl alcohol | ?100 | ?100 | ?100 | ?100 | ?100 |
| Ethanol (95%) | ?200 | ?220 | ?200 | ?230 | ?260 |
| Pure water | In right amount | In right amount | In right amount | In right amount | In right amount |
Method for making:
Make syrup by separately amount weighing mentioned component and according to the method for Pharmacopeia of Japan rules of preparations (syrup) preparation.Syrup is packed in the Brown Glass Brown glass bottles and jars only.
(experimental example 1)
Antacid is tried material to the inhibitory action of the gastric mucosa injury that loxoprofen causes
The loxoprofen sodium dihydrate is synthetic by Sankyo company.Ibuprofen, lactose (lactose of Pharmacopeia of Japan defined), Caffeine Anhydrous and magnesium oxide (magnesium oxide of Pharmacopeia of Japan defined) are respectively available from Sigma chemical company, Kozakai pharmaceutical factory, Wako Pure chemical plant and Yoshida pharmaceutical factory.Above-mentioned substances was made solution or suspension with 0.5% tragakanta in administration the same day.Oral administration dosage is per kilogram of body weight 5mL.Matched group is given 0.5% tragakanta solution of same dose in the same way.
Animal
(Institute for Animal Reproduction) buys from the animal reproduction center 5 age in week the Wistar-Imamichi male rat, wherein 5-6 only closes in a rustless steel mouse cage, put into temperature and be controlled at 20-26 ℃, humidity is at 30-70%, illumination in 12 hours (lighting hours: raise in the environment control feeding system (Environmental Controlled Rearing System) 7:00-19:00) (Japanese Clea company make).Animal can ad lib (Mus solid feed F-2, Funabashi agricultural corporation) and drinks through the filtering tap water of post filter by Automatic Water System.After 8 days, rat carried out perusal in preceding 1 day and selected healthy rat in test in pre-raising, and every group of 5 random packet are treated test usefulness.
Method:
Before the test, to judge that earlier loxoprofen and ibuprofen cause the dosage (incidence rate: 100%) of gastric mucosa damage respectively.Follow-up test is all according to this dosed administration.
Animal begins fasting when testing preceding 1 day 16:00, test oral administration on the same day, after the administration 3.5 hours, etherization, bilateral carotid arteries sacrificed by exsanguination rat, extract stomach, prolonging greater gastric curvature and cutting, slightly cleaning with normal saline, then in stereoscopic microscope (Olympus Optical Co., Ltd, amplification: 10 * 10) observe the gastric wall down, detect the petechia.As gastric indicator, the main shaft of petechia (major axis) is the summation that unit calculates all animal gastrorrhagia point main shafts with 0.5mm.According to single with the loxoprofen sodium dihydrate, single with ibuprofen, share the ulcer index of the rat of processing such as loxoprofen and magnesium oxide, press the column count formula and calculate ulcer index suppression ratio separately:
(equation 1)
Suppression ratio (100%)=[1-B/A] * 100
Wherein:
A: list produces the (incidence rate: the 100%) ulcer index of the rat of dosage processing of gastric mucosa injurys with ibuprofen to cause all rats with loxoprofen sodium dihydrate or list.
B: administering drug combinations group (being added with adding ingredient) rat ulcer index.
The loxoprofen sodium dihydrate causes that the dosage of all rat pipe film injuries (incidence rate 100%) is 50mg/Kg, and ibuprofen is 100mg/Kg.Following experimental result is based on these two dosage.
Result of the test:
Each administering drug combinations group antiulcer form suppression ratio result as table 5 as described in the table 7, each numerical value is the meansigma methods of every group of 5 rats.
LxNa and Ibu represent loxoprofen sodium dihydrate and ibuprofen respectively in the table.In addition, Ox Mg and Caf represent magnesium oxide and caffeine respectively.In addition, content is than referring to that each is tried the dosage rate of material and loxoprofen sodium dihydrate.
(table 5-1)
| Tried material (dosage: mg/kg) | The content ratio | Ulcer inhibition rate (%) |
| ?LxNa(50)+Ox?Mg(1) | ?[1/50] | ?22 |
| ?LxNa(50)+Ox?Mg(3) | ?[1/17] | ?36 |
| ?LxNa(50)+Ox?Mg(10) | ?[1/5] | ?31 |
| ?LxNa(50)+Ox?Mg(25) | ?[1/2] | ?27 |
| ?LxNa(50)+Ox?Mg(50) | ?[1/1] | ?55 |
| ?LxNa(50)+Ox?Mg(100) | ?[2/1] | ?46 |
| ?LxNa(50)+Ox?Mg(200) | ?[4/1] | ?81 |
| ?LxNa(50)+Ox?Mg(400) | ?[8/1] | ?100 |
Table 5-1 described " content ratio " refers to the weight ratio of magnesium oxide and loxoprofen sodium dihydrate (calculating with 1).
(table 5-2)
| Tried material (dosage: mg/kg) | The content ratio | Ulcer inhibition rate (%) |
| ?Ibu(100)+Ox?Mg(2) | ?[1/50] | ?-51 |
| ?Ibu(100)+Ox?Mg(6) | ?[1/17] | ?-37 |
| ?Ibu(100)+Ox?Mg(20) | ?[1/5] | ?-151 |
| ?Ibu(100)+Ox?Mg(50) | ?[1/2] | ?-114 |
| ?Ibu(100)+Ox?Mg(100) | ?[1/1] | ?32 |
| ?Ibu(100)+Ox?Mg(200) | ?[2/1] | ?29 |
| ?Ibu(100)+Ox?Mg(400) | ?[4/1] | ?71 |
| ?Ibu(100)+Ox?Mg(800) | ?[8/1] | ?91 |
Table 5-2 described " content ratio " refers to the weight ratio of magnesium oxide and ibuprofen (calculating with 1).
As show as described in 5-1 and the table 5-2, when magnesium oxide and loxoprofen sodium dihydrate or ibuprofen were united use, magnesian suppression ratio was significantly different.When magnesium oxide used with the loxoprofen sodium dihydrate, the inhibition effect of the ulcer that the anti-loxoprofen sodium dihydrate of magnesium oxide causes, suppressed than 8 to high-load than 0.02 fully from low content.Yet when the NSAIDS class medicine ibuprofen that is all the Phenpropionate analog derivative with another one and loxoprofen sodium dihydrate when magnesium oxide used, magnesium oxide can not suppress the ulcer that ibuprofen causes fully.(content than 0.02 to O.75) magnesium oxide even the ulcer that increases ibuprofen produce active in addition, in some cases.
From all these results, we disclose for the first time when antacid is united use with loxoprofen with all content ratios of being investigated, and the ulcer that loxoprofen causes is inhibited.
(table 6)
| Tried material (dosage: mg/kg) | Lactose [content ratio] | Ulcer suppression ratio (%) |
| ?LxNa(50)+Ox?Mg(50) | + lactose [0] | ?55 |
| ?LxNa(50)+Ox?Mg(50) | + lactose [1/4] | ?88 |
| ?Ibu(100)+Ox?Mg(100) | + lactose [0] | ?32 |
| ?Ibu(100)+Ox?Mg(100) | + lactose [1/4] | ?-107 |
" content ratio " in the table 6 refers to the weight ratio of lactose and loxoprofen sodium dihydrate or ibuprofen (calculating with 1).
As shown in table 6, when adding lactose in loxoprofen sodium dihydrate and the magnesium oxide composition of medicine, the ulcer that the loxoprofen sodium dihydrate causes is further suppressed.Though ibuprofen and loxoprofen are all the Phenpropionate non-steroid antiphlogistic, yet when lactose joined in ibuprofen and the magnesium oxide composition of medicine, the gastric ulcer that ibuprofen causes aggravated.
Table 7
| Tried material (dosage: mg/kg) | Caffeine [content ratio] | Ulcer inhibition rate (%) |
| ?LxNa(50)+Ox?Mg(0) | ?+Caf[1/1] | ?-94 |
| ?LxNa(50)+Ox?Mg(50) | ?+Caf[1/1] | ?34 |
| ?LxNa(50)+Ox?Mg(100) | ?+Caf[1/1] | ?95 |
| ?LxNa(50)+Ox?Mg(50) | ?+Caf[0] | ?55 |
| ?LxNa(50)+Ox?Mg(100) | ?+Caf[0] | ?46 |
| ?Ibu(100)+Ox?Mg(0) | ?+Caf[1/1] | ?-2 |
" content ratio " in the table 7 refers to the weight ratio of caffeine and loxoprofen sodium dihydrate or ibuprofen (calculating with 1).
As shown in table 7, to compare with the loxoprofen sodium dihydrate with single, caffeine and loxoprofen sodium dihydrate are united when using, the gastric ulcer aggravation that the loxoprofen sodium dihydrate causes.And when further adding the antacid magnesium oxide, gastric mucosa injury is eased, and when the dosage of antacid doubled, gastric mucosa injury almost completely was inhibited.On the other hand, when caffeine used with ibuprofen, the gastric mucosa injury that ibuprofen causes is aggravation not.
[industrial usability]
Pharmaceutical composition of the present invention can greatly reduce gastric mucosa damage (particularly as take medicine between needs meal and/or the Long-term taking medicine patient maybe needs to limit eclipse limit water patient's antipyretic, analgestic, anti-inflammatory agent and Coritab) as medicine.
Claims (19)
1. combination of oral medication, described compositions comprises loxoprofen and antacid.
2. the pharmaceutical composition of claim 1 wherein also is added with lactose.
3. the pharmaceutical composition of claim 1 wherein also is added with xanthine derivative.
4. claim 1 each pharmaceutical composition to the claim 3, wherein loxoprofen is a loxoprofen sodium.
5. claim 1 each pharmaceutical composition to the claim 3, wherein loxoprofen is the loxoprofen sodium dihydrate.
6. claim 1 each pharmaceutical composition to the claim 5, wherein antacid is that one or more are selected from following antacid: anhydrous gel aluminum hydroxide, Magnesiumaluminumsilicate, magnesium silicate, synthetic aluminium silicate, natural aluminium silicate, synthetic hydrotalcite, magnesium oxide, magnesium hydroxide-aluminium hydroxide coprecipitate, gel aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, magnesium carbonate, winnofil, positive Magnesiumaluminumsilicate, calcium phosphate dibasic anhydrous, calcium hydrogen phosphate, conch meal and glycine.
7. claim 1 each pharmaceutical composition to the claim 5, wherein antacid is that one or more are selected from following antacid: magnesium oxide, winnofil, sodium bicarbonate and glycine.
8. claim 1 each pharmaceutical composition to the claim 5, wherein antacid is a magnesium oxide.
9. claim 3 each pharmaceutical composition to the claim 8, wherein xanthine derivative is that one or more are selected from following xanthine derivative: caffeine derivant, theophylline, aminophylline, theobromine, diprophylline, brontyl and pentoxifylline.
10. claim 3 each pharmaceutical composition to the claim 8, wherein xanthine derivative is that one or more are selected from following xanthine derivative: caffeine derivant, theophylline and aminophylline.
11. claim 3 each pharmaceutical composition to the claim 8, wherein xanthine derivative is that one or more are selected from following xanthine derivative: caffeine, Caffeine Anhydrous, caffeine sodium benzoate, caffeine hydrochloride and caffeine citrate.
12. claim 3 each pharmaceutical composition to the claim 8, wherein xanthine derivative is that one or more are selected from following xanthine derivative: caffeine and Caffeine Anhydrous.
13. claim 1 each pharmaceutical composition to the claim 12, described compositions is as antipyretic.
14. claim 1 each pharmaceutical composition to the claim 12, described compositions is as analgesics.
15. claim 1 each pharmaceutical composition to the claim 12, described compositions is as antiinflammatory.
16. claim 1 each pharmaceutical composition to the claim 12, described compositions is as Coritab.
17. claim 1 each pharmaceutical composition to the claim 16, described compositions is taken between serving the meals.
18. claim 1 each pharmaceutical composition to the claim 16, the patient that described compositions supply and demand will be taken medicine for a long time takes.
19. claim 1 each pharmaceutical composition to the claim 16, described compositions is taken for limit food or the patient that restricts water supply.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP205934/2004 | 2004-07-13 | ||
| JP2004205934 | 2004-07-13 |
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| CN101014333A true CN101014333A (en) | 2007-08-08 |
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| CNA2005800303268A Pending CN101014333A (en) | 2004-07-13 | 2005-07-12 | Loxoprofen-containing composition for oral administration |
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| JP (6) | JP2012051949A (en) |
| KR (1) | KR20070034576A (en) |
| CN (1) | CN101014333A (en) |
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| JP2008195705A (en) * | 2007-01-15 | 2008-08-28 | Daiichi Sankyo Healthcare Co Ltd | Loxoprofen-containing oral composition |
| JP5681430B2 (en) * | 2009-09-30 | 2015-03-11 | 興和株式会社 | Loxoprofen-containing pharmaceutical composition |
| JP2011132226A (en) * | 2009-11-27 | 2011-07-07 | Kowa Co | Loxoprofen-containing medicinal composition and medicinal preparation containing the composition |
| JP6139050B2 (en) * | 2010-08-27 | 2017-05-31 | 興和株式会社 | Medicine |
| CN105501856B (en) * | 2015-12-11 | 2017-11-17 | 江苏大学 | A kind of powder filled rate detection means of spiral quantitative charger feeding-distribution device and method |
| CN113631731A (en) | 2019-03-13 | 2021-11-09 | 杰富意钢铁株式会社 | Thick steel plate and method for producing same |
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| JP2704721B2 (en) * | 1987-02-12 | 1998-01-26 | ライオン株式会社 | Ibuprofen formulation |
| JP3122748B2 (en) * | 1991-11-29 | 2001-01-09 | ライオン株式会社 | Antipyretic analgesic containing ibuprofen |
| JP4113267B2 (en) * | 1997-04-03 | 2008-07-09 | 日医工株式会社 | Loxoprofen sodium-containing tablets |
| JP4936579B2 (en) * | 1997-09-05 | 2012-05-23 | 第一三共株式会社 | Loxoprofen-containing pharmaceutical preparation |
| JP2001172175A (en) * | 1999-12-14 | 2001-06-26 | Taisho Pharmaceut Co Ltd | Composition for the cold |
| JP2001181190A (en) * | 1999-12-22 | 2001-07-03 | Takeda Chem Ind Ltd | Medicine composition |
| JP2001199882A (en) * | 2000-01-20 | 2001-07-24 | Taisho Pharmaceut Co Ltd | Composition for cold and rhinitis |
| JP2002226366A (en) * | 2001-02-02 | 2002-08-14 | Yuutoku Yakuhin Kogyo Kk | Liniment preparation for external use |
| JP4365107B2 (en) * | 2001-05-25 | 2009-11-18 | エスエス製薬株式会社 | Pharmaceutical composition |
| JP4614640B2 (en) * | 2002-07-04 | 2011-01-19 | 第一三共株式会社 | Antipyretic composition |
| JP2004161667A (en) * | 2002-11-13 | 2004-06-10 | Saiseido Yakuhin Kk | Crude drug-formulated pharmaceutical composition |
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| JP6106727B2 (en) | 2017-04-05 |
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| KR20070034576A (en) | 2007-03-28 |
| JP2016056195A (en) | 2016-04-21 |
| BRPI0513186A (en) | 2008-04-29 |
| JP2014132038A (en) | 2014-07-17 |
| JP2012051950A (en) | 2012-03-15 |
| JP5833157B2 (en) | 2015-12-16 |
| JP6192751B2 (en) | 2017-09-06 |
| JP2012051949A (en) | 2012-03-15 |
| JP2016027058A (en) | 2016-02-18 |
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